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Hsp40 gene therapy exerts therapeutic effects on polyglutamine disease mice via a non-cell autonomous mechanism.

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H Akiko Popiel

Full Text Available The polyglutamine (polyQ diseases such as Huntington's disease (HD, are neurodegenerative diseases caused by proteins with an expanded polyQ stretch, which misfold and aggregate, and eventually accumulate as inclusion bodies within neurons. Molecules that inhibit polyQ protein misfolding/aggregation, such as Polyglutamine Binding Peptide 1 (QBP1 and molecular chaperones, have been shown to exert therapeutic effects in vivo by crossing of transgenic animals. Towards developing a therapy using these aggregation inhibitors, we here investigated the effect of viral vector-mediated gene therapy using QBP1 and molecular chaperones on polyQ disease model mice. We found that injection of adeno-associated virus type 5 (AAV5 expressing QBP1 or Hsp40 into the striatum both dramatically suppresses inclusion body formation in the HD mouse R6/2. AAV5-Hsp40 injection also ameliorated the motor impairment and extended the lifespan of R6/2 mice. Unexpectedly, we found even in virus non-infected cells that AAV5-Hsp40 appreciably suppresses inclusion body formation, suggesting a non-cell autonomous therapeutic effect. We further show that Hsp40 inhibits secretion of the polyQ protein from cultured cells, implying that it inhibits the recently suggested cell-cell transmission of the polyQ protein. Our results demonstrate for the first time the therapeutic effect of Hsp40 gene therapy on the neurological phenotypes of polyQ disease mice.
Therapeutic application of multipotent stem cells

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Mirzaei, Hamed; Sahebkar, Amirhossein; Sichani, Laleh Shiri

2018-01-01

Cell therapy is an emerging fields in the treatment of various diseases such as cardiovascular, pulmonary, hepatic, and neoplastic diseases. Stem cells are an integral tool for cell therapy. Multipotent stem cells are an important class of stem cells which have the ability to self-renew through...... been showed that multipotent stem cells exert their therapeutic effects via inhibition/activation of a sequence of cellular and molecular pathways. Although the advantages of multipotent stem cells are numerous, further investigation is still necessary to clarify the biology and safety of these cells...... before they could be considered as a potential treatment for different types of diseases. This review summarizes different features of multipotent stem cells including isolation, differentiation, and therapeutic applications....
Exosomes and Their Therapeutic Potentials of Stem Cells

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Chao Han

2016-01-01

Full Text Available Exosomes, a group of vesicles originating from the multivesicular bodies (MVBs, are released into the extracellular space when MVBs fuse with the plasma membrane. Numerous studies indicate that exosomes play important roles in cell-to-cell communication, and exosomes from specific cell types and conditions display multiple functions such as exerting positive effects on regeneration in many tissues. It is widely accepted that the therapeutic potential of stem cells may be mediated largely by the paracrine factors, so harnessing the paracrine effects of stem and progenitor cells without affecting these living, replicating, and potentially pluripotent cell populations is an advantage in terms of safety and complexity. Ascending evidence indicated that exosomes might be the main components of paracrine factors; thus, understanding the role of exosomes in each subtype of stem cells is far-reaching. In this review, we discuss the functions of exosomes from different types of stem cells and emphasize the therapeutic potentials of exosomes, providing an alternative way of developing strategies to cure diseases.
Intravenous administration of mesenchymal stem cells exerts therapeutic effects on parkinsonian model of rats: Focusing on neuroprotective effects of stromal cell-derived factor-1α

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Tayra Judith

2010-04-01

Full Text Available Abstract Background Mesenchymal stem cells (MSCs are pluripotent stem cells derived from bone marrow with secretory functions of various neurotrophic factors. Stromal cell-derived factor-1α (SDF-1α is also reported as one of chemokines released from MSCs. In this research, the therapeutic effects of MSCs through SDF-1α were explored. 6-hydroxydopamine (6-OHDA, 20 μg was injected into the right striatum of female SD rats with subsequent administration of GFP-labeled MSCs, fibroblasts, (i.v., 1 × 107 cells, respectively or PBS at 2 hours after 6-OHDA injection. All rats were evaluated behaviorally with cylinder test and amphetamine-induced rotation test for 1 month with consequent euthanasia for immunohistochemical evaluations. Additionally, to explore the underlying mechanisms, neuroprotective effects of SDF-1α were explored using 6-OHDA-exposed PC12 cells by using dopamine (DA assay and TdT-mediated dUTP-biotin nick-end labeling (TUNEL staining. Results Rats receiving MSC transplantation significantly ameliorated behaviorally both in cylinder test and amphetamine-induced rotation test compared with the control groups. Correspondingly, rats with MSCs displayed significant preservation in the density of tyrosine hydroxylase (TH-positive fibers in the striatum and the number of TH-positive neurons in the substantia nigra pars compacta (SNc compared to that of control rats. In the in vitro study, SDF-1α treatment increased DA release and suppressed cell death induced by 6-OHDA administration compared with the control groups. Conclusions Consequently, MSC transplantation might exert neuroprotection on 6-OHDA-exposed dopaminergic neurons at least partly through anti-apoptotic effects of SDF-1α. The results demonstrate the potentials of intravenous MSC administration for clinical applications, although further explorations are required.
Focus on Extracellular Vesicles: Therapeutic Potential of Stem Cell-Derived Extracellular Vesicles

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Bin Zhang

2016-02-01

Full Text Available The intense research focus on stem and progenitor cells could be attributed to their differentiation potential to generate new cells to replace diseased or lost cells in many highly intractable degenerative diseases, such as Alzheimer disease, multiple sclerosis, and heart diseases. However, experimental and clinical studies have increasingly attributed the therapeutic efficacy of these cells to their secretion. While stem and progenitor cells secreted many therapeutic molecules, none of these molecules singly or in combination could recapitulate the functional effects of stem cell transplantations. Recently, it was reported that extracellular vesicles (EVs could recapitulate the therapeutic effects of stem cell transplantation. Based on the observations reported thus far, the prevailing hypothesis is that stem cell EVs exert their therapeutic effects by transferring biologically active molecules such as proteins, lipids, mRNA, and microRNA from the stem cells to injured or diseased cells. In this respect, stem cell EVs are similar to EVs from other cell types. They are both primarily vehicles for intercellular communication. Therefore, the differentiating factor is likely due to the composition of their cargo. The cargo of EVs from different cell types are known to include a common set of proteins and also proteins that reflect the cell source of the EVs and the physiological or pathological state of the cell source. Hence, elucidation of the stem cell EV cargo would provide an insight into the multiple physiological or biochemical changes necessary to affect the many reported stem cell-based therapeutic outcomes in a variety of experimental models and clinical trials.
Regulatory T Cell Induced by Poria cocos Bark Exert Therapeutic Effects in Murine Models of Atopic Dermatitis and Food Allergy

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Min-Jung Bae

2016-01-01

Full Text Available The prevalence of allergic disorders including atopic dermatitis (AD and food allergy (FA has increased dramatically in pediatric populations, but there is no effective drug available for their management. Therefore, trials are required for the development of safe therapeutic agents such as herbal medicines. We determined whether orally administered Poria cocos bark (PCB extract could exert immunosuppressive effects on allergic and inflammatory symptoms of AD and FA. For both AD, which was induced using house dust mite extract, and FA, which was induced by exposure to ovalbumin, model mice were orally treated with PCB extract for 62 days and 18 days, respectively. We also investigated the inductive effect of PCB extract on the generation and maintenance of Foxp3+CD4+ regulatory T cells (Tregs. The symptoms of AD and FA were ameliorated by the administration of PCB extract. Furthermore, PCB extract inhibited the Th2-related cytokines and increased the population of Foxp3+CD4+ Tregs in both AD and FA models. In ex vivo experiments, PCB extract promoted the functional differentiation of Foxp3+CD4+ Tregs, which is dependent on aryl hydrocarbon receptor activation. Thus, PCB extract has potential as an oral immune suppressor for the treatment of AD and FA through the generation of Tregs.
Traction forces exerted by epithelial cell sheets

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Saez, A; Anon, E; Ghibaudo, M; Di Meglio, J-M; Hersen, P; Ladoux, B; Du Roure, O; Silberzan, P; Buguin, A

2010-01-01

Whereas the adhesion and migration of individual cells have been well described in terms of physical forces, the mechanics of multicellular assemblies is still poorly understood. Here, we study the behavior of epithelial cells cultured on microfabricated substrates designed to measure cell-to-substrate interactions. These substrates are covered by a dense array of flexible micropillars whose deflection enables us to measure traction forces. They are obtained by lithography and soft replica molding. The pillar deflection is measured by video microscopy and images are analyzed with home-made multiple particle tracking software. First, we have characterized the temporal and spatial distributions of traction forces of cellular assemblies of various sizes. The mechanical force balance within epithelial cell sheets shows that the forces exerted by neighboring cells strongly depend on their relative position in the monolayer: the largest deformations are always localized at the edge of the islands of cells in the active areas of cell protrusions. The average traction stress rapidly decreases from its maximum value at the edge but remains much larger than the inherent noise due to the force resolution of our pillar tracking software, indicating an important mechanical activity inside epithelial cell islands. Moreover, these traction forces vary linearly with the rigidity of the substrate over about two decades, suggesting that cells exert a given amount of deformation rather than a force. Finally, we engineer micropatterned substrates supporting pillars with anisotropic stiffness. On such substrates cellular growth is aligned with respect to the stiffest direction in correlation with the magnitude of the applied traction forces.
Plumbagin exerts an immunosuppressive effect on human T-cell acute lymphoblastic leukemia MOLT-4 cells

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Bae, Kyoung Jun; Lee, Yura [Department of Biomedical Laboratory Science, Daejeon 34824 (Korea, Republic of); Kim, Soon Ae [Department of Pharmacology, School of Medicine, Daejeon 34824 (Korea, Republic of); Kim, Jiyeon, E-mail: yeon@eulji.ac.kr [Department of Biomedical Laboratory Science, Daejeon 34824 (Korea, Republic of)

2016-04-22

Of the hematological disorders typified by poor prognoses and survival rates, T-cell acute lymphoblastic leukemia (T-ALL) is one of the most commonly diagnosed. Despite the development of new therapeutic agents, the treatment options for this cancer remain limited. In this manuscript, we investigated the anti-proliferative effects of plumbagin, mediated by the activation of mitogen-activated protein kinase (MAPK) pathways, and inhibition of NF-κB signaling; the human T-ALL MOLT-4 cell line was used as our experimental system. Plumbagin is a natural, plant derived compound, which exerts an anti-proliferative activity against many types of human cancer. Our experiments confirm that plumbagin induces a caspase-dependent apoptosis of MOLT-4 cells, with no significant cytotoxicity seen for normal peripheral blood mononuclear cells (PBMCs). Plumbagin also inhibited LPS-induced phosphorylation of p65, and the transcription of NF-κB target genes. Our results now show that plumbagin is a potent inhibitor of the NF-κB signaling pathway, and suppressor of T-ALL cell proliferation. - Highlights: • Plumbagin induces caspase-dependent apoptosis in T-ALL MOLT-4 cells. • Plumbagin activates phosphorylation of stress-activated protein kinase (SAPK) JNK and p38. • Plumbagin inhibits LPS-mediated NF-κB signaling cascade. • Plumbagin inhibits LPS-mediated transcriptional activity of pro-inflammatory cytokines.
Pathological and therapeutic roles of innate lymphoid cells in diverse diseases.

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Kim, Jisu; Kim, Geon; Min, Hyeyoung

2017-11-01

Innate lymphoid cells (ILCs) are a recently defined type of innate-immunity cells that belong to the lymphoid lineage and have lymphoid morphology but do not express an antigen-specific B cell or T-cell receptor. ILCs regulate immune functions prior to the formation of adaptive immunity and exert effector functions through a cytokine release. ILCs have been classified into three groups according to the transcription factors that regulate their development and function and the effector cytokines they produce. Of note, ILCs resemble T helper (Th) cells, such as Th1, Th2, and Th17 cells, and show a similar dependence on transcription factors and distinct cytokine production. Despite their short history in immunology, ILCs have received much attention, and numerous studies have revealed biological functions of ILCs including host defense against pathogens, inflammation, tissue repair, and metabolic homeostasis. Here, we describe recent findings about the roles of ILCs in the pathogenesis of various diseases and potential therapeutic targets.
Traction Stresses Exerted by Adherent Cells: From Angiogenesis to Metastasis

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Reinhart-King, Cynthia

2010-03-01

Cells exert traction stresses against their substrate that mediate their ability to sense the mechanical properties of their microenvironment. These same forces mediate cell adhesion, migration and the formation of stable cell-cell contacts during tissue formation. In this talk, I will present our data on the traction stresses generated by endothelial cells and metastatic breast cancer cells focused on understanding the processes of angiogenesis and metastasis, respectively. In the context of capillary formation, our data indicate that the mechanics of the substrate play a critical role in establishing endothelial cell-cell contacts. On more compliant substrates, endothelial cell shape and traction stresses polarize and promote the formation of stable cell-cell contacts. On stiffer substrates, traction stresses are less polarized and cell connectivity is disrupted. These data indicate that the mechanical properties of the microenvironment may drive cell connectivity and the formation of stable cell-cell contacts through the reorientation of traction stresses. In our studies of metastatic cell migration, we have found that traction stresses increase with increasing metastatic potential. We investigated three lines of varying metastatic potential (MCF10A, MCF7 and MDAMB231). MDAMB231, which are the most invasive, exert the most significant forces as measured by Traction Force Microscopy. These data present the possibility that cellular traction stress generation aids in the ability of metastatic cells to migrate through the matrix-dense tumor microenvironment. Such measurements are integral to link the mechanical and chemical microenvironment with the resulting response of the cell in health and disease.
Resveratrol Exerts Dosage and Duration Dependent Effect on Human Mesenchymal Stem Cell Development

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Peltz, Lindsay; Gomez, Jessica; Marquez, Maribel; Alencastro, Frances; Atashpanjeh, Negar; Quang, Tara; Bach, Thuy; Zhao, Yuanxiang

2012-01-01

Studies in the past have illuminated the potential benefit of resveratrol as an anticancer (pro-apoptosis) and life-extending (pro-survival) compound. However, these two different effects were observed at different concentration ranges. Studies of resveratrol in a wide range of concentrations on the same cell type are lacking, which is necessary to comprehend its diverse and sometimes contradictory cellular effects. In this study, we examined the effects of resveratrol on cell self-renewal and differentiation of human mesenchymal stem cells (hMSCs), a type of adult stem cells that reside in a number of tissues, at concentrations ranging from 0.1 to 10 µM after both short- and long-term exposure. Our results reveal that at 0.1 µM, resveratrol promotes cell self-renewal by inhibiting cellular senescence, whereas at 5 µM or above, resveratrol inhibits cell self-renewal by increasing senescence rate, cell doubling time and S-phase cell cycle arrest. At 1 µM, its effect on cell self-renewal is minimal but after long-term exposure it exerts an inhibitory effect, accompanied with increased senescence rate. At all concentrations, resveratrol promotes osteogenic differentiation in a dosage dependent manner, which is offset by its inhibitory effect on cell self-renewal at high concentrations. On the contrary, resveratrol suppresses adipogenic differentiation during short-term exposure but promotes this process after long-term exposure. Our study implicates that resveratrol is the most beneficial to stem cell development at 0.1 µM and caution should be taken in applying resveratrol as an anticancer therapeutic agent or nutraceutical supplement due to its dosage dependent effect on hMSCs. PMID:22615926
Acacetin enhances the therapeutic efficacy of doxorubicin in non-small-cell lung carcinoma cells.

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Reenu Punia

Full Text Available Anthracyclines are efficient and potent agents to treat broad range of cancers but cytotoxicity induced by them limits their use in therapeutics. Use of plant-derived agents help to prevent or delay the process of cancer progression and their combination increases the anti-cancer potential of mainstream compound. However, multidrug resistance is major cause of treatment failure in cancer patients.In this study, combination treatments of fisetin or acacetin with doxorubicin were explored for their potential synergistic effect on non-small-cell lung carcinoma (NSCLC cells.During this study, NSCLC model cell lines A549 and H1299 were used to determine the combinatorial effect of phytochemicals namly acacetin and fisetin with doxorubicin.The effects of individual compounds and their combination on cell viability, clonogenic potential and cell cycle progression were studied. Efflux of doxorubicin was measured by spectrofluorophotometer, whereas accumulation inside the cells was analyzed by flow cytometry and confocal microscopy. Expression of MDR1 was checked by semi-quantitative PCR.The results showed that the cell viability of A549 and H1299 cells were significantly decreased in time- and dose-dependent manner, although A549 cells showed more sensitivity toward doxorubicin than H1299 cells. Mostly, combination of doxorubicin showed good synergy with acacetin in both the cell lines whereas, fisetin exerted synergistic effect only at 72 h of treatment in H1299 cells. Acacetin with doxorubicin caused G2/M arrest by downregulating CDK-cyclin complex in A549 cells. Acacetin-doxorubicin combination decreased the clonogenic potential of A549 and H1299 cells upto 82% and 59%, respectively, as compared to control. Acacetin also decreased efflux of doxorubicin by 59% after 30 mins of exposure to A549 cells and further increased accumulation of doxorubicin inside the cells upto 55% in 2 h. The modulatory effect of acacetin-doxorubicin combination on
The endoplasmic reticulum exerts control over organelle streaming during cell expansion.

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Stefano, Giovanni; Renna, Luciana; Brandizzi, Federica

2014-03-01

Cytoplasmic streaming is crucial for cell homeostasis and expansion but the precise driving forces are largely unknown. In plants, partial loss of cytoplasmic streaming due to chemical and genetic ablation of myosins supports the existence of yet-unknown motors for organelle movement. Here we tested a role of the endoplasmic reticulum (ER) as propelling force for cytoplasmic streaming during cell expansion. Through quantitative live-cell analyses in wild-type Arabidopsis thaliana cells and mutants with compromised ER structure and streaming, we demonstrate that cytoplasmic streaming undergoes profound changes during cell expansion and that it depends on motor forces co-exerted by the ER and the cytoskeleton.
Melittin exerts an antitumor effect on non‑small cell lung cancer cells.

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Zhang, Su-Fang; Chen, Zhe

2017-09-01

Lung cancer accounts for a significant percentage of all cancer‑associated mortalities in men and women, with non‑small cell lung cancer being the most frequently occurring type of lung cancer. Melittin is the principal active component of apitoxin (bee venom) that has been reported to exert anti‑chronic inflammatory and anti‑cancer effects. In the present study, the antitumor effect of melittin was evaluated using in vivo and in vitro analyses. The results demonstrated that melittin significantly inhibited the epidermal growth factor‑induced invasion and migration of non‑small cell lung cancer cells. Subcutaneous injection of melittin at doses of 1 and 10 mg/kg significantly suppressed non‑small cell lung cancer tumor growth by 27 and 61%, respectively. In addition, melittin significantly inhibited the secretion of vascular endothelial growth factor (VEGF) in non‑small cell lung cancer cells. Furthermore, melittin decreased the protein expression of VEGF and hypoxia‑inducible factor 1‑α. Therefore, the antitumor activity of melittin may be associated with the anti‑angiogenic actions of inhibiting the VEGF and hypoxia‑inducible factor signaling pathways.
Psychological stress exerts an adjuvant effect on skin dendritic cell functions in vivo.

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Saint-Mezard, Pierre; Chavagnac, Cyril; Bosset, Sophie; Ionescu, Marius; Peyron, Eric; Kaiserlian, Dominique; Nicolas, Jean-Francois; Bérard, Frédéric

2003-10-15

Psychological stress affects the pathophysiology of infectious, inflammatory, and autoimmune diseases. However, the mechanisms by which stress could modulate immune responses in vivo are poorly understood. In this study, we report that application of a psychological stress before immunization exerts an adjuvant effect on dendritic cell (DC), resulting in increased primary and memory Ag-specific T cell immune responses. Acute stress dramatically enhanced the skin delayed-type hypersensitivity reaction to haptens, which is mediated by CD8(+) CTLs. This effect was due to increased migration of skin DCs, resulting in augmented CD8(+) T cell priming in draining lymph nodes and enhanced recruitment of CD8(+) T cell effectors in the skin upon challenge. This adjuvant effect of stress was mediated by norepinephrine (NE), but not corticosteroids, as demonstrated by normalization of the skin delayed-type hypersensitivity reaction and DC migratory properties following selective depletion of NE. These results suggest that release of NE by sympathetic nerve termini during a psychological stress exerts an adjuvant effect on DC by promoting enhanced migration to lymph nodes, resulting in increased Ag-specific T cell responses. Our findings may open new ways in the treatment of inflammatory diseases, e.g., psoriasis, allergic contact dermatitis, and atopic dermatitis.
Perspectives for Preventive and Therapeutic HPV Vaccines

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Lin, Ken; Doolan, Kimberley; Hung, Chien-Fu; Wu, T-C

2010-01-01

Cervical cancer is the second most common cause of female cancer death worldwide. Persistent infection with `high risk' HPV genotypes is the major etiological factor in cervical cancer and thus effective vaccination against HPV provides an opportunity to reduce the morbidity and mortality associated with HPV. The FDA has approved two preventive vaccines to limit the spread of HPV. However, these are unlikely to impact upon HPV prevalence and cervical cancer rates for many years. Furthermore, preventive vaccines do not exert therapeutic effects on pre-existing HPV infections and HPV-associated lesions. In order to further impact upon the burden of HPV infections worldwide, therapeutic vaccines are being developed. These vaccines aim to generate a cell-mediated immune response to infected cells. This review discusses current preventive and therapeutic HPV vaccines and their future directions. PMID:20123582
Advancing Stem Cell Biology toward Stem Cell Therapeutics

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Scadden, David; Srivastava, Alok

2012-01-01

Here, the International Society for Stem Cell Research (ISSCR) Clinical Translation Committee introduces a series of articles outlining the current status, opportunities, and challenges surrounding the clinical translation of stem cell therapeutics for specific medical conditions.
Silybin-mediated inhibition of Notch signaling exerts antitumor activity in human hepatocellular carcinoma cells.

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Song Zhang

Full Text Available Hepatocellular carcinoma (HCC is a global health burden that is associated with limited treatment options and poor patient prognoses. Silybin (SIL, an antioxidant derived from the milk thistle plant (Silybum marianum, has been reported to exert hepatoprotective and antitumorigenic effects both in vitro and in vivo. While SIL has been shown to have potent antitumor activity against various types of cancer, including HCC, the molecular mechanisms underlying the effects of SIL remain largely unknown. The Notch signaling pathway plays crucial roles in tumorigenesis and immune development. In the present study, we assessed the antitumor activity of SIL in human HCC HepG2 cells in vitro and in vivo and explored the roles of the Notch pathway and of the apoptosis-related signaling pathway on the activity of SIL. SIL treatment resulted in a dose- and time-dependent inhibition of HCC cell viability. Additionally, SIL exhibited strong antitumor activity, as evidenced not only by reductions in tumor cell adhesion, migration, intracellular glutathione (GSH levels and total antioxidant capability (T-AOC but also by increases in the apoptotic index, caspase3 activity, and reactive oxygen species (ROS. Furthermore, SIL treatment decreased the expression of the Notch1 intracellular domain (NICD, RBP-Jκ, and Hes1 proteins, upregulated the apoptosis pathway-related protein Bax, and downregulated Bcl2, survivin, and cyclin D1. Notch1 siRNA (in vitro or DAPT (a known Notch1 inhibitor, in vivo further enhanced the antitumor activity of SIL, and recombinant Jagged1 protein (a known Notch ligand in vitro attenuated the antitumor activity of SIL. Taken together, these data indicate that SIL is a potent inhibitor of HCC cell growth that targets the Notch signaling pathway and suggest that the inhibition of Notch signaling may be a novel therapeutic intervention for HCC.
Combination of gefitinib and DNA methylation inhibitor decitabine exerts synergistic anti-cancer activity in colon cancer cells.

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Yun-feng Lou

Full Text Available Despite recent advances in the treatment of human colon cancer, the chemotherapy efficacy against colon cancer is still unsatisfactory. In the present study, effects of concomitant inhibition of the epidermal growth factor receptor (EGFR and DNA methyltransferase were examined in human colon cancer cells. We demonstrated that decitabine (a DNA methyltransferase inhibitor synergized with gefitinib (an EGFR inhibitor to reduce cell viability and colony formation in SW1116 and LOVO cells. However, the combination of the two compounds displayed minimal toxicity to NCM460 cells, a normal human colon mucosal epithelial cell line. The combination was also more effective at inhibiting the AKT/mTOR/S6 kinase pathway. In addition, the combination of decitabine with gefitinib markedly inhibited colon cancer cell migration. Furthermore, gefitinib synergistically enhanced decitabine-induced cytotoxicity was primarily due to apoptosis as shown by Annexin V labeling that was attenuated by z-VAD-fmk, a pan caspase inhibitor. Concomitantly, cell apoptosis resulting from the co-treatment of gefitinib and decitabine was accompanied by induction of BAX, cleaved caspase 3 and cleaved PARP, along with reduction of Bcl-2 compared to treatment with either drug alone. Interestingly, combined treatment with these two drugs increased the expression of XIAP-associated factor 1 (XAF1 which play an important role in cell apoptosis. Moreover, small interfering RNA (siRNA depletion of XAF1 significantly attenuated colon cancer cells apoptosis induced by the combination of the two drugs. Our findings suggested that gefitinib in combination with decitabine exerted enhanced cell apoptosis in colon cancer cells were involved in mitochondrial-mediated pathway and induction of XAF1 expression. In conclusion, based on the observations from our study, we suggested that the combined administration of these two drugs might be considered as a novel therapeutic regimen for treating colon
Dual effects exerted in vitro by micromolar concentrations of deoxynivalenol on undifferentiated caco-2 cells.

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Manda, Gina; Mocanu, Mihaela Andreea; Marin, Daniela Eliza; Taranu, Ionelia

2015-02-16

Contamination of crops used for food and feed production with Fusarium mycotoxins, such as deoxynivalenol (DON), raise important health and economic issues all along the food chain. Acute exposure to high DON concentrations can alter the intestinal barrier, while chronic exposure to lower doses may exert more subtle effects on signal transduction pathways, leading to disturbances in cellular homeostasis. Using real-time cellular impedance measurements, we studied the effects exerted in vitro by low concentrations of DON (0.37-1.50 μM), relevant for mycotoxin-contaminated food, on the proliferation of undifferentiated Caco-2 cells presenting a tumorigenic phenotype. A 1.5 μM concentration of DON maintained cell adherence of non-proliferating Caco-2 cells, whilst arresting the growth of actively proliferating cells compared with control Caco-2 cells in vitro. At 0.37 μM, DON enhanced Caco-2 cell metabolism, thereby triggering a moderate increase in cell proliferation. The results of the current study suggested that low concentrations of DON commonly detected in food may either limit or sustain the proliferation of colon cancer cells, depending on their proliferation status and on DON concentration. Soluble factors released by Lactobacillus strains can partially counteract the inhibitory action of DON on actively proliferating colon cancer cells. The study also emphasized that real-time cellular impedance measurements were a valuable tool for investigating the dynamics of cellular responses to xenobiotics.

Cell kinetics and therapeutic efficiency

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Andreeff, M.; Abenhardt, W.; Gruner, B.; Stoffner, D.; Mainz Univ.

1976-01-01

The study shows that cell kinetics effects correlate with the effects of cytostatic drugs in the tumour model investigated here. It should, however, be noted that even genetically related tumour cell types may react differently to the same cytostatic drug, and that the cell kinetics effects, due to the changes in the cell cycle, cannot be predicted but should be followed with a very fast method, e.g. sequential flan fluorescence cytophotometry, for optimal therapeutic results. (orig./GSE) [de
Biological and therapeutic activities, and anticancer properties of curcumin.

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Perrone, Donatella; Ardito, Fatima; Giannatempo, Giovanni; Dioguardi, Mario; Troiano, Giuseppe; Lo Russo, Lucio; DE Lillo, Alfredo; Laino, Luigi; Lo Muzio, Lorenzo

2015-11-01

Curcumin (diferuloylmethane) is a polyphenol derived from the Curcuma longa plant. Curcumin has been used extensively in Ayurvedic medicine, as it is nontoxic and exhibits a variety of therapeutic properties, including antioxidant, analgesic, anti-inflammatory and antiseptic activities. Recently, certain studies have indicated that curcumin may exert anticancer effects in a variety of biological pathways involved in mutagenesis, apoptosis, tumorigenesis, cell cycle regulation and metastasis. The present study reviewed previous studies in the literature, which support the therapeutic activity of curcumin in cancer. In addition, the present study elucidated a number of the challenges concerning the use of curcumin as an adjuvant chemotherapeutic agent. All the studies reviewed herein suggest that curcumin is able to exert anti-inflammatory, antiplatelet, antioxidative, hepatoprotective and antitumor activities, particularly against cancers of the liver, skin, pancreas, prostate, ovary, lung and head neck, as well as having a positive effect in the treatment of arthritis.
Fifty Years of Research in ARDS. Cell-based Therapy for Acute Respiratory Distress Syndrome. Biology and Potential Therapeutic Value.

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Laffey, John G; Matthay, Michael A

2017-08-01

On the basis of several preclinical studies, cell-based therapy has emerged as a potential new therapeutic for acute respiratory distress syndrome (ARDS). Of the various cell-based therapy options, mesenchymal stem/stromal cells (MSCs) from bone marrow, adipose tissue, and umbilical cord have the most experimental data to support their potential efficacy for lung injury from both infectious and noninfectious causes. Mechanistically, MSCs exert their beneficial effects by release of paracrine factors, microvesicles, and transfer of mitochondria, all of which have antiinflammatory and pro-resolving effects on injured lung endothelium and alveolar epithelium, including enhancing the resolution of pulmonary edema by up-regulating sodium-dependent alveolar fluid clearance. MSCs also have antimicrobial effects mediated by release of antimicrobial factors and by up-regulating monocyte/macrophage phagocytosis. Phase 2a clinical trials to establish safety in ARDS are in progress, and two phase 1 trials did not report any serious adverse events. Several issues need further study, including: determining the optimal methods for large-scale production, reconstitution of cryopreserved cells for clinical use, defining cell potency assays, and determining the therapeutic potential of conditioned media derived from MSCs. Because ARDS is a heterogeneous syndrome, targeting MSCs to patients with ARDS with a more hyperinflammatory endotype may further enhance their potential for efficacy.
Therapeutic potential of stem cells in veterinary practice

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Nitin E Gade

Full Text Available Stem cell research acquired great attention during last decade inspite of incredible therapeutic potential of these cells the ethical controversies exists. Stem cells have enormous uses in animal cloning, drug discovery, gene targeting, transgenic production and regenerative therapy. Stem cells are the naïve cells of body which can self-renew and differentiate into other cell types to carry out multiple functions, these properties have been utilized in therapeutic application of stem cells in human and veterinary medicine. The application of stem cells in human medicine is well established and it is commonly used for chronic and accidental injuries. In Veterinary sciences previous studies mostly focused on establishing protocols for isolation and their characterization but with advancement in array of techniques for in vitro studies, stem cells rapidly became a viable tool for regenerative therapy of chronic, debilitating and various unresponsive clinical diseases and disorders. Multipotent adult stem cells have certain advantages over embryonic stem cells like easy isolation and expansion from numerous sources, less immunogenicity and no risk of teratoma formation hence their use is preferred in therapeutics. Adult stem cells have been utilized for treatment of spinal injuries, tendonitis, cartilage defects, osteoarthritis and ligament defects, liver diseases, wounds, cardiac and bone defects in animals. The multi-potential capability of these cells can be better utilized in near future to overcome the challenges faced by the clinicians. This review will emphasize on the therapeutic utilization and success of stem cell therapies in animals. [Vet. World 2012; 5(8.000: 499-507
Targeting the Epidermal Growth Factor Receptor Can Counteract the Inhibition of Natural Killer Cell Function Exerted by Colorectal Tumor-Associated Fibroblasts

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Delfina Costa

2018-05-01

Full Text Available Mesenchymal stromal cells (MSC present in the tumor microenvironment [usually named tumor-associated fibroblasts (TAF] can exert immunosuppressive effects on T and natural killer (NK lymphocytes, favoring tumor immune escape. We have analyzed this mechanism in colorectal carcinoma (CRC and found that co-culture of NK cells with TAF can prevent the IL-2-mediated NKG2D upregulation. This leads to the impairment of NKG2D-mediated recognition of CRC cells, sparing the NK cell activation through DNAM1 or FcγRIIIA (CD16. In situ, TAF express detectable levels of epidermal growth factor receptor (EGFR; thus, the therapeutic anti-EGFR humanized antibody cetuximab can trigger the antibody-dependent cellular cytotoxicity of TAF, through the engagement of FcγRIIIA on NK cells. Importantly, in the tumor, we found a lymphoid infiltrate containing NKp46+CD3− NK cells, enriched in CD16+ cells. This population, sorted and cultured with IL-2, could be triggered via CD16 and via NKG2D. Of note, ex vivo NKp46+CD3− cells were able to kill autologous TAF; in vivo, this might represent a control mechanism to reduce TAF-mediated regulatory effect on NK cell function. Altogether, these findings suggest that MSC from the neoplastic mucosa (TAF of CRC patients can downregulate the immune cell recognition of CRC tumor cells. This immunosuppression can be relieved by the anti-EGFR antibody used in CRC immunotherapy.
Targeting the Epidermal Growth Factor Receptor Can Counteract the Inhibition of Natural Killer Cell Function Exerted by Colorectal Tumor-Associated Fibroblasts

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Costa, Delfina; Venè, Roberta; Benelli, Roberto; Romairone, Emanuele; Scabini, Stefano; Catellani, Silvia; Rebesco, Barbara; Mastracci, Luca; Grillo, Federica; Minghelli, Simona; Loiacono, Fabrizio; Zocchi, Maria Raffaella; Poggi, Alessandro

2018-01-01

Mesenchymal stromal cells (MSC) present in the tumor microenvironment [usually named tumor-associated fibroblasts (TAF)] can exert immunosuppressive effects on T and natural killer (NK) lymphocytes, favoring tumor immune escape. We have analyzed this mechanism in colorectal carcinoma (CRC) and found that co-culture of NK cells with TAF can prevent the IL-2-mediated NKG2D upregulation. This leads to the impairment of NKG2D-mediated recognition of CRC cells, sparing the NK cell activation through DNAM1 or FcγRIIIA (CD16). In situ, TAF express detectable levels of epidermal growth factor receptor (EGFR); thus, the therapeutic anti-EGFR humanized antibody cetuximab can trigger the antibody-dependent cellular cytotoxicity of TAF, through the engagement of FcγRIIIA on NK cells. Importantly, in the tumor, we found a lymphoid infiltrate containing NKp46+CD3− NK cells, enriched in CD16+ cells. This population, sorted and cultured with IL-2, could be triggered via CD16 and via NKG2D. Of note, ex vivo NKp46+CD3− cells were able to kill autologous TAF; in vivo, this might represent a control mechanism to reduce TAF-mediated regulatory effect on NK cell function. Altogether, these findings suggest that MSC from the neoplastic mucosa (TAF) of CRC patients can downregulate the immune cell recognition of CRC tumor cells. This immunosuppression can be relieved by the anti-EGFR antibody used in CRC immunotherapy. PMID:29910806
Dual Effects Exerted in Vitro by Micromolar Concentrations of Deoxynivalenol on Undifferentiated Caco-2 Cells

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Gina Manda

2015-02-01

Full Text Available Contamination of crops used for food and feed production with Fusarium mycotoxins, such as deoxynivalenol (DON, raise important health and economic issues all along the food chain. Acute exposure to high DON concentrations can alter the intestinal barrier, while chronic exposure to lower doses may exert more subtle effects on signal transduction pathways, leading to disturbances in cellular homeostasis. Using real-time cellular impedance measurements, we studied the effects exerted in vitro by low concentrations of DON (0.37–1.50 μM, relevant for mycotoxin-contaminated food, on the proliferation of undifferentiated Caco-2 cells presenting a tumorigenic phenotype. A 1.5 μM concentration of DON maintained cell adherence of non-proliferating Caco-2 cells, whilst arresting the growth of actively proliferating cells compared with control Caco-2 cells in vitro. At 0.37 μM, DON enhanced Caco-2 cell metabolism, thereby triggering a moderate increase in cell proliferation. The results of the current study suggested that low concentrations of DON commonly detected in food may either limit or sustain the proliferation of colon cancer cells, depending on their proliferation status and on DON concentration. Soluble factors released by Lactobacillus strains can partially counteract the inhibitory action of DON on actively proliferating colon cancer cells. The study also emphasized that real-time cellular impedance measurements were a valuable tool for investigating the dynamics of cellular responses to xenobiotics.
Allogenic banking of dental pulp stem cells for innovative therapeutics.

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Collart-Dutilleul, Pierre-Yves; Chaubron, Franck; De Vos, John; Cuisinier, Frédéric J

2015-08-26

Medical research in regenerative medicine and cell-based therapy has brought encouraging perspectives for the use of stem cells in clinical trials. Multiple types of stem cells, from progenitors to pluripotent stem cells, have been investigated. Among these, dental pulp stem cells (DPSCs) are mesenchymal multipotent cells coming from the dental pulp, which is the soft tissue within teeth. They represent an interesting adult stem cell source because they are recovered in large amount in dental pulps with non-invasive techniques compared to other adult stem cell sources. DPSCs can be obtained from discarded teeth, especially wisdom teeth extracted for orthodontic reasons. To shift from promising preclinical results to therapeutic applications to human, DPSCs must be prepared in clinical grade lots and transformed into advanced therapy medicinal products (ATMP). As the production of patient-specific stem cells is costly and time-consuming, allogenic biobanking of clinical grade human leukocyte antigen (HLA)-typed DPSC lines provides efficient innovative therapeutic products. DPSC biobanks represent industrial and therapeutic innovations by using discarded biological tissues (dental pulps) as a source of mesenchymal stem cells to produce and store, in good manufacturing practice (GMP) conditions, DPSC therapeutic batches. In this review, we discuss about the challenges to transfer biological samples from a donor to HLA-typed DPSC therapeutic lots, following regulations, GMP guidelines and ethical principles. We also present some clinical applications, for which there is no efficient therapeutics so far, but that DPSCs-based ATMP could potentially treat.
Phenotypic Plasticity Determines Cancer Stem Cell Therapeutic Resistance in Oral Squamous Cell Carcinoma

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Adrian Biddle

2016-02-01

Full Text Available Cancer stem cells (CSCs drive tumour spread and therapeutic resistance, and can undergo epithelial-to-mesenchymal transition (EMT and mesenchymal-to-epithelial transition (MET to switch between epithelial and post-EMT sub-populations. Examining oral squamous cell carcinoma (OSCC, we now show that increased phenotypic plasticity, the ability to undergo EMT/MET, underlies increased CSC therapeutic resistance within both the epithelial and post-EMT sub-populations. The post-EMT CSCs that possess plasticity exhibit particularly enhanced therapeutic resistance and are defined by a CD44highEpCAMlow/−CD24+ cell surface marker profile. Treatment with TGFβ and retinoic acid (RA enabled enrichment of this sub-population for therapeutic testing, through which the endoplasmic reticulum (ER stressor and autophagy inhibitor Thapsigargin was shown to selectively target these cells. Demonstration of the link between phenotypic plasticity and therapeutic resistance, and development of an in vitro method for enrichment of a highly resistant CSC sub-population, provides an opportunity for the development of improved chemotherapeutic agents that can eliminate CSCs.
Phenotypic Plasticity Determines Cancer Stem Cell Therapeutic Resistance in Oral Squamous Cell Carcinoma.

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Biddle, Adrian; Gammon, Luke; Liang, Xiao; Costea, Daniela Elena; Mackenzie, Ian C

2016-02-01

Cancer stem cells (CSCs) drive tumour spread and therapeutic resistance, and can undergo epithelial-to-mesenchymal transition (EMT) and mesenchymal-to-epithelial transition (MET) to switch between epithelial and post-EMT sub-populations. Examining oral squamous cell carcinoma (OSCC), we now show that increased phenotypic plasticity, the ability to undergo EMT/MET, underlies increased CSC therapeutic resistance within both the epithelial and post-EMT sub-populations. The post-EMT CSCs that possess plasticity exhibit particularly enhanced therapeutic resistance and are defined by a CD44(high)EpCAM(low/-) CD24(+) cell surface marker profile. Treatment with TGFβ and retinoic acid (RA) enabled enrichment of this sub-population for therapeutic testing, through which the endoplasmic reticulum (ER) stressor and autophagy inhibitor Thapsigargin was shown to selectively target these cells. Demonstration of the link between phenotypic plasticity and therapeutic resistance, and development of an in vitro method for enrichment of a highly resistant CSC sub-population, provides an opportunity for the development of improved chemotherapeutic agents that can eliminate CSCs.
Promising Therapeutic Strategies for Mesenchymal Stem Cell-Based Cardiovascular Regeneration: From Cell Priming to Tissue Engineering

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Seung Taek Ji

2017-01-01

Full Text Available The primary cause of death among chronic diseases worldwide is ischemic cardiovascular diseases, such as stroke and myocardial infarction. Recent evidence indicates that adult stem cell therapies involving cardiovascular regeneration represent promising strategies to treat cardiovascular diseases. Owing to their immunomodulatory properties and vascular repair capabilities, mesenchymal stem cells (MSCs are strong candidate therapeutic stem cells for use in cardiovascular regeneration. However, major limitations must be overcome, including their very low survival rate in ischemic lesion. Various attempts have been made to improve the poor survival and longevity of engrafted MSCs. In order to develop novel therapeutic strategies, it is necessary to first identify stem cell modulators for intracellular signal triggering or niche activation. One promising therapeutic strategy is the priming of therapeutic MSCs with stem cell modulators before transplantation. Another is a tissue engineering-based therapeutic strategy involving a cell scaffold, a cell-protein-scaffold architecture made of biomaterials such as ECM or hydrogel, and cell patch- and 3D printing-based tissue engineering. This review focuses on the current clinical applications of MSCs for treating cardiovascular diseases and highlights several therapeutic strategies for promoting the therapeutic efficacy of MSCs in vitro or in vivo from cell priming to tissue engineering strategies, for use in cardiovascular regeneration.
Autophagy regulates the therapeutic potential of mesenchymal stem cells in experimental autoimmune encephalomyelitis.

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Dang, Shipeng; Xu, Huanbai; Xu, Congfeng; Cai, Wei; Li, Qian; Cheng, Yiji; Jin, Min; Wang, Ru-Xing; Peng, Yongde; Zhang, Yi; Wu, Changping; He, Xiaozhou; Wan, Bing; Zhang, Yanyun

2014-07-01

Mesenchymal stem cell (MSC)-based therapy is a promising approach to treat various inflammatory disorders including multiple sclerosis. However, the fate of MSCs in the inflammatory microenvironment is largely unknown. Experimental autoimmune encephalomyelitis (EAE) is a well-studied animal model of multiple sclerosis. We demonstrated that autophagy occurred in MSCs during their application for EAE treatment. Inflammatory cytokines, e.g., interferon gamma and tumor necrosis factor, induced autophagy in MSCs synergistically by inducing expression of BECN1/Beclin 1. Inhibition of autophagy by knockdown of Becn1 significantly improved the therapeutic effects of MSCs on EAE, which was mainly attributable to enhanced suppression upon activation and expansion of CD4(+) T cells. Mechanistically, inhibition of autophagy increased reactive oxygen species generation and mitogen-activated protein kinase 1/3 activation in MSCs, which were essential for PTGS2 (prostaglandin-endoperoxide synthase 2 [prostaglandin G/H synthase and cyclooxygenase]) and downstream prostaglandin E2 expression to exert immunoregulatory function. Furthermore, pharmacological treatment of MSCs to inhibit autophagy increased their immunosuppressive effects on T cell-mediated EAE. Our findings indicate that inflammatory microenvironment-induced autophagy downregulates the immunosuppressive function of MSCs. Therefore, modulation of autophagy in MSCs would provide a novel strategy to improve MSC-based immunotherapy.
17β-estradiol exerts anticancer effects in anoikis-resistant hepatocellular carcinoma cell lines by targeting IL-6/STAT3 signaling

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Lee, Seulki, E-mail: sl10f@naver.com [Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, 103 Daehak-ro, Jongno-gu, Seoul, 110-799 (Korea, Republic of); Lee, Minjong, E-mail: minjonglee2@naver.com [Division of Gastroenterology, Department of Internal Medicine, Kangwon National University Hospital, 156 Baengnyeong-ro, Chuncheon-si, Gangwon-do (Korea, Republic of); Kim, Jong Bin, E-mail: kkimjp@hanmail.net [Hormel Institute, University of Minnesota, 801 16th Ave NE, Austin, MN, 55912 (United States); Jo, Ara, E-mail: loveara0315@naver.com [Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, 103 Daehak-ro, Jongno-gu, Seoul, 110-799 (Korea, Republic of); Cho, Eun Ju, E-mail: creatioex@gmail.com [Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, 103 Daehak-ro, Jongno-gu, Seoul, 110-799 (Korea, Republic of); Yu, Su Jong, E-mail: ydoctor2@hanmail.net [Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, 103 Daehak-ro, Jongno-gu, Seoul, 110-799 (Korea, Republic of); Lee, Jeong-Hoon, E-mail: pindra@empal.com [Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, 103 Daehak-ro, Jongno-gu, Seoul, 110-799 (Korea, Republic of); Yoon, Jung-Hwan, E-mail: yoonjh@snu.ac.kr [Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, 103 Daehak-ro, Jongno-gu, Seoul, 110-799 (Korea, Republic of); Kim, Yoon Jun, E-mail: yoonjun@snu.ac.kr [Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, 103 Daehak-ro, Jongno-gu, Seoul, 110-799 (Korea, Republic of)

2016-05-13

17β-Estradiol (E2) has been proven to exert protective effects against HCC; however, its mechanism on HCC proliferation and suppression of invasion remains to be further explored. Because HCC up-regulates serum Interleukin-6 (IL-6) levels and Signal Transducer and Activator of Transcription 3 (STAT3), molecular agents that attenuate IL-6/STAT3 signaling can potentially suppress HCC development. In this study, we examined involvement of E2 in anoikis resistance that induces invasion capacities and chemo-resistance. Huh-BAT and HepG2 cells grown under anchorage-independent condition were selected. The anoikis-resistant (AR) cells showed stronger chemo-resistance against sorafenib, doxorubicin, 5-fluorouracil and cisplatin compared to adherent HCC cells. AR HCC cells exhibited decreased expression of E-cadherin and increased expression of the N-cadherin and vimentin compared to adherent HCC cells. We then demonstrated that E2 suppressed cell proliferation in AR HCC cells. IL-6 treatment enhanced invasive characteristics, and E2 reversed it. Regarding mechanism of E2, it decreased in the phosphorylation of STAT3 that overexpressed on AR HCC cells. The inhibitory effect of E2 on cell growth was accompanied with cell cycle arrest at G2/M phase and caspase-3/9/PARP activation through c-Jun N-terminal Kinase (JNK) phosphorylation. Taken together, these findings suggested that E2 inhibited the proliferation of AR HCC cells through down-regulation of IL-6/STAT3 signaling. Thus, E2 can be a potential therapeutic drug for treatment of metastatic or chemo-resistant HCC. -- Highlights: •Anoikis-resistant HCC cells characterized chemo-resistant and metastatic potentials. •17β-Estradiol down-regulated IL-6/STAT3 signaling in anoikis-resistant HCC cells. •17β-Estradiol suppressed cell proliferation by inducing G2/M phase arrest and apoptosis though JNK phosphorylation.
Cancer Stem Cell Plasticity Drives Therapeutic Resistance

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Mary R. Doherty

2016-01-01

Full Text Available The connection between epithelial-mesenchymal (E-M plasticity and cancer stem cell (CSC properties has been paradigm-shifting, linking tumor cell invasion and metastasis with therapeutic recurrence. However, despite their importance, the molecular pathways involved in generating invasive, metastatic, and therapy-resistant CSCs remain poorly understood. The enrichment of cells with a mesenchymal/CSC phenotype following therapy has been interpreted in two different ways. The original interpretation posited that therapy kills non-CSCs while sparing pre-existing CSCs. However, evidence is emerging that suggests non-CSCs can be induced into a transient, drug-tolerant, CSC-like state by chemotherapy. The ability to transition between distinct cell states may be as critical for the survival of tumor cells following therapy as it is for metastatic progression. Therefore, inhibition of the pathways that promote E-M and CSC plasticity may suppress tumor recurrence following chemotherapy. Here, we review the emerging appreciation for how plasticity confers therapeutic resistance and tumor recurrence.
Insights into cell-free therapeutic approach: Role of stem cell "soup-ernatant".

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Raik, Shalini; Kumar, Ajay; Bhattacharyya, Shalmoli

2018-03-01

Current advances in medicine have revolutionized the field of regenerative medicine dramatically with newly evolved therapies for repair or replacement of degenerating or injured tissues. Stem cells (SCs) can be harvested from different sources for clinical therapeutics, which include fetal tissues, umbilical cord blood, embryos, and adult tissues. SCs can be isolated and differentiated into desired lineages for tissue regeneration and cell replacement therapy. However, several loopholes need to be addressed properly before this can be extended for large-scale therapeutic application. These include a careful approach for patient safety during SC treatments and tolerance of recipients. SC treatments are associated with a number of risk factors and require successful integration and survival of transplanted cells in the desired microenvironment with concurrent tissue regeneration. Recent studies have focused on developing alternatives that can replace the cell-based therapy using paracrine factors. The development of stem "cell free" therapies can be devoted mainly to the use of soluble factors (secretome), extracellular vesicles, and mitochondrial transfer. The present review emphasizes on the paradigms related to the use of SC-based therapeutics and the potential applications of a cell-free approach as an alternative to cell-based therapy in the area of regenerative medicine. © 2017 International Union of Biochemistry and Molecular Biology, Inc.
Stem Cell Therapy: A Promising Therapeutic Method for Intracerebral Hemorrhage.

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Gao, Liansheng; Xu, Weilin; Li, Tao; Chen, Jingyin; Shao, Anwen; Yan, Feng; Chen, Gao

2018-01-01

Spontaneous intracerebral hemorrhage (ICH) is one type of the most devastating cerebrovascular diseases worldwide, which causes high morbidity and mortality. However, efficient treatment is still lacking. Stem cell therapy has shown good neuroprotective and neurorestorative effect in ICH and is a promising treatment. In this study, our aim was to review the therapeutic effects, strategies, related mechanisms and safety issues of various types of stem cell for ICH treatment. Numerous studies had demonstrated the therapeutic effects of diverse stem cell types in ICH. The potential mechanisms include tissue repair and replacement, neurotrophy, promotion of neurogenesis and angiogenesis, anti-apoptosis, immunoregulation and anti-inflammation and so forth. The microenvironment of the central nervous system (CNS) can also influence the effects of stem cell therapy. The detailed therapeutic strategies for ICH treatment such as cell type, the number of cells, time window, and the routes of medication delivery, varied greatly among different studies and had not been determined. Moreover, the safety issues of stem cell therapy for ICH should not be ignored. Stem cell therapy showed good therapeutic effect in ICH, making it a promising treatment. However, safety should be carefully evaluated, and more clinical trials are required before stem cell therapy can be extensively applied to clinical use.
Cell mediated therapeutics for cancer treatment: Tumor homing cells as therapeutic delivery vehicles

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Balivada, Sivasai

Many cell types were known to have migratory properties towards tumors and different research groups have shown reliable results regarding cells as delivery vehicles of therapeutics for targeted cancer treatment. Present report discusses proof of concept for 1. Cell mediated delivery of Magnetic nanoparticles (MNPs) and targeted Magnetic hyperthermia (MHT) as a cancer treatment by using in vivo mouse cancer models, 2. Cells surface engineering with chimeric proteins for targeted cancer treatment by using in vitro models. 1. Tumor homing cells can carry MNPs specifically to the tumor site and tumor burden will decrease after alternating magnetic field (AMF) exposure. To test this hypothesis, first we loaded Fe/Fe3O4 bi-magnetic NPs into neural progenitor cells (NPCs), which were previously shown to migrate towards melanoma tumors. We observed that NPCs loaded with MNPs travel to subcutaneous melanoma tumors. After alternating magnetic field (AMF) exposure, the targeted delivery of MNPs by the NPCs resulted in a mild decrease in tumor size (Chapter-2). Monocytes/macrophages (Mo/Ma) are known to infiltrate tumor sites, and also have phagocytic activity which can increase their uptake of MNPs. To test Mo/Ma-mediated MHT we transplanted Mo/Ma loaded with MNPs into a mouse model of pancreatic peritoneal carcinomatosis. We observed that MNP-loaded Mo/Ma infiltrated pancreatic tumors and, after AMF treatment, significantly prolonged the lives of mice bearing disseminated intraperitoneal pancreatic tumors (Chapter-3). 2. Targeted cancer treatment could be achieved by engineering tumor homing cell surfaces with tumor proteases cleavable, cancer cell specific recombinant therapeutic proteins. To test this, Urokinase and Calpain (tumor specific proteases) cleavable; prostate cancer cell (CaP) specific (CaP1 targeting peptide); apoptosis inducible (Caspase3 V266ED3)- rCasp3V266ED3 chimeric protein was designed in silico. Hypothesized membrane anchored chimeric protein (rCasp3V
Cell-based therapeutic strategies for multiple sclerosis

DEFF Research Database (Denmark)

Scolding, Neil J; Pasquini, Marcelo; Reingold, Stephen C

2017-01-01

and none directly promotes repair. Cell-based therapies, including immunoablation followed by autologous haematopoietic stem cell transplantation, mesenchymal and related stem cell transplantation, pharmacologic manipulation of endogenous stem cells to enhance their reparative capabilities......, and transplantation of oligodendrocyte progenitor cells, have generated substantial interest as novel therapeutic strategies for immune modulation, neuroprotection, or repair of the damaged central nervous system in multiple sclerosis. Each approach has potential advantages but also safety concerns and unresolved...
Oleoylethanolamide exerts anti-inflammatory effects on LPS-induced THP-1 cells by enhancing PPARα signaling and inhibiting the NF-κB and ERK1/2/AP-1/STAT3 pathways.

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Yang, Lichao; Guo, Han; Li, Ying; Meng, Xianglan; Yan, Lu; Dan Zhang; Wu, Sangang; Zhou, Hao; Peng, Lu; Xie, Qiang; Jin, Xin

2016-10-10

The present study aimed to examine the anti-inflammatory actions of oleoylethanolamide (OEA) in lipopolysaccharide (LPS)-induced THP-1 cells. The cells were stimulated with LPS (1 μg/ml) in the presence or absence of OEA (10, 20 and 40 μM). The pro-inflammatory cytokines were evaluated by qRT-PCR and ELISA. The THP-1 cells were transiently transfected with PPARα small-interfering RNA, and TLR4 activity was determined with a blocking test using anti-TLR4 antibody. Additionally, a special inhibitor was used to analyse the intracellular signaling pathway. OEA exerted a potent anti-inflammatory effect by reducing the production of pro-inflammatory cytokines and TLR4 expression, and by enhancing PPARα expression. The modulatory effects of OEA on LPS-induced inflammation depended on PPARα and TLR4. Importantly, OEA inhibited LPS-induced NF-κB activation, IκBα degradation, expression of AP-1, and the phosphorylation of ERK1/2 and STAT3. In summary, our results demonstrated that OEA exerts anti-inflammatory effects by enhancing PPARα signaling, inhibiting the TLR4-mediated NF-κB signaling pathway, and interfering with the ERK1/2-dependent signaling cascade (TLR4/ERK1/2/AP-1/STAT3), which suggests that OEA may be a therapeutic agent for inflammatory diseases.
NK cell-released exosomes

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Fais, Stefano

2013-01-01

We have recently reported that human natural killer (NK) cells release exosomes that express both NK-cell markers and cytotoxic molecules. Similar results were obtained with circulating exosomes from human healthy donors. Both NK-cell derived and circulating exosomes exerted a full functional activity and killed both tumor and activated immune cells. These findings indicate that NK-cell derived exosomes might constitute a new promising therapeutic tool. PMID:23482694

Radioresistant head and neck squamous cell carcinoma cells: Intracellular signaling, putative biomarkers for tumor recurrences and possible therapeutic targets

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Skvortsov, Sergej; Jimenez, Connie R.; Knol, Jaco C.; Eichberger, Paul; Schiestl, Bernhard; Debbage, Paul; Skvortsova, Ira; Lukas, Peter

2011-01-01

Purpose: Treatment of local and distant head and neck cancer recurrences after radiotherapy remains an unsolved problem. In order to identify potential targets for use in effective therapy of recurrent tumors, we have investigated protein patterns in radioresistant (FaDu-IRR and SCC25-IRR, “IRR cells”) as compared to parental (FaDu and SCC25) head and neck carcinoma cells. Methods and materials: Radiation resistant IRR cells were derived from parental cells after repeated exposure to ionizing radiation 10 times every two weeks at a single dose of 10 Gy, resulting in a total dose of 100 Gy. Protein profiling in parental and IRR cells was carried out using two-dimensional differential gel electrophoresis (2D-DIGE) followed by MALDI-TOF/TOF mass spectrometry. Cell viability, cell migration assays and Western blot analysis were used to confirm results obtained using the proteome approach. Results: Forty-five proteins that were similarly modulated in FaDu-IRR and SCC25-IRR cells compared to parental cells were selected to analyze their common targets. It was found that these either up- or down-regulated proteins are closely related to the enhancement of cell migration which is regulated by Rac1 protein. Further investigations confirmed that Rac1 is up-regulated in IRR cells, and inhibiting its action reduces the migratory abilities of these cells. Additionally, the Rac1 inhibitor exerts cytostatic effects in HNSCC cells, mostly in migratory cells. Conclusions: Based on these results, we conclude that radioresistant HNSCC cells possess enhanced metastatic abilities that are regulated by a network of migration-related proteins. Rac1 protein may be considered as a putative biomarker of HNSCC radiation resistance, and as a potential therapeutic target for treating local and distant HNSCC recurrences.
Mechanisms of therapeutic resistance in cancer (stem cells with emphasis on thyroid cancer cells.

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Sabine eHombach-Klonisch

2014-03-01

Full Text Available Tissue invasion, metastasis and therapeutic resistance to anti-cancer treatments are common and main causes of death in cancer patients. Tumor cells mount complex and still poorly understood molecular defense mechanisms to counteract and evade oxygen deprivation, nutritional restrictions as well as radio- and chemotherapeutic treatment regimens aimed at destabilizing their genomes and important cellular processes. In thyroid cancer, as in other tumors, such defense strategies include the reactivation in cancer cells of early developmental programs normally active exclusively in stem cells, the stimulation of cancer stem-like cells resident within the tumor tissue and the recruitment of bone marrow-derived progenitors into the tumor (Thomas et al., 2008;Klonisch et al., 2009;Derwahl, 2011. Metastasis and therapeutic resistance in cancer (stem cells involves the epithelial-to-mesenchymal transition- (EMT- mediated enhancement in cellular plasticity, which includes coordinated dynamic biochemical and nuclear changes (Ahmed et al., 2010. The purpose of the present review is to provide an overview of the role of DNA repair mechanisms contributing to therapeutic resistance in thyroid cancer and highlight the emerging roles of autophagy and damage associated molecular pattern (DAMP responses in EMT and chemoresistance in tumor cells. Finally, we use the stem cell factor and nucleoprotein High Mobility Group A2 (HMGA2 as an example to demonstrate how factors intended to protect stem cells are wielded by cancer (stem cells to gain increased transformative cell plasticity which enhances metastasis, therapeutic resistance and cell survival. Wherever possible, we have included information on these cellular processes and associated factors as they relate to thyroid cancer cells.
Cancer stem cells in hepatocellular carcinoma: Therapeutic implications based on stem cell biology.

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Chiba, Tetsuhiro; Iwama, Atsushi; Yokosuka, Osamu

2016-01-01

Hepatocellular carcinoma (HCC) is the sixth most common cancer and the third most frequent cause of cancer-related death worldwide. Despite advances in its diagnosis and treatment, the prognosis of patients with advanced HCC remains unfavorable. Recent advances in stem cell biology and associated technologies have enabled the identification of minor components of tumorigenic cells, termed cancer stem cells (CSC) or tumor-initiating cells, in cancers such as HCC. Furthermore, because CSC play a central role in tumor development, metastasis and recurrence, they are considered to be a therapeutic target in cancer treatment. Hepatic CSC have been successfully identified using functional and cell surface markers. The analysis of purified hepatic CSC has revealed the molecular machinery and signaling pathways involved in their maintenance. In addition, epigenetic transcriptional regulation has been shown to be important in the development and maintenance of CSC. Although inhibitors of CSC show promise as CSC-targeting drugs, novel therapeutic approaches for the eradication of CSC are yet to be established. In this review, we describe recent progress in hepatic CSC research and provide a perspective on the available therapeutic approaches based on stem cell biology. © 2015 The Japan Society of Hepatology.
Inhibition of Hypoxia Inducible Factor Alpha and Astrocyte-Elevated Gene-1 Mediates Cryptotanshinone Exerted Antitumor Activity in Hypoxic PC-3 Cells

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Hyo-Jeong Lee

2012-01-01

Full Text Available Although cryptotanshinone (CT was known to exert antitumor activity in several cancers, its molecular mechanism under hypoxia still remains unclear. Here, the roles of AEG-1 and HIF-1α in CT-induced antitumor activity were investigated in hypoxic PC-3 cells. CT exerted cytotoxicity against prostate cancer cells and suppressed HIF-1α accumulation and AEG-1 expression in hypoxic PC-3 cells. Also, AEG-1 was overexpressed in prostate cancer cells. Interestingly, HIF-1α siRNA transfection enhanced the cleavages of caspase-9,3, and PAPR and decreased expression of Bcl-2 and AEG1 induced by CT in hypoxic PC-3 cells. Of note, DMOG enhanced the stability of AEG-1 and HIF-1α during hypoxia. Additionally, CT significantly reduced cellular level of VEGF in PC-3 cells and disturbed tube formation of HUVECs. Consistently, ChIP assay revealed that CT inhibited the binding of HIF-1α to VEGF promoter. Furthermore, CT at 10 mg/kg suppressed the growth of PC-3 cells in BALB/c athymic nude mice by 46.4% compared to untreated control. Consistently, immunohistochemistry revealed decreased expression of Ki-67, CD34, VEGF, carbonic anhydrase IX, and AEG-1 indices in CT-treated group compared to untreated control. Overall, our findings suggest that CT exerts antitumor activity via inhibition of HIF-1α, AEG1, and VEGF as a potent chemotherapeutic agent.
Mesenchymal Stromal Cell Secreted Sphingosine 1-Phosphate (S1P) Exerts a Stimulatory Effect on Skeletal Myoblast Proliferation

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Tani, Alessia; Anderloni, Giulia; Pierucci, Federica; Matteini, Francesca; Chellini, Flaminia; Zecchi Orlandini, Sandra; Meacci, Elisabetta

2014-01-01

Bone-marrow-derived mesenchymal stromal cells (MSCs) have the potential to significantly contribute to skeletal muscle healing through the secretion of paracrine factors that support proliferation and enhance participation of the endogenous muscle stem cells in the process of repair/regeneration. However, MSC-derived trophic molecules have been poorly characterized. The aim of this study was to investigate paracrine signaling effects of MSCs on skeletal myoblasts. It was found, using a biochemical and morphological approach that sphingosine 1-phosphate (S1P), a natural bioactive lipid exerting a broad range of muscle cell responses, is secreted by MSCs and represents an important factor by which these cells exert their stimulatory effects on C2C12 myoblast and satellite cell proliferation. Indeed, exposure to conditioned medium obtained from MSCs cultured in the presence of the selective sphingosine kinase inhibitor (iSK), blocked increased cell proliferation caused by the conditioned medium from untreated MSCs, and the addition of exogenous S1P in the conditioned medium from MSCs pre-treated with iSK further increased myoblast proliferation. Finally, we also demonstrated that the myoblast response to MSC-secreted vascular endothelial growth factor (VEGF) involves the release of S1P from C2C12 cells. Our data may have important implications in the optimization of cell-based strategies to promote skeletal muscle regeneration. PMID:25264785
Therapeutic targeting of the p53 pathway in cancer stem cells

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Prabhu, Varun V.; Allen, Joshua E.; Hong, Bo; Zhang, Shengliang; Cheng, Hairong; El-Deiry, Wafik S.

2013-01-01

Introduction Cancer stem cells are a high profile drug target for cancer therapeutics due to their indispensable role in cancer progression, maintenance, and therapeutic resistance. Restoring wild-type p53 function is an attractive new therapeutic approach for the treatment of cancer due to the well-described powerful tumor suppressor function of p53. As emerging evidence intimately links p53 and stem cell biology, this approach also provides an opportunity to target cancer stem cells. Areas covered Therapeutic approaches to restore the function of wild-type p53, cancer and normal stem cell biology in relation to p53, and the downstream effects of p53 on cancer stem cells. Expert opinion The restoration of wild-type p53 function by targeting p53 directly, its interacting proteins, or its family members holds promise as a new class of cancer therapies. This review examines the impact that such therapies may have on normal and cancer stem cells based on the current evidence linking p53 signaling with these populations. PMID:22998602
Therapeutic potential of adult stem cells

DEFF Research Database (Denmark)

Serakinci, Nedime; Keith, W. Nicol

2006-01-01

is the necessity to be able to identify, select, expand and manipulate cells outside the body. Recent advances in adult stem cell technologies and basic biology have accelerated therapeutic opportunities aimed at eventual clinical applications. Adult stem cells with the ability to differentiate down multiple...... lineages are an attractive alternative to human embryonic stem cells (hES) in regenerative medicine. In many countries, present legislation surrounding hES cells makes their use problematic, and indeed the origin of hES cells may represent a controversial issue for many communities. However, adult stem...... cells are not subject to these issues. This review will therefore focus on adult stem cells. Based on their extensive differentiation potential and, in some cases, the relative ease of their isolation, adult stem cells are appropriate for clinical development. Recently, several observations suggest...
Cancer Stem Cells and Their Microenvironment: Biology and Therapeutic Implications

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Eunice Yuen-Ting Lau

2017-01-01

Full Text Available Tumor consists of heterogeneous cancer cells including cancer stem cells (CSCs that can terminally differentiate into tumor bulk. Normal stem cells in normal organs regulate self-renewal within a stem cell niche. Likewise, accumulating evidence has also suggested that CSCs are maintained extrinsically within the tumor microenvironment, which includes both cellular and physical factors. Here, we review the significance of stromal cells, immune cells, extracellular matrix, tumor stiffness, and hypoxia in regulation of CSC plasticity and therapeutic resistance. With a better understanding of how CSC interacts with its niche, we are able to identify potential therapeutic targets for the development of more effective treatments against cancer.
Breast cancer stem cells, EMT and therapeutic targets

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Kotiyal, Srishti; Bhattacharya, Susinjan, E-mail: s.bhattacharya@jiit.ac.in

2014-10-10

Highlights: • Therapeutic targeting or inhibition of the key molecules of signaling pathways can control growth of breast cancer stem cells (BCSCs). • Development of BCSCs also involves miRNA interactions. • Therapeutic achievement can be done by targeting identified targets in the BCSC pathways. - Abstract: A small heterogeneous population of breast cancer cells acts as seeds to induce new tumor growth. These seeds or breast cancer stem cells (BCSCs) exhibit great phenotypical plasticity which allows them to undergo “epithelial to mesenchymal transition” (EMT) at the site of primary tumor and a future reverse transition. Apart from metastasis they are also responsible for maintaining the tumor and conferring it with drug and radiation resistance and a tendency for post-treatment relapse. Many of the signaling pathways involved in induction of EMT are involved in CSC generation and regulation. Here we are briefly reviewing the mechanism of TGF-β, Wnt, Notch, TNF-α, NF-κB, RTK signalling pathways which are involved in EMT as well as BCSCs maintenance. Therapeutic targeting or inhibition of the key/accessory players of these pathways could control growth of BCSCs and hence malignant cancer. Additionally several miRNAs are dysregulated in cancer stem cells indicating their roles as oncogenes or tumor suppressors. This review also lists the miRNA interactions identified in BCSCs and discusses on some newly identified targets in the BCSC regulatory pathways like SHIP2, nicastrin, Pin 1, IGF-1R, pro-inflammatory cytokines and syndecan which can be targeted for therapeutic achievements.
Targeting NK-1 Receptors to Prevent and Treat Pancreatic Cancer: A New Therapeutic Approach

International Nuclear Information System (INIS)

Muñoz, Miguel; Coveñas, Rafael

2015-01-01

Pancreatic cancer (PC) is the fourth leading cause of cancer related-deaths in both men and women, and the 1- and 5-year relative survival rates are 25% and 6%, respectively. It is known that smoking, alcoholism and psychological stress are risk factors that can promote PC and increase PC progression. To date, the prevention of PC is crucial because there is no curative treatment. After binding to the neurokinin-1 (NK-1) receptor (a receptor coupled to the stimulatory G-protein Gαs that activates adenylate cyclase), the peptide substance P (SP)—at high concentrations—is involved in many pathophysiological functions, such as depression, smoking, alcoholism, chronic inflammation and cancer. It is known that PC cells and samples express NK-1 receptors; that the NK-1 receptor is overexpressed in PC cells in comparison with non-tumor cells, and that nanomolar concentrations of SP induce PC cell proliferation. By contrast, NK-1 receptor antagonists exert antidepressive, anxiolytic and anti-inflammatory effects and anti-alcohol addiction. These antagonists also exert an antitumor action since in vitro they inhibit PC cell proliferation (PC cells death by apoptosis), and in a xenograft PC mouse model they exert both antitumor and anti-angiogenic actions. NK-1 receptor antagonists could be used for the treatment of PC and hence the NK-1 receptor could be a new promising therapeutic target in PC
Targeting NK-1 Receptors to Prevent and Treat Pancreatic Cancer: A New Therapeutic Approach

Energy Technology Data Exchange (ETDEWEB)

Muñoz, Miguel, E-mail: mmunoz@cica.es [Research Laboratory on Neuropeptides (IBIS), Virgen del Rocío University Hospital, 41013 Sevilla (Spain); Coveñas, Rafael [Laboratory of Neuroanatomy of the Peptidergic System (Lab. 14), Institute of Neurosciences of Castilla y León (INCYL), University of Salamanca, 37008 Salamanca (Spain)

2015-07-06

Pancreatic cancer (PC) is the fourth leading cause of cancer related-deaths in both men and women, and the 1- and 5-year relative survival rates are 25% and 6%, respectively. It is known that smoking, alcoholism and psychological stress are risk factors that can promote PC and increase PC progression. To date, the prevention of PC is crucial because there is no curative treatment. After binding to the neurokinin-1 (NK-1) receptor (a receptor coupled to the stimulatory G-protein Gαs that activates adenylate cyclase), the peptide substance P (SP)—at high concentrations—is involved in many pathophysiological functions, such as depression, smoking, alcoholism, chronic inflammation and cancer. It is known that PC cells and samples express NK-1 receptors; that the NK-1 receptor is overexpressed in PC cells in comparison with non-tumor cells, and that nanomolar concentrations of SP induce PC cell proliferation. By contrast, NK-1 receptor antagonists exert antidepressive, anxiolytic and anti-inflammatory effects and anti-alcohol addiction. These antagonists also exert an antitumor action since in vitro they inhibit PC cell proliferation (PC cells death by apoptosis), and in a xenograft PC mouse model they exert both antitumor and anti-angiogenic actions. NK-1 receptor antagonists could be used for the treatment of PC and hence the NK-1 receptor could be a new promising therapeutic target in PC.
MIS416 Enhances Therapeutic Functions of Human Umbilical Cord Blood-Derived Mesenchymal Stem Cells Against Experimental Colitis by Modulating Systemic Immune Milieu

Directory of Open Access Journals (Sweden)

Byung-Chul Lee

2018-05-01

Full Text Available Human adult stem cells, including umbilical cord blood-derived mesenchymal stem cells (hUCB-MSCs, have recently been considered a promising alternative treatment for inflammatory bowel disease (IBD due to their unique immunomodulatory properties and ability to promote tissue regeneration. However, despite many years of research and pre-clinical studies, results from clinical trials using these cells have been diverse and conflicting. This discrepancy is caused by several factors, such as poor engraftment, low survival rate, and donor-dependent variation of the cells. Enhancement of consistency and efficacy of MSCs remains a challenge for the feasibility of cell-based therapy. In this study, we investigated whether administration of MIS416, a novel microparticle that activates NOD2 and TLR9 signaling, could enhance the therapeutic efficacy of hUCB-MSCs against Crohn’s disease, using dextran sulfate sodium (DSS-induced colitis model. Colitis was experimentally induced in mice by using 3% DSS, and mice were administered a retro-orbital injection of MIS416 and subsequent intraperitoneal injection of hUCB-MSCs. Mice were examined grossly, and blood, spleen, and colon tissues were subsequently collected for further ex vivo analyses. To explore the effects of MIS416 on the therapeutic process, hUCB-MSCs and primary isolated immune cells were cultured with MIS416, and in vitro assays were performed. Compared to the single administration of hUCB-MSCs, co-administration with MIS416 improved the therapeutic efficiency of the stem cells by significantly alleviating the symptoms of IBD. Interestingly, MIS416 did not exert any direct effect on the immunomodulatory capacity of hUCB-MSCs. Instead, systemically injected MIS416 altered the immune milieu in the colon which caused hUCB-MSCs to be more readily recruited toward the lesion site and to suppress inflammation more efficiently. In addition, considerable numbers of regulatory immune cells were stimulated
Sevoflurane improves gaseous exchange and exerts protective ...

African Journals Online (AJOL)

Sevoflurane improves gaseous exchange and exerts protective effects in ... Lung water content and cell count were estimated by standard protocols. ... It reversed LPS-induced oxidative stress, as demonstrated by increase in total antioxidant ...
Myeloid derived suppressor cells as therapeutic target in hematological malignancies

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Kim eDe Veirman

2014-12-01

Full Text Available Myeloid derived suppressor cells (MDSC are a heterogeneous population of immature myeloid cells that accumulate during pathological conditions such as cancer and are associated with a poor clinical outcome. MDSC expansion hampers the host anti-tumor immune response by inhibition of T cell proliferation, cytokine secretion and recruitment of regulatory T cells. In addition, MDSC exert non-immunological functions including the promotion of angiogenesis, tumor invasion and metastasis. Recent years, MDSC are considered as a potential target in solid tumors and hematological malignancies to enhance the effects of currently used immune modulating agents. This review focuses on the characteristics, distribution, functions, cell-cell interactions and targeting of MDSC in hematological malignancies including multiple myeloma, lymphoma and leukemia.
Supraphysiological Doses of Performance Enhancing Anabolic-Androgenic Steroids Exert Direct Toxic Effects on Neuron-like Cells

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John Robert Basile

2013-05-01

Full Text Available Anabolic-androgenic steroids (AAS are lipophilic hormones often taken in excessive quantities by athletes and bodybuilders to enhance performance and increase muscle mass. AAS exert well known toxic effects on specific cell and tissue types and organ systems. The attention that androgen abuse has received lately should be used as an opportunity to educate both athletes and the general population regarding their adverse effects. Among numerous commercially available steroid hormones, very few have been specifically tested for direct neurotoxicity. We evaluated the effects of supraphysiological doses of methandienone and 17-α-methyltestosterone on sympathetic-like neuron cells. Vitality and apoptotic effects were analyzed, and immunofluorescence staining and western blot performed. In this study, we demonstrate that exposure of supraphysiological doses of methandienone and 17-α-methyltestosterone are toxic to the neuron-like differentiated pheochromocytoma cell line PC12, as confirmed by toxicity on neurite networks responding to nerve growth factor and the modulation of the survival and apoptosis-related proteins ERK, caspase-3, poly (ADP-ribose polymerase and heat-shock protein 90. We observe, in contrast to some previous reports but in accordance with others, expression of the androgen receptor (AR in neuron-like cells, which when inhibited mitigated the toxic effects of AAS tested, suggesting that the AR could be binding these steroid hormones to induce genomic effects. We also note elevated transcription of neuritin in treated cells, a neurotropic factor likely expressed in an attempt to resist neurotoxicity. Taken together, these results demonstrate that supraphysiological exposure to the AAS methandienone and 17-α-methyltestosterone exert neurotoxic effects by an increase in the activity of the intrinsic apoptotic pathway and alterations in neurite networks.
Polyethylenimine-based siRNA nanocomplexes reprogram tumor-associated dendritic cells via TLR5 to elicit therapeutic antitumor immunity.

Science.gov (United States)

Cubillos-Ruiz, Juan R; Engle, Xavier; Scarlett, Uciane K; Martinez, Diana; Barber, Amorette; Elgueta, Raul; Wang, Li; Nesbeth, Yolanda; Durant, Yvon; Gewirtz, Andrew T; Sentman, Charles L; Kedl, Ross; Conejo-Garcia, Jose R

2009-08-01

The success of clinically relevant immunotherapies requires reversing tumor-induced immunosuppression. Here we demonstrated that linear polyethylenimine-based (PEI-based) nanoparticles encapsulating siRNA were preferentially and avidly engulfed by regulatory DCs expressing CD11c and programmed cell death 1-ligand 1 (PD-L1) at ovarian cancer locations in mice. PEI-siRNA uptake transformed these DCs from immunosuppressive cells to efficient antigen-presenting cells that activated tumor-reactive lymphocytes and exerted direct tumoricidal activity, both in vivo and in situ. PEI triggered robust and selective TLR5 activation in vitro and elicited the production of hallmark TLR5-inducible cytokines in WT mice, but not in Tlr5-/- littermates. Thus, PEI is a TLR5 agonist that, to our knowledge, was not previously recognized. In addition, PEI-complexed nontargeting siRNA oligonucleotides stimulated TLR3 and TLR7. The nonspecific activation of multiple TLRs (specifically, TLR5 and TLR7) reversed the tolerogenic phenotype of human and mouse ovarian tumor-associated DCs. In ovarian carcinoma-bearing mice, this induced T cell-mediated tumor regression and prolonged survival in a manner dependent upon myeloid differentiation primary response gene 88 (MyD88; i.e., independent of TLR3). Furthermore, gene-specific siRNA-PEI nanocomplexes that silenced immunosuppressive molecules on mouse tumor-associated DCs elicited discernibly superior antitumor immunity and enhanced therapeutic effects compared with nontargeting siRNA-PEI nanocomplexes. Our results demonstrate that the intrinsic TLR5 and TLR7 stimulation of siRNA-PEI nanoparticles synergizes with the gene-specific silencing activity of siRNA to transform tumor-infiltrating regulatory DCs into DCs capable of promoting therapeutic antitumor immunity.
Therapeutic effects of the joint administration of magnesium aspartate and adenosine monophosphate in gamma-irradiated mice

International Nuclear Information System (INIS)

Pospisil, M.; Netikova, J.; Pipalova, I.; Kozubik, A.

1990-01-01

The joint administration of magnesium aspartate and adenosine monophosphate, injected on days 1 to 4 post radiation, has been found to exert stimulatory effects on the recovery of hemopoietic functions in sublethally gamma-irradiated mice. These therapeutical effects were enhanced in animals protected by peroral administration of cystamine. The treatment scheme used did not modify survival of lethally irradiated mice. The therapeutic effects of magnesium aspartate and adenosine monophosphate in sublethally irradiated mice are explained by the stimulatory action of these drugs on the cell adenylate cyclase system, which influences the erythropoietic functions. (author)
Progenitor cells in the kidney: biology and therapeutic perspectives

NARCIS (Netherlands)

Rookmaaker, M.B.; Verhaar, M.C.; Zonneveld, A.J. van; Rabelink, T.J.

2004-01-01

Progenitor cells in the kidney: Biology and therapeutic perspectives. The stem cell may be viewed as an engineer who can read the blue print and become the building. The role of this fascinating cell in physiology and pathophysiology has recently attracted a great deal of interest. The archetype of
NK cell-released exosomes: Natural nanobullets against tumors.

Science.gov (United States)

Fais, Stefano

2013-01-01

We have recently reported that human natural killer (NK) cells release exosomes that express both NK-cell markers and cytotoxic molecules. Similar results were obtained with circulating exosomes from human healthy donors. Both NK-cell derived and circulating exosomes exerted a full functional activity and killed both tumor and activated immune cells. These findings indicate that NK-cell derived exosomes might constitute a new promising therapeutic tool.
Juglans regia Hexane Extract Exerts Antitumor Effect, Apoptosis ...

African Journals Online (AJOL)

Original Research Article. Juglans regia Hexane Extract Exerts Antitumor Effect,. Apoptosis Induction and Cell Circle Arrest in Prostate. Cancer Cells In vitro. Wei Li1, De-Yuan Li2*, ... composition of walnut is juglone (5-hydroxy-1, 4- naphthoquinone), the .... extract was confirmed by studying apoptotic body formation using ...

Combining antiangiogenic therapy with adoptive cell immunotherapy exerts better antitumor effects in non-small cell lung cancer models.

Directory of Open Access Journals (Sweden)

Shujing Shi

Full Text Available INTRODUCTION: Cytokine-induced killer cells (CIK cells are a heterogeneous subset of ex-vivo expanded T lymphocytes which are characterized with a MHC-unrestricted tumor-killing activity and a mixed T-NK phenotype. Adoptive CIK cells transfer, one of the adoptive immunotherapy represents a promising nontoxic anticancer therapy. However, in clinical studies, the therapeutic activity of adoptive CIK cells transfer is not as efficient as anticipated. Possible explanations are that abnormal tumor vasculature and hypoxic tumor microenvironment could impede the infiltration and efficacy of lymphocytes. We hypothesized that antiangiogenesis therapy could improve the antitumor activity of CIK cells by normalizing tumor vasculature and modulating hypoxic tumor microenvironment. METHODS: We combined recombinant human endostatin (rh-endostatin and CIK cells in the treatment of lung carcinoma murine models. Intravital microscopy, dynamic contrast enhanced magnetic resonance imaging, immunohistochemistry, and flow cytometry were used to investigate the tumor vasculature and hypoxic microenvironment as well as the infiltration of immune cells. RESULTS: Our results indicated that rh-endostatin synergized with adoptive CIK cells transfer to inhibit the growth of lung carcinoma. We found that rh-endostatin normalized tumor vasculature and reduced hypoxic area in the tumor microenvironment. Hypoxia significantly inhibited the proliferation, cytotoxicity and migration of CIK cells in vitro and impeded the homing of CIK cells into tumor parenchyma ex vivo. Furthermore, we found that treatment with rh-endostatin significantly increased the homing of CIK cells and decreased the accumulation of suppressive immune cells in the tumor tissue. In addition, combination therapy produced higher level of tumor-infiltration lymphocytes compared with other treatments. CONCLUSIONS: Our results demonstrate that rh-endostatin improves the therapeutic effect of adoptive CIK cells
Exertional heat stroke management strategies in United States high school football.

Science.gov (United States)

Kerr, Zachary Y; Marshall, Stephen W; Comstock, R Dawn; Casa, Douglas J

2014-01-01

The 5-year period of 2005-2009 saw more exertional heat stroke-related deaths in organized sports than any other 5-year period in the past 35 years. The risk of exertional heat stroke appears highest in football, particularly during the preseason. To estimate the incidence of exertional heat stroke events and assess the utilization of exertional heat stroke management strategies during the 2011 preseason in United States high school football programs. Cross-sectional study; Level of evidence, 3. A self-administered online questionnaire addressing the incidence of exertional heat stroke events and utilization of exertional heat stroke management strategies (eg, removing athlete's football equipment, calling Emergency Medical Services [EMS]) was completed in May to June 2012 by 1142 (18.0%) athletic trainers providing care to high school football athletes during the 2011 preseason. Among all respondents, 20.3% reported treating at least 1 exertional heat stroke event. An average of 0.50 ± 1.37 preseason exertional heat stroke events were treated per program. Athletic trainers responding to exertional heat stroke reported using an average of 6.6 ± 1.8 management strategies. The most common management strategies were low-level therapeutic interventions such as removing the athlete's football equipment (98.2%) and clothing (77.8%) and moving the athlete to a shaded area (91.6%). Few athletic trainers reported active management strategies such as calling EMS (29.3%) or using a rectal thermometer to check core body temperature (0.9%). Athletic trainers in states with mandated preseason heat acclimatization guidelines reported a higher utilization of management strategies such as cooling the athlete through air conditioning (90.1% vs 65.0%, respectively; P football programs. The standard of care is (and should be) to treat proactively; therefore, treatment is not a perfect proxy for incidence. Nevertheless, there is an urgent need for improved education and awareness of
Therapeutic approaches to preventing cell death in Huntington disease.

Science.gov (United States)

Kaplan, Anna; Stockwell, Brent R

2012-12-01

Neurodegenerative diseases affect the lives of millions of patients and their families. Due to the complexity of these diseases and our limited understanding of their pathogenesis, the design of therapeutic agents that can effectively treat these diseases has been challenging. Huntington disease (HD) is one of several neurological disorders with few therapeutic options. HD, like numerous other neurodegenerative diseases, involves extensive neuronal cell loss. One potential strategy to combat HD and other neurodegenerative disorders is to intervene in the execution of neuronal cell death. Inhibiting neuronal cell death pathways may slow the development of neurodegeneration. However, discovering small molecule inhibitors of neuronal cell death remains a significant challenge. Here, we review candidate therapeutic targets controlling cell death mechanisms that have been the focus of research in HD, as well as an emerging strategy that has been applied to developing small molecule inhibitors-fragment-based drug discovery (FBDD). FBDD has been successfully used in both industry and academia to identify selective and potent small molecule inhibitors, with a focus on challenging proteins that are not amenable to traditional high-throughput screening approaches. FBDD has been used to generate potent leads, pre-clinical candidates, and has led to the development of an FDA approved drug. This approach can be valuable for identifying modulators of cell-death-regulating proteins; such compounds may prove to be the key to halting the progression of HD and other neurodegenerative disorders. Copyright © 2012 Elsevier Ltd. All rights reserved.
The Promise and Perils of Stem Cell Therapeutics

OpenAIRE

Daley, George Q.

