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Sample records for therapy induces autophagic

  1. N-Desmethyldauricine Induces Autophagic Cell Death in Apoptosis-Defective Cells via Ca(2+) Mobilization.

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    Law, Betty Y K; Mok, Simon W F; Chen, Juan; Michelangeli, Francesco; Jiang, Zhi-Hong; Han, Yu; Qu, Yuan Q; Qiu, Alena C L; Xu, Su-Wei; Xue, Wei-Wei; Yao, Xiao-Jun; Gao, Jia Y; Javed, Masood-Ul-Hassan; Coghi, Paolo; Liu, Liang; Wong, Vincent K W

    2017-01-01

    Resistance of cancer cells to chemotherapy remains a significant problem in oncology. Mechanisms regulating programmed cell death, including apoptosis, autophagy or necrosis, in the treatment of cancers have been extensively investigated over the last few decades. Autophagy is now emerging as an important pathway in regulating cell death or survival in cancer therapy. Recent studies demonstrated variety of natural small-molecules could induce autophagic cell death in apoptosis-resistant cancer cells, therefore, discovery of novel autophagic enhancers from natural products could be a promising strategy for treatment of chemotherapy-resistant cancer. By computational virtual docking analysis, biochemical assays, and advanced live-cell imaging techniques, we have identified N-desmethyldauricine (LP-4), isolated from rhizoma of Menispermum dauricum DC as a novel inducer of autophagy. LP-4 was shown to induce autophagy via the Ulk-1-PERK and Ca(2+)/Calmodulin-dependent protein kinase kinase β (CaMKKβ)-AMPK-mTOR signaling cascades, via mobilizing calcium release through inhibition of SERCA, and importantly, lead to autophagic cell death in a panel of cancer cells, apoptosis-defective and apoptosis-resistant cells. Taken together, this study provides detailed insights into the cytotoxic mechanism of a novel autophagic compound that targeting the apoptosis resistant cancer cells, and new implication on drug discovery from natural products for drug resistant cancer therapy.

  2. SWCNTs induced autophagic cell death in human bronchial epithelial cells.

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    Park, Eun-Jung; Zahari, Nur Elida M; Lee, Eun-Woo; Song, Jaewhan; Lee, Jae-Hyeok; Cho, Myung-Haing; Kim, Jae-Ho

    2014-04-01

    Carbon nanotubes are being actively introduced in electronics, computer science, aerospace, and other industries. Thus, the urgent need for toxicological studies on CNTs is mounting. In this study, we investigated the alterations in cellular response with morphological changes induced by single-walled carbon nanotubes (SWCNTs) in BEAS-2B cells, a human bronchial epithelial cell line. At 24h after exposure, SWCNTs rapidly decreased ATP production and cell viability as well a slight increase in the number of cells in the subG1 and G1 phases. In addition, SWCNTs increased the expression of superoxide dismutase (SOD)-1, but not SOD-2, and the number of cells generating ROS. The concentration of Cu and Zn ions also increased in a dose-dependent manner in cells exposed to SWCNTs. SWCNTs significantly enhanced the release of nitric oxide, interleukin (IL)-6, and IL-8 and up-regulated the expression of chemokine- and cytokine-related genes. Furthermore, the levels of autophagy-related genes, especially the DRAM1 gene, and the autophagosome formation-related proteins, were clearly up-regulated together with an increase of autophagosome-like vacuoles. Based on these results, we suggest that SWCNTs induce autophagic cell death through mitochondrial dysfunction and cytosolic damage in human bronchial epithelial cells. Copyright © 2014 Elsevier Ltd. All rights reserved.

  3. Bortezomib induces autophagic death in proliferating human endothelial cells

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    Belloni, Daniela; Veschini, Lorenzo [Myeloma Unit, Department of Oncology, IRCCS H San Raffaele, Milan (Italy); Foglieni, Chiara [Department of Cardiology, IRCCS H San Raffaele, Milan (Italy); Dell' Antonio, Giacomo [Department of Pathology, IRCCS H San Raffaele, Milan (Italy); Caligaris-Cappio, Federico [Myeloma Unit, Department of Oncology, IRCCS H San Raffaele, Milan (Italy); Universita Vita-Salute IRCCS H San Raffaele, Milan (Italy); Ferrarini, Marina [Myeloma Unit, Department of Oncology, IRCCS H San Raffaele, Milan (Italy); Ferrero, Elisabetta, E-mail: elisabetta.ferrero@hsr.it [Myeloma Unit, Department of Oncology, IRCCS H San Raffaele, Milan (Italy)

    2010-04-01

    The proteasome inhibitor Bortezomib has been approved for the treatment of relapsed/refractory multiple myeloma (MM), thanks to its ability to induce MM cell apoptosis. Moreover, Bortezomib has antiangiogenic properties. We report that endothelial cells (EC) exposed to Bortezomib undergo death to an extent that depends strictly on their activation state. Indeed, while quiescent EC are resistant to Bortezomib, the drug results maximally toxic in EC switched toward angiogenesis with FGF, and exerts a moderate effect on subconfluent HUVEC. Moreover, EC activation state deeply influences the death pathway elicited by Bortezomib: after treatment, angiogenesis-triggered EC display typical features of apoptosis. Conversely, death of subconfluent EC is preceded by ROS generation and signs typical of autophagy, including intense cytoplasmic vacuolization with evidence of autophagosomes at electron microscopy, and conversion of the cytosolic MAP LC3 I form toward the autophagosome-associated LC3 II form. Treatment with the specific autophagy inhibitor 3-MA prevents both LC3 I/LC3 II conversion and HUVEC cell death. Finally, early removal of Bortezomib is accompanied by the recovery of cell shape and viability. These findings strongly suggest that Bortezomib induces either apoptosis or autophagy in EC; interfering with the autophagic response may potentiate the antiangiogenic effect of the drug.

  4. The natural product peiminine represses colorectal carcinoma tumor growth by inducing autophagic cell death

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    Lyu, Qing [School of Life Sciences, Tsinghua University, Beijing, 100084 (China); Key Lab in Healthy Science and Technology, Division of Life Science, Graduate School at Shenzhen, Tsinghua University, Shenzhen, 518055 (China); Tou, Fangfang [Jiangxi Provincial Key Lab of Oncology Translation Medicine, Jiangxi Cancer Hospital, Nanchang, 330029 (China); Su, Hong; Wu, Xiaoyong [First Affiliated Hospital, Guiyang College of Traditional Chinese Medicine, Guiyang, 550002 (China); Chen, Xinyi [Department of Hematology and Oncology, Beijing University of Chinese Medicine, Beijing, 100029 (China); Zheng, Zhi, E-mail: zheng_sheva@hotmail.com [Jiangxi Provincial Key Lab of Oncology Translation Medicine, Jiangxi Cancer Hospital, Nanchang, 330029 (China)

    2015-06-19

    Autophagy is evolutionarily conservative in eukaryotic cells that engulf cellular long-lived proteins and organelles, and it degrades the contents through fusion with lysosomes, via which the cell acquires recycled building blocks for the synthesis of new molecules. In this study, we revealed that peiminine induces cell death and enhances autophagic flux in colorectal carcinoma HCT-116 cells. We determined that peiminine enhances the autophagic flux by repressing the phosphorylation of mTOR through inhibiting upstream signals. Knocking down ATG5 greatly reduced the peiminine-induced cell death in wild-type HCT-116 cells, while treating Bax/Bak-deficient cells with peiminine resulted in significant cell death. In summary, our discoveries demonstrated that peiminine represses colorectal carcinoma cell proliferation and cell growth by inducing autophagic cell death. - Highlights: • Peiminine induces autophagy and upregulates autophagic flux. • Peiminine represses colorectal carcinoma tumor growth. • Peiminine induces autophagic cell death. • Peiminine represses mTOR phosphorylation by influencing PI3K/Akt and AMPK pathway.

  5. Conessine Interferes with Oxidative Stress-Induced C2C12 Myoblast Cell Death through Inhibition of Autophagic Flux.

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    Hyunju Kim

    Full Text Available Conessine, a steroidal alkaloid isolated from Holarrhena floribunda, has anti-malarial activity and interacts with the histamine H3 receptor. However, the cellular effects of conessine are poorly understood. Accordingly, we evaluated the involvement of conessine in the regulation of autophagy. We searched natural compounds that modulate autophagy, and conessine was identified as an inhibitor of autophagic flux. Conessine treatment induced the formation of autophagosomes, and p62, an autophagic adapter, accumulated in the autophagosomes. Reactive oxygen species such as hydrogen peroxide (H2O2 result in muscle cell death by inducing excessive autophagic flux. Treatment with conessine inhibited H2O2-induced autophagic flux in C2C12 myoblast cells and also interfered with cell death. Our results indicate that conessine has the potential effect to inhibit muscle cell death by interfering with autophagic flux.

  6. Conessine Interferes with Oxidative Stress-Induced C2C12 Myoblast Cell Death through Inhibition of Autophagic Flux.

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    Kim, Hyunju; Lee, Kang Il; Jang, Minsu; Namkoong, Sim; Park, Rackhyun; Ju, Hyunwoo; Choi, Inho; Oh, Won Keun; Park, Junsoo

    2016-01-01

    Conessine, a steroidal alkaloid isolated from Holarrhena floribunda, has anti-malarial activity and interacts with the histamine H3 receptor. However, the cellular effects of conessine are poorly understood. Accordingly, we evaluated the involvement of conessine in the regulation of autophagy. We searched natural compounds that modulate autophagy, and conessine was identified as an inhibitor of autophagic flux. Conessine treatment induced the formation of autophagosomes, and p62, an autophagic adapter, accumulated in the autophagosomes. Reactive oxygen species such as hydrogen peroxide (H2O2) result in muscle cell death by inducing excessive autophagic flux. Treatment with conessine inhibited H2O2-induced autophagic flux in C2C12 myoblast cells and also interfered with cell death. Our results indicate that conessine has the potential effect to inhibit muscle cell death by interfering with autophagic flux.

  7. Cobalt chloride treatment induces autophagic apoptosis in human glioma cells via a p53-dependent pathway.

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    Cheng, Bor-Chin; Chen, Jui-Tai; Yang, Shun-Tai; Chio, Chung-Ching; Liu, Shing-Hwa; Chen, Ruei-Ming

    2017-03-01

    Malignant glioma is the most aggressive brain tumor. Hypoxic condition has been explored for killing cancer stem cells or drug-resistant tumor cells. This study investigated the effects of hypoxia on autophagic death and the possible mechanisms. Exposure of human malignant glioma U87-MG cells to cobalt chloride (CoCl2) increased cellular hypoxia-inducible factor-1α levels and concurrently decreased cell viability concentration- and time-dependently. In parallel, treatment with CoCl2 suppressed proliferation of human U87-MG cells. Autophagic cells and levels of LC3-II were concentration- and time-dependently induced in human U87-MG cells after exposure to CoCl2. However, pretreatment with 3-mehyladenine (3-MA) and chloroquine, inhibitors of cell autophagy, caused significant alleviations in CoCl2-induced cell autophagy. In contrast, exposure to rapamycin, an inducer of cell autophagy, synergistically induced hypoxia-induced autophagy of U87-MG cells. Administration of human U87-MG cells with CoCl2 triggered caspase-3 activation and cell apoptosis. Interestingly, pretreatment with 3-MA and chloroquine remarkably suppressed CoCl2-induced caspase-3 activation and cell apoptosis. Application of p53 small interference (si)RNA into human U87-MG cells downregulated levels of this protein and simultaneously lowered hypoxia- and 3-MA-induced alterations in cell autophagy, apoptosis, and death. The hypoxia-induced autophagy and apoptosis of DBTRG-05MG cells were significantly lowered by 3-MA pretreatment and p53 knockdown. Therefore, the present study shows that CoCl2 treatment can induce autophagy of human glioma cells and subsequent autophagic apoptosis via a p53-dependent pathway. Hypoxia-induced autophagic apoptosis may be applied as a therapeutic strategy for treatment of glioma patients.

  8. MnSOD upregulation induces autophagic programmed cell death in senescent keratinocytes.

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    Emeric Deruy

    Full Text Available Senescence is a state of growth arrest resulting mainly from telomere attrition and oxidative stress. It ultimately leads to cell death. We have previously shown that, in keratinocytes, senescence is induced by NF-kappaB activation, MnSOD upregulation and H(2O(2 overproduction. We have also shown that senescent keratinocytes do not die by apoptosis but as a result of high macroautophagic activity that targets the primary vital cell components. Here, we investigated the mechanisms that activate this autophagic cell death program. We show that corpses occurring at the senescence plateau display oxidatively-damaged mitochondria and nucleus that colocalize with autophagic vacuoles. The occurrence of such corpses was decreased by specifically reducing the H(2O(2 level with catalase, and, conversely, reproduced by overexpressing MnSOD or applying subtoxic doses of H(2O(2. This H(2O(2-induced cell death did occur through autophagy since it was accompanied by an accumulation of autophagic vesicles as evidenced by Lysotracker staining, LC3 vesiculation and transmission electron microscopy. Most importantly, it was partly abolished by 3-methyladenine, the specific inhibitor of autophagosome formation, and by anti-Atg5 siRNAs. Taken together these results suggest that autophagic cell death is activated in senescent keratinocytes because of the upregulation of MnSOD and the resulting accumulation of oxidative damages to nucleus and mitochondria.

  9. Graphene Oxide Nanoribbons Induce Autophagic Vacuoles in Neuroblastoma Cell Lines

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    Emanuela Mari

    2016-11-01

    Full Text Available Since graphene nanoparticles are attracting increasing interest in relation to medical applications, it is important to understand their potential effects on humans. In the present study, we prepared graphene oxide (GO nanoribbons by oxidative unzipping of single-wall carbon nanotubes (SWCNTs and analyzed their toxicity in two human neuroblastoma cell lines. Neuroblastoma is the most common solid neoplasia in children. The hallmark of these tumors is the high number of different clinical variables, ranging from highly metastatic, rapid progression and resistance to therapy to spontaneous regression or change into benign ganglioneuromas. Patients with neuroblastoma are grouped into different risk groups that are characterized by different prognosis and different clinical behavior. Relapse and mortality in high risk patients is very high in spite of new advances in chemotherapy. Cell lines, obtained from neuroblastomas have different genotypic and phenotypic features. The cell lines SK-N-BE(2 and SH-SY5Y have different genetic mutations and tumorigenicity. Cells were exposed to low doses of GO for different times in order to investigate whether GO was a good vehicle for biological molecules delivering individualized therapy. Cytotoxicity in both cell lines was studied by measuring cellular oxidative stress (ROS, mitochondria membrane potential, expression of lysosomial proteins and cell growth. GO uptake and cytoplasmic distribution of particles were studied by Transmission Electron Microscopy (TEM for up to 72 h. The results show that GO at low concentrations increased ROS production and induced autophagy in both neuroblastoma cell lines within a few hours of exposure, events that, however, are not followed by growth arrest or death. For this reason, we suggest that the GO nanoparticle can be used for therapeutic delivery to the brain tissue with minimal effects on healthy cells.

  10. Cationic polystyrene nanospheres induce autophagic cell death through the induction of endoplasmic reticulum stress

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    Chiu, Hui-Wen; Xia, Tian; Lee, Yu-Hsuan; Chen, Chun-Wan; Tsai, Jui-Chen; Wang, Ying-Jan

    2014-12-01

    Nanoparticles (NPs) have been used to produce a wide range of products that have applications in imaging and drug delivery in medicine. Due to their chemical stability, well-controlled sizes and surface charges, polystyrene (PS) NPs have been developed as biosensors and drug delivery carriers. However, the possible adverse biological effects and underlying mechanisms are still unclear. Recently, autophagy has been implicated in the regulation of cell death. In this study, we evaluated a library of PS NPs with different surface charges. We found that NH2-labeled polystyrene (NH2-PS) nanospheres were highly toxic with enhanced uptake in macrophage (RAW 264.7) and lung epithelial (BEAS-2B) cells. Furthermore, NH2-PS could induce autophagic cell death. NH2-PS increased autophagic flux due to reactive oxygen species (ROS) generation and endoplasmic reticulum (ER) stress caused by misfolded protein aggregation. The inhibition of ER stress decreased cytotoxicity and autophagy in the NH2-PS-treated cells. In addition, the Akt/mTOR and AMPK signaling pathways were involved in the regulation of NH2-PS-triggered autophagic cell death. These results suggest an important role of autophagy in cationic NP-induced cell death and provide mechanistic insights into the inhibition of the toxicity and safe material design.Nanoparticles (NPs) have been used to produce a wide range of products that have applications in imaging and drug delivery in medicine. Due to their chemical stability, well-controlled sizes and surface charges, polystyrene (PS) NPs have been developed as biosensors and drug delivery carriers. However, the possible adverse biological effects and underlying mechanisms are still unclear. Recently, autophagy has been implicated in the regulation of cell death. In this study, we evaluated a library of PS NPs with different surface charges. We found that NH2-labeled polystyrene (NH2-PS) nanospheres were highly toxic with enhanced uptake in macrophage (RAW 264.7) and lung

  11. Cyclic Mechanical Stretching Induces Autophagic Cell Death in Tenofibroblasts Through Activation of Prostaglandin E2 Production

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    Hua Chen

    2015-04-01

    Full Text Available Background/Aims: Autophagic cell death has recently been implicated in the pathophysiology of tendinopathy. Prostaglandin E2 (PGE2, a known inflammatory mediator of tendinitis, inhibits tenofibroblast proliferation in vitro; however, the underlying mechanism is unclear. The present study investigated the relationship between PGE2 production and autophagic cell death in mechanically loaded human patellar tendon fibroblasts (HPTFs in vitro. Methods: Cultured HPTFs were subjected to exogenous PGE2 treatment or repetitive cyclic mechanical stretching. Cell death was determined by flow cytometry with acridine orange/ethidium bromide staining. Induction of autophagy was assessed by autophagy markers including the formation of autophagosomes and autolysosomes (by electron microscopy, AO staining, and formation of GPF-LC3-labeled vacuoles and the expression of LC3-II and BECN1 (by western blot. Stretching-induced PGE2 release was determined by ELISA. Results: Exogenous PGE2 significantly induced cell death and autophagy in HPTFs in a dose-dependent manner. Blocking autophagy using inhibitors 3-methyladenine and chloroquine, or small interfering RNAs against autophagy genes Becn-1 and Atg-5 prevented PGE2-induced cell death. Cyclic mechanical stretching at 8% and 12% magnitudes for 24 h significantly stimulated PGE2 release by HPTFs in a magnitude-dependent manner. In addition, mechanical stretching induced autophagy and cell death. Blocking PGE2 production using COX inhibitors indomethacin and celecoxib significantly reduced stretching-induced autophagy and cell death. Conclusion: Taken together, cyclic mechanical stretching induces autophagic cell death in tenofibroblasts through activation of PGE2 production.

  12. Cyclosporine A induces apoptotic and autophagic cell death in rat pituitary GH3 cells.

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    Kim, Han Sung; Choi, Seung-Il; Jeung, Eui-Bae; Yoo, Yeong-Min

    2014-01-01

    Cyclosporine A (CsA) is a powerful immunosuppressive drug with side effects including the development of chronic nephrotoxicity. In this study, we investigated CsA treatment induced apoptotic and autophagic cell death in pituitary GH3 cells. CsA treatment (0.1 to 10 µM) decreased survival of GH3 cells in a dose-dependent manner. Cell viability decreased significantly with increasing CsA concentrations largely due to an increase in apoptosis, while cell death rates due to autophagy altered only slightly. Several molecular and morphological features correlated with cell death through these distinct pathways. At concentrations ranging from 1.0 to 10 µM, CsA induced a dose-dependent increase in expression of the autophagy markers LC3-I and LC3-II. Immunofluorescence staining revealed markedly increased levels of both LC3 and lysosomal-associated membrane protein 2 (Lamp2), indicating increases in autophagosomes. At the same CsA doses, apoptotic cell death was apparent as indicated by nuclear and DNA fragmentation and increased p53 expression. In apoptotic or autophagic cells, p-ERK levels were highest at 1.0 µM CsA compared to control or other doses. In contrast, Bax levels in both types of cell death were increased in a dose-dependent manner, while Bcl-2 levels showed dose-dependent augmentation in autophagy and were decreased in apoptosis. Manganese superoxide dismutase (Mn-SOD) showed a similar dose-dependent reduction in cells undergoing apoptosis, while levels of the intracellular calcium ion exchange maker calbindin-D9k were decreased in apoptosis (1.0 to 5 µM CsA), but unchanged in autophagy. In conclusion, these results suggest that CsA induction of apoptotic or autophagic cell death in rat pituitary GH3 cells depends on the relative expression of factors and correlates with Bcl-2 and Mn-SOD levels.

  13. Metformin represses glucose starvation induced autophagic response in microvascular endothelial cells and promotes cell death.

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    Samuel, Samson Mathews; Ghosh, Suparna; Majeed, Yasser; Arunachalam, Gnanapragasam; Emara, Mohamed M; Ding, Hong; Triggle, Chris R

    2017-05-15

    Metformin, the most frequently administered drug for the treatment of type 2 diabetes, is being investigated for its potential in the treatment of various types of cancer; however, the cellular basis for this putative anti-cancer action remains controversial. In the current study we examined the effect of metformin on endoplasmic reticulum (ER) stress and autophagy in glucose-starved micro-vascular endothelial cells (MECs). The rationale for our experimental protocol is that in a growing tumor MECs are subjected to hypoxia and nutrient/glucose starvation that results from the reduced supply and relatively high consumption of glucose. Mouse MECs (MMECs) were glucose-starved for up to 48h in the absence or presence of metformin (50μM and 2mM) and the status of ER stress, autophagic, cell survival and apoptotic markers were assessed. Activation of ER stress and autophagy was observed in glucose starved MECs as evidenced by the significant increase in the levels of ER stress and autophagic markers while accumulation of LC3B stained punctae in the MECs confirmed autophagic activation. Treatment with 2mM metformin, independent of AMPK, significantly reversed glucose starvation induced ER stress and autophagy in MECs, but, at 24h, did not decrease cell viability; however, at 48h, persistent ER stress and metformin associated inhibition of autophagy decreased cell viability, caused cell cycle arrest in G2/M and increased the number of cells in the sub-G0/G1 phase of cell cycle. Treatment with metformin reduced phosphorylation of Akt and mTOR and inhibited downstream targets of mTOR. Our findings support the argument that treatment with metformin when used in combination with glycolytic inhibitors will inhibit pro-survival autophagy and promote cell death and potentially prove to be the basis for an effective anti-cancer strategy. Copyright © 2017 Elsevier Inc. All rights reserved.

  14. Zinc oxide nanoparticle induced autophagic cell death and mitochondrial damage via reactive oxygen species generation.

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    Yu, Kyeong-Nam; Yoon, Tae-Jong; Minai-Tehrani, Arash; Kim, Ji-Eun; Park, Soo Jin; Jeong, Min Sook; Ha, Shin-Woo; Lee, Jin-Kyu; Kim, Jun Sung; Cho, Myung-Haing

    2013-06-01

    Zinc oxide nanoparticles (ZnO-np) are used in an increasing number of industrial products such as paint, coating and cosmetics, and in other biological applications. There have been many suggestions of a ZnO-np toxicity paradigm but the underlying molecular mechanisms about the toxicity of ZnO-np remain unclear. This study was done to determine the potential toxicity of ZnO-np and to assess the toxicity mechanism in normal skin cells. Synthesized ZnO-np generated reactive oxygen species (ROS), as determined by electron spin resonance. After uptake into cells, ZnO-np induced ROS in a concentration- and time-dependent manner. To demonstrate ZnO-np toxicity mechanism related to ROS, we detected abnormal autophagic vacuoles accumulation and mitochondria dysfunction after ZnO-np treatment. Furthermore mitochondria membrane potential and adenosine-5'-triphosphate (ATP) production are decreased for culture with ZnO-np. We conclude that ZnO-np leads to cell death through autophagic vacuole accumulation and mitochondria damage in normal skin cells via ROS induction. Accordingly, ZnO-np may cause toxicity and the results highlight and need for careful regulation of ZnO-np production and use. Copyright © 2013 Elsevier Ltd. All rights reserved.

  15. The roles of mitochondria in radiation-induced autophagic cell death in cervical cancer cells.

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    Chen, Zongyan; Wang, Benli; Yu, Feifei; Chen, Qiao; Tian, Yuxi; Ma, Shumei; Liu, Xiaodong

    2016-03-01

    Mitochondria as the critical powerhouse of eukaryotic cells play important roles in regulating cell survival or cell death. Under numerous stimuli, impaired mitochondria will generate massive reactive oxygen species (ROS) which participate in the regulation of vital signals and could even determine the fate of cancer cells. While the roles of mitochondria in radiation-induced autophagic cell death still need to be elucidated. Human cervical cancer cell line, Hela, was used, and the SOD2 silencing model (SOD2-Ri) was established by gene engineering. Cell viability was detected by methyl thiazolyl tetrazolium (MTT) assays, MitoTracker Green staining was used to detect mitochondrial mass, Western blot was used to detect protein expression, and the level of ROS, autophagy, and mitochondrial membrane potential (MMP) were analyzed by flow cytometry. Ionizing radiation (IR) could induce the increase of MAPLC3-II/MAPLC3-I ratio, Beclin1 expression, and ROS generation but decrease the MMP in a time-dependent manner. After SOD2 silencing, the IR-induced changes of ROS and the MMP were significantly enhanced. Moreover, both the radio sensitivity and autophagy increased in SOD2-Ri cells. Whereas, compared with SOD2-Ri, the opposite results were obtained by NAC, an antioxidant. After the treatment with the inhibitor of mitochondrial electron-transport chain complex II, thenoyltrifluoroacetone (TTFA), the rate of autophagy, ROS, and the total cell death induced by IR increased. In addition, the decrease of MMP was more obvious. However, these results were reversed by cyclosporine A (CsA). IR could induce ROS generation and mitochondrial damage which lead to autophagic cell death in Hela cells.

  16. Hypercalcemia induces targeted autophagic degradation of aquaporin-2 at the onset of nephrogenic diabetes insipidus.

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    Khositseth, Sookkasem; Charngkaew, Komgrid; Boonkrai, Chatikorn; Somparn, Poorichaya; Uawithya, Panapat; Chomanee, Nusara; Payne, D Michael; Fenton, Robert A; Pisitkun, Trairak

    2017-05-01

    Hypercalcemia can cause renal dysfunction such as nephrogenic diabetes insipidus (NDI), but the mechanisms underlying hypercalcemia-induced NDI are not well understood. To elucidate the early molecular changes responsible for this disorder, we employed mass spectrometry-based proteomic analysis of inner medullary collecting ducts (IMCD) isolated from parathyroid hormone-treated rats at onset of hypercalcemia-induced NDI. Forty-one proteins, including the water channel aquaporin-2, exhibited significant changes in abundance, most of which were decreased. Bioinformatic analysis revealed that many of the downregulated proteins were associated with cytoskeletal protein binding, regulation of actin filament polymerization, and cell-cell junctions. Targeted LC-MS/MS and immunoblot studies confirmed the downregulation of 16 proteins identified in the initial proteomic analysis and in additional experiments using a vitamin D treatment model of hypercalcemia-induced NDI. Evaluation of transcript levels and estimated half-life of the downregulated proteins suggested enhanced protein degradation as the possible regulatory mechanism. Electron microscopy showed defective intercellular junctions and autophagy in the IMCD cells from both vitamin D- and parathyroid hormone-treated rats. A significant increase in the number of autophagosomes was confirmed by immunofluorescence labeling of LC3. Colocalization of LC3 and Lamp1 with aquaporin-2 and other downregulated proteins was found in both models. Immunogold electron microscopy revealed aquaporin-2 in autophagosomes in IMCD cells from both hypercalcemia models. Finally, parathyroid hormone withdrawal reversed the NDI phenotype, accompanied by termination of aquaporin-2 autophagic degradation and normalization of both nonphoshorylated and S256-phosphorylated aquaporin-2 levels. Thus, enhanced autophagic degradation of proteins plays an important role in the initial mechanism of hypercalcemic-induced NDI. Copyright © 2016

  17. Deoxycholate, an Endogenous Cytotoxin/Genotoxin, Induces the Autophagic Stress-Survival Pathway: Implications for Colon Carcinogenesis

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    Claire M. Payne

    2009-01-01

    Full Text Available We report that deoxycholate (DOC, a hydrophobic bile acid associated with a high-fat diet, activates the autophagic pathway in non-cancer colon epithelial cells (NCM-460, and that this activation contributes to cell survival. The DOC-induced increase in autophagy was documented by an increase in autophagic vacuoles (detected using transmission electron microscopy, increased levels of LC3-I and LC3-II (western blotting, an increase in acidic vesicles (fluorescence spectroscopy of monodansycadaverine and lysotracker red probes, and increased expression of the autophagic protein, beclin-1 (immunohistochemistry/western blotting. The DOC-induced increase in beclin-1 expression was ROS-dependent. Rapamycin (activator of autophagy pre-treatment of NCM-460 cells significantly (P<.05 decreased, and 3-MA (inhibitor of autophagy significantly (P<.05 increased the cell loss caused by DOC treatment, alone. Rapamycin pre-treatment of the apoptosis-resistant colon cancer cell line, HCT-116RC (developed in our laboratory, resulted in a significant decrease in DOC-induced cell death. Bafilomycin A1 and hydroxychloroquine (inhibitors of the autophagic process increased the DOC-induced percentage of apoptotic cells in HCT-116RC cells. It was concluded that the activation of autophagy by DOC has important implications for colon carcinogenesis and for the treatment of colon cancer in conjunction with commonly used chemotherapeutic agents.

  18. Cyclosporine A induces apoptotic and autophagic cell death in rat pituitary GH3 cells.

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    Han Sung Kim

    Full Text Available Cyclosporine A (CsA is a powerful immunosuppressive drug with side effects including the development of chronic nephrotoxicity. In this study, we investigated CsA treatment induced apoptotic and autophagic cell death in pituitary GH3 cells. CsA treatment (0.1 to 10 µM decreased survival of GH3 cells in a dose-dependent manner. Cell viability decreased significantly with increasing CsA concentrations largely due to an increase in apoptosis, while cell death rates due to autophagy altered only slightly. Several molecular and morphological features correlated with cell death through these distinct pathways. At concentrations ranging from 1.0 to 10 µM, CsA induced a dose-dependent increase in expression of the autophagy markers LC3-I and LC3-II. Immunofluorescence staining revealed markedly increased levels of both LC3 and lysosomal-associated membrane protein 2 (Lamp2, indicating increases in autophagosomes. At the same CsA doses, apoptotic cell death was apparent as indicated by nuclear and DNA fragmentation and increased p53 expression. In apoptotic or autophagic cells, p-ERK levels were highest at 1.0 µM CsA compared to control or other doses. In contrast, Bax levels in both types of cell death were increased in a dose-dependent manner, while Bcl-2 levels showed dose-dependent augmentation in autophagy and were decreased in apoptosis. Manganese superoxide dismutase (Mn-SOD showed a similar dose-dependent reduction in cells undergoing apoptosis, while levels of the intracellular calcium ion exchange maker calbindin-D9k were decreased in apoptosis (1.0 to 5 µM CsA, but unchanged in autophagy. In conclusion, these results suggest that CsA induction of apoptotic or autophagic cell death in rat pituitary GH3 cells depends on the relative expression of factors and correlates with Bcl-2 and Mn-SOD levels.

  19. High-Fat Diet-Induced Lysosomal Dysfunction and Impaired Autophagic Flux Contribute to Lipotoxicity in the Kidney.

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    Yamamoto, Takeshi; Takabatake, Yoshitsugu; Takahashi, Atsushi; Kimura, Tomonori; Namba, Tomoko; Matsuda, Jun; Minami, Satoshi; Kaimori, Jun-Ya; Matsui, Isao; Matsusaka, Taiji; Niimura, Fumio; Yanagita, Motoko; Isaka, Yoshitaka

    2017-05-01

    Excessive fat intake contributes to the progression of metabolic diseases via cellular injury and inflammation, a process termed lipotoxicity. Here, we investigated the role of lysosomal dysfunction and impaired autophagic flux in the pathogenesis of lipotoxicity in the kidney. In mice, a high-fat diet (HFD) resulted in an accumulation of phospholipids in enlarged lysosomes within kidney proximal tubular cells (PTCs). In isolated PTCs treated with palmitic acid, autophagic degradation activity progressively stagnated in association with impaired lysosomal acidification and excessive lipid accumulation. Pulse-chase experiments revealed that the accumulated lipids originated from cellular membranes. In mice with induced PTC-specific ablation of autophagy, PTCs of HFD-mice exhibited greater accumulation of ubiquitin-positive protein aggregates normally removed by autophagy than did PTCs of mice fed a normal diet. Furthermore, HFD-mice had no capacity to augment autophagic activity upon another pathologic stress. Autophagy ablation also exaggerated HFD-induced mitochondrial dysfunction and inflammasome activation. Moreover, renal ischemia-reperfusion induced greater injury in HFD-mice than in mice fed a normal diet, and ablation of autophagy further exacerbated this effect. Finally, we detected similarly enhanced phospholipid accumulation in enlarged lysosomes and impaired autophagic flux in the kidneys of obese patients compared with nonobese patients. These findings provide key insights regarding the pathophysiology of lipotoxicity in the kidney and clues to a novel treatment for obesity-related kidney diseases. Copyright © 2017 by the American Society of Nephrology.

  20. Punicalagin induces apoptotic and autophagic cell death in human U87MG glioma cells.

    Science.gov (United States)

    Wang, Shyang-guang; Huang, Ming-hung; Li, Jui-hsiang; Lai, Fu-i; Lee, Horng-mo; Hsu, Yuan-nian

    2013-11-01

    To investigate the effects of punicalagin, a polyphenol isolated from Punica granatum, on human U87MG glioma cells in vitro. The viability of human U87MG glioma cells was evaluated using MTT assay. Cell cycle was detected with flow cytometry analysis. The levels of Bcl-2, cleaved caspase-9, cleaved poly(ADP-ribose) polymerase (PARP), phosphor-AMPK and phosphor-p27 at Thr198 were measured using immunoblot analyses. Caspase-3 activity was determined with spectrophotometer. To determine autophagy, LC3 cleavage and punctate patterns were examined. Punicalagin (1-30 μg/mL) dose-dependently inhibited the cell viability in association with increased cyclin E level and decreased cyclin B and cyclin A levels. The treatment also induced apoptosis as shown by the cleavage of PARP, activation of caspase-9, and increase of caspase-3 activity in the cells. However, pretreatment of the cells with the pan-caspase inhibitor z-DEVD-fmk (50 μmol/L) did not completely prevent the cell death. On the other hand, punicalagin treatment increased LC3-II cleavage and caused GFP-LC3-II-stained punctate pattern in the cells. Suppressing autophagy of cells with chloroquine (1-10 μmol/L) dose-dependently alleviated the cell death caused by punicalagin. Punicalagin (1-30 μg/mL) also increased the levels phosphor-AMPK and phosphor-p27 at Thr198 in the cells, which were correlated with the induction of autophagic cell death. Punicalagin induces human U87MG glioma cell death through both apoptotic and autophagic pathways.

  1. Inhibition of autophagic flux by ROS promotes apoptosis during DTT-induced ER/oxidative stress in HeLa cells.

    Science.gov (United States)

    Xiang, Xi-Yan; Yang, Xiao-Chun; Su, Jin; Kang, Jing-Song; Wu, Yao; Xue, Ya-Nan; Dong, Yu-Tong; Sun, Lian-Kun

    2016-06-01

    As targets for cancer therapy, endoplasmic reticulum (ER) stress and autophagy are closely linked. However, the signaling pathways responsible for induction of autophagy in response to ER stress and its cellular consequences appear to vary with cell type and stimulus. In the present study, we showed that dithiothreitol (DTT) induced ER stress in HeLa cells in a time- and dose-dependent fashion. With increased ER stress, reactive oxygen species (ROS) production increased and autophagy flux, assessed by intracellular accumulation of LC3B-II and p62, was inhibited. N-acetyl-L-cysteine (NAC), a classic antioxidant, exacerbated cell death induced by 3.2 mM of DTT, but attenuated that induced by 6.4 mM DTT. Low cytotoxic doses of DTT transiently activated c-JNU N-terminal kinase (JNK) and p38, whereas high dose of DTT persistently activated JNK and p38 and simultaneously reduced extracellular signal-regulated kinase (ERK) activity. Combined treatment with DTT and U0126, an inhibitor of ERK upstream activators mitogen-activated protein kinase (MAPK) kinase 1 and 2 (MEK1/2), blocked autophagy flux in HeLa cells. This effect was similar to that caused by a combination of DTT and chloroquine (CQ). These data suggested that insufficient autophagy was accompanied by increased ROS production during DTT-induced ER stress. ROS appeared to regulate MAPK signaling, switching from a pro-survival to a pro-apoptotic signal as ER stress increased. ERK inhibition by ROS during severe ER stress blocked autophagic flux. Impaired autophagic flux, in turn, aggravated ER stress, ultimately leading to cell death. Taken together, our data provide the first reported evidence that ROS may control cell fate through regulating the MAPK pathways and autophagic flux during DTT-induced ER/oxidative stress.

  2. The Protective Effect of Gangliosides on Lead (Pb-Induced Neurotoxicity Is Mediated by Autophagic Pathways

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    Hongtao Meng

    2016-03-01

    Full Text Available Lead (Pb is a ubiquitous environmental and industrial pollutant and can affect intelligence development and the learning ability and memory of children. Therefore, necessary measures should be taken to protect the central nervous system (CNS from Pb toxicity. Gangliosides are sialic acid-containing glycosphingolipids that are constituents of mammalian cell membranes and are more abundantly expressed in the CNS. Studies have shown that gangliosides constitute a useful tool in the attempt to promote functional recovery of CNS and can reverse Pb-induced impairments of synaptic plasticity in rats. However, the detailed mechanisms have yet to be fully understood. In our present study, we tried to investigate the role of gangliosides in Pb-induced injury in hippocampus neurons and to further confirm the detailed mechanism. Our results show that Pb-induced injuries in the spatial reference memory were associated with a reduction of cell viability and cell apoptosis, and treatment with gangliosides markedly ameliorated the Pb-induced injury by inhibition of apoptosis action. Gangliosides further attenuated Pb-induced the abnormal autophagic process by regulation of mTOR pathways. In summary, our study establishes the efficacy of gangliosides as neuroprotective agents and provides a strong rationale for further studies on the underlying mechanisms of their neuroprotective functions.

  3. Eclalbasaponin II induces autophagic and apoptotic cell death in human ovarian cancer cells

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    Yoon Jin Cho

    2016-09-01

    Full Text Available Triterpenoids echinocystic acid and its glycosides, isolated from several Eclipta prostrata, have been reported to possess various biological activities such as anti-inflammatory, anti-bacterial, and anti-diabetic activity. However, the cytotoxicity of the triterpenoids in human cancer cells and their molecular mechanism of action are poorly understood. In the present study, we found that eclalbasaponin II with one glucose moiety has potent cytotoxicity in three ovarian cancer cells and two endometrial cancer cells compared to an aglycone echinocystic acid and eclalbasaponin I with two glucose moiety. Eclalbasaponin II treatment dose-dependently increased sub G1 population. Annexin V staining revealed that eclalbasaponin II induced apoptosis in SKOV3 and A2780 ovarian cancer cells. In addition, eclalbasaponin II-induced cell death was associated with characteristics of autophagy; an increase in acidic vesicular organelle content and elevation of the levels of LC3-II. Interestingly, autophagy inhibitor BaF1 suppressed the eclalbasaponin II-induced apoptosis. Moreover, eclalbasaponin II activated JNK and p38 signaling and inhibited the mTOR signaling. We further demonstrated that pre-treatment with a JNK and p38 inhibitor and mTOR activator attenuated the eclalbasaponin II-induced autophagy. This suggests that eclalbasaponin II induces apoptotic and autophagic cell death through the regulation of JNK, p38, and mTOR signaling in human ovarian cancer cells.

  4. Ethambutol induces impaired autophagic flux and apoptosis in the rat retina

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    Shun-Ping Huang

    2015-08-01

    Full Text Available Ethambutol (EMB, an effective first-line antituberculosis agent, can cause serious visual impairment or irreversible vision loss in a significant number of patients. However, the mechanism underlying this ocular cytotoxicity remains to be elucidated. In this study, we found that there were statistically significant dose- and time-dependent increases in the number of cytoplasmic vacuoles and the level of cell death in EMB-treated RGC-5 cells (retinal ganglion cells. The protein kinase C (PKCδ inhibitor rottlerin markedly reduced the EMB-induced activation of caspase-3 and the subsequent apoptosis of RGC-5 cells. Western blot analysis revealed that the expression levels of class III PI3K, Beclin-1, p62 and LC3-II were upregulated, and LC3 immunostaining results showed activation of the early phase and inhibition of the late stage of autophagy in retinas of the EMB-intraperitoneal (IP-injected rat model. We further demonstrated that exposure to EMB induces autophagosome accumulation, which results from the impaired autophagic flux that is mediated by a PKCδ-dependent pathway, inhibits the PI3K/Akt/mTOR signaling pathway and leads to apoptotic death in retina neuronal cells. These results indicate that autophagy dysregulation in retinal neuronal cells might play a substantial role in EMB-induced optic neuroretinopathy.

  5. Lapatinib induces autophagic cell death and differentiation in acute myeloblastic leukemia

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    Chen YJ

    2016-07-01

    Full Text Available Yu-Jen Chen,1–4 Li-Wen Fang,5 Wen-Chi Su,6,7 Wen-Yi Hsu,1 Kai-Chien Yang,1 Huey-Lan Huang8 1Department of Medical Research, 2Department of Radiation Oncology, Mackay Memorial Hospital, 3Institute of Traditional Medicine, School of Medicine, National Yang-Ming University, 4Institute of Pharmacology, Taipei Medical University, Taipei, 5Department of Nutrition, I-Shou University, Kaohsiung, 6Research Center for Emerging Viruses, China Medical University Hospital, 7Graduate Institute of Clinical Medical Science, China Medical University, Taichung, 8Department of Bioscience Technology, College of Health Science, Chang Jung Christian University, Tainan, Taiwan, Republic of China Abstract: Lapatinib is an oral-form dual tyrosine kinase inhibitor of epidermal growth factor receptor (EGFR or ErbB/Her superfamily members with anticancer activity. In this study, we examined the effects and mechanism of action of lapatinib on several human leukemia cells lines, including acute myeloid leukemia (AML, chronic myeloid leukemia (CML, and acute lymphoblastic leukemia (ALL cells. We found that lapatinib inhibited the growth of human AML U937, HL-60, NB4, CML KU812, MEG-01, and ALL Jurkat T cells. Among these leukemia cell lines, lapatinib induced apoptosis in HL-60, NB4, and Jurkat cells, but induced nonapoptotic cell death in U937, K562, and MEG-01 cells. Moreover, lapatinib treatment caused autophagic cell death as shown by positive acridine orange staining, the massive formation of vacuoles as seen by electronic microscopy, and the upregulation of LC3-II, ATG5, and ATG7 in AML U937 cells. Furthermore, autophagy inhibitor 3-methyladenine and knockdown of ATG5, ATG7, and Beclin-1 using short hairpin RNA (shRNA partially rescued lapatinib-induced cell death. In addition, the induction of phagocytosis and ROS production as well as the upregulation of surface markers CD14 and CD68 was detected in lapatinib-treated U937 cells, suggesting the induction of

  6. Clozapine Induces Autophagic Cell Death in Non-Small Cell Lung Cancer Cells

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    Yu-Chun Yin

    2015-02-01

    Full Text Available Background/Aims: Previous studies have shown that patients with schizophrenia have a lower incidence of cancer than the general population, and several antipsychotics have been demonstrated to have cytotoxic effects on cancer cells. However, the mechanisms underlying these results remain unclear. The present study aimed to investigate the effect of clozapine, which is often used to treat patients with refractory schizophrenia, on the growth of non-small cell lung carcinoma cell lines and to examine whether autophagy contributes to its effects. Methods: A549 and H1299 cells were treated with clozapine, and cell cytotoxicity, cell cycle and autophagy were then assessed. The autophagy inhibitor bafilomycin A1 and siRNA-targeted Atg7 were used to determine the role of autophagy in the effect of clozapine. Results: Clozapine inhibited A549 and H1299 proliferation and increased p21 and p27 expression levels, leading to cell cycle arrest. Clozapine also induced a high level of autophagy, but not apoptosis, in both cell lines, and the growth inhibitory effect of clozapine was blunted by treatment with the autophagy inhibitor bafilomycin A1 or with an siRNA targeting atg7. Conclusions: Clozapine inhibits cell proliferation by inducing autophagic cell death in two non-small cell lung carcinoma cell lines. These findings may provide insights into the relationship between clozapine use and the lower incidence of lung cancer among patients with schizophrenia.

  7. Endurance exercise training induces fat depot-specific differences in basal autophagic activity

    Energy Technology Data Exchange (ETDEWEB)

    Tanaka, Goki; Kato, Hisashi; Izawa, Tetsuya, E-mail: tizawa@mail.doshisha.ac.jp

    2015-10-23

    autophagosome associated LC3-II in WAT. • Exercise-induced changes in p62 and ATG7 were WAT-type specific. • Exercise-induced basal autophagic activity shows fat depot-specific differences.

  8. Conessine Interferes with Oxidative Stress-Induced C2C12 Myoblast Cell Death through Inhibition of Autophagic Flux

    OpenAIRE

    Hyunju Kim; Kang Il Lee; Minsu Jang; Sim Namkoong; Rackhyun Park; Hyunwoo Ju; Inho Choi; Won Keun Oh; Junsoo Park

    2016-01-01

    Conessine, a steroidal alkaloid isolated from Holarrhena floribunda, has anti-malarial activity and interacts with the histamine H3 receptor. However, the cellular effects of conessine are poorly understood. Accordingly, we evaluated the involvement of conessine in the regulation of autophagy. We searched natural compounds that modulate autophagy, and conessine was identified as an inhibitor of autophagic flux. Conessine treatment induced the formation of autophagosomes, and p62, an autophagi...

  9. Quinones Derived from Polychlorinated Biphenyls Induce ROS-Dependent Autophagy by Evoking an Autophagic Flux and Inhibition of mTOR/p70S6k.

    Science.gov (United States)

    Shi, Qiong; Song, Xiufang; Liu, Zixuan; Wang, Yawen; Wang, Yuxin; Fu, Juanli; Su, Chuanyang; Xia, Xiaomin; Song, Erqun; Song, Yang

    2016-07-18

    Autophagy is a "self-eating" destructive process that eliminates damaged organelles to maintain cellular homeostasis. Polychlorinated biphenyls (PCBs) are one of the most infamous industrial pollutants, which are ubiquitous in nature. In the present study, we found that an active, quinone-type PCB metabolite (PCB29-pQ) treatment causes an autophagic response through mTOR/p70S6k inhibition in HepG2 and MDA-MB-231 cells. Furthermore, our data suggested that PCB29-pQ enhances autophagosome formation through autophagic vacuole (AV) biogenesis, which evokes autophagic flux and induces AV-lysosome colocalization. The inhibition of autophagy enhanced PCB29-pQ-caused cytotoxicity, suggesting that autophagy serves as pro-survival machinery that plays a protective role in the early stage of PCB29-pQ-induced insult. However, higher concentration of PCB29-pQ exposure (>5 μM) caused autophagic cell death, which implied a shift from "pro-survival" to "pro-death" upon autophagic signaling. N-Acetylcysteine suppressed PCB29-pQ-induced autophagy and cytotoxicity, suggesting that ROS plays an important role in the regulation of PCB29-pQ-induced autophagy. Because autophagy shows significant implications in various human diseases and conditions, our current study provides a new mechanism for PCB-associated toxicity.

  10. Copper Oxide Nanoparticles Induce Autophagic Cell Death in A549 Cells

    Science.gov (United States)

    Zhao, Yan; Guo, Feng; Jiang, Chengyu

    2012-01-01

    Metal oxide nanoparticles (NPs) are among the most highly produced nanomaterials, and have many diverse functions in catalysis, environmental remediation, as sensors, and in the production of personal care products. In this study, the toxicity of several widely used metal oxide NPs such as copper oxide, silica, titanium oxide and ferric oxide NPs, were evaluated In vitro. We exposed A549, H1650 and CNE-2Z cell lines to metal oxide NPs, and found CuO NPs to be the most toxic, SiO2 mild toxic, while the other metal oxide NPs had little effect on cell viability. Furthermore, the autophagic biomarker LC3-II significantly increased in A549 cells treated with CuO NPs, and the use of the autophagy inhibitors wortmannin and 3-methyladenin significantly improved cell survival. These results indicate that the cytoxicity of CuO NPs may involve the autophagic pathway in A549 cells. PMID:22916263

  11. Mycobacterium marinum antagonistically induces an autophagic response while repressing the autophagic flux in a TORC1- and ESX-1-dependent manner.

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    Elena Cardenal-Muñoz

    2017-04-01

    Full Text Available Autophagy is a eukaryotic catabolic process also participating in cell-autonomous defence. Infected host cells generate double-membrane autophagosomes that mature in autolysosomes to engulf, kill and digest cytoplasmic pathogens. However, several bacteria subvert autophagy and benefit from its machinery and functions. Monitoring infection stages by genetics, pharmacology and microscopy, we demonstrate that the ESX-1 secretion system of Mycobacterium marinum, a close relative to M. tuberculosis, upregulates the transcription of autophagy genes, and stimulates autophagosome formation and recruitment to the mycobacteria-containing vacuole (MCV in the host model organism Dictyostelium. Antagonistically, ESX-1 is also essential to block the autophagic flux and deplete the MCV of proteolytic activity. Activators of the TORC1 complex localize to the MCV in an ESX-1-dependent manner, suggesting an important role in the manipulation of autophagy by mycobacteria. Our findings suggest that the infection by M. marinum activates an autophagic response that is simultaneously repressed and exploited by the bacterium to support its survival inside the MCV.

  12. Mycobacterium marinum antagonistically induces an autophagic response while repressing the autophagic flux in a TORC1- and ESX-1-dependent manner.

    Science.gov (United States)

    Cardenal-Muñoz, Elena; Arafah, Sonia; López-Jiménez, Ana Teresa; Kicka, Sébastien; Falaise, Alexandra; Bach, Frauke; Schaad, Olivier; King, Jason S; Hagedorn, Monica; Soldati, Thierry

    2017-04-01

    Autophagy is a eukaryotic catabolic process also participating in cell-autonomous defence. Infected host cells generate double-membrane autophagosomes that mature in autolysosomes to engulf, kill and digest cytoplasmic pathogens. However, several bacteria subvert autophagy and benefit from its machinery and functions. Monitoring infection stages by genetics, pharmacology and microscopy, we demonstrate that the ESX-1 secretion system of Mycobacterium marinum, a close relative to M. tuberculosis, upregulates the transcription of autophagy genes, and stimulates autophagosome formation and recruitment to the mycobacteria-containing vacuole (MCV) in the host model organism Dictyostelium. Antagonistically, ESX-1 is also essential to block the autophagic flux and deplete the MCV of proteolytic activity. Activators of the TORC1 complex localize to the MCV in an ESX-1-dependent manner, suggesting an important role in the manipulation of autophagy by mycobacteria. Our findings suggest that the infection by M. marinum activates an autophagic response that is simultaneously repressed and exploited by the bacterium to support its survival inside the MCV.

  13. Tiron and trolox potentiate the autophagic cell death induced by magnolol analog Ery5 by activation of Bax in HL-60 cells.

    Science.gov (United States)

    Kumar, Suresh; Kumar, Ajay; Pathania, Anup Singh; Guru, Santosh Kumar; Jada, Srinivas; Sharma, Parduman Raj; Bhushan, Shashi; Saxena, Ajit Kumar; Kumar, H M Sampath; Malik, Fayaz

    2013-05-01

    This study describes the mechanism of trolox and tiron induced potentiation of cytotoxicity caused by Ery5, an analog of magnolol, in human myeloid leukemia HL-60 cells. Ery5 induced cytotoxicity in HL-60 cells by involving activation of bax and cleavage of caspase 3, which contributed towards activation of both apoptotic and autophagic pathways. Trolox and tiron, even at non-toxic concentrations, contributed to the cytotoxicity of Ery5 by activation of autophagic proteins like ATG7, ATG12 and LC3-II. Z-VAD-fmk mediated reduction in the cytotoxicity and expression of autophagic proteins, further suggested that autophagy induced by Ery5 is largely dependent upon caspases. Interestingly, Ery5 induced autophagy was accompanied by the downregulation of PI3K/AKT pathway whereas, trolox and tiron strongly enhanced this effect. In addition to that treatment of cells with Ery5, trolox and tiron individually, displayed a marked upregulation of Bax. The involvement of Bax in trolox and tiron induced enhancement of the cytotoxicity of Ery5 was confirmed, when siRNA induced silencing of Bax led to increased viability of the cells and exerted a strong inhibitory effect on LC3-II accumulation and p62 degradation in case of cells treated by the combination of Ery5 with trolox or tiron. Additionally, an important role of PARP in Ery5 mediated cell death has been suggested by PARP silencing experiments, however, potentiation of autophagic cytotoxicity by trolox and tiron did not seem to be dependent on PARP-1. Therefore, Bax seems to play a vital role in trolox and tiron mediated potentiation of autophagic cell death by Ery5 in HL-60 cells.

  14. Blocking the interleukin 2 (IL2)-induced systemic autophagic syndrome promotes profound antitumor effects and limits toxicity.

    Science.gov (United States)

    Lotze, Michael T; Buchser, William J; Liang, Xiaoyan

    2012-08-01

    Cancer is the leading cause of death in the United States in those dying under the age of 85. Although cancer is increasingly controlled as a chronic disease, true cures of patients with metastatic epithelial malignancies have rarely been obtained with currently available systemic therapies. For example, administration of high-dose recombinant interleukin 2 (IL2), enhancing cytolytic immune cell proliferation and delivery, promotes complete antitumor responses in IL2 promotes both T-cell and NK cell induction of immune cell-mediated autophagy (iC-MA) in tumor targets. We have demonstrated that HMGB1 is detected at high levels in the serum of IL2-treated mice with translocation to the cytoplasm from the nucleus in the liver, consistent with HMGB1's release in response to stress, and ability to sustain autophagy. Limiting autophagy in mice with coadministration of chloroquine (CQ) diminishes serum levels of HMGB1, cytokines (IFNG and IL6 but not IL18), and autophagic flux, attenuating weight gain, enhancing DC, T-cell and NK cell numbers, and promoting long-term tumor control in a murine hepatic metastases model. Autophagy (programmed cell survival) is a metabolic process associated with promotion of late cancer growth. In tumor cell lines, CQ treatment limits ATP production through inhibition of oxidative phosphorylation and promotion of apoptosis. CQ increases autophagic vacuoles and LC3-II levels in tumor cells, associated with increased annexin V(+)/PI(-) cells, cleaved-PARP, cleaved-CASP3, and cytochrome c release from mitochondria. These observations, limiting toxicity and prolonging antitumor effects, with a combination of IL2 and autophagy inhibition in murine models are now being tested by the Cytokine Working Group in patients with advanced renal cell carcinoma.

  15. Paraquat, but not maneb, induces synucleinopathy and tauopathy in striata of mice through inhibition of proteasomal and autophagic pathways.

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    Jonathan Wills

    Full Text Available SNCA and MAPT genes and environmental factors are important risk factors of Parkinson's disease [PD], the second-most common neurodegenerative disease. The agrichemicals maneb and paraquat selectively target dopaminergic neurons, leading to parkinsonism, through ill-defined mechanisms. In the current studies we have analyzed the ability of maneb and paraquat, separately and together, to induce synucleinopathy and tauopathy in wild type mice. Maneb was ineffective in increasing α-synuclein [α-Syn] or p-Tau levels. By contrast, paraquat treatment of mice resulted in robust accumulation of α-Syn and hyperphosphorylation of Tau in striata, through activation of p-GSK-3β, a major Tau kinase. Co-treatment with maneb did not enhance the effects of paraquat. Increased hyperacetylation of α-tubulin was observed in paraquat-treated mice, suggesting cytoskeleton remodeling. Paraquat, but not maneb, inhibited soluble proteasomal activity on a peptide substrate but this was not associated with a decreased expression of 26S proteasome subunits. Both paraquat and maneb treatments increased levels of the autophagy inhibitor, mammalian target of rapamycin, mTOR, suggesting impaired axonal autophagy, despite increases in certain autophagic proteins, such as beclin 1 and Agt12. Autophagic flux was also impaired, as ratios of LC3 II to LC3 I were reduced in treated animals. Increased mTOR was also observed in postmortem human PD striata, where there was a reduction in the LC3 II to LC3 I ratio. Heat shock proteins were either increased or unchanged upon paraquat-treatment suggesting that chaperone-mediated autophagy is not hampered by the agrichemicals. These studies provide novel insight into the mechanisms of action of these agrichemicals, which indicate that paraquat is much more toxic than maneb, via its inhibitory effects on proteasomes and autophagy, which lead to accumulation of α-Syn and p-Tau.

  16. miR-34a Modulates Angiotensin II-Induced Myocardial Hypertrophy by Direct Inhibition of ATG9A Expression and Autophagic Activity

    Science.gov (United States)

    Huang, He; Ye, Jing; Pan, Wei; Zhong, Yun; Cheng, Chuanfang; You, Xiangyu; Liu, Benrong; Xiong, Longgen; Liu, Shiming

    2014-01-01

    Cardiac hypertrophy is characterized by thickening myocardium and decreasing in heart chamber volume in response to mechanical or pathological stress, but the underlying molecular mechanisms remain to be defined. This study investigated altered miRNA expression and autophagic activity in pathogenesis of cardiac hypertrophy. A rat model of myocardial hypertrophy was used and confirmed by heart morphology, induction of cardiomyocyte autophagy, altered expression of autophagy-related ATG9A, LC3 II/I and p62 proteins, and decrease in miR-34a expression. The in vitro data showed that in hypertrophic cardiomyocytes induced by Ang II, miR-34a expression was downregulated, whereas ATG9A expression was up-regulated. Moreover, miR-34a was able to bind to ATG9A 3′-UTR, but not to the mutated 3′-UTR and inhibited ATG9A protein expression and autophagic activity. The latter was evaluated by autophagy-related LC3 II/I and p62 levels, TEM, and flow cytometry in rat cardiomyocytes. In addition, ATG9A expression induced either by treatment of rat cardiomyocytes with Ang II or ATG9A cDNA transfection upregulated autophagic activity and cardiomyocyte hypertrophy in both morphology and expression of hypertrophy-related genes (i.e., ANP and β-MHC), whereas knockdown of ATG9A expression downregulated autophagic activity and cardiomyocyte hypertrophy. However, miR-34a antagonized Ang II-stimulated myocardial hypertrophy, whereas inhibition of miR-34a expression aggravated Ang II-stimulated myocardial hypertrophy (such as cardiomyocyte hypertrophy-related ANP and β-MHC expression and cardiomyocyte morphology). This study indicates that miR-34a plays a role in regulation of Ang II-induced cardiomyocyte hypertrophy by inhibition of ATG9A expression and autophagic activity. PMID:24728149

  17. G9a Inhibition Induces Autophagic Cell Death via AMPK/mTOR Pathway in Bladder Transitional Cell Carcinoma.

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    Feng Li

    Full Text Available G9a has been reported to highly express in bladder transitional cell carcinoma (TCC and G9a inhibition significantly attenuates cell proliferation, but the underlying mechanism is not fully understood. The present study aimed at examining the potential role of autophagy in the anti-proliferation effect of G9a inhibition on TCC T24 and UMUC-3 cell lines in vitro. We found that both pharmaceutical and genetical G9a inhibition significantly attenuated cell proliferation by MTT assay, Brdu incorporation assay and colony formation assay. G9a inhibition induced autophagy like morphology as determined by transmission electron microscope and LC-3 fluorescence assay. In addition, autophagy flux was induced by G9a inhibition in TCC cells, as determined by p62 turnover assay and LC-3 turnover assay. The autophagy induced positively contributed to the inhibition of cell proliferation because the growth attenuation capacity of G9a inhibition was reversed by autophagy inhibitors 3-MA. Mechanically, AMPK/mTOR pathway was identified to be involved in the regulation of G9a inhibition induced autophagy. Intensively activating mTOR by Rheb overexpression attenuated autophagy and autophagic cell death induced by G9a inhibition. In addition, pre-inhibiting AMPK by Compound C attenuated autophagy together with the anti-proliferation effect induced by G9a inhibition while pre-activating AMPK by AICAR enhanced them. In conclusion, our results indicate that G9a inhibition induces autophagy through activating AMPK/mTOR pathway and the autophagy induced positively contributes to the inhibition of cell proliferation in TCC cells. These findings shed some light on the functional role of G9a in cell metabolism and suggest that G9a might be a therapeutic target in bladder TCC in the future.

  18. Icariside II-induced mitochondrion and lysosome mediated apoptosis is counterbalanced by an autophagic salvage response in hepatoblastoma.

    Science.gov (United States)

    Geng, Ya-di; Zhang, Chao; Shi, Ya-Min; Xia, Yuan-Zheng; Guo, Chao; Yang, Lei; Kong, Ling-Yi

    2015-09-28

    In this study, the anti-cancer effect of Icariside II (IS), a natural plant flavonoid, against hepatoblastoma cells and the underlying mechanisms were investigated. The in vitro and in vivo studies show that IS decreased the viability of human hepatoblastoma HepG2 cells in a concentration- and time-dependent manner and inhibited tumor growth in mice transplanted with H22 liver carcinomas. IS impaired mitochondria and lysosomes as evidenced by signs of induced mitochondrial and lysosomal membrane permeabilization, resulting in caspase activation and apoptosis. SQSTM1 up-regulation and autophagic flux measurements demonstrated that IS exposure also impaired autophagosome degradation which resulted in autophagosome accumulation, which plays a pro-survival role as the genetic knockdown of LC3B further sensitized the IS-treated cells. Electron microscopy images showed that autophagosome engulfs IS-impaired mitochondria and lysosomes, thus blocking cytotoxicity induced by further leakage of the hydrolases from lysosomes and pro-apoptosis members from mitochondria. In conclusion, these data suggest that IS plays multiple roles as a promising chemotherapeutic agent that induces cell apoptosis involving both mitochondrial and lysosomal damage. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

  19. Hypoxia induces apoptosis and autophagic cell death in human periodontal ligament cells through HIF-1α pathway.

    Science.gov (United States)

    Song, Z-C; Zhou, W; Shu, R; Ni, J

    2012-06-01

    Oxygen deficiency caused by occlusal trauma and smoking can be present in patients with periodontitis. However, biochemical events important in periodontal tissues during hypoxia remain unclear. The aim of this study was to investigate effects of hypoxia on apoptosis and autophagy of human periodontal ligament cells (PDLCs) in vitro. Human PDLCs were obtained and cultured in vitro. Cell viability, apoptosis, autophagy and gene and protein expression were measured in presence and absence of cobalt chloride (CoCl(2)). CoCl(2) induced cytotoxicity of human PDLCs in a concentration-dependent manner dependent on macromolecular synthesis, and resulted in apoptosis and mitochondrial dysfunction. CoCl(2) also induced redistribution of autophagy marker LC3, increased ratio of LC3-IIto LC3-Iand function of lysosomes. Furthermore, CoCl(2) promoted expression of HIF-1α following upregulation of expressions of Bnip3. Significant increases in expression of IL-1β and MMP-8 were also observed. All these results were reversed by pre-treatment with antioxidant N-acetylcysteine. Our data showed that CoCl(2) could induce cytotoxicity through mitochondria- apoptotic and autophagic pathways involved in HIF-1α. CoCl(2 -treated PDLCs may serve as an in vitro model for studies of molecular mechanisms in periodontitis. © 2012 Blackwell Publishing Ltd.

  20. Autophagic Mechanism in Anti-Cancer Immunity: Its Pros and Cons for Cancer Therapy

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    Ying-Ying Li

    2017-06-01

    Full Text Available Autophagy, a self-eating machinery, has been reported as an adaptive response to maintain metabolic homeostasis when cancer cells encounter stress. It has been appreciated that autophagy acts as a double-edge sword to decide the fate of cancer cells upon stress factors, molecular subtypes, and microenvironmental conditions. Currently, the majority of evidence support that autophagy in cancer cells is a vital mechanism bringing on resistance to current and prospective treatments, yet whether autophagy affects the anticancer immune response remains unclear and controversial. Accumulated studies have demonstrated that triggering autophagy is able to facilitate anticancer immunity due to an increase in immunogenicity, whereas other studies suggested that autophagy is likely to disarm anticancer immunity mediated by cytotoxic T cells and nature killer (NK cells. Hence, this contradiction needs to be elucidated. In this review, we discuss the role of autophagy in cancer cells per se and in cancer microenvironment as well as its dual regulatory roles in immune surveillance through modulating presentation of tumor antigens, development of immune cells, and expression of immune checkpoints. We further focus on emerging roles of autophagy induced by current treatments and its impact on anticancer immune response, and illustrate the pros and cons of utilizing autophagy in cancer immunotherapy based on preclinical references.

  1. Betulinic acid-induced mitochondria-dependent cell death is counterbalanced by an autophagic salvage response

    NARCIS (Netherlands)

    Potze, L.; Mullauer, F. B.; Colak, S.; Kessler, J. H.; Medema, J. P.

    2014-01-01

    Betulinic acid (BetA) is a plant-derived pentacyclic triterpenoid that exerts potent anti-cancer effects in vitro and in vivo. It was shown to induce apoptosis via a direct effect on mitochondria. This is largely independent of proapoptotic BAK and BAX, but can be inhibited by cyclosporin A (CsA),

  2. Anti-cancer fatty-acid derivative induces autophagic cell death through modulation of PKM isoform expression profile mediated by bcr-abl in chronic myeloid leukemia.

    Science.gov (United States)

    Shinohara, Haruka; Taniguchi, Kohei; Kumazaki, Minami; Yamada, Nami; Ito, Yuko; Otsuki, Yoshinori; Uno, Bunji; Hayakawa, Fumihiko; Minami, Yosuke; Naoe, Tomoki; Akao, Yukihiro

    2015-04-28

    The fusion gene bcr-abl develops chronic myeloid leukemia (CML), and stimulates PI3K/Akt/mTOR signaling, leading to impaired autophagy. PI3K/Akt/mTOR signaling also plays an important role in cell metabolism. The Warburg effect is a well-recognized hallmark of cancer energy metabolism, and is regulated by the mTOR/c-Myc/hnRNP/PKM signaling cascade. To develop a new strategy for the treatment of CML, we investigated the associations among bcr-abl, the cascade related to cancer energy metabolism, and autophagy induced by a fatty-acid derivative that we had previously reported as being an autophagy inducer. Here we report that a fatty-acid derivative, AIC-47, induced transcriptional repression of the bcr-abl gene and modulated the expression profile of PKM isoforms, resulting in autophagic cell death. We show that c-Myc functioned as a transcriptional activator of bcr-abl, and regulated the hnRNP/PKM cascade. AIC-47, acting through the PPARγ/β-catenin pathway, induced down-regulation of c-Myc, leading to the disruption of the bcr-abl/mTOR/hnRNP signaling pathway, and switching of the expression of PKM2 to PKM1. This switching caused autophagic cell death through an increase in the ROS level. Our findings suggest that AIC-47 induced autophagic cell death through the PPARγ/β-catenin/bcr-abl/mTOR/hnRNP/PKM cascade. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

  3. Methylglyoxal-induced AMPK activation leads to autophagic degradation of thioredoxin 1 and glyoxalase 2 in HT22 nerve cells.

    Science.gov (United States)

    Dafre, Alcir Luiz; Schmitz, Ariana Ern; Maher, Pamela

    2017-07-01

    Methylglyoxal (MGO) is a major glycating agent that reacts with basic residues of proteins and promotes the formation of advanced glycation end products which are believed to play key roles in a number of pathologies, such as diabetes, Alzheimer's disease, and inflammation. We previously showed that MGO treatment targets the thioredoxin and the glyoxalase systems, leading to a decrease in Trx1 and Glo2 proteins in immortalized mouse hippocampal HT22 nerve cells. Here, we propose that autophagy is the underlying mechanism leading to Glo2 and Trx1 loss induced by MGO. The autophagic markers p62, and the lipidated and active form of LC3, were increased by MGO (0.5mM). Autophagy inhibition with bafilomycin or chloroquine prevented the decrease in Trx1 and Glo2 at 6 and 18h after MGO treatment. Proteasome inhibition by MG132 exacerbated the effect of MGO on Trx1 and Glo2 degradation (18h), further suggesting a role for autophagy. ATG5 small interfering RNA protected Trx1 and Glo2 from MGO-induced degradation, confirming Trx1 and Glo2 loss is mediated by autophagy. In the search for the signals that control autophagy, we found that AMPK activation, a known autophagy inducer, was markedly increased by MGO treatment. AMPK activation was confirmed by increased acetyl coenzyme A carboxylase phosphorylation, a direct AMPK substrate and by decreased mTOR phosphorylation, an indirect marker of AMPK activation. To confirm that MGO-mediated Trx1 and Glo2 degradation was AMPK-dependent, AMPK-deficient mouse embryonic fibroblasts (MEFs) were treated with MGO. Wildtype MEFs presented the expected decrease in Trx1 and Glo2, while MGO was ineffective in decreasing these proteins in AMPK-deficient cells. Overall, the data indicate that MGO activates autophagy in an AMPK-dependent manner, and that autophagy was responsible for Trx1 and Glo2 degradation, confirming that Trx1 and Glo2 are molecular targets of MGO. Copyright © 2017 Elsevier Inc. All rights reserved.