2012-01-01

Stem cells are the seeds of tissue repair and regeneration and a promising source for novel therapies. However, apart from hematopoietic stem cell (HSC) transplantation for hematologic disease, essentially all other stem cell treatments remain experimental. High hopes have inspired numerous clinical trials, but it has been difficult to obtain unequivocal evidence for robust clinical benefit, likely owing to our primitive state of knowledge about therapeutic mechanisms. Outside the standard cl...
Binase Immobilized on Halloysite Nanotubes Exerts Enhanced Cytotoxicity toward Human Colon Adenocarcinoma Cells

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Vera Khodzhaeva

2017-09-01

Full Text Available Many ribonucleases (RNases are considered as promising tools for antitumor therapy because of their selective cytotoxicity toward cancer cells. Binase, the RNase from Bacillus pumilus, triggers apoptotic response in cancer cells expressing RAS oncogene which is mutated in a large percentage of prevalent and deadly malignancies including colorectal cancer. The specific antitumor effect of binase toward RAS-transformed cells is due to its direct binding of RAS protein and inhibition of downstream signaling. However, the delivery of proteins to the intestine is complicated by their degradation in the digestive tract and subsequent loss of therapeutic activity. Therefore, the search of new systems for effective delivery of therapeutic proteins is an actual task. This study is aimed to the investigation of antitumor effect of binase immobilized on natural halloysite nanotubes (HNTs. Here, we have developed the method of binase immobilization on HNTs and optimized the conditions for the enzyme loading and release (i; we have found the non-toxic concentration of pure HNTs which allows to distinguish HNTs- and binase-induced cytotoxic effects (ii; using dark-field and fluorescent microscopy we have proved the absorption of binase-loaded HNTs on the cell surface (iii and demonstrated that binase-halloysite nanoformulations possessed twice enhanced cytotoxicity toward tumor colon cells as compared to the cytotoxicity of binase itself (iv. The enhanced antitumor activity of biocompatible binase-HNTs complex confirms the advisability of its future development for clinical practice.
Ganoderma lucidum exerts anti-tumor effects on ovarian cancer cells and enhances their sensitivity to cisplatin.

Science.gov (United States)

Zhao, Sufen; Ye, Gang; Fu, Guodong; Cheng, Jian-Xin; Yang, Burton B; Peng, Chun

2011-05-01

Ganoderma lucidum is a herbal mushroom known to have many health benefits, including the inhibition of tumor cell growth. However, the effect of Ganoderma lucidum on epithelial ovarian cancer (EOC), the most fatal gynecological malignancy, has not yet been reported. In this study, we determined whether Ganoderma lucidum regulates EOC cell activity. Using several cell lines derived from EOC, we found that Ganoderma lucidum strongly decreased cell numbers in a dose-dependent manner. Ganoderma lucidum also inhibited colony formation, cell migration and spheroid formation. In particular, Ganoderma lucidum was effective in inhibiting cell growth in both chemosensitive and chemoresistant cells and the treatment with Ganoderma lucidum significantly enhanced the effect of cisplatin on EOC cells. Furthermore, Ganoderma lucidum induced cell cycle arrest at the G2/M phase and also induced apoptosis by activating caspase 3. Finally, Ganoderma lucidum increased p53 but inhibited Akt expression. Taken together, these findings suggest that Ganoderma lucidum exerts multiple anti-tumor effects on ovarian cancer cells and can enhance the sensitivity of EOC cells to cisplatin.
Generation of autologous tumor-specific T cells for adoptive transfer based on vaccination, in vitro restimulation and CD3/CD28 dynabead-induced T cell expansion

DEFF Research Database (Denmark)

Brimnes, Marie Klinge; Gang, Anne Ortved; Donia, Marco

2012-01-01

Adoptive cell transfer (ACT) of in vitro expanded autologous tumor-infiltrating lymphocytes (TIL) has been shown to exert therapeutic efficacy in melanoma patients. We aimed to develop an ACT protocol based on tumor-specific T cells isolated from peripheral blood and in vitro expanded by Dynabeads...
Human multipotent adult progenitor cells are nonimmunogenic and exert potent immunomodulatory effects on alloreactive T-cell responses.

Science.gov (United States)

Jacobs, Sandra A; Pinxteren, Jef; Roobrouck, Valerie D; Luyckx, Ariane; van't Hof, Wouter; Deans, Robert; Verfaillie, Catherine M; Waer, Mark; Billiau, An D; Van Gool, Stefaan W

2013-01-01

Multipotent adult progenitor cells (MAPCs) are bone marrow-derived nonhematopoietic stem cells with a broad differentiation potential and extensive expansion capacity. A comparative study between human mesenchymal stem cells (hMSCs) and human MAPCs (hMAPCs) has shown that hMAPCs have clearly distinct phenotypical and functional characteristics from hMSCs. In particular, hMAPCs express lower levels of MHC class I than hMSCs and cannot only differentiate into typical mesenchymal cell types but can also differentiate in vitro and in vivo into functional endothelial cells. The use of hMSCs as cellular immunomodulatory stem cell products gained much interest since their immunomodulatory capacities in vitro became evident over the last decade. Currently, the clinical grade stem cell product of hMAPCs is already used in clinical trials to prevent graft-versus-host disease (GVHD), as well as for the treatment of acute myocardial infarct, ischemic stroke, and Crohn's disease. Therefore, we studied the immune phenotype, immunogenicity, and immunosuppressive effect of hMAPCs in vitro. We demonstrated that hMAPCs are nonimmunogenic for T-cell proliferation and cytokine production. In addition, hMAPCs exert strong immunosuppressive effects on T-cell alloreactivity and on T-cell proliferation induced by mitogens and recall antigens. This immunomodulatory effect was not MHC restricted, which makes off-the-shelf use promising. The immunosuppressive effect of hMAPCs is partially mediated via soluble factors and dependent on indoleamine 2,3-dioxygenase (IDO) activity. At last, we isolated hMAPCs, the clinical grade stem cell product of hMAPCs, named MultiStem, and hMSCs from one single donor and observed that both the immunogenicity and the immunosuppressive capacities of all three stem cell products are comparable in vitro. In conclusion, hMAPCs have potent immunomodulatory properties in vitro and can serve as a valuable cell source for the clinical use of immunomodulatory cellular
Analysis of radiation pressure force exerted on a biological cell induced by high-order Bessel beams using Debye series

International Nuclear Information System (INIS)

Li, Renxian; Ren, Kuan Fang; Han, Xiang'e; Wu, Zhensen; Guo, Lixin; Gong, Shuxi

2013-01-01

Debye series expansion (DSE) is employed to the analysis of radiation pressure force (RPF) exerted on biological cells induced by high-order Bessel beams (BB). The beam shape coefficients (BSCs) for high-order Bessel beams are calculated using analytical expressions obtained by the integral localized approximation (ILA). Different types of cells, including a real Chinese Hamster Ovary (CHO) cell and a lymphocyte which are respectively modeled by a coated and five-layered sphere, are considered. The RPF induced by high-order Bessel beams is compared with that by Gaussian beams and zeroth-order Bessel beams, and the effect of different scattering processes on RPF is studied. Numerical calculations show that high-order Bessel beams with zero central intensity can also transversely trap particle in the beam center, and some scattering processes can provide longitudinal pulling force. -- Highlights: ► BSCs for high-order Bessel beam (HOBB) is derived using ILA. ► DSE is employed to study the RPF induced by HOBB exerted on multilayered cells. ► RPF is decided by radius relative to the interval of peaks in intensity profile. ► HOBB can also transversely trap high-index particle in the vicinity of beam axis. ► RPF for some scattering processes can longitudinally pull particles back
Designer exosomes produced by implanted cells intracerebrally deliver therapeutic cargo for Parkinson's disease treatment.

Science.gov (United States)

Kojima, Ryosuke; Bojar, Daniel; Rizzi, Giorgio; Hamri, Ghislaine Charpin-El; El-Baba, Marie Daoud; Saxena, Pratik; Ausländer, Simon; Tan, Kelly R; Fussenegger, Martin

2018-04-03

Exosomes are cell-derived nanovesicles (50-150 nm), which mediate intercellular communication, and are candidate therapeutic agents. However, inefficiency of exosomal message transfer, such as mRNA, and lack of methods to create designer exosomes have hampered their development into therapeutic interventions. Here, we report a set of EXOsomal transfer into cells (EXOtic) devices that enable efficient, customizable production of designer exosomes in engineered mammalian cells. These genetically encoded devices in exosome producer cells enhance exosome production, specific mRNA packaging, and delivery of the mRNA into the cytosol of target cells, enabling efficient cell-to-cell communication without the need to concentrate exosomes. Further, engineered producer cells implanted in living mice could consistently deliver cargo mRNA to the brain. Therapeutic catalase mRNA delivery by designer exosomes attenuated neurotoxicity and neuroinflammation in in vitro and in vivo models of Parkinson's disease, indicating the potential usefulness of the EXOtic devices for RNA delivery-based therapeutic applications.
Cell-Specific Aptamers as Emerging Therapeutics

Directory of Open Access Journals (Sweden)

Cindy Meyer

2011-01-01

Full Text Available Aptamers are short nucleic acids that bind to defined targets with high affinity and specificity. The first aptamers have been selected about two decades ago by an in vitro process named SELEX (systematic evolution of ligands by exponential enrichment. Since then, numerous aptamers with specificities for a variety of targets from small molecules to proteins or even whole cells have been selected. Their applications range from biosensing and diagnostics to therapy and target-oriented drug delivery. More recently, selections using complex targets such as live cells have become feasible. This paper summarizes progress in cell-SELEX techniques and highlights recent developments, particularly in the field of medically relevant aptamers with a focus on therapeutic and drug-delivery applications.
Remote control of therapeutic T cells through a small molecule-gated chimeric receptor

Science.gov (United States)

Wu, Chia-Yung; Roybal, Kole T.; Puchner, Elias M.; Onuffer, James; Lim, Wendell A.

2016-01-01

There is growing promise in using engineered cells as therapeutic agents. For example, synthetic Chimeric Antigen Receptors (CARs) can redirect T cells to recognize and eliminate tumor cells expressing specific antigens. Despite promising clinical results, excessive activity and poor control over such engineered T cells can cause severe toxicities. We present the design of “ON-switch” CARs that enable small molecule-control over T cell therapeutic functions, while still retaining antigen specificity. In these split receptors, antigen binding and intracellular signaling components only assemble in the presence of a heterodimerizing small molecule. This titratable pharmacologic regulation could allow physicians to precisely control the timing, location, and dosage of T cell activity, thereby mitigating toxicity. This work illustrates the potential of combining cellular engineering with orthogonal chemical tools to yield safer therapeutic cells that tightly integrate both cell autonomous recognition and user control. PMID:26405231
Indications of hematopoietic stem cell transplantations and therapeutic strategies of accidental irradiations

International Nuclear Information System (INIS)

2003-01-01

Produced by a group of experts, this document first discusses the issue of accidental irradiations in terms of medical management. They notably outline the peculiar characteristics of these irradiations with respect to therapeutic irradiations. They agreed on general principles regarding casualty sorting criteria and process, and their medical treatment (systematic hematopoiesis stimulation, allogeneic transplantation of hematopoietic stem cells). They discuss some practical aspects of these issues: casualty sorting within a therapeutic perspective (actions to be performed within 48 hours), therapeutic strategies (support therapy, use of cytokines, and therapy by hematopoietic stem cell transplant). They state a set of recommendations regarding the taking into care and diagnosis, therapeutic strategies, research perspectives, and teaching
Interleukin-1 exerts distinct actions on different cell types of the brain in vitro

Directory of Open Access Journals (Sweden)

Ying An

2011-01-01

Full Text Available Ying An, Qun Chen, Ning QuanDepartment of Oral Biology, Ohio State University, Columbus, OH, USAAbstract: Interleukin-1 (IL-1 is a critical neuroinflammatory mediator in the central nervous system (CNS. In this study, we investigated the effect of IL-1 on inducing inflammation-related gene expression in three astrocyte, two microglial, and one brain endothelial cell line. Interleukin-1 beta (IL-1β is found to be produced by the two microglial cell lines constitutively, but these cells do not respond to IL-1β stimulation. The three astrocyte cell lines responded to IL-1ß stimulation by expressing MCP-1, CXCL-1, and VCAM-1, but different subtypes of astrocytes exhibited different expression profiles after IL-1β stimulation. The brain endothelial cells showed strongest response to IL-1β by producing MCP-1, CXCL-1, VCAM-1, ICAM-1, IL-6, and COX-2 mRNA. The induction of endothelial COX-2 mRNA is shown to be mediated by p38 MAPK pathway, whereas the induction of other genes is mediated by the NF-κB pathway. These results demonstrate that IL-1 exerts distinct cell type-specific action in CNS cells and suggest that IL-1-mediated neuroinflammation is the result of the summation of multiple responses from different cell types in the CNS to IL-1.Keywords: astrocyte, microglia, endothelial cells, signal transduction pathways, gene expression
Remote control of therapeutic T cells through a small molecule-gated chimeric receptor.

Science.gov (United States)

Wu, Chia-Yung; Roybal, Kole T; Puchner, Elias M; Onuffer, James; Lim, Wendell A

2015-10-16

There is growing interest in using engineered cells as therapeutic agents. For example, synthetic chimeric antigen receptors (CARs) can redirect T cells to recognize and eliminate tumor cells expressing specific antigens. Despite promising clinical results, these engineered T cells can exhibit excessive activity that is difficult to control and can cause severe toxicity. We designed "ON-switch" CARs that enable small-molecule control over T cell therapeutic functions while still retaining antigen specificity. In these split receptors, antigen-binding and intracellular signaling components assemble only in the presence of a heterodimerizing small molecule. This titratable pharmacologic regulation could allow physicians to precisely control the timing, location, and dosage of T cell activity, thereby mitigating toxicity. This work illustrates the potential of combining cellular engineering with orthogonal chemical tools to yield safer therapeutic cells that tightly integrate cell-autonomous recognition and user control. Copyright © 2015, American Association for the Advancement of Science.
Bovine lactoferrin and lactoferricin exert antitumor activities on human colorectal cancer cells (HT-29) by activating various signaling pathways.

Science.gov (United States)

Jiang, Rulan; Lönnerdal, Bo

2017-02-01

Lactoferrin (Lf) is an iron-binding glycoprotein that is present at high concentrations in milk. Bovine lactoferricin (LfcinB) is a peptide fragment generated by pepsin proteolysis of bovine lactoferrin (bLf). LfcinB consists of amino acid residues 17-41 proximal to the N-terminus of bLf and a disulfide bond between residues 19 and 36, forming a loop. Both bLf and LfcinB have been demonstrated to have antitumor activities. Colorectal cancer is the second most common cause of cancer death in developed countries. We hypothesized that bLf and LfcinB exert antitumor activities on colon cancer cells (HT-29) by triggering various signaling pathways. bLf and LfcinB significantly induced apoptosis in HT-29 cells but not in normal human intestinal epithelial cells, as revealed by the ApoTox-Glo Triplex Assay. The LIVE/DEAD cell viability assay showed that both bLf and LfcinB reduced the viability of HT-29 cells. Transcriptome analysis indicated that bLf, cyclic LfcinB, and linear LfcinB exerted antitumor activities by differentially activating diverse signaling pathways, including p53, apoptosis, and angiopoietin signaling. Immunoblotting results confirmed that both bLf and LfcinBs increased expression of caspase-8, p53, and p21, critical proteins in tumor suppression. These results provide valuable information regarding bLf and LfcinB for potential clinical applications in colon cancer therapy.
Beyond the therapeutic shackles of the monoamines: New mechanisms in bipolar disorder biology.

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Data-Franco, João; Singh, Ajeet; Popovic, Dina; Ashton, Melanie; Berk, Michael; Vieta, Eduard; Figueira, M L; Dean, Olivia M

2017-01-04

Multiple novel biological mechanisms putatively involved in the etiology of bipolar disorders are being explored. These include oxidative stress, altered glutamatergic neurotransmission, mitochondrial dysfunction, inflammation, cell signaling, apoptosis and impaired neurogenesis. Important clinical translational potential exists for such mechanisms to help underpin development of novel therapeutics - much needed given limitations of current therapies. These new mechanisms also help improve our understanding of how current therapeutics might exert their effects. Lithium, for example, appears to have antioxidant, immunomodulatory, signaling, anti-apoptotic and neuroprotective properties. Similar properties have been attributed to other mood stabilizers such as valproate, lamotrigine, and quetiapine. Perhaps of greatest translational value has been the recognition of such mechanisms leading to the emergence of novel therapeutics for bipolar disorders. These include the antioxidant N-acetylcysteine, the anti-inflammatory celecoxib, and ketamine - with effects on the glutamatergic system and microglial inhibition. We review these novel mechanisms and emerging therapeutics, and comment on next steps in this space. Copyright © 2016 Elsevier Inc. All rights reserved.
Synthetic Immunology: Hacking Immune Cells to Expand Their Therapeutic Capabilities.

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Roybal, Kole T; Lim, Wendell A

2017-04-26

The ability of immune cells to survey tissues and sense pathologic insults and deviations makes them a unique platform for interfacing with the body and disease. With the rapid advancement of synthetic biology, we can now engineer and equip immune cells with new sensors and controllable therapeutic response programs to sense and treat diseases that our natural immune system cannot normally handle. Here we review the current state of engineered immune cell therapeutics and their unique capabilities compared to small molecules and biologics. We then discuss how engineered immune cells are being designed to combat cancer, focusing on how new synthetic biology tools are providing potential ways to overcome the major roadblocks for treatment. Finally, we give a long-term vision for the use of synthetic biology to engineer immune cells as a general sensor-response platform to precisely detect disease, to remodel disease microenvironments, and to treat a potentially wide range of challenging diseases.
Gap junctions and hemichannels composed of connexins: potential therapeutic targets for neurodegenerative diseases

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Hideyuki eTakeuchi

2014-09-01

Full Text Available Microglia are macrophage-like resident immune cells that contribute to the maintenance of homeostasis in the central nervous system (CNS. Abnormal activation of microglia can cause damage in the CNS, and accumulation of activated microglia is a characteristic pathological observation in neurologic conditions such as trauma, stroke, inflammation, epilepsy, and neurodegenerative diseases. Activated microglia secrete high levels of glutamate, which damages CNS cells and has been implicated as a major cause of neurodegeneration in these conditions. Glutamate-receptor blockers and microglia inhibitors (e.g. minocycline have been examined as therapeutic candidates for several neurodegenerative diseases; however, these compounds exerted little therapeutic benefit because they either perturbed physiological glutamate signals or suppressed the actions of protective microglia. The ideal therapeutic approach would hamper the deleterious roles of activated microglia without diminishing their protective effects. We recently found that abnormally activated microglia secrete glutamate via gap-junction hemichannels on the cell surface. Moreover, administration of gap-junction inhibitors significantly suppressed excessive microglial glutamate release and improved disease symptoms in animal models of neurologic conditions such as stroke, multiple sclerosis, amyotrophic lateral sclerosis, and Alzheimer’s disease. Recent evidence also suggests that neuronal and glial communication via gap junctions amplifies neuroinflammation and neurodegeneration. Elucidation of the precise pathologic roles of gap junctions and hemichannels may lead to a novel therapeutic strategies that can slow and halt the progression of neurodegenerative diseases.
Development of the Fibulin-3 protein therapeutics of non small cell lung cancer stem cells

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Kim, In Gyu; Kim, Kugchan; Jung, Il Lae; Kim, Seo Yeon; Choi, Su Im; Lee, Jae Ha

2013-09-15

This study focuses on developing an efficient bioprocess for large-scale production of fibulin-3 using Chinese Hamster Ovary cell expression system and evaluating its therapeutic potential for the treatment of cancer. The specific aims are as follows: Isolation and establishment of CSCs using FACS based on cell surface markers and high ALDH1 activity. Identification and characterization of lung cancer stem cells that acquire features of CSC upon exposure to ionizing radiation. Evaluation of the fibulin-3 effects on the stem traits and signaling pathways required for the generation and maintenance of CSCs. In vivo validation of fivulin-3 for tumor prognosis and therapeutic efficacy against lung cancer using animal model.

In vitro and in vivo delivery of therapeutic proteins using cell penetrating peptides.

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Bolhassani, Azam; Jafarzade, Behnaz Sadat; Mardani, Golnaz

2017-01-01

The failure of proteins to penetrate mammalian cells or target tumor cells restricts their value as therapeutic tools in a variety of diseases such as cancers. Recently, protein transduction domains (PTDs) or cell penetrating peptides (CPPs) have been shown to promote the delivery of therapeutic proteins or peptides into live cells. The successful delivery of proteins mainly depends on their physicochemical properties. Although, linear cell penetrating peptides are one of the most effective delivery vehicles; but currently, cyclic CPPs has been developed to potently transport bioactive full-length proteins into cells. Up to now, several small protein transduction domains from viral proteins including Tat or VP22 could be fused to other peptides or proteins to entry them in various cell types at a dose-dependent approach. A major disadvantage of PTD-fusion proteins is primary uptake into endosomal vesicles leading to inefficient release of the fusion proteins into the cytosol. Recently, non-covalent complex formation (Chariot) between proteins and CPPs has attracted a special interest to overcome some delivery limitations (e.g., toxicity). Many preclinical and clinical trials of CPP-based delivery are currently under evaluation. Generally, development of more efficient protein transduction domains would significantly increase the potency of protein therapeutics. Moreover, the synergistic or combined effects of CPPs with other delivery systems for protein/peptide drug delivery would promote their therapeutic effects in cancer and other diseases. In this review, we will describe the functions and implications of CPPs for delivering the therapeutic proteins or peptides in preclinical and clinical studies. Copyright © 2016 Elsevier Inc. All rights reserved.
Superparamagnetic iron oxide nanoparticles exert different cytotoxic effects on cells grown in monolayer cell culture versus as multicellular spheroids

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Theumer, Anja; Gräfe, Christine; Bähring, Franziska [Department of Hematology and Oncology, Jena University Hospital, Erlanger Allee 101, 07747 Jena (Germany); Bergemann, Christian [Chemicell GmbH, Eresburgstrasse 22–23, 12103 Berlin (Germany); Hochhaus, Andreas [Department of Hematology and Oncology, Jena University Hospital, Erlanger Allee 101, 07747 Jena (Germany); Clement, Joachim H., E-mail: joachim.clement@med.uni-jena.de [Department of Hematology and Oncology, Jena University Hospital, Erlanger Allee 101, 07747 Jena (Germany)

2015-04-15

The aim of this study was to investigate the interaction of superparamagnetic iron oxide nanoparticles (SPION) with human blood–brain barrier-forming endothelial cells (HBMEC) in two-dimensional cell monolayers as well as in three-dimensional multicellular spheroids. The precise nanoparticle localisation and the influence of the NP on the cellular viability and the intracellular Akt signalling were studied in detail. Long-term effects of different polymer-coated nanoparticles (neutral fluidMAG-D, anionic fluidMAG-CMX and cationic fluidMAG-PEI) and the corresponding free polymers on cellular viability of HBMEC were investigated by real time cell analysis studies. Nanoparticles exert distinct effects on HBMEC depending on the nanoparticles' surface charge and concentration, duration of incubation and cellular context. The most severe effects were caused by PEI-coated nanoparticles. Concentrations above 25 µg/ml led to increased amounts of dead cells in monolayer culture as well as in multicellular spheroids. On the level of intracellular signalling, context-dependent differences were observed. Monolayer cultures responded on nanoparticle incubation with an increase in Akt phosphorylation whereas spheroids on the whole show a decreased Akt activity. This might be due to the differential penetration and distribution of PEI-coated nanoparticles.
Synthetic biology in mammalian cells: Next generation research tools and therapeutics

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Lienert, Florian; Lohmueller, Jason J; Garg, Abhishek; Silver, Pamela A

2014-01-01

Recent progress in DNA manipulation and gene circuit engineering has greatly improved our ability to programme and probe mammalian cell behaviour. These advances have led to a new generation of synthetic biology research tools and potential therapeutic applications. Programmable DNA-binding domains and RNA regulators are leading to unprecedented control of gene expression and elucidation of gene function. Rebuilding complex biological circuits such as T cell receptor signalling in isolation from their natural context has deepened our understanding of network motifs and signalling pathways. Synthetic biology is also leading to innovative therapeutic interventions based on cell-based therapies, protein drugs, vaccines and gene therapies. PMID:24434884
T-Cell Traffic Jam in Hodgkin's Lymphoma: Pathogenetic and Therapeutic Implications

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Claudio Fozza

2011-01-01

Full Text Available In hematologic malignancies, the microenvironment is often characterized by nonneoplastic cells with peculiar phenotypic and functional features. This is particularly true in Hodgkin's lymphoma (HL, in which T lymphocytes surrounding Hodgkin's Reed-Sternberg cells are essentially polarized towards a memory T-helper type 2 phenotype. In this paper we will first evaluate the main processes modulating T-cell recruitment towards the lymph node microenvironment in HL, especially focusing on the role played by cytokines. We will then consider the most relevant mechanisms of immune escape exerted by neoplastic cells in order to evade antitumor immunity. The potential pathogenetic and prognostic impact of regulatory T cells in such a context will be also described. We will finally overview some of the strategies of cellular immunotherapy applied in patients with HL.
Towards the therapeutic use of vascular smooth muscle progenitor cells.

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Merkulova-Rainon, Tatyana; Broquères-You, Dong; Kubis, Nathalie; Silvestre, Jean-Sébastien; Lévy, Bernard I

2012-07-15

Recent advances in the development of alternative proangiogenic and revascularization processes, including recombinant protein delivery, gene therapy, and cell therapy, hold the promise of greater efficacy in the management of cardiovascular disease in the coming years. In particular, vascular progenitor cell-based strategies have emerged as an efficient treatment approach to promote vessel formation and repair and to improve tissue perfusion. During the past decade, considerable progress has been achieved in understanding therapeutic properties of endothelial progenitor cells, while the therapeutic potential of vascular smooth muscle progenitor cells (SMPC) has only recently been explored; the number of the circulating SMPC being correlated with cardiovascular health. Several endogenous SMPC populations with varying phenotypes have been identified and characterized in the peripheral blood, bone marrow, and vascular wall. While the phenotypic entity of vascular SMPC is not fully defined and remains an evolving area of research, SMPC are increasingly recognized to play a special role in cardiovascular biology. In this review, we describe the current approaches used to define vascular SMPC. We further summarize the data on phenotype and functional properties of SMPC from various sources in adults. Finally, we discuss the role of SMPC in cardiovascular disease, including the contribution of SMPC to intimal proliferation, angiogenesis, and atherosclerotic plaque instability as well as the benefits resulting from the therapeutic use of SMPC.
European regulation for therapeutic use of stem cells.

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Ferry, Nicolas

2017-01-01

The regulation for the use of stem cells has evolved during the past decade with the aim of ensuring a high standard of quality and safety for human derived products throughout Europe to comply with the provision of the Lisbon treaty. To this end, new regulations have been issued and the regulatory status of stem cells has been revised. Indeed, stem cells used for therapeutic purposes can now be classified as a cell preparation, or as advanced therapy medicinal products depending on the clinical indication and on the procedure of cell preparation. Furthermore, exemptions to the European regulation are applicable for stem cells prepared and used within the hospital. The aim of this review is to give the non-specialized reader a broad overview of this particular regulatory landscape.
[Pt(O,O'-acac)(gamma-acac)(DMS)], a new Pt compound exerting fast cytotoxicity in MCF-7 breast cancer cells via the mitochondrial apoptotic pathway.

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Muscella, A; Calabriso, N; Fanizzi, F P; De Pascali, S A; Urso, L; Ciccarese, A; Migoni, D; Marsigliante, S

2008-01-01

We showed previously that a new Pt complex containing an O,O'-chelated acetylacetonate ligand (acac) and a dimethylsulphide in the Pt coordination sphere, [Pt(O,O'-acac)(gamma-acac)(DMS)], induces apoptosis in HeLa cells. The objective of this study was to investigate the hypothesis that [Pt(O,O'-acac)(gamma-acac)(DMS)] is also cytotoxic in a MCF-7 breast cancer cell line relatively insensitive to cisplatin, and to gain a more detailed analysis of the cell death pathways. Cells were treated with Pt compounds and cytotoxicity tests were performed, together with Western blotting of various proteins involved in apoptosis. The mitochondrial membrane potential was assessed by fluorescence microscopy and spectrofluorometry and the Pt bound to cell fractions was measured by atomic absorption spectrometry. In contrast to cisplatin, the cytotoxicity of [Pt(O,O'-acac)(gamma-acac)(DMS)] correlated with cellular accumulation but not with DNA binding. Also, the Pt content in DNA bases was considerably higher for cisplatin than for [Pt(O,O'-acac)(gamma-acac)(DMS)], thus excluding DNA as a target of [Pt(O,O'-acac)(gamma-acac)(DMS)]. [Pt(O,O'-acac)(gamma-acac)(DMS)] exerted high and fast apoptotic processes in MCF-7 cells since it provoked: (a) mitochondria depolarization; (b) cytochrome c accumulation in the cytosol; (c) translocation of Bax and truncated-Bid from cytosol to mitochondria and decreased expression of Bcl-2; (d) cleavage of caspases -7 and -9, and PARP degradation; (e) chromatin condensation and DNA fragmentation. [Pt(O,O'-acac)(gamma-acac)(DMS)] is highly cytotoxic for MCF-7 cells, cells relatively resistant to many chemotherapeutic agents, as it activates the mitochondrial apoptotic pathway. Hence, [Pt(O,O'-acac)(gamma-acac)(DMS)] has the potential to provide us with new opportunities for therapeutic intervention.
Bone Marrow-Derived Cells as a Therapeutic Approach to Optic Nerve Diseases

Directory of Open Access Journals (Sweden)

Louise A. Mesentier-Louro

2016-01-01

Full Text Available Following optic nerve injury associated with acute or progressive diseases, retinal ganglion cells (RGCs of adult mammals degenerate and undergo apoptosis. These diseases have limited therapeutic options, due to the low inherent capacity of RGCs to regenerate and due to the inhibitory milieu of the central nervous system. Among the numerous treatment approaches investigated to stimulate neuronal survival and axonal extension, cell transplantation emerges as a promising option. This review focuses on cell therapies with bone marrow mononuclear cells and bone marrow-derived mesenchymal stem cells, which have shown positive therapeutic effects in animal models of optic neuropathies. Different aspects of available preclinical studies are analyzed, including cell distribution, potential doses, routes of administration, and mechanisms of action. Finally, published and ongoing clinical trials are summarized.
Cell-based therapeutic strategies for multiple sclerosis.

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Scolding, Neil J; Pasquini, Marcelo; Reingold, Stephen C; Cohen, Jeffrey A

2017-11-01

The availability of multiple disease-modifying medications with regulatory approval to treat multiple sclerosis illustrates the substantial progress made in therapy of the disease. However, all are only partially effective in preventing inflammatory tissue damage in the central nervous system and none directly promotes repair. Cell-based therapies, including immunoablation followed by autologous haematopoietic stem cell transplantation, mesenchymal and related stem cell transplantation, pharmacologic manipulation of endogenous stem cells to enhance their reparative capabilities, and transplantation of oligodendrocyte progenitor cells, have generated substantial interest as novel therapeutic strategies for immune modulation, neuroprotection, or repair of the damaged central nervous system in multiple sclerosis. Each approach has potential advantages but also safety concerns and unresolved questions. Moreover, clinical trials of cell-based therapies present several unique methodological and ethical issues. We summarize here the status of cell-based therapies to treat multiple sclerosis and make consensus recommendations for future research and clinical trials. © The Author (2017). Published by Oxford University Press on behalf of the Guarantors of Brain.
Host manipulation by cancer cells: Expectations, facts, and therapeutic implications.

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Tissot, Tazzio; Arnal, Audrey; Jacqueline, Camille; Poulin, Robert; Lefèvre, Thierry; Mery, Frédéric; Renaud, François; Roche, Benjamin; Massol, François; Salzet, Michel; Ewald, Paul; Tasiemski, Aurélie; Ujvari, Beata; Thomas, Frédéric

2016-03-01

Similar to parasites, cancer cells depend on their hosts for sustenance, proliferation and reproduction, exploiting the hosts for energy and resources, and thereby impairing their health and fitness. Because of this lifestyle similarity, it is predicted that cancer cells could, like numerous parasitic organisms, evolve the capacity to manipulate the phenotype of their hosts to increase their own fitness. We claim that the extent of this phenomenon and its therapeutic implications are, however, underappreciated. Here, we review and discuss what can be regarded as cases of host manipulation in the context of cancer development and progression. We elaborate on how acknowledging the applicability of these principles can offer novel therapeutic and preventive strategies. The manipulation of host phenotype by cancer cells is one more reason to adopt a Darwinian approach in cancer research. © 2016 WILEY Periodicals, Inc.
Lung Regeneration: Endogenous and Exogenous Stem Cell Mediated Therapeutic Approaches.

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Akram, Khondoker M; Patel, Neil; Spiteri, Monica A; Forsyth, Nicholas R

2016-01-19

The tissue turnover of unperturbed adult lung is remarkably slow. However, after injury or insult, a specialised group of facultative lung progenitors become activated to replenish damaged tissue through a reparative process called regeneration. Disruption in this process results in healing by fibrosis causing aberrant lung remodelling and organ dysfunction. Post-insult failure of regeneration leads to various incurable lung diseases including chronic obstructive pulmonary disease (COPD) and idiopathic pulmonary fibrosis. Therefore, identification of true endogenous lung progenitors/stem cells, and their regenerative pathway are crucial for next-generation therapeutic development. Recent studies provide exciting and novel insights into postnatal lung development and post-injury lung regeneration by native lung progenitors. Furthermore, exogenous application of bone marrow stem cells, embryonic stem cells and inducible pluripotent stem cells (iPSC) show evidences of their regenerative capacity in the repair of injured and diseased lungs. With the advent of modern tissue engineering techniques, whole lung regeneration in the lab using de-cellularised tissue scaffold and stem cells is now becoming reality. In this review, we will highlight the advancement of our understanding in lung regeneration and development of stem cell mediated therapeutic strategies in combating incurable lung diseases.
NF-κB functions as a molecular link between tumor cells and Th1/Tc1 T cells in the tumor microenvironment to exert radiation-mediated tumor suppression

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Simon, Priscilla S.; Bardhan, Kankana; Chen, May R.; Paschall, Amy V.; Lu, Chunwan; Bollag, Roni J.; Kong, Feng-Chong; Jin, JianYue; Kong, Feng-Ming; Waller, Jennifer L.; Pollock, Raphael E.; Liu, Kebin

2016-01-01

Radiation modulates both tumor cells and immune cells in the tumor microenvironment to exert its anti-tumor activity; however, the molecular connection between tumor cells and immune cells that mediates radiation-exerted tumor suppression activity in the tumor microenvironment is largely unknown. We report here that radiation induces rapid activation of the p65/p50 and p50/p50 NF-κB complexes in human soft tissue sarcoma (STS) cells. Radiation-activated p65/p50 and p50/p50 bind to the TNFα promoter to activate its transcription in STS cells. Radiation-induced TNFα induces tumor cell death in an autocrine manner. A sublethal dose of Smac mimetic BV6 induces cIAP1 and cIAP2 degradation to increase tumor cell sensitivity to radiation-induced cell death in vitro and to enhance radiation-mediated suppression of STS xenografts in vivo. Inhibition of caspases, RIP1, or RIP3 blocks radiation/TNFα-induced cell death, whereas inhibition of RIP1 blocks TNFα-induced caspase activation, suggesting that caspases and RIP1 act sequentially to mediate the non-compensatory cell death pathways. Furthermore, we determined in a syngeneic sarcoma mouse model that radiation up-regulates IRF3, IFNβ, and the T cell chemokines CCL2 and CCL5 in the tumor microenvironment, which are associated with activation and increased infiltration of Th1/Tc1 T cells in the tumor microenvironment. Moreover, tumor-infiltrating T cells are in their active form since both the perforin and FasL pathways are activated in irradiated tumor tissues. Consequently, combined BV6 and radiation completely suppressed tumor growth in vivo. Therefore, radiation-induced NF-κB functions as a molecular link between tumor cells and immune cells in the tumor microenvironment for radiation-mediated tumor suppression. PMID:27014915
Technological progress and challenges towards cGMP manufacturing of human pluripotent stem cells based therapeutic products for allogeneic and autologous cell therapies.

Science.gov (United States)

Abbasalizadeh, Saeed; Baharvand, Hossein

2013-12-01

Recent technological advances in the generation, characterization, and bioprocessing of human pluripotent stem cells (hPSCs) have created new hope for their use as a source for production of cell-based therapeutic products. To date, a few clinical trials that have used therapeutic cells derived from hESCs have been approved by the Food and Drug Administration (FDA), but numerous new hPSC-based cell therapy products are under various stages of development in cell therapy-specialized companies and their future market is estimated to be very promising. However, the multitude of critical challenges regarding different aspects of hPSC-based therapeutic product manufacturing and their therapies have made progress for the introduction of new products and clinical applications very slow. These challenges include scientific, technological, clinical, policy, and financial aspects. The technological aspects of manufacturing hPSC-based therapeutic products for allogeneic and autologous cell therapies according to good manufacturing practice (cGMP) quality requirements is one of the most important challenging and emerging topics in the development of new hPSCs for clinical use. In this review, we describe main critical challenges and highlight a series of technological advances in all aspects of hPSC-based therapeutic product manufacturing including clinical grade cell line development, large-scale banking, upstream processing, downstream processing, and quality assessment of final cell therapeutic products that have brought hPSCs closer to clinical application and commercial cGMP manufacturing. © 2013.
A short synthetic peptide fragment of human C2ORF40 has therapeutic potential in breast cancer

Energy Technology Data Exchange (ETDEWEB)

Lin, Chaoyang [Shandong Univ., Jinan (China); Zhang, Pengju [Shandong Univ., Jinan (China); Jiang, Anli [Shandong Univ., Jinan (China); Mao, Jian-Hua [Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States); Wei, Guangwei [Shandong Univ. School of Medicine, Jinan (China)

2017-03-30

C2ORF40 encodes a secreted protein which is cleaved to generate soluble peptides by proteolytic processing and this process is believed to be necessary for C2ORF40 to exert cell type specific biological activity. Here, we reported a short mimic peptide of human C2ORF40 acts potential therapeutic efficacy in human cancer cells in vitro and in vivo. We synthesized a short peptide of human C2ORF40, named C2ORF40 mimic peptide fragment and assessed its biological function on cancer cell growth, migration and tumorigenesis. Cell growth assay showed that C2ORF40 mimic peptide fragment significantly suppressed cell proliferation of breast and lung cancer cells. Moreover, C2ORF40 mimic peptide fragment significantly inhibited the migration and invasion of breast cancer cells. Furthermore, we showed that this peptide suppressed tumorigenesis in breast tumor xenograft model. Cell cycle assay indicated that the C2ORF40 mimic peptide fragment suppressed the growth of tumor cells through inducing mitotic phase arrest. In conclusion, our results firstly suggested that this short synthetic peptide of human C2ORF40 may be a candidate tumor therapeutic agent.
Transcriptional Control of Vascular Smooth Muscle Cell Proliferation by Peroxisome Proliferator-Activated Receptor-γ: Therapeutic Implications for Cardiovascular Diseases

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Florence Gizard

2008-01-01

Full Text Available Proliferation of vascular smooth muscle cells (SMCs is a critical process for the development of atherosclerosis and complications of procedures used to treat atherosclerotic diseases, including postangioplasty restenosis, vein graft failure, and transplant vasculopathy. Peroxisome proliferator-activated receptor (PPAR γ is a member of the nuclear hormone receptor superfamily and the molecular target for the thiazolidinediones (TZD, used clinically to treat insulin resistance in patients with type 2 diabetes. In addition to their efficacy to improve insulin sensitivity, TZD exert a broad spectrum of pleiotropic beneficial effects on vascular gene expression programs. In SMCs, PPARγ is prominently upregulated during neointima formation and suppresses the proliferative response to injury of the arterial wall. Among the molecular target genes regulated by PPARγ in SMCs are genes encoding proteins involved in the regulation of cell-cycle progression, cellular senescence, and apoptosis. This inhibition of SMC proliferation is likely to contribute to the prevention of atherosclerosis and postangioplasty restenosis observed in animal models and proof-of-concept clinical studies. This review will summarize the transcriptional target genes regulated by PPARγ in SMCs and outline the therapeutic implications of PPARγ activation for the treatment and prevention of atherosclerosis and its complications.
Neutron sample cell suitable for the diffraction of aligned biomaterials and capable of exerting up to 370 MPa of hydrostatic pressure

International Nuclear Information System (INIS)

Watson, M.J.; Nieh, M.-P.; Harroun, T.A.; Katsaras, J.

2003-01-01

We describe a temperature controlled sample cell suitable for the study of biomimetic materials (e.g., lipid bilayers) using neutron diffraction, and capable of exerting hydrostatic pressures of up to 370 MPa. The advantage of this sample cell, compared to previous high-pressure cells of its type, is that it allows for the use of samples aligned on a solid support which, compared to 'powder' or so-called liposomal preparations, requires only small amounts of sample and allows for the clear differentiation between in-plane and out-of-plane structure
Gastric cancer stem cells: A novel therapeutic target

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Singh, Shree Ram

2013-01-01

Gastric cancer remains one of the leading causes of global cancer mortality. Multipotent gastric stem cells have been identified in both mouse and human stomachs, and they play an essential role in the self-renewal and homeostasis of gastric mucosa. There are several environmental and genetic factors known to promote gastric cancer. In recent years, numerous in vitro and in vivo studies suggest that gastric cancer may originate from normal stem cells or bone marrow–derived mesenchymal cells, and that gastric tumors contain cancer stem cells. Cancer stem cells are believed to share a common microenvironment with normal niche, which play an important role in gastric cancer and tumor growth. This mini-review presents a brief overview of the recent developments in gastric cancer stem cell research. The knowledge gained by studying cancer stem cells in gastric mucosa will support the development of novel therapeutic strategies for gastric cancer. PMID:23583679
Mesenchymal stem cells as therapeutic delivery vehicles targeting tumor stroma

DEFF Research Database (Denmark)

Serakinci, Nedime; Christensen, Rikke; Sørensen, Flemming Brandt

2011-01-01

The field of stem cell biology continues to evolve by characterization of further types of stem cells and by exploring their therapeutic potential for experimental and clinical applications. Human mesenchymal stem cells (hMSCs) are one of the most promising candidates simply because...... better understanding and in vivo supporting data. The homing ability of hMSCs was investigated by creating a human xenograft model by transplanting an ovarian cancer cell line into immunocompromised mice. Then, genetically engineered hMSC-telo1 cells were injected through the tail vein...
Engineering Specificity and Function of Therapeutic Regulatory T Cells

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Jenny L. McGovern

2017-11-01

Full Text Available Adoptive therapy with polyclonal regulatory T cells (Tregs has shown efficacy in suppressing detrimental immune responses in experimental models of autoimmunity and transplantation. The lack of specificity is a potential limitation of Treg therapy, as studies in mice have demonstrated that specificity can enhance the therapeutic potency of Treg. We will discuss that vectors encoding T cell receptors or chimeric antigen receptors provide an efficient gene-transfer platform to reliably produce Tregs of defined antigen specificity, thus overcoming the considerable difficulties of isolating low-frequency, antigen-specific cells that may be present in the natural Treg repertoire. The recent observations that Tregs can polarize into distinct lineages similar to the Th1, Th2, and Th17 subsets described for conventional T helper cells raise the possibility that Th1-, Th2-, and Th17-driven pathology may require matching Treg subsets for optimal therapeutic efficacy. In the future, genetic engineering may serve not only to enforce FoxP3 expression and a stable Treg phenotype but it may also enable the expression of particular transcription factors that drive differentiation into defined Treg subsets. Together, established and recently developed gene transfer and editing tools provide exciting opportunities to produce tailor-made antigen-specific Treg products with defined functional activities.
Perspectives on Exertional Rhabdomyolysis.

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Rawson, Eric S; Clarkson, Priscilla M; Tarnopolsky, Mark A

2017-03-01

Exertional (exercise-induced) rhabdomyolysis is a potentially life threatening condition that has been the subject of research, intense discussion, and media attention. The causes of rhabdomyolysis are numerous and can include direct muscle injury, unaccustomed exercise, ischemia, extreme temperatures, electrolyte abnormalities, endocrinologic conditions, genetic disorders, autoimmune disorders, infections, drugs, toxins, and venoms. The objective of this article is to review the literature on exertional rhabdomyolysis, identify precipitating factors, and examine the role of the dietary supplement creatine monohydrate. PubMed and SPORTDiscus databases were searched using the terms rhabdomyolysis, muscle damage, creatine, creatine supplementation, creatine monohydrate, and phosphocreatine. Additionally, the references of papers identified through this search were examined for relevant studies. A meta-analysis was not performed. Although the prevalence of rhabdomyolysis is low, instances still occur where exercise is improperly prescribed or used as punishment, or incomplete medical history is taken, and exertional rhabdomyolysis occurs. Creatine monohydrate does not appear to be a precipitating factor for exertional rhabdomyolysis. Healthcare professionals should be able to recognize the basic signs of exertional rhabdomyolysis so prompt treatment can be administered. For the risk of rhabdomyolysis to remain low, exercise testing and prescription must be properly conducted based on professional standards.

Therapeutic Potential of Mesenchymal Stem Cell-Derived Exosomes in the Treatment of Eye Diseases.

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Harrell, C Randall; Simovic Markovic, Bojana; Fellabaum, Crissy; Arsenijevic, Aleksandar; Djonov, Valentin; Arsenijevic, Nebojsa; Volarevic, Vladislav

2018-05-18

Mesenchymal stem cells (MSCs) were, due to their immunomodulatory and pro-angiogenic characteristics, extensively explored as new therapeutic agents in cell-based therapy of uveitis, glaucoma, retinal and ocular surface diseases.Since it was recently revealed that exosomes play an important role in biological functions of MSCs, herewith we summarized current knowledge about the morphology, structure, phenotype and functional characteristics of MSC-derived exosomes emphasizing their therapeutic potential in the treatment of eye diseases.MSC-derived exosomes were as efficient as transplanted MSCs in limiting the extent of eye injury and inflammation. Immediately after intravitreal injection, MSC-derived exosomes, due to nano-dimension, diffused rapidly throughout the retina and significantly attenuated retinal damage and inflammation. MSC-derived exosomes successfully delivered trophic and immunomodulatory factors to the inner retina and efficiently promoted survival and neuritogenesis of injured retinal ganglion cells. MSC-derived exosomes efficiently suppressed migration of inflammatory cells, attenuated detrimental Th1 and Th17 cell-driven immune response and ameliorated experimental autoimmune uveitis. MSC-derived exosomes were able to fuse with the lysosomes within corneal cells, enabling delivering of MSC-derived active β-glucuronidase and consequent catabolism of accumulated glycosaminoglycans, indicating their therapeutic potential in the treatment of Mucopolysaccharidosis VII (Sly Syndrome). Importantly, beneficent effects were noticed only in animals that received MSC-derived exosomes and were not seen after therapy with fibroblasts-derived exosomes confirming specific therapeutic potential of MSCs and their products in the treatment of eye diseases.In conclusion, MSC-derived exosomes represent potentially new therapeutic agents in the therapy of degenerative and inflammatory ocular diseases.
The definition of exertion-related cardiac events.

Science.gov (United States)

Rai, M; Thompson, P D

2011-02-01

Vigorous physical activity increases the risk of sudden cardiac death (SCD) and acute myocardial infarction (AMI) but there is no standard definition as to what constitutes an exertion-related cardiac event, specifically the time interval between physical exertion and cardiac event. A systematic review of studies related to exertion-related cardiac events was performed and the time interval between exertion and the event or the symptoms leading to the event was looked for in all the articles selected for inclusion. A total of 12 of 26 articles "suggested" or "defined" exertion-related events as those events whose symptoms started during or within 1 h of exertion. Others used definitions of 0.5 h, 2 h, "during exertion", "during or immediately post exertion" and "during or within several hours after exertion". It is suggested, therefore, that the definition of an exertion-related cardiac event be established as a cardiac event in which symptoms started during or within 1 h of physical exertion.
Function and Therapeutic Potential of Mesenchymal Stem Cells in Atherosclerosis

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Feifei Li

2017-05-01

Full Text Available Atherosclerosis is a complicated disorder and largely attributable to dyslipidaemia and chronic inflammation. Despite therapeutic advances over past decades, atherosclerosis remains the leading cause of mortality worldwide. Due to their capability of immunomodulation and tissue regeneration, mesenchymal stem cells (MSCs have evolved as an attractive therapeutic agent in various diseases including atherosclerosis. Accumulating evidences support the protective role of MSCs in all stages of atherosclerosis. In this review, we highlight the current understanding of MSCs including their characteristics such as molecular markers, tissue distribution, migratory property, immune-modulatory competence, etc. We also summarize MSC functions in animal models of atherosclerosis. MSC transplantation is able to modulate cytokine and chemokine secretion, reduce endothelial dysfunction, promote regulatory T cell function, decrease dyslipidemia, and stabilize vulnerable plaques during atherosclerosis development. In addition, MSCs may migrate to lesions where they develop into functional cells during atherosclerosis formation. Finally, the perspectives of MSCs in clinical atherosclerosis therapy are discussed.
Interference with PSMB4 Expression Exerts an Anti-Tumor Effect by Decreasing the Invasion and Proliferation of Human Glioblastoma Cells

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Yu-Chen Cheng

2018-01-01

matrix metallopeptidase 9 in vivo. Conclusion: PSMB4 inhibition in combination with TMZ may exert an anti-tumor effect by decreasing cell proliferation and invasion as well as by promoting apoptosis in human glioblastoma cells. This research may improve the therapeutic efficacy of glioblastoma treatment.
[Transgenic cell cultures that synthesize neurotrophic factors and the possibility of therapeutic use of its cells].

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Pavlova, G V; Kanaĭkina, N N; Panteleev, D Iu; Okhotin, V E; Revishchin, A V

2012-01-01

Under the leadership of Corresponding Member of the Russian Academy of Sciences L.I. Korochkin, the Laboratory of Neurogenetics and Developmental Genetics (Institute of Gene Biology, Russian Academy of Sciences) for many years has been conducting studies of nervous system development, neural cell differentiation, and application of gene and cell technology to cure neurodegenerative diseases. The results of the study initiated by L.I. Korochkin and continued by his scientific successors support the direction of allocation of transgenic neurotrofic factors and heat-shock proteins as neuroprotectors for cell therapy. Potential for usage of promoter of HSP70 heat-shock gene of Drosophila to create transgenic constructs for therapy has been shown. Further improvement of technology of nonvirus transfer for therapeutic genes, as well as production of multicomponent genetic constructs coding several therapeutic factors with synergy effect, would stimulate creation of efficient cell medicals to cure neurodegenerative diseases.
Therapeutic immunization with HIV-1 Tat reduces immune activation and loss of regulatory T-cells and improves immune function in subjects on HAART.

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Barbara Ensoli

2010-11-01

Full Text Available Although HAART suppresses HIV replication, it is often unable to restore immune homeostasis. Consequently, non-AIDS-defining diseases are increasingly seen in treated individuals. This is attributed to persistent virus expression in reservoirs and to cell activation. Of note, in CD4(+ T cells and monocyte-macrophages of virologically-suppressed individuals, there is continued expression of multi-spliced transcripts encoding HIV regulatory proteins. Among them, Tat is essential for virus gene expression and replication, either in primary infection or for virus reactivation during HAART, when Tat is expressed, released extracellularly and exerts, on both the virus and the immune system, effects that contribute to disease maintenance. Here we report results of an ad hoc exploratory interim analysis (up to 48 weeks on 87 virologically-suppressed HAART-treated individuals enrolled in a phase II randomized open-label multicentric clinical trial of therapeutic immunization with Tat (ISS T-002. Eighty-eight virologically-suppressed HAART-treated individuals, enrolled in a parallel prospective observational study at the same sites (ISS OBS T-002, served for intergroup comparison. Immunization with Tat was safe, induced durable immune responses, and modified the pattern of CD4(+ and CD8(+ cellular activation (CD38 and HLA-DR together with reduction of biochemical activation markers and persistent increases of regulatory T cells. This was accompanied by a progressive increment of CD4(+ T cells and B cells with reduction of CD8(+ T cells and NK cells, which were independent from the type of antiretroviral regimen. Increase in central and effector memory and reduction in terminally-differentiated effector memory CD4(+ and CD8(+ T cells were accompanied by increases of CD4(+ and CD8(+ T cell responses against Env and recall antigens. Of note, more immune-compromised individuals experienced greater therapeutic effects. In contrast, these changes were opposite
Natural killer (NK) cells inhibit systemic metastasis of glioblastoma cells and have therapeutic effects against glioblastomas in the brain.

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Lee, Se Jeong; Kang, Won Young; Yoon, Yeup; Jin, Ju Youn; Song, Hye Jin; Her, Jung Hyun; Kang, Sang Mi; Hwang, Yu Kyeong; Kang, Kyeong Jin; Joo, Kyeung Min; Nam, Do-Hyun

2015-12-24

Glioblastoma multiforme (GBM) is characterized by extensive local invasion, which is in contrast with extremely rare systemic metastasis of GBM. Molecular mechanisms inhibiting systemic metastasis of GBM would be a novel therapeutic candidate for GBM in the brain. Patient-derived GBM cells were primarily cultured from surgical samples of GBM patients and were inoculated into the brains of immune deficient BALB/c-nude or NOD-SCID IL2Rgamma(null) (NSG) mice. Human NK cells were isolated from peripheral blood mononucleated cells and expanded in vitro. Patient-derived GBM cells in the brains of NSG mice unexpectedly induced spontaneous lung metastasis although no metastasis was detected in BALB/c-nude mice. Based on the difference of the innate immunity between two mouse strains, NK cell activities of orthotopic GBM xenograft models based on BALB/c-nude mice were inhibited. NK cell inactivation induced spontaneous lung metastasis of GBM cells, which indicated that NK cells inhibit the systemic metastasis. In vitro cytotoxic activities of human NK cells against GBM cells indicated that cytotoxic activity of NK cells against GBM cells prevents systemic metastasis of GBM and that NK cells could be effective cell therapeutics against GBM. Accordingly, NK cells transplanted into orthotopic GBM xenograft models intravenously or intratumorally induced apoptosis of GBM cells in the brain and showed significant therapeutic effects. Our results suggest that innate NK immunity is responsible for rare systemic metastasis of GBM and that sufficient supplementation of NK cells could be a promising immunotherapeutic strategy for GBM in the brain.
Application of Mesenchymal Stem Cells for Therapeutic Agent Delivery in Anti-tumor Treatment

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Daria S. Chulpanova

2018-03-01

Full Text Available Mesenchymal stem cells (MSCs are non-hematopoietic progenitor cells, which can be isolated from different types of tissues including bone marrow, adipose tissue, tooth pulp, and placenta/umbilical cord blood. There isolation from adult tissues circumvents the ethical concerns of working with embryonic or fetal stem cells, whilst still providing cells capable of differentiating into various cell lineages, such as adipocytes, osteocytes and chondrocytes. An important feature of MSCs is the low immunogenicity due to the lack of co-stimulatory molecules expression, meaning there is no need for immunosuppression during allogenic transplantation. The tropism of MSCs to damaged tissues and tumor sites makes them a promising vector for therapeutic agent delivery to tumors and metastatic niches. MSCs can be genetically modified by virus vectors to encode tumor suppressor genes, immunomodulating cytokines and their combinations, other therapeutic approaches include MSCs priming/loading with chemotherapeutic drugs or nanoparticles. MSCs derived membrane microvesicles (MVs, which play an important role in intercellular communication, are also considered as a new therapeutic agent and drug delivery vector. Recruited by the tumor, MSCs can exhibit both pro- and anti-oncogenic properties. In this regard, for the development of new methods for cancer therapy using MSCs, a deeper understanding of the molecular and cellular interactions between MSCs and the tumor microenvironment is necessary. In this review, we discuss MSC and tumor interaction mechanisms and review the new therapeutic strategies using MSCs and MSCs derived MVs for cancer treatment.
A cell-penetrating peptide analogue, P7, exerts antimicrobial activity against Escherichia coli ATCC25922 via penetrating cell membrane and targeting intracellular DNA.

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Li, Lirong; Shi, Yonghui; Cheng, Xiangrong; Xia, Shufang; Cheserek, Maureen Jepkorir; Le, Guowei

2015-01-01

The antibacterial activities and mechanism of a new P7 were investigated in this study. P7 showed antimicrobial activities against five harmful microorganisms which contaminate and spoil food (MIC=4-32 μM). Flow cytometry and scanning electron microscopy analyses demonstrated that P7 induced pore-formation on the cell surface and led to morphological changes but did not lyse cell. Confocal fluorescence microscopic observations and flow cytometry analysis expressed that P7 could penetrate the Escherichia coli cell membrane and accumulate in the cytoplasm. Moreover, P7 possessed a strong DNA binding affinity. Further cell cycle analysis and change in gene expression analysis suggested that P7 induced a decreased expression in the genes involved in DNA replication. Up-regulated expression genes encoding DNA damage repair. This study suggests that P7 could be applied as a candidate for the development of new food preservatives as it exerts its antibacterial activities by penetrating cell membranes and targets intracellular DNA. Copyright © 2014 Elsevier Ltd. All rights reserved.
Developments in stem cell research and therapeutic cloning: Islamic ethical positions, a review.

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Fadel, Hossam E

2012-03-01

Stem cell research is very promising. The use of human embryos has been confronted with objections based on ethical and religious positions. The recent production of reprogrammed adult (induced pluripotent) cells does not - in the opinion of scientists - reduce the need to continue human embryonic stem cell research. So the debate continues. Islam always encouraged scientific research, particularly research directed toward finding cures for human disease. Based on the expectation of potential benefits, Islamic teachings permit and support human embryonic stem cell research. The majority of Muslim scholars also support therapeutic cloning. This permissibility is conditional on the use of supernumerary early pre-embryos which are obtained during infertility treatment in vitro fertilization (IVF) clinics. The early pre-embryos are considered in Islamic jurisprudence as worthy of respect but do not have the full sanctity offered to the embryo after implantation in the uterus and especially after ensoulment. In this paper the Islamic positions regarding human embryonic stem cell research and therapeutic cloning are reviewed in some detail, whereas positions in other religious traditions are mentioned only briefly. The status of human embryonic stem cell research and therapeutic cloning in different countries, including the USA and especially in Muslim countries, is discussed. © 2010 Blackwell Publishing Ltd.
Breast Cancer Stem Cell Therapeutics, Multiple Strategies Versus Using Engineered Mesenchymal Stem Cells With Notch Inhibitory Properties: Possibilities and Perspectives.

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Bose, Bipasha; Sen, Utsav; Shenoy P, Sudheer

2018-01-01

Relapse cases of cancers are more vigorous and difficult to control due to the preponderance of cancer stem cells (CSCs). Such CSCs that had been otherwise dormant during the first incidence of cancer gradually appear as radiochemoresistant cancer cells. Hence, cancer therapeutics aimed at CSCs would be an effective strategy for mitigating the cancers during relapse. Alternatively, CSC therapy can also be proposed as an adjuvant therapy, along-with the conventional therapies. As regenerative stem cells (RSCs) are known for their trophic effects, anti-tumorogenicity, and better migration toward an injury site, this review aims to address the use of adult stem cells such as dental pulp derived; cord blood derived pure populations of regenerative stem cells for targeting CSCs. Indeed, pro-tumorogenicity of RSCs is of concern and hence has also been dealt with in relation to breast CSC therapeutics. Furthermore, as notch signaling pathways are upregulated in breast cancers, and anti-notch antibody based and sh-RNA based therapies are already in the market, this review focuses the possibilities of engineering RSCs to express notch inhibitory proteins for breast CSC therapeutics. Also, we have drawn a comparison among various possibilities of breast CSC therapeutics, about, notch1 inhibition. J. Cell. Biochem. 119: 141-149, 2018. © 2017 Wiley Periodicals, Inc. © 2017 Wiley Periodicals, Inc.
Therapeutic targeting strategies using endogenous cells and proteins.

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Parayath, Neha N; Amiji, Mansoor M

2017-07-28

Targeted drug delivery has become extremely important in enhancing efficacy and reducing the toxicity of therapeutics in the treatment of various disease conditions. Current approaches include passive targeting, which relies on naturally occurring differences between healthy and diseased tissues, and active targeting, which utilizes various ligands that can recognize targets expressed preferentially at the diseased site. Clinical translation of these mechanisms faces many challenges including the immunogenic and toxic effects of these non-natural systems. Thus, use of endogenous targeting systems is increasingly gaining momentum. This review is focused on strategies for employing endogenous moieties, which could serve as safe and efficient carriers for targeted drug delivery. The first part of the review involves cells and cellular components as endogenous carriers for therapeutics in multiple disease states, while the second part discusses the use of endogenous plasma components as endogenous carriers. Further understanding of the biological tropism with cells and proteins and the newer generation of delivery strategies that exploits these endogenous approaches promises to provide better solutions for site-specific delivery and could further facilitate clinical translations. Copyright © 2017 Elsevier B.V. All rights reserved.
Anti-podocalyxin antibody exerts antitumor effects via antibody-dependent cellular cytotoxicity in mouse xenograft models of oral squamous cell carcinoma.

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Itai, Shunsuke; Ohishi, Tomokazu; Kaneko, Mika K; Yamada, Shinji; Abe, Shinji; Nakamura, Takuro; Yanaka, Miyuki; Chang, Yao-Wen; Ohba, Shun-Ichi; Nishioka, Yasuhiko; Kawada, Manabu; Harada, Hiroyuki; Kato, Yukinari

2018-04-27

Podocalyxin (PODXL) overexpression is associated with progression, metastasis, and poor outcomes in cancers. We recently produced the novel anti-PODXL monoclonal antibody (mAb) PcMab-47 (IgG 1 , kappa). Herein, we engineered PcMab-47 into 47-mG 2a , a mouse IgG 2a -type mAb, to add antibody-dependent cellular cytotoxicity (ADCC). We further developed 47-mG 2a -f, a core fucose-deficient type of 47-mG 2a to augment its ADCC. Immunohistochemical analysis of oral cancer tissues using PcMab-47 and 47-mG 2a revealed that the latter stained oral squamous cell carcinoma (OSCC) cells in a cytoplasmic pattern at a much lower concentration. PcMab-47 and 47-mG 2a detected PODXL in 163/201 (81.1%) and in 197/201 (98.0%) OSCC samples, respectively. 47-mG 2a -f also detected PODXL in OSCCs at a similar frequency as 47-mG 2a . In vitro analysis revealed that both 47-mG 2a and 47-mG 2a -f exhibited strong complement-dependent cytotoxicity (CDC) against CHO/hPODXL cells. In contrast, 47-mG 2a -f exhibited much stronger ADCC than 47-mG 2a against OSCC cells, indicating that ADCC and CDC of those anti-PODXL mAbs depend on target cells. In vivo analysis revealed that both 47-mG 2a and 47-mG 2a -f exerted antitumor activity in CHO/hPODXL xenograft models at a dose of 100 μg or 500 μg/mouse/week administered twice. 47-mG 2a -f, but not 47-mG 2a , exerted antitumor activity in SAS and HSC-2 xenograft models at a dose of 100 μg/mouse/week administered three times. Although both 47-mG 2a and 47-mG 2a -f exerted antitumor activity in HSC-2 xenograft models at a dose of 500 μg/mouse/week administered twice, 47-mG 2a -f also showed higher antitumor activity than 47-mG 2a . These results suggested that a core fucose-deficient anti-PODXL mAb could be useful for antibody-based therapy against PODXL-expressing OSCCs.
Production Methods for a Mesenchymal Stem Cell Therapeutic as a Medical Defense Countermeasure

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2012-02-01

mesenchymal stem cell (MSC) efficacy in a variety of injury models demonstrate the unique qualities of this reparative cell population to adapt to the...therapeutic product. Characterization of stem cell properties of culture-expanded MSCs is shown by in vitro differentiation to form mature cell types. The
Effect of kinase inhibitors on the therapeutic properties of monoclonal antibodies.

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Duong, Minh Ngoc; Matera, Eva-Laure; Mathé, Doriane; Evesque, Anne; Valsesia-Wittmann, Sandrine; Clémenceau, Béatrice; Dumontet, Charles

2015-01-01

Targeted therapies of malignancies currently consist of therapeutic monoclonal antibodies and small molecule kinase inhibitors. The combination of these novel agents raises the issue of potential antagonisms. We evaluated the potential effect of 4 kinase inhibitors, including the Bruton tyrosine kinase inhibitor ibrutinib, and 3 PI3K inhibitors idelalisib, NVP-BEZ235 and LY294002, on the effects of the 3 monoclonal antibodies, rituximab and obinutuzumab (directed against CD20) and trastuzumab (directed against HER2). We found that ibrutinib potently inhibits antibody-dependent cell-mediated cytotoxicity exerted by all antibodies, with a 50% inhibitory concentration of 0.2 microM for trastuzumab, 0.5 microM for rituximab and 2 microM for obinutuzumab, suggesting a lesser effect in combination with obinutuzumab than with rituximab. The 4 kinase inhibitors were found to inhibit phagocytosis by fresh human neutrophils, as well as antibody-dependent cellular phagocytosis induced by the 3 antibodies. Conversely co-administration of ibrutinib with rituximab, obinutuzumab or trastuzumab did not demonstrate any inhibitory effect of ibrutinib in vivo in murine xenograft models. In conclusion, some kinase inhibitors, in particular, ibrutinib, are likely to exert inhibitory effects on innate immune cells. However, these effects do not compromise the antitumor activity of monoclonal antibodies in vivo in the models that were evaluated.
A novel oral dual amylin and calcitonin receptor agonist (KBP-042) exerts antiobesity and antidiabetic effects in rats

DEFF Research Database (Denmark)

Andreassen, Kim V; Feigh, Michael; Hjuler, Sara T

2014-01-01

-induced obese (DIO) and Zucker diabetic fatty (ZDF) rats. In vitro, KBP-042 demonstrated superior binding affinity and activation of amylin and calcitonin receptors, and ex vivo, KBP-042 exerted inhibitory action on stimulated insulin and glucagon release from isolated islets. In vivo, KBP-042 induced...... a superior and pronounced reduction in food intake in conjunction with a sustained pair-fed corrected weight loss in DIO rats. Concomitantly, KBP-042 improved glucose homeostasis and reduced hyperinsulinemia and hyperleptinemia in conjunction with enhanced insulin sensitivity. In ZDF rats, KBP-042 induced...... antiobesity and antidiabetic efficacy by dual modulation of insulin sensitivity and directly decelerating stress on the pancreatic α- and β-cells. These results could provide the basis for oral KBP-042 as a novel therapeutic agent in type 2 diabetes....
Therapeutic strategies with oral fluoropyrimidine anticancer agent, S-1 against oral cancer.

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Harada, Koji; Ferdous, Tarannum; Ueyama, Yoshiya

2017-08-01

Oral cancer has been recognized as a tumor with low sensitivity to anticancer agents. However, introduction of S-1, an oral cancer agent is improving treatment outcome for patients with oral cancer. In addition, S-1, as a main drug for oral cancer treatment in Japan can be easily available for outpatients. In fact, S-1 exerts high therapeutic effects with acceptable side effects. Moreover, combined chemotherapy with S-1 shows higher efficacy than S-1 alone, and combined chemo-radiotherapy with S-1 exerts remarkable therapeutic effects. Furthermore, we should consider the combined therapy of S-1 and molecular targeting agents right now as these combinations were reportedly useful for oral cancer treatment. Here, we describe our findings related to S-1 that were obtained experimentally and clinically, and favorable therapeutic strategies with S-1 against oral cancer with bibliographic considerations.
Does mental exertion alter maximal muscle activation?

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Vianney eRozand

2014-09-01

Full Text Available Mental exertion is known to impair endurance performance, but its effects on neuromuscular function remain unclear. The purpose of this study was to test the hypothesis that mental exertion reduces torque and muscle activation during intermittent maximal voluntary contractions of the knee extensors. Ten subjects performed in a randomized order three separate mental exertion conditions lasting 27 minutes each: i high mental exertion (incongruent Stroop task, ii moderate mental exertion (congruent Stroop task, iii low mental exertion (watching a movie. In each condition, mental exertion was combined with ten intermittent maximal voluntary contractions of the knee extensor muscles (one maximal voluntary contraction every 3 minutes. Neuromuscular function was assessed using electrical nerve stimulation. Maximal voluntary torque, maximal muscle activation and other neuromuscular parameters were similar across mental exertion conditions and did not change over time. These findings suggest that mental exertion does not affect neuromuscular function during intermittent maximal voluntary contractions of the knee extensors.
Targeting lipid metabolism of cancer cells: A promising therapeutic strategy for cancer.

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Liu, Qiuping; Luo, Qing; Halim, Alexander; Song, Guanbin

2017-08-10

One of the most important metabolic hallmarks of cancer cells is deregulation of lipid metabolism. In addition, enhancing de novo fatty acid (FA) synthesis, increasing lipid uptake and lipolysis have also been considered as means of FA acquisition in cancer cells. FAs are involved in various aspects of tumourigenesis and tumour progression. Therefore, targeting lipid metabolism is a promising therapeutic strategy for human cancer. Recent studies have shown that reprogramming lipid metabolism plays important roles in providing energy, macromolecules for membrane synthesis, and lipid signals during cancer progression. Moreover, accumulation of lipid droplets in cancer cells acts as a pivotal adaptive response to harmful conditions. Here, we provide a brief review of the crucial roles of FA metabolism in cancer development, and place emphasis on FA origin, utilization and storage in cancer cells. Understanding the regulation of lipid metabolism in cancer cells has important implications for exploring a new therapeutic strategy for management and treatment of cancer. Copyright © 2017 Elsevier B.V. All rights reserved.
Lactobacillus casei Exerts Anti-Proliferative Effects Accompanied by Apoptotic Cell Death and Up-Regulation of TRAIL in Colon Carcinoma Cells

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Santarmaki, Valentina; Aindelis, Georgios; Tompoulidou, Evgenia; Lamprianidou, Eleftheria E.; Saxami, Georgia; Ypsilantis, Petros; Lampri, Evangeli S.; Simopoulos, Constantinos; Kotsianidis, Ioannis; Galanis, Alex; Kourkoutas, Yiannis; Dimitrellou, Dimitra; Chlichlia, Katerina

2016-01-01

Probiotic microorganisms such as lactic acid bacteria (LAB) exert a number of strain-specific health-promoting activities attributed to their immunomodulatory, anti-inflammatory and anti-carcinogenic properties. Despite recent attention, our understanding of the biological processes involved in the beneficial effects of LAB strains is still limited. To this end, the present study investigated the growth-inhibitory effects of Lactobacillus casei ATCC 393 against experimental colon cancer. Administration of live Lactobacillus casei (as well as bacterial components thereof) on murine (CT26) and human (HT29) colon carcinoma cell lines raised a significant concentration- and time-dependent anti-proliferative effect, determined by cell viability assays. Specifically, a dramatic decrease in viability of colon cancer cells co-incubated with 109 CFU/mL L. casei for 24 hours was detected (78% for HT29 and 52% for CT26 cells). In addition, live L. casei induced apoptotic cell death in both cell lines as revealed by annexin V and propidium iodide staining. The significance of the in vitro anti-proliferative effects was further confirmed in an experimental tumor model. Oral daily administration of 109 CFU live L. casei for 13 days significantly inhibited in vivo growth of colon carcinoma cells, resulting in approximately 80% reduction in tumor volume of treated mice. Tumor growth inhibition was accompanied by L. casei-driven up-regulation of the TNF-related apoptosis-inducing ligand TRAIL and down-regulation of Survivin. Taken together, these findings provide evidence for beneficial tumor-inhibitory, anti-proliferative and pro-apoptotic effects driven by this probiotic LAB strain. PMID:26849051

Lactobacillus casei Exerts Anti-Proliferative Effects Accompanied by Apoptotic Cell Death and Up-Regulation of TRAIL in Colon Carcinoma Cells.

Directory of Open Access Journals (Sweden)

Angeliki Tiptiri-Kourpeti

Full Text Available Probiotic microorganisms such as lactic acid bacteria (LAB exert a number of strain-specific health-promoting activities attributed to their immunomodulatory, anti-inflammatory and anti-carcinogenic properties. Despite recent attention, our understanding of the biological processes involved in the beneficial effects of LAB strains is still limited. To this end, the present study investigated the growth-inhibitory effects of Lactobacillus casei ATCC 393 against experimental colon cancer. Administration of live Lactobacillus casei (as well as bacterial components thereof on murine (CT26 and human (HT29 colon carcinoma cell lines raised a significant concentration- and time-dependent anti-proliferative effect, determined by cell viability assays. Specifically, a dramatic decrease in viability of colon cancer cells co-incubated with 10(9 CFU/mL L. casei for 24 hours was detected (78% for HT29 and 52% for CT26 cells. In addition, live L. casei induced apoptotic cell death in both cell lines as revealed by annexin V and propidium iodide staining. The significance of the in vitro anti-proliferative effects was further confirmed in an experimental tumor model. Oral daily administration of 10(9 CFU live L. casei for 13 days significantly inhibited in vivo growth of colon carcinoma cells, resulting in approximately 80% reduction in tumor volume of treated mice. Tumor growth inhibition was accompanied by L. casei-driven up-regulation of the TNF-related apoptosis-inducing ligand TRAIL and down-regulation of Survivin. Taken together, these findings provide evidence for beneficial tumor-inhibitory, anti-proliferative and pro-apoptotic effects driven by this probiotic LAB strain.
Lactobacillus casei Exerts Anti-Proliferative Effects Accompanied by Apoptotic Cell Death and Up-Regulation of TRAIL in Colon Carcinoma Cells.

Science.gov (United States)

Tiptiri-Kourpeti, Angeliki; Spyridopoulou, Katerina; Santarmaki, Valentina; Aindelis, Georgios; Tompoulidou, Evgenia; Lamprianidou, Eleftheria E; Saxami, Georgia; Ypsilantis, Petros; Lampri, Evangeli S; Simopoulos, Constantinos; Kotsianidis, Ioannis; Galanis, Alex; Kourkoutas, Yiannis; Dimitrellou, Dimitra; Chlichlia, Katerina

2016-01-01

Probiotic microorganisms such as lactic acid bacteria (LAB) exert a number of strain-specific health-promoting activities attributed to their immunomodulatory, anti-inflammatory and anti-carcinogenic properties. Despite recent attention, our understanding of the biological processes involved in the beneficial effects of LAB strains is still limited. To this end, the present study investigated the growth-inhibitory effects of Lactobacillus casei ATCC 393 against experimental colon cancer. Administration of live Lactobacillus casei (as well as bacterial components thereof) on murine (CT26) and human (HT29) colon carcinoma cell lines raised a significant concentration- and time-dependent anti-proliferative effect, determined by cell viability assays. Specifically, a dramatic decrease in viability of colon cancer cells co-incubated with 10(9) CFU/mL L. casei for 24 hours was detected (78% for HT29 and 52% for CT26 cells). In addition, live L. casei induced apoptotic cell death in both cell lines as revealed by annexin V and propidium iodide staining. The significance of the in vitro anti-proliferative effects was further confirmed in an experimental tumor model. Oral daily administration of 10(9) CFU live L. casei for 13 days significantly inhibited in vivo growth of colon carcinoma cells, resulting in approximately 80% reduction in tumor volume of treated mice. Tumor growth inhibition was accompanied by L. casei-driven up-regulation of the TNF-related apoptosis-inducing ligand TRAIL and down-regulation of Survivin. Taken together, these findings provide evidence for beneficial tumor-inhibitory, anti-proliferative and pro-apoptotic effects driven by this probiotic LAB strain.
Therapeutic approaches for treating hemophilia A using embryonic stem cells.

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Kasuda, Shogo; Tatsumi, Kohei; Sakurai, Yoshihiko; Shima, Midori; Hatake, Katsuhiko

2016-06-01

Hemophilia A is an X-linked rescessive bleeding disorder that results from F8 gene aberrations. Previously, we established embryonic stem (ES) cells (tet-226aa/N6-Ainv18) that secrete human factor VIII (hFVIII) by introducing the human F8 gene in mouse Ainv18 ES cells. Here, we explored the potential of cell transplantation therapy for hemophilia A using the ES cells. Transplant tet-226aa/N6-Ainv18 ES cells were injected into the spleens of severe combined immunodeficiency (SCID) mice, carbon tetrachloride (CCl4)-pretreated wild-type mice, and CCl4-pretreated hemophilia A mice. F8 expression was induced by doxycycline in drinking water, and hFVIII-antigen production was assessed in all cell transplantation experiments. Injecting the ES cells into SCID mice resulted in an enhanced expression of the hFVIII antigen; however, teratoma generation was confirmed in the spleen. Transplantation of ES cells into wild-type mice after CCl4-induced liver injury facilitated survival and engraftment of transplanted cells without teratoma formation, resulting in hFVIII production in the plasma. Although CCl4 was lethal to most hemophilia A mice, therapeutic levels of FVIII activity, as well as the hFVIII antigen, were detected in surviving hemophilia A mice after cell transplantation. Immunolocalization results for hFVIII suggested that transplanted ES cells might be engrafted at the periportal area in the liver. Although the development of a safer induction method for liver regeneration is required, our results suggested the potential for developing an effective ES-cell transplantation therapeutic model for treating hemophilia A in the future. Copyright © 2016 King Faisal Specialist Hospital & Research Centre. Published by Elsevier Ltd. All rights reserved.
Stem cell transplantation for amyotrophic lateral sclerosis: therapeutic potential and perspectives on clinical translation.

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Faravelli, Irene; Riboldi, Giulietta; Nizzardo, Monica; Simone, Chiara; Zanetta, Chiara; Bresolin, Nereo; Comi, Giacomo P; Corti, Stefania

2014-09-01

Amyotrophic lateral sclerosis (ALS) is a fatal neurological disease characterized by degeneration of upper and lower motor neurons. There are currently no clinically impactful treatments for this disorder. Death occurs 3-5 years after diagnosis, usually due to respiratory failure. ALS pathogenesis seems to involve several pathological mechanisms (i.e., oxidative stress, inflammation, and loss of the glial neurotrophic support, glutamate toxicity) with different contributions from environmental and genetic factors. This multifaceted combination highlights the concept that an effective therapeutic approach should counteract simultaneously different aspects: stem cell therapies are able to maintain or rescue motor neuron function and modulate toxicity in the central nervous system (CNS) at the same time, eventually representing the most comprehensive therapeutic approach for ALS. To achieve an effective cell-mediated therapy suitable for clinical applications, several issues must be addressed, including the identification of the most performing cell source, a feasible administration protocol, and the definition of therapeutic mechanisms. The method of cell delivery represents a major issue in developing cell-mediated approaches since the cells, to be effective, need to be spread across the CNS, targeting both lower and upper motor neurons. On the other hand, there is the need to define a strategy that could provide a whole distribution without being too invasive or burdened by side effects. Here, we review the recent advances regarding the therapeutic potential of stem cells for ALS with a focus on the minimally invasive strategies that could facilitate an extensive translation to their clinical application.
ALS Pathogenesis and Therapeutic Approaches: The Role of Mesenchymal Stem Cells and Extracellular Vesicles.

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Bonafede, Roberta; Mariotti, Raffaella

2017-01-01

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by progressive muscle paralysis determined by the degeneration of motoneurons in the motor cortex brainstem and spinal cord. The ALS pathogenetic mechanisms are still unclear, despite the wealth of studies demonstrating the involvement of several altered signaling pathways, such as mitochondrial dysfunction, glutamate excitotoxicity, oxidative stress and neuroinflammation. To date, the proposed therapeutic strategies are targeted to one or a few of these alterations, resulting in only a minimal effect on disease course and survival of ALS patients. The involvement of different mechanisms in ALS pathogenesis underlines the need for a therapeutic approach targeted to multiple aspects. Mesenchymal stem cells (MSC) can support motoneurons and surrounding cells, reduce inflammation, stimulate tissue regeneration and release growth factors. On this basis, MSC have been proposed as promising candidates to treat ALS. However, due to the drawbacks of cell therapy, the possible therapeutic use of extracellular vesicles (EVs) released by stem cells is raising increasing interest. The present review summarizes the main pathological mechanisms involved in ALS and the related therapeutic approaches proposed to date, focusing on MSC therapy and their preclinical and clinical applications. Moreover, the nature and characteristics of EVs and their role in recapitulating the effect of stem cells are discussed, elucidating how and why these vesicles could provide novel opportunities for ALS treatment.
Exertional dyspnoea in obesity

Directory of Open Access Journals (Sweden)

Vipa Bernhardt

2016-12-01

Full Text Available The purpose of cardiopulmonary exercise testing (CPET in the obese person, as in any cardiopulmonary exercise test, is to determine the patient's exercise tolerance, and to help identify and/or distinguish between the various physiological factors that could contribute to exercise intolerance. Unexplained dyspnoea on exertion is a common reason for CPET, but it is an extremely complex symptom to explain. Sometimes obesity is the simple answer by elimination of other possibilities. Thus, distinguishing among multiple clinical causes for exertional dyspnoea depends on the ability to eliminate possibilities while recognising response patterns that are unique to the obese patient. This includes the otherwise healthy obese patient, as well as the obese patient with potentially multiple cardiopulmonary limitations. Despite obvious limitations in lung function, metabolic disease and/or cardiovascular dysfunction, obesity may be the most likely reason for exertional dyspnoea. In this article, we will review the more common cardiopulmonary responses to exercise in the otherwise healthy obese adult with special emphasis on dyspnoea on exertion.
BiovaxID, a personalized therapeutic vaccine against B-cell lymphomas

Czech Academy of Sciences Publication Activity Database

Reiniš, Milan

2008-01-01

Roč. 10, č. 5 (2008), s. 526-534 ISSN 1464-8431 Institutional research plan: CEZ:AV0Z50520514 Keywords : B-cell lymphomas * tumor antigen * therapeutic vaccine Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 2.913, year: 2008
Andrographolide Exerts Pro-Osteogenic Effect by Activation of Wnt/β-Catenin Signaling Pathway in Vitro

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Tongmeng Jiang

2015-07-01

Full Text Available Background/Aims: Osteoporosis is a metabolic bone disorders that tortures about millions of people worldwide. Recent studies showed that Andrographolide (AP is a promising natural compound for the treatment of osteoclast-related bone diseases. However, its potential in treatment of osteoporosis has not been fully explored. Methods: In this study, the effect of AP on osteoblasts metabolism was investigated via the detection of cell proliferation, cell viability, ALP activity, the expression of osteogenic specific genes including runt-related transcription factor 2 (RUNX2, bone sialoprotein (BSP, osteocalcin (OCN, Bone morphogenic protein-2 (BMP2 and Alkaline phosphatase(ALP for 3, 5 and 7 days respectively. Further exploration of the association of AP with WNT/β-catenin signaling pathway was performed by examination of the expression of WNT related genes and proteins. Results: Results showed that AP of 4.46 and 8.92 µM, especially 8.92 µM was beneficial to osteogenic differentiation by upregulating ALP activity and expression of osteogenic related genes (PConclusion: This study indicates that AP exerts its pro-osteogenic potential via activation of the WNT/β-catenin in osteoblasts and thus may represent a candidate of therapeutic agent for osteoporosis.
Mesangial cell biology

Energy Technology Data Exchange (ETDEWEB)

Abboud, Hanna E., E-mail: Abboud@uthscsa.edu

2012-05-15

Mesangial cells originate from the metanephric mesenchyme and maintain structural integrity of the glomerular microvascular bed and mesangial matrix homeostasis. In response to metabolic, immunologic or hemodynamic injury, these cells undergo apoptosis or acquire an activated phenotype and undergo hypertrophy, proliferation with excessive production of matrix proteins, growth factors, chemokines and cytokines. These soluble factors exert autocrine and paracrine effects on the cells or on other glomerular cells, respectively. MCs are primary targets of immune-mediated glomerular diseases such as IGA nephropathy or metabolic diseases such as diabetes. MCs may also respond to injury that primarily involves podocytes and endothelial cells or to structural and genetic abnormalities of the glomerular basement membrane. Signal transduction and oxidant stress pathways are activated in MCs and likely represent integrated input from multiple mediators. Such responses are convenient targets for therapeutic intervention. Studies in cultured MCs should be supplemented with in vivo studies as well as examination of freshly isolated cells from normal and diseases glomeruli. In addition to ex vivo morphologic studies in kidney cortex, cells should be studied in their natural environment, isolated glomeruli or even tissue slices. Identification of a specific marker of MCs should help genetic manipulation as well as selective therapeutic targeting of these cells. Identification of biological responses of MCs that are not mediated by the renin–angiotensin system should help development of novel and effective therapeutic strategies to treat diseases characterized by MC pathology.
Mesangial cell biology

International Nuclear Information System (INIS)

Abboud, Hanna E.

2012-01-01

Mesangial cells originate from the metanephric mesenchyme and maintain structural integrity of the glomerular microvascular bed and mesangial matrix homeostasis. In response to metabolic, immunologic or hemodynamic injury, these cells undergo apoptosis or acquire an activated phenotype and undergo hypertrophy, proliferation with excessive production of matrix proteins, growth factors, chemokines and cytokines. These soluble factors exert autocrine and paracrine effects on the cells or on other glomerular cells, respectively. MCs are primary targets of immune-mediated glomerular diseases such as IGA nephropathy or metabolic diseases such as diabetes. MCs may also respond to injury that primarily involves podocytes and endothelial cells or to structural and genetic abnormalities of the glomerular basement membrane. Signal transduction and oxidant stress pathways are activated in MCs and likely represent integrated input from multiple mediators. Such responses are convenient targets for therapeutic intervention. Studies in cultured MCs should be supplemented with in vivo studies as well as examination of freshly isolated cells from normal and diseases glomeruli. In addition to ex vivo morphologic studies in kidney cortex, cells should be studied in their natural environment, isolated glomeruli or even tissue slices. Identification of a specific marker of MCs should help genetic manipulation as well as selective therapeutic targeting of these cells. Identification of biological responses of MCs that are not mediated by the renin–angiotensin system should help development of novel and effective therapeutic strategies to treat diseases characterized by MC pathology.
Introduction to thematic minireview series: Development of human therapeutics based on induced pluripotent stem cell (iPSC) technology.

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Rao, Mahendra; Gottesfeld, Joel M

2014-02-21

With the advent of human induced pluripotent stem cell (hiPSC) technology, it is now possible to derive patient-specific cell lines that are of great potential in both basic research and the development of new therapeutics for human diseases. Not only do hiPSCs offer unprecedented opportunities to study cellular differentiation and model human diseases, but the differentiated cell types obtained from iPSCs may become therapeutics themselves. These cells can also be used in the screening of therapeutics and in toxicology assays for potential liabilities of therapeutic agents. The remarkable achievement of transcription factor reprogramming to generate iPSCs was recognized by the award of the Nobel Prize in Medicine to Shinya Yamanaka in 2012, just 6 years after the first publication of reprogramming methods to generate hiPSCs (Takahashi, K., Tanabe, K., Ohnuki, M., Narita, M., Ichisaka, T., Tomoda, K., and Yamanaka, S. (2007) Cell 131, 861-872). This minireview series highlights both the promises and challenges of using iPSC technology for disease modeling, drug screening, and the development of stem cell therapeutics.
Novel small-molecule AMPK activator orally exerts beneficial effects on diabetic db/db mice

Energy Technology Data Exchange (ETDEWEB)

Li, Yuan-Yuan; Yu, Li-Fang; Zhang, Li-Na; Qiu, Bei-Ying; Su, Ming-Bo; Wu, Fang; Chen, Da-Kai; Pang, Tao; Gu, Min; Zhang, Wei; Ma, Wei-Ping; Jiang, Hao-Wen; Li, Jing-Ya, E-mail: jyli@mail.shcnc.ac.cn; Nan, Fa-Jun, E-mail: fjnan@mail.shcnc.ac.cn; Li, Jia, E-mail: jli@mail.shcnc.ac.cn

2013-12-01

AMP-activated protein kinase (AMPK), which is a pivotal guardian of whole-body energy metabolism, has become an attractive therapeutic target for metabolic syndrome. Previously, using a homogeneous scintillation proximity assay, we identified the small-molecule AMPK activator C24 from an optimization based on the original allosteric activator PT1. In this paper, the AMPK activation mechanism of C24 and its potential beneficial effects on glucose and lipid metabolism on db/db mice were investigated. C24 allosterically stimulated inactive AMPK α subunit truncations and activated AMPK heterotrimers by antagonizing autoinhibition. In primary hepatocytes, C24 increased the phosphorylation of AMPK downstream target acetyl-CoA carboxylase dose-dependently without changing intracellular AMP/ATP ratio, indicating its allosteric activation in cells. Through activating AMPK, C24 decreased glucose output by down-regulating mRNA levels of phosphoenolpyruvate carboxykinase (PEPCK) and glucose-6-phosphatase (G6Pase) in primary hepatocytes. C24 also decreased the triglyceride and cholesterol contents in HepG2 cells. Due to its improved bioavailability, chronic oral treatment with multiple doses of C24 significantly reduced blood glucose and lipid levels in plasma, and improved the glucose tolerance of diabetic db/db mice. The hepatic transcriptional levels of PEPCK and G6Pase were reduced. These results demonstrate that this orally effective activator of AMPK represents a novel approach to the treatment of metabolic syndrome. - Highlights: • C24 activates AMPK through antagonizing autoinhibition within α subunit. • C24 activates AMPK in hepatocytes and decreases glucose output via AMPK. • C24 exerts beneficial effects on diabetic db/db mice. • C24 represents a novel therapeutic for treatment of metabolic syndrome.
Novel small-molecule AMPK activator orally exerts beneficial effects on diabetic db/db mice

International Nuclear Information System (INIS)

Li, Yuan-Yuan; Yu, Li-Fang; Zhang, Li-Na; Qiu, Bei-Ying; Su, Ming-Bo; Wu, Fang; Chen, Da-Kai; Pang, Tao; Gu, Min; Zhang, Wei; Ma, Wei-Ping; Jiang, Hao-Wen; Li, Jing-Ya; Nan, Fa-Jun; Li, Jia

2013-01-01

AMP-activated protein kinase (AMPK), which is a pivotal guardian of whole-body energy metabolism, has become an attractive therapeutic target for metabolic syndrome. Previously, using a homogeneous scintillation proximity assay, we identified the small-molecule AMPK activator C24 from an optimization based on the original allosteric activator PT1. In this paper, the AMPK activation mechanism of C24 and its potential beneficial effects on glucose and lipid metabolism on db/db mice were investigated. C24 allosterically stimulated inactive AMPK α subunit truncations and activated AMPK heterotrimers by antagonizing autoinhibition. In primary hepatocytes, C24 increased the phosphorylation of AMPK downstream target acetyl-CoA carboxylase dose-dependently without changing intracellular AMP/ATP ratio, indicating its allosteric activation in cells. Through activating AMPK, C24 decreased glucose output by down-regulating mRNA levels of phosphoenolpyruvate carboxykinase (PEPCK) and glucose-6-phosphatase (G6Pase) in primary hepatocytes. C24 also decreased the triglyceride and cholesterol contents in HepG2 cells. Due to its improved bioavailability, chronic oral treatment with multiple doses of C24 significantly reduced blood glucose and lipid levels in plasma, and improved the glucose tolerance of diabetic db/db mice. The hepatic transcriptional levels of PEPCK and G6Pase were reduced. These results demonstrate that this orally effective activator of AMPK represents a novel approach to the treatment of metabolic syndrome. - Highlights: • C24 activates AMPK through antagonizing autoinhibition within α subunit. • C24 activates AMPK in hepatocytes and decreases glucose output via AMPK. • C24 exerts beneficial effects on diabetic db/db mice. • C24 represents a novel therapeutic for treatment of metabolic syndrome
Liver cell-targeted delivery of therapeutic molecules.

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Kang, Jeong-Hun; Toita, Riki; Murata, Masaharu

2016-01-01

The liver is the largest internal organ in mammals and is involved in metabolism, detoxification, synthesis of proteins and lipids, secretion of cytokines and growth factors and immune/inflammatory responses. Hepatitis, alcoholic or non-alcoholic liver disease, hepatocellular carcinoma, hepatic veno-occlusive disease, and liver fibrosis and cirrhosis are the most common liver diseases. Safe and efficient delivery of therapeutic molecules (drugs, genes or proteins) into the liver is very important to increase the clinical efficacy of these molecules and to reduce their side effects in other organs. Several liver cell-targeted delivery systems have been developed and tested in vivo or ex vivo/in vitro. In this review, we discuss the literature concerning liver cell-targeted delivery systems, with a particular emphasis on the results of in vivo studies.
Ovarian steroids, stem cells and uterine leiomyoma: therapeutic implications.

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Moravek, Molly B; Yin, Ping; Ono, Masanori; Coon, John S; Dyson, Matthew T; Navarro, Antonia; Marsh, Erica E; Chakravarti, Debabrata; Kim, J Julie; Wei, Jian-Jun; Bulun, Serdar E

2015-01-01

Uterine leiomyoma is the most common benign tumor in women and is thought to arise from the clonal expansion of a single myometrial smooth muscle cell transformed by a cellular insult. Leiomyomas cause a variety of symptoms, including abnormal uterine bleeding, pelvic pain, bladder or bowel dysfunction, and recurrent pregnancy loss, and are the most common indication for hysterectomy in the USA. A slow rate of cell proliferation, combined with the production of copious amounts of extracellular matrix, accounts for tumor expansion. A common salient feature of leiomyomas is their responsiveness to steroid hormones, thus providing an opportunity for intervention. A comprehensive search of PUBMED was conducted to identify peer-reviewed literature published since 1980 pertinent to the roles of steroid hormones and somatic stem cells in leiomyoma, including literature on therapeutics that target steroid hormone action in leiomyoma. Reviewed articles were restricted to English language only. Studies in both animals and humans were reviewed for the manuscript. Estrogen stimulates the growth of leiomyomas, which are exposed to this hormone not only through ovarian steroidogenesis, but also through local conversion of androgens by aromatase within the tumors themselves. The primary action of estrogen, together with its receptor estrogen receptor α (ERα), is likely mediated via induction of progesterone receptor (PR) expression, thereby allowing leiomyoma responsiveness to progesterone. Progesterone has been shown to stimulate the growth of leiomyoma through a set of key genes that regulate both apoptosis and proliferation. Given these findings, aromatase inhibitors and antiprogestins have been developed for the treatment of leiomyoma, but neither treatment results in complete regression of leiomyoma, and tumors recur after treatment is stopped. Recently, distinct cell populations were discovered in leiomyomas; a small population showed stem-progenitor cell properties, and
Ibuprofen delivered by poly(lactic-co-glycolic acid) (PLGA) nanoparticles to human gastric cancer cells exerts antiproliferative activity at very low concentrations

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Bonelli, Patrizia; Tuccillo, Franca M; Federico, Antonella; Napolitano, Maria; Borrelli, Antonella; Melisi, Daniela; Rimoli, Maria G; Palaia, Raffaele; Arra, Claudio; Carinci, Francesco

2012-01-01

Purpose Epidemiological, clinical, and laboratory studies have suggested that ibuprofen, a commonly used nonsteroidal anti-inflammatory drug, inhibits the promotion and proliferation of certain tumors. Recently, we demonstrated the antiproliferative effects of ibuprofen on the human gastric cancer cell line MKN-45. However, high doses of ibuprofen were required to elicit these antiproliferative effects in vitro. The present research compared the antiproliferative effects of ibuprofen delivered freely and released by poly(lactic-co-glycolic acid) (PLGA) nanoparticles (NPs) in MKN-45 cells. Methods MKN-45 human gastric adenocarcinoma cells were treated with ibuprofen-loaded PLGA NPs. The proliferation of MKN-45 cells was then assessed by cell counting. The uptake of NPs was imaged by fluorescence microscopy and flow cytometry. The release of ibuprofen from ibuprofen-loaded PLGA NPs in the cells was evaluated by gas chromatography–mass spectrometry. Results Dramatic inhibition of cellular proliferation was observed in cells treated with ibuprofen-loaded PLGA NPs versus those treated with free ibuprofen at the same concentration. The localization of NPs was cytoplasmic. The initiation of ibuprofen release was rapid, commencing within 2 hours, and then increased slowly over time, reaching a maximum concentration at 24 hours. The inhibition of proliferation was confirmed to be due to the intracellular release of ibuprofen from the NPs. Using PLGA NPs as carriers, ibuprofen exerted an antiproliferative activity at concentrations > 100 times less than free ibuprofen, suggesting greater efficiency and less cellular toxicity. In addition, when carried by PLGA NPs, ibuprofen more quickly induced the expression of transcripts involved in proliferation and invasiveness processes. Conclusion Ibuprofen exerted an antiproliferative effect on MKN-45 cells at low concentrations. This effect was achieved using PLGA NPs as carriers of low doses of ibuprofen. PMID:23180963
Therapeutic limitations in tumor-specific CD8+ memory T cell engraftment

International Nuclear Information System (INIS)

Bathe, Oliver F; Dalyot-Herman, Nava; Malek, Thomas R

2003-01-01

Adoptive immunotherapy with cytotoxic T lymphocytes (CTL) represents an alternative approach to treating solid tumors. Ideally, this would confer long-term protection against tumor. We previously demonstrated that in vitro-generated tumor-specific CTL from the ovalbumin (OVA)-specific OT-I T cell receptor transgenic mouse persisted long after adoptive transfer as memory T cells. When recipient mice were challenged with the OVA-expressing E.G7 thymoma, tumor growth was delayed and sometimes prevented. The reasons for therapeutic failures were not clear. OT-I CTL were adoptively transferred to C57BL/6 mice 21 – 28 days prior to tumor challenge. At this time, the donor cells had the phenotypical and functional characteristics of memory CD8+ T cells. Recipients which developed tumor despite adoptive immunotherapy were analyzed to evaluate the reason(s) for therapeutic failure. Dose-response studies demonstrated that the degree of tumor protection was directly proportional to the number of OT-I CTL adoptively transferred. At a low dose of OT-I CTL, therapeutic failure was attributed to insufficient numbers of OT-I T cells that persisted in vivo, rather than mechanisms that actively suppressed or anergized the OT-I T cells. In recipients of high numbers of OT-I CTL, the E.G7 tumor that developed was shown to be resistant to fresh OT-I CTL when examined ex vivo. Furthermore, these same tumor cells no longer secreted a detectable level of OVA. In this case, resistance to immunotherapy was secondary to selection of clones of E.G7 that expressed a lower level of tumor antigen. Memory engraftment with tumor-specific CTL provides long-term protection against tumor. However, there are several limitations to this immunotherapeutic strategy, especially when targeting a single antigen. This study illustrates the importance of administering large numbers of effectors to engraft sufficiently efficacious immunologic memory. It also demonstrates the importance of targeting several
Strategy to prime the host and cells to augment therapeutic efficacy of progenitor cells for patients with myocardial infarction

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Jeehoon Kang

2016-11-01

Full Text Available Cell therapy in myocardial infarction (MI is an innovative strategy that is regarded as a rescue therapy to repair the damaged myocardium and to promote neovascularization for the ischemic border zone. Among several stem cell sources for this purpose, autologous progenitors from bone marrow or peripheral blood would be the most feasible and safest cell-source. Despite the theoretical benefit of cell therapy, this method is not widely adopted in the actual clinical practice due to its low therapeutic efficacy. Various methods have been used to augment the efficacy of cell therapy in MI, such as using different source of progenitors, genetic manipulation of cells, or priming of the cells or hosts (patients with agents. Among these methods, the strategy to augment the therapeutic efficacy of the autologous peripheral blood mononuclear cells by priming agents may be the most feasible and the safest method that can be applied directly to the clinic. In this review, we will discuss the current status and future directions of priming peripheral blood mononuclear cells or patients, as for cell therapy of MI.
Omentin-1 effects on mesenchymal stem cells: proliferation, apoptosis, and angiogenesis in vitro

OpenAIRE

Yin, Li; Huang, Dan; Liu, Xinxin; Wang, Yongshun; Liu, Jingjin; Liu, Fang; Yu, Bo

2017-01-01

Background Mesenchymal stem cells (MSCs) are emerging as an extremely promising therapeutic agent for tissue repair. However, limitations exist such as the low numbers of MSCs obtained from donors, and the poor survival and function of donor cells. Omentin-1, a new fat depot-specific secretory adipokine, exerts proproliferation, prosurvival, and proangiogenic functions in certain cells via an Akt-dependent mechanism; however, little is known about the influence of omentin-1 on MSCs. Methods M...
Exerting Capacity.

Science.gov (United States)

Leger, J Michael; Phillips, Carolyn A

2017-05-01

Patient safety has been at the forefront of nursing research since the release of the Institute of Medicine's report estimating the number of preventable adverse events in hospital settings; yet no research to date has incorporated the perspectives of bedside nurses using classical grounded theory (CGT) methodology. This CGT study explored the perceptions of bedside registered nurses regarding patient safety in adult acute care hospitals. Data analysis used three techniques unique to CGT-the constant comparative method, coding, and memoing-to explore the values, realities, and beliefs of bedside nurses about patient safety. The analysis resulted in a substantive theory, Exerting Capacity, which explained how bedside nurses balance the demands of keeping their patients safe. Exerting Capacity has implications for health care organization leaders, nursing leaders, and bedside nurses; it also has indications for future research into the concept of patient safety.

The role of apoptosis repressor with a CARD domain (ARC) in the therapeutic resistance of renal cell carcinoma (RCC): the crucial role of ARC in the inhibition of extrinsic and intrinsic apoptotic signalling.

Science.gov (United States)

Toth, Csaba; Funke, Sarah; Nitsche, Vanessa; Liverts, Anna; Zlachevska, Viktoriya; Gasis, Marcia; Wiek, Constanze; Hanenberg, Helmut; Mahotka, Csaba; Schirmacher, Peter; Heikaus, Sebastian

2017-05-02

Renal cell carcinomas (RCCs) display broad resistance against conventional radio- and chemotherapies, which is due at least in part to impairments in both extrinsic and intrinsic apoptotic pathways. One important anti-apoptotic factor that is strongly overexpressed in RCCs and known to inhibit both apoptotic pathways is ARC (apoptosis repressor with a CARD domain). Expression and subcellular distribution of ARC in RCC tissue samples and RCC cell lines were determined by immunohistochemistry and fluorescent immunohistochemistry, respectively. Extrinsic and intrinsic apoptosis signalling were induced by TRAIL (TNF-related apoptosis-inducing ligand), ABT-263 or topotecan. ARC knock-down was performed in clearCa-12 cells using lentiviral transduction of pGIPZ. shRNAmir constructs. Extrinsic respectively intrinsic apoptosis were induced by TRAIL (TNF-related apoptosis-inducing ligand), ABT263 or topotecan. Potential synergistic effects were tested by pre-treatment with topotecan and subsequent treatment with ABT263. Activation of different caspases and mitochondrial depolarisation (JC-1 staining) were analysed by flow cytometry. Protein expression of Bcl-2 family members and ARC in RCC cell lines was measured by Western blotting. Statistical analysis was performed by Student's t-test. Regarding the extrinsic pathway, ARC knockdown strongly enhanced TRAIL-induced apoptosis by increasing the activation level of caspase-8. Regarding the intrinsic pathway, ARC, which was only weakly expressed in the nuclei of RCCs in vivo, exerted its anti-apoptotic effect by impairing mitochondrial activation rather than inhibiting p53. Topotecan- and ABT-263-induced apoptosis was strongly enhanced following ARC knockdown in RCC cell lines. In addition, topotecan pre-treatment enhanced ABT-263-induced apoptosis and this effect was amplified in ARC-knockdown cells. Taken together, our results are the first to demonstrate the importance of ARC protein in the inhibition of both the extrinsic
Emerging Therapeutic Strategies for Targeting Chronic Myeloid Leukemia Stem Cells

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Ahmad Hamad

2013-01-01

Full Text Available Chronic myeloid leukemia (CML is a clonal myeloproliferative disorder. Current targeted therapies designed to inhibit the tyrosine kinase activity of the BCR-ABL oncoprotein have made a significant breakthrough in the treatment of CML patients. However, CML remains a chronic disease that a patient must manage for life. Although tyrosine kinase inhibitors (TKI therapy has completely transformed the prognosis of CML, it has made the therapeutic management more complex. The interruption of TKI treatment results in early disease progression because it does not eliminate quiescent CML stem cells which remain a potential reservoir for disease relapse. This highlights the need to develop new therapeutic strategies for CML to achieve a permanent cure, and to allow TKI interruption. This review summarizes recent research done on alternative targeted therapies with a particular focus on some important signaling pathways (such as Alox5, Hedgehog, Wnt/b-catenin, autophagy, and PML that have the potential to target CML stem cells and potentially provide cure for CML.
Enavatuzumab, a Humanized Anti-TWEAK Receptor Monoclonal Antibody, Exerts Antitumor Activity through Attracting and Activating Innate Immune Effector Cells

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Shiming Ye

2017-01-01

Full Text Available Enavatuzumab is a humanized IgG1 anti-TWEAK receptor monoclonal antibody that was evaluated in a phase I clinical study for the treatment of solid malignancies. The current study was to determine whether and how myeloid effector cells were involved in postulated mechanisms for its potent antitumor activity in xenograft models. The initial evidence for a role of effector cells was obtained in a subset of tumor xenograft mouse models whose response to enavatuzumab relied on the binding of Fc of the antibody to Fcγ receptor. The involvement of effector cells was further confirmed by immunohistochemistry, which revealed strong infiltration of CD45+ effector cells into tumor xenografts in responding models, but minimal infiltration in nonresponders. Consistent with the xenograft studies, human effector cells preferentially migrated toward in vivo-responsive tumor cells treated by enavatuzumab in vitro, with the majority of migratory cells being monocytes. Conditioned media from enavatuzumab-treated tumor cells contained elevated levels of chemokines, which might be responsible for enavatuzumab-triggered effector cell migration. These preclinical studies demonstrate that enavatuzumab can exert its potent antitumor activity by actively recruiting and activating myeloid effectors to kill tumor cells. Enavatuzumab-induced chemokines warrant further evaluation in clinical studies as potential biomarkers for such activity.
PPARs: Key Regulators of Airway Inflammation and Potential Therapeutic Targets in Asthma

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Asoka Banno

2018-01-01

Full Text Available Asthma affects approximately 300 million people worldwide, significantly impacting quality of life and healthcare costs. While current therapies are effective in controlling many patients' symptoms, a large number continue to experience exacerbations or treatment-related adverse effects. Alternative therapies are thus urgently needed. Accumulating evidence has shown that the peroxisome proliferator-activated receptor (PPAR family of nuclear hormone receptors, comprising PPARα, PPARβ/δ, and PPARγ, is involved in asthma pathogenesis and that ligand-induced activation of these receptors suppresses asthma pathology. PPAR agonists exert their anti-inflammatory effects primarily by suppressing pro-inflammatory mediators and antagonizing the pro-inflammatory functions of various cell types relevant to asthma pathophysiology. Experimental findings strongly support the potential clinical benefits of PPAR agonists in the treatment of asthma. We review current literature, highlighting PPARs' key role in asthma pathogenesis and their agonists' therapeutic potential. With additional research and rigorous clinical studies, PPARs may become attractive therapeutic targets in this disease.
Enhancement of cell-based therapeutic angiogenesis using a novel type of injectable scaffolds of hydroxyapatite-polymer nanocomposite microspheres.

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Yohei Mima

Full Text Available BACKGROUND: Clinical trials demonstrate the effectiveness of cell-based therapeutic angiogenesis in patients with severe ischemic diseases; however, their success remains limited. Maintaining transplanted cells in place are expected to augment the cell-based therapeutic angiogenesis. We have reported that nano-hydroxyapatite (HAp coating on medical devices shows marked cell adhesiveness. Using this nanotechnology, HAp-coated poly(l-lactic acid (PLLA microspheres, named nano-scaffold (NS, were generated as a non-biological, biodegradable and injectable cell scaffold. We investigate the effectiveness of NS on cell-based therapeutic angiogenesis. METHODS AND RESULTS: Bone marrow mononuclear cells (BMNC and NS or control PLLA microspheres (LA were intramuscularly co-implanted into mice ischemic hindlimbs. When BMNC derived from enhanced green fluorescent protein (EGFP-transgenic mice were injected into ischemic muscle, the muscle GFP level in NS+BMNC group was approximate fivefold higher than that in BMNC or LA+BMNC groups seven days after operation. Kaplan-Meier analysis demonstrated that NS+BMNC markedly prevented hindlimb necrosis (P<0.05 vs. BMNC or LA+BMNC. NS+BMNC revealed much higher induction of angiogenesis in ischemic tissues and collateral blood flow confirmed by three-dimensional computed tomography angiography than those of BMNC or LA+BMNC groups. NS-enhanced therapeutic angiogenesis and arteriogenesis showed good correlations with increased intramuscular levels of vascular endothelial growth factor and fibroblast growth factor-2. NS co-implantation also prevented apoptotic cell death of transplanted cells, resulting in prolonged cell retention. CONCLUSION: A novel and feasible injectable cell scaffold potentiates cell-based therapeutic angiogenesis, which could be extremely useful for the treatment of severe ischemic disorders.
Identifying and engineering promoters for high level and sustainable therapeutic recombinant protein production in cultured mammalian cells.

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Ho, Steven C L; Yang, Yuansheng

2014-08-01

Promoters are essential on plasmid vectors to initiate transcription of the transgenes when generating therapeutic recombinant proteins expressing mammalian cell lines. High and sustained levels of gene expression are desired during therapeutic protein production while gene expression is useful for cell engineering. As many finely controlled promoters exhibit cell and product specificity, new promoters need to be identified, optimized and carefully evaluated before use. Suitable promoters can be identified using techniques ranging from simple molecular biology methods to modern high-throughput omics screenings. Promoter engineering is often required after identification to either obtain high and sustained expression or to provide a wider range of gene expression. This review discusses some of the available methods to identify and engineer promoters for therapeutic recombinant protein expression in mammalian cells.
[Nuclear transfer and therapeutic cloning].

Science.gov (United States)

Xu, Xiao-Ming; Lei, An-Min; Hua, Jin-Lian; Dou, Zhong-Ying

2005-03-01

Nuclear transfer and therapeutic cloning have widespread and attractive prospects in animal agriculture and biomedical applications. We reviewed that the quality of oocytes and nuclear reprogramming of somatic donor cells were the main reasons of the common abnormalities in cloned animals and the low efficiency of cloning and showed the problems and outlets in therapeutic cloning, such as some basic problems in nuclear transfer affected clinical applications of therapeutic cloning. Study on isolation and culture of nuclear transfer embryonic stem (ntES) cells and specific differentiation of ntES cells into important functional cells should be emphasized and could enhance the efficiency. Adult stem cells could help to cure some great diseases, but could not replace therapeutic cloning. Ethics also impeded the development of therapeutic cloning. It is necessary to improve many techniques and reinforce the research of some basic theories, then somatic nuclear transfer and therapeutic cloning may apply to agriculture reproduction and benefit to human life better.
Therapeutic Potential of Invariant Natural Killer T Cells in Autoimmunity

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Luc Van Kaer

2018-03-01

Full Text Available Tolerance against self-antigens is regulated by a variety of cell types with immunoregulatory properties, such as CD1d-restricted invariant natural killer T (iNKT cells. In many experimental models of autoimmunity, iNKT cells promote self-tolerance and protect against autoimmunity. These findings are supported by studies with patients suffering from autoimmune diseases. Based on these studies, the therapeutic potential of iNKT cells in autoimmunity has been explored. Many of these studies have been performed with the potent iNKT cell agonist KRN7000 or its structural variants. These findings have generated promising results in several autoimmune diseases, although mechanisms by which iNKT cells modulate autoimmunity remain incompletely understood. Here, we will review these preclinical studies and discuss the prospects for translating their findings to patients suffering from autoimmune diseases.
Engineering Therapeutic T Cells: From Synthetic Biology to Clinical Trials.

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Esensten, Jonathan H; Bluestone, Jeffrey A; Lim, Wendell A

2017-01-24

Engineered T cells are currently in clinical trials to treat patients with cancer, solid organ transplants, and autoimmune diseases. However, the field is still in its infancy. The design, and manufacturing, of T cell therapies is not standardized and is performed mostly in academic settings by competing groups. Reliable methods to define dose and pharmacokinetics of T cell therapies need to be developed. As of mid-2016, there are no US Food and Drug Administration (FDA)-approved T cell therapeutics on the market, and FDA regulations are only slowly adapting to the new technologies. Further development of engineered T cell therapies requires advances in immunology, synthetic biology, manufacturing processes, and government regulation. In this review, we outline some of these challenges and discuss the contributions that pathologists can make to this emerging field.
NBPF1, a tumor suppressor candidate in neuroblastoma, exerts growth inhibitory effects by inducing a G1 cell cycle arrest

International Nuclear Information System (INIS)

Andries, Vanessa; Vandepoele, Karl; Staes, Katrien; Berx, Geert; Bogaert, Pieter; Van Isterdael, Gert; Ginneberge, Daisy; Parthoens, Eef; Vandenbussche, Jonathan; Gevaert, Kris; Roy, Frans van

2015-01-01

NBPF1 (Neuroblastoma Breakpoint Family, member 1) was originally identified in a neuroblastoma patient on the basis of its disruption by a chromosomal translocation t(1;17)(p36.2;q11.2). Considering this genetic defect and the frequent genomic alterations of the NBPF1 locus in several cancer types, we hypothesized that NBPF1 is a tumor suppressor. Decreased expression of NBPF1 in neuroblastoma cell lines with loss of 1p36 heterozygosity and the marked decrease of anchorage-independent clonal growth of DLD1 colorectal carcinoma cells with induced NBPF1 expression further suggest that NBPF1 functions as tumor suppressor. However, little is known about the mechanisms involved. Expression of NBPF was analyzed in human skin and human cervix by immunohistochemistry. The effects of NBPF1 on the cell cycle were evaluated by flow cytometry. We investigated by real-time quantitative RT-PCR the expression profile of a panel of genes important in cell cycle regulation. Protein levels of CDKN1A-encoded p21 CIP1/WAF1 were determined by western blotting and the importance of p53 was shown by immunofluorescence and by a loss-of-function approach. LC-MS/MS analysis was used to investigate the proteome of DLD1 colon cancer cells with induced NBPF1 expression. Possible biological interactions between the differentially regulated proteins were investigated with the Ingenuity Pathway Analysis tool. We show that NBPF is expressed in the non-proliferative suprabasal layers of squamous stratified epithelia of human skin and cervix. Forced expression of NBPF1 in HEK293T cells resulted in a G1 cell cycle arrest that was accompanied by upregulation of the cyclin-dependent kinase inhibitor p21 CIP1/WAF1 in a p53-dependent manner. Additionally, forced expression of NBPF1 in two p53-mutant neuroblastoma cell lines also resulted in a G1 cell cycle arrest and CDKN1A upregulation. However, CDKN1A upregulation by NBPF1 was not observed in the DLD1 cells, which demonstrates that NBPF1 exerts cell
[Cancer stem cells as the therapeutic target of tomorrow].

Science.gov (United States)

Hatina, Jiří

2017-02-01

The concept of hierarchical organization of tumour cell population, with cancer stem cells positioned at the apex of the cell hierarchy, can explain at least some crucial aspects of biological and clinical behaviour of cancer, like its propensity to relapse as well as the development of therapeutic resistance. The underlying biological properties of cancer stem cells are crucially dependent on various signals, inhibition of which provides an attractive opportunity to attack pharmacologically cancer stem cells. Currently, a lot of such stemness-inhibitors undergo various phases of clinical testing. Interestingly, numerous old drugs that are in routine use in human and veterinary medicine for non-oncological indications appear to be able to specifically target cancer stem cells as well. As cancer stem cells, at least for most tumours, represent usually only a minor tumour cell fraction, it is quite probable that the main focus of the clinical use of the stemness inhibitors would consist in their rational combinations with traditional anticancer treatment modalities. A highly important goal for the future research is to identify reliable and clinically applicable predictive markers that would allow to apply these novel anticancer drugs on the individual basis within the context of personalized medicine.
Stem cells in degenerative orthopaedic pathologies: effects of aging on therapeutic potential.

Science.gov (United States)

Atesok, Kivanc; Fu, Freddie H; Sekiya, Ichiro; Stolzing, Alexandra; Ochi, Mitsuo; Rodeo, Scott A

2017-02-01

The purpose of this study was to summarize the current evidence on the use of stem cells in the elderly population with degenerative orthopaedic pathologies and to highlight the pathophysiologic mechanisms behind today's therapeutic challenges in stem cell-based regeneration of destructed tissues in the elderly patients with osteoarthritis (OA), degenerative disc disease (DDD), and tendinopathies. Clinical and basic science studies that report the use of stem cells in the elderly patients with OA, DDD, and tendinopathies were identified using a PubMed search. The studies published in English have been assessed, and the best and most recent evidence was included in the current study. Evidence suggests that, although short-term results regarding the effects of stem cell therapy in degenerative orthopaedic pathologies can be promising, stem cell therapies do not appear to reverse age-related tissue degeneration. Causes of suboptimal outcomes can be attributed to the decrease in the therapeutic potential of aged stem cell populations and the regenerative capacity of these cells, which might be negatively influenced in an aged microenvironment within the degenerated tissues of elderly patients with OA, DDD, and tendinopathies. Clinical protocols guiding the use of stem cells in the elderly patient population are still under development, and high-level randomized controlled trials with long-term outcomes are lacking. Understanding the consequences of age-related changes in stem cell function and responsiveness of the in vivo microenvironment to stem cells is critical when designing cell-based therapies for elderly patients with degenerative orthopaedic pathologies.
Cell-based therapeutic strategies for replacement and preservation in retinal degenerative diseases

Science.gov (United States)

Jones, Melissa K.; Lu, Bin; Girman, Sergey; Wang, Shaomei

2017-01-01

Cell-based therapeutics offer diverse options for treating retinal degenerative diseases, such as age-related macular degeneration (AMD) and retinitis pigmentosa (RP). AMD is characterized by both genetic and environmental risks factors, whereas RP is mainly a monogenic disorder. Though treatments exist for some patients with neovascular AMD, a majority of retinal degenerative patients have no effective therapeutics, thus indicating a need for universal therapies to target diverse patient populations. Two main cell-based mechanistic approaches are being tested in clinical trials. Replacement therapies utilize cell-derived retinal pigment epithelial (RPE) cells to supplant lost or defective host RPE cells. These cells are similar in morphology and function to native RPE cells and can potentially supplant the responsibilities of RPE in vivo. Preservation therapies utilize supportive cells to aid in visual function and photoreceptor preservation partially by neurotrophic mechanisms. The goal of preservation strategies is to halt or slow the progression of disease and maintain remaining visual function. A number of clinical trials are testing the safety of replacement and preservation cell therapies in patients; however, measures of efficacy will need to be further evaluated. In addition, a number of prevailing concerns with regards to the immune-related response, longevity, and functionality of the grafted cells will need to be addressed in future trials. This review will summarize the current status of cell-based preclinical and clinical studies with a focus on replacement and preservation strategies and the obstacles that remain regarding these types of treatments. PMID:28111323
Imatinib mesylate exerts anti-proliferative effects on osteosarcoma cells and inhibits the tumour growth in immunocompetent murine models.

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Bérengère Gobin

Full Text Available Osteosarcoma is the most common primary malignant bone tumour characterized by osteoid production and/or osteolytic lesions of bone. A lack of response to chemotherapeutic treatments shows the importance of exploring new therapeutic methods. Imatinib mesylate (Gleevec, Novartis Pharma, a tyrosine kinase inhibitor, was originally developed for the treatment of chronic myeloid leukemia. Several studies revealed that imatinib mesylate inhibits osteoclast differentiation through the M-CSFR pathway and activates osteoblast differentiation through PDGFR pathway, two key cells involved in the vicious cycle controlling the tumour development. The present study investigated the in vitro effects of imatinib mesylate on the proliferation, apoptosis, cell cycle, and migration ability of five osteosarcoma cell lines (human: MG-63, HOS; rat: OSRGA; mice: MOS-J, POS-1. Imatinib mesylate was also assessed as a curative and preventive treatment in two syngenic osteosarcoma models: MOS-J (mixed osteoblastic/osteolytic osteosarcoma and POS-1 (undifferentiated osteosarcoma. Imatinib mesylate exhibited a dose-dependent anti-proliferative effect in all cell lines studied. The drug induced a G0/G1 cell cycle arrest in most cell lines, except for POS-1 and HOS cells that were blocked in the S phase. In addition, imatinib mesylate induced cell death and strongly inhibited osteosarcoma cell migration. In the MOS-J osteosarcoma model, oral administration of imatinib mesylate significantly inhibited the tumour development in both preventive and curative approaches. A phospho-receptor tyrosine kinase array kit revealed that PDGFRα, among 7 other receptors (PDFGFRβ, Axl, RYK, EGFR, EphA2 and 10, IGF1R, appears as one of the main molecular targets for imatinib mesylate. In the light of the present study and the literature, it would be particularly interesting to revisit therapeutic evaluation of imatinib mesylate in osteosarcoma according to the tyrosine-kinase receptor
[Mantle cell lymphoma: Towards a personalized therapeutic strategy?].

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Navarro Matilla, Belén; García-Marco, José A

2015-06-22

Mantle cell lymphoma (MCL) is a clinically heterogeneous non-Hodgkin lymphoma with an aggressive clinical behaviour and short survival in some cases and an indolent course in others. Advances in the biology and pathogenesis of MCL have unveiled several genes involved in deregulation of cell cycle checkpoints and the finding of subclonal populations with specific recurrent mutations (p53, ATM, NOTCH2) with an impact on disease progression and refractoriness to treatment. Prognostic stratification helps to distinguish between indolent and aggressive forms of MCL. Currently, younger fit patients benefit from more intensive front line chemotherapy regimens and consolidation with autologous transplantation, while older or frail patients are treated with less intensive regimens and rituximab maintenance. For relapsing disease, the introduction of bortezomib and lenalidomide containing regimens and B-cell receptor pathway inhibitors such as ibrutinib and idelalisib in combination with immunochemotherapy have emerged as therapeutic agents with promising clinical outcomes. Copyright © 2014 Elsevier España, S.L.U. All rights reserved.
Extracellular vesicles derived from mesenchymal stromal cells: a therapeutic option in respiratory diseases?

Science.gov (United States)

Abreu, Soraia C; Weiss, Daniel J; Rocco, Patricia R M

2016-04-14

Extracellular vesicles (EVs) are plasma membrane-bound fragments released from several cell types, including mesenchymal stromal cells (MSCs), constitutively or under stimulation. EVs derived from MSCs and other cell types transfer molecules (such as DNA, proteins/peptides, mRNA, microRNA, and lipids) and/or organelles with reparative and anti-inflammatory properties to recipient cells. The paracrine anti-inflammatory effects promoted by MSC-derived EVs have attracted significant interest in the regenerative medicine field, including for potential use in lung injuries. In the present review, we describe the characteristics, biological activities, and mechanisms of action of MSC-derived EVs. We also review the therapeutic potential of EVs as reported in relevant preclinical models of acute and chronic respiratory diseases, such as pneumonia, acute respiratory distress syndrome, asthma, and pulmonary arterial hypertension. Finally, we discuss possible approaches for potentiating the therapeutic effects of MSC-derived EVs so as to enable use of this therapy in clinical practice.
Therapeutic action of taurine on the postirradiation recovery of the yeast cells

International Nuclear Information System (INIS)

Benevolenskij, V.N.; Yartsev, E.I.; Novosteltseva, S.D.; Yakovlev, V.G.

1975-01-01

It has been shown on X-irradiated Saccharomyces ellipsoides cells that taurine-potassium phosphate applied after the exposure has a therapeutic action, that is, it intensifies the natural process of intracellular dark repair
Effects of ascorbic acid and α-tocopherol on the therapeutic index of amphotericin B.

Science.gov (United States)

Belhachemi, M H; Boucherit, K; Boucherit-Otmani, Z; Belmir, S; Benbekhti, Z

2014-12-01

Amphotericin B (AmB) remains the antifungal polyene of choice in deep fungal infections, but its high toxicity to mammalian cells limits its use. This toxicity is partly due to lipid peroxidation exerted by amphotericin B in cell membranes. The work we have undertaken focused on the one part the evaluation of the efficacy of amphotericin B in the presence of some antioxidants vitamins (vitamin C "ascorbic acid" and vitamin E "α-tocopherol") against the yeast Candida albicans ATCC 10231. Secondly, we have tested the cytotoxicity of these formulations on human red blood cells. The results showed a significant improvement in the efficiency of our formulations tested from 7% to 12% compared with amphotericin B alone at therapeutic concentrations. Furthermore, the addition of vitamin C and vitamin E protects human red blood cells against the cytotoxicity induced by amphotericin B with 17%. This is due may be to the antioxidant power of vitamins which confer protection against the autoxidation of the molecule of amphotericin B. On the other hand, it is noticed that the yeast regrows after 24h whatever in complex with vitamin C or vitamin E of the stock solution. On completion of this study, the incorporation of antioxidant vitamins that we propose to the reaction medium of antifungal improved the therapeutic index of amphotericin B. Copyright © 2014 Elsevier Masson SAS. All rights reserved.
Antitumoral Effect of Hibiscus sabdariffa on Human Squamous Cell Carcinoma and Multiple Myeloma Cells.

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Malacrida, Alessio; Maggioni, Daniele; Cassetti, Arianna; Nicolini, Gabriella; Cavaletti, Guido; Miloso, Mariarosaria

2016-10-01

Cancer is a leading cause of death worldwide. Despite therapeutic improvements, some cancers are still untreatable. Recently there has been an increasing interest in the use of natural substances for cancer prevention and treatment. Hibiscus sabdariffa (HS) is a plant, belonging to Malvaceae family, widespread in South Asia and Central Africa. HS extract (HSE) used in folk medicine, gained researchers' interest thanks to its antioxidant, anti-inflammatory, and chemopreventive properties. In the present study, we initially assessed HSE effect on a panel of human tumor cell lines. Then we focused our study on the following that are most sensitive to HSE action cell lines: Multiple Myeloma (MM) cells (RPMI 8226) and Oral Squamous Cell Carcinoma (OSCC) cells (SCC-25). In both RPMI 8226 and SCC-25 cells, HSE impaired cell growth, exerted a reversible cytostatic effect, and reduced cell motility and invasiveness. We evaluated the involvement of MAPKs ERK1/2 and p38 in HSE effects by using specific inhibitors, U0126 and SB203580, respectively. For both SCC-25 and RPMI 8226, HSE cytostatic effect depends on p38 activation, whereas ERK1/2 modulation is crucial for cell motility and invasiveness. Our results suggest that HSE may be a potential therapeutic agent against MM and OSCC.
Combined Gemcitabine and Metronidazole Is a Promising Therapeutic Strategy for Cancer Stem-like Cholangiocarcinoma.

Science.gov (United States)

Kawamoto, Makoto; Umebayashi, Masayo; Tanaka, Hiroto; Koya, Norihiro; Nakagawa, Sinichiro; Kawabe, Ken; Onishi, Hideya; Nakamura, Masafumi; Morisaki, Takashi

2018-05-01

Metronidazole (MNZ) is a common antibiotic that exerts disulfiram-like effects when taken together with alcohol. However, the relationship between MNZ and aldehyde dehydrogenase (ALDH) activity remains unclear. This study investigated whether MNZ reduces cancer stemness by suppressing ALDH activity and accordingly reducing the malignancy of cholangiocarcinoma (CCA). We developed gemcitabine (GEM)-resistant TFK-1 cells and originally established CCA cell line from a patient with GEM-resistant CCA. Using these cell lines, we analyzed the impacts of MNZ for cancer stem cell markers, invasiveness, and chemosensitivity. MNZ reduced ALDH activity in GEM-resistant CCA cells, leading to decreased invasiveness and enhanced chemosensitivity. MNZ diminished the invasiveness by inducing mesenchymal-epithelial transition and enhancing chemosensitivity by increasing ENT1 (equilibrative nucleoside transporter 1) and reducing RRM1 (ribonucleotide reductase M1). MNZ reduced cancer stemness in GEM-resistant CCA cells. Combined GEM and MNZ would be a promising therapeutic strategy for cancer stem-like CAA. Copyright© 2018, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

Therapeutic cloning: The ethical limits

International Nuclear Information System (INIS)

Whittaker, Peter A.

2005-01-01

A brief outline of stem cells, stem cell therapy and therapeutic cloning is given. The position of therapeutic cloning with regard to other embryonic manipulations - IVF-based reproduction, embryonic stem formation from IVF embryos and reproductive cloning - is indicated. The main ethically challenging stages in therapeutic cloning are considered to be the nuclear transfer process including the source of eggs for this and the destruction of an embryo to provide stem cells for therapeutic use. The extremely polarised nature of the debate regarding the status of an early human embryo is noted, and some potential alternative strategies for preparing immunocompatible pluripotent stem cells are indicated
Engineering Multi-Walled Carbon Nanotube Therapeutic Bionanofluids to Selectively Target Papillary Thyroid Cancer Cells.

Directory of Open Access Journals (Sweden)

Idit Dotan

Full Text Available The incidence of papillary thyroid carcinoma (PTC has risen steadily over the past few decades as well as the recurrence rates. It has been proposed that targeted ablative physical therapy could be a therapeutic modality in thyroid cancer. Targeted bio-affinity functionalized multi-walled carbon nanotubes (BioNanofluid act locally, to efficiently convert external light energy to heat thereby specifically killing cancer cells. This may represent a promising new cancer therapeutic modality, advancing beyond conventional laser ablation and other nanoparticle approaches.Thyroid Stimulating Hormone Receptor (TSHR was selected as a target for PTC cells, due to its wide expression. Either TSHR antibodies or Thyrogen or purified TSH (Thyrotropin were chemically conjugated to our functionalized Bionanofluid. A diode laser system (532 nm was used to illuminate a PTC cell line for set exposure times. Cell death was assessed using Trypan Blue staining.TSHR-targeted BioNanofluids were capable of selectively ablating BCPAP, a TSHR-positive PTC cell line, while not TSHR-null NSC-34 cells. We determined that a 2:1 BCPAP cell:α-TSHR-BioNanofluid conjugate ratio and a 30 second laser exposure killed approximately 60% of the BCPAP cells, while 65% and >70% of cells were ablated using Thyrotropin- and Thyrogen-BioNanofluid conjugates, respectively. Furthermore, minimal non-targeted killing was observed using selective controls.A BioNanofluid platform offering a potential therapeutic path for papillary thyroid cancer has been investigated, with our in vitro results suggesting the development of a potent and rapid method of selective cancer cell killing. Therefore, BioNanofluid treatment emphasizes the need for new technology to treat patients with local recurrence and metastatic disease who are currently undergoing either re-operative neck explorations, repeated administration of radioactive iodine and as a last resort external beam radiation or chemotherapy, with
Nanoparticle-labeled stem cells: a novel therapeutic vehicle

Directory of Open Access Journals (Sweden)

Abir O El-Sadik

2010-03-01

Full Text Available Abir O El-Sadik1, Afaf El-Ansary2, Sherif M Sabry31Stem Cell Unit, Anatomy Department, College of Medicine, Health Science Colleges; 2Biochemistry Department, Science College, King Saud University; 3Anatomy Department, Faculty of Medicine, Cairo University, Cairo, EgyptAbstract: Nanotechnology has been described as a general purpose technology. It has already generated a range of inventions and innovations. Development of nanotechnology will provide clinical medicine with a range of new diagnostic and therapeutic opportunities such as medical imaging, medical diagnosis, drug delivery, and cancer detection and management. Nanoparticles such as manganese, polystyrene, silica, titanium oxide, gold, silver, carbon, quantum dots, and iron oxide have received enormous attention in the creation of new types of analytical tools for biotechnology and life sciences. Labeling of stem cells with nanoparticles overcame the problems in homing and fixing stem cells to their desired site and guiding extension of stem cells to specific directions. Although the biologic effects of some nanoparticles have already been assessed, information on toxicity and possible mechanisms of various particle types remains inadequate. The aim of this review is to give an overview of the mechanisms of internalization and distribution of nanoparticles inside stem cells, as well as the influence of different types of nanoparticles on stem cell viability, proliferation, differentiation, and cytotoxicity, and to assess the role of nanoparticles in tracking the fate of stem cells used in tissue regeneration.Keywords: nanoparticles, stem cells, uptake, differentiation, cytotoxicity, tracking
Mitochondrial uncoupler exerts a synthetic lethal effect against β-catenin mutant tumor cells.

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Shikata, Yuki; Kiga, Masaki; Futamura, Yushi; Aono, Harumi; Inoue, Hiroyuki; Kawada, Manabu; Osada, Hiroyuki; Imoto, Masaya

2017-04-01

The wingless/int-1 (Wnt) signal transduction pathway plays a central role in cell proliferation, survival, differentiation and apoptosis. When β-catenin: a component of the Wnt pathway, is mutated into an active form, cell growth signaling is hyperactive and drives oncogenesis. As β-catenin is mutated in a wide variety of tumors, including up to 10% of all sporadic colon carcinomas and 20% of hepatocellular carcinomas, it has been considered a promising target for therapeutic interventions. Therefore, we screened an in-house natural product library for compounds that exhibited synthetic lethality towards β-catenin mutations and isolated nonactin, an antibiotic mitochondrial uncoupler, as a hit compound. Nonactin, as well as other mitochondrial uncouplers, induced apoptosis selectively in β-catenin mutated tumor cells. Significant tumor regression was observed in the β-catenin mutant HCT 116 xenograft model, but not in the β-catenin wild type A375 xenograft model, in response to daily administration of nonactin in vivo. Furthermore, we found that expression of an active mutant form of β-catenin induced a decrease in the glycolysis rate. Taken together, our results demonstrate that tumor cells with mutated β-catenin depend on mitochondrial oxidative phosphorylation for survival. Therefore, they undergo apoptosis in response to mitochondrial dysfunction following the addition of mitochondrial uncouplers, such as nonactin. These results suggest that targeting mitochondria is a potential chemotherapeutic strategy for tumor cells that harbor β-catenin mutations. © 2017 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.
The controversial origin of pericytes during angiogenesis - Implications for cell-based therapeutic angiogenesis and cell-based therapies.

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Blocki, Anna; Beyer, Sebastian; Jung, Friedrich; Raghunath, Michael

2018-01-01

Pericytes reside within the basement membrane of small vessels and are often in direct cellular contact with endothelial cells, fulfilling important functions during blood vessel formation and homeostasis. Recently, these pericytes have been also identified as mesenchymal stem cells. Mesenchymal stem cells, and especially their specialized subpopulation of pericytes, represent promising candidates for therapeutic angiogenesis applications, and have already been widely applied in pre-clinical and clinical trials. However, cell-based therapies of ischemic diseases (especially of myocardial infarction) have not resulted in significant long-term improvement. Interestingly, pericytes from a hematopoietic origin were observed in embryonic skin and a pericyte sub-population expressing leukocyte and monocyte markers was described during adult angiogenesis in vivo. Since mesenchymal stem cells do not express hematopoietic markers, the latter cell type might represent an alternative pericyte population relevant to angiogenesis. Therefore, we sourced blood-derived angiogenic cells (BDACs) from monocytes that closely resembled hematopoietic pericytes, which had only been observed in vivo thus far. BDACs displayed many pericytic features and exhibited enhanced revascularization and functional tissue regeneration in a pre-clinical model of critical limb ischemia. Comparison between BDACs and mesenchymal pericytes indicated that BDACs (while resembling hematopoietic pericytes) enhanced early stages of angiogenesis, such as endothelial cell sprouting. In contrast, mesenchymal pericytes were responsible for blood vessel maturation and homeostasis, while reducing endothelial sprouting.Since the formation of new blood vessels is crucial during therapeutic angiogenesis or during integration of implants into the host tissue, hematopoietic pericytes (and therefore BDACs) might offer an advantageous addition or even an alternative for cell-based therapies.
Self-focusing therapeutic gene delivery with intelligent gene vector swarms: intra-swarm signalling through receptor transgene expression in targeted cells.

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Tolmachov, Oleg E

2015-01-01

Gene delivery in vivo that is tightly focused on the intended target cells is essential to maximize the benefits of gene therapy and to reduce unwanted side-effects. Cell surface markers are immediately available for probing by therapeutic gene vectors and are often used to direct gene transfer with these vectors to specific target cell populations. However, it is not unusual for the choice of available extra-cellular markers to be too scarce to provide a reliable definition of the desired therapeutically relevant set of target cells. Therefore, interrogation of intra-cellular determinants of cell-specificity, such as tissue-specific transcription factors, can be vital in order to provide detailed cell-guiding information to gene vector particles. An important improvement in cell-specific gene delivery can be achieved through auto-buildup in vector homing efficiency using intelligent 'self-focusing' of swarms of vector particles on target cells. Vector self-focusing was previously suggested to rely on the release of diffusible chemo-attractants after a successful target-specific hit by 'scout' vector particles. I hypothesize that intelligent self-focusing behaviour of swarms of cell-targeted therapeutic gene vectors can be accomplished without the employment of difficult-to-use diffusible chemo-attractants, instead relying on the intra-swarm signalling through cells expressing a non-diffusible extra-cellular receptor for the gene vectors. In the proposed model, cell-guiding information is gathered by the 'scout' gene vector particles, which: (1) attach to a variety of cells via a weakly binding (low affinity) receptor; (2) successfully facilitate gene transfer into these cells; (3) query intra-cellular determinants of cell-specificity with their transgene expression control elements and (4) direct the cell-specific biosynthesis of a vector-encoded strongly binding (high affinity) cell-surface receptor. Free members of the vector swarm loaded with therapeutic cargo
Recent Advances in Stem Cell-Based Therapeutics for Stroke

OpenAIRE

Napoli, Eleonora; Borlongan, Cesar V.

2016-01-01

Regenerative medicine for central nervous system disorders, including stroke, has challenged the non-regenerative capacity of the brain. Among the many treatment strategies tailored towards repairing the injured brain, stem cell-based therapeutics have been demonstrated as safe and effective in animal models of stroke, and are being tested in limited clinical trials. We address here key lab-to-clinic translational research that relate to efficacy, safety, and mechanism of action underlying st...
Therapeutic potential and challenges of Natural killer cells in treatment of solid tumors

Directory of Open Access Journals (Sweden)

Andrea eGras Navarro

2015-04-01

Full Text Available Natural killer (NK cells are innate lymphoid cells that hold tremendous potential for effective immunotherapy for a broad range of cancers. Due to the mode of NK cell killing requiring one–to-one target engagement and site directed release of cytolytic granules, the therapeutic potential of NK cells has been most extensively explored in hematological malignancies. However, their ability to precisely kill antibody coated cells, cancer stem cells (CSCs and genotoxically altered cells, while maintaining tolerance to healthy cells makes them appealing therapeutic effectors for all cancer forms, including metastases. Due to their release of pro-inflammatory cytokines, NK cells may potently reverse the anti-inflammatory tumor microenvironment (TME and augment adaptive immune responses by promoting differentiation, activation and/ or recruitment of accessory immune cells to sites of malignancy. Nevertheless, integrated and coordinated mechanisms of subversion of NK cell activity against the tumor and its microenvironment exist. Although our understanding of the receptor ligand interactions that regulate NK cell functionality has evolved remarkably, the diversity of ligands and receptors is complex, as is their mechanistic foundations in regulating NK cell function. In this article, we review the literature and highlight how the TME manipulates the NK cell phenotypes, genotypes and tropism to evade tumor recognition and elimination. We discuss counter strategies that may be adopted to augment the efficacy of NK cell anti-tumor surveillance, the clinical trials that have been undertaken so far in solid malignancies, critically weighing the challenges and opportunities with this approach.
Design Strategies for Balancing Exertion Games

DEFF Research Database (Denmark)

Jensen, Mads Møller; Grønbæk, Kaj

2016-01-01

In sports, if players' physical and technical abilities are mismatched, the competition is often uninteresting for them. With the emergence of exertion games, this could be changing. Player balancing, known from video games, allows players with different skill levels to compete, however, it is un......In sports, if players' physical and technical abilities are mismatched, the competition is often uninteresting for them. With the emergence of exertion games, this could be changing. Player balancing, known from video games, allows players with different skill levels to compete, however......, it is unclear how balancing mechanisms should be applied in exertion games, where physical and digital elements are fused. In this paper, we present an exertion game and three approaches for balancing it; a physical, an explicit-digital and an implicit-digital balancing approach. A user study that compares...... these three approaches is used to investigate the qualities and challenges within each approach and explore how the player experience is affected by them. Based on these findings, we suggest four design strategies for balancing exertion games, so that players will stay engaged in the game and contain...
Exertional Dyspnoea in Chronic Respiratory Diseases: From Physiology to Clinical Application.

Science.gov (United States)

Dubé, Bruno-Pierre; Vermeulen, François; Laveneziana, Pierantonio

2017-02-01

Dyspnoea is a complex, highly personalized and multidimensional sensory experience, and its underlying cause and mechanisms are still being investigated. Exertional dyspnoea is one of the most frequently encountered symptoms of patients with cardiopulmonary diseases, and is a common reason for seeking medical help. As the symptom usually progresses with the underlying disease, it can lead to an avoidance of physical activity, peripheral muscle deconditioning and decreased quality of life. Dyspnoea is closely associated with quality of life, exercise (in)tolerance and prognosis in various conditions, including chronic obstructive pulmonary disease, heart failure, interstitial lung disease and pulmonary hypertension, and is therefore an important therapeutic target. Effective management and treatment of dyspnoea is an important challenge for caregivers, and therapeutic options that attempt to reverse its underlying cause have been only partially successful This "review" will attempt to shed light on the physiological mechanisms underlying dyspnoea during exercise and to translate/apply them to a broad clinical spectrum of cardio-respiratory disorders. Copyright © 2016 SEPAR. Publicado por Elsevier España, S.L.U. All rights reserved.
Achieving the Promise of Therapeutic Extracellular Vesicles: The Devil is in Details of Therapeutic Loading.

Science.gov (United States)

Sutaria, Dhruvitkumar S; Badawi, Mohamed; Phelps, Mitch A; Schmittgen, Thomas D

2017-05-01

Extracellular vesicles (EVs) represent a class of cell secreted organelles which naturally contain biomolecular cargo such as miRNA, mRNA and proteins. EVs mediate intercellular communication, enabling the transfer of functional nucleic acids from the cell of origin to the recipient cells. In addition, EVs make an attractive delivery vehicle for therapeutics owing to their increased stability in circulation, biocompatibility, low immunogenicity and toxicity profiles. EVs can also be engineered to display targeting moieties on their surfaces which enables targeting to desired tissues, organs or cells. While much has been learned on the role of EVs as cell communicators, the field of therapeutic EV application is currently under development. Critical to the future success of EV delivery system is the description of methods by which therapeutics can be successfully and efficiently loaded within the EVs. Two methods of loading of EVs with therapeutic cargo exist, endogenous and exogenous loading. We have therefore focused this review on describing the various published approaches for loading EVs with therapeutics.
Cannabis and endocannabinoid modulators: Therapeutic promises and challenges

Science.gov (United States)

Grant, Igor; Cahn, B. Rael

2008-01-01

The discovery that botanical cannabinoids such as delta-9 tetrahydrocannabinol exert some of their effect through binding specific cannabinoid receptor sites has led to the discovery of an endocannabinoid signaling system, which in turn has spurred research into the mechanisms of action and addiction potential of cannabis on the one hand, while opening the possibility of developing novel therapeutic agents on the other. This paper reviews current understanding of CB1, CB2, and other possible cannabinoid receptors, their arachidonic acid derived ligands (e.g. anandamide; 2 arachidonoyl glycerol), and their possible physiological roles. CB1 is heavily represented in the central nervous system, but is found in other tissues as well; CB2 tends to be localized to immune cells. Activation of the endocannabinoid system can result in enhanced or dampened activity in various neural circuits depending on their own state of activation. This suggests that one function of the endocannabinoid system may be to maintain steady state. The therapeutic action of botanical cannabis or of synthetic molecules that are agonists, antagonists, or which may otherwise modify endocannabinoid metabolism and activity indicates they may have promise as neuroprotectants, and may be of value in the treatment of certain types of pain, epilepsy, spasticity, eating disorders, inflammation, and possibly blood pressure control. PMID:18806886
Preclinical evaluation of NF-kappa B-triggered dendritic cells expressing the viral oncogenic driver of Merkel cell carcinoma for therapeutic vaccination

DEFF Research Database (Denmark)

Gerer, Kerstin F.; Erdmann, Michael; Hadrup, Sine Reker

2017-01-01

Background: Merkel cell carcinoma (MCC) is a rare but very aggressive skin tumor that develops after integration of a truncated form of the large T-antigen (truncLT) of the Merkel cell polyomavirus (MCV) into the host's genome. Therapeutic vaccination with dendritic cells (DCs) loaded with tumor ...
Cancer Stem Cell Hypothesis for Therapeutic Innovation in Clinical Oncology? Taking the Root Out, Not Chopping the Leaf.

Science.gov (United States)

Dzobo, Kevin; Senthebane, Dimakatso Alice; Rowe, Arielle; Thomford, Nicholas Ekow; Mwapagha, Lamech M; Al-Awwad, Nasir; Dandara, Collet; Parker, M Iqbal

2016-12-01

Clinical oncology is in need of therapeutic innovation. New hypotheses and concepts for translation of basic research to novel diagnostics and therapeutics are called for. In this context, the cancer stem cell (CSC) hypothesis rests on the premise that tumors comprise tumor cells and a subset of tumor-initiating cells, CSCs, in a quiescent state characterized by slow cell cycling and expression of specific stem cell surface markers with the capability to maintain a tumor in vivo. The CSCs have unlimited self-renewal abilities and propagate tumors through division into asymmetric daughter cells. This differentiation is induced by both genetic and environmental factors. Another characteristic of CSCs is their therapeutic resistance, which is due to their quiescent state and slow dividing. Notably, the CSC phenotype differs greatly between patients and different cancer types. The CSCs may differ genetically and phenotypically and may include primary CSCs and metastatic stem cells circulating within the blood system. Targeting CSCs will require the knowledge of distinct stem cells within the tumor. CSCs can differentiate into nontumorigenic cells and this has been touted as the source of heterogeneity observed in many solid tumors. The latter cannot be fully explained by epigenetic regulation or by the clonal evolution theory. This heterogeneity markedly influences how tumors respond to therapy and prognosis. The present expert review offers an analysis and synthesis of the latest research and concepts on CSCs, with a view to truly disruptive innovation for future diagnostics and therapeutics in clinical oncology.
Impact of plant extracts tested in attention-deficit/hyperactivity disorder treatment on cell survival and energy metabolism in human neuroblastoma SH-SY5Y cells.

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Schmidt, Andreas Johannes; Krieg, Jürgen-Christian; Hemmeter, Ulrich Michael; Kircher, Tilo; Schulz, Eberhard; Clement, Hans-Willi; Heiser, Philip

2010-10-01

Plant extracts such as Hypericum perforatum and Pycnogenol have been tested as alternatives to the classical ADHD drugs. It has been possible to describe neuroprotective effects of such plant extracts. A reduction of ADHD symptoms could be shown in clinical studies after the application of Pycnogenol, which is a pine bark extract. The impacts of the standardized herbal extracts Hypericum perforatum, Pycnogenol and Enzogenol up to a concentration of 5000 ng/mL on cell survival and energy metabolism in human SH-SY5Y neuroblastoma cells has been investigated in the present examination. Hypericum perforatum significantly decreased the survival of cells after treatment with a concentration of 5000 ng/mL, whereas lower concentrations exerted no significant effects. Pycnogenol( induced a significant increase of cell survival after incubation with a concentration of 32.25 ng/mL and a concentration of 250 ng/mL. Other applied concentrations of Pycnogenol failed to exert significant effects. Treatment with Enzogenol did not lead to significant changes in cell survival.Concerning energy metabolism, the treatment of cells with a concentration of 5000 ng/mL Hypericum perforatum led to a significant increase of ATP levels, whereas treatment with a concentration of 500 ng/mL had no significant effect. Incubation of cells with Pycnogenol and Enzogenol exerted no significant effects.None of the tested substances caused any cytotoxic effect when used in therapeutically relevant concentrations. Copyright © 2010 John Wiley & Sons, Ltd.
Hepatic leukemia factor promotes resistance to cell death: Implications for therapeutics and chronotherapy

International Nuclear Information System (INIS)

Waters, Katrina M.; Sontag, Ryan L.; Weber, Thomas J.

2013-01-01

Physiological variation related to circadian rhythms and aberrant gene expression patterns are believed to modulate therapeutic efficacy, but the precise molecular determinants remain unclear. Here we examine the regulation of cell death by hepatic leukemia factor (HLF), which is an output regulator of circadian rhythms and is aberrantly expressed in human cancers, using an ectopic expression strategy in JB6 mouse epidermal cells and human keratinocytes. Ectopic HLF expression inhibited cell death in both JB6 cells and human keratinocytes, as induced by serum-starvation, tumor necrosis factor alpha and ionizing radiation. Microarray analysis indicates that HLF regulates a complex multi-gene transcriptional program encompassing upregulation of anti-apoptotic genes, downregulation of pro-apoptotic genes, and many additional changes that are consistent with an anti-death program. Collectively, our results demonstrate that ectopic expression of HLF, an established transcription factor that cycles with circadian rhythms, can recapitulate many features associated with circadian-dependent physiological variation. - Highlights: ► Circadian-dependent physiological variation impacts therapeutic efficacy. ► Hepatic leukemia factor inhibits cell death and is a candidate circadian factor. ► Hepatic leukemia factor anti-death program is conserved in murine and human cells. ► Transcriptomics indicates the anti-death program results from a systems response
Hepatic leukemia factor promotes resistance to cell death: Implications for therapeutics and chronotherapy

Energy Technology Data Exchange (ETDEWEB)

Waters, Katrina M. [Computational Biology and Bioinformatics, Pacific Northwest National Laboratory, Richland, WA 99354 (United States); Sontag, Ryan L. [Systems Toxicology Groups, Pacific Northwest National Laboratory, Richland, WA 99354 (United States); Weber, Thomas J., E-mail: Thomas.Weber@pnl.gov [Systems Toxicology Groups, Pacific Northwest National Laboratory, Richland, WA 99354 (United States)

2013-04-15

Physiological variation related to circadian rhythms and aberrant gene expression patterns are believed to modulate therapeutic efficacy, but the precise molecular determinants remain unclear. Here we examine the regulation of cell death by hepatic leukemia factor (HLF), which is an output regulator of circadian rhythms and is aberrantly expressed in human cancers, using an ectopic expression strategy in JB6 mouse epidermal cells and human keratinocytes. Ectopic HLF expression inhibited cell death in both JB6 cells and human keratinocytes, as induced by serum-starvation, tumor necrosis factor alpha and ionizing radiation. Microarray analysis indicates that HLF regulates a complex multi-gene transcriptional program encompassing upregulation of anti-apoptotic genes, downregulation of pro-apoptotic genes, and many additional changes that are consistent with an anti-death program. Collectively, our results demonstrate that ectopic expression of HLF, an established transcription factor that cycles with circadian rhythms, can recapitulate many features associated with circadian-dependent physiological variation. - Highlights: ► Circadian-dependent physiological variation impacts therapeutic efficacy. ► Hepatic leukemia factor inhibits cell death and is a candidate circadian factor. ► Hepatic leukemia factor anti-death program is conserved in murine and human cells. ► Transcriptomics indicates the anti-death program results from a systems response.
Multifunctional quantum dots-based cancer diagnostics and stem cell therapeutics for regenerative medicine.

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Onoshima, Daisuke; Yukawa, Hiroshi; Baba, Yoshinobu

2015-12-01

A field of recent diagnostics and therapeutics has been advanced with quantum dots (QDs). QDs have developed into new formats of biomolecular sensing to push the limits of detection in biology and medicine. QDs can be also utilized as bio-probes or labels for biological imaging of living cells and tissues. More recently, QDs has been demonstrated to construct a multifunctional nanoplatform, where the QDs serve not only as an imaging agent, but also a nanoscaffold for diagnostic and therapeutic modalities. This review highlights the promising applications of multi-functionalized QDs as advanced nanosensors for diagnosing cancer and as innovative fluorescence probes for in vitro or in vivo stem cell imaging in regenerative medicine. Copyright © 2015 Elsevier B.V. All rights reserved.
Development of Quorum-Based Anti-Virulence Therapeutics Targeting Gram-Negative Bacterial Pathogens

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Wen Shan Yew

2013-08-01

Full Text Available Quorum sensing is a cell density-dependent signaling phenomenon used by bacteria for coordination of population-wide phenotypes, such as expression of virulence genes, antibiotic resistance and biofilm formation. Lately, disruption of bacterial communication has emerged as an anti-virulence strategy with enormous therapeutic potential given the increasing incidences of drug resistance in pathogenic bacteria. The quorum quenching therapeutic approach promises a lower risk of resistance development, since interference with virulence generally does not affect the growth and fitness of the bacteria and, hence, does not exert an associated selection pressure for drug-resistant strains. With better understanding of bacterial communication networks and mechanisms, many quorum quenching methods have been developed against various clinically significant bacterial pathogens. In particular, Gram-negative bacteria are an important group of pathogens, because, collectively, they are responsible for the majority of hospital-acquired infections. Here, we discuss the current understanding of existing quorum sensing mechanisms and present important inhibitory strategies that have been developed against this group of pathogenic bacteria.
Adiponectin and plant-derived mammalian adiponectin homolog exert a protective effect in murine colitis

KAUST Repository

Arsenescu, Violeta

2011-04-11

Background: Hypoadiponectinemia has been associated with states of chronic inflammation in humans. Mesenteric fat hypertrophy and low adiponectin have been described in patients with Crohn\\'s disease. We investigated whether adiponectin and the plant-derived homolog, osmotin, are beneficial in a murine model of colitis. Methods: C57BL/6 mice were injected (i.v.) with an adenoviral construct encoding the full-length murine adiponectin gene (AN+DSS) or a reporter-LacZ (Ctr and V+DSS groups) prior to DSS colitis protocol. In another experiment, mice with DSS colitis received either osmotin (Osm+DSS) or saline (DSS) via osmotic pumps. Disease progression and severity were evaluated using body weight, stool consistency, rectal bleeding, colon lengths, and histology. In vitro experiments were carried out in bone marrow-derived dendritic cells. Results: Mice overexpressing adiponectin had lower expression of proinflammatory cytokines (TNF, IL-1β), adipokines (angiotensin, osteopontin), and cellular stress and apoptosis markers. These mice had higher levels of IL-10, alternative macrophage marker, arginase 1, and leukoprotease inhibitor. The plant adiponectin homolog osmotin similarly improved colitis outcome and induced robust IL-10 secretion. LPS induced a state of adiponectin resistance in dendritic cells that was reversed by treatment with PPARγ agonist and retinoic acid. Conclusion: Adiponectin exerted protective effects during murine DSS colitis. It had a broad activity that encompassed cytokines, chemotactic factors as well as processes that assure cell viability during stressful conditions. Reducing adiponectin resistance or using plant-derived adiponectin homologs may become therapeutic options in inflammatory bowel disease. © 2011 Springer Science+Business Media, LLC.

Immortalized human myotonic dystrophy muscle cell lines to assess therapeutic compounds

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Arandel, Ludovic; Polay Espinoza, Micaela; Matloka, Magdalena; Bazinet, Audrey; De Dea Diniz, Damily; Naouar, Naïra; Rau, Frédérique; Jollet, Arnaud; Edom-Vovard, Frédérique; Mamchaoui, Kamel; Tarnopolsky, Mark; Puymirat, Jack; Battail, Christophe; Boland, Anne; Deleuze, Jean-Francois; Mouly, Vincent; Klein, Arnaud F.

2017-01-01

ABSTRACT Myotonic dystrophy type 1 (DM1) and type 2 (DM2) are autosomal dominant neuromuscular diseases caused by microsatellite expansions and belong to the family of RNA-dominant disorders. Availability of cellular models in which the DM mutation is expressed within its natural context is essential to facilitate efforts to identify new therapeutic compounds. Here, we generated immortalized DM1 and DM2 human muscle cell lines that display nuclear RNA aggregates of expanded repeats, a hallmark of myotonic dystrophy. Selected clones of DM1 and DM2 immortalized myoblasts behave as parental primary myoblasts with a reduced fusion capacity of immortalized DM1 myoblasts when compared with control and DM2 cells. Alternative splicing defects were observed in differentiated DM1 muscle cell lines, but not in DM2 lines. Splicing alterations did not result from differentiation delay because similar changes were found in immortalized DM1 transdifferentiated fibroblasts in which myogenic differentiation has been forced by overexpression of MYOD1. As a proof-of-concept, we show that antisense approaches alleviate disease-associated defects, and an RNA-seq analysis confirmed that the vast majority of mis-spliced events in immortalized DM1 muscle cells were affected by antisense treatment, with half of them significantly rescued in treated DM1 cells. Immortalized DM1 muscle cell lines displaying characteristic disease-associated molecular features such as nuclear RNA aggregates and splicing defects can be used as robust readouts for the screening of therapeutic compounds. Therefore, immortalized DM1 and DM2 muscle cell lines represent new models and tools to investigate molecular pathophysiological mechanisms and evaluate the in vitro effects of compounds on RNA toxicity associated with myotonic dystrophy mutations. PMID:28188264
Immortalized human myotonic dystrophy muscle cell lines to assess therapeutic compounds

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Ludovic Arandel

2017-04-01

Full Text Available Myotonic dystrophy type 1 (DM1 and type 2 (DM2 are autosomal dominant neuromuscular diseases caused by microsatellite expansions and belong to the family of RNA-dominant disorders. Availability of cellular models in which the DM mutation is expressed within its natural context is essential to facilitate efforts to identify new therapeutic compounds. Here, we generated immortalized DM1 and DM2 human muscle cell lines that display nuclear RNA aggregates of expanded repeats, a hallmark of myotonic dystrophy. Selected clones of DM1 and DM2 immortalized myoblasts behave as parental primary myoblasts with a reduced fusion capacity of immortalized DM1 myoblasts when compared with control and DM2 cells. Alternative splicing defects were observed in differentiated DM1 muscle cell lines, but not in DM2 lines. Splicing alterations did not result from differentiation delay because similar changes were found in immortalized DM1 transdifferentiated fibroblasts in which myogenic differentiation has been forced by overexpression of MYOD1. As a proof-of-concept, we show that antisense approaches alleviate disease-associated defects, and an RNA-seq analysis confirmed that the vast majority of mis-spliced events in immortalized DM1 muscle cells were affected by antisense treatment, with half of them significantly rescued in treated DM1 cells. Immortalized DM1 muscle cell lines displaying characteristic disease-associated molecular features such as nuclear RNA aggregates and splicing defects can be used as robust readouts for the screening of therapeutic compounds. Therefore, immortalized DM1 and DM2 muscle cell lines represent new models and tools to investigate molecular pathophysiological mechanisms and evaluate the in vitro effects of compounds on RNA toxicity associated with myotonic dystrophy mutations.
Immortalized human myotonic dystrophy muscle cell lines to assess therapeutic compounds.

Science.gov (United States)

Arandel, Ludovic; Polay Espinoza, Micaela; Matloka, Magdalena; Bazinet, Audrey; De Dea Diniz, Damily; Naouar, Naïra; Rau, Frédérique; Jollet, Arnaud; Edom-Vovard, Frédérique; Mamchaoui, Kamel; Tarnopolsky, Mark; Puymirat, Jack; Battail, Christophe; Boland, Anne; Deleuze, Jean-Francois; Mouly, Vincent; Klein, Arnaud F; Furling, Denis

2017-04-01

Myotonic dystrophy type 1 (DM1) and type 2 (DM2) are autosomal dominant neuromuscular diseases caused by microsatellite expansions and belong to the family of RNA-dominant disorders. Availability of cellular models in which the DM mutation is expressed within its natural context is essential to facilitate efforts to identify new therapeutic compounds. Here, we generated immortalized DM1 and DM2 human muscle cell lines that display nuclear RNA aggregates of expanded repeats, a hallmark of myotonic dystrophy. Selected clones of DM1 and DM2 immortalized myoblasts behave as parental primary myoblasts with a reduced fusion capacity of immortalized DM1 myoblasts when compared with control and DM2 cells. Alternative splicing defects were observed in differentiated DM1 muscle cell lines, but not in DM2 lines. Splicing alterations did not result from differentiation delay because similar changes were found in immortalized DM1 transdifferentiated fibroblasts in which myogenic differentiation has been forced by overexpression of MYOD1. As a proof-of-concept, we show that antisense approaches alleviate disease-associated defects, and an RNA-seq analysis confirmed that the vast majority of mis-spliced events in immortalized DM1 muscle cells were affected by antisense treatment, with half of them significantly rescued in treated DM1 cells. Immortalized DM1 muscle cell lines displaying characteristic disease-associated molecular features such as nuclear RNA aggregates and splicing defects can be used as robust readouts for the screening of therapeutic compounds. Therefore, immortalized DM1 and DM2 muscle cell lines represent new models and tools to investigate molecular pathophysiological mechanisms and evaluate the in vitro effects of compounds on RNA toxicity associated with myotonic dystrophy mutations. © 2017. Published by The Company of Biologists Ltd.
Therapeutic strategies in Sickle Cell Anemia: The past present and future.

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Fernandes, Queenie

2017-06-01

Sickle Cell Anemia (SCA) was one of the first hemoglobinopathies to be discovered. It is distinguished by the mutation-induced expression of a sickle cell variant of hemoglobin (HbS) that triggers erythrocytes to take a characteristic sickled conformation. The complex physiopathology of the disease and its associated clinical complications has initiated multi-disciplinary research within its field. This review attempts to lay emphasis on the evolution, current standpoint and future scope of therapeutic strategies in SCA. Copyright © 2017 Elsevier Inc. All rights reserved.
Induced-Decay of Glycine Decarboxylase Transcripts as an Anticancer Therapeutic Strategy for Non-Small-Cell Lung Carcinoma

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Jing Lin

2017-12-01

Full Text Available Self-renewing tumor-initiating cells (TICs are thought to be responsible for tumor recurrence and chemo-resistance. Glycine decarboxylase, encoded by the GLDC gene, is reported to be overexpressed in TIC-enriched primary non-small-cell lung carcinoma (NSCLC. GLDC is a component of the mitochondrial glycine cleavage system, and its high expression is required for growth and tumorigenic capacity. Currently, there are no therapeutic agents against GLDC. As a therapeutic strategy, we have designed and tested splicing-modulating steric hindrance antisense oligonucleotides (shAONs that efficiently induce exon skipping (half maximal inhibitory concentration [IC50] at 3.5–7 nM, disrupt the open reading frame (ORF of GLDC transcript (predisposing it for nonsense-mediated decay, halt cell proliferation, and prevent colony formation in both A549 cells and TIC-enriched NSCLC tumor sphere cells (TS32. One candidate shAON causes 60% inhibition of tumor growth in mice transplanted with TS32. Thus, our shAONs candidates can effectively inhibit the expression of NSCLC-associated metabolic enzyme GLDC and may have promising therapeutic implications.
Conventional and novel stem cell based therapies for androgenic alopecia.

Science.gov (United States)

Talavera-Adame, Dodanim; Newman, Daniella; Newman, Nathan

2017-01-01

The prevalence of androgenic alopecia (AGA) increases with age and it affects both men and women. Patients diagnosed with AGA may experience decreased quality of life, depression, and feel self-conscious. There are a variety of therapeutic options ranging from prescription drugs to non-prescription medications. Currently, AGA involves an annual global market revenue of US$4 billion and a growth rate of 1.8%, indicating a growing consumer market. Although natural and synthetic ingredients can promote hair growth and, therefore, be useful to treat AGA, some of them have important adverse effects and unknown mechanisms of action that limit their use and benefits. Biologic factors that include signaling from stem cells, dermal papilla cells, and platelet-rich plasma are some of the current therapeutic agents being studied for hair restoration with milder side effects. However, most of the mechanisms exerted by these factors in hair restoration are still being researched. In this review, we analyze the therapeutic agents that have been used for AGA and emphasize the potential of new therapies based on advances in stem cell technologies and regenerative medicine.
Therapeutically engineered induced neural stem cells are tumour-homing and inhibit progression of glioblastoma

OpenAIRE

Bag?, Juli R.; Alfonso-Pecchio, Adolfo; Okolie, Onyi; Dumitru, Raluca; Rinkenbaugh, Amanda; Baldwin, Albert S.; Miller, C. Ryan; Magness, Scott T.; Hingtgen, Shawn D.

2016-01-01

Transdifferentiation (TD) is a recent advancement in somatic cell reprogramming. The direct conversion of TD eliminates the pluripotent intermediate state to create cells that are ideal for personalized cell therapy. Here we provide evidence that TD-derived induced neural stem cells (iNSCs) are an efficacious therapeutic strategy for brain cancer. We find that iNSCs genetically engineered with optical reporters and tumouricidal gene products retain the capacity to differentiate and induced ap...
Androgen-Forming Stem Leydig cells: Identification, Function and Therapeutic Potential

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Yunhui Zhang

2008-01-01

Full Text Available Leydig cells are the primary source of testosterone in the male, and differentiation of Leydig cells in the testes is one of the primary events in the development of the male body and fertility. Stem Leydig cells (SLCs exist in the testis throughout postnatal life, but a lack of cell surface markers previously hindered attempts to obtain purified SLC fractions. Once isolated, the properties of SLCs provide interesting clues for the ontogeny of these cells within the embryo. Moreover, the clinical potential of SLCs might be used to reverse age-related declines in testosterone levels in aging men, and stimulate reproductive function in hypogonadal males. This review focuses on the source, identification and outlook for therapeutic applications of SLCs. Separate pools of SLCs may give rise to fetal and adult generations of Leydig cell, which may account for their observed functional differences. These differences should in turn be taken into account when assessing the consequences of environmental pollutants such as the phthalate ester, diethylhexylphthalate (DEHP.
When exercise causes exertional rhabdomyolysis.

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Furman, Janet

2015-04-01

Exertional rhabdomyolysis is a clinical condition caused by intense, repetitive exercise or a sudden increase in exercise in an untrained person, although rhabdomyolysis can occur in trained athletes. In many cases, the presentation of early, uncomplicated rhabdomyolysis is subtle, but serious complications such as renal failure, compartment syndrome, and dysrhythmias may arise if severe exertional rhabdomyolysis is undiagnosed or untreated. Management is further complicated by the lack of concrete management guidelines for treating rhabdomyolysis and returning patients to activity.
Trans-differentiation of neural stem cells: a therapeutic mechanism against the radiation induced brain damage.

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Kyeung Min Joo

Full Text Available Radiation therapy is an indispensable therapeutic modality for various brain diseases. Though endogenous neural stem cells (NSCs would provide regenerative potential, many patients nevertheless suffer from radiation-induced brain damage. Accordingly, we tested beneficial effects of exogenous NSC supplementation using in vivo mouse models that received whole brain irradiation. Systemic supplementation of primarily cultured mouse fetal NSCs inhibited radiation-induced brain atrophy and thereby preserved brain functions such as short-term memory. Transplanted NSCs migrated to the irradiated brain and differentiated into neurons, astrocytes, or oligodendrocytes. In addition, neurotrophic factors such as NGF were significantly increased in the brain by NSCs, indicating that both paracrine and replacement effects could be the therapeutic mechanisms of NSCs. Interestingly, NSCs also differentiated into brain endothelial cells, which was accompanied by the restoration the cerebral blood flow that was reduced from the irradiation. Inhibition of the VEGF signaling reduced the migration and trans-differentiation of NSCs. Therefore, trans-differentiation of NSCs into brain endothelial cells by the VEGF signaling and the consequential restoration of the cerebral blood flow would also be one of the therapeutic mechanisms of NSCs. In summary, our data demonstrate that exogenous NSC supplementation could prevent radiation-induced functional loss of the brain. Therefore, successful combination of brain radiation therapy and NSC supplementation would provide a highly promising therapeutic option for patients with various brain diseases.
Potential antitumor therapeutic strategies of human amniotic membrane and amniotic fluid-derived stem cells.

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Kang, N-H; Hwang, K-A; Kim, S U; Kim, Y-B; Hyun, S-H; Jeung, E-B; Choi, K-C

2012-08-01

As stem cells are capable of self-renewal and can generate differentiated progenies for organ development, they are considered as potential source for regenerative medicine and tissue replacement after injury or disease. Along with this capacity, stem cells have the therapeutic potential for treating human diseases including cancers. According to the origins, stem cells are broadly classified into two types: embryonic stem cells (ESCs) and adult stem cells. In terms of differentiation potential, ESCs are pluripotent and adult stem cells are multipotent. Amnion, which is a membranous sac that contains the fetus and amniotic fluid and functions in protecting the developing embryo during gestation, is another stem cell source. Amnion-derived stem cells are classified as human amniotic membrane-derived epithelial stem cells, human amniotic membrane-derived mesenchymal stem cells and human amniotic fluid-derived stem cells. They are in an intermediate stage between pluripotent ESCs and lineage-restricted adult stem cells, non-tumorigenic, and contribute to low immunogenicity and anti-inflammation. Furthermore, they are easily available and do not cause any controversial issues in their recovery and applications. Not only are amnion-derived stem cells applicable in regenerative medicine, they have anticancer capacity. In non-engineered stem cells transplantation strategies, amnion-derived stem cells effectively target the tumor and suppressed the tumor growth by expressing cytotoxic cytokines. Additionally, they also have a potential as novel delivery vehicles transferring therapeutic genes to the cancer formation sites in gene-directed enzyme/prodrug combination therapy. Owing to their own advantageous properties, amnion-derived stem cells are emerging as a new candidate in anticancer therapy.
Triggering receptor expressed on myeloid cells 2 (TREM2): a potential therapeutic target for Alzheimer disease?

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Deming, Yuetiva; Li, Zeran; Benitez, Bruno A; Cruchaga, Carlos

2018-06-20

There are currently no effective therapeutics for Alzheimer disease (AD). Clinical trials targeting amyloid beta thus far have shown very little benefit and only in the earliest stages of disease. These limitations have driven research to identify alternative therapeutic targets, one of the most promising is the triggering receptor expressed on myeloid cells 2 (TREM2). Areas covered: Here, we review the literature to-date and discuss the potentials and pitfalls for targeting TREM2 as a potential therapeutic for AD. We focus on research in animal and cell models for AD and central nervous system injury models which may help in understanding the role of TREM2 in disease. Expert opinion: Studies suggest TREM2 plays a key role in AD pathology; however, results have been conflicting about whether TREM2 is beneficial or harmful. More research is necessary before designing TREM2-targeting therapies. Successful therapeutics will most likely be administered early in disease.
Cell-based Therapy for Acute Organ Injury: Preclinical Evidence and On-going Clinical Trials Using Mesenchymal Stem Cells

Science.gov (United States)

Monsel, Antoine; Zhu, Ying-gang; Gennai, Stephane; Hao, Qi; Liu, Jia; Lee, Jae W.

2014-01-01

Critically ill patients often suffer from multiple organ failures involving lung, kidney, liver or brain. Genomic, proteomic and metabolomic approaches highlight common injury mechanisms leading to acute organ failure. This underlines the need to focus on therapeutic strategies affecting multiple injury pathways. The use of adult stem cells such as mesenchymal stem or stromal cells (MSC) may represent a promising new therapeutic approach as increasing evidence shows that MSC can exert protective effects following injury through the release of pro-mitotic, anti-apoptotic, anti-inflammatory and immunomodulatory soluble factors. Furthermore, they can mitigate metabolomic and oxidative stress imbalance. In this work, we review the biological capabilities of MSC and the results of clinical trials using MSC as therapy in acute organ injuries. Although preliminary results are encouraging, more studies concerning safety and efficacy of MSC therapy are needed to determine their optimal clinical use. PMID:25211170
Toxoplasmosis Complications and Novel Therapeutic Synergism Combination of Diclazuril plus Atovaquone

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Helieh S Oz

2014-09-01

Full Text Available Toxoplasmosis is a major cause of foodborne disease, congenital complication and morbidity. There is an urgent need for safe and effective therapies to encounter congenital and persisting toxoplasmosis. The hypothesis was: Combination Diclazuril plus Atovaquone to exert a novel therapeutic synergy to prevent toxoplasmosis syndromes. Methods. Pregnant dams were treated with Diclazuril and Atovaquone monotherapy or combination therapy and infected intraperitoneally with Toxoplasma tachyzoites (600. Results. Infected dams developed severe toxoplasmosis associated syndrome with increases in the abdominal adiposity surrounding uteri, gansterointestinal and other internal organs and excessive weight gain. Numerous organisms along with infiltration of inflammatory cells were detected scattered into adipose tissues. Combination therapy (p< 0.01 and to a lesser extent Diclazuril (p< 0.05 protected dams from inflammatory fat and excess weight gains. This was consistent with pancreatitis development in infected dams (versus normal p< 0.05 with infiltration of inflammatory cells, degeneration and necrosis of pancreatic cells followed by the degeneration and loss of islets. Combination and monotherapy protected dams from these inflammatory and pathological aspects of pancreatitis. Infected dams exhibited severe colitis, and colonic tissues significantly shortened in length. Brush border epithelial cells were replaced with infiltration of lymphocytes, granulocytes, and microabscess formations into cryptic microstructures. Combination therapy synergistically preserved colonic structure and normalized pathological damages (p< 0.001 and to a lesser degree Diclazuril monotherapy protected dams from colitis (p< 0.05 and gastrointestinal toxoplasmosis. Other complications included severe splenitis (p<0.001 and hepatitis (p<0.001 which were normalized with combination therapy. Conclusions. Combination Diclazuril plus Atovaquone was safe and with a novel therapeutic
Ran GTPase-activating protein 1 is a therapeutic target in diffuse large B-cell lymphoma.