  4. Araguspongine C Induces Autophagic Death in Breast Cancer Cells through Suppression of c-Met and HER2 Receptor Tyrosine Kinase Signaling

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    Mohamed R. Akl

    2015-01-01

    Full Text Available Receptor tyrosine kinases are key regulators of cellular growth and proliferation. Dysregulations of receptor tyrosine kinases in cancer cells may promote tumorigenesis by multiple mechanisms including enhanced cell survival and inhibition of cell death. Araguspongines represent a group of macrocyclic oxaquinolizidine alkaloids isolated from the marine sponge Xestospongia species. This study evaluated the anticancer activity of the known oxaquinolizidine alkaloids araguspongines A, C, K and L, and xestospongin B against breast cancer cells. Araguspongine C inhibited the proliferation of multiple breast cancer cell lines in vitro in a dose-dependent manner. Interestingly, araguspongine C-induced autophagic cell death in HER2-overexpressing BT-474 breast cancer cells was characterized by vacuole formation and upregulation of autophagy markers including LC3A/B, Atg3, Atg7, and Atg16L. Araguspongine C-induced autophagy was associated with suppression of c-Met and HER2 receptor tyrosine kinase activation. Further in-silico docking studies and cell-free Z-LYTE assays indicated the potential of direct interaction between araguspongine C and the receptor tyrosine kinases c-Met and HER2 at their kinase domains. Remarkably, araguspongine C treatment resulted in the suppression of PI3K/Akt/mTOR signaling cascade in breast cancer cells undergoing autophagy. Induction of autophagic death in BT-474 cells was also associated with decreased levels of inositol 1,4,5-trisphosphate receptor upon treatment with effective concentration of araguspongine C. In conclusion, results of this study are the first to reveal the potential of araguspongine C as an inhibitor to receptor tyrosine kinases resulting in the induction of autophagic cell death in breast cancer cells.

  5. HSpin1, a transmembrane protein interacting with Bcl-2/Bcl-xL, induces a caspase-independent autophagic cell death.

    Science.gov (United States)

    Yanagisawa, H; Miyashita, T; Nakano, Y; Yamamoto, D

    2003-07-01

    The Drosophila spinster (spin) gene product is required for programmed cell death in the nervous and reproductive systems. We have identified a human homologue of the Drosophila spin gene product (HSpin1). HSpin1 bound to Bcl-2 and apoptosis regulator Bcl-X (Bcl-xL), but not to proapoptotic members such as Bcl-2-associated X protein and Bcl-2 homologous antagonist killer, in cells treated with TNF-alpha. Exogenous expression of HSpin1 resulted in the cell death without inducing a release of cytochrome c from mitochondria. Overexpression of Bcl-xL inhibited the HSpin1-induced cell death. Interestingly, a necrosis inhibitor, pyrrolidine dithiocarbomate, but not the pancaspase inhibitors, carbobenzoxy-VAD-fluoromethyl ketone and p35, blocked the HSpin1-induced cell death. HSpin1-induced cell death increases autophagic vacuole and mature form of cathepsin D, suggesting a novel caspase-independent cell death, which is link to autophagy.

  6. Carbon and nitrogen depletion-induced nucleophagy and selective autophagic sequestration of a whole nucleus in multinucleate cells of the filamentous fungus Aspergillus oryzae.

    Science.gov (United States)

    Kikuma, Takashi; Mitani, Takahiro; Kohara, Takahiro; Maruyama, Jun-Ichi; Kitamoto, Katsuhiko

    2017-05-12

    Autophagy is a conserved cellular degradation process in eukaryotes, in which cytoplasmic components and organelles are digested in vacuoles/lysosomes. Recently, autophagic degradation of nuclear materials, termed "nucleophagy", has been reported. In the multinucleate filamentous fungus Aspergillus oryzae, a whole nucleus is degraded by nucleophagy after prolonged culture. While developing an H2B-EGFP processing assay for the evaluation of nucleophagy in A. oryzae, we found that nucleophagy is efficiently induced by carbon or nitrogen depletion. Microscopic observations in a carbon depletion condition clearly demonstrated that autophagosomes selectively sequester a particular nucleus, despite the presence of multiple nuclei in the same cell. Furthermore, AoNsp1, the A. oryzae homolog of the yeast nucleoporin Nsp1p, mainly localized at the nuclear periphery, but its localization was restricted to the opposite side of the autophagosome being formed around a nucleus. In contrast, the perinuclear ER visualized with the calnexin AoClxA was not morphologically affected by nucleophagy. The findings of nucleophagy-inducing conditions enabled us to characterize the morphological process of autophagic degradation of a whole nucleus in multinucleate cells.

  7. Characterization of HJ-PI01 as a novel Pim-2 inhibitor that induces apoptosis and autophagic cell death in triple-negative human breast cancer.

    Science.gov (United States)

    Zhao, Yu-Qian; Yin, Yi-Qiong; Liu, Jie; Wang, Gui-Hua; Huang, Jian; Zhu, Ling-Juan; Wang, Jin-Hui

    2016-09-01

    Pim-2 is a short-lived serine/threonine kinase, which plays a key role in metastasis of breast cancer through persistent activation of STAT3. Although the crystal structure of Pim-2 has been reported, but thus far no specific Pim-2-targeted compounds have been reported. In this study, we identified a novel Pim-2 inhibitor, HJ-PI01, by in silico analysis and experimental validation. The protein-protein interaction (PPI) network, chemical synthesis, molecular docking, and molecular dynamics (MD) simulations were used to design and discover the new Pim-2 inhibitor HJ-PI01. The anti-tumor effects of HJ-PI01 were evaluated in human breast MDA-MB-231, MDA-MB-468, MDA-MB-436, MCF-7 cells in vitro and in MDA-MB-231 xenograft mice, which were treated with HJ-PI01 (40 mg·kg(-1)·d(-1), ig) with or without lienal polypeptide (50 mg·kg(-1)·d(-1), ip) for 10 d. The apoptosis/autophage-inducing mechanisms of HJ-PI01 were elucidated using Western blots, immunoblots, flow cytometry, transmission electron microscopy and fluorescence microscopy. Based on the PrePPI network, the potential partners interacting with Pim-2 in regulating apoptosis (160 protein pairs) and autophagy (47 protein pairs) were identified. Based on the structural characteristics of Pim-2, a total of 15 compounds (HJ-PI01 to HJ-P015) were synthesized, which showed moderate or remarkable anti-proliferative potency in the human breast cancer cell lines tested. The most effective compound HJ-PI01 exerted a robust inhibition on MDA-MB-231 cells compared with chlorpromazine and the pan-Pim inhibitor PI003. Molecular dynamics (MD) simulation revealed that HJ-PI01 had a good binding score with Pim-2. Moreover, HJ-PI01 (300 nmol/L) induced death receptor-dependent and mitochondrial apoptosis as well as autophagic death in MDA-MB-231 cells. In MDA-MB-231 xenograft mice, administration of HJ-PI01 remarkably inhibited the tumor growth and induced tumor cell apoptosis in vivo. Co-administration of HJ-PI01 with lienal

  8. Mutations in TrkA Causing Congenital Insensitivity to Pain with Anhidrosis (CIPA) Induce Misfolding, Aggregation, and Mutation-dependent Neurodegeneration by Dysfunction of the Autophagic Flux.

    Science.gov (United States)

    Franco, María Luisa; Melero, Cristina; Sarasola, Esther; Acebo, Paloma; Luque, Alfonso; Calatayud-Baselga, Isabel; García-Barcina, María; Vilar, Marçal

    2016-10-07

    Congenital insensitivity to pain with anhidrosis (CIPA) is a rare autosomal recessive disorder characterized by insensitivity to noxious stimuli and variable intellectual disability (ID) due to mutations in the NTRK1 gene encoding the NGF receptor TrkA. To get an insight in the effect of NTRK1 mutations in the cognitive phenotype we biochemically characterized three TrkA mutations identified in children diagnosed of CIPA with variable ID. These mutations are located in different domains of the protein; L213P in the extracellular domain, Δ736 in the kinase domain, and C300stop in the extracellular domain, a new mutation causing CIPA diagnosed in a Spanish teenager. We found that TrkA mutations induce misfolding, retention in the endoplasmic reticulum (ER), and aggregation in a mutation-dependent manner. The distinct mutations are degraded with a different kinetics by different ER quality control mechanisms; although C300stop is rapidly disposed by autophagy, Δ736 degradation is sensitive to the proteasome and to autophagy inhibitors, and L213P is a long-lived protein refractory to degradation. In addition L213P enhances the formation of autophagic vesicles triggering an increase in the autophagic flux with deleterious consequences. Mouse cortical neurons expressing L213P showed the accumulation of LC3-GFP positive puncta and dystrophic neurites. Our data suggest that TrkA misfolding and aggregation induced by some CIPA mutations disrupt the autophagy homeostasis causing neurodegeneration. We propose that distinct disease-causing mutations of TrkA generate different levels of cell toxicity, which may provide an explanation of the variable intellectual disability observed in CIPA patients. © 2016 by The American Society for Biochemistry and Molecular Biology, Inc.

  9. MP Resulting in Autophagic Cell Death of Microglia through Zinc Changes against Spinal Cord Injury

    Directory of Open Access Journals (Sweden)

    Dingding Li

    2016-01-01

    Full Text Available Methylprednisolone pulse therapy (MPPT, as a public recognized therapy of spinal cord injury (SCI, is doubted recently, and the exact mechanism of MP on SCI is unclear. This study sought to investigate the exact effect of MP on SCI. We examined the effect of MP in a model of SCI in vivo and an LPS induced model in vitro. We found that administration of MP produced an increase in the Basso, Beattie, and Bresnahan scores and motor neurons counts of injured rats. Besides the number of activated microglia was apparently reduced by MP in vivo, and Beclin-1 dependent autophagic cell death of microglia was induced by MP in LPS induced model. At the same time, MP increases cellular zinc concentration and level of ZIP8, and TPEN could revert effect of MP on autophagic cell death of microglia. Finally, we have found that MP could inhibit NF-κβ in LPS induced model. These results show that the MP could result in autophagic cell death of microglia, which mainly depends on increasing cellular labile zinc, and may be associated with inhibition of NF-κβ, and that MP can produce neuroprotective effect in SCI.

  10. 1,1-Bis(3'-indolyl-1-(p-substituted phenylmethanes induce autophagic cell death in estrogen receptor negative breast cancer

    Directory of Open Access Journals (Sweden)

    Chadalapaka Gayathri

    2010-12-01

    Full Text Available Abstract Background A novel series of methylene-substituted DIMs (C-DIMs, namely 1,1-bis(3'-indolyl-1-(p-substituted phenylmethanes containing t-butyl (DIM-C-pPhtBu and phenyl (DIM-C-pPhC6H5 groups inhibit proliferation of invasive estrogen receptor-negative MDA-MB-231 and MDA-MB-453 human breast cancer cell lines with IC50 values between 1-5 uM. The main purpose of this study was to investigate the pathways of C-DIM-induced cell death. Methods The effects of the C-DIMs on apoptotic, necrotic and autophagic cell death were determined using caspase inhibitors, measurement of lactate dehydrogenase release, and several markers of autophagy including Beclin and light chain associated protein 3 expression (LC3. Results The C-DIM compounds did not induce apoptosis and only DIM-C-pPhCF3 exhibited necrotic effects. However, treatment of MDA-MB-231 and MDA-MB-453 cells with C-DIMs resulted in accumulation of LC3-II compared to LC3-I protein, a characteristic marker of autophagy, and transient transfection of green fluorescent protein-LC3 also revealed that treatment with C-DIMs induced a redistribution of LC3 to autophagosomes after C-DIM treatment. In addition, the autofluorescent drug monodansylcadaverine (MDC, a specific autophagolysosome marker, accumulated in vacuoles after C-DIM treatment, and western blot analysis of lysates from cells treated with C-DIMs showed that the Beclin 1/Bcl-2 protein ratio increased. Conclusion The results suggest that C-DIM compounds may represent a new mechanism-based agent for treating drug-resistant ER-negative breast tumors through induction of autophagy.

  11. Evidence for autophagic gridlock in aging and neurodegeneration.

    Science.gov (United States)

    Bakhoum, Mathieu F; Bakhoum, Christine Y; Ding, Zhixia; Carlton, Susan M; Campbell, Gerald A; Jackson, George R

    2014-07-01

    Autophagy is essential to neuronal homeostasis, and its impairment is implicated in the development of neurodegenerative pathology. However, the underlying mechanisms and consequences of this phenomenon remain a matter of conjecture. We show that misexpression of human tau in Drosophila induces accumulation of autophagic intermediates with a preponderance of large vacuoles, which we term giant autophagic bodies (GABs), which are reminiscent of dysfunctional autophagic entities. Lowering basal autophagy reduces GABs, whereas increasing autophagy decreases mature autolysosomes. Induction of autophagy is also associated with rescue of the tauopathy phenotype, suggesting that formation of GABs may be a compensatory mechanism rather than a trigger of neurodegeneration. Last, we show that the peculiar Biondi bodies observed in the choroid epithelium of both elderly and Alzheimer's disease human brains express immunoreactive markers similar to those of GABs. Collectively, these data indicate that autophagic gridlock contributes to the development of pathology in aging and neurodegeneration. Published by Mosby, Inc.

  12. Hesperidin induces apoptosis and triggers autophagic markers through inhibition of Aurora-A mediated phosphoinositide-3-kinase/Akt/mammalian target of rapamycin and glycogen synthase kinase-3 beta signalling cascades in experimental colon carcinogenesis.

    Science.gov (United States)

    Saiprasad, Gowrikumar; Chitra, Palanivel; Manikandan, Ramar; Sudhandiran, Ganapasam

    2014-09-01

    Abnormalities in the homeostasis mechanisms involved in cell survival and apoptosis are contributing factors for colon carcinogenesis. Interventions of these mechanisms by pharmacologically safer agents gain predominance in colon cancer prevention. We previously reported the chemopreventive efficacy of hesperidin against colon carcinogenesis. In the present study, we aimed at investigating the potential of hesperidin over the abrogated Aurora-A coupled pro-survival phosphoinositide-3-kinase (PI3K)/Akt signalling cascades. Further, the role of hesperidin over apoptosis and mammalian target of rapamycin (mTOR) mediated autophagic responses were studied. Azoxymethane (AOM) induced mouse model of colon carcinogenesis was involved in this study. Hesperidin treatment was provided either in initiation/post-initiation mode respectively. Hesperidin significantly altered AOM mediated anti-apoptotic scenario by modulating Bax/Bcl-2 ratio together with enhanced cytochrome-c release and caspase-3, 9 activations. In addition, hesperidin enhanced p53-p21 axis with concomitant decrease in cell cycle regulator. Hesperidin treatment caused significant up-regulation of tumour suppressor phosphatase and tensin homologue (PTEN) with a reduction in the expression of AOM mediated p-PI3K and p-Akt. Additionally, hesperidin administration exhibited inhibition against p-mTOR expression which in turn led to stimulation of autophagic markers Beclin-1 and LC3-II. Aurora-A an upstream regulator of PI3K/Akt pathway was significantly inhibited by hesperidin. Furthermore, hesperidin administration restored glycogen synthase kinase-3 beta (GSK-3β) activity which in turn prevented the accumulation of oncoproteins β-catenin, c-jun and c-myc. Taken together, hesperidin supplementation initiated apoptosis via targeted inhibition of constitutively activated Aurora-A mediated PI3K/Akt/GSK-3β and mTOR pathways coupled with autophagic stimulation against AOM induced colon carcinogenesis. Copyright

  13. Physiological response of Pichia pastoris GS115 to methanol-induced high level production of the Hepatitis B surface antigen: catabolic adaptation, stress responses, and autophagic processes.

    Science.gov (United States)

    Vanz, Ana Leticia; Lünsdorf, Heinrich; Adnan, Ahmad; Nimtz, Manfred; Gurramkonda, Chandrasekhar; Khanna, Navin; Rinas, Ursula

    2012-08-08

    Pichia pastoris is an established eukaryotic host for the production of recombinant proteins. Most often, protein production is under the control of the strong methanol-inducible aox1 promoter. However, detailed information about the physiological alterations in P. pastoris accompanying the shift from growth on glycerol to methanol-induced protein production under industrial relevant conditions is missing. Here, we provide an analysis of the physiological response of P. pastoris GS115 to methanol-induced high-level production of the Hepatitis B virus surface antigen (HBsAg). High product titers and the retention of the protein in the endoplasmic reticulum (ER) are supposedly of major impact on the host physiology. For a more detailed understanding of the cellular response to methanol-induced HBsAg production, the time-dependent changes in the yeast proteome and ultrastructural cell morphology were analyzed during the production process. The shift from growth on glycerol to growth and HBsAg production on methanol was accompanied by a drastic change in the yeast proteome. In particular, enzymes from the methanol dissimilation pathway started to dominate the proteome while enzymes from the methanol assimilation pathway, e.g. the transketolase DAS1, increased only moderately. The majority of methanol was metabolized via the energy generating dissimilatory pathway leading to a corresponding increase in mitochondrial size and numbers. The methanol-metabolism related generation of reactive oxygen species induced a pronounced oxidative stress response (e.g. strong increase of the peroxiredoxin PMP20). Moreover, the accumulation of HBsAg in the ER resulted in the induction of the unfolded protein response (e.g. strong increase of the ER-resident disulfide isomerase, PDI) and the ER associated degradation (ERAD) pathway (e.g. increase of two cytosolic chaperones and members of the AAA ATPase superfamily) indicating that potential degradation of HBsAg could proceed via the

  14. Physiological response of Pichia pastoris GS115 to methanol-induced high level production of the Hepatitis B surface antigen: catabolic adaptation, stress responses, and autophagic processes

    Science.gov (United States)

    2012-01-01

    Background Pichia pastoris is an established eukaryotic host for the production of recombinant proteins. Most often, protein production is under the control of the strong methanol-inducible aox1 promoter. However, detailed information about the physiological alterations in P. pastoris accompanying the shift from growth on glycerol to methanol-induced protein production under industrial relevant conditions is missing. Here, we provide an analysis of the physiological response of P. pastoris GS115 to methanol-induced high-level production of the Hepatitis B virus surface antigen (HBsAg). High product titers and the retention of the protein in the endoplasmic reticulum (ER) are supposedly of major impact on the host physiology. For a more detailed understanding of the cellular response to methanol-induced HBsAg production, the time-dependent changes in the yeast proteome and ultrastructural cell morphology were analyzed during the production process. Results The shift from growth on glycerol to growth and HBsAg production on methanol was accompanied by a drastic change in the yeast proteome. In particular, enzymes from the methanol dissimilation pathway started to dominate the proteome while enzymes from the methanol assimilation pathway, e.g. the transketolase DAS1, increased only moderately. The majority of methanol was metabolized via the energy generating dissimilatory pathway leading to a corresponding increase in mitochondrial size and numbers. The methanol-metabolism related generation of reactive oxygen species induced a pronounced oxidative stress response (e.g. strong increase of the peroxiredoxin PMP20). Moreover, the accumulation of HBsAg in the ER resulted in the induction of the unfolded protein response (e.g. strong increase of the ER-resident disulfide isomerase, PDI) and the ER associated degradation (ERAD) pathway (e.g. increase of two cytosolic chaperones and members of the AAA ATPase superfamily) indicating that potential degradation of HBsAg could

  15. Physiological response of Pichia pastoris GS115 to methanol-induced high level production of the Hepatitis B surface antigen: catabolic adaptation, stress responses, and autophagic processes

    Directory of Open Access Journals (Sweden)

    Vanz Ana Leticia

    2012-08-01

    Full Text Available Abstract Background Pichia pastoris is an established eukaryotic host for the production of recombinant proteins. Most often, protein production is under the control of the strong methanol-inducible aox1 promoter. However, detailed information about the physiological alterations in P. pastoris accompanying the shift from growth on glycerol to methanol-induced protein production under industrial relevant conditions is missing. Here, we provide an analysis of the physiological response of P. pastoris GS115 to methanol-induced high-level production of the Hepatitis B virus surface antigen (HBsAg. High product titers and the retention of the protein in the endoplasmic reticulum (ER are supposedly of major impact on the host physiology. For a more detailed understanding of the cellular response to methanol-induced HBsAg production, the time-dependent changes in the yeast proteome and ultrastructural cell morphology were analyzed during the production process. Results The shift from growth on glycerol to growth and HBsAg production on methanol was accompanied by a drastic change in the yeast proteome. In particular, enzymes from the methanol dissimilation pathway started to dominate the proteome while enzymes from the methanol assimilation pathway, e.g. the transketolase DAS1, increased only moderately. The majority of methanol was metabolized via the energy generating dissimilatory pathway leading to a corresponding increase in mitochondrial size and numbers. The methanol-metabolism related generation of reactive oxygen species induced a pronounced oxidative stress response (e.g. strong increase of the peroxiredoxin PMP20. Moreover, the accumulation of HBsAg in the ER resulted in the induction of the unfolded protein response (e.g. strong increase of the ER-resident disulfide isomerase, PDI and the ER associated degradation (ERAD pathway (e.g. increase of two cytosolic chaperones and members of the AAA ATPase superfamily indicating that potential

  16. Exposure to low-dose X-rays promotes peculiar autophagic cell death in Drosophila melanogaster, an effect that can be regulated by the inducible expression of Hml dsRNA

    Energy Technology Data Exchange (ETDEWEB)

    Kanao, Tomoko [Department of Radiological Sciences, International University of Health and Welfare, Kitakanemaru 2600-1, Ohtawara-shi, Tochigi-ken 324-8501 (Japan); Miyachi, Yukihisa [Department of Radiological Sciences, International University of Health and Welfare, Kitakanemaru 2600-1, Ohtawara-shi, Tochigi-ken 324-8501 (Japan)]. E-mail: ymiyachi@iuhw.ac.jp

    2006-03-20

    We previously reported that to induce an early emergence effect with low-dose X-irradiation in Drosophila, exposure during the prepupae stage is necessary. The present study examined the mechanism by which low-dose radiation rapidly eliminates larval cells and activates the formation of the imaginal discs during metamorphosis. Upon exposure to 0.5 Gy X-rays at 2 h after puparium formation (APF), the larval salivary glands swelled and were surrounded by remarkably thick structures containing an acid phosphatase (Acph) enzyme, implicating a peculiar autophagic cell death. TUNEL staining revealed the presence of DNA fragmentations compared with cells from sham controls which remained unchanged until 12 h APF. Additionally, the salivary glands of exposed flies were completely destroyed by 10 h APF. Furthermore, exposure to 0.5 Gy X-rays also facilitated the activity of the engulfment function of dendritic cells (DCs); they were generated in the larval salivary glands, engulfed the cell corpses and finally moved to the fat body. Data from an experiment demonstrating the inducible expression of Hml double-stranded RNA (dsRNA) indicate that a slow rate of engulfment of larval cells results in a longer time to emergence. Thus, the animals subjected to low-dose X-rays activated autophagic processes, resulting in significantly faster adult eclosion.

  17. Pirarubicin induces an autophagic cytoprotective response through suppression of the mammalian target of rapamycin signaling pathway in human bladder cancer cells

    Energy Technology Data Exchange (ETDEWEB)

    Li, Kuiqing; Chen, Xu [Department of Urology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120 (China); Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120 (China); Liu, Cheng [Department of Urology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120 (China); Gu, Peng; Li, Zhuohang; Wu, Shaoxu [Department of Urology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120 (China); Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120 (China); Xu, Kewei [Department of Urology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120 (China); Lin, Tianxin, E-mail: tianxinl@sina.com [Department of Urology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120 (China); Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120 (China); Huang, Jian, E-mail: urolhj@sina.com [Department of Urology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120 (China)

    2015-05-01

    Pirarubicin is widely used in intravesical chemotherapy for bladder cancer, but its efficacy is limited due to drug resistance; the mechanism has not been well studied. Emerging evidence shows that autophagy can be a novel target for cancer therapy. This study aimed to investigate the role of autophagy in pirarubicin-treated bladder cancer cells. Bladder cancer cells EJ and J82 were treated with pirarubicin, siRNA, 3-methyladenine or hydroxychloroquine. Cell proliferation and apoptosis were tested by cell survival assay and flow cytometric analysis, respectively. Autophagy was evaluated by immunoblotting before and after the treatments. The phosphorylated mammalian target of rapamycin, serine/threonine kinase p70 S6 kinase, and eukaryotic translation initiation factor 4E binding protein 1 were also investigated by immunoblotting. We found that pirarubicin could induce autophagy in bladder cancer cells. Inhibition of autophagy by 3-methyladenine, hydroxychloroquine or knockdown of autophagy related gene 3 significantly increased apoptosis in pirarubicin-treated bladder cancer cells. Pirarubicin-induced autophagy was mediated via the mTOR/p70S6K/4E-BP1 signaling pathway. In conclusion, autophagy induced by pirarubicin plays a cytoprotective role in bladder cancer cells, suggesting that inhibition of autophagy may improve efficacy over traditional pirarubicin chemotherapy in bladder cancer patients. - Highlights: • Pirarubicin induced autophagy in bladder cancer cells. • Inhibition of autophagy enhanced pirarubicin-induced apoptosis. • Pirarubicin induced autophagy through inhibition of mTOR signaling pathway.

  18. Attenuation of Aβ{sub 25–35}-induced parallel autophagic and apoptotic cell death by gypenoside XVII through the estrogen receptor-dependent activation of Nrf2/ARE pathways

    Energy Technology Data Exchange (ETDEWEB)

    Meng, Xiangbao; Wang, Min [Key Laboratory of Bioactive Substances and Resources Utilization of Chinese Herbal Medicine, Ministry of Education, Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100193 (China); Sun, Guibo, E-mail: sunguibo@126.com [Key Laboratory of Bioactive Substances and Resources Utilization of Chinese Herbal Medicine, Ministry of Education, Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100193 (China); Ye, Jingxue [Jilin Agricultural University, Changchun, Jilin 130021 (China); Zhou, Yanhui [Center of Cardiology, People' s Hospital of Jilin Province, Changchun, 130021, Jilin (China); Dong, Xi [Wenzhou Medical University, Wenzhou, Zhejiang 325035 (China); Wang, Tingting; Lu, Shan [Key Laboratory of Bioactive Substances and Resources Utilization of Chinese Herbal Medicine, Ministry of Education, Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100193 (China); Sun, Xiaobo, E-mail: sun_xiaobo163@163.com [Key Laboratory of Bioactive Substances and Resources Utilization of Chinese Herbal Medicine, Ministry of Education, Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100193 (China)

    2014-08-15

    Amyloid-beta (Aβ) has a pivotal function in the pathogenesis of Alzheimer's disease. To investigate Aβ neurotoxicity, we used an in vitro model that involves Aβ{sub 25–35}-induced cell death in the nerve growth factor-induced differentiation of PC12 cells. Aβ{sub 25–35} (20 μM) treatment for 24 h caused apoptotic cell death, as evidenced by significant cell viability reduction, LDH release, phosphatidylserine externalization, mitochondrial membrane potential disruption, cytochrome c release, caspase-3 activation, PARP cleavage, and DNA fragmentation in PC12 cells. Aβ{sub 25–35} treatment led to autophagic cell death, as evidenced by augmented GFP-LC3 puncta, conversion of LC3-I to LC3-II, and increased LC3-II/LC3-I ratio. Aβ{sub 25–35} treatment induced oxidative stress, as evidenced by intracellular ROS accumulation and increased production of mitochondrial superoxide, malondialdehyde, protein carbonyl, and 8-OHdG. Phytoestrogens have been proved to be protective against Aβ-induced neurotoxicity and regarded as relatively safe targets for AD drug development. Gypenoside XVII (GP-17) is a novel phytoestrogen isolated from Gynostemma pentaphyllum or Panax notoginseng. Pretreatment with GP-17 (10 μM) for 12 h increased estrogen response element reporter activity, activated PI3K/Akt pathways, inhibited GSK-3β, induced Nrf2 nuclear translocation, augmented antioxidant responsive element enhancer activity, upregulated heme oxygenase 1 (HO-1) expression and activity, and provided protective effects against Aβ{sub 25–35}-induced neurotoxicity, including oxidative stress, apoptosis, and autophagic cell death. In conclusion, GP-17 conferred protection against Aβ{sub 25–35}-induced neurotoxicity through estrogen receptor-dependent activation of PI3K/Akt pathways, inactivation of GSK-3β and activation of Nrf2/ARE/HO-1 pathways. This finding might provide novel insights into understanding the mechanism for neuroprotective effects of phytoestrogens

  19. T315 Decreases Acute Myeloid Leukemia Cell Viability through a Combination of Apoptosis Induction and Autophagic Cell Death

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    Chang-Fang Chiu

    2016-08-01

    Full Text Available T315, an integrin-linked kinase (ILK inhibitor, has been shown to suppress the proliferation of breast cancer, stomach cancer and chronic lymphocytic leukemia cells. Here we demonstrate that T315 decreases cell viability of acute myeloid leukemia (AML cell lines (HL-60 and THP-1 and primary leukemia cells from AML patients in a dose-responsive manner. Normal human bone marrow cells are less sensitive than leukemia cells to T315. T315 down regulates protein kinase B (Akt and p-Akt and induces caspase activation, poly-ADP-ribose polymerase (PARP cleavage, apoptosis and autophagy through an ILK-independent manner. Interestingly, pretreatment with autophagy inhibitors rescues cells from apoptosis and concomitant PARP cleavage, which implicates a key role of autophagic cell death in T315-mediated cytotoxicity. T315 also demonstrates efficacy in vivo, suppressing the growth of THP-1 xenograft tumors in athymic nude mice when administered intraperitoneally. This study shows that autophagic cell death and apoptosis cooperatively contribute to the anticancer activity of T315 in AML cells. In conclusion, the complementary roles of apoptotic and autophagic cell death should be considered in the future assessment of the translational value of T315 in AML therapy.

  20. Autophagic/lysosomal dysfunction in Alzheimer's disease.

    Science.gov (United States)

    Orr, Miranda E; Oddo, Salvatore

    2013-01-01

    Autophagy serves as the sole catabolic mechanism for degrading organelles and protein aggregates. Increasing evidence implicates autophagic dysfunction in Alzheimer's disease (AD) and other neurodegenerative diseases associated with protein misprocessing and accumulation. Under physiologic conditions, the autophagic/lysosomal system efficiently recycles organelles and substrate proteins. However, reduced autophagy function leads to the accumulation of proteins and autophagic and lysosomal vesicles. These vesicles contain toxic lysosomal hydrolases as well as the proper cellular machinery to generate amyloid-beta, the major component of AD plaques. Here, we provide an overview of current research focused on the relevance of autophagic/lysosomal dysfunction in AD pathogenesis as well as potential therapeutic targets aimed at restoring autophagic/lysosomal pathway function.

  1. Testosterone regulates the autophagic clearance of androgen binding protein in rat Sertoli cells

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    Ma, Yi; Yang, Hao-Zheng; Xu, Long-Mei; Huang, Yi-Ran; Dai, Hui-Li; Kang, Xiao-Nan

    2015-01-01

    Dysregulation of androgen-binding protein (ABP) is associated with a number of endocrine and andrology diseases. However, the ABP metabolism in Sertoli cells is largely unknown. We report that autophagy degrades ABP in rat Sertoli cells, and the autophagic clearance of ABP is regulated by testosterone, which prolongs the ABP biological half-life by inhibiting autophagy. Further studies identified that the autophagic clearance of ABP might be selectively regulated by testosterone, independent of stress (hypoxia)-induced autophagic degradation. These data demonstrate that testosterone up-regulates ABP expression at least partially by suppressing the autophagic degradation. We report a novel finding with respect to the mechanisms by which ABP is cleared, and by which the process is regulated in Sertoli cells. PMID:25745956

  2. Autophagic components contribute to hypersensitive cell death in Arabidopsis

    DEFF Research Database (Denmark)

    Hofius, Daniel; Schultz-Larsen, Torsten; Joensen, Jan

    2009-01-01

    expression. Here, we examined receptor-mediated HR PCD responses in autophagy-deficient Arabidopsis knockout mutants (atg), and show that infection-induced lesions are contained in atg mutants. We also provide evidence that HR cell death initiated via Toll/Interleukin-1 (TIR)-type immune receptors through...... the defense regulator EDS1 is suppressed in atg mutants. Furthermore, we demonstrate that PCD triggered by coiled-coil (CC)-type immune receptors via NDR1 is either autophagy-independent or engages autophagic components with cathepsins and other unidentified cell death mediators. Thus, autophagic cell death......Autophagy has been implicated as a prosurvival mechanism to restrict programmed cell death (PCD) associated with the pathogen-triggered hypersensitive response (HR) during plant innate immunity. This model is based on the observation that HR lesions spread in plants with reduced autophagy gene...

  3. MAPK/JNK1 activation protects cells against cadmium-induced autophagic cell death via differential regulation of catalase and heme oxygenase-1 in oral cancer cells.

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    So, Keum-Young; Kim, Sang-Hun; Jung, Ki-Tae; Lee, Hyun-Young; Oh, Seon-Hee

    2017-10-01

    Antioxidant enzymes are related to oral diseases. We investigated the roles of heme oxygenase-1 (HO-1) and catalase in cadmium (Cd)-induced oxidative stress and the underlying molecular mechanism in oral cancer cells. Exposing YD8 cells to Cd reduced the expression levels of catalase and superoxide dismutase 1/2 and induced the expression of HO-1 as well as autophagy and apoptosis, which were reversed by N-acetyl-l-cysteine (NAC). Cd-exposed YD10B cells exhibited milder effects than YD8 cells, indicating that Cd sensitivity is associated with antioxidant enzymes and autophagy. Autophagy inhibition via pharmacologic and genetic modulations enhanced Cd-induced HO-1 expression, caspase-3 cleavage, and the production of reactive oxygen species (ROS). Ho-1 knockdown increased autophagy and apoptosis. Hemin treatment partially suppressed Cd-induced ROS production and apoptosis, but enhanced autophagy and CHOP expression, indicating that autophagy induction is associated with cellular stress. Catalase inhibition by pharmacological and genetic modulations increased Cd-induced ROS production, autophagy, and apoptosis, but suppressed HO-1, indicating that catalase is required for HO-1 induction. p38 inhibition upregulated Cd-induced phospho-JNK and catalase, but suppressed HO-1, autophagy, apoptosis. JNK suppression exhibited contrary results, enhancing the expression of phospho-p38. Co-suppression of p38 and JNK1 failed to upregulate catalase and procaspase-3, which were upregulated by JNK1 overexpression. Overall, the balance between the responses of p38 and JNK activation to Cd appears to have an important role in maintaining cellular homeostasis via the regulation of antioxidant enzymes and autophagy induction. In addition, the upregulation of catalase by JNK1 activation can play a critical role in cell protection against Cd-induced oxidative stress. Copyright © 2017 Elsevier Inc. All rights reserved.

  4. Walsuronoid B induces mitochondrial and lysosomal dysfunction leading to apoptotic rather than autophagic cell death via ROS/p53 signaling pathways in liver cancer.

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    Geng, Ya-di; Zhang, Chao; Lei, Jian-Li; Yu, Pei; Xia, Yuan-Zheng; Zhang, Hao; Yang, Lei; Kong, Ling-Yi

    2017-10-15

    Walsuronoid B is a limonoid compound extracted from Walsura robusta. Previous studies have shown that limonoid compounds possess anti-cancer potential, although the molecular mechanism of this activity remains elusive. In this study, we demonstrated for the first time that walsuronoid B inhibited cell proliferation in several human cancer lines. Liver cancer cells (HepG2 and Bel-7402) were chosen for their high sensitivity to walsuronoid B. Walsuronoid B induced cell death through G2/M phase arrest and apoptosis and induced the accumulation of autophagosomes through the suppression of mTOR signaling, which serves as a cell survival mechanism and prevents cell death. We further examined the molecular mechanisms and found that walsuronoid B-induced dysfunction of the mitochondria and lysosomes rather than the endoplasmic reticulum contributed to its cell death effect. Walsuronoid B enhanced the generation of hydrogen peroxide, nitric oxide and superoxide anion radical, resulting in elevated levels of reactive oxygen species (ROS). In addition, ROS induced by walsuronoid B upregulated p53 levels; conversely, p53 stimulated ROS. These results suggested that ROS and p53 reciprocally promoted each other's production and cooperated to induce liver cancer cell death. We found that the induction of ROS and p53 significantly triggered G2/M phase arrest and mitochondrial and lysosomal apoptosis. Finally, walsuronoid B suppressed tumor growth in vivo with few side effects. In summary, our findings demonstrated that walsuronoid B caused G2/M phase arrest and induced mitochondrial and lysosomal apoptosis through the ROS/p53 signaling pathway in human liver cancer cells in vitro and in vivo. Copyright © 2017 Elsevier Inc. All rights reserved.

  5. Alpha-tocopheryl succinate inhibits autophagic survival of prostate cancer cells induced by vitamin K3 and ascorbate to trigger cell death.

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    Marco Tomasetti

    Full Text Available BACKGROUND: The redox-silent vitamin E analog α-tocopheryl succinate (α-TOS was found to synergistically cooperate with vitamin K3 (VK3 plus ascorbic acid (AA in the induction of cancer cell-selective apoptosis via a caspase-independent pathway. Here we investigated the molecular mechanism(s underlying cell death induced in prostate cancer cells by α-TOS, VK3 and AA, and the potential use of targeted drug combination in the treatment of prostate cancer. METHODOLOGY/PRINCIPAL FINDINGS: The generation of ROS, cellular response to oxidative stress, and autophagy were investigated in PC3 prostate cancer cells by using drugs at sub-toxic doses. We evaluated whether PARP1-mediated apoptosis-inducing factor (AIF release plays a role in apoptosis induced by the combination of the agents. Next, the effect of the combination of α-TOS, VK3 and AA on tumor growth was examined in nude mice. VK3 plus AA induced early ROS formation associated with induction of autophagy in response to oxidative stress, which was reduced by α-TOS, preventing the formation of autophagosomes. α-TOS induced mitochondrial destabilization leading to the release of AIF. Translocation of AIF from mitochondria to the nucleus, a result of the combinatorial treatment, was mediated by PARP1 activation. The inhibition of AIF as well as of PARP1 efficiently attenuated apoptosis triggered by the drug combination. Using a mouse model of prostate cancer, the combination of α-TOS, VK3 and AA was more efficient in tumor suppression than when the drugs were given separately, without deleterious side effects. CONCLUSIONS/SIGNIFICANCE: α-TOS, a mitochondria-targeting apoptotic agent, switches at sub-apoptotic doses from autophagy-dependent survival of cancer cells to their demise by promoting the induction of apoptosis. Given the grim prognosis for cancer patients, this finding is of potential clinical relevance.

  6. Chikungunya triggers an autophagic process which promotes viral replication

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    Briant Laurence

    2011-09-01

    Full Text Available Abstract Background Chikungunya Virus (ChikV surprised by a massive re-emerging outbreak in Indian Ocean in 2006, reaching Europe in 2007 and exhibited exceptional severe physiopathology in infants and elderly patients. In this context, it is important to analyze the innate immune host responses triggered against ChikV. Autophagy has been shown to be an important component of the innate immune response and is involved in host defense elimination of different pathogens. However, the autophagic process was recently observed to be hijacked by virus for their own replication. Here we provide the first evidence that hallmarks of autophagy are specifically found in HEK.293 infected cells and are involved in ChikV replication. Methods To test the capacity of ChikV to mobilize the autophagic machinery, we performed fluorescence microscopy experiments on HEK.GFP.LC3 stable cells, and followed the LC3 distribution during the time course of ChikV infection. To confirm this, we performed electron microscopy on HEK.293 infected cells. To test the effect of ChikV-induced-autophagy on viral replication, we blocked the autophagic process, either by pharmacological (3-MA or genetic inhibition (siRNA against the transcript of Beclin 1, an autophagic protein, and analyzed the percentage of infected cells and the viral RNA load released in the supernatant. Moreover, the effect of induction of autophagy by Rapamycin on viral replication was tested. Results The increasing number of GFP-LC3 positive cells with a punctate staining together with the enhanced number of GFP-LC3 dots per cell showed that ChikV triggered an autophagic process in HEK.293 infected cells. Those results were confirmed by electron microscopy analysis since numerous membrane-bound vacuoles characteristic of autophagosomes were observed in infected cells. Moreover, we found that inhibition of autophagy, either by biochemical reagent and RNA interference, dramatically decreases ChikV replication

  7. Autophagic activity and aging in human odontoblasts.

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    Couve, E; Schmachtenberg, O

    2011-04-01

    Odontoblasts are long-lived post-mitotic cells in the dental pulp, whose function is to form and maintain dentin. The survival mechanisms that preserve the viability of terminally differentiated odontoblasts during the life of a healthy tooth have not been described. In the present study, we characterized the autophagic-lysosomal system of human odontoblasts with transmission electron microscopy and immunocytochemistry, to analyze the mechanisms that maintain the functional viability of these dentinogenic cells. Odontoblasts were found to develop an autophagic-lysosomal system organized mainly by large autophagic vacuoles that are acid-phosphatase-positive to various degrees. These vacuoles expressed the autophagosomal and lysosomal markers LC3 and LAMP2, respectively, in an age-related pattern indicating the organization of a dynamic autophagic machinery. Progressive accumulation of lipofuscin within lysosomes indicates reduced lysosomal activity as a function of odontoblast aging. Our results suggest that autophagic activity in odontoblasts is a fundamental mechanism to ensure turnover and degradation of subcellular components. A reduction in the efficacy of this system might compromise cell viability and dentinogenic secretory capacity. In adult teeth, this condition is described as an 'old odontoblast' stage.

  8. Anti-osteoclastogenesis of Mineral Trioxide Aggregate through Inhibition of the Autophagic Pathway.

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    Cheng, Xue; Zhu, Lingxin; Zhang, Jie; Yu, Jingjing; Liu, Shan; Lv, Fengyuan; Lin, Ying; Liu, Guojing; Peng, Bin

    2017-05-01

    Mineral trioxide aggregate (MTA) regulates bone remodeling, particularly osteoclast differentiation. However, intracellular mechanisms underlying the anti-osteoclastogenesis of MTA remain unclear. This study aimed to evaluate the potential alterations of autophagic pathway during anti-osteoclastogenic effects by MTA in vitro and investigate their underlying mechanisms. Osteoclast precursors were treated with MTA extracts containing the receptor activator of nuclear factor-kappa B ligand (RANKL). Rapamycin was used to activate autophagy. RANKL-induced osteoclast differentiation was stained with tartrate-resistant acid phosphatase. Several specific autophagy features in osteoclast precursors were measured by using immunofluorescence, monodansylcadaverine, and transmission electron microscope. Autophagy-related proteins were investigated via Western blot analysis. The mRNA expression involved in autophagic and osteoclastic activities was detected with quantitative real-time polymerase chain reaction. MTA extracts inhibited osteoclast differentiation via preventing the fusion of osteoclast precursors without cytotoxicity. MTA extracts interrupted RANKL-induced acidic vesicular organelle formation and autophagic vacuole appearance in osteoclast precursors. Moreover, autophagic genes and proteins stimulated with RANKL diminished with MTA extracts. Notably, autophagy activation through rapamycin promoted multinucleated osteoclasts formation and increased osteoclastic genes expression, which almost reversed MTA-mediated anti-osteoclastogenic effects. MTA inhibited osteoclastogenesis for bone repair through attenuating the autophagic pathway. Copyright © 2017 American Association of Endodontists. Published by Elsevier Inc. All rights reserved.

  9. Natural Compounds from Herbs that can Potentially Execute as Autophagy Inducers for Cancer Therapy.

    Science.gov (United States)

    Lin, Shian-Ren; Fu, Yaw-Syan; Tsai, May-Jywan; Cheng, Henrich; Weng, Ching-Feng

    2017-07-01

    Accumulated evidence indicates that autophagy is a response of cancer cells to various anti-cancer therapies. Autophagy is designated as programmed cell death type II, and is characterized by the formation of autophagic vacuoles in the cytoplasm. Numerous herbs, including Chinese herbs, have been applied to cancer treatments as complementary and alternative medicines, supplements, or nutraceuticals to dampen the side or adverse effects of chemotherapy drugs. Moreover, the tumor suppressive actions of herbs and natural products induced autophagy that may lead to cell senescence, increase apoptosis-independent cell death or complement apoptotic processes. Hereby, the underlying mechanisms of natural autophagy inducers are cautiously reviewed in this article. Additionally, three natural compounds-curcumin, 16-hydroxycleroda-3,13-dien-15,16-olide, and prodigiosin-are presented as candidates for autophagy inducers that can trigger cell death in a supplement or alternative medicine for cancer therapy. Despite recent advancements in therapeutic drugs or agents of natural products in several cancers, it warrants further investigation in preclinical and clinical studies.

  10. Natural Compounds from Herbs that can Potentially Execute as Autophagy Inducers for Cancer Therapy

    Directory of Open Access Journals (Sweden)

    Shian-Ren Lin

    2017-07-01

    Full Text Available Accumulated evidence indicates that autophagy is a response of cancer cells to various anti-cancer therapies. Autophagy is designated as programmed cell death type II, and is characterized by the formation of autophagic vacuoles in the cytoplasm. Numerous herbs, including Chinese herbs, have been applied to cancer treatments as complementary and alternative medicines, supplements, or nutraceuticals to dampen the side or adverse effects of chemotherapy drugs. Moreover, the tumor suppressive actions of herbs and natural products induced autophagy that may lead to cell senescence, increase apoptosis-independent cell death or complement apoptotic processes. Hereby, the underlying mechanisms of natural autophagy inducers are cautiously reviewed in this article. Additionally, three natural compounds—curcumin, 16-hydroxycleroda-3,13-dien-15,16-olide, and prodigiosin—are presented as candidates for autophagy inducers that can trigger cell death in a supplement or alternative medicine for cancer therapy. Despite recent advancements in therapeutic drugs or agents of natural products in several cancers, it warrants further investigation in preclinical and clinical studies.

  11. Dihydroartemisinin Exerts Anti-Tumor Activity by Inducing Mitochondrion and Endoplasmic Reticulum Apoptosis and Autophagic Cell Death in Human Glioblastoma Cells

    Directory of Open Access Journals (Sweden)

    Chengbin Qu

    2017-09-01

    Full Text Available Glioblastoma (GBM is the most advanced and aggressive form of gliomas. Dihydroartemisinin (DHA has been shown to exhibit anti-tumor activity in various cancer cells. However, the effect and molecular mechanisms underlying its anti-tumor activity in human GBM cells remain to be elucidated. Our results proved that DHA treatment significantly reduced cell viability in a dose- and time-dependent manner by CCK-8 assay. Further investigation identified that the cell viability was rescued by pretreatment either with Z-VAD-FMK, 3-methyladenine (3-MA or in combination. Moreover, DHA induced apoptosis of GBM cells through mitochondrial membrane depolarization, release of cytochrome c and activation of caspases-9. Enhanced expression of GRP78, CHOP and eIF2α and activation of caspase 12 were additionally confirmed that endoplasmic reticulum (ER stress pathway of apoptosis was involved in the cytotoxicity of DHA. DHA-treated GBM cells exhibited the morphological and biochemical changes typical of autophagy. Co-treatment with chloroquine (CQ significantly induced the above effects. Furthermore, ER stress and mitochondrial dysfunction were involved in the DHA-induced autophagy. Further study revealed that accumulation of reactive oxygen species (ROS was attributed to the DHA induction of apoptosis and autophagy. The illustration of these molecular mechanisms will present a novel insight for the treatment of human GBM.

  12. Combined efficacy of cediranib and quinacrine in glioma is enhanced by hypoxia and causally linked to autophagic vacuole accumulation.

    Science.gov (United States)

    Lobo, Merryl R; Wang, Xiaoyan; Gillespie, G Yancey; Woltjer, Randall L; Pike, Martin M

    2014-01-01

    We have previously reported that the in vivo anti-glioma efficacy of the anti-angiogenic receptor tyrosine kinase inhibitor cediranib is substantially enhanced via combination with the late-stage autophagy inhibitor quinacrine. The current study investigates the role of hypoxia and autophagy in combined cediranib/quinacrine efficacy. EF5 immunostaining revealed a prevalence of hypoxia in mouse intracranial 4C8 glioma, consistent with high-grade glioma. MTS cell viability assays using 4C8 glioma cells revealed that hypoxia potentiated the efficacy of combined cediranib/quinacrine: cell viability reductions induced by 1 µM cediranib +2.5 µM quinacrine were 78±7% (hypoxia) vs. 31±3% (normoxia), pvacuole biomarker LC3-II increased robustly in response to cediranib, quinacrine, or hypoxia. Combined cediranib/quinacrine increased LC3-II further, with the largest increases occurring with combined cediranib/quinacrine/hypoxia. Early stage autophagy inhibitor 3-MA prevented LC3-II accumulation with combined cediranib/quinacrine/hypoxia and substantially attenuated the associated reduction in cell viability. Combined efficacy of cediranib with bafilomycin A1, another late-stage autophagy inhibitor, was additive but lacked substantial potentiation by hypoxia. Substantially lower LC3-II accumulation was observed with bafilomycin A1 in comparison to quinacrine. Cediranib and quinacrine each strongly inhibited Akt phosphoryation, while bafilomycin A1 had no effect. Our results provide compelling evidence that autophagic vacuole accumulation plays a causal role in the anti-glioma cytotoxic efficacy of combined cediranib/quinacrine. Such accumulation is likely related to stimulation of autophagosome induction by hypoxia, which is prevalent in the glioma tumor microenvironment, as well as Akt signaling inhibition from both cediranib and quinacrine. Quinacrine's unique ability to inhibit both Akt and autophagic vacuole degradation may enhance its ability to drive cytotoxic

  13. Photodynamic therapy (PDT) resistance by PARP1 regulation on PDT-induced apoptosis with autophagy in head and neck cancer cells.

    Science.gov (United States)

    Kim, Jisun; Lim, Wonbong; Kim, Sangwoo; Jeon, Sangmi; Hui, Zheng; Ni, Kou; Kim, Changsu; Im, Yeonggwan; Choi, Hongran; Kim, Okjoon

    2014-10-01

    Photodynamic therapy (PDT) is an anticancer treatment that generates excessive reactive oxygen species after photosensitizer treatments following specific wavelength irradiation. In another reports, PDT was regulated with autophagic cell death and apoptotic cell death. However, the mechanism of PDT resistance in PDT-stimulated cell death is unclear. In this study, we determined PDT resistance by autophagy and apoptosis in HP-PDT-treated oral cancer cells. Cells were treated hematoporphyrin and then irradiation with or without inhibitor. Cell lysates were checked protein expression with specific antibody. PDT resistance cells were generated with PDT repeated treatments. In HP-PDT, PDT induced autophagy through mTOR, ATG5, and LC3 in dose-dependent manners. Also, PDT at high dose induced apoptosis through caspase activation and PARP-1. Moreover, PARP-1 inhibitor protected cells against HP-PDT-induced cell death, but not by caspase inhibitor. At low dose of HP, autophagy inhibitor partially protected from HP-PDT-induced cell death. In autophagy phases, at low doses, HP-PDT regulated autophagic cell death through the inhibition of LC3II. Although autophagy inhibitor did not alter cell death directly, autophagy has associated with HP-PDT-induced apoptotic cell death by PARP-1 regulation. Taken together, HP-PDT induces apoptotic cell death with autophagy in oral cancer cells. PDT resistance is related to autophagy by PARP-1 regulation in oral cancer cells. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  14. Titanium Dioxide Nanoparticles Induce Endoplasmic Reticulum Stress-Mediated Autophagic Cell Death via Mitochondria-Associated Endoplasmic Reticulum Membrane Disruption in Normal Lung Cells.

    Directory of Open Access Journals (Sweden)

    Kyeong-Nam Yu

    Full Text Available Nanomaterials are used in diverse fields including food, cosmetic, and medical industries. Titanium dioxide nanoparticles (TiO2-NP are widely used, but their effects on biological systems and mechanism of toxicity have not been elucidated fully. Here, we report the toxicological mechanism of TiO2-NP in cell organelles. Human bronchial epithelial cells (16HBE14o- were exposed to 50 and 100 μg/mL TiO2-NP for 24 and 48 h. Our results showed that TiO2-NP induced endoplasmic reticulum (ER stress in the cells and disrupted the mitochondria-associated endoplasmic reticulum membranes (MAMs and calcium ion balance, thereby increasing autophagy. In contrast, an inhibitor of ER stress, tauroursodeoxycholic acid (TUDCA, mitigated the cellular toxic response, suggesting that TiO2-NP promoted toxicity via ER stress. This novel mechanism of TiO2-NP toxicity in human bronchial epithelial cells suggests that further exhaustive research on the harmful effects of these nanoparticles in relevant organisms is needed for their safe application.

  15. Suppression of PC-1/PrLZ sensitizes prostate cancer cells to ionizing radiation by attenuating DNA damage repair and inducing autophagic cell death.

    Science.gov (United States)

    Shang, Zeng-Fu; Wei, Qiang; Yu, Lan; Huang, Fang; Xiao, Bei-Bei; Wang, Hongtao; Song, Man; Wang, Li; Zhou, Jianguang; Wang, Jian; Li, Shanhu

    2016-09-20

    Radiotherapy is promising and effective for treating prostate cancer but the addition of a tumor cell radiosensitizer would improve therapeutic outcomes. PC-1/PrLZ, a TPD52 protein family member is frequently upregulated in advanced prostate cancer cells and may be a biomarker of aggressive prostate cancer. Therefore, we investigated the potential role of PC-1/PrLZ for increasing radioresistance in human prostate cancer cell lines. Growth curves and survival assays after g-ray irradiation confirmed that depletion of endogenous PC-1/PrLZ significantly increased prostate cancer cell radiosensitivity. Irradiation (IR) increased PC-1/PrLZ expression in a dose- and time-dependent manner and increased radiosensitivity in PC-1/PrLZ-suppressed cells was partially due to decreased DNA double strand break (DBS) repair which was measured with comet and gH2AX foci assays. Furthermore, depletion of PC-1/PrLZ impaired the IR-induced G2/M checkpoint, which has been reported to be correlate with radioresistance in cancer cells. PC-1/PrLZ-deficient cells exhibited higher level of autophagy when compared with control cells. Thus, specific inhibition of PC-1/PrLZ might provide a novel therapeutic strategy for radiosensitizing prostate cancer cells.

  16. Autophagic flux is highly active in early mitosis and differentially regulated throughout the cell cycle

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    Li, Zhiyuan; Ji, Xinmiao; Wang, Dongmei; Liu, Juanjuan; Zhang, Xin

    2016-01-01

    Mitosis is a fast process that involves dramatic cellular remodeling and has a high energy demand. Whether autophagy is active or inactive during the early stages of mitosis in a naturally dividing cell is still debated. Here we aimed to use multiple assays to resolve this apparent discrepancy. Although the LC3 puncta number was reduced in mitosis, the four different cell lines we tested all have active autophagic flux in both interphase and mitosis. In addition, the autophagic flux was highly active in nocodazole-induced, double-thymidine synchronization released as well as naturally occurring mitosis in HeLa cells. Multiple autophagy proteins are upregulated in mitosis and the increased Beclin-1 level likely contributes to the active autophagic flux in early mitosis. It is interesting that although the autophagic flux is active throughout the cell cycle, early mitosis and S phase have relatively higher autophagic flux than G1 and late G2 phases, which might be helpful to degrade the damaged organelles and provide energy during S phase and mitosis. PMID:27213594

  17. Heterogeneity of autophagic status in pancreatic β cells under metabolic stress.

    Science.gov (United States)

    Kamitani, Mai; Miyatsuka, Takeshi; Miura, Masaki; Azuma, Kosuke; Suzuki, Luka; Himuro, Miwa; Katahira, Takehiro; Nishida, Yuya; Fujitani, Yoshio; Watada, Hirotaka

    2018-02-05

    Autophagy in β cells has been demonstrated to play a pivotal role in cellular homeostasis and the progression of glucose intolerance. Although autophagic activity is affected by metabolic stress both in vivo and in vitro, it remains unclear as to what extent the autophagic status in each β cell is different from its neighboring cells. To address this question, GFP-LC3 reporter mice, which can visualize the autophagic status of each β cell as green-fluorescent puncta, were crossed with obese diabetic db/db mice. Imaging of green-fluorescent puncta in the islets of GFP-LC3 mice revealed that β cells are a heterogeneous population, as the density of GFP-LC3 puncta in each cell was variable. Furthermore, the variability was greater in GFP-LC3; db/db mice than in non-diabetic GFP-LC3; db/+ mice. Furthermore, when GFP-LC3 mice were treated with a low dose of S961, which antagonizes insulin signaling without inducing overt hyperglycemia, the number of β cells with a high density of GFP puncta was increased, suggesting that insulin resistance affects autophagic status independently of glucose profiles. These results suggest that pancreatic β cells under metabolic stress are heterogeneous regarding their autophagic status, which provides insights into the cellular dynamics of each β cell rather than the whole β-cell population. Copyright © 2018 Elsevier Inc. All rights reserved.

  18. Lung autophagic response following exposure of mice to whole body irradiation, with and without amifostine

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    Zois, Christos E. [Department of Radiotherapy - Oncology, Democritus University of Thrace, Alexandroupolis 68100 (Greece); Giatromanolaki, Alexandra [Department of Pathology, Democritus University of Thrace, Alexandroupolis (Greece); Kainulainen, Heikki [Department of Biology of Physical Activity, University of Jyvaeskylae (Finland); Botaitis, Sotirios [Department of Experimental Surgery, Democritus University of Thrace, Alexandroupolis (Greece); Torvinen, Sira [Department of Biology of Physical Activity, University of Jyvaeskylae (Finland); Simopoulos, Constantinos [Department of Experimental Surgery, Democritus University of Thrace, Alexandroupolis (Greece); Kortsaris, Alexandros [Department of Biochemistry, Democritus University of Thrace, Alexandroupolis (Greece); Sivridis, Efthimios [Department of Pathology, Democritus University of Thrace, Alexandroupolis (Greece); Koukourakis, Michael I., E-mail: targ@her.forthnet.gr [Department of Radiotherapy - Oncology, Democritus University of Thrace, Alexandroupolis 68100 (Greece)

    2011-01-07

    Research highlights: {yields} We investigated the effect 6 Gy of WBI on the autophagic machinery of normal mouse lung. {yields} Irradiation induces dysfunction of the autophagic machinery in normal lung, characterized by decreased transcription of the LC3A/Beclin-1 mRNA and accumulation of the LC3A, and p62 proteins. {yields} The membrane bound LC3A-II protein levels increased in the cytosolic fraction (not in the pellet), contrasting the patterns noted after starvation-induced autophagy. {yields} Administration of amifostine, reversed all the LC3A and p62 findings, suggesting protection of the normal autophagic function. -- Abstract: Purpose: The effect of ionizing irradiation on the autophagic response of normal tissues is largely unexplored. Abnormal autophagic function may interfere the protein quality control leading to cell degeneration and dysfunction. This study investigates its effect on the autophagic machinery of normal mouse lung. Methods and materials: Mice were exposed to 6 Gy of whole body {gamma}-radiation and sacrificed at various time points. The expression of MAP1LC3A/LC3A/Atg8, beclin-1, p62/sequestosome-1 and of the Bnip3 proteins was analyzed. Results: Following irradiation, the LC3A-I and LC3A-II protein levels increased significantly at 72 h and 7 days. Strikingly, LC3A-II protein was increased (5.6-fold at 7 days; p < 0.001) only in the cytosolic fraction, but remained unchanged in the membrane fraction. The p62 protein, was significantly increased in both supernatant and pellet fraction (p < 0.001), suggesting an autophagosome turnover deregulation. These findings contrast the patterns of starvation-induced autophagy up-regulation. Beclin-1 levels remained unchanged. The Bnip3 protein was significantly increased at 8 h, but it sharply decreased at 72 h (p < 0.05). Administration of amifostine (200 mg/kg), 30 min before irradiation, reversed all the LC3A and p62 findings on blots, suggesting restoration of the normal autophagic function

  19. Combined efficacy of cediranib and quinacrine in glioma is enhanced by hypoxia and causally linked to autophagic vacuole accumulation.

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    Merryl R Lobo

    Full Text Available We have previously reported that the in vivo anti-glioma efficacy of the anti-angiogenic receptor tyrosine kinase inhibitor cediranib is substantially enhanced via combination with the late-stage autophagy inhibitor quinacrine. The current study investigates the role of hypoxia and autophagy in combined cediranib/quinacrine efficacy. EF5 immunostaining revealed a prevalence of hypoxia in mouse intracranial 4C8 glioma, consistent with high-grade glioma. MTS cell viability assays using 4C8 glioma cells revealed that hypoxia potentiated the efficacy of combined cediranib/quinacrine: cell viability reductions induced by 1 µM cediranib +2.5 µM quinacrine were 78±7% (hypoxia vs. 31±3% (normoxia, p<0.05. Apoptosis was markedly increased for cediranib/quinacrine/hypoxia versus all other groups. Autophagic vacuole biomarker LC3-II increased robustly in response to cediranib, quinacrine, or hypoxia. Combined cediranib/quinacrine increased LC3-II further, with the largest increases occurring with combined cediranib/quinacrine/hypoxia. Early stage autophagy inhibitor 3-MA prevented LC3-II accumulation with combined cediranib/quinacrine/hypoxia and substantially attenuated the associated reduction in cell viability. Combined efficacy of cediranib with bafilomycin A1, another late-stage autophagy inhibitor, was additive but lacked substantial potentiation by hypoxia. Substantially lower LC3-II accumulation was observed with bafilomycin A1 in comparison to quinacrine. Cediranib and quinacrine each strongly inhibited Akt phosphoryation, while bafilomycin A1 had no effect. Our results provide compelling evidence that autophagic vacuole accumulation plays a causal role in the anti-glioma cytotoxic efficacy of combined cediranib/quinacrine. Such accumulation is likely related to stimulation of autophagosome induction by hypoxia, which is prevalent in the glioma tumor microenvironment, as well as Akt signaling inhibition from both cediranib and quinacrine

  20. The cycloartane triterpenoid ADCX impairs autophagic degradation through Akt overactivation and promotes apoptotic cell death in multidrug-resistant HepG2/ADM cells.

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    Sun, Haiyan; Huang, Maohua; Yao, Nan; Hu, Jianyang; Li, Yingjie; Chen, Liping; Hu, Nan; Ye, Wencai; Chi-Shing Tai, William; Zhang, Dongmei; Chen, Sibao

    2017-12-15

    Multidrug resistance is the main obstacle in cancer chemotherapy. Emerging evidence demonstrates the important role of autophagy in cancer cell resistance to chemotherapy. Therefore, autophagy inhibition by natural compounds may be a promising strategy for overcoming drug resistance in liver cancer cells. Here, we found that ADCX, a natural cycloartane triterpenoid extracted from the traditional Chinese medicine (TCM) source Cimicifugae rhizoma (Shengma), impaired autophagic degradation by suppressing lysosomal cathepsin B (CTSB) expression in multidrug-resistant liver cancer HepG2/ADM cells, thereby leading to autophagic flux inhibition. Moreover, impairing autophagic flux promoted ADCX-induced apoptotic cell death in HepG2/ADM cells. Interestingly, Akt was overactivated by ADCX treatment, which downregulated CTSB and inhibited autophagic flux. Together, our results provide the first demonstration that an active TCM constituent can overcome multidrug resistance in liver cancer cells via Akt-mediated inhibition of autophagic degradation. Copyright © 2017 Elsevier Inc. All rights reserved.

  1. Normal autophagic activity in macrophages from mice lacking Gαi3, AGS3, or RGS19.

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    Ali Vural

    Full Text Available In macrophages autophagy assists antigen presentation, affects cytokine release, and promotes intracellular pathogen elimination. In some cells autophagy is modulated by a signaling pathway that employs Gαi3, Activator of G-protein Signaling-3 (AGS3/GPSM1, and Regulator of G-protein Signaling 19 (RGS19. As macrophages express each of these proteins, we tested their importance in regulating macrophage autophagy. We assessed LC3 processing and the formation of LC3 puncta in bone marrow derived macrophages prepared from wild type, Gnai3(-/-, Gpsm1(-/-, or Rgs19(-/- mice following amino acid starvation or Nigericin treatment. In addition, we evaluated rapamycin-induced autophagic proteolysis rates by long-lived protein degradation assays and anti-autophagic action after rapamycin induction in wild type, Gnai3(-/-, and Gpsm1(-/- macrophages. In similar assays we compared macrophages treated or not with pertussis toxin, an inhibitor of GPCR (G-protein couple receptor triggered Gαi nucleotide exchange. Despite previous findings, the level of basal autophagy, autophagic induction, autophagic flux, autophagic degradation and the anti-autophagic action in macrophages that lacked Gαi3, AGS3, or RGS19; or had been treated with pertussis toxin, were similar to controls. These results indicate that while Gαi signaling may impact autophagy in some cell types it does not in macrophages.

  2. The Autophagic Machinery in Enterovirus Infection

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    Jeffrey K. F. Lai

    2016-01-01

    Full Text Available The Enterovirus genus of the Picornaviridae family comprises many important human pathogens, including polioviruses, rhinovirus, enterovirus A71, and enterovirus D68. They cause a wide variety of diseases, ranging from mild to severe life-threatening diseases. Currently, no effective vaccine is available against enteroviruses except for poliovirus. Enteroviruses subvert the autophagic machinery to benefit their assembly, maturation, and exit from host. Some enteroviruses spread between cells via a process described as autophagosome-mediated exit without lysis (AWOL. The early and late phases of autophagy are regulated through various lipids and their metabolizing enzymes. Some of these lipids and enzymes are specifically regulated by enteroviruses. In the present review, we summarize the current understanding of the regulation of autophagic machinery by enteroviruses, and provide updates on recent developments in this field.

  3. Factitious panniculitis induced by cupping therapy.

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    Moon, Suk-Ho; Han, Hyun-Ho; Rhie, Jong-Won

    2011-11-01

    Cupping therapy is an alternative medical procedure that has been widely performed in Asian countries to relieve pain. It is known that there is no complication to this therapy, so many non-health care professionals have performed this procedure. However, there have been few reports on complications, such as iron deficiency anemia, hemorrhagic bullae, kelloids, vasovagal syncope, and foreign body reactions. Masses associated with panniculitis induced by cupping are extremely rare, and they require a unique approach.A 56-year-old woman presented with a 10-month history of multiple masses in the posterior neck and right shoulder areas. The patient repeatedly attempted cupping therapy by herself, and multiple palpable masses developed in the posterior neck and right shoulder area where cupping therapy had been performed. The masses were enlarged by repeated cupping, and they decreased in size when cupping was stopped. Among all lesions, the 2 masses with tenderness were surgically excised. The remaining masses resolved after cupping therapy was ceased. When a patient with subcutaneous mass has a history of cupping or trace of cupping marks, panniculitis induced by cupping should be suspected. The lesion seems to spontaneously resolve unless they are repeatedly stimulated. However, surgical resection is considered in patients with infections or severe tenderness as a complication.

  4. Autophagic clearance of bacterial pathogens: molecular recognition of intracellular microorganisms.

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    Pareja, Maria Eugenia Mansilla; Colombo, Maria I

    2013-01-01

    Autophagy is involved in several physiological and pathological processes. One of the key roles of the autophagic pathway is to participate in the first line of defense against the invasion of pathogens, as part of the innate immune response. Targeting of intracellular bacteria by the autophagic machinery, either in the cytoplasm or within vacuolar compartments, helps to control bacterial proliferation in the host cell, controlling also the spreading of the infection. In this review we will describe the means used by diverse bacterial pathogens to survive intracellularly and how they are recognized by the autophagic molecular machinery, as well as the mechanisms used to avoid autophagic clearance.

  5. Autophagic cell death: Loch Ness monster or endangered species?

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    Shen, Han-Ming; Codogno, Patrice

    2011-05-01

    The concept of autophagic cell death was first established based on observations of increased autophagic markers in dying cells. The major limitation of such a morphology-based definition of autophagic cell death is that it fails to establish the functional role of autophagy in the cell death process, and thus contributes to the confusion in the literature regarding the role of autophagy in cell death and cell survival. Here we propose to define autophagic cell death as a modality of non-apoptotic or necrotic programmed cell death in which autophagy serves as a cell death mechanism, upon meeting the following set of criteria: (i) cell death occurs without the involvement of apoptosis; (ii) there is an increase of autophagic flux, and not just an increase of the autophagic markers, in the dying cells; and (iii) suppression of autophagy via both pharmacological inhibitors and genetic approaches is able to rescue or prevent cell death. In light of this new definition, we will discuss some of the common problems and difficulties in the study of autophagic cell death and also revisit some well-reported cases of autophagic cell death, aiming to achieve a better understanding of whether autophagy is a real killer, an accomplice or just an innocent bystander in the course of cell death. At present, the physiological relevance of autophagic cell death is mainly observed in lower eukaryotes and invertebrates such as Dictyostelium discoideum and Drosophila melanogaster. We believe that such a clear definition of autophagic cell death will help us study and understand the physiological or pathological relevance of autophagic cell death in mammals.