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Kung-Chao Chang

Full Text Available Lymphoma-specific biomarkers contribute to therapeutic strategies and the study of tumorigenesis. Diffuse large B-cell lymphoma (DLBCL is the most common type of malignant lymphoma. However, only 50% of patients experience long-term survival after current treatment; therefore, developing novel therapeutic strategies is warranted. Comparative proteomic analysis of two DLBCL lines with a B-lymphoblastoid cell line (LCL showed differential expression of Ran GTPase-activating protein 1 (RanGAP1 between them, which was confirmed using immunoblotting. Immunostaining showed that the majority of DLBCLs (92%, 46/50 were RanGAP1(+, while reactive lymphoid hyperplasia (n = 12 was RanGAP1(+ predominantly in germinal centers. RanGAP1 was also highly expressed in other B-cell lymphomas (BCL, n = 180 with brisk mitotic activity (B-lymphoblastic lymphoma/leukemia: 93%, and Burkitt lymphoma: 95% or cell-cycle dysregulation (mantle cell lymphoma: 83%, and Hodgkin's lymphoma 91%. Interestingly, serum RanGAP1 level was higher in patients with high-grade BCL (1.71 ± 2.28 ng/mL, n = 62 than in low-grade BCL (0.75 ± 2.12 ng/mL, n = 52 and healthy controls (0.55 ± 1.58 ng/mL, n = 75 (high-grade BCL vs. low-grade BCL, p = 0.002; high-grade BCL vs. control, p < 0.001, Mann-Whitney U test. In vitro, RNA interference of RanGAP1 showed no effect on LCL but enhanced DLBCL cell death (41% vs. 60%; p = 0.035 and cell-cycle arrest (G0/G1: 39% vs. 49%, G2/M: 19.0% vs. 7.5%; p = 0.030 along with decreased expression of TPX2 and Aurora kinases, the central regulators of mitotic cell division. Furthermore, ON 01910.Na (Estybon, a multikinase inhibitor induced cell death, mitotic cell arrest, and hyperphosphorylation of RanGAP1 in DLBCL cell lines but no effects in normal B and T cells. Therefore, RanGAP1 is a promising marker and therapeutic target for aggressive B-cell lymphoma, especially DLBCL.
Therapeutic cloning in individual parkinsonian mice

Science.gov (United States)

Tabar, Viviane; Tomishima, Mark; Panagiotakos, Georgia; Wakayama, Sayaka; Menon, Jayanthi; Chan, Bill; Mizutani, Eiji; Al-Shamy, George; Ohta, Hiroshi; Wakayama, Teruhiko; Studer, Lorenz

2009-01-01

Cell transplantation with embryonic stem (ES) cell progeny requires immunological compatibility with host tissue. ‘Therapeutic cloning’ is a strategy to overcome this limitation by generating nuclear transfer (nt)ES cells that are genetically matched to an individual. Here we establish the feasibility of treating individual mice via therapeutic cloning. Derivation of 187 ntES cell lines from 24 parkinsonian mice, dopaminergic differentiation, and transplantation into individually matched host mice showed therapeutic efficacy and lack of immunological response. PMID:18376409
Experimental Methodology used by Cell Cultures Laboratory from INRMFB to assess the therapeutic effect of natural factors

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Munteanu Constantin

2010-11-01

Full Text Available The experimental study design on cell cultures allows the direct biological evaluation at the cellular level, of the therapeutic effect that natural factors can play over the organism.Techniques for obtaining cell cultures requires a complex and laborious task that starts from live tissue sampling, continuous with isolation of cells and their preparation for sowing a culture plate. This preparation involves mechanical and enzymatic action from the researcher on biological material. Derived cell cultures are monitored morphologically by high-performance inverted biological microscope, with video camera for image acquisition. In the final stage, the cells are scraped, and through biochemical and molecular techniques, the therapeutic efficiency hypothesis of the investigated natural factor is verified experimentally. The cell cultures can be crioconservated in special containers with liquid nitrogen.
Therapeutic potential of CAR-T cell-derived exosomes: a cell-free modality for targeted cancer therapy.

Science.gov (United States)

Tang, Xiang-Jun; Sun, Xu-Yong; Huang, Kuan-Ming; Zhang, Li; Yang, Zhuo-Shun; Zou, Dan-Dan; Wang, Bin; Warnock, Garth L; Dai, Long-Jun; Luo, Jie

2015-12-29

Chimeric antigen receptor (CAR)-based T-cell adoptive immunotherapy is a distinctively promising therapy for cancer. The engineering of CARs into T cells provides T cells with tumor-targeting capabilities and intensifies their cytotoxic activity through stimulated cell expansion and enhanced cytokine production. As a novel and potent therapeutic modality, there exists some uncontrollable processes which are the potential sources of adverse events. As an extension of this impactful modality, CAR-T cell-derived exosomes may substitute CAR-T cells to act as ultimate attackers, thereby overcoming some limitations. Exosomes retain most characteristics of parent cells and play an essential role in intercellular communications via transmitting their cargo to recipient cells. The application of CAR-T cell-derived exosomes will make this cell-based therapy more clinically controllable as it also provides a cell-free platform to diversify anticancer mediators, which responds effectively to the complexity and volatility of cancer. It is believed that the appropriate application of both cellular and exosomal platforms will make this effective treatment more practicable.
IL-7 and CCL19 expression in CAR-T cells improves immune cell infiltration and CAR-T cell survival in the tumor.

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Adachi, Keishi; Kano, Yosuke; Nagai, Tomohiko; Okuyama, Namiko; Sakoda, Yukimi; Tamada, Koji

2018-04-01

Infiltration, accumulation, and survival of chimeric antigen receptor T (CAR-T) cells in solid tumors is crucial for tumor clearance. We engineered CAR-T cells to express interleukin (IL)-7 and CCL19 (7 × 19 CAR-T cells), as these factors are essential for the maintenance of T-cell zones in lymphoid organs. In mice, 7 × 19 CAR-T cells achieved complete regression of pre-established solid tumors and prolonged mouse survival, with superior anti-tumor activity compared to conventional CAR-T cells. Histopathological analyses showed increased infiltration of dendritic cells (DC) and T cells into tumor tissues following 7 × 19 CAR-T cell therapy. Depletion of recipient T cells before 7 × 19 CAR-T cell administration dampened the therapeutic effects of 7 × 19 CAR-T cell treatment, suggesting that CAR-T cells and recipient immune cells collaborated to exert anti-tumor activity. Following treatment of mice with 7 × 19 CAR-T cells, both recipient conventional T cells and administered CAR-T cells generated memory responses against tumors.
Potential of Stem Cell-Based Therapy for Ischemic Stroke

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Hany E. Marei

2018-02-01

Full Text Available Ischemic stroke is one of the major health problems worldwide. The only FDA approved anti-thrombotic drug for acute ischemic stroke is the tissue plasminogen activator. Several studies have been devoted to assessing the therapeutic potential of different types of stem cells such as neural stem cells (NSCs, mesenchymal stem cells, embryonic stem cells, and human induced pluripotent stem cell-derived NSCs as treatments for ischemic stroke. The results of these studies are intriguing but many of them have presented conflicting results. Additionally, the mechanism(s by which engrafted stem/progenitor cells exert their actions are to a large extent unknown. In this review, we will provide a synopsis of different preclinical and clinical studies related to the use of stem cell-based stroke therapy, and explore possible beneficial/detrimental outcomes associated with the use of different types of stem cells. Due to limited/short time window implemented in most of the recorded clinical trials about the use of stem cells as potential therapeutic intervention for stroke, further clinical trials evaluating the efficacy of the intervention in a longer time window after cellular engraftments are still needed.

Fetal stem cells and skeletal muscle regeneration: a therapeutic approach

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Michela ePozzobon

2014-08-01

Full Text Available More than 40% of the body mass is represented by muscle tissue, which possesses the innate ability to regenerate after damage through the activation of muscle specific stem cell, namely satellite cells. Muscle diseases, in particular chronic degenerative state of skeletal muscle such as dystrophies, lead to a perturbation of the regenerative process, which causes the premature exhaustion of satellite cell reservoir due to continue cycles of degeneration/regeneration. Nowadays, the research is focused on different therapeutic approaches, ranging from gene and cell to pharmacological therapy, but still there is not a definitive cure in particular for genetic muscle disease. Taking this in mind, in this article we will give special consideration to muscle diseases and the use of fetal derived stem cells as new approach for therapy. Cells of fetal origin, from cord blood to placenta and amniotic fluid, can be easily obtained without ethical concern, expanded and differentiated in culture, and possess immunemodulatory properties. The in vivo approach in animal models can be helpful to study the mechanism underneath the operating principle of the stem cell reservoir, namely the niche, which holds great potential to understand the onset of muscle pathologies.
New Therapeutic Approaches to Prevent or Delay Beta-Cell Failure in Diabetes

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Ionica Floriana Elvira

2015-09-01

Full Text Available Background and aims: The most recent estimates of International Diabetes Federation indicate that 382 million people have diabetes, and the incidence of this disease is increasing. While in type 1 diabetes mellitus (T1DM beta-cell death is autoimmunemediated, type 2 diabetes mellitus (T2DM results from an interaction between genetic and environmental factors that impair beta-cell function and insulin action. Many people with T2DM remain unaware of their illness for a long time because symptoms may take years to appear or be recognized, while the body is affected by excess blood glucose. These patients are often diagnosed only when diabetes complications have already developed. The aim of this article was to perform a review based on literature data on therapeutic modalities to prevent/delay beta cell function decline. Material and Methods: We searched MEDLINE from 2000 to the present to identify the therapeutic approaches to prevent or delay beta-cell failure in patients with T2DM. Results and conclusions: Several common polymorphisms in genes linked to monogenic forms of diabetes appear to influence the response to T2DM pharmacotherapy. Recent studies report the role of the G protein coupled receptor 40 (GPR40, also known as Free Fatty Acids Receptor 1 (FFAR1 in the regulation of beta-cell function- CNX-011-67 (a GPR40 agonist has the potential to provide good and durable glycemic control in T2DM patients.
A single exercise bout augments adenovirus-specific T-cell mobilization and function.

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Kunz, Hawley E; Spielmann, Guillaume; Agha, Nadia H; O'Connor, Daniel P; Bollard, Catherine M; Simpson, Richard J

2018-04-30

Adoptive transfer of virus-specific T-cells (VSTs) effectively treats viral infections following allogeneic hematopoietic stem cell transplantation (alloHSCT), but logistical difficulties have limited widespread availability of VSTs as a post-transplant therapeutic. A single exercise bout mobilizes VSTs specific for latent herpesviruses (i.e. CMV and EBV) to peripheral blood and augments their ex vivo expansion. We investigated whether exercise exerts similar effects on T-cells specific for a NON-latent virus such as adenovirus, which is a major contributor to infection-related morbidity and mortality after alloHSCT. Thirty minutes of cycling exercise increased circulating adenovirus-specific T-cells 2.0-fold and augmented their ex vivo expansion by ~33% compared to rest without altering antigen and MHC-specific autologous target cell killing capabilities. We conclude that exercise is a simple and economical adjuvant to boost the isolation and manufacture of therapeutic VSTs specific to latent and non-latent viruses from healthy donors. Copyright © 2018. Published by Elsevier Inc.
Glioblastoma: Molecular Pathways, Stem Cells and Therapeutic Targets

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Jhanwar-Uniyal, Meena; Labagnara, Michael; Friedman, Marissa; Kwasnicki, Amanda; Murali, Raj

2015-01-01

Glioblastoma (GBM), a WHO-defined Grade IV astrocytoma, is the most common and aggressive CNS malignancy. Despite current treatment modalities, the survival time remains dismal. The main cause of mortality in patients with this disease is reoccurrence of the malignancy, which is attributed to treatment-resistant cancer stem cells within and surrounding the primary tumor. Inclusion of novel therapies, such as immuno- and DNA-based therapy, may provide better means of treating GBM. Furthermore, manipulation of recently discovered non-coding microRNAs, some of which regulate tumor growth through the development and maintenance of GBM stem cells, could provide new prospective therapies. Studies conducted by The Cancer Genome Atlas (TCGA) also demonstrate the role of molecular pathways, specifically the activated PI3K/AKT/mTOR pathway, in GBM tumorigenesis. Inhibition of the aforementioned pathway may provide a more direct and targeted method to GBM treatment. The combination of these treatment modalities may provide an innovative therapeutic approach for the management of GBM
Novel therapeutic options for relapsed hairy cell leukemia.

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Jain, Preetesh; Polliack, Aaron; Ravandi, Farhad

2015-01-01

The majority of patients with hairy cell leukemia (HCL) achieve a response to therapy with cladribine or pentostatin with or without rituximab. However, late relapses can occur. Treatment of relapsed HCL can be difficult due to a poor tolerance to chemotherapy, increased risk of infections and decreased responsiveness to chemotherapy. The identification of BRAFV600E mutations and the role of aberrant MEK kinase and Bruton's tyrosine kinase (BTK) pathways in the pathogenesis of HCL have helped to develop novel targeted therapies for these patients. Currently, the most promising therapeutic strategies for relapsed or refractory HCL include recombinant immunoconjugates targeting CD22 (e.g. moxetumomab pasudotox), BRAF inhibitors such as vemurafenib and B cell receptor signaling kinase inhibitors such as ibrutinib. Furthermore, the VH4-34 molecular variant of classic HCL has been identified to be less responsive to chemotherapy. Herein, we review the results of the ongoing clinical trials and potential future therapies for relapsed/refractory HCL.
Glioblastoma: Molecular Pathways, Stem Cells and Therapeutic Targets

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Jhanwar-Uniyal, Meena, E-mail: meena_jhanwar@nymc.edu; Labagnara, Michael; Friedman, Marissa; Kwasnicki, Amanda; Murali, Raj [Department of Neurosurgery, New York Medical College, Valhalla, NY 10595 (United States)

2015-03-25

Glioblastoma (GBM), a WHO-defined Grade IV astrocytoma, is the most common and aggressive CNS malignancy. Despite current treatment modalities, the survival time remains dismal. The main cause of mortality in patients with this disease is reoccurrence of the malignancy, which is attributed to treatment-resistant cancer stem cells within and surrounding the primary tumor. Inclusion of novel therapies, such as immuno- and DNA-based therapy, may provide better means of treating GBM. Furthermore, manipulation of recently discovered non-coding microRNAs, some of which regulate tumor growth through the development and maintenance of GBM stem cells, could provide new prospective therapies. Studies conducted by The Cancer Genome Atlas (TCGA) also demonstrate the role of molecular pathways, specifically the activated PI3K/AKT/mTOR pathway, in GBM tumorigenesis. Inhibition of the aforementioned pathway may provide a more direct and targeted method to GBM treatment. The combination of these treatment modalities may provide an innovative therapeutic approach for the management of GBM.
The Therapeutic Effect of Human Embryonic Stem Cell-Derived Multipotent Mesenchymal Stem Cells on Chemical-Induced Cystitis in Rats

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Sang Wook Lee

2018-01-01

Full Text Available Purpose To evaluate the therapeutic effect of human embryonic stem cell (hESC-derived multipotent mesenchymal stem cells (M-MSCs on ketamine-induced cystitis (KC in rats. Methods To induce KC, 10-week-old female rats were injected with 25-mg/kg ketamine hydrochloride twice weekly for 12 weeks. In the sham group, phosphate buffered saline (PBS was injected instead of ketamine. One week after the final injection of ketamine, the indicated doses (0.25, 0.5, and 1×106 cells of M-MSCs (KC+M-MSC group or PBS vehicle (KC group were directly injected into the bladder wall. One week after M-MSC injection, the therapeutic outcomes were evaluated via cystometry, histological analyses, and measurement of gene expression. Next, we compared the efficacy of M-MSCs at a low dose (1×105 cells to that of an identical dose of adult bone marrow (BM-derived MSCs. Results Rats in the KC group exhibited increased voiding frequency and reduced bladder capacity compared to rats of the sham group. However, these parameters recovered after transplantation of M-MSCs at all doses tested. KC bladders exhibited markedly increased mast cell infiltration, apoptosis, and tissue fibrosis. Administration of M-MSCs significantly reversed these characteristic histological alterations. Gene expression analyses indicated that several genes associated with tissue fibrosis were markedly upregulated in KC bladders. However the expression of these genes was significantly suppressed by the administration of M-MSCs. Importantly, M-MSCs ameliorated bladder deterioration in KC rats after injection of a low dose (1×105 of cells, at which point BM-derived MSCs did not substantially improve bladder function. Conclusions This study demonstrates for the first time the therapeutic efficacy of hESC-derived M-MSCs on KC in rats. M-MSCs restored bladder function more effectively than did BM-derived MSCs, protecting against abnormal changes including mast cell infiltration, apoptosis and fibrotic
Identification of unique expression signatures and therapeutic targets in esophageal squamous cell carcinoma

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Yan Wusheng

2012-01-01

Full Text Available Abstract Background Esophageal squamous cell carcinoma (ESCC, the predominant histological subtype of esophageal cancer, is characterized by high mortality. Previous work identified important mRNA expression differences between normal and tumor cells; however, to date there are limited ex vivo studies examining expression changes occurring during normal esophageal squamous cell differentiation versus those associated with tumorigenesis. In this study, we used a unique tissue microdissection strategy and microarrays to measure gene expression profiles associated with cell differentiation versus tumorigenesis in twelve cases of patient-matched normal basal squamous epithelial cells (NB, normal differentiated squamous epithelium (ND, and squamous cell cancer. Class comparison and pathway analysis were used to compare NB versus tumor in a search for unique therapeutic targets. Results As a first step towards this goal, gene expression profiles and pathways were evaluated. Overall, ND expression patterns were markedly different from NB and tumor; whereas, tumor and NB were more closely related. Tumor showed a general decrease in differentially expressed genes relative to NB as opposed to ND that exhibited the opposite trend. FSH and IgG networks were most highly dysregulated in normal differentiation and tumorigenesis, respectively. DNA repair pathways were generally elevated in NB and tumor relative to ND indicating involvement in both normal and pathological growth. PDGF signaling pathway and 12 individual genes unique to the tumor/NB comparison were identified as therapeutic targets, and 10 associated ESCC gene-drug pairs were identified. We further examined the protein expression level and the distribution patterns of four genes: ODC1, POSTN, ASPA and IGF2BP3. Ultimately, three genes (ODC1, POSTN, ASPA were verified to be dysregulated in the same pattern at both the mRNA and protein levels. Conclusions These data reveal insight into genes and
PRGF exerts more potent proliferative and anti-inflammatory effects than autologous serum on a cell culture inflammatory model.

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Anitua, E; Muruzabal, F; de la Fuente, M; Riestra, A; Merayo-Lloves, J; Orive, G

2016-10-01

Ocular graft versus host disease (oGVHD) is part of a systemic inflammatory disease that usually affects ocular surface tissues manifesting as a dry eye syndrome. Current treatments provide unsatisfactory results. Blood-derived products, like plasma rich in growth factors (PRGF) emerge as a potential therapy for this disease. The purpose of this study was to evaluate the tissue regeneration and anti-inflammatory capability of PRGF, an autologous platelet enriched plasma eye-drop, compared to autologous serum (AS) obtained from oGVHD patients on ocular surface cells cultured in a pro-inflammatory environment. PRGF and AS were obtained from four GVHD patients. Cell proliferation and inflammation markers, intercellular adhesion molecule-1 (ICAM-1) and cyclooxygenase-2 (COX-2), were measured in corneal and conjunctival fibroblastic cells cultured under pro-inflammatory conditions and after treatment with PRGF or AS eye drops. Moreover, cell proliferation increased after treatment with PRGF and AS, though this enhancement in the case of keratocytes was significantly higher with PRGF. PRGF eye drops showed a significant reduction of both inflammatory markers with respect to the initial inflammatory situation and to the AS treatment. Our results concluded that PRGF exerts more potent regenerative and anti-inflammatory effects than autologous serum on ocular surface fibroblasts treated with pro-inflammatory IL-1β and TNFα. Copyright © 2016 Elsevier Ltd. All rights reserved.
Prophylactic and therapeutic adenoviral vector-based multivirus-specific T-cell immunotherapy for transplant patients

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Vijayendra Dasari

2016-01-01

Full Text Available Viral infections including cytomegalovirus, Epstein-Barr virus, adenovirus, and BK virus are a common and predictable problem in transplant recipients. While cellular immune therapies have been successfully used to tackle infectious complications in transplant recipients, manufacturing immunotherapies to address the multitude of possible pathogens can be technically challenging and labor-intensive. Here we describe a novel adenoviral antigen presentation platform (Ad-MvP as a tool for rapid generation of multivirus-specific T-cells in a single step. Ad-MvP encodes 32 CD8+ T-cell epitopes from cytomegalovirus, Epstein-Barr virus, adenovirus, and BK virus as a contiguous polyepitope. We demonstrate that Ad-MvP vector can be successfully used for rapid in vitro expansion of multivirus-specific T-cells from transplant recipients and in vivo priming of antiviral T-cell immunity. Most importantly, using an in vivo murine model of Epstein-Barr virus-induced lymphoma, we also show that adoptive immunotherapy with Ad-MvP expanded autologous and allogeneic multivirus-specific T-cells is highly effective in controlling Epstein-Barr virus tumor outgrowth and improving overall survival. We propose that Ad-MvP has wide ranging therapeutic applications in greatly facilitating in vivo priming of antiviral T-cells, the generation of third-party T-cell banks as “off-the-shelf” therapeutics as well as autologous T-cell therapies for transplant patients.
Ibuprofen delivered by poly(lactic-co-glycolic acid (PLGA nanoparticles to human gastric cancer cells exerts antiproliferative activity at very low concentrations

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Bonelli P

2012-11-01

concentration at 24 hours. The inhibition of proliferation was confirmed to be due to the intracellular release of ibuprofen from the NPs. Using PLGA NPs as carriers, ibuprofen exerted an antiproliferative activity at concentrations > 100 times less than free ibuprofen, suggesting greater efficiency and less cellular toxicity. In addition, when carried by PLGA NPs, ibuprofen more quickly induced the expression of transcripts involved in proliferation and invasiveness processes.Conclusion: Ibuprofen exerted an antiproliferative effect on MKN-45 cells at low concentrations. This effect was achieved using PLGA NPs as carriers of low doses of ibuprofen.Keywords: nonsteroidal anti-inflammatory drug (NSAID, proliferation, uptake, MKN-45 cells
Evaluation of somatostatin and nucleolin receptors for therapeutic delivery in non-small cell lung cancer stem cells applying the somatostatin-analog DOTATATE and the nucleolin-targeting aptamer AS1411.

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Sif Holmboe

Full Text Available Cancer stem cells represent the putative tumor-driving subpopulation thought to account for drug resistance, relapse, and metastatic spread of epithelial and other cancer types. Accordingly, cell surface markers for therapeutic delivery to cancer stem cells are subject of intense research. Somatostatin receptor 2 and nucleolin are known to be overexpressed by various cancer types, which have elicited comprehensive efforts to explore their therapeutic utilization. Here, we evaluated somatostatin receptor 2 targeting and nucleolin targeting for therapeutic delivery to cancer stem cells from lung cancer. Nucleolin is expressed highly but not selectively, while somatostatin receptor 2 is expressed selectively but not highly by cancer cells. The non-small cell lung cancer cell lines A549 and H1299, displayed average levels of both surface molecules as judged based on analysis of a larger cell line panel. H1299 compared to A549 cells showed significantly elevated sphere-forming capacity, indicating higher cancer stem cell content, thus qualifying as suitable test system. Nucleolin-targeting 57Co-DOTA-AS1411 aptamer showed efficient internalization by cancer cells and, remarkably, at even higher efficiency by cancer stem cells. In contrast, somatostatin receptor 2 expression levels were not sufficiently high in H1299 cells to confer efficient uptake by either non-cancer stem cells or cancer stem cells. The data provides indication that the nucleolin-targeting AS1411 aptamer might be used for therapeutic delivery to non-small cell lung cancer stem cells.
Primary nodal peripheral T-cell lymphomas: diagnosis and therapeutic considerations

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Luis Alberto de Pádua Covas Lage

2015-08-01

Full Text Available Nodal peripheral T-cell lymphomas are a rare group of neoplasms derived from post-thymic and activated T lymphocytes. A review of scientific articles listed in PubMed, Lilacs, and the Cochrane Library databases was performed using the term "peripheral T-cell lymphomas". According to the World Health Organization classification of hematopoietic tissue tumors, this group of neoplasms consists of peripheral T-cell lymphoma not otherwise specified (PTCL-NOS, angioimmunoblastic T-cell lymphoma (AITL, anaplastic large cell lymphoma-anaplastic lymphoma kinase positive (ALCL-ALK+, and a provisional entity called anaplastic large cell lymphoma-anaplastic lymphoma kinase negative (ALCL-ALK-. Because the treatment and prognoses of these neoplasms involve different principles, it is essential to distinguish each one by its clinical, immunophenotypic, genetic, and molecular features. Except for anaplastic large cell lymphoma-anaplastic lymphoma kinase positive, which has no adverse international prognostic index, the prognosis of nodal peripheral T-cell lymphomas is worse than that of aggressive B-cell lymphomas. Chemotherapy based on anthracyclines provides poor outcomes because these neoplasms frequently have multidrug-resistant phenotypes. Based on this, the current tendency is to use intensified cyclophosphamide, doxorubicin, vincristine, prednisolone (CHOP regimens with the addition of new drugs, and autologous hematopoietic stem cell transplantation. This paper describes the clinical features and diagnostic methods, and proposes a therapeutic algorithm for nodal peripheral T-cell lymphoma patients.
Neural induction with neurogenin 1 enhances the therapeutic potential of mesenchymal stem cells in an amyotrophic lateral sclerosis mouse model.

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Chan-Il, Choi; Young-Don, Lee; Heejaung, Kim; Kim, Seung Hyun; Suh-Kim, Haeyoung; Kim, Sung-Soo

2013-01-01

Amyotrophic lateral sclerosis (ALS) is characterized by progressive dysfunction and degeneration of motor neurons in the central nervous system (CNS). In the absence of effective drug treatments for ALS, stem cell treatment has emerged as a candidate therapy for this disease. To date, however, there is no consensus protocol that stipulates stem cell types, transplantation timing, or frequency. Using an ALS mouse model carrying a high copy number of a mutant human superoxide dismutase-1 (SOD1)(G93A) transgene, we investigated the effect of neural induction on the innate therapeutic potential of mesenchymal stem cells (MSCs) in relation to preclinical transplantation parameters. In our study, the expression of monocyte chemoattractant protein-1 (MCP-1) was elevated in the ALS mouse spinal cord. Neural induction of MSCs with neurogenin 1 (Ngn1) upregulated the expression level of the MCP-1 receptor, CCR2, and enhanced the migration activity toward MCP-1 in vitro. Ngn1-expressing MSCs (MSCs-Ngn1) showed a corresponding increase in tropism to the CNS after systemic transplantation in ALS mice. Notably, MSCs-Ngn1 delayed disease onset if transplanted during preonset ages,whereas unprocessed MSCs failed to do so. If transplanted near the onset ages, a single treatment with MSCs-Ngn1 was sufficient to enhance motor functions during the symptomatic period (15–17 weeks), whereas unprocessed MSCs required repeated transplantation to achieve similar levels of motor function improvement. Our data indicate that systemically transplanted MSCs-Ngn1 can migrate to the CNS and exert beneficial effects on host neural cells for an extended period of time through paracrine functions, suggesting a potential benefit of neural induction of transplanted MSCs in long-term treatment of ALS.
CIMAvax-EGF®: Therapeutic Vaccine Against Non-small Cell Lung Cancer in Advanced Stages

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Diana Rosa Fernández Ruiz

2017-02-01

Full Text Available Biotechnology is one of the scientific activities deployed by the Cuban State, which shows greater results and impact on the of the Cuban population health. It has increased the therapeutic repertoire in dealing with oncological diseases with products such as CIMAvax-EGF®, the first therapeutic vaccine of its kind, from the Molecular Immunology Center, against non-small cell lung cancer in advanced stages IIIB IV. The application of this product already extends to Primary Health Care with encouraging results, by prolonging the survival of patients with higher quality of life.
Anti-inflammatory effect of transduced PEP-1-heme oxygenase-1 in Raw 264.7 cells and a mouse edema model

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Kwon, Soon Won; Sohn, Eun Jeong; Kim, Dae Won; Jeong, Hoon Jae; Kim, Mi Jin; Ahn, Eun Hee; Kim, Young Nam; Dutta, Suman; Kim, Duk-Soo; Park, Jinseu; Eum, Won Sik; Hwang, Hyun Sook; Choi, Soo Young

2011-01-01

Highlights: → Recombinant PEP-1 heme oxygenase-1 expression vector was constructed and overexpressed. → We investigated transduction efficiency of PEP-1-HO-1 protein in Raw 264.7 cells. → PEP-1-HO-1 was efficiently transduced into Raw 264.7 cells in a dose and time dependent manner. → PEP-1-HO-1 exerted anti-inflammatory activity in Raw 264.7 cells and in a mice edema model. → PEP-1-HO-1 could be used as a therapeutic drug against inflammatory diseases. -- Abstract: Heme oxygenase-1 (HO-1), which catalyzes the degradation of free heme to biliverdin, carbon monoxide (CO), and free iron (Fe 2+ ), is up-regulated by several cellular stress and cell injuries, including inflammation, ischemia and hypoxia. In this study, we examined whether fusion of HO-1 with PEP-1, a protein transduction domain that is able to deliver exogenous molecules to living cells or tissues, would facilitate HO-1 delivery to target cells and tissues, and thereby effectively exert a therapeutically useful response against inflammation. Western blot analysis demonstrated that PEP-1-HO-1 fusion proteins were transduced into Raw 264.7 cells in time- and dose-dependent manners, and were stably maintained in the cells for about 60 h. In addition, fluorescence analysis revealed that only PEP-1-HO-1 fusion proteins were significantly transduced into the cytoplasm of cells, while HO-1 proteins failed to be transduced. In lipopolysaccharide (LPS)-stimulated Raw 264.7 cells and 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced mouse edema model, transduced PEP-1-HO-1 fusion proteins effectively inhibited the overexpression of pro-inflammatory mediators and cytokines. Also, histological analysis demonstrated that PEP-1-HO-1 remarkably suppressed ear edema. The results suggest that the PEP-1-HO-1 fusion protein can be used as a therapeutic molecule against reactive oxygen species-related inflammatory diseases.
Hormone Use for Therapeutic Amenorrhea and Contraception During Hematopoietic Cell Transplantation

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Chang, Katherine; Merideth, Melissa A.; Stratton, Pamela

2015-01-01

There is a growing population of women who have or will undergo hematopoietic stem cell transplant for a variety of malignant and benign conditions. Gynecologists play an important role in addressing the gynecologic and reproductive health concerns for these women throughout the transplant process. As women undergo cell transplantation, they should avoid becoming pregnant and are at risk of uterine bleeding. Thus, counseling about and implementing hormonal treatments such as gonadotropin-releasing hormone agonists, combined hormonal contraceptives, and progestin-only methods help to achieve therapeutic amenorrhea and can serve as contraception during the peritransplant period. In this commentary, we summarize the timing, risks and benefits of the hormonal options just prior, during and for the year after hematopoietic stem cell transplantation. PMID:26348182
Cell-derived microparticles: new targets in the therapeutic management of disease.

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Roseblade, Ariane; Luk, Frederick; Rawling, Tristan; Ung, Alison; Grau, Georges E R; Bebawy, Mary

2013-01-01

Intercellular communication is essential to maintain vital physiological activities and to regulate the organism's phenotype. There are a number of ways in which cells communicate with one another. This can occur via autocrine signaling, endocrine signaling or by the transfer of molecular mediators across gap junctions. More recently communication via microvesicular shedding has gained important recognition as a significant pathway by which cells can coordinate the spread and dominance of selective traits within a population. Through this communication apparatus, cells can now acquire and secure a survival advantage, particularly in the context of malignant disease. This review aims to highlight some of the functions and implications of microparticles in physiology of various disease states, and present a novel therapeutic strategy through the regulation of microparticle production.
Recruiting endogenous stem cells: a novel therapeutic approach for erectile dysfunction

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Zhong-Cheng Xin

2016-01-01

Full Text Available Transplanted stem cells (SCs, owing to their regenerative capacity, represent one of the most promising methods to restore erectile dysfunction (ED. However, insufficient source, invasive procedures, ethical and regulatory issues hamper their use in clinical applications. The endogenous SCs/progenitor cells resident in organ and tissues play critical roles for organogenesis during development and for tissue homeostasis in adulthood. Even without any therapeutic intervention, human body has a robust self-healing capability to repair the damaged tissues or organs. Therefore, SCs-for-ED therapy should not be limited to a supply-side approach. The resident endogenous SCs existing in patients could also be a potential target for ED therapy. The aim of this review was to summarize contemporary evidence regarding: (1 SC niche and SC biological features in vitro; (2 localization and mobilization of endogenous SCs; (3 existing evidence of penile endogenous SCs and their possible mode of mobilization. We performed a search on PubMed for articles related to these aspects in a wide range of basic studies. Together, numerous evidences hold the promise that endogenous SCs would be a novel therapeutic approach for the therapy of ED.
Natural Killer (NK- and T-Cell Engaging Antibody-Derived Therapeutics

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Christoph Stein

2012-06-01

Full Text Available Unmodified antibodies (abs have been successful in the treatment of hematologic malignancies, but less so for the treatment of solid tumors. They trigger anti-tumor effects through their Fc-domains, and one way to improve their efficacy is to optimize their interaction with the effectors through Fc-engineering. Another way to empower abs is the design of bispecific abs and related fusion proteins allowing a narrower choice of effector cells. Here we review frequently chosen classes of effector cells, as well as common trigger molecules. Natural Killer (NK- and T-cells are the most investigated populations in therapeutical approaches with bispecific agents until now. Catumaxomab, the first bispecific ab to receive drug approval, targets the tumor antigen Epithelial Cell Adhesion Molecule (EpCAM and recruits T-cells via a binding site for the cell surface protein CD3. The next generation of recombinant ab-derivatives replaces the broadly reactive Fc-domain by a binding domain for a single selected trigger. Blinatumomab is the first clinically successful member of this class, targeting cancer cells via CD19 and engaging T-cells by CD3. Other investigators have developed related recombinant fusion proteins to recruit effectors, such as NK-cells and macrophages. The first such agents currently in preclinical and clinical development will be discussed.

Regulation of matriptase and HAI-1 system, a novel therapeutic target in human endometrial cancer cells.

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Sun, Pengming; Xue, Lifang; Song, Yiyi; Mao, Xiaodan; Chen, Lili; Dong, Binhua; Braicu, Elena Loana; Sehouli, Jalid

2018-02-27

The effects of specific and non-specific regulation of matriptase on endometrial cancer cells in vitro were investigated. Messenger ribonucleic acid (mRNA) and protein expression of matriptase and hepatocyte growth factor activator inhibitor-1 (HAI-1) in RL-952, HEC-1A, and HEC-1B endometrial cancer cells were detected by real-time quantitative PCR (RT-qPCR) and western blot. The cells were infected with lentivirus-mediated small-interfering RNA (siRNA) targeted on matriptase (MA-siRNA) or treated with different cisplatin (DDP) concentrations. After treatment, invasion, migration, and cellular apoptosis were analyzed. Matriptase mRNA and protein expression significantly decreased to 80% after infection with MA-siRNA ( P scratch and trans-well chamber assays showed significant inhibition of invasiveness and metastasis. Upon incubation with cisplatin at concentrations higher than the therapeutic dose for 24 h, the expressions of matriptase and HAI-1 significantly decreased ( P endometrial cancer cells were significantly decreased ( P endometrial cancer cells showed promising therapeutic features.
Stem cell transplantation therapy for multifaceted therapeutic benefits after stroke.

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Wei, Ling; Wei, Zheng Z; Jiang, Michael Qize; Mohamad, Osama; Yu, Shan Ping

2017-10-01

One of the exciting advances in modern medicine and life science is cell-based neurovascular regeneration of damaged brain tissues and repair of neuronal structures. The progress in stem cell biology and creation of adult induced pluripotent stem (iPS) cells has significantly improved basic and pre-clinical research in disease mechanisms and generated enthusiasm for potential applications in the treatment of central nervous system (CNS) diseases including stroke. Endogenous neural stem cells and cultured stem cells are capable of self-renewal and give rise to virtually all types of cells essential for the makeup of neuronal structures. Meanwhile, stem cells and neural progenitor cells are well-known for their potential for trophic support after transplantation into the ischemic brain. Thus, stem cell-based therapies provide an attractive future for protecting and repairing damaged brain tissues after injury and in various disease states. Moreover, basic research on naïve and differentiated stem cells including iPS cells has markedly improved our understanding of cellular and molecular mechanisms of neurological disorders, and provides a platform for the discovery of novel drug targets. The latest advances indicate that combinatorial approaches using cell based therapy with additional treatments such as protective reagents, preconditioning strategies and rehabilitation therapy can significantly improve therapeutic benefits. In this review, we will discuss the characteristics of cell therapy in different ischemic models and the application of stem cells and progenitor cells as regenerative medicine for the treatment of stroke. Copyright © 2017 Elsevier Ltd. All rights reserved.
Therapeutic potential of the metabolic modulator Metformin on osteosarcoma cancer stem-like cells.

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Paiva-Oliveira, Daniela I; Martins-Neves, Sara R; Abrunhosa, Antero J; Fontes-Ribeiro, Carlos; Gomes, Célia M F

2018-01-01

Osteosarcoma is the most common primary bone tumour appearing in children and adolescents. Recent studies demonstrate that osteosarcoma possesses a stem-like cell subset, so-called cancer stem-like cells, refractory to conventional chemotherapeutics and pointed out as responsible for relapses frequently observed in osteosarcoma patients. Here, we explored the therapeutic potential of Metformin on osteosarcoma stem-like cells, alone and as a chemosensitizer of doxorubicin. Stem-like cells were isolated from human osteosarcoma cell lines, MNNG/HOS and MG-63, using the sphere-forming assay. Metformin cytotoxicity alone and combined with doxorubicin were evaluated using MTT/BrdU assays. Protein levels of AMPK and AKT were evaluated by Western Blot. Cellular metabolic status was assessed based on [ 18 F]-FDG uptake and lactate production measurements. Sphere-forming efficiency and expression of pluripotency transcription factors analysed by qRT-PCR were tested as readout of Metformin effects on stemness features. Metformin induced a concentration-dependent decrease in the metabolic activity and proliferation of sphere-forming cells and improved doxorubicin-induced cytotoxicity. This drug also down-regulated the expression of master regulators of pluripotency (OCT4, SOX2, NANOG), and decreased spheres' self-renewal ability. Metformin effects on mitochondria led to the activation and phosphorylation of the energetic sensor AMPK along with an upregulation of the pro-survival AKT pathway in both cell populations. Furthermore, Metformin-induced mitochondrial stress increased [ 18 F]-FDG uptake and lactate production in parental cells but not in the quiescent stem-like cells, suggesting the inability of the latter to cope with the energy crisis induced by metformin. This preclinical study suggests that Metformin may be a potentially useful therapeutic agent and chemosensitizer of osteosarcoma stem-like cells to doxorubicin.
Safety and function of a new clinical intracerebral microinjection instrument for stem cells and therapeutics examined in the Göttingen minipig

DEFF Research Database (Denmark)

Bjarkam, Carsten R; GLUD, AN; Margolin, Lee

2010-01-01

Safety and function of a new clinical intracerebral microinjection instrument for stem cells and therapeutics examined in the Göttingen minipig......Safety and function of a new clinical intracerebral microinjection instrument for stem cells and therapeutics examined in the Göttingen minipig...
Exertion Testing in Youth with Mild Traumatic Brain Injury/Concussion.

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Dematteo, Carol; Volterman, Kimberly A; Breithaupt, Peter G; Claridge, Everett A; Adamich, John; Timmons, Brian W

2015-11-01

The decision regarding return to activity (RTA) after mild traumatic brain injuries/concussion is one of the most difficult and controversial areas in concussion management, particularly for youth. This study investigated how youth with postconcussion syndrome (PCS) are affected by exertion and whether standardized exertion testing using the McMaster All-Out Progressive Continuous Cycling Test can contribute to clinical decision making for safe RTA. Fifty-four youth (8.5-18.3 yr) with a previously confirmed concussion participated in the study. Each participant performed exertion testing on a cycle ergometer and completed a Postconcussion Symptom scale at the following time points: before exertion (baseline), 5 and 30 min, and 24 h after exertion. A modified Postconcussion Symptom scale was administered at 2-min intervals during exertion. Participants had a mean ± SD symptom duration of 6.3 ± 6.9 months after the most recent concussive injury, with a median of 4.1 months (range, 0.7-35 months). Sixty-three percent of participants had symptoms during exertion testing. Symptom profile (number and severity) significantly affected perception of exertion at 50% peak mechanical power. During acute assessment of symptoms (30-min after exertion), headache (P = 0.39), nausea (P = 0.63), and dizziness (P = 0.35) did not change. However, both the number and severity of symptoms significantly improved over 24 h, with 56.8% of youth showing improvements. The time from the most recent injury had a significant effect on the symptom score at baseline, 30 min after exertion, and 24 h after exertion. Exertion testing has an important role in the evaluation of symptoms and readiness to RTA, particularly in youth who are slow to recover. Overall, controlled exertion seemed to lesson symptoms for most youth.
Mesenchymal stem cells as therapeutic target of biophysical stimulation for the treatment of musculoskeletal disorders.

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Viganò, Marco; Sansone, Valerio; d'Agostino, Maria Cristina; Romeo, Pietro; Perucca Orfei, Carlotta; de Girolamo, Laura

2016-12-16

Musculoskeletal disorders are regarded as a major cause of worldwide morbidity and disability, and they result in huge costs for national health care systems. Traditional therapies frequently turned out to be poorly effective in treating bone, cartilage, and tendon disorders or joint degeneration. As a consequence, the development of novel biological therapies that can treat more effectively these conditions should be the highest priority in regenerative medicine. Mesenchymal stem cells (MSCs) represent one of the most promising tools in musculoskeletal tissue regenerative medicine, thanks to their proliferation and differentiation potential and their immunomodulatory and trophic ability. Indeed, MSC-based approaches have been proposed for the treatment of almost all orthopedic conditions, starting from different cell sources, alone or in combination with scaffolds and growth factors, and in one-step or two-step procedures. While all these approaches would require cell harvesting and transplantation, the possibility to stimulate the endogenous MSCs to enhance their tissue homeostasis activity represents a less-invasive and cost-effective therapeutic strategy. Nowadays, the role of tissue-specific resident stem cells as possible therapeutic target in degenerative pathologies is underinvestigated. Biophysical stimulations, and in particular extracorporeal shock waves treatment and pulsed electromagnetic fields, are able to induce proliferation and support differentiation of MSCs from different origins and affect their paracrine production of growth factors and cytokines. The present review reports the attempts to exploit the resident stem cell potential in musculoskeletal pathologies, highlighting the role of MSCs as therapeutic target of currently applied biophysical treatments.
Exertional Rhabdomyolysis after Spinning.

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Jeong, Youjin; Kweon, Hyuk-Jung; Oh, Eun-Jung; Ahn, Ah-Leum; Choi, Jae-Kyung; Cho, Dong-Yung

2016-11-01

Any strenuous muscular exercise may trigger rhabdomyolysis. We report an episode of clinically manifested exertional rhabdomyolysis due to stationary cycling, commonly known as spinning. Reports of spinning-related rhabdomyolysis are rare in the English literature, and the current case appears to be the first such case reported in South Korea. A previously healthy 21-year-old Asian woman presented with severe thigh pain and reddish-brown urinary discoloration 24-48 hours after attending a spinning class at a local gymnasium. Paired with key laboratory findings, her symptoms were suggestive of rhabdomyolysis. She required hospital admission to sustain renal function through fluid resuscitation therapy and fluid balance monitoring. Because exertional rhabdomyolysis may occur in any unfit but otherwise healthy individual who indulges in stationary cycling, the potential health risks of this activity must be considered.
Kinase Gene Expression Profiling of Metastatic Clear Cell Renal Cell Carcinoma Tissue Identifies Potential New Therapeutic Targets.

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Pooja Ghatalia

Full Text Available Kinases are therapeutically actionable targets. Kinase inhibitors targeting vascular endothelial growth factor receptors (VEGFR and mammalian target of rapamycin (mTOR improve outcomes in metastatic clear cell renal cell carcinoma (ccRCC, but are not curative. Metastatic tumor tissue has not been comprehensively studied for kinase gene expression. Paired intra-patient kinase gene expression analysis in primary tumor (T, matched normal kidney (N and metastatic tumor tissue (M may assist in identifying drivers of metastasis and prioritizing therapeutic targets. We compared the expression of 519 kinase genes using NanoString in T, N and M in 35 patients to discover genes over-expressed in M compared to T and N tissue. RNA-seq data derived from ccRCC tumors in The Cancer Genome Atlas (TCGA were used to demonstrate differential expression of genes in primary tumor tissue from patients that had metastasis at baseline (n = 79 compared to those that did not develop metastasis for at least 2 years (n = 187. Functional analysis was conducted to identify key signaling pathways by using Ingenuity Pathway Analysis. Of 10 kinase genes overexpressed in metastases compared to primary tumor in the discovery cohort, 9 genes were also differentially expressed in TCGA primary tumors with metastasis at baseline compared to primary tumors without metastasis for at least 2 years: EPHB2, AURKA, GSG2, IKBKE, MELK, CSK, CHEK2, CDC7 and MAP3K8; p<0.001. The top pathways overexpressed in M tissue were pyridoxal 5'-phosphate salvage, salvage pathways of pyrimidine ribonucleotides, NF-kB signaling, NGF signaling and cell cycle control of chromosomal replication. The 9 kinase genes validated to be over-expressed in metastatic ccRCC may represent currently unrecognized but potentially actionable therapeutic targets that warrant functional validation.
A 4-Phenoxyphenol Derivative Exerts Inhibitory Effects on Human Hepatocellular Carcinoma Cells through Regulating Autophagy and Apoptosis Accompanied by Downregulating α-Tubulin Expression

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Wen-Tsan Chang

2017-05-01

Full Text Available Hepatocellular carcinoma (HCC is a leading cancer worldwide. Advanced HCCs are usually resistant to anticancer drugs, causing unsatisfactory chemotherapy outcomes. In this study, we showed that a 4-phenoxyphenol derivative, 4-[4-(4-hydroxyphenoxyphenoxy]phenol (4-HPPP, exerts an inhibitory activity against two HCC cell lines, Huh7 and Ha22T. We further investigated the anti-HCC activities of 4-HPPP, including anti-proliferation and induction of apoptosis. Our results showed that higher dosage of 4-HPPP downregulates the expression of α-tubulin and causes nuclear enlargement in both the Huh-7 and Ha22T cell lines. Interestingly, the colony formation results showed a discrepancy in the inhibitory effect of 4-HPPP on HCC and rat liver epithelial Clone 9 cells, suggesting the selective cytotoxicity of 4-HPPP toward HCC cells. Furthermore, the cell proliferation and apoptosis assay results illustrated the differences between the two HCC cell lines. The results of cellular proliferation assays, including trypan blue exclusion and colony formation, revealed that 4-HPPP inhibits the growth of Huh7 cells, but exerts less cytotoxicity in Ha22T cells. Furthermore, the annexin V assay performed for detecting the apoptosis showed similar results. Western blotting results showed 4-HPPP caused the increase of pro-apoptotic factors including cleaved caspase-3, Bid and Bax in HCC cells, especially in Huh-7. Furthermore, an increase of autophagy-associated protein microtubule-associated protein-1 light chain-3B (LC3B-II and the decrease of Beclin-1 and p62/SQSTM1 were observed following 4-HPPP treatment. Additionally, the level of γH2A histone family, member X (γH2AX, an endogenous DNA damage biomarker, was dramatically increased in Huh7 cells after 4-HPPP treatment, suggesting the involvement of DNA damage pathway in 4-HPPP-induced apoptosis. On the contrary, the western blotting results showed that treatment up-regulates pro-survival proteins, including the
20 CFR 404.1567 - Physical exertion requirements.

Science.gov (United States)

2010-04-01

... activities. If someone can do light work, we determine that he or she can also do sedentary work, unless... Physical exertion requirements. To determine the physical exertion requirements of work in the national... making disability determinations under this subpart, we use the following definitions: (a) Sedentary work...
20 CFR 416.967 - Physical exertion requirements.

Science.gov (United States)

2010-04-01

... activities. If someone can do light work, we determine that he or she can also do sedentary work, unless... Physical exertion requirements. To determine the physical exertion requirments of work in the national... making disability determinations under this subpart, we use the following definitions: (a) Sedentary work...
Non-cell autonomous or secretory tumor suppression.

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Chua, Christelle En Lin; Chan, Shu Ning; Tang, Bor Luen

2014-10-01

Many malignancies result from deletions or loss-of-function mutations in one or more tumor suppressor genes, the products of which curb unrestrained growth or induce cell death in those with dysregulated proliferative capacities. Most tumor suppressors act in a cell autonomous manner, and only very few proteins are shown to exert a non-cell autonomous tumor suppressor function on other cells. Examples of these include members of the secreted frizzled-related protein (SFRP) family and the secreted protein acidic and rich in cysteine (SPARC)-related proteins. Very recent findings have, however, considerably expanded our appreciation of non-cell autonomous tumor suppressor functions. Broadly, this may occur in two ways. Intracellular tumor suppressor proteins within cells could in principle inhibit aberrant growth of neighboring cells by conditioning an antitumor microenvironment through secreted factors. This is demonstrated by an apparent non-cell autonomous tumor suppressing property of p53. On the other hand, a tumor suppressor produced by a cell may be secreted extracellularly, and taken up by another cell with its activity intact. Intriguingly, this has been recently shown to occur for the phosphatase and tensin homolog (PTEN) by both conventional and unconventional modes of secretion. These recent findings would aid the development of therapeutic strategies that seek to reinstate tumor suppression activity in therapeutically recalcitrant tumor cells, which have lost it in the first place. © 2014 Wiley Periodicals, Inc.
PIM kinases as potential therapeutic targets in a subset of peripheral T cell lymphoma cases.

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Esperanza Martín-Sánchez

Full Text Available Currently, there is no efficient therapy for patients with peripheral T cell lymphoma (PTCL. The Proviral Integration site of Moloney murine leukemia virus (PIM kinases are important mediators of cell survival. We aimed to determine the therapeutic value of PIM kinases because they are overexpressed in PTCL patients, T cell lines and primary tumoral T cells. PIM kinases were inhibited genetically (using small interfering and short hairpin RNAs and pharmacologically (mainly with the pan-PIM inhibitor (PIMi ETP-39010 in a panel of 8 PTCL cell lines. Effects on cell viability, apoptosis, cell cycle, key proteins and gene expression were evaluated. Individual inhibition of each of the PIM genes did not affect PTCL cell survival, partially because of a compensatory mechanism among the three PIM genes. In contrast, pharmacological inhibition of all PIM kinases strongly induced apoptosis in all PTCL cell lines, without cell cycle arrest, in part through the induction of DNA damage. Therefore, pan-PIMi synergized with Cisplatin. Importantly, pharmacological inhibition of PIM reduced primary tumoral T cell viability without affecting normal T cells ex vivo. Since anaplastic large cell lymphoma (ALK+ ALCL cell lines were the most sensitive to the pan-PIMi, we tested the simultaneous inhibition of ALK and PIM kinases and found a strong synergistic effect in ALK+ ALCL cell lines. Our findings suggest that PIM kinase inhibition could be of therapeutic value in a subset of PTCL, especially when combined with ALK inhibitors, and might be clinically beneficial in ALK+ ALCL.
Musings on genome medicine: is there hope for ethical and safe stem cell therapeutics?

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Rao, Mahendra; Condic, Maureen L

2009-07-14

Although most stem cell therapy has been non-controversial, therapy based on pluripotent stem cells has raised both ethical and safety concerns. Despite these concerns, the use of cells derived from pluripotent stem cells has recently been approved for clinical trials. We suggest that recent advances in the field have provided avenues to develop pluripotent cells that raise far fewer ethical concerns. Moreover, advances in cell sorting, gene modification and screening have allowed the development of safer therapeutic approaches. Continued advances in this rapidly evolving field are likely to allow therapy to be delivered in a safe and effective manner without socially divisive ethical controversy in the not-so-distant future.
Isometric Thumb Exertion Induces B Cell and T Cell Lymphocytosis in Trained and Untrained Males: Physical Aptitude Determines Response Profiles

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Adam Michael Szlezak

2016-01-01

Full Text Available Purpose: The present study examined the effect of low-dose thumb exertion on lymphocyte subpopulation trafficking. The potential role of blood lactate in mediating lymphocyte redistribution was also investigated. Methods: 27 male participants (18 weightlifting-trained; 9 untrained were separated into 3 groups of 9 (Weightlifting and Untrained Experimental: WLEXP, UTEXP; Weightlifting Placebo: WLPLA. WLEXP and UTEXP performed 4x60 second isometric thumb intervals separated by 60 second rest intervals in a single-blinded placebo-controlled study. Participants were assessed over a 60 minute post-intervention recovery period for pain, blood lactate and lymphocyte subpopulation counts. Results: WLPLA did not change for any measured variable (p>0.05. The two experimentalgroups increased significantly (p0.05. No differences in cell count were seen for CD56+/CD16+ lymphocytes across time for any group (p>0.05. UTEXP showed an early significant increase (20 min post-intervention in CD4+CD3+ (20.78%, p0.05. Conversely, WLEXP group showed no early increase followed by a delayed increase in cell count evident at the final time-point; CD4+CD3+ (19.06%, p<0.01, CD8+CD3+ (11.46%, p=0.033 and CD19+ (28.87%, p<0.01. Blood lactate was not correlated with lymphocyte counts. Conclusions: Physical aptitude and not cellular energy demand influences the lymphocyte response to resistance-exercise. Keywords: B-Lymphocytes; Exercise; Lactic Acid; Lymphocytosis; Resistance Training; T-Lymphocytes
Perspectives of purinergic signaling in stem cell differentiation and tissue regeneration.

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Glaser, Talita; Cappellari, Angélica Regina; Pillat, Micheli Mainardi; Iser, Isabele Cristiana; Wink, Márcia Rosângela; Battastini, Ana Maria Oliveira; Ulrich, Henning

2012-09-01

Replacement of lost or dysfunctional tissues by stem cells has recently raised many investigations on therapeutic applications. Purinergic signaling has been shown to regulate proliferation, differentiation, cell death, and successful engraftment of stem cells originated from diverse origins. Adenosine triphosphate release occurs in a controlled way by exocytosis, transporters, and lysosomes or in large amounts from damaged cells, which is then subsequently degraded into adenosine. Paracrine and autocrine mechanisms induced by immune responses present critical factors for the success of stem cell therapy. While P1 receptors generally exert beneficial effects including anti-inflammatory activity, P2 receptor-mediated actions depend on the subtype of stimulated receptors and localization of tissue repair. Pro-inflammatory actions and excitatory tissue damages mainly result from P2X7 receptor activation, while other purinergic receptor subtypes participate in proliferation and differentiation, thereby providing adequate niches for stem cell engraftment and novel mechanisms for cell therapy and endogenous tissue repair. Therapeutic applications based on regulation of purinergic signaling are foreseen for kidney and heart muscle regeneration, Clara-like cell replacement for pulmonary and bronchial epithelial cells as well as for induction of neurogenesis in case of neurodegenerative diseases.
Cell targeting peptides as smart ligands for targeting of therapeutic or diagnostic agents: a systematic review.

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Mousavizadeh, Ali; Jabbari, Ali; Akrami, Mohammad; Bardania, Hassan

2017-10-01

Cell targeting peptides (CTP) are small peptides which have high affinity and specificity to a cell or tissue targets. They are typically identified by using phage display and chemical synthetic peptide library methods. CTPs have attracted considerable attention as a new class of ligands to delivery specifically therapeutic and diagnostic agents, because of the fact they have several advantages including easy synthesis, smaller physical sizes, lower immunogenicity and cytotoxicity and their simple and better conjugation to nano-carriers and therapeutic or diagnostic agents compared to conventional antibodies. In this systematic review, we will focus on the basic concepts concerning the use of cell-targeting peptides (CTPs), following the approaches of selecting them from peptide libraries. We discuss several developed strategies for cell-specific delivery of different cargos by CTPs, which are designed for drug delivery and diagnostic applications. Copyright © 2017 Elsevier B.V. All rights reserved.
3D culture of Her2+ breast cancer cells promotes AKT to MAPK switching and a loss of therapeutic response.

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Gangadhara, Sharath; Smith, Chris; Barrett-Lee, Peter; Hiscox, Stephen

2016-06-01

The Her2 receptor is overexpressed in up to 25 % of breast cancers and is associated with a poor prognosis. Around half of Her2+ breast cancers also express the estrogen receptor and treatment for such tumours can involve both endocrine and Her2-targeted therapies. However, despite preclinical data supporting the effectiveness of these agents, responses can vary widely in the clinical setting. In light of the increasing evidence pointing to the interplay between the tumour and its extracellular microenvironment as a significant determinant of therapeutic sensitivity and response here we investigated the impact of 3D matrix culture of breast cancer cells on their therapeutic sensitivity. A 3D Matrigel-based culture system was established and optimized for the growth of ER+/Her2+ breast cancer cell models. Growth of cells in response to trastuzumab and endocrine agents in 3D culture versus routine monolayer culture were assessed using cell counting and Ki67 staining. Endogenous and trastuzumab-modulated signalling pathway activity in 2D and 3D cultures were assessed using Western blotting. Breast cancer cells in 3D culture displayed an attenuated response to both endocrine agents and trastuzumab compared with cells cultured in traditional 2D monolayers. Underlying this phenomenon was an apparent matrix-induced shift from AKT to MAPK signalling; consequently, suppression of MAPK in 3D cultures restores therapeutic response. These data suggest that breast cancer cells in 3D culture display a reduced sensitivity to therapeutic agents which may be mediated by internal MAPK-mediated signalling. Targeting of adaptive pathways that maintain growth in 3D culture may represent an effective strategy to improve therapeutic response clinically.
Therapeutic dendritic cell vaccination of patients with metastatic renal cell carcinoma: a clinical phase 1/2 trial

DEFF Research Database (Denmark)

Berntsen, Annika; Trepiakas, Redas; Wenandy, Lynn

2008-01-01

Therapeutic dendritic cell (DC) vaccination against cancer is a strategy aimed at activating the immune system to recognize and destroy tumor cells. In this nonrandomized phase 1/2 trial, we investigated the safety, feasibility, induction of T-cell response, and clinical response after treatment...... with a DC-based vaccine in patients with metastatic renal cell carcinoma. Twenty-seven patients with progressive cytokine-refractory metastatic renal cell carcinoma were vaccinated with DCs loaded with either a cocktail of survivin and telomerase peptides or tumor lysate depending on their HLA-A2 haplotype......, and low-dose IL-2 was administered concomitantly. Tumor response, immune response, and serum IL-6 and YKL-40 were measured during treatment. Vaccine generation was successful in all patients and no serious adverse events were observed. None of the patients had an objective response but 13/27 patients...
Autophagy‑mediated adaptation of hepatocellular carcinoma cells to hypoxia‑mimicking conditions constitutes an attractive therapeutic target.

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Owada, Satoshi; Endo, Hitoshi; Shida, Yukari; Okada, Chisa; Ito, Kanako; Nezu, Takahiro; Tatemichi, Masayuki

2018-04-01

Hepatocellular carcinoma has extremely poor prognosis. In cancerous liver tissues, aberrant proliferation of cancer cells leads to the creation of an area where an immature vascular network is formed. Since oxygen is supplied to cancer tissues through the bloodstream, a part of the tumor is exposed to hypoxic conditions. As hypoxia is known to severely reduce the effectiveness of existing anticancer agents, novel valid therapeutic targets must be identified for the treatment of hepatocellular carcinoma. Generally, autophagy has been reported to play an important role in the adaptation of cancer cells to hypoxia. However, the exact role and significance of this process vary depending on the cancer type, requiring detailed analysis in individual primary tumors and cell lines. In the present study, we examined autophagy induced by cobalt chloride, a hypoxia‑mimicking agent, in hepatocellular carcinoma cells with the aim to evaluate the validity of this process as a potential therapeutic target. We observed that treatment with cobalt chloride induced autophagy, including the intracellular quality control mechanism, in an AMPK‑dependent manner. Furthermore, treatment with autophagy inhibitors (bafilomycin and LY294002) resulted in significant, highly‑selective cytotoxicity and apoptosis activation under hypoxia‑mimicking conditions. The knockdown of AMPK also revealed significant cytotoxicity in hypoxia‑mimicking conditions. These results clearly demonstrated that autophagy, especially mitophagy, was induced by the AMPK pathway when hepatocellular carcinoma cells were subjected to hypoxic conditions and played an important role in the adaptation of these cells to such conditions. Thus, autophagy may constitute an attractive therapeutic target for the treatment of hepatocellular carcinoma.

Therapeutic cloning in the mouse

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Mombaerts, Peter

2003-01-01

Nuclear transfer technology can be applied to produce autologous differentiated cells for therapeutic purposes, a concept termed therapeutic cloning. Countless articles have been published on the ethics and politics of human therapeutic cloning, reflecting the high expectations from this new opportunity for rejuvenation of the aging or diseased body. Yet the research literature on therapeutic cloning, strictly speaking, is comprised of only four articles, all in the mouse. The efficiency of derivation of embryonic stem cell lines via nuclear transfer is remarkably consistent among these reports. However, the efficiency is so low that, in its present form, the concept is unlikely to become widespread in clinical practice. PMID:12949262
Stem Cell Therapy and Breast Cancer Treatment: review of stem cell research and potential therapeutic impact against cardiotoxicities due to breast cancer treatment

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Thomas E. Sharp

2014-11-01

Full Text Available A new problem has emerged with the ever-increasing number of breast cancer survivors. While early screening and advances in treatment have allowed these patients to overcome their cancer, these treatments often have adverse cardiovascular side effects that can produce abnormal cardiovascular function. Chemotherapeutic and radiation therapy have both been linked to cardiotoxicity; these therapeutics can cause a loss of cardiac muscle and deterioration of vascular structure that can eventually lead to heart failure (HF. This cardiomyocyte toxicity can leave the breast cancer survivor with a probable diagnosis of dilated or restrictive cardiomyopathy (DCM or RCM. While current HF standard of care can alleviate symptoms, other than heart transplantation, there is no therapy that replaces cardiac myocytes that are killed during cancer therapies. There is a need to develop novel therapeutics that can either prevent or reverse the cardiac injury caused by cancer therapeutics. These new therapeutics should promote the regeneration of lost or deteriorating myocardium. Over the last several decades the therapeutic potential of cell-based therapy has been investigated for HF patients. In this review we discuss the progress of preclinical and clinical stem cell research for the diseased heart and discuss the possibility of utilizing these novel therapies to combat cardiotoxicity observed in breast cancer survivors.
Optimal Therapeutic Strategy for Non-small Cell Lung Cancer with Mutated Epidermal Growth Factor Receptor

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Zhong SHI

2015-02-01

Full Text Available Although epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs have been widely used in non-small cell lung cancer (NSCLC patients, it is still controversial about how to combine EGFR-TKI with chemotherapy and other targeted drugs. We have made a summary on the current therapeutic models of EGFR-TKI combined with chemotherapy/bevacizumab in this review and aimed to find the optimal therapeutic strategy for NSCLC patients with EGFR mutation.
The therapeutic implications of plasticity of the cancer stem cell phenotype.

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Kevin Leder

2010-12-01

Full Text Available The cancer stem cell hypothesis suggests that tumors contain a small population of cancer cells that have the ability to undergo symmetric self-renewing cell division. In tumors that follow this model, cancer stem cells produce various kinds of specified precursors that divide a limited number of times before terminally differentiating or undergoing apoptosis. As cells within the tumor mature, they become progressively more restricted in the cell types to which they can give rise. However, in some tumor types, the presence of certain extra- or intracellular signals can induce committed cancer progenitors to revert to a multipotential cancer stem cell state. In this paper, we design a novel mathematical model to investigate the dynamics of tumor progression in such situations, and study the implications of a reversible cancer stem cell phenotype for therapeutic interventions. We find that higher levels of dedifferentiation substantially reduce the effectiveness of therapy directed at cancer stem cells by leading to higher rates of resistance. We conclude that plasticity of the cancer stem cell phenotype is an important determinant of the prognosis of tumors. This model represents the first mathematical investigation of this tumor trait and contributes to a quantitative understanding of cancer.
Self-Assembling Peptide Amphiphiles for Therapeutic Delivery of Proteins, Drugs, and Stem Cells

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Lee, Sungsoo Seth

Biomaterials are used to help regenerate or replace the structure and function of damaged tissues. In order to elicit desired therapeutic responses in vivo, biomaterials are often functionalized with bioactive agents, such as growth factors, small molecule drugs, or even stem cells. Therefore, the strategies used to incorporate these bioactive agents in the microstructures and nanostructures of biomaterials can strongly influence the their therapeutic efficacy. Using self-assembling peptide amphiphiles (PAs), this work has investigated supramolecular nanostructures with improved interaction with three types of therapeutic agents: bone morphogenetic protein 2 (BMP-2) which promotes osteogenic differentiation and bone growth, anti-inflammatory drug naproxen which is used to treat osteo- and rheumatoid arthritis, and neural stem cells that could differentiate into neurons to treat neurodegenerative diseases. For BMP-2 delivery, two specific systems were investigated with affinity for BMP-2: 1) heparin-binding nanofibers that display the natural ligand of the osteogenic protein, and 2) nanofibers that display a synthetic peptide ligand discovered in our laboratory through phage display to directly bind BMP-2. Both systems promoted enhanced osteoblast differentiation of pluripotent C2C12 cells and augmented bone regeneration in two in vivo models, a rat critical-size femur defect model and spinal arthrodesis model. The thesis also describes the use of PA nanofibers to improve the delivery of the anti-inflammatory drug naproxen. To promote a controlled release, naproxen was chemically conjugated to the nanofiber surface via an ester bond that would only be cleaved by esterases, which are enzymes found naturally in the body. In the absence of esterases, the naproxen remained conjugated to the nanofibers and was non-bioactive. On the other hand, in the presence of esterases, naproxen was slowly released and inhibited cyclooxygenase-2 (COX-2) activity, an enzyme responsible
Ginkgolide B Exerts Cardioprotective Properties against Doxorubicin-Induced Cardiotoxicity by Regulating Reactive Oxygen Species, Akt and Calcium Signaling Pathways In Vitro and In Vivo.

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Gao, Junqing; Chen, Tao; Zhao, Deqiang; Zheng, Jianpu; Liu, Zongjun

2016-01-01

The aim of this study was to evaluate the effect of Ginkgolide B (GB) on doxorubicin (DOX) induced cardiotoxicity in vitro and in vivo. Rat cardiomyocyte cell line H9c2 was pretreated with GB and subsequently subjected to doxorubicin treatment. Cell viability and cell apoptosis were assessed by MTT assay and Hoechst staining, respectively. Reactive oxygen species (ROS), Akt phosphorylation and intracellular calcium were equally determined in order to explore the underlying molecular mechanism. To verify the in vivo therapeutic effect of GB, we established a mouse model of cardiotoxicity and determined left ventricle ejection fraction (LVEF) and left ventricular mass (LVM). The in vitro experimental results indicated that pretreatment with GB significantly decreases the viability and apoptosis of H9c2 cells by decreasing ROS and intracellular calcium levels and activating Akt phosphorylation. In the in vivo study, we recorded an improved LVEF and a decreased LVM in the group of cardiotoxic rats treated with GB. Altogether, our findings anticipate that GB exerts a cardioprotective effect through possible regulation of the ROS, Akt and calcium pathways. The findings suggest that combination of GB with DOX in chemotherapy could help avoid the cardiotoxic side effects of GB.
Therapeutic Effect of Ligustilide-Stimulated Adipose-Derived Stem Cells in a Mouse Thromboembolic Stroke Model.

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Chi, Kang; Fu, Ru-Huei; Huang, Yu-Chuen; Chen, Shih-Yin; Lin, Shinn-Zong; Huang, Pi-Chun; Lin, Po-Cheng; Chang, Fu-Kuei; Liu, Shih-Ping

2016-01-01

Stroke is a result of cerebral ischemia that triggers a cascade of both physiological and biochemical events. No effective treatment is available for stroke; however, stem cells have the potential to rescue tissue from the effects of stroke. Adipose-derived stem cells (ADSCs) are an abundant source of adult stem cells; therefore, ADSC therapy can be considered as a future strategy for regenerative medicine. However, more research is required to improve the effectiveness of transplanted ADSCs as a treatment for stroke in the mouse stroke model. Ligustilide, isolated from the herb Angelica sinensis, exhibits a protective effect on neurons and inhibits inflammation. We also demonstrated that ligustilide treatment increases the expression levels of homing factors such as SDF-1 and CXCR4. In the present study, we evaluated the therapeutic effects of ADSC transplantation and ligustilide treatment in a mouse thromboembolic stroke model by behavioral tests, including beam walking, locomotor activity, and rotarod analysis. ADSCs pretreated with ligustilide were transplanted into the brains of stroke mice. The results showed that the therapeutic effect of ADSCs pretreated with ligustilide was better than that of ADSCs without ligustilide pretreatment. There was no difference between the recovery of mice treated by ADSC transplantation combined with subcutaneous ligustilide injection and that of mice treated only with ADSCs. The TUNEL assay showed fewer apoptotic cells in the brains of mice transplanted with ADSCs pretreated with ligustilide as well as in those without pretreatment. In summary, pretreatment of ADSCs with ligustilide improves the therapeutic efficacy of ADSC transplantation. The results of this study will help improve stem cell therapies being developed for future clinical applications.
Human umbilical cord mesenchymal stem cells hUC-MSCs exert immunosuppressive activities through a PGE2-dependent mechanism.

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Chen, Ke; Wang, Ding; Du, Wei Ting; Han, Zhi-Bo; Ren, He; Chi, Ying; Yang, Shao Guang; Zhu, Delin; Bayard, Francis; Han, Zhong Chao

2010-06-01

Human umbilical-cord-derived mesenchymal stem cells (hUC-MSCs) constitute an attractive alternative to bone-marrow-derived MSCs for potential clinical applications because of easy preparation and lower risk of viral contamination. In this study, both proliferation of human peripheral blood mononuclear cells (hPBMCs) and their IFN-gamma production in response to mitogenic or allogeneic stimulus were effectively inhibited by hUC-MSCs. Co-culture experiments in transwell systems indicated that the suppression was largely mediated by soluble factor(s). Blocking experiments identified prostaglandin E(2) (PGE(2)) as the major factor, because inhibition of PGE(2) synthesis almost completely mitigated the immunosuppressive effects, whereas neutralization of TGF-beta, IDO, and NO activities had little effects. Moreover, the inflammatory cytokines, IFN-gamma and IL-1beta, produced by hPBMCs upon activation notably upregulated the expression of cyclooxygenase-2 (COX-2) and the production of PGE(2) by hUC-MSCs. In conclusion, our data have demonstrated for the first time the PGE(2)-mediated mechanism by which hUC-MSCs exert their immunomodulatory effects. Copyright 2010 Elsevier Inc. All rights reserved.
Musical agency reduces perceived exertion during strenuous physical performance.

Science.gov (United States)

Fritz, Thomas Hans; Hardikar, Samyogita; Demoucron, Matthias; Niessen, Margot; Demey, Michiel; Giot, Olivier; Li, Yongming; Haynes, John-Dylan; Villringer, Arno; Leman, Marc

2013-10-29

Music is known to be capable of reducing perceived exertion during strenuous physical activity. The current interpretation of this modulating effect of music is that music may be perceived as a diversion from unpleasant proprioceptive sensations that go along with exhaustion. Here we investigated the effects of music on perceived exertion during a physically strenuous task, varying musical agency, a task that relies on the experience of body proprioception, rather than simply diverting from it. For this we measured psychologically indicated exertion during physical workout with and without musical agency while simultaneously acquiring metabolic values with spirometry. Results showed that musical agency significantly decreased perceived exertion during workout, indicating that musical agency may actually facilitate physically strenuous activities. This indicates that the positive effect of music on perceived exertion cannot always be explained by an effect of diversion from proprioceptive feedback. Furthermore, this finding suggests that the down-modulating effect of musical agency on perceived exertion may be a previously unacknowledged driving force for the development of music in humans: making music makes strenuous physical activities less exhausting.
Regulatory T cell derived Exosomes: possible therapeutic and diagnostic tools in transplantation

Directory of Open Access Journals (Sweden)

Akansha eAgarwal

2014-11-01

Full Text Available Exosomes are extracellular vesicles released by many cells of the body. These small vesicles play an important part in intercellular communication both in the local environment and systemically, facilitating in the transfer of proteins, cytokines as well as miRNA between cells. The observation that exosomes isolated from immune cells such as dendritic cells (DCs modulate the immune response has paved the way for these structures to be considered as potential immunotherapeutic reagents. Indeed clinical trials using DC derived exosomes to facilitate immune responses to specific cancer antigens are now underway. Exosomes can also have a negative effect on the immune response and exosomes isolated from regulatory T cells (Tregs and other subsets of T cells have been shown to have immune suppressive capacities. Here we review what is currently known about Treg derived exosomes and their contribution to immune regulation, as well as highlighting their possible therapeutic potential for preventing graft rejection, and their possible use as diagnostic tools to assess transplant outcome.
Novel therapeutic strategies to target leukemic cells that hijack compartmentalized continuous hematopoietic stem cell niches.

Science.gov (United States)

Hira, Vashendriya V V; Van Noorden, Cornelis J F; Carraway, Hetty E; Maciejewski, Jaroslaw P; Molenaar, Remco J

2017-08-01

Acute myeloid leukemia and acute lymphoblastic leukemia cells hijack hematopoietic stem cell (HSC) niches in the bone marrow and become leukemic stem cells (LSCs) at the expense of normal HSCs. LSCs are quiescent and resistant to chemotherapy and can cause relapse of the disease. HSCs in niches are needed to generate blood cell precursors that are committed to unilineage differentiation and eventually production of mature blood cells, including red blood cells, megakaryocytes, myeloid cells and lymphocytes. Thus far, three types of HSC niches are recognized: endosteal, reticular and perivascular niches. However, we argue here that there is only one type of HSC niche, which consists of a periarteriolar compartment and a perisinusoidal compartment. In the periarteriolar compartment, hypoxia and low levels of reactive oxygen species preserve the HSC pool. In the perisinusoidal compartment, hypoxia in combination with higher levels of reactive oxygen species enables proliferation of progenitor cells and their mobilization into the circulation. Because HSC niches offer protection to LSCs against chemotherapy, we review novel therapeutic strategies to inhibit homing of LSCs in niches for the prevention of dedifferentiation of leukemic cells into LSCs and to stimulate migration of leukemic cells out of niches. These strategies enhance differentiation and proliferation and thus sensitize leukemic cells to chemotherapy. Finally, we list clinical trials of therapies that tackle LSCs in HSC niches to circumvent their protection against chemotherapy. Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.
Therapeutic effect of mesenchymal multipotent stromal cells on memory in animals with Alzheimer-type neurodegeneration.

Science.gov (United States)

Bobkova, N V; Poltavtseva, R A; Samokhin, A N; Sukhikh, G T

2013-11-01

Transplantation of human mesenchymal multipotent stromal cells improved spatial memory in bulbectomized mice with Alzheimer-type neurodegeneration. The positive effect was observed in 1 month after intracerebral transplantation and in 3 months after systemic injection of mesenchymal multipotent stromal cells. No cases of malignant transformation were noted. These findings indicate prospects of using mesenchymal multipotent stromal cells for the therapy of Alzheimer disease and the possibility of their systemic administration for attaining the therapeutic effect.
The In Vitro Anti-Tumor Activity of Phycocyanin against Non-Small Cell Lung Cancer Cells

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Shuai Hao

2018-05-01

Full Text Available Phycocyanin, a type of functional food colorant, is shown to have a potent anti-cancer property. Non-small cell lung cancer (NSCLC is one of the most aggressive form of cancers with few effective therapeutic options. Previous studies have demonstrated that phycocyanin exerts a growth inhibitory effect on NSCLC A549 cells. However, its biological function and underlying regulatory mechanism on other cells still remain unknown. Here, we investigated the in vitro function of phycocyanin on three typical NSCLC cell lines, NCI-H1299, NCI-H460, and LTEP-A2, for the first time. The results showed that phycocyanin could significantly induce apoptosis, cell cycle arrest, as well as suppress cell migration, proliferation, and the colony formation ability of NSCLC cells through regulating multiple key genes. Strikingly, phycocyanin was discovered to affect the cell phenotype through regulating the NF-κB signaling of NSCLC cells. Our findings demonstrated the anti-neoplastic function of phycocyanin and provided valuable information for the regulation of phycocyanin in NSCLC cells.
Therapeutic Vaccination Using Cationic Liposome-Adjuvanted HIV Type 1 Peptides Representing HLA-Supertype-Restricted Subdominant T Cell Epitopes

DEFF Research Database (Denmark)

Román, Victor Raúl Gómez; Jensen, Kristoffer Jarlov; Jensen, Sanne Skov

2013-01-01

We have designed a therapeutic HIV-1 vaccine concept based on peptides together with the adjuvant CAF01. Peptides represented 15 HLA-supertype-restricted subdominant and conserved CD8 T cell epitopes and three CD4 T-helper cell epitopes. In this phase I clinical trial, safety and immunogenicity...... were assessed in untreated HIV-1-infected individuals in Guinea-Bissau, West Africa. Twenty-three HIV-1-infected individuals were randomized to receive placebo (n=5) or vaccine (n=18). Safety was appraised by clinical follow-up combined with monitoring of biochemistry, hematology, CD4 T cell counts......, and HIV-1 viral loads. T cell immunogenicity was monitored longitudinally by interferon (IFN)-γ ELISpot. New vaccine-specific T cell responses were induced in 6/14 vaccinees for whom ELISpot data were valid. CD4 T cell counts and viral loads were stable. The study shows that therapeutic immunization...
Enhancement of therapeutic drug and DNA delivery into cells by electroporation

Energy Technology Data Exchange (ETDEWEB)

Rabussay, Dietmar [Genetronics, Inc., Department of Research and Development, 11199 Sorrento Valley Road, San Diego, CA (United States); Dev, Nagendu B [Genetronics, Inc., Department of Research and Development, 11199 Sorrento Valley Road, San Diego, CA (United States); Fewell, Jason [Valentis, Inc., 8301 New Trails Drive, The Woodlands, TX (United States); Smith, Louis C [Valentis, Inc., 8301 New Trails Drive, The Woodlands, TX (United States); Widera, Georg [Genetronics, Inc., Department of Research and Development, 11199 Sorrento Valley Road, San Diego, CA (United States); Zhang Lei [Genetronics, Inc., Department of Research and Development, 11199 Sorrento Valley Road, San Diego, CA (United States)

2003-02-21

The effectiveness of potentially powerful therapeutics, including DNA, is often limited by their inability to permeate the cell membrane efficiently. Electroporation (EP) also referred to as 'electropermeabilization' of the outer cell membrane renders this barrier temporarily permeable by inducing 'pores' across the lipid bilayer. For in vivo EP, the drug or DNA is delivered into the interstitial space of the target tissue by conventional means, followed by local EP. EP pulses of micro- to millisecond duration and field strengths of 100-1500 V cm{sup -1} generally enhance the delivery of certain chemotherapeutic drugs by three to four orders of magnitude and intracellular delivery of DNA several hundred-fold. We have used EP in clinical studies for human cancer therapy and in animals for gene therapy and DNA vaccination. Late stage squamous cell carcinomas of the head and neck were treated with intratumoural injection of bleomycin and subsequent EP. Of the 69 tumours treated, 25% disappeared completely and another 32% were reduced in volume by more than half. Residence time of bleomycin in electroporated tumours was significantly greater than in non-electroporated lesions. Histological findings and gene expression patterns after bleomycin-EP treatment indicated rapid apoptosis of the majority of tumour cells. In animals, we demonstrated the usefulness of EP for enhanced DNA delivery by achieving normalization of blood clotting times in haemophilic dogs, and by substantially increasing transgene expression in smooth muscle cells of arterial walls using a novel porous balloon EP catheter. Finally, we have found in animal experiments that the immune response to DNA vaccines can be dramatically enhanced and accelerated by EP and co-injection of micron-sized particles. We conclude that EP represents an effective, economical and safe approach to enhance the intracellular delivery, and thus potency, of important drugs and genes for therapeutic purposes
Enhancement of therapeutic drug and DNA delivery into cells by electroporation

International Nuclear Information System (INIS)

Rabussay, Dietmar; Dev, Nagendu B; Fewell, Jason; Smith, Louis C; Widera, Georg; Zhang Lei

2003-01-01

The effectiveness of potentially powerful therapeutics, including DNA, is often limited by their inability to permeate the cell membrane efficiently. Electroporation (EP) also referred to as 'electropermeabilization' of the outer cell membrane renders this barrier temporarily permeable by inducing 'pores' across the lipid bilayer. For in vivo EP, the drug or DNA is delivered into the interstitial space of the target tissue by conventional means, followed by local EP. EP pulses of micro- to millisecond duration and field strengths of 100-1500 V cm -1 generally enhance the delivery of certain chemotherapeutic drugs by three to four orders of magnitude and intracellular delivery of DNA several hundred-fold. We have used EP in clinical studies for human cancer therapy and in animals for gene therapy and DNA vaccination. Late stage squamous cell carcinomas of the head and neck were treated with intratumoural injection of bleomycin and subsequent EP. Of the 69 tumours treated, 25% disappeared completely and another 32% were reduced in volume by more than half. Residence time of bleomycin in electroporated tumours was significantly greater than in non-electroporated lesions. Histological findings and gene expression patterns after bleomycin-EP treatment indicated rapid apoptosis of the majority of tumour cells. In animals, we demonstrated the usefulness of EP for enhanced DNA delivery by achieving normalization of blood clotting times in haemophilic dogs, and by substantially increasing transgene expression in smooth muscle cells of arterial walls using a novel porous balloon EP catheter. Finally, we have found in animal experiments that the immune response to DNA vaccines can be dramatically enhanced and accelerated by EP and co-injection of micron-sized particles. We conclude that EP represents an effective, economical and safe approach to enhance the intracellular delivery, and thus potency, of important drugs and genes for therapeutic purposes. The safety and pharmaco
Conventional and novel stem cell based therapies for androgenic alopecia

Directory of Open Access Journals (Sweden)

Talavera-Adame D

2017-08-01

Full Text Available Dodanim Talavera-Adame,1 Daniella Newman,2 Nathan Newman1 1American Advanced Medical Corp. (Private Practice, Beverly Hills, CA, 2Western University of Health Sciences, Pomona, CA, USA Abstract: The prevalence of androgenic alopecia (AGA increases with age and it affects both men and women. Patients diagnosed with AGA may experience decreased quality of life, depression, and feel self-conscious. There are a variety of therapeutic options ranging from prescription drugs to non-prescription medications. Currently, AGA involves an annual global market revenue of US$4 billion and a growth rate of 1.8%, indicating a growing consumer market. Although natural and synthetic ingredients can promote hair growth and, therefore, be useful to treat AGA, some of them have important adverse effects and unknown mechanisms of action that limit their use and benefits. Biologic factors that include signaling from stem cells, dermal papilla cells, and platelet-rich plasma are some of the current therapeutic agents being studied for hair restoration with milder side effects. However, most of the mechanisms exerted by these factors in hair restoration are still being researched. In this review, we analyze the therapeutic agents that have been used for AGA and emphasize the potential of new therapies based on advances in stem cell technologies and regenerative medicine. Keywords: stem cells, stem cell therapies, hair follicle, dermal papilla, androgenic alopecia, laser, hair regeneration
Does vitamin C have the ability to augment the therapeutic effect of bone marrow-derived mesenchymal stem cells on spinal cord injury?

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Nesrine Salem

2017-01-01

Full Text Available Methylprednisolone (MP is currently the only drug confirmed to exhibit a neuroprotective effect on acute spinal cord injury (SCI. Vitamin C (VC is a natural water-soluble antioxidant that exerts neuroprotective effects through eliminating free radical damage to nerve cells. Bone marrow mesenchymal stem cells (BMMSCs, as multipotent stem cells, are promising candidates in SCI repair. To evaluate the therapeutic effects of MP, VC and BMMSCs on traumatic SCI, 80 adult male rats were randomly divided into seven groups: control, SCI (SCI induction by weight-drop method, MP (SCI induction, followed by administration of 30 mg/kg MP via the tail vein, once every other 6 hours, for five times, VC (SCI induction, followed by intraperitoneal administration of 100 mg/kg VC once a day, for 28 days, MP + VC (SCI induction, followed by administration of MP and VC as the former, BMMSCs (SCI induction, followed by injection of 3 × 106 BMMSCs at the injury site, and BMMSCs + VC (SCI induction, followed by BMMSCs injection and VC administration as the former. Locomotor recovery was assessed using the Basso Mouse Scale. Injured spinal cord tissue was evaluated using hematoxylin-eosin staining and immunohistochemical staining. Expression of transforming growth factor-beta, tumor necrosis factor-alpha, and matrix metalloproteinase-2 genes was determined using real-time quantitative PCR. BMMSCs intervention better promoted recovery of nerve function of rats with SCI, mitigated nerve cell damage, and decreased expression of transforming growth factor-beta, tumor necrosis factor-alpha, and matrix metalloproteinase-2 genes than MP and/or VC. More importantly, BMMSCs in combination with VC induced more obvious improvements. These results suggest that VC can enhance the neuroprotective effects of BMMSCs against SCI.
Telmisartan Exerts Anti-Tumor Effects by Activating Peroxisome Proliferator-Activated Receptor-γ in Human Lung Adenocarcinoma A549 Cells

Directory of Open Access Journals (Sweden)

Juan Li

2014-03-01

Full Text Available Telmisartan, a member of the angiotensin II type 1 receptor blockers, is usually used for cardiovascular diseases. Recent studies have showed that telmisartan has the property of PPARγ activation. Meanwhile, PPARγ is essential for tumor proliferation, invasion and metastasis. In this work we explore whether telmisartan could exert anti-tumor effects through PPARγ activation in A549 cells. MTT and trypan blue exclusion assays were included to determine the survival rates and cell viabilities. RT-PCR and western blotting were used to analyze the expression of ICAM-1, MMP-9 and PPARγ. DNA binding activity of PPARγ was evaluated by EMSA. Our data showed that the survival rates and cell viabilities of A549 cells were all reduced by telmisartan in a time- and concentration-dependent manner. Meanwhile, our results also demonstrated that telmisartan dose-dependently inhibited the expression of ICAM-1 and MMP-9. Moreover, the cytotoxic and anti-proliferative effects, ICAM-1 and MMP-9 inhibitive properties of telmisartan were totally blunted by the PPARγ antagonist GW9662. Our findings also showed that the expression of PPARγ was up-regulated by telmisartan in a dose dependent manner. And, the EMSA results also figured out that DNA binding activity of PPARγ was dose-dependently increased by telmisartan. Additionally, our data also revealed that telmisartan-induced PPARγ activation was abrogated by GW9662. Taken together, our results indicated that telmisartan inhibited the expression of ICAM-1 and MMP-9 in A549 cells, very likely through the up-regulation of PPARγ synthesis.
Epigonal Conditioned Media from Bonnethead Shark, Sphyrna tiburo, Induces Apoptosis in a T-Cell Leukemia Cell Line, Jurkat E6-1

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Courtney Bennett

2013-08-01

Full Text Available Representatives of Subclass Elasmobranchii are cartilaginous fish whose members include sharks, skates, and rays. Because of their unique phylogenetic position of being the most primitive group of vertebrates to possess all the components necessary for an adaptive immune system, the immune regulatory compounds they possess may represent the earliest evolutionary forms of novel compounds with the potential for innovative therapeutic applications. Conditioned medium, generated from short term culture of cells from the epigonal organ of bonnethead sharks (Sphyrna tiburo, has been shown to have potent reproducible cytotoxic activity against a variety of human tumor cell lines in vitro. Existing data suggest that epigonal conditioned medium (ECM exerts this cytotoxic activity through induction of apoptosis in target cells. This manuscript describes apoptosis induction in a representative tumor cell line, Jurkat E6-1, in response to treatment with ECM at concentrations of 1 and 2 mg/mL. Data indicate that ECM exposure initiates the mitochondrial pathway of apoptosis through activation of caspase enzymes. Future purification of ECM components may result in the isolation of an immune-regulatory compound with potential therapeutic benefit for treatment of human cancer.

Immortalized human myotonic dystrophy muscle cell lines to assess therapeutic compounds

OpenAIRE

Arandel, Ludovic; Polay Espinoza, Micaela; Matloka, Magdalena; Bazinet, Audrey; De Dea Diniz, Damily; Naouar, Na?ra; Rau, Fr?d?rique; Jollet, Arnaud; Edom-Vovard, Fr?d?rique; Mamchaoui, Kamel; Tarnopolsky, Mark; Puymirat, Jack; Battail, Christophe; Boland, Anne; Deleuze, Jean-Francois

2017-01-01

International audience; Myotonic dystrophy type 1 (DM1) and type 2 (DM2) are autosomal dominant neuromuscular diseases caused by microsatellite expansions and belong to the family of RNA-dominant disorders. Availability of cellular models in which the DM mutation is expressed within its natural context is essential to facilitate efforts to identify new therapeutic compounds. Here, we generated immortalized DM1 and DM2 human muscle cell lines that display nuclear RNA aggregates of expanded rep...
First-in-class inhibitor of the T cell receptor for the treatment of autoimmune diseases.

Science.gov (United States)

Borroto, Aldo; Reyes-Garau, Diana; Jiménez, M Angeles; Carrasco, Esther; Moreno, Beatriz; Martínez-Pasamar, Sara; Cortés, José R; Perona, Almudena; Abia, David; Blanco, Soledad; Fuentes, Manuel; Arellano, Irene; Lobo, Juan; Heidarieh, Haleh; Rueda, Javier; Esteve, Pilar; Cibrián, Danay; Martinez-Riaño, Ana; Mendoza, Pilar; Prieto, Cristina; Calleja, Enrique; Oeste, Clara L; Orfao, Alberto; Fresno, Manuel; Sánchez-Madrid, Francisco; Alcamí, Antonio; Bovolenta, Paola; Martín, Pilar; Villoslada, Pablo; Morreale, Antonio; Messeguer, Angel; Alarcon, Balbino

2016-12-21

Modulating T cell activation is critical for treating autoimmune diseases but requires avoiding concomitant opportunistic infections. Antigen binding to the T cell receptor (TCR) triggers the recruitment of the cytosolic adaptor protein Nck to a proline-rich sequence in the cytoplasmic tail of the TCR's CD3ε subunit. Through virtual screening and using combinatorial chemistry, we have generated an orally available, low-molecular weight inhibitor of the TCR-Nck interaction that selectively inhibits TCR-triggered T cell activation with an IC 50 (median inhibitory concentration) ~1 nM. By modulating TCR signaling, the inhibitor prevented the development of psoriasis and asthma and, furthermore, exerted a long-lasting therapeutic effect in a model of autoimmune encephalomyelitis. However, it did not prevent the generation of a protective memory response against a mouse pathogen, suggesting that the compound might not exert its effects through immunosuppression. These results suggest that inhibiting an immediate TCR signal has promise for treating a broad spectrum of human T cell-mediated autoimmune and inflammatory diseases. Copyright © 2016, American Association for the Advancement of Science.
Colon-targeted delivery of piceatannol enhances anti-colitic effects of the natural product: potential molecular mechanisms for therapeutic enhancement

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Yum S

2015-08-01

Full Text Available Soohwan Yum, Seongkeun Jeong, Sunyoung Lee, Joon Nam, Wooseong Kim, Jin-Wook Yoo, Min-Soo Kim, Bok Luel Lee, Yunjin Jung College of Pharmacy, Pusan National University, Busan, Republic of Korea Abstract: Piceatannol (PCT, an anti-colitic natural product, undergoes extensive Phase II hepatic metabolism, resulting in very low bioavailability. We investigated whether colon-targeted delivery of PCT could enhance anti-colitic effects and how therapeutic enhancement occurred at the molecular level. Molecular effects of PCT were examined in human colon carcinoma cells and inflamed colons. The anti-colitic effects of PCT in a colon-targeted capsule (colon-targeted PCT were compared with PCT in a gelatin capsule (conventional PCT in a trinitrobenzene sulfonic acid-induced rat colitis model. Colon-targeted PCT elicited greatly enhanced recovery of the colonic inflammation. In HCT116 cells, PCT inhibited nuclear factor kappaB while activating anti-colitic transcription factors, nuclear factor-erythroid 2 (NF-E2 p45-related factor 2, and hypoxia-inducible factor-1. Colon-targeted PCT, but not conventional PCT, modulated production of the target gene products of the transcription factors in the inflamed colonic tissues. Rectal administration of PCT, which simulates the therapeutic action of colon-targeted PCT, also ameliorated rat colitis and reproduced the molecular effects in the inflamed colonic tissues. Colon-targeted delivery increased therapeutic efficacy of PCT against colitis, likely resulting from multitargeted effects exerted by colon-targeted PCT. The drug delivery technique may be useful for therapeutic optimization of anti-colitic lead compounds including natural products. Keywords: piceatannol, colitis, colon-targeted delivery, multitarget, polypharmacology
Regulatory B cells: an exciting target for future therapeutics in transplantation

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Alexandre eNouël

2014-01-01

Full Text Available Transplantation is the preferred treatment for most end-stage solid organ diseases. Despite potent immunosuppressive agents, chronic rejection remains a real problem in transplantation. For many years, the predominant immunological focus of research into transplant rejection has been T cells. The pillar of immunotherapy in clinical practice is T cell-directed, which efficiently prevents acute T cell-mediated allograft rejection. However, the root of late allograft failure is chronic rejection and the humoral arm of the immune response now emerges as an important factor in transplantation. Thus, the potential effects of Abs and B cell infiltrates on transplants have cast B cells as major actors in late graft rejection. Consequently, a number of recent drugs target either B cells or plasma cells. However, immunotherapies, such as the anti-CD20 B cell-depleting Ab, can generate deleterious effects on the transplant, likely due to the deletion of beneficial population. The positive contribution of regulatory B (Breg cells -or B10 cells- has been reported in the case of transplantation, mainly in mice models and highlights the primordial role that some populations of B cells can play in graft tolerance. Yet, this regulatory aspect remains poorly characterized in clinical transplantation. Thus, total B cell depletion treatments should be avoided and novel approaches should be considered that manipulate the different B cell subsets. This article provides an overview of the current knowledge on the link between Breg cells and grafts, and reports a number of data advising Breg cells as a new target for future therapeutic approaches.
Therapeutic effect of cortistatin on experimental arthritis by downregulating inflammatory and Th1 responses.

Science.gov (United States)

Gonzalez-Rey, Elena; Chorny, Alejo; Del Moral, Raimundo G; Varela, Nieves; Delgado, Mario

2007-05-01

Rheumatoid arthritis is a chronic autoimmune disease of unknown aetiology characterised by chronic inflammation in the joints and subsequent destruction of the cartilage and bone. To propose a new strategy for the treatment of arthritis based on the administration of cortistatin, a newly discovered neuropeptide with anti-inflammatory actions. DBA/1J mice with collagen-induced arthritis were treated with cortistatin after the onset of disease, and the clinical score and joint histopathology were evaluated. Inflammatory response was determined by measuring the levels of various inflammatory mediators (cytokines and chemokines) in joints and serum. T helper cell type 1 (Th1)-mediated autoreactive response was evaluated by determining the proliferative response and cytokine profile of draining lymph node cells stimulated with collagen and by assaying the content of serum autoantibodies. Cortistatin treatment significantly reduced the severity of established collagen-induced arthritis, completely abrogating joint swelling and destruction of cartilage and bone. The therapeutic effect of cortistatin was associated with a striking reduction in the two deleterious components of the disease-that is, the Th1-driven autoimmune and inflammatory responses. Cortistatin downregulated the production of various inflammatory cytokines and chemokines, decreased the antigen-specific Th1-cell expansion, and induced the production of regulatory cytokines, such as interleukin 10 and transforming growth factor beta1. Cortistatin exerted its effects on synovial cells through both somatostatin and ghrelin receptors, showing a higher effect than both peptides protecting against experimental arthritis. This work provides a powerful rationale for the assessment of the efficacy of cortistatin as a novel therapeutic approach to the treatment of rheumatoid arthritis.
[Cardiac invasion of ATLL cells and therapeutic effects of local along with systemic treatments].

Science.gov (United States)

Imoto, S; Nakagawa, T; Ito, M

1989-07-01

We report a rare case of adult T cell leukemia/lymphoma (ATLL) in which cardiac invasion was clinically demonstrated and treated effectively. A 45-year-old female was admitted because of exertional dyspnea and cervical tumors. The leukocyte count was 19,100/microliters with 20% of flower cells. HTLV-I antibody was positive. She was diagnosed as ATLL and treated with VEPA. She got remission for a short duration which was followed by relapse. OPEC was started as salvage therapy. In the course, extensive pericardial effusion was found in chest X-P. Pericardial puncture demonstrated ATLL cells and high titer of free IL-2 receptor (57,400U/ml) in the effusion. It was diagnosed as pericardial invasion of ATLL cells. Chemotherapy was started with new combination of drugs (cisplatin, mitoxantrone, ifosfamide, and prednisolone). Concomitantly pericardial drainage was performed and the drugs were administered directly into the pericardial cavity. The clinical improvement was obtained and pericardial effusion did not appear thereafter. She died 4 months after the diagnosis of cardiac invasion. On autopsy myocardial invasion was identified. The pericardium widely adhered and effusion measured 42 ml.
The use of mesenchymal stem cells (MSCs) for amyotrophic lateral sclerosis (ALS) therapy - a perspective on cell biological mechanisms.

Science.gov (United States)

Tang, Bor Luen

2017-10-26

Recent clinical trials of mesenchymal stem cells (MSCs) transplantation have demonstrated procedural safety and clinical proof of principle with a modest indication of benefit in patients with amyotrophic lateral sclerosis (ALS). While replacement therapy remained unrealistic, the clinical efficacy of this therapeutic option could be potentially enhanced if we could better decipher the mechanisms underlying some of the beneficial effects of transplanted cells, and work toward augmenting or combining these in a strategic manner. Novel ways whereby MSCs could act in modifying disease progression should also be explored. In this review, I discuss the known, emerging and postulated mechanisms of action underlying effects that transplanted MSCs may exert to promote motor neuron survival and/or to encourage regeneration in ALS. I shall also speculate on how transplanted cells may alter the diseased environment so as to minimize non-neuron cell autonomous damages by immune cells and astrocytes.
A highly efficient method for generation of therapeutic quality human pluripotent stem cells by using naive induced pluripotent stem cells nucleus for nuclear transfer.

Science.gov (United States)

Sanal, Madhusudana Girija

2014-01-01

Even after several years since the discovery of human embryonic stem cells and induced pluripotent stem cells (iPSC), we are still unable to make any significant therapeutic benefits out of them such as cell therapy or generation of organs for transplantation. Recent success in somatic cell nuclear transfer (SCNT) made it possible to generate diploid embryonic stem cells, which opens up the way to make high-quality pluripotent stem cells. However, the process is highly inefficient and hence expensive compared to the generation of iPSC. Even with the latest SCNT technology, we are not sure whether one can make therapeutic quality pluripotent stem cell from any patient's somatic cells or by using oocytes from any donor. Combining iPSC technology with SCNT, that is, by using the nucleus of the candidate somatic cell which got reprogrammed to pluripotent state instead that of the unmodified nucleus of the candidate somatic cell, would boost the efficiency of the technique, and we would be able to generate therapeutic quality pluripotent stem cells. Induced pluripotent stem cell nuclear transfer (iPSCNT) combines the efficiency of iPSC generation with the speed and natural reprogramming environment of SCNT. The new technique may be called iPSCNT. This technique could prove to have very revolutionary benefits for humankind. This could be useful in generating organs for transplantation for patients and for reproductive cloning, especially for childless men and women who cannot have children by any other techniques. When combined with advanced gene editing techniques (such as CRISPR-Cas system) this technique might also prove useful to those who want to have healthy children but suffer from inherited diseases. The current code of ethics may be against reproductive cloning. However, this will change with time as it happened with most of the revolutionary scientific breakthroughs. After all, it is the right of every human to have healthy offspring and it is the question of
A highly efficient method for generation of therapeutic quality human pluripotent stem cells by using naive induced pluripotent stem cells nucleus for nuclear transfer

Directory of Open Access Journals (Sweden)

Madhusudana Girija Sanal

2014-09-01

Full Text Available Even after several years since the discovery of human embryonic stem cells and induced pluripotent stem cells (iPSC, we are still unable to make any significant therapeutic benefits out of them such as cell therapy or generation of organs for transplantation. Recent success in somatic cell nuclear transfer (SCNT made it possible to generate diploid embryonic stem cells, which opens up the way to make high-quality pluripotent stem cells. However, the process is highly inefficient and hence expensive compared to the generation of iPSC. Even with the latest SCNT technology, we are not sure whether one can make therapeutic quality pluripotent stem cell from any patient’s somatic cells or by using oocytes from any donor. Combining iPSC technology with SCNT, that is, by using the nucleus of the candidate somatic cell which got reprogrammed to pluripotent state instead that of the unmodified nucleus of the candidate somatic cell, would boost the efficiency of the technique, and we would be able to generate therapeutic quality pluripotent stem cells. Induced pluripotent stem cell nuclear transfer (iPSCNT combines the efficiency of iPSC generation with the speed and natural reprogramming environment of SCNT. The new technique may be called iPSCNT. This technique could prove to have very revolutionary benefits for humankind. This could be useful in generating organs for transplantation for patients and for reproductive cloning, especially for childless men and women who cannot have children by any other techniques. When combined with advanced gene editing techniques (such as CRISPR-Cas system this technique might also prove useful to those who want to have healthy children but suffer from inherited diseases. The current code of ethics may be against reproductive cloning. However, this will change with time as it happened with most of the revolutionary scientific breakthroughs. After all, it is the right of every human to have healthy offspring and it is
Vaticaffinol, a resveratrol tetramer, exerts more preferable immunosuppressive activity than its precursor in vitro and in vivo through multiple aspects against activated T lymphocytes

Energy Technology Data Exchange (ETDEWEB)

Feng, Li-Li; Wu, Xue-Feng; Liu, Hai-Liang; Guo, Wen-Jie; Luo, Qiong; Tao, Fei-Fei; Ge, Hui-Ming; Shen, Yan; Tan, Ren-Xiang; Xu, Qiang, E-mail: molpharm@163.com; Sun, Yang, E-mail: yangsun@nju.edu.cn

2013-03-01

In the present study, we aimed to investigate the immunosuppressive activity of vaticaffinol, a resveratrol tetramer isolated from Vatica mangachapoi, on T lymphocytes both in vitro and in vivo, and further explored its potential molecular mechanism. Resveratrol had a wide spectrum of healthy beneficial effects with multiple targets. Interestingly, its tetramer, vaticaffinol, exerted more intensive immunosuppressive activity than resveratrol. Vaticaffinol significantly inhibited T cells proliferation activated by concanavalin A (Con A) or anti-CD3 plus anti-CD28 in a dose- and time-dependent manner. It also induced Con A-activated T cells undergoing apoptosis through mitochondrial pathway. Moreover, this compound prevented cells from entering S phase and G2/M phase during T cells activation. In addition, vaticaffinol inhibited ERK and AKT signaling pathways in Con A-activated T cells. Furthermore, vaticaffinol significantly ameliorated ear swelling in a mouse model of picryl chloride-induced ear contact dermatitis in vivo. In most of the aforementioned experiments, however, resveratrol had only slight effects on the inhibition of T lymphocytes compared with vaticaffinol. Taken together, our findings suggest that vaticaffinol exerts more preferable immunosuppressive activity than its precursor resveratrol both in vitro and in vivo by affecting multiple targets against activated T cells. - Graphical abstract: Vaticaffinol, a resveratrol tetramer isolated from Vatica mangachapoi, exerts more intensive immunosuppressive activity than its precursor resveratrol does in vitro and in vivo. Its mechanism may involve multiple effects against activated T cells: regulation of signalings involved in cell proliferation, G0/G1 arrest of T cells, as well as an apoptosis induction in activated effector T cells. Highlights: ► Vaticaffinol, a resveratrol tetramer, exerts more potent activity than its precursor. ► It inhibited T cells proliferation and prevented them from entering
Vaticaffinol, a resveratrol tetramer, exerts more preferable immunosuppressive activity than its precursor in vitro and in vivo through multiple aspects against activated T lymphocytes

International Nuclear Information System (INIS)

Feng, Li-Li; Wu, Xue-Feng; Liu, Hai-Liang; Guo, Wen-Jie; Luo, Qiong; Tao, Fei-Fei; Ge, Hui-Ming; Shen, Yan; Tan, Ren-Xiang; Xu, Qiang; Sun, Yang

2013-01-01

In the present study, we aimed to investigate the immunosuppressive activity of vaticaffinol, a resveratrol tetramer isolated from Vatica mangachapoi, on T lymphocytes both in vitro and in vivo, and further explored its potential molecular mechanism. Resveratrol had a wide spectrum of healthy beneficial effects with multiple targets. Interestingly, its tetramer, vaticaffinol, exerted more intensive immunosuppressive activity than resveratrol. Vaticaffinol significantly inhibited T cells proliferation activated by concanavalin A (Con A) or anti-CD3 plus anti-CD28 in a dose- and time-dependent manner. It also induced Con A-activated T cells undergoing apoptosis through mitochondrial pathway. Moreover, this compound prevented cells from entering S phase and G2/M phase during T cells activation. In addition, vaticaffinol inhibited ERK and AKT signaling pathways in Con A-activated T cells. Furthermore, vaticaffinol significantly ameliorated ear swelling in a mouse model of picryl chloride-induced ear contact dermatitis in vivo. In most of the aforementioned experiments, however, resveratrol had only slight effects on the inhibition of T lymphocytes compared with vaticaffinol. Taken together, our findings suggest that vaticaffinol exerts more preferable immunosuppressive activity than its precursor resveratrol both in vitro and in vivo by affecting multiple targets against activated T cells. - Graphical abstract: Vaticaffinol, a resveratrol tetramer isolated from Vatica mangachapoi, exerts more intensive immunosuppressive activity than its precursor resveratrol does in vitro and in vivo. Its mechanism may involve multiple effects against activated T cells: regulation of signalings involved in cell proliferation, G0/G1 arrest of T cells, as well as an apoptosis induction in activated effector T cells. Highlights: ► Vaticaffinol, a resveratrol tetramer, exerts more potent activity than its precursor. ► It inhibited T cells proliferation and prevented them from entering
Pomegranate exerts chemoprevention of experimentally induced mammary tumorigenesis by suppression of cell proliferation and induction of apoptosis.

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Bishayee, Anupam; Mandal, Animesh; Bhattacharyya, Piyali; Bhatia, Deepak

2016-01-01

Breast cancer is the second leading cause of cancer-related death in women in the United States and discovery and development of safe chemopreventive drugs is urgently needed. The fruit pomegranate (Punica granatum) is gaining importance because of its various health benefits. This study was initiated to investigate chemopreventive potential of a pomegranate emulsion (PE) against 7,12-dimethylbenz(a)anthracene (DMBA) rat mammary carcinogenesis. The animals were orally administered with PE (0.2-5.0 g/kg), starting 2 wk before and 16 wk following DMBA treatment. PE exhibited a striking reduction of DMBA-induced mammary tumor incidence, total tumor burden, and reversed histopathological changes. PE dose-dependently suppressed cell proliferation and induced apoptosis in mammary tumors. Immunohistochemical studies showed that PE increased intratumor Bax, decreased Bcl2 and manifested a proapoptotic shift in Bax/Bcl2 ratio. In addition, our gene expression study showed PE-mediated upregulation of Bad, caspase-3, caspase-7, caspase-9, poly (ADP ribose) polymerase and cytochrome c in mammary tumors. Thus, PE exerts chemoprevention of mammary carcinogenesis by suppressing cell proliferation and inducing apoptosis mediated through upregulation of Bax and downregulation of Bcl2 in concert with caspase cascades. Pomegranate bioactive phytoconstituents could be developed as a chemopreventive drug to reduce the risk of breast cancer.
Possible Therapeutic Application of Targeting Type II Natural Killer T Cell-Mediated Suppression of Tumor Immunity

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Kato, Shingo; Berzofsky, Jay A.; Terabe, Masaki

2018-01-01

Natural killer T (NKT) cells are a unique T cell subset that exhibits characteristics from both the innate immune cells and T cells. There are at least two subsets of NKT cells, type I and type II. These two subsets of NKT cells have opposite functions in antitumor immunity. Type I NKT cells usually enhance and type II NKT cells suppress antitumor immunity. In addition, these two subsets of NKT cells cross-regulate each other. In this review, we mainly focus on immunosuppressive NKT cells, type II NKT cells. After summarizing their definition, experimental tools to study them, and subsets of them, we will discuss possible therapeutic applications of type II NKT cell pathway targeted therapies. PMID:29520281
Mast cell inhibition as a therapeutic approach in fibrodysplasia ossificans progressiva (FOP).

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Brennan, Tracy A; Lindborg, Carter M; Bergbauer, Christian R; Wang, Haitao; Kaplan, Frederick S; Pignolo, Robert J

2018-04-01

Episodic flare-ups of fibrodysplasia ossificans progressiva (FOP) are characterized clinically by severe, often posttraumatic, connective tissue swelling and intramuscular edema, followed histologically by an intense and highly angiogenic fibroproliferative reaction. This early inflammatory and angiogenic fibroproliferative response is accompanied by the presence of abundant mast cells far in excess of other reported myopathies. Using an injury-induced, constitutively-active transgenic mouse model of FOP we show that mast cell inhibition by cromolyn, but not aprepitant, results in a dramatic reduction of heterotopic ossification. Cromolyn, but not aprepitant, significantly decreases the total number of mast cells in FOP lesions. Furthermore, cromolyn specifically diminishes the number of degranulating and resting degranulated mast cells in pre-osseous lesions. This work demonstrates that consideration of FOP as a type of localized mastocytosis may offer new therapeutic interventions for treatment of this devastating condition. Copyright © 2017 Elsevier Inc. All rights reserved.
RBP-J-interacting and tubulin-associated protein induces apoptosis and cell cycle arrest in human hepatocellular carcinoma by activating the p53–Fbxw7 pathway

International Nuclear Information System (INIS)

Wang, Haihe; Yang, Zhanchun; Liu, Chunbo; Huang, Shishun; Wang, Hongzhi; Chen, Yingli; Chen, Guofu

2014-01-01

Highlights: • RITA overexpression increased protein expression of p53 and Fbxw7 and downregulated the expression of cyclin D1, cyclin E, CDK2, Hes-1 and NF-κB p65. • RITA can significantly inhibit the in vitro growth of SMMC7721 and HepG2 cells. • RITA exerts tumor-suppressive effects in hepatocarcinogenesis through induction of G0/G1 cell cycle arrest and apoptosis and suggest a therapeutic application of RITA in HCC. - Abstract: Aberrant Notch signaling is observed in human hepatocellular carcinoma (HCC) and has been associated with the modulation of cell growth. However, the role of Notch signaling in HCC and its underlying mechanism remain elusive. RBP-J-interacting and tubulin-associated (RITA) mediates the nuclear export of RBP-J to tubulin fibers and downregulates Notch-mediated transcription. In this study, we found that RITA overexpression increased protein expression of p53 and Fbxw7 and downregulated the expression of cyclin D1, cyclin E, CDK2, Hes-1 and NF-κB p65. These changes led to growth inhibition and induced G0/G1 cell cycle arrest and apoptosis in SMMC7721 and HepG2 cells. Our findings indicate that RITA exerts tumor-suppressive effects in hepatocarcinogenesis through induction of G0/G1 cell cycle arrest and apoptosis and suggest a therapeutic application of RITA in HCC
Cell-mediated immune response: a clinical review of the therapeutic potential of human papillomavirus vaccination.

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Meyer, Sonja Izquierdo; Fuglsang, Katrine; Blaakaer, Jan

2014-12-01

This clinical review aims to assess the efficacy of human papillomavirus 16/18 (HPV16/18) vaccination on the cell-mediated immune response in women with existing cervical intraepithelial neoplasia or cervical cancer induced by HPV16 or HPV18. A focused and thorough literature search conducted in five different databases found 996 publications. Six relevant articles were chosen for further review. In total, 154 patients (>18 years of age) were enrolled in prospective study trials with 3-15 months of follow up. The vaccine applications were administered two to four times. The vaccines contained different combinations of HPV16 and HPV18 and early proteins, E6 and E7. The primary outcome was the cell-mediated immune response. Correlation to clinical outcome (histopathology) and human leukocyte antigen genes were secondary endpoints. All vaccines triggered a detectable cell-mediated immune response, some of which were statistically significant. Correlations between immunological response and clinical outcome (histopathology) were not significant, so neoplasms may not be susceptible to vaccine-generated cytotoxic T cells (CD8(+)). Prophylactic HPV vaccines have been introduced to reduce the incidence of cervical cancer in young women. Women already infected with HPV could benefit from a therapeutic HPV vaccination. Hence, it is important to continue the development of therapeutic HPV vaccines to lower the rate of HPV-associated malignancies and crucial to evaluate vaccine efficacy clinically. This clinical review represents an attempt to elucidate the theories supporting the development of an HPV vaccine with a therapeutic effect on human papillomavirus-induced malignancies of the cervix. © 2014 Nordic Federation of Societies of Obstetrics and Gynecology.
Identification of novel therapeutic targets in microdissected clear cell ovarian cancers.

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Michael P Stany

Full Text Available Clear cell ovarian cancer is an epithelial ovarian cancer histotype that is less responsive to chemotherapy and carries poorer prognosis than serous and endometrioid histotypes. Despite this, patients with these tumors are treated in a similar fashion as all other ovarian cancers. Previous genomic analysis has suggested that clear cell cancers represent a unique tumor subtype. Here we generated the first whole genomic expression profiling using epithelial component of clear cell ovarian cancers and normal ovarian surface specimens isolated by laser capture microdissection. All the arrays were analyzed using BRB ArrayTools and PathwayStudio software to identify the signaling pathways. Identified pathways validated using serous, clear cell cancer cell lines and RNAi technology. In vivo validations carried out using an orthotopic mouse model and liposomal encapsulated siRNA. Patient-derived clear cell and serous ovarian tumors were grafted under the renal capsule of NOD-SCID mice to evaluate the therapeutic potential of the identified pathway. We identified major activated pathways in clear cells involving in hypoxic cell growth, angiogenesis, and glucose metabolism not seen in other histotypes. Knockdown of key genes in these pathways sensitized clear cell ovarian cancer cell lines to hypoxia/glucose deprivation. In vivo experiments using patient derived tumors demonstrate that clear cell tumors are exquisitely sensitive to antiangiogenesis therapy (i.e. sunitinib compared with serous tumors. We generated a histotype specific, gene signature associated with clear cell ovarian cancer which identifies important activated pathways critical for their clinicopathologic characteristics. These results provide a rational basis for a radically different treatment for ovarian clear cell patients.
LUBAC-Recruited CYLD and A20 Regulate Gene Activation and Cell Death by Exerting Opposing Effects on Linear Ubiquitin in Signaling Complexes

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Peter Draber

2015-12-01

Full Text Available Ubiquitination and deubiquitination are crucial for assembly and disassembly of signaling complexes. LUBAC-generated linear (M1 ubiquitin is important for signaling via various immune receptors. We show here that the deubiquitinases CYLD and A20, but not OTULIN, are recruited to the TNFR1- and NOD2-associated signaling complexes (TNF-RSC and NOD2-SC, at which they cooperate to limit gene activation. Whereas CYLD recruitment depends on its interaction with LUBAC, but not on LUBAC’s M1-chain-forming capacity, A20 recruitment requires this activity. Intriguingly, CYLD and A20 exert opposing effects on M1 chain stability in the TNF-RSC and NOD2-SC. While CYLD cleaves M1 chains, and thereby sensitizes cells to TNF-induced death, A20 binding to them prevents their removal and, consequently, inhibits cell death. Thus, CYLD and A20 cooperatively restrict gene activation and regulate cell death via their respective activities on M1 chains. Hence, the interplay between LUBAC, M1-ubiquitin, CYLD, and A20 is central for physiological signaling through innate immune receptors.
Inhibition of HSP27 alone or in combination with pAKT inhibition as therapeutic approaches to target SPARC-induced glioma cell survival

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Schultz Chad R

2012-04-01

Full Text Available Abstract Background The current treatment regimen for glioma patients is surgery, followed by radiation therapy plus temozolomide (TMZ, followed by 6 months of adjuvant TMZ. Despite this aggressive treatment regimen, the overall survival of all surgically treated GBM patients remains dismal, and additional or different therapies are required. Depending on the cancer type, SPARC has been proposed both as a therapeutic target and as a therapeutic agent. In glioma, SPARC promotes invasion via upregulation of the p38 MAPK/MAPKAPK2/HSP27 signaling pathway, and promotes tumor cell survival by upregulating pAKT. As HSP27 and AKT interact to regulate the activity of each other, we determined whether inhibition of HSP27 was better than targeting SPARC as a therapeutic approach to inhibit both SPARC-induced glioma cell invasion and survival. Results Our studies found the following. 1 SPARC increases the expression of tumor cell pro-survival and pro-death protein signaling in balance, and, as a net result, tumor cell survival remains unchanged. 2 Suppressing SPARC increases tumor cell survival, indicating it is not a good therapeutic target. 3 Suppressing HSP27 decreases tumor cell survival in all gliomas, but is more effective in SPARC-expressing tumor cells due to the removal of HSP27 inhibition of SPARC-induced pro-apoptotic signaling. 4 Suppressing total AKT1/2 paradoxically enhanced tumor cell survival, indicating that AKT1 or 2 are poor therapeutic targets. 5 However, inhibiting pAKT suppresses tumor cell survival. 6 Inhibiting both HSP27 and pAKT synergistically decreases tumor cell survival. 7 There appears to be a complex feedback system between SPARC, HSP27, and AKT. 8 This interaction is likely influenced by PTEN status. With respect to chemosensitization, we found the following. 1 SPARC enhances pro-apoptotic signaling in cells exposed to TMZ. 2 Despite this enhanced signaling, SPARC protects cells against TMZ. 3 This protection can be reduced
Glyceraldehyde-3-phosphate dehydrogenase aggregation inhibitor peptide: A potential therapeutic strategy against oxidative stress-induced cell death.

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Itakura, Masanori; Nakajima, Hidemitsu; Semi, Yuko; Higashida, Shusaku; Azuma, Yasu-Taka; Takeuchi, Tadayoshi

2015-11-13

The glycolytic enzyme glyceraldehyde-3-phosphate dehydrogenase (GAPDH) has multiple functions, including mediating oxidative stress-induced neuronal cell death. This process is associated with disulfide-bonded GAPDH aggregation. Some reports suggest a link between GAPDH and the pathogenesis of several oxidative stress-related diseases. However, the pathological significance of GAPDH aggregation in disease pathogenesis remains unclear due to the lack of an effective GAPDH aggregation inhibitor. In this study, we identified a GAPDH aggregation inhibitor (GAI) peptide and evaluated its biological profile. The decapeptide GAI specifically inhibited GAPDH aggregation in a concentration-dependent manner. Additionally, the GAI peptide did not affect GAPDH glycolytic activity or cell viability. The GAI peptide also exerted a protective effect against oxidative stress-induced cell death in SH-SY5Y cells. This peptide could potentially serve as a tool to investigate GAPDH aggregation-related neurodegenerative and neuropsychiatric disorders and as a possible therapy for diseases associated with oxidative stress-induced cell death. Copyright © 2015 Elsevier Inc. All rights reserved.

Globular Adiponectin Inhibits the Apoptosis of Mesenchymal Stem Cells Induced by Hypoxia and Serum Deprivation via the AdipoR1-Mediated Pathway

OpenAIRE

Xia-Qiu Tian; Yue-Jin Yang; Qing Li; Pei-Sen Huang; Xiang-Dong Li; Chen Jin; Kang Qi; Lei-Pei Jiang; Gui-Hao Chen

2016-01-01

Background/Aims: Poor viability of transplanted mesenchymal stem cells (MSCs) within the ischemic heart limits their therapeutic potential for cardiac repair. Globular adiponectin (gAPN) exerts anti-apoptotic effects on several types of stem cells. Herein, we investigated the effect of gAPN on the MSCs against apoptosis induced by hypoxia and serum deprivation (H/SD). Methods: MSCs exposed to H/SD conditions were treated with different concentrations of gAPN. To identify the main type of rece...
The therapeutic CD38 monoclonal antibody daratumumab induces programmed cell death via fcg receptor-mediated cross-linking

DEFF Research Database (Denmark)

Overdijk, Marije B.; Jansen, J. H. Marco; Nederend, Maaike

2016-01-01

RIIb as well as activating FcgRs induce DARA cross-linking-mediated PCD. In conclusion, our in vitro and in vivo data show that FcgRmediated cross-linking of DARA induces PCD of CD38-expressing multiple myeloma tumor cells, which potentially contributes to the depth of response observed in DARA......Emerging evidence suggests that FcgR-mediated cross-linking of tumor-bound mAbs may induce signaling in tumor cells that contributes to their therapeutic activity. In this study, we show that daratumumab (DARA), a therapeutic human CD38 mAb with a broad-spectrum killing activity, is able to induce...... programmed cell death (PCD) of CD38+ multiple myeloma tumor cell lines when cross-linked in vitro by secondary Abs or via an FcgR. By comparing DARA efficacy in a syngeneic in vivo tumor model using FcRg-chain knockout or NOTAM mice carrying a signaling-inactive FcRg-chain, we found that the inhibitory Fcg...
Therapeutic potential of umbilical cord blood cells for type 1 diabetes mellitus.

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He, Binbin; Li, Xia; Yu, Haibo; Zhou, Zhiguang

2015-11-01

Type 1 diabetes mellitus (T1DM) is a chronic disorder that results from autoimmune-mediated destruction of pancreatic islet β-cells. However, to date, no conventional intervention has successfully treated the disease. The optimal therapeutic method for T1DM should effectively control the autoimmunity, restore immune homeostasis, preserve residual β-cells, reverse β-cell destruction, and protect the regenerated insulin-producing cells against re-attack. Umbilical cord blood is rich in regulatory T (T(reg)) cells and multiple types of stem cells that exhibit immunomodulating potential and hold promise in their ability to restore peripheral tolerance towards pancreatic islet β-cells through remodeling of immune responses and suppression of autoreactive T cells. Recently, reinfusion of autologous umbilical cord blood or immune cells from cord blood has been proposed as a novel therapy for T1DM, with the advantages of no risk to the donors, minimal ethical concerns, a low incidence of graft-versus-host disease and easy accessibility. In this review, we revisit the role of autologous umbilical cord blood or immune cells from cord blood-based applications for the treatment of T1DM. © 2015 Ruijin Hospital, Shanghai Jiaotong University School of Medicine and Wiley Publishing Asia Pty Ltd.
Dynamics of Receptor-Mediated Nanoparticle Internalization into Endothelial Cells

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Gonzalez-Rodriguez, David; Barakat, Abdul I.

2015-01-01

Nanoparticles offer a promising medical tool for targeted drug delivery, for example to treat inflamed endothelial cells during the development of atherosclerosis. To inform the design of such therapeutic strategies, we develop a computational model of nanoparticle internalization into endothelial cells, where internalization is driven by receptor-ligand binding and limited by the deformation of the cell membrane and cytoplasm. We specifically consider the case of nanoparticles targeted against ICAM-1 receptors, of relevance for treating atherosclerosis. The model computes the kinetics of the internalization process, the dynamics of binding, and the distribution of stresses exerted between the nanoparticle and the cell membrane. The model predicts the existence of an optimal nanoparticle size for fastest internalization, consistent with experimental observations, as well as the role of bond characteristics, local cell mechanical properties, and external forces in the nanoparticle internalization process. PMID:25901833
Toward a new generation of therapeutics: artificial cell targeted delivery of live cells for therapy.

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Prakash, Satya; Martoni, Christopher

2006-01-01

Scientific evidence in the prevention and treatment of various disorders is accumulating regarding probiotics. The health benefits supported by adequate clinical data include increased resistance to infectious disease, decreased duration of diarrhea, management of inflammatory bowel disease, reduction of serum cholesterol, prevention of allergy, modulation of cytokine gene expression, and suppression of carcinogen production. Recent ventures in metabolic engineering and heterologous protein expression have enhanced the enzymatic and immunomodulatory effects of probiotics and, with time, may allow more active intervention among critical care patients. In addition, a number of approaches are currently being explored, including the physical and chemical protection of cells, to increase probiotic viability and its health benefits. Traditional immobilization of probiotics in gel matrices, most notably calcium alginate and kappa-carrageenan, has frequently been employed, with noted improvements in viability during freezing and storage. Conflicting reports exist, however, on the protection offered by immobilization from harsh physiologic environments. An alternative approach, microencapsulation in "artificial cells," builds on immobilization technologies by combining enhanced mechanical stability of the capsule membrane with improved mass transport, increased cell loading, and greater control of parameters. This review summarizes the current clinical status of probiotics, examines the promises and challenges of current immobilization technologies, and presents the concept of artificial cells for effective delivery of therapeutic bacterial cells.
Mesenchymal stem cell-based gene therapy: A promising therapeutic strategy.

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Mohammadian, Mozhdeh; Abasi, Elham; Akbarzadeh, Abolfazl

2016-08-01

Mesenchymal stem cells (MSCs) are multipotent stromal cells that exist in bone marrow, fat, and so many other tissues, and can differentiate into a variety of cell types including osteoblasts, chondrocytes, and adipocytes, as well as myocytes and neurons. Moreover, they have great capacity for self-renewal while maintaining their multipotency. Their capacity for proliferation and differentiation, in addition to their immunomodulatory activity, makes them very promising candidates for cell-based regenerative medicine. Moreover, MSCs have the ability of mobilization to the site of damage; therefore, they can automatically migrate to the site of injury via their chemokine receptors following intravenous transplantation. In this respect, they can be applied for MSC-based gene therapy. In this new therapeutic method, genes of interest are introduced into MSCs via viral and non-viral-based methods that lead to transgene expression in them. Although stem cell-based gene therapy is a relatively new strategy, it lights a new hope for the treatment of a variety of genetic disorders. In the near future, MSCs can be of use in a vast number of clinical applications, because of their uncomplicated isolation, culture, and genetic manipulation. However, full consideration is still crucial before they are utilized for clinical trials, because the number of studies that signify the advantageous effects of MSC-based gene therapy are still limited.
Paracrine effects and heterogeneity of marrow-derived stem/progenitor cells: relevance for the treatment of respiratory diseases.

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Conese, Massimo; Carbone, Annalucia; Castellani, Stefano; Di Gioia, Sante

2013-01-01

Stem cell-based treatment may represent a hope for the treatment of acute lung injury and pulmonary fibrosis, and other chronic lung diseases, such as cystic fibrosis, asthma and chronic obstructive pulmonary disease (COPD). It is well established in preclinical models that bone marrow-derived stem and progenitor cells exert beneficial effects on inflammation, immune responses and repairing of damage in virtually all lung-borne diseases. While it was initially thought that the positive outcome was due to a direct engraftment of these cells into the lung as endothelial and epithelial cells, paracrine factors are now considered the main mechanism through which stem and progenitor cells exert their therapeutic effect. This knowledge has led to the clinical use of marrow cells in pulmonary hypertension with endothelial progenitor cells (EPCs) and in COPD with mesenchymal stromal (stem) cells (MSCs). Bone marrow-derived stem cells, including hematopoietic stem/progenitor cells, MSCs, EPCs and fibrocytes, encompass a wide array of cell subsets with different capacities of engraftment and injured tissue-regenerating potential. The characterization/isolation of the stem cell subpopulations represents a major challenge to improve the efficacy of transplantation protocols used in regenerative medicine and applied to lung disorders. Copyright © 2013 S. Karger AG, Basel.
A highly efficient method for generation of therapeutic quality human pluripotent stem cells by using naive induced pluripotent stem cells nucleus for nuclear transfer

OpenAIRE

Sanal, Madhusudana Girija

2014-01-01

Even after several years since the discovery of human embryonic stem cells and induced pluripotent stem cells (iPSC), we are still unable to make any significant therapeutic benefits out of them such as cell therapy or generation of organs for transplantation. Recent success in somatic cell nuclear transfer (SCNT) made it possible to generate diploid embryonic stem cells, which opens up the way to make high-quality pluripotent stem cells. However, the process is highly inefficient and hence e...
Magnetic catechin-dextran conjugate as targeted therapeutic for pancreatic tumour cells.

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Vittorio, Orazio; Voliani, Valerio; Faraci, Paolo; Karmakar, Biswajit; Iemma, Francesca; Hampel, Silke; Kavallaris, Maria; Cirillo, Giuseppe

2014-06-01

Catechin-dextran conjugates have recently attracted a lot of attention due to their anticancer activity against a range of cancer cells. Magnetic nanoparticles have the ability to concentrate therapeutically important drugs due to their magnetic-spatial control and provide opportunities for targeted drug delivery. Enhancement of the anticancer efficiency of catechin-dextran conjugate by functionalisation with magnetic iron oxide nanoparticles. Modification of the coating shell of commercial magnetic nanoparticles (Endorem) composed of dextran with the catechin-dextran conjugate. Catechin-dextran conjugated with Endorem (Endo-Cat) increased the intracellular concentration of the drug and it induced apoptosis in 98% of pancreatic tumour cells placed under magnetic field. The conjugation of catechin-dextran with Endorem enhances the anticancer activity of this drug and provides a new strategy for targeted drug delivery on tumour cells driven by magnetic field. The ability to spatially control the delivery of the catechin-dextran by magnetic field makes it a promising agent for further application in cancer therapy.
Therapeutic Potential of Umbilical Cord Blood Stem Cells on Brain Damage of a Model of Stroke

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Mohammad Reza Nikravesh

2011-11-01

Full Text Available Introduction: Human cord blood-derived stem cells are a rich source of stem cells as well as precursors. With regard to the researchers have focused on the therapeutic potential of stem cell in the neurological disease such as stroke, the aim of this study was the investiga-tion of the therapeutic effects of human cord blood-derived stem cells in cerebral ischemia on rat. Methods: This study was carried out on young rats. Firstly, to create a laboratory model of ischemic stroke, carotid artery of animals was occluded for 30 minutes. Then, umbilical cord blood cells were isolated and labeled using bromodeoxyuridine and 2×105 cells were injected into the experimental group via the tail vein. Rats with hypoxic condi-tions were used as a sham group. A group of animals did not receive any injection or sur-geries were used as a control. Results: Obtained results were evaluated based on behavior-al responses and immunohistochemistry, with emphasis on areas of putamen and caudate nucleus in the control, sham and experimental groups. Our results indicated that behavioral recovery was observed in the experimental group compared to the either the sham or the control group. However, histological studies demonstrated a low percent of tissue injury in the experimental group in comparison with the sham group. Conclusion: Stem cell trans-plantation is beneficial for the brain tissue reparation after hypoxic ischemic cell death.
IL8-CXCR2 pathway inhibition as a therapeutic strategy against MDS and AML stem cells.

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Schinke, Carolina; Giricz, Orsolya; Li, Weijuan; Shastri, Aditi; Gordon, Shanisha; Barreyro, Laura; Barreryo, Laura; Bhagat, Tushar; Bhattacharyya, Sanchari; Ramachandra, Nandini; Bartenstein, Matthias; Pellagatti, Andrea; Boultwood, Jacqueline; Wickrema, Amittha; Yu, Yiting; Will, Britta; Wei, Sheng; Steidl, Ulrich; Verma, Amit

2015-05-14

Acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS) are associated with disease-initiating stem cells that are not eliminated by conventional therapies. Novel therapeutic targets against preleukemic stem cells need to be identified for potentially curative strategies. We conducted parallel transcriptional analysis of highly fractionated stem and progenitor populations in MDS, AML, and control samples and found interleukin 8 (IL8) to be consistently overexpressed in patient samples. The receptor for IL8, CXCR2, was also significantly increased in MDS CD34(+) cells from a large clinical cohort and was predictive of increased transfusion dependence. High CXCR2 expression was also an adverse prognostic factor in The Cancer Genome Atlas AML cohort, further pointing to the critical role of the IL8-CXCR2 axis in AML/MDS. Functionally, CXCR2 inhibition by knockdown and pharmacologic approaches led to a significant reduction in proliferation in several leukemic cell lines and primary MDS/AML samples via induction of G0/G1 cell cycle arrest. Importantly, inhibition of CXCR2 selectively inhibited immature hematopoietic stem cells from MDS/AML samples without an effect on healthy controls. CXCR2 knockdown also impaired leukemic growth in vivo. Together, these studies demonstrate that the IL8 receptor CXCR2 is an adverse prognostic factor in MDS/AML and is a potential therapeutic target against immature leukemic stem cell-enriched cell fractions in MDS and AML. © 2015 by The American Society of Hematology.
[Cell-based therapies - an innovative therapeutic option in ophthalmology: Treating corneal diseases with stem cells].

Science.gov (United States)

Bakker, Ann-Christin; Langer, Barbara

2015-11-01

Pathological changes and disorders of the cornea are a major cause of severe visual impairment and blindness. Replacement of a pathologically altered cornea with healthy corneal tissue from the eye of a suitable donor is among the most common and successful transplantation procedures in medicine. In Germany, approximately 5000-6000 corneal transplantations are performed each year, but the total demand per year is estimated to be twice as high. With a success rate of 90%, the outcome of cornea transplantation is very favourable. However, long-term maintenance and regeneration of a healthy new cornea requires tissue-specific corneal stem cells residing at the basal layer of the limbus, which is the annular transition zone between the cornea and sclera. When this important limbal stem cell population is destroyed or dysfunctional, a pathological condition known as limbal stem cell deficiency (LSCD) manifests. Limbal stem cell deficiency describes conditions associated with impaired corneal wound healing and regeneration. In this situation, transplantation of healthy limbal stem cells is the only curative treatment approach for restoration of an intact and functional ocular surface. To date, treatment of LSCD presents a great challenge for ophthalmologists. However, innovative, cell-therapeutic approaches may open new, promising treatment perspectives. In February 2015, the European Commission granted marketing authorization to the first stem cell-based treatment in the European Union. The product named Holoclar® is an advanced therapy medicinal product (ATMP) for the treatment of moderate to severe LSCD due to physical and chemical burns in adults. Further cell-based treatment approaches are in clinical development.
Mesenchymal Stem Cells as New Therapeutic Agents for the Treatment of Primary Biliary Cholangitis

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Aleksandar Arsenijevic

2017-01-01

Full Text Available Primary biliary cholangitis (PBC is a chronic autoimmune cholestatic liver disease characterized by the progressive destruction of small- and medium-sized intrahepatic bile ducts with resultant cholestasis and progressive fibrosis. Ursodeoxycholic acid and obethicholic acid are the only agents approved by the US Food and Drug Administration (FDA for the treatment of PBC. However, for patients with advanced, end-stage PBC, liver transplantation is still the most effective treatment. Accordingly, the alternative approaches, such as mesenchymal stem cell (MSC transplantation, have been suggested as an effective alternative therapy for these patients. Due to their immunomodulatory characteristics, MSCs are considered as promising therapeutic agents for the therapy of autoimmune liver diseases, including PBC. In this review, we have summarized the therapeutic potential of MSCs for the treatment of these diseases, emphasizing molecular and cellular mechanisms responsible for MSC-based effects in an animal model of PBC and therapeutic potential observed in recently conducted clinical trials. We have also presented several outstanding problems including safety issues regarding unwanted differentiation of transplanted MSCs which limit their therapeutic use. Efficient and safe MSC-based therapy for PBC remains a challenging issue that requires continuous cooperation between clinicians, researchers, and patients.
New technology for ultrasensitive detection and isolation of rare cells for clinical diagnostics and therapeutics

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Leary, James F.; McLaughlin, Scott R.

1995-04-01

A high-speed, 11-parameter, 6-color fluorescence, laser flow cytometer/cell sorter with a number of special and unique features has been built for ultrasensitive detection and isolation of rare cells for clinical diagnostics and therapeutics. The software for real-time data acquisition and sort control, written as C++ programming language modules with a WindowsTM graphical user interface, runs on a 66-MHz 80486 computer joined by an extended bus to 23 sophisticated multi-layered boards of special data acquisition and sorting electronics. Special features include: high-speed (> 100,000 cells/sec) real-time data classification module (U.S. Patent 5,204,884 (1993)); real-time principal component cell sorting; multi-queue signal-processing system with multiple hardware and software event buffers to reduce instrument dead time, LUT charge-pulse definition, high-resolution `flexible' sorting for optimal yield/purity sort strategies (U.S. Patent 5,199,576); pre-focusing optical wavelength correction for a second laser beam; and two trains of three fluorescence detectors-- each adjustable for spatial separation to interrogate only one of two laser beams, syringe- driven or pressure-driven fluidics, and time-windowed parameters. The system has been built to be both expandable and versatile through the use of LUT's and a modular hardware and software design. The instrument is especially useful at detection and isolation of rare cell subpopulations for which our laboratory is well-known. Cell subpopulations at frequencies as small as 10-7 have been successfully studied with this system. Current applications in clinical diagnostics and therapeutics include detection and isolation of (1) fetal cells from material blood for prenatal diagnosis of birth defects, (2) hematopoietic stem and precursor cells for autologous bone marrow transplantation, (3) metastatic breast cancer cells for molecular characterization, and (4) HIV-infected maternal cells in newborn blood to study mother
Myeloid-derived suppressor cells in breast cancer.

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Markowitz, Joseph; Wesolowski, Robert; Papenfuss, Tracey; Brooks, Taylor R; Carson, William E

2013-07-01

Myeloid-derived suppressor cells (MDSCs) are a population of immature myeloid cells defined by their suppressive actions on immune cells such as T cells, dendritic cells, and natural killer cells. MDSCs typically are positive for the markers CD33 and CD11b but express low levels of HLADR in humans. In mice, MDSCs are typically positive for both CD11b and Gr1. These cells exert their suppressive activity on the immune system via the production of reactive oxygen species, arginase, and cytokines. These factors subsequently inhibit the activity of multiple protein targets such as the T cell receptor, STAT1, and indoleamine-pyrrole 2,3-dioxygenase. The numbers of MDSCs tend to increase with cancer burden while inhibiting MDSCs improves disease outcome in murine models. MDSCs also inhibit immune cancer therapeutics. In light of the poor prognosis of metastatic breast cancer in women and the correlation of increasing levels of MDSCs with increasing disease burden, the purposes of this review are to (1) discuss why MDSCs may be important in breast cancer, (2) describe model systems used to study MDSCs in vitro and in vivo, (3) discuss mechanisms involved in MDSC induction/function in breast cancer, and (4) present pre-clinical and clinical studies that explore modulation of the MDSC-immune system interaction in breast cancer. MDSCs inhibit the host immune response in breast cancer patients and diminishing MDSC actions may improve therapeutic outcomes.
Therapeutic activity of a Saccharomyces cerevisiae-based probiotic and inactivated whole yeast on vaginal candidiasis.

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Pericolini, Eva; Gabrielli, Elena; Ballet, Nathalie; Sabbatini, Samuele; Roselletti, Elena; Cayzeele Decherf, Amélie; Pélerin, Fanny; Luciano, Eugenio; Perito, Stefano; Jüsten, Peter; Vecchiarelli, Anna

2017-01-02

Vulvovaginal candidiasis is the most prevalent vaginal infection worldwide and Candida albicans is its major agent. Vulvovaginal candidiasis is characterized by disruption of the vaginal microbiota composition, as happens following large spectrum antibiotic usage. Recent studies support the effectiveness of oral and local probiotic treatment for prevention of recurrent vulvovaginal candidiasis. Saccharomyces cerevisiae is a safe yeast used as, or for, the production of ingredients for human nutrition and health. Here, we demonstrate that vaginal administration of probiotic Saccharomyces cerevisiae live yeast (GI) and, in part, inactivated whole yeast Saccharomyces cerevisiae (IY), used as post-challenge therapeutics, was able to positively influence the course of vaginal candidiasis by accelerating the clearance of the fungus. This effect was likely due to multiple interactions of Saccharomyces cerevisiae with Candida albicans. Both live and inactivated yeasts induced coaggregation of Candida and consequently inhibited its adherence to epithelial cells. However, only the probiotic yeast was able to suppress some major virulence factors of Candida albicans such as the ability to switch from yeast to mycelial form and the capacity to express several aspartyl proteases. The effectiveness of live yeast was higher than that of inactivated whole yeast suggesting that the synergy between mechanical effects and biological effects were dominant over purely mechanical effects. The protection of epithelial cells to Candida-induced damage was also observed. Overall, our data show for the first time that Saccharomyces cerevisiae-based ingredients, particularly the living cells, can exert beneficial therapeutic effects on a widespread vaginal mucosal infection.
Bim and Mcl-1 exert key roles in regulating JAK2V617F cell survival

International Nuclear Information System (INIS)

Rubert, Joëlle; Qian, Zhiyan; Andraos, Rita; Guthy, Daniel A; Radimerski, Thomas

2011-01-01

The JAK2 V617F mutation plays a major role in the pathogenesis of myeloproliferative neoplasms and is found in the vast majority of patients suffering from polycythemia vera and in roughly every second patient suffering from essential thrombocythemia or from primary myelofibrosis. The V617F mutation is thought to provide hematopoietic stem cells and myeloid progenitors with a survival and proliferation advantage. It has previously been shown that activated JAK2 promotes cell survival by upregulating the anti-apoptotic STAT5 target gene Bcl-xL. In this study, we have investigated the role of additional apoptotic players, the pro-apoptotic protein Bim as well as the anti-apoptotic protein Mcl-1. Pharmacological inhibition of JAK2/STAT5 signaling in JAK2 V617F mutant SET-2 and MB-02 cells was used to study effects on signaling, cell proliferation and apoptosis by Western blot analysis, WST-1 proliferation assays and flow cytometry. Cells were transfected with siRNA oligos to deplete candidate pro- and anti-apoptotic proteins. Co-immunoprecipitation assays were performed to assess the impact of JAK2 inhibition on complexes of pro- and anti-apoptotic proteins. Treatment of JAK2 V617F mutant cell lines with a JAK2 inhibitor was found to trigger Bim activation. Furthermore, Bim depletion by RNAi suppressed JAK2 inhibitor-induced cell death. Bim activation following JAK2 inhibition led to enhanced sequestration of Mcl-1, besides Bcl-xL. Importantly, Mcl-1 depletion by RNAi was sufficient to compromise JAK2 V617F mutant cell viability and sensitized the cells to JAK2 inhibition. We conclude that Bim and Mcl-1 have key opposing roles in regulating JAK2 V617F cell survival and propose that inactivation of aberrant JAK2 signaling leads to changes in Bim complexes that trigger cell death. Thus, further preclinical evaluation of combinations of JAK2 inhibitors with Bcl-2 family antagonists that also tackle Mcl-1, besides Bcl-xL, is warranted to assess the therapeutic potential
Therapeutic potential of mesenchymal stem cells to treat Achilles tendon injuries.

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Vieira, M H C; Oliveira, R J; Eça, L P M; Pereira, I S O; Hermeto, L C; Matuo, R; Fernandes, W S; Silva, R A; Antoniolli, A C M B

2014-12-12

Rupture of the Achilles tendon diminishes quality of life. The gold-standard therapy is a surgical suture, but this presents complications, including wound formation and inflammation. These complications spurred evaluation of the therapeutic potential of mesenchymal stem cells (MSCs) from adipose tissue. New Zealand rabbits were divided into 6 groups (three treatments with two time points each) evaluated at either 14 or 28 days after surgery: cross section of the Achilles tendon (CSAT); CSAT + Suture; and CSAT + MSC. A comparison between all groups at both time points showed a statistically significant increase in capillaries and in the structural organization of collagen in the healed tendon in the CSAT + Suture and CSAT + MSC groups at the 14-day assessment. Comparison between the two time points within the same group showed a statistically significant decrease in the inflammatory process and an increase in the structural organization of collagen in the CSAT and CSAT + MSC groups. A study of the genomic integrity of the cells suggested a linear correlation between an increase of injuries and culture time. Thus, MSC transplantation is a good alternative for treatment of Achilles tendon ruptures because it may be conducted without surgery and tendon suture and, therefore, has no risk of adverse effects resulting from the surgical wound or inflammation caused by nonabsorbable sutures. Furthermore, this alternative treatment exhibits a better capacity for wound healing and maintaining the original tendon architecture, depending on the arrangement of the collagen fibers, and has important therapeutic potential.
Improving the Post-Stroke Therapeutic Potency of Mesenchymal Multipotent Stromal Cells by Cocultivation With Cortical Neurons: The Role of Crosstalk Between Cells.

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Babenko, Valentina A; Silachev, Denis N; Zorova, Ljubava D; Pevzner, Irina B; Khutornenko, Anastasia A; Plotnikov, Egor Y; Sukhikh, Gennady T; Zorov, Dmitry B

2015-09-01

The goal of the present study was to maximally alleviate the negative impact of stroke by increasing the therapeutic potency of injected mesenchymal multipotent stromal cells (MMSCs). To pursue this goal, the intercellular communications of MMSCs and neuronal cells were studied in vitro. As a result of cocultivation of MMSCs and rat cortical neurons, we proved the existence of intercellular contacts providing transfer of cellular contents from one cell to another. We present evidence of intercellular exchange with fluorescent probes specifically occupied by cytosol with preferential transfer from neurons toward MMSCs. In contrast, we observed a reversed transfer of mitochondria (from MMSCs to neural cells). Intravenous injection of MMSCs in a postischemic period alleviated the pathological indexes of a stroke, expressed as a lower infarct volume in the brain and partial restoration of neurological status. Also, MMSCs after cocultivation with neurons demonstrated more profound neuroprotective effects than did unprimed MMSCs. The production of the brain-derived neurotrophic factor was slightly increased in MMSCs, and the factor itself was redistributed in these cells after cocultivation. The level of Miro1 responsible for intercellular traffic of mitochondria was increased in MMSCs after cocultivation. We conclude that the exchange by cellular compartments between neural and stem cells improves MMSCs' protective abilities for better rehabilitation after stroke. This could be used as an approach to enhance the therapeutic benefits of stem cell therapy to the damaged brain. The idea of priming stem cells before practical use for clinical purposes was applied. Thus, cells were preconditioned by coculturing them with the targeted cells (i.e., neurons for the treatment of brain pathological features) before the transfusion of stem cells to the organism. Such priming improved the capacity of stem cells to treat stroke. Some additional minimal study will be required to
Complex DNA repair pathways as possible therapeutic targets to overcome temozolomide resistance in glioblastoma

International Nuclear Information System (INIS)

Yoshimoto, Koji; Mizoguchi, Masahiro; Hata, Nobuhiro; Murata, Hideki; Hatae, Ryusuke; Amano, Toshiyuki; Nakamizo, Akira; Sasaki, Tomio

2012-01-01

Many conventional chemotherapeutic drugs exert their cytotoxic function by inducing DNA damage in the tumor cell. Therefore, a cell-inherent DNA repair pathway, which reverses the DNA-damaging effect of the cytotoxic drugs, can mediate therapeutic resistance to chemotherapy. The monofunctional DNA-alkylating agent temozolomide (TMZ) is a commonly used chemotherapeutic drug and the gold standard treatment for glioblastoma (GBM). Although the activity of DNA repair protein O6-methylguanine-DNA methyltransferase (MGMT) has been described as the main modulator to determine the sensitivity of GBM to TMZ, a subset of GBM does not respond despite MGMT inactivation, suggesting that another DNA repair mechanism may also modulate the tolerance to TMZ. Considerable interest has focused on MGMT, mismatch repair (MMR), and the base excision repair (BER) pathway in the mechanism of mediating TMZ resistance, but emerging roles for the DNA strand-break repair pathway have been demonstrated. In the first part of this review article, we briefly review the significant role of MGMT, MMR, and the BER pathway in the tolerance to TMZ; in the last part, we review the recent publications that demonstrate possible roles of DNA strand-break repair pathways, such as single-strand break repair and double-strand break repair, as well as the Fanconi anemia pathway in the repair process after alkylating agent-based therapy. It is possible that all of these repair pathways have a potential to modulate the sensitivity to TMZ and aid in overcoming the therapeutic resistance in the clinic.

Complex DNA repair pathways as possible therapeutic targets to overcome temozolomide resistance in glioblastoma

Energy Technology Data Exchange (ETDEWEB)

Yoshimoto, Koji; Mizoguchi, Masahiro; Hata, Nobuhiro; Murata, Hideki; Hatae, Ryusuke; Amano, Toshiyuki; Nakamizo, Akira; Sasaki, Tomio, E-mail: kyoshimo@ns.med.kyushu-u.ac.jp [Department of Neurosurgery, Graduate School of Medical Sciences, Kyushu University, Fukuoka (Japan)

2012-12-05

Many conventional chemotherapeutic drugs exert their cytotoxic function by inducing DNA damage in the tumor cell. Therefore, a cell-inherent DNA repair pathway, which reverses the DNA-damaging effect of the cytotoxic drugs, can mediate therapeutic resistance to chemotherapy. The monofunctional DNA-alkylating agent temozolomide (TMZ) is a commonly used chemotherapeutic drug and the gold standard treatment for glioblastoma (GBM). Although the activity of DNA repair protein O6-methylguanine-DNA methyltransferase (MGMT) has been described as the main modulator to determine the sensitivity of GBM to TMZ, a subset of GBM does not respond despite MGMT inactivation, suggesting that another DNA repair mechanism may also modulate the tolerance to TMZ. Considerable interest has focused on MGMT, mismatch repair (MMR), and the base excision repair (BER) pathway in the mechanism of mediating TMZ resistance, but emerging roles for the DNA strand-break repair pathway have been demonstrated. In the first part of this review article, we briefly review the significant role of MGMT, MMR, and the BER pathway in the tolerance to TMZ; in the last part, we review the recent publications that demonstrate possible roles of DNA strand-break repair pathways, such as single-strand break repair and double-strand break repair, as well as the Fanconi anemia pathway in the repair process after alkylating agent-based therapy. It is possible that all of these repair pathways have a potential to modulate the sensitivity to TMZ and aid in overcoming the therapeutic resistance in the clinic.
A Phenotypic Cell-Binding Screen Identifies a Novel Compound Targeting Triple-Negative Breast Cancer.

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Chen, Luxi; Long, Chao; Youn, Jonghae; Lee, Jiyong

2018-06-11

We describe a "phenotypic cell-binding screen" by which therapeutic candidate targeting cancer cells of a particular phenotype can be isolated without knowledge of drug targets. Chemical library beads are incubated with cancer cells of the phenotype of interest in the presence of cancer cells lacking the phenotype of interest, and then the beads bound to only cancer cells of the phenotype of interest are selected as hits. We have applied this screening strategy in discovering a novel compound (LC129-8) targeting triple-negative breast cancer (TNBC). LC129-8 displayed highly specific binding to TNBC in cancer cell lines and patient-derived tumor tissues. LC129-8 exerted anti-TNBC activity by inducing apoptosis, inhibiting proliferation, reversing epithelial-mesenchymal transition, downregulating cancer stem cell activity and blocking in vivo tumor growth.
Combination of Tramadol with Minocycline Exerted Synergistic Effects on a Rat Model of Nerve Injury-Induced Neuropathic Pain

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Xiao-Peng Mei

2012-09-01

Full Text Available Neuropathic pain is a refractory clinical problem. Certain drugs, such as tramadol, proved useful for the treatment of neuropathic pain by inhibiting the activity of nociceptive neurons. Moreover, studies indicated that suppression or modulation of glial activation could prevent or reverse neuropathic pain, for example with the microglia inhibitor minocycline. However, few present clinical therapeutics focused on both neuronal and glial participation when treating neuropathic pain. Therefore, the present study hypothesized that combination of tramadol with minocycline as neuronal and glial activation inhibitor may exert some synergistic effects on spinal nerve ligation (SNL-induced neuropathic pain. Intrathecal tramadol or minocycline relieved SNL-induced mechanical allodynia in a dose-dependent manner. SNL-induced spinal dorsal horn Fos or OX42 expression was downregulated by intrathecal tramadol or minocycline. Combination of tramadol with minocycline exerted powerful and synergistic effects on SNL-induced neuropathic pain also in a dose-dependent manner. Moreover, the drug combination enhanced the suppression effects on SNL-induced spinal dorsal horn Fos and OX42 expression, compared to either drug administered alone. These results indicated that combination of tramadol with minocycline could exert synergistic effects on peripheral nerve injury-induced neuropathic pain; thus, a new strategy for treating neuropathic pain by breaking the interaction between neurons and glia bilaterally was also proposed.
Do placebo expectations influence perceived exertion during physical exercise?

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Hendrik Mothes

Full Text Available This study investigates the role of placebo expectations in individuals' perception of exertion during acute physical exercise. Building upon findings from placebo and marketing research, we examined how perceived exertion is affected by expectations regarding a the effects of exercise and b the effects of the exercise product worn during the exercise. We also investigated whether these effects are moderated by physical self-concept. Seventy-eight participants conducted a moderate 30 min cycling exercise on an ergometer, with perceived exertion (RPE measured every 5 minutes. Beforehand, each participant was randomly assigned to 1 of 4 conditions and watched a corresponding film clip presenting "scientific evidence" that the exercise would or would not result in health benefits and that the exercise product they were wearing (compression garment would additionally enhance exercise benefits or would only be worn for control purposes. Participants' physical self-concept was assessed via questionnaire. Results partially demonstrated that participants with more positive expectations experienced reduced perceived exertion during the exercise. Furthermore, our results indicate a moderator effect of physical self-concept: Individuals with a high physical self-concept benefited (in terms of reduced perceived exertion levels in particular from an induction of generally positive expectations. In contrast, individuals with a low physical self-concept benefited when positive expectations were related to the exercise product they were wearing. In sum, these results suggest that placebo expectations may be a further, previously neglected class of psychological factors that influence the perception of exertion.
The Immunomodulatory Properties of Amniotic Cells: The Two Sides of the Coin.

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Magatti, Marta; Vertua, Elsa; Cargnoni, Anna; Silini, Antonietta; Parolini, Ornella

2018-01-01

Among the many cell types useful in developing therapeutic treatments, human amniotic cells from placenta have been proposed as valid candidates. Both human amniotic epithelial and mesenchymal stromal cells, and the conditioned medium generated from their culture, exert multiple immunosuppressive activities. Indeed, they inhibit T and B cell proliferation, suppress inflammatory properties of monocytes, macrophages, dendritic cells, neutrophils, and natural killer cells, while promoting induction of cells with regulatory functions such as regulatory T cells and anti-inflammatory M2 macrophages. These properties have laid the foundation for their use for the treatment of inflammatory-based diseases, and encouraging results have been obtained in different preclinical disease models where exacerbated inflammation is present. Moreover, an immune-privileged status of amniotic cells has been often highlighted. However, even if long-term engraftment of amniotic cells has been reported into immunocompetent animals, only few cells survive after infusion. Furthermore, amniotic cells have been shown to be able to induce immune responses in vivo and, under specific culture conditions, they can stimulate T cell proliferation in vitro. Although immunosuppressive properties are a widely recognized characteristic of amniotic cells, immunogenic and stimulatory activities appear to be less reported, sporadic events. In order to improve therapeutic outcome, the mechanisms responsible for the suppressive versus stimulatory activity need to be carefully addressed. In this review, both the immunosuppressive and immunostimulatory activity of amniotic cells will be discussed.
Targeting of tolerogenic dendritic cells towards heat-shock proteins: a novel therapeutic strategy for autoimmune diseases?

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Jansen, Manon A A; Spiering, Rachel; Broere, Femke; van Laar, Jacob M; Isaacs, John D; van Eden, Willem; Hilkens, Catharien M U

2018-01-01

Tolerogenic dendritic cells (tolDCs) are a promising therapeutic tool to restore immune tolerance in autoimmune diseases. The rationale of using tolDCs is that they can specifically target the pathogenic T-cell response while leaving other, protective, T-cell responses intact. Several ways of generating therapeutic tolDCs have been described, but whether these tolDCs should be loaded with autoantigen(s), and if so, with which autoantigen(s), remains unclear. Autoimmune diseases, such as rheumatoid arthritis, are not commonly defined by a single, universal, autoantigen. A possible solution is to use surrogate autoantigens for loading of tolDCs. We propose that heat-shock proteins may be a relevant surrogate antigen, as they are evolutionarily conserved between species, ubiquitously expressed in inflamed tissues and have been shown to induce regulatory T cells, ameliorating disease in various arthritis mouse models. In this review, we provide an overview on how immune tolerance may be restored by tolDCs, the problem of selecting relevant autoantigens for loading of tolDCs, and why heat-shock proteins could be used as surrogate autoantigens. © 2017 John Wiley & Sons Ltd.
Drug-releasing nano-engineered titanium implants: therapeutic efficacy in 3D cell culture model, controlled release and stability

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Gulati, Karan [School of Chemical Engineering, The University of Adelaide, SA 5005 (Australia); Kogawa, Masakazu; Prideaux, Matthew; Findlay, David M. [Discipline of Orthopaedics and Trauma, The University of Adelaide, SA 5005 (Australia); Atkins, Gerald J., E-mail: gerald.atkins@adelaide.edu.au [Discipline of Orthopaedics and Trauma, The University of Adelaide, SA 5005 (Australia); Losic, Dusan, E-mail: dusan.losic@adelaide.edu.au [School of Chemical Engineering, The University of Adelaide, SA 5005 (Australia)

2016-12-01

There is an ongoing demand for new approaches for treating localized bone pathologies. Here we propose a new strategy for treatment of such conditions, via local delivery of hormones/drugs to the trauma site using drug releasing nano-engineered implants. The proposed implants were prepared in the form of small Ti wires/needles with a nano-engineered oxide layer composed of array of titania nanotubes (TNTs). TNTs implants were inserted into a 3D collagen gel matrix containing human osteoblast-like, and the results confirmed cell migration onto the implants and their attachment and spread. To investigate therapeutic efficacy, TNTs/Ti wires loaded with parathyroid hormone (PTH), an approved anabolic therapeutic for the treatment of severe bone fractures, were inserted into 3D gels containing osteoblast-like cells. Gene expression studies revealed a suppression of SOST (sclerostin) and an increase in RANKL (receptor activator of nuclear factor kappa-B ligand) mRNA expression, confirming the release of PTH from TNTs at concentrations sufficient to alter cell function. The performance of the TNTs wire implants using an example of a drug needed at relatively higher concentrations, the anti-inflammatory drug indomethacin, is also demonstrated. Finally, the mechanical stability of the prepared implants was tested by their insertion into bovine trabecular bone cores ex vivo followed by retrieval, which confirmed the robustness of the TNT structures. This study provides proof of principle for the suitability of the TNT/Ti wire implants for localized bone therapy, which can be customized to cater for specific therapeutic requirements. - Highlights: • Ti wire with titania nanotubes (TNTs) are proposed as ‘in-bone’ therapeutic implants. • 3D cell culture model is used to confirm therapeutic efficacy of drug releasing implants. Osteoblasts migrated and firmly attached to the TNTs and the micro-scale cracks. • Tailorable drug loading from few nanograms to several hundred
Artesunate Exerts a Direct Effect on Endothelial Cell Activation and NF-κB Translocation in a Mechanism Independent of Plasmodium Killing

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Mariana C. Souza

2012-01-01

Full Text Available Artemisinin and its derivates are an important class of antimalarial drug and are described to possess immunomodulatory activities. Few studies have addressed the effect of artesunate in the murine malaria model or its effect on host immune response during malaria infection. Herein, we study the effect of artesunate treatment and describe an auxiliary mechanism of artesunate in modulating the inflammatory response during experimental malaria infection in mice. Treatment with artesunate did not reduce significantly the parasitemia within 12 h, however, reduced BBB breakdown and TNF-α mRNA expression in the brain tissue of artesunate-treated mice. Conversely, mefloquine treatment was not able to alter clinical features. Notably, artesunate pretreatment failed to modulate the expression of LFA-1 in splenocytes stimulated with parasitized red blood cells (pRBCs in vitro; however, it abrogated the expression of ICAM-1 in pRBC-stimulated endothelial cells. Accordingly, a cytoadherence in vitro assay demonstrated that pRBCs did not adhere to artesunate-treated vascular endothelial cells. In addition, NF-κB nuclear translocation in endothelial cells stimulated with pRBCs was impaired by artesunate treatment. Our results suggest that artesunate is able to exert a protective effect against the P. berghei-induced inflammatory response by inhibiting NF-κB nuclear translocation and the subsequent expression of ICAM-1.
Biomaterials that promote cell-cell interactions enhance the paracrine function of MSCs.

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Qazi, Taimoor H; Mooney, David J; Duda, Georg N; Geissler, Sven

2017-09-01

Mesenchymal stromal cells (MSCs) secrete paracrine factors that play crucial roles during tissue regeneration. Whether this paracrine function is influenced by the properties of biomaterials in general, and those used for cell delivery in particular, largely remains unexplored. Here, we investigated if three-dimensional culture in distinct microenvironments - nanoporous hydrogels (mean pore size ∼5 nm) and macroporous scaffolds (mean pore size ∼120 μm) - affects the secretion pattern of MSCs, and consequently leads to differential paracrine effects on target progenitor cells such as myoblasts. We report that compared to MSCs encapsulated in hydrogels, scaffold seeded MSCs show an enhanced secretion profile and exert beneficial paracrine effects on various myoblast functions including migration and proliferation. Additionally, we show that the heightened paracrine effects of scaffold seeded cells can in part be attributed to N-cadherin mediated cell-cell interactions during culture. In hydrogels, this physical interaction between cells is prevented by the encapsulating matrix. Functionally blocking N-cadherin negatively affected the secretion profile and paracrine effects of MSCs on myoblasts, with stronger effects observed for scaffold seeded compared to hydrogel encapsulated cells. Together, these findings demonstrate that the therapeutic potency of MSCs can be enhanced by biomaterials that promote cell-cell interactions. Copyright © 2017 Elsevier Ltd. All rights reserved.
Different therapeutic effects of cells derived from human amniotic membrane on premature ovarian aging depend on distinct cellular biological characteristics.

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Ding, Chenyue; Li, Hong; Wang, Yun; Wang, Fuxin; Wu, Huihua; Chen, Rulei; Lv, Jinghuan; Wang, Wei; Huang, Boxian

2017-07-27

Many reports have shown that various kinds of stem cells have the ability to recover premature ovarian aging (POA) function. Transplantation of human amniotic epithelial cells (hAECs) improves ovarian function damaged by chemotherapy in a mice model. Understanding of how to evaluate the distinct effects of adult stem cells in curing POA and how to choose stem cells in clinical application is lacking. To build a different degrees of POA model, mice were administered different doses of cyclophosphamide: light dose (70 mg/kg, 2 weeks), medium dose (70 mg/kg, 1 week; 120 mg/kg, 1 week), and high dose (120 mg/kg, 2 weeks). Enzyme-linked immunosorbent assay detected serum levels of sex hormones, and hematoxylin and eosin staining allowed follicle counting and showed the ovarian tissue structure. DiIC 18 (5)-DS was employed to label human amniotic mesenchymal stem cells (hAMSCs) and hAECs for detecting the cellular retention time in ovaries by a live imaging system. Proliferation of human ovarian granule cells (ki67, AMH, FSHR, FOXL2, and CYP19A1) and immunological rejection of human peripheral blood mononuclear cells (CD4, CD11b, CD19, and CD56) were measured by flow cytometry (fluorescence-activated cell sorting (FACS)). Distinction of cellular biological characteristics between hAECs and hAMSCs was evaluated, such as collagen secretory level (collagen I, II, III, IV, and VI), telomerase activity, pluripotent markers tested by western blot, expression level of immune molecules (HLA-ABC and HLA-DR) analyzed by FACS, and cytokines (growth factors, chemotactic factors, apoptosis factors, and inflammatory factors) measured by a protein antibody array methodology. After hAMSCs and hAECs were transplanted into a different degrees of POA model, hAMSCs exerted better therapeutic activity on mouse ovarian function in the high-dose administration group, promoting the proliferation rate of ovarian granular cells from premature ovarian failure patients, but also provoking immune
Macromolecular therapeutics.

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Yang, Jiyuan; Kopeček, Jindřich

2014-09-28

This review covers water-soluble polymer-drug conjugates and macromolecules that possess biological activity without attached low molecular weight drugs. The main design principles of traditional and backbone degradable polymer-drug conjugates as well as the development of a new paradigm in nanomedicines - (low molecular weight) drug-free macromolecular therapeutics are discussed. To address the biological features of cancer, macromolecular therapeutics directed to stem/progenitor cells and the tumor microenvironment are deliberated. Finally, the future perspectives of the field are briefly debated. Copyright © 2014 Elsevier B.V. All rights reserved.
Potential therapeutic applications of biosurfactants.

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Gudiña, Eduardo J; Rangarajan, Vivek; Sen, Ramkrishna; Rodrigues, Lígia R

2013-12-01

Biosurfactants have recently emerged as promising molecules for their structural novelty, versatility, and diverse properties that are potentially useful for many therapeutic applications. Mainly due to their surface activity, these molecules interact with cell membranes of several organisms and/or with the surrounding environments, and thus can be viewed as potential cancer therapeutics or as constituents of drug delivery systems. Some types of microbial surfactants, such as lipopeptides and glycolipids, have been shown to selectively inhibit the proliferation of cancer cells and to disrupt cell membranes causing their lysis through apoptosis pathways. Moreover, biosurfactants as drug delivery vehicles offer commercially attractive and scientifically novel applications. This review covers the current state-of-the-art in biosurfactant research for therapeutic purposes, providing new directions towards the discovery and development of molecules with novel structures and diverse functions for advanced applications. Copyright © 2013 Elsevier Ltd. All rights reserved.
Inhibition of miR-155, a therapeutic target for breast cancer, prevented in cancer stem cell formation.

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Zuo, Jiangcheng; Yu, Yalan; Zhu, Man; Jing, Wei; Yu, Mingxia; Chai, Hongyan; Liang, Chunzi; Tu, Jiancheng

2018-02-06

Breast cancer is a common cancer in women of worldwide. Cancer cells with stem-like properties played important roles in breast cancer, such as relapse, metastasis and treatment resistance. Micro-RNA-155 (miR-155) is a well-known oncogenic miRNA overexpressed in many human cancers. The expression levels of miR-155 in 38 pairs of cancer tissues and adjacent normal tissues from breast cancer patients were detected using quantitative real-time PCR. The invasive cell line MDA-MB-231 was used to quantify the expression of miR-155 by tumor-sphere forming experiment. Soft agar colony formation assay and tumor xenografts was used to explore whether the inhibition of miR-155 could reduce proliferation of cancer cells in vivo and vitro. In the study, we found miR-155 was upregulated in BC. Soft agar colony formation assay and tumor xenografts showed inhibition of miR-155 could significantly reduce proliferation of cancer cells in vivo and vitro, which confirmed that miR-155 is an effective therapeutic target of breast cancer. Sphere-forming experiment showed that overexpression of miR-155 significantly correlated with stem-like properties. Expressions of ABCG2, CD44 and CD90 were repressed by inhibition of miR-155, but CD24 was promoted. Interestingly, inhibition of miR-155 rendered MDA-MB-231 cells more sensitive to Doxorubicinol, which resulted in an increase of inhibition rate from 20.23% to 68.72%. Expression of miR-155 not only was a therapeutic target but also was associated with cancer stem cell formation and Doxorubicinol sensitivity. Our results underscore the importance of miR-155 as a therapeutic target and combination of Doxorubicinol and miR-155-silencing would be a potential way to cure breast cancer.
Safety paradigm: genetic evaluation of therapeutic grade human embryonic stem cells.

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Stephenson, Emma; Ogilvie, Caroline Mackie; Patel, Heema; Cornwell, Glenda; Jacquet, Laureen; Kadeva, Neli; Braude, Peter; Ilic, Dusko

2010-12-06

The use of stem cells for regenerative medicine has captured the imagination of the public, with media attention contributing to rising expectations of clinical benefits. Human embryonic stem cells (hESCs) are the best model for capital investment in stem cell therapy and there is a clear need for their robust genetic characterization before scaling-up cell expansion for that purpose. We have to be certain that the genome of the starting material is stable and normal, but the limited resolution of conventional karyotyping is unable to give us such assurance. Advanced molecular cytogenetic technologies such as array comparative genomic hybridization for identifying chromosomal imbalances, and single nucleotide polymorphism analysis for identifying ethnic background and loss of heterozygosity should be introduced as obligatory diagnostic tests for each newly derived hESC line before it is deposited in national stem cell banks. If this new quality standard becomes a requirement, as we are proposing here, it would facilitate and accelerate the banking process, since end-users would be able to select the most appropriate line for their particular application, thus improving efficiency and streamlining the route to manufacturing therapeutics. The pharmaceutical industry, which may use hESC-derived cells for drug screening, should not ignore their genomic profile as this may risk misinterpretation of results and significant waste of resources.
Therapeutic peptides for cancer therapy. Part II - cell cycle inhibitory peptides and apoptosis-inducing peptides.

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Raucher, Drazen; Moktan, Shama; Massodi, Iqbal; Bidwell, Gene L

2009-10-01

Therapeutic peptides have great potential as anticancer agents owing to their ease of rational design and target specificity. However, their utility in vivo is limited by low stability and poor tumor penetration. The authors review the development of peptide inhibitors with potential for cancer therapy. Peptides that arrest the cell cycle by mimicking CDK inhibitors or induce apoptosis directly are discussed. The authors searched Medline for articles concerning the development of therapeutic peptides and their delivery. Inhibition of cancer cell proliferation directly using peptides that arrest the cell cycle or induce apoptosis is a promising strategy. Peptides can be designed that interact very specifically with cyclins and/or cyclin-dependent kinases and with members of apoptotic cascades. Use of these peptides is not limited by their design, as a rational approach to peptide design is much less challenging than the design of small molecule inhibitors of specific protein-protein interactions. However, the limitations of peptide therapy lie in the poor pharmacokinetic properties of these large, often charged molecules. Therefore, overcoming the drug delivery hurdles could open the door for effective peptide therapy, thus making an entirely new class of molecules useful as anticancer drugs.
Small cell ovarian carcinoma: genomic stability and responsiveness to therapeutics.

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Gamwell, Lisa F; Gambaro, Karen; Merziotis, Maria; Crane, Colleen; Arcand, Suzanna L; Bourada, Valerie; Davis, Christopher; Squire, Jeremy A; Huntsman, David G; Tonin, Patricia N; Vanderhyden, Barbara C

2013-02-21

The biology of small cell ovarian carcinoma of the hypercalcemic type (SCCOHT), which is a rare and aggressive form of ovarian cancer, is poorly understood. Tumourigenicity, in vitro growth characteristics, genetic and genomic anomalies, and sensitivity to standard and novel chemotherapeutic treatments were investigated in the unique SCCOHT cell line, BIN-67, to provide further insight in the biology of this rare type of ovarian cancer. The tumourigenic potential of BIN-67 cells was determined and the tumours formed in a xenograft model was compared to human SCCOHT. DNA sequencing, spectral karyotyping and high density SNP array analysis was performed. The sensitivity of the BIN-67 cells to standard chemotherapeutic agents and to vesicular stomatitis virus (VSV) and the JX-594 vaccinia virus was tested. BIN-67 cells were capable of forming spheroids in hanging drop cultures. When xenografted into immunodeficient mice, BIN-67 cells developed into tumours that reflected the hypercalcemia and histology of human SCCOHT, notably intense expression of WT-1 and vimentin, and lack of expression of inhibin. Somatic mutations in TP53 and the most common activating mutations in KRAS and BRAF were not found in BIN-67 cells by DNA sequencing. Spectral karyotyping revealed a largely normal diploid karyotype (in greater than 95% of cells) with a visibly shorter chromosome 20 contig. High density SNP array analysis also revealed few genomic anomalies in BIN-67 cells, which included loss of heterozygosity of an estimated 16.7 Mb interval on chromosome 20. SNP array analyses of four SCCOHT samples also indicated a low frequency of genomic anomalies in the majority of cases. Although resistant to platinum chemotherapeutic drugs, BIN-67 cell viability in vitro was reduced by > 75% after infection with oncolytic viruses. These results show that SCCOHT differs from high-grade serous carcinomas by exhibiting few chromosomal anomalies and lacking TP53 mutations. Although BIN-67 cells are
MANUFACTURING NATURAL KILLER CELLS AS MEDICINAL PRODUCTS

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Christian CHABANNON

2016-11-01

Full Text Available Natural Killer (NK cells are Innate Lymphoid Cells (ILC with cytotoxic and regulatory properties. Their functions are tightly regulated by an array of inhibitory and activating receptors, and their mechanisms of activation strongly differ from antigen recognition in the context of HLA presentation as needed for T-cell activation. NK cells thus offer unique opportunities for new and improved therapeutic manipulation, either in vivo or in vitro, in a variety of human diseases, including cancers. NK cell activity can possibly be modulated in vivo through direct or indirect actions exerted by small molecules or monoclonal antibodies. NK cells can also be adoptively transferred following more or less substantial modifications through cell and gene manufacturing, in order to empower them with new or improved functions and ensure their controlled persistence and activity in the recipient. In the present review, we will focus on the technological and regulatory challenges of NK cell manufacturing, and discuss conditions in which these innovative cellular therapies can be brought to the clinic.
Characterization of acetate transport in colorectal cancer cells and potential therapeutic implications

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Ferro, Suellen; Azevedo-Silva, João; Casal, Margarida; Côrte-Real, Manuela; Baltazar, Fatima; Preto, Ana

2016-01-01

Acetate, together with other short chain fatty acids has been implicated in colorectal cancer (CRC) prevention/therapy. Acetate was shown to induce apoptosis in CRC cells. The precise mechanism underlying acetate transport across CRC cells membrane, that may be implicated in its selectivity towards CRC cells, is not fully understood and was addressed here. We also assessed the effect of acetate in CRC glycolytic metabolism and explored its use in combination with the glycolytic inhibitor 3-bromopyruvate (3BP). We provide evidence that acetate enters CRC cells by the secondary active transporters MCT1 and/or MCT2 and SMCT1 as well as by facilitated diffusion via aquaporins. CRC cell exposure to acetate upregulates the expression of MCT1, MCT4 and CD147, while promoting MCT1 plasma membrane localization. We also observed that acetate increases CRC cell glycolytic phenotype and that acetate-induced apoptosis and anti-proliferative effect was potentiated by 3BP. Our data suggest that acetate selectivity towards CRC cells might be explained by the fact that aquaporins and MCTs are found overexpressed in CRC clinical cases. Our work highlights the importance that acetate transport regulation has in the use of drugs such as 3BP as a new therapeutic strategy for CRC. PMID:28874966
Transplantation of autologous adipose stem cells lacks therapeutic efficacy in the experimental autoimmune encephalomyelitis model.