  6. Autophagic regulation of smooth muscle cell biology

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    Joshua K. Salabei

    2015-04-01

    Full Text Available Autophagy regulates the metabolism, survival, and function of numerous cell types, including those comprising the cardiovascular system. In the vasculature, changes in autophagy have been documented in atherosclerotic and restenotic lesions and in hypertensive vessels. The biology of vascular smooth muscle cells appears particularly sensitive to changes in the autophagic program. Recent evidence indicates that stimuli or stressors evoked during the course of vascular disease can regulate autophagic activity, resulting in modulation of VSMC phenotype and viability. In particular, certain growth factors and cytokines, oxygen tension, and pharmacological drugs have been shown to trigger autophagy in smooth muscle cells. Importantly, each of these stimuli has a redox component, typically associated with changes in the abundance of reactive oxygen, nitrogen, or lipid species. Collective findings support the hypothesis that autophagy plays a critical role in vascular remodeling by regulating smooth muscle cell phenotype transitions and by influencing the cellular response to stress. In this graphical review, we summarize current knowledge on the role of autophagy in the biology of the smooth muscle cell in (pathophysiology.

  7. Monitoring Autophagic Responses in Caenorhabditis elegans.

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    Papandreou, M E; Tavernarakis, N

    2017-01-01

    Autophagy, from the Greek auto (self) and phagy (eating), is a self-degradative process critical for eukaryotic cell homeostasis. Its rapidly responsive, highly dynamic nature renders this process essential for adapting to and offsetting acute/harsh conditions such as starvation, organelle dysfunction, and deoxyribonucleic acid (DNA) damage. Autophagy involves an intricate network of interacting factors with multiple levels of control. Importantly, dysregulation of autophagy has been linked to numerous debilitating pathologies, including cancer and neurodegenerative conditions in humans. Methods to monitor and quantify autophagic activity reliably are essential both for studying the basic mechanisms of autophagy and for dissecting its involvement in disease. The nematode Caenorhabditis elegans is a particularly suitable model organism to effectively visualize and study autophagy, in vivo, in a physiological and pathological context due to its optical transparency, experimental malleability, and precise developmental and anatomical characterization. Here, we outline the main tools and approaches to monitor and measure autophagic responses in C. elegans. © 2017 Elsevier Inc. All rights reserved.

  8. ROS-Dependent Activation of Autophagy through the PI3K/Akt/mTOR Pathway Is Induced by Hydroxysafflor Yellow A-Sonodynamic Therapy in THP-1 Macrophages

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    Yueqing Jiang

    2017-01-01

    Full Text Available Monocyte-derived macrophages participate in infaust inflammatory responses by secreting various types of proinflammatory factors, resulting in further inflammatory reactions in atherosclerotic plaques. Autophagy plays an important role in inhibiting inflammation; thus, increasing autophagy may be a therapeutic strategy for atherosclerosis. In the present study, hydroxysafflor yellow A-mediated sonodynamic therapy was used to induce autophagy and inhibit inflammation in THP-1 macrophages. Following hydroxysafflor yellow A-mediated sonodynamic therapy, autophagy was induced as shown by the conversion of LC3-II/LC3-I, increased expression of beclin 1, degradation of p62, and the formation of autophagic vacuoles. In addition, inflammatory factors were inhibited. These effects were blocked by Atg5 siRNA, the autophagy inhibitor 3-methyladenine, and the reactive oxygen species scavenger N-acetyl cysteine. Moreover, AKT phosphorylation at Ser473 and mTOR phosphorylation at Ser2448 decreased significantly after HSYA-SDT. These effects were inhibited by the PI3K inhibitor LY294002, the AKT inhibitor triciribine, the mTOR inhibitor rapamycin, mTOR siRNA, and N-acetyl cysteine. Our results demonstrate that HSYA-SDT induces an autophagic response via the PI3K/Akt/mTOR signaling pathway and inhibits inflammation by reactive oxygen species in THP-1 macrophages.

  9. Evidence for the recruitment of autophagic vesicles in human brain after stroke.

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    Frugier, Tony; Taylor, Juliet M; McLean, Catriona; Bye, Nicole; Beart, Philip M; Devenish, Rodney J; Crack, Peter J

    2016-06-01

    Autophagy is a homeostatic process for recycling proteins and organelles that is increasingly being proposed as a therapeutic target for acute and chronic neurodegenerative diseases, including stroke. Confirmation that autophagy is present in the human brain after stroke is imperative before prospective therapies can begin the translational process into clinical trials. Our current study using human post-mortem tissue observed an increase in staining in microtubule-associated protein 1 light chain 3 (LC3), sequestosome 1 (SQSTM1; also known as p62) and the increased appearance of autophagic vesicles after stroke. These data confirm that alterations in autophagy take place in the human brain after stroke and suggest that targeting autophagic processes after stroke may have clinical significance. Copyright © 2016 Elsevier Ltd. All rights reserved.

  10. Methylene blue photodynamic therapy induces selective and massive cell death in human breast cancer cells.

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    Dos Santos, Ancély F; Terra, Letícia F; Wailemann, Rosangela A M; Oliveira, Talita C; Gomes, Vinícius de Morais; Mineiro, Marcela Franco; Meotti, Flávia Carla; Bruni-Cardoso, Alexandre; Baptista, Maurício S; Labriola, Leticia

    2017-03-15

    Breast cancer is the main cause of mortality among women. The disease presents high recurrence mainly due to incomplete efficacy of primary treatment in killing all cancer cells. Photodynamic therapy (PDT), an approach that causes tissue destruction by visible light in the presence of a photosensitizer (Ps) and oxygen, appears as a promising alternative therapy that could be used adjunct to chemotherapy and surgery for curing cancer. However, the efficacy of PDT to treat breast tumours as well as the molecular mechanisms that lead to cell death remain unclear. In this study, we assessed the cell-killing potential of PDT using methylene blue (MB-PDT) in three breast epithelial cell lines that represent non-malignant conditions and different molecular subtypes of breast tumours. Cells were incubated in the absence or presence of MB and irradiated or not at 640 nm with 4.5 J/cm 2 . We used a combination of imaging and biochemistry approaches to assess the involvement of classical autophagic and apoptotic pathways in mediating the cell-deletion induced by MB-PDT. The role of these pathways was investigated using specific inhibitors, activators and gene silencing. We observed that MB-PDT differentially induces massive cell death of tumour cells. Non-malignant cells were significantly more resistant to the therapy compared to malignant cells. Morphological and biochemical analysis of dying cells pointed to alternative mechanisms rather than classical apoptosis. MB-PDT-induced autophagy modulated cell viability depending on the cell model used. However, impairment of one of these pathways did not prevent the fatal destination of MB-PDT treated cells. Additionally, when using a physiological 3D culture model that recapitulates relevant features of normal and tumorous breast tissue morphology, we found that MB-PDT differential action in killing tumour cells was even higher than what was detected in 2D cultures. Finally, our observations underscore the potential of MB

  11. Autophagic-lysosomal dysregulation downstream of cathepsin B inactivation in human skin fibroblasts exposed to UVA.

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    Lamore, Sarah D; Wondrak, Georg T

    2012-01-01

    Recently, using 2D-DIGE proteomics we have identified cathepsin B as a novel target of UVA in human Hs27 skin fibroblasts. In response to chronic exposure to noncytotoxic doses of UVA (9.9 J cm(-2), twice a week, 3 weeks), photooxidative impairment of cathepsin B enzymatic activity occurred with accumulation of autofluorescent aggregates colocalizing with lysosomes, an effect mimicked by pharmacological antagonism of cathepsin B using the selective inhibitor CA074Me. Here, we have further explored the mechanistic involvement of cathepsin B inactivation in UVA-induced autophagic-lysosomal alterations using autophagy-directed PCR expression array analysis as a discovery tool. Consistent with lysosomal expansion, UVA upregulated cellular protein levels of the lysosomal marker glycoprotein Lamp-1, and increased levels of the lipidated autophagosomal membrane constituent LC3-II were detected. UVA did not alter expression of beclin 1 (BECN1), an essential factor for initiation of autophagy, but upregulation of p62 (sequestosome 1, SQSTM1), a selective autophagy substrate, and α-synuclein (SNCA), an autophagic protein substrate and aggresome component, was observed at the mRNA and protein level. Moreover, UVA downregulated transglutaminase-2 (TGM2), an essential enzyme involved in autophagolysosome maturation. Strikingly, UVA effects on Lamp-1, LC3-II, beclin 1, p62, α-synuclein, and transglutaminase-2 were mimicked by CA074Me treatment. Taken together, our data suggest that UVA-induced autophagic-lysosomal alterations occur as a consequence of impaired autophagic flux downstream of cathepsin B inactivation, a novel molecular mechanism potentially involved in UVA-induced skin photodamage. This journal is © The Royal Society of Chemistry and Owner Societies 2012

  12. Active Component of Antrodia cinnamomea Mycelia Targeting Head and Neck Cancer Initiating Cells through Exaggerated Autophagic Cell Death

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    Ching-Wen Chang

    2013-01-01

    Full Text Available Head and neck squamous cell carcinoma (HNSCC is a highly lethal cancer. Previously, we identify head and neck cancer initiating cells (HN-CICs, which are highly tumorigenic and resistant to conventional therapy. Therefore, development of drug candidates that effectively target HN-CICs would benefit future head and neck cancer therapy. In this study, we first successfully screened for an active component, named YMGKI-1, from natural products of Antrodia cinnamomea Mycelia (ACM, which can target the stemness properties of HNSCC. Treatment of YMGKI-1 significantly downregulated the aldehyde dehydrogenase (ALDH activity, one of the characteristics of CIC in HNSCC cells. Additionally, the tumorigenic properties of HNSCC cells were attenuated by YMGKI-1 treatment in vivo. Further, the stemness properties of HN-CICs, which are responsible for the malignancy of HNSCC, were also diminished by YMGKI-1 treatment. Strikingly, YMGKI-1 also effectively suppressed the cell viability of HN-CICs but not normal stem cells. Finally, YMGKI-1 induces the cell death of HN-CICs by dysregulating the exaggerated autophagic signaling pathways. Together, our results indicate that YMGKI-1 successfully lessens stemness properties and tumorigenicity of HN-CICs. These findings provide a new drug candidate from purified components of ACM as an alternative therapy for head and neck cancer in the future.

  13. Epigallocatechin-3-Gallate Attenuates Impairment of Learning and Memory in Chronic Unpredictable Mild Stress-Treated Rats by Restoring Hippocampal Autophagic Flux

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    Tang, Ya-Ling; Zeng, Yang; Jing, Kai-Quan; Zheng, Xi-Long; Liao, Duan-Fang

    2014-01-01

    Epigallocatechin gallate (EGCG) is a major polyphenol in green tea with beneficial effects on the impairment in learning and memory. Autophagy is a cellular process that protects neurons from stressful conditions. The present study was designed to investigate whether EGCG can rescue chronic unpredictable mild stress (CUMS)-induced cognitive impairment in rats and whether its protective effect involves improvement of autophagic flux. As expected, our results showed that CUMS significantly impaired memory performance and inhibited autophagic flux as indicated by elevated LC3-II and p62 protein levels. At the same time, we observed an increased neuronal loss and activated mammalian target of rapamycin (mTOR)/p70 ribosomal protein S6 kinase (p70S6k) signaling in the CA1 regions. Interestingly, chronic treatment with EGCG (25 mg/kg, i.p.) significantly improved those behavioral alterations, attenuated histopathological abnormalities in hippocampal CA1 regions, reduced amyloid beta1–42 (Aβ1−42) levels, and restored autophagic flux. However, blocking autophagic flux with chloroquine, an inhibitor of autophagic flux, reversed these effects of EGCG. Taken together, these findings suggest that the impaired autophagy in CA1 regions of CUMS rats may contribute to learning and memory impairment. Therefore, we conclude that EGCG attenuation of CUMS-induced learning and memory impairment may be through rescuing autophagic flux. PMID:25393306

  14. Coronary atherosclerosis: Significance of autophagic armour.

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    Arora, Mansi; Kaul, Deepak

    2012-09-26

    Autophagy is a lysosomal degradation pathway of cellular components such as organelles and long-lived proteins. Though a protective role for autophagy has been established in various patho-physiologic conditions such as cancer, neurodegeneration, aging and heart failure, a growing body of evidence now reveals a protective role for autophagy in atherosclerosis, mainly by removing oxidatively damaged organelles and proteins and also by promoting cholesterol egress from the lipid-laden cells. Recent studies by Razani et al and Liao et al unravel novel pathways that might be involved in autophagic protection and in this commentary we highlight the importance of autophagy in atherosclerosis in the light of these two recent papers.

  15. HTLV-1 Tax deregulates autophagy by recruiting autophagic molecules into lipid raft microdomains.

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    Ren, T; Takahashi, Y; Liu, X; Loughran, T P; Sun, S-C; Wang, H-G; Cheng, H

    2015-01-15

    The retroviral oncoprotein Tax from human T-cell leukemia virus type 1 (HTLV-1), an etiological factor that causes adult T-cell leukemia and lymphoma, has a crucial role in initiating T-lymphocyte transformation by inducing oncogenic signaling activation. We here report that Tax is a determining factor for dysregulation of autophagy in HTLV-1-transformed T cells and Tax-immortalized CD4 memory T cells. Tax facilitated autophagic process by activating inhibitor of κB (IκB) kinase (IKK) complex, which subsequently recruited an autophagy molecular complex containing Beclin1 and Bif-1 to the lipid raft microdomains. Tax engaged a crosstalk between IKK complex and autophagic molecule complex by directly interacting with both complexes, promoting assembly of LC3+ autophagosomes. Moreover, expression of lipid raft-targeted Bif-1 or Beclin1 was sufficient to induce formation of LC3+ autophagosomes, suggesting that Tax recruitment of autophagic molecules to lipid rafts is a dominant strategy to deregulate autophagy in the context of HTLV-1 transformation of T cells. Furthermore, depletion of autophagy molecules such as Beclin1 and PI3 kinase class III resulted in impaired growth of HTLV-1-transformed T cells, indicating a critical role of Tax-deregulated autophagy in promoting survival and transformation of virally infected T cells.

  16. DAPK2 Downregulation Associates With Attenuated Adipocyte Autophagic Clearance in Human Obesity.

    Science.gov (United States)

    Soussi, Hedi; Reggio, Sophie; Alili, Rohia; Prado, Cecilia; Mutel, Sonia; Pini, Maria; Rouault, Christine; Clément, Karine; Dugail, Isabelle

    2015-10-01

    Adipose tissue dysfunction in obesity has been linked to low-grade inflammation causing insulin resistance. Transcriptomic studies have identified death-associated protein kinase 2 (DAPK2) among the most strongly downregulated adipose tissue genes in human obesity, but the role of this kinase is unknown. We show that mature adipocytes rather than the stromal vascular cells in adipose tissue mainly expressed DAPK2 and that DAPK2 mRNA in obese patients gradually recovered after bariatric surgery-induced weight loss. DAPK2 mRNA is also downregulated in high-fat diet-induced obese mice. Adenoviral-mediated DAPK2 overexpression in 3T3-L1 adipocytes did not affect lipid droplet size or cell viability but did increase autophagic clearance in nutrient-rich conditions, dependent on protein kinase activity. Conversely, DAPK2 inhibition in human preadipocytes by small interfering RNA decreased LC3-II accumulation rates with lysosome inhibitors. This led us to assess autophagic clearance in adipocytes freshly isolated from subcutaneous adipose tissue of obese patients. Severe reduction in autophagic flux was observed in obese adipocytes compared with control adipocytes, inversely correlated to fat cell lipids. After bariatric surgery, adipocyte autophagic clearance partially recovered proportional to the extent of fat cell size reduction. This study links adipocyte expression of an autophagy-regulating kinase, lysosome-mediated clearance and fat cell lipid accumulation; it demonstrates obesity-related attenuated autophagy in adipocytes, and identifies DAPK2 dependence in this regulation. © 2015 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.

  17. Effects of Epigallocatechin-3-Gallate on Autophagic Lipolysis in Adipocytes

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    Sang-Nam Kim

    2017-06-01

    Full Text Available Previous studies demonstrated effects of green tea on weight loss; however, green tea-induced modulation of adipocyte function is not fully understood. Here, we investigated effects of the major green tea phytochemical, epigallocatechin-3-gallate (EGCG on triglyceride contents, lipolysis, mitochondrial function, and autophagy, in adipocytes differentiated from C3H10T1/2 cells and immortalized pre-adipocytes in vitro. EGCG reduced the triglycerol content significantly in adipocytes by 25%, comparable to the nutrient starvation state. EGCG did not affect protein kinase A signaling or brown adipocyte marker expression in adipocytes; however, EGCG increased autophagy, as measured by autophagy flux analysis and immunoblot analysis of LC3B, ATG7, and Beclin1. EGCG treatment reduced mitochondrial membrane potential by 56.8% and intracellular ATP levels by 49.1% compared to controls. Although mammalian target of rapamycin signaling was not upregulated by EGCG treatment, EGCG treatment induced AMP-activated protein kinase phosphorylation, indicating an energy-depleted state. In addition, EGCG increased the association between RAB7 and lipid droplets, suggesting that lipophagy was activated. Finally, knockdown of Rab7 attenuated the EGCG-dependent reduction in lipid contents. Collectively, these results indicated that EGCG upregulated autophagic lipolysis in adipocytes, supporting the therapeutic potential of EGCG as a caloric restriction mimetic to prevent obesity and obesity-related metabolic diseases.

  18. Characterization of Autophagic Responses in Drosophila melanogaster.

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    Xu, T; Kumar, S; Denton, D

    2017-01-01

    Drosophila is an excellent model system for studying autophagy during animal development due to the availability of genetic reagents and opportunity for in vivo cell biological analysis. The regulation and mechanism of autophagy are highly evolutionarily conserved and the role of autophagy has been characterized during various stages of Drosophila development as well as following starvation. Studies in Drosophila have revealed novel insights into the role of distinct components of the autophagy machinery. This chapter describes protocols for examining autophagy during Drosophila development. A crucial step in the induction of autophagy is the incorporation of Atg8a into the autophagosome. This can be measured as autophagic puncta using live fluorescent imaging, immunostaining, or immunoblot analysis of LC3/Atg8a processing. The level of autophagy can also be examined using other specific components of the autophagy pathway as markers detected by immunofluorescent imaging. Based on the distinct morphology of autophagy, it can also be examined by transmission electron microscopy. In addition, one of the advantages of using Drosophila as a model is the ability to undertake genetic analysis of individual components of the autophagy machinery. Current approaches that can be used to monitor autophagy, including the overall flux and individual steps in Drosophila melanogaster, will be discussed. © 2017 Elsevier Inc. All rights reserved.

  19. Autophagic activity as an indicator for selecting good quality embryos.

    Science.gov (United States)

    Tsukamoto, Satoshi

    2015-04-01

    Is it possible to predict the quality of embryos that appear to be morphologically identical when viewed under a microscope? Thirty-five years have passed since the world's first human birth from in vitro fertilization. While the dissemination of assisted reproduction technologies during this time has been remarkable, the evaluation of embryo quality in both humans and mice currently relies entirely on morphological observation. More efficient infertility treatments will likely be possible if high-quality embryos can be selected by screening. To develop a novel quality evaluation method that does not rely on morphology, we focused on autophagy, one of the molecular mechanisms essential for the early embryonic development. Autophagy is a massive cytoplasmic degradation pathway mediated by the lysosome. Our previous studies have demonstrated that fertilization-induced autophagy is essential for preimplantation embryonic development. This autophagy is thought to supply the nutrients and amino acids necessary for maintaining subsequent embryo development, through the bulk degradation of maternal cytoplasmic factors that are accumulated during oogenesis. Here, we briefly summarize autophagy and its physiological function, and describe a recently developed method for using autophagic activity as an indicator to predict embryo quality.

  20. Rose Bengal acetate photodynamic therapy (RBAc-PDT) induces exposure and release of Damage-Associated Molecular Patterns (DAMPs) in human HeLa cells.

    Science.gov (United States)

    Panzarini, Elisa; Inguscio, Valentina; Fimia, Gian Maria; Dini, Luciana

    2014-01-01

    The new concept of Immunogenic Cell Death (ICD), associated with Damage Associated Molecular Patterns (DAMPs) exposure and/or release, is recently becoming very appealing in cancer treatment. In this context, PhotoDynamic Therapy (PDT) can give rise to ICD and to immune response upon dead cells removal. The list of PhotoSensitizers (PSs) able to induce ICD is still short and includes Photofrin, Hypericin, Foscan and 5-ALA. The goal of the present work was to investigate if Rose Bengal Acetate (RBAc), a powerful PS able to trigger apoptosis and autophagy, enables photosensitized HeLa cells to expose and/or release pivotal DAMPs, i.e. ATP, HSP70, HSP90, HMGB1, and calreticulin (CRT), that characterize ICD. We found that apoptotic HeLa cells after RBAc-PDT exposed and released, early after the treatment, high amount of ATP, HSP70, HSP90 and CRT; the latter was distributed on the cell surface as uneven patches and co-exposed with ERp57. Conversely, autophagic HeLa cells after RBAc-PDT exposed and released HSP70, HSP90 but not CRT and ATP. Exposure and release of HSP70 and HSP90 were always higher on apoptotic than on autophagic cells. HMGB1 was released concomitantly to secondary necrosis (24 h after RBAc-PDT). Phagocytosis assay suggests that CRT is involved in removal of RBAc-PDT generated apoptotic HeLa cells. Altogether, our data suggest that RBAc has all the prerequisites (i.e. exposure and/or release of ATP, CRT, HSP70 and HSP90), that must be verified in future vaccination experiments, to be considered a good PS candidate to ignite ICD. We also showed tha CRT is involved in the clearance of RBAc photokilled HeLa cells. Interestingly, RBAc-PDT is the first cancer PDT protocol able to induce the translocation of HSP90 and plasma membrane co-exposure of CRT with ERp57.

  1. Intravesical ozone therapy for progressive radiation-induced hematuria.

    Science.gov (United States)

    Clavo, Bernardino; Gutiérrez, Dominga; Martín, Dionisio; Suárez, Gerardo; Hernández, María A; Robaina, Francisco

    2005-06-01

    Progressive radiation-induced cystitis can become a serious clinical problem the therapeutic solution of which is limited and almost invariably aggressive. Ozone therapy is a nonconventional therapy that has been reported to offer benefits in late-onset wound healing and ischemic disorders. This report describes a patient with progressive radiation-induced hematuria from standard conservative treatment that was further treated with ozone therapy. Ozone therapy was achieved by intravesical instillation of ozonized bi-distilled water over a period of 30 minutes, three sessions per week during the first weeks. Later, ozone therapy sessions were decreased and involved ozonized water or direct intravesicular instillation of ozone at 20-25 microg/mL. Hematuria was successfully controlled by intravesical application of ozone therapy. The successes achieved with this technique suggest that intravesicular instillation of ozonized bi-distilled water or ozone merits further investigation with a view to its application to counter this radiation-induced side-effect.

  2. Intermittent fasting is neuroprotective in focal cerebral ischemia by minimizing autophagic flux disturbance and inhibiting apoptosis.

    Science.gov (United States)

    Jeong, Ji Heun; Yu, Kwang Sik; Bak, Dong Ho; Lee, Je Hun; Lee, Nam Seob; Jeong, Young Gil; Kim, Dong Kwan; Kim, Jwa-Jin; Han, Seung-Yun

    2016-11-01

    Previous studies have demonstrated that autophagy induced by caloric restriction (CR) is neuroprotective against cerebral ischemia. However, it has not been determined whether intermittent fasting (IF), a variation of CR, can exert autophagy-related neuroprotection against cerebral ischemia. Therefore, the neuroprotective effect of IF was evaluated over the course of two weeks in a rat model of focal cerebral ischemia, which was induced by middle cerebral artery occlusion and reperfusion (MCAO/R). Specifically, the role of autophagy modulation as a potential underlying mechanism for this phenomenon was investigated. It was demonstrated that IF reduced infarct volume and brain edema, improved neurobehavioral deficits, and rescued neuronal loss after MCAO/R. Furthermore, neuronal apoptosis was decreased by IF in the rat cortex. An increase in the number of autophagosomes (APs) was demonstrated in the cortices of IF-treated rats, using immunofluorescence staining and transmission electron microscopy. Using immunoblots, an IF-induced increase was detected in microtubule-associated protein 1 light chain 3 (LC3)-II, Rab7, and cathepsin D protein levels, which corroborated previous morphological studies. Notably, IF reduced the accumulation of APs and p62, demonstrating that IF attenuated the MCAO/R-induced disturbance of autophagic flux in neurons. The findings of the present study suggest that IF-induced neuroprotection in focal cerebral ischemia is due, at least in part, to the minimization of autophagic flux disturbance and inhibition of apoptosis.

  3. Naringin Attenuates Autophagic Stress and Neuroinflammation in Kainic Acid-Treated Hippocampus In Vivo

    Directory of Open Access Journals (Sweden)

    Kyoung Hoon Jeong

    2015-01-01

    Full Text Available Kainic acid (KA is well known as a chemical compound to study epileptic seizures and neuronal excitotoxicity. KA-induced excitotoxicity causes neuronal death by induction of autophagic stress and microglia-derived neuroinflammation, suggesting that the control of KA-induced effects may be important to inhibit epileptic seizures with neuroprotection. Naringin, a flavonoid in grapefruit and citrus fruits, has anti-inflammatory and antioxidative activities, resulting in neuroprotection in animal models from neurodegenerative diseases such as Parkinson’s disease and Alzheimer’s disease. In the present study, we examined its beneficial effects involved in antiautophagic stress and antineuroinflammation in the KA-treated hippocampus. Our results showed that naringin treatment delayed the onset of KA-induced seizures and decreased the occurrence of chronic spontaneous recurrent seizures (SRS in KA-treated mice. Moreover, naringin treatment protected hippocampal CA1 neurons in the KA-treated hippocampus, ameliorated KA-induced autophagic stress, confirmed by the expression of microtubule-associated protein light chain 3 (LC3, and attenuated an increase in tumor necrosis factor-α (TNFα in activated microglia. These results suggest that naringin may have beneficial effects of preventing epileptic events and neuronal death through antiautophagic stress and antineuroinflammation in the hippocampus in vivo.

  4. Effect of modified constrained induced movement therapy on ...

    African Journals Online (AJOL)

    Ehab M. Abdel-Kafy

    2012-12-21

    Dec 21, 2012 ... Effect of modified constrained induced movement therapy on improving arm function in children with obstetric brachial plexus injury. Ehab M. Abdel-Kafy, Hebatallah M. Kamal *, Samah A. Elshemy. Department of Physical Therapy for Disturbances of Growth and Developmental Disorders in Children and its ...

  5. Routine Western blot to check autophagic flux : Cautions and recommendations

    NARCIS (Netherlands)

    Gomez-Sanchez, Ruben; Pizarro-Estrella, Elisa; Yakhine-Diop, Sokhna M. S.; Rodriguez-Arribas, Mario; Bravo-San Pedro, Jose M.; Fuentes, Jose M.; Gonzalez-Polo, Rosa A.

    2015-01-01

    At present, the analysis of autophagic flux by Western blotting (WB), which measures two of the most important markers of autophagy, i.e., microtubule-associated protein 1 light chain 3 (LC3) and p62, is widely accepted in the scientific community. In this study, we addressed the possible

  6. Pain induced by photodynamic therapy of warts

    DEFF Research Database (Denmark)

    Stender, I-M; Borgbjerg, F Molke; Villumsen, J

    2006-01-01

    Photodynamic therapy with topical 5-aminolevulinic acid (ALA), followed by irradiation with red light (ALA-PDT), is used for non-melanoma skin cancer and other dermatological diseases. Pain during and after light exposure is a well-known adverse advent that may be a limiting factor for treatment...

  7. Radiation-Induced Second Cancer Risk Estimates From Radionuclide Therapy

    Science.gov (United States)

    Bednarz, Bryan; Besemer, Abigail

    2017-09-01

    The use of radionuclide therapy in the clinical setting is expected to increase significantly over the next decade. There is an important need to understand the radiation-induced second cancer risk associated with these procedures. In this study the radiation-induced cancer risk in five radionuclide therapy patients was investigated. These patients underwent serial SPECT imaging scans following injection as part of a clinical trial testing the efficacy of a 131Iodine-labeled radiopharmaceutical. Using these datasets the committed absorbed doses to multiple sensitive structures were calculated using RAPID, which is a novel Monte Carlo-based 3D dosimetry platform developed for personalized dosimetry. The excess relative risk (ERR) for radiation-induced cancer in these structures was then derived from these dose estimates following the recommendations set forth in the BEIR VII report. The radiation-induced leukemia ERR was highest among all sites considered reaching a maximum value of approximately 4.5. The radiation-induced cancer risk in the kidneys, liver and spleen ranged between 0.3 and 1.3. The lifetime attributable risks (LARs) were also calculated, which ranged from 30 to 1700 cancers per 100,000 persons and were highest for leukemia and the liver for both males and females followed by radiation-induced spleen and kidney cancer. The risks associated with radionuclide therapy are similar to the risk associated with external beam radiation therapy.

  8. Mitochondrial ROS generation for regulation of autophagic pathways in cancer.

    Science.gov (United States)

    Li, Zi-yue; Yang, Yu; Ming, Miao; Liu, Bo

    2011-10-14

    Mitochondria, the main source of reactive oxygen species (ROS), are required for cell survival; yet also orchestrate programmed cell death (PCD), referring to apoptosis and autophagy. Autophagy is an evolutionarily conserved lysosomal degradation process implicated in a wide range of pathological processes, most notably cancer. Accumulating evidence has recently revealed that mitochondria may generate massive ROS that play the essential role for autophagy regulation, and thus sealing the fate of cancer cell. In this review, we summarize mitochondrial function and ROS generation, and also highlight ROS-modulated core autophagic pathways involved in ATG4-ATG8/LC3, Beclin-1, p53, PTEN, PI3K-Akt-mTOR and MAPK signaling in cancer. Therefore, a better understanding of the intricate relationships between mitochondrial ROS and autophagy may ultimately allow cancer biologists to harness mitochondrial ROS-mediated autophagic pathways for cancer drug discovery. Copyright © 2011 Elsevier Inc. All rights reserved.

  9. Comedones induced by vascular laser therapy

    Directory of Open Access Journals (Sweden)

    Gulsen Tukenmez Demirci

    2016-01-01

    Full Text Available A 21-year-old female presented with acne-like blackheads on brownish areas located on the cheek. She had been treated with neodymium-doped yttrium aluminium garnet (Nd-YAG laser (1071 nm, 160 j/cm 2 , three months ago for erythema and telangiectasia of her face. Afterwards, she developed atrophic, slightly depressed, hyperpigmented, 3-4 mm scars with superimposed tiny comedones within the treated areas. Topical treatment with tretinoin 0.05% cream on alternate days, and Sun Protection Factor (SPF 50 sunscreen daily were commenced. After 2 months, comedones and hyperpigmentation mostly resolved but mild superficial atrophy persisted. According to our knowledge, this is the first case of atrophic scars studded with open comedones, developing shortly after laser therapy used for facial telangiectasia.

  10. Molecular Basis of Autophagic Cell Death in Prostate Cancer

    Science.gov (United States)

    2009-03-01

    of phosphatidylinositol 3-phosphate into the vacuole via autophagic membranes in Saccharomyces cerevisiae . Genes Cells 2008;13:537–47. [PubMed...PARP) (Santa Cruz Biotechnology), anti-LC3 (MBL), and anti--actin (Oncogene Research Prod- ucts). Subsequently, blots were incubated with goat anti...apoL1 antibody, secondary goat anti-rabbit antibody conjugated with horseradish peroxidase, and ECL detection and imaging. RESULTS ApoL1 Is a BH3 Domain

  11. Regulation of autophagic flux by CHIP

    National Research Council Canada - National Science Library

    Dongkai Guo Zheng Ying Hongfeng Wang Dong Chen Feng Gao Haigang Ren Guanghui Wang

    2015-01-01

    ... (carboxy-terminus of HscT0-interacting protein). Knockdown of CHIP induced autophagosome formation through increasing the PTEN protein level and decreasing the AKT/mTOR activity as well as decreasing phosphorylation of ULK1 on Ser757...

  12. Protection against neurotoxicity by an autophagic mechanism

    Energy Technology Data Exchange (ETDEWEB)

    Liu, Kangyong; Huang, Jiankang; Chen, Rongfu; Zhang, Ting [Department of Neurology, Affiliated Sixth People' s Hospital, Shanghai Jiaotong University, Shanghai (China); Shen, Liwei [Department of Neurology, Fifth People' s Hospital, Fudan University, Shanghai (China); Yang, Jiajun; Sun, Xiaojiang [Department of Neurology, Affiliated Sixth People' s Hospital, Shanghai Jiaotong University, Shanghai (China)

    2012-03-23

    The objective of the present study was to investigate the effects of 3-n-butylphthalide (NBP) on a 1-methyl-4-phenylpyridinium (MPP{sup +})-induced cellular model of Parkinson's disease (PD) and to illustrate the potential mechanism of autophagy in this process. For this purpose, rat PC12 pheochromocytoma cells were treated with MPP{sup +} (1 mM) for 24 h following pretreatment with NBP (0.1 mM). Cell metabolic viability was determined by the MTT assay and cell ultrastructure was examined by transmission electron microscopy. The intracellular distribution and expression of α-synuclein and microtubule-associated protein light chain 3 (LC3) were detected by immunocytochemistry and Western blotting. Our results demonstrated that: 1) NBP prevented MPP{sup +}-induced cytotoxicity in PC12 cells by promoting metabolic viability. 2) NBP induced the accumulation of autophagosomes in MPP{sup +}-treated PC12 cells. 3) Further study of the molecular mechanism demonstrated that NBP enhanced the colocalization of α-synuclein and LC3 and up-regulated the protein level of LC3-II. These results demonstrate that NBP protects PC12 cells against MPP{sup +}-induced neurotoxicity by activating autophagy-mediated α-synuclein degradation, implying that it may be a potential effective therapeutic agent for the treatment of PD.

  13. Protection against neurotoxicity by an autophagic mechanism

    Directory of Open Access Journals (Sweden)

    Kangyong Liu

    2012-05-01

    Full Text Available The objective of the present study was to investigate the effects of 3-n-butylphthalide (NBP on a 1-methyl-4-phenylpyridinium (MPP+-induced cellular model of Parkinson’s disease (PD and to illustrate the potential mechanism of autophagy in this process. For this purpose, rat PC12 pheochromocytoma cells were treated with MPP+ (1 mM for 24 h following pretreatment with NBP (0.1 mM. Cell metabolic viability was determined by the MTT assay and cell ultrastructure was examined by transmission electron microscopy. The intracellular distribution and expression of α-synuclein and microtubule-associated protein light chain 3 (LC3 were detected by immunocytochemistry and Western blotting. Our results demonstrated that: 1 NBP prevented MPP+-induced cytotoxicity in PC12 cells by promoting metabolic viability. 2 NBP induced the accumulation of autophagosomes in MPP+-treated PC12 cells. 3 Further study of the molecular mechanism demonstrated that NBP enhanced the colocalization of α-synuclein and LC3 and up-regulated the protein level of LC3-II. These results demonstrate that NBP protects PC12 cells against MPP+-induced neurotoxicity by activating autophagy-mediated α-synuclein degradation, implying that it may be a potential effective therapeutic agent for the treatment of PD.

  14. Intermittent injections of osteocalcin reverse autophagic dysfunction and endoplasmic reticulum stress resulting from diet-induced obesity in the vascular tissue via the NFκB-p65-dependent mechanism.

    Science.gov (United States)

    Zhou, Bo; Li, Huixia; Liu, Jiali; Xu, Lin; Zang, Weijin; Wu, Shufang; Sun, Hongzhi

    2013-06-15

    The osteoblast-specific secreted molecule osteocalcin behaves as a hormone-regulating glucose and lipid metabolism, but the role of osteocalcin in cardiovascular disease (CVD) is not fully understood. In the present study, we investigated the effect of osteocalcin on autophagy and endoplasmic reticulum (ER) stress secondary to diet-induced obesity in the vascular tissue of mice and in vascular cell models and clarified the intracellular events responsible for osteocalcin-mediated effects. The evidences showed that intermittent injections of osteocalcin in mice fed the high-fat diet were associated with a reduced body weight gain, decreased blood glucose and improved insulin sensitivity compared with mice fed the high-fat diet receiving vehicle. Simultaneously, the administration of osteocalcin not only attenuated autophagy and ER stress but also rescued impaired insulin signaling in vascular tissues of mice fed a high-fat diet. Consistent with these results in vivo, the addition of osteocalcin reversed autophagy and ER stress and restored defective insulin sensitivity in vascular endothelial cells (VECs) and vascular smooth muscle cells (VSMCs) in the presence of tunicamycin or in knockout XBP-1 (a transcription factor which mediates ER stress response) cells or in Atg7(-/-) cells. The protective effects of osteocalcin were nullified by suppression of Akt, mammalian target of rapamycin (mTOR) or nuclear factor kappa B (NFκB), suggesting that osteocalcin inhibits autophagy, ER stress and improves insulin signaling in the vascular tissue and cells under insulin resistance in a NFκB-dependent manner, which may be a promising therapeutic strategies of cardiovascular dysfunction secondary to obesity.

  15. Varicella-Zoster Virus Infectious Cycle: ER Stress, Autophagic Flux, and Amphisome-Mediated Trafficking.

    Science.gov (United States)

    Grose, Charles; Buckingham, Erin M; Carpenter, John E; Kunkel, Jeremy P

    2016-12-10

    Varicella-zoster virus (VZV) induces abundant autophagy. Of the nine human herpesviruses, the VZV genome is the smallest (~124 kbp), lacking any known inhibitors of autophagy, such as the herpes simplex virus ICP34.5 neurovirulence gene. Therefore, this review assesses the evidence for VZV-induced cellular stress, endoplasmic-reticulum-associated degradation (ERAD), and autophagic flux during the VZV infectious cycle. Even though VZV is difficult to propagate in cell culture, the biosynthesis of the both N - and O -linked viral glycoproteins was found to be abundant. In turn, this biosynthesis provided evidence of endoplasmic reticulum (ER) stress, including a greatly enlarged ER and a greatly diminished production of cellular glycoproteins. Other signs of ER stress following VZV infection included detection of the alternatively spliced higher-molecular-weight form of XBP1 as well as CHOP. VZV infection in cultured cells leads to abundant autophagosome production, as was visualized by the detection of the microtubule-associated protein 1 light chain 3-II (LC3-II). The degree of autophagy induced by VZV infection is comparable to that induced in uninfected cells by serum starvation. The inhibition of autophagic flux by chemicals such as 3-methyladenine or ATG5 siRNA, followed by diminished virus spread and titers, has been observed. Since the latter observation pointed to the virus assembly/trafficking compartments, we purified VZ virions by ultracentrifugation and examined the virion fraction for components of the autophagy pathway. We detected LC3-II protein (an autophagy marker) as well as Rab11 protein, a component of the endosomal pathway. We also observed that the virion-containing vesicles were single-walled; thus, they are not autophagosomes. These results suggested that some VZ virions after secondary envelopment were transported to the outer cell membrane in a vesicle derived from both the autophagy and endosomal pathways, such as an amphisome. Thus, these

  16. Effect of modified constrained induced movement therapy on ...

    African Journals Online (AJOL)

    Many children who sustain birth injuries to the brachial plexus suffer significant functional limitations due to various sequelae affecting the shoulder and elbow or forearm. The aim of this study was to test the feasibility of a treatment program based on the elements of the modified constraint induced movement therapy ...

  17. Understanding and Prevention of “Therapy-” Induced Dyskinesias

    Directory of Open Access Journals (Sweden)

    Iciar Aviles-Olmos

    2012-01-01

    Full Text Available L-dopa is the most effective, currently available treatment for Parkinson’s disease (PD, but it leads to the development of involuntary movements known as L-dopa-induced dyskinesia (LID in the majority of patients after long-term use. Both gene and cell therapy approaches are the subject of multiple ongoing studies as potential ways of relieving symptoms of PD without the complication of dyskinesia. However, the spectre of dyskinesia in the absence of L-dopa, the so-called “off-phase” or graft-induced dyskinesia (GID, remains a major obstacle particularly in the further development of cell therapy in PD, but it is also a concern for proponents of gene therapy approaches. LID results from nonphysiological dopamine release, supersensitivity of dopamine receptors, and consequent abnormal signalling through mechanisms of synaptic plasticity. Restoration of physiological circuitry within the basal ganglia loops is ultimately the aim of all cell and gene therapy approaches but each using distinctive strategies and accompanied by risks of exacerbation of LID or development of “off-phase”/GID. In this paper we discuss the details of what is understood regarding the development of dyskinesias with relevance to cell and gene therapy and potential strategies to minimize their occurrence.

  18. Spinster is required for autophagic lysosome reformation and mTOR reactivation following starvation.

    Science.gov (United States)

    Rong, Yueguang; McPhee, Christina K; McPhee, Christina; Deng, Shuangshen; Huang, Lei; Chen, Lilian; Liu, Mei; Tracy, Kirsten; Baehrecke, Eric H; Baehreck, Eric H; Yu, Li; Lenardo, Michael J

    2011-05-10

    Autophagy is a conserved cellular process to degrade and recycle cytoplasmic components. During autophagy, lysosomes fuse with an autophagosome to form an autolysosome. Sequestered components are degraded by lysosomal hydrolases and presumably released into the cytosol by lysosomal efflux permeases. Following starvation-induced autophagy, lysosome homeostasis is restored by autophagic lysosome reformation (ALR) requiring activation of the "target of rapamycin" (TOR) kinase. Spinster (Spin) encodes a putative lysosomal efflux permease with the hallmarks of a sugar transporter. Drosophila spin mutants accumulate lysosomal carbohydrates and enlarged lysosomes. Here we show that defects in spin lead to the accumulation of enlarged autolysosomes. We find that spin is essential for mTOR reactivation and lysosome reformation following prolonged starvation. Further, we demonstrate that the sugar transporter activity of Spin is essential for ALR.

  19. Intensive pediatric constraint-induced therapy for children with cerebral palsy: randomized, controlled, crossover trial.

    Science.gov (United States)

    Deluca, Stephanie C; Echols, Karen; Law, Charles R; Ramey, Sharon L

    2006-11-01

    A randomized crossover trial of a new form of pediatric rehabilitation was conducted with 18 children with hemiparesis. Half were randomly assigned to receive pediatric constraint-induced therapy involving constraint of the functional upper extremity and intensive therapy with the hemiparetic upper extremity. Controls received conventional physical and occupational therapy and then were crossed over to receive pediatric constraint-induced therapy. Pediatric constraint-induced therapy produced significantly greater gains than conventional rehabilitation services.

  20. Hyperbaric oxygen therapy for radiation-induced hemorrhagic cystitis

    Energy Technology Data Exchange (ETDEWEB)

    Miyazato, Tomonori; Yusa, Toshiko; Onaga, Tomohiro; Sugaya, Kimio; Koyama, Yuzo; Hatano, Tadashi; Ogawa, Yoshihide [Ryukyus Univ., Nishihara, Okinawa (Japan). Faculty of Medicine

    1998-05-01

    Radiation therapy has widely been used for cancers in the pelvis. Radiation cystitis, one of the late complications, presents often as hemorrhagic cystitis, which is refractory to the conventional therapy and may threaten the patient`s life. We used hyperbaric oxygen therapy on patients with radiation cystitis to test its potential benefit. Ten patients aged from 46 to 81 years with a mean of 62 years underwent one or more courses of hyperbaric oxygen therapy according to their symptoms, consisting of 20 sessions (3 to 5 sessions a week) at the Department of Hyperbaric Medicine, the University of the Ryukyus Hospital in the 9-year period from 1985 to 1994. They included 8 patients having a history of cervical cancer, one with external genital cancer and one with vaginal cancer. During the 75 min hyperbaric oxygen therapy patients received 100% oxygen at 2 absolute atmosphere pressure in the Multiplace Hyperbaric Chamber. Hematuria subsided and subjective symptoms including urinary frequency improved in seven patients. Cystoscopic findings including mucosal edema, redness, and capillary dilation were partially improved. The procedure subjectively and objectively palliated the 10 patients in a favorable manner. To date we have not armed any active procedure to control radiation-induced refractory hemorrhagic cystitis in terms of efficacy, invasiveness, and adverse effects. Therefore, in consideration of our clinical results, hyperbaric oxygen therapy appears to be useful for radiation cystitis. (author)

  1. Targeted approaches to induce immune tolerance for Pompe disease therapy

    Science.gov (United States)

    Doerfler, Phillip A; Nayak, Sushrusha; Corti, Manuela; Morel, Laurence; Herzog, Roland W; Byrne, Barry J

    2016-01-01

    Enzyme and gene replacement strategies have developed into viable therapeutic approaches for the treatment of Pompe disease (acid α-glucosidase (GAA) deficiency). Unfortunately, the introduction of GAA and viral vectors encoding the enzyme can lead to detrimental immune responses that attenuate treatment benefits and can impact patient safety. Preclinical and clinical experience in addressing humoral responses toward enzyme and gene therapy for Pompe disease have provided greater understanding of the immunological consequences of the provided therapy. B- and T-cell modulation has been shown to be effective in preventing infusion-associated reactions during enzyme replacement therapy in patients and has shown similar success in the context of gene therapy. Additional techniques to induce humoral tolerance for Pompe disease have been the targeted expression or delivery of GAA to discrete cell types or tissues such as the gut-associated lymphoid tissues, red blood cells, hematopoietic stem cells, and the liver. Research into overcoming preexisting immunity through immunomodulation and gene transfer are becoming increasingly important to achieve long-term efficacy. This review highlights the advances in therapies as well as the improved understanding of the molecular mechanisms involved in the humoral immune response with emphasis on methods employed to overcome responses associated with enzyme and gene therapies for Pompe disease. PMID:26858964

  2. Differential autophagic effects of vital dyes in retinal pigment epithelial ARPE-19 and photoreceptor 661W cells.

    Science.gov (United States)

    Sheu, Shwu-Jiuan; Chen, Jiunn-Liang; Bee, Youn-Shen; Chen, Yi-An; Lin, Shi-Han; Shu, Chih-Wen

    2017-01-01

    Indocyanine green (ICG) and brilliant blue G (BBG) are commonly used vital dyes to remove internal limiting membrane (ILM) in vitreoretinal surgery. The vital dyes have shown cytotoxic effects in ocular cells. Autophagy is a stress responsive pathway for either protecting cells or promoting cell death. However, the role of autophagy in ocular cells in response to the vital dyes remains unknown. In this study, we found that ICG and BBG reduced cell viability in both human retinal pigment epithelial ARPE-19 and mouse photoreceptor 661W cells. ICG and BBG induced lipidated GFP-LC3-II and LC3-II in ARPE-19 and 661W cells. Combination treatment with the autophagy inhibitor chloroquine indicated that ICG and BBG reduced autophagic flux in ARPE-19 cells, whereas the vital dyes induced autophagic flux in 661W cells. Moreover, genetic and pharmacological ablation of autophagy enhanced vital dyes-induced cytotoxicity in ocular cells. Dietary supplements, including resveratrol, lutein, and CoQ10, induced autophagy and diminished the cytotoxic effects of ICG and BBG in ocular cells. These results suggest that autophagy may protect ARPE-19 and 661W cells from vital dyes-induced damage.

  3. Upper extremity constraint-induced movement therapy in infantile hemiplegia

    OpenAIRE

    Selvam Ramachandran; Preeti Thakur

    2011-01-01

    Infantile hemiplegia is one of the clinical forms of cerebral palsy that refers to impaired motor function of one half of the body owing to contralateral brain damage due to prenatal, perinatal and postnatal causes amongst which vascular lesion is the most common causative factor. We report here the effects of constraint-induced movement therapy in a five-year-old female child with infantile hemiplegia on improvement of upper extremity motor skills.

  4. Speech language pathologists' opinions of constraint-induced language therapy.

    Science.gov (United States)

    Page, Stephen J; Wallace, Sarah E

    2014-01-01

    Constraint-induced language therapy (CILT) has received recent attention as a possible intervention to improve expressive language in people with nonfluent aphasia. Difficulties have been reported with the practical implementation of constraint-induced movement therapy due to its intensive treatment parameters. It remains unknown whether similar challenges may exist with CILT. To determine the opinions of speech-language pathologists (SLPs) about CILT for people with nonfluent aphasia. One hundred sixty-seven SLPs completed an electronic survey assessing their opinions of various aspects of CILT. Over 60% of participants felt that people with aphasia would be very unlikely or somewhat unlikely to adhere to CILT. The majority felt that people with aphasia would hold high or moderate concerns with the number of hours spent in therapy (high, 41.8%; moderate, 31.4%), the number of days spent in therapy (high, 44.4%; moderate, 24.8%), likelihood for managed care reimbursement (high, 74.8%; moderate, 15.2%), and other logistical issues (high, 39.2%; moderate, 30.7%). With respect to providing CILT, participants cited the number of hours of therapy (high, 37.3%; moderate, 21.6%) and the number of consecutive days of therapy (high, 29.4%; moderate, 20.3%) as concerns. There were 70.6% who indicated that their facilities lacked resources to provide CILT, and 90.9% felt that most facilitates do not have the resources to provide CILT. Some SLPs hold significant concerns with the administration of CILT, particularly related to its dosing and reimbursement parameters. Additional work is needed to investigate the issues that were identified in this survey using qualitative methods with SLPs and people with aphasia and to examine modified CILT protocols.

  5. Carbazole alkaloids from Murraya koenigii trigger apoptosis and autophagic flux inhibition in human oral squamous cell carcinoma cells.

    Science.gov (United States)

    Utaipan, Tanyarath; Athipornchai, Anan; Suksamrarn, Apichart; Jirachotikoon, Canussanun; Yuan, Xiaohong; Lertcanawanichakul, Monthon; Chunglok, Warangkana

    2017-01-01

    Carbazole alkaloids, a major constituent of Murraya koenigii (L.) Sprengel (Rutaceae), exhibit biological effects such as anticancer activity via the induction of apoptosis, and they represent candidate chemotherapeutic agents. Oral squamous cell carcinoma (OSCC) is the most prevalent cancer of the oral cavity and a growing and serious health problem worldwide. In this study, we investigated the anticancer properties and mechanisms of action of two carbazole alkaloids derived from M. koenigii leaves, mahanine and isomahanine, in the OSCC cell line CLS-354. At 15 μM, mahanine and isomahanine were cytotoxic to CLS-354 cells, triggering apoptosis via caspase-dependent and -independent mechanisms. Autophagosomes, visualised using monodansylcadaverine (MDC) labelling, were numerous in carbazole alkaloid-treated cells. Mahanine and isomahanine markedly induced the expression of the autophagosome marker microtubule-associated protein 1 light chain 3, type II (LC3B-II). Genetic and chemical inhibition of autophagy via silencing of the Autophagy protein 5 gene and exposure to bafilomycin A1 (BafA1), respectively, did not arrest carbazole alkaloid-induced apoptosis, indicating that it occurs independently of autophagic activation. Surprisingly, both carbazole alkaloids caused increased accumulation of p62/sequestosome1 (p62/SQSTM1), with coordinated expression of LC3B-II and cleaved caspase-3, suggesting inhibition of autophagic flux. Our results suggest that inhibition of autophagic flux is associated with carbazole alkaloid-induced apoptosis. Our findings provide evidence of a novel cytotoxic action of natural carbazole alkaloids and support their use as candidate chemotherapeutic agents for the treatment of OSCC.

  6. Zanthoxylum fruit extract from Japanese pepper promotes autophagic cell death in cancer cells.

    Science.gov (United States)

    Nozaki, Reo; Kono, Toru; Bochimoto, Hiroki; Watanabe, Tsuyoshi; Oketani, Kaori; Sakamaki, Yuichi; Okubo, Naoto; Nakagawa, Koji; Takeda, Hiroshi

    2016-10-25

    Zanthoxylum fruit, obtained from the Japanese pepper plant (Zanthoxylum piperitum De Candolle), and its extract (Zanthoxylum fruit extract, ZFE) have multiple physiological activities (e.g., antiviral activity). However, the potential anticancer activity of ZFE has not been fully examined. In this study, we investigated the ability of ZFE to induce autophagic cell death (ACD). ZFE caused remarkable autophagy-like cytoplasmic vacuolization, inhibited cell proliferation, and ultimately induced cell death in the human cancer cell lines DLD-1, HepG2, and Caco-2, but not in A549, MCF-7, or WiDr cells. ZFE increased the level of LC3-II protein, a marker of autophagy. Knockdown of ATG5 using siRNA inhibited ZFE-induced cytoplasmic vacuolization and cell death. Moreover, in cancer cells that could be induced to undergo cell death by ZFE, the extract increased the phosphorylation of c-Jun N-terminal kinase (JNK), and the JNK inhibitor SP600125 attenuated both vacuolization and cell death. Based on morphology and expression of marker proteins, ZFE-induced cell death was neither apoptosis nor necrosis. Normal intestinal cells were not affected by ZFE. Taken together, our findings show that ZFE induces JNK-dependent ACD, which appears to be the main mechanism underlying its anticancer activity, suggesting a promising starting point for anticancer drug development.

  7. [Therapy of trauma-induced coagulopathy - what is the evidence?].

    Science.gov (United States)

    Guth, Matthias C; Kaufner, Lutz; Kleber, Christian; von Heymann, Christian

    2012-09-01

    The increasing understanding of trauma-induced coagulopathy has led to an expansion of treatment strategies in the acute management of trauma patients. The aim of this manuscript is to give a summary of current recommendations for the treatment of trauma-induced coagulopathy based on current literature and valid guidelines. Thetrauma-induced coagulopathyis an independentacutemultifactorial diseasewith significantimpact on the mortalityof severelyinjured patients. Largely responsible for the occurrence and severity of trauma-induced coagulopathy seems to be tissue trauma and shock-induced hypoperfusion. Coagulopathy is amplified by accompanying factors such as hypothermia or dilution. Diagnosis and therapy of deranged coagulation should start as soon as possible. Routinely tested coagulation parameters are of limited use to confirm diagnosis. Therapy follows the concept of "damage control resuscitation". Infusion of large volumes should be avoided and a mean arterial pressure of 65mmHg (in consideration of contraindications!) may be aimed.A specific protocol for massive transfusion should be introduced and continued.Acidaemia should be prevented and treated by appropriate shock therapy.Loss of body temperature should be prevented and treated. Hypocalcaemia trauma the use of tranexamic acid should be considered at an early stage. Fibrinogen should be substituted at levels <1,5g/l (4,41μmol/l). Prothrombin complex concentrates may be helpfull for treatment of diffuse bleeding or anticoagulativemedikation. In acute bleeding, platelets may be transfused at a platet count <100000/μl. For diffuse bleeding or thrombocytopathic patients desmopressin might be a therapeutic option.If a factor XIII (FXIII) measurement is not promptly available, a factor XIII blind-dose should be considered in severe ongoing bleeding. The use of recombinant activated coagulation factor VII (rFVIIa) be considered if major bleeding persists despite standard attempts to control bleeding and best

  8. Neuroprotective effects of Activin A on endoplasmic reticulum stress-mediated apoptotic and autophagic PC12 cell death

    Directory of Open Access Journals (Sweden)

    Long-xing Xue

    2017-01-01

    Full Text Available Activin A, a member of the transforming growth factor-beta superfamily, plays a neuroprotective role in multiple neurological diseases. Endoplasmic reticulum (ER stress-mediated apoptotic and autophagic cell death is implicated in a wide range of diseases, including cerebral ischemia and neurodegenerative diseases. Thapsigargin was used to induce PC12 cell death, and Activin A was used for intervention. Our results showed that Activin A significantly inhibited morphological changes in thapsigargin-induced apoptotic cells, and the expression of apoptosis-associated proteins [cleaved-caspase-12, C/EBP homologous protein (CHOP and cleaved-caspase-3] and biomarkers of autophagy (Beclin-1 and light chain 3, and downregulated the expression of thapsigargin-induced ER stress-associated proteins [inositol requiring enzyme-1 (IRE1, tumor necrosis factor receptor-associated factor 2 (TRAF2, apoptosis signal-regulating kinase 1 (ASK1, c-Jun N-terminal kinase (JNK and p38]. The inhibition of thapsigargin-induced cell death was concentration-dependent. These findings suggest that administration of Activin A protects PC12 cells against ER stress-mediated apoptotic and autophagic cell death by inhibiting the activation of the IRE1-TRAF2-ASK1-JNK/p38 cascade.

  9. Hyperbaric oxygen therapy for refractory radiation-induced hemorrhagic cystitis.

    Science.gov (United States)

    Ribeiro de Oliveira, Tiago M; Carmelo Romão, António J; Gamito Guerreiro, Francisco M; Matos Lopes, Tomé M

    2015-10-01

    To analyze the efficacy of hyperbaric oxygen for the treatment of radiation-induced hemorrhagic cystitis and to identify factors associated with successful treatment. Clinical records from 176 patients with refractory radiation-induced hemorrhagic cystitis treated at the Portuguese Navy Center for Underwater and Hyperbaric Medicine, during a 15-year period, were retrospectively analyzed. Evolution of macroscopic hematuria was used to analyze treatment efficacy and correlated with other external variables. From a total of 176 treated patients, 23.9% evidenced other radiation-induced soft tissue lesions. After an average on 37 sessions, 89.8% of patients showed resolution of hematuria, with only 1.7% of adverse events. In our sample, hematuria resolution after treatment with hyperbaric oxygen was statistically associated to the need for transfusion therapy (P = 0.026) and the number of sessions of hyperbaric oxygen (P = 0.042). No relationship was found with the remaining variables. Refractory radiation-induced hemorrhagic cystitis can be successfully and safely treated with hyperbaric oxygen. Treatment effectiveness seems to be correlated with the need for transfusion therapy and the number of sessions performed. © 2015 The Japanese Urological Association.

  10. Sepsis-induced immune dysfunction: can immune therapies reduce mortality?

    Science.gov (United States)

    Delano, Matthew J.; Ward, Peter A.

    2016-01-01

    Sepsis is a systemic inflammatory response induced by an infection, leading to organ dysfunction and mortality. Historically, sepsis-induced organ dysfunction and lethality were attributed to the interplay between inflammatory and antiinflammatory responses. With advances in intensive care management and goal-directed interventions, early sepsis mortality has diminished, only to surge later after “recovery” from acute events, prompting a search for sepsis-induced alterations in immune function. Sepsis is well known to alter innate and adaptive immune responses for sustained periods after clinical “recovery,” with immunosuppression being a prominent example of such alterations. Recent studies have centered on immune-modulatory therapy. These efforts are focused on defining and reversing the persistent immune cell dysfunction that is associated with mortality long after the acute events of sepsis have resolved. PMID:26727230

  11. PF-4708671, a specific inhibitor of p70 ribosomal S6 kinase 1, activates Nrf2 by promoting p62-dependent autophagic degradation of Keap1

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    Park, Jeong Su [Severance Biomedical Science Institute (Korea, Republic of); Yonsei Biomedical Research Institute, Yonsei University College of Medicine, 50 Yonsei-ro, Seodaemun-gu, Seoul 120-752 (Korea, Republic of); Kang, Dong Hoon [Department of Life Science and Ewha Research Center for Systems Biology (Korea, Republic of); The Research Center for Cell Homeostasis, Ewha Womans University, Seoul 127-750 (Korea, Republic of); Lee, Da Hyun [Severance Biomedical Science Institute (Korea, Republic of); Yonsei Biomedical Research Institute, Yonsei University College of Medicine, 50 Yonsei-ro, Seodaemun-gu, Seoul 120-752 (Korea, Republic of); Bae, Soo Han, E-mail: soohanbae@yuhs.ac [Severance Biomedical Science Institute (Korea, Republic of); Yonsei Biomedical Research Institute, Yonsei University College of Medicine, 50 Yonsei-ro, Seodaemun-gu, Seoul 120-752 (Korea, Republic of)

    2015-10-23

    p70 ribosomal S6 kinase 1 (S6K1) is an important serine/threonine kinase and downstream target of the mechanistic target of rapamycin complex 1 (mTORC1) signaling pathway. PF-4708671 is a specific inhibitor of S6K1, and prevents S6K1-mediated phosphorylation of the S6 protein. PF-4708671 treatment often leads to apoptotic cell death. However, the protective mechanism against PF-4708671-induced cell death has not been elucidated. The nuclear factor erythroid 2-related factor 2 (Nrf2)-Kelch-like ECH-associated protein 1 (Keap1) pathway is essential for protecting cells against oxidative stress. p62, an adaptor protein in the autophagic process, enhances Nrf2 activation through the impairment of Keap1 activity. In this study, we showed that PF-4708671 induces autophagic Keap1 degradation-mediated Nrf2 activation in p62-dependent manner. Furthermore, p62-dependent Nrf2 activation plays a crucial role in protecting cells from PF-4708671-mediated apoptosis. - Highlights: • PF-4708671, a S6K1-specific inhibitor, prevents S6K1-mediated S6 phosphorylation. • However, PF-4708671 treatment often leads to apoptotic cell death. • Protective mechanism against PF-4708671-induced cell death remains to be elucidated. • PF-4708671 induced p62-dependent, autophagic Keap1 degradation-mediated Nrf2 activation. • p62-dependent Nrf2 activation protects cells from PF-4708671-mediated apoptosis.

  12. Listeria phospholipases subvert host autophagic defenses by stalling pre-autophagosomal structures

    Science.gov (United States)

    Tattoli, Ivan; Sorbara, Matthew T; Yang, Chloe; Tooze, Sharon A; Philpott, Dana J; Girardin, Stephen E

    2013-01-01

    Listeria can escape host autophagy defense pathways through mechanisms that remain poorly understood. We show here that in epithelial cells, Listeriolysin (LLO)-dependent cytosolic escape of Listeria triggered a transient amino-acid starvation host response characterized by GCN2 phosphorylation, ATF3 induction and mTOR inhibition, the latter favouring a pro-autophagic cellular environment. Surprisingly, rapid recovery of mTOR signalling was neither sufficient nor necessary for Listeria avoidance of autophagic targeting. Instead, we observed that Listeria phospholipases PlcA and PlcB reduced autophagic flux and phosphatidylinositol 3-phosphate (PI3P) levels, causing pre-autophagosomal structure stalling and preventing efficient targeting of cytosolic bacteria. In co-infection experiments, wild-type Listeria protected PlcA/B-deficient bacteria from autophagy-mediated clearance. Thus, our results uncover a critical role for Listeria phospholipases C in the inhibition of autophagic flux, favouring bacterial escape from host autophagic defense. PMID:24162724

  13. Spastic paraplegia proteins spastizin and spatacsin mediate autophagic lysosome reformation.

    Science.gov (United States)

    Chang, Jaerak; Lee, Seongju; Blackstone, Craig

    2014-12-01

    Autophagy allows cells to adapt to changes in their environment by coordinating the degradation and recycling of cellular components and organelles to maintain homeostasis. Lysosomes are organelles critical for terminating autophagy via their fusion with mature autophagosomes to generate autolysosomes that degrade autophagic materials; therefore, maintenance of the lysosomal population is essential for autophagy-dependent cellular clearance. Here, we have demonstrated that the two most common autosomal recessive hereditary spastic paraplegia gene products, the SPG15 protein spastizin and the SPG11 protein spatacsin, are pivotal for autophagic lysosome reformation (ALR), a pathway that generates new lysosomes. Lysosomal targeting of spastizin required an intact FYVE domain, which binds phosphatidylinositol 3-phosphate. Loss of spastizin or spatacsin resulted in depletion of free lysosomes, which are competent to fuse with autophagosomes, and an accumulation of autolysosomes, reflecting a failure in ALR. Moreover, spastizin and spatacsin were essential components for the initiation of lysosomal tubulation. Together, these results link dysfunction of the autophagy/lysosomal biogenesis machinery to neurodegeneration.

  14. Radiation-induced pseudotumor following therapy for soft tissue sarcoma

    Energy Technology Data Exchange (ETDEWEB)

    Moore, Lacey F.; Kransdorf, Mark J. [Mayo Clinic, Department of Radiology, Jacksonville, FL (United States); Buskirk, Steven J. [Mayo Clinic, Department of Radiation Oncology, Jacksonville, FL (United States); O' Connor, Mary I. [Mayo Clinic, Department of Orthopedic Surgery, Jacksonville, FL (United States); Menke, David M. [Mayo Clinic, Department of Pathology, Jacksonville, FL (United States)

    2009-06-15

    The purpose of this study was to describe the prevalence and imaging appearance of radiation induced pseudotumors in patients following radiation therapy for extremity soft tissue sarcomas. We retrospectively reviewed the serial magnetic resonance (MR) images of 24 patients following radiation therapy for extremity soft tissue sarcomas. A total of 208 exams were reviewed (mean, 8.7 exams per patient) and included all available studies following the start of radiation therapy. Exams were analyzed for the identification of focal signal abnormalities within the surgical bed suggesting local tumor recurrence. Histopathologic correlation was available in nine patients suspected of having local tumor recurrence. Additional information recorded included patient demographics, tumor type and location, radiation type, and dose. The study group consisted of 12 men and 12 women, having an average age of 63 years (range, 39-88 years). Primary tumors were malignant fibrous histiocytoma (n = 13), leiomyosarcoma (n = 6), liposarcoma (n = 3), synovial sarcoma (n = 1), and extraskeletal chondrosarcoma (n = 1). All lesions were high-grade sarcomas, except for two myxoid liposarcomas. Average patient radiation dose was 5,658 cGy (range, 4,500-8,040 cGy). Average follow-up time was 63 months (range, 3-204 months). Focal signal abnormalities suggesting local recurrence were seen in nine (38%) patients. Three of the nine patients with these signal abnormalities were surgically proven to have radiation-induced pseudotumor. The pseudotumors developed between 11 and 61 months following the initiation of radiation therapy (mean, 38 months), with an average radiation dose of 5,527 cGy (range, 5,040-6,500 cGy). MR imaging demonstrated a relatively ill-defined ovoid focus of abnormal signal and intense heterogeneous enhancement with little or no associated mass effect. MR imaging of radiation-induced pseudotumor typically demonstrates a relatively ill-defined ovoid mass-like focus of intense

  15. Long term exposure to antiangiogenic therapy, bevacizumab, induces osteonecrosis.

    Science.gov (United States)

    Tabouret, Tessa; Gregory, Thomas; Dhooge, Marion; Brezault, Catherine; Mir, Olivier; Dréanic, Johann; Chaussade, Stanislas; Coriat, Romain

    2015-10-01

    Bevacizumab, a monoclonal VEGF-A antibody, has been identified as an aetiology of osteonecrosis of the femoral head. Long exposure to anti VEGF therapy induced chronic hypoperfusion of normal tissues. Osteonecrosis is a musculo-skeletal disease secondary to cellular death of bone component mainly induced by corticosteroids, alcohol use, or connective tissue disorders. The medical records of patients with metastatic colorectal carcinoma receiving Bevacizumab between January 2006 and November 2013 were retrospectively reviewed and we had looked for osteonecrosis. Every disorder of musculoskeletal mobility were examined by orthopaedist and evaluated by imaging. We report on osteonecrosis of humeral and femoral head in patient with metastatic colon adenocarcinoma receiving a long-term exposure to anti angiogenic based treatment (>6 months), lack of other factors predisposing to osteonecrosis. These observations, according to literature, suggests that long exposure to anti VEGF-A, Bevacizumab, promote bone hypoperfusion and may induced osteonecrosis either on the femoral head or the humeral head with an incidence of 4 out of 1000 patients. With an incidence of 4 out of 1000 patients osteonecrosis is a rare side effect of anti-angiogenic agent. With the increasing utilisation and duration of exposure of anti-VEGF therapy some rare side effect due to chronic ischemia may appear. The clinician should be aware about uncommon symptoms.

  16. Antioxidant therapy for management of oxidative stress induced hypertension.

    Science.gov (United States)

    Ahmad, Khalil Ali; Yuan Yuan, Dai; Nawaz, Waqas; Ze, Hong; Zhuo, Chen Xue; Talal, Bashar; Taleb, Abdoh; Mais, Enos; Qilong, Ding

    2017-04-01

    Hypertension is considered as the most common risk factor for cardiovascular diseases, also is regarded as a leading cause of the mortality and morbidity worldwide. The mechanisms underlying the pathological process of hypertension are not completely explained. However, there is growing evidence that increased oxidative stress plays an important role in the pathophysiology of hypertension. Several preclinical studies and clinical trials have indicated that antioxidant therapy is important for management of hypertension, using antioxidants compounds such as alpha tocopherol (Vit E) and ascorbic acid (Vit C), polyphenols with others and some antihypertensive drugs that are now in clinical use (e.g. ACEIs, ARBs, novel B-blockers, dihydropyridine CCBs) which have antioxidative pleiotropic effects. The purpose of this review is to highlight the importance of antioxidant therapy for management of oxidative stress induced hypertension. Furthermore, we review the current knowledge in the oxidative stress and its significance in hypertension.