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Xiujuan Zhang

Full Text Available Multiple sclerosis (MS, characterized by chronic inflammation, demyelination, and axonal damage, is a complicated neurological disease of the human central nervous system. Recent interest in adipose stromal/stem cell (ASCs for the treatment of CNS diseases has promoted further investigation in order to identify the most suitable ASCs. To investigate whether MS affects the biologic properties of ASCs and whether autologous ASCs from MS-affected sources could serve as an effective source for stem cell therapy, cells were isolated from subcutaneous inguinal fat pads of mice with established experimental autoimmune encephalomyelitis (EAE, a murine model of MS. ASCs from EAE mice and their syngeneic wild-type mice were cultured, expanded, and characterized for their cell morphology, surface antigen expression, osteogenic and adipogenic differentiation, colony forming units, and inflammatory cytokine and chemokine levels in vitro. Furthermore, the therapeutic efficacy of the cells was assessed in vivo by transplantation into EAE mice. The results indicated that the ASCs from EAE mice displayed a normal phenotype, typical MSC surface antigen expression, and in vitro osteogenic and adipogenic differentiation capacity, while their osteogenic differentiation capacity was reduced in comparison with their unafflicted control mice. The ASCs from EAE mice also demonstrated increased expression of pro-inflammatory cytokines and chemokines, specifically an elevation in the expression of monocyte chemoattractant protein-1 and keratin chemoattractant. In vivo, infusion of wild type ASCs significantly ameliorate the disease course, autoimmune mediated demyelination and cell infiltration through the regulation of the inflammatory responses, however, mice treated with autologous ASCs showed no therapeutic improvement on the disease progression.
[Ethical aspects of regenerative medicine, with special reference to embryonic stem cells and therapeutic cloning].

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Imura, Hiroo

2003-03-01

Regenerative medicine is expected to be new therapeutic means for treating incurable diseases but requires serious bioethical consideration. Embryonic stem(ES) cells, that are pleuripotent cells suitable to regenerative medicine, can be used in Japan for investigative use under a strict control by guide-lines. On the other hand, use of embryo produced by nuclear transfer has not been allowed in Japan and further serious consideration is required. Some other ethical aspects of regenerative medicine are also discussed.

Therapeutic iodine 125 for hyperthyroidism: evidence for a special radiobiological effect on the follicular cell

International Nuclear Information System (INIS)

Gray, H.W.; Greig, W.R.; Gillespie, F.C.; Western Regional Hospital Board, Glasgow

1982-01-01

An IV perchlorate test was used qualitatively to detect a functional abnormality of the colloid-follicular cell interface in patients given 131 I or 125 I for hyperthyroidism. Radiation damage, manifest as abnormal iodide organification, was more prolonged after 125 I and more often accompanied by unremitting hyperthyroidism than after 131 I. These results conform with theoretical and laboratory data which predict a gradient of deposited radiation across the human follicular cell after therapeutic 125 I. (author)
New cancer diagnostics and therapeutics from a ninth 'hallmark of cancer': symmetric self-renewal by mutated distributed stem cells.

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Sherley, James L

2013-11-01

A total of eight cellular alterations associated with human carcinogenesis have been framed as the 'hallmarks of cancer'. This representation overlooks a ninth hallmark of cancer: the requirement for tumor-originating distributed stem cells to shift sufficiently from asymmetric to symmetric self-renewal kinetics for attainment of the high cell production rate necessary to form clinically significant tumors within a human lifespan. Overlooking this ninth hallmark costs opportunities for discovery of more selective molecular targets for development of improved cancer therapeutics and missing cancer stem cell biomarkers of greater specificity. Here, the biological basis for the ninth hallmark of cancer is considered toward highlighting its importance in human carcinogenesis and, as such, its potential for revealing unique molecules for targeting cancer diagnostics and therapeutics.
Distemper virus encephalitis exerts detrimental effects on hippocampal neurogenesis.

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von Rüden, E-L; Avemary, J; Zellinger, C; Algermissen, D; Bock, P; Beineke, A; Baumgärtner, W; Stein, V M; Tipold, A; Potschka, H

2012-08-01

Despite knowledge about the impact of brain inflammation on hippocampal neurogenesis, data on the influence of virus encephalitis on dentate granule cell neurogenesis are so far limited. Canine distemper is considered an interesting model of virus encephalitis, which can be associated with a chronic progressing disease course and can cause symptomatic seizures. To determine the impact of canine distemper virus (CDV) infection on hippocampal neurogenesis, we compared post-mortem tissue from dogs with infection with and without seizures, from epileptic dogs with non-viral aetiology and from dogs without central nervous system diseases. The majority of animals with infection and with epilepsy of non-viral aetiology exhibited neuronal progenitor numbers below the age average in controls. Virus infection with and without seizures significantly decreased the mean number of neuronal progenitor cells by 43% and 76% as compared to age-matched controls. Ki-67 labelling demonstrated that hippocampal cell proliferation was neither affected by infection nor by epilepsy of non-viral aetiology. Analysis of CDV infection in cells expressing caspase-3, doublecortin or Ki-67 indicated that infection of neuronal progenitor cells is extremely rare and suggests that infection might damage non-differentiated progenitor cells, hamper neuronal differentiation and promote glial differentiation. A high inter-individual variance in the number of lectin-reactive microglial cells was evident in dogs with distemper infection. Statistical analyses did not reveal a correlation between the number of lectin-reactive microglia cells and neuronal progenitor cells. Our data demonstrate that virus encephalitis with and without seizures can exert detrimental effects on hippocampal neurogenesis, which might contribute to long-term consequences of the disease. The lack of a significant impact of distemper virus on Ki-67-labelled cells indicates that the infection affected neuronal differentiation and
Forsythoside A exerts antipyretic effect on yeast-induced pyrexia mice via inhibiting transient receptor potential vanilloid 1 function

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Liu, Cuiling; Su, Hongchang; Wan, Hongye; Qin, Qingxia; Wu, Xuan; Kong, Xiangying; Lin, Na

2017-01-01

Transient receptor potential vanilloid 1 (TRPV1) is a non-selective cation channel gated by noxious heat, playing major roles in thermoregulation. Forsythoside A (FT-A) is the most abundant phenylethanoid glycosides in Fructus Forsythiae, which has been prescribed as a medicinal herb for treating fever in China for a long history. However, how FT-A affects pyrexia and what is the underlying molecular mechanism remain largely unknown. Here we found that FT-A exerted apparent antipyretic effect through decreasing the levels of prostaglandin E2 (PGE2) and interleukin 8 (IL-8) in a dose-dependent fashion on the yeast induced pyrexia mice. Interestingly, FT-A significantly downregulated TRPV1 expression in the hypothalamus and dorsal root ganglion (DRG) of the yeast induced pyrexia mice. Moreover, FT-A inhibited IL-8 and PGE2 secretions, and calcium influx in the HEK 293T-TRPV1 cells after stimulated with capsaicin, the specific TRPV1 agonist. Further investigation of the molecular mechanisms revealed that FT-A treatment rapidly inhibited phosphorylation of extracellular signal-regulated kinase (ERK), Jun N-terminal kinase (JNK) and p38 in both yeast induced pyrexia mice and HEK 293T-TRPV1 cells. These results suggest that FT-A may serve as a potential antipyretic agent and the therapeutic action of Fructus Forsythiae on pyretic related disease is, in part, due to the FT-A activities. PMID:28123347
Cell therapeutics to treat diseases of the retina

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Natarajan S

2008-11-01

Full Text Available Background: The adult Bone Marrow Stem Cells (BMSCs have distinct advantages over the other types of stem cells. They are multipotent, can be stored for upto 10 years and considered to be one of the best sources of hematopoietic and mesenchymal stem cells in an adult body. Genetically inherited diseases such as Retinitis Pigmentosa and Degenerative diseases such as Age Related Macular Degeneration remain unsolved as no definitive treatment is available to repair the damages caused to the RPE and Photoreceptors as of now. In this scenario, the technique of Bone Marrow aspiration & isolation of Mono Nucleated Cells (MNCs & intra-vitreal injection of a very small volume of MNCs in human retinal disorders has been standardized and is safe and feasible for human studies (Mohanty et al and autotransplantation of RPEs from periphery to affected area are underpractice(Coffey et al. In this study we report our research work on different approaches to the above diseases using cell therapeuticsStudy 1 Materials & methods: Ciliary Pigment Epithelium was harvested from donor eyes from Aditya Jyot Eye Hospital, Mumbai and was taken to and grown at NCRM lab. The cells were grown in the earlier reported methodology of Brenda et al (Science 2004. Results: The CPE derived Retinal stem cells grew well in the lab. However, the practical difficulties of harvesting the same in patients limited our further steps in this study. Study II:? Materials & methods: Cadaver eye RPE cells were harvested and grown using polymer scaffolds after transporting them over 6 to 12 Hrs. The RPEs were grown on conventional methods and in polymer scaffolds and were subjected to RT-PCR. Results: Human RPEs were able to grow without amniotic membrane and the same was proven by RT-PCR. This would make it possible for the peripheral RPEs taken from patients to be stored and later expanded and used for replacing the diseased cells of the central portion of the retina in future, without having
The stem cell secretome and its role in brain repair.

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Drago, Denise; Cossetti, Chiara; Iraci, Nunzio; Gaude, Edoardo; Musco, Giovanna; Bachi, Angela; Pluchino, Stefano

2013-12-01

Compelling evidence exists that non-haematopoietic stem cells, including mesenchymal (MSCs) and neural/progenitor stem cells (NPCs), exert a substantial beneficial and therapeutic effect after transplantation in experimental central nervous system (CNS) disease models through the secretion of immune modulatory or neurotrophic paracrine factors. This paracrine hypothesis has inspired an alternative outlook on the use of stem cells in regenerative neurology. In this paradigm, significant repair of the injured brain may be achieved by injecting the biologics secreted by stem cells (secretome), rather than implanting stem cells themselves for direct cell replacement. The stem cell secretome (SCS) includes cytokines, chemokines and growth factors, and has gained increasing attention in recent years because of its multiple implications for the repair, restoration or regeneration of injured tissues. Thanks to recent improvements in SCS profiling and manipulation, investigators are now inspired to harness the SCS as a novel alternative therapeutic option that might ensure more efficient outcomes than current stem cell-based therapies for CNS repair. This review discusses the most recent identification of MSC- and NPC-secreted factors, including those that are trafficked within extracellular membrane vesicles (EVs), and reflects on their potential effects on brain repair. It also examines some of the most convincing advances in molecular profiling that have enabled mapping of the SCS. Copyright © 2013 The Authors. Published by Elsevier Masson SAS.. All rights reserved.
Fighting Viral Infections and Virus-Driven Tumors with Cytotoxic CD4+ T Cells

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Muraro, Elena; Merlo, Anna; Martorelli, Debora; Cangemi, Michela; Dalla Santa, Silvia; Dolcetti, Riccardo; Rosato, Antonio

2017-01-01

CD4+ T cells have been and are still largely regarded as the orchestrators of immune responses, being able to differentiate into distinct T helper cell populations based on differentiation signals, transcription factor expression, cytokine secretion, and specific functions. Nonetheless, a growing body of evidence indicates that CD4+ T cells can also exert a direct effector activity, which depends on intrinsic cytotoxic properties acquired and carried out along with the evolution of several pathogenic infections. The relevant role of CD4+ T cell lytic features in the control of such infectious conditions also leads to their exploitation as a new immunotherapeutic approach. This review aims at summarizing currently available data about functional and therapeutic relevance of cytotoxic CD4+ T cells in the context of viral infections and virus-driven tumors. PMID:28289418
Therapeutic journery of nitrogen mustard as alkylating anticancer agents: Historic to future perspectives.

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Singh, Rajesh K; Kumar, Sahil; Prasad, D N; Bhardwaj, T R

2018-05-10

Cancer is considered as one of the most serious health problems today. The discovery of nitrogen mustard as an alkylating agent in 1942, opened a new era in the cancer chemotherapy. This valuable class of alkylating agent exerts its biological activity by binding to DNA, cross linking two strands, preventing DNA replication and ultimate cell death. At the molecular level, nitrogen lone pairs of nitrogen mustard generate a strained intermediate "aziridinium ion" which is very reactive towards DNA of tumor cell as well as normal cell resulting in various adverse side effects alogwith therapeutic implications. Over the last 75 years, due to its high reactivity and peripheral cytotoxicity, numerous modifications have been made in the area of nitrogen mustard to improve its efficacy as well as enhancing drug delivery specifically to tumor cells. This review mainly discusses the medicinal chemistry aspects in the development of various classes of nitrogen mustards (mechlorethamine, chlorambucil, melphalan, cyclophosphamide and steroidal based nitrogen mustards). The literature collection includes the historical and the latest developments in these areas. This comprehensive review also attempted to showcase the recent progress in the targeted delivery of nitrogen mustards that includes DNA directed nitrogen mustards, antibody directed enzyme prodrug therapy (ADEPT), gene directed enzyme prodrug therapy (GDEPT), nitrogen mustard activated by glutathione transferase, peptide based nitrogen mustards and CNS targeted nitrogen mustards. Copyright © 2018 Elsevier Masson SAS. All rights reserved.
Mesenchymal stem cells derived from normal gingival tissue inhibit the proliferation of oral cancer cells in vitro and in vivo.

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Ji, Xiaoli; Zhang, Zhihui; Han, Ying; Song, Jiangyuan; Xu, Xiangliang; Jin, Jianqiu; Su, Sha; Mu, Dongdong; Liu, Xiaodan; Xu, Si; Cui, Hongwei; Zhao, Zhongfang; Wang, Yixiang; Liu, Hongwei

2016-11-01

The interplay between tumor cells and mesenchymal stem cells (MSCs) within tumor microenvironment plays a significant role in tumor development, and thus might be exploited for therapeutic intervention. In this study, we isolated MSCs from normal gingival tissue (GMSCs), and detected the effect of GMSCs on oral cancer cells via direct co-culture and indirect co-culture systems. The cell proliferation assay of direct co-culture showed that GMSCs could inhibit the growth of oral cancer cells. Conditioned medium derived from GMSCs (GMSCs-CM) also exerted an anticancer effect, which indicates that soluble factors in GMSCs-CM played a dominant role in GMSCs-induced cancer cell growth inhibition. To investigate the mechanism, we performed apoptosis assay by flow cytometry, and confirmed that cancer cell apoptosis induced by GMSCs could be a reason for the effect of GMSCs on the growth of oral cancer cells. Western blotting also confirmed that GMSCs could upregulate expression of pro-apoptotic genes including p-JNK, cleaved PARP, cleaved caspase-3, Bax expression and downregulate proliferation- and anti-apoptosis-related gene expression such as p-ERK1/2, Bcl-2, CDK4, cyclin D1, PCNA and survivin. Importantly, the inhibitory effect of GMSCs on cancer cells can partially be restored by blockade of JNK pathway. Moreover, animal studies showed that GMSCs exerted an anticancer effect after oral cancer cells and GMSCs were co-injected with oral cancer cells. Taken together, our data suggest that GMSCs can suppress oral cancer cell growth in vitro and in vivo via altering the surrounding microenvironment of oral cancer cells, which indicates that GMSCs have a potential use in the management of oral dysplasia and oral cancer in future.
Accumulation of a soluble form of human nectin-2 is required for exerting the resistance against herpes simplex virus type 2 infection in transfected cells.

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Fujimoto, Y; Ozaki, K; Iwamori, N; Takakuwa, H; Ono, E

2016-03-01

Cell entry of herpes simplex virus type 2 (HSV-2) requires the interaction of viral glycoprotein D (gD) with the receptor nectin-1 and herpesvirus entry mediator (HVEM). In addition, it is known that nectin-2 is also functional as a receptor for HSV-2, although the binding to the gD is weak. To examine an antiviral potential of a soluble form of human nectin-2 (hNectin-2Ig), transfected Vero cells expressing the entire ectodomain of nectin-2 fused to the Fc portion of human IgG were established. Specific binding of hNectin-2Ig to HSV-2 gD was confirmed by ELISA. Competitive ELISA demonstrated that accumulation of hNectin-2Ig in transfected cells increased significantly in a cell culture time dependent manner. Viral growth of several HSV-2 strains was significantly inhibited in the transfected cells that were cultured for 72 hr compared with control Vero cells, but not in cells that were cultured for 24 hr. These results indicate that accumulation of a soluble form of nectin-2 is required for exerting the resistance against HSV-2 infection.
The intersection of cancer, cancer stem cells, and the immune system: therapeutic opportunities.

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Silver, Daniel J; Sinyuk, Maksim; Vogelbaum, Michael A; Ahluwalia, Manmeet S; Lathia, Justin D

2016-02-01

During brain neoplasia, malignant cells subjugate the immune system to provide an environment that favors tumor growth. These mechanisms capitalize on tumor-promoting functions of various immune cell types and typically result in suppression of tumor immune rejection. Immunotherapy efforts are underway to disrupt these mechanisms and turn the immune system against developing tumors. While many of these therapies are already in early-stage clinical trials, understanding how these therapies impact various tumor cell populations, including self-renewing cancer stem cells, may help to predict their efficacy and clarify their mechanisms of action. Moreover, interrogating the biology of glioma cell, cancer stem cell, and immune cell interactions may provide additional therapeutic targets to leverage against disease progression. In this review, we begin by highlighting a series of investigations into immune cell-mediated tumor promotion that do not parse the tumor into stem and non-stem components. We then take a closer look at the immune-suppressive mechanisms derived specifically from cancer stem cell interactions with the immune system and end with an update on immunotherapy and cancer stem cell-directed clinical trials in glioblastoma. © The Author(s) 2015. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.
Betulinic Acid Exerts Cytotoxic Activity Against Multidrug-Resistant Tumor Cells via Targeting Autocrine Motility Factor Receptor (AMFR

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Mohamed E. M. Saeed

2018-05-01

Full Text Available Betulinic acid (BetA is a naturally occurring pentacyclic triterpene isolated from the outer bark of white-barked birch trees and many other medicinal plants. Here, we studied betulinic acid's cytotoxic activity against drug-resistant tumor cell lines. P-glycoprotein (MDR1/ABCB1 and BCRP (ABCG2 are known ATP-binding cassette (ABC drug transporters that mediating MDR. ABCB5 is a close relative to ABCB1, which also mediates MDR. Constitutive activation of the EGF receptor is tightly linked to the development of chemotherapeutic resistance. BetA inhibited P-gp, BCRP, ABCB5 and mutation activated EGFR overexpressing cells with similar efficacy as their drug-sensitive parental counterparts. Furthermore, the mRNA expressions of ABCB1, BCRP, ABCB5 and EGFR were not related to the 50% inhibition concentrations (IC50 for BetA in a panel of 60 cell lines of the National Cancer Institute (NCI, USA. In addition to well-established MDR mechanisms, we attempted to identify other molecular mechanisms that play a role in mediating BetA's cytotoxic activity. For this reason, we performed COMPARE and hierarchical cluster analyses of the transcriptome-wide microarray-based mRNA expression of the NCI cell lines panel. Various genes significantly correlating to BetA's activity were involved in different biological processes, e.g., cell cycle regulation, microtubule formation, signal transduction, transcriptional regulation, chromatin remodeling, cell adhesion, tumor suppression, ubiquitination and proteasome degradation. Immunoblotting and in silico analyses revealed that the inhibition of AMFR activity might be one of the mechanisms for BetA to overcome MDR phenotypes. In conclusion, BetA may have therapeutic potential for the treatment of refractory tumors.
Biomaterials-based 3D cell printing for next-generation therapeutics and diagnostics.

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Jang, Jinah; Park, Ju Young; Gao, Ge; Cho, Dong-Woo

2018-02-01

Building human tissues via 3D cell printing technology has received particular attention due to its process flexibility and versatility. This technology enables the recapitulation of unique features of human tissues and the all-in-one manufacturing process through the design of smart and advanced biomaterials and proper polymerization techniques. For the optimal engineering of tissues, a higher-order assembly of physiological components, including cells, biomaterials, and biomolecules, should meet the critical requirements for tissue morphogenesis and vascularization. The convergence of 3D cell printing with a microfluidic approach has led to a significant leap in the vascularization of engineering tissues. In addition, recent cutting-edge technology in stem cells and genetic engineering can potentially be adapted to the 3D tissue fabrication technique, and it has great potential to shift the paradigm of disease modeling and the study of unknown disease mechanisms required for precision medicine. This review gives an overview of recent developments in 3D cell printing and bioinks and provides technical requirements for engineering human tissues. Finally, we propose suggestions on the development of next-generation therapeutics and diagnostics. Copyright © 2017 Elsevier Ltd. All rights reserved.
Targeting tissue factor as a novel therapeutic oncotarget for eradication of cancer stem cells isolated from tumor cell lines, tumor xenografts and patients of breast, lung and ovarian cancer.

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Hu, Zhiwei; Xu, Jie; Cheng, Jijun; McMichael, Elizabeth; Yu, Lianbo; Carson, William E

2017-01-03

Targeting cancer stem cell (CSC) represents a promising therapeutic approach as it can potentially fight cancer at its root. The challenge is to identify a surface therapeutic oncotarget on CSC. Tissue factor (TF) is known as a common yet specific surface target for cancer cells and tumor neovasculature in several solid cancers. However, it is unknown if TF is expressed by CSCs. Here we demonstrate that TF is constitutively expressed on CD133 positive (CD133+) or CD24-CD44+ CSCs isolated from human cancer cell lines, tumor xenografts from mice and breast tumor tissues from patients. TF-targeted agents, i.e., a factor VII (fVII)-conjugated photosensitizer (fVII-PS for targeted photodynamic therapy) and fVII-IgG1Fc (Immunoconjugate or ICON for immunotherapy), can eradicate CSC via the induction of apoptosis and necrosis and via antibody-dependent cellular cytotoxicity and complement-dependent cytotoxicity, respectively. In conclusion, these results demonstrate that TF is a novel surface therapeutic oncotarget for CSC, in addition to cancer cell TF and tumor angiogenic vascular endothelial TF. Moreover, this research highlights that TF-targeting therapeutics can effectively eradicate CSCs, without drug resistance, isolated from breast, lung and ovarian cancer with potential to translate into other most commonly diagnosed solid cancer, in which TF is also highly expressed.
Cellular Therapeutics for Heart Failure: Focus on Mesenchymal Stem Cells

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Amitabh C. Pandey

2017-01-01

Full Text Available Resulting from a various etiologies, the most notable remains ischemia; heart failure (HF manifests as the common end pathway of many cardiovascular processes and remains among the top causes for hospitalization and a major cause of morbidity and mortality worldwide. Current pharmacologic treatment for HF utilizes pharmacologic agents to control symptoms and slow further deterioration; however, on a cellular level, in a patient with progressive disease, fibrosis and cardiac remodeling can continue leading to end-stage heart failure. Cellular therapeutics have risen as the new hope for an improvement in the treatment of HF. Mesenchymal stem cells (MSCs have gained popularity given their propensity of promoting endogenous cellular repair of a myriad of disease processes via paracrine signaling through expression of various cytokines, chemokines, and adhesion molecules resulting in activation of signal transduction pathways. While the exact mechanism remains to be completely elucidated, this remains the primary mechanism identified to date. Recently, MSCs have been incorporated as the central focus in clinical trials investigating the role how MSCs can play in the treatment of HF. In this review, we focus on the characteristics of MSCs that give them a distinct edge as cellular therapeutics and present results of clinical trials investigating MSCs in the setting of ischemic HF.
Physical Exertion and Immediate Classroom Mental Performance Among Elementary School Children.

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Gabbard, Carl

This study was designed (1) to investigate the relationship between physical exertion and mental performance in elementary school children and (2) to determine if male or female mental performances are more affected by physical exertion. A total of 95 second graders participated in six treatments of induced physical exertion during their regularly…
THERAPEUTIC ANTISENSE OLIGONUCLEOTIDES AGAINST CANCER: HURDLING TO THE CLINIC

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Pedro Miguel Duarte Moreno

2014-10-01

Full Text Available Under clinical development since the early 90’s and with two successfully approved drugs (Fomivirsen and Mipomersen, oligonucleotide-based therapeutics have not yet delivered a clinical drug to the market in the cancer field. Whilst many pre-clinical data has been generated, a lack of understanding still exists on how to efficiently tackle all the different challenges presented for cancer targeting in a clinical setting. Namely, effective drug vectorization, careful choice of target gene or synergistic multi-gene targeting are surely decisive, while caution must be exerted to avoid potential toxic, often misleading off-target-effects. Here a brief overview will be given on the nucleic acid chemistry advances that established oligonucleotide technologies as a promising therapeutic alternative and ongoing cancer related clinical trials. Special attention will be given towards a perspective on the hurdles encountered specifically in the cancer field by this class of therapeutic oligonucleotides and a view on possible avenues for success is presented, with particular focus on the contribution from nanotechnology to the field.
Therapeutic Potential of Human Adipose-Derived Stem/Stromal Cell Microspheroids Prepared by Three-Dimensional Culture in Non-Cross-Linked Hyaluronic Acid Gel.

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Mineda, Kazuhide; Feng, Jingwei; Ishimine, Hisako; Takada, Hitomi; Doi, Kentaro; Kuno, Shinichiro; Kinoshita, Kahori; Kanayama, Koji; Kato, Harunosuke; Mashiko, Takanobu; Hashimoto, Ichiro; Nakanishi, Hideki; Kurisaki, Akira; Yoshimura, Kotaro

2015-12-01

Three-dimensional culture of mesenchymal stem/stromal cells for spheroid formation is known to enhance their therapeutic potential for regenerative medicine. Spheroids were prepared by culturing human adipose-derived stem/stromal cells (hASCs) in a non-cross-linked hyaluronic acid (HA) gel and compared with dissociated hASCs and hASC spheroids prepared using a nonadherent dish. Preliminary experiments indicated that a 4% HA gel was the most appropriate for forming hASC spheroids with a relatively consistent size (20-50 µm) within 48 hours. Prepared spheroids were positive for pluripotency markers (NANOG, OCT3/4, and SOX-2), and 40% of the cells were SSEA-3-positive, a marker of the multilineage differentiating stress enduring or Muse cell. In contrast with dissociated ASCs, increased secretion of cytokines such as hepatocyte growth factor was detected in ASC spheroids cultured under hypoxia. On microarray ASC spheroids showed upregulation of some pluripotency markers and downregulation of genes related to the mitotic cell cycle. After ischemia-reperfusion injury to the fat pad in SCID mice, local injection of hASC spheroids promoted tissue repair and reduced the final atrophy (1.6%) compared with that of dissociated hASCs (14.3%) or phosphate-buffered saline (20.3%). Part of the administered hASCs differentiated into vascular endothelial cells. ASC spheroids prepared in a HA gel contain undifferentiated cells with therapeutic potential to promote angiogenesis and tissue regeneration after damage. This study shows the therapeutic value of human adipose-derived stem cell spheroids prepared in hyarulonic acid gel. The spheroids have various benefits as an injectable cellular product and show therapeutic potential to the stem cell-depleted conditions such as diabetic chronic skin ulcer. ©AlphaMed Press.
Cuban experience with the therapeutic use of adult stem cells

International Nuclear Information System (INIS)

Hernandez Ramirez, Porfirio; Alfonso Simon, Amel; Aparicio Suarez, Jose L

2011-01-01

The basic and clinical researches carried out during past years on the stem cells and its therapeutic possibilities are at present times, one of the most interesting subjects of the contemporaneous medicine. There are advances in the study and application of adult stem cells showing remarkable advantages on the embryonic ones, since its handling is more simple, economic and they are obtained from the own subject to be treated. For the introduction in Cuba of the regenerative cellular therapy in the Institute of Hematology and Immunology the cellular sources selected were the adult stem cells derived from bone marrow and the mobilized ones to the peripheral blood. To make easy the expansion of treatment to other hospital centers, authors standardized a technique for the mobilization of the hematopoietic stem cells to peripheral blood using a granulocyte colony-stimulating factor (Filgrastim, of national production) developing a simple, economic and more tolerable method for patients. In this way, the cellular therapy has been expanded to 6 Cuban provinces and until April, 2009 562 cases with autologous adult stem cells transplant have been treated, from which the 81.7% to correspond to patients presenting with Angiology diseases with a significant reduction of major amputations. Also, the results have been very promising in the bone lesions and periodontal processes among other diseases treated. The results obtained until now may be considered as a new achievement of revolutionary science and of our national health systems and of science and technique. The method used is an economic and feasible procedure for the institutions with scarce resources
[Regulatory role of NKT cells in the prevention of type 1 diabetes].

Science.gov (United States)

Ghazarian, Liana; Simoni, Yannick; Pingris, Karine; Beaudoin, Lucie; Lehuen, Agnès

2013-01-01

Type 1 diabetes is an autoimmune disease resulting from the destruction of pancreatic β cells by the immune system. NKT cells are innate-like T cells that can exert potent immuno-regulatory functions. The regulatory role of NKT cells was initially proposed after the observed decreased frequency of this subset in mouse models of type 1 diabetes, as well as in patients developing various autoimmune pathologies. Increasing NKT cell frequency and function prevent the development of type 1 diabetes in mouse models. Several mechanisms including IL-4 and IL-10 production by NKT cells and the accumulation of tolerogenic dendritic cells are critical for the dampening of pathogenic anti-islet T cell responses by NKT cells. Importantly, these cells can at the same time prevent diabetes and promote efficient immune responses against infectious agents. These results strengthen the potential role of NKT cells as a key target for the development of therapeutic strategies against type 1 diabetes. © 2013 médecine/sciences – Inserm.

Therapeutic Applications of Interleukin 24 (IL24): A Review ...

African Journals Online (AJOL)

IL24 has growth suppressive properties in a wide variety of human cancer cell lines without inducing harmful effects in normal cells. This review is focused on the role of IL 24 on tumor cell biology and its potential therapeutic applications. Keywords: Melanoma differentiation, Protein, Therapeutics, Interleukin, ...
Cell death induced by ozone and various non-thermal plasmas: therapeutic perspectives and limitations

Czech Academy of Sciences Publication Activity Database

Lunov, Oleg; Zablotskyy, Vitaliy A.; Churpita, Olexandr; Chánová, Eliška; Syková, Eva; Dejneka, Alexandr; Kubinová, Šárka

2014-01-01

Roč. 4, NOV (2014), "7129-1"-"7129-11" ISSN 2045-2322 R&D Projects: GA MŠk LO1309 Grant - others:AV ČR(CZ) M100101219 Institutional support: RVO:68378271 ; RVO:61389013 ; RVO:68378041 Keywords : cell death * non-thermal plasma * therapeutic perspectives Subject RIV: BO - Biophysics; FH - Neurology (UEM-P); CD - Macromolecular Chemistry (UMCH-V) Impact factor: 5.578, year: 2014
Poly ADP-ribose polymerase-1 as a potential therapeutic target in Merkel cell carcinoma.

Science.gov (United States)

Ferrarotto, Renata; Cardnell, Robert; Su, Shirley; Diao, Lixia; Eterovic, A Karina; Prieto, Victor; Morrisson, William H; Wang, Jing; Kies, Merrill S; Glisson, Bonnie S; Byers, Lauren Averett; Bell, Diana

2018-03-23

Patients with metastatic Merkel cell carcinoma are treated similarly to small cell lung cancer (SCLC). Poly ADP-ribose polymerase-1 (PARP1) is overexpressed in SCLC and response to PARP inhibitors have been reported in patients with SCLC. Our study explores PARP as a therapeutic target in Merkel cell carcinoma. We evaluated PARP1 expression and Merkel cell polyomavirus (MCPyV) in 19 patients with Merkel cell carcinoma. Target exome-sequencing was performed in 14 samples. Sensitivity to olaparib was tested in 4 Merkel cell carcinoma cell lines. Most Merkel cell carcinomas (74%) express PARP1 at high levels. Mutations in DNA-damage repair genes were identified in 9 samples (64%), occurred exclusively in head neck primaries, and correlated with TP53/RB1 mutations. The TP53/RB1 mutations were more frequent in MCPyV-negative tumors. Sensitivity to olaparib was seen in the Merkel cell carcinoma line with highest PARP1 expression. Based on PARP1 overexpression, DNA-damage repair gene mutations, platinum sensitivity, and activity of olaparib in a Merkel cell carcinoma line, clinical trials with PARP inhibitors are warranted in Merkel cell carcinoma. © 2018 Wiley Periodicals, Inc.
Induction of Type I Interferons by Therapeutic Nanoparticle-Based Vaccination Is Indispensable to Reinforce Cytotoxic CD8+ T Cell Responses During Chronic Retroviral Infection

Science.gov (United States)

Knuschke, Torben; Rotan, Olga; Bayer, Wibke; Kollenda, Sebastian; Dickow, Julia; Sutter, Kathrin; Hansen, Wiebke; Dittmer, Ulf; Lang, Karl S.; Epple, Matthias; Buer, Jan; Westendorf, Astrid M.

2018-01-01

T cell dysfunction and immunosuppression are characteristic for chronic viral infections and contribute to viral persistence. Overcoming these burdens is the goal of new therapeutic strategies to cure chronic infectious diseases. We recently described that therapeutic vaccination of chronic retrovirus infected mice with a calcium phosphate (CaP) nanoparticle (NP)-based vaccine carrier, functionalized with CpG and viral peptides is able to efficiently reactivate the CD8+ T cell response and improve the eradication of virus infected cells. However, the mechanisms underlying this effect were largely unclear. While type I interferons (IFNs I) are considered to drive T cell exhaustion by persistent immune activation during chronic viral infection, we here describe an indispensable role of IFN I induced by therapeutic vaccination to efficiently reinforce cytotoxic CD8+ T cells (CTL) and improve control of chronic retroviral infection. The induction of IFN I is CpG dependent and leads to significant IFN signaling indicated by upregulation of IFN stimulated genes. By vaccinating chronically retrovirus-infected mice lacking the IFN I receptor (IFNAR−/−) or by blocking IFN I signaling in vivo during therapeutic vaccination, we demonstrate that IFN I signaling is necessary to drive full reactivation of CTLs. Surprisingly, we also identified an impaired suppressive capability of regulatory T cells in the presence of IFNα, which implicates an important role for vaccine-induced IFNα in the regulation of the T cell response during chronic retroviral infection. Our data suggest that inducing IFN I signaling in conjunction with the presentation of viral antigens can reactivate immune functions and reduce viral loads in chronic infections. Therefore, we propose CaP NPs as potential therapeutic tool to treat chronic infections. PMID:29740425
Evaluation of somatostatin and nucleolin receptors for therapeutic delivery in non-small cell lung cancer stem cells applying the somatostatin-analog DOTATATE and the nucleolin-targeting aptamer AS1411

DEFF Research Database (Denmark)

Holmboe, Sif; Hansen, Pernille Lund; Thisgaard, Helge

2017-01-01

Cancer stem cells represent the putative tumor-driving subpopulation thought to account for drug resistance, relapse, and metastatic spread of epithelial and other cancer types. Accordingly, cell surface markers for therapeutic delivery to cancer stem cells are subject of intense research. Somato...
IL17/IL17RA as a Novel Signaling Axis Driving Mesenchymal Stem Cell Therapeutic Function in Experimental Autoimmune Encephalomyelitis

Directory of Open Access Journals (Sweden)

Mónica Kurte

2018-04-01

Full Text Available The therapeutic effect of mesenchymal stem cells (MSCs in multiple sclerosis (MS and the experimental autoimmune encephalomyelitis (EAE model has been well described. This effect is, in part, mediated through the inhibition of IL17-producing cells and the generation of regulatory T cells. While proinflammatory cytokines such as IFNγ, TNFα, and IL1β have been shown to enhance MSCs immunosuppressive function, the role of IL17 remains poorly elucidated. The aim of this study was, therefore, to investigate the role of the IL17/IL17R pathway on MSCs immunoregulatory effects focusing on Th17 cell generation in vitro and on Th17-mediated EAE pathogenesis in vivo. In vitro, we showed that the immunosuppressive effect of MSCs on Th17 cell proliferation and differentiation is partially dependent on IL17RA expression. This was associated with a reduced expression level of MSCs immunosuppressive mediators such as VCAM1, ICAM1, and PD-L1 in IL17RA−/− MSCs as compared to wild-type (WT MSCs. In the EAE model, we demonstrated that while WT MSCs significantly reduced the clinical scores of the disease, IL17RA−/− MSCs injected mice exhibited a clinical worsening of the disease. The disability of IL17RA−/− MSCs to reduce the progression of the disease paralleled the inability of these cells to reduce the frequency of Th17 cells in the draining lymph node of the mice as compared to WT MSCs. Moreover, we showed that the therapeutic effect of MSCs was correlated with the generation of classical Treg bearing the CD4+CD25+Foxp3+ signature in an IL17RA-dependent manner. Our findings reveal a novel role of IL17RA on MSCs immunosuppressive and therapeutic potential in EAE and suggest that the modulation of IL17RA in MSCs could represent a novel method to enhance their therapeutic effect in MS.
The Role and Potential Therapeutic Application of Myeloid-Derived Suppressor Cells in Allo- and Autoimmunity

Directory of Open Access Journals (Sweden)

Qi Zhang

2015-01-01

Full Text Available Myeloid-derived suppressor cells (MDSCs are a heterogeneous population of cells that consists of myeloid progenitor cells and immature myeloid cells. They have been identified as a cell population that may affect the activation of CD4+ and CD8+ T-cells to regulate the immune response negatively, which makes them attractive targets for the treatment of transplantation and autoimmune diseases. Several studies have suggested the potential suppressive effect of MDSCs on allo- and autoimmune responses. Conversely, MDSCs have also been found at various stages of differentiation, accumulating during pathological situations, not only during tumor development but also in a variety of inflammatory immune responses, bone marrow transplantation, and some autoimmune diseases. These findings appear to be contradictory. In this review, we summarize the roles of MDSCs in different transplantation and autoimmune diseases models as well as the potential to target these cells for therapeutic benefit.
Prostate Stem Cell Antigen: A Prospective Therapeutic and Diagnostic Target

Science.gov (United States)

Raff, Adam B.; Gray, Andrew; Kast, W. Martin

2009-01-01

The development of novel clinical tools to combat cancer is an intense field of research and recent efforts have been directed at the identification of proteins that may provide diagnostic, prognostic and/or therapeutic applications due to their restricted expression. To date, a number of protein candidates have emerged as potential clinical tools in the treatment of prostate cancer. Discovered over ten year ago, prostate stem cell antigen (PSCA) is a cell surface antigen that belongs to the Ly-6/Thy-1 family of glycosylphosphatidylinositol-anchored proteins. PSCA is highly overexpressed in human prostate cancer, with limited expression in normal tissues, making it an ideal target for both diagnosis and therapy. Several studies have now clearly correlated the expression of PSCA with relevant clinical benchmarks, such as Gleason score and metastasis, while others have demonstrated the efficacy of PSCA targeting in treatment through various modalities. The purpose of this review is to present the current body of knowledge about PSCA and its potential role in the treatment of human prostate cancer. PMID:18838214
Overexpression of Notch ligand Delta-like-1 by dendritic cells enhances their immunoregulatory capacity and exerts antiallergic effects on Th2-mediated allergic asthma in mice.

Science.gov (United States)

Lee, Chen-Chen; Lin, Chu-Lun; Leu, Sy-Jye; Lee, Yueh-Lun

2018-02-01

Dendritic cells (DCs) are professional antigen-presenting cells, and Notch ligand Delta-like-1 (DLL1) on DCs was implicated in type 1T helper (Th1) differentiation. In this study, we produced genetically engineered bone marrow-derived DCs that expressed DLL1 (DLL1-DCs) by adenoviral transduction. DLL1-DCs exerted a fully mature phenotype, and had positive effects on expression levels of interleukin (IL)-12 and costimulatory molecules. Coculture of allogeneic T cells with ovalbumin (OVA)-pulsed DLL1-DCs enhanced T cell proliferative responses and promoted Th1 cell differentiation. Furthermore, adoptive transfer of OVA-stimulated DLL1-DCs into asthmatic mice alleviated the cardinal features of allergic asthma, including immunoglobulin E (IgE) production, airway hyperresponsiveness (AHR), airway inflammation, and production of Th2-type cytokines. Notably, enhanced levels of the Th1-biased IgG 2a response and interferon (IFN)-γ production were observed in these mice. Taken together, these data indicate that DLL1-DCs promoted Th1 cell development to alter the Th1/Th2 ratio and ameliorate Th2-mediated allergic asthma in mice. Copyright © 2017 Elsevier Inc. All rights reserved.
Recent Progress in Functional Micellar Carriers with Intrinsic Therapeutic Activities for Anticancer Drug Delivery.

Science.gov (United States)

Qu, Ying; Chu, BingYang; Shi, Kun; Peng, JinRong; Qian, ZhiYong

2017-12-01

Polymeric micelles have presented superior delivery properties for poorly water-soluble chemotherapeutic agents. However, it remains discouraging that there may be some additional short or long-term toxicities caused by the metabolites of high quantities of carriers. If carriers had simultaneous therapeutic effects with the drug, these issues would not be a concern. For this, carriers not only simply act as drug carriers, but also exert an intrinsic therapeutic effect as a therapeutic agent. The functional micellar carriers would be beneficial to maximize the anticancer effect, overcome the drug resistance and reduce the systemic toxicity. In this review, we aim to summarize the recent progress on the development of functional micellar carriers with intrinsic anticancer activities for the delivery of anticancer drugs. This review focuses on the design strategies, properties of carriers and the drug loading behavior. In addition, the combinational therapeutic effects between carriers and chemotherapeutic agents are also discussed.
Amplexicaule A exerts anti-tumor effects by inducing apoptosis in human breast cancer

Science.gov (United States)

Shu, Guangwen; Wan, Dingrong; He, Feng; Loaec, Morgann; Ding, Yali; Li, Jun; Dovat, Sinisa; Yang, Gaungzhong; Song, Chunhua

2016-01-01

Chemotherapy is the main treatment for patients with breast cancer metastases, but natural alternatives have been receiving attention for their potential as novel anti-tumor reagents. Amplexicaule A (APA) is a flavonoid glucoside isolated from rhizomes of Polygonum amplexicaule D. Don var. sinense Forb (PADF). We found that APA has anti-tumor effects in a breast cancer xenograft mouse model and induces apoptosis in breast cancer cell lines. APA increased levels of cleaved caspase-3,-8,-9 and PARP, which resulted from suppression of MCL-1 and BCL-2 expression in the cells. APA also inactivated the Akt/mTOR pathway in breast cancer cells. Thus, APA exerts a strong anti-tumor effect on breast cancer cells, most likely through induction of apoptosis. Our study is the first to identify this novel anti-tumor compound and provides a new strategy for isolation and separation of single compounds from herbs. PMID:26943775
CD20-based Immunotherapy of B-cell Derived Hematologic Malignancies.

Science.gov (United States)

Shanehbandi, Dariush; Majidi, Jafar; Kazemi, Tohid; Baradaran, Behzad; Aghebati-Maleki, Leili

2017-01-01

CD20 is a surface antigen, which is expressed at certain stages of B-cell differentiation. Targeting the CD20-positive B-cells with therapeutic monoclonal antibodies (MAbs) has been an effectual strategy in the treatment of hematologic malignancies such as non-Hodgkin's lymphoma (NHL) and chronic lymphocytic leukemia (CLL). Initial success with Rituximab (RTX) has encouraged the creation and development of more effective CD20 based therapeutics. However, treatment with conventional MAbs has not been adequate to overcome the problems such as refractory/ relapsed disease. In this regard, new generations of MAbs with enhanced affinity or improved anti-tumor properties have been developed. CD20 directed therapeutics have heterogeneous features and mechanisms of action. Hence, having sufficient knowledge on the immunological and molecular aspects of CD20 based cancer therapy is necessary for predicting the clinical outcomes and taking the necessary measures. An extensive search was performed in PubMed and similar databases for peer-reviewed articles concerning the biology, function and characteristics of CD20 molecule as well as the mechanisms of action and evolutionary process of CD20 targeting agents. This review provides information about the current situation of CD20 targeting immunotherapeutics including MAbs, bispecific antibodies (which exert multiple functions or involve Tcells in tumor elimination) and CAR T-cells (engineered T-cells armed with chimeric antigen receptors). Moreover, limitations, challenges and available solutions regarding the application of CD20 targeting treatments are addressed. Utilization of CD20-targeted therapeutics, due to their diverse properties, requires special considerations. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.
Ilexgenin A exerts anti-inflammation and anti-angiogenesis effects through inhibition of STAT3 and PI3K pathways and exhibits synergistic effects with Sorafenib on hepatoma growth

Energy Technology Data Exchange (ETDEWEB)

Yang, Hao [Medical and Pharmaceutical Institute, Yangzhou University, Yangzhou 225001, Jiangsu (China); College of Medicine, Yangzhou University, Yangzhou 225001, Jiangsu (China); Institute of Pharmacology and Toxicology, Jiangsu Kanion Pharmaceutical Co., Ltd., Lianyungang 222000, Jiangsu (China); Wang, Juan [Medical and Pharmaceutical Institute, Yangzhou University, Yangzhou 225001, Jiangsu (China); College of Medicine, Yangzhou University, Yangzhou 225001, Jiangsu (China); Fan, Jin-hong; Zhang, Ya-qi; Zhao, Jun-xian [Medical and Pharmaceutical Institute, Yangzhou University, Yangzhou 225001, Jiangsu (China); Dai, Xiao-jun [Medical and Pharmaceutical Institute, Yangzhou University, Yangzhou 225001, Jiangsu (China); Chinese Medicine Hospital of Yangzhou City, Yangzhou 225009, Jiangsu (China); Liu, Qi; Shen, Yan-jun [Medical and Pharmaceutical Institute, Yangzhou University, Yangzhou 225001, Jiangsu (China); College of Medicine, Yangzhou University, Yangzhou 225001, Jiangsu (China); Liu, Chang [Medical and Pharmaceutical Institute, Yangzhou University, Yangzhou 225001, Jiangsu (China); Sun, Wei-dong, E-mail: zyykjc@sina.com [Medical and Pharmaceutical Institute, Yangzhou University, Yangzhou 225001, Jiangsu (China); Chinese Medicine Hospital of Yangzhou City, Yangzhou 225009, Jiangsu (China); Sun, Yun, E-mail: ysun@yzu.edu.cn [Medical and Pharmaceutical Institute, Yangzhou University, Yangzhou 225001, Jiangsu (China); College of Medicine, Yangzhou University, Yangzhou 225001, Jiangsu (China)

2017-01-15

Recently, we reported that Ilexgenin A exhibits anti-cancer activities and induces cell arrest. Here, we investigated the effect of Ilexgenin A on the inflammation, angiogenesis and tumor growth of hepatocellular carcinoma (HCC). Our current study revealed that Ilexgenin A significantly inhibited the inflammatory cytokines TNF-α and IL-6 levels and downregulated pro-angiogenic factor VEGF production and transcription in HepG2 cells. The underlying mechanism for Ilexgenin A effects appears to be through inhibiting STAT3 and PI3K pathways. Furthermore, we found that not only Ilexgenin A inhibited STAT3 and PI3K pathways in HepG2 cells but also blocked these signaling pathways in HUVECs. Most importantly, by employing two HCC xenografts models - HepG2 and H22, we showed that Ilexgenin A reduced tumor growth and exhibited synergy effect with Sorafenib. ELISA assay, histological analysis and immunohistochemistry examination revealed that the expression of VEGF and MVD was significantly decreased after the treatment with Ilexgenin A and the combination. Moreover, Ilexgenin A could enhance caspase-3/7 activity in vitro and transmission electron microscope indicated that the combination induced evident apoptosis of tumor cells and caused the structural changes of mitochondria in vivo. Although no apparent adverse effects occurred during the treatment period, Sorafenib monotherapy elicited hepatotoxicity for specific expression in the increased level of AST and the ratio of AST/ALT. However, the combination could remedy this adverse effect. In conclusion, the results described in the present study identifies Ilexgenin A as a promising therapeutic candidate that modulates inflammation, angiogenesis, and HCC growth. - Highlights: • Ilexgenin A exerts anti-inflammatory and anti-angiogenesis effects in hepatoma. • Ilexgenin A may exert these effects through inhibition of STAT3 and PI3K pathways. • Ilexgenin A exhibits synergistic effects with Sorafenib on hepatoma growth
Therapeutic effects of antibiotic drug tigecycline against cervical squamous cell carcinoma by inhibiting Wnt/β-catenin signaling

Energy Technology Data Exchange (ETDEWEB)

Li, Hui; Jiao, Shun [Department of Obstetrics and Gynaecology, JingZhou Hospital Affiliated to Huazhong University of Science and Technology, Jingzhou (China); Li, Xin [Department of Obstetrics and Gynaecology, RenMin Hospital of Wuhan University, Wuhan (China); Banu, Hasina; Hamal, Shreejana [Department of Clinical Medicine, Medical School of Yangtze University, Jingzhou (China); Wang, Xianrong, E-mail: Dr.XianRong.Wang@hotmail.com [Department of Obstetrics and Gynaecology, JingZhou Hospital Affiliated to Huazhong University of Science and Technology, Jingzhou (China)

2015-11-06

Aberrant activation of the Wnt/β-catenin signaling pathway is common in human cervical cancers and has great potential therapeutic value. We show that tigecycline, a FDA-approved antibiotic drug, targets cervical squamous cell carcinoma through inhibiting Wnt/β-catenin signaling pathway. Tigecycline is effective in inducing apoptosis, inhibiting proliferation and anchorage-independent colony formation of Hela cells. The inhibitory effects of tigecycline are further enhanced upon combination with paclitaxel, a most commonly used chemotherapeutic drug for cervical cancer. In a cervical xenograft model, tigecycline inhibits tumor growth as a single agent and its combination with paclitaxel significantly inhibits more tumor growth throughout the duration of treatment. We further show that tigecycline decreases level of both cytoplasmic and nuclear β-catenin and suppressed Wnt/β-catenin-mediated transcription through increasing levels of Axin 1 in Hela cells. In addition, stabilization or overexpression of β-catenin using pharmacological and genetic approaches abolished the effects of tigecycline in inhibiting proliferation and inducing apoptosis of Hela cells. Our study suggests that tigecycline is a useful addition to the treatment armamentarium for cervical cancer and targeting Wnt/β-catenin represents a potential therapeutic strategy in cervical cancer. - Highlights: • We repurposed the antibiotic drug tigecycline for cervical cancer treatment. • Tigecycline is effectively against cervical cancer cells in vitro and in vivo. • Combination of tigecycline and paclitaxel is synergistic in targeting Hela cells. • Tigecycline acts on Hela cells through inhibiting Wnt/β-catenin signaling.
Therapeutic effects of antibiotic drug tigecycline against cervical squamous cell carcinoma by inhibiting Wnt/β-catenin signaling

International Nuclear Information System (INIS)

Li, Hui; Jiao, Shun; Li, Xin; Banu, Hasina; Hamal, Shreejana; Wang, Xianrong

2015-01-01

Aberrant activation of the Wnt/β-catenin signaling pathway is common in human cervical cancers and has great potential therapeutic value. We show that tigecycline, a FDA-approved antibiotic drug, targets cervical squamous cell carcinoma through inhibiting Wnt/β-catenin signaling pathway. Tigecycline is effective in inducing apoptosis, inhibiting proliferation and anchorage-independent colony formation of Hela cells. The inhibitory effects of tigecycline are further enhanced upon combination with paclitaxel, a most commonly used chemotherapeutic drug for cervical cancer. In a cervical xenograft model, tigecycline inhibits tumor growth as a single agent and its combination with paclitaxel significantly inhibits more tumor growth throughout the duration of treatment. We further show that tigecycline decreases level of both cytoplasmic and nuclear β-catenin and suppressed Wnt/β-catenin-mediated transcription through increasing levels of Axin 1 in Hela cells. In addition, stabilization or overexpression of β-catenin using pharmacological and genetic approaches abolished the effects of tigecycline in inhibiting proliferation and inducing apoptosis of Hela cells. Our study suggests that tigecycline is a useful addition to the treatment armamentarium for cervical cancer and targeting Wnt/β-catenin represents a potential therapeutic strategy in cervical cancer. - Highlights: • We repurposed the antibiotic drug tigecycline for cervical cancer treatment. • Tigecycline is effectively against cervical cancer cells in vitro and in vivo. • Combination of tigecycline and paclitaxel is synergistic in targeting Hela cells. • Tigecycline acts on Hela cells through inhibiting Wnt/β-catenin signaling.
Factors associated with high physical exertion during manual lifting

DEFF Research Database (Denmark)

Andersen, Lars L.; Sundstrup, Emil; Brandt, Mikkel

2018-01-01

BACKGROUND: High physical exertion during work is a risk factor for back pain and long-term sickness absence. OBJECTIVE: To investigate which factors are associated with physical exertion during manual lifting. METHODS: From 14 workplaces across Denmark, 200 blue-collar workers reported perceived...... physical exertion (Borg-CR10) during manual lifting from floor to table height of 5, 10, 20 and 30 kg at the beginning and end of the working day. The workers also responded to a questionnaire and went through testing of isometric back muscle strength. Associations were modelled using logistic regression...... during manual lifting in blue-collar workers. These factors should be considered when planning work with manual lifting for individual workers....
Exertional Rhabdomyolysis after Spinning

OpenAIRE

Jeong, Youjin; Kweon, Hyuk-Jung; Oh, Eun-Jung; Ahn, Ah-Leum; Choi, Jae-Kyung; Cho, Dong-Yung

2016-01-01

Any strenuous muscular exercise may trigger rhabdomyolysis. We report an episode of clinically manifested exertional rhabdomyolysis due to stationary cycling, commonly known as spinning. Reports of spinning-related rhabdomyolysis are rare in the English literature, and the current case appears to be the first such case reported in South Korea. A previously healthy 21-year-old Asian woman presented with severe thigh pain and reddish-brown urinary discoloration 24?48 hours after attending a spi...
Update: Exertional rhabdomyolysis, active component, U.S. Armed Forces, 2012-2016.

Science.gov (United States)

2017-03-01

Among active component service members in 2016, there were 525 incident diagnoses of rhabdomyolysis likely due to physical exertion and/or heat stress ("exertional rhabdomyolysis"). The crude incidence rate in 2016 was 40.7 cases per 100,000 person-years. Annual rates of incident diagnoses of exertional rhabdomyolysis increased 46.2% between 2013 and 2016, with the greatest percentage change occurring between 2014 and 2015. In 2016, relative to their respective counterparts, the highest incidence rates of exertional rhabdomyolysis affected service members who were male; younger than 20 years of age; and black, non-Hispanic. During the surveillance period, annual incidence rates were highest among service members of the Marine Corps, intermediate among those in the Army, and lowest among those in the Air Force and Navy. Most cases of exertional rhabdomyolysis were diagnosed at installations that support basic combat/recruit training or major ground combat units of the Army or the Marine Corps. Medical care providers should consider exertional rhabdomyolysis in the differential diagnosis when service members (particularly recruits) present with muscular pain or swelling, limited range of motion, or the excretion of dark urine (possibly due to myoglobinuria) after strenuous physical activity, particularly in hot, humid weather.
Ion channel expression patterns in glioblastoma stem cells with functional and therapeutic implications for malignancy.

Directory of Open Access Journals (Sweden)

Julia Pollak

Full Text Available Ion channels and transporters have increasingly recognized roles in cancer progression through the regulation of cell proliferation, migration, and death. Glioblastoma stem-like cells (GSCs are a source of tumor formation and recurrence in glioblastoma multiforme, a highly aggressive brain cancer, suggesting that ion channel expression may be perturbed in this population. However, little is known about the expression and functional relevance of ion channels that may contribute to GSC malignancy. Using RNA sequencing, we assessed the enrichment of ion channels in GSC isolates and non-tumor neural cell types. We identified a unique set of GSC-enriched ion channels using differential expression analysis that is also associated with distinct gene mutation signatures. In support of potential clinical relevance, expression of selected GSC-enriched ion channels evaluated in human glioblastoma databases of The Cancer Genome Atlas and Ivy Glioblastoma Atlas Project correlated with patient survival times. Finally, genetic knockdown as well as pharmacological inhibition of individual or classes of GSC-enriched ion channels constrained growth of GSCs compared to normal neural stem cells. This first-in-kind global examination characterizes ion channels enriched in GSCs and explores their potential clinical relevance to glioblastoma molecular subtypes, gene mutations, survival outcomes, regional tumor expression, and experimental responses to loss-of-function. Together, the data support the potential biological and therapeutic impact of ion channels on GSC malignancy and provide strong rationale for further examination of their mechanistic and therapeutic importance.
Ion channel expression patterns in glioblastoma stem cells with functional and therapeutic implications for malignancy.

Science.gov (United States)

Pollak, Julia; Rai, Karan G; Funk, Cory C; Arora, Sonali; Lee, Eunjee; Zhu, Jun; Price, Nathan D; Paddison, Patrick J; Ramirez, Jan-Marino; Rostomily, Robert C

2017-01-01

Ion channels and transporters have increasingly recognized roles in cancer progression through the regulation of cell proliferation, migration, and death. Glioblastoma stem-like cells (GSCs) are a source of tumor formation and recurrence in glioblastoma multiforme, a highly aggressive brain cancer, suggesting that ion channel expression may be perturbed in this population. However, little is known about the expression and functional relevance of ion channels that may contribute to GSC malignancy. Using RNA sequencing, we assessed the enrichment of ion channels in GSC isolates and non-tumor neural cell types. We identified a unique set of GSC-enriched ion channels using differential expression analysis that is also associated with distinct gene mutation signatures. In support of potential clinical relevance, expression of selected GSC-enriched ion channels evaluated in human glioblastoma databases of The Cancer Genome Atlas and Ivy Glioblastoma Atlas Project correlated with patient survival times. Finally, genetic knockdown as well as pharmacological inhibition of individual or classes of GSC-enriched ion channels constrained growth of GSCs compared to normal neural stem cells. This first-in-kind global examination characterizes ion channels enriched in GSCs and explores their potential clinical relevance to glioblastoma molecular subtypes, gene mutations, survival outcomes, regional tumor expression, and experimental responses to loss-of-function. Together, the data support the potential biological and therapeutic impact of ion channels on GSC malignancy and provide strong rationale for further examination of their mechanistic and therapeutic importance.

Comparison of exosomes secreted by induced pluripotent stem cell-derived mesenchymal stem cells and synovial membrane-derived mesenchymal stem cells for the treatment of osteoarthritis.

Science.gov (United States)

Zhu, Yu; Wang, Yuchen; Zhao, Bizeng; Niu, Xin; Hu, Bin; Li, Qing; Zhang, Juntao; Ding, Jian; Chen, Yunfeng; Wang, Yang

2017-03-09

Osteoarthritis (OA) is the most common joint disease worldwide. In the past decade, mesenchymal stem cells (MSCs) have been used widely for the treatment of OA. A potential mechanism of MSC-based therapies has been attributed to the paracrine secretion of trophic factors, in which exosomes may play a major role. In this study, we aimed to compare the effectiveness of exosomes secreted by synovial membrane MSCs (SMMSC-Exos) and exosomes secreted by induced pluripotent stem cell-derived MSCs (iMSC-Exos) on the treatment of OA. Induced pluripotent stem cell-derived MSCs and synovial membrane MSCs were characterized by flow cytometry. iMSC-Exos and SMMSC-Exos were isolated using an ultrafiltration method. Tunable resistive pulse-sensing analysis, transmission electron microscopy, and western blots were used to identify exosomes. iMSC-Exos and SMMSC-Exos were injected intra-articularly in a mouse model of collagenase-induced OA and the efficacy of exosome injections was assessed by macroscopic, histological, and immunohistochemistry analysis. We also evaluated the effects of iMSC-Exos and SMMSC-Exos on proliferation and migration of human chondrocytes by cell-counting and scratch assays, respectively. The majority of iMSC-Exos and SMMSC-Exos were approximately 50-150 nm in diameter and expressed CD9, CD63, and TSG101. The injection of iMSC-Exos and SMMSC-Exos both attenuated OA in the mouse OA model, but iMSC-Exos had a superior therapeutic effect compared with SMMSC-Exos. Similarly, chondrocyte migration and proliferation were stimulated by both iMSC-Exos and SMMSC-Exos, with iMSC-Exos exerting a stronger effect. The present study demonstrated that iMSC-Exos have a greater therapeutic effect on OA than SMMSC-Exos. Because autologous iMSCs are theoretically inexhaustible, iMSC-Exos may represent a novel therapeutic approach for the treatment of OA.
Placental extract ameliorates non-alcoholic steatohepatitis (NASH by exerting protective effects on endothelial cells

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Akihiro Yamauchi

2017-09-01

Full Text Available Non-alcoholic steatohepatitis (NASH is a severe form of fatty liver disease that is defined by the presence of inflammation and fibrosis, ultimately leading to cirrhosis and hepatocellular carcinoma. Treatment with human placental extract (HPE reportedly ameliorates the hepatic injury. We evaluated the effect of HPE treatment in a mouse model of NASH. In the methione- and choline-deficient (MCD diet-induced liver injury model, fibrosis started from regions adjacent to the sinusoids. We administered the MCD diet with high-salt loading (8% NaCl in the drinking water to mice deficient in the vasoprotective molecule RAMP2 for 5 weeks, with or without HPE. In both the HPE and control groups, fibrosis was seen in regions adjacent to the sinusoids, but the fibrosis was less pronounced in the HPE-treated mice. Levels of TNF-α and MMP9 expression were also significantly reduced in HPE-treated mice, and oxidative stress was suppressed in the perivascular region. In addition, HPE dose-dependently increased survival of cultured endothelial cells exposed to 100 μM H2O2, and it upregulated expression of eNOS and the anti-apoptotic factors bcl-2 and bcl-xL. From these observations, we conclude that HPE ameliorates NASH-associated pathologies by suppressing inflammation, oxidative stress and fibrosis. These beneficially effects of HPE are in part attributable to its protective effects on liver sinusoidal endothelial cells. HPE could thus be an attractive therapeutic candidate with which to suppress progression from simple fatty liver to NASH.
Mesenchymal Stem/Stromal Cell-Derived Extracellular Vesicles and Their Potential as Novel Immunomodulatory Therapeutic Agents

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Verena Börger

2017-07-01

Full Text Available Extracellular vesicles (EVs, such as exosomes and microvesicles, have been identified as mediators of a newly-discovered intercellular communication system. They are essential signaling mediators in various physiological and pathophysiological processes. Depending on their origin, they fulfill different functions. EVs of mesenchymal stem/stromal cells (MSCs have been found to promote comparable therapeutic activities as MSCs themselves. In a variety of in vivo models, it has been observed that they suppress pro-inflammatory processes and reduce oxidative stress and fibrosis. By switching pro-inflammatory into tolerogenic immune responses, MSC-EVs very likely promote tissue regeneration by creating a pro-regenerative environment allowing endogenous stem and progenitor cells to successfully repair affected tissues. Accordingly, MSC-EVs provide a novel, very promising therapeutic agent, which has already been successfully applied to humans. However, the MSC-EV production process has not been standardized, yet. Indeed, a collection of different protocols has been used for the MSC-EV production, characterization and application. By focusing on kidney, heart, liver and brain injuries, we have reviewed the major outcomes of published MSC-EV in vivo studies.
The ginsenoside PPD exerts anti-endometriosis effects by suppressing estrogen receptor-mediated inhibition of endometrial stromal cell autophagy and NK cell cytotoxicity.

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Zhang, Bing; Zhou, Wen-Jie; Gu, Chun-Jie; Wu, Ke; Yang, Hui-Li; Mei, Jie; Yu, Jia-Jun; Hou, Xiao-Fan; Sun, Jian-Song; Xu, Feng-Yuan; Li, Da-Jin; Jin, Li-Ping; Li, Ming-Qing

2018-05-14

Endometriosis (EMS) is an estrogen-dependent gynecological disease with a low autophagy level of ectopic endometrial stromal cells (eESCs). Impaired NK cell cytotoxic activity is involved in the clearance obstruction of the ectopic endometrial tissue in the abdominopelvic cavity. Protopanaxadiol (PPD) and protopanaxatriol (PPT) are two metabolites of ginsenosides, which have profound biological functions, such as anti-cancer activities. However, the role and mechanism of ginsenosides and metabolites in endometriosis are completely unknown. Here, we found that the compounds PPD, PPT, ginsenoside-Rg3 (G-Rg3), ginsenoside-Rh2 (G-Rh2), and esculentoside A (EsA) led to significant decreases in the viability of eESCs, particularly PPD (IC50 = 30.64 µM). In vitro and in vivo experiments showed that PPD promoted the expression of progesterone receptor (PR) and downregulated the expression of estrogen receptor α (ERα) in eESCs. Treatment with PPD obviously induced the autophagy of eESCs and reversed the inhibitory effect of estrogen on eESC autophagy. In addition, eESCs pretreated with PPD enhanced the cytotoxic activity of NK cells in response to eESCs. PPD decreased the numbers and suppressed the growth of ectopic lesions in a mouse EMS model. These results suggest that PPD plays a role in anti-EMS activation, possibly by restricting estrogen-mediated autophagy regulation and enhancing the cytotoxicity of NK cells. This result provides a scientific basis for potential therapeutic strategies to treat EMS by PPD or further structural modification.
Merkel Cell Carcinoma: Chemotherapy and Emerging New Therapeutic Options

International Nuclear Information System (INIS)

Desch, L.; Kunstfeld, R.

2013-01-01

Merkel cell carcinoma (MCC) is a rare neuroendocrine skin tumor that typically occurs in elderly, immunosuppressed patients. Infection with Merkel cell virus (MCV) and immunosuppression play an important role in the development of MCC. Different staging systems make it difficult to compare the existing clinical data. Furthermore, there predominantly exist single case reports and case series, but no randomized controlled trials. However, it is necessary to develop further therapy options because MCC tends to grow rapidly and metastasizes early. In the metastatic disease, therapeutic attempts were made with various chemotherapeutic combination regimens. Because of the high toxicity of these combinations, especially those established in SCLC, and regarding the unsatisfying results, the challenge is to balance the pros and cons of chemotherapy individually and carefully. Up to now, emerging new therapy options as molecular-targeted agents, for example, pipebuzone, imatinib, or somatostatin analogues as well as immunologic als, for example, imiquimod and interferons, also showed less success concerning the disease-free response rates. According to the literature, neither chemotherapy nor molecular-targeted agents or immunotherapeutic strategies have shown promising effects in the therapy of the metastatic disease of MCC so far. There is a great demand for randomized controlled studies and a need for an MCC registry and multicenter clinical trials due to the tumors curiosity.
Exertional headache and coronary ischemia despite normal electrocardiographic stress testing.

Science.gov (United States)

Cutrer, F Michael; Huerter, Karina

2006-01-01

Exertional headaches may under certain conditions reflect coronary ischemia. We report the case of a patient seen in a neurology referral practice whose exertional headaches, even in the face of two normal electrocardiographic stress tests and in the absence of underlying chest pain were the sole symptoms of coronary ischemia as detected by Tc-99m Sestamibi testing SPECT stress testing. Stent placement resulted in complete resolution of headaches. Exertional headache in the absence of chest pain may reflect underlying symptomatic coronary artery disease (CAD) even when conventional electrocardiographic stress testing does not indicate ischemia.
Lactobacillus casei Exerts Anti-Proliferative Effects Accompanied by Apoptotic Cell Death and Up-Regulation of TRAIL in Colon Carcinoma Cells

OpenAIRE

Tiptiri-Kourpeti, Angeliki; Spyridopoulou, Katerina; Santarmaki, Valentina; Aindelis, Georgios; Tompoulidou, Evgenia; Lamprianidou, Eleftheria E.; Saxami, Georgia; Ypsilantis, Petros; Lampri, Evangeli S.; Simopoulos, Constantinos; Kotsianidis, Ioannis; Galanis, Alex; Kourkoutas, Yiannis; Dimitrellou, Dimitra; Chlichlia, Katerina

2016-01-01

Probiotic microorganisms such as lactic acid bacteria (LAB) exert a number of strain-specific health-promoting activities attributed to their immunomodulatory, anti-inflammatory and anti-carcinogenic properties. Despite recent attention, our understanding of the biological processes involved in the beneficial effects of LAB strains is still limited. To this end, the present study investigated the growth-inhibitory effects of Lactobacillus casei ATCC 393 against experimental colon cancer. Admi...
Modulation of Immune Responses by Exosomes Derived from Antigen-Presenting Cells

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Botros B. Shenoda

2016-01-01

Full Text Available Exosome-mediated signaling is important in mediating the inflammatory response. To exert their biological or pathophysiological functions in the recipient cells, exosomes deliver a diverse array of biomacromolecules including long and short coding and non-coding RNAs, proteins, and lipids. Exosomes secreted by antigen-presenting cells can confer therapeutic benefits by attenuating or stimulating the immune response. Exosomes play a crucial role in carrying and presenting functional major histocompatibility peptide complexes to modulate antigen-specific T cell responses. Exosomes from Dendritic Cells (DCs can activate T and B cells and have been explored for their immunostimulatory properties in cancer therapy. The immunosuppressive properties of exosomes derived from macrophages and DCs can reduce inflammation in animal models for several inflammatory disorders. This review focuses on the protective role of exosomes in attenuating inflammation or augmenting immune response, emphasizing studies on exosomes derived from DCs and macrophages.
Power in the hypnotic relationship: therapeutic or abusive?

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Walling, D P; Levine, R E

1997-01-01

The unique relationship between hypnotist and subject has been theorized as one explanation for the effectiveness of hypnosis. This relationship carries a power differential, present in most therapeutic relationships, but accentuated by hypnosis. The power differential is sometimes perceived as the ability of the hypnotist to control the subject. Perceptions of hypnosis offered by stage hypnotists, the popular media, and some clinicians perpetuate the notion that the hypnotist has the ability to exert undue influence upon the client. The present article examines the relationship between hypnotist and subject focusing on issues of power and control. The authors examine the unique dynamics accompanying the use of hypnosis and their impact on the therapeutic dyad. Evidence is offered demonstrating the power differential, and how this differential can serve as either a positive or negative agent of change. Therapists should be aware of the dynamics created by using hypnosis. Implications for training therapists in the use of hypnosis are suggested.
Mast Cells and Innate Lymphoid Cells: Underappreciated Players in CNS Autoimmune Demyelinating Disease.

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Brown, Melissa A; Weinberg, Rebecca B

2018-01-01

Multiple sclerosis (MS) and its mouse model, experimental autoimmune encephalomyelitis, are autoimmune CNS inflammatory diseases. As a result of a breakdown in the relatively impermeable blood-brain barrier (BBB) in affected individuals, myelin-specific CD4 + and CD8 + T cells gain entry into the immune privileged CNS and initiate myelin, oligodendrocyte, and nerve axon destruction. However, despite the absolute requirement for T cells, there is increasing evidence that innate immune cells also play critical amplifying roles in disease pathogenesis. By modulating the character and magnitude of the myelin-reactive T cell response and regulating BBB integrity, innate cells affect both disease initiation and progression. Two classes of innate cells, mast cells and innate lymphoid cells (ILCs), have been best studied in models of allergic and gastrointestinal inflammatory diseases. Yet, there is emerging evidence that these cell types also exert a profound influence in CNS inflammatory disease. Both cell types are residents within the meninges and can be activated early in disease to express a wide variety of disease-modifying cytokines and chemokines. In this review, we discuss how mast cells and ILCs can have either disease-promoting or -protecting effects on MS and other CNS inflammatory diseases and how sex hormones may influence this outcome. These observations suggest that targeting these cells and their unique mediators can be exploited therapeutically.
Induction of Type I Interferons by Therapeutic Nanoparticle-Based Vaccination Is Indispensable to Reinforce Cytotoxic CD8+ T Cell Responses During Chronic Retroviral Infection

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Torben Knuschke

2018-04-01

Full Text Available T cell dysfunction and immunosuppression are characteristic for chronic viral infections and contribute to viral persistence. Overcoming these burdens is the goal of new therapeutic strategies to cure chronic infectious diseases. We recently described that therapeutic vaccination of chronic retrovirus infected mice with a calcium phosphate (CaP nanoparticle (NP-based vaccine carrier, functionalized with CpG and viral peptides is able to efficiently reactivate the CD8+ T cell response and improve the eradication of virus infected cells. However, the mechanisms underlying this effect were largely unclear. While type I interferons (IFNs I are considered to drive T cell exhaustion by persistent immune activation during chronic viral infection, we here describe an indispensable role of IFN I induced by therapeutic vaccination to efficiently reinforce cytotoxic CD8+ T cells (CTL and improve control of chronic retroviral infection. The induction of IFN I is CpG dependent and leads to significant IFN signaling indicated by upregulation of IFN stimulated genes. By vaccinating chronically retrovirus-infected mice lacking the IFN I receptor (IFNAR−/− or by blocking IFN I signaling in vivo during therapeutic vaccination, we demonstrate that IFN I signaling is necessary to drive full reactivation of CTLs. Surprisingly, we also identified an impaired suppressive capability of regulatory T cells in the presence of IFNα, which implicates an important role for vaccine-induced IFNα in the regulation of the T cell response during chronic retroviral infection. Our data suggest that inducing IFN I signaling in conjunction with the presentation of viral antigens can reactivate immune functions and reduce viral loads in chronic infections. Therefore, we propose CaP NPs as potential therapeutic tool to treat chronic infections.
IGFBP1 increases β-cell regeneration by promoting α- to β-cell transdifferentiation.

Science.gov (United States)

Lu, Jing; Liu, Ka-Cheuk; Schulz, Nadja; Karampelias, Christos; Charbord, Jérémie; Hilding, Agneta; Rautio, Linn; Bertolino, Philippe; Östenson, Claes-Göran; Brismar, Kerstin; Andersson, Olov

2016-09-15

There is great interest in therapeutically harnessing endogenous regenerative mechanisms to increase the number of β cells in people with diabetes. By performing whole-genome expression profiling of zebrafish islets, we identified 11 secreted proteins that are upregulated during β-cell regeneration. We then tested the proteins' ability to potentiate β-cell regeneration in zebrafish at supraphysiological levels. One protein, insulin-like growth factor (Igf) binding-protein 1 (Igfbp1), potently promoted β-cell regeneration by potentiating α- to β-cell transdifferentiation. Using various inhibitors and activators of the Igf pathway, we show that Igfbp1 exerts its regenerative effect, at least partly, by inhibiting Igf signaling. Igfbp1's effect on transdifferentiation appears conserved across species: Treating mouse and human islets with recombinant IGFBP1 in vitro increased the number of cells co-expressing insulin and glucagon threefold. Moreover, a prospective human study showed that having high IGFBP1 levels reduces the risk of developing type-2 diabetes by more than 85%. Thus, we identify IGFBP1 as an endogenous promoter of β-cell regeneration and highlight its clinical importance in diabetes. © 2016 The Authors. Published under the terms of the CC BY NC ND 4.0 license.
Reprogramming Medulloblastoma-Propagating Cells by a Combined Antagonism of Sonic Hedgehog and CXCR4.

Science.gov (United States)

Ward, Stacey A; Warrington, Nicole M; Taylor, Sara; Kfoury, Najla; Luo, Jingqin; Rubin, Joshua B

2017-03-15

The CXCR4 chemokine and Sonic Hedgehog (SHH) morphogen pathways are well-validated therapeutic targets in cancer, including medulloblastoma. However, single-agent treatments with SHH or CXCR4 antagonists have not proven efficacious in clinical trials to date. Here, we discovered that dual inhibition of the SHH and CXCR4 pathways in a murine model of SHH-subtype medulloblastoma exerts potent antitumor effects. This therapeutic synergy resulted in the suppression of tumor-propagating cell function and correlated with increased histone H3 lysine 27 trimethylation within the promoters of stem cell genes, resulting in their decreased expression. These results demonstrate that CXCR4 contributes to the epigenetic regulation of a tumor-propagating cell phenotype. Moreover, they provide a mechanistic rationale to evaluate the combination of SHH and CXCR4 inhibitors in clinical trials for the treatment of medulloblastoma, as well as other cancers driven by SHH that coexpress high levels of CXCR4. Cancer Res; 77(6); 1416-26. ©2016 AACR . ©2016 American Association for Cancer Research.
Transplantation of mesenchymal stem cells overexpressing IL10 attenuates cardiac impairments in rats with myocardial infarction.

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Meng, Xin; Li, Jianping; Yu, Ming; Yang, Jian; Zheng, Minjuan; Zhang, Jinzhou; Sun, Chao; Liang, Hongliang; Liu, Liwen

2018-01-01

Mesenchymal stem cell (MSC) has been well known to exert therapeutic potential for patients with myocardial infarction (MI). In addition, interleukin-10 (IL10) could attenuate MI through suppressing inflammation. Thus, the combination of MSC implantation with IL10 delivery may extend health benefits to ameliorate cardiac injury after MI. Here we established overexpression of IL10 in bone marrow-derived MSC through adenoviral transduction. Cell viability, apoptosis, and IL10 secretion under ischemic challenge in vitro were examined. In addition, MSC was transplanted into the injured hearts in a rat model of MI. Four weeks after the MI induction, MI, cardiac functions, apoptotic cells, and inflammation cytokines were assessed. In response to in vitro oxygen-glucose deprivation (OGD), IL10 overexpression in MSC (Ad.IL10-MSC) enhanced cell viability, decreased apoptosis, and increased IL10 secretion. Consistently, the implantation of Ad.IL10-MSCs into MI animals resulted in more reductions in myocardial infarct size, cardiac impairment, and cell apoptosis, compared to the individual treatments of either MSC or IL10 administration. Moreover, the attenuation of both systemic and local inflammations was most prominent for Ad.IL10-MSC treatment. IL10 overexpression and MSC may exert a synergistic anti-inflammatory effect to alleviate cardiac injury after MI. © 2017 Wiley Periodicals, Inc.
Examination of thromboxane synthase as a prognostic factor and therapeutic target in non-small cell lung cancer.

LENUS (Irish Health Repository)

Cathcart, Mary-Clare

2011-03-01

Thromboxane synthase (TXS) metabolises prostaglandin H2 into thromboxanes, which are biologically active on cancer cells. TXS over-expression has been reported in a range of cancers, and associated with a poor prognosis. TXS inhibition induces cell death in-vitro, providing a rationale for therapeutic intervention. We aimed to determine the expression profile of TXS in NSCLC and if it is prognostic and\\/or a survival factor in the disease.
Trans-species Engineering of Glycosylated Therapeutic Proteins

DEFF Research Database (Denmark)

Yang, Zhang

important to address. Whenever glycosylation has been found to be an important PTM for function or bioactivity, human therapeutics have generally been produced in mammalian Chinese hamster ovary (CHO) cell line. Oglycosylation is one of the most complex regulated PTMs of proteins but also one of the least...... understood. Currently, mammalian cells are required for human O-glycosylation. Increasing efforts have been devoted to engineering non-mammalian cells for production of recombinant proteins with “human-like” glycosylation. Substantial success has been achieved with designed N-glycosylation in both lower......Recombinant expression of therapeutic proteins is one of the major tasks in modern biomedicine. One of the most important factors with respect to therapeutic use in human is posttranslational modifications (PTMs) of the recombinant proteins, of which protein glycosylation is by far the most...
Influence of permittivity on gradient force exerted on Mie spheres.

Science.gov (United States)

Chen, Jun; Li, Kaikai; Li, Xiao

2018-04-01

In optical trapping, whether a particle could be stably trapped into the focus region greatly depends on the strength of the gradient force. Individual theoretical study on gradient force exerted on a Mie particle is rare because the mathematical separation of the gradient force and the scattering force in the Mie regime is difficult. Based on the recent forces separation work by Du et al. [Sci. Rep.7, 18042 (2017)SRCEC32045-232210.1038/s41598-017-17874-1], we investigate the influence of permittivity (an important macroscopic physical quantity) on the gradient force exerted on a Mie particle by cooperating numerical calculation using fast Fourier transform and analytical analysis using multipole expansion. It is revealed that gradient forces exerted on small spheres are mainly determined by the electric dipole moment except for certain permittivity with which the real part of polarizability of the electric dipole approaches zero, and gradient forces exerted on larger spheres are complex because of the superposition of the multipole moments. The classification of permittivity corresponding to different varying tendencies of gradient forces exerted on small spheres or larger Mie particles are illustrated. Absorption of particles favors the trapping of small spheres by gradient force, while it is bad for the trapping of larger particles. Moreover, the absolute values of the maximal gradient forces exerted on larger Mie particles decline greatly versus the varied imaginary part of permittivity. This work provides elaborate investigation on the different varying tendencies of gradient forces versus permittivity, which favors more accurate and free optical trapping.
Comparison of cell-based and non-cell-based assay platforms for the detection of clinically relevant anti-drug neutralizing antibodies for immunogenicity assessment of therapeutic proteins.

Science.gov (United States)

Hu, Jenny; Wala, Iwona; Han, Hong; Nagatani, Janice; Barger, Troy; Civoli, Francesca; Kaliyaperumal, Arunan; Zhuang, Yao; Gupta, Shalini

2015-04-01

Anti-drug neutralizing antibodies (NAbs) formed due to unwanted immunogenicity of a therapeutic protein point towards a mature immune response. NAb detection is important in interpreting the therapeutic's efficacy and safety in vivo. In vitro cell-based NAb assays provide a physiological system for NAb detection, however are complex assays. Non-cell-based competitive ligand binding (CLB) approaches are also employed for NAb detection. Instead of cells, CLB assays use soluble receptor and conjugated reagents and are easier to perform, however have reduced physiological relevance. The aim of this study was to compare the performance of CLB assays to established cell-based assays to determine the former's ability to detect clinically relevant NAbs towards therapeutics that (i) acted as an agonist or (ii) acted as antagonists by binding to a target receptor. We performed a head-to-head comparison of the performance of cell-based and CLB NAb assays for erythropoietin (EPO) and two anti-receptor monoclonal antibodies (AMG-X and AMG 317). Clinically relevant NAb-positive samples identified previously by a cell-based assay were assessed in the corresponding CLB format(s). A panel of 12 engineered fully human anti-EPO monoclonal antibodies (MAbs) was tested in both EPO NAb assay formats. Our results showed that the CLB format was (i) capable of detecting human anti-EPO MAbs of differing neutralizing capabilities and affinities and (ii) provided similar results as the cell-based assay for detecting NAbs in patient samples. The cell-based and CLB assays also behaved comparably in detecting NAbs in clinical samples for AMG-X. In the case of anti-AMG 317 NAbs, the CLB format failed to detect NAbs in more than 50% of the tested samples. We conclude that assay sensitivity, drug tolerance and the selected assay matrix played an important role in the inability of AMG 317 CLB assays to detect clinically relevant NAbs. Copyright © 2015 Elsevier B.V. All rights reserved.
Petiveria alliacea exerts mnemonic and learning effects on rats.

Science.gov (United States)

Silva, Mallone Lopes; Luz, Diandra Araújo; Paixão, Thiago Portal da; Silva, João Paulo Bastos; Belém-Filho, Ivaldo Jesus Almeida; Fernandes, Luanna Melo Pereira; Gonçalves, Ana Cristina Baetas; Fontes-Júnior, Enéas Andrade; de Andrade, Marciene Ataíde; Maia, Cristiane Socorro Ferraz

2015-07-01

Petiveria alliacea L. (Phytolaccaceae) is a perennial shrub native to the Amazon region and other tropical areas such as Central America and the Caribbean. Popularly known as mucuracaá, P. alliacea is used in the folk medicine for a broad variety of therapeutic purpose and also in religious ceremonies by slaves as a sedative, which highlights its properties on the Central Nervous System (CNS). The present study evaluated the effects of the P. alliacea leaves hydroalcoholic extract (PaLHE) on the cognition, including learning and memory. Three-month-old male and female Wistar rats (n=8-10/group) were administered with 900mg/kg of PaLHE. The behavioral assays included Step-down Inhibitory avoidance (IA) and Morris Water Maze (MWM) tests. Consistent with our previous reports, P. alliacea improved long-term memory. It also exerted previously unreported effects on short-term and spatial memory improvement, and increased learning in the tasks. The P. alliacea extract elicited mnemonic effects and improved the learning process in both IA and MWM tests. Our results highlight the importance of further studies in order to identify the active substances of the PaLHE and investigate the pharmacological mechanisms that underlies the reported effects. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.
Andrographolide, a diterpene lactone from Andrographis paniculata and its therapeutic promises in cancer.

Science.gov (United States)

Islam, Muhammad Torequl; Ali, Eunüs S; Uddin, Shaikh Jamal; Islam, Md Amirul; Shaw, Subrata; Khan, Ishaq N; Saravi, Seyed Soheil Saeedi; Ahmad, Saheem; Rehman, Shahnawaz; Gupta, Vijai Kumar; Găman, Mihnea-Alexandru; Găman, Amelia Maria; Yele, Santosh; Das, Asish Kumar; de Castro E Sousa, João Marcelo; de Moura Dantas, Sandra Maria Mendes; Rolim, Hercília Maria Lins; de Carvalho Melo-Cavalcante, Ana Amélia; Mubarak, Mohammad S; Yarla, Nagendra Sastry; Shilpi, Jamil A; Mishra, Siddhartha Kumar; Atanasov, Atanas G; Kamal, Mohammad Amjad

2018-04-28

The diterpene lactone andrographolide, isolated from Andrographis paniculata, has been proven to possess several important protective biological activities, including antioxidant, anti-inflammatory, immunomodulatory, antiseptic, antimicrobial, cytotoxic, hypolipidemic, cardioprotective, hepatoprotective, and neuroprotective effects. In addition, it has been reported to play a therapeutic role in the treatment of major human diseases, such as Parkinson's disease, rheumatoid arthritis, and colitis. This systematic review aims to highlight andrographolide as a promising agent in cancer treatment. To this purpose, a number of databases were used to search for the cytotoxic/anticancer effects of andrographolide in pre-clinical and clinical studies. Among 1703 identified literature articles, 139 were included in this review; 109 were investigated as non-clinical, whereas 24, 3, and 3 were pre-clinical, clinical, and non-pre-clinical trials, respectively. Among the model systems, cultured cell lines appeared as the most frequently (79.14%) used, followed by in vivo models using rodents, among others. Furthermore, andrographolide was found to exert cytotoxic/anticancer effects on almost all types of cell lines with the underlying mechanisms involving oxidative stress, cell cycle arrest, anti-inflammatory and immune system mediated effects, apoptosis, necrosis, autophagy, inhibition of cell adhesion, proliferation, migration, invasion, anti-angiogenic activity, and other miscellaneous actions. After careful consideration of the relevant evidence, we suggest that andrographolide can be one of the potential agents in the treatment of cancer in the near future. Copyright © 2018 Elsevier B.V. All rights reserved.