  17. Renal replacement therapy in sepsis-induced acute renal failure

    Directory of Open Access Journals (Sweden)

    Rajapakse Senaka

    2009-01-01

    Full Text Available Acute renal failure (ARF is a common complication of sepsis and carries a high mortality. Renal replacement therapy (RRT during the acute stage is the mainstay of therapy. Va-rious modalities of RRT are available. Continuous RRT using convective methods are preferred in sepsis-induced ARF, especially in hemodynamically unstable patients, although clear evidence of benefit over intermittent hemodialysis is still not available. Peritoneal dialysis is clearly inferior, and is not recommended. Early initiation of RRT is probably advantageous, although the optimal timing of dialysis is yet unknown. Higher doses of RRT are more likely to be beneficial. Use of bio-compatible membranes and bicarbonate buffer in the dialysate are preferred. Anticoagulation during dialysis must be carefully adjusted and monitored.

  18. Peptide Receptor Radionuclide Therapy-Induced Gitelman-like Syndrome.

    Science.gov (United States)

    Negro, Aurelio; Rossi, Giovanni M; Nicoli, Davide; Versari, Annibale; Farnetti, Enrico; Santi, Rosaria; De Pietri, Stefano

    2017-11-01

    Peptide receptor radionuclide therapy (PRRT) is a molecular-targeted therapy in which a somatostatin analogue (a small peptide) is coupled with a radioligand so that the radiation dose is selectively administered to somatostatin receptor-expressing metastasized neuroendocrine tumors, particularly gastroenteropancreatic. Reported toxicities include myelotoxicity and nephrotoxicity, the latter manifesting as decreased kidney function, often developing months to years after treatment completion. We present a case of PRRT-induced kidney toxicity manifesting as a severe Gitelman-like tubulopathy with preserved kidney function. Because profound hypokalemia and hypocalcemia can lead to life-threatening arrhythmias, we highlight the necessity for careful monitoring of serum and urine electrolytes in patients receiving PRRT. Copyright © 2017 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.

  19. The vector-related influences of autophagic microRNA delivery by Lipofectamine 2000 and polyethylenimine 25K on mouse embryonic fibroblast cells.

    Science.gov (United States)

    Lin, Chia-Wei; Jan, Ming-Shiou; Kuo, Jung-Hua Steven

    2017-04-01

    Despite the greater potential for clinical applications of autophagic microRNA (miRNA) delivery, the vector-related effects of such delivery on cells have not been fully explored. In this study, autophagic mmu-miR-494-3p (miR-494) in mouse embryonic fibroblast (MEF) cells was selected as a cargo miRNA, and two commonly used non-viral carriers (Lipofectamine 2000 (Lipo) and polyethylenimine 25K (PEI)), were used as delivery vectors to mechanistically elucidate its vector-related effects. The cellular uptake, nuclear localization, and quantitative miR-494 levels of the complexes of miR-494 with Lipo (miR-494 lipoplexes) were lower than those of the complexes of miR-494 with PEI (miR-494 polyplexes) in MEF cells. The indicator of autophagic activity (LC3 (microtubule-associated protein 1 light chain 3)-II/LC3-I ratio) in cells treated with miR-494 lipoplexes was higher than that in cells treated with miR-494 polyplexes. Lipo alone and PEI alone induced slight increases in the quantitative levels of miR-494 in cells, but Lipo resulted in higher gene and protein expressions of target Igf1, higher LC3-II/LC3-I ratios, and higher autophagosome formation than PEI. We also demonstrated that the delivery of miR-494 by Lipo was more involved in apoptotic caspase-3 pathways than such delivery by PEI. By applying knock-out atg5 gene in MEF cells, we found that autophagy played a protective role in cell survival and also affected cellular uptake, the quantitative level of miR-494, and target gene Igf1 regulation of delivery systems. Taken together, these results indicate that there are different degrees of responses in MEF cells for autophagic miR-494 delivery through the use of Lipo or PEI vectors that also induce autophagy in cells. Therefore, Lipo and PEI vectors cannot be treated as inert molecules, and their effects must be known and evaluated when they are used in autophagic miRNA delivery systems. Most importantly, understanding these vector-related effects on cells will

  20. Sitaxsentan-Induced Acute Severe Hepatitis Treated with Glucocorticoid Therapy

    Directory of Open Access Journals (Sweden)

    Marcus W Chin

    2012-01-01

    Full Text Available Endothelin receptor antagonists are commonly used in the treatment of pulmonary hypertension. Sitaxsentan, a selective endothelin A receptor blocker, induces a mild transaminitis in approximately 3% to 5% of patients, but rarely an acute severe hepatitis. A case involving a 61-year-old female with sitaxsentan-induced acute severe liver failure is presented. Depite withdrawal of therapy, her liver tests failed to improve. After six weeks of monitoring, the patient was administered high-dose corticosteroids, with a good clinical and biochemical response. While endothelin receptor antagonists are postulated to cause hepatitis by inhibition of a bile salt transporter pump, an immune-mediated or idiosyncratic mechanism should be considered.

  1. Signalome-wide RNAi screen identifies GBA1 as a positive mediator of autophagic cell death

    Science.gov (United States)

    Dasari, Santosh K; Bialik, Shani; Levin-Zaidman, Smadar; Levin-Salomon, Vered; Merrill, Alfred H; Futerman, Anthony H; Kimchi, Adi

    2017-01-01

    Activating alternative cell death pathways, including autophagic cell death, is a promising direction to overcome the apoptosis resistance observed in various cancers. Yet, whether autophagy acts as a death mechanism by over consumption of intracellular components is still controversial and remains undefined at the ultrastructural and the mechanistic levels. Here we identified conditions under which resveratrol-treated A549 lung cancer cells die by a mechanism that fulfills the previous definition of autophagic cell death. The cells displayed a strong and sustained induction of autophagic flux, cell death was prevented by knocking down autophagic genes and death occurred in the absence of apoptotic or necroptotic pathway activation. Detailed ultrastructural characterization revealed additional critical events, including a continuous increase over time in the number of autophagic vacuoles, in particular autolysosomes, occupying most of the cytoplasm at terminal stages. This was followed by loss of organelles, disruption of intracellular membranes including the swelling of perinuclear space and, occasionally, a unique type of nuclear shedding. A signalome-wide shRNA-based viability screen was applied to identify positive mediators of this type of autophagic cell death. One top hit was GBA1, the Gaucher disease-associated gene, which encodes glucocerebrosidase, an enzyme that metabolizes glucosylceramide to ceramide and glucose. Interestingly, glucocerebrosidase expression levels and activity were elevated, concomitantly with increased intracellular ceramide levels, both of which correlated in time with the appearance of the unique death characteristics. Transfection with siGBA1 attenuated the increase in glucocerebrosidase activity and the intracellular ceramide levels. Most importantly, GBA1 knockdown prevented the strong increase in LC3 lipidation, and many of the ultrastructural changes characteristic of this type of autophagic cell death, including a significant

  2. Autophagic or necrotic cell death triggered by distinct motifs of the differentiation factor DIF-1.

    Science.gov (United States)

    Luciani, M F; Kubohara, Y; Kikuchi, H; Oshima, Y; Golstein, P

    2009-04-01

    Autophagic or necrotic cell death (ACD and NCD, respectively), studied in the model organism Dictyostelium which offers unique advantages, require triggering by the same differentiation-inducing factor DIF-1. To initiate these two types of cell death, does DIF-1 act through only one or through two distinct recognition structures? Such distinct structures may recognize distinct motifs of DIF-1. To test this albeit indirectly, DIF-1 was modified at one or two of several positions, and the corresponding derivatives were tested for their abilities to induce ACD or NCD. The results strongly indicated that distinct biochemical motifs of DIF-1 were required to trigger ACD or NCD, and that these motifs were separately recognized at the onset of ACD or NCD. In addition, both ACD and NCD were induced more efficiently by DIF-1 than by either its precursors or its immediate catabolite. These results showed an unexpected relation between a differentiation factor, the cellular structures that recognize it, the cell death types it can trigger and the metabolic state of the cell. The latter seems to guide the choice of the signaling pathway to cell death, which in turn imposes the cell death type and the recognition pattern of the differentiation factor.

  3. Mechanisms of prolonged lithium therapy-induced nephrogenic diabetes insipidus.

    Science.gov (United States)

    Behl, Tapan; Kotwani, Anita; Kaur, Ishneet; Goel, Heena

    2015-05-15

    Nephrogenic diabetes insipidus is a clinical sub-type of a diversely expounded disorder, named diabetes insipidus. It is characterized by inability of the renal cells to sense and respond to the stimulus of vasopressin. Amongst its various etiologies, one of the most inevitable causes includes lithium-induced instigation. Numerous studies reported marked histological damage to the kidneys upon long-term treatment with lithium. The recent researches have hypothesized many lithium-mediated mechanisms to explain the damage and dysfunction caused in the kidneys following lithium exposure. These mechanisms, widely, intend to justify the lithium-induced electrolyte imbalance, its interference with some vital proteins and a specific steroidal hormone, obstruction caused to a certain imperative transducer pathway and the renal tubular acidification defect produced on its prolonged therapy. Thorough study of such mechanisms aids in better understanding of the role of lithium in the pathophysiology of this disorder. Hence, the ameliorated knowledge regarding disease-pathology might prove beneficial in developing therapies that aim on disrupting the various lithium-mediated pathways. Hence, this may effectively lead to the demonstration of a novel treatment for nephrogenic diabetes insipidus, which is, at present, limited to the use of diuretics which block lithium reuptake into the body. Copyright © 2015 Elsevier B.V. All rights reserved.

  4. Treatment of amiodarone-induced thyrotoxicosis resistant to conventional therapy

    Directory of Open Access Journals (Sweden)

    Nišić Tanja

    2017-01-01

    Full Text Available Introduction: Amiodarone as an antiarrhythmic medication is necessary in the prevention and treatment of malignant ventricular arrhythmias, however, it can induce thyroid dysfunction. Thyroid dysfunction may be either hypothyroidism or thyrotoxicosis, however, 50% of patients who have used amiodarone are euthyroid. Case report: A 27-year-old female patient, hospitalized at the Clinic for Endocrinology due to type 2 amiodarone-induced thyrotoxicosis. The patient had previously received amiodarone for two years. At age 25, the patient was diagnosed with dilated cardiomyopathy (EF 25%, EDD/ESD 56-57/47 mm with mild Ebstein’s anomaly, WPW Sy and recorded episodes of non-sustained VT. In order to reduce the risk of sudden death and prevent malignant ventricular arrhythmias, ICD-VR was implanted and amiodarone was prescribed. Treatment with propylthiouracil (PTU and dexamethasone was initiated after thyrotoxicosis was diagnosed. Three weeks after the introduction of PTU, hepatotoxicity was registered, thus the medication was discontinued. Thyrozol, which regulates the hepatotoxicity parameters, was introduced. Sodium perchlorate and glucocorticoid (per os, IV and intrathyroidal therapy was introduced. The treatment had lasted for fifty days and laboratory signs of thyrotoxicosis were still present, which is why a total of eight plasmapheresis sessions were performed. Each plasmapheresis resulted in a significant decrease in FT4 and a slight decrease in FT3. After seventy two days of treatment, an optimal hormonal status of the thyroid gland was established and total thyroidectomy was performed. Conclusion: Patient was treated for amiodarone-induced thyrotoxicosis (AIT type 2, which was resistant to conventional therapy for a long period of time. Successful treatment was achieved by applying plasmapheresis although the effect of perchlorate and glucocorticoids application cannot be disregarded.

  5. Hyperbaric Oxygen Therapy for Radiation-Induced Cystitis and Proctitis

    Energy Technology Data Exchange (ETDEWEB)

    Oliai, Caspian; Fisher, Brandon; Jani, Ashish; Wong, Michael; Poli, Jaganmohan; Brady, Luther W. [Department of Radiation Oncology, Drexel University College of Medicine, Philadelphia, Pennsylvania (United States); Komarnicky, Lydia T., E-mail: lydia.komarnicky-kocher@drexelmed.edu [Department of Radiation Oncology, Drexel University College of Medicine, Philadelphia, Pennsylvania (United States)

    2012-11-01

    Purpose: To provide a retrospective analysis of the efficacy of hyperbaric oxygen therapy (HBOT) for treating hemorrhagic cystitis (HC) and proctitis secondary to pelvic- and prostate-only radiotherapy. Methods and Materials: Nineteen patients were treated with HBOT for radiation-induced HC and proctitis. The median age at treatment was 66 years (range, 15-84 years). The range of external-beam radiation delivered was 50.0-75.6 Gy. Bleeding must have been refractory to other therapies. Patients received 100% oxygen at 2.0 atmospheres absolute pressure for 90-120 min per treatment in a monoplace chamber. Symptoms were retrospectively scored according to the Late Effects of Normal Tissues-Subjective, Objective, Management, Analytic (LENT-SOMA) scale to evaluate short-term efficacy. Recurrence of hematuria/hematochezia was used to assess long-term efficacy. Results: Four of the 19 patients were lost to follow-up. Fifteen patients were evaluated and received a mean of 29.8 dives: 11 developed HC and 4 proctitis. All patients experienced a reduction in their LENT-SOMA score. After completion of HBOT, the mean LENT-SOMA score was reduced from 0.78 to 0.20 in patients with HC and from 0.66 to 0.26 in patients with proctitis. Median follow-up was 39 months (range, 7-70 months). No cases of hematuria were refractory to HBOT. Complete resolution of hematuria was seen in 81% (n = 9) and partial response in 18% (n = 2). Recurrence of hematuria occurred in 36% (n = 4) after a median of 10 months. Complete resolution of hematochezia was seen in 50% (n = 2), partial response in 25% (n = 1), and refractory bleeding in 25% (n = 1). Conclusions: Hyperbaric oxygen therapy is appropriate for radiation-induced HC once less time-consuming therapies have failed to resolve the bleeding. In these conditions, HBOT is efficacious in the short and long term, with minimal side effects.

  6. Low Dose Administration of Glutamate Triggers a Non-Apoptotic, Autophagic Response in PC12 Cells

    Directory of Open Access Journals (Sweden)

    Eleni Stamoula

    2015-11-01

    Full Text Available Background/Aims: Increasing amounts of the neurotransmitter glutamate are associated with excitotoxicity, a phenomenon related both to homeostatic processes and neurodegenerative diseases such as multiple sclerosis. Methods: PC12 cells (rat pheochromocytoma were treated with various concentrations of the non-essential amino acid glutamate for 0.5-24 hours. The effect of glutamate on cell morphology was monitored with electron microscopy and haematoxylin-eosin staining. Cell survival was calculated with the MTT assay. Expression analysis of chaperones associated with the observed phenotype was performed using either Western Blotting at the protein level or qRT-PCR at the mRNA level. Results: Administration of glutamate in PC12 cells in doses as low as 10 μM causes an up-regulation of GRP78, GRP94 and HSC70 protein levels, while their mRNA levels show the opposite kinetics. At the same time, GAPDH and GRP75 show reduced protein levels, irrespective of their transcriptional rate. On a cellular level, low concentrations of glutamate induce an autophagy-mediated pro-survival phenotype, which is further supported by induction of the autophagic marker LC3. Conclusion: The findings in the present study underline a discrete effect of glutamate on neuronal cell fate depending on its concentration. It was also shown that a low dose of glutamate orchestrates a unique expression signature of various chaperones and induces cell autophagy, which acts in a neuroprotective fashion.

  7. Fetoscopic laser coagulation of intertwin anastomoses reduces discordant placental autophagic activities in discordant twin growth

    Directory of Open Access Journals (Sweden)

    Yao-Lung Chang

    2015-10-01

    Conclusion: The discordance of placenta autophagic activity in the monochorionic twin with sIUGR was reduced after laser coagulation of the intertwin anastomoses, which may result from the effect of correction of the discordant intertwin placenta perfusion.

  8. Removal of the BH4 Domain from Bcl-2 Protein Triggers an Autophagic Process that Impairs Tumor Growth

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    Daniela Trisciuoglio

    2013-03-01

    Full Text Available Here, we show that forced expression of a B-cell lymphoma 2 (bcl-2 protein lacking residues 1 to 36 at the N-terminal, including the entire Bcl-2 homology 4 (BH4 domain, determines reduction of in vitro and in vivo human melanoma growth. Noteworthy, melanoma cells in vivo exhibit markedly increased autophagy, as response to expression of bcl-2 protein deleted of its BH4 domain. This observation led to the identification of a novel gain of function for bcl-2 protein lacking the BH4 domain. In particular, upon different autophagic stimuli in vitro, overexpression of bcl-2 protein deleted of BH4 domain induces autophagosome accumulation, conversion of microtubule-associated protein 1 light chain 3B-II, reduced expression of p62/SQSTM1 protein, and thereby enhanced autophagic flux. The relevance of Beclin-1 is evidenced by the fact that 1 the autophagy-promoting and growth-inhibiting properties are partially rescued by Beclin-1 knockdown in cells expressing bcl-2 protein lacking the BH4 domain, 2 Beclin-1 only interacts with wild-type but not with deleted bcl-2, and 3 BH4 domain removal from bcl-2 protein does not influence in vitro and in vivo growth of tumor cells expressing low levels of endogenous Beclin-1. These results provide new insight into molecular mechanism of bcl-2 functions and represent a rationale for the development of agents interfering with the BH4 domain of bcl-2 protein.

  9. A fluorescence-microscopic and cytofluorometric system for monitoring the turnover of the autophagic substrate p62/SQSTM1.

    Science.gov (United States)

    BenYounès, Amena; Tajeddine, Nicolas; Tailler, Maximilien; Malik, Shoaib Ahmad; Shen, Shensi; Métivier, Didier; Kepp, Oliver; Vitale, Ilio; Maiuri, Maria Chiara; Kroemer, Guido

    2011-08-01

    Autophagic flux can be measured by determining the declining abundance of autophagic substrates such as sequestosome 1 (SQSTM1, better known as p62), which is sequestered in autophagosomes upon its direct interaction with LC3. However, the total amount of p62 results from two opposed processes, namely its synthesis (which can be modulated by some cellular stressors including autophagy inducers) and its degradation. To avoid this problem, we generated a stable cell line expressing a chimeric protein composed by p62 and the HaloTag (®) protein, which serves as a receptor for fluorescent HaloTag (®) ligands. Upon labeling with HaloTag (®) ligands (which form covalent, near-to-undissociable bonds with the Halotag (®) receptor) and washing, the resulting fluorescent labeling is not influenced by de novo protein synthesis, therefore allowing for the specific monitoring of the fusion protein decline without any interference by protein synthesis. We demonstrate that a HaloTag (®) -p62 fusion protein stably expressed in suitable cell lines can be used to monitor autophagy by flow cytometry and automated fluorescence microscopy. We surmise that this system could be adapted to high-throughput applications.

  10. Antiretroviral therapy-induced Leber’s hereditary optic neuropathy

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    Anand Moodley

    2014-05-01

    Full Text Available Optic neuropathy in HIV-infected patients results from the HIV infection itself, post-infectious auto-immune disease, opportunistic infections and drugs. Nucleoside reverse transcriptase inhibitors (NRTIs such as zidovudine and stavudine have known mitochondrial toxicity and can cause mitochondrial myopathies, neuropathies, hyperlactataemia, and can induce mitochondrial genetic disorders. Individuals with the mutation for Leber’s hereditary optic neuropathy (LHON, a mitochondrial disorder, are usually asymptomatic but develop visual loss when exposed to external triggers such as smoking. We report on two HIV-infected patients with LHON mutations (m.14484T>C and m.11778G>A who developed profound visual loss with antiretroviral therapy. We postulate that the phenotypic expression of LHON in these genetically predisposed individuals was triggered by NRTI drugs lamivudine and tenofovir when used in combination, despite their relatively weak mitochondrial toxic effects. 

  11. Induced Pluripotent Stem Cell Therapies for Cervical Spinal Cord Injury.

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    Doulames, Vanessa M; Plant, Giles W

    2016-04-09

    Cervical-level injuries account for the majority of presented spinal cord injuries (SCIs) to date. Despite the increase in survival rates due to emergency medicine improvements, overall quality of life remains poor, with patients facing variable deficits in respiratory and motor function. Therapies aiming to ameliorate symptoms and restore function, even partially, are urgently needed. Current therapeutic avenues in SCI seek to increase regenerative capacities through trophic and immunomodulatory factors, provide scaffolding to bridge the lesion site and promote regeneration of native axons, and to replace SCI-lost neurons and glia via intraspinal transplantation. Induced pluripotent stem cells (iPSCs) are a clinically viable means to accomplish this; they have no major ethical barriers, sources can be patient-matched and collected using non-invasive methods. In addition, the patient's own cells can be used to establish a starter population capable of producing multiple cell types. To date, there is only a limited pool of research examining iPSC-derived transplants in SCI-even less research that is specific to cervical injury. The purpose of the review herein is to explore both preclinical and clinical recent advances in iPSC therapies with a detailed focus on cervical spinal cord injury.

  12. Induced Pluripotent Stem Cell Therapies for Cervical Spinal Cord Injury

    Science.gov (United States)

    Doulames, Vanessa M.; Plant, Giles W.

    2016-01-01

    Cervical-level injuries account for the majority of presented spinal cord injuries (SCIs) to date. Despite the increase in survival rates due to emergency medicine improvements, overall quality of life remains poor, with patients facing variable deficits in respiratory and motor function. Therapies aiming to ameliorate symptoms and restore function, even partially, are urgently needed. Current therapeutic avenues in SCI seek to increase regenerative capacities through trophic and immunomodulatory factors, provide scaffolding to bridge the lesion site and promote regeneration of native axons, and to replace SCI-lost neurons and glia via intraspinal transplantation. Induced pluripotent stem cells (iPSCs) are a clinically viable means to accomplish this; they have no major ethical barriers, sources can be patient-matched and collected using non-invasive methods. In addition, the patient’s own cells can be used to establish a starter population capable of producing multiple cell types. To date, there is only a limited pool of research examining iPSC-derived transplants in SCI—even less research that is specific to cervical injury. The purpose of the review herein is to explore both preclinical and clinical recent advances in iPSC therapies with a detailed focus on cervical spinal cord injury. PMID:27070598

  13. HIV-Antiretroviral Therapy Induced Liver, Gastrointestinal, and Pancreatic Injury

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    Manuela G. Neuman

    2012-01-01

    Full Text Available The present paper describes possible connections between antiretroviral therapies (ARTs used to treat human immunodeficiency virus (HIV infection and adverse drug reactions (ADRs encountered predominantly in the liver, including hypersensitivity syndrome reactions, as well as throughout the gastrointestinal system, including the pancreas. Highly active antiretroviral therapy (HAART has a positive influence on the quality of life and longevity in HIV patients, substantially reducing morbidity and mortality in this population. However, HAART produces a spectrum of ADRs. Alcohol consumption can interact with HAART as well as other pharmaceutical agents used for the prevention of opportunistic infections such as pneumonia and tuberculosis. Other coinfections that occur in HIV, such as hepatitis viruses B or C, cytomegalovirus, or herpes simplex virus, further complicate the etiology of HAART-induced ADRs. The aspect of liver pathology including liver structure and function has received little attention and deserves further evaluation. The materials used provide a data-supported approach. They are based on systematic review and analysis of recently published world literature (MedLine search and the experience of the authors in the specified topic. We conclude that therapeutic and drug monitoring of ART, using laboratory identification of phenotypic susceptibilities, drug interactions with other medications, drug interactions with herbal medicines, and alcohol intake might enable a safer use of this medication.

  14. TNFα Impairs Rhabdoviral Clearance by Inhibiting the Host Autophagic Antiviral Response.

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    Raquel Espín-Palazón

    2016-06-01

    Full Text Available TNFα is a pleiotropic pro-inflammatory cytokine with a key role in the activation of the immune system to fight viral infections. Despite its antiviral role, a few viruses might utilize the host produced TNFα to their benefit. Some recent reports have shown that anti-TNFα therapies could be utilized to treat certain viral infections. However, the underlying mechanisms by which TNFα can favor virus replication have not been identified. Here, a rhabdoviral infection model in zebrafish allowed us to identify the mechanism of action by which Tnfa has a deleterious role for the host to combat certain viral infections. Our results demonstrate that Tnfa signals through its receptor Tnfr2 to enhance viral replication. Mechanistically, Tnfa does not affect viral adhesion and delivery from endosomes to the cytosol. In addition, the host interferon response was also unaffected by Tnfa levels. However, Tnfa blocks the host autophagic response, which is required for viral clearance. This mechanism of action provides new therapeutic targets for the treatment of SVCV-infected fish, and advances our understanding of the previously enigmatic deleterious role of TNFα in certain viral infections.

  15. Acupuncture promotes mTOR-independent autophagic clearance of aggregation-prone proteins in mouse brain.

    Science.gov (United States)

    Tian, Tian; Sun, Yanhong; Wu, Huangan; Pei, Jian; Zhang, Jing; Zhang, Yi; Wang, Lu; Li, Bin; Wang, Lihua; Shi, Jiye; Hu, Jun; Fan, Chunhai

    2016-01-21

    Acupuncture has historically been practiced to treat medical disorders by mechanically stimulating specific acupoints with fine needles. Despite its well-documented efficacy, its biological basis remains largely elusive. In this study, we found that mechanical stimulation at the acupoint of Yanglingquan (GB34) promoted the autophagic clearance of α-synuclein (α-syn), a well known aggregation-prone protein closely related to Parkinson's disease (PD), in the substantia nigra par compacta (SNpc) of the brain in a PD mouse model. We found the protein clearance arose from the activation of the autophagy-lysosome pathway (ALP) in a mammalian target of rapamycin (mTOR)-independent approach. Further, we observed the recovery in the activity of dopaminergic neurons in SNpc, and improvement in the motor function at the behavior level of PD mice. Whereas acupuncture and rapamycin, a chemical mTOR inhibitor, show comparable α-syn clearance and therapeutic effects in the PD mouse model, the latter adopts a distinctly different, mTOR-dependent, autophagy induction process. Due to this fundamental difference, acupuncture may circumvent adverse effects of the rapamycin treatment. The newly discovered connection between acupuncture and autophagy not only provides a new route to understanding the molecular mechanism of acupuncture but also sheds new light on cost-effective and safe therapy of neurodegenerative diseases.

  16. Ozone therapy ameliorates paraquat-induced lung injury in rats.

    Science.gov (United States)

    Kaldirim, Umit; Uysal, Bulent; Yuksel, Ramazan; Macit, Enis; Eyi, Yusuf E; Toygar, Mehmet; Tuncer, Salim K; Ardic, Sukru; Arziman, Ibrahim; Aydin, Ibrahim; Oztas, Yesim; Karslioglu, Yildirim; Topal, Turgut

    2014-12-01

    Paraquat (PQ) overdose can cause acute lung injury and death. Ozone therapy (OT) was previously demonstrated to alleviate inflammation and necrosis in various pathologies. We therefore hypothesized that OT has ameliorative and preventive effects on PQ-induced lung damage due to anti-inflammatory and antioxidants properties. Sprague-Dawley rats (n = 24) were separated into three groups: sham, PQ, and PQ+OT groups. 15 mg/kg PQ was administered intraperitoneally in PQ and PQ+OT groups to induce experimental lung injury. One hour after PQ treatment, PQ+OT group was administered a single dose of ozone-oxygen mixture (1 mg/kg/day) by intraperitoneal route for four consecutive days. The animals were sacrificed on fifth day after PQ administration. Blood samples and lung tissues were collected to evaluate the inflammatory processes, antioxidant defense and pulmonary damage. Serum lactate dehydrogenase (LDH) and neopterin levels, tissue oxidative stress parameters, total TGF-β1 levels, and histological injury scores in PQ+OT group were significantly lower than PQ group (Ptherapy. © 2014 by the Society for Experimental Biology and Medicine.

  17. Nicotinamide reduces photodynamic therapy-induced immunosuppression in humans.

    Science.gov (United States)

    Thanos, S M; Halliday, G M; Damian, D L

    2012-09-01

    The immune suppressive effects of topical photodynamic therapy (PDT) are potential contributors to treatment failure after PDT for nonmelanoma skin cancer. Nicotinamide (vitamin B(3) ) prevents immune suppression by ultraviolet radiation, but its effects on PDT-induced immunosuppression are unknown. To determine the effects of topical and oral nicotinamide on PDT-induced immunosuppression in humans. Twenty healthy Mantoux-positive volunteers received 5% nicotinamide lotion or vehicle to either side of the back daily for 3 days. Another group of 30 volunteers received 500 mg oral nicotinamide or placebo twice daily for 1 week in a randomized, double-blinded, crossover design. In each study, methylaminolaevulinate cream was applied to discrete areas on the back, followed by narrowband red light irradiation (37 J cm(-2) ) delivered at high (75 mW cm(-2) ) or low (15 mW cm(-2) ) irradiance rates. Adjacent, nonirradiated sites served as controls. Delayed-type hypersensitivity (Mantoux) reactions were assessed at treatment and control sites to determine immunosuppression. High irradiance rate PDT with vehicle or with placebo caused significant immunosuppression (equivalent to 48% and 50% immunosuppression, respectively; both P nicotinamide reduced this immunosuppression by 59% and 66%, respectively (both P nicotinamide study (15% immunosuppression, not significant), but caused 22% immunosuppression in the oral study (placebo arm; P = 0·006); nicotinamide reduced this immunosuppression by 69% (P = 0·045). While the clinical relevance of these findings is currently unknown, nicotinamide may provide an inexpensive means of preventing PDT-induced immune suppression and enhancing PDT cure rates. © 2012 The Authors. BJD © 2012 British Association of Dermatologists.

  18. BH3 Mimetics Reactivate Autophagic Cell Death in Anoxia-Resistant Malignant Glioma Cells

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    Holger Hetschko

    2008-08-01

    Full Text Available Here, we investigated the specific roles of Bcl-2 family members in anoxia tolerance of malignant glioma. Flow cytometry analysis of cell death in 17 glioma cell lines revealed drastic differences in their sensitivity to oxygen withdrawal (<0.1% O2. Cell death correlated with mitochondrial depolarization, cytochrome C release, and translocation of green fluorescent protein (GFP-tagged light chain 3 to autophagosomes but occurred in the absence of caspase activation or phosphatidylserine exposure. In both sensitive and tolerant glioma cell lines, anoxia caused a significant up-regulation of BH3-only genes previously implicated in mediating anoxic cell death in other cell types (BNIP3, NIX, PUMA, and Noxa. In contrast, we detected a strong correlation between anoxia resistance and high expression levels of antiapoptotic Bcl-2 family proteins Bcl-xL, Bcl-2, and Mcl-1 that function to neutralize the proapoptotic activity of BH3-only proteins. Importantly, inhibition of both Bcl-2 and Bcl-xL with the small-molecule BH3 mimetics HA14-1 and BH3I-2′ and by RNA interference reactivated anoxia-induced autophagic cell death in previously resistant glioma cells. Our data suggest that endogenous BH3-only protein induction may not be able to compensate for the high expression of antiapoptotic Bcl-2 family proteins in anoxia-resistant astrocytomas. They also support the conjecture that BH3 mimetics may represent an exciting new approach for the treatment of malignant glioma.

  19. ATG12-ATG3 interacts with Alix to promote basal autophagic flux and late endosome function.

    Science.gov (United States)

    Murrow, Lyndsay; Malhotra, Ritu; Debnath, Jayanta

    2015-03-01

    The ubiquitin-like molecule ATG12 is required for the early steps of autophagy. Recently, we identified ATG3, the E2-like enzyme required for LC3 lipidation during autophagy, as an ATG12 conjugation target. Here, we demonstrate that cells lacking ATG12-ATG3 have impaired basal autophagic flux, accumulation of perinuclear late endosomes, and impaired endolysosomal trafficking. Furthermore, we identify an interaction between ATG12-ATG3 and the ESCRT-associated protein Alix (also known as PDCD6IP) and demonstrate that ATG12-ATG3 controls multiple Alix-dependent processes including late endosome distribution, exosome biogenesis and viral budding. Similar to ATG12-ATG3, Alix is functionally required for efficient basal, but not starvation-induced, autophagy. Overall, these results identify a link between the core autophagy and ESCRT machineries and uncover a role for ATG12-ATG3 in late endosome function that is distinct from the canonical role of either ATG in autophagosome formation.

  20. HAMLET (human alpha-lactalbumin made lethal to tumor cells) triggers autophagic tumor cell death.

    Science.gov (United States)

    Aits, Sonja; Gustafsson, Lotta; Hallgren, Oskar; Brest, Patrick; Gustafsson, Mattias; Trulsson, Maria; Mossberg, Ann-Kristin; Simon, Hans-Uwe; Mograbi, Baharia; Svanborg, Catharina

    2009-03-01

    HAMLET, a complex of partially unfolded alpha-lactalbumin and oleic acid, kills a wide range of tumor cells. Here we propose that HAMLET causes macroautophagy in tumor cells and that this contributes to their death. Cell death was accompanied by mitochondrial damage and a reduction in the level of active mTOR and HAMLET triggered extensive cytoplasmic vacuolization and the formation of double-membrane-enclosed vesicles typical of macroautophagy. In addition, HAMLET caused a change from uniform (LC3-I) to granular (LC3-II) staining in LC3-GFP-transfected cells reflecting LC3 translocation during macroautophagy, and this was blocked by the macroautophagy inhibitor 3-methyladenine. HAMLET also caused accumulation of LC3-II detected by Western blot when lysosomal degradation was inhibited suggesting that HAMLET caused an increase in autophagic flux. To determine if macroautophagy contributed to cell death, we used RNA interference against Beclin-1 and Atg5. Suppression of Beclin-1 and Atg5 improved the survival of HAMLET-treated tumor cells and inhibited the increase in granular LC3-GFP staining. The results show that HAMLET triggers macroautophagy in tumor cells and suggest that macroautophagy contributes to HAMLET-induced tumor cell death.

  1. Investigational therapies for renal disease-induced anemia.

    Science.gov (United States)

    Schmid, Holger; Jelkmann, Wolfgang

    2016-08-01

    The main pillars for the treatment of chronic kidney disease (CKD) associated anemia are peptidic erythropoiesis stimulating agents (ESAs) and iron preparations. Both approaches benefit from long-term efficacy and safety data but are surrounded by clinical and economic concerns, driving the search for novel anti-anemic drugs. By answering pivotal questions, the authors describe the recent developments of next generation ESAs, introduce cutting-edge iron formulations and focus on investigational approaches that interact with pathways involved in erythropoietin (Epo) synthesis and myeloid hematopoiesis. Finally, the challenges encountered with these drug candidates are discussed. Current peptidic ESAs are effective and well-tolerated, but are costly, require parenteral application and iron supplementation. ESA resistance may develop calling for increased doses. Therefore, orally available hypoxia-inducible factor (HIF) stabilizing compounds are attractive alternatives, which may be approved in the near future. Prominent compounds are molidustat, daprodustat and roxadustat. HIF stabilizers suppress hepcidin production and improve iron balance as the present ESAs, but also raise safety concerns in association with their pleiotropic actions. Other investigational erythropoietic biologics are growth-differentiation factor-11 (GDF11) ligand traps (sotatercept, luspatercept), which are also well advanced in development. Possibly, they will provide an add-on for established therapies. However, immunogenicity of these compounds still needs to be carefully investigated.

  2. Characterization of macrolesions induced by myocardial contrast enabled therapy (MCET)

    Science.gov (United States)

    Zhu, Yiying I.; Miller, Douglas L.; Dou, Chunyan; Kripfgans, Oliver D.

    2017-03-01

    Intermittent high intensity ultrasound pulses with circulating contrast agent microbubbles can induce scattered cavitation microlesions of potential value for myocardial reduction therapy. In this study, a computer-aided evaluation scheme of the effective treated volume was implemented in order to optimize ultrasound pulse parameters, exposure duration, and contrast agent dose. Rats with Evans blue injections were treated with 1.5 MHz focused ultrasound bursts. Evans blue staining indicates lethal cardiomyocytic injury. After frozen in compound on dry ice, each heart was sectioned to provide samples covering the entire exposed myocardial volume. Both brightfield and fluorescence images of 25 tissue sections were taken. Tissue detection and microlesion detection were first done based on the 2D images to form microlesion masks containing the outline of the heart and the dead cell regions. Image registration was then performed on the microlesion masks to reconstruct a volume-based model according to the morphology of the heart. The therapeutic beam path was estimated from 3D stacked microlesions, and finally the total impacted volume with microlesions, here termed macrolesion, was characterized along the therapeutic beam axis. Radially symmetric fractional macrolesions were characterized via stepping disks of variable radius determined by the local distribution of microlesions. Treated groups show significant macrolesions with approximately 100 µL volume, an average radius of 2.5 mm, 6 mm length, and 13% lesion density compared to zero radius, length and lesion density for the sham group.

  3. Medical ozone therapy reduces shock wave therapy-induced renal injury.

    Science.gov (United States)

    Uğuz, Sami; Demirer, Zafer; Uysal, Bulent; Alp, Bilal Firat; Malkoc, Ercan; Guragac, Ali; Turker, Turker; Ateş, Ferhat; Karademir, Kenan; Ozcan, Ayhan; Yildirim, Ibrahim; Korkmaz, Ahmet; Guven, Ahmet

    2016-07-01

    Extracorporeal shock wave (ESW) lithotripsy is the preferred treatment modality for uncomplicated kidney stones. More recently free oxygen radical production following ESW application has been considered to be crucial in shock wave-induced renal damage. It has been shown that ozone therapy (OT) has ameliorative and preventive effects against various pathological conditions due to increased nitro-oxidative stress. In current study, we aimed to evaluate the efficacy of OT against ESW-induced renal injury. Twenty-four male Sprague-Dawley rats were divided into three groups: sham-operated, ESW, and ESW + OT groups. All groups except sham-operated group were subjected to ESW procedure. ESW + OT group received 1 mg/kg/day of oxygen/ozone mixture intraperitoneally at 2 h before ESW, and OT was continued once a day for consecutive three days. The animals were killed at the 4th day, and kidney tissue and blood samples were harvested for biochemical and histopathologic analysis. Serum ALT and AST levels, serum neopterin, tissue nitrite/nitrate levels, and tissue oxidative stress parameters were increased in the ESW group and almost came close to control values in the treatment group (p < 0.05, ESW vs. ESW + OT). Histopathological injury scores were significantly lower in treatment group than the ESW group (p < 0.05, ESW vs. ESW + OT). Immunohistochemical iNOS staining scores in ESW group were higher than those of sham-operated group (p < 0.05, ESW vs. sham-operated), iNOS staining scores in OT group were significantly lower than the ESW group (p < 0.05, ESW + OT vs. ESW). OT ameliorates nitro-oxidative stress and reduces the severity of pathological changes in the experimental ESW-induced renal injury of rat model.

  4. Electroconvulsive therapy-induced mania: a case report

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    Saatcioglu Omer

    2009-11-01

    Full Text Available Abstract Introduction Despite its controversial history, electroconvulsive therapy is generally an effective treatment with few serious side effects. One rare but troublesome side effect of electroconvulsive therapy is mania. Case presentation A 33-year-old Turkish woman developed mania on three separate occasions after receiving electroconvulsive therapy for severe depressive episodes. Conclusion Patients who experience electroconvulsive therapy-related mania should be evaluated for alternative treatments when presenting with severe depression.

  5. Emblica officinalis extract induces autophagy and inhibits human ovarian cancer cell proliferation, angiogenesis, growth of mouse xenograft tumors.

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    Alok De

    Full Text Available Patients with ovarian cancer (OC may be treated with surgery, chemotherapy and/or radiation therapy, although none of these strategies are very effective. Several plant-based natural products/dietary supplements, including extracts from Emblicaofficinalis (Amla, have demonstrated potent anti-neoplastic properties. In this study we determined that Amla extract (AE has anti-proliferative effects on OC cells under both in vitro and in vivo conditions. We also determined the anti-proliferative effects one of the components of AE, quercetin, on OC cells under in vitro conditions. AE did not induce apoptotic cell death, but did significantly increase the expression of the autophagic proteins beclin1 and LC3B-II under in vitro conditions. Quercetin also increased the expression of the autophagic proteins beclin1 and LC3B-II under in vitro conditions. AE also significantly reduced the expression of several angiogenic genes, including hypoxia-inducible factor 1α (HIF-1α in OVCAR3 cells. AE acted synergistically with cisplatin to reduce cell proliferation and increase expression of the autophagic proteins beclin1 and LC3B-II under in vitro conditions. AE also had anti-proliferative effects and induced the expression of the autophagic proteins beclin1 and LC3B-II in mouse xenograft tumors. Additionally, AE reduced endothelial cell antigen - CD31 positive blood vessels and HIF-1α expression in mouse xenograft tumors. Together, these studies indicate that AE inhibits OC cell growth both in vitro and in vivo possibly via inhibition of angiogenesis and activation of autophagy in OC. Thus AE may prove useful as an alternative or adjunct therapeutic approach in helping to fight OC.

  6. Constraint-induced movement therapy promotes brain functional reorganization in stroke patients with hemiplegia

    Science.gov (United States)

    Wang, Wenqing; Wang, Aihui; Yu, Limin; Han, Xuesong; Jiang, Guiyun; Weng, Changshui; Zhang, Hongwei; Zhou, Zhiqiang

    2012-01-01

    Stroke patients with hemiplegia exhibit flexor spasms in the upper limb and extensor spasms in the lower limb, and their movement patterns vary greatly. Constraint-induced movement therapy is an upper limb rehabilitation technique used in stroke patients with hemiplegia; however, studies of lower extremity rehabilitation are scarce. In this study, stroke patients with lower limb hemiplegia underwent conventional Bobath therapy for 4 weeks as baseline treatment, followed by constraint-induced movement therapy for an additional 4 weeks. The 10-m maximum walking speed and Berg balance scale scores significantly improved following treatment, and lower extremity motor function also improved. The results of functional MRI showed that constraint-induced movement therapy alleviates the reduction in cerebral functional activation in patients, which indicates activation of functional brain regions and a significant increase in cerebral blood perfusion. These results demonstrate that constraint-induced movement therapy promotes brain functional reorganization in stroke patients with lower limb hemiplegia. PMID:25337108

  7. Constraint-induced movement therapy promotes brain functional reorganization in stroke patients with hemiplegia.

    Science.gov (United States)

    Wang, Wenqing; Wang, Aihui; Yu, Limin; Han, Xuesong; Jiang, Guiyun; Weng, Changshui; Zhang, Hongwei; Zhou, Zhiqiang

    2012-11-15

    Stroke patients with hemiplegia exhibit flexor spasms in the upper limb and extensor spasms in the lower limb, and their movement patterns vary greatly. Constraint-induced movement therapy is an upper limb rehabilitation technique used in stroke patients with hemiplegia; however, studies of lower extremity rehabilitation are scarce. In this study, stroke patients with lower limb hemiplegia underwent conventional Bobath therapy for 4 weeks as baseline treatment, followed by constraint-induced movement therapy for an additional 4 weeks. The 10-m maximum walking speed and Berg balance scale scores significantly improved following treatment, and lower extremity motor function also improved. The results of functional MRI showed that constraint-induced movement therapy alleviates the reduction in cerebral functional activation in patients, which indicates activation of functional brain regions and a significant increase in cerebral blood perfusion. These results demonstrate that constraint-induced movement therapy promotes brain functional reorganization in stroke patients with lower limb hemiplegia.

  8. Autophagic clearance of mitochondria in the kidney copes with metabolic acidosis.

    Science.gov (United States)

    Namba, Tomoko; Takabatake, Yoshitsugu; Kimura, Tomonori; Takahashi, Atsushi; Yamamoto, Takeshi; Matsuda, Jun; Kitamura, Harumi; Niimura, Fumio; Matsusaka, Taiji; Iwatani, Hirotsugu; Matsui, Isao; Kaimori, Junya; Kioka, Hidetaka; Isaka, Yoshitaka; Rakugi, Hiromi

    2014-10-01

    Metabolic acidosis, a common complication of CKD, causes mitochondrial stress by undefined mechanisms. Selective autophagy of impaired mitochondria, called mitophagy, contributes toward maintaining cellular homeostasis in various settings. We hypothesized that mitophagy is involved in proximal tubular cell adaptations to chronic metabolic acidosis. In transgenic mice expressing green fluorescent protein-tagged microtubule-associated protein 1 light chain 3 (GFP-LC3), NH4Cl loading increased the number of GFP puncta exclusively in the proximal tubule. In vitro, culture in acidic medium produced similar results in proximal tubular cell lines stably expressing GFP-LC3 and facilitated the degradation of SQSTM1/p62 in wild-type cells, indicating enhanced autophagic flux. Upon acid loading, proximal tubule-specific autophagy-deficient (Atg5-deficient) mice displayed significantly reduced ammonium production and severe metabolic acidosis compared with wild-type mice. In vitro and in vivo, acid loading caused Atg5-deficient proximal tubular cells to exhibit reduced mitochondrial respiratory chain activity, reduced mitochondrial membrane potential, and fragmented morphology with marked swelling in mitochondria. GFP-LC3-tagged autophagosomes colocalized with ubiquitinated mitochondria in proximal tubular cells cultured in acidic medium, suggesting that metabolic acidosis induces mitophagy. Furthermore, restoration of Atg5-intact nuclei in Atg5-deficient proximal tubular cells increased mitochondrial membrane potential and ammoniagenesis. In conclusion, metabolic acidosis induces autophagy in proximal tubular cells, which is indispensable for maintaining proper mitochondrial functions including ammoniagenesis, and thus for adapted urinary acid excretion. Our results provide a rationale for the beneficial effect of alkali supplementation in CKD, a condition in which autophagy may be reduced, and suggest a new therapeutic option for acidosis by modulating autophagy. Copyright

  9. Ischemic preconditioning enhances autophagy but suppresses autophagic cell death in rat spinal neurons following ischemia-reperfusion.

    Science.gov (United States)

    Fan, Jin; Zhang, Zitao; Chao, Xie; Gu, Jun; Cai, Weihua; Zhou, Wei; Yin, Guoyong; Li, Qingqing

    2014-05-08

    Autophagy serves to eliminate damaged proteins and organelles under normal physiological conditions and can be accelerated by pathological stress, possibly as a cytoprotective mechanism. Brief periods of ischemia (ischemic preconditioning or IPC) can reduce neuronal death in response to subsequent severe ischemic insults. Ischemic preconditioning also induces autophagy, but the contribution of autophagy to IPC-associated neuroprotection remains unclear. We investigated the contribution of autophagy to IPC-mediated neuroprotection in rats subjected to ischemic spinal cord injury. Fifty adult rats were randomly assigned to either (1) a sham group receiving anesthesia and surgical preparation (n=5), (2) an ischemia/reperfusion (I/R) group (n=20) subjected to 0.5 h ischemia followed by 3, 6, 12, or 24 h reperfusion, (3) an IPC group receiving three cycles of 5 min ischemia followed by 5 min of reperfusion (n=5), or (4) an IPC+I/R group (n=20). Hematoxylin-eosin (HE) and immunohistochemical staining were performed to evaluate spinal neuron survival in the four treatment groups. Autophagic activity was investigated by electron microscopy and by immunohistochemical and Western blot analyses of the autophagosome marker LC3-II and the autophagy-associated BH3 protein Beclin-1. Changes in Bcl-2/Beclin-1 complex association and Bcl-2 phosphorylation (p-Bcl-2) were examined by co-immunoprecipitation and Western blot analyses. In the I/R group, LC3-II was significantly elevated after 3h of reperfusion, but declined significantly by 24 h. At 24 h, I/R rats exhibited extensive spinal damage and decreased neuronal survival. In the IPC+IR group, neuronal death was reduced and expression of LC3-II sustained throughout the 24 h reperfusion period. In the I/R group, expression of (inactive) p-Bcl-2(Ser70) was increased significantly during reperfusion and was accompanied by dissociation of the Bcl-2/Beclin-1 complex and increased Beclin-1 expression. Preconditioning inhibited these

  10. Nutrigenomics Therapy of Hepatisis C Virus Induced-hepatosteatosis

    Science.gov (United States)

    2010-01-01

    Nutrigenomics is a relatively new branch of nutrition science, which aim is to study the impact of the foods we eat on the function of our genes. Hepatosteatosis is strongly associated with hepatitis C virus infection, which is known to increase the risk of the disease progression and reduce the likelihood of responding to anti- virus treatment. It is well documented that hepatitis C virus can directly alter host cell lipid metabolism through nuclear transcription factors. To date, only a limited number of studies have been on the effect of human foods on the nuclear transcription factors of hepatitis C virus -induced hepatosteatosis. Three nutrients, selected among 46 different nutrients: β-carotene, vitamin D2, and linoleic acid were found in a cell culture system to inhibit hepatitis C virus RNA replication. In addition, polyunsaturated fatty acids (PUFAs) especially arachidonic acid (AA), docosahexaenoic acid (DHA), and eicosapentaenoic acid (EPA) have been demonstrated to inhibit hepatitis C virus RNA replication. These PUFAs, in particular the highly unsaturated n-3 fatty acids change the gene expression of PPARa and SREBP, suppress the expression of mRNAs encoding key metabolic enzymes and hereby suppress hepatic lipogenesis and triglyceride synthesis, as well as secretion and accumulation in tissues. A recent prospective clinical trial of 1,084 chronic hepatitis C patients compared to 2,326 healthy subjects suggests that chronic hepatitis C patients may benefit from strict dietary instructions. Increasing evidence suggest that some crucial nuclear transcription factors related to hepatitis C virus -associated hepatosteatosis and hepatitis C virus RNA itself can be controlled by specific anti- hepatitis C virus nutrition. It seems important that these findings are taken into account and specific nutritional supplements developed to be used in combination with interferon as adjunctive therapy with the aim to improve both the early as well as the sustained

  11. Nutrigenomics therapy of hepatisis C virus induced-hepatosteatosis.

    Science.gov (United States)

    Liu, Qing; Bengmark, Stig; Qu, Shen

    2010-05-20

    Nutrigenomics is a relatively new branch of nutrition science, which aim is to study the impact of the foods we eat on the function of our genes. Hepatosteatosis is strongly associated with hepatitis C virus infection, which is known to increase the risk of the disease progression and reduce the likelihood of responding to anti- virus treatment. It is well documented that hepatitis C virus can directly alter host cell lipid metabolism through nuclear transcription factors. To date, only a limited number of studies have been on the effect of human foods on the nuclear transcription factors of hepatitis C virus -induced hepatosteatosis.Three nutrients, selected among 46 different nutrients: beta-carotene, vitamin D2, and linoleic acid were found in a cell culture system to inhibit hepatitis C virus RNA replication. In addition, polyunsaturated fatty acids (PUFAs) especially arachidonic acid (AA), docosahexaenoic acid (DHA), and eicosapentaenoic acid (EPA) have been demonstrated to inhibit hepatitis C virus RNA replication. These PUFAs, in particular the highly unsaturated n-3 fatty acids change the gene expression of PPARa and SREBP, suppress the expression of mRNAs encoding key metabolic enzymes and hereby suppress hepatic lipogenesis and triglyceride synthesis, as well as secretion and accumulation in tissues. A recent prospective clinical trial of 1,084 chronic hepatitis C patients compared to 2,326 healthy subjects suggests that chronic hepatitis C patients may benefit from strict dietary instructions.Increasing evidence suggest that some crucial nuclear transcription factors related to hepatitis C virus -associated hepatosteatosis and hepatitis C virus RNA itself can be controlled by specific anti- hepatitis C virus nutrition. It seems important that these findings are taken into account and specific nutritional supplements developed to be used in combination with interferon as adjunctive therapy with the aim to improve both the early as well as the sustained

  12. Three-dimensional tumor cell growth stimulates autophagic flux and recapitulates chemotherapy resistance

    Science.gov (United States)

    Bingel, Corinna; Koeneke, Emily; Ridinger, Johannes; Bittmann, Annika; Sill, Martin; Peterziel, Heike; Wrobel, Jagoda K; Rettig, Inga; Milde, Till; Fernekorn, Uta; Weise, Frank; Schober, Andreas; Witt, Olaf; Oehme, Ina

    2017-01-01

    Current preclinical models in tumor biology are limited in their ability to recapitulate relevant (patho-) physiological processes, including autophagy. Three-dimensional (3D) growth cultures have frequently been proposed to overcome the lack of correlation between two-dimensional (2D) monolayer cell cultures and human tumors in preclinical drug testing. Besides 3D growth, it is also advantageous to simulate shear stress, compound flux and removal of metabolites, e.g., via bioreactor systems, through which culture medium is constantly pumped at a flow rate reflecting physiological conditions. Here we show that both static 3D growth and 3D growth within a bioreactor system modulate key hallmarks of cancer cells, including proliferation and cell death as well as macroautophagy, a recycling pathway often activated by highly proliferative tumors to cope with metabolic stress. The autophagy-related gene expression profiles of 2D-grown cells are substantially different from those of 3D-grown cells and tumor tissue. Autophagy-controlling transcription factors, such as TFEB and FOXO3, are upregulated in tumors, and 3D-grown cells have increased expression compared with cells grown in 2D conditions. Three-dimensional cultures depleted of the autophagy mediators BECN1, ATG5 or ATG7 or the transcription factor FOXO3, are more sensitive to cytotoxic treatment. Accordingly, combining cytotoxic treatment with compounds affecting late autophagic flux, such as chloroquine, renders the 3D-grown cells more susceptible to therapy. Altogether, 3D cultures are a valuable tool to study drug response of tumor cells, as these models more closely mimic tumor (patho-)physiology, including the upregulation of tumor relevant pathways, such as autophagy. PMID:28837150

  13. Effect of immunomodulatory therapy on the endometrial inflammatory response to induced infectious endometritis in susceptible mares

    DEFF Research Database (Denmark)

    Christoffersen, Mette; Woodward, Elizabeth; Bojesen, Anders Miki

    2012-01-01

    The objective of the present study was to evaluate the effect of immunomodulatory therapy (glucocorticoids (GC) and mycobacterium cell wall extract (MCWE)) on the endometrial gene expression of inflammatory cytokines in susceptible mares with induced infectious endometritis. Endometrial gene expr...

  14. Molecular Hydrogen Therapy Ameliorates Organ Damage Induced by Sepsis

    Directory of Open Access Journals (Sweden)

    Yijun Zheng

    2016-01-01

    Full Text Available Since it was proposed in 2007, molecular hydrogen therapy has been widely concerned and researched. Many animal experiments were carried out in a variety of disease fields, such as cerebral infarction, ischemia reperfusion injury, Parkinson syndrome, type 2 diabetes mellitus, metabolic syndrome, chronic kidney disease, radiation injury, chronic hepatitis, rheumatoid arthritis, stress ulcer, acute sports injuries, mitochondrial and inflammatory disease, and acute erythema skin disease and other pathological processes or diseases. Molecular hydrogen therapy is pointed out as there is protective effect for sepsis patients, too. The impact of molecular hydrogen therapy against sepsis is shown from the aspects of basic vital signs, organ functions (brain, lung, liver, kidney, small intestine, etc., survival rate, and so forth. Molecular hydrogen therapy is able to significantly reduce the release of inflammatory factors and oxidative stress injury. Thereby it can reduce damage of various organ functions from sepsis and improve survival rate. Molecular hydrogen therapy is a prospective method against sepsis.

  15. SET overexpression in HEK293 cells regulates mitochondrial uncoupling proteins levels within a mitochondrial fission/reduced autophagic flux scenario

    Energy Technology Data Exchange (ETDEWEB)

    Almeida, Luciana O.; Goto, Renata N. [Department of Clinical Analyses, Toxicology and Food Sciences, School of Pharmaceutical Sciences of Ribeirão Preto, University of São Paulo, Ribeirão Preto, SP (Brazil); Neto, Marinaldo P.C. [Department of Physics and Chemistry, School of Pharmaceutical Sciences of Ribeirão Preto, University of São Paulo, Ribeirão Preto, SP (Brazil); Sousa, Lucas O. [Department of Clinical Analyses, Toxicology and Food Sciences, School of Pharmaceutical Sciences of Ribeirão Preto, University of São Paulo, Ribeirão Preto, SP (Brazil); Curti, Carlos [Department of Physics and Chemistry, School of Pharmaceutical Sciences of Ribeirão Preto, University of São Paulo, Ribeirão Preto, SP (Brazil); Leopoldino, Andréia M., E-mail: andreiaml@usp.br [Department of Clinical Analyses, Toxicology and Food Sciences, School of Pharmaceutical Sciences of Ribeirão Preto, University of São Paulo, Ribeirão Preto, SP (Brazil)

    2015-03-06

    We hypothesized that SET, a protein accumulated in some cancer types and Alzheimer disease, is involved in cell death through mitochondrial mechanisms. We addressed the mRNA and protein levels of the mitochondrial uncoupling proteins UCP1, UCP2 and UCP3 (S and L isoforms) by quantitative real-time PCR and immunofluorescence as well as other mitochondrial involvements, in HEK293 cells overexpressing the SET protein (HEK293/SET), either in the presence or absence of oxidative stress induced by the pro-oxidant t-butyl hydroperoxide (t-BHP). SET overexpression in HEK293 cells decreased UCP1 and increased UCP2 and UCP3 (S/L) mRNA and protein levels, whilst also preventing lipid peroxidation and decreasing the content of cellular ATP. SET overexpression also (i) decreased the area of mitochondria and increased the number of organelles and lysosomes, (ii) increased mitochondrial fission, as demonstrated by increased FIS1 mRNA and FIS-1 protein levels, an apparent accumulation of DRP-1 protein, and an increase in the VDAC protein level, and (iii) reduced autophagic flux, as demonstrated by a decrease in LC3B lipidation (LC3B-II) in the presence of chloroquine. Therefore, SET overexpression in HEK293 cells promotes mitochondrial fission and reduces autophagic flux in apparent association with up-regulation of UCP2 and UCP3; this implies a potential involvement in cellular processes that are deregulated such as in Alzheimer's disease and cancer. - Highlights: • SET, UCPs and autophagy prevention are correlated. • SET action has mitochondrial involvement. • UCP2/3 may reduce ROS and prevent autophagy. • SET protects cell from ROS via UCP2/3.

  16. A Novel Combination of Thermal Ablation and Heat-Inducible Gene therapy for Breast Cancer Treatment

    Science.gov (United States)

    2009-04-01

    intensity focused ultrasound ( HIFU ) has been developed as an emerging non-invasive strategy for cancer treatment by thermal ablation of tumor tissue. The...feasibility of synergistic combination of HIFU thermal ablation and HIFU -induced gene therapy is interpreted both in vitro and in vivo using cancer...distribution. This work opens up a new paradigm for synergistic combination of HIFU thermal ablation with heat-induced gene therapy to improve the overall

  17. A systematic review of trismus induced by cancer therapies in head and neck cancer patients

    NARCIS (Netherlands)

    Bensadoun, Rene-Jean; Riesenbeck, Dorothea; Lockhart, Peter B.; Elting, Linda S.; Spijkervet, Fred K. L.; Brennan, Mike T.

    This systematic review represents a thorough evaluation of the literature to clarify the impact of cancer therapies on the prevalence, quality of life and economic impact, and management strategies for cancer-therapy-induced trismus. A systematic literature search was conducted with assistance from

  18. Tooth discoloration induced by endodontic phenothiazine dyes in photodynamic therapy.

    Science.gov (United States)

    Figueiredo, Rômulo Aguiar; Anami, Lilian Costa; Mello, Isabel; Carvalho, Erica dos Santos; Habitante, Sandra Márcia; Raldi, Denise Pontes

    2014-08-01

    This study sought to assess if discoloration of tooth structures occurs after photodynamic therapy (PDT) and to determine the efficacy of a protocol to remove the photosensitizers. PDT has been used in root canal treatment to enhance cleaning and disinfection of the root canal system. PDT uses a low power laser in association with a dye as a photosensitizer. Photosensitizers can induce staining of the dental structures, resulting in an unaesthetic appearance. Forty teeth were randomly divided into four groups according to the photosensitizer used and pre-irradiation time: 0.01% methylene blue for 5 min (MB5); 0.01% methylene blue for 10 min (MB10); 0.01% toluidine blue for 5 min (TB5); and 0.01% toluidine blue for 10 min (TB10). Specimens were irradiated with a 660 nm diode laser with a 300 μm diameter optical fiber, at 40 mW power setting for 3 min. Immediately after, the photosensitizers were removed with Endo-PTC cream+2.5% sodium hypochlorite (NaOCl). The shade was measured by a Vita Easyshade spectrophotometer based on the CIELAB color system (L*a*b* values) at three different experimental times: before PDT (T0), immediately after PDT (T1), and after removal of the photosensitizer (T2). The results showed a decrease in the averages of the L*a*b* coordinate values after PDT (T1) in all the groups, when compared with the number at T0, with a significant statistical difference in group MB10. After photosensitizer removal (T2), all the values of the coordinates increased with significant statistical differences (p<0.05) between T1 and T2 in L* and a*. It can be concluded that both methylene blue and toluidine blue dyes cause tooth discoloration, and that Endo-PTC cream associated with 2.5% NaOCl effectively remove these dyes, regardless of the pre-irradiation time used for PDT.

  19. Acute NMDA toxicity in cultured rat cerebellar granule neurons is accompanied by autophagy induction and late onset autophagic cell death phenotype

    Directory of Open Access Journals (Sweden)

    Kobeissy Firas H

    2010-02-01

    Full Text Available Abstract Background Autophagy, an intracellular response to stress, is characterized by double membrane cytosolic vesicles called autophagosomes. Prolonged autophagy is known to result in autophagic (Type II cell death. This study examined the potential role of an autophagic response in cultured cerebellar granule neurons challenged with excitotoxin N-methyl-D-aspartate (NMDA. Results NMDA exposure induced light chain-3 (LC-3-immunopositive and monodansylcadaverine (MDC fluorescent dye-labeled autophagosome formation in both cell bodies and neurites as early as 3 hours post-treatment. Elevated levels of Beclin-1 and the autophagosome-targeting LC3-II were also observed following NMDA exposure. Prolonged exposure of the cultures to NMDA (8-24 h generated MDC-, LC3-positive autophagosomal bodies, concomitant with the neurodegenerative phase of NMDA challenge. Lysosomal inhibition studies also suggest that NMDA-treatment diverted the autophagosome-associated LC3-II from the normal lysosomal degradation pathway. Autophagy inhibitor 3-methyladenine significantly reduced NMDA-induced LC3-II/LC3-I ratio increase, accumulation of autophagosomes, and suppressed NMDA-mediated neuronal death. ATG7 siRNA studies also showed neuroprotective effects following NMDA treatment. Conclusions Collectively, this study shows that autophagy machinery is robustly induced in cultured neurons subjected to prolonged exposure to excitotoxin, while autophagosome clearance by lysosomal pathway might be impaired. Our data further show that prolonged autophagy contributes to cell death in NMDA-mediated excitotoxicity.

  20. Idarubicin induces mTOR-dependent cytotoxic autophagy in leukemic cells

    Energy Technology Data Exchange (ETDEWEB)

    Ristic, Biljana [Institute of Microbiology and Immunology, School of Medicine, University of Belgrade, Dr. Subotica 1, 11000 Belgrade (Serbia); Bosnjak, Mihajlo [Institute of Histology and Embryology, School of Medicine, University of Belgrade, Belgrade (Serbia); Arsikin, Katarina [Institute of Microbiology and Immunology, School of Medicine, University of Belgrade, Dr. Subotica 1, 11000 Belgrade (Serbia); Mircic, Aleksandar; Suzin-Zivkovic, Violeta [Institute of Histology and Embryology, School of Medicine, University of Belgrade, Belgrade (Serbia); Bogdanovic, Andrija [Clinic for Hematology, Clinical Centre of Serbia, School of Medicine, University of Belgrade, Belgrade (Serbia); Perovic, Vladimir [Institute of Microbiology and Immunology, School of Medicine, University of Belgrade, Dr. Subotica 1, 11000 Belgrade (Serbia); Martinovic, Tamara; Kravic-Stevovic, Tamara; Bumbasirevic, Vladimir [Institute of Histology and Embryology, School of Medicine, University of Belgrade, Belgrade (Serbia); Trajkovic, Vladimir, E-mail: vtrajkovic@med.bg.ac.rs [Institute of Microbiology and Immunology, School of Medicine, University of Belgrade, Dr. Subotica 1, 11000 Belgrade (Serbia); Harhaji-Trajkovic, Ljubica, E-mail: buajk@yahoo.com [Institute for Biological Research, University of Belgrade, Belgrade, Despot Stefan Blvd. 142, 11000 Belgrade (Serbia)

    2014-08-01

    We investigated if the antileukemic drug idarubicin induces autophagy, a process of programmed cellular self-digestion, in leukemic cell lines and primary leukemic cells. Transmission electron microscopy and acridine orange staining demonstrated the presence of autophagic vesicles and intracellular acidification, respectively, in idarubicin-treated REH leukemic cell line. Idarubicin increased punctuation/aggregation of microtubule-associated light chain 3B (LC3B), enhanced the conversion of LC3B-I to autophagosome-associated LC3B-II in the presence of proteolysis inhibitors, and promoted the degradation of the selective autophagic target p62, thus indicating the increase in autophagic flux. Idarubicin inhibited the phosphorylation of the main autophagy repressor mammalian target of rapamycin (mTOR) and its downstream target p70S6 kinase. The treatment with the mTOR activator leucine prevented idarubicin-mediated autophagy induction. Idarubicin-induced mTOR repression was associated with the activation of the mTOR inhibitor AMP-activated protein kinase and down-regulation of the mTOR activator Akt. The suppression of autophagy by pharmacological inhibitors or LC3B and beclin-1 genetic knockdown rescued REH cells from idarubicin-mediated oxidative stress, mitochondrial depolarization, caspase activation and apoptotic DNA fragmentation. Idarubicin also caused mTOR inhibition and cytotoxic autophagy in K562 leukemic cell line and leukocytes from chronic myeloid leukemia patients, but not healthy controls. By demonstrating mTOR-dependent cytotoxic autophagy in idarubicin-treated leukemic cells, our results warrant caution when considering combining idarubicin with autophagy inhibitors in leukemia therapy. - Highlights: • Idarubicin induces autophagy in leukemic cell lines and primary leukemic cells. • Idarubicin induces autophagy by inhibiting mTOR in leukemic cells. • mTOR suppression by idarubicin is associated with AMPK activation and Akt blockade.

  1. Anthracycline-induced cardiomyopathy: favourable effects of cardiac resynchronization therapy

    DEFF Research Database (Denmark)

    Ahlehoff, Ole; Galløe, Anders M; Hansen, Peter R

    2010-01-01

    We report a case of severe refractory congestive heart failure after anthracycline chemotherapy in a patient with a narrow QRS interval on the electrocardiogram and echocardiographic evidence of left ventricular dyssynchrony, where cardiac resynchronization therapy resulted in normalization of left...

  2. Combined statin-fibrate therapy-induced rhabdomyolysis: Case report

    Directory of Open Access Journals (Sweden)

    Jozić Tanja L.

    2014-01-01

    Full Text Available Introduction Rhabdomyolysis is a rare, but serious and potentially fatal adverse reaction of the statin application that may be developed in any time of therapy. It is characterized by massive destruction of muscles associated with the large increase of creatine kinase (CK leading to myoglobinuria and potential acute renal failure. Combined statin-fibrate therapy increases the risk of rhabdomyolysis, especially in elderly and diabetic patients. Case report An 81-year-old male was admitted to Coronary Care Unit of the Emergency Center, Clinical Center of Serbia (CCS with the clinical picture and electrocardiogram of the acute anterior wall myocardial infarction complicated with pulmonary edema. Laboratory tests on admission showed higher elevated values of serum creatinine 179 μmol/L and BUN 9.2 mmol/L (eGFR 32 mL/min/1.73m2, CK 309 U/L (on day 2: 3476 U/L and mixed hyperlipidemia (total cholesterol 10.3 mmol/L, HDL 2.26 mmol/L, TG 4.85 mmol/L. The patient was treated with thrombolysis medication therapy (Alteplase, anticoagulant and dual antiplatelet therapy, diuretics, organic nitrates, angiotensin-converting enzyme (ACE inhibitors, antibiotics, and proton pump inhibitors. During seven days, his therapy included combined pravastatin 20 mg and fenofibrate (160 mg, which was discontinued due to pains and weakness of muscles and significantly elevated CC to 7080 U/L (upper limit 200 U/L, but no significant deterioration of renal function was observed. Discontinuation of therapy resulted in CC level normalization and improvement of clinical condition. Conclusion Combined statin and fibrate therapy requires strict clinical control and monitoring of CK i transaminases. Four-time or higher increase of CK requires discontinuation of therapy. In addition, patients are advised to report immediately any pains in muscles, sensibility, weakness or cramps.

  3. Phenytoin Induced Erythema Multiforme after Cranial Radiation Therapy.

    Science.gov (United States)

    Kazanci, Atilla; Tekkök, İsmail Hakkı

    2015-08-01

    The prophylactic use of phenytoin during and after brain surgery and cranial irradiation is a common measure in brain tumor therapy. Phenytoin has been associated with variety of adverse skin reactions including urticaria, erythroderma, erythema multiforme (EM), Stevens-Johnson syndrome, and toxic epidermal necrolysis. EM associated with phenytoin and cranial radiation therapy (EMPACT) is a rare specific entity among patients with brain tumors receiving radiation therapy while on prophylactic anti-convulsive therapy. Herein we report a 41-year-old female patient with left temporal glial tumor who underwent surgery and then received whole brain radiation therapy and chemotherapy. After 24 days of continous prophylactic phenytoin therapy the patient developed minor skin reactions and 2 days later the patient returned with generalized erythamatous and itchy maculopapuler rash involving neck, chest, face, trunk, extremities. There was significant periorbital and perioral edema. Painful mucosal lesions consisting of oral and platal erosions also occurred and prevented oral intake significantly. Phenytoin was discontinued gradually. Systemic admistration of corticosteroids combined with topical usage of steroids for oral lesions resulted in complete resolution of eruptions in 3 weeks. All cutaneous lesions in patients with phenytoin usage with the radiotherapy must be evoluated with suspicion for EM.

  4. Analysis of autophagic flux in response to sulforaphane in metastatic prostate cancer cells

    Science.gov (United States)

    Watson, Gregory W; Wickramasekara, Samanthi; Fang, Yufeng; Palomera-Sanchez, Zoraya; Maier, Claudia S; Williams, David E; Dashwood, Roderick H; Perez, Viviana I; Ho, Emily

    2015-01-01

    Scope The phytochemical sulforaphane has been shown to decrease prostate cancer metastases in a genetic mouse model of prostate carcinogenesis, though the mechanism of action is not fully known. Sulforaphane has been reported to stimulate autophagy, and modulation of autophagy has been proposed to influence sulforaphane cytotoxicity; however, no conclusions about autophagy can be drawn without assessing autophagic flux, which has not been characterized in prostate cancer cells following sulforaphane treatment. Methods and Results We conducted an investigation to assess the impact of sulforaphane on autophagic flux in two metastatic prostate cancer cell lines at a concentration shown to decrease metastasis in vivo. Autophagic flux was assessed by multiple autophagy related proteins and substrates. We found that sulforaphane can stimulate autophagic flux and cell death only at high concentrations, above what has been observed in vivo. Conclusion These results suggest that sulforaphane does not directly stimulate autophagy or cell death in metastatic prostate cancer cells under physiologically relevant conditions, but instead supports the involvement of in vivo factors as important effectors of sulforaphane- mediated prostate cancer suppression. PMID:26108801

  5. Inhibition of hypoxia inducible factor 1 and topoisomerase with acriflavine sensitizes perihilar cholangiocarcinomas to photodynamic therapy

    NARCIS (Netherlands)

    Weijer, R.; Broekgaarden, M.; Krekorian, M.; Alles, L.K.; van Wijk, A.C; Mackaaij, C.; Verheij, J.; van der Wal, A.C.; van Gullik, T.M.; Storm, Gerrit; Heger, M.

    2016-01-01

    Background: Photodynamic therapy (PDT) induces tumor cell death by oxidative stress and hypoxia but also survival signaling through activation of hypoxia-inducible factor 1 (HIF-1). Since perihilar cholangiocarcinomas are relatively recalcitrant to PDT, the aims were to (1) determine the expression

  6. Inhibition of hypoxia inducible factor 1 and topoisomerase with acriflavine sensitizes perihilar cholangiocarcinomas to photodynamic therapy

    NARCIS (Netherlands)

    Weijer, Ruud; Broekgaarden, Mans; Krekorian, Massis; Alles, Lindy K.; van Wijk, Albert C.; Mackaaij, Claire; Verheij, Joanne; van der Wal, Allard C.; van Gulik, Thomas M.; Storm, Gert; Heger, Michal

    2016-01-01

    Photodynamic therapy (PDT) induces tumor cell death by oxidative stress and hypoxia but also survival signaling through activation of hypoxia-inducible factor 1 (HIF-1). Since perihilar cholangiocarcinomas are relatively recalcitrant to PDT, the aims were to (1) determine the expression levels of

  7. Cell Death Pathways and Phthalocyanine as an Efficient Agent for Photodynamic Cancer Therapy

    Science.gov (United States)

    Mfouo-Tynga, Ivan; Abrahamse, Heidi

    2015-01-01

    The mechanisms of cell death can be predetermined (programmed) or not and categorized into apoptotic, autophagic and necrotic pathways. The process of Hayflick limits completes the execution of death-related mechanisms. Reactive oxygen species (ROS) are associated with oxidative stress and subsequent cytodamage by oxidizing and degrading cell components. ROS are also involved in immune responses, where they stabilize and activate both hypoxia-inducible factors and phagocytic effectors. ROS production and presence enhance cytodamage and photodynamic-induced cell death. Photodynamic cancer therapy (PDT) uses non-toxic chemotherapeutic agents, photosensitizer (PS), to initiate a light-dependent and ROS-related cell death. Phthalocyanines (PCs) are third generation and stable PSs with improved photochemical abilities. They are effective inducers of cell death in various neoplastic models. The metallated PCs localize in critical cellular organelles and are better inducers of cell death than other previous generation PSs as they favor mainly apoptotic cell death events. PMID:25955645

  8. Cell Death Pathways and Phthalocyanine as an Efficient Agent for Photodynamic Cancer Therapy

    Directory of Open Access Journals (Sweden)

    Ivan Mfouo-Tynga

    2015-05-01

    Full Text Available The mechanisms of cell death can be predetermined (programmed or not and categorized into apoptotic, autophagic and necrotic pathways. The process of Hayflick limits completes the execution of death-related mechanisms. Reactive oxygen species (ROS are associated with oxidative stress and subsequent cytodamage by oxidizing and degrading cell components. ROS are also involved in immune responses, where they stabilize and activate both hypoxia-inducible factors and phagocytic effectors. ROS production and presence enhance cytodamage and photodynamic-induced cell death. Photodynamic cancer therapy (PDT uses non-toxic chemotherapeutic agents, photosensitizer (PS, to initiate a light-dependent and ROS-related cell death. Phthalocyanines (PCs are third generation and stable PSs with improved photochemical abilities. They are effective inducers of cell death in various neoplastic models. The metallated PCs localize in critical cellular organelles and are better inducers of cell death than other previous generation PSs as they favor mainly apoptotic cell death events.

  9. Disruption of the vacuolar-type H(+)-ATPase complex in liver causes MTORC1-independent accumulation of autophagic vacuoles and lysosomes.

    Science.gov (United States)

    Kissing, Sandra; Rudnik, Sönke; Damme, Markus; Lüllmann-Rauch, Renate; Ichihara, Atsuhiro; Kornak, Uwe; Eskelinen, Eeva-Liisa; Jabs, Sabrina; Heeren, Jörg; De Brabander, Jef K; Haas, Albert; Saftig, Paul

    2017-04-03

    The vacuolar-type H(+)-translocating ATPase (v-H(+)-ATPase) has been implicated in the amino acid-dependent activation of the mechanistic target of rapamycin complex 1 (MTORC1), an important regulator of macroautophagy. To reveal the mechanistic links between the v-H(+)-ATPase and MTORC1, we destablilized v-H(+)-ATPase complexes in mouse liver cells by induced deletion of the essential chaperone ATP6AP2. ATP6AP2-mutants are characterized by massive accumulation of endocytic and autophagic vacuoles in hepatocytes. This cellular phenotype was not caused by a block in endocytic maturation or an impaired acidification. However, the degradation of LC3-II in the knockout hepatocytes appeared to be reduced. When v-H(+)-ATPase levels were decreased, we observed lysosome association of MTOR and normal signaling of MTORC1 despite an increase in autophagic marker proteins. To better understand why MTORC1 can be active when v-H(+)-ATPase is depleted, the activation of MTORC1 was analyzed in ATP6AP2-deficient fibroblasts. In these cells, very little amino acid-elicited activation of MTORC1 was observed. In contrast, insulin did induce MTORC1 activation, which still required intracellular amino acid stores. These results suggest that in vivo the regulation of macroautophagy depends not only on v-H(+)-ATPase-mediated regulation of MTORC1.

  10. cAMP and EPAC are key players in the regulation of the signal transduction pathway involved in the α-hemolysin autophagic response.

    Directory of Open Access Journals (Sweden)

    María Belén Mestre

    Full Text Available Staphylococcus aureus is a microorganism that causes serious diseases in the human being. This microorganism is able to escape the phagolysosomal pathway, increasing intracellular bacterial survival and killing the eukaryotic host cell to spread the infection. One of the key features of S. aureus infection is the production of a series of virulence factors, including secreted enzymes and toxins. We have shown that the pore-forming toxin α-hemolysin (Hla is the S. aureus-secreted factor responsible for the activation of the autophagic pathway and that this response occurs through a PI3K/Beclin1-independent form. In the present report we demonstrate that cAMP has a key role in the regulation of this autophagic response. Our results indicate that cAMP is able to inhibit the autophagy induced by Hla and that PKA, the classical cAMP effector, does not participate in this regulation. We present evidence that EPAC and Rap2b, through calpain activation, are the proteins involved in the regulation of Hla-induced autophagy. Similar results were obtained in cells infected with different S. aureus strains. Interestingly, in this report we show, for the first time to our knowledge, that both EPAC and Rap2b are recruited to the S. aureus-containing phagosome. We believe that our findings have important implications in understanding innate immune processes involved in intracellular pathogen invasion of the host cell.

  11. cAMP and EPAC Are Key Players in the Regulation of the Signal Transduction Pathway Involved in the α-Hemolysin Autophagic Response

    Science.gov (United States)

    Mestre, María Belén; Colombo, María Isabel

    2012-01-01

    Staphylococcus aureus is a microorganism that causes serious diseases in the human being. This microorganism is able to escape the phagolysosomal pathway, increasing intracellular bacterial survival and killing the eukaryotic host cell to spread the infection. One of the key features of S. aureus infection is the production of a series of virulence factors, including secreted enzymes and toxins. We have shown that the pore-forming toxin α-hemolysin (Hla) is the S. aureus–secreted factor responsible for the activation of the autophagic pathway and that this response occurs through a PI3K/Beclin1-independent form. In the present report we demonstrate that cAMP has a key role in the regulation of this autophagic response. Our results indicate that cAMP is able to inhibit the autophagy induced by Hla and that PKA, the classical cAMP effector, does not participate in this regulation. We present evidence that EPAC and Rap2b, through calpain activation, are the proteins involved in the regulation of Hla-induced autophagy. Similar results were obtained in cells infected with different S. aureus strains. Interestingly, in this report we show, for the first time to our knowledge, that both EPAC and Rap2b are recruited to the S. aureus–containing phagosome. We believe that our findings have important implications in understanding innate immune processes involved in intracellular pathogen invasion of the host cell. PMID:22654658

  12. Pineapple bromelain induces autophagy, facilitating apoptotic response in mammary carcinoma cells.

    Science.gov (United States)

    Bhui, Kulpreet; Tyagi, Shilpa; Prakash, Bharti; Shukla, Yogeshwer

    2010-01-01

    Bromelain, from pineapple, possesses potent anticancer effects. We investigated autophagic phenomenon in mammary carcinoma cells (estrogen receptor positive and negative) under bromelain treatment and also illustrated the relationship between autophagy and apoptosis in MCF-7 cells. MCF-7 cells exposed to bromelain showed delayed growth inhibitory response and induction of autophagy, identified by monodansylcadaverine localization. It was succeeded by apoptotic cell death, evident by sub-G1 cell fraction and apoptotic features like chromatin condensation and nuclear cleavage. 3-Methyladenine (MA, autophagy inhibitor) pretreatment reduced the bromelain-induced autophagic level, also leading to decline in apoptotic population, indicating that here autophagy facilitates apoptosis. However, addition of caspase-9 inhibitor Z-LEHD-FMK augmented the autophagy levels, inhibited morphological apoptosis but did not prevent cell death. Next, we found that bromelain downregulated the phosphorylation of extracellular signal-regulated kinase ½ (ERK½), whereas that of c-jun N-terminal kinase (JNK) and p38 kinase were upregulated. Also, MA had no influence on bromelain-suppressed ERK½ activation, yet, it downregulated JNK and p38 activation. Also, addition of mitogen-activated protein kinase (MAPK) inhibitors enhanced the autophagic ratios, which suggested the role of MAP kinases in bromelain-induced autophagy. All three MAPKs were seen to be constantly activated over the time. Bromelain was seen to induce the expressions of autophagy-related proteins, light chain 3 protein B II (LC3BII), and beclin-1. Using ERK½ inhibitor, expressions of LC3BII and beclin-1 increased, whereas p38 and JNK inhibitors decreased this protein expression, indicating that bromelain-induced autophagy was positively regulated by p38 and JNK but negatively regulated by ERK½. Autophagy-inducing property of bromelain can be further exploited in breast cancer therapy. Copyright © 2010 International Union

  13. UVRAG Deficiency Exacerbates Doxorubicin-Induced Cardiotoxicity

    Science.gov (United States)

    An, Lin; Hu, Xiao-wen; Zhang, Shasha; Hu, Xiaowen; Song, Zongpei; Naz, Amber; Zi, Zhenguo; Wu, Jian; Li, Can; Zou, Yunzeng; He, Lin; Zhu, Hongxin

    2017-01-01

    Doxorubicin (DOX) is an effective chemotherapeutic drug in the treatment of various types of cancers. However, its clinical application has been largely limited by potential development of cardiotoxicity. Previously we have shown that ultra-violet radiation resistance-associated gene (UVRAG), an autophagy-related protein, is essential for the maintenance of autophagic flux in the heart under physiological conditions. Here, we sought to determine the role of UVRAG-mediated autophagy in DOX-induced cardiotoxicity. Mouse models of acute or chronic DOX-induced cardiotoxicity were established. UVRAG deficiency exacerbated DOX-induced mortality and cardiotoxicity manifested by increased cytoplasmic vacuolization, enhanced collagen accumulation, elevated serum activities of lactate dehydrogenase and myocardial muscle creatine kinase, higher ROS levels, aggravated apoptosis and more depressed cardiac function. Autophagic flux was impaired in DOX-induced cardiotoxicity. UVRAG deficiency aggravated impaired autophagic flux in DOX-induced cardiotoxicity. Intermittent fasting restored autophagy and ameliorated pathological alterations of DOX-induced cardiotoxicity. Collectively, our data suggest that UVRAG deficiency exacerbates DOX-induced cardiotoxicity, at least in part, through aggravation of DOX-induced impaired autophagic flux. Intermittent fasting, which restores blunted autophagic flux and ameliorates pathology in the mouse models of DOX-induced cardiotoxicity, may be used as a potential preventive or therapeutic approach for DOX cardiotoxicity. PMID:28225086

  14. Antiretroviral therapy-induced Leber's hereditary optic neuropathy ...

    African Journals Online (AJOL)

    Nucleoside reverse transcriptase inhibitors (NRTIs) such as zidovudine and stavudine have known mitochondrial toxicity and can cause mitochondrial myopathies, neuropathies, hyperlactataemia, and can induce mitochondrial genetic disorders. Individuals with the mutation for Leber's hereditary optic neuropathy (LHON), ...

  15. Constraint-induced movement therapy for the upper paretic limb in acute or sub-acute stroke: a systematic review.

    Science.gov (United States)

    Nijland, Rinske; Kwakkel, Gert; Bakers, Japie; van Wegen, Erwin

    2011-10-01

    Constraint-induced movement therapy is a commonly used intervention to improve upper limb function after stroke. However, the effectiveness of constraint-induced movement therapy and its optimal dosage during acute or sub-acute stroke is still under debate. To examine the literature on the effects of constraint-induced movement therapy in acute or sub-acute stroke. A literature search was performed to identify randomized, controlled trials; studies with the same outcome measure were pooled by calculating the mean difference. Separate quantitative analyses for high-intensity and low-intensity constraint-induced movement therapy were applied when possible. Five randomized, controlled trials were included, comprising 106 participants. The meta-analysis demonstrated significant mean differences in favor of constraint-induced movement therapy for the Fugl-Meyer arm, the Action Research Arm Test, the Motor Activity Log, Quality of Movement and the Grooved Pegboard Test. Nonsignificant mean difference in favor of constraint-induced movement therapy were found for the Motor Activity Log, Amount of Use. Separate analyses for high-intensity and low-intensity constraint-induced movement therapy resulted in significant favorable mean differences for low-intensity constraint-induced movement therapy for all outcome measures, in contrast to high-intensity constraint-induced movement therapy. This meta-analysis demonstrates a trend toward positive effects of high-intensity and low-intensity constraint-induced movement therapy in acute or sub-acute stroke, but also suggests that low-intensity constraint-induced movement therapy may be more beneficial during this period than high-intensity constraint-induced movement therapy. However, these results were based on a small number of studies. Therefore, more trials are needed applying different doses of therapy early after stroke and a better understanding is needed about the different time windows in which underlying mechanisms of

  16. Modulators of Response to Tumor Necrosis-Related Apoptosis-Inducing Ligand (TRAIL) Therapy in Ovarian Cancer

    National Research Council Canada - National Science Library

    Behbakht, Kian

    2008-01-01

    .... More effective therapies are urgently needed. One of the most promising therapies in development for ovarian cancer is the use of either the Tumor Necrosis Factor-related Apoptosis Inducing Ligand (TRAIL...

  17. Targeting the hallmarks of cancer with therapy-induced endoplasmic reticulum (ER) stress

    Science.gov (United States)

    Garg, Abhishek D; Maes, Hannelore; van Vliet, Alexander R; Agostinis, Patrizia

    2015-01-01

    The endoplasmic reticulum (ER) is at the center of a number of vital cellular processes such as cell growth, death, and differentiation, crosstalk with immune or stromal cells, and maintenance of proteostasis or homeostasis, and ER functions have implications for various pathologies including cancer. Recently, a number of major hallmarks of cancer have been delineated that are expected to facilitate the development of anticancer therapies. However, therapeutic induction of ER stress as a strategy to broadly target multiple hallmarks of cancer has been seldom discussed despite the fact that several primary or secondary ER stress-inducing therapies have been found to exhibit positive clinical activity in cancer patients. In the present review we provide a brief historical overview of the major discoveries and milestones in the field of ER stress biology with important implications for anticancer therapy. Furthermore, we comprehensively discuss possible strategies enabling the targeting of multiple hallmarks of cancer with therapy-induced ER stress. PMID:27308392

  18. Ozone Therapy in the Management of Persistent Radiation-Induced Rectal Bleeding in Prostate Cancer Patients

    OpenAIRE

    Bernardino Clavo; Norberto Santana-Rodriguez; Pedro Llontop; Dominga Gutierrez; Daniel Ceballos; Charlin Méndez; Gloria Rovira; Gerardo Suarez; Dolores Rey-Baltar; Laura Garcia-Cabrera; Gregorio Martínez-Sánchez; Dolores Fiuza

    2015-01-01

    Introduction. Persistent radiation-induced proctitis and rectal bleeding are debilitating complications with limited therapeutic options. We present our experience with ozone therapy in the management of such refractory rectal bleeding. Methods. Patients (n = 12) previously irradiated for prostate cancer with persistent or severe rectal bleeding without response to conventional treatment were enrolled to receive ozone therapy via rectal insufflations and/or topical application of ozonized-oil...

  19. Köebner phenomenon induced by cupping therapy in a psoriasis patient

    OpenAIRE

    Yu, Rui-xing; Hui, Yun; Li, Cheng-Rang

    2013-01-01

    Psoriasis is a chronic, immune-mediated inflammatory and refractory disease. The koebner phenomenon, which can be induced by trauma, is common in psoriasis patients. Herein, we report a patient with psoriasis who was treated by cupping therapy and subsequently developed the koebner phenomenon (KP) at the cupped sites. To our knowledge, it is the first report about cupping therapy leading to KP in a psoriasis patient.

  20. Knee joint angle of intracerebral hemorrhage-induced rats after extracorporeal shock wave therapy

    OpenAIRE

    Lee, Jung-Ho

    2016-01-01

    [Purpose] The purpose of this study was to investigate the impact on rat knee joints of extracorporeal shock wave therapy after experimentally induced intracerebral hemorrhage. [Subjects and Methods] Sprague-Dawley (SD) rats were divided into an experimental group that received extracorporeal shock wave therapy after central nervous system injury (n=10) and a control group that did not receive any therapeutic intervention after central nervous system injury (n=10). The Dartfish program was us...

  1. Köebner phenomenon induced by cupping therapy in a psoriasis patient.

    Science.gov (United States)

    Yu, Rui-Xing; Hui, Yun; Li, Cheng-Rang

    2013-06-15

    Psoriasis is a chronic, immune-mediated inflammatory and refractory disease. The koebner phenomenon, which can be induced by trauma, is common in psoriasis patients. Herein, we report a patient with psoriasis who was treated by cupping therapy and subsequently developed the koebner phenomenon (KP) at the cupped sites. To our knowledge, it is the first report about cupping therapy leading to KP in a psoriasis patient.

  2. Nanoparticles modulate autophagic effect in a dispersity-dependent manner

    National Research Council Canada - National Science Library

    Huang, Dengtong; Zhou, Hualu; Gao, Jinhao

    2015-01-01

    .... However, the underlying mechanisms and universal rules remain unclear. Here, for the first time, we show a reliable and general mechanism by which nanoparticles induce autophagy and then successfully modulate autophagy via tuning their dispersity...

  3. An Inducible Caspase-9 Suicide Gene to Improve the Safety of Therapy Using Human Induced Pluripotent Stem Cells.

    Science.gov (United States)

    Yagyu, Shigeki; Hoyos, Valentina; Del Bufalo, Francesca; Brenner, Malcolm K

    2015-09-01

    Human induced pluripotent stem cells (hiPSC) hold promise for regenerative therapies, though there are several safety concerns including the risk of oncogenic transformation or unwanted adverse effects associated with hiPSC or their differentiated progeny. Introduction of the inducible caspase-9 (iC9) suicide gene, which is activated by a specific chemical inducer of dimerization (CID), is one of the most appealing safety strategies for cell therapies and is currently being tested in multicenter clinical trials. Here, we show that the iC9 suicide gene with a human EF1α promoter can be introduced into hiPSC by lentiviral transduction. The transduced hiPSC maintain their pluripotency, including their capacity for unlimited self-renewal and the potential to differentiate into three germ layer tissues. Transduced hiPSC are eliminated within 24 hours of exposure to pharmacological levels of CID in vitro, with induction of apoptosis in 94-99% of the cells. Importantly, the iC9 suicide gene can eradicate tumors derived from hiPSC in vivo. In conclusion, we have developed a direct and efficient hiPSC killing system that provides a necessary safety mechanism for therapies using hiPSC. We believe that our iC9 suicide gene will be of value in clinical applications of hiPSC-based therapy.

  4. Mesenchymal stem cell therapy in proteoglycan induced arthritis

    NARCIS (Netherlands)

    Swart, J. F.; de Roock, S.; Hofhuis, F. M.; Rozemuller, H.; van den Broek, T.; Moerer, P.; Broere, F.|info:eu-repo/dai/nl/264075323; van Wijk, F.; Kuis, W.; Prakken, B. J.; Martens, a.c.m|info:eu-repo/dai/nl/375286063; Wulffraat, N. M.

    2015-01-01

    Objectives: To explore the immunosuppressive effect and mechanism of action of intraperitoneal (ip) and intra-articular (ia) mesenchymal stem cell (MSC) injection in proteoglycan induced arthritis (PGIA). Methods: MSC were administered ip or ia after establishment of arthritis. We used serial

  5. Systematic review of hyperbaric oxygen therapy for the treatment of radiation-induced skin necrosis.

    Science.gov (United States)

    Borab, Zachary; Mirmanesh, Michael D; Gantz, Madeleine; Cusano, Alessandro; Pu, Lee L Q

    2017-04-01

    Every year, 1.2 million cancer patients receive radiation therapy in the United States. Late radiation tissue injury occurs in an estimated 5-15% of these patients. Tissue injury can include skin necrosis, which can lead to chronic nonhealing wounds. Despite many treatments available to help heal skin necrosis such as hyperbaric oxygen therapy, no clinical guidelines exist and evidence is lacking. The purpose of this review is to identify and comprehensively summarize studies published to date to evaluate the effectiveness of hyperbaric oxygen therapy for the treatment of radiation-induced skin necrosis. Adhering to PRISMA guidelines, a systematic review of currently published articles was performed, evaluating the use of hyperbaric oxygen to treat skin necrosis. Eight articles were identified, including one observational cohort, five case series, and two case reports. The articles describe changes in symptoms and alteration in wound healing of radiation-induced skin necrosis after treatment with hyperbaric oxygen therapy. Hyperbaric oxygen therapy is a safe intervention with promising outcomes; however, additional evidence is needed to endorse its application as a relevant therapy in the treatment of radiation-induced skin necrosis. Copyright © 2016 British Association of Plastic, Reconstructive and Aesthetic Surgeons. Published by Elsevier Ltd. All rights reserved.

  6. ER Stress and Autophagic Perturbations Lead to Elevated Extracellular α-Synuclein in GBA-N370S Parkinson's iPSC-Derived Dopamine Neurons

    Directory of Open Access Journals (Sweden)

    Hugo J.R. Fernandes

    2016-03-01

    Full Text Available Heterozygous mutations in the glucocerebrosidase gene (GBA represent the strongest common genetic risk factor for Parkinson's disease (PD, the second most common neurodegenerative disorder. However, the molecular mechanisms underlying this association are still poorly understood. Here, we have analyzed ten independent induced pluripotent stem cell (iPSC lines from three controls and three unrelated PD patients heterozygous for the GBA-N370S mutation, and identified relevant disease mechanisms. After differentiation into dopaminergic neurons, we observed misprocessing of mutant glucocerebrosidase protein in the ER, associated with activation of ER stress and abnormal cellular lipid profiles. Furthermore, we observed autophagic perturbations and an enlargement of the lysosomal compartment specifically in dopamine neurons. Finally, we found increased extracellular α-synuclein in patient-derived neuronal culture medium, which was not associated with exosomes. Overall, ER stress, autophagic/lysosomal perturbations, and elevated extracellular α-synuclein likely represent critical early cellular phenotypes of PD, which might offer multiple therapeutic targets.

  7. TNF-related apoptosis-inducing ligand (TRAIL): a new path to anti-cancer therapies.

    Science.gov (United States)

    Holoch, Peter A; Griffith, Thomas S

    2009-12-25

    Since its discovery in 1995, tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), a member of the tumor necrosis factor super family, has been under intense focus because of its remarkable ability to induce apoptosis in malignant human cells while leaving normal cells unscathed. Consequently, activation of the apoptotic signaling pathway from the death-inducing TRAIL receptors provides an attractive, biologically-targeted approach to cancer therapy. A great deal of research has focused on deciphering the TRAIL receptor signaling cascade and intracellular regulation of this pathway, as many human tumor cells possess mechanisms of resistance to TRAIL-induced apoptosis. This review focuses on the current state of knowledge regarding TRAIL signaling and resistance, the preclinical development of therapies targeted at TRAIL receptors and modulators of the pathway, and the results of clinical trials for cancer treatment that have emerged from this base of knowledge. TRAIL-based approaches to cancer therapy vary from systemic administration of recombinant, soluble TRAIL protein with or without the combination of traditional chemotherapy, radiation or novel anti-cancer agents to agonistic monoclonal antibodies directed against functional TRAIL receptors to TRAIL gene transfer therapy. A better understanding of TRAIL resistance mechanisms may allow for the development of more effective therapies that exploit this cell-mediated pathway to apoptosis.

  8. Ozone Therapy in the Management of Persistent Radiation-Induced Rectal Bleeding in Prostate Cancer Patients.

    Science.gov (United States)

    Clavo, Bernardino; Santana-Rodriguez, Norberto; Llontop, Pedro; Gutierrez, Dominga; Ceballos, Daniel; Méndez, Charlin; Rovira, Gloria; Suarez, Gerardo; Rey-Baltar, Dolores; Garcia-Cabrera, Laura; Martínez-Sánchez, Gregorio; Fiuza, Dolores

    2015-01-01

    Introduction. Persistent radiation-induced proctitis and rectal bleeding are debilitating complications with limited therapeutic options. We present our experience with ozone therapy in the management of such refractory rectal bleeding. Methods. Patients (n = 12) previously irradiated for prostate cancer with persistent or severe rectal bleeding without response to conventional treatment were enrolled to receive ozone therapy via rectal insufflations and/or topical application of ozonized-oil. Ten (83%) patients had Grade 3 or Grade 4 toxicity. Median follow-up after ozone therapy was 104 months (range: 52-119). Results. Following ozone therapy, the median grade of toxicity improved from 3 to 1 (p ozone therapy, respectively (p = 0.008). Ozone therapy was well tolerated and no adverse effects were noted, except soft and temporary flatulence for some hours after each session. Conclusions. Ozone therapy was effective in radiation-induced rectal bleeding in prostate cancer patients without serious adverse events. It proved useful in the management of rectal bleeding and merits further evaluation.

  9. Ozone Therapy in the Management of Persistent Radiation-Induced Rectal Bleeding in Prostate Cancer Patients

    Directory of Open Access Journals (Sweden)

    Bernardino Clavo

    2015-01-01

    Full Text Available Introduction. Persistent radiation-induced proctitis and rectal bleeding are debilitating complications with limited therapeutic options. We present our experience with ozone therapy in the management of such refractory rectal bleeding. Methods. Patients (n=12 previously irradiated for prostate cancer with persistent or severe rectal bleeding without response to conventional treatment were enrolled to receive ozone therapy via rectal insufflations and/or topical application of ozonized-oil. Ten (83% patients had Grade 3 or Grade 4 toxicity. Median follow-up after ozone therapy was 104 months (range: 52–119. Results. Following ozone therapy, the median grade of toxicity improved from 3 to 1 (p<0.001 and the number of endoscopy treatments from 37 to 4 (p=0.032. Hemoglobin levels changed from 11.1 (7–14 g/dL to 13 (10–15 g/dL, before and after ozone therapy, respectively (p=0.008. Ozone therapy was well tolerated and no adverse effects were noted, except soft and temporary flatulence for some hours after each session. Conclusions. Ozone therapy was effective in radiation-induced rectal bleeding in prostate cancer patients without serious adverse events. It proved useful in the management of rectal bleeding and merits further evaluation.

  10. Success of rechallenging dabrafenib and trametinib combination therapy after trametinib-induced rhabdomyolysis: a case report.

    Science.gov (United States)

    Muto, Yusuke; Ng, William; Namikawa, Kenjiro; Takahashi, Akira; Tsutsumida, Arata; Nishida, Makiko; Yamazaki, Naoya

    2018-01-29

    The mitogen-activated protein kinase pathway regulates cell growth and differentiation and is activated by BRAF mutations. BRAF mutations are present in about 40-50% of cutaneous melanomas. More than 90% of BRAF mutations are the V600E type. BRAF inhibitor (dabrafenib or vemurafenib) and MEK inhibitor (trametinib or cobimetinib) combination therapies are effective for BRAF-mutant advanced melanomas. A variety of side effects have been observed with combination therapy including pyrexia, fatigue, nausea, and vomiting. Rhabdomyolysis is one of the most severe adverse events, but it is very rare. Only two cases of rhabdomyolysis have been reported in clinical trials. A 41-year-old Japanese woman with cutaneous melanoma was started on a combination of dabrafenib and trametinib therapy after failure of immune checkpoint therapy. One month later, she complained of myalgia and fatigue and was shifted to our hospital. She was diagnosed with trametinib-induced rhabdomyolysis and showed improvement only with a high volume of fluid infusion. We stopped combination therapy, but there were no useful treatment options for her. After resuming dabrafenib, followed by trametinib, she did not have any problems. This is the first case of a patient with metastatic cutaneous melanoma who could recommence combination therapy after trametinib-associated rhabdomyolysis. We assume that not all patients experience recurrence of rhabdomyolysis in trametinib-induced rhabdomyolysis. As few cases have been reported, more information is needed. We have to evaluate safety carefully if rechallenging combination therapy.

  11. How Toxoplasma and malaria parasites defy first, then exploit host autophagic and endocytic pathways for growth.

    Science.gov (United States)

    Coppens, Isabelle

    2017-12-01

    Infections caused by the apicomplexan parasites Plasmodium and Toxoplasma are wide-spread, life-threatening and therapeutically challenging. These pathogens are obligate intracellular microorganisms that invade mammalian cells by forming a self-made niche, the parasitophorous vacuole that is impervious to host lysosomal fusion. Shortly after invasion, a noncanonical xenophagic pathway resembling LC3-associated phagocytosis is activated by the host cell to control infections. However, Plasmodium and Toxoplasma have elaborated strategies to avoid clearance by the sentinel activities of the host autophagic system. After this initial confrontation, replicating Plasmodium and Toxoplasma adeptly usurp, for their own benefit, host autophagic and endocytic structures by attracting these organelles to their vacuole, likely to access their nutrient-rich content. The pleomorphic function of the autophagy system, from microbial defense to nutrient supply, is reflected by its ambivalent role during the intracellular development of these apicomplexan parasites. Copyright © 2017 Elsevier Ltd. All rights reserved.

  12. Death by over-eating: The Gaucher disease associated gene GBA1, identified in a screen for mediators of autophagic cell death, is necessary for developmental cell death in Drosophila midgut

    Science.gov (United States)

    Schejter, Eyal; Bialik, Shani; Levin-Zaidman, Smadar; Kimchi, Adi

    2017-01-01

    ABSTRACT Autophagy is critical for homeostasis and cell survival during stress, but can also lead to cell death, a little understood process that has been shown to contribute to developmental cell death in lower model organisms, and to human cancer cell death. We recently reported1 on our thorough molecular and morphologic characterization of an autophagic cell death system involving resveratrol treatment of lung carcinoma cells. To gain mechanistic insight into this death program, we performed a signalome-wide RNAi screen for genes whose functions are necessary for resveratrol-induced death. The screen identified GBA1, the gene encoding the lysosomal enzyme glucocerebrosidase, as an important mediator of autophagic cell death. Here we further show the physiological relevance of GBA1 to developmental cell death in midgut regression during Drosophila metamorphosis. We observed a delay in midgut cell death in two independent Gba1a RNAi lines, indicating the critical importance of Gba1a for midgut development. Interestingly, loss-of-function GBA1 mutations lead to Gaucher Disease and are a significant risk factor for Parkinson Disease, which have been associated with defective autophagy. Thus GBA1 is a conserved element critical for maintaining proper levels of autophagy, with high levels leading to autophagic cell death. PMID:28933588

  13. Effective Infusion Therapy of Drug-Induced Liver and Pancreas Injuries in Patients with Pulmonary Tuberculosis

    Directory of Open Access Journals (Sweden)

    N.B. Gubergrits

    2013-08-01

    Full Text Available The authors examined 328 patients with pulmonary tuberculosis who had drug-induced hepatitis and drug-induced pancreatitis due to polychemotherapy. Patients had metabolic intoxication syndrome associated with increasing level of «average molecules» in the blood. Not only reliable decrease of this indicator but also its normalization was achieved under the influence of treatment with a usage of succinic acid preparation for infusion therapy.

  14. Inflammation-Induced Plasticity in Melanoma Therapy and Metastasis.

    Science.gov (United States)

    Hölzel, Michael; Tüting, Thomas

    2016-06-01

    Phenotype switching contributes to nongenomic heterogeneity in melanoma and other cancers. These dynamic and in part reversible phenotype changes impose diagnostic and therapeutic challenges. Understanding the reciprocal coevolution of melanoma and immune cell phenotypes during disease progression and in response to therapy is a prerequisite to improve current treatment strategies. Here we discuss how proinflammatory signals promote melanoma cell plasticity and govern interactions of melanoma and immune cells in the tumor microenvironment. We examine phenotypic plasticity and heterogeneity in different melanoma mouse models with respect to their utility for translational research and emphasize the interplay between melanoma cells and neutrophils as a critical driver of metastasis. Copyright © 2016 Elsevier Ltd. All rights reserved.

  15. Clinical observation of taste disturbance induced by radiation therapy

    Energy Technology Data Exchange (ETDEWEB)

    Murakami, Yuzuru; Sera, Koshi; Nagasawa, Hiroshi; Fukushima, Noriyuki; Yajin, Koji; Harada, Yasuo (Hiroshima Univ. (Japan). School of Medicine)

    1984-02-01

    Qualitative gustometry (filter paper disc method) was performed in six patients who underwent radiation therapy. Following results were obtained. 1) Subjective taste disturbance appeared when irradiation dosage amounted to 1000-2000 rad. Whereas, it disappeared in 1 to 3 months after the termination of irradiation. 2) The longer the period of irradiation, the more slowly taste disturbance recovered. 3) Disgeusia was noticed in 44.3% of S, 66.7% of N, 70% of T and 36.2% of Q tests. 4) Taste thresholds in the apical tongue region improved almost parallel to subjective recovery of the taste. Occasionally taste disturbance was prolonged over a month. This is possibly due to delayed regeneration of the gustatory buds. Furthermore, conditions of the oral cavity, such as infection, or mechanical stimulation, may well influence degree of taste disturbance and the process of regeneration.

  16. Photodynamic therapy induces an immune response against a bacterial pathogen.

    Science.gov (United States)

    Huang, Ying-Ying; Tanaka, Masamitsu; Vecchio, Daniela; Garcia-Diaz, Maria; Chang, Julie; Morimoto, Yuji; Hamblin, Michael R

    2012-07-01

    Photodynamic therapy (PDT) employs the triple combination of photosensitizers, visible light and ambient oxygen. When PDT is used for cancer, it has been observed that both arms of the host immune system (innate and adaptive) are activated. When PDT is used for infectious disease, however, it has been assumed that the direct antimicrobial PDT effect dominates. Murine arthritis caused by methicillin-resistant Staphylococcus aureus in the knee failed to respond to PDT with intravenously injected Photofrin(®). PDT with intra-articular Photofrin produced a biphasic dose response that killed bacteria without destroying host neutrophils. Methylene blue was the optimum photosensitizer to kill bacteria while preserving neutrophils. We used bioluminescence imaging to noninvasively monitor murine bacterial arthritis and found that PDT with intra-articular methylene blue was not only effective, but when used before infection, could protect the mice against a subsequent bacterial challenge. The data emphasize the importance of considering the host immune response in PDT for infectious disease.

  17. Trauma-induced coagulopathy: from biology to therapy.

    Science.gov (United States)

    Noel, Pierre; Cashen, Steven; Patel, Bhavesh

    2013-07-01

    Trauma is a leading cause of death and disability. Hemorrhage is the major mechanism responsible for death during the first 24 hours following trauma. One quarter of severely injured patients present in the emergency room with acute coagulopathy of trauma and shock (ACOT). The drivers of ACOT are tissue hypoperfusion, inflammation, and activation of the neurohumoral system. ACOT is a result of protein C activation with cleavage of activated factor VIII and V and inhibition of plasminogen activator inhibitor-1 (PAI-1). The resuscitation-associated coagulopathy (RAC) is secondary to a combination of acidosis, hypothermia and dilution from intravenous blood and fluid therapy. RAC may further aggravate acidosis and hypoxia resulting in a vicious cycle. This review focuses on the biology of the trauma-associated coagulopathy, and reviews current therapeutic strategies. Copyright © 2013 Elsevier Inc. All rights reserved.

  18. Ozone therapy ameliorates tubulointerstitial inflammation by regulating TLR4 in adenine-induced CKD rats.

    Science.gov (United States)

    Chen, Zhiyuan; Liu, Xiuheng; Yu, Gang; Chen, Hui; Wang, Lei; Wang, Zhishun; Qiu, Tao; Weng, Xiaodong

    2016-06-01

    Tubulointerstitium inflammation is a common pathway aggravating chronic kidney disease (CKD) progression and the mechanism is partly associated with excessive activation of toll-like receptor 4 (TLR4) in tubulointerstitium. Ozone therapy is demonstrated to alleviate inflammation in some experiments. The aim of this study is to examine whether ozone therapy could ameliorate chronic tubulointerstitium inflammation by suppressing TLR4 in adenine-induced CKD rats. Sprague-Dawley rats were fed with 0.75% adenine-containing diet to induce CKD and tubulointerstitium inflammation injury. Ozone therapy (1.1 mg/kg) was simultaneously administrated by rectal insufflations (i.r.). After 4 weeks, serum and kidney samples were collected for detection. Renal function and systemic electrolyte were detected. Renal pathological changes were assessed by hematoxylin-eosin (H&E) staining and Masson trichrome (MT) staining. Immunohistochemistry, Western blot and Real-time PCR were applied to evaluate tubulointerstitium inflammation as well as the expression of TLR4 and phosphorylated nuclear factor kappa B P65 (p-NF-κB P65) in rats. The results showed ozone therapy improved serious renal insufficiency, systemic electrolyte disorder and tubulointerstitium morphology damages in adenine-induced CKD rats. In addition, ozone therapy suppressed excessive activation of TLR4 and p-NF-κB P65 in the tubulointerstitium of adenine-induced CKD rats, accompanied by the reduction of inflammation-related cytokines including monocyte chemoattractant protein-1 (MCP-1), tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β) and interleukin-6 (IL-6). The protein expression of TLR4 was positively correlated with the protein expression levels of MCP-1 (r = 0.7863, p ozone therapy could attenuate tubulointerstitium inflammation injury in adenine-induced CKD rats and the mechanism might associate with the mediation of TLR4.

  19. Morphologic magnetic resonance imaging features of therapy-induced cerebral necrosis.

    Science.gov (United States)

    Rogers, L R; Gutierrez, J; Scarpace, L; Schultz, L; Ryu, S; Lord, B; Movsas, B; Honsowetz, J; Jain, R

    2011-01-01

    To describe the morphologic magnetic resonance imaging (MRI) findings in histologically proven therapy-induced cerebral necrosis. We retrospectively reviewed the morphologic MRI findings in patients with therapy-induced cerebral necrosis. Images were reviewed for size, location, and characteristics of signal intensity abnormalities and T1-contrast enhancement. Images were also assessed for mass effect, necrosis, cyst, atrophy, cortical thinning, and leukoencephalopathy. The individual imaging characteristics were correlated with clinical and treatment variables. There were 44 patients. Seventy percent had a glioma, all patients had received radiation, and 57% had received chemotherapy in close proximity to radiation. All images demonstrated contrast enhancement, predominantly in the white matter. Enhancement was present in the periventricular/subependymal region in 50% of cases and the corpus callosum in 27%. The most common pattern of lesion peripheral enhancement was "spreading wavefront" and of interior enhancement was "Swiss cheese/soap bubble." The enhancing lesion was single in 60% of cases. Mass effect was present in 93% of patients. Location and patterns of enhancement were significantly associated with the interval from brain radiation to the diagnosis of therapy-induced cerebral necrosis, tumor histology, patient age, type of radiation, and administration of systemic chemotherapy. This is the largest study of the morphologic conventional MRI findings in pathologically confirmed therapy-induced cerebral necrosis. We characterized the imaging findings in a variety of tumor types following a variety of radiation treatments and other antineoplastic therapy. These findings may be of value in identifying therapy-induced cerebral necrosis in patients treated for a brain tumor.

  20. Contemplating stem cell therapy for epilepsy-induced neuropsychiatric symptoms

    Directory of Open Access Journals (Sweden)

    Rao G

    2017-02-01

    Full Text Available Gautam Rao, Sherwin Mashkouri, David Aum, Paul Marcet, Cesar V Borlongan Department of Neurosurgery and Brain Repair, Center of Excellence for Aging and Brain Repair, University of South Florida Morsani College of Medicine, Tampa, FL, USA Abstract: Epilepsy is a debilitating disease that impacts millions of people worldwide. While unprovoked seizures characterize its cardinal symptom, an important aspect of epilepsy that remains to be addressed is the neuropsychiatric component. It has been documented for millennia in paintings and literature that those with epilepsy can suffer from bouts of aggression, depression, and other psychiatric ailments. Current treatments for epilepsy include the use of antiepileptic drugs and surgical resection. Antiepileptic drugs reduce the overall firing of the brain to mitigate the rate of seizure occurrence. Surgery aims to remove a portion of the brain that is suspected to be the source of aberrant firing that leads to seizures. Both options treat the seizure-generating neurological aspect of epilepsy, but fail to directly address the neuropsychiatric components. A promising new treatment for epilepsy is the use of stem cells to treat both the biological and psychiatric components. Stem cell therapy has been shown efficacious in treating experimental models of neurological disorders, including Parkinson’s disease, and neuropsychiatric diseases, such as depression. Additional research is necessary to see if stem cells can treat both neurological and neuropsychiatric aspects of epilepsy. Currently, there is no animal model that recapitulates all the clinical hallmarks of epilepsy. This could be due to difficulty in characterizing the neuropsychiatric component of the disease. In advancing stem cell therapy for treating epilepsy, experimental testing of the safety and efficacy of allogeneic and autologous transplantation will require the optimization of cell dosage, delivery, and timing of transplantation in a

  1. Targeting autophagic cancer stem-cells to reverse chemoresistance in human triple negative breast cancer.

    Science.gov (United States)

    Bousquet, Guilhem; El Bouchtaoui, Morad; Sophie, Tan; Leboeuf, Christophe; de Bazelaire, Cédric; Ratajczak, Philippe; Giacchetti, Sylvie; de Roquancourt, Anne; Bertheau, Philippe; Verneuil, Laurence; Feugeas, Jean-Paul; Espié, Marc; Janin, Anne

    2017-05-23

    There is growing evidence for the role of cancer stem-cells in drug resistance, but with few in situ studies on human tumor samples to decipher the mechanisms by which they resist anticancer agents.Triple negative breast cancer (TNBC) is the most severe sub-type of breast cancer, occurring in younger women and associated with poor prognosis even when treated at a localized stage.We investigated here the relationship between complete pathological response after chemotherapy and breast cancer stem-cell characteristics in pre-treatment biopsies of 78 women with triple negative breast carcinoma (TNBC).We found that chemoresistance was associated with large numbers of breast cancer stem-cells, and that these cancer stem-cells were neither proliferative nor apoptotic, but in an autophagic state related to hypoxia. Using relevant pharmacological models of patient-derived TNBC xenografts, we further investigated the role of autophagy in chemoresistance of breast cancer stem-cells. We demonstrated that hypoxia increased drug resistance of autophagic TNBC stem-cells, and showed that molecular or chemical inhibition of autophagic pathway was able to reverse chemoresistance.Our results support breast cancer stem-cell evaluation in pre-treatment biopsies of TNBC patients, and the need for further research on autophagy inhibition to reverse resistance to chemotherapy.

  2. Simultaneous bilateral laser therapy accelerates recovery after noise-induced hearing loss in a rat model.

    Science.gov (United States)

    Lee, Jae-Hun; Chang, So-Young; Moy, Wesley J; Oh, Connie; Kim, Se-Hyung; Rhee, Chung-Ku; Ahn, Jin-Chul; Chung, Phil-Sang; Jung, Jae Yun; Lee, Min Young

    2016-01-01

    Noise-induced hearing loss is a common type of hearing loss. The effects of laser therapy have been investigated from various perspectives, including in wound healing, inflammation reduction, and nerve regeneration, as well as in hearing research. A promising feature of the laser is its capability to penetrate soft tissue; depending on the wavelength, laser energy can penetrate into the deepest part of the body without damaging non-target soft tissues. Based on this idea, we developed bilateral transtympanic laser therapy, which uses simultaneous laser irradiation in both ears, and evaluated the effects of bilateral laser therapy on cochlear damage caused by noise overexposure. Thus, the purpose of this research was to assess the benefits of simultaneous bilateral laser therapy compared with unilateral laser therapy and a control. Eighteen Sprague-Dawley rats were exposed to narrow-band noise at 115 dB SPL for 6 h. Multiple auditory brainstem responses were measured after each laser irradiation, and cochlear hair cells were counted after the 15th such irradiation. The penetration depth of the 808 nm laser was also measured after sacrifice. Approximately 5% of the laser energy reached the contralateral cochlea. Both bilateral and unilateral laser therapy decreased the hearing threshold after noise overstimulation in the rat model. The bilateral laser therapy group showed faster functional recovery at all tested frequencies compared with the unilateral laser therapy group. However, there was no difference in the endpoint ABR results or final hair cell survival, which was analyzed histologically.

  3. Burns induced by cupping therapy in a burn center in northeast china.

    Science.gov (United States)

    Jing-Chun, Zhao; Jia-Ao, Yu; Chun-Jing, Xian; Kai, Shi; Lai-Jin, Lu

    2014-07-01

    Cupping therapy as a curative skill has been developed and applied throughout history. Despite reports of adverse effects, this therapy is considered to be relatively safe with no systemic reviews documenting negative side effects. The aim of this study was to explore methods that avoid the adverse effects sometimes associated with this therapy. Clinical records of 14 outpatients and inpatients that visited the First Hospital of Jilin University (Changchun, China) for management of burn injuries caused by cupping therapy were retrospectively reviewed. Characteristics, history of injury, and treatment of each patient was collected and analyzed. Burn injury induced by cupping therapy was not uncommon. Most of the injuries were mild to moderate and cured by conservative methods without severe complications. The use of wet cupping was more prevalent among injured patients than dry cupping. Cupping therapy as an ancient alternative treatment is still popular with a large number of devoted practitioners. Although there is the potential for injury during the application of this therapy, this is mostly preventable. Standardized training for health care professionals and increased the awareness among the public about the proper methods to administer this therapy to avoid adverse effects is important.

  4. Hyperbaric oxygen therapy for the treatment of radiation-induced macular ischemia

    Directory of Open Access Journals (Sweden)

    Shamim A Haji

    2010-05-01

    Full Text Available Shamim A Haji1,2, Ronald EP Frenkel1,2,31Eye Research Foundation, Stuart, FL, USA; 2East Florida Eye Institute, Stuart, FL, USA; 3Bascom Palmer Eye Institute, Miami, FL, USAPurpose: To report a case of radiation-induced macular ischemia where vision and macular perfusion improved after hyperbaric oxygen (HBO therapy.Methods: A 62-year-old male patient developed radiation-induced macular ischemia after he was treated with radiation for brain glioma. The patient presented with best spectacle-corrected visual acuity (BSCVA acuity of 20/400 in his right eye. Optical coherence tomography (OCT showed central macular thickness of 468 μm. The patient received focal laser, intravitreal triamcinolone, and HBO therapy.Results: The patient’s vision improved from 20/400 to 20/100 after focal laser and intravitreal triamcinolone. His central macular thickness improved from 468 μm to 132 μm. After receiving HBO therapy, his VA improved to 20/50 and fluorescein angiography showed improvement in macular perfusion.Conclusion: HBO therapy improves macular perfusion in patients with radiation-induced macular ischemia.Keywords: macular ischemia, visual acuity, hyperbaric oxygen therapy, macular perfusion

  5. A systematic review of salivary gland hypofunction and xerostomia induced by cancer therapies

    DEFF Research Database (Denmark)

    Jensen, S.B.; Pedersen, A.M.L.; Vissink, A.

    2010-01-01

    This systematic review aimed to assess the literature for prevalence, severity, and impact on quality of life of salivary gland hypofunction and xerostomia induced by cancer therapies. The electronic databases of MEDLINE/PubMed and EMBASE were searched for articles published in English since the ...

  6. Stem Cell Therapy to Reduce Radiation-Induced Normal Tissue Damage

    NARCIS (Netherlands)

    Coppes, Rob P.; van der Goot, Annemieke; Lombaert, Isabelle M. A.

    Normal tissue damage after radiotherapy is still a major problem in cancer treatment. Stem cell therapy may provide a means to reduce radiation-induced side effects and improve the quality of life of patients. This review discusses the current status in stem cell research with respect to their

  7. Shortened constraint-induced movement therapy in subacute stroke - no effect of using a restraint

    DEFF Research Database (Denmark)

    Brogårdh, Christina; Vestling, Monika; Sjölund, Bengt H

    2009-01-01

    , no statistically significant differences between the groups were found in any measures at any point in time. CONCLUSION: In this study, no effect of using a restraint in patients with subacute stroke was found. Thus, this component in the constraint-induced therapy concept seems to be of minor importance...

  8. A Safeguard System for Induced Pluripotent Stem Cell-Derived Rejuvenated T Cell Therapy

    Directory of Open Access Journals (Sweden)

    Miki Ando

    2015-10-01

    Full Text Available The discovery of induced pluripotent stem cells (iPSCs has created promising new avenues for therapies in regenerative medicine. However, the tumorigenic potential of undifferentiated iPSCs is a major safety concern for clinical translation. To address this issue, we demonstrated the efficacy of suicide gene therapy by introducing inducible caspase-9 (iC9 into iPSCs. Activation of iC9 with a specific chemical inducer of dimerization (CID initiates a caspase cascade that eliminates iPSCs and tumors originated from iPSCs. We introduced this iC9/CID safeguard system into a previously reported iPSC-derived, rejuvenated cytotoxic T lymphocyte (rejCTL therapy model and confirmed that we can generate rejCTLs from iPSCs expressing high levels of iC9 without disturbing antigen-specific killing activity. iC9-expressing rejCTLs exert antitumor effects in vivo. The system efficiently and safely induces apoptosis in these rejCTLs. These results unite to suggest that the iC9/CID safeguard system is a promising tool for future iPSC-mediated approaches to clinical therapy.

  9. Re: Engineered Nanoparticles Induce Cell Apoptosis: Potential for Cancer Therapy

    Directory of Open Access Journals (Sweden)

    Fehmi Narter

    2016-09-01

    Full Text Available Engineered nanoparticles (ENPs have been widely applied in industry, biology and medicine recently (i.e. clothes, sunscreens, cosmetics, foods, diagnostic medicine, imaging and drug delivery. There are many kinds of manufactured nanomaterial products including TiO2, ZnO, CeO2, Fe2O3, and CuO (as metal oxide nanoparticles as well as gold, silver, platinum and palladium (as metal nanoparticles, and other carbon-based ENP’s such as carbon nanotububes and quantum dots. ENPs with their sizes no larger than 100 nm are able to enter the human body and accumulate in organs and cause toxic effects. In many researches, ENP effects on the cancer cells of different organs with related cell apoptosis were noted (AgNP, nano-Cr2O3, Au-Fe2O3 NPs, nano-TiO2, nano-HAP, nano-Se, MoO3 nanoplate, Realgar nanoparticles. ENPs, with their unique properties, such as surface charge, particle size, composition and surface modification with tissue recognition ligands or antibodies, has been increasingly explored as a tool to carry small molecular weight drugs as well as macromolecules for cancer therapy, thus generating the new concept “nanocarrier”. Direct induction of cell apoptosis by ENPs provides an opportunity for cancer treatment. In the century of nanomedicine that depends on development of the nanotechnology, ENPs have a great potential for application in cancer treatment with minimal side effects.

  10. [A case of erythema multiforme induced by regorafenib therapy for metastatic colon cancer].

    Science.gov (United States)

    Mii, Yasuhiko; Fukuoka, Eiji; Murata, Kouichi; Otsubo, Dai; Sawa, Hidehiro; Oka, Shigeteru; Iwatani, Yoshiteru; Kuroda, Daisuke

    2014-11-01

    A 47-year-old woman underwent colectomy for advanced colon cancer and thereafter received regorafenib therapy as fourth-line chemotherapy. On treatment day 12, the patient developed erythema multiforme (EM) induced by the regorafenib therapy. Immediately after regorafenib was withdrawn, the patient was treated with oral bepotastine and steroid ointment, which relieved the EM without progressing to Stevens-Johnson syndrome (SJS). Regorafenib is used for third- or fourth-line chemotherapy. Progression of regorafenib-induced EM to SJS may cause critical dysfunction among patients. Before administering regorafenib therapy, the patient should be made aware of this potential adverse effect and be advised to withdraw the treatment and visit the hospital immediately if symptoms of EM are observed.

  11. Cytokine-induced killer (CIK cell therapy for patients with hepatocellular carcinoma: efficacy and safety

    Directory of Open Access Journals (Sweden)

    Ma Yue

    2012-04-01

    Full Text Available Abstract Purpose To evaluate the efficacy of cytokine-induced killer (CIK cell therapy in the treatment of hepatocellular carcinoma. Materials and methods Randomized phase II and III trials on CIK cell-based therapy were identified by electronic searches using a combination of "hepatocellular carcinoma" and "cytokine-induced killer cells". Results The analysis showed significant survival benefit (one-year survival, p p p p p p +, CD4+, CD4+CD8+ and CD3+CD4+ T cells significantly increased in the CIK group, compared with the non-CIK group (p Conclusions CIK cell therapy demonstrated a significant superiority in prolonging the median overall survival, PFS, DCR, ORR and QoL of HCC patients. These results support further larger scale randomized controlled trials for HCC patients with or without the combination of other therapeutic methods.

  12. Inhibition of mTOR improves the impairment of acidification in autophagic vesicles caused by hepatic steatosis

    Energy Technology Data Exchange (ETDEWEB)

    Nakadera, Eisuke [Department of Gastroenterology, Juntendo University School of Medicine, Hongo 2-1-1, Bunkyo-ku, Tokyo 113-8421 (Japan); Yamashina, Shunhei, E-mail: syamashi@juntendo.ac.jp [Department of Gastroenterology, Juntendo University School of Medicine, Hongo 2-1-1, Bunkyo-ku, Tokyo 113-8421 (Japan); Izumi, Kousuke; Inami, Yoshihiro; Sato, Toshifumi; Fukushima, Hirofumi; Kon, Kazuyoshi; Ikejima, Kenichi [Department of Gastroenterology, Juntendo University School of Medicine, Hongo 2-1-1, Bunkyo-ku, Tokyo 113-8421 (Japan); Ueno, Takashi [Division of Proteomics and Biomolecular Science, Juntendo University, School of Medicine, Hongo 2-1-1, Bunkyo-ku, Tokyo 113-8421 (Japan); Watanabe, Sumio [Department of Gastroenterology, Juntendo University School of Medicine, Hongo 2-1-1, Bunkyo-ku, Tokyo 113-8421 (Japan)

    2016-01-22

    Recent investigations revealed that dysfunction of autophagy involved in the progression of chronic liver diseases such as alcoholic and nonalcoholic steatohepatitis and hepatocellular neoplasia. Previously, it was reported that hepatic steatosis disturbs autophagic proteolysis via suppression of both autophagic induction and lysosomal function. Here, we demonstrate that autophagic acidification was altered by a decrease in lysosomal proton pump vacuolar-ATPase (V-ATPase) in steatohepatitis. The number of autophagic vesicles was increased in hepatocytes from obese KKAy mice as compared to control. Similarly, autophagic membrane protein LC3-II and lysosomal protein LAMP-2 expression were enhanced in KKAy mice liver. Nevertheless, both phospho-mTOR and p62 expression were augmented in KKAy mice liver. More than 70% of autophagosomes were stained by LysoTracker Red (LTR) in hepatocytes from control mice; however, the percentage of acidic autolysosomes was decreased in hepatocytes from KKAy mice significantly (40.1 ± 3.48%). Both protein and RNA level of V-ATPase subunits ATP6v1a, ATP6v1b, ATP6v1d in isolated lysosomes were suppressed in KKAy mice as compared to control. Interestingly, incubation with mTOR inhibitor rapamycin increased in the rate of LTR-positive autolysosomes in hepatocytes from KKAy mice and suppressed p62 accumulation in the liver from KKAy mice which correlated to an increase in the V-ATPase subunits expression. These results indicate that down-regulation of V-ATPase due to hepatic steatosis causes autophagic dysfunction via disruption of lysosomal and autophagic acidification. Moreover, activation of mTOR plays a pivotal role on dysregulation of lysosomal and autophagic acidification by modulation of V-ATPase expression and could therefore be a useful therapeutic target to ameliorate dysfunction of autophagy in NAFLD. - Highlights: • Hepatic steatosis causes accumulation of autophagic vesicles in hepatocytes. • Hepatic steatosis disturbs

  13. Constraint-induced movement therapy for the upper paretic limb in acute or sub-acute stroke : a systematic review

    NARCIS (Netherlands)

    Nijland, Rinske; Kwakkel, Gert; Bakers, Japie; van Wegen, Erwin

    2011-01-01

    Constraint-induced movement therapy is a commonly used intervention to improve upper limb function after stroke. However, the effectiveness of constraint-induced movement therapy and its optimal dosage during acute or sub-acute stroke is still under debate. To examine the literature on the effects

  14. Constraint-induced movement therapy for the upper paretic limb in acute or sub-acute stroke: a systematic review

    NARCIS (Netherlands)

    Nijland, R.H.M.; Kwakkel, G.; Bakers, J.; van Wegen, E.E.H.

    2011-01-01

    Constraint-induced movement therapy is a commonly used intervention to improve upper limb function after stroke. However, the effectiveness of constraint-induced movement therapy and its optimal dosage during acute or sub-acute stroke is still under debate. To examine the literature on the effects

  15. Dopaminergic neuronal loss, reduced neurite complexity and autophagic abnormalities in transgenic mice expressing G2019S mutant LRRK2.

    Directory of Open Access Journals (Sweden)

    David Ramonet

    2011-04-01

    Full Text Available Mutations in the leucine-rich repeat kinase 2 (LRRK2 gene cause late-onset, autosomal dominant familial Parkinson's disease (PD and also contribute to idiopathic PD. LRRK2 mutations represent the most common cause of PD with clinical and neurochemical features that are largely indistinguishable from idiopathic disease. Currently, transgenic mice expressing wild-type or disease-causing mutants of LRRK2 have failed to produce overt neurodegeneration, although abnormalities in nigrostriatal dopaminergic neurotransmission have been observed. Here, we describe the development and characterization of transgenic mice expressing human LRRK2 bearing the familial PD mutations, R1441C and G2019S. Our study demonstrates that expression of G2019S mutant LRRK2 induces the degeneration of nigrostriatal pathway dopaminergic neurons in an age-dependent manner. In addition, we observe autophagic and mitochondrial abnormalities in the brains of aged G2019S LRRK2 mice and markedly reduced neurite complexity of cultured dopaminergic neurons. These new LRRK2 transgenic mice will provide important tools for understanding the mechanism(s through which familial mutations precipitate neuronal degeneration and PD.

  16. Beneficial bacteria affect Danio rerio development by the modulation of maternal factors involved in autophagic, apoptotic and dorsalizing processes.

    Science.gov (United States)

    Miccoli, Andrea; Gioacchini, Giorgia; Maradonna, Francesca; Benato, Francesca; Skobo, Tatjana; Carnevali, Oliana

    2015-01-01

    Probiotic strains have been recognized to exert important roles in many biological systems, including immune response, growth, development and reproduction. However, to date, no studies have focused either on the relation among probiotics and maternal factors or on probiotics' ability to qualitatively and/or quantitatively modulate maternal transcripts. In this study, the effects of Lactobacillus rhamnosus administered to parental fish on the control of maternal factors involved in autophagic, apoptotic and dorsalizing processes during zebrafish embryo development were assessed through q-PCRs, WMISH and TUNEL assay. The results we obtained show that probiotic induced significant changes in both maternal and zygotic mRNA levels involved in embryo development. The maternal autophagy-regulating genes herein investigated--ambra1a, ambra1b, beclin, lc3-, as well as those involved in the apoptotic process--caspase3, bcl2, bax--were modulated in disfavor and favor of the treated group, respectively. Also, the key transcripts ruling the dorsalizing process--goosecoid and chordin--were subject to a significant regulation of their gene expression. The results we acquired demonstrated that parentally administered Lactobacillus rhamnosus is able to modulate important physiological processes involved in zebrafish embryo development. © 2015 S. Karger AG, Basel.

  17. Permeability of Brain Tumor Vessels Induced by Uniform or Spatially Microfractionated Synchrotron Radiation Therapies.

    Science.gov (United States)

    Bouchet, Audrey; Potez, Marine; Coquery, Nicolas; Rome, Claire; Lemasson, Benjamin; Bräuer-Krisch, Elke; Rémy, Chantal; Laissue, Jean; Barbier, Emmanuel L; Djonov, Valentin; Serduc, Raphael

    2017-08-01

    To compare the blood-brain barrier permeability changes induced by synchrotron microbeam radiation therapy (MRT, which relies on spatial fractionation of the incident x-ray beam into parallel micron-wide beams) with changes induced by a spatially uniform synchrotron x-ray radiation therapy. Male rats bearing malignant intracranial F98 gliomas were randomized into 3 groups: untreated, exposed to MRT (peak and valley dose: 241 and 10.5 Gy, respectively), or exposed to broad beam irradiation (BB) delivered at comparable doses (ie, equivalent to MRT valley dose); both applied by 2 arrays, intersecting orthogonally the tumor region. Vessel permeability was monitored in vivo by magnetic resonance imaging 1 day before (T-1) and 1, 2, 7, and 14 days after treatment start. To determine whether physiologic parameters influence vascular permeability, we evaluated vessel integrity in the tumor area with different values for cerebral blood flow, blood volume, edema, and tissue oxygenation. Microbeam radiation therapy does not modify the vascular permeability of normal brain tissue. Microbeam radiation therapy-induced increase of tumor vascular permeability was detectable from T2 with a maximum at T7 after exposure, whereas BB enhanced vessel permeability only at T7. At this stage MRT was more efficient at increasing tumor vessel permeability (BB vs untreated: +19.1%; P=.0467; MRT vs untreated: +44.8%; Ptumor than BB. Microbeam radiation therapy-induced increased tumor vascular permeability is: (1) significantly greater; (2) earlier and more prolonged than that induced by BB irradiation, especially in highly proliferative tumor areas; and (3) targets all tumor areas discriminated by physiologic characteristics, including those not damaged by homogeneous irradiation. Copyright © 2017 Elsevier Inc. All rights reserved.

  18. Knee joint angle of intracerebral hemorrhage-induced rats after extracorporeal shock wave therapy

    Science.gov (United States)

    Lee, Jung-Ho

    2016-01-01

    [Purpose] The purpose of this study was to investigate the impact on rat knee joints of extracorporeal shock wave therapy after experimentally induced intracerebral hemorrhage. [Subjects and Methods] Sprague-Dawley (SD) rats were divided into an experimental group that received extracorporeal shock wave therapy after central nervous system injury (n=10) and a control group that did not receive any therapeutic intervention after central nervous system injury (n=10). The Dartfish program was used to evaluate the SD rats’ locomotion. [Results] There was a significant difference between the control group and the experimental group in the change of knee joint angle during midstance after the intervention. [Conclusion] In conclusion, at extracorporeal shock wave therapy for central nervous system injury was confirmed to be effective at reducing knee joint angle, confirming it is a good physical therapy intervention, based on its efficacy. PMID:27942132

  19. QSOX1 Inhibits Autophagic Flux in Breast Cancer Cells

    Science.gov (United States)

    Poillet, Laura; Pernodet, Nicolas; Boyer-Guittaut, Michaël; Adami, Pascale; Borg, Christophe; Jouvenot, Michèle; Delage-Mourroux, Régis; Despouy, Gilles

    2014-01-01

    The QSOX1 protein (Quiescin Sulfhydryl oxidase 1) catalyzes the formation of disulfide bonds and is involved in the folding and stability of proteins. More recently, QSOX1 has been associated with tumorigenesis and protection against cellular stress. It has been demonstrated in our laboratory that QSOX1 reduces proliferation, migration and invasion of breast cancer cells in vitro and reduces tumor growth in vivo. In addition, QSOX1 expression has been shown to be induced by oxidative or ER stress and to prevent cell death linked to these stressors. Given the function of QSOX1 in these two processes, which have been previously linked to autophagy, we wondered whether QSOX1 might be regulated by autophagy inducers and play a role in this catabolic process. To answer this question, we used in vitro models of breast cancer cells in which QSOX1 was overexpressed (MCF-7) or extinguished (MDA-MB-231). We first showed that QSOX1 expression is induced following amino acid starvation and maintains cellular homeostasis. Our results also indicated that QSOX1 inhibits autophagy through the inhibition of autophagosome/lysosome fusion. Moreover, we demonstrated that inhibitors of autophagy mimic the effect of QSOX1 on cell invasion, suggesting that its role in this process is linked to the autophagy pathway. Previously published data demonstrated that extinction of QSOX1 promotes tumor growth in NOG mice. In this study, we further demonstrated that QSOX1 null tumors present lower levels of the p62 protein. Altogether, our results demonstrate for the first time a role of QSOX1 in autophagy in breast cancer cells and tumors. PMID:24475161

  20. International Patterns of Practice in the Management of Radiation Therapy-induced Nausea and Vomiting

    Energy Technology Data Exchange (ETDEWEB)

    Dennis, Kristopher; Zhang Liying [Odette Cancer Centre, Sunnybrook Health Sciences Centre, University of Toronto, Toronto, Ontario (Canada); Lutz, Stephen [Blanchard Valley Health Systems, Findlay, Ohio (United States); Baardwijk, Angela van [Department of Radiation Oncology (MAASTRO Clinic), GROW-School for Oncology and Developmental Biology, Maastricht University Medical Centre, Maastricht (Netherlands); Linden, Yvette van der [Leiden University Medical Center, Leiden (Netherlands); Holt, Tanya [Radiation Oncology Mater Centre, Princess Alexandra Hospital, Brisbane (Australia); Arnalot, Palmira Foro [Parc de Salut Mar. Universitat Pompeu Fabra Barcelona (Spain); Lagrange, Jean-Leon [AP-HP Hopital Henri-Mondor, Universite Paris Est Creteil, Creteil (France); Maranzano, Ernesto [' S. Maria' Hospital, Terni (Italy); Liu, Rico [Queen Mary Hospital, Hong Kong (China); Wong, Kam-Hung [Queen Elizabeth Hospital, Hong Kong (Hong Kong); Wong, Lea-Choung [National University Cancer Institute (Singapore); Vassiliou, Vassilios [Bank of Cyprus Oncology Centre, Nicosia (Cyprus); Corn, Benjamin W. [Tel Aviv Medical Center, Tel Aviv (Israel); De Angelis, Carlo; Holden, Lori; Wong, C. Shun [Odette Cancer Centre, Sunnybrook Health Sciences Centre, University of Toronto, Toronto, Ontario (Canada); Chow, Edward, E-mail: Edward.Chow@sunnybrook.ca [Odette Cancer Centre, Sunnybrook Health Sciences Centre, University of Toronto, Toronto, Ontario (Canada)

    2012-09-01

    Purpose: To investigate international patterns of practice in the management of radiation therapy-induced nausea and vomiting (RINV). Methods and Materials: Oncologists prescribing radiation therapy in the United States, Canada, The Netherlands, Australia, New Zealand, Spain, Italy, France, Hong Kong, Singapore, Cyprus, and Israel completed a Web-based survey that was based on 6 radiation therapy-only clinical cases modeled after the minimal-, low-, moderate-, and high-emetic risk levels defined in the antiemetic guidelines of the American Society of Clinical Oncology and the Multinational Association of Supportive Care in Cancer. For each case, respondents estimated the risks of nausea and vomiting separately and committed to an initial management approach. Results: In total, 1022 responses were received. Risk estimates and management decisions for the minimal- and high-risk cases varied little and were in line with guideline standards, whereas those for the low- and moderate-risk cases varied greatly. The most common initial management strategies were as follows: rescue therapy for a minimal-risk case (63% of respondents), 2 low-risk cases (56% and 80%), and 1 moderate-risk case (66%); and prophylactic therapy for a second moderate-risk case (75%) and a high-risk case (95%). The serotonin (5-HT){sub 3} receptor antagonists were the most commonly recommended prophylactic agents. On multivariate analysis, factors predictive of a decision for prophylactic or rescue therapy were risk estimates of nausea and vomiting, awareness of the American Society of Clinical Oncology antiemetic guideline, and European Society for Therapeutic Radiology and Oncology membership. Conclusions: Risk estimates and management strategies for RINV varied, especially for low- and moderate-risk radiation therapy cases. Radiation therapy-induced nausea and vomiting are under-studied treatment sequelae. New observational and translational studies are needed to allow for individual patient risk

  1. Radiation Sialadenitis Induced by High-dose Radioactive Iodine Therapy

    Energy Technology Data Exchange (ETDEWEB)

    Jeong, Shin Young; Lee, Jaetae [Kyungpook National University Hospital, Daegu (Korea, Republic of)

    2010-06-15

    Radioactive iodine ({sup 131}I) is accumulated in the thyroid tissue and plays an important role in the treatment of differentiated papillary and follicular cancers after thyroidectomy. Simultaneously, {sup 131}I is concentrated in the salivary glands and secreted into the saliva. Dose-related damage to the salivary parenchyma results from the {sup 131}I irradiation. Salivary gland swelling and pain, usually involving the parotid, can be seen. The symptoms may develop immediately after a therapeutic dose of {sup 131}I and/or months later and progress in intensity with time. In conjunction with the radiation sialadenitis, secondary complications reported include xerostomia, taste alterations, infection, increases in caries, facial nerve involvement, candidiasis, and neoplasia. Prevention of {sup 131}I sialadenitis may involve the use of sialogogic agents to hasten the transit time of the radioactive iodine through the salivary glands. However, studies are not available to delineate the efficacy of this approach. Treatment of the varied complications that may develop encompass numerous approaches and include gland massage, sialogogic agents, duct probing, antibiotics, mouthwashes, good oral hygiene, and adequate hydration. Recently interventional sialoendoscopy has been introduced an effective tool for the management of patients with {sup 131}I-induced sialadenitis that is unresponsive to medical treatment.