[Cell signaling pathways interaction in cellular proliferation: Potential target for therapeutic interventionism].

Science.gov (United States)

Valdespino-Gómez, Víctor Manuel; Valdespino-Castillo, Patricia Margarita; Valdespino-Castillo, Víctor Edmundo

2015-01-01

Nowadays, cellular physiology is best understood by analysing their interacting molecular components. Proteins are the major components of the cells. Different proteins are organised in the form of functional clusters, pathways or networks. These molecules are ordered in clusters of receptor molecules of extracellular signals, transducers, sensors and biological response effectors. The identification of these intracellular signaling pathways in different cellular types has required a long journey of experimental work. More than 300 intracellular signaling pathways have been identified in human cells. They participate in cell homeostasis processes for structural and functional maintenance. Some of them participate simultaneously or in a nearly-consecutive progression to generate a cellular phenotypic change. In this review, an analysis is performed on the main intracellular signaling pathways that take part in the cellular proliferation process, and the potential use of some components of these pathways as target for therapeutic interventionism are also underlined. Copyright © 2015 Academia Mexicana de Cirugía A.C. Published by Masson Doyma México S.A. All rights reserved.
Curcumin and trans-resveratrol exert cell cycle-dependent radioprotective or radiosensitizing effects as elucidated by the PCC and G2-assay

Energy Technology Data Exchange (ETDEWEB)

Sebastià, N., E-mail: natividad.sebastia@uv.es [Radiation Protection Service, IIS La Fe, Health Research Institute La Fe, Valencia (Spain); Montoro, A. [Radiation Protection Service, Universitary and Politechnic Hospital La Fe, Valencia (Spain); Grupo de Investigación Biomédica en Imagen GIBI230, IIS La Fe, Health Research Institute La Fe, Valencia (Spain); Unidad Mixta de Investigación en Endocrinología, Nutrición y Dietética Clínica, IIS La Fe, Health Research Institute La Fe, Valencia (Spain); Hervás, D. [Biostatistics Unit, IIS La Fe, Health Research Institute La Fe, Valencia (Spain); Pantelias, G.; Hatzi, V.I. [Institute of Nuclear and Radiological Sciences and Technology, Energy and Safety, National Centre for Scientific Research “Demokritos”, Aghia Paraskevi, Athens (Greece); Soriano, J.M. [Grupo de Investigación Biomédica en Imagen GIBI230, IIS La Fe, Health Research Institute La Fe, Valencia (Spain); Unidad Mixta de Investigación en Endocrinología, Nutrición y Dietética Clínica, IIS La Fe, Health Research Institute La Fe, Valencia (Spain); Department of Preventive Medicine and Public Health, Faculty of Pharmacy, University of Valencia, Burjassot, Valencia (Spain); Villaescusa, J.I. [Radiation Protection Service, Universitary and Politechnic Hospital La Fe, Valencia (Spain); and others

2014-08-15

Highlights: • Curcumin and trans-resveratrol can exert radioprotective or radiosensitizing effects. • The mechanisms underlying such dual action were elucidated using the PCC and G2-assay. • Radioprotection occurs in non-cycling cells exposed to curcumin and resveratrol. • Radiosensitization occurs in cycling cells exposed to the chemicals. • G2-checkpoint abrogation by the chemicals underlies the radiosensitizing mechanism. - Abstract: Curcumin and trans-resveratrol are well-known antioxidant polyphenols with radiomodulatory properties, radioprotecting non-cancerous cells while radiosensitizing tumor cells. This dual action may be the result of their radical scavenging properties and their effects on cell-cycle checkpoints that are activated in response to radiation-induced chromosomal damage. It could be also caused by their effect on regulatory pathways with impact on detoxification enzymes, the up-regulation of endogenous protective systems, and cell-cycle-dependent processes of DNA damage. This work aims to elucidate the mechanisms underlying the dual action of these polyphenols and investigates under which conditions they exhibit radioprotecting or radiosensitizing properties. The peripheral blood lymphocyte test system was used, applying concentrations ranging from 1.4 to 140 μM curcumin and 2.2 to 220 μM trans-resveratrol. The experimental design focuses first on their radioprotective effects in non-cycling lymphocytes, as uniquely visualized using cell fusion-mediated premature chromosome condensation, excluding, thus, cell-cycle interference to repair processes and activation of checkpoints. Second, the radiosensitizing potential of these chemicals on the induction of chromatid breaks in cultured lymphocytes following G2-phase irradiation was evaluated by a standardized G2-chromosomal radiosensitivity predictive assay. This assay uses caffeine for G2-checkpoint abrogation and it was applied to obtain an internal control for radiosensitivity
Curcumin and trans-resveratrol exert cell cycle-dependent radioprotective or radiosensitizing effects as elucidated by the PCC and G2-assay

International Nuclear Information System (INIS)

Sebastià, N.; Montoro, A.; Hervás, D.; Pantelias, G.; Hatzi, V.I.; Soriano, J.M.; Villaescusa, J.I.

2014-01-01

Highlights: • Curcumin and trans-resveratrol can exert radioprotective or radiosensitizing effects. • The mechanisms underlying such dual action were elucidated using the PCC and G2-assay. • Radioprotection occurs in non-cycling cells exposed to curcumin and resveratrol. • Radiosensitization occurs in cycling cells exposed to the chemicals. • G2-checkpoint abrogation by the chemicals underlies the radiosensitizing mechanism. - Abstract: Curcumin and trans-resveratrol are well-known antioxidant polyphenols with radiomodulatory properties, radioprotecting non-cancerous cells while radiosensitizing tumor cells. This dual action may be the result of their radical scavenging properties and their effects on cell-cycle checkpoints that are activated in response to radiation-induced chromosomal damage. It could be also caused by their effect on regulatory pathways with impact on detoxification enzymes, the up-regulation of endogenous protective systems, and cell-cycle-dependent processes of DNA damage. This work aims to elucidate the mechanisms underlying the dual action of these polyphenols and investigates under which conditions they exhibit radioprotecting or radiosensitizing properties. The peripheral blood lymphocyte test system was used, applying concentrations ranging from 1.4 to 140 μM curcumin and 2.2 to 220 μM trans-resveratrol. The experimental design focuses first on their radioprotective effects in non-cycling lymphocytes, as uniquely visualized using cell fusion-mediated premature chromosome condensation, excluding, thus, cell-cycle interference to repair processes and activation of checkpoints. Second, the radiosensitizing potential of these chemicals on the induction of chromatid breaks in cultured lymphocytes following G2-phase irradiation was evaluated by a standardized G2-chromosomal radiosensitivity predictive assay. This assay uses caffeine for G2-checkpoint abrogation and it was applied to obtain an internal control for radiosensitivity
Dysregulated choline metabolism in T-cell lymphoma: role of choline kinase-α and therapeutic targeting

International Nuclear Information System (INIS)

Xiong, J; Bian, J; Wang, L; Zhou, J-Y; Wang, Y; Zhao, Y; Wu, L-L; Hu, J-J; Li, B; Chen, S-J; Yan, C; Zhao, W-L

2015-01-01

Cancer cells have distinct metabolomic profile. Metabolic enzymes regulate key oncogenic signaling pathways and have an essential role on tumor progression. Here, serum metabolomic analysis was performed in 45 patients with T-cell lymphoma (TCL) and 50 healthy volunteers. The results showed that dysregulation of choline metabolism occurred in TCL and was related to tumor cell overexpression of choline kinase-α (Chokα). In T-lymphoma cells, pharmacological and molecular silencing of Chokα significantly decreased Ras-GTP activity, AKT and ERK phosphorylation and MYC oncoprotein expression, leading to restoration of choline metabolites and induction of tumor cell apoptosis/necropotosis. In a T-lymphoma xenograft murine model, Chokα inhibitor CK37 remarkably retarded tumor growth, suppressed Ras-AKT/ERK signaling, increased lysophosphatidylcholine levels and induced in situ cell apoptosis/necropotosis. Collectively, as a regulatory gene of aberrant choline metabolism, Chokα possessed oncogenic activity and could be a potential therapeutic target in TCL, as well as other hematological malignancies with interrupted Ras signaling pathways
Aqueous Extract of Paeonia suffruticosa Inhibits Migration and Metastasis of Renal Cell Carcinoma Cells via Suppressing VEGFR-3 Pathway

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Shih-Chin Wang

2012-01-01

Full Text Available Renal cell carcinoma (RCC cells are characterized by strong drug resistance and high metastatic incidence. In this study, the effects of ten kinds of Chinese herbs on RCC cell migration and proliferation were examined. Aqueous extract of Paeonia suffruticosa (PS-A exerted strong inhibitory effects on cancer cell migration, mobility, and invasion. The results of mouse xenograft experiments showed that the treatment of PS-A significantly suppressed tumor growth and pulmonary metastasis. We further found that PS-A markedly decreased expression of VEGF receptor-3 (VEGFR-3 and phosphorylation of FAK in RCC cells. Moreover, the activation of Rac-1, a modulator of cytoskeletal dynamics, was remarkably reduced by PS-A. Additionally, PS-A suppressed polymerization of actin filament as demonstrated by confocal microscopy analysis and decreased the ratio of F-actin to G-actin in RCC cells, suggesting that PS-A inhibits RCC cell migration through modulating VEGFR-3/FAK/Rac-1 pathway to disrupt actin filament polymerization. In conclusion, this research elucidates the effects and molecular mechanism for antimigration of PS-A on RCC cells and suggests PS-A to be a therapeutic or adjuvant strategy for the patients with aggressive RCC.
Stem cell therapy for ischemic heart diseases.

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Yu, Hong; Lu, Kai; Zhu, Jinyun; Wang, Jian'an

2017-01-01

Ischemic heart diseases, especially the myocardial infarction, is a major hazard problem to human health. Despite substantial advances in control of risk factors and therapies with drugs and interventions including bypass surgery and stent placement, the ischemic heart diseases usually result in heart failure (HF), which could aggravate social burden and increase the mortality rate. The current therapeutic methods to treat HF stay at delaying the disease progression without repair and regeneration of the damaged myocardium. While heart transplantation is the only effective therapy for end-stage patients, limited supply of donor heart makes it impossible to meet the substantial demand from patients with HF. Stem cell-based transplantation is one of the most promising treatment for the damaged myocardial tissue. Key recent published literatures and ClinicalTrials.gov. Stem cell-based therapy is a promising strategy for the damaged myocardial tissue. Different kinds of stem cells have their advantages for treatment of Ischemic heart diseases. The efficacy and potency of cell therapies vary significantly from trial to trial; some clinical trials did not show benefit. Diverged effects of cell therapy could be affected by cell types, sources, delivery methods, dose and their mechanisms by which delivered cells exert their effects. Understanding the origin of the regenerated cardiomyocytes, exploring the therapeutic effects of stem cell-derived exosomes and using the cell reprogram technology to improve the efficacy of cell therapy for cardiovascular diseases. Recently, stem cell-derived exosomes emerge as a critical player in paracrine mechanism of stem cell-based therapy. It is promising to exploit exosomes-based cell-free therapy for ischemic heart diseases in the future. © The Author 2017. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com
c-Met in esophageal squamous cell carcinoma: an independent prognostic factor and potential therapeutic target.

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Ozawa, Yohei; Nakamura, Yasuhiro; Fujishima, Fumiyoshi; Felizola, Saulo J A; Takeda, Kenichiro; Okamoto, Hiroshi; Ito, Ken; Ishida, Hirotaka; Konno, Takuro; Kamei, Takashi; Miyata, Go; Ohuchi, Noriaki; Sasano, Hironobu

2015-06-03

c-Met is widely known as a poor prognostic factor in various human malignancies. Previous studies have suggested the involvement of c-Met and/or its ligand, hepatocyte growth factor (HGF), in esophageal squamous cell carcinoma (ESCC), but the correlation between c-Met status and clinical outcome remains unclear. Furthermore, the identification of a novel molecular therapeutic target might potentially help improve the clinical outcome of ESCC patients. The expression of c-Met and HGF was immunohistochemically assessed in 104 surgically obtained tissue specimens. The correlation between c-Met/HGF expression and patients' clinicopathological features, including survival, was evaluated. We also investigated changes in cell functions and protein expression of c-Met and its downstream signaling pathway components under treatments with HGF and/or c-Met inhibitor in ESCC cell lines. Elevated expression of c-Met was significantly correlated with tumor depth and pathological stage. Patients with high c-Met expression had significantly worse survival. In addition, multivariate analysis identified the high expression of c-Met as an independent prognostic factor. Treatment with c-Met inhibitor under HGF stimulation significantly inhibited the invasive capacity of an ESCC cell line with elevated c-Met mRNA expression. Moreover, c-Met and its downstream signaling inactivation was also detected after treatment with c-Met inhibitor. The results of our study identified c-Met expression as an independent prognostic factor in ESCC patients and demonstrated that c-Met could be a potential molecular therapeutic target for the treatment of ESCC with elevated c-Met expression.
Curcumin: A review of anti-cancer properties and therapeutic activity in head and neck squamous cell carcinoma

Science.gov (United States)

2011-01-01

Curcumin (diferuloylmethane) is a polyphenol derived from the Curcuma longa plant, commonly known as turmeric. Curcumin has been used extensively in Ayurvedic medicine for centuries, as it is nontoxic and has a variety of therapeutic properties including anti-oxidant, analgesic, anti-inflammatory and antiseptic activity. More recently curcumin has been found to possess anti-cancer activities via its effect on a variety of biological pathways involved in mutagenesis, oncogene expression, cell cycle regulation, apoptosis, tumorigenesis and metastasis. Curcumin has shown anti-proliferative effect in multiple cancers, and is an inhibitor of the transcription factor NF-κB and downstream gene products (including c-myc, Bcl-2, COX-2, NOS, Cyclin D1, TNF-α, interleukins and MMP-9). In addition, curcumin affects a variety of growth factor receptors and cell adhesion molecules involved in tumor growth, angiogenesis and metastasis. Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer worldwide and treatment protocols include disfiguring surgery, platinum-based chemotherapy and radiation, all of which may result in tremendous patient morbidity. As a result, there is significant interest in developing adjuvant chemotherapies to augment currently available treatment protocols, which may allow decreased side effects and toxicity without compromising therapeutic efficacy. Curcumin is one such potential candidate, and this review presents an overview of the current in vitro and in vivo data supporting its therapeutic activity in head and neck cancer as well as some of the challenges concerning its development as an adjuvant chemotherapeutic agent. PMID:21299897
Ursodeoxycholic Acid (UDCA) Exerts Anti-Atherogenic Effects by Inhibiting Endoplasmic Reticulum (ER) Stress Induced by Disturbed Flow.

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Chung, Jihwa; Kim, Kyoung Hwa; Lee, Seok Cheol; An, Shung Hyun; Kwon, Kihwan

2015-10-01

Disturbed blood flow with low-oscillatory shear stress (OSS) is a predominant atherogenic factor leading to dysfunctional endothelial cells (ECs). Recently, it was found that disturbed flow can directly induce endoplasmic reticulum (ER) stress in ECs, thereby playing a critical role in the development and progression of atherosclerosis. Ursodeoxycholic acid (UDCA), a naturally occurring bile acid, has long been used to treat chronic cholestatic liver disease and is known to alleviate endoplasmic reticulum (ER) stress at the cellular level. However, its role in atherosclerosis remains unexplored. In this study, we demonstrated the anti-atherogenic activity of UDCA via inhibition of disturbed flow-induced ER stress in atherosclerosis. UDCA effectively reduced ER stress, resulting in a reduction in expression of X-box binding protein-1 (XBP-1) and CEBP-homologous protein (CHOP) in ECs. UDCA also inhibits the disturbed flow-induced inflammatory responses such as increases in adhesion molecules, monocyte adhesion to ECs, and apoptosis of ECs. In a mouse model of disturbed flow-induced atherosclerosis, UDCA inhibits atheromatous plaque formation through the alleviation of ER stress and a decrease in adhesion molecules. Taken together, our results revealed that UDCA exerts anti-atherogenic activity in disturbed flow-induced atherosclerosis by inhibiting ER stress and the inflammatory response. This study suggests that UDCA may be a therapeutic agent for prevention or treatment of atherosclerosis.
Arctigenin exerts anti-colitis efficacy through inhibiting the differentiation of Th1 and Th17 cells via an mTORC1-dependent pathway.

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Wu, Xin; Dou, Yannong; Yang, Yan; Bian, Difei; Luo, Jinque; Tong, Bei; Xia, Yufeng; Dai, Yue

2015-08-15

Arctigenin, the main effective constituent of Arctium lappa L. fruit, has previously been proven to dramatically attenuate dextran sulfate sodium (DSS)-induced colitis in mice, a frequently used animal model of inflammatory bowel disease (IBD). As Th1 and Th17 cells play a crucial role in the pathogenesis of IBD, the present study addressed whether and how arctigenin exerted anti-colitis efficacy by interfering with the differentiation and activation of Th1/Th17 cells. In vitro, arctigenin was shown to markedly inhibit the differentiation of Th17 cells from naïve T cells, and moderately inhibit the differentiation of Th1 cells, which was accompanied by lowered phosphorylation of STAT3 and STAT4, respectively. In contrast, arctigenin was lack of marked effect on the differentiation of either Th2 or regulatory T cells. Furthermore, arctigenin was shown to suppress the mammalian target of rapamycin complex 1 (mTORC1) pathway in T cells as demonstrated by down-regulated phosphorylation of the downstream target genes p70S6K and RPS6, and it functioned independent of two well-known upstream kinases PI3K/AKT and ERK. Arctigenin was also able to inhibit the activity of mTORC1 by dissociating raptor from mTOR. Interestingly, the inhibitory effect of arctigenin on T cell differentiation disappeared under a status of mTORC1 overactivation via knockdown of tuberous sclerosis complex 2 (TSC2, a negative regulator of mTORC1) or pretreatment of leucine (an agonist of mTOR). In DSS-induced mice, the inhibition of Th1/Th17 responses and anti-colitis effect of arctigenin were abrogated by leucine treatment. In conclusion, arctigenin ameliorates colitis through down-regulating the differentiation of Th1 and Th17 cells via mTORC1 pathway. Copyright © 2015 Elsevier Inc. All rights reserved.
Pituitary adenylate cyclase activating polypeptide (PACAP signalling exerts chondrogenesis promoting and protecting effects: implication of calcineurin as a downstream target.

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Tamás Juhász

Full Text Available Pituitary adenylate cyclase activating polypeptide (PACAP is an important neurotrophic factor influencing differentiation of neuronal elements and exerting protecting role during traumatic injuries or inflammatory processes of the central nervous system. Although increasing evidence is available on its presence and protecting function in various peripheral tissues, little is known about the role of PACAP in formation of skeletal components. To this end, we aimed to map elements of PACAP signalling in developing cartilage under physiological conditions and during oxidative stress. mRNAs of PACAP and its receptors (PAC1,VPAC1, VPAC2 were detectable during differentiation of chicken limb bud-derived chondrogenic cells in micromass cell cultures. Expression of PAC1 protein showed a peak on days of final commitment of chondrogenic cells. Administration of either the PAC1 receptor agonist PACAP 1-38, or PACAP 6-38 that is generally used as a PAC1 antagonist, augmented cartilage formation, stimulated cell proliferation and enhanced PAC1 and Sox9 protein expression. Both variants of PACAP elevated the protein expression and activity of the Ca-calmodulin dependent Ser/Thr protein phosphatase calcineurin. Application of PACAPs failed to rescue cartilage formation when the activity of calcineurin was pharmacologically inhibited with cyclosporine A. Moreover, exogenous PACAPs prevented diminishing of cartilage formation and decrease of calcineurin activity during oxidative stress. As an unexpected phenomenon, PACAP 6-38 elicited similar effects to those of PACAP 1-38, although to a different extent. On the basis of the above results, we propose calcineurin as a downstream target of PACAP signalling in differentiating chondrocytes either in normal or pathophysiological conditions. Our observations imply the therapeutical perspective that PACAP can be applied as a natural agent that may have protecting effect during joint inflammation and/or may promote
Exertional Rhabdomyolysis: What Is It and Why Should We Care?

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Thomas, David Q.; Carlson, Kelli A.; Marzano, Amy; Garrahy, Deborah

2012-01-01

Exertional rhabdomyolysis gained increased attention recently when 13 football players from the University of Iowa developed this condition after an especially demanding practice session and were hospitalized. Exertional rhabdomyolysis may lead to severe kidney stress, kidney failure, and even sudden death. Anyone who does physical exercise at a…
MESENCHYMAL STEM CELLS AS A THERAPEUTIC STRATEGY FOR MULTIPLE SCLEROSIS: ISSUES AND PERSPECTIVES

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M. M. Zafranskaya

2017-01-01

Full Text Available The ability of mesenchymal stem cells (MSC to influence the regulatory/suppressive effect in the autoimmune process and promote remyelination allows to consider them a new method of multiple sclerosis (MS therapy, by means of modifying the disease activity. Genetic stability, proliferative potential, ability to migrate into the damaged tissue areas and agreed protocols for isolation and culture are the main advantages for successful autologous, as well as allogeneic MSC therapy. Preliminary results from clinical studies using MSC application in MS patients show efficiency and safety of this therapeutic approach. Nevertheless, successful demonstration of the cell therapy in MS is only possible after detailed analysis and understanding of MSC biology and mechanisms of appropriate intercellular interactions. The article reviews general experience in usage of immunomodulatory and neuroprotective properties of MSС in MS, and highlights the issues of validity in cell-based therapy taking into account both in vitro и in vivo studies.
Therapeutic effect of adipose-derived mesenchymal stem cells on radiation enteritis

International Nuclear Information System (INIS)

Chang Pengyu; Cui Shuang; Luo Jinghua; Qu Chao; Jiang Xin; Qu Yaqin; Dong Lihua

2014-01-01

Objective: To evaluate the therapeutic effect of adipose-derived mesenchymal stem cells on radiation enteritis. Methods: A total of 52 male Sprague-Dawley rats were used in the present study. Herein, 46 rats were randomly selected and irradiated with a dose of 15 Gy at their abdomens. Two hours post-irradiation, 23 rats were randomly selected and infused intraperitoneally with adipose-derived mesenchymal stem cells in passage 6 from young-female donor. The other 23 rats were intraperitoneally infused with PBS. The rest 6 rats were set as normal control. During the first 10 days post-irradiation, peripheral blood-samples from irradiated rats were harvested for testing the levels of IL-10 in serum using ELISA assay. Additionally, after isolating the thymic cells and peripheral blood mononuclear cells, the percentages of CD4/CD25/Foxp(3)-positive regulatory T cells in thymus and peripheral blood were tested by flow-cytometry. Finally, infiltration of inflammatory cells and deposition of collagens within irradiated small intestine were analyzed by H&E staining and Masson Trichrome staining, respectively. Based on the MPO-immunohistochemistry staining, the type of infiltrated cells was identified. The Kaplan-Meier method was used for analyzing the survival rate of irradiated rats. Results: During a period of 30 days post-irradiation, the irradiated rats receiving adipose-derived mesenchymal stem cells survived longer than those receiving PBS (t = 4.53, P < 0.05). Compared to the irradiated rats with PBS-treatment, adipose-derived mesenchymal stem cells could elevate the level of IL-10 in serum (7 d: t = 13.93, P < 0.05) and increase the percentages of CD4/CD25/Foxp(3)-positive regulatory T cells in both peripheral blood (3.5 d: t = 7.72, 7 d: t = 11.11, 10 d: t = 6.99, P < 0.05) and thymus (7 d: t = 16.17, 10 d: t = 12.12, P < 0.05). Moreover, infiltration of inflammatory cells and deposition of collagens within irradiated small intestine were mitigated by adipose
A fully automated primary screening system for the discovery of therapeutic antibodies directly from B cells.

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Tickle, Simon; Howells, Louise; O'Dowd, Victoria; Starkie, Dale; Whale, Kevin; Saunders, Mark; Lee, David; Lightwood, Daniel

2015-04-01

For a therapeutic antibody to succeed, it must meet a range of potency, stability, and specificity criteria. Many of these characteristics are conferred by the amino acid sequence of the heavy and light chain variable regions and, for this reason, can be screened for during antibody selection. However, it is important to consider that antibodies satisfying all these criteria may be of low frequency in an immunized animal; for this reason, it is essential to have a mechanism that allows for efficient sampling of the immune repertoire. UCB's core antibody discovery platform combines high-throughput B cell culture screening and the identification and isolation of single, antigen-specific IgG-secreting B cells through a proprietary technique called the "fluorescent foci" method. Using state-of-the-art automation to facilitate primary screening, extremely efficient interrogation of the natural antibody repertoire is made possible; more than 1 billion immune B cells can now be screened to provide a useful starting point from which to identify the rare therapeutic antibody. This article will describe the design, construction, and commissioning of a bespoke automated screening platform and two examples of how it was used to screen for antibodies against two targets. © 2014 Society for Laboratory Automation and Screening.
Dimethyl sulfoxide inhibits spontaneous diabetes and autoimmune recurrence in non-obese diabetic mice by inducing differentiation of regulatory T cells

International Nuclear Information System (INIS)

Lin, Gu-Jiun; Sytwu, Huey-Kang; Yu, Jyh-Cherng; Chen, Yuan-Wu; Kuo, Yu-Liang; Yu, Chiao-Chi; Chang, Hao-Ming; Chan, De-Chuan; Huang, Shing-Hwa

2015-01-01

Type 1 diabetes mellitus (T1D) is caused by the destruction of insulin-producing β cells in pancreatic islets by autoimmune T cells. Islet transplantation has been established as an effective therapeutic strategy for T1D. However, the survival of islet grafts can be disrupted by recurrent autoimmunity. Dimethyl sulfoxide (DMSO) is a solvent for organic and inorganic substances and an organ-conserving agent used in solid organ transplantations. DMSO also exerts anti-inflammatory, reactive oxygen species scavenger and immunomodulatory effects and therefore exhibits therapeutic potential for the treatment of several human inflammatory diseases. In this study, we investigated the therapeutic potential of DMSO in the inhibition of autoimmunity. We treated an animal model of islet transplantation (NOD mice) with DMSO. The survival of the syngeneic islet grafts was significantly prolonged. The population numbers of CD8, DC and Th1 cells were decreased, and regulatory T (Treg) cell numbers were increased in recipients. The expression levels of IFN-γ and proliferation of T cells were also reduced following DMSO treatment. Furthermore, the differentiation of Treg cells from naive CD4 T cells was significantly increased in the in vitro study. Our results demonstrate for the first time that in vivo DMSO treatment suppresses spontaneous diabetes and autoimmune recurrence in NOD mice by inhibiting the Th1 immune response and inducing the differentiation of Treg cells. - Highlights: • We report a therapeutic potential of DMSO in autoimmune diabetes. • DMSO exhibits an immune modulatory effect. • DMSO treatment increases regulatory T cell differentiation. • The increase in STAT5 signaling pathway explains the effect of DMSO in Tregs
Dimethyl sulfoxide inhibits spontaneous diabetes and autoimmune recurrence in non-obese diabetic mice by inducing differentiation of regulatory T cells

Energy Technology Data Exchange (ETDEWEB)

Lin, Gu-Jiun [Department of Biology and Anatomy, National Defense Medical Center, Taipei, Taiwan, ROC (China); Sytwu, Huey-Kang [Department of Microbiology and Immunology, National Defense Medical Center, Taipei, Taiwan, ROC (China); Yu, Jyh-Cherng [Department of General Surgery, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan, ROC (China); Chen, Yuan-Wu [School of Dentistry, National Defense Medical Center, Taipei, Taiwan, ROC (China); Department of Oral and Maxillofacial Surgery, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan, ROC (China); Kuo, Yu-Liang [Department of Medical Imaging, Chung Shan Medical University Hospital, Taichung, Taiwan, ROC (China); School of Medical Imaging and Radiological Sciences, Chung Shan Medical University, Taichung, Taiwan, ROC (China); Yu, Chiao-Chi [Department of Biology and Anatomy, National Defense Medical Center, Taipei, Taiwan, ROC (China); Department of General Surgery, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan, ROC (China); Chang, Hao-Ming; Chan, De-Chuan [Department of General Surgery, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan, ROC (China); Huang, Shing-Hwa, E-mail: h610129@gmail.com [Department of Biology and Anatomy, National Defense Medical Center, Taipei, Taiwan, ROC (China); Department of General Surgery, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan, ROC (China)

2015-01-15

Type 1 diabetes mellitus (T1D) is caused by the destruction of insulin-producing β cells in pancreatic islets by autoimmune T cells. Islet transplantation has been established as an effective therapeutic strategy for T1D. However, the survival of islet grafts can be disrupted by recurrent autoimmunity. Dimethyl sulfoxide (DMSO) is a solvent for organic and inorganic substances and an organ-conserving agent used in solid organ transplantations. DMSO also exerts anti-inflammatory, reactive oxygen species scavenger and immunomodulatory effects and therefore exhibits therapeutic potential for the treatment of several human inflammatory diseases. In this study, we investigated the therapeutic potential of DMSO in the inhibition of autoimmunity. We treated an animal model of islet transplantation (NOD mice) with DMSO. The survival of the syngeneic islet grafts was significantly prolonged. The population numbers of CD8, DC and Th1 cells were decreased, and regulatory T (Treg) cell numbers were increased in recipients. The expression levels of IFN-γ and proliferation of T cells were also reduced following DMSO treatment. Furthermore, the differentiation of Treg cells from naive CD4 T cells was significantly increased in the in vitro study. Our results demonstrate for the first time that in vivo DMSO treatment suppresses spontaneous diabetes and autoimmune recurrence in NOD mice by inhibiting the Th1 immune response and inducing the differentiation of Treg cells. - Highlights: • We report a therapeutic potential of DMSO in autoimmune diabetes. • DMSO exhibits an immune modulatory effect. • DMSO treatment increases regulatory T cell differentiation. • The increase in STAT5 signaling pathway explains the effect of DMSO in Tregs.
Priming with ceramide-1 phosphate promotes the therapeutic effect of mesenchymal stem/stromal cells on pulmonary artery hypertension

International Nuclear Information System (INIS)

Lim, Jisun; Kim, YongHwan; Heo, Jinbeom; Kim, Kang-Hyun; Lee, Seungun; Lee, Sei Won; Kim, Kyunggon; Kim, In-Gyu; Shin, Dong-Myung

2016-01-01

Some molecules enriched in damaged organs can contribute to tissue repair by stimulating the mobilization of stem cells. These so-called “priming” factors include bioactive lipids, complement components, and cationic peptides. However, their therapeutic significance remains to be determined. Here, we show that priming of mesenchymal stromal/stem cells (MSCs) with ceramide-1 phosphate (C1P), a bioactive lipid, enhances their therapeutic efficacy in pulmonary artery hypertension (PAH). Human bone marrow (BM)-derived MSCs treated with 100 or 200 μM C1P showed improved migration activity in Transwell assays compared with non-primed MSCs and concomitantly activated MAPK p42/44 and AKT signaling cascades. Although C1P priming had little effect on cell surface marker phenotypes and the multipotency of MSCs, it potentiated their proliferative, colony-forming unit-fibroblast, and anti-inflammatory activities. In a monocrotaline-induced PAH animal model, a single administration of human MSCs primed with C1P significantly attenuated the PAH-related increase in right ventricular systolic pressure, right ventricular hypertrophy, and thickness of α-smooth muscle actin-positive cells around the vessel wall. Thus, this study shows that C1P priming increases the effects of MSC therapy by enhancing the migratory, self-renewal, and anti-inflammatory activity of MSCs and that MSC therapy optimized with priming protocols might be a promising option for the treatment of PAH patients. - Highlights: • Human BM-derived MSCs primed with C1P have enhanced migratory activity. • C1P primed MSCs increase proliferation, self-renewal, and anti-inflammatory capacity. • C1P priming enhances the therapeutic capacity of MSCs in a PAH animal model.
Priming with ceramide-1 phosphate promotes the therapeutic effect of mesenchymal stem/stromal cells on pulmonary artery hypertension

Energy Technology Data Exchange (ETDEWEB)

Lim, Jisun [Department of Biomedical Sciences, University of Ulsan College of Medicine, Seoul (Korea, Republic of); Department of Physiology, University of Ulsan College of Medicine, Seoul (Korea, Republic of); Department of Biochemistry and Molecular Biology, Seoul National University College of Medicine, 88 Olympic-ro 43 gil, Songpa-gu, Seoul 05505 (Korea, Republic of); Kim, YongHwan; Heo, Jinbeom; Kim, Kang-Hyun; Lee, Seungun [Department of Biomedical Sciences, University of Ulsan College of Medicine, Seoul (Korea, Republic of); Department of Physiology, University of Ulsan College of Medicine, Seoul (Korea, Republic of); Lee, Sei Won [Department of Pulmonary and Critical Care Medicine and Clinical Research Center for Chronic Obstructive Airway Diseases, University of Ulsan College of Medicine, Seoul (Korea, Republic of); Kim, Kyunggon [Department of Convergence Medicine, University of Ulsan College of Medicine, Seoul (Korea, Republic of); Clinical Proteomics Core Lab, Asan Medical Center, University of Ulsan College of Medicine, Seoul (Korea, Republic of); Kim, In-Gyu, E-mail: igkim@plaza.snu.ac.kr [Department of Biochemistry and Molecular Biology, Seoul National University College of Medicine, 88 Olympic-ro 43 gil, Songpa-gu, Seoul 05505 (Korea, Republic of); Shin, Dong-Myung, E-mail: d0shin03@amc.seoul.kr [Department of Biomedical Sciences, University of Ulsan College of Medicine, Seoul (Korea, Republic of); Department of Physiology, University of Ulsan College of Medicine, Seoul (Korea, Republic of)

2016-04-22

Some molecules enriched in damaged organs can contribute to tissue repair by stimulating the mobilization of stem cells. These so-called “priming” factors include bioactive lipids, complement components, and cationic peptides. However, their therapeutic significance remains to be determined. Here, we show that priming of mesenchymal stromal/stem cells (MSCs) with ceramide-1 phosphate (C1P), a bioactive lipid, enhances their therapeutic efficacy in pulmonary artery hypertension (PAH). Human bone marrow (BM)-derived MSCs treated with 100 or 200 μM C1P showed improved migration activity in Transwell assays compared with non-primed MSCs and concomitantly activated MAPK{sup p42/44} and AKT signaling cascades. Although C1P priming had little effect on cell surface marker phenotypes and the multipotency of MSCs, it potentiated their proliferative, colony-forming unit-fibroblast, and anti-inflammatory activities. In a monocrotaline-induced PAH animal model, a single administration of human MSCs primed with C1P significantly attenuated the PAH-related increase in right ventricular systolic pressure, right ventricular hypertrophy, and thickness of α-smooth muscle actin-positive cells around the vessel wall. Thus, this study shows that C1P priming increases the effects of MSC therapy by enhancing the migratory, self-renewal, and anti-inflammatory activity of MSCs and that MSC therapy optimized with priming protocols might be a promising option for the treatment of PAH patients. - Highlights: • Human BM-derived MSCs primed with C1P have enhanced migratory activity. • C1P primed MSCs increase proliferation, self-renewal, and anti-inflammatory capacity. • C1P priming enhances the therapeutic capacity of MSCs in a PAH animal model.
Mesenchymal stem/stromal cells as a pharmacological and therapeutic approach to accelerate angiogenesis.

Science.gov (United States)

Bronckaers, Annelies; Hilkens, Petra; Martens, Wendy; Gervois, Pascal; Ratajczak, Jessica; Struys, Tom; Lambrichts, Ivo

2014-08-01

Mesenchymal stem cells or multipotent stromal cells (MSCs) have initially captured attention in the scientific world because of their differentiation potential into osteoblasts, chondroblasts and adipocytes and possible transdifferentiation into neurons, glial cells and endothelial cells. This broad plasticity was originally hypothesized as the key mechanism of their demonstrated efficacy in numerous animal models of disease as well as in clinical settings. However, there is accumulating evidence suggesting that the beneficial effects of MSCs are predominantly caused by the multitude of bioactive molecules secreted by these remarkable cells. Numerous angiogenic factors, growth factors and cytokines have been discovered in the MSC secretome, all have been demonstrated to alter endothelial cell behavior in vitro and induce angiogenesis in vivo. As a consequence, MSCs have been widely explored as a promising treatment strategy in disorders caused by insufficient angiogenesis such as chronic wounds, stroke and myocardial infarction. In this review, we will summarize into detail the angiogenic factors found in the MSC secretome and their therapeutic mode of action in pathologies caused by limited blood vessel formation. Also the application of MSC as a vehicle to deliver drugs and/or genes in (anti-)angiogenesis will be discussed. Furthermore, the literature describing MSC transdifferentiation into endothelial cells will be evaluated critically. Copyright © 2014 Elsevier Inc. All rights reserved.

Anticancer effect of triterpenes from Ganoderma lucidum in human prostate cancer cells.

Science.gov (United States)

Qu, Lijun; Li, Sumei; Zhuo, Yumin; Chen, Jianfan; Qin, Xiaoping; Guo, Guoqing

2017-12-01

Ganoderma lucidum , within the Polyporaceae family of Basidiomycota, is a popular traditional remedy medicine used in Asia to promote health and longevity. Compounds extracted from G. lucidum have revealed anticancer, antioxidant and liver protective effects. G. lucidum has been associated with prostate cancer cells. G. lucidum extracts contain numerous bioactive components; however, the exact functional monomer is unknown and the role of triterpenes from G. lucidum (GLT) in prostate cancer remain obscure. The present study investigated the effects of GLT on cell viability, migration, invasion and apoptosis in DU-145 human prostate cancer cells. The results demonstrated that a high dose (2 mg/ml) of GLT inhibits cell viability in a dose- and time-dependent manner by the regulation of matrix metalloproteases. Furthermore, GLT induced apoptosis of DU-145 cells. In general, GLT exerts its effect on cancer cells via numerous mechanisms and may have potential therapeutic use for the prevention and treatment of cancer.
Exertional rhabdomyolysis: physiological response or manifestation of an underlying myopathy?

Science.gov (United States)

Scalco, Renata S; Snoeck, Marc; Quinlivan, Ros; Treves, Susan; Laforét, Pascal; Jungbluth, Heinz; Voermans, Nicol C

2016-01-01

Exertional rhabdomyolysis is characterised by muscle breakdown associated with strenuous exercise or normal exercise under extreme circumstances. Key features are severe muscle pain and sudden transient elevation of serum creatine kinase (CK) levels with or without associated myoglobinuria. Mild cases may remain unnoticed or undiagnosed. Exertional rhabdomyolysis is well described among athletes and military personnel, but may occur in anybody exposed to unaccustomed exercise. In contrast, exertional rhabdomyolysis may be the first manifestation of a genetic muscle disease that lowers the exercise threshold for developing muscle breakdown. Repeated episodes of exertional rhabdomyolysis should raise the suspicion of such an underlying disorder, in particular in individuals in whom the severity of the rhabdomyolysis episodes exceeds the expected response to the exercise performed. The present review aims to provide a practical guideline for the acute management and postepisode counselling of patients with exertional rhabdomyolysis, with a particular emphasis on when to suspect an underlying genetic disorder. The pathophysiology and its clinical features are reviewed, emphasising four main stepwise approaches: (1) the clinical significance of an acute episode, (2) risks of renal impairment, (3) clinical indicators of an underlying genetic disorders and (4) when and how to recommence sport activity following an acute episode of rhabdomyolysis. Genetic backgrounds that appear to be associated with both enhanced athletic performance and increased rhabdomyolysis risk are briefly reviewed.
Exertional rhabdomyolysis: physiological response or manifestation of an underlying myopathy?

Science.gov (United States)

Scalco, Renata S; Snoeck, Marc; Quinlivan, Ros; Treves, Susan; Laforét, Pascal; Jungbluth, Heinz; Voermans, Nicol C

2016-01-01

Exertional rhabdomyolysis is characterised by muscle breakdown associated with strenuous exercise or normal exercise under extreme circumstances. Key features are severe muscle pain and sudden transient elevation of serum creatine kinase (CK) levels with or without associated myoglobinuria. Mild cases may remain unnoticed or undiagnosed. Exertional rhabdomyolysis is well described among athletes and military personnel, but may occur in anybody exposed to unaccustomed exercise. In contrast, exertional rhabdomyolysis may be the first manifestation of a genetic muscle disease that lowers the exercise threshold for developing muscle breakdown. Repeated episodes of exertional rhabdomyolysis should raise the suspicion of such an underlying disorder, in particular in individuals in whom the severity of the rhabdomyolysis episodes exceeds the expected response to the exercise performed. The present review aims to provide a practical guideline for the acute management and postepisode counselling of patients with exertional rhabdomyolysis, with a particular emphasis on when to suspect an underlying genetic disorder. The pathophysiology and its clinical features are reviewed, emphasising four main stepwise approaches: (1) the clinical significance of an acute episode, (2) risks of renal impairment, (3) clinical indicators of an underlying genetic disorders and (4) when and how to recommence sport activity following an acute episode of rhabdomyolysis. Genetic backgrounds that appear to be associated with both enhanced athletic performance and increased rhabdomyolysis risk are briefly reviewed. PMID:27900193
Adipose-derived Stem Cells Stimulated with n-Butylidenephthalide Exhibit Therapeutic Effects in a Mouse Model of Parkinson's Disease.

Science.gov (United States)

Chi, Kang; Fu, Ru-Huei; Huang, Yu-Chuen; Chen, Shih-Yin; Hsu, Ching-Ju; Lin, Shinn-Zong; Tu, Chi-Tang; Chang, Li-Hsun; Wu, Ping-An; Liu, Shih-Ping

2018-03-01

Parkinson's disease (PD) causes motor dysfunction and dopaminergic cell death. Drug treatments can effectively reduce symptoms but often cause unwanted side effects. Stem cell therapies using cell replacement or indirect beneficial secretomes have recently emerged as potential therapeutic strategies. Although various types of stem cells have been proposed as possible candidates, adipose-derived stem cells (ADSCs) are easily obtainable, more abundant, less ethically disputed, and able to differentiate into multiple cell lineages. However, treatment of PD using adult stem cells is known to be less efficacious than neuron or embryonic stem cell transplantation. Therefore, improved therapies are urgently needed. n-Butylidenephthalide (BP), which is extracted from Angelica sinensis, has been shown to have anti-inflammatory and neuroprotective effects. Indeed, we previously demonstrated that BP treatment of ADSCs enhances the expression of neurogenesis and homing factors such as nuclear receptor related 1 protein, stromal-derived factor 1, and brain-derived neurotrophic factor. In the present study, we examined the ability of BP-pretreated ADSC transplantation to improve PD motor symptoms and protect dopamine neurons in a mouse model of PD. We evaluated the results using neuronal behavior tests such as beam walking, rotarod, and locomotor activity tests. ADSCs with or without BP pretreatment were transplanted into the striatum. Our findings demonstrated that ADSC transplantation improved motor abilities with varied efficacies and that BP stimulation improved the therapeutic effects of transplantation. Dopaminergic cell numbers returned to normal in ADSC-transplanted mice after 22 d. In summary, stimulating ADSCs with BP improved PD recovery efficiency. Thus, our results provide important new strategies to improve stem cell therapies for neurodegenerative diseases in future studies.
The therapeutic effect of memantine through the stimulation of synapse formation and dendritic spine maturation in autism and fragile X syndrome.

Directory of Open Access Journals (Sweden)

Hongen Wei

Full Text Available Although the pathogenic mechanisms that underlie autism are not well understood, there is evidence showing that metabotropic and ionotropic glutamate receptors are hyper-stimulated and the GABAergic system is hypo-stimulated in autism. Memantine is an uncompetitive antagonist of NMDA receptors and is widely prescribed for treatment of Alzheimer's disease treatment. Recently, it has been shown to improve language function, social behavior, and self-stimulatory behaviors of some autistic subjects. However the mechanism by which memantine exerts its effect remains to be elucidated. In this study, we used cultured cerebellar granule cells (CGCs from Fmr1 knockout (KO mice, a mouse model for fragile X syndrome (FXS and syndromic autism, to examine the effects of memantine on dendritic spine development and synapse formation. Our results show that the maturation of dendritic spines is delayed in Fmr1-KO CGCs. We also detected reduced excitatory synapse formation in Fmr1-KO CGCs. Memantine treatment of Fmr1-KO CGCs promoted cell adhesion properties. Memantine also stimulated the development of mushroom-shaped mature dendritic spines and restored dendritic spine to normal levels in Fmr1-KO CGCs. Furthermore, we demonstrated that memantine treatment promoted synapse formation and restored the excitatory synapses to a normal range in Fmr1-KO CGCs. These findings suggest that memantine may exert its therapeutic capacity through a stimulatory effect on dendritic spine maturation and excitatory synapse formation, as well as promoting adhesion of CGCs.
Curcumin attenuates paraquat-induced cell death in human neuroblastoma cells through modulating oxidative stress and autophagy.

Science.gov (United States)

Jaroonwitchawan, Thiranut; Chaicharoenaudomrung, Nipha; Namkaew, Jirapat; Noisa, Parinya

2017-01-01

Paraquat is a neurotoxic agent, and oxidative stress plays an important role in neuronal cell death after paraquat exposure. In this study, we assessed the neuroprotective effect of curcumin against paraquat and explored the underlying mechanisms of curcumin in vitro. Curcumin treatment prevented paraquat-induced reactive oxygen species (ROS) and apoptotic cell death. Curcumin also exerted a neuroprotective effect by increasing the expression of anti-apoptotic and antioxidant genes. The pretreatment of curcumin significantly decreased gene expression and protein production of amyloid precursor protein. The activation of autophagy process was found defective in paraquat-induced cells, indicated by the accumulation and reduction of LC3I/II. Noteworthy, curcumin restored LC3I/II expression after the pretreatment. Collectively, curcumin demonstrated as a prominent suppressor of ROS, and could reverse autophagy induction in SH-SY5Y cells. The consequences of this were the reduction of APP production and prevention of SH-SY5Y cells from apoptosis. Altogether, curcumin potentially serves as a therapeutic agent of neurodegenerative diseases, associated with ROS overproduction and autophagy dysfunction. Copyright Â© 2016 Elsevier Ireland Ltd. All rights reserved.
Individualised cancer therapeutics: dream or reality? Therapeutics construction.

Science.gov (United States)

Shen, Yuqiao; Senzer, Neil; Nemunaitis, John

2005-11-01

The analysis of DNA microarray and proteomic data, and the subsequent integration into functional expression sets, provides a circuit map of the hierarchical cellular networks responsible for sustaining the viability and environmental competitiveness of cancer cells, that is, their robust systematics. These technologies can be used to 'snapshot' the unique patterns of molecular derangements and modified interactions in cancer, and allow for strategic selection of therapeutics that best match the individual profile of the tumour. This review highlights technology that can be used to selectively disrupt critical molecular targets and describes possible vehicles to deliver the synthesised molecular therapeutics to the relevant cellular compartments of the malignant cells. RNA interference (RNAi) involves a group of evolutionarily conserved gene silencing mechanisms in which small sequences of double-stranded RNA or intrinsic antisense RNA trigger mRNA cleavage or translational repression, respectively. Although RNAi molecules can be synthesised to 'silence' virtually any gene, even if upregulated, a mechanism for selective delivery of RNAi effectors to sites of malignant disease remains challenging. The authors will discuss gene-modified conditionally replicating viruses as candidate vehicles for the delivery of RNAi.
TPL2 (Therapeutic Targeting Tumor Progression Locus-2)/ATF4 (Activating Transcription Factor-4)/SDF1α (Chemokine Stromal Cell-Derived Factor-α) Axis Suppresses Diabetic Retinopathy.

Science.gov (United States)

Lai, De-Wei; Lin, Keng-Hung; Sheu, Wayne Huey-Herng; Lee, Maw-Rong; Chen, Chung-Yu; Lee, Wen-Jane; Hung, Yi-Wen; Shen, Chin-Chang; Chung, Tsung-Ju; Liu, Shing-Hwa; Sheu, Meei-Ling

2017-09-01

Diabetic retinopathy is characterized by vasopermeability, vascular leakage, inflammation, blood-retinal barrier breakdown, capillary degeneration, and neovascularization. However, the mechanisms underlying the association between diabetes mellitus and progression retinopathy remain unclear. TPL2 (tumor progression locus 2), a serine-threonine protein kinase, exerts a pathological effect on vascular angiogenesis. This study investigated the role of N ε -(carboxymethyl)lysine, a major advanced glycation end products, and the involved TPL2-related molecular signals in diabetic retinopathy using models of in vitro and in vivo and human samples. Serum N ε -(carboxymethyl)lysine levels and TPL2 kinase activity were significantly increased in clinical patients and experimental animals with diabetic retinopathy. Intravitreal administration of pharmacological blocker or neutralizing antibody inhibited TPL2 and effectively suppressed the pathological characteristics of retinopathy in streptozotocin-induced diabetic animal models. Intravitreal VEGF (vascular endothelial growth factor) neutralization also suppressed the diabetic retinopathy in diabetic animal models. Mechanistic studies in primary human umbilical vein endothelial cells and primary retinal microvascular endothelial cells from streptozotocin-diabetic rats, db/db mice, and samples from patients with diabetic retinopathy revealed a positive parallel correlation between N ε -(carboxymethyl)lysine and the TPL2/chemokine SDF1α (stromal cell-derived factor-α) axis that is dependent on endoplasmic reticulum stress-related molecules, especially ATF4 (activating transcription factor-4). This study demonstrates that inhibiting the N ε -(carboxymethyl)lysine-induced TPL2/ATF4/SDF1α axis can effectively prevent diabetes mellitus-mediated retinal microvascular dysfunction. This signaling axis may include the therapeutic potential for other diseases involving pathological neovascularization or macular edema. © 2017
Insights into the Molecular Pathogenesis of Activated B-Cell-like Diffuse Large B-Cell Lymphoma and Its Therapeutic Implications

Directory of Open Access Journals (Sweden)

Georg Lenz

2015-05-01

Full Text Available Within the last couple of years, the understanding of the molecular mechanisms that drive the pathogenesis of diffuse large B-cell lymphoma (DLBCL has significantly improved. Large-scale gene expression profiling studies have led to the discovery of several molecularly defined subtypes that are characterized by specific oncogene addictions and significant differences in their outcome. Next generation sequencing efforts combined with RNA interference screens frequently identify crucial oncogenes that lead to constitutive activation of various signaling pathways that drive lymphomagenesis. This review summarizes our current understanding of the molecular pathogenesis of the activated B-cell-like (ABC DLBCL subtype that is characterized by poor prognosis. A special emphasis is put on findings that might impact therapeutic strategies of affected patients.
Insights into the Molecular Pathogenesis of Activated B-Cell-like Diffuse Large B-Cell Lymphoma and Its Therapeutic Implications

Energy Technology Data Exchange (ETDEWEB)

Lenz, Georg [Translational Oncology, Department of Medicine A, Albert-Schweitzer Campus 1, University Hospital Münster, 48149 Münster (Germany); Cluster of Excellence EXC 1003, Cells in Motion, 48149 Münster (Germany)

2015-05-22

Within the last couple of years, the understanding of the molecular mechanisms that drive the pathogenesis of diffuse large B-cell lymphoma (DLBCL) has significantly improved. Large-scale gene expression profiling studies have led to the discovery of several molecularly defined subtypes that are characterized by specific oncogene addictions and significant differences in their outcome. Next generation sequencing efforts combined with RNA interference screens frequently identify crucial oncogenes that lead to constitutive activation of various signaling pathways that drive lymphomagenesis. This review summarizes our current understanding of the molecular pathogenesis of the activated B-cell-like (ABC) DLBCL subtype that is characterized by poor prognosis. A special emphasis is put on findings that might impact therapeutic strategies of affected patients.
Examination of thromboxane synthase as a prognostic factor and therapeutic target in non-small cell lung cancer

LENUS (Irish Health Repository)

Cathcart, Mary-Clare

2011-03-09

Abstract Background Thromboxane synthase (TXS) metabolises prostaglandin H2 into thromboxanes, which are biologically active on cancer cells. TXS over-expression has been reported in a range of cancers, and associated with a poor prognosis. TXS inhibition induces cell death in-vitro, providing a rationale for therapeutic intervention. We aimed to determine the expression profile of TXS in NSCLC and if it is prognostic and\\/or a survival factor in the disease. Methods TXS expression was examined in human NSCLC and matched controls by western analysis and IHC. TXS metabolite (TXB2) levels were measured by EIA. A 204-patient NSCLC TMA was stained for COX-2 and downstream TXS expression. TXS tissue expression was correlated with clinical parameters, including overall survival. Cell proliferation\\/survival and invasion was examined in NSCLC cells following both selective TXS inhibition and stable TXS over-expression. Results TXS was over-expressed in human NSCLC samples, relative to matched normal controls. TXS and TXB2 levels were increased in protein (p < 0.05) and plasma (p < 0.01) NSCLC samples respectively. TXS tissue expression was higher in adenocarcinoma (p < 0.001) and female patients (p < 0.05). No significant correlation with patient survival was observed. Selective TXS inhibition significantly reduced tumour cell growth and increased apoptosis, while TXS over-expression stimulated cell proliferation and invasiveness, and was protective against apoptosis. Conclusion TXS is over-expressed in NSCLC, particularly in the adenocarcinoma subtype. Inhibition of this enzyme inhibits proliferation and induces apoptosis. Targeting thromboxane synthase alone, or in combination with conventional chemotherapy is a potential therapeutic strategy for NSCLC.
Profiling Prostate Cancer Therapeutic Resistance

OpenAIRE

Cameron A. Wade; Natasha Kyprianou

2018-01-01

The major challenge in the treatment of patients with advanced lethal prostate cancer is therapeutic resistance to androgen-deprivation therapy (ADT) and chemotherapy. Overriding this resistance requires understanding of the driving mechanisms of the tumor microenvironment, not just the androgen receptor (AR)-signaling cascade, that facilitate therapeutic resistance in order to identify new drug targets. The tumor microenvironment enables key signaling pathways promoting cancer cell survival ...
Protective and therapeutic effects of cannabis plant extract on liver cancer induced by dimethylnitrosamine in mice

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Neveen Abd El Moneim Hussein

2014-09-01

Conclusion: The protective effect of cannabis extract is more pronounced in group taking cannabis before DMNA. Cannabinoids might exert their anti-tumor effects by the direct induction of apoptosis and can decrease telomerase activity by inhibiting the expression of the TERT gene. Coordination between inhibition of telomerase activity and induction of apoptosis might be a potential therapeutic agent for cancer treatment.
Ovatodiolide of Anisomeles indica Exerts the Anticancer Potential on Pancreatic Cancer Cell Lines through STAT3 and NF-κB Regulation

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Ya-Ju Hsieh

2016-01-01

Full Text Available Pancreatic cancer is the eighth leading cause of cancer death worldwide. Patients with pancreatic cancer are normally diagnosed at an advanced stage and present poor survival rate. Ovatodiolide (OV, a bioactive macrocyclic diterpenoid isolated from Anisomeles indica, showed cytotoxicity effects in pancreatic cancer cells by inhibiting cell proliferation and inducing apoptosis. Moreover, not only were cell adhesion and invasion markedly suppressed in a dose-dependent manner, but the mRNA expression of matrix metalloproteinase-9 (MMP-9 and focal adhesion kinase (FAK was also significantly decreased. Western blot analysis indicated that OV potently suppressed the phosphorylation of STAT-3 and its upstream kinase including ERK1/2, P38, and AKT Ser473. Meanwhile, OV inactivated the nuclear factor kappa B (NF-κB by inhibiting IκB kinase (IKK α/β activation and the subsequent suppression of inhibitor of kappa B (IκB phosphorylation. These results demonstrated that OV could potentially inhibit Mia-PaCa2 cancer cells proliferation and induce apoptosis through modulation of NF-κB and STAT3 pathway. Moreover, OV suppressed cell invasiveness and interfered with cell-matrix adhesion in Mia-PaCa2 cancer cells by reducing MMP-9 and FAK transcription through suppressing NF-κB and STAT3 pathway. Taken together, our findings reveal a new therapeutic and antimetastatic potential of ovatodiolide for pancreatic cancer remedy.
Exertional Heat Illness and Human Gene Expression

National Research Council Canada - National Science Library

Sonna, L.A; Sawka, M. N; Lilly, C. M

2007-01-01

Microarray analysis of gene expression at the level of RNA has generated new insights into the relationship between cellular responses to acute heat shock in vitro, exercise, and exertional heat illness...
Exertional heat illness: emerging concepts and advances in prehospital care.

Science.gov (United States)

Pryor, Riana R; Roth, Ronald N; Suyama, Joe; Hostler, David

2015-06-01

Exertional heat illness is a classification of disease with clinical presentations that are not always diagnosed easily. Exertional heat stroke is a significant cause of death in competitive sports, and the increasing popularity of marathons races and ultra-endurance competitions will make treating many heat illnesses more common for Emergency Medical Services (EMS) providers. Although evidence is available primarily from case series and healthy volunteer studies, the consensus for treating exertional heat illness, coupled with altered mental status, is whole body rapid cooling. Cold or ice water immersion remains the most effective treatment to achieve this goal. External thermometry is unreliable in the context of heat stress and direct internal temperature measurement by rectal or esophageal probes must be used when diagnosing heat illness and during cooling. With rapid recognition and implementation of effective cooling, most patients suffering from exertional heat stroke will recover quickly and can be discharged home with instructions to rest and to avoid heat stress and exercise for a minimum of 48 hours; although, further research pertaining to return to activity is warranted.
First-In-Class Small Molecule ONC201 Induces DR5 and Cell Death in Tumor but Not Normal Cells to Provide a Wide Therapeutic Index as an Anti-Cancer Agent.

Science.gov (United States)

Allen, Joshua E; Crowder, Roslyn N; Crowder, Roslyn; El-Deiry, Wafik S

2015-01-01

We previously identified ONC201 (TIC10) as a first-in-class orally active small molecule with robust antitumor activity that is currently in clinical trials in advanced cancers. Here, we further investigate the safety characteristics of ONC201 in preclinical models that reveal an excellent safety profile at doses that exceed efficacious doses by 10-fold. In vitro studies indicated a strikingly different dose-response relationship when comparing tumor and normal cells where maximal effects are much stronger in tumor cells than in normal cells. In further support of a wide therapeutic index, investigation of tumor and normal cell responses under identical conditions demonstrated large apoptotic effects in tumor cells and modest anti-proliferative effects in normal cells that were non-apoptotic and reversible. Probing the underlying mechanism of apoptosis indicated that ONC201 does not induce DR5 in normal cells under conditions that induce DR5 in tumor cells; DR5 is a pro-apoptotic TRAIL receptor previously linked to the anti-tumor mechanism of ONC201. GLP toxicology studies in Sprague-Dawley rats and beagle dogs at therapeutic and exaggerated doses revealed no dose-limiting toxicities. Observations in both species at the highest doses were mild and reversible at doses above 10-fold the expected therapeutic dose. The no observed adverse event level (NOAEL) was ≥42 mg/kg in dogs and ≥125 mg/kg in rats, which both correspond to a human dose of approximately 1.25 g assuming standard allometric scaling. These results provided the rationale for the 125 mg starting dose in dose escalation clinical trials that began in 2015 in patients with advanced cancer.
First-In-Class Small Molecule ONC201 Induces DR5 and Cell Death in Tumor but Not Normal Cells to Provide a Wide Therapeutic Index as an Anti-Cancer Agent.

Directory of Open Access Journals (Sweden)

Joshua E Allen

Full Text Available We previously identified ONC201 (TIC10 as a first-in-class orally active small molecule with robust antitumor activity that is currently in clinical trials in advanced cancers. Here, we further investigate the safety characteristics of ONC201 in preclinical models that reveal an excellent safety profile at doses that exceed efficacious doses by 10-fold. In vitro studies indicated a strikingly different dose-response relationship when comparing tumor and normal cells where maximal effects are much stronger in tumor cells than in normal cells. In further support of a wide therapeutic index, investigation of tumor and normal cell responses under identical conditions demonstrated large apoptotic effects in tumor cells and modest anti-proliferative effects in normal cells that were non-apoptotic and reversible. Probing the underlying mechanism of apoptosis indicated that ONC201 does not induce DR5 in normal cells under conditions that induce DR5 in tumor cells; DR5 is a pro-apoptotic TRAIL receptor previously linked to the anti-tumor mechanism of ONC201. GLP toxicology studies in Sprague-Dawley rats and beagle dogs at therapeutic and exaggerated doses revealed no dose-limiting toxicities. Observations in both species at the highest doses were mild and reversible at doses above 10-fold the expected therapeutic dose. The no observed adverse event level (NOAEL was ≥42 mg/kg in dogs and ≥125 mg/kg in rats, which both correspond to a human dose of approximately 1.25 g assuming standard allometric scaling. These results provided the rationale for the 125 mg starting dose in dose escalation clinical trials that began in 2015 in patients with advanced cancer.
Simultaneous silencing of ACSL4 and induction of GADD45B in hepatocellular carcinoma cells amplifies the synergistic therapeutic effect of aspirin and sorafenib

Science.gov (United States)

Xia, Hongping; Lee, Kee Wah; Chen, Jianxiang; Kong, Shik Nie; Sekar, Karthik; Deivasigamani, Amudha; Seshachalam, Veerabrahma Pratap; Goh, Brian Kim Poh; Ooi, London Lucien; Hui, Kam M

2017-01-01

Sorafenib is currently the only US Food and Drug Administration (FDA)-approved molecular inhibitor for the systemic therapy of advanced hepatocellular carcinoma (HCC). Aspirin has been studied extensively as an anti-inflammation, cancer preventive and therapeutic agent. However, the potential synergistic therapeutic effects of sorafenib and aspirin on advanced HCC treatment have not been well studied. Drug combination studies and their synergy quantification were performed using the combination index method of Chou-Talalay. The synergistic therapeutic effects of sorafenib and aspirin were evaluated using an orthotopic mouse model of HCC and comprehensive gene profiling analyses were conducted to identify key factors mediating the synergistic therapeutic effects of sorafenib and aspirin. Sorafenib was determined to act synergistically on HCC cells with aspirin in vitro. Using Hep3B and HuH7 HCC cells, it was demonstrated that sorafenib and aspirin acted synergistically to induce apoptosis. Mechanistic studies demonstrated that combining sorafenib and aspirin yielded significant synergistically anti-tumor effects by simultaneously silencing ACSL4 and the induction of GADD45B expression in HCC cells both in vitro and in the orthotopic HCC xenograft mouse model. Importantly, clinical evidence has independently corroborated that survival of HCC patients expressing ACSL4highGADD45Blow was significantly poorer compared to patients with ACSL4lowGADD45Bhigh, thus demonstrating the potential clinical value of combining aspirin and sorafenib for HCC patients expressing ACSL4highGADD45Blow. In conclusion, sorafenib and aspirin provide synergistic therapeutic effects on HCC cells that are achieved through simultaneous silencing of ACSL4 and induction of GADD45B expression. Targeting HCC with ACSL4highGADD45Blow expression with aspirin and sorafenib could provide potential synergistic therapeutic benefits. PMID:28900541
Adjuvant effects of therapeutic glycolipids administered to a cohort of NKT cell-diverse pigs.

Science.gov (United States)

Artiaga, Bianca L; Whitener, Robert L; Staples, Charles R; Driver, John P

2014-11-15

CD1d-restricted natural killer T (NKT) cells are a unique lymphocyte population that makes important contributions to host defense against numerous microbial pathogens. The powerful immunomodulatory effects of these cells can be exploited in mice by cognate antigens for multiple therapeutic purposes, including for protection from infectious diseases and as adjuvants to improve vaccines against microbial organisms. These applications have potential to treat and prevent infectious diseases in livestock species that express NKT cells, including pigs. In this study, immune tissues from commercial swine of mixed genetic background were compared for NKT cell frequency, cytokine secretion and subset ratios. Pigs were also injected with the model antigen hen-egg lysozyme (HEL) in conjunction with one of three glycosphingolipids, alpha-galactosylceramide (αGC), OCH and C-glycoside that selectively activate NKT cells, to assess the adjuvant potential of each. There was significant variation between individual pigs for all NKT cell parameters measured. The NKT cell agonists elicited HEL-specific immune responses of different quality, but only αGC increased the systemic concentration of NKT cells. Peripheral blood NKT cell frequency measured prior to treatment was a poor predictor of how individual animals responded to NKT cell therapy. However, our results show that although NKT cells vary considerably between pigs, there exists considerable potential to harness these cells to protect swine from infectious diseases. Copyright © 2014 Elsevier B.V. All rights reserved.

c-Met in esophageal squamous cell carcinoma: an independent prognostic factor and potential therapeutic target

International Nuclear Information System (INIS)

Ozawa, Yohei; Nakamura, Yasuhiro; Fujishima, Fumiyoshi; Felizola, Saulo JA; Takeda, Kenichiro; Okamoto, Hiroshi; Ito, Ken; Ishida, Hirotaka; Konno, Takuro; Kamei, Takashi; Miyata, Go; Ohuchi, Noriaki; Sasano, Hironobu

2015-01-01

c-Met is widely known as a poor prognostic factor in various human malignancies. Previous studies have suggested the involvement of c-Met and/or its ligand, hepatocyte growth factor (HGF), in esophageal squamous cell carcinoma (ESCC), but the correlation between c-Met status and clinical outcome remains unclear. Furthermore, the identification of a novel molecular therapeutic target might potentially help improve the clinical outcome of ESCC patients. The expression of c-Met and HGF was immunohistochemically assessed in 104 surgically obtained tissue specimens. The correlation between c-Met/HGF expression and patients’ clinicopathological features, including survival, was evaluated. We also investigated changes in cell functions and protein expression of c-Met and its downstream signaling pathway components under treatments with HGF and/or c-Met inhibitor in ESCC cell lines. Elevated expression of c-Met was significantly correlated with tumor depth and pathological stage. Patients with high c-Met expression had significantly worse survival. In addition, multivariate analysis identified the high expression of c-Met as an independent prognostic factor. Treatment with c-Met inhibitor under HGF stimulation significantly inhibited the invasive capacity of an ESCC cell line with elevated c-Met mRNA expression. Moreover, c-Met and its downstream signaling inactivation was also detected after treatment with c-Met inhibitor. The results of our study identified c-Met expression as an independent prognostic factor in ESCC patients and demonstrated that c-Met could be a potential molecular therapeutic target for the treatment of ESCC with elevated c-Met expression. The online version of this article (doi:10.1186/s12885-015-1450-3) contains supplementary material, which is available to authorized users
Chimeric Antigen Receptor-Engineered NK-92 Cells: An Off-the-Shelf Cellular Therapeutic for Targeted Elimination of Cancer Cells and Induction of Protective Antitumor Immunity

Directory of Open Access Journals (Sweden)

Congcong Zhang

2017-05-01

Full Text Available Significant progress has been made in recent years toward realizing the potential of natural killer (NK cells for cancer immunotherapy. NK cells can respond rapidly to transformed and stressed cells and have the intrinsic potential to extravasate and reach their targets in almost all body tissues. In addition to donor-derived primary NK cells, also the established NK cell line NK-92 is being developed for adoptive immunotherapy, and general safety of infusion of irradiated NK-92 cells has been established in phase I clinical trials with clinical responses observed in some of the cancer patients treated. To enhance their therapeutic utility, NK-92 cells have been modified to express chimeric antigen receptors (CARs composed of a tumor-specific single chain fragment variable antibody fragment fused via hinge and transmembrane regions to intracellular signaling moieties such as CD3ζ or composite signaling domains containing a costimulatory protein together with CD3ζ. CAR-mediated activation of NK cells then bypasses inhibitory signals and overcomes NK resistance of tumor cells. In contrast to primary NK cells, CAR-engineered NK-92 cell lines suitable for clinical development can be established from molecularly and functionally well-characterized single cell clones following good manufacturing practice-compliant procedures. In preclinical in vitro and in vivo models, potent antitumor activity of NK-92 variants targeted to differentiation antigens expressed by hematologic malignancies, and overexpressed or mutated self-antigens associated with solid tumors has been found, encouraging further development of CAR-engineered NK-92 cells. Importantly, in syngeneic mouse tumor models, induction of endogenous antitumor immunity after treatment with CAR-expressing NK-92 cells has been demonstrated, resulting in cures and long-lasting immunological memory protecting against tumor rechallenge at distant sites. Here, we summarize the current status and future
Live-Cell Imaging of Protease Activity: Assays to Screen Therapeutic Approaches.

Science.gov (United States)

Chalasani, Anita; Ji, Kyungmin; Sameni, Mansoureh; Mazumder, Samia H; Xu, Yong; Moin, Kamiar; Sloane, Bonnie F

2017-01-01

Methodologies to image and quantify the activity of proteolytic enzymes have been developed in an effort to identify protease-related druggable pathways that are involved in malignant progression of cancer. Our laboratory has pioneered techniques for functional live-cell imaging of protease activity in pathomimetic avatars for breast cancer. We analyze proteolysis in the context of proliferation and formation of structures by tumor cells in 3-D cultures over time (4D). In order to recapitulate the cellular composition and architecture of tumors in the pathomimetic avatars, we include other tumor-associated cells (e.g., fibroblasts, myoepithelial cells, microvascular endothelial cells). We also model noncellular aspects of the tumor microenvironment such as acidic pericellular pH. Use of pathomimetic avatars in concert with various types of imaging probes has allowed us to image, quantify, and follow the dynamics of proteolysis in the tumor microenvironment and to test interventions that impact directly or indirectly on proteolytic pathways. To facilitate use of the pathomimetic avatars for screening of therapeutic modalities, we have designed and fabricated custom 3D culture chambers with multiple wells that are either individual or connected by a channel to allow cells to migrate between wells. Optical glass microscope slides underneath an acrylic plate allow the cultures to be imaged with an inverted microscope. Fluid ports in the acrylic plate are at a level above the 3D cultures to allow introduction of culture media and test agents such as drugs into the wells and the harvesting of media conditioned by the cultures for immunochemical and biochemical analyses. We are using the pathomimetic avatars to identify druggable pathways, screen drug and natural product libraries and accelerate entry of validated drugs or natural products into clinical trials.
Current issues of RNAi therapeutics delivery and development.

Science.gov (United States)

Haussecker, D

2014-12-10

12 years following the discovery of the RNAi mechanism in Man, a number of RNAi therapeutics development candidates have emerged with profiles suggesting that they could become drugs of significant medical importance for diseases like TTR amyloidosis, HBV, solid cancers, and hemophilia. Despite this robust progress, the perception of RNAi therapeutics has been on a roller-coaster ride driven not only by science, but also regulatory trends, the stock markets, and Big Pharma business development decisions [1]. This presentation provides an update on the current state of RNAi therapeutics development with a particular focus on what RNAi delivery can achieve today and key challenges to be overcome to expand therapeutic opportunities. The delivery of RNAi triggers to disease-relevant cell types clearly represents the rate-limiting factor in broadly expanding the applicability of RNAi therapeutics. Today, with at least 3 delivery options (lipid nanoparticles/LNPs, GalNAc-siRNA conjugates, Dynamic PolyConjugates/DPCs) for which profound gene knockdowns have been demonstrated in non-human primates and in the clinic, RNAi therapeutics should in principle be able to address most diseases related to gene expression in the liver. Given the central importance of the liver in systemic physiology, this already represents a significant therapeutic and commercial opportunity rivaling that of e.g. monoclonal antibodies. Beyond the liver, there is a reason to believe that current RNAi therapeutics technologies can address a number of solid tumors (e.g. LNPs), diseases of the eye (e.g. self-delivering RNAi triggers) as well as diseases involving the respiratory epithelium (e.g. aerosolized LNPs), certain phagocytic cells (LNPs), hematopoietic stem cells and their progeny (lentiviral DNA-directed RNAi), vascular endothelial cells (cationic lipoplexes), and certain cell types in the kidney (self-delivering RNAi triggers, DPCs; Table 1). Despite this success, there has been a sense that
Usp7 promotes medulloblastoma cell survival and metastasis by activating Shh pathway

International Nuclear Information System (INIS)

Zhan, Meixiao; Sun, Xiaohan; Liu, Jinxiao; Li, Yan; Li, Yong; He, Xu; Zhou, Zizhang; Lu, Ligong

2017-01-01

The ubiquitin-specific protease Usp7 plays roles in multiple cellular processes through deubiquitinating and stabilizing numerous substrates, including P53, Pten and Gli. Aberrant Usp7 activity has been implicated in many disorders and tumorigenesis, making it as a potential target for therapeutic intervention. Although it is clear that Usp7 is involved in many types of cancer, its role in regulating medulloblastoma (MB) is still unknown. In this study, we show that knockdown of Usp7 inhibits the proliferation and migration of MB cells, while Usp7 overexpression exerts an opposite effect. Furthermore, we establish Usp7 knockout MB cell line using the CRISPR/Cas9 system and further confirm that Usp7 knockout also blocks MB cell proliferation and metastasis. In addition, we reveal that knockdown of Usp7 compromises Shh pathway activity and decrease Gli protein levels, while P53 level and P53 target gene expression have no obvious changes. Finally, we find that Usp7 inhibitors apparently inhibit MB cell viability and migration. Taken together, our findings suggest that Usp7 is important for MB cell proliferation and metastasis by activating Shh pathway, and is a putative therapeutic target for MBs. - Highlights: • Loss of usp7 blocks the proliferation and metastasis of MB cells. • Usp7 regulates MB cell growth and migration through stimulating Shh pathway. • Usp7 inhibitors hamper MB cell proliferation and migration. • Usp7 inhibitors could attenuate Shh pathway activity.
Neural stem cells for disease modeling of Wolman disease and evaluation of therapeutics.

Science.gov (United States)

Aguisanda, Francis; Yeh, Charles D; Chen, Catherine Z; Li, Rong; Beers, Jeanette; Zou, Jizhong; Thorne, Natasha; Zheng, Wei

2017-06-28

Wolman disease (WD) is a rare lysosomal storage disorder that is caused by mutations in the LIPA gene encoding lysosomal acid lipase (LAL). Deficiency in LAL function causes accumulation of cholesteryl esters and triglycerides in lysosomes. Fatality usually occurs within the first year of life. While an enzyme replacement therapy has recently become available, there is currently no small-molecule drug treatment for WD. We have generated induced pluripotent stem cells (iPSCs) from two WD patient dermal fibroblast lines and subsequently differentiated them into neural stem cells (NSCs). The WD NSCs exhibited the hallmark disease phenotypes of neutral lipid accumulation, severely deficient LAL activity, and increased LysoTracker dye staining. Enzyme replacement treatment dramatically reduced the WD phenotype in these cells. In addition, δ-tocopherol (DT) and hydroxypropyl-beta-cyclodextrin (HPBCD) significantly reduced lysosomal size in WD NSCs, and an enhanced effect was observed in DT/HPBCD combination therapy. The results demonstrate that these WD NSCs are valid cell-based disease models with characteristic disease phenotypes that can be used to evaluate drug efficacy and screen compounds. DT and HPBCD both reduce LysoTracker dye staining in WD cells. The cells may be used to further dissect the pathology of WD, evaluate compound efficacy, and serve as a platform for high-throughput drug screening to identify new compounds for therapeutic development.
Bone Marrow Stem Cell Derived Paracrine Factors for Regenerative Medicine: Current Perspectives and Therapeutic Potential

Directory of Open Access Journals (Sweden)

Tom J. Burdon

2011-01-01

Full Text Available During the past several years, there has been intense research in the field of bone marrow-derived stem cell (BMSC therapy to facilitate its translation into clinical setting. Although a lot has been accomplished, plenty of challenges lie ahead. Furthermore, there is a growing body of evidence showing that administration of BMSC-derived conditioned media (BMSC-CM can recapitulate the beneficial effects observed after stem cell therapy. BMSCs produce a wide range of cytokines and chemokines that have, until now, shown extensive therapeutic potential. These paracrine mechanisms could be as diverse as stimulating receptor-mediated survival pathways, inducing stem cell homing and differentiation or regulating the anti-inflammatory effects in wounded areas. The current review reflects the rapid shift of interest from BMSC to BMSC-CM to alleviate many logistical and technical issues regarding cell therapy and evaluates its future potential as an effective regenerative therapy.
Optimization of Intracellular Transportation of Gene Therapeutic DNA in Small Cell Lung Cancer (Ph.d.)

DEFF Research Database (Denmark)

Cramer, Frederik

2013-01-01

Small cell lung cancer (SCLC) is a highly malignant disease characterized as being very aggressive and metastasizing at a rapid pace. The malevolent pace of SCLC cell migration results in almost three out of four SCLC patients having disseminated SCLC at the time of diagnosis. Unfortunately...... has to be able to repeated systemic delivery of gene therapy to cancer cells in a both safe and efficient way. Non-viral delivery vectors fulfill many of these requirements except the latter. It is currently very difficult to systemically transport sufficient amounts of therapeutic DNA, by a non......-viral delivery system, to the nuclei of the SCLC cells. As a result, the gene therapy expression obtained is too low to have any clinical relevance. We have at the Department of Radiation Biology developed a transcriptionally targeting suicide gene therapy system which is built on a double stranded DNA plasmid...
Impaired Player-Coach Perceptions of Exertion and Recovery During Match Congestion

NARCIS (Netherlands)

Doeven, Steven H.; Brink, Michel S.; Frencken, Wouter G. P.; Lemmink, Koen A. P. M.

2017-01-01

During intensified phases of competition, attunement of exertion and recovery is crucial to maintain performance. Although a mismatch between coach' and players' perceptions of training load is demonstrated, it is unknown if these discrepancies also exist for match exertion and recovery. PURPOSE:
Purging of acute myeloid leukaemia cells from stem cell grafts by hyperthermia : enhancement of the therapeutic index by the tetrapeptide AcSDKP and the alkyl-lysophospholipid ET-18-OCH3

NARCIS (Netherlands)

Wierenga, PK; Setroikromo, R; Vellenga, E; Kampinga, HH

2000-01-01

Hyperthermia has been shown to be a potential purging modality in autologous stem cell transplantation settings owing to its selective toxicity towards leukaemic cells, We describe two approaches to further increase the therapeutic index of the hyperthermic purging modality by using normal murine
Recommendations for the validation of cell-based assays used for the detection of neutralizing antibody immune responses elicited against biological therapeutics.

Science.gov (United States)

Gupta, Shalini; Devanarayan, Viswanath; Finco, Deborah; Gunn, George R; Kirshner, Susan; Richards, Susan; Rup, Bonita; Song, An; Subramanyam, Meena

2011-07-15

The administration of biological therapeutics may result in the development of anti-drug antibodies (ADAs) in treated subjects. In some cases, ADA responses may result in the loss of therapeutic efficacy due to the formation of neutralizing ADAs (NAbs). An important characteristic of anti-drug NAbs is their direct inhibitory effect on the pharmacological activity of the therapeutic. Neutralizing antibody responses are of particular concern for biologic products with an endogenous homolog whose activity can be potentially dampened or completely inhibited by the NAbs leading to an autoimmune-type deficiency syndrome. Therefore, it is important that ADAs are detected and characterized appropriately using sensitive and reliable methods. The design, development and optimization of cell-based assays used for detection of NAbs have been published previously by Gupta et al. 2007 [1]. This paper provides recommendations on best practices for the validation of cell-based NAb assay and suggested validation parameters based on the experience of the authors. Copyright © 2011 Elsevier B.V. All rights reserved.
Exertional Tolerance Assessments After Mild Traumatic Brain Injury: A Systematic Review.

Science.gov (United States)

Quatman-Yates, Catherine; Bailes, Anna; Constand, Sara; Sroka, Mary Claire; Nissen, Katharine; Kurowski, Brad; Hugentobler, Jason

2018-05-01

To review the literature to identify and summarize strategies for evaluating responses to physical exertion after mild traumatic brain injury (mTBI) for clinical and research purposes. PubMed and EBSCOhost through December 31, 2016. Two independent reviewers selected studies based on the following criteria: (1) inclusion of participants with mTBI/concussion, (2) use of a measurement of physiological or psychosomatic response to exertion, (3) a repeatable description of the exertion protocol was provided, (4) a sample of at least 10 participants with a mean age between 8 and 65 years, and (5) the article was in English. The search process yielded 2685 articles, of which 14 studies met the eligibility requirements. A quality assessment using a checklist was conducted for each study by 2 independent study team members and verified by a third team member. Data were extracted by one team member and verified by a second team member. A qualitative synthesis of the studies revealed that most protocols used a treadmill or cycle ergometer as the exercise modality. Protocol methods varied across studies including differences in initial intensity determination, progression parameters, and exertion duration. Common outcome measures were self-reported symptoms, heart rate, and blood pressure. The strongest evidence indicates that exertional assessments can provide important insight about mTBI recovery and should be administered using symptoms as a guide. Additional studies are needed to verify optimal modes and protocols for post-mTBI exertional assessments. Copyright © 2017 American Congress of Rehabilitation Medicine. Published by Elsevier Inc. All rights reserved.
Protein based therapeutic delivery agents: Contemporary developments and challenges.

Science.gov (United States)

Yin, Liming; Yuvienco, Carlo; Montclare, Jin Kim

2017-07-01

As unique biopolymers, proteins can be employed for therapeutic delivery. They bear important features such as bioavailability, biocompatibility, and biodegradability with low toxicity serving as a platform for delivery of various small molecule therapeutics, gene therapies, protein biologics and cells. Depending on size and characteristic of the therapeutic, a variety of natural and engineered proteins or peptides have been developed. This, coupled to recent advances in synthetic and chemical biology, has led to the creation of tailor-made protein materials for delivery. This review highlights strategies employing proteins to facilitate the delivery of therapeutic matter, addressing the challenges for small molecule, gene, protein and cell transport. Copyright © 2017 Elsevier Ltd. All rights reserved.
Exploiting Herpes Simplex Virus Entry for Novel Therapeutics

Directory of Open Access Journals (Sweden)

Deepak Shukla

2013-06-01

Full Text Available Herpes Simplex virus (HSV is associated with a variety of diseases such as genital herpes and numerous ocular diseases. At the global level, high prevalence of individuals who are seropositive for HSV, combined with its inconspicuous infection, remains a cause for major concern. At the molecular level, HSV entry into a host cell involves multiple steps, primarily the interaction of viral glycoproteins with various cell surface receptors, many of which have alternate substitutes. The molecular complexity of the virus to enter a cell is also enhanced by the existence of different modes of viral entry. The availability of many entry receptors, along with a variety of entry mechanisms, has resulted in a virus that is capable of infecting virtually all cell types. While HSV uses a wide repertoire of viral and host factors in establishing infection, current therapeutics aimed against the virus are not as diversified. In this particular review, we will focus on the initial entry of the virus into the cell, while highlighting potential novel therapeutics that can control this process. Virus entry is a decisive step and effective therapeutics can translate to less virus replication, reduced cell death, and detrimental symptoms.
Investigating the effects of Pentoxifylline on human breast cancer cells using Raman spectroscopy

Directory of Open Access Journals (Sweden)

Peeyush N. Goel

2015-03-01

Full Text Available Breast cancer is one of the leading causes of cancer-related deaths in a global scenario. In the present study, biochemical changes exerted upon Pentoxifylline (PTX treatment had been appraised in human breast cancer cells using Raman spectroscopy. There are no clinically approved methods to monitor such therapeutic responses available. The spectral profiling is suggestive of changes in DNA, protein and lipid contents showing a linear relationship with drug dosage. Further, multivariate analysis using principal-component based linear-discriminant-analysis (PC-LDA was employed for classifying the control and the PTX treated groups. These findings support the feasibility of Raman spectroscopy as an alternate/adjunct label-free, objective method for monitoring drug-induced modifications against breast cancer cells.
Potential role of mTORC2 as a therapeutic target in clear cell carcinoma of the ovary.

Science.gov (United States)

Hisamatsu, Takeshi; Mabuchi, Seiji; Matsumoto, Yuri; Kawano, Mahiru; Sasano, Tomoyuki; Takahashi, Ryoko; Sawada, Kenjiro; Ito, Kimihiko; Kurachi, Hirohisa; Schilder, Russell J; Testa, Joseph R; Kimura, Tadashi

2013-07-01

The goal of this study was to examine the role of mTOR complex 2 (mTORC2) as a therapeutic target in ovarian clear cell carcinoma (CCC), which is regarded as an aggressive, chemoresistant histologic subtype. Using tissue microarrays of 98 primary ovarian cancers [52 CCCs and 46 serous adenocarcinomas (SAC)], activation of mTORC2 was assessed by immunohistochemistry. Then, the growth-inhibitory effect of mTORC2-targeting therapy, as well as the role of mTORC2 signaling as a mechanism for acquired resistance to the mTOR complex 1 (mTORC1) inhibitor RAD001 in ovarian CCC, were examined using two pairs of RAD001-sensitive parental (RMG2 and HAC2) and RAD001-resistant CCC cell lines (RMG2-RR and HAC2-RR). mTORC2 was more frequently activated in CCCs than in SACs (71.2% vs. 45.7%). Simultaneous inhibition of mTORC1 and mTORC2 by AZD8055 markedly inhibited the proliferation of both RAD001-sensitive and -resistant cells in vitro. Treatment with RAD001 induced mTORC2-mediated AKT activation in RAD001-sensitive CCC cells. Moreover, increased activation of mTORC2-AKT signaling was observed in RAD001-resistant CCC cells compared with the respective parental cells. Inhibition of mTORC2 during RAD001 treatment enhanced the antitumor effect of RAD001 and prevented CCC cells from acquiring resistance to RAD001. In conclusion, mTORC2 is frequently activated, and can be a promising therapeutic target, in ovarian CCCs. Moreover, mTORC2-targeted therapy may be efficacious in a first-line setting as well as for second-line treatment of recurrent disease developing after RAD001-treatment.
[Xenogeneic cell therapeutics: Treatment of type 1 diabetes using porcine pancreatic islets and islet cells].