  2. Role of apoptosis and necrosis in cell death induced by nanoparticle-mediated photothermal therapy

    Science.gov (United States)

    Pattani, Varun P.; Shah, Jay; Atalis, Alexandra; Sharma, Anirudh; Tunnell, James W.

    2015-01-01

    Current cancer therapies can cause significant collateral damage due to a lack of specificity and sensitivity. Therefore, we explored the cell death pathway response to gold nanorod (GNR)-mediated photothermal therapy as a highly specific cancer therapeutic to understand the role of apoptosis and necrosis during intense localized heating. By developing this, we can optimize photothermal therapy to induce a maximum of `clean' cell death pathways, namely apoptosis, thereby reducing external damage. GNRs were targeted to several subcellular localizations within colorectal tumor cells in vitro, and the cell death pathways were quantitatively analyzed after photothermal therapy using flow cytometry. In this study, we found that the cell death response to photothermal therapy was dependent on the GNR localization. Furthermore, we demonstrated that nanorods targeted to the perinuclear region irradiated at 37.5 W/cm2 laser fluence rate led to maximum cell destruction with the `cleaner' method of apoptosis, at similar percentages as other anti-cancer targeted therapies. We believe that this indicates the therapeutic potential for GNR-mediated photothermal therapy to treat cancer effectively without causing damage to surrounding tissue.

  3. Role of apoptosis and necrosis in cell death induced by nanoparticle-mediated photothermal therapy

    Energy Technology Data Exchange (ETDEWEB)

    Pattani, Varun P., E-mail: varun.pattani@utexas.edu; Shah, Jay; Atalis, Alexandra; Sharma, Anirudh; Tunnell, James W. [The University of Texas at Austin, Department of Biomedical Engineering (United States)

    2015-01-15

    Current cancer therapies can cause significant collateral damage due to a lack of specificity and sensitivity. Therefore, we explored the cell death pathway response to gold nanorod (GNR)-mediated photothermal therapy as a highly specific cancer therapeutic to understand the role of apoptosis and necrosis during intense localized heating. By developing this, we can optimize photothermal therapy to induce a maximum of ‘clean’ cell death pathways, namely apoptosis, thereby reducing external damage. GNRs were targeted to several subcellular localizations within colorectal tumor cells in vitro, and the cell death pathways were quantitatively analyzed after photothermal therapy using flow cytometry. In this study, we found that the cell death response to photothermal therapy was dependent on the GNR localization. Furthermore, we demonstrated that nanorods targeted to the perinuclear region irradiated at 37.5 W/cm{sup 2} laser fluence rate led to maximum cell destruction with the ‘cleaner’ method of apoptosis, at similar percentages as other anti-cancer targeted therapies. We believe that this indicates the therapeutic potential for GNR-mediated photothermal therapy to treat cancer effectively without causing damage to surrounding tissue.

  4. Nutrient excess and autophagic deficiency: explaining metabolic diseases in obesity.

    Science.gov (United States)

    van Niekerk, Gustav; duToit, André; Loos, Ben; Engelbrecht, Anna-Mart

    2017-12-28

    Over-nutrition and a sedentary lifestyle are the driving forces behind the development of metabolic diseases. Conversely, caloric restriction and exercise have proven to be the most effective strategies in combating metabolic diseases. Interestingly, exercise and caloric restriction share a common feature: both represent a potent mechanism for upregulating autophagy. Autophagy is rapidly induced by nutrient deprivation, and conversely, inactivated by amino acids as well as growth factors (e.g. insulin). Here, we review evidence demonstrating that autophagy may indeed be attenuated in metabolic tissue such as liver, muscle, and adipose, in the context of obesity. We also highlight the mechanistic basis by which defective autophagy may contribute to the manifestation of metabolic diseases. This includes a compromised ability of the cell to perform quality control on the mitochondrial matrix, since autophagy plays a pivotal role in the degradation of defective mitochondria. Similarly, autophagy also plays an indispensable role in the clearance of protein aggregates and redundant large protein platforms such as inflammasomes. Autophagy might also play a key role in the metabolism of endotoxins, implicating the importance of autophagy in the pathogenesis of metabolic endotoxemia. These observations underpin an unprecedented role of autophagy in the manifestation of obesity-induced metabolic derangement. Copyright © 2017. Published by Elsevier Inc.

  5. Metabolic, autophagic, and mitophagic activities in cancer initiation and progression

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    Anita Hjelmeland

    2016-04-01

    Full Text Available Cancer is a complex disease marked by uncontrolled cell growth and invasion. These processes are driven by the accumulation of genetic and epigenetic alterations that promote cancer initiation and progression. Contributing to genome changes are the regulation of oxidative stress and reactive species-induced damage to molecules and organelles. Redox regulation, metabolic plasticity, autophagy, and mitophagy play important and interactive roles in cancer hallmarks including sustained proliferation, activated invasion, and replicative immortality. However, the impact of these processes can differ depending on the signaling pathways altered in cancer, tumor type, tumor stage, and/or the differentiation state. Here, we highlight some of the representative studies on the impact of oxidative and nitrosative activities, mitochondrial bioenergetics, metabolism, and autophagy and mitophagy in the context of tumorigenesis. We discuss the implications of these processes for cellular activities in cancer for anti-cancer-based therapeutics.

  6. A Becn1 mutation mediates hyperactive autophagic sequestration of amyloid oligomers and improved cognition in Alzheimer's disease.

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    Altea Rocchi

    2017-08-01

    Full Text Available Impairment of the autophagy pathway has been observed during the pathogenesis of Alzheimer's disease (AD, a neurodegenerative disorder characterized by abnormal deposition of extracellular and intracellular amyloid β (Aβ peptides. Yet the role of autophagy in Aβ production and AD progression is complex. To study whether increased basal autophagy plays a beneficial role in Aβ clearance and cognitive improvement, we developed a novel genetic model to hyperactivate autophagy in vivo. We found that knock-in of a point mutation F121A in the essential autophagy gene Beclin 1/Becn1 in mice significantly reduces the interaction of BECN1 with its inhibitor BCL2, and thus leads to constitutively active autophagy even under non-autophagy-inducing conditions in multiple tissues, including brain. Becn1F121A-mediated autophagy hyperactivation significantly decreases amyloid accumulation, prevents cognitive decline, and restores survival in AD mouse models. Using an immunoisolation method, we found biochemically that Aβ oligomers are autophagic substrates and sequestered inside autophagosomes in the brain of autophagy-hyperactive AD mice. In addition to genetic activation of autophagy by Becn1 gain-of-function, we also found that ML246, a small-molecule autophagy inducer, as well as voluntary exercise, a physiological autophagy inducer, exert similar Becn1-dependent protective effects on Aβ removal and memory in AD mice. Taken together, these results demonstrate that genetically disrupting BECN1-BCL2 binding hyperactivates autophagy in vivo, which sequestrates amyloid oligomers and prevents AD progression. The study establishes new approaches to activate autophagy in the brain, and reveals the important function of Becn1-mediated autophagy hyperactivation in the prevention of AD.

  7. Ribavirin-induced anemia in hepatitis C virus patients undergoing combination therapy.

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    Sheeja M Krishnan

    2011-02-01

    Full Text Available The current standard of care for hepatitis C virus (HCV infection - combination therapy with pegylated interferon and ribavirin - elicits sustained responses in only ∼50% of the patients treated. No alternatives exist for patients who do not respond to combination therapy. Addition of ribavirin substantially improves response rates to interferon and lowers relapse rates following the cessation of therapy, suggesting that increasing ribavirin exposure may further improve treatment response. A key limitation, however, is the toxic side-effect of ribavirin, hemolytic anemia, which often necessitates a reduction of ribavirin dosage and compromises treatment response. Maximizing treatment response thus requires striking a balance between the antiviral and hemolytic activities of ribavirin. Current models of viral kinetics describe the enhancement of treatment response due to ribavirin. Ribavirin-induced anemia, however, remains poorly understood and precludes rational optimization of combination therapy. Here, we develop a new mathematical model of the population dynamics of erythrocytes that quantitatively describes ribavirin-induced anemia in HCV patients. Based on the assumption that ribavirin accumulation decreases erythrocyte lifespan in a dose-dependent manner, model predictions capture several independent experimental observations of the accumulation of ribavirin in erythrocytes and the resulting decline of hemoglobin in HCV patients undergoing combination therapy, estimate the reduced erythrocyte lifespan during therapy, and describe inter-patient variations in the severity of ribavirin-induced anemia. Further, model predictions estimate the threshold ribavirin exposure beyond which anemia becomes intolerable and suggest guidelines for the usage of growth hormones, such as erythropoietin, that stimulate erythrocyte production and avert the reduction of ribavirin dosage, thereby improving treatment response. Our model thus facilitates, in

  8. Constraint-induced movement therapy improves upper limb activity and participation in hemiplegic cerebral palsy: a systematic review

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    Hsiu-Ching Chiu

    2016-07-01

    Full Text Available Questions: Does constraint-induced movement therapy improve activity and participation in children with hemiplegic cerebral palsy? Does it improve activity and participation more than the same dose of upper limb therapy without restraint? Is the effect of constraint-induced movement therapy related to the duration of intervention or the age of the children? Design: Systematic review of randomised trials with meta-analysis. Participants: Children with hemiplegic cerebral palsy with any level of motor disability. Intervention: The experimental group received constraint-induced movement therapy (defined as restraint of the less affected upper limb during supervised activity practice of the more affected upper limb. The control group received no intervention, sham intervention, or the same dose of upper limb therapy. Outcome measures: Measures of upper limb activity and participation were used in the analysis. Results: Constraint-induced movement therapy was more effective than no/sham intervention in terms of upper limb activity (SMD 0.63, 95% CI 0.20 to 1.06 and participation (SMD 1.21, 95% CI 0.41 to 2.02. However, constraint-induced movement therapy was no better than the same dose of upper limb therapy without restraint either in terms of upper limb activity (SMD 0.05, 95% CI –0.21 to 0.32 or participation (SMD –0.02, 95% CI –0.34 to 0.31. The effect of constraint-induced movement therapy was not related to the duration of intervention or the age of the children. Conclusions: This review suggests that constraint-induced movement therapy is more effective than no intervention, but no more effective than the same dose of upper limb practice without restraint. Registration: PROSPERO CRD42015024665. [Chiu H-C, Ada L (2016 Constraint-induced movement therapy improves upper limb activity and participation in hemiplegic cerebral palsy: a systematic review. Journal of Physiotherapy 62: 130–137

  9. Fatal hemorrhagic cystitis induced by pelvic irradiation and cyclophosphamide therapy. Case reports and review

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    Price, W.E.; Keldahl, L.R.

    1990-05-01

    The potent cytotoxic drug cyclophosphamide has been used extensively for neoplastic and non-neoplastic diseases. Patients taking this drug may have received or may be receiving pelvic irradiation concurrently. This report describes two patients who developed fatal hemorrhagic cystitis induced by pelvic irradiation and cyclophosphamide therapy. Etiology, incidence, pathologic descriptions, and diagnostic and therapeutic aspects of this entity are described. The incidence and risk of serious, life-threatening bladder hemorrhage from cyclophosphamide therapy is increased by prior or concurrent pelvic irradiation. Alternative cytotoxic, non-urotoxic chemotherapy should be used in these high-risk patients.

  10. Modulating autophagy in cancer therapy: advancements and challenges for cancer cell death sensitization.

    Science.gov (United States)

    Bhat, Punya; Kriel, Jurgen; Shubha Priya, Babu; Salundi, Basappa; Shivananju, Nanjunda Swamy; Loos, Ben

    2017-12-01

    Autophagy is a major protein degradation pathway capable of upholding cellular metabolism under nutrient limiting conditions, making it a valuable resource to highly proliferating tumour cells. Although the regulatory machinery of the autophagic pathway has been well characterized, accurate modulation of this pathway remains complex in the context of clinical translatability for improved cancer therapies. In particular, the dynamic relationship between the rate of protein degradation through autophagy, i.e. autophagic flux, and the susceptibility of tumours to undergo apoptosis remains largely unclear. Adding to inefficient clinical translation is the lack of measurement techniques that accurately depict autophagic flux. Paradoxically, both increased autophagic flux as well as autophagy inhibition have been shown to sensitize cancer cells to undergo cell death, indicating the highly context dependent nature of this pathway. In this article, we aim to disentangle the role of autophagy modulation in tumour suppression by assessing existing literature in the context of autophagic flux and cellular metabolism at the interface of mitochondrial function. We highlight the urgency to not only assess autophagic flux more accurately, but also to center autophagy manipulation within the unique and inherent metabolic properties of cancer cells. Lastly, we discuss the challenges faced when targeting autophagy in the clinical setting. In doing so, it is hoped that a better understanding of autophagy in cancer therapy is revealed in order to overcome tumour chemoresistance through more controlled autophagy modulation in the future. Copyright © 2017. Published by Elsevier Inc.

  11. The Autophagic Lysosomal System in Outflow Pathway Physiology and Pathophysiology

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    Liton, Paloma B.

    2015-01-01

    Malfunction of the trabecular meshwork (TM)/schlemm’s canal (SC) conventional outflow pathway is associated with elevated intraocular pressure (IOP) and, therefore, increased risk of developing glaucoma, a potentially blinding disease affecting more than 70 million people worldwide. This TM/SC tissue is subjected to different types of stress, including mechanical, oxidative, and phagocytic stress. Long-term exposure to these stresses is believed to lead to a progressive accumulation of damaged cellular and tissue structures causing permanent alterations in the tissue physiology, and contribute to the pathologic increase in aqueous humor (AH) outflow resistance. Autophagy is emerging as an essential cellular survival mechanism against a variety of stressors. In addition to performing basal functions, autophagy acts as a cellular survival pathway and represents an essential mechanism by which organisms can adapt to acute stress conditions and repair stress-induced damage. A decline in autophagy has been observed in most tissues with aging and has been considered responsible, at least in part, for the accumulation of damaged cellular components in almost all tissues of aging organisms. Dysfunction in the autophagy pathway is associated with several human diseases, from infectious diseases to cancer and neurodegeneration. In this review, we will summarize our current knowledge of the emerging roles of autophagy in outflow tissue physiology and pathophysiology, including novel evidence suggesting compromised autophagy in the glaucomatous outflow pathway. PMID:26226231

  12. Structural neuroplastic change after constraint-induced movement therapy in children with cerebral palsy.

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    Sterling, Chelsey; Taub, Edward; Davis, Drew; Rickards, Tyler; Gauthier, Lynne V; Griffin, Angi; Uswatte, Gitendra

    2013-05-01

    Research from the present laboratory with adult stroke patients showed that structural neuroplastic changes are correlated with clinical improvements due to constraint-induced movement (CI) therapy. This pilot study evaluated whether comparable changes occur in children receiving CI therapy. Ten children (6 boys) with congenital hemiparesis (mean age: 3 years, 3 months) underwent MRI scans 3 weeks before, immediately before, and immediately after receiving 3 weeks of CI therapy. Longitudinal voxel-based morphometry was performed on MRI scans to determine gray matter change. In addition, the Pediatric Motor Activity Log-Revised was administered at these time points to assess arm use in daily life before and after treatment. Children exhibited large improvements after CI therapy in spontaneous use of the more-affected arm (P < .001, d' = 3.24). A significant increase in gray matter volume occurred in the sensorimotor cortex contralateral to the more-affected arm (P = .04); there was a trend for these changes to be correlated with motor improvement (r = 0.63, P = .063). Trends were also observed for increases in gray matter volume in the ipsilateral motor cortex (P = .055) and contralateral hippocampus (P = .1). No significant gray matter change was seen during the 3 weeks before treatment. These findings suggest that CI therapy produces gray matter increases in the developing nervous system and provide additional evidence that CI therapy is associated with structural remodeling of the human brain while producing motor improvement in patients with disabling central nervous system diseases.

  13. Constraint-induced aphasia therapy versus intensive semantic treatment in fluent aphasia.

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    Wilssens, Ineke; Vandenborre, Dorien; van Dun, Kim; Verhoeven, Jo; Visch-Brink, Evy; Mariën, Peter

    2015-05-01

    The authors compared the effectiveness of 2 intensive therapy methods: Constraint-Induced Aphasia Therapy (CIAT; Pulvermüller et al., 2001) and semantic therapy (BOX; Visch-Brink & Bajema, 2001). Nine patients with chronic fluent aphasia participated in a therapy program to establish behavioral treatment outcomes. Participants were randomly assigned to one of two groups (CIAT or BOX). Intensive therapy significantly improved verbal communication. However, BOX treatment showed a more pronounced improvement on two communication-namely, a standardized assessment for verbal communication, the Amsterdam Nijmegen Everyday Language Test (Blomert, Koster, & Kean, 1995), and a subjective rating scale, the Communicative Effectiveness Index (Lomas et al., 1989). All participants significantly improved on one (or more) subtests of the Aachen Aphasia Test (Graetz, de Bleser, & Willmes, 1992), an impairment-focused assessment. There was a treatment-specific effect. BOX treatment had a significant effect on language comprehension and semantics, whereas CIAT treatment affected language production and phonology. The findings indicate that in patients with fluent aphasia, (a) intensive treatment has a significant effect on language and verbal communication, (b) intensive therapy results in selective treatment effects, and (c) an intensive semantic treatment shows a more striking mean improvement on verbal communication in comparison with communication-based CIAT treatment.

  14. Cathepsin E deficiency impairs autophagic proteolysis in macrophages.

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    Takayuki Tsukuba

    Full Text Available Cathepsin E is an endosomal aspartic proteinase that is predominantly expressed in immune-related cells. Recently, we showed that macrophages derived from cathepsin E-deficient (CatE(-/- mice display accumulation of lysosomal membrane proteins and abnormal membrane trafficking. In this study, we demonstrated that CatE(-/- macrophages exhibit abnormalities in autophagy, a bulk degradation system for aggregated proteins and damaged organelles. CatE(-/- macrophages showed increased accumulation of autophagy marker proteins such as LC3 and p62, and polyubiquitinated proteins. Cathepsin E deficiency also altered autophagy-related signaling pathways such as those mediated by the mammalian target of rapamycin (mTOR, Akt, and extracellular signal-related kinase (ERK. Furthermore, immunofluorescence microscopy analyses showed that LC3-positive vesicles were merged with acidic compartments in wild-type macrophages, but not in CatE(-/- macrophages, indicating inhibition of fusion of autophagosome with lysosomes in CatE(-/- cells. Delayed degradation of LC3 protein was also observed under starvation-induced conditions. Since the autophagy system is involved in the degradation of damaged mitochondria, we examined the accumulation of damaged mitochondria in CatE(-/- macrophages. Several mitochondrial abnormalities such as decreased intracellular ATP levels, depolarized mitochondrial membrane potential, and decreased mitochondrial oxygen consumption were observed. Such mitochondrial dysfunction likely led to the accompanying oxidative stress. In fact, CatE(-/- macrophages showed increased reactive oxygen species (ROS production and up-regulation of oxidized peroxiredoxin-6, but decreased antioxidant glutathione. These results indicate that cathepsin E deficiency causes autophagy impairment concomitantly with increased aberrant mitochondria as well as increased oxidative stress.

  15. Bovine seminal ribonuclease triggers Beclin1-mediated autophagic cell death in pancreatic cancer cells.

    Science.gov (United States)

    Fiorini, Claudia; Gotte, Giovanni; Donnarumma, Federica; Picone, Delia; Donadelli, Massimo

    2014-05-01

    Among the large number of variants belonging to the pancreatic-type secretory ribonuclease (RNase) superfamily, bovine pancreatic ribonuclease (RNase A) is the proto-type and bovine seminal RNase (BS-RNase) represents the unique natively dimeric member. In the present manuscript, we evaluate the anti-tumoral property of these RNases in pancreatic adenocarcinoma cell lines and in nontumorigenic cells as normal control. We demonstrate that BS-RNase stimulates a strong anti-proliferative and pro-apoptotic effect in cancer cells, while RNase A is largely ineffective. Notably, we reveal for the first time that BS-RNase triggers Beclin1-mediated autophagic cancer cell death, providing evidences that high proliferation rate of cancer cells may render them more susceptible to autophagy by BS-RNase treatment. Notably, to improve the autophagic response of cancer cells to BS-RNase we used two different strategies: the more basic (as compared to WT enzyme) G38K mutant of BS-RNase, known to interact more strongly than wt with the acidic membrane of cancer cells, or BS-RNase oligomerization (tetramerization or formation of larger oligomers). Both mutant BS-RNase and BS-RNase oligomers potentiated autophagic cell death as compared to WT native dimer of BS-RNase, while the various RNase A oligomers remained completely ineffective. Altogether, our results shed more light on the mechanisms lying at the basis of BS-RNase antiproliferative effect in cancer cells, and support its potential use to develop new anti-cancer strategies. Copyright © 2014 Elsevier B.V. All rights reserved.

  16. A new concept in prophylaxis and therapy: paramunization by poxvirus inducers

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    Anton Mayr

    1999-07-01

    Full Text Available The so-called primitive, innate or paraspecific immune system is the phylogenetically older part of the complex immune system. It enables the organism to immediately attack various foreign substances, infectious pathogens, toxins and transformed cells of the organism itself. ,,Paramunity" is defined as an optimal regulated and activated, antigen-nonspecific defence, acquired through continuous active and succesful confrontation with endogenous and exogenous noxes or by means of ,,paramunization" with so called ,,paramunity inducers". Paramunity inducers based on different pox virus species (e.g. Baypamun®, Duphapind®, Conpind have turned out to be effective and safe when applied with human beings as well as with animals. Pox virus inducers activate phagocytosis and NK-cells in addition to regulation of various cytokines, notably interferon a and g, IL 1, 2, CSF and TNF which comprise the network of the complex paraspecific immune system. The results of experimental work as well as practical use in veterinary medicine have shown that paramunization by pox inducers goes far beyond the common understanding of so-called ,,immuno-therapy". They are ,,bioregulators", because they have 1. a regulatory effect on a disturbed immune system in the sense of an optimal homoeostasis, and 2. simultaneously a regulatory effect between the immune, nervous, circulatory and hormone system. Therefore, the use of paramunization by pox inducers opens a new way of prophylaxis and therapy, not only with regard to infections, but also with regard to different other indications.

  17. [A case of prednisolone therapy for radiation-induced hemorrhagic cystitis].

    Science.gov (United States)

    Yanagi, Masato; Nishimura, Taiji; Kurita, Susumu; Lee, Chorsu; Kondo, Yukihiro; Yamazaki, Keiichi

    2011-05-01

    Hemorrhagic cystitis resulting from radiation to pelvic visceral malignant lesions often might be incurable and there have been no established definitive treatment. We experienced a case with severe radiation-induced hemorrhagic cystitis refractory to conventional therapy. The treatment with oral administration of prednisolone was performed and obtained a successful result. Gross hematuria disappeared in 2 weeks in this case. This experience suggested that oral administration of prednisolone could be considered the treatment for patients with radiation-induced hemorrhagic cystitis when usual treatments including transurethral electro-coagulation are unsuccessful.

  18. Hyperbaric oxygen therapy in the successful treatment of two cases of radiation-induced hemorrhagic cystitis

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    Akiyama, Akihito; Ohkubo, Yuhei; Takashima, Rikiya; Furugen, Nobuaki; Tochimoto, Masato; Tsuchiya, Akira (Tokyo Medical Coll. (Japan). Kasumigaura Hospital)

    1994-08-01

    Hemorrhagic cystitis resulting from radiation to pelvic visceral malignant lesions often might be incurable and there have been established no definitive treatment. We experienced 2 cases of radiation-induced severe hemorrhagic cystitis refractory to conventional therapy. The treatment with hyperbaric oxygen to control hematuria was performed and obtained successful results. Gross hematuria was disappeared and cystoscopic figure was remarkably improved. No remarkable side-effect was observed in both patients. This experience suggested that hyperbaric oxygen could be considered as the primary treatment for patient with radiation-induced hemorrhagic cystitis instead of usual treatment. (author).

  19. Magnetic Resonance-Guided Laser Induced Thermal Therapy for Glioblastoma Multiforme: A Review

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    Sarah E. Norred

    2014-01-01

    Full Text Available Magnetic resonance-guided laser induced thermotherapy (MRgLITT has become an increasingly relevant therapy for tumor ablation due to its minimally invasive approach and broad applicability across many tissue types. The current state of the art applies laser irradiation via cooled optical fiber applicators in order to generate ablative heat and necrosis in tumor tissue. Magnetic resonance temperature imaging (MRTI is used concurrently with this therapy to plan treatments and visualize tumor necrosis. Though application in neurosurgery remains in its infancy, MRgLITT has been found to be a promising therapy for many types of brain tumors. This review examines the current use of MRgLITT with regard to the special clinical challenge of glioblastoma multiforme and examines the potential applications of next-generation nanotherapy specific to the treatment of glioblastoma.

  20. A review of Constraint-Induced Therapy applied to aphasia rehabilitation in stroke patients

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    Joana Bisol Balardin

    Full Text Available Abstract Constraint-induced aphasia therapy (CIAT is an intensive therapy model based on the forced use of verbal oral language as the sole channel of communication, while any alternative communication mode such as writing, gesturing or pointing are prevented. Objectives: This critical review involved the analysis of studies examining CIAT applied to stroke patients. Methods and Results: Using keywords, the Medline database was searched for relevant studies published between 2001 and 2008 (Medline 2001-2008. The critical evaluation of the articles was based on the classifications described by the ASNS (Cicerone adaptation. Two studies were categorized as level Ia, two as level II and one study as level IV. Conclusions: These recommendations should be interpreted with caution, given the small number of studies involved, but serve as a guideline for future studies in aphasia therapy.

  1. Advances in Induced Pluripotent Stem Cells, Genomics, Biomarkers, and Antiplatelet Therapy

    Science.gov (United States)

    Barbato, Emanuele; Lara-Pezzi, Enrique; Stolen, Craig; Taylor, Angela; Barton, Paul J.; Bartunek, Jozef; Iaizzo, Paul; Judge, Daniel P.; Kirshenbaum, Lorrie; Blaxall, Burns C.; Terzic, Andre; Hall, Jennifer L.

    2014-01-01

    The Journal provides the clinician and scientist with the latest advances in discovery research, emerging technologies, pre-clinical research design and testing, and clinical trials. We highlight advances in areas of induced pluripotent stem cells, genomics, biomarkers, multi-modality imaging and antiplatelet biology and therapy. The top publications are critically discussed and presented along with anatomical reviews and FDA insight to provide context. PMID:24659088

  2. Intense pulsed light therapy (IPL) induced iritis following treatment for a medial canthal capillary malformation.

    Science.gov (United States)

    Crabb, Matthew; Chan, Weng Onn; Taranath, Deepa; Huilgol, Shyamala C

    2014-11-01

    The popularity of intense pulsed light (IPL) therapy continues to increase due to its relative safety, high skin coverage rate and ability to treat both vascular and pigmented lesions. An often-overlooked risk is the potential for IPL-induced ocular damage. The damage sustained can cause significant, persistent morbidity and can occur even with very limited IPL exposure to the eye. © 2014 The Australasian College of Dermatologists.

  3. TARGETED RADIOFREQUENCY THERAPY FOR TRAINING INDUCED MUSCLE FATIGUE EFFECTIVE OR NOT

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    Ondrej Prouza

    2016-12-01

    Full Text Available Background: Training induced muscle fatigue (hereinafter also referred as TIMF is leading to unwanted consequences among sportsmen and actively sporting people such as decreased muscle strength and additional painful discomfort and mobility issues. The knowledge about the mechanisms of influencing the fatigue induced processes in muscle tissue is not comprehensive. The conventional manual techniques, cold patches and conventional physiotherapy have some effect in improving these conditions, however, finding effective methods to influence these consequences appears beneficial in sports medicine. Such method could be Radiofrequency therapy up to 0.5 MHz, known as Targeted Radiofrequency Therapy (hereinafter also referred as TR-Therapy. Aim of this self-controlled study is to evaluate the effect of the TR-Therapy for over-exertion management including the effect on decreased muscle strength, limited range of motion and possible painful discomfort. Materials: 7 healthy and actively sporting participants underwent through 2 stages (Active stage – including overexertion of the forearm flexors and subsequent TR-Therapy session; and Control stage - including overexertion of the forearm flexors and subsequent resting period. Data for muscle strength in kg, active Range of Motion (ROM in (º and Pain and discomfort perception by 10 point Visual Analog Scale (VAS were obtained and evaluated. Results: 31% increase in the muscle strength during the active stage was observed and respectively 12% during the control stage, with level of significance p0.05. Conclusions: The results of this study suggest TR-Therapy as effective solution for muscle strength restoration after TIMF.

  4. Effects of medical ozone therapy on acetaminophen-induced nephrotoxicity in rats.

    Science.gov (United States)

    Demirbag, Suzi; Uysal, Bulent; Guven, Ahmet; Cayci, Tuncer; Ozler, Mehmet; Ozcan, Ayhan; Kaldirim, Umit; Surer, Ilhami; Korkmaz, Ahmet

    2010-05-01

    Acetaminophen (APAP), also known as paracetamol, is the commonest cause of toxic ingestion in the world. Because overdose of APAP has life-threatening effects on kidney, treatment of APAP-induced nephrotoxicity has life-saving importance. Aim of the study was to evaluate the efficacy of medical ozone therapy in experimental model of APAP toxication. Twenty-one male Wistar rats (200-250 g) were randomly assigned into three groups containing seven rats each: Sham, control (only APAP treated), and APAP + ozone therapy groups. Rats were killed 48 hours after administration of APAP. Urea, creatinine levels in the blood, and malondialdehyde (MDA), superoxide dismutase (SOD), and glutathione peroxidase (GSH-Px) activity in renal tissue were measured. Kidney tissues were stained with hematoxylin and eosin for histological assessment. APAP administration deteriorated the renal functions and significantly elevated renal MDA levels and depleted SOD and GSH-Px activities. Ozone therapy significantly reduced the MDA level, increased the SOD and GSH-Px activities, and normalized the renal histology. In conclusion, our study results are consistent with encouraging data for ozone therapy on APAP-induced nephrotoxicity in rats by improving antioxidant mechanism and oxidative stress.

  5. [Anabolic therapy of induced osteoporosis in beta-thalassaemia major: case report and literature review].

    Science.gov (United States)

    Trotta, A; Corrado, A; Cantatore, F P

    2010-01-01

    Transfusion program and chelating therapy treatment has extended the life expectancy of thalassaemic patient; osteoporosis is considered an important cause of morbidity in adult patients who display increased fracture risk. This is a case report is about a thalassaemic young female with multiple spine fractures (D11, D12 e L2) and lumbar spine DEXA - T score = -3,1 and femoral = -3,4. This was in spite of therapy with alendronate 70 mg/week from January 2006 to September 2007. The patient was subsequentently treated for 18 months with 1-34 recombinant human parathyroid hormone and colecalciferol (100.000 U/monthly). After 4 months of therapy, the patient showed a decrease in spinal pain (Roland and Morris Disability Questionnaire) and an improvement of quality of life (Qualeffo) with normalization of osteocalcin and 25-OHcolecalciferol haematic levels after 6 months. Lumbar spine and femoral DEXA - Tscore, at 18 months, rose respectively to -2,5 and -2,4. Thalassaemia-induced osteoporosis is multifactorial and its management is very difficult. Bone marrow expansion, endocrine dysfunction, iron overload and genetic factors all seem to play important roles in the development of low bone mass in these patients. Bisphosfonates have been used in the management of thalassemia induced osteoporosis but there is no data about fracture risk. Anabolic therapy for thalassemic patients requests additional study on a large scale.

  6. Anabolic therapy in b-thalassaemia major induced osteoporosis: case report and literature review

    Directory of Open Access Journals (Sweden)

    F.P. Cantatore

    2011-06-01

    Full Text Available Transfusion program and chelating therapy treatment has extended the life expectancy of thalassaemic patient; osteoporosis is considered an important cause of morbidity in adult patients who display increased fracture risk. This is a case report is about a thalassaemic young female with multiple spine fractures (D11, D12 e L2 and lumbar spine DEXA - Tscore = -3,1 and femoral = -3,4. This was in spite of therapy with alendronate 70 mg/week from January 2006 to September 2007. The patient was subsequentently treated for 18 months with 1-34 recombinant human parathyroid hormone and colecalciferol (100.000 U/monthly. After 4 months of therapy, the patient showed a decrease in spinal pain (Roland and Morris Disability Questionnaire and an improvement of quality of life (Qualeffo with normalization of osteocalcin and 25-OHcolecalciferol haematic levels after 6 months. Lumbar spine and femoral DEXA - Tscore, at 18 months, rose respectively to -2,5 and -2,4. Thalassaemia-induced osteoporosis is multifactorial and its management is very difficult. Bone marrow expansion, endocrine dysfunction, iron overload and genetic factors all seem to play important roles in the development of low bone mass in these patients. Bisphosfonates have been used in the management of thalassemia induced osteoporosis but there is no data about fracture risk. Anabolic therapy for thalassemic patients requests additional study on a large scale.

  7. Fluticasone furoate induced iatrogenic Cushing syndrome in a pediatric patient receiving anti-retroviral therapy.

    Science.gov (United States)

    van den Berg, S A A; van 't Veer, N E; Emmen, J M A; van Beek, R H T

    2017-01-01

    We present a case of iatrogenic Cushing's syndrome, induced by treatment with fluticasone furoate (1-2 dd, 27.5 µg in each nostril) in a pediatric patient treated for congenital HIV. The pediatric patient described in this case report is a young girl of African descent, treated for congenital HIV with a combination therapy of Lopinavir/Ritonavir (1 dd 320/80 mg), Lamivudine (1 dd 160 mg) and Abacavir (1 dd 320 mg). Our pediatric patient presented with typical Cushingoid features (i.e. striae of the upper legs, full moon face, increased body and facial hair) within weeks after starting fluticasone furoate therapy, which was exacerbated after increasing the dose to 2 dd because of complaints of unresolved rhinitis. Biochemical analysis fitted iatrogenic Cushing's syndrome, with a repeatedly low cortisol (iatrogenic Cushing's syndrome in patients treated for HIV due to the strong inhibition of CYP3 enzymes by Ritonavir. Upon discontinuation of fluticasone treatment, the pediatric patient improved both clinically and biochemically with normalisation of cortisol and ACTH within a couple of weeks. Fluticasone therapy may induce iatrogenic Cushing's syndrome in a patient treated with anti-retroviral therapy.Pharmacogenetic analysis, in particular CYP3A genotyping, provides useful information in patients treated for HIV with respect to possible future steroid treatment.Fluticasone furoate is not detected in the Siemens Immulite cortisol binding assay.

  8. A Review on Novel Breast Cancer Therapies: Photodynamic Therapy and Plant Derived Agent Induced Cell Death Mechanisms.

    Science.gov (United States)

    George, Blassan Plackal Adimuriyil; Abrahamse, Heidi

    2016-01-01

    This review article presents an extensive examination of risk factors for breast cancer, treatment strategies with special attention to photodynamic therapy and natural product based treatments. Breast cancer remains the most commonly occurring cancer in women worldwide and the detection, treatment, and prevention are prominent concerns in public health. Background information on current developments in treatment helps to update the approach towards risk assessment. Breast cancer risk is linked to many factors such as hereditary, reproductive and lifestyle factors. Minimally invasive Photodynamic therapy (PDT) can be used in the management of various cancers; it uses a light sensitive drug (a photosensitizer, PS) and a light of visible wavelength, to destroy targeted cancer cells. State of the art analyses has been carried out to investigate advancement in the search for the cure and control of cancer progression using natural products. Traditional medicinal plants have been used as lead compounds for drug discovery in modern medicine. Both PDT and plant derived drugs induce cell death via different mechanisms including apoptosis, necrosis, autophagy, cell cycle regulation and even the regulation of various cell signalling pathways.

  9. Metronomic chemotherapy prevents therapy-induced stromal activation and induction of tumor-initiating cells

    Science.gov (United States)

    Chan, Tze-Sian; Pai, Vincent C.; Tan, Kok-Tong; Yen, Chia-Jui; Hsu, Shu-Ching; Chen, Wei-Yu; Shan, Yan-Shen; Lee, Michael T.; Chu, Jui-Mei

    2016-01-01

    Although traditional chemotherapy kills a fraction of tumor cells, it also activates the stroma and can promote the growth and survival of residual cancer cells to foster tumor recurrence and metastasis. Accordingly, overcoming the host response induced by chemotherapy could substantially improve therapeutic outcome and patient survival. In this study, resistance to treatment and metastasis has been attributed to expansion of stem-like tumor-initiating cells (TICs). Molecular analysis of the tumor stroma in neoadjuvant chemotherapy–treated human desmoplastic cancers and orthotopic tumor xenografts revealed that traditional maximum-tolerated dose chemotherapy, regardless of the agents used, induces persistent STAT-1 and NF-κB activity in carcinoma-associated fibroblasts. This induction results in the expression and secretion of ELR motif–positive (ELR+) chemokines, which signal through CXCR-2 on carcinoma cells to trigger their phenotypic conversion into TICs and promote their invasive behaviors, leading to paradoxical tumor aggression after therapy. In contrast, the same overall dose administered as a low-dose metronomic chemotherapy regimen largely prevented therapy-induced stromal ELR+ chemokine paracrine signaling, thus enhancing treatment response and extending survival of mice carrying desmoplastic cancers. These experiments illustrate the importance of stroma in cancer therapy and how its impact on treatment resistance could be tempered by altering the dosing schedule of systemic chemotherapy. PMID:27881732

  10. The role of autophagy in Alzheimer's disease and its potential for therapy

    Directory of Open Access Journals (Sweden)

    Min LIU

    2014-05-01

    Full Text Available Autophagy, the basic intracellular mechanism for catabolic and continuous clearance of unnecessary or dysfunctional components, occupies a crucial role in Alzheimer's disease (AD. Multiple studies both in vitro and in vivo have demonstrated that amyloid-β protein (Aβ can be generated during autophagy, while lysosomal system is also directly implicated in the elimination of A β and tau protein. Pathophysically, both in AD models and AD patients, lysosomal dysfunction and autophagic vacuoles accumulation provide direct and objective evidence of impaired dynamic process of autophagy, which leads to the aggregation of Aβ and tau and thus contributes to the pathogenesis of AD. Accumulating studies in vivo have shown promising therapies targeting autophagic process, as activating autophagy may be beneficial to the early stages of AD and restoring lysosomal proteolysis may be favorable for the late stages of AD. This review mainly discusses the mechanism of autophagy-induced AD and the promising autophagy-related treatments for AD. doi: 10.3969/j.issn.1672-6731.2014.05.015

  11. In vivo induction of the autophagic machinery in human bone marrow cells during Leishmania donovani complex infection.

    Science.gov (United States)

    Mitroulis, Ioannis; Kourtzelis, Ioannis; Papadopoulos, Vassileios P; Mimidis, Konstantinos; Speletas, Matthaios; Ritis, Konstantinos

    2009-12-01

    Autophagy is a homeostatic process promoting cell survival in periods of stress. The induction of the autophagic machinery has also been implicated in both innate and adaptive immunity. Leishmania donovani, which is the causative pathogen of visceral leishmaniasis, is an intracellular parasite that invades and multiplies in bone marrow macrophages. We describe the induction of host cell autophagic machinery during acute natural bone marrow infection by L. donovani complex, detected by LC3B immunoblot. The successful treatment with liposomal amphotericin B resulted in the resolution of this phenomenon. Even though the role of autophagy in parasite biology has been previously studied, our findings show for the first time the in vivo host cell LC3B conversion as a marker of the induction of the autophagic machinery during infection with Leishmania parasite in real time conditions.

  12. Case report of a patient with chemotherapy-induced peripheral neuropathy treated with manual therapy (massage).

    Science.gov (United States)

    Cunningham, Joan Elizabeth; Kelechi, Teresa; Sterba, Katherine; Barthelemy, Nikki; Falkowski, Paul; Chin, Steve H

    2011-09-01

    Chemotherapy-induced peripheral neuropathy (CIPN) is a common, miserable, potentially severe, and often dose-limiting side effect of several first and second-line anti-cancer agents with little in the way of effective, acceptable treatment. Although mechanisms of damage differ, manual therapy (therapeutic massage) has effectively reduced symptoms and improved quality of life in patients with diabetic peripheral neuropathy. Here, we describe application of manual therapy (techniques of effleurage and petrissage) to the extremities in a patient with grade 2 CIPN subsequent to prior treatment with docetaxel and cisplatin for stage III esophageal adenocarcinoma. Superficial cutaneous temperature was monitored using infrared thermistry as proxy for microvascular blood flow. By the end of the course of manual therapy without any change in medications, CIPN symptoms were greatly reduced to grade 1, with corresponding improvement in quality of life. Improvements in superficial temperature were observed in fingers and toes. Manual therapy was associated with almost complete resolution of the tingling and numbness and pain of CIPN in this patient. Concurrently increased superficial temperature suggests improvements in CIPN symptoms may have involved changes in blood circulation. To our knowledge, this is the first report of using manual therapy for amelioration of CIPN.

  13. Extended ceftiofur therapy for treatment of experimentally-induced Streptococcus uberis mastitis in lactating dairy cattle.

    Science.gov (United States)

    Oliver, S P; Almeida, R A; Gillespie, B E; Headrick, S J; Dowlen, H H; Johnson, D L; Lamar, K C; Chester, S T; Moseley, W M

    2004-10-01

    Streptococcus uberis is an important cause of mastitis in dairy cows throughout the world, particularly during the dry period, the period around calving, and during early lactation. Strategies for controlling Strep. uberis mastitis are poorly defined and are currently inadequate. Objectives of the present study were to evaluate efficacy of ceftiofur, a new broad-spectrum cephalosporin antibiotic, for treatment of experimentally induced Strep. uberis intramammary infections (IMI) in lactating dairy cows during early lactation and to determine whether extended therapy regimens enhanced efficacy of ceftiofur. Efficacy of extended ceftiofur intramammary therapy regimens was investigated in 37 mammary quarters of 23 dairy cows that developed clinical mastitis following experimental infection with Strep. uberis during early lactation. Cows that developed clinical mastitis during the challenge period were allocated randomly to 3 groups representing 3 different ceftiofur treatment regimens: 2-d (n = 7 mammary quarters), 5-d (n = 16 mammary quarters), and 8-d (n = 14 mammary quarters) treatment regimens. For all groups, 125 mg of ceftiofur hydrochloride was administered via intramammary infusion. A bacteriological cure was defined as an experimentally infected quarter that was treated and was bacteriologically negative for the presence of Strep. uberis at 7, 14, 21, and 28 d posttreatment. Percentage of Strep. uberis IMI eliminated was 43, 88, and 100% for the 2-, 5-, and 8-d ceftiofur treatment regimens, respectively. Both the 5- and 8-d ceftiofur extended therapy treatment regimens had significantly higher bacterial cure rates than the standard 2-d ceftiofur treatment regimen. The bacterial cure rate of the 8-d ceftiofur extended therapy group was marginally better (P = 0.052) than the 5-d ceftiofur extended therapy group. Results of this study indicate that ceftiofur therapy was effective for eliminating Strep. uberis experimental IMI, and 5- and 8-d extended ceftiofur

  14. Combination therapy with atorvastatin and amlodipine suppresses angiotensin II-induced aortic aneurysm formation.

    Directory of Open Access Journals (Sweden)

    Kikuyo Takahashi

    Full Text Available BACKGROUND: Abdominal aortic aneurysm (AAA is a life-threatening vascular disease. It is controversial whether statin and calcium channel blockers (CCBs has an inhibitory effect on the expansion of AAA. Some studies reported that CCBs have an inhibitory effect on Rho-kinase activity. Rho-kinase plays an important role in the pathogenesis of various cardiovascular diseases. However, there is no study reporting of the association between Rho-kinase and human AAAs. METHODS AND RESULTS: Experimental AAA was induced in Apolipoprotein E-deficient (ApoE(-/- mice infused with angiotensin II (AngII for 28 days. They were randomly divided into the following 5 groups; saline infusion alone (sham, AngII infusion alone, AngII infusion plus atorvastatin (10 mg/kg/day, AngII infusion plus amlodipine (1 mg/kg/day, and AngII infusion plus combination therapy with atorvastatin (10 mg/kg/day and amlodipine (1 mg/kg/day. The combination therapy significantly suppressed AngII-induced increase in maximal aortic diameter as compared with sham, whereas each monotherapy had no inhibitory effects. The combination therapy significantly reduced AngII-induced apoptosis and elastin degradation at the AAA lesion, whereas each monotherapy did not. Moreover, Rho-kinase activity, as evaluated by the extent of phosphorylation of myosin-binding subunit (a substrate of Rho-kinase and matrix metalloproteinase activity were significantly increased in the AngII-induced AAA lesion as compared with sham, both of which were again significantly suppressed by the combination therapy. In human aortic samples, immunohistochemistory revealed that the activity and expression of Rho-kinase was up-regulated in AAA lesion as compared with abdominal aorta from control subjects. CONCLUSIONS: Rho-kinase is up-regulated in the aortic wall of human AAA. The combination therapy with amlodipine and Atorvastatin, but not each monotherapy, suppresses AngII-induced AAA formation in mice in vivo, for which

  15. Insulin-induced enhancement of MCF-7 breast cancer cell response to 5-fluorouracil and cyclophosphamide.

    Science.gov (United States)

    Agrawal, Siddarth; Łuc, Mateusz; Ziółkowski, Piotr; Agrawal, Anil Kumar; Pielka, Ewa; Walaszek, Kinga; Zduniak, Krzysztof; Woźniak, Marta

    2017-06-01

    The study was designed to evaluate the potential use of insulin for cancer-specific treatment. Insulin-induced sensitivity of MCF-7 breast cancer cells to chemotherapeutic agents 5-fluorouracil and cyclophosphamide was evaluated. To investigate and establish the possible mechanisms of this phenomenon, we assessed cell proliferation, induction of apoptosis, activation of apoptotic and autophagic pathways, expression of glucose transporters 1 and 3, formation of reactive oxygen species, and wound-healing assay. Additionally, we reviewed the literature regarding theuse of insulin in cancer-specific treatment. We found that insulin increases the cytotoxic effect of 5-fluorouracil and cyclophosphamide in vitro up to two-fold. The effect was linked to enhancement of apoptosis, activation of apoptotic and autophagic pathways, and overexpression of glucose transporters 1 and 3 as well as inhibition of cell proliferation and motility. We propose a model for insulin-induced sensitization process. Insulin acts as a sensitizer of cancer cells to cytotoxic therapy through various mechanisms opening a possibility for metronomic insulin-based treatments.

  16. Phellinus linteus Mycelium Alleviates Myocardial Ischemia-Reperfusion Injury through Autophagic Regulation

    Science.gov (United States)

    Su, Hsing-Hui; Chu, Ya-Chun; Liao, Jiuan-Miaw; Wang, Yi-Hsin; Jan, Ming-Shiou; Lin, Chia-Wei; Wu, Chiu-Yeh; Tseng, Chin-Yin; Yen, Jiin-Cherng; Huang, Shiang-Suo

    2017-01-01

    The incidence of myocardial ischemia-reperfusion (IR) injury is rapidly increasing around the world and this disease is a major contributor to global morbidity and mortality. It is known that regulation of programmed cell death including apoptosis and autophagy reduces the impact of myocardial IR injury. In this study, the cardioprotective effects and underlying mechanisms of Phellinus linteus (Berk. and Curt.) Teng, Hymenochaetaceae (PL), a type of medicinal mushroom, were examined in rats subjected to myocardial IR injury. The left main coronary artery of rats was ligated for 1 h and reperfused for 3 h. The arrhythmia levels were monitored during the entire process and the infarct size was evaluated after myocardial IR injury. Furthermore, the expression levels of proteins in apoptotic and autophagic pathways were observed. Pretreatment with PL mycelium (PLM) significantly reduced ventricular arrhythmia and mortality due to myocardial IR injury. PLM also significantly decreased myocardial infarct size and plasma lactate dehydrogenase level after myocardial IR injury. Moreover, PLM administration resulted in decreased caspase 3 and caspase 9 activation and increased Bcl-2/Bax ratio. Phosphorylation level of AMPK was elevated while mTOR level was reduced. Becline-1 and p62 levels decreased. These findings suggest that PLM is effective in protecting the myocardium against IR injury. The mechanism involves mediation through suppressed pro-apoptotic signaling and regulation of autophagic signaling, including stimulation of AMPK-dependent pathway and inhibition of beclin-1-dependent pathway, resulting in enhancement of protective autophagy and inhibition of excessive autophagy. PMID:28420993

  17. Precise temporal regulation of roughest is required for correct salivary gland autophagic cell death in Drosophila.

    Science.gov (United States)

    Simon, Claudio R; Moda, Livia M R; Octacilio-Silva, Shirlei; Anhezini, Lucas; Machado-Gitai, Luciana C H; Ramos, Ricardo Guelerman P

    2009-07-01

    The Drosophila roughest (rst) locus encodes an immunoglobulin superfamily transmembrane glycoprotein implicated in a variety of embryonic and postembryonic developmental processes. Here we demonstrate a previously unnoticed role for this gene in the autophagic elimination of larval salivary glands during early pupal stages by showing that overexpression of the Rst protein ectodomain in early pupa leads to persistence of salivary glands up to at least 12 hours after head eversion, although with variable penetrance. The same phenotype is observed in individuals carrying the dominant regulatory allele rst(D), but not in loss of function alleles. Analysis of persistent glands at the ultrastructural level showed that programmed cell death starts at the right time but is arrested at an early stage of the process. Finally we describe the expression pattern and intracellular distribution of Rst in wild type and rst(D) mutants, showing that its downregulation in salivary glands at the beginning of pupal stage is an important factor in the correct implementation of the autophagic program of this tissue in space and time. 2009 Wiley-Liss, Inc.

  18. Abnormal accumulation of autophagic vesicles correlates with axonal and synaptic pathology in young Alzheimer's mice hippocampus.

    Science.gov (United States)

    Sanchez-Varo, Raquel; Trujillo-Estrada, Laura; Sanchez-Mejias, Elisabeth; Torres, Manuel; Baglietto-Vargas, David; Moreno-Gonzalez, Ines; De Castro, Vanessa; Jimenez, Sebastian; Ruano, Diego; Vizuete, Marisa; Davila, Jose Carlos; Garcia-Verdugo, Jose Manuel; Jimenez, Antonio Jesus; Vitorica, Javier; Gutierrez, Antonia

    2012-01-01

    Dystrophic neurites associated with amyloid plaques precede neuronal death and manifest early in Alzheimer's disease (AD). In this work we have characterized the plaque-associated neuritic pathology in the hippocampus of young (4- to 6-month-old) PS1(M146L)/APP(751SL) mice model, as the initial degenerative process underlying functional disturbance prior to neuronal loss. Neuritic plaques accounted for almost all fibrillar deposits and an axonal origin of the dystrophies was demonstrated. The early induction of autophagy pathology was evidenced by increased protein levels of the autophagosome marker LC3 that was localized in the axonal dystrophies, and by electron microscopic identification of numerous autophagic vesicles filling and causing the axonal swellings. Early neuritic cytoskeletal defects determined by the presence of phosphorylated tau (AT8-positive) and actin-cofilin rods along with decreased levels of kinesin-1 and dynein motor proteins could be responsible for this extensive vesicle accumulation within dystrophic neurites. Although microsomal Aβ oligomers were identified, the presence of A11-immunopositive Aβ plaques also suggested a direct role of plaque-associated Aβ oligomers in defective axonal transport and disease progression. Most importantly, presynaptic terminals morphologically disrupted by abnormal autophagic vesicle buildup were identified ultrastructurally and further supported by synaptosome isolation. Finally, these early abnormalities in axonal and presynaptic structures might represent the morphological substrate of hippocampal dysfunction preceding synaptic and neuronal loss and could significantly contribute to AD pathology in the preclinical stages.

  19. A systematic review of salivary gland hypofunction and xerostomia induced by cancer therapies

    DEFF Research Database (Denmark)

    Jensen, S.B.; Pedersen, A.M.L.; Vissink, A.

    2010-01-01

    This systematic review aimed to assess the literature for prevalence, severity, and impact on quality of life of salivary gland hypofunction and xerostomia induced by cancer therapies. The electronic databases of MEDLINE/PubMed and EMBASE were searched for articles published in English since...... met by 184 articles covering salivary gland hypofunction and xerostomia induced by conventional, 3D conformal radiotherapy or intensity-modulated radiotherapy in head and neck cancer patients, cancer chemotherapy, total body irradiation/hematopoietic stem cell transplantation, radioactive iodine...... treatment, and immunotherapy. Salivary gland hypofunction and xerostomia are induced by radiotherapy in the head and neck region depending on the cumulative radiation dose to the gland tissue. Treatment focus should be on optimized/new approaches to further reduce the dose to the parotids, and particularly...

  20. Combination therapy with spironolactone and candesartan protects against streptozotocin-induced diabetic nephropathy in rats.

    Science.gov (United States)

    Hofni, Amal; El-Moselhy, Mohamed A; Taye, Ashraf; Khalifa, Mohamed M

    2014-12-05

    Diabetic nephropathy is one of the most common causes of end-stage kidney disease. Aldosterone and angiotensin II appear to play a crucial role in the pathogenesis of this disease. The present study aimed to investigate effects of the combination therapy with spironolactone and candesartan on diabetic nephropathy and elucidate the underlying mechanism(s) involved. Diabetes was induced in rats by a single intraperitoneal injection of streptozotocin (STZ) (55 mg/kg). The diabetic rats were orally treated with spironolactone (50 mg/kg/day) and/or candesartan (1 mg/kg/day) for 8 weeks. Administration of STZ caused a marked elevation in the serum level of creatinine, urea and urinary albumin-creatinine ratio (ACR). This was associated with upregulated renal protein levels of nuclear factor-kappa B (NF-κB), transforming growth factor (TGF)-β, inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) alongside increasing the renal superoxide anion (O2(-)) production, malondialdehyde (MDA) level and the systolic blood pressure. There was a marked decrease in nitric oxide (NO) bioavailability and antioxidant enzyme capacity. The combined therapy of spironolactone and candesartan significantly normalized the oxidative stress and fibrotic/inflammatory alterations. Additionally, the elevated blood pressure was attenuated by administration of candesartan alone or in combination. This was associated with improving the renal function parameters. The combined therapy exhibited more profound response compared to the monotherapy. In conclusion, our results demonstrate that the combined therapy of spironolactone and candesartan can confer an additive benefit over the use of either drug alone against STZ-induced diabetic nephropathy, presumably via attenuating the inflammatory responses and oxidative status markers. Copyright © 2014 Elsevier B.V. All rights reserved.

  1. Effect of class IV laser therapy on chemotherapy-induced oral mucositis: a clinical and experimental study.

    Science.gov (United States)

    Ottaviani, Giulia; Gobbo, Margherita; Sturnega, Mauro; Martinelli, Valentina; Mano, Miguel; Zanconati, Fabrizio; Bussani, Rossana; Perinetti, Giuseppe; Long, Carlin S; Di Lenarda, Roberto; Giacca, Mauro; Biasotto, Matteo; Zacchigna, Serena

    2013-12-01

    Oral mucositis (OM) is a serious and acute side effect in patients with cancer who receive chemotherapy or radiotherapy, often leading to the suspension of therapy and a need for opioid analgesic and enteral/parenteral nutrition, with an effect on patient survival. Among the various interventions proposed in OM management, laser therapy is becoming a recommended treatment option but has limitations due to its heterogeneous laser parameters. Here, we report on our successful clinical experience on the use of class IV laser therapy to treat OM induced by different chemotherapy regimens. To shed light on the mechanisms of action of laser therapy in improving OM resolution, we have developed an animal model of chemotherapy-induced OM, in which we compare the efficacy of the standard low-power laser therapy protocol with an innovative protocol, defined as high-power laser therapy. We show that high-power laser therapy is more effective than low-power laser therapy in improving OM lesion healing, reducing the inflammatory burden, and preserving tissue integrity. In addition, high-power laser therapy has been particularly effective in promoting the formation of new arterioles within the granulation tissue. Our results provide important insights into the mechanism of action of biostimulating laser therapy on OM in vivo and pave a way for clinical experimentation with the use of high-power laser therapy. Copyright © 2013 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.

  2. Mimulone-induced autophagy through p53-mediated AMPK/mTOR pathway increases caspase-mediated apoptotic cell death in A549 human lung cancer cells.

    Directory of Open Access Journals (Sweden)

    Hyun-Kyu An

    Full Text Available Anticancer properties and mechanisms of mimulone (MML, C-geranylflavonoid isolated from the Paulownia tomentosa fruits, were firstly elucidated in this study. MML prevented cell proliferation in a dose- and time-dependent way and triggered apoptosis through the extrinsic pathway in A549 human lung adenocarcinoma cells. Furthermore, MML-treated cells displayed autophagic features, such as the formation of autophagic vacuoles, a primary morphological feature of autophagy, and the accumulation of microtubule-associated protein 1 light chain 3 (LC3 puncta, another typical maker of autophagy, as determined by FITC-conjugated immunostaining and monodansylcadaverine (MDC staining, respectively. The expression levels of LC3-I and LC3-II, specific markers of autophagy, were also augmented by MML treatment. Autophagy inhibition by 3-methyladenine (3-MA, pharmacological autophagy inhibitor, and shRNA knockdown of Beclin-1 reduced apoptotic cell death induced by MML. Autophagic flux was not significantly affected by MML treatment and lysosomal inhibitor, chloroquine (CQ suppressed MML-induced autophagy and apoptosis. MML-induced autophagy was promoted by decreases in p53 and p-mTOR levels and increase of p-AMPK. Moreover, inhibition of p53 transactivation by pifithrin-α (PFT-α and knockdown of p53 enhanced induction of autophagy and finally promoted apoptotic cell death. Overall, the results demonstrate that autophagy contributes to the cytotoxicity of MML in cancer cells harboring wild-type p53. This study strongly suggests that MML is a potential candidate for an anticancer agent targeting both autophagy and apoptotic cell death in human lung cancer. Moreover, co-treatment of MML and p53 inhibitor would be more effective in human lung cancer therapy.

  3. Interleukin-6 counteracts therapy-induced cellular oxidative stress in multiple myeloma by up-regulating manganese superoxide dismutase

    OpenAIRE

    Brown, Charles O.; Salem, Kelley; Wagner, Brett A.; Bera, Soumen; Singh, Neeraj; Tiwari, Ajit; Choudhury, Amit; Buettner, Garry R.; Goel, Apollina

    2012-01-01

    IL (interleukin)-6, an established growth factor for multiple myeloma cells, induces myeloma therapy resistance, but the resistance mechanisms remain unclear. The present study determines the role of IL-6 in re-establishing intracellular redox homoeostasis in the context of myeloma therapy. IL-6 treatment increased myeloma cell resistance to agents that induce oxidative stress, including IR (ionizing radiation) and Dex (dexamethasone). Relative to IR alone, myeloma cells treated with IL-6 plu...

  4. Partial mastectomy and m. latissimus dorsi reconstruction for radiation-induced fibrosis after breast-conserving cancer therapy

    NARCIS (Netherlands)

    A.N. van Geel (Albert); T. Lans (Titia); R. Haen (Roel); R.T.J. Wai (Rudi Tjong Joe); M. Menke-Pluijmers

    2011-01-01

    textabstractBackground: Patients with severe complaints of radiation-induced fibrosis after breast-conserving therapy and not responding to conservative therapy, were treated by partial mastectomy and m. latissimus dorsi reconstruction. Method: To determine the feasibility and outcome of this

  5. Gene expression analysis reveals inhibition of radiation- induced TGFβ-signaling by hyperbaric oxygen therapy in mouse salivary glands

    NARCIS (Netherlands)

    L. Spiegelberg (Linda); S.M.A. Swagemakers (Sigrid); W.F.J. van IJcken (Wilfred); E. Oole (Edwin); E.B. Wolvius (Eppo); J. Essers (Jeroen); M.A.H. Braks (Marieta)

    2014-01-01

    textabstractA side effect of radiation therapy in the head and neck region is injury to surrounding healthy tissues such as irreversible impaired function of the salivary glands. Hyperbaric oxygen therapy (HBOT is clinically used to treat radiation-induced damage but its mechanism of action is

  6. Mechanisms of Action Involved in Ozone Therapy: Is healing induced via a mild oxidative stress?

    Directory of Open Access Journals (Sweden)

    Sagai Masaru

    2011-12-01

    Full Text Available Abstract The potential mechanisms of action of ozone therapy are reviewed in this paper. The therapeutic efficacy of ozone therapy may be partly due the controlled and moderate oxidative stress produced by the reactions of ozone with several biological components. The line between effectiveness and toxicity of ozone may be dependent on the strength of the oxidative stress. As with exercise, it is well known that moderate exercise is good for health, whereas excessive exercise is not. Severe oxidative stress activates nuclear transcriptional factor kappa B (NFκB, resulting in an inflammatory response and tissue injury via the production of COX2, PGE2, and cytokines. However, moderate oxidative stress activates another nuclear transcriptional factor, nuclear factor-erythroid 2-related factor 2 (Nrf2. Nrf2 then induces the transcription of antioxidant response elements (ARE. Transcription of ARE results in the production of numerous antioxidant enzymes, such as SOD, GPx, glutathione-s-transferase(GSTr, catalase (CAT, heme-oxygenase-1 (HO-1, NADPH-quinone-oxidoreductase (NQO-1, phase II enzymes of drug metabolism and heat shock proteins (HSP. Both free antioxidants and anti-oxidative enzymes not only protect cells from oxidation and inflammation but they may be able to reverse the chronic oxidative stress. Based on these observations, ozone therapy may also activate Nrf2 via moderate oxidative stress, and suppress NFκB and inflammatory responses. Furthermore, activation of Nrf2 results in protection against neurodegenerative diseases, such as Alzheimer's and Parkinson's diseases. Mild immune responses are induced via other nuclear transcriptional factors, such as nuclear factor of activated T-cells (NFAT and activated protein-1 (AP-1. Additionally, the effectiveness of ozone therapy in vascular diseases may also be explained by the activation of another nuclear transcriptional factor, hypoxia inducible factor-1α (HIF-1a, which is also induced via

  7. Mechanisms of Action Involved in Ozone Therapy: Is healing induced via a mild oxidative stress?

    Science.gov (United States)

    Sagai, Masaru; Bocci, Velio

    2011-12-20

    The potential mechanisms of action of ozone therapy are reviewed in this paper. The therapeutic efficacy of ozone therapy may be partly due the controlled and moderate oxidative stress produced by the reactions of ozone with several biological components. The line between effectiveness and toxicity of ozone may be dependent on the strength of the oxidative stress. As with exercise, it is well known that moderate exercise is good for health, whereas excessive exercise is not.Severe oxidative stress activates nuclear transcriptional factor kappa B (NFκB), resulting in an inflammatory response and tissue injury via the production of COX2, PGE2, and cytokines. However, moderate oxidative stress activates another nuclear transcriptional factor, nuclear factor-erythroid 2-related factor 2 (Nrf2). Nrf2 then induces the transcription of antioxidant response elements (ARE). Transcription of ARE results in the production of numerous antioxidant enzymes, such as SOD, GPx, glutathione-s-transferase(GSTr), catalase (CAT), heme-oxygenase-1 (HO-1), NADPH-quinone-oxidoreductase (NQO-1), phase II enzymes of drug metabolism and heat shock proteins (HSP). Both free antioxidants and anti-oxidative enzymes not only protect cells from oxidation and inflammation but they may be able to reverse the chronic oxidative stress. Based on these observations, ozone therapy may also activate Nrf2 via moderate oxidative stress, and suppress NFκB and inflammatory responses. Furthermore, activation of Nrf2 results in protection against neurodegenerative diseases, such as Alzheimer's and Parkinson's diseases. Mild immune responses are induced via other nuclear transcriptional factors, such as nuclear factor of activated T-cells (NFAT) and activated protein-1 (AP-1).Additionally, the effectiveness of ozone therapy in vascular diseases may also be explained by the activation of another nuclear transcriptional factor, hypoxia inducible factor-1α (HIF-1a), which is also induced via moderate oxidative

  8. Mechanisms of Action Involved in Ozone Therapy: Is healing induced via a mild oxidative stress?

    Science.gov (United States)

    2011-01-01

    The potential mechanisms of action of ozone therapy are reviewed in this paper. The therapeutic efficacy of ozone therapy may be partly due the controlled and moderate oxidative stress produced by the reactions of ozone with several biological components. The line between effectiveness and toxicity of ozone may be dependent on the strength of the oxidative stress. As with exercise, it is well known that moderate exercise is good for health, whereas excessive exercise is not. Severe oxidative stress activates nuclear transcriptional factor kappa B (NFκB), resulting in an inflammatory response and tissue injury via the production of COX2, PGE2, and cytokines. However, moderate oxidative stress activates another nuclear transcriptional factor, nuclear factor-erythroid 2-related factor 2 (Nrf2). Nrf2 then induces the transcription of antioxidant response elements (ARE). Transcription of ARE results in the production of numerous antioxidant enzymes, such as SOD, GPx, glutathione-s-transferase(GSTr), catalase (CAT), heme-oxygenase-1 (HO-1), NADPH-quinone-oxidoreductase (NQO-1), phase II enzymes of drug metabolism and heat shock proteins (HSP). Both free antioxidants and anti-oxidative enzymes not only protect cells from oxidation and inflammation but they may be able to reverse the chronic oxidative stress. Based on these observations, ozone therapy may also activate Nrf2 via moderate oxidative stress, and suppress NFκB and inflammatory responses. Furthermore, activation of Nrf2 results in protection against neurodegenerative diseases, such as Alzheimer's and Parkinson's diseases. Mild immune responses are induced via other nuclear transcriptional factors, such as nuclear factor of activated T-cells (NFAT) and activated protein-1 (AP-1). Additionally, the effectiveness of ozone therapy in vascular diseases may also be explained by the activation of another nuclear transcriptional factor, hypoxia inducible factor-1α (HIF-1a), which is also induced via moderate

  9. Inflammatory myopathy and severe rhabdomyolysis induced by leuprolide acetate therapy for prostate cancer: a case report

    Directory of Open Access Journals (Sweden)

    Rohacek Martin

    2011-08-01

    Full Text Available Abstract Introduction Leuprolide acetate is a synthetic analog of gonadotropin-releasing hormone used for the treatment of prostate cancer. Its side effects are hot flashes, nausea, and fatigue. We report a case of a patient with proximal inflammatory myopathy accompanied by severe rhabdomyolysis and renal failure following the second application of leuprolide acetate. Drug withdrawal and steroid therapy resulted in remission within six weeks of the diagnosis. To the best of our knowledge, our case report describes the second case of leuprolide acetate-induced inflammatory myopathy and the first case of severe leuprolide acetate-induced rhabdomyolysis and renal failure in the literature. Case presentation A 64-year-old Swiss Caucasian man was admitted to the hospital because of progressive proximal muscle weakness, dyspnea, and oliguria. He had been treated twice with leuprolide acetate in monthly doses. We performed a muscle biopsy, which excluded other causes of myopathy. The patient's renal failure and rhabdomyolysis were treated with rehydration and steroid therapy. Conclusion The aim of our case report is to highlight the rare but severe side effects associated with leuprolide acetate therapy used to treat patients with inflammatory myopathy: severe rhabdomyolysis and renal failure.

  10. Chemotherapy-induced sclerosing cholangitis: long-term response to endoscopic therapy.

    Science.gov (United States)

    Alazmi, Waleed M; McHenry, Lee; Watkins, James L; Fogel, Evan L; Schmidt, Suzette; Sherman, Stuart; Lehman, Glen L

    2006-04-01

    Hepatic arterial infusion of fluoropyrimidines has been widely used for the treatment of hepatic metastasis from colorectal cancer. One major complication of such treatment is biliary sclerosis resembling primary sclerosing cholangitis, which has an incidence ranging from 8% to 26%. We evaluated the efficacy and long-term outcome of endoscopic therapy in the management of chemotherapy-induced sclerosing cholangitis (CISC). With the use of an endoscopic retrograde cholangiopancreatography (ERCP) database, all patients with a diagnosis of CISC who had endoscopic therapy between March 1995 and March 2005 were identified. The indications, findings, therapies, and complications for all patients undergoing ERCP were recorded in this database. Additional information was obtained by review of medical records. Eleven patients (six men and five women) were identified. The mean age at presentation was 59.5 years (range, 36-76 years). Cholangiogram findings revealed stricture confined to the common hepatic duct in two patients, involving the hilum in seven patients, involving the right and/or left main hepatic ducts in nine patients, and extending to the intrahepatic radicals in two patients. All patients had successful endoscopic therapy to alleviate the presenting symptom. The grade and extent of biliary strictures did not change in five patients, improved in one patient, recurred in two patients, and progressed in two patients over the follow-up period of 28.2 months (range, 4-60 months). Although long-term follow-up of patients with CISC is limited by the dismal prognosis of the underlying malignancy, CISC has a recalcitrant pattern that rarely improves with endoscopic therapy. However, endoscopic therapy seems to be an effective method of palliation.

  11. Nicotine therapy sampling to induce quit attempts among smokers unmotivated to quit: a randomized clinical trial.

    Science.gov (United States)

    Carpenter, Matthew J; Hughes, John R; Gray, Kevin M; Wahlquist, Amy E; Saladin, Michael E; Alberg, Anthony J

    2011-11-28

    Rates of smoking cessation have not changed in a decade, accentuating the need for novel approaches to prompt quit attempts. Within a nationwide randomized clinical trial (N = 849) to induce further quit attempts and cessation, smokers currently unmotivated to quit were randomized to a practice quit attempt (PQA) alone or to nicotine replacement therapy (hereafter referred to as nicotine therapy), sampling within the context of a PQA. Following a 6-week intervention period, participants were followed up for 6 months to assess outcomes. The PQA intervention was designed to increase motivation, confidence, and coping skills. The combination of a PQA plus nicotine therapy sampling added samples of nicotine lozenges to enhance attitudes toward pharmacotherapy and to promote the use of additional cessation resources. Primary outcomes included the incidence of any ever occurring self-defined quit attempt and 24-hour quit attempt. Secondary measures included 7-day point prevalence abstinence at any time during the study (ie, floating abstinence) and at the final follow-up assessment. Compared with PQA intervention, nicotine therapy sampling was associated with a significantly higher incidence of any quit attempt (49% vs 40%; relative risk [RR], 1.2; 95% CI, 1.1-1.4) and any 24-hour quit attempt (43% vs 34%; 1.3; 1.1-1.5). Nicotine therapy sampling was marginally more likely to promote floating abstinence (19% vs 15%; RR, 1.3; 95% CI, 1.0-1.7); 6-month point prevalence abstinence rates were no different between groups (16% vs 14%; 1.2; 0.9-1.6). Nicotine therapy sampling during a PQA represents a novel strategy to motivate smokers to make a quit attempt. clinicaltrials.gov Identifier: NCT00706979.

  12. Nicotine Therapy Sampling to Induce Quit Attempts Among Smokers Unmotivated to Quit

    Science.gov (United States)

    Carpenter, Matthew J.; Hughes, John R.; Gray, Kevin M.; Wahlquist, Amy E.; Saladin, Michael E.; Alberg, Anthony J.

    2012-01-01

    Background Rates of smoking cessation have not changed in a decade, accentuating the need for novel approaches to prompt quit attempts. Methods Within a nationwide randomized clinical trial (N=849) to induce further quit attempts and cessation, smokers currently unmotivated to quit were randomized to a practice quit attempt (PQA) alone or to nicotine replacement therapy (hereafter referred to as nicotine therapy), sampling within the context of a PQA. Following a 6-week intervention period, participants were followed up for 6 months to assess outcomes. The PQA intervention was designed to increase motivation, confidence, and coping skills. The combination of a PQA plus nicotine therapy sampling added samples of nicotine lozenges to enhance attitudes toward pharmacotherapy and to promote the use of additional cessation resources. Primary outcomes included the incidence of any ever occurring self-defined quit attempt and 24-hour quit attempt. Secondary measures included 7-day point prevalence abstinence at any time during the study (ie, floating abstinence) and at the final follow-up assessment. Results Compared with PQA intervention, nicotine therapy sampling was associated with a significantly higher incidence of any quit attempt (49% vs 40%; relative risk [RR], 1.2; 95% CI, 1.1–1.4) and any 24-hour quit attempt (43% vs 34%; 1.3; 1.1–1.5). Nicotine therapy sampling was marginally more likely to promote floating abstinence (19% vs 15%; RR, 1.3; 95% CI, 1.0–1.7); 6-month point prevalence abstinence rates were no different between groups (16% vs 14%; 1.2; 0.9–1.6). Conclusion Nicotine therapy sampling during a PQA represents a novel strategy to motivate smokers to make a quit attempt. Trial Registration clinicaltrials.gov Identifier: NCT00706979 PMID:22123796

  13. Alpha-1 Antitrypsin Gene Therapy Ameliorates Bone Loss in Ovariectomy-Induced Osteoporosis Mouse Model.

    Science.gov (United States)

    Akbar, Mohammad Ahsanul; Cao, Jay J; Lu, Yuanqing; Nardo, David; Chen, Mong-Jen; Elshikha, Ahmed S; Ahamed, Rubina; Brantly, Mark; Holliday, L Shannon; Song, Sihong

    2016-09-01

    Osteoporosis is a major healthcare burden affecting mostly postmenopausal women characterized by compromised bone strength and increased risk of fragility fracture. Although pathogenesis of this disease is complex, elevated proinflammatory cytokine production is clearly involved in bone loss at menopause. Therefore, anti-inflammatory strategies hold a great potential for the prevention of postmenopausal osteoporosis. In this study, we investigated the effect of gene therapy of recombinant adeno-associated virus (rAAV)-mediated human alpha-1 antitrypsin (hAAT), a multifunctional protein that has anti-inflammatory property, on bone loss in an ovariectomy-induced osteoporosis mouse model. Adult ovariectomized (OVX) mice were intraperitoneally (i.p.) injected with hAAT (protein therapy), rAAV8-CB-hAAT (gene therapy), or phosphate buffer saline (PBS). Age-matched and sham-operated animals were used as controls. Eight weeks after the treatment, animals were sacrificed and bone-related biomarkers and vertebral bone structure were evaluated. Results showed that hAAT gene therapy significantly decreased serum IL-6 level and receptor activator of NF-κB (RANK) gene expression in bone. Importantly, hAAT gene therapy increased bone volume/total volume and decreased structure model index (SMI) compared to PBS injection in OVX mice. These results demonstrate that hAAT gene therapy by rAAV vector efficiently mitigates bone loss possibly through inhibition of proinflammatory cytokine IL-6 and RANK gene expression. Considering the safety profile of hAAT and rAAV vector in humans, our results provide a new alternative for the treatment of osteoporosis.

  14. Cognitive-behavioral therapy induces sensorimotor and specific electrocortical changes in chronic tic and Tourette's disorder.

    Science.gov (United States)

    Morand-Beaulieu, Simon; O'Connor, Kieron P; Sauvé, Geneviève; Blanchet, Pierre J; Lavoie, Marc E

    2015-12-01

    Tic disorders, such as the Gilles de la Tourette syndrome and persistent tic disorder, are neurodevelopmental movement disorders involving impaired motor control. Hence, patients show repetitive unwanted muscular contractions in one or more parts of the body. A cognitive-behavioral therapy, with a particular emphasis on the psychophysiology of tic expression and sensorimotor activation, can reduce the frequency and intensity of tics. However, its impact on motor activation and inhibition is not fully understood. To study the effects of a cognitive-behavioral therapy on electrocortical activation, we recorded the event-related potentials (ERP) and lateralized readiness potentials (LRP), before and after treatment, of 20 patients with tic disorders and 20 healthy control participants (matched on age, sex and intelligence), during a stimulus-response compatibility inhibition task. The cognitive-behavioral therapy included informational, awareness training, relaxation, muscle discrimination, cognitive restructuration and relapse prevention strategies. Our results revealed that prior to treatment; tic patients had delayed stimulus-locked LRP onset latency, larger response-locked LRP peak amplitude, and a frontal overactivation during stimulus inhibition processing. Both stimulus-locked LRP onset latency and response-locked LRP peak amplitude normalized after the cognitive behavioral therapy completion. However, the frontal overactivation related to inhibition remained unchanged following therapy. Our results showed that P300 and reaction times are sensitive to stimulus-response compatibility, but are not related to tic symptoms. Secondly, overactivity of the frontal LPC and impulsivity in TD patients were not affected by treatment. Finally, CBT had normalizing effects on the activation of the pre-motor and motor cortex in TD patients. These results imply specific modifications of motor processes following therapy, while inhibition processes remained unchanged. Given

  15. Studying p53 family proteins in yeast: Induction of autophagic cell death and modulation by interactors and small molecules

    Energy Technology Data Exchange (ETDEWEB)

    Leão, Mariana; Gomes, Sara; Bessa, Cláudia; Soares, Joana; Raimundo, Liliana [REQUIMTE, Laboratório de Microbiologia, Departamento de Ciências Biológicas, Faculdade de Farmácia, Universidade do Porto, Rua de Jorge Viterbo Ferreira n. 164, 4050-313 Porto (Portugal); Monti, Paola; Fronza, Gilberto [Mutagenesis Unit, Istituto di Ricerca e Cura a Carattere Scientifico Azienda Ospedaliera Universitaria San Martino-IST-Istituto Nazionale per la Ricerca sul Cancro, 16132 Genoa (Italy); Pereira, Clara [REQUIMTE, Laboratório de Microbiologia, Departamento de Ciências Biológicas, Faculdade de Farmácia, Universidade do Porto, Rua de Jorge Viterbo Ferreira n. 164, 4050-313 Porto (Portugal); Saraiva, Lucília, E-mail: lucilia.saraiva@ff.up.pt [REQUIMTE, Laboratório de Microbiologia, Departamento de Ciências Biológicas, Faculdade de Farmácia, Universidade do Porto, Rua de Jorge Viterbo Ferreira n. 164, 4050-313 Porto (Portugal)

    2015-01-01

    In this work, the yeast Saccharomyces cerevisiae was used to individually study human p53, p63 (full length and truncated forms) and p73. Using this cell system, the effect of these proteins on cell proliferation and death, and the influence of MDM2 and MDMX on their activities were analyzed. When expressed in yeast, wild-type p53, TAp63, ΔNp63 and TAp73 induced growth inhibition associated with S-phase cell cycle arrest. This growth inhibition was accompanied by reactive oxygen species production and autophagic cell death. Furthermore, they stimulated rapamycin-induced autophagy. On the contrary, none of the tested p53 family members induced apoptosis either per se or after apoptotic stimuli. As previously reported for p53, also TAp63, ΔNp63 and TAp73 increased actin expression levels and its depolarization, suggesting that ACT1 is also a p63 and p73 putative yeast target gene. Additionally, MDM2 and MDMX inhibited the activity of all tested p53 family members in yeast, although the effect was weaker on TAp63. Moreover, Nutlin-3a and SJ-172550 were identified as potential inhibitors of the p73 interaction with MDM2 and MDMX, respectively. Altogether, the yeast-based assays herein developed can be envisaged as a simplified cell system to study the involvement of p53 family members in autophagy, the modulation of their activities by specific interactors (MDM2 and MDMX), and the potential of new small molecules to modulate these interactions. - Highlights: • p53, p63 and p73 are individually studied in the yeast S. cerevisiae. • p53 family members induce ROS production, cell cycle arrest and autophagy in yeast. • p53 family members increase actin depolarization and expression levels in yeast. • MDM2 and MDMX inhibit the activity of p53 family members in yeast. • Yeast can be a useful tool to study the biology and drugability of p53, p63 and p73.

  16. A systematic review of trismus induced by cancer therapies in head and neck cancer patients.

    Science.gov (United States)

    Bensadoun, Rene-Jean; Riesenbeck, Dorothea; Lockhart, Peter B; Elting, Linda S; Spijkervet, Fred K L; Brennan, Mike T

    2010-08-01

    This systematic review represents a thorough evaluation of the literature to clarify the impact of cancer therapies on the prevalence, quality of life and economic impact, and management strategies for cancer-therapy-induced trismus. A systematic literature search was conducted with assistance from a research librarian in the databases MEDLINE/PubMed and EMBASE for articles published between January 1, 1990 and December 31, 2008. Each study was independently assessed by two reviewers. Taking into account predetermined quality measures, a weighted prevalence was calculated for the prevalence of trismus. The level of evidence, recommendation grade, and guideline (if possible) were given for published preventive and management strategies for trismus. We reviewed a total of 22 published studies between 1990 and 2008. Most of them assessed the prevalence of this complication, and few focused on management. The weighted prevalence for trismus was 25.4% in patients who received conventional radiotherapy and 5% for the few intensity-modulated radiation therapy studies. No clear guideline recommendations could be made for the prevention or management of trismus. Newer radiation modalities may decrease the prevalence of trismus compared to conventional radiotherapy. Few studies have addressed the quality of life impact of trismus, and no studies were identified to assess the economic impact of trismus. The few preventive and management trials identified in the literature showed some promise, although larger, well-designed studies are required to appropriately assess these therapies before recommendations can be provided.

  17. Hypoxia-Inducible Regulation of a Prodrug-Activating Enzyme for Tumor-Specific Gene Therapy

    Directory of Open Access Journals (Sweden)

    Toru Shibata

    2002-01-01

    Full Text Available Previous studies have suggested that tumor hypoxia could be exploited for cancer gene therapy. Using hypoxia-responsive elements derived from the human vascular endothelial growth factor gene, we have generated vectors expressing a bacterial nitroreductase. (20NTR gene that can activate the anticancer prodrug CB1954. Stable transfectants of human HT1080 tumor cells with hypoxia-inducible vectors were established with G418 selection. Hypoxic induction of NTR protein correlated with increased sensitivity to in vitro exposure of HT 1080 cells to the prodrug. Growth delay assays were performed with established tumor xenografts derived from the same cells to detect the in vivo efficacy of CB1954 conversion to its cytotoxic form. Significant antitumor effects were achieved with intraperitoneal injections of CB1954 both in tumors that express NTR constitutively or with a hypoxia-inducible promoter. In addition, respiration of 10% O2 increased tumor hypoxia in vivo and enhanced the antitumor effects. Taken together, these results demonstrate that hypoxia-inducible vectors may be useful for tumor-selective gene therapy, although the problem of delivery of the vector to the tumors, particularly to the hypoxic cells in the tumors, is not addressed by these studies.

  18. Novel Oral Therapies for Opioid-induced Bowel Dysfunction in Patients with Chronic Noncancer Pain.

    Science.gov (United States)

    Holder, Renee M; Rhee, Diane

    2016-03-01

    Opioid analgesics are frequently prescribed and play an important role in chronic pain management. Opioid-induced bowel dysfunction, which includes constipation, hardened stool, incomplete evacuation, gas, and nausea and vomiting, is the most common adverse event associated with opioid use. Mu-opioid receptors are specifically responsible for opioid-induced bowel dysfunction, resulting in reduced peristaltic and secretory actions. Agents that reverse these actions in the bowel without reversing pain control in the central nervous system may be preferred over traditional laxatives. The efficacy and safety of these agents in chronic noncancer pain were assessed from publications identified through Ovid and PubMed database searches. Trials that evaluated the safety and efficacy of oral agents for opioid-induced constipation or opioid-induced bowel dysfunction, excluding laxatives, were reviewed. Lubiprostone and naloxegol are approved in the United States by the Food and Drug Administration for use in opioid-induced constipation. Axelopran (TD-1211) and sustained-release naloxone have undergone phase 2 and phase 1 studies, respectively, for the same indication. Naloxegol and axelopran are peripherally acting μ-opioid receptor antagonists. Naloxone essentially functions as a peripherally acting μ-opioid receptor antagonist when administered orally in a sustained-release formulation. Lubiprostone is a locally acting chloride channel (CIC-2) activator that increases secretions and peristalsis. All agents increase spontaneous bowel movements and reduce other bowel symptoms compared with placebo in patients with noncancer pain who are chronic opioid users. The most common adverse events were gastrointestinal in nature, and none of the drugs were associated with severe adverse or cardiovascular events. Investigations comparing these agents to regimens using standard laxative and combination therapy and trials in special populations and patients with active cancer are

  19. Early and individualized goal-directed therapy for trauma-induced coagulopathy

    Directory of Open Access Journals (Sweden)

    Schöchl Herbert

    2012-02-01

    Full Text Available Abstract Severe trauma-related bleeding is associated with high mortality. Standard coagulation tests provide limited information on the underlying coagulation disorder. Whole-blood viscoelastic tests such as rotational thromboelastometry or thrombelastography offer a more comprehensive insight into the coagulation process in trauma. The results are available within minutes and they provide information about the initiation of coagulation, the speed of clot formation, and the quality and stability of the clot. Viscoelastic tests have the potential to guide coagulation therapy according to the actual needs of each patient, reducing the risks of over- or under-transfusion. The concept of early, individualized and goal-directed therapy is explored in this review and the AUVA Trauma Hospital algorithm for managing trauma-induced coagulopathy is presented.

  20. The Effects of Massage Therapy to Induce Sleep in Infants Born Preterm

    Science.gov (United States)

    Yates, Charlotte C.; Mitchell, Anita J.; Booth, Melissa Y.; Williams, D. Keith; Lowe, Leah M.; Hall, Richard Whit

    2014-01-01

    Purpose The aim of this study was to determine if massage therapy can be used as an adjunct intervention to induce sleep in infants born preterm. Methods Thirty infants born at a minimum of 28 weeks gestational age (GA), who were at the time of the study between 32-48 weeks adjusted GA, were randomly assigned to receive massage therapy on 1 day and not receive massage on an alternate day. The Motionlogger® Micro Sleep Watch® Actigraph recorded lower extremity activity on the morning of each day. Results No significant difference was found between groups for sleep efficiency (P=.13) for the time period evaluated. Groups differed significantly during the time period after the massage ended with more infants sleeping on the non-massage day (Χ2= 4.9802, P=.026). Conclusions Massage is well tolerated in infants born preterm and infants do not fall asleep faster after massage than without massage. PMID:25251794

  1. Early and individualized goal-directed therapy for trauma-induced coagulopathy

    Science.gov (United States)

    2012-01-01

    Severe trauma-related bleeding is associated with high mortality. Standard coagulation tests provide limited information on the underlying coagulation disorder. Whole-blood viscoelastic tests such as rotational thromboelastometry or thrombelastography offer a more comprehensive insight into the coagulation process in trauma. The results are available within minutes and they provide information about the initiation of coagulation, the speed of clot formation, and the quality and stability of the clot. Viscoelastic tests have the potential to guide coagulation therapy according to the actual needs of each patient, reducing the risks of over- or under-transfusion. The concept of early, individualized and goal-directed therapy is explored in this review and the AUVA Trauma Hospital algorithm for managing trauma-induced coagulopathy is presented. PMID:22364525

  2. Mesenchymal Stem Cells and Induced Pluripotent Stem Cells as Therapies for Multiple Sclerosis

    Directory of Open Access Journals (Sweden)

    Juan Xiao

    2015-04-01

    Full Text Available Multiple sclerosis (MS is a chronic, autoimmune, inflammatory demyelinating disorder of the central nervous system that leads to permanent neurological deficits. Current MS treatment regimens are insufficient to treat the irreversible neurological disabilities. Tremendous progress in the experimental and clinical applications of cell-based therapies has recognized stem cells as potential candidates for regenerative therapy for many neurodegenerative disorders including MS. Mesenchymal stem cells (MSC and induced pluripotent stem cell (iPSCs derived precursor cells can modulate the autoimmune response in the central nervous system (CNS and promote endogenous remyelination and repair process in animal models. This review highlights studies involving the immunomodulatory and regenerative effects of mesenchymal stem cells and iPSCs derived cells in animal models, and their translation into immunomodulatory and neuroregenerative treatment strategies for MS.

  3. Seeking optimal management for radioactive iodine therapy-induced adverse effects

    Directory of Open Access Journals (Sweden)

    Andreas Charalambous

    2017-01-01

    Full Text Available Radioactive iodine therapy (RAIT is one of the important treatment modalities in the management of differentiated thyroid cancer (DTC. RAIT with iodine-131 has long been used in the management of DTC for the ablation of residual thyroid or treatment of its metastases. Despite being reasonably safe, radioiodine therapy is not always without side effects. Even relatively low administered activities of RAIT used for remnant ablation have been associated with the more clinically significant side effects of sialadenitis, xerostomia, salivary gland pain and swelling, dry eyes, excessive tearing, or alterations in taste in as many as 25% of patients. Given that there is a lack of comprehensive management of these RAIT-induced adverse effects, this paper explores the use of other nonpharmacological measures and their effectiveness as interventions to minimize salivary gland damage.

  4. Salt-induced aggregation of gold nanoparticles for photoacoustic imaging and photothermal therapy of cancer

    Science.gov (United States)

    Sun, Mengmeng; Liu, Fei; Zhu, Yukun; Wang, Wansheng; Hu, Jin; Liu, Jing; Dai, Zhifei; Wang, Kun; Wei, Yen; Bai, Jing; Gao, Weiping

    2016-02-01

    The challenge in photothermal therapy (PTT) is to develop biocompatible photothermal transducers that can absorb and convert near-infrared (NIR) light into heat with high efficiency. Herein, we report salt-induced aggregation of gold nanoparticles (GNPs) in biological media to form highly efficient and biocompatible NIR photothermal transducers for PTT and photothermal/photoacoustic (PT/PA) imaging of cancer. The GNP depots in situ formed by salt-induced aggregation of GNPs show strong NIR absorption induced by plasmonic coupling between adjacent GNPs and very high photothermal conversion efficiency (52%), enabling photothermal destruction of tumor cells. More interestingly, GNPs in situ aggregate in tumors to form GNP depots, enabling simultaneous PT/PA imaging and PTT of the tumors. These findings may provide a simple and effective way to develop a new class of intelligent and biocompatible NIR photothermal transducers with high efficiency for PT/PA imaging and PTT.The challenge in photothermal therapy (PTT) is to develop biocompatible photothermal transducers that can absorb and convert near-infrared (NIR) light into heat with high efficiency. Herein, we report salt-induced aggregation of gold nanoparticles (GNPs) in biological media to form highly efficient and biocompatible NIR photothermal transducers for PTT and photothermal/photoacoustic (PT/PA) imaging of cancer. The GNP depots in situ formed by salt-induced aggregation of GNPs show strong NIR absorption induced by plasmonic coupling between adjacent GNPs and very high photothermal conversion efficiency (52%), enabling photothermal destruction of tumor cells. More interestingly, GNPs in situ aggregate in tumors to form GNP depots, enabling simultaneous PT/PA imaging and PTT of the tumors. These findings may provide a simple and effective way to develop a new class of intelligent and biocompatible NIR photothermal transducers with high efficiency for PT/PA imaging and PTT. Electronic supplementary

  5. Serratia marcescens Is Able to Survive and Proliferate in Autophagic-Like Vacuoles inside Non-Phagocytic Cells

    Science.gov (United States)

    Colombo, María Isabel; García Véscovi, Eleonora

    2011-01-01

    Serratia marcescens is an opportunistic human pathogen that represents a growing problem for public health, particularly in hospitalized or immunocompromised patients. However, little is known about factors and mechanisms that contribute to S. marcescens pathogenesis within its host. In this work, we explore the invasion process of this opportunistic pathogen to epithelial cells. We demonstrate that once internalized, Serratia is able not only to persist but also to multiply inside a large membrane-bound compartment. This structure displays autophagic-like features, acquiring LC3 and Rab7, markers described to be recruited throughout the progression of antibacterial autophagy. The majority of the autophagic-like vacuoles in which Serratia resides and proliferates are non-acidic and have no degradative properties, indicating that the bacteria are capable to either delay or prevent fusion with lysosomal compartments, altering the expected progression of autophagosome maturation. In addition, our results demonstrate that Serratia triggers a non-canonical autophagic process before internalization. These findings reveal that S. marcescens is able to manipulate the autophagic traffic, generating a suitable niche for survival and proliferation inside the host cell. PMID:21901159

  6. Robot-assisted mechanical therapy attenuates stroke-induced limb skeletal muscle injury.

    Science.gov (United States)

    Sen, Chandan K; Khanna, Savita; Harris, Hallie; Stewart, Richard; Balch, Maria; Heigel, Mallory; Teplitsky, Seth; Gnyawali, Surya; Rink, Cameron

    2017-03-01

    The efficacy and optimization of poststroke physical therapy paradigms is challenged in part by a lack of objective tools available to researchers for systematic preclinical testing. This work represents a maiden effort to develop a robot-assisted mechanical therapy (RAMT) device to objectively address the significance of mechanical physiotherapy on poststroke outcomes. Wistar rats were subjected to right hemisphere middle-cerebral artery occlusion and reperfusion. After 24 h, rats were split into control (RAMT-) or RAMT+ groups (30 min daily RAMT over the stroke-affected gastrocnemius) and were followed up to poststroke d 14. RAMT+ increased perfusion 1.5-fold in stroke-affected gastrocnemius as compared to RAMT- controls. Furthermore, RAMT+ rats demonstrated improved poststroke track width (11% wider), stride length (21% longer), and travel distance (61% greater), as objectively measured using software-automated testing platforms. Stroke injury acutely increased myostatin (3-fold) and lowered brain-derived neurotrophic factor (BDNF) expression (0.6-fold) in the stroke-affected gastrocnemius, as compared to the contralateral one. RAMT attenuated the stroke-induced increase in myostatin and increased BDNF expression in skeletal muscle. Additional RAMT-sensitive myokine targets in skeletal muscle (IL-1ra and IP-10/CXCL10) were identified from a cytokine array. Taken together, outcomes suggest stroke acutely influences signal transduction in hindlimb skeletal muscle. Regimens based on mechanical therapy have the clear potential to protect hindlimb function from such adverse influence.-Sen, C. K., Khanna, S., Harris, H., Stewart, R., Balch, M., Heigel, M., Teplitsky, S., Gnyawali, S., Rink, C. Robot-assisted mechanical therapy attenuates stroke-induced limb skeletal muscle injury. © FASEB.

  7. Inhibition of autophagy induced by TSA sensitizes colon cancer cell to radiation.

    Science.gov (United States)

    He, Gang; Wang, Yan; Pang, Xueli; Zhang, Bo

    2014-02-01

    Radiotherapy is one of the main treatments for clinical cancer therapy. However, its application was limited due to lack of radiosensitivity in some cancers. Trichostatin A (TSA) is a classic histone deacetylases inhibitor (HDACi) that specifically inhibits the biochemical functions of HDAC and is demonstrated to be an active anticancer drug. However, whether it could sensitize colon cancer to radiation is not clear. Our results showed that TSA enhanced the radiosensitivity of colon cancer cells as determined by CCK-8 and clonogenic survival assay. Moreover, apoptotic cell death induced by radiation was enhanced by TSA treatment. Additionally, TSA also induced autophagic response in colon cancer cells, while autophagy inhibition led to cell apoptosis and enhanced the radiosensitivity of colon cancer cells. Our data suggested that inhibition of cytoprotective autophagy sensitizes cancer cell to radiation, which might be further investigated for clinical cancer radiotherapy.

  8. Low Level Laser Therapy Reduces the Development of Lung Inflammation Induced by Formaldehyde Exposure.

    Directory of Open Access Journals (Sweden)

    Cristiane Miranda da Silva

    Full Text Available Lung diseases constitute an important public health problem and its growing level of concern has led to efforts for the development of new therapies, particularly for the control of lung inflammation. Low Level Laser Therapy (LLLT has been highlighted as a non-invasive therapy with few side effects, but its mechanisms need to be better understood and explored. Considering that pollution causes several harmful effects on human health, including lung inflammation, in this study, we have used formaldehyde (FA, an environmental and occupational pollutant, for the induction of neutrophilic lung inflammation. Our objective was to investigate the local and systemic effects of LLLT after FA exposure. Male Wistar rats were exposed to FA (1% or vehicle (distillated water during 3 consecutive days and treated or not with LLLT (1 and 5 hours after each FA exposure. Non-manipulated rats were used as control. 24 h after the last FA exposure, we analyzed the local and systemic effects of LLLT. The treatment with LLLT reduced the development of neutrophilic lung inflammation induced by FA, as observed by the reduced number of leukocytes, mast cells degranulated, and a decreased myeloperoxidase activity in the lung. Moreover, LLLT also reduced the microvascular lung permeability in the parenchyma and the intrapulmonary bronchi. Alterations on the profile of inflammatory cytokines were evidenced by the reduced levels of IL-6 and TNF-α and the elevated levels of IL-10 in the lung. Together, our results showed that LLLT abolishes FA-induced neutrophilic lung inflammation by a reduction of the inflammatory cytokines and mast cell degranulation. This study may provide important information about the mechanisms of LLLT in lung inflammation induced by a pollutant.

  9. Nanomaterial-induced autophagy: a new reversal MDR tool in cancer therapy?

    Science.gov (United States)

    Panzarini, Elisa; Dini, Luciana

    2014-08-04

    Most of the therapeutic strategies to counteract cancer imply killing of malignant cells. The most exploited cell death mechanism in cancer therapies is apoptosis, but recently, a lot of papers report that other mechanisms, mainly autophagy, could represent a new line of attack in the fight against cancer. One of the limitations for the effectiveness of the approved clinical treatments is the phenomenon of multidrug resistance (MDR) which enables the cancer cells to develop resistance to therapy, especially for chemotherapy. The MDR mechanisms include (a) decreased uptake of drug, (b) reduced intracellular drug concentration by efflux pumps, (c) altered cell cycle checkpoints, (d) altered drug targets, (e) increased metabolism of drugs, (f) induced emergency response genes to impair apoptotic pathway, and (g) altered drug detoxification. Great efforts have been made to reverse MDR. Currently, autophagy and nanosized drug delivery systems (DDSs) belonging to nanomaterials (NMs) provide alternative strategies to circumvent MDR. Nanosized DDSs are very promising tools to accumulate chemotherapeutics at targeting sites and control temporal and spatial drug release into tumor cells. On the other hand, autophagy could overrule drug resistance upon its activation by ensuring cell death via switching its prosurvival role to a prodeath one or by mediating the occurrence of cell death, i.e., apoptosis or necrosis. Likewise, the autophagy inhibition could counteract MDR by sensitizing the cells to anticancer molecules, i.e., Src family tyrosine kinase (SFK) inhibitors or 5-fluorouracil. Noteworthy, autophagy has been recently indicated to be a common cellular response to NMs, corroborating the fascinating idea of the exploitation of NM-induced autophagy in nanomedicine therapy. This review focuses on recently published literature about the relationship between MDR reversal and NMs or autophagy pointing to hypothesize a pivotal role of autophagy modulation induced by NMs in

  10. Connecting the Dots: Therapy-Induced Senescence and a Tumor-Suppressive Immune Microenvironment.

    Science.gov (United States)

    Vilgelm, Anna E; Johnson, C Andrew; Prasad, Nripesh; Yang, Jinming; Chen, Sheau-Chiann; Ayers, Gregory D; Pawlikowski, Jeff S; Raman, Dayanidhi; Sosman, Jeffrey A; Kelley, Mark; Ecsedy, Jeffrey A; Shyr, Yu; Levy, Shawn E; Richmond, Ann

    2016-06-01

    Tumor cell senescence is a common outcome of anticancer therapy. Here we investigated how therapy-induced senescence (TIS) affects tumor-infiltrating leukocytes (TILs) and the efficacy of immunotherapy in melanoma. Tumor senescence was induced by AURKA or CDK4/6 inhibitors (AURKAi, CDK4/6i). Transcriptomes of six mouse tumors with differential response to AURKAi were analyzed by RNA sequencing, and TILs were characterized by flow cytometry. Chemokine RNA and protein expression were determined by quantitative real-time polymerase chain reaction and enzyme-linked immunosorbent assay. Therapeutic response was queried in immunodeficient mice, in mice with CCL5-deficient tumors, and in mice cotreated with CD137 agonist to activate TILs. CCL5 expression in reference to TIS and markers of TILs was studied in human melanoma tumors using patient-derived xenografts (n = 3 patients, n = 3 mice each), in AURKAi clinical trial samples (n = 3 patients, before/after therapy), and in The Cancer Genome Atlas (n = 278). All statistical tests were two-sided. AURKAi response was associated with induction of the immune transcriptome (P = 3.5 x 10-29) while resistance inversely correlated with TIL numbers (Spearman r = -0.87, P tumors regressed, P = .01) and in mice bearing CCL5-deficient vs control tumors (P = .61 vs P = .02); however, AURKAi response was greatly enhanced in mice also receiving T-cell-activating immunotherapy (P tumors, CCL5 expression was also induced by AURKAi (P ≤ .02) and CDK4/6i (P = .01) and was associated with increased immune marker expression (P = 1.40 x 10-93). Senescent melanoma cells secret CCL5, which promotes recruitment of TILs. Combining TIS with immunotherapy that enhances tumor cell killing by TILs is a promising novel approach to improve melanoma outcomes. © The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

  11. Episcleritis Related to Drug-Induced Lupus Erythematosus following Infliximab Therapy: A Case Report

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    Irini P. Chatziralli

    2011-01-01

    Full Text Available Drug-induced lupus erythematosus is defined as a lupus-like syndrome temporally related to continuous drug exposure which resolves after discontinuation of the offending drug. Herein, we describe a patient with distinct clinical manifestations of anti-TNF-associated DILE related to infliximab therapy. The patient exhibited clinical and laboratory findings of lupus-like illnesses as well as ocular disorders, such as episcleritis. The main message is that the symptoms of DILE should not be overlooked, although sometimes other systematic conditions may underlie them. As a result, it is very important for the clinicians to evaluate the symptoms of DILE and manage appropriately these cases.

  12. Stevens-Johnson syndrome induced by combined treatment: carbamazepine and cranial radiation therapy. A case of EMDART?

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    Anna Waśkiel

    2017-07-01

    Full Text Available Introduction . In 1988, Delattre et al. described the first case of erythema multiforme associated with phenytoin and cranial radiation therapy. In 2004, Ahmed et al. coined the term EMPACT syndrome (Erythema Multiforme associated with Phenytoin And Cranial Radiation Therapy. Case report. A 61-year-old patient with glioblastoma was admitted to our hospital with mucosal and cutaneous involvement diagnosed as Stevens-Johnson syndrome induced by combined treatment consisting of carbamazepine and radiation therapy. The cutaneous and mucosal lesions were successfully treated with prednisone and discontinuation of carbamazepine, chemotherapy and radiation therapy. Conclusions. A discussion is ongoing in the literature about a possible association between radiation therapy, anticonvulsant treatment and Stevens-Johnson syndrome. We present a rare case of Stevens-Johnson syndrome induced by carbamazepine combined with radiation therapy and suggest a new acronym – EMDART (Erythema Multiforme associated with Drug And Radiation Therapy for the description of this entity, as a wider term compared to EMPACT. The newly suggested term includes all diseases in the spectrum of erythema multiforme (also Stevens-Johnson syndrome and toxic epidermal necrolysis induced by all drugs (not only phenytoin in association with radiation therapy in all locations.

  13. Ex-Vivo Uterine Environment (EVE Therapy Induced Limited Fetal Inflammation in a Premature Lamb Model.

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    Yuichiro Miura

    Full Text Available Ex-vivo uterine environment (EVE therapy uses an artificial placenta to provide gas exchange and nutrient delivery to a fetus submerged in an amniotic fluid bath. Development of EVE may allow us to treat very premature neonates without mechanical ventilation. Meanwhile, elevations in fetal inflammation are associated with adverse neonatal outcomes. In the present study, we analysed fetal survival, inflammation and pulmonary maturation in preterm lambs maintained on EVE therapy using a parallelised umbilical circuit system with a low priming volume.Ewes underwent surgical delivery at 115 days of gestation (term is 150 days, and fetuses were transferred to EVE therapy (EVE group; n = 5. Physiological parameters were continuously monitored; fetal blood samples were intermittently obtained to assess wellbeing and targeted to reference range values for 2 days. Age-matched animals (Control group; n = 6 were surgically delivered at 117 days of gestation. Fetal blood and tissue samples were analysed and compared between the two groups.Fetal survival time in the EVE group was 27.0 ± 15.5 (group mean ± SD hours. Only one fetus completed the pre-determined study period with optimal physiological parameters, while the other 4 animals demonstrated physiological deterioration or death prior to the pre-determined study end point. Significant elevations (p0.05 in surfactant protein mRNA expression level between the two groups.In this study, we achieved limited fetal survival using EVE therapy. Despite this, EVE therapy only induced a modest fetal inflammatory response and did not promote lung maturation. These data provide additional insight into markers of treatment efficacy for the assessment of future studies.

  14. Antimicrobial photodynamic therapy using chlorin e6 with halogen light for acne bacteria-induced inflammation.

    Science.gov (United States)

    Jeon, Yu-Mi; Lee, Hwan-Suk; Jeong, Dongjun; Oh, Hae-Keun; Ra, Kyu-Hwan; Lee, Mi-Young

    2015-03-01

    The present study was designed to evaluate the therapeutic potential of antimicrobial photodynamic therapy (PDT) using chlorin e6 with halogen light against acne bacteria-induced inflammation. Highly purified chlorin e6 (Ce6), as a second generation photosensitizer, was synthesized from Spirulina chlorophyll. To evaluate the antimicrobial property of Ce6-mediated PDT with halogen light, the broth microdilution method and two-color fluorescence assay were used. The free radicals generated upon irradiating Ce6 with halogen light were measured using 2,7-dichlorofluorescin diacetate. Propionibacterium acnes was intradermally injected into the left ear of the ICR mice, and the anti-inflammatory effect of Ce6-mediated PDT with halogen light was measured by the histological examination. The expressions of cyclooxygenase-2 (COX-2), inducible nitric oxide synthase (iNOS) as well as pro-inflammatory cytokines were also measured by Western blotting. Chlorin e6-mediated PDT with halogen light (30,000 lx) inactivated various skin bacteria, including P. acnes in a dose-dependent manner. The MIC99 value against P. acnes (KCTC3314) of Ce6 with light was >0.49 μg/ml, whereas the MIC99 for Ce6 alone was >31.25 μg/ml. Ce6-mediated PDT suppressed the expression of P. acnes-induced pro-inflammatory cytokines and iNOS, but not COX-2 in a mouse model. This study showed a remarkable therapeutic effect of chlorin e6-mediated PDT with halogen light against P. acnes-induced inflammation. Our results suggest for the first time the potential of Ce6-mediated PDT with halogen light as a more effective and safer alternative treatment to antibiotic therapy against pathogenic infections of the skin. Copyright © 2015 Elsevier Inc. All rights reserved.

  15. Radionuclides in radiation-induced bystander effect; may it share in radionuclide therapy?

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    Widel, M

    2017-01-01

    For many years in radiobiology and radiotherapy predominated the conviction that cellular DNA is the main target for ionizing radiation, however, the view has changed in the past 20 years. Nowadays, it is assumed that not only directed (targeted) radiation effect, but also an indirect (non-targeted) effect may contribute to the result of radiation treatment. Non-targeted effect is relatively well recognized after external beam irradiation in vitro and in vivo, and comprises such phenomena like radiation-induced bystander effect (RIBE), genomic instability, adaptive response and abscopal (out of field) effect. These stress-induced and molecular signaling mediated phenomena appear in non-targeted cells as variety responses resembling that observed in directly hit cells. Bystander effects can be both detrimental and beneficial in dependence on dose, dose-rate, cell type, genetic status and experimental condition. Less is known about radionuclide-induced non-targeted effects in radionuclide therapy, although, based on characteristics of the radionuclide radiation, on experiments in vitro utilizing classical and 3-D cell cultures, and preclinical study on animals it seems obvious that exposure to radionuclide is accompanied by various bystander effects, mostly damaging, less often protective. This review summarizes existing data on radionuclide induced bystander effects comprising radionuclides emitting beta- and alpha-particles and Auger electrons used in tumor radiotherapy and diagnostics. So far, separation of the direct effect of radionuclide decay from crossfire and bystander effects in clinical targeted radionuclide therapy is impossible because of the lack of methods to assess whether, and to what extent bystander effect is involved in human organism. Considerations on this topic are also included.

  16. Radiographic assessment of photodynamic therapy as an adjunctive treatment on induced periodontitis in immunosuppressed rats

    Science.gov (United States)

    FERNANDES, Leandro Araújo; MARTINS, Thiago Marchi; de ALMEIDA, Juliano Milanezi; THEODORO, Letícia Helena; GARCIA, Valdir Gouveia

    2010-01-01

    Objective The aim of this study was to assess radiographically the effect of photodynamic therapy (PDT) as an adjunctive treatment to scaling and root planing (SRP) on induced periodontitis in dexamethasone-induced immunosuppressed rats. Material and Methods The animals were divided into 2 groups: ND group (n=60): saline treatment; D group (n=60): dexamethasone treatment. In both ND and D groups, periodontal disease was induced by the placement of a ligature in the left first mandibular molar. After 7 days, ligature was removed and all animals received SRP, being divided according to the following treatments: SRP: saline and PDT: phenothiazinium dye (TBO) plus laser irradiation. Ten animals per treatment were killed at 7, 15 and 30 days. The distance between the cementoenamel junction and the height of the alveolar bone crest in the mesial surface of the mandibular left first molars was determined in millimeters in each radiograph. The radiographic values were analyzed statistically by ANOVA and Tukey's test at a p value periodontitis in dexamethasone-induced immunosuppressed rats. PMID:20857000

  17. Hyperbaric Oxygen Therapy Can Induce Angiogenesis and Regeneration of Nerve Fibers in Traumatic Brain Injury Patients

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    Sigal Tal

    2017-10-01

    Full Text Available Background: Recent clinical studies in stroke and traumatic brain injury (TBI victims suffering chronic neurological injury present evidence that hyperbaric oxygen therapy (HBOT can induce neuroplasticity.Objective: To assess the neurotherapeutic effect of HBOT on prolonged post-concussion syndrome (PPCS due to TBI, using brain microstructure imaging.Methods: Fifteen patients afflicted with PPCS were treated with 60 daily HBOT sessions. Imaging evaluation was performed using Dynamic Susceptibility Contrast-Enhanced (DSC and Diffusion Tensor Imaging (DTI MR sequences. Cognitive evaluation was performed by an objective computerized battery (NeuroTrax.Results: HBOT was initiated 6 months to 27 years (10.3 ± 3.2 years from injury. After HBOT, DTI analysis showed significantly increased fractional anisotropy values and decreased mean diffusivity in both white and gray matter structures. In addition, the cerebral blood flow and volume were increased significantly. Clinically, HBOT induced significant improvement in the memory, executive functions, information processing speed and global cognitive scores.Conclusions: The mechanisms by which HBOT induces brain neuroplasticity can be demonstrated by highly sensitive MRI techniques of DSC and DTI. HBOT can induce cerebral angiogenesis and improve both white and gray microstructures indicating regeneration of nerve fibers. The micro structural changes correlate with the neurocognitive improvements.

  18. Photodynamic therapy for the treatment of induced mammary tumor in rats.

    Science.gov (United States)

    Ferreira, Isabelle; Ferreira, Juliana; Vollet-Filho, José Dirceu; Moriyama, Lilian T; Bagnato, Vanderlei S; Salvadori, Daisy Maria Favero; Rocha, Noeme S

    2013-02-01

    The objective of this work was to evaluate photodynamic therapy (PDT) by using a hematoporphyrin derivative as a photosensitizer and light-emitting diodes (LEDs) as light source in induced mammary tumors of Sprague-Dawley (SD) rats. Twenty SD rats with mammary tumors induced by DMBA were used. Animals were divided into four groups: control (G1), PDT only (G2), surgical removal of tumor (G3), and submitted to PDT immediately after surgical removal of tumor (G4). Tumors were measured over 6 weeks. Lesions and surgical were LEDs lighted up (200 J/cm(2) dose). The light distribution in vivo study used two additional animals without mammary tumors. In the control group, the average growth of tumor diameter was approximately 0.40 cm/week. While for PDT group, a growth of less than 0.15 cm/week was observed, suggesting significant delay in tumor growth. Therefore, only partial irradiation of the tumors occurred with a reduction in development, but without elimination. Animals in G4 had no tumor recurrence during the 12 weeks, after chemical induction, when compared with G3 animals that showed 60 % recurrence rate after 12 weeks of chemical induction. PDT used in the experimental model of mammary tumor as a single therapy was effective in reducing tumor development, so the surgery associated with PDT is a safe and efficient destruction of residual tumor, preventing recurrence of the tumor.

  19. Neuroprotective effects of bee venom acupuncture therapy against rotenone-induced oxidative stress and apoptosis.

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    Khalil, Wagdy K B; Assaf, Naglaa; ElShebiney, Shaimaa A; Salem, Neveen A

    2015-01-01

    Parkinson's disease (PD), the most common neurodegenerative movement disorder, is characterized by dopaminergic neurodegeneration, mitochondrial impairment, and oxidative stress. Exposure of animals to rotenone induces a range of responses characteristic of PD, including reactive oxygen species production and dopaminergic cell death. Although l-dopa is the drug of choice for improving core symptoms of PD, it is associated with involuntary movements. The current study was directed to evaluate the neuroprotective effect of bee venom acupuncture therapy (BVA) against rotenone-induced oxidative stress, neuroinflammation, and apoptosis in PD mouse model. Forty male Swiss mice were divided into four groups: (1) received saline solution orally and served as normal control, (2) received rotenone (1.5 mg/kg, s.c. every other day for 6 doses), (3) received rotenone concomitantly with l-dopa (25 mg/kg, daily, p.o. for 6 days), and finally (4) received rotenone concomitantly with BVA (0.02 ml once every 3 days for two weeks). Rotenone-treated mice showed impairment in locomotor behavior and a significant reduction in brain dopamine, serotonin, norepinephrine, GSH levels, and paraoxonase activity, whereas a significant increase was observed in brain malondialdehyde, tumor necrosis factor-α, interleukin-β levels besides DNA damage, and over-expression of caspase-3, Bax, and Bcl-2 genes. Significant improvement of the aforementioned parameters was demonstrated after BVA compared to l-dopa therapy. In conclusion, bee venom normalized all the neuroinflammatory and apoptotic markers and restored brain neurochemistry after rotenone injury. Therefore, BVA is a promising neuroprotective therapy for PD. Copyright © 2014 Elsevier Ltd. All rights reserved.

  20. Pharmaco-induced vasospasm therapy for acute lower gastrointestinal bleeding: A preliminary report

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    Liang, Huei-Lung, E-mail: hlliang@vghks.gov.tw [Department of Radiology, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan (China); National Yang-Ming University, Taipei, Taiwan (China); Chiang, Chia-Ling [Department of Radiology, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan (China); Chen, Matt Chiung-Yu [Department of Radiology, Yuan' s General Hospital, Kaohsiung. Taiwan (China); Lin, Yih-Huie; Huang, Jer-Shyung; Pan, Huay-Ben [Department of Radiology, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan (China); National Yang-Ming University, Taipei, Taiwan (China)

    2014-10-15

    Purpose: To report a novel technique and preliminary clinical outcomes in managing lower gastrointestinal bleeding (LGIB). Materials and methods: Eighteen LGIB patients (11 men and 7 women, mean age: 66.2 years) were treated with artificially induced vasospasm therapy by semi-selective catheterization technique. Epinephrine bolus injection was used to initiate the vascular spasm, and followed by a small dose vasopressin infusion (3–5 units/h) for 3 h. The technical success, clinical success, recurrent bleeding and major complications of this study were evaluated and reported. Results: Sixteen bleeders were in the superior mesenteric artery and 2 in the inferior mesenteric artery. All patients achieved successful immediate hemostasis. Early recurrent bleeding (<30 days) was found in 4 patients with local and new-foci re-bleeding in 2 (11.1%) each. Repeated vasospasm therapy was given to 3 patients, with clinical success in 2. Technical success for the 21 bleeding episodes was 100%. Lesion-based and patient-based primary and overall clinical successes were achieved in 89.4% (17/19) and 77.7% (14/18), and 94.7% (18/19) and 88.8% (16/18), respectively. None of our patients had complications of bowel ischemia or other major procedure-related complications. The one year survival of our patients was 72.2 ± 10.6%. Conclusions: Pharmaco-induced vasospasm therapy seems to be a safe and effective method to treat LGIB from our small patient-cohort study. Further evaluation with large series study is warranted. Considering the advanced age and complex medical problems of these patients, this treatment may be considered as an alternative approach for interventional radiologists in management of LGIB.

  1. Clinical predictors of aminoglycoside-induced ototoxicity in drug-resistant Tuberculosis patients on intensive therapy.

    Science.gov (United States)

    Sogebi, Olusola Ayodele; Adefuye, Bolanle Olufunlola; Adebola, Stephen Oluwatosin; Oladeji, Susan Modupe; Adedeji, Taiwo Olugbemiga

    2017-08-01

    The study objectives were to determine the incidence of aminoglycoside-induced ototoxicity in institutionalized patients on intensive phase of therapy for drug-resistant Tuberculosis (DR Tb) and also to assess clinical factors which could predict the ototoxicity. The study was a prospective analytical study among consecutive DR Tb patients who were admitted for intensive phase of therapy (of 4 months) at the DR-Tb center over a 12-month period. Patients were diagnosed as DR Tb using the Gene Xpert machine to confirm Rifampicin resistance. All eligible 70 out of 87 consenting patients were consecutively recruited into the study. Patients had baseline (admission) and serial pure tone audiometries (PTAs) performed at 4 weekly intervals until discharge after 4 months of admission. Audiometric confirmation of aminoglycoside-induced ototoxicity was done by comparing serial with baseline PTA. Among the 70 patients the male:female ratio was 1.7:1. Nine patients (12.9%) were retroviral-positive, and 16 patients (22.9%) were confirmed to have ototoxicity by audiometric criteria. The duration of treatment when ototoxicity was detected in the patients ranged 4-17 (Mean±SD; 9.4±3.4) weeks. Ototoxicity was detected in the audiometric low frequency ranges in 7 (43.8%) and at the high frequencies in 4 (25.0%) of the patients. Univariate analyses of clinical parameters found that age, underlying diabetes mellitus, deranged baseline PTAv >25dB HL, BMI on admission and retroviral status were significantly associated, while sex and previous drug regimen failure were not associated with ototoxicity. Multivariate adjusted logistic regression analyses, controlling for sex, revealed age (OR=1.068, p=0.018), BMI on admission (OR=0.673, p=0.012) and retroviral positivity (OR=8.822, p=0.014) of patients could significantly predict aminoglycoside-induced ototoxicity. Incidence of aminoglycoside-induced ototoxicity in DR Tb patients was 22.9%. The clinical predictors for ototoxicity were age

  2. Thrombin preferentially induces autophagy in glia cells in the rat central nervous system.

    Science.gov (United States)

    Hu, Shukun; Wu, Gang; Ding, Xin; Zhang, Yi

    2016-09-06

    Autophagy widely occurs after intracerebral hemorrhage (ICH). In our previous study, we demonstrated that thrombin, a serine protease produced after hematoma, contributes to ICH-induced autophagy. However, whether thrombin plays a neuronal and/or astrocytic role in autophagy induction is largely unknown. Here, we examined the autophagic role of thrombin on neurons and glia cells, respectively. In vivo, we found that intracaudate injection of thrombin specifically elevated the astrocytic expression of beclin-1 and LC3, two autophagic markers, and promoted the formation of autophagic vacuoles within astrocytes rather than neurons in the ipsilateral basal ganglia. Consistent with this, thrombin enhanced the LC3-II level and increased the number of MDC-labeled autophagic vacuoles in cultured astrocytes. These results indicated that thrombin preferentially activated astrocytic autophagy after ICH, and therefore provided novel insights into the pathophysiological mechanisms and therapeutic targets for hemorrhage stroke and brain trauma. Copyright © 2016. Published by Elsevier Ireland Ltd.

  3. Porphyromonas gingivalis induces autophagy in THP-1-derived macrophages.

    Science.gov (United States)

    Park, M H; Jeong, S Y; Na, H S; Chung, J

    2017-02-01

    Autophagy provides a mechanism for the turnover of cellular organelles and proteins through a lysosome-dependent degradation pathway and is a possible mechanism in inflammatory disease. Periodontitis is an inflammatory disease caused by periodontal pathogens. Porphyromonas gingivalis, an important periodontal pathogen, activates cellular autophagy to provide a replicative niche while suppressing apoptosis in endothelial cells. However, the molecular basis for a causal relationship between P. gingivalis and autophagy is unclear. This research examines the involvement of P. gingivalis in autophagy through light chain 3 (LC3) and autophagic proteins, and the role of P. gingivalis-induced autophagy in the clearance of P. gingivalis and inflammation. To investigate the molecular mechanism of autophagy induced by P. gingivalis, PMA-differentiated THP-1-derived macrophages were infected with live P. gingivalis. The P. gingivalis increased the formation of autophagosomes in a multiplicity of infection-dependent manner, as well as autophagolysosomes. Porphyromonas gingivalis activated LC3-I/LC3-II conversion and increased the conjugation of autophagy-related 5 (ATG5) -ATG12 and the expression of Beclin1. The expressions of Beclin1, ATG5-ATG12 conjugate, and LC3-II were significantly inhibited by the presence of 3-methyladenine, an autophagy inhibitor. Interestingly, 3-methyladenine increased the survival of P. gingivalis and proinflammatory cytokine interleukin-1β production. The data indicate that P. gingivalis induces autophagy in PMA-differentiated THP-1-derived macrophages and in turn, macrophages eliminate P. gingivalis through an autophagic response, which can lead to the restriction of an excessive inflammatory response by downregulating interleukin-1β production. The induction of autophagy by P. gingivalis may play an important role in the periodontal inflammatory process and serve as a target for the development of new therapies. © 2016 John Wiley

  4. The Effects of Modified Constraint-Induced Movement Therapy in Acute Subcortical Cerebral Infarction

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    Changshen Yu

    2017-05-01

    Full Text Available Background: Constraint-induced movement therapy (CIMT promotes upper extremity recovery post stroke, however, it is difficult to implement clinically due to its high resource demand and safety of the restraint. Therefore, we propose that modified CIMT (mCIMT be used to treat individuals with acute subcortical infarction.Objective: To evaluate the therapeutic effects of mCIMT in patients with acute subcortical infarction, and investigate the possible mechanisms underlying the effect.Methods: The role of mCIMT was investigated in 26 individuals experiencing subcortical infarction in the preceding 14 days. Patients were randomly assigned to either mCIMT or standard therapy. mCIMT group was treated daily for 3 h over 10 consecutive working days, using a mitt on the unaffected arm for up to 30% of waking hours. The control group was treated with an equal dose of occupational therapy and physical therapy. During the 3-month follow-up, the motor functions of the affected limb were assessed by the Wolf Motor Function Test (WMFT and Motor Activity Log (MAL. Altered cortical excitability was assessed via transcranial magnetic stimulation (TMS.Results: Treatment significantly improved the movement in the mCIMT group compared with the control group. The mean WMF score was significantly higher in the mCIMT group compared with the control group. Further, the appearance of motor-evoked potentials (MEPs were significantly higher in the mCIMT group compared with the baseline data. A significant change in ipsilesional silent period (SP occurred in the mCIMT group compared with the control group. However, we found no difference between two groups in motor function or electrophysiological parameters after 3 months of follow-up.Conclusions: mCIMT resulted in significant functional changes in timed movement immediately following treatment in patients with acute subcortical infarction. Further, early mCIMT improved ipsilesional cortical excitability. However, no long

  5. BEMER Electromagnetic Field Therapy Reduces Cancer Cell Radioresistance by Enhanced ROS Formation and Induced DNA Damage.

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    Katja Storch

    Full Text Available Each year more than 450,000 Germans are expected to be diagnosed with cancer subsequently receiving standard multimodal therapies including surgery, chemotherapy and radiotherapy. On top, molecular-targeted agents are increasingly administered. Owing to intrinsic and acquired resistance to these therapeutic approaches, both the better molecular understanding of tumor biology and the consideration of alternative and complementary therapeutic support are warranted and open up broader and novel possibilities for therapy personalization. Particularly the latter is underpinned by the increasing utilization of non-invasive complementary and alternative medicine by the population. One investigated approach is the application of low-dose electromagnetic fields (EMF to modulate cellular processes. A particular system is the BEMER therapy as a Physical Vascular Therapy for which a normalization of the microcirculation has been demonstrated by a low-frequency, pulsed EMF pattern. Open remains whether this EMF pattern impacts on cancer cell survival upon treatment with radiotherapy, chemotherapy and the molecular-targeted agent Cetuximab inhibiting the epidermal growth factor receptor. Using more physiological, three-dimensional, matrix-based cell culture models and cancer cell lines originating from lung, head and neck, colorectal and pancreas, we show significant changes in distinct intermediates of the glycolysis and tricarboxylic acid cycle pathways and enhanced cancer cell radiosensitization associated with increased DNA double strand break numbers and higher levels of reactive oxygen species upon BEMER treatment relative to controls. Intriguingly, exposure of cells to the BEMER EMF pattern failed to result in sensitization to chemotherapy and Cetuximab. Further studies are necessary to better understand the mechanisms underlying the cellular alterations induced by the BEMER EMF pattern and to clarify the application areas for human disease.

  6. BEMER Electromagnetic Field Therapy Reduces Cancer Cell Radioresistance by Enhanced ROS Formation and Induced DNA Damage.

    Science.gov (United States)

    Storch, Katja; Dickreuter, Ellen; Artati, Anna; Adamski, Jerzy; Cordes, Nils

    2016-01-01

    Each year more than 450,000 Germans are expected to be diagnosed with cancer subsequently receiving standard multimodal therapies including surgery, chemotherapy and radiotherapy. On top, molecular-targeted agents are increasingly administered. Owing to intrinsic and acquired resistance to these therapeutic approaches, both the better molecular understanding of tumor biology and the consideration of alternative and complementary therapeutic support are warranted and open up broader and novel possibilities for therapy personalization. Particularly the latter is underpinned by the increasing utilization of non-invasive complementary and alternative medicine by the population. One investigated approach is the application of low-dose electromagnetic fields (EMF) to modulate cellular processes. A particular system is the BEMER therapy as a Physical Vascular Therapy for which a normalization of the microcirculation has been demonstrated by a low-frequency, pulsed EMF pattern. Open remains whether this EMF pattern impacts on cancer cell survival upon treatment with radiotherapy, chemotherapy and the molecular-targeted agent Cetuximab inhibiting the epidermal growth factor receptor. Using more physiological, three-dimensional, matrix-based cell culture models and cancer cell lines originating from lung, head and neck, colorectal and pancreas, we show significant changes in distinct intermediates of the glycolysis and tricarboxylic acid cycle pathways and enhanced cancer cell radiosensitization associated with increased DNA double strand break numbers and higher levels of reactive oxygen species upon BEMER treatment relative to controls. Intriguingly, exposure of cells to the BEMER EMF pattern failed to result in sensitization to chemotherapy and Cetuximab. Further studies are necessary to better understand the mechanisms underlying the cellular alterations induced by the BEMER EMF pattern and to clarify the application areas for human disease.

  7. Constraint-Induced Aphasia Therapy in the Acute Stage: What Is the Key Factor for Efficacy? A Randomized Controlled Study.

    Science.gov (United States)

    Woldag, Hartwig; Voigt, Nancy; Bley, Maria; Hummelsheim, Horst

    2017-01-01

    Constraint-induced aphasia therapy (CIAT) has proven effective in patients with subacute and chronic forms of aphasia. It has remained unclear, however, whether intensity of therapy or constraint is the relevant factor. Data about intensive speech and language therapy (SLT) are conflicting. To identify the effective component of CIAT and assess the feasibility of SLT in the acute stage after stroke. A total of 60 patients with aphasia (68.2 ± 11.7 years) were enrolled 18.9 days after first-ever stroke. They were randomly distributed into 3 groups: (1) CIAT group receiving therapy for 3 hours per day (10 workdays, total 30 hours); (2) conventional communication treatment group, with same intensity without constraints; and (3) control group receiving individual therapy twice a day as well as group therapy (total 14 hours). Patients were assessed pretreatment and posttreatment using the Aachener Aphasia Test (primary end point: token test) and the Communicative Activity Log (CAL). Pretreatment, there were no between-group differences. Posttreatment, all groups showed significant improvements without between-group differences. It was found that 14 hours of aphasia therapy administered within 2 weeks as individual therapy, focusing on individual deficits, combined with group sessions has proven to be most efficient. This approach yielded the same outcome as 30 hours of group therapy, either in the form of CIAT or group therapy without constraints. SLT in an intensive treatment schedule is feasible and was well tolerated in the acute stage after stroke. © The Author(s) 2016.

  8. Acid-activatable oxidative stress-inducing polysaccharide nanoparticles for anticancer therapy.

    Science.gov (United States)

    Yoo, Wooyoung; Yoo, Donghyuck; Hong, Eunmi; Jung, Eunkyeong; Go, Yebin; Singh, S V Berwin; Khang, Gilson; Lee, Dongwon

    2018-01-10

    Drug delivery systems have been extensively developed to enhance the therapeutic efficacy of drugs by altering their pharmacokinetics and biodistribution. However, the use of high quantities of drug delivery systems can cause toxicity due to their poor metabolism and elimination. In this study, we developed polysaccharide-based drug delivery systems which exert potent therapeutic effects and could display synergistic therapeutic effects with drug payloads, leading to dose reduction. Cinnamaldehyde, a major component of cinnamon is known to induce anticancer activity by generating ROS (reactive oxygen species). We developed cinnamaldehyde-conjugated maltodextrin (CMD) as a polymeric prodrug of cinnamaldehyde and a drug carrier. Cinnamaldehyde was conjugated to the hydroxyl groups of maltodextrin via acid-cleavable acetal linkages, allowing facile formulation of nanoparticles and drug encapsulation. CMD nanoparticles induced acid-triggered ROS generation to induce apoptotic cell death. Camptothecin (CPT) was used as a model drug to investigate the potential of CMD nanoparticles as a drug carrier and also evaluate the synergistic anticancer effects with CMD nanoparticles. CPT-loaded CMD nanoparticles exhibited significantly higher anticancer activity than empty CMD nanoparticles and CPT alone in the study of mouse xenograft models, demonstrating the synergistic therapeutic effects of CMD with CPT. Taken together, we believe that CMD nanoparticles hold tremendous potential as a polymeric prodrug of cinnamaldehyde and a drug carrier in anticancer therapy. Copyright © 2017 Elsevier B.V. All rights reserved.

  9. Radiation-induced myocardial perfusion abnormalities in breast cancer patients following external beam radiation therapy

    Directory of Open Access Journals (Sweden)

    Mohammad Eftekhari

    2015-01-01

    Full Text Available Objective(s: Radiation therapy for breast cancer can induce myocardial capillary injury and increase cardiovascular morbidity and mortality. A prospective cohort was conducted to study the prevalence of myocardial perfusion abnormalities following radiation therapy of left-sided breast cancer patients as compared to those with right–sided cancer. Methods: To minimize potential confounding factors, only those patients with low 10-year risk of coronary artery disease (based on Framingham risk scoring were included. All patients were initially treated by modified radical mastectomy and then were managed by postoperative 3D Conformal Radiation Therapy (CRT to the surgical bed with an additional 1-cm margin, delivered by 46-50 Gy (in 2 Gy daily fractions over a 5-week course. The same dose-adjusted chemotherapy regimen (including anthracyclines, cyclophosphamide and taxol was given to all patients. Six months after radiation therapy, all patients underwent cardiac SPECT for the evaluation of myocardial perfusion. Results: A total of 71 patients with a mean age of 45.3±7.2 years [35 patients with leftsided breast cancer (exposed and 36 patients with right-sided cancer (controls] were enrolled. Dose-volume histogram (DVH [showing the percentage of the heart exposed to >50% of radiation] was significantly higher in patients with left-sided breast cancer. Visual interpretation detected perfusion abnormalities in 42.9% of cases and 16.7% of controls (P=0.02, Odds ratio=1.46. In semiquantitative segmental analysis, only apical (28.6% versus 8.3%, P=0.03 and anterolateral (17.1% versus 2.8%, P=0.049 walls showed significantly reduced myocardial perfusion in the exposed group. Summed Stress Score (SSS of>3 was observed in twelve cases (34.3%, while in five of the controls (13.9%,(Odds ratio=1.3. There was no significant difference between the groups regarding left ventricular ejection fraction. Conclusion: The risk of radiation induced myocardial

  10. Low Frequency Magnetic Fields Induce Autophagy-associated Cell Death in Lung Cancer through miR-486-mediated Inhibition of Akt/mTOR Signaling Pathway.

    Science.gov (United States)

    Xu, Yujun; Wang, Yizhong; Yao, Anran; Xu, Zhen; Dou, Huan; Shen, Sunan; Hou, Yayi; Wang, Tingting

    2017-09-18

    Low frequency magnetic fields (LF-MFs) can affect cell proliferation in a cell-type and intensity-dependent way. Previous study has reported the anti-tumor effect of LF-MFs in lung cancers. Our previous study also optimized the intensity and duration of LF-MFs to effectively inhibit the proliferation of lung cancer cells. However, the anti-tumor mechanism of LF-MFs remains unclear, which limit the clinical application of LF-MFs in anti-tumor therapy. Here, in a well-established Lewis Lung Cancer (LLC) mouse model, we found that LF-MFs inhibit tumor growth and induce an autophagic cell death in lung cancer. We also found that LF-MFs could up-regulate the expression level of miR-486, which was involved in LF-MFs activated cell autophagy. Furthermore, we found B-cell adaptor for phosphatidylinositol 3-kinase (BCAP) is a direct target of miR-486. miR-486 inhibit AKT/mTOR signaling through inhibiting expression of BCAP. Moreover, a decreased expression of miR-486 and an increased expression of BCAP were found in tumor tissues of lung cancer patients. Taken together, this study proved that LF-MFs can inhibit lung cancers through miR-486 induced autophagic cell death, which suggest a clinical application of LF-MFs in cancer treatment.

  11. Bobath Concept versus constraint-induced movement therapy to improve arm functional recovery in stroke patients: a randomized controlled trial.

    Science.gov (United States)

    Huseyinsinoglu, Burcu Ersoz; Ozdincler, Arzu Razak; Krespi, Yakup

    2012-08-01

    To compare the effects of the Bobath Concept and constraint-induced movement therapy on arm functional recovery among stroke patients with a high level of function on the affected side. A single-blinded, randomized controlled trial. Outpatient physiotherapy department of a stroke unit. A total of 24 patients were randomized to constraint-induced movement therapy or Bobath Concept group. The Bobath Concept group was treated for 1 hour whereas the constraint-induced movement therapy group received training for 3 hours per day during 10 consecutive weekdays. Main measures were the Motor Activity Log-28, the Wolf Motor Function Test, the Motor Evaluation Scale for Arm in Stroke Patients and the Functional Independence Measure. The two groups were found to be homogeneous based on demographic variables and baseline measurements. Significant improvements were seen after treatment only in the 'Amount of use' and 'Quality of movement' subscales of the Motor Activity Log-28 in the constraint-induced movement therapy group over the the Bobath Concept group (P = 0.003; P = 0.01 respectively). There were no significant differences in Wolf Motor Function Test 'Functional ability' (P = 0.137) and 'Performance time' (P = 0.922), Motor Evaluation Scale for Arm in Stroke Patients (P = 0.947) and Functional Independence Measure scores (P = 0.259) between the two intervention groups. Constraint-induced movement therapy and the Bobath Concept have similar efficiencies in improving functional ability, speed and quality of movement in the paretic arm among stroke patients with a high level of function. Constraint-induced movement therapy seems to be slightly more efficient than the Bobath Concept in improving the amount and quality of affected arm use.