Science.gov (United States)

Godehardt, Antonia W; Schilling-Leiß, Dagmar; Sanzenbacher, Ralf; Tönjes, Ralf R

2015-11-01

In view of the existing shortage of human donor organs and tissues, xenogeneic cell therapeutics (xCT) offer an alternative for adequate treatment. In particular, porcine pancreatic islets and islet cells have already entered the field of experimental therapy for type-1 diabetes mellitus (T1DM) patients. Thereby, xCT depict challenging products with a glance on medical, ethical, and regulatory questions. With cross-species transplantation (xenotransplantation), the risk of immunological graft rejection as well as the risk of infectious transmission of microbial and viral pathogens must be considered. This includes the bidirectional transmission of microorganisms from graft to host as well as from host to graft. Crossing the border of species requires a critical risk-benefit evaluation as well as a thorough longtime surveillance of transplant recipients after treatment. The international legal and regulatory requirements for xCT are inter alia based on the World Health Organization criteria summarized in the Changsha Communiqué (2008). In the European Union, they were reflected by the European Medicines Agency (EMA) Guideline on Xenogeneic Cell-based Medicinal Products following the implementation of the Regulation on Advanced Therapies (ATMP). On the basis of this regulation, the first non-clinical and clinical experiences were obtained for porcine islets. The results suggest that supportive treatment of T1DM risk patients with xCT may be an alternative to established allogeneic organ transplantation in the future.
Implication of fractionated dose exposures in therapeutic gain

International Nuclear Information System (INIS)

Kim, Hye-Jin; Lee, Min-Ho; Kim, Eun-Hee

2016-01-01

Radiation therapy pursues killing tumor cells while sparing normal cells from the radiation exposure. Stereotactic radiosurgery (SRS) is a cancer treatment modality that delivers a high dose in a single operation. This high-dose single operation shortens the treatment course, but can increase the risk of normal cell damage. Normal cell damage can be reduced by employing multi-directional exposures for an increasing number of isocenters. In this study, we investigated whether therapeutic benefits would be expected by employing new dose fractionation patterns at a high-dose single operation. The conventional single-dose operation in brain tumor radiosurgery is performed by delivering fractionated uniform doses. According to Figs. 2 and 3, the conventional radiosurgery might have obtained some therapeutic benefit by employing the fractionated uniform-dose exposures instead of a single-dose exposure. We suggest that further therapeutic gain be expected by employing the fractionated radiation exposures in an increasing dose pattern. Until ensuring our suggestion, the significance in gain of cell surviving should be verified for all three dose patterns with both normal and tumor cells. The investigation whether normal and tumor cells show the same responses to the fractionated dose exposures at lower and higher than 15 Gy of total dose is also reserved for future work
Therapeutic Potential of Non-Psychotropic Cannabidiol in Ischemic Stroke

Directory of Open Access Journals (Sweden)

Michihiro Fujiwara

2010-07-01

Full Text Available Cannabis contains the psychoactive component delta9-tetrahydrocannabinol (delta9-THC, and the non-psychoactive components cannabidiol (CBD, cannabinol, and cannabigerol. It is well-known that delta9-THC and other cannabinoid CB1 receptor agonists are neuroprotective during global and focal ischemic injury. Additionally, delta9-THC also mediates psychological effects through the activation of the CB1 receptor in the central nervous system. In addition to the CB1 receptor agonists, cannabis also contains therapeutically active components which are CB1 receptor independent. Of the CB1 receptor-independent cannabis, the most important is CBD. In the past five years, an increasing number of publications have focused on the discovery of the anti-inflammatory, anti-oxidant, and neuroprotective effects of CBD. In particular, CBD exerts positive pharmacological effects in ischemic stroke and other chronic diseases, including Parkinson’s disease, Alzheimer’s disease, and rheumatoid arthritis. The cerebroprotective action of CBD is CB1 receptor-independent, long-lasting, and has potent anti-oxidant activity. Importantly, CBD use does not lead to tolerance. In this review, we will discuss the therapeutic possibility of CBD as a cerebroprotective agent, highlighting recent pharmacological advances, novel mechanisms, and therapeutic time window of CBD in ischemic stroke.
Therapeutic HIV Peptide Vaccine

DEFF Research Database (Denmark)

Fomsgaard, Anders

2015-01-01

Therapeutic vaccines aim to control chronic HIV infection and eliminate the need for lifelong antiretroviral therapy (ART). Therapeutic HIV vaccine is being pursued as part of a functional cure for HIV/AIDS. We have outlined a basic protocol for inducing new T cell immunity during chronic HIV-1...... infection directed to subdominant conserved HIV-1 epitopes restricted to frequent HLA supertypes. The rationale for selecting HIV peptides and adjuvants are provided. Peptide subunit vaccines are regarded as safe due to the simplicity, quality, purity, and low toxicity. The caveat is reduced immunogenicity...

Combined antitumor activity of the nitroreductase/CB1954 suicide gene system and γ-rays in HeLa cells in vitro

Science.gov (United States)

Teng, Geling; Ju, Yuanrong; Yang, Yepeng; Hua, Hu; Chi, Jingyu; Mu, Xiuan

2016-01-01

Escherichia coli nitroreductase (NTR) may convert the prodrug CB1954 (5-(aziridin-1-yl)-2,4-dinitrobenzamide) into a bifunctional alkylating agent, which may lead to DNA crosslinks and the apoptosis of cancer cells. NTR/CB1954 has been demonstrated to be an effective gene therapy in cancer cells. The present study examined whether the NTR/CB1954 suicide gene system had cytotoxic effects on HeLa cells and may improve the radiosensitivity of HeLa cells to γ-rays. It was observed that the NTR/CB1954 suicide gene system exerted marked cytotoxic effects on HeLa cells. The combined therapeutic effects of NTR/CB1954 and γ-rays on HeLa cells demonstrated a synergistic effect. CB1954 at concentrations of 12.5 and 25 µmol/l increased the sensitization enhancement ratio of HeLa cells to 1.54 and 1.66, respectively. Therefore, when compared with monotherapy, the combined therapy of NTR/CB1954 and γ-rays may increase the apoptotic rate and enhance the radiosensitivity of HeLa cells. The combined therapy of γ-ray radiation and the NTR/CB1954 suicide gene system may be a novel and potent therapeutic method for the treatment of cervical carcinoma. PMID:27840931
Identification of repaglinide as a therapeutic drug for glioblastoma multiforme

International Nuclear Information System (INIS)

Xiao, Zui Xuan; Chen, Ruo Qiao; Hu, Dian Xing; Xie, Xiao Qiang; Yu, Shang Bin; Chen, Xiao Qian

2017-01-01

Glioblastoma multiforme (GBM) is a highly aggressive brain tumor with a median survival time of only 14 months after treatment. It is urgent to find new therapeutic drugs that increase survival time of GBM patients. To achieve this goal, we screened differentially expressed genes between long-term and short-term survived GBM patients from Gene Expression Omnibus database and found gene expression signature for the long-term survived GBM patients. The signaling networks of all those differentially expressed genes converged to protein binding, extracellular matrix and tissue development as revealed in BiNGO and Cytoscape. Drug repositioning in Connectivity Map by using the gene expression signature identified repaglinide, a first-line drug for diabetes mellitus, as the most promising novel drug for GBM. In vitro experiments demonstrated that repaglinide significantly inhibited the proliferation and migration of human GBM cells. In vivo experiments demonstrated that repaglinide prominently prolonged the median survival time of mice bearing orthotopic glioma. Mechanistically, repaglinide significantly reduced Bcl-2, Beclin-1 and PD-L1 expression in glioma tissues, indicating that repaglinide may exert its anti-cancer effects via apoptotic, autophagic and immune checkpoint signaling. Taken together, repaglinide is likely to be an effective drug to prolong life span of GBM patients. - Highlights: • Gene expression signarue in long-term survived GBM patients are identified from Gene Expression Omnibus database. • Repaglinide is identified as a survival-related drug for GBM via drug repositioning in CMap. • Repaglinide effectively kills GBM cells, inhibits GBM cell migration and increases survival of mice bearing orthotopic glioma. • Repaglinide reduces Bcl-2, Beclin-1 and PD-L1 in GBM tissues.
Sevoflurane improves gaseous exchange and exerts protective ...

African Journals Online (AJOL)

mice, and exerted protective effects against acute LPS-induced lung injury. ... This is an Open Access article that uses a funding model which does not charge readers .... field microscope [20]. ... by Tukey's test were used for statistical analysis.
Enzymatic detachment of therapeutic mesenchymal stromal cells grown on glass carriers in a bioreactor.

Science.gov (United States)

Salzig, Denise; Schmiermund, Alexandra; P Grace, Pablo; Elseberg, Christiane; Weber, Christian; Czermak, Peter

2013-01-01

Cell therapies require the in vitro expansion of adherent cells such as mesenchymal stromal cells (hMSCs) in bioreactor systems or other culture environments, followed by cell harvest. As hMSCs are strictly adherent cells, cell harvest requires cell detachment. The use of hMSCs for cell therapy requires GMP production in accordance with the guidelines for advanced therapeutic medical products. Therefore, several GMP-conform available proteolytic enzymes were investigated for their ability to promote hMSC detachment. An allogeneic hMSC cell line (hMSC-TERT) that is used in clinical trials in the form of alginate cell capsules was chosen as a model. This study investigated the influence of several factors on the outcome of proteolytic hMSC-TERT detachment. Therefore, hMSC-TERT detachment was analyzed in different cultivation systems (static, dynamic) and in combination with further cell processing including encapsulation. Only two of the commercially available enzymes (AccutaseTM, TrypZeanTM) that fulfill all process requirements (commercial availability, cost, GMP conditions during manufacturing and non-animal origin) are found to be generally suitable for detaching hMSC-TERT. Combining cell detachment with encapsulation demonstrated a high impact of the experimental set up on cell damage. It was preferable to reduce the temperature during detachment and limit the detachment time to a maximum of 20 minutes. Cell detachment in static systems was not comparable with detachment in dynamic systems. Detachment yields in dynamic systems were lower and cell damage was higher for the same experimental conditions. Finally, only TrypZeanTM seemed to be suitable for the detachment of hMSC-TERT from dynamic reactor systems.
Chronic exertional compartment syndrome with medial tibial stress syndrome in twins.

Science.gov (United States)

Banerjee, Purnajyoti; McLean, Christopher

2011-06-14

Chronic exertional compartment syndrome and medial tibial stress syndrome are uncommon conditions that affect long-distance runners or players involved in team sports that require extensive running. We report 2 cases of bilateral chronic exertional compartment syndrome, with medial tibial stress syndrome in identical twins diagnosed with the use of a Kodiag monitor (B. Braun Medical, Sheffield, United Kingdom) fulfilling the modified diagnostic criteria for chronic exertional compartment syndrome as described by Pedowitz et al, which includes: (1) pre-exercise compartment pressure level >15 mm Hg; (2) 1 minute post-exercise pressure >30 mm Hg; and (3) 5 minutes post-exercise pressure >20 mm Hg in the presence of clinical features. Both patients were treated with bilateral anterior fasciotomies through minimal incision and deep posterior fasciotomies with tibial periosteal stripping performed through longer anteromedial incisions under direct vision followed by intensive physiotherapy resulting in complete symptomatic recovery. The etiology of chronic exertional compartment syndrome is not fully understood, but it is postulated abnormal increases in intramuscular pressure during exercise impair local perfusion, causing ischemic muscle pain. No familial predisposition has been reported to date. However, some authors have found that no significant difference exists in the relative perfusion, in patients, diagnosed with chronic exertional compartment syndrome. Magnetic resonance images of affected compartments have indicated that the pain is not due to ischemia, but rather from a disproportionate oxygen supply versus demand. We believe this is the first report of chronic exertional compartment syndrome with medial tibial stress syndrome in twins, raising the question of whether there is a genetic predisposition to the causation of these conditions. Copyright 2011, SLACK Incorporated.
Cell-based therapeutics from an economic perspective: primed for a commercial success or a research sinkhole?

Science.gov (United States)

McAllister, Todd N; Dusserre, Nathalie; Maruszewski, Marcin; L'heureux, Nicolas

2008-11-01

Despite widespread hype and significant investment through the late 1980s and 1990s, cell-based therapeutics have largely failed from both a clinical and financial perspective. While the early pioneers were able to create clinically efficacious products, small margins coupled with small initial indications made it impossible to produce a reasonable return on the huge initial investments that had been made to support widespread research activities. Even as US FDA clearance opened up larger markets, investor interest waned, and the crown jewels of cell-based therapeutics went bankrupt or were rescued by corporate bailout. Despite the hard lessons learned from these pioneering companies, many of today's regenerative medicine companies are supporting nearly identical strategies. It remains to be seen whether or not our proposed tenets for investment and commercialization strategy yield an economic success or whether the original model can produce a return on investment sufficient to justify the large up-front investments. Irrespective of which approach yields a success, it is critically important that more of the second-generation products establish profitability if the field is to enjoy continued investment from both public and private sectors.
The E3 ligase Cbl-b and TAM receptors regulate cancer metastasis via natural killer cells.

Science.gov (United States)

Paolino, Magdalena; Choidas, Axel; Wallner, Stephanie; Pranjic, Blanka; Uribesalgo, Iris; Loeser, Stefanie; Jamieson, Amanda M; Langdon, Wallace Y; Ikeda, Fumiyo; Fededa, Juan Pablo; Cronin, Shane J; Nitsch, Roberto; Schultz-Fademrecht, Carsten; Eickhoff, Jan; Menninger, Sascha; Unger, Anke; Torka, Robert; Gruber, Thomas; Hinterleitner, Reinhard; Baier, Gottfried; Wolf, Dominik; Ullrich, Axel; Klebl, Bert M; Penninger, Josef M

2014-03-27

Tumour metastasis is the primary cause of mortality in cancer patients and remains the key challenge for cancer therapy. New therapeutic approaches to block inhibitory pathways of the immune system have renewed hopes for the utility of such therapies. Here we show that genetic deletion of the E3 ubiquitin ligase Cbl-b (casitas B-lineage lymphoma-b) or targeted inactivation of its E3 ligase activity licenses natural killer (NK) cells to spontaneously reject metastatic tumours. The TAM tyrosine kinase receptors Tyro3, Axl and Mer (also known as Mertk) were identified as ubiquitylation substrates for Cbl-b. Treatment of wild-type NK cells with a newly developed small molecule TAM kinase inhibitor conferred therapeutic potential, efficiently enhancing anti-metastatic NK cell activity in vivo. Oral or intraperitoneal administration using this TAM inhibitor markedly reduced murine mammary cancer and melanoma metastases dependent on NK cells. We further report that the anticoagulant warfarin exerts anti-metastatic activity in mice via Cbl-b/TAM receptors in NK cells, providing a molecular explanation for a 50-year-old puzzle in cancer biology. This novel TAM/Cbl-b inhibitory pathway shows that it might be possible to develop a 'pill' that awakens the innate immune system to kill cancer metastases.
Pulmonary antioxidants exert differential protective effects against ...

Indian Academy of Sciences (India)

Unknown

PM collections from both urban and industrial sites caused 50% oxidative degradation of DNA in vitro at concentrations as low ... chemical analysis in order that progress can be made in ... One popular hypothesis is that PM exerts toxic effects.
Overexpression of GDNF in the uninjured DRG exerts analgesic effects on neuropathic pain following segmental spinal nerve ligation in mice.

Science.gov (United States)

Takasu, Kumiko; Sakai, Atsushi; Hanawa, Hideki; Shimada, Takashi; Suzuki, Hidenori

2011-11-01

Glial cell line-derived neurotrophic factor (GDNF), a survival-promoting factor for a subset of nociceptive small-diameter neurons, has been shown to exert analgesic effects on neuropathic pain. However, its detailed mechanisms of action are still unknown. In the present study, we investigated the site-specific analgesic effects of GDNF in the neuropathic pain state using lentiviral vector-mediated GDNF overexpression in mice with left fifth lumbar (L5) spinal nerve ligation (SNL) as a neuropathic pain model. A lentiviral vector expressing both GDNF and enhanced green fluorescent protein (EGFP) was constructed and injected into the left dorsal spinal cord, uninjured fourth lumbar (L4) dorsal root ganglion (DRG), injured L5 DRG, or plantar skin of mice. In SNL mice, injection of the GDNF-EGFP-expressing lentivirus into the dorsal spinal cord or uninjured L4 DRG partially but significantly reduced the mechanical allodynia in association with an increase in GDNF protein expression in each virus injection site, whereas injection into the injured L5 DRG or plantar skin had no effects. These results suggest that GDNF exerts its analgesic effects in the neuropathic pain state by acting on the central terminals of uninjured DRG neurons and/or on the spinal cells targeted by the uninjured DRG neurons. This article shows that GDNF exerts its analgesic effects on neuropathic pain by acting on the central terminals of uninjured DRG neurons and/or on the spinal cells targeted by these neurons. Therefore, research focusing on these GDNF-dependent neurons in the uninjured DRG would provide a new strategy for treating neuropathic pain. Copyright Â© 2011 American Pain Society. Published by Elsevier Inc. All rights reserved.
Human adipose-derived mesenchymal stromal cell pigment epithelium-derived factor cytotherapy modifies genetic and epigenetic profiles of prostate cancer cells.

Science.gov (United States)

Zolochevska, Olga; Shearer, Joseph; Ellis, Jayne; Fokina, Valentina; Shah, Forum; Gimble, Jeffrey M; Figueiredo, Marxa L

2014-03-01

Adipose-derived mesenchymal stromal cells (ASCs) are promising tools for delivery of cytotherapy against cancer. However, ASCs can exert profound effects on biological behavior of tumor cells. Our study aimed to examine the influence of ASCs on gene expression and epigenetic methylation profiles of prostate cancer cells as well as the impact of expressing a therapeutic gene on modifying the interaction between ASCs and prostate cancer cells. ASCs were modified by lentiviral transduction to express either green fluorescent protein as a control or pigment epithelium-derived factor (PEDF) as a therapeutic molecule. PC3 prostate cancer cells were cultured in the presence of ASC culture-conditioned media (CCM), and effects on PC3 or DU145. Ras cells were examined by means of real-time quantitative polymerase chain reaction, EpiTect methyl prostate cancer-focused real-time quantitative polymerase chain reaction arrays, and luciferase reporter assays. ASCs transduced with lentiviral vectors were able to mediate expression of several tumor-inhibitory genes, some of which correlated with epigenetic methylation changes on cocultured PC3 prostate cancer cells. When PC3 cells were cultured with ASC-PEDF CCM, we observed a shift in the balance of gene expression toward tumor inhibition, which suggests that PEDF reduces the potential tumor-promoting activity of unmodified ASCs. These results suggest that ASC-PEDF CCM can promote reprogramming of tumor cells in a paracrine manner. An improved understanding of genetic and epigenetic events in prostate cancer growth in response to PEDF paracrine therapy would enable a more effective use of ASC-PEDF, with the goal of achieving safer yet more potent anti-tumor effects. Copyright © 2014 International Society for Cellular Therapy. Published by Elsevier Inc. All rights reserved.
Extracellular histones reduce survival and angiogenic responses of late outgrowth progenitor and mature endothelial cells.

Science.gov (United States)

Mena, H A; Carestia, A; Scotti, L; Parborell, F; Schattner, M; Negrotto, S

2016-02-01

ESSENTIALS: Extracellular histones are highly augmented in sites of neovessel formation, such as regeneration tissues. We studied histone effect on survival and angiogenic activity of mature and progenitor endothelial cells. Extracellular histones trigger apoptosis and pyroptosis and reduce angiogenesis in vivo and in vitro. Histone blockade can be useful as a therapeutic strategy to improve angiogenesis and tissue regeneration. Extracellular histones are highly augmented in sites of neovessel formation, like regeneration tissues. Their cytotoxic effect has been studied in endothelial cells, although the mechanism involved and their action on endothelial colony-forming cells (ECFCs) remain unknown. To study the effect of histones on ECFC survival and angiogenic functions and compare it with mature endothelial cells. Nuclear morphology analysis showed that each human recombinant histone triggered both apoptotic-like and necrotic-like cell deaths in both mature and progenitor endothelial cells. While H1 and H2A exerted a weak toxicity, H2B, H3 and H4 were the most powerful. The percentage of apoptosis correlated with the percentage of ECFCs exhibiting caspase-3 activation and was zeroed by the pan-caspase inhibitor Z-VAD-FMK. Necrotic-like cell death was also suppressed by this compound and the caspase-1 inhibitor Ac-YVAD-CMK, indicating that histones triggered ECFC pyroptosis. All histones, at non-cytotoxic concentrations, reduced migration and H2B, H3 and H4 induced cell cycle arrest and impaired tubulogenesis via p38 activation. Neutrophil-derived histones exerted similar effects. In vivo blood vessel formation in the quail chorioallantoic membrane was also reduced by H2B, H3 and H4. Their cytotoxic and antiangiogenic effects were suppressed by unfractioned and low-molecular-weight heparins and the combination of TLR2 and TLR4 blocking antibodies. Histones trigger both apoptosis and pyroptosis of ECFCs and inhibit their angiogenic functions. Their cytotoxic and
The Role of Stem Cell Therapeutics in Wound Healing: Current Understanding and Future Directions.

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Sorice, Sarah; Rustad, Kristine C; Li, Alexander Y; Gurtner, Geoffrey C

2016-09-01

Chronic wounds present unique challenges for healthcare providers as they place patients at increased risk for various morbidities and mortality. Advances in wound care technology have expanded the treatment options available for wound management, but few products fully address the underlying core deficiencies responsible for the development of poorly healing wounds. In the future, addressing these derangements will undoubtedly play a key role in the treatment of these patients. Broad enthusiasm has surrounded the field of stem cell biology, which has shown great promise in repairing damaged tissues across numerous disease phenotypes. In this review, we provide a comprehensive review of the literature and evaluate the present landscape of wound therapeutics while discussing the rationales and allure behind stem cell-based products. We further propose 2 challenges that remain as new stem cell-based therapies are being developed and as this technology moves toward clinical translation. Given the relatively young age of this newer technology in wound healing, numerous challenges continue to surround its effective use including identifying the ideal population of stem cells to use and determining the optimal cell delivery method. However, significant forward progress has been made, with several clinical trials beginning to demonstrate reliable clinical benefit. The upward trajectory of stem cell technologies provides an exciting opportunity to positively impact patient outcomes through the controlled application of regenerative cell-based therapy.
Dysfunctional Hematopoietic Stem Cell Biology: Underlying Mechanisms and Potential Therapeutic Strategies

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Anja Geiselhart

2012-01-01

Full Text Available Fanconi anemia (FA is the most common inherited bone marrow failure syndrome. FA patients suffer to varying degrees from a heterogeneous range of developmental defects and, in addition, have an increased likelihood of developing cancer. Almost all FA patients develop a severe, progressive bone marrow failure syndrome, which impacts upon the production of all hematopoietic lineages and, hence, is thought to be driven by a defect at the level of the hematopoietic stem cell (HSC. This hypothesis would also correlate with the very high incidence of MDS and AML that is observed in FA patients. In this paper, we discuss the evidence that supports the role of dysfunctional HSC biology in driving the etiology of the disease. Furthermore, we consider the different model systems currently available to study the biology of cells defective in the FA signaling pathway and how they are informative in terms of identifying the physiologic mediators of HSC depletion and dissecting their putative mechanism of action. Finally, we ask whether the insights gained using such disease models can be translated into potential novel therapeutic strategies for the treatment of the hematologic disorders in FA patients.
Do ABO blood group antigens hamper the therapeutic efficacy of mesenchymal stromal cells?

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Moll, Guido; Hult, Annika; von Bahr, Lena; Alm, Jessica J; Heldring, Nina; Hamad, Osama A; Stenbeck-Funke, Lillemor; Larsson, Stella; Teramura, Yuji; Roelofs, Helene; Nilsson, Bo; Fibbe, Willem E; Olsson, Martin L; Le Blanc, Katarina

2014-01-01

Investigation into predictors for treatment outcome is essential to improve the clinical efficacy of therapeutic multipotent mesenchymal stromal cells (MSCs). We therefore studied the possible harmful impact of immunogenic ABO blood groups antigens - genetically governed antigenic determinants - at all given steps of MSC-therapy, from cell isolation and preparation for clinical use, to final recipient outcome. We found that clinical MSCs do not inherently express or upregulate ABO blood group antigens after inflammatory challenge or in vitro differentiation. Although antigen adsorption from standard culture supplements was minimal, MSCs adsorbed small quantities of ABO antigen from fresh human AB plasma (ABP), dependent on antigen concentration and adsorption time. Compared to cells washed in non-immunogenic human serum albumin (HSA), MSCs washed with ABP elicited stronger blood responses after exposure to blood from healthy O donors in vitro, containing high titers of ABO antibodies. Clinical evaluation of hematopoietic stem cell transplant (HSCT) recipients found only very low titers of anti-A/B agglutination in these strongly immunocompromised patients at the time of MSC treatment. Patient analysis revealed a trend for lower clinical response in blood group O recipients treated with ABP-exposed MSC products, but not with HSA-exposed products. We conclude, that clinical grade MSCs are ABO-neutral, but the ABP used for washing and infusion of MSCs can contaminate the cells with immunogenic ABO substance and should therefore be substituted by non-immunogenic HSA, particularly when cells are given to immunocompentent individuals.
Identification of cell surface targets for HIV-1 therapeutics using genetic screens

International Nuclear Information System (INIS)

Dunn, Stephen J.; Khan, Imran H.; Chan, Ursula A.; Scearce, Robin L.; Melara, Claudia L.; Paul, Amber M.; Sharma, Vikram; Bih, Fong-Yih; Holzmayer, Tanya A.; Luciw, Paul A.; Abo, Arie

2004-01-01

Human immunodeficiency virus (HIV) drugs designed to interfere with obligatory utilization of certain host cell factors by virus are less likely to encounter development of resistant strains than drugs directed against viral components. Several cellular genes required for productive infection by HIV were identified by the use of genetic suppressor element (GSE) technology as potential targets for anti-HIV drug development. Fragmented cDNA libraries from various pools of human peripheral blood mononuclear cells (PBMC) were expressed in vitro in human immunodeficiency virus type 1 (HIV-1)-susceptible cell lines and subjected to genetic screens to identify GSEs that interfered with viral replication. After three rounds of selection, more than 15 000 GSEs were sequenced, and the cognate genes were identified. The GSEs that inhibited the virus were derived from a diverse set of genes including cell surface receptors, cytokines, signaling proteins, transcription factors, as well as genes with unknown function. Approximately 2.5% of the identified genes were previously shown to play a role in the HIV-1 life cycle; this finding supports the biological relevance of the assay. GSEs were derived from the following 12 cell surface proteins: CXCR4, CCR4, CCR7, CD11C, CD44, CD47, CD68, CD69, CD74, CSF3R, GABBR1, and TNFR2. Requirement of some of these genes for viral infection was also investigated by using RNA interference (RNAi) technology; accordingly, 10 genes were implicated in early events of the viral life cycle, before viral DNA synthesis. Thus, these cell surface proteins represent novel targets for the development of therapeutics against HIV-1 infection and AIDS
Novel Biomarker Discovery for Diagnostic and Therapeutic Strategies in Prostate Cancer

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2015-06-01

Task 2: Prepare fluorinated RNA aptamer library for screening indolent and aggressive LNCaP cells. The pool of RNA aptamers is amplified from the...transcribed Fluorination of the nucleic acid backbone stabilizes the RNA aptamers against RNAse degradation. Status: completed. Task 3: Perform first...to metastasis-prone prostate cancer cell surface targets, and exert cell- specific toxicity . We propose that these aptamers may help to discriminate between progressive and indolent prostate cancer in clinical applications.
Pressure exerted by a vesicle on a surface

International Nuclear Information System (INIS)

Owczarek, A L; Prellberg, T

2014-01-01

Several recent works have considered the pressure exerted on a wall by a model polymer. We extend this consideration to vesicles attached to a wall, and hence include osmotic pressure. We do this by considering a two-dimensional directed model, namely that of area-weighted Dyck paths. Not surprisingly, the pressure exerted by the vesicle on the wall depends on the osmotic pressure inside, especially its sign. Here, we discuss the scaling of this pressure in the different regimes, paying particular attention to the crossover between positive and negative osmotic pressure. In our directed model, there exists an underlying Airy function scaling form, from which we extract the dependence of the bulk pressure on small osmotic pressures. (paper)
Fascaplysin Exerts Anti-Cancer Effects through the Downregulation of Survivin and HIF-1α and Inhibition of VEGFR2 and TRKA

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Taek-In Oh

2017-09-01

Full Text Available Fascaplysin has been reported to exert anti-cancer effects by inhibiting cyclin-dependent kinase 4 (CDK4; however, the precise mode of action by which fascaplysin suppresses tumor growth is not clear. Here, we found that fascaplysin has stronger anti-cancer effects than other CDK4 inhibitors, including PD0332991 and LY2835219, on lung cancer cells that are wild-type or null for retinoblastoma (RB, indicating that unknown target molecules might be involved in the inhibition of tumor growth by fascaplysin. Fascaplysin treatment significantly decreased tumor angiogenesis and increased cleaved-caspase-3 in xenografted tumor tissues. In addition, survivin and HIF-1α were downregulated in vitro and in vivo by suppressing 4EBP1-p70S6K1 axis-mediated de novo protein synthesis. Kinase screening assays and drug-protein docking simulation studies demonstrated that fascaplysin strongly inhibited vascular endothelial growth factor receptor 2 (VEGFR2 and tropomyosin-related kinase A (TRKA via DFG-out non-competitive inhibition. Overall, these results suggest that fascaplysin inhibits TRKA and VEGFR2 and downregulates survivin and HIF-1α, resulting in suppression of tumor growth. Fascaplysin, therefore, represents a potential therapeutic approach for the treatment of multiple types of solid cancer.
Combined antitumor activity of the nitroreductase/CB1954 suicide gene system and γ-rays in HeLa cells in vitro.

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Teng, Geling; Ju, Yuanrong; Yang, Yepeng; Hua, Hu; Chi, Jingyu; Mu, Xiuan

2016-12-01

Escherichia coli nitroreductase (NTR) may convert the prodrug CB1954 (5-(aziridin-1-yl)-2,4-dinitrobenzamide) into a bifunctional alkylating agent, which may lead to DNA crosslinks and the apoptosis of cancer cells. NTR/CB1954 has been demonstrated to be an effective gene therapy in cancer cells. The present study examined whether the NTR/CB1954 suicide gene system had cytotoxic effects on HeLa cells and may improve the radiosensitivity of HeLa cells to γ‑rays. It was observed that the NTR/CB1954 suicide gene system exerted marked cytotoxic effects on HeLa cells. The combined therapeutic effects of NTR/CB1954 and γ‑rays on HeLa cells demonstrated a synergistic effect. CB1954 at concentrations of 12.5 and 25 µmol/l increased the sensitization enhancement ratio of HeLa cells to 1.54 and 1.66, respectively. Therefore, when compared with monotherapy, the combined therapy of NTR/CB1954 and γ‑rays may increase the apoptotic rate and enhance the radiosensitivity of HeLa cells. The combined therapy of γ‑ray radiation and the NTR/CB1954 suicide gene system may be a novel and potent therapeutic method for the treatment of cervical carcinoma.
Design of therapeutic vaccines as a novel antibody therapy for cardiovascular diseases.

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Nakagami, Hironori

2017-09-01

Vaccines are primarily used worldwide as a preventive medicine for infectious diseases and have recently been applied to cancer. We and others have developed therapeutic vaccines designed for cardiovascular diseases that are notably different from previous vaccines. In the case of cancer vaccines, a specific protein in cancer cells is a target antigen, and the activation of cytotoxic T cells (CTL) is required to kill and remove the antigen-presenting cancer cells. Our therapeutic vaccines work against hypertension by targeting angiotensin II (Ang II) as the antigen, which is an endogenous hormone. Therapeutic vaccines must avoid CTL activation and induce the blocking antibodies for Ang II. The goal of our therapeutic vaccine for cardiovascular diseases is to induce the specific antibody response toward the target protein without inducing T-cell or antibody-mediated inflammation through the careful selection of the target antigen, carrier protein and adjuvants. The goal of our therapeutic vaccine is similar to that of antibody therapy. Recently, multiple antibody-based drugs have been developed for cancer, immune-related diseases, and dyslipidemia, which are efficient but expensive. If the effect of a therapeutic vaccine is nearly equivalent to antibody therapy as an alternative approach, the lower medical cost and improvement in drug adherence can be advantages of therapeutic vaccines. In this review, we will describe our concept of therapeutic vaccines for cardiovascular diseases and the future directions of therapeutic vaccines as novel antibody therapies. Copyright © 2017. Published by Elsevier Ltd.

Redirecting Therapeutic T Cells against Myelin-Specific T Lymphocytes Using a Humanized Myelin Basic Protein-HLA-DR2-{zeta} Chimeric Receptor

DEFF Research Database (Denmark)

Moisini, Ioana; Nguyen, Phuong; Fugger, Lars

2008-01-01

Therapies that Ag-specifically target pathologic T lymphocytes responsible for multiple sclerosis (MS) and other autoimmune diseases would be expected to have improved therapeutic indices compared with Ag-nonspecific therapies. We have developed a cellular immunotherapy that uses chimeric receptors...... mouse model system. Finally, the chimeric receptor-modified CTL ameliorated or blocked experimental allergic encephalomyelitis (EAE) disease mediated by MBP(84-102)/DR2-specific T lymphocytes. These results provide support for the further development of redirected therapeutic T cells able to counteract...... pathologic, self-specific T lymphocytes, and specifically validate humanized MBP-DR2-zeta chimeric receptors as a potential therapeutic in MS. Udgivelsesdato: 2008-Mar-1...
Bone Marrow Regeneration Promoted by Biophysically Sorted Osteoprogenitors From Mesenchymal Stromal Cells

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Poon, Zhiyong; Lee, Wong Cheng; Guan, Guofeng; Nyan, Lin Myint; Lim, Chwee Teck; Han, Jongyoon

2015-01-01

Human tissue repair deficiencies can be supplemented through strategies to isolate, expand in vitro, and reimplant regenerative cells that supplant damaged cells or stimulate endogenous repair mechanisms. Bone marrow-derived mesenchymal stromal cells (MSCs), a subset of which is described as mesenchymal stem cells, are leading candidates for cell-mediated bone repair and wound healing, with hundreds of ongoing clinical trials worldwide. An outstanding key challenge for successful clinical translation of MSCs is the capacity to produce large quantities of cells in vitro with uniform and relevant therapeutic properties. By leveraging biophysical traits of MSC subpopulations and label-free microfluidic cell sorting, we hypothesized and experimentally verified that MSCs of large diameter within expanded MSC cultures were osteoprogenitors that exhibited significantly greater efficacy over other MSC subpopulations in bone marrow repair. Systemic administration of osteoprogenitor MSCs significantly improved survival rates (>80%) as compared with other MSC subpopulations (0%) for preclinical murine bone marrow injury models. Osteoprogenitor MSCs also exerted potent therapeutic effects as “cell factories” that secreted high levels of regenerative factors such as interleukin-6 (IL-6), interleukin-8 (IL-8), vascular endothelial growth factor A, bone morphogenetic protein 2, epidermal growth factor, fibroblast growth factor 1, and angiopoietin-1; this resulted in increased cell proliferation, vessel formation, and reduced apoptosis in bone marrow. This MSC subpopulation mediated rescue of damaged marrow tissue via restoration of the hematopoiesis-supporting stroma, as well as subsequent hematopoiesis. Together, the capabilities described herein for label-freeisolation of regenerative osteoprogenitor MSCs can markedly improve the efficacy of MSC-based therapies. PMID:25411477
Using therapeutic cloning to fight human disease: a conundrum or reality?

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Hall, Vanessa J; Stojkovic, Petra; Stojkovic, Miodrag

2006-07-01

The development and transplantation of autologous cells derived from nuclear transfer embryonic stem cell (NT-ESC) lines to treat patients suffering from disease has been termed therapeutic cloning. Human NT is still a developing field, with further research required to improve somatic cell NT and human embryonic stem cell differentiation to deliver safe and effective cell replacement therapies. Furthermore, the implications of transferring mitochondrial heteroplasmic cells, which may harbor aberrant epigenetic gene expression profiles, are of concern. The production of human NT-ESC lines also remains plagued by ethical dilemmas, societal concerns, and controversies. Recently, a number of alternate therapeutic strategies have been proposed to circumvent the moral implications surrounding human nuclear transfer. It will be critical to overcome these biological, legislative, and moral restraints to maximize the potential of this therapeutic strategy and to alleviate human disease.
Does heavy physical exertion trigger myocardial infarction?

DEFF Research Database (Denmark)

Hallqvist, J; Möller, J; Ahlbom, A

2000-01-01

To study possible triggering of first events of acute myocardial infarction by heavy physical exertion, the authors conducted a case-crossover analysis (1993-1994) within a population-based case-referent study in Stockholm County, Sweden (the Stockholm Heart Epidemiology Program). Interviews were...
Effects of fitness and self-confidence on time perception during exertion

Directory of Open Access Journals (Sweden)

2015-09-01

Full Text Available Aims: Human physical and psychological features influence perceptions of the environment during activity. If during exercise an individual over-estimates time, they may interpret this as spending longer than necessary under a potentially aversive state of exertion. This may in turn decrease one’s sense of exercise success and tendency to persevere with exercise. We tested if experimentally manipulating sense of exercise self-efficacy would affect time perception during standardised physical exertion. Method: Exercise Self-Efficacy (ESE of 18 -73 year olds (N=51 was measured before and after an exercise challenge of moderate intensity. Height, weight and body fat composition were measured before participants were randomly allocated to one of three groups. After a 4-minute treadmill fitness test, participants were presented with either bogus feedback about their performance (positive or negative or no feedback (control. Before and during exercise, participants estimated a prescribed 2-minute time interval. Ratings of perceived exertion were also measured periodically. Results: Feedback on performance had no significant effect on time perception, even when controlling for individual exertion level. Reported ESE was also unaffected by whether someone received positive, negative or no feedback. Age was again found to be significantly correlated with VO2max, r(51 = .62, p < .001, but in contrast to prior findings, estimates of general fitness such as VO2max, BMI and waist circumference were unrelated to changes in time perception due to exertion. Conclusions: These findings failed to support prior findings and anecdotal evidence suggesting that exertion might alter one’s perception of time. We also failed to find any support for effects on ESE when participants were given explicit performance feedback. Finally, participants’ physical characteristics appear to be unrelated to time perception whilst exercising at moderate intensity.
Physical exercise at the workplace reduces perceived physical exertion during healthcare work

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Jakobsen, Markus Due; Sundstrup, Emil; Brandt, Mikkel

2015-01-01

BACKGROUND: High physical exertion during work is a risk factor for musculoskeletal pain and long-term sickness absence. Physical exertion (RPE) reflects the balance between physical work demands and physical capacity of the individual. Thus, increasing the physical capacity through physical......: 3.1 on a scale of 0 to 10, average WRPE: 3.6 on a scale of 0 to 10) from 18 departments at three participating hospitals. Participants were randomly allocated at the cluster level to 10 weeks of: (1) workplace physical exercise (WORK) performed in groups during working hours for 5×10 minutes per...... exercise may decrease physical exertion during work. This study investigates the effect of workplace-based versus home-based physical exercise on physical exertion during work (WRPE) among healthcare workers. METHODS: 200 female healthcare workers (age: 42.0, body mass index: 24.1, average pain intensity...
Manufacturing of Human Extracellular Vesicle-Based Therapeutics for Clinical Use

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Mario Gimona

2017-06-01

Full Text Available Extracellular vesicles (EVs derived from stem and progenitor cells may have therapeutic effects comparable to their parental cells and are considered promising agents for the treatment of a variety of diseases. To this end, strategies must be designed to successfully translate EV research and to develop safe and efficacious therapies, whilst taking into account the applicable regulations. Here, we discuss the requirements for manufacturing, safety, and efficacy testing of EVs along their path from the laboratory to the patient. Development of EV-therapeutics is influenced by the source cell types and the target diseases. In this article, we express our view based on our experience in manufacturing biological therapeutics for routine use or clinical testing, and focus on strategies for advancing mesenchymal stromal cell (MSC-derived EV-based therapies. We also discuss the rationale for testing MSC-EVs in selected diseases with an unmet clinical need such as critical size bone defects, epidermolysis bullosa and spinal cord injury. While the scientific community, pharmaceutical companies and clinicians are at the point of entering into clinical trials for testing the therapeutic potential of various EV-based products, the identification of the mode of action underlying the suggested potency in each therapeutic approach remains a major challenge to the translational path.
Vitamins K2, K3 and K5 exert antitumor effects on established colorectal cancer in mice by inducing apoptotic death of tumor cells.

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Ogawa, Mutsumi; Nakai, Seiji; Deguchi, Akihiro; Nonomura, Takako; Masaki, Tsutomu; Uchida, Naohito; Yoshiji, Hitoshi; Kuriyama, Shigeki

2007-08-01

Although a number of studies have shown that vitamin K possesses antitumor activities on various neoplastic cell lines, there are few reports demonstrating in vivo antitumor effects of vitamin K, and the antitumor effect on colorectal cancer (CRC) remains to be examined. Therefore, antitumor effects of vitamin K on CRC were examined both in vitro and in vivo. Vitamins K2, K3 and K5 suppressed the proliferation of colon 26 cells in a dose-dependent manner, while vitamin K1 did not. On flow cytometry, induction of apoptosis by vitamins K2, K3 and K5 was suggested by population in sub-G1 phase of the cell cycle. Hoechst 33342 staining and a two-color flow cytometric assay using fluorescein isothiocyanate-conjugated annexin V and propidium iodide confirmed that vitamins K2, K3 and K5 induced apoptotic death of colon 26 cells. Enzymatic activity of caspase-3 in colon 26 cells was significantly up-regulated by vitamins K2, K3 and K5. The pan-caspase inhibitor, benzyloxycarbonyl-Val-Ala-Asp-fluoromethyl ketone, substantially prevented vitamin K-mediated apoptosis. In vivo study using syngeneic mice with subcutaneously established colon 26 tumors demonstrated that intravenous administration of vitamins K2, K3 and K5 significantly suppressed the tumor growth. The number of apoptotic tumor cells was significantly larger in the vitamin K-treated groups than in the control group. These results suggest that vitamins K2, K3 and K5 exerted effective antitumor effects on CRC in vitro and in vivo by inducing caspase-dependent apoptotic death of tumor cells, suggesting that these K vitamins may be promising agents for the treatment of patients with CRC.
ROCK as a therapeutic target for ischemic stroke.

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Sladojevic, Nikola; Yu, Brian; Liao, James K

2017-12-01

Stroke is a major cause of disability and the fifth leading cause of death. Currently, the only approved acute medical treatment of ischemic stroke is tissue plasminogen activator (tPA), but its effectiveness is greatly predicated upon early administration of the drug. There is, therefore, an urgent need to find new therapeutic options for acute stroke. Areas covered: In this review, we summarize the role of Rho-associated coiled-coil containing kinase (ROCK) and its potential as a therapeutic target in stroke pathophysiology. ROCK is a major regulator of cell contractility, motility, and proliferation. Many of these ROCK-mediated processes in endothelial cells, vascular smooth muscle cells, pericytes, astrocytes, glia, neurons, leukocytes, and platelets are important in stroke pathophysiology, and the inhibition of such processes could improve stroke outcome. Expert commentary: ROCK is a potential therapeutic target for cardiovascular disease and ROCK inhibitors have already been approved for human use in Japan and China for the treatment of acute stroke. Further studies are needed to determine the role of ROCK isoforms in the pathophysiology of cerebral ischemia and whether there are further therapeutic benefits with selective ROCK inhibitors.
Influence of ornithine decarboxylase antizymes and antizyme inhibitors on agmatine uptake by mammalian cells

DEFF Research Database (Denmark)

Ramos-Molina, Bruno; López-Contreras, Andrés J; Lambertos, Ana

2015-01-01

Agmatine (4-aminobutylguanidine), a dicationic molecule at physiological pH, exerts relevant modulatory actions at many different molecular target sites in mammalian cells, having been suggested that the administration of this compound may have therapeutic interest. Several plasma membrane...... transporters have been implicated in agmatine uptake by mammalian cells. Here we report that in kidney-derived COS-7cell line, at physiological agmatine levels, the general polyamine transporter participates in the plasma membrane translocation of agmatine, with an apparent Km of 44 ± 7 µM and V max of 17.......3 ± 3.3 nmol h(-1) mg(-1) protein, but that at elevated concentrations, agmatine can be also taken up by other transport systems. In the first case, the physiological polyamines (putrescine, spermidine and spermine), several diguanidines and bis(2-aminoimidazolines) and the polyamine transport inhibitor...
Alternative therapeutic approach to renal-cell carcinoma: induction of apoptosis with combination of vitamin K3 and D-fraction.

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Degen, Michael; Alexander, Bobby; Choudhury, Muhammad; Eshghi, Majid; Konno, Sensuke

2013-12-01

Because of a dismal prognosis for advanced renal-cell carcinoma (RCC), an alternative therapeutic approach, using vitamin K3 (VK3) and D-fraction (DF) was investigated. VK3 is a synthetic VK derivative and DF is a bioactive mushroom extract, and they have been shown to have antitumor activity. We examined if the combination of VK3 and DF would exhibit the improved anticancer effect on RCC in vitro. Human RCC, ACHN cell line, were treated with varying concentrations of VK3, DF, or a combination of the two. Cell viability was assessed at 72 hours by MTT assay. To explore the possible anticancer mechanism, studies on cell cycle, chromatin modifications, and apoptosis were conducted. VK3 alone led to a ~20% reduction in cell viability at 4 μM, while DF alone induced a 20% to 45% viability reduction at ≥ 500 μg/mL. A combination of VK3 (4 μM) and DF (300 μg/mL) led to a drastic >90% viability reduction, however. Cell cycle analysis indicated that VK3/DF treatment induced a G1 cell cycle arrest, accompanied by the up-regulation of p21(WAF1) and p27(Kip1). Histone deacetylase (HDAC) was also significantly (~60%) inactivated, indicating chromatin modifications. In addition, Western blot analysis revealed that the up-regulation of Bax and activation of poly-(ADP-ribose)-polymerase (PARP) were seen in VK3/DF-treated cells, indicating induction of apoptosis. The combination of VK3 and DF can lead to a profound reduction in ACHN cell viability, through a p21(WAF1)-mediated G1 cell cycle arrest, and ultimately induces apoptosis. Therefore, the combination of VK3/DF may have clinical implications as an alternative, improved therapeutic modality for advanced RCC.
Targeted adenovirus mediated inhibition of NF-κB-dependent inflammatory gene expression in endothelial cells in vitro and in vivo.

Science.gov (United States)

Kułdo, J M; Ásgeirsdóttir, S A; Zwiers, P J; Bellu, A R; Rots, M G; Schalk, J A C; Ogawara, K I; Trautwein, C; Banas, B; Haisma, H J; Molema, G; Kamps, J A A M

2013-02-28

In chronic inflammatory diseases the endothelium expresses mediators responsible for harmful leukocyte infiltration. We investigated whether targeted delivery of a therapeutic transgene that inhibits nuclear factor κB signal transduction could silence the proinflammatory activation status of endothelial cells. For this, an adenovirus encoding dominant-negative IκB (dnIκB) as a therapeutic transgene was employed. Selectivity for the endothelial cells was achieved by introduction of antibodies specific for inflammatory endothelial adhesion molecules E-selectin or VCAM-1 chemically linked to the virus via polyethylene glycol. In vitro, the retargeted adenoviruses selectively infected cytokine-activated endothelial cells to express functional transgene. The comparison of transductional capacity of both retargeted viruses revealed that E-selectin based transgene delivery exerted superior pharmacological effects. Targeted delivery mediated dnIκB transgene expression in endothelial cells inhibited the induced expression of several inflammatory genes, including adhesion molecules, cytokines, and chemokines. In vivo, in mice suffering from glomerulonephritis, E-selectin-retargeted adenovirus selectively homed in the kidney to microvascular glomerular endothelium. Subsequent downregulation of endothelial adhesion molecule expression 2 days after induction of inflammation demonstrated the pharmacological potential of this gene therapy approach. The data justify further studies towards therapeutic virus design and optimization of treatment schedules to investigate their capacity to interfere with inflammatory disease progression. Copyright © 2012 Elsevier B.V. All rights reserved.
Effects of Neuropeptide Y on Stem Cells and Their Potential Applications in Disease Therapy

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Song Peng

2017-01-01

Full Text Available Neuropeptide Y (NPY, a 36-amino acid peptide, is widely distributed in the central and peripheral nervous systems and other peripheral tissues. It takes part in regulating various biological processes including food intake, circadian rhythm, energy metabolism, and neuroendocrine secretion. Increasing evidence indicates that NPY exerts multiple regulatory effects on stem cells. As a kind of primitive and undifferentiated cells, stem cells have the therapeutic potential to replace damaged cells, secret paracrine molecules, promote angiogenesis, and modulate immunity. Stem cell-based therapy has been demonstrated effective and considered as one of the most promising treatments for specific diseases. However, several limitations still hamper its application, such as poor survival and low differentiation and integration rates of transplanted stem cells. The regulatory effects of NPY on stem cell survival, proliferation, and differentiation may be helpful to overcome these limitations and facilitate the application of stem cell-based therapy. In this review, we summarized the regulatory effects of NPY on stem cells and discussed their potential applications in disease therapy.
Dendritic cell-based vaccination in cancer: therapeutic implications emerging from murine models

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Soledad eMac Keon

2015-05-01

Full Text Available Dendritic cells (DCs play a pivotal role in the orchestration of immune responses, and are thus key targets in cancer vaccine design. Since the 2010 FDA approval of the first cancer DC-based vaccine (Sipuleucel T there has been a surge of interest in exploiting these cells as a therapeutic option for the treatment of tumors of diverse origin. In spite of the encouraging results obtained in the clinic, many elements of DC-based vaccination strategies need to be optimized. In this context, the use of experimental cancer models can help direct efforts towards an effective vaccine design. This paper reviews recent findings in murine models regarding the antitumoral mechanisms of DC-based vaccination, covering issues related to antigen sources, the use of adjuvants and maturing agents, and the role of DC subsets and their interaction in the initiation of antitumoral immune responses. The summary of such diverse aspects will highlight advantages and drawbacks in the use of murine models, and contribute to the design of successful DC-based translational approaches for cancer treatment.
How to optimize therapeutic ratio in brachytherapy of head and neck squamous cell carcinoma?

International Nuclear Information System (INIS)

Mazeron, J.J.; Simon, J.M.; Hardiman, C.; Gerbaulet, A.

1998-01-01

Considerable experience has been accumulated with low dose rate (LDR) brachytherapy in the treatment of squamous cell carcinoma of the oral cavity and oropharynx, 4 cm or less in diameter. Recent analysis of large clinical series provided data indicating that modalities of LDR brachytherapy should be optimized in treating these tumours for increasing therapeutic ratio. LDR brachytherapy is now challenged by high dose rate (HDR) brachytherapy and pulsed dose rate (PDR) brachytherapy. Preliminary results obtained with the last two modalities are discussed in comparison with those achieved with LDR brachytherapy. (orig.)
Bladder Cancer Stem-Like Cells: Their Origin and Therapeutic Perspectives

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Tomokazu Ohishi

2015-12-01

Full Text Available Bladder cancer (BC, the most common cancer arising from the human urinary tract, consists of two major clinicopathological phenotypes: muscle-invasive bladder cancer (MIBC and non-muscle-invasive bladder cancer (NMIBC. MIBC frequently metastasizes and is associated with an unfavorable prognosis. A certain proportion of patients with metastatic BC can achieve a remission with systemic chemotherapy; however, the disease relapses in most cases. Evidence suggests that MIBC comprises a small population of cancer stem cells (CSCs, which may be resistant to these treatments and may be able to form new tumors in the bladder or other organs. Therefore, the unambiguous identification of bladder CSCs and the development of targeted therapies are urgently needed. Nevertheless, it remains unclear where bladder CSCs originate and how they are generated. We review recent studies on bladder CSCs, specifically focusing on their proposed origin and the possible therapeutic options based on the CSC theory.
Bcl-xL Genetic Modification Enhanced the Therapeutic Efficacy of Mesenchymal Stem Cell Transplantation in the Treatment of Heart Infarction.

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Xue, Xiaodong; Liu, Yu; Zhang, Jian; Liu, Tao; Yang, Zhonglu; Wang, Huishan

2015-01-01

Objectives. Low survival rate of mesenchymal stem cells (MSCs) severely limited the therapeutic efficacy of cell therapy in the treatment of myocardial infarction (MI). Bcl-xL genetic modification might enhance MSC survival after transplantation. Methods. Adult rat bone marrow MSCs were modified with human Bcl-xL gene (hBcl-xL-MSCs) or empty vector (vector-MSCs). MSC apoptosis and paracrine secretions were characterized using flow cytometry, TUNEL, and ELISA in vitro. In vivo, randomized adult rats with MI received myocardial injections of one of the three reagents: hBcl-xL-MSCs, vector-MSCs, or culture medium. Histochemistry, TUNEL, and echocardiography were carried out to evaluate cell engraftment, apoptosis, angiogenesis, scar formation, and cardiac functional recovery. Results. In vitro, cell apoptosis decreased 43%, and vascular endothelial growth factor (VEGF), insulin-like growth factor-1 (IGF-1), and plate-derived growth factor (PDGF) increased 1.5-, 0.7-, and 1.2-fold, respectively, in hBcl-xL-MSCs versus wild type and vector-MSCs. In vivo, cell apoptosis decreased 40% and 26% in hBcl-xL-MSC group versus medium and vector-MSC group, respectively. Similar results were observed in cell engraftment, angiogenesis, scar formation, and cardiac functional recovery. Conclusions. Genetic modification of MSCs with hBcl-xL gene could be an intriguing strategy to improve the therapeutic efficacy of cell therapy in the treatment of heart infarction.
Fucoxanthin exerts differing effects on 3T3-L1 cells according to differentiation stage and inhibits glucose uptake in mature adipocytes

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Kang, Seong-Il; Ko, Hee-Chul; Shin, Hye-Sun; Kim, Hyo-Min; Hong, Youn-Suk; Lee, Nam-Ho; Kim, Se-Jae

2011-01-01

Highlights: → Fucoxanthin enhances 3T3-L1 adipocyte differentiation at an early stage. → Fucoxanthin inhibits 3T3-L1 adipocyte differentiation at intermediate and late stages. → Fucoxanthin attenuates glucose uptake by inhibiting the phosphorylation of IRS in mature 3T3-L1 adipocytes. → Fucoxanthin exerts its anti-obesity effect by inhibiting the differentiation of adipocytes at both intermediate and late stages, as well as glucose uptake in mature adipocytes. -- Abstract: Progression of 3T3-L1 preadipocyte differentiation is divided into early (days 0-2, D0-D2), intermediate (days 2-4, D2-D4), and late stages (day 4 onwards, D4-). In this study, we investigated the effects of fucoxanthin, isolated from the edible brown seaweed Petalonia binghamiae, on adipogenesis during the three differentiation stages of 3T3-L1 preadipocytes. When fucoxanthin was applied during the early stage of differentiation (D0-D2), it promoted 3T3-L1 adipocyte differentiation, as evidenced by increased triglyceride accumulation. At the molecular level, fucoxanthin increased protein expression of peroxisome proliferator-activated receptor γ (PPARγ), CCAAT/enhancer-binding protein α (C/EBPα), sterol regulatory element-binding protein 1c (SREBP1c), and aP2, and adiponectin mRNA expression, in a dose-dependent manner. However, it reduced the expression of PPARγ, C/EBPα, and SREBP1c during the intermediate (D2-D4) and late stages (D4-D7) of differentiation. It also inhibited the uptake of glucose in mature 3T3-L1 adipocytes by reducing the phosphorylation of insulin receptor substrate 1 (IRS-1). These results suggest that fucoxanthin exerts differing effects on 3T3-L1 cells of different differentiation stages and inhibits glucose uptake in mature adipocytes.
Ref-1/APE1 as a Transcriptional Regulator and Novel Therapeutic Target in Pediatric T-cell Leukemia.

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Ding, Jixin; Fishel, Melissa L; Reed, April M; McAdams, Erin; Czader, Magdalena B; Cardoso, Angelo A; Kelley, Mark R

2017-07-01

The increasing characterization of childhood acute lymphoblastic leukemia (ALL) has led to the identification of multiple molecular targets but has yet to translate into more effective targeted therapies, particularly for high-risk, relapsed T-cell ALL. Searching for master regulators controlling multiple signaling pathways in T-ALL, we investigated the multifunctional protein redox factor-1 (Ref-1/APE1), which acts as a signaling "node" by exerting redox regulatory control of transcription factors important in leukemia. Leukemia patients' transcriptome databases showed increased expression in T-ALL of Ref-1 and other genes of the Ref-1/SET interactome. Validation studies demonstrated that Ref-1 is expressed in high-risk leukemia T cells, including in patient biopsies. Ref-1 redox function is active in leukemia T cells, regulating the Ref-1 target NF-κB, and inhibited by the redox-selective Ref-1 inhibitor E3330. Ref-1 expression is not regulated by Notch signaling, but is upregulated by glucocorticoid treatment. E3330 disrupted Ref-1 redox activity in functional studies and resulted in marked inhibition of leukemia cell viability, including T-ALL lines representing different genotypes and risk groups. Potent leukemia cell inhibition was seen in primary cells from ALL patients, relapsed and glucocorticoid-resistant T-ALL cells, and cells from a murine model of Notch-induced leukemia. Ref-1 redox inhibition triggered leukemia cell apoptosis and downregulation of survival genes regulated by Ref-1 targets. For the first time, this work identifies Ref-1 as a novel molecular effector in T-ALL and demonstrates that Ref-1 redox inhibition results in potent inhibition of leukemia T cells, including relapsed T-ALL. These data also support E3330 as a specific Ref-1 small-molecule inhibitor for leukemia. Mol Cancer Ther; 16(7); 1401-11. ©2017 AACR . ©2017 American Association for Cancer Research.
The relative contribution of paracine effect versus direct differentiation on adipose-derived stem cell transplantation mediated cardiac repair.

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Dezhong Yang

Full Text Available BACKGROUND: Recent studies have demonstrated that transplantation of adipose-derived stem cell (ADSC can improve cardiac function in animal models of myocardial infarction (MI. However, the mechanisms underlying the beneficial effect are not fully understood. In this study, we characterized the paracrine effect of transplanted ADSC and investigated its relative importance versus direct differentiation in ADSC transplantation mediated cardiac repair. METHODOLOGY/PRINCIPAL FINDINGS: MI was experimentally induced in mice by ligation of the left anterior descending coronary artery. Either human ADSC, conditioned medium (CM collected from the same amount of ADSC or control medium was injected into the peri-infarct region immediately after MI. Compared with the control group, both ADSC and ADSC-CM significantly reduced myocardial infarct size and improved cardiac function. The therapeutic efficacy of ADSC was moderately superior to ADSC-CM. ADSC-CM significantly reduced cardiomyocyte apoptosis in the infarct border zone, to a similar degree with ADSC treatment. ADSC enhanced angiogenesis in the infarct border zone, but to a stronger degree than that seen in the ADSC-CM treatment. ADSC was able to differentiate to endothelial cell and smooth muscle cell in post-MI heart; these ADSC-derived vascular cells amount to about 9% of the enhanced angiogenesis. No cardiomyocyte differentiated from ADSC was found. CONCLUSIONS: ADSC-CM is sufficient to improve cardiac function of infarcted hearts. The therapeutic function of ADSC transplantation is mainly induced by paracrine-mediated cardioprotection and angiogenesis, while ADSC differentiation contributes a minor benefit by being involved in angiogenesis. Highlights 1 ADSC-CM is sufficient to exert a therapeutic potential. 2. ADSC was able to differentiate to vascular cells but not cardiomyocyte. 3. ADSC derived vascular cells amount to about 9% of the enhanced angiogenesis. 4. Paracrine effect is the major

Multiple therapeutic effects of progranulin on experimental acute ischaemic stroke.

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Kanazawa, Masato; Kawamura, Kunio; Takahashi, Tetsuya; Miura, Minami; Tanaka, Yoshinori; Koyama, Misaki; Toriyabe, Masafumi; Igarashi, Hironaka; Nakada, Tsutomu; Nishihara, Masugi; Nishizawa, Masatoyo; Shimohata, Takayoshi

2015-07-01

In the central nervous system, progranulin, a glycoprotein growth factor, plays a crucial role in maintaining physiological functions, and progranulin gene mutations cause TAR DNA-binding protein-43-positive frontotemporal lobar degeneration. Although several studies have reported that progranulin plays a protective role against ischaemic brain injury, little is known about temporal changes in the expression level, cellular localization, and glycosylation status of progranulin after acute focal cerebral ischaemia. In addition, the precise mechanisms by which progranulin exerts protective effects on ischaemic brain injury remains unknown. Furthermore, the therapeutic potential of progranulin against acute focal cerebral ischaemia, including combination treatment with tissue plasminogen activator, remains to be elucidated. In the present study, we aimed to determine temporal changes in the expression and localization of progranulin after ischaemia as well as the therapeutic effects of progranulin on ischaemic brain injury using in vitro and in vivo models. First, we demonstrated a dynamic change in progranulin expression in ischaemic Sprague-Dawley rats, including increased levels of progranulin expression in microglia within the ischaemic core, and increased levels of progranulin expression in viable neurons as well as induction of progranulin expression in endothelial cells within the ischaemic penumbra. We also demonstrated that the fully glycosylated mature secretory isoform of progranulin (∼88 kDa) decreased, whereas the glycosylated immature isoform of progranulin (58-68 kDa) markedly increased at 24 h and 72 h after reperfusion. In vitro experiments using primary cells from C57BL/6 mice revealed that the glycosylated immature isoform was secreted only from the microglia. Second, we demonstrated that progranulin could protect against acute focal cerebral ischaemia by a variety of mechanisms including attenuation of blood-brain barrier disruption
Mechanisms of Plasma Therapeutics

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Graves, David

2015-09-01

In this talk, I address research directed towards biomedical applications of atmospheric pressure plasma such as sterilization, surgery, wound healing and anti-cancer therapy. The field has seen remarkable growth in the last 3-5 years, but the mechanisms responsible for the biomedical effects have remained mysterious. It is known that plasmas readily create reactive oxygen species (ROS) and reactive nitrogen species (RNS). ROS and RNS (or RONS), in addition to a suite of other radical and non-radical reactive species, are essential actors in an important sub-field of aerobic biology termed ``redox'' (or oxidation-reduction) biology. It is postulated that cold atmospheric plasma (CAP) can trigger a therapeutic shielding response in tissue in part by creating a time- and space-localized, burst-like form of oxy-nitrosative stress on near-surface exposed cells through the flux of plasma-generated RONS. RONS-exposed surface layers of cells communicate to the deeper levels of tissue via a form of the ``bystander effect,'' similar to responses to other forms of cell stress. In this proposed model of CAP therapeutics, the plasma stimulates a cellular survival mechanism through which aerobic organisms shield themselves from infection and other challenges.
The Influence of a Bout of Exertion on Novice Barefoot Running Dynamics.

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Hashish, Rami; Samarawickrame, Sachithra D; Baker, Lucinda; Salem, George J

2016-06-01

Barefoot, forefoot strike (FFS) running has recently risen in popularity. Relative to shod, rear-foot strike (RFS) running, employing a FFS is associated with heightened triceps surae muscle activation and ankle mechanical demand. Novice to this pattern, it is plausible that habitually shod RFS runners exhibit fatigue to the triceps surae when acutely transitioning to barefoot running, thereby limiting their ability to attenuate impact. Therefore, the purpose was to determine how habitually shod RFS runners respond to an exertion bout of barefoot running, operationally defined as a barefoot run 20% of mean daily running distance. Twenty-one RFS runners performed novice barefoot running, before and after exertion. Ankle peak torque, triceps surae EMG median frequency, foot-strike patterns, joint energy absorption, and loading rates were evaluated. Of the 21 runners, 6 maintained a RFS, 10 adopted a mid-foot strike (MFS), and 5 adopted a FFS during novice barefoot running. In-response to exertion, MFS and FFS runners demonstrated reductions in peak torque, median frequency, and ankle energy absorption, and an increase in loading rate. RFS runners demonstrated reductions in peak torque and loading rate. These results indicate that a short bout of running may elicit fatigue to novice barefoot runners, limiting their ability to attenuate impact. Key pointsIn response to exertion, novice barefoot runners demonstrate fatigue to their soleus.In response to exertion, novice barefoot runners demonstrate a reduction in ankle energy absorptionIn response to exertion, novice barefoot runners demonstrate an increase in loading rate.
20 CFR 220.132 - Physical exertion requirements.

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2010-04-01

... 20 Employees' Benefits 1 2010-04-01 2010-04-01 false Physical exertion requirements. 220.132 Section 220.132 Employees' Benefits RAILROAD RETIREMENT BOARD REGULATIONS UNDER THE RAILROAD RETIREMENT... of walking and standing is often necessary in carrying out job duties. Jobs are sedentary if walking...
Melatonin-Based Therapeutics for Neuroprotection in Stroke

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Cesar V. Borlongan

2013-04-01

Full Text Available The present review paper supports the approach to deliver melatonin and to target melatonin receptors for neuroprotection in stroke. We discuss laboratory evidence demonstrating neuroprotective effects of exogenous melatonin treatment and transplantation of melatonin-secreting cells in stroke. In addition, we describe a novel mechanism of action underlying the therapeutic benefits of stem cell therapy in stroke, implicating the role of melatonin receptors. As we envision the clinical entry of melatonin-based therapeutics, we discuss translational experiments that warrant consideration to reveal an optimal melatonin treatment strategy that is safe and effective for human application.
Motivational incentives lead to a strong increase in lateral prefrontal activity after self-control exertion.

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Luethi, Matthias S; Friese, Malte; Binder, Julia; Boesiger, Peter; Luechinger, Roger; Rasch, Björn

2016-10-01

Self-control is key to success in life. Initial acts of self-control temporarily impair subsequent self-control performance. Why such self-control failures occur is unclear, with prominent models postulating a loss of a limited resource vs a loss of motivation, respectively. Here, we used functional magnetic resonance imaging to identify the neural correlates of motivation-induced benefits on self-control. Participants initially exerted or did not exert self-control. In a subsequent Stroop task, participants performed worse after exerting self-control, but not if they were motivated to perform well by monetary incentives. On the neural level, having exerted self-control resulted in decreased activation in the left inferior frontal gyrus. Increasing motivation resulted in a particularly strong activation of this area specifically after exerting self-control. Thus, after self-control exertion participants showed more prefrontal neural activity without improving performance beyond baseline level. These findings suggest that impaired performance after self-control exertion may not exclusively be due to a loss of motivation. © The Author (2016). Published by Oxford University Press. For Permissions, please email: journals.permissions@oup.com.
Regulatory T cells, maternal-foetal immune tolerance and recurrent miscarriage: new therapeutic challenging opportunities.

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Alijotas-Reig, Jaume; Melnychuk, Taisiia; Gris, Josep Maria

2015-03-15

Because maternal alloreactive lymphocytes are not depleted during pregnancy, local and/or systemic mechanisms have to play a key role in altering the maternal immune response. Peripheral T regulatory cells (pTregs) at the maternal-foetal interface are necessary in situ to prevent early abortion, but only those pTregs that have been previously exposed to paternal alloantigens. It has been showed that pregnancy selectively stimulates the accumulation of maternal Foxp3(+)CD4(+)CD25(+) (Foxp3Tregs) cells with foetal specificity. Interestingly, after delivery, foetal-specific pTregs persist at elevated levels, maintain tolerance to pre-existing foetal antigen, and rapidly re-accumulate during subsequent pregnancy. pTreg up-regulation could be hypothesized as a possible future therapeutic strategy in humans. Copyright © 2014 Elsevier España, S.L.U. All rights reserved.
Downregulation of miR-210 expression inhibits proliferation, induces apoptosis and enhances radiosensitivity in hypoxic human hepatoma cells in vitro

International Nuclear Information System (INIS)

Yang, Wei; Sun, Ting; Cao, Jianping; Liu, Fenju; Tian, Ye; Zhu, Wei

2012-01-01

Hypoxia is a common feature of solid tumors and an important contributor to tumor radioresistance. miR-210 is the most consistently and robustly induced microRNA under hypoxia in different types of tumor cells and normal cells. In the present study, to explore the feasibility of miR-210 as an effective therapeutic target, lentiviral-mediated anti-sense miR-210 gene transfer technique was employed to downregulate miR-210 expression in hypoxic human hepatoma SMMC-7721, HepG2 and HuH7 cells, and phenotypic changes of which were analyzed. Hypoxia led to an increased hypoxia inducible factor-1α (HIF-1α) and miR-210 expression and cell arrest in the G 0 /G 1 phase in all cell lines. miR-210 downregulation significantly suppressed cell viability, induced cell arrest in the G 0 /G 1 phase, increased apoptotic rate and enhanced radiosensitivity in hypoxic human hepatoma cells. Moreover, apoptosis-inducing factor, mitochondrion-associated, 3 (AIFM3) was identified as a direct target gene of miR-210. AIFM3 downregulation by siRNA attenuated radiation induced apoptosis in miR-210 downregulated hypoxic human hepatoma cells. Taken together, these data suggest that miR-210 might be a potential therapeutic target and specific inhibition of miR-210 expression in combination with radiotherapy might be expected to exert strong anti-tumor effect on hypoxic human hepatoma cells. -- Highlights: ► miR-210 downregulation radiosensitized hypoxic hepatoma. ► AIFM3 was identified as a direct target gene of miR-210. ► miR-210 might be a therapeutic target to hypoxic hepatoma.
Implementation of nanoparticles in therapeutic radiation oncology

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Beeler, Erik; Gabani, Prashant; Singh, Om V.

2017-05-01

Development and progress of cancer is a very complex disease process to comprehend because of the multiple changes in cellular physiology, pathology, and pathophysiology resulting from the numerous genetic changes from which cancer originates. As a result, most common treatments are not directed at the molecular level but rather at the tissue level. While personalized care is becoming an increasingly aim, the most common cancer treatments are restricted to chemotherapy, radiation, and surgery, each of which has a high likelihood of resulting in rather severe adverse side effects. For example, currently used radiation therapy does not discriminate between normal and cancerous cells and greatly relies on the external targeting of the radiation beams to specific cells and organs. Because of this, there is an immediate need for the development of new and innovative technologies that help to differentiate tumor cells and micrometastases from normal cells and facilitate the complete destruction of those cells. Recent advancements in nanoscience and nanotechnology have paved a way for the development of nanoparticles (NPs) as multifunctional carriers to deliver therapeutic radioisotopes for tumor targeted radiation therapy, to monitor their delivery, and improve the therapeutic index of radiation and tumor response to the treatment. The application of NPs in radiation therapy has aimed to improve outcomes in radiation therapy by increasing therapeutic effect in tumors and reducing toxicity on normal tissues. Because NPs possess unique properties, such as preferential accumulation in tumors and minimal uptake in normal tissues, it makes them ideal for the delivery of radiotherapy. This review provides an overview of the recent development of NPs for carrying and delivering therapeutic radioisotopes for systemic radiation treatment for a variety of cancers in radiation oncology.
Real-time cellular and molecular dynamics of bi-metallic self-therapeutic nanoparticle in cancer cells

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Vishwakarma, Sandeep Kumar; Bardia, Avinash; Lakkireddy, Chandrakala; Paspala, Syed Ameer Basha; Habeeb, Md. Aejaz; Khan, Aleem Ahmed

2018-02-01

Since last decades various kinds of nanoparticles have been functionalized to improve their biomedical applications. However, the biological effect of un-modified/non-functionalized bi-metallic magnetic nanoparticles remains under investigated. Herein we demonstrate a multifaceted non-functionalized bi-metallic inorganic Gd-SPIO nanoparticle which passes dual high MRI contrast and can kill the cancer cells through several mechanisms. The results of the present study demonstrate that Gd-SPIO nanoparticles have potential to induce cancer cell death by production of reactive oxygen species and apoptotic events. Furthermore, Gd-SPIO nanoparticles also enhance the expression levels of miRNA-199a and miRNA-181a-7p which results in decreased levels of cancer markers such as C-met, TGF-β and hURP. One very interesting finding of this study reveals side scatter-based real-time analysis of nanoparticle uptake in cancer cells using flow cytometry analysis. In conclusion, this study paves a way for future investigation of un-modified inorganic nanoparticles to purport enhanced therapeutic effect in combination with potential anti-tumor drugs/molecules in cancer cells.
Immunotherapeutic strategies targeting Natural killer T cell responses in cancer

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Shissler, Susannah C.; Bollino, Dominique R.; Tiper, Irina V.; Bates, Joshua; Derakhshandeh, Roshanak; Webb, Tonya J.

2017-01-01

Natural killer T (NKT) cells are a unique subset of lymphocytes that bridge the innate and adaptive immune system. NKT cells possess a classic αβ T-cell receptor (TCR) that is able to recognize self and foreign glycolipid antigens presented by the nonclassical class I major histocompatibility complex (MHC) molecule, CD1d. Type I NKT cells (referred to as invariant NKT cells) express a semi-invariant Vα14Jα18 TCR in mice and Vα24Jα18 TCR in humans. Type II NKT cells are CD1d-restricted T cells that express a more diverse set of TCR α chains. The two types of NKT cells often exert opposing effects especially in tumor immunity, where Type II cells generally suppress tumor immunity while Type I NKT cells can enhance antitumor immune responses. In this review, we focus on the role of NKT cells in cancer. We discuss their effector and suppressive functions, as well as describe preclinical and clinical studies utilizing therapeutic strategies focused on harnessing their potent anti-tumor effector functions, and conclude with a discussion on potential next steps for the utilization of NKT cell targeted therapies for the treatment of cancer. PMID:27393665
Therapeutic Effect of Bone Marrow Mesenchymal Stem Cells on Laser-Induced Retinal Injury in Mice

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Yuanfeng Jiang

2014-05-01

Full Text Available Stem cell therapy has shown encouraging results for neurodegenerative diseases. The retina provides a convenient locus to investigate stem cell functions and distribution in the nervous system. In the current study, we investigated the therapeutic potential of bone marrow mesenchymal stem cells (MSCs by systemic transplantation in a laser-induced retinal injury model. MSCs from C57BL/6 mice labeled with green fluorescent protein (GFP were injected via the tail vein into mice after laser photocoagulation. We found that the average diameters of laser spots and retinal cell apoptosis were decreased in the MSC-treated group. Interestingly, GFP-MSCs did not migrate to the injured retina. Further examination revealed that the mRNA expression levels of glial fibrillary acidic protein and matrix metalloproteinase-2 were lower in the injured eyes after MSC transplantation. Our results suggest that intravenously injected MSCs have the ability to inhibit retinal cell apoptosis, reduce the inflammatory response and limit the spreading of damage in the laser-injured retina of mice. Systemic MSC therapy might play a role in neuroprotection, mainly by regulation of the intraocular microenvironment.
Influence of the number and interval of treatment cycles on cytokine-induced killer cells and their adjuvant therapeutic effects in advanced non-small-cell lung cancer (NSCLC).

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Gu, Yuanlong; Lv, Huimin; Zhao, Juan; Li, Qi; Mu, Guannan; Li, Jiade; Wuyang, Jiazi; Lou, Ge; Wang, Ruitao; Zhang, Yanqiao; Huang, Xiaoyi

2017-09-01

Cytokine-induced killer (CIK) cells have important therapeutic effects in adoptive cell transfer (ACT) for the treatment of various malignancies. In this study, we focused on in vitro expansion of CIK cells and their clinical efficacy in combination with chemotherapy in patients with advanced non-small-cell lung cancer (NSCLC). A total of 64 patients with NSCLC (enrolled from 2011 to 2012), including 32 patients who received chemotherapy alone or with sequential radiotherapy (conventional treatment, control group) and 32 patients who received conventional treatment and sequential CIK infusion (study group), were retrospectively analyzed. The time to progression (TTP), overall survival (OS) and adverse effects were analyzed and the phenotype of lymphocytes in CIK population was also determined by flow cytometry. After in vitro expansion, the average percentage of CIK cells was 26.35%. During the 54-month follow up, the median OS and TTP were significantly longer in the study group than in the control group (P=0.0189 and P=0.0129, respectively). The median OS of the ACT≥4cycles subgroup was significantly longer than that of the ACTcells in patients who received ≥4cycles of ACT was higher than that in patients treated with cells were difficult to expand in vitro in some patients after the first ACT cycle but became much easier as the treatment cycles increased monthly. Longer treatment interval negatively impacted the expansion of CIK cells. Systematic immune levels can be increasingly boosted by reinfusion of ACT. Conventional treatment plus CIK cells is an effective therapeutic strategy to prevent progression and prolong survival of patients with advanced NSCLC. Copyright © 2017. Published by Elsevier B.V.
Triterpenoids and Polysaccharide Fractions of Ganoderma tsugae Exert Different Effects on Antiallergic Activities

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Miaw-Ling Chen

2015-01-01

Full Text Available This study was to investigate antiallergic effects of triterpenoids (Gt-TRE and polysaccharide (Gt-PS extracts from Ganoderma tsugae, using mast cell line RBL-2H3, T cell line EL4, primary T cells, and transfected RAW264.7 macrophage cells. The results showed that histamine secreted from activated RBL-2H3 mast cells was significantly suppressed by Gt-TRE but not Gt-PS. Interleukin- (IL- 4 secreted from activated EL4 cells was significantly suppressed by Gt-TRE but not Gt-PS. Further primary CD4+ T cells cultures also confirmed that Gt-TRE (5~50 µg/mL significantly suppressed Th2 cytokines IL-4 and IL-5 secretions but had no effect on Th1 cytokines IL-2 and interferon (IFN-γ. Gt-PS did not affect IL-4 and IL-5 secretions until higher doses (400, 500 µg/mL and significantly suppressed IFNγ secretions but enhanced IL-2 at these high doses. The reporter gene assay indicated that Gt-TRE inhibited but Gt-PS enhanced the transcriptional activity of NF-κB in activated transfected RAW264.7 cells and transfected EL4 cells. IL-4 secreted by this transfected EL-4 cells was also significantly decreased by Gt-TRE but not by Gt-PS, suggesting that these two fractions may exert different effects on NF-κB related cytokines expression. These data suggested that triterpenoids fraction of Ganoderma tsugae might be the main constituents to alleviate allergic asthma.
Cerium oxide nanoparticles, combining antioxidant and UV shielding properties, prevent UV-induced cell damage and mutagenesis

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Caputo, Fanny; de Nicola, Milena; Sienkiewicz, Andrzej; Giovanetti, Anna; Bejarano, Ignacio; Licoccia, Silvia; Traversa, Enrico; Ghibelli, Lina

2015-09-01

Efficient inorganic UV shields, mostly based on refracting TiO2 particles, have dramatically changed the sun exposure habits. Unfortunately, health concerns have emerged from the pro-oxidant photocatalytic effect of UV-irradiated TiO2, which mediates toxic effects on cells. Therefore, improvements in cosmetic solar shield technology are a strong priority. CeO2 nanoparticles are not only UV refractors but also potent biological antioxidants due to the surface 3+/4+ valency switch, which confers anti-inflammatory, anti-ageing and therapeutic properties. Herein, UV irradiation protocols were set up, allowing selective study of the extra-shielding effects of CeO2vs. TiO2 nanoparticles on reporter cells. TiO2 irradiated with UV (especially UVA) exerted strong photocatalytic effects, superimposing their pro-oxidant, cell-damaging and mutagenic action when induced by UV, thereby worsening the UV toxicity. On the contrary, irradiated CeO2 nanoparticles, via their Ce3+/Ce4+ redox couple, exerted impressive protection on UV-treated cells, by buffering oxidation, preserving viability and proliferation, reducing DNA damage and accelerating repair; strikingly, they almost eliminated mutagenesis, thus acting as an important tool to prevent skin cancer. Interestingly, CeO2 nanoparticles also protect cells from the damage induced by irradiated TiO2, suggesting that these two particles may also complement their effects in solar lotions. CeO2 nanoparticles, which intrinsically couple UV shielding with biological and genetic protection, appear to be ideal candidates for next-generation sun shields.
PRX1 knockdown potentiates vitamin K3 toxicity in cancer cells: a potential new therapeutic perspective for an old drug.

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He, Tiantian; Hatem, Elie; Vernis, Laurence; Lei, Ming; Huang, Meng-Er

2015-12-21

Many promising anticancer molecules are abandoned during the course from bench to bedside due to lack of clear-cut efficiency and/or severe side effects. Vitamin K3 (vitK3) is a synthetic naphthoquinone exhibiting significant in vitro and in vivo anticancer activity against multiple human cancers, and has therapeutic potential when combined with other anticancer molecules. The major mechanism for the anticancer activity of vitK3 is the generation of cytotoxic reactive oxygen species (ROS). We thus reasoned that a rational redox modulation of cancer cells could enhance vitK3 anticancer efficiency. Cancer cell lines with peroxiredoxin 1 (PRX1) gene transiently or stably knocked-down and corresponding controls were exposed to vitK3 as well as a set of anticancer molecules, including vinblastine, taxol, doxorubicin, daunorubicin, actinomycin D and 5-fluorouracil. Cytotoxic effects and cell death events were evaluated by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT)-based assay, cell clonogenic assay, measurement of mitochondrial membrane potential and annexin V/propidium iodide double staining. Global ROS accumulation and compartment-specific H2O2 generation were determined respectively by a redox-sensitive chemical probe and H2O2-sensitive sensor HyPer. Oxidation of endogenous antioxidant proteins including TRX1, TRX2 and PRX3 was monitored by redox western blot. We observed that the PRX1 knockdown in HeLa and A549 cells conferred enhanced sensitivity to vitK3, reducing substantially the necessary doses to kill cancer cells. The same conditions (combination of vitK3 and PRX1 knockdown) caused little cytotoxicity in non-cancerous cells, suggesting a cancer-cell-selective property. Increased ROS accumulation had a crucial role in vitK3-induced cell death in PRX1 knockdown cells. The use of H2O2-specific sensors HyPer revealed that vitK3 lead to immediate accumulation of H2O2 in the cytosol, nucleus, and mitochondrial matrix. PRX1 silencing
Chlorogenic acid complex (CGA7, standardized extract from green coffee beans exerts anticancer effects against cultured human colon cancer HCT-116 cells

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K. Gouthamchandra

2017-09-01

Full Text Available Coffee is commonly consumed beverage in the world and it has been suggested to have beneficial effect. Chlorogenic acids (CGAs are main ingredient of coffee beans which has been extensively used in nutraceuticals and medicine. Recently, various therapeutic effects of chlorogenic acids have been investigated. However, there are limited studies to investigate its anticancer properties. In the present study, we have used chlorogenic acid complex (CGA7 a decaffeinated water soluble green coffee bean extract to evaluate its cytotoxic effect on human and mouse cancer cell lines by using different approaches. From our results we found CGA7 treatment induces cell death in a dose and time dependent manner in different cancer cell lines. Further, CGA7 induced apoptosis was characterized by DNA fragmentation, PARP-1 cleavage, caspase-9 activation, and down regulation of Bcl-2, an anti-apoptotic protein and up regulation of pro-apoptotic protein BAX. Overall findings indicated that CGA7 complex a potent anticancer molecule found in green coffee beans could be a safe bioactive ingredient for prevention of cancer.
Combination therapy with andrographolide and D-penicillamine enhanced therapeutic advantage over monotherapy with D-penicillamine in attenuating fibrogenic response and cell death in the periportal zone of liver in rats during copper toxicosis

International Nuclear Information System (INIS)

Roy, Dijendra Nath; Sen, Gargi; Chowdhury, Kaustav Dutta; Biswas, Tuli

2011-01-01

Long treatment regime with D-penicillamine is needed before it can exert clinically meaningful benefits in the treatment of copper toxicosis. The consequence of long-term D-penicillamine treatment is associated with numerous side effects. The limitations of D-penicillamine monotherapy prompted us to search for more effective treatment strategies that could decrease the duration of D-penicillamine therapy. The present study was designed to evaluate the therapeutic potential of D-penicillamine in combination with another hepatoprotective drug, andrographolide in treatment of copper toxicosis in rats. D-penicillamine treatment led to the excretion of copper through urine. Addition of andrographolide to D-penicillamine regime appeared to increase protection of liver by increasing the biliary excretion of copper and reduction in cholestatic injury. The early removal of the causative agent copper during combination treatment was the most effective therapeutic intervention that contributed to the early rectification of fibrosis in liver. Combination treatment reduced Kupffer cells accumulation and TNFα production in liver of copper exposed rats. In particular, andrographolide mediated the anti-inflammatory effect by inhibiting the cytokine production. However, another possible mechanism of cytoprotection of andrographolide was decreasing mitochondrial production of superoxide anions that resulted in better restoration of mitochondrial dysfunction during combination therapy than monotherapy. Furthermore, ROS inhibition by combination regimen resulted in significant decline in activation of caspase cascade. Inhibition of caspases attenuated apoptosis of hepatocytes, induced by chronic copper exposure. In summary, this study suggested that added benefit of combination treatment over use of either agent alone in alleviating the hepatotoxicity and fibrosis associated with copper toxicosis.
A novel compound NSC745885 exerts an anti-tumor effect on tongue cancer SAS cells in vitro and in vivo.

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Yuan-Wu Chen

Full Text Available Oral squamous cell carcinoma (OSCC is a prevalent cancer, especially in developing countries. Anthracyclines and their anthraquinone derivatives, such as doxorubicin, exhibit a cell growth inhibitory effect and have been used as anti-cancer drugs for many years. However, the cardiotoxicity of anthracycline antibiotics is a major concern in their clinical application. NSC745885 is a novel compound synthesized from 1,2-diaminoanthraquinone, which subsequently reacts with thionyl chloride and triethylamine. The present study aimed to investigate the anti-oral cancer potential and the safety of NSC745885.We investigated the anti-cancer potential of NSC745885 in oral squamous carcinoma cell lines and in an in vivo oral cancer xenograft mouse model. The expression of apoptotic related genes were evaluated by real-time RT-PCR and western bloting, and the in vivo assessment of apoptotic marker were measured by immunohistochemical staining. The anti-tumor efficiency and safety between doxorubicin and NSC745885 were also compared.Our results demonstrated that NSC745885 exhibits anti-oral cancer activity through the induction of apoptosis in cancer cells and in tumor-bearing mice, and this treatment did not induce marked toxicity in experimental mice. This compound also exhibits a comparable anti-tumor efficiency and a higher safety in experimental mice when compared to doxorubicin.The data of this study provide evidence for NSC745885 as a potential novel therapeutic drug for the treatment of human OSCC.
Hypothermia broadens the therapeutic time window of mesenchymal stem cell transplantation for severe neonatal hypoxic ischemic encephalopathy.

Science.gov (United States)

Ahn, So Yoon; Chang, Yun Sil; Sung, Dong Kyung; Sung, Se In; Park, Won Soon

2018-05-16

Recently, we have demonstrated that concurrent hypothermia and mesenchymal stem cells (MSCs) transplantation synergistically improved severe neonatal hypoxic ischemic encephalopathy (HIE). The current study was designed to determine whether hypothermia could extend the therapeutic time window of MSC transplantation for severe neonatal HIE. To induce HIE, newborn rat pups were exposed to 8% oxygen for 2 h following unilateral carotid artery ligation on postnatal day (P) 7. After approving severe HIE involving >50% of the ipsilateral hemisphere volume, hypothermia (32 °C) for 2 days was started. MSCs were transplanted 2 days after HIE modeling. Follow-up brain MRI, sensorimotor function tests, assessment of inflammatory cytokines in the cerebrospinal fluid (CSF), and histological evaluation of peri-infarction area were performed. HIE induced progressively increasing brain infarction area over time, increased cell death, reactive gliosis and brain inflammation, and impaired sensorimotor function. All these damages observed in severe HIE showed better, robust improvement with a combination treatment of hypothermia and delayed MSC transplantation than with either stand-alone therapy. Hypothermia itself did not significantly reduce brain injury, but broadened the therapeutic time window of MSC transplantation for severe newborn HIE.

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