  12. Effect of modified constraint induced movement therapy on weight bearing and protective extension in children with hemiplegic cerebral palsy

    Directory of Open Access Journals (Sweden)

    Masoud Gharib

    2012-01-01

    Full Text Available Background: Constraint induced movement therapy is one of the new therapeutic interventions that limits the performance of intact upper limb with increased use of the affected limb. Aim of this study was to investigate the effects of modified constraint induced movement therapy on weight bearing & protective extension in children with hemiplegic cerebral palsy.Methods: 21 hemiplegic children were selected and randomly divided into experimental and control groups. Common Practices of Occupational Therapy applied for 6 weeks in both groups equally and test group received constrain induced movement therapy for three hours every day. Weight-bearing and protective extension was measured based on quality of test skills of upper limbs (QUEST. Data analyzed using appropriated statistical methods. Results: 11 children in the experimental group (7 girls, 4 boys with mean age 47.2 ± 55.5 months and 10 children in the control group (5 girls, 5 boys with mean age 19.2 ± 10.5 months were studied. No significant difference observed before and after six weeks intervention between two groups (P>0.05. There was a significant change before and after six weeks intervention in both subscales (P<0.05.Conclusion: This study showed that modified constraint induced movement therapy may affect weight bearing, but has no effect on the protective extension.

  13. Short-term outcome of fluoroscopic-guided steroid injection therapy of lumber facet cyst-induced radicular pain

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    Kwon, Mi Ri; Kwon, Jong Won; Lee, Jong Seo; Kim, Eu Sang [Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul (Korea, Republic of)

    2015-04-15

    To determine the short-term effect of fluoroscopic-guided steroid injection therapy of lumbar facet cyst-induced radicular pain. Seventeen patients with radiculopathy due to lumbar synovial cysts, who were treated with fluoroscopically guided injection, were retrospectively evaluated. All plain radiographic images and MR images before the therapy were reviewed. Five patients underwent only the facet joint injection, whereas twelve patients underwent the facet joint injection with perineural injection therapy. The clinical course of pain was evaluated on the first follow-up after therapy. Effective pain relief was achieved in 11 (64.7%) of the 17 patients. Among 12 patients who underwent facet joint injection with perineural injection, 9 patients (75%) had an effective pain relief. Of 5 patients, 2 (40%) patients only took the facet joint injection and had an effective pain relief. Fluoroscopic-guided steroid injection therapy shows a good short-term effect in patients with symptomatic lumbar facet joint synovial cysts.

  14. Consensus Recommendations on Initiating Prescription Therapies for Opioid‐Induced Constipation

    Science.gov (United States)

    Argoff, Charles E.; Brennan, Michael J.; Camilleri, Michael; Davies, Andrew; Fudin, Jeffrey; Galluzzi, Katherine E.; Gudin, Jeffrey; Lembo, Anthony; Stanos, Steven P.

    2015-01-01

    Abstract Objective Aims of this consensus panel were to determine (1) an optimal symptom‐based method for assessing opioid‐induced constipation in clinical practice and (2) a threshold of symptom severity to prompt consideration of prescription therapy. Methods A multidisciplinary panel of 10 experts with extensive knowledge/experience with opioid‐associated adverse events convened to discuss the literature on assessment methods used for opioid‐induced constipation and reach consensus on each objective using the nominal group technique. Results Five validated assessment tools were evaluated: the Patient Assessment of Constipation–Symptoms (PAC‐SYM), Patient Assessment of Constipation–Quality of Life (PAC‐QOL), Stool Symptom Screener (SSS), Bowel Function Index (BFI), and Bowel Function Diary (BF‐Diary). The 3‐item BFI and 4‐item SSS, both clinician administered, are the shortest tools. In published trials, the BFI and 12‐item PAC‐SYM are most commonly used. The 11‐item BF‐Diary is highly relevant in opioid‐induced constipation and was developed and validated in accordance with US Food and Drug Administration guidelines. However, the panel believes that the complex scoring for this tool and the SSS, PAC‐SYM, and 28‐item PAC‐QOL may be unfeasible for clinical practice. The BFI is psychometrically validated and responsive to changes in symptom severity; scores range from 0 to 100, with higher scores indicating greater severity and scores >28.8 points indicating constipation. Conclusions The BFI is a simple assessment tool with a validated threshold of clinically significant constipation. Prescription treatments for opioid‐induced constipation should be considered for patients who have a BFI score of ≥30 points and an inadequate response to first‐line interventions. PMID:26582720

  15. Pediatric constraint-induced movement therapy: a promising intervention for childhood hemiparesis.

    Science.gov (United States)

    Pidcock, Frank S; Garcia, Teressa; Trovato, Melissa K; Schultz, Scott; Brady, Kathleen D

    2009-01-01

    Experimental and clinical evidence is accumulating that supports the assertion that the damaged human brain is capable of responding to sensory stimulation in a sufficient manner to result in sustainable and useful benefits. The intensity and duration of therapeutic maneuvers that elicit improvement are under active investigation. Recent studies in animals, adults, and children with hemiparesis have shown that constraint of the less involved upper limb coupled with a behavioral program that repetitively encourages graded unilateral movements can result in long-term "new" functional activities. Constraint-induced movement therapy (CIMT) is a promising approach for treatment of children with stroke-related hemiparesis from either prenatal or postnatal causes due to the enhanced neuroplasticity of the brain during early life.

  16. Boron analysis for neutron capture therapy using particle-induced gamma-ray emission.

    Science.gov (United States)

    Nakai, Kei; Yamamoto, Yohei; Okamoto, Emiko; Yamamoto, Tetsuya; Yoshida, Fumiyo; Matsumura, Akira; Yamada, Naoto; Kitamura, Akane; Koka, Masashi; Satoh, Takahiro

    2015-12-01

    The neutron source of BNCT is currently changing from reactor to accelerator, but peripheral facilities such as a dose-planning system and blood boron analysis have still not been established. To evaluate the potential application of particle-induced gamma-ray emission (PIGE) for boron measurement in clinical boron neutron capture therapy, boronophenylalanine dissolved within a cell culture medium was measured using PIGE. PIGE detected 18 μgB/mL f-BPA in the culture medium, and all measurements of any given sample were taken within 20 min. Two hours of f-BPA exposure was required to create a boron distribution image. However, even though boron remained in the cells, the boron on the cell membrane could not be distinguished from the boron in the cytoplasm. Copyright © 2015 Elsevier Ltd. All rights reserved.

  17. Constraint-induced movement therapy for children with acquired brain injury

    DEFF Research Database (Denmark)

    Pedersen, Kristina Schmidt; Pallesen, Hanne; Kristensen, Hanne Kaae

    2016-01-01

    An estimated 125–137 Danish children with acquired brain injury (ABI) require rehabilitation annually, 30–40 of these at a highly specialized level. Constraint-induced movement therapy (CIMT) has shown significant effects in increasing function in children with cerebral palsy. More knowledge of how...... CIMT can be adapted for the rehabilitation of children with ABI is needed. The primary purpose of the study was to generate new knowledge about the pedagogical initiatives and frameworks involved in children’s participation in and activities during CIMT. Four children with ABI participated in the 60 h...... intervention. Data generation consisted of qualitative research through participant observations and healthcare professional evaluations. A didactical approach with individualization and a solid structural framework enhanced the possibility of securing the children’s motivation for and participation...

  18. Constraint-induced movement therapy for children with acquired brain injury

    DEFF Research Database (Denmark)

    Schmidt Pedersen, Kristina; Pallesen, H.; Kristensen, H. K.

    2016-01-01

    An estimated 125-137 Danish children with acquired brain injury (ABI) require rehabilitation annually, 30-40 of these at a highly specialized level. Constraint-induced movement therapy (CIMT) has shown significant effects in increasing function in children with cerebral palsy. More knowledge of how...... CIMT can be adapted for the rehabilitation of children with ABI is needed. The primary purpose of the study was to generate new knowledge about the pedagogical initiatives and frameworks involved in childrens participation in and activities during CIMT. Four children with ABI participated in the 60 h...... intervention. Data generation consisted of qualitative research through participant observations and healthcare professional evaluations. A didactical approach with individualization and a solid structural framework enhanced the possibility of securing the childrens motivation for and participation...

  19. Hyperbaric oxygen therapy attenuates central sensitization induced by a thermal injury in humans

    DEFF Research Database (Denmark)

    Rasmussen, V M; Borgen, A E; Jansen, E C

    2015-01-01

    BACKGROUND: Hyperbaric oxygen (HBO2 ) treatment has in animal experiments demonstrated antinociceptive effects. It was hypothesized that these effects would attenuate secondary hyperalgesia areas (SHAs), an expression of central sensitization, after a first-degree thermal injury in humans. METHODS...... was demonstrated. However, in the nine volunteers starting with the control session, a statistical significant attenuation of SHAs was demonstrated in the HBO2 session (P = 0.004). CONCLUSIONS: The results indicate that HBO2 therapy in humans attenuates central sensitization induced by a thermal skin injury......, compared with control. These new and original findings in humans corroborate animal experimental data. The thermal injury model may give impetus to future human neurophysiological studies exploring the central effects of hyperbaric oxygen treatment....

  20. Addressing the value of novel therapies in chemotherapy-induced nausea and vomiting.

    Science.gov (United States)

    Schwartzberg, Lee

    2014-12-01

    Chemotherapy-induced nausea and vomiting (CINV) is a troubling side effect of cancer treatment and is often poorly controlled. As a consequence, CINV is associated with substantially increased costs of care and significant interference with patients' lives. Inadequate control over CINV results from factors that include failure to provide guideline-adherent prophylactic medication and limitations in available therapies. Newer serotonin receptor antagonists, such as palonosetron, and addition of neurokinin-1 (NK-1) receptor antagonists to treatment have significantly decreased both acute and delayed CINV. A fixed-dose combination of palonosetron and a new NK-1 receptor, netupitant, is significantly superior to palonosetron alone and has small, but consistent, numerical advantages over aprepitant plus palonosetron for prevention of CINV. The combination of a serotonin receptor antagonist plus an NK-1 receptor antagonist has been shown to be cost-effective for prevention of CINV and the availability of a fixed-dose combination of netupitant and palonosetron may enhance this benefit.

  1. ECT: its brain enabling effects: a review of electroconvulsive therapy-induced structural brain plasticity.

    Science.gov (United States)

    Bouckaert, Filip; Sienaert, Pascal; Obbels, Jasmien; Dols, Annemieke; Vandenbulcke, Mathieu; Stek, Max; Bolwig, Tom

    2014-06-01

    Since the past 2 decades, new evidence for brain plasticity has caused a shift in both preclinical and clinical ECT research from falsifying the "brain damage hypothesis" toward exploring ECT's enabling brain (neuro)plasticity effects. By reviewing the available animal and human literature, we examined the theory that seizure-induced structural changes are crucial for the therapeutic efficacy of ECT. Both animal and human studies suggest electroconvulsive stimulation/electroconvulsive therapy (ECT)-related neuroplasticity (neurogenesis, synaptogenesis, angiogenesis, or gliogenesis). It remains unclear whether structural changes might explain the therapeutic efficacy and/or be related to the (transient) learning and memory impairment after ECT. Methods to assess in vivo brain plasticity of patients treated with ECT will be of particular importance for future longitudinal studies to give support to the currently available correlational data.

  2. Antimicrobial photodynamic therapy minimizes the deleterious effect of nicotine in female rats with induced periodontitis.

    Science.gov (United States)

    Gualberto, Erivan Clementino; Theodoro, Letícia Helena; Longo, Mariellén; Novaes, Vivian Cristina Noronha; Nagata, Maria José Hitomi; Ervolino, Edilson; Garcia, Valdir Gouveia

    2016-01-01

    The aim of this study was to compare the use of antimicrobial photodynamic therapy (aPDT) as an adjunct to scaling and root planing (SRP) in the treatment of experimentally induced periodontitis in female rats that were systemically treated with or without nicotine. Female rats (n = 180) were divided into two groups: vehicle administration (Veh) and nicotine administration (Nic). Mini-pumps containing either vehicle or nicotine were implanted in the rats 30 days before the induction of experimental periodontitis (EP). EP was induced by placing a cotton ligature around the left mandibular first molar. After 7 days, the ligature was removed, and the rats were randomly divided into three treatment subgroups: SRP (only SRP), DL (SRP plus diode laser), and aPDT (SRP plus aPDT). The aPDT consisted of phenothiazine photosensitizer deposition followed by diode laser irradiation. Ten rats from each subgroup were euthanized at 7, 15, and 30 days after treatment. Alveolar bone loss (ABL) in the furcation region was evaluated using histological, histometric, and immunohistochemical analyses. The rats that were treated with nicotine showed more ABL compared to those treated with vehicle. In both the Veh and Nic groups, SRP plus aPDT treatment resulted in reduced ABL, smaller numbers of both TRAP- and RANKL-positive cells, and higher numbers of PCNA-positive cells compared to SRP treatment alone. aPDT was an effective adjunctive therapy for the treatment of periodontitis in female rats regardless of whether they received nicotine.

  3. Acoustic radiation force for noninvasive evaluation of corneal biomechanical changes induced by cross-linking therapy.

    Science.gov (United States)

    Urs, Raksha; Lloyd, Harriet O; Silverman, Ronald H

    2014-08-01

    To noninvasively measure changes in corneal biomechanical properties induced by ultraviolet-activated riboflavin cross-linking therapy using acoustic radiation force (ARF). Cross-linking was performed on the right eyes of 6 rabbits, with the left eyes serving as controls. Acoustic radiation force was used to assess corneal stiffness before treatment and weekly for 4 weeks after treatment. Acoustic power levels were within US Food and Drug Administration guidelines for ophthalmic safety. Strain, determined from ARF-induced displacement of the front and back surfaces of the cornea, was fit to the Kelvin-Voigt model to determine the elastic modulus (E) and coefficient of viscosity (η). The stiffness factor, the ratio of E after treatment to E before treatment, was calculated for treated and control eyes. At the end of 4 weeks, ex vivo thermal shrinkage temperature analysis was performed for comparison with in vivo stiffness measurements. One-way analysis of variance and Student t tests were performed to test for differences in E, η, the stiffness factor, and corneal thickness. Biomechanical stiffening was immediately evident in cross-linking-treated corneas. At 4 weeks after treatment, treated corneas were 1.3 times stiffer and showed significant changes in E (P= .006) and η (P= .007), with no significant effect in controls. Corneal thickness increased immediately after treatment but did not differ significantly from the pretreatment value at 4 weeks. Our findings demonstrate a statistically significant increase in stiffness in cross-linking-treated rabbit corneas based on in vivo axial stress/strain measurements obtained using ARF. The capacity to noninvasively monitor corneal stiffness offers the potential for clinical monitoring of cross-linking therapy. © 2014 by the American Institute of Ultrasound in Medicine.

  4. Catalase therapy corrects oxidative stress-induced pathophysiology in incipient diabetic retinopathy.

    Science.gov (United States)

    Giordano, Courtney R; Roberts, Robin; Krentz, Kendra A; Bissig, David; Talreja, Deepa; Kumar, Ashok; Terlecky, Stanley R; Berkowitz, Bruce A

    2015-05-01

    Preclinical studies have highlighted retinal oxidative stress in the pathogenesis of diabetic retinopathy. We evaluated whether a treatment designed to enhance cellular catalase reduces oxidative stress in retinal cells cultured in high glucose and in diabetic mice corrects an imaging biomarker responsive to antioxidant therapy (manganese-enhanced magnetic resonance imaging [MEMRI]). Human retinal Müller and pigment epithelial cells were chronically exposed to normal or high glucose levels and treated with a cell-penetrating derivative of the peroxisomal enzyme catalase (called CAT-SKL). Hydrogen peroxide (H2O2) levels were measured using a quantitative fluorescence-based assay. For in vivo studies, streptozotocin (STZ)-induced diabetic C57Bl/6 mice were treated subcutaneously once a week for 3 to 4 months with CAT-SKL; untreated age-matched nondiabetic controls and untreated diabetic mice also were studied. MEMRI was used to analytically assess the efficacy of CAT-SKL treatment on diabetes-evoked oxidative stress-related pathophysiology in vivo. Similar analyses were performed with difluoromethylornithine (DFMO), an irreversible inhibitor of ornithine decarboxylase. After catalase transduction, high glucose-induced peroxide production was significantly lowered in both human retinal cell lines. In diabetic mice in vivo, subnormal intraretinal uptake of manganese was significantly improved by catalase supplementation. In addition, in the peroxisome-rich liver of treated mice catalase enzyme activity increased and oxidative damage (as measured by lipid peroxidation) declined. On the other hand, DFMO was largely without effect in these in vitro or in vivo assays. This proof-of-concept study raises the possibility that augmentation of catalase is a therapy for treating the retinal oxidative stress associated with diabetic retinopathy.

  5. Acoustic Radiation Force for Noninvasive Evaluation of Corneal Biomechanical Changes Induced by Cross-linking Therapy

    Science.gov (United States)

    Urs, Raksha; Lloyd, Harriet O.; Silverman, Ronald H.

    2015-01-01

    Objectives To noninvasively measure changes in corneal biomechanical properties induced by ultraviolet-activated riboflavin cross-linking therapy using acoustic radiation force (ARF). Methods Cross-linking was performed on the right eyes of 6 rabbits, with the left eyes serving as controls. Acoustic radiation force was used to assess corneal stiffness before treatment and weekly for 4 weeks after treatment. Acoustic power levels were within US Food and Drug Administration guidelines for ophthalmic safety. Strain, determined from ARF-induced displacement of the front and back surfaces of the cornea, was fit to the Kelvin-Voigt model to determine the elastic modulus (E) and coefficient of viscosity (η). The stiffness factor, the ratio of E after treatment to E before treatment, was calculated for treated and control eyes. At the end of 4 weeks, ex vivo thermal shrinkage temperature analysis was performed for comparison with in vivo stiffness measurements. One-way analysis of variance and Student t tests were performed to test for differences in E, η, the stiffness factor, and corneal thickness. Results Biomechanical stiffening was immediately evident in cross-linking–treated corneas. At 4 weeks after treatment, treated corneas were 1.3 times stiffer and showed significant changes in E(P= .006) and η (P= .007), with no significant effect in controls. Corneal thickness increased immediately after treatment but did not differ significantly from the pretreatment value at 4 weeks. Conclusions Our findings demonstrate a statistically significant increase in stiffness in cross-linking–treated rabbit corneas based on in vivo axial stress/strain measurements obtained using ARF. The capacity to noninvasively monitor corneal stiffness offers the potential for clinical monitoring of cross-linking therapy. PMID:25063407

  6. Efficacy of AZM therapy in patients with gingival overgrowth induced by Cyclosporine A: a systematic review

    Directory of Open Access Journals (Sweden)

    Deli Giorgio

    2008-12-01

    Full Text Available Abstract Background In daily clinical practice of a dental department it's common to find gingival overgrowth (GO in periodontal patients under treatment with Cyclosporine A (CsA. The pathogenesis of GO and the mechanism of action of Azithromycin (AZM are unclear. A systematic review was conducted in order to evaluate the efficacy of Azithromycin in patients with gingival overgrowth induced by assumption of Cyclosporine A. Methods A bibliographic search was performed using the online databases MEDLINE, EMBASE and Cochrane Central of Register Controlled Trials (CENTRAL in the time period between 1966 and September 2008. Results The literature search retrieved 24 articles; only 5 were Randomised Controlled Trials (RCTs, published in English, fulfilled the inclusion criteria. A great heterogeneity between proposed treatments and outcomes was found, and this did not allow to conduct a quantitative meta-analysis. The systematic review revealed that a 5-day course of Azithromycin with Scaling and Root Planing reduces the degree of gingival overgrowth, while a 7-day course of metronidazole is only effective on concomitant bacterial over-infection. Conclusion Few RCTs on the efficacy of systemic antibiotic therapy in case of GO were found in the literature review. A systemic antibiotic therapy without plaque and calculus removal is not able to reduce gingival overgrowth. The great heterogeneity of diagnostic data and outcomes is due to the lack of precise diagnostic methods and protocols about GO. Future studies need to improve both diagnostic methods and tools and adequate classification aimed to determine a correct prognosis and an appropriate therapy for gingival overgrowth.

  7. Photodynamic therapy can induce non-specific protective immunity against a bacterial infection

    Science.gov (United States)

    Tanaka, Masamitsu; Mroz, Pawel; Dai, Tianhong; Kinoshita, Manabu; Morimoto, Yuji; Hamblin, Michael R.

    2012-03-01

    Photodynamic therapy (PDT) for cancer is known to induce an immune response against the tumor, in addition to its well-known direct cell-killing and vascular destructive effects. PDT is becoming increasingly used as a therapy for localized infections. However there has not to date been a convincing report of an immune response being generated against a microbial pathogen after PDT in an animal model. We have studied PDT as a therapy for bacterial arthritis caused by Staphylococcus aureus infection in the mouse knee. We had previously found that PDT of an infection caused by injection of MRSA (5X107 CFU) into the mouse knee followed 3 days later by 1 μg of Photofrin and 635- nm diode laser illumination with a range of fluences within 5 minutes, gave a biphasic dose response. The greatest reduction of MRSA CFU was seen with a fluence of 20 J/cm2, whereas lower antibacterial efficacy was observed with fluences that were either lower or higher. We then tested the hypothesis that the host immune response mediated by neutrophils was responsible for most of the beneficial antibacterial effect. We used bioluminescence imaging of luciferase expressing bacteria to follow the progress of the infection in real time. We found similar results using intra-articular methylene blue and red light, and more importantly, that carrying out PDT of the noninfected joint and subsequently injecting bacteria after PDT led to a significant protection from infection. Taken together with substantial data from studies using blocking antibodies we believe that the pre-conditioning PDT regimen recruits and stimulates neutrophils into the infected joint which can then destroy bacteria that are subsequently injected and prevent infection.

  8. Antigen-Specific Gene Therapy after Immunisation Reduces the Severity of Collagen-Induced Arthritis

    Directory of Open Access Journals (Sweden)

    Tove Eneljung

    2013-01-01

    Full Text Available Reestablishment of tolerance induction in rheumatoid arthritis (RA would be an optimal treatment with few, if any, side effects. However, to develop such a treatment further insights in the immunological mechanisms governing tolerance are needed. We have developed a model of antigen-specific tolerance in collagen type II (CII induced arthritis (CIA using lentivirus-based gene therapy. The immunodominant epitope of CII was inserted into a lentivirus vector to achieve expression on the MHC class II molecule and the lentiviral particles were subsequently intravenously injected at different time points during CIA. Injection of lentiviral particles in early phases of CIA, that is, at day 7 or day 26 after CII immunisation, partially prevented development of arthritis, decreased the serum levels of CII-specific IgG antibodies, and enhanced the suppressive function of CII-specific T regulatory cells. When lentiviral particles were injected during manifest arthritis, that is, at day 31 after CII immunisation, the severity of arthritis progression was ameliorated, the levels of CII-specific IgG antibodies decreased and the proportion of T regulatory cells increased. Thus, antigen-specific gene therapy is effective when administered throughout the inflammatory course of arthritis and offers a good model for investigation of the basic mechanisms during tolerance in CIA.

  9. Ozone Therapy in Ethidium Bromide-Induced Demyelination in Rats: Possible Protective Effect.

    Science.gov (United States)

    Salem, Neveen A; Assaf, Naglaa; Ismail, Manal F; Khadrawy, Yasser A; Samy, Mohga

    2016-08-01

    Multiple sclerosis, an autoimmune inflammatory disease of the central nervous system, is characterized by excessive demyelination. The study aimed to investigate the possible protective effect of ozone (O3) therapy in ethidium bromide (EB)-induced demyelination in rats either alone or in combination with corticosteroids in order to decrease the dose of steroid therapy. Rats were divided into Group (1) normal control rats received saline, Group (2) Sham-operated rats received saline, Group (3) Sham-operated rats received vehicle (oxygen), Group (4) EB-treated rats received EB, Group (5) EB-treated rats received O3, Group (6) EB-treated rats received methylprednisolone (MP), and Group (7) EB-treated rats received half the dose of MP concomitant with O3. EB-treated rats showed a significant increase in the number of footfalls in the grid walk test, decreased brain GSH, and paraoxonase-1 enzyme activity, whereas brain MDA, TNF-α, IL-1β, INF-γ, Cox-2 immunoreactivity, and p53 protein levels were increased. A significant decline in brain serotonin, dopamine, norepinephrine, and MBP immunoreactivity was also reported. Significant improvement of the above-mentioned parameters was demonstrated with the administration of either MP or O3, whereas best amelioration was achieved by combining half the dose of MP with ozone.

  10. Joint Intratracheal Surfactant-Antibacterial Therapy in Experimental Pseudomonas-Induced Pneumonia.

    Science.gov (United States)

    Birkun, Alexei A; Kubyshkin, Anatoly V; Novikov, Nikolai Y; Krivorutchenko, Yuri L; Fedosov, Michael I; Postnikova, Olga N; Snitser, Anatoly A

    2015-08-01

    The application of an exogenous pulmonary surfactant as a carrier for intratracheally administered antimicrobials represents a promising therapeutic modality that is still on its way to clinical practice. Owing to its ability to decrease surface tension, exogenous surfactant may enhance delivery of antibiotics into foci of pulmonary infection, thus increasing efficiency and safety of topical antimicrobial therapy in bacterial lung diseases. To assess potential interactions between exogenous surfactant and amikacin in vitro, and to study the effects of their joint intratracheal instillation in rats with acute pneumonia caused by Pseudomonas aeruginosa. The antibacterial and surface-active properties of amikacin (Amicil, Kievmedpreparat, Ukraine), porcine pulmonary surfactant (Suzacrin, Docpharm, Ukraine), and their combination were studied in vitro using standard microbiologic procedures and modified Pattle method (estimation of bubble diameter). Similar methods were utilized to study bacterial contamination of lungs and blood, and to assess the surface activity of bronchoalveolar wash (BAW) in 119 Wistar rats, including infected (intratracheal introduction of P. aeruginosa ATCC 27853) and noninfected animals. Histopathologic findings, differential leukocyte counts, and oxygenation parameters were recorded. Antibacterial and surface-active properties of the surfactant and amikacin remained unimpaired in vitro. In rats anti-pseudomonal and anti-inflammatory effects of the surfactant-amikacin mixture were more pronounced (psurfactant-amikacin therapy of Pseudomonas-induced pneumonia may suggest further clinical trials.

  11. Induced pluripotent stem cell-derived mesenchymal stem cells: A leap toward personalized therapies.

    Science.gov (United States)

    Whitt, Jason; Vallabhaneni, Krishna C; Penfornis, Patrice; Pochampally, Radhika

    2016-01-01

    Mesenchymal Stem/stromal cell (MSCs) transplantation procedures have been used since the 1960's to treat leukemia and other diseases, but due to the risks involved only patients with life threatening illnesses were typically subjected to the transplantation procedure until the last decade. Recent advancements in transplantation techniques have made it more feasible to use it for non-life-threatening diseases. However, the potential uses for stem cells are still limited by their rarity, and, in the case of allogeneic transplants, graft-vs.-host complications. An evolving alternative to conventional stem cell therapies is induced pluripotent stem-cell derived mesenchymal stem/stromal cells (iPSC- MSCs), which have a multi-lineage potential comparable to conventionally acquired MSCs with the added benefit of being less immunoreactive. However there are still many hurdles left to be overcome before they can be used regularly for personalized therapies. This review will focus on recent advancements that have been made regarding the role MSCs play in tumor development and the potential uses iPSC-MSCs may have in future cancer treatment.

  12. Enzyme replacement therapy induces T-cell responses in late-onset Pompe disease.

    Science.gov (United States)

    Banati, Miklos; Hosszu, Zsolt; Trauninger, Anita; Szereday, Laszlo; Illes, Zsolt

    2011-11-01

    Enzyme replacement therapy (ERT) in ultra-orphan Pompe disease generates anti-rhGAA antibodies, which may interfere with efficacy. rhGAA-specific T-cell responses were examined at different time-points in 6 Hungarian patients treated with rhGAA and compared with 1 untreated patient and 5 healthy controls. The ex vivo percentage of activated T cells was increased in treated patients. rhGAA stimulation in vitro generated a dose-dependent increase in intracellular interferon-gamma (IFN-γ) expression in CD4(+) and CD8(+) T cells. Isolated CD4(+) and CD8(+) T cells produced increased amounts of IFN-γ and tumor necrosis factor-alpha (TNF-α) in half of the patients after in vitro stimulation with rhGAA, whereas interleukin (IL)-4, IL-6, and IL-17 levels were not elevated. Expression of cytotoxic FasL and perforin molecules by natural killer (NK), NKT-like, and CD8(+) T cells were not increased ex vivo. We found that enzyme replacement therapy (ERT) induces pro-inflammatory T-cell responses in addition to the antibody response in Pompe disease. Copyright © 2011 Wiley Periodicals, Inc.

  13. Antimonial Therapy Induces Circulating Proinflammatory Cytokines in Patients with Cutaneous Leishmaniasis

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    Kocyigit, Abdurrahim; Gur, Selahaddin; Gurel, Mehmet S.; Bulut, Vedat; Ulukanligil, Mustafa

    2002-01-01

    The objective of this study was to evaluate the association between antimonial therapy and circulating levels of proinflammatory cytokines in patients with cutaneous leishmaniasis (CL). Patients were treated with conventional chemotherapy by using pentavalent antimonium salts (Glucantime) for 3 weeks. Circulating plasma levels of the proinflammatory cytokines interleukin-1β (IL-1β), IL-6, IL-8, and tumor necrosis factor alpha (TNF-α) were determined for CL patients and healthy subjects before and 3 weeks after the treatment was started. Plasma IL-1β, IL-6, IL-8, and TNF-α levels were significantly higher for pretreatment CL patients than for healthy subjects. Proinflammatory cytokines significantly increased after 21 days postinfection compared to levels for the pretreatment patients. These increments were approximately 3-fold for IL-1β and TNF-α levels, 10-fold for IL-6 levels, and 20-fold for IL-8 levels in patients with CL. Taken together these results indicate that circulating proinflammatory cytokine levels were increased in patients with CL as a consequence of host defense strategies, and antimonial therapy may induce these cytokines by affecting the macrophage or other components of the host defense system. PMID:12438329

  14. Chemotherapy-Induced Macrophage Infiltration into Tumors Enhances Nanographene-Based Photodynamic Therapy.

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    Zhao, Yang; Zhang, Chenran; Gao, Liquan; Yu, Xinhe; Lai, Jianhao; Lu, Dehua; Bao, Rui; Wang, Yanpu; Jia, Bing; Wang, Fan; Liu, Zhaofei

    2017-11-01

    Increased recruitment of tumor-associated macrophages (TAM) to tumors following chemotherapy promotes tumor resistance and recurrence and correlates with poor prognosis. TAM depletion suppresses tumor growth, but is not highly effective due to the effects of tumorigenic mediators from other stromal sources. Here, we report that adoptive macrophage transfer led to a dramatically enhanced photodynamic therapy (PDT) effect of 2-(1-hexyloxyethyl)-2-devinyl pyropheophor-bide-alpha (HPPH)-coated polyethylene glycosylated nanographene oxide [GO(HPPH)-PEG] by increasing its tumor accumulation. Moreover, tumor treatment with commonly used chemotherapeutic drugs induced an increase in macrophage infiltration into tumors, which also enhanced tumor uptake and the PDT effects of GO(HPPH)-PEG, resulting in tumor eradication. Macrophage recruitment to tumors after chemotherapy was visualized noninvasively by near-infrared fluorescence and single-photon emission CT imaging using F4/80-specific imaging probes. Our results demonstrate that chemotherapy combined with GO(HPPH)-PEG PDT is a promising strategy for the treatment of tumors, especially those resistant to chemotherapy. Furthermore, TAM-targeted molecular imaging could potentially be used to predict the efficacy of combination therapy and select patients who would most benefit from this treatment approach. Cancer Res; 77(21); 6021-32. ©2017 AACR. ©2017 American Association for Cancer Research.

  15. Experimental Comparison of Photothermal Conversion Efficiency of Gold Nanotriangle and Nanorod in Laser Induced Thermal Therapy.

    Science.gov (United States)

    2017-11-26

    An experimental comparison of the photothermal conversion efficiency (PCE) for gold nanotriangles (GNTs) and nanorods (GNRs) was carried out in the present work. The discrete dipole approximation method was applied to identify the spectral characteristic of GNTs and GNRs with different aspect ratios. On this basis, the PCE of GNTs and GNRs in photothermal therapy were compared theoretically. Afterwards, an in vitro experiment was adopted to investigate the thermal effect of porcine muscle induced by laser irradiation, with and without injected GNTs and GNRs. The influences of laser total power, nanoparticle concentration, and nanoparticle type were investigated. It was found that for the commonly-used wavelengths for photothermal therapy, the PCE of GNTs is higher than that of the GNRs. Furthermore, for GNRs loaded in tissue in vitro, high laser power and high concentration of nanoparticles leads to the degeneration and even carbonization of tissue. However, for the GNTs with the same situation (laser power, nanoparticle volume concentration, and heating time), it could lead to the tissue's evaporation instead of carbonization.

  16. Emerging therapies for patients with symptoms of opioid-induced bowel dysfunction

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    Leppert W

    2015-04-01

    Full Text Available Wojciech Leppert Chair and Department of Palliative Medicine, Poznan University of Medical Sciences, Poznan, Poland Abstract: Opioid-induced bowel dysfunction (OIBD comprises gastrointestinal (GI symptoms, including dry mouth, nausea, vomiting, gastric stasis, bloating, abdominal pain, and opioid-induced constipation, which significantly impair patients’ quality of life and may lead to undertreatment of pain. Traditional laxatives are often prescribed for OIBD symptoms, although they display limited efficacy and exert adverse effects. Other strategies include prokinetics and change of opioids or their administration route. However, these approaches do not address underlying causes of OIBD associated with opioid effects on mostly peripheral opioid receptors located in the GI tract. Targeted management of OIBD comprises purely peripherally acting opioid receptor antagonists and a combination of opioid receptor agonist and antagonist. Methylnaltrexone induces laxation in 50%–60% of patients with advanced diseases and OIBD who do not respond to traditional oral laxatives without inducing opioid withdrawal symptoms with similar response (45%–50% after an oral administration of naloxegol. A combination of prolonged-release oxycodone with prolonged-release naloxone (OXN in one tablet (a ratio of 2:1 provides analgesia with limited negative effect on the bowel function, as oxycodone displays high oral bioavailability and naloxone demonstrates local antagonist effect on opioid receptors in the GI tract and is totally inactivated in the liver. OXN in daily doses of up to 80 mg/40 mg provides equally effective analgesia with improved bowel function compared to oxycodone administered alone in patients with chronic non-malignant and cancer-related pain. OIBD is a common complication of long-term opioid therapy and may lead to quality of life deterioration and undertreatment of pain. Thus, a complex assessment and management that addresses underlying

  17. Autophagic signaling and proteolytic enzyme activity in cardiac and skeletal muscle of spontaneously hypertensive rats following chronic aerobic exercise.

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    Elliott M McMillan

    Full Text Available Hypertension is a cardiovascular disease associated with deleterious effects in skeletal and cardiac muscle. Autophagy is a degradative process essential to muscle health. Acute exercise can alter autophagic signaling. Therefore, we aimed to characterize the effects of chronic endurance exercise on autophagy in skeletal and cardiac muscle of normotensive and hypertensive rats. Male Wistar Kyoto (WKY and spontaneously hypertensive rats (SHR were assigned to a sedentary condition or 6 weeks of treadmill running. White gastrocnemius (WG of hypertensive rats had higher (p<0.05 caspase-3 and proteasome activity, as well as elevated calpain activity. In addition, skeletal muscle of hypertensive animals had elevated (p<0.05 ATG7 and LC3I protein, LAMP2 mRNA, and cathepsin activity, indicative of enhanced autophagic signaling. Interestingly, chronic exercise training increased (p<0.05 Beclin-1, LC3, and p62 mRNA as well as proteasome activity, but reduced (p<0.05 Beclin-1 and ATG7 protein, as well as decreased (p<0.05 caspase-3, calpain, and cathepsin activity. Left ventricle (LV of hypertensive rats had reduced (p<0.05 AMPKα and LC3II protein, as well as elevated (p<0.05 p-AKT, p-p70S6K, LC3I and p62 protein, which collectively suggest reduced autophagic signaling. Exercise training had little effect on autophagy-related signaling factors in LV; however, exercise training increased (p<0.05 proteasome activity but reduced (p<0.05 caspase-3 and calpain activity. Our results suggest that autophagic signaling is altered in skeletal and cardiac muscle of hypertensive animals. Regular aerobic exercise can effectively alter the proteolytic environment in both cardiac and skeletal muscle, as well as influence several autophagy-related factors in skeletal muscle of normotensive and hypertensive rats.

  18. A systematic review with meta-analysis of the effect of low-level laser therapy (LLLT) in cancer therapy-induced oral mucositis.

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    Bjordal, Jan Magnus; Bensadoun, Rene-Jean; Tunèr, Jan; Frigo, Lucio; Gjerde, Kjersti; Lopes-Martins, Rodrigo Ab

    2011-08-01

    The purpose of this study is to review the effects of low-level laser therapy (LLLT) in the prevention and treatment of cancer therapy-induced oral mucositis (OM). A systematic review and meta-analysis of randomised placebo-controlled trials of LLLT performed during chemotherapy or radiation therapy in head and neck cancer patients. We found 11 randomised placebo-controlled trials with a total of 415 patients; methodological quality was acceptable at 4.10 (SD ± 0.74) on the 5-point Jadad scale. The relative risk (RR) for developing OM was significantly (p = 0.02) reduced after LLLT compared with placebo LLLT (RR = 2.03 (95% CI, 1.11 to 3.69)). This preventive effect of LLLT improved to RR = 2.72 (95% CI, 1.98 to 3.74) when only trials with adequate doses above 1 J were included. For treatment of OM ulcers, the number of days with OM grade 2 or worse was significantly reduced after LLLT to 4.38 (95% CI, 3.35 to 5.40) days less than placebo LLLT. Oral mucositis severity was also reduced after LLLT with a standardised mean difference of 1.33 (95% CI, 0.68 to 1.98) over placebo LLLT. All studies registered possible side-effects, but they were not significantly different from placebo LLLT. There is consistent evidence from small high-quality studies that red and infrared LLLT can partly prevent development of cancer therapy-induced OM. LLLT also significantly reduced pain, severity and duration of symptoms in patients with cancer therapy-induced OM.

  19. Effects of music therapy and guided visual imagery on chemotherapy-induced anxiety and nausea-vomiting.

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    Karagozoglu, Serife; Tekyasar, Filiz; Yilmaz, Figen Alp

    2013-01-01

    To reveal the effects of music therapy and visual imagery on chemotherapy-induced anxiety and nausea-vomiting. Behavioural techniques such as music therapy and visual imagery are becoming increasingly important in dealing with chemotherapy-induced anxiety, nausea and vomiting. The study is an experimental and cross-sectional one and performed on a single sample group with the pre-post-test design consisting of 40 individuals. The individuals in the sample group comprised both the control and the case group of the study. To obtain the study data, the following forms were used: the Personal Information Form, Spielberger State-Trait Anxiety Inventory, The Visual Analogue Scale and Individual Evaluation Form for Nausea and Vomiting adapted from The Morrow Assessment of Nausea and Vomiting. In the study, the participants' state and trait anxiety levels decreased significantly (p Music therapy and visual imagery reduced the severity and duration of chemotherapy-induced nausea and vomiting significantly (p music therapy and guided visual imagery were implemented. It was determined that complementary approaches comprising music therapy and visual imagery had positive effects on chemotherapy-induced anxiety, nausea and vomiting, which are suffered too often and affect the patients' whole lives adversely. This study is worthy of interest as it has revealed that music therapy and visual imagery which have been proven to be effective in many health problems in different areas are also important, and practical complementary approaches that are effective in getting chemotherapy-induced anxiety, nausea and vomiting under control. © 2012 Blackwell Publishing Ltd.

  20. Autophagic degradation of dBruce controls DNA fragmentation in nurse cells during late Drosophila melanogaster oogenesis

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    Shravage, Bhupendra V.; Sagona, Antonia P.; Lamark, Trond; Bjørkøy, Geir; Johansen, Terje; Rusten, Tor Erik; Brech, Andreas; Baehrecke, Eric H.

    2010-01-01

    Autophagy is an evolutionarily conserved pathway responsible for degradation of cytoplasmic material via the lysosome. Although autophagy has been reported to contribute to cell death, the underlying mechanisms remain largely unknown. In this study, we show that autophagy controls DNA fragmentation during late oogenesis in Drosophila melanogaster. Inhibition of autophagy by genetically removing the function of the autophagy genes atg1, atg13, and vps34 resulted in late stage egg chambers that contained persisting nurse cell nuclei without fragmented DNA and attenuation of caspase-3 cleavage. The Drosophila inhibitor of apoptosis (IAP) dBruce was found to colocalize with the autophagic marker GFP-Atg8a and accumulated in autophagy mutants. Nurse cells lacking Atg1 or Vps34 in addition to dBruce contained persisting nurse cell nuclei with fragmented DNA. This indicates that autophagic degradation of dBruce controls DNA fragmentation in nurse cells. Our results reveal autophagic degradation of an IAP as a novel mechanism of triggering cell death and thereby provide a mechanistic link between autophagy and cell death. PMID:20713604

  1. Mediation of autophagic cell death by type 3 ryanodine receptor (RyR3 in adult hippocampal neural stem cells

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    Kyung Min eChung

    2016-05-01

    Full Text Available Cytoplasmic Ca2+ actively engages in diverse intracellular processes from protein synthesis, folding and trafficking to cell survival and death. Dysregulation of intracellular Ca2+ levels is observed in various neuropathological states including Alzheimer’s and Parkinson’s diseases. Ryanodine receptors (RyRs and IP3 receptors (IP3Rs, the main Ca2+ release channels located in endoplasmic reticulum (ER membranes, are known to direct various cellular events such as autophagy and apoptosis. Here we investigated the intracellular Ca2+-mediated regulation of survival and death of adult hippocampal neural stem (HCN cells utilizing an insulin withdrawal model of autophagic cell death. Despite comparable expression levels of RyR and IP3R transcripts in HCN cells at normal state, the expression levels of RyRs — especially RyR3 — were markedly upregulated upon insulin withdrawal. While treatment with the RyR agonist caffeine significantly promoted the autophagic death of insulin-deficient HCN cells, treatment with its inhibitor dantrolene prevented the induction of autophagy following insulin withdrawal. Furthermore, CRISPR/Cas9-mediated knockout of the RyR3 gene abolished autophagic cell death of HCN cells. This study delineates a distinct, RyR3-mediated ER Ca2+ regulation of autophagy and programmed cell death in neural stem cells. Our findings provide novel insights into the critical, yet understudied mechanisms underlying the regulatory function of ER Ca2+ in neural stem cell biology.

  2. Effects of ozone (O3) therapy on cisplatin-induced ototoxicity in rats.

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    Koçak, Hasan Emre; Taşkın, Ümit; Aydın, Salih; Oktay, Mehmet Faruk; Altınay, Serdar; Çelik, Duygu Sultan; Yücebaş, Kadir; Altaş, Bengül

    2016-12-01

    The aim of this study is to investigate the effect of rectal ozone and intratympanic ozone therapy on cisplatin-induced ototoxicity in rats. Eighteen female Wistar albino rats were included in our study. External auditory canal and tympanic membrane examinations were normal in all rats. The rats were randomly divided into three groups. Initially, all the rats were tested with distortion product otoacoustic emissions (DPOAE), and emissions were measured normally. All rats were injected with 5-mg/kg/day cisplatin for 3 days intraperitoneally. Ototoxicy had developed in all rats, as confirmed with DPOAE after 1 week. Rectal and intratympanic ozone therapy group was Group 1. No treatment was administered for the rats in Group 2 as the control group. The rats in Group 3 were treated with rectal ozone. All the rats were tested with DPOAE under general anesthesia, and all were sacrificed for pathological examination 1 week after ozone administration. Their cochleas were removed. The outer hair cell damage and stria vascularis damage were examined. In the statistical analysis conducted, a statistically significant difference between Group 1 and Group 2 was observed in all frequencies according to the DPOAE test. In addition, between Group 2 and Group 3, a statistically significant difference was observed in the DPOAE test. However, a statistically significant difference was not observed between Group 1 and Group 3 according to the DPOAE test. According to histopathological scoring, the outer hair cell damage score was statistically significantly high in Group 2 compared with Group 1. In addition, the outer hair cell damage score was also statistically significantly high in Group 2 compared with Group 3. Outer hair cell damage scores were low in Group 1 and Group 3, but there was no statistically significant difference between these groups. There was no statistically significant difference between the groups in terms of stria vascularis damage score examinations

  3. The apoptosis induced by HMME-based photodynamic therapy in rabbit vascular smooth muscle cells

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    Yin, Huijuan; Li, Xiaoyuan; Lin, Hong; Liu, Jianzhong; Yu, Hongkui

    2007-02-01

    Objective To study the effects of HMME-based photodynamic therapy on proliferation and apoptosis of rabbit vascular smooth muscle cells(VSMCs). Method The cytotoxic effect of HMME-PDT on rabbit vascular smooth muscle cells was studied by means of Trypan Blue assay, HMME at 10μg/ml concentration and the light dose at 2.4~4.8 J/cm2 were selected in the studies. The morphological character 24h post-PDT was investigated by HE Staining. Annexin V and propidium iodide (PI) binding assays were performed to analyze the characteristics of cell death after HMME-PDT. Furthermore, The intracellular distributions of the HMME were measured by the confocal laser scanning microscope. Result It was showed the photocytotoxity to VSMC cells was dose related by Trypan Blue assay. Histology observing suggests HMME-PDT could induce cell death through apoptosis or necrosis, and the apoptosic rate was up to 50.5% by AnnexinV /PI assay. Moreover, the fluorescence images of HMME intracellular localization demonstrated that the HMME diffused into the mitochondria. Conclusion HMME-PDT could significantly inhibite VSMC proliferation and induce apoptosis.

  4. Hormone replacement therapy in morphine-induced hypogonadic male chronic pain patients

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    Ravaioli Laura

    2011-02-01

    Full Text Available Abstract Background In male patients suffering from chronic pain, opioid administration induces severe hypogonadism, leading to impaired physical and psychological conditions such as fatigue, anaemia and depression. Hormone replacement therapy is rarely considered for these hypogonadic patients, notwithstanding the various pharmacological solutions available. Methods To treat hypogonadism and to evaluate the consequent endocrine, physical and psychological changes in male chronic pain patients treated with morphine (epidural route, we tested the administration of testosterone via a gel formulation for one year. Hormonal (total testosterone, estradiol, free testosterone, DHT, cortisol, pain (VAS and other pain questionnaires, andrological (Ageing Males' Symptoms Scale - AMS and psychological (POMS, CES-D and SF-36 parameters were evaluated at baseline (T0 and after 3, 6 and 12 months (T3, T6, T12 respectively. Results The daily administration of testosterone increased total and free testosterone and DHT at T3, and the levels remained high until T12. Pain rating indexes (QUID progressively improved from T3 to T12 while the other pain parameters (VAS, Area% remained unchanged. The AMS sexual dimension and SF-36 Mental Index displayed a significant improvement over time. Conclusions In conclusion, our results suggest that a constant, long-term supply of testosterone can induce a general improvement of the male chronic pain patient's quality of life, an important clinical aspect of pain management.

  5. Beneficial effects of minocycline and botulinum toxin-induced constraint physical therapy following experimental traumatic brain injury.

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    Lam, Tina I; Bingham, Deborah; Chang, Ting Ju; Lee, Chih Cheng; Shi, Jian; Wang, Dongmin; Massa, Stephen; Swanson, Raymond A; Liu, Jialing

    2013-01-01

    Effective recovery from functional impairments caused by traumatic brain injury (TBI) requires appropriate rehabilitation therapy. Multiple pathways are involved in secondary injury and recovery suggesting a role for multimodal approaches. Here, we examined the efficacy of the anti-inflammatory agent minocycline and botulinum toxin (botox)-induced limb constraint with structured physical therapy, delivered alone or in combination, after a severe TBI produced by a controlled cortical impact in rats. Minocycline was administered at 25 mg/kg daily for 2 weeks beginning 1 day after TBI or sham surgery. For constraint/physical therapy, botox-type A was injected into the nonaffected forearm muscle 1 day after injury and 2 weeks of physical therapy commenced at 5 days after injury. Functional evaluations were conducted 8 weeks after injury. Minocycline, either as a monotherapy or as combination treatment with botox/physical therapy significantly reduced impairments of spatial learning and memory in the water maze test, whereas botox/physical therapy reduced forelimb motor asymmetry and improved manual dexterity in the cylinder and vermicelli handling tests, A synergistic effect between the 2 treatments was observed when rats performed tasks requiring dexterity. Inflammation was attenuated in the peri-contusion cortex and hippocampus in all TBI groups receiving mono or combination therapies, though there was no significant difference in lesion size among groups. These data provide a rationale for incorporating anti-inflammatory treatment during rehabilitation therapy.

  6. Radiation Therapy Induces Macrophages to Suppress T-Cell Responses Against Pancreatic Tumors in Mice.

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    Seifert, Lena; Werba, Gregor; Tiwari, Shaun; Giao Ly, Nancy Ngoc; Nguy, Susanna; Alothman, Sara; Alqunaibit, Dalia; Avanzi, Antonina; Daley, Donnele; Barilla, Rocky; Tippens, Daniel; Torres-Hernandez, Alejandro; Hundeyin, Mautin; Mani, Vishnu R; Hajdu, Cristina; Pellicciotta, Ilenia; Oh, Philmo; Du, Kevin; Miller, George

    2016-06-01

    The role of radiation therapy in the treatment of patients with pancreatic ductal adenocarcinoma (PDA) is controversial. Randomized controlled trials investigating the efficacy of radiation therapy in patients with locally advanced unresectable PDA have reported mixed results, with effects ranging from modest benefit to worse outcomes compared with control therapies. We investigated whether radiation causes inflammatory cells to acquire an immune-suppressive phenotype that limits the therapeutic effects of radiation on invasive PDAs and accelerates progression of preinvasive foci. We investigated the effects of radiation therapy in p48(Cre);LSL-Kras(G12D) (KC) and p48(Cre);LSLKras(G12D);LSL-Trp53(R172H) (KPC) mice, as well as in C57BL/6 mice with orthotopic tumors grown from FC1242 cells derived from KPC mice. Some mice were given neutralizing antibodies against macrophage colony-stimulating factor 1 (CSF1 or MCSF) or F4/80. Pancreata were exposed to doses of radiation ranging from 2 to 12 Gy and analyzed by flow cytometry. Pancreata of KC mice exposed to radiation had a higher frequency of advanced pancreatic intraepithelial lesions and more foci of invasive cancer than pancreata of unexposed mice (controls); radiation reduced survival time by more than 6 months. A greater proportion of macrophages from radiation treated invasive and preinvasive pancreatic tumors had an immune-suppressive, M2-like phenotype compared with control mice. Pancreata from mice exposed to radiation had fewer CD8(+) T cells than controls, and greater numbers of CD4(+) T cells of T-helper 2 and T-regulatory cell phenotypes. Adoptive transfer of T cells from irradiated PDA to tumors of control mice accelerated tumor growth. Radiation induced production of MCSF by PDA cells. A neutralizing antibody against MCSF prevented radiation from altering the phenotype of macrophages in tumors, increasing the anti-tumor T-cell response and slowing tumor growth. Radiation treatment causes macrophages

  7. St John's Wort (Hypericum perforatum L. photomedicine: hypericin-photodynamic therapy induces metastatic melanoma cell death.

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    Britta Kleemann

    Full Text Available Hypericin, an extract from St John's Wort (Hypericum perforatum L., is a promising photosensitizer in the context of clinical photodynamic therapy due to its excellent photosensitizing properties and tumoritropic characteristics. Hypericin-PDT induced cytotoxicity elicits tumor cell death by various mechanisms including apoptosis, necrosis and autophagy-related cell death. However, limited reports on the efficacy of this photomedicine for the treatment of melanoma have been published. Melanoma is a highly aggressive tumor due to its metastasizing potential and resistance to conventional cancer therapies. The aim of this study was to investigate the response mechanisms of melanoma cells to hypericin-PDT in an in vitro tissue culture model. Hypericin was taken up by all melanoma cells and partially co-localized to the endoplasmic reticulum, mitochondria, lysosomes and melanosomes, but not the nucleus. Light activation of hypericin induced a rapid, extensive modification of the tubular mitochondrial network into a beaded appearance, loss of structural details of the endoplasmic reticulum and concomitant loss of hypericin co-localization. Surprisingly the opposite was found for lysosomal-related organelles, suggesting that the melanoma cells may be using these intracellular organelles for hypericin-PDT resistance. In line with this speculation we found an increase in cellular granularity, suggesting an increase in pigmentation levels in response to hypericin-PDT. Pigmentation in melanoma is related to a melanocyte-specific organelle, the melanosome, which has recently been implicated in drug trapping, chemotherapy and hypericin-PDT resistance. However, hypericin-PDT was effective in killing both unpigmented (A375 and 501mel and pigmented (UCT Mel-1 melanoma cells by specific mechanisms involving the externalization of phosphatidylserines, cell shrinkage and loss of cell membrane integrity. In addition, this treatment resulted in extrinsic (A375 and

  8. Clinical efficacy of glucocorticoid therapy in treatment of drug-induced cholestatic liver disease

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    GE Hongyan

    2015-10-01

    Full Text Available ObjectiveTo analyze the clinical efficacy of glucocorticoid therapy in addition to conventional treatment for patients with drug-induced cholestatic liver disease. MethodsA total of 115 patients with drug-induced cholestatic liver disease who were admitted to Affiliated Hospital of Inner Mongolia University for the Nationalities from January 2010 to December 2014 were collected and divided into glucocorticoid treatment group and non-glucocorticoid treatment group. The glucocorticoid treatment group was given methylprednisolone sodium succinate 120 mg once daily by intravenous injection in addition to conventional treatment. The indicator for glucocorticoid response was defined as 10% decrease of total bilirubin (TBil on the third day or 30% decrease on the seventh day. Then the patients were orally given prednisone tablets 10 mg three times daily based on the level of TBil, and the administration of prednisone tablets was adjusted to twice daily a week later. The course of treatment was less than three weeks. Comparison of continuous data in normal distribution between the two groups was made by t test, and comparison of continuous data not in normal distribution between the two groups was made by rank sum test. ResultsThe levels of gamma-glutamyl transpeptidase (GGT, alanine aminotransferase (ALT, and TBil in the glucocorticoid treatment group decreased significantly on days 3, 7, and 14 of treatment compared with those before treatment (tGGT=3.64, 13.08, 16.22; tALT=2.39, 4.73, 8.36; tTBil=3.46, 7.41, 13.17; all P<0.05. Compared with the non-glucocorticoid treatment group, the glucocorticoid treatment group had significantly lower AST and ALT levels before treatment and on days 3 and 7 of treatment (all P>0.05. The GGT, AST, and TBil levels in the glucocorticoid treatment group were significantly lower than those in the non-glucocorticoid treatment group on day 14 of treatment (t=7.074, 2.929, 2.018; all P<0.05. The average decreasing

  9. Development of an inducible caspase-9 safety switch for pluripotent stem cell–based therapies

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    Chuanfeng Wu

    2014-01-01

    Full Text Available Induced pluripotent stem cell (iPSC therapies offer a promising path for patient-specific regenerative medicine. However, tumor formation from residual undifferentiated iPSC or transformation of iPSC or their derivatives is a risk. Inclusion of a suicide gene is one approach to risk mitigation. We introduced a dimerizable-“inducible caspase-9” (iCasp9 suicide gene into mouse iPSC (miPSC and rhesus iPSC (RhiPSC via a lentivirus, driving expression from either a cytomegalovirus (CMV, elongation factor-1 α (EF1α or pluripotency-specific EOS-C(3+ promoter. Exposure of the iPSC to the synthetic chemical dimerizer, AP1903, in vitro induced effective apoptosis in EF1α-iCasp9-expressing (EF1α-iPSC, with less effective killing of EOS-C(3+-iPSC and CMV-iPSC, proportional to transgene expression in these cells. AP1903 treatment of EF1α-iCasp9 miPSC in vitro delayed or prevented teratomas. AP1903 administration following subcutaneous or intravenous delivery of EF1α-iPSC resulted in delayed teratoma progression but did not ablate tumors. EF1α-iCasp9 expression was downregulated during in vitro and in vivo differentiation due to DNA methylation at CpG islands within the promoter, and methylation, and thus decreased expression, could be reversed by 5-azacytidine treatment. The level and stability of suicide gene expression will be important for the development of suicide gene strategies in iPSC regenerative medicine.

  10. Can ultrasounds induce cytotoxicity in presence of hematoporphyrin derivative as photodynamic therapy?

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    Meunier, Anne; Guillemin, Francois H.; Merlin, Jean-Louis; Eikermann, Karine; Schmitt, Sabine; Stoss, Markus; Hopfel, Dieter; Barth, Gerhard; Bolotina-Bezdetnaya, Lina

    1996-01-01

    Ultrasounds were described by a few authors as possibly inducing sonodynamic reaction, with singlet oxygen production, as photodynamic therapy. The aim of this project was to evidence this effect and to try to explain its different mechanisms. A specific device was developed with a strict control of temperature to avoid hyperthermia and of acoustical intensity: the characteristics of the US beam and the reproducibility of treatment conditions were strictly evaluated. We studied the frequency of 2.21 MHz using an antiresonance frequency of a transducer. US treatment was applied continuously or in pulsed mode. Human colorectal adenocarcinoma cells (HT-29) were used to test the cytotoxicity using trypan blue exclusion test. Analyses were performed using cell suspensions. Different intensities were studied ranging from 0 to 3.7 W/cm2. Moreover, fluorescence emission spectra of hematoporphyrine derivative (HpD) were recorded before and after US treatment. Results of viability showed a higher cytotoxicity with US alone or with HpD in cell suspensions from 3.7 W/cm2 (20% survival). These results show that cavitation alone can account for the cytotoxic effects of sonotherapy. In fact, cavitation is higher with continuous than with pulsed US treatment. No significant difference was found with or without HpD. HpD fluorescence spectra did not differ before and after US treatment suggesting that no modification of HpD structure was induced by US. Fluorescence spectra showed a very slow and small decrease in fluorescence intensity with time probably caused by the low interfering light used for the experiment. In conclusion, in our experiments, ultrasounds do not seem to induce any chemical reaction with photosensitizers, conversely to what was already reported. However, other photosensitizers, molecules and different cell lines (less resistant) must be studied in order to conclude about the absence of cytotoxicity of this technique.

  11. Muscle Recruitment and Coordination following Constraint-Induced Movement Therapy with Electrical Stimulation on Children with Hemiplegic Cerebral Palsy: A Randomized Controlled Trial.

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    Kaishou Xu

    Full Text Available To investigate changes of muscle recruitment and coordination following constraint-induced movement therapy, constraint-induced movement therapy plus electrical stimulation, and traditional occupational therapy in treating hand dysfunction.In a randomized, single-blind, controlled trial, children with hemiplegic cerebral palsy were randomly assigned to receive constraint-induced movement therapy (n = 22, constraint-induced movement therapy plus electrical stimulation (n = 23, or traditional occupational therapy (n = 23. Three groups received a 2-week hospital-based intervention and a 6-month home-based exercise program following hospital-based intervention. Constraint-induced movement therapy involved intensive functional training of the involved hand during which the uninvolved hand was constrained. Electrical stimulation was applied on wrist extensors of the involved hand. Traditional occupational therapy involved functional unimanual and bimanual training. All children underwent clinical assessments and surface electromyography (EMG at baseline, 2 weeks, 3 and 6 months after treatment. Surface myoelectric signals were integrated EMG, root mean square and cocontraction ratio. Clinical measures were grip strength and upper extremity functional test.Constraint-induced movement therapy plus electrical stimulation group showed both a greater rate of improvement in integrated EMG of the involved wrist extensors and cocontraction ratio compared to the other two groups at 3 and 6 months, as well as improving in root mean square of the involved wrist extensors than traditional occupational therapy group (p<0.05. Positive correlations were found between both upper extremity functional test scores and integrated EMG of the involved wrist as well as grip strength and integrated EMG of the involved wrist extensors (p<0.05.Constraint-induced movement therapy plus electrical stimulation is likely to produce the best outcome in improving muscle recruitment

  12. Autophagic degradation of farnesylated prelamin A as a therapeutic approach to lamin-linked progeria

    Directory of Open Access Journals (Sweden)

    V. Cenni

    2011-10-01

    Full Text Available Farnesylated prelamin A is a processing intermediate produced in the lamin A maturation pathway. Accumulation of a truncated farnesylated prelamin A form, called progerin, is a hallmark of the severe premature ageing syndrome, Hutchinson-Gilford progeria. Progerin elicits toxic effects in cells, leading to chromatin damage and cellular senescence and ultimately causes skin and endothelial defects, bone resorption, lipodystrophy and accelerated ageing. Knowledge of the mechanism underlying prelamin A turnover is critical for the development of clinically effective protein inhibitors that can avoid accumulation to toxic levels without impairing lamin A/C expression, which is essential for normal biological functions. Little is known about specific molecules that may target farnesylated prelamin A to elicit protein degradation. Here, we report the discovery of rapamycin as a novel inhibitor of progerin, which dramatically and selectively decreases protein levels through a mechanism involving autophagic degradation. Rapamycin treatment of progeria cells lowers progerin, as well as wild-type prelamin A levels, and rescues the chromatin phenotype of cultured fibroblasts, including histone methylation status and BAF and LAP2alpha distribution patterns. Importantly, rapamycin treatment does not affect lamin C protein levels, but increases the relative expression of the prelamin A endoprotease ZMPSTE24. Thus, rapamycin, an antibiotic belonging to the class of macrolides, previously found to increase longevity in mouse models, can serve as a therapeutic tool, to eliminate progerin, avoid farnesylated prelamin A accumulation, and restore chromatin dynamics in progeroid laminopathies.

  13. Endo-lysosomal and autophagic dysfunction: a driving factor in Alzheimer's disease?

    Science.gov (United States)

    Whyte, Lauren S; Lau, Adeline A; Hemsley, Kim M; Hopwood, John J; Sargeant, Timothy J

    2017-03-01

    Alzheimer's disease (AD) is the most common cause of dementia, and its prevalence will increase significantly in the coming decades. Although important progress has been made, fundamental pathogenic mechanisms as well as most hereditary contributions to the sporadic form of the disease remain unknown. In this review, we examine the now substantial links between AD pathogenesis and lysosomal biology. The lysosome hydrolyses and processes cargo delivered by multiple pathways, including endocytosis and autophagy. The endo-lysosomal and autophagic networks are central to clearance of cellular macromolecules, which is important given there is a deficit in clearance of amyloid-β in AD. Numerous studies show prominent lysosomal dysfunction in AD, including perturbed trafficking of lysosomal enzymes and accumulation of the same substrates that accumulate in lysosomal storage disorders. Examination of the brain in lysosomal storage disorders shows the accumulation of amyloid precursor protein metabolites, which further links lysosomal dysfunction with AD. This and other evidence leads us to hypothesise that genetic variation in lysosomal genes modifies the disease course of sporadic AD. © 2016 International Society for Neurochemistry.

  14. A systematic review of salivary gland hypofunction and xerostomia induced by cancer therapies: management strategies and economic impact

    DEFF Research Database (Denmark)

    Jensen, Siri Beier; Pedersen, Anne Marie Lynge; Vissink, Arjan

    2010-01-01

    This systematic review aimed to assess the literature for management strategies and economic impact of salivary gland hypofunction and xerostomia induced by cancer therapies and to determine the quality of evidence-based management recommendations. The electronic databases of MEDLINE/PubMed and E...

  15. Hyperbaric oxygen therapy for late radiation-induced tissue toxicity: prospectively patient-reported outcome measures in breast cancer patients

    NARCIS (Netherlands)

    Teguh, David N.; Bol Raap, René; Struikmans, Henk; Verhoef, Cees; Koppert, Linetta B.; Koole, Arne; Huang, Yadi; van Hulst, Rob A.

    2016-01-01

    This study examines patient reported outcome measures of women undergoing hyperbaric oxygen treatment (HBOT) after breast-conserving therapy. Included were 57 women treated with HBOT for late radiation-induced tissue toxicity (LRITT) referred in the period January 2014-December 2015. HBOT consisted

  16. Hyperbaric oxygen therapy for late radiation-induced tissue toxicity: Prospectively patient-reported outcome measures in breast cancer patients

    NARCIS (Netherlands)

    D.N. Teguh (David); R. Bol Raap (René); H. Struikmans (Henk); C. Verhoef (Kees); L.B. Koppert (Lisa); A. Koole (Arne); Y. Huang (Yadi); R.A. van Hulst (R.)

    2016-01-01

    markdownabstract__Introduction:__ This study examines patient reported outcome measures of women undergoing hyperbaric oxygen treatment (HBOT) after breast-conserving therapy. __Method:__ Included were 57 women treated with HBOT for late radiation-induced tissue toxicity (LRITT) referred in the

  17. Introduction to "The Behavior-Analytic Origins of Constraint-Induced Movement Therapy: An Example of Behavioral Neurorehabilitation"

    Science.gov (United States)

    Schaal, David W.

    2012-01-01

    This article presents an introduction to "The Behavior-Analytic Origins of Constraint-Induced Movement Therapy: An Example of Behavioral Neurorehabilitation," by Edward Taub and his colleagues (Taub, 2012). Based on extensive experimentation with animal models of peripheral nerve injury, Taub and colleagues have created an approach to overcoming…

  18. Constraint-Induced Movement Therapy for Children with Obstetric Brachial Plexus Palsy: Two Single-Case Series

    Science.gov (United States)

    Buesch, Francisca Eugster

    2010-01-01

    The objective of this pilot study was to investigate the feasibility of constraint-induced movement therapy (CIMT) in children with obstetric brachial plexus palsy and receive preliminary information about functional improvements. Two patients (age 12 years) with obstetric brachial plexus palsy were included for a 126-h home-based CIMT…

  19. In vivo protection against NMDA-induced neurodegeneration by MK-801 and nimodipine : Combined therapy and temporal course of protection

    NARCIS (Netherlands)

    Stuiver, BT; Douma, BRK; Bakker, R; Nyakas, C; Luiten, PGM

    Neuroprotection against excitotoxicity by a combined therapy with the N-methyl-D-aspartate (NMDA) receptor antagonist MK-801 and the L-type Ca2+ channel blocker nimodipine was examined using an in vivo rat model of NMDA-induced neurodegeneration. Attention was focused on the neuroprotective

  20. A systematic review of salivary gland hypofunction and xerostomia induced by cancer therapies : management strategies and economic impact

    NARCIS (Netherlands)

    Jensen, S. B.; Pedersen, A. M. L.; Vissink, A.; Andersen, E.; Brown, C. G.; Davies, A. N.; Dutilh, J.; Fulton, J. S.; Jankovic, L.; Lopes, N. N. F.; Mello, A. L. S.; Muniz, L. V.; Murdoch-Kinch, C. A.; Nair, R. G.; Napenas, J. J.; Nogueira-Rodrigues, A.; Saunders, D.; Stirling, B.; von Bueltzingsloewen, I.; Weikel, D. S.; Spijkervet, F. K. L.; Brennan, M. T.; Elting, L.

    This systematic review aimed to assess the literature for management strategies and economic impact of salivary gland hypofunction and xerostomia induced by cancer therapies and to determine the quality of evidence-based management recommendations. The electronic databases of MEDLINE/PubMed and

  1. Integrative analysis of kinase networks in TRAIL-induced apoptosis provides a source of potential targets for combination therapy

    DEFF Research Database (Denmark)

    So, Jonathan; Pasculescu, Adrian; Dai, Anna Y.

    2015-01-01

    /threonine kinase (PXK) and AP2-associated kinase 1 (AAK1), which promote receptor endocytosis and may enable cells to resist TRAIL-induced apoptosis by enhancing endocytosis of the TRAIL receptors. We assembled protein interaction maps using mass spectrometry-based protein interaction analysis and quantitative...... combination therapies to selectively kill cancer cells....

  2. Long-term therapy of interferon-alpha induced pulmonary arterial hypertension with different PDE-5 inhibitors: a case report

    Directory of Open Access Journals (Sweden)

    Baumann Gert

    2005-09-01

    Full Text Available Abstract background Interferon alpha2 is widely used in hepatitis and high-risk melanoma. Interferon-induced pulmonary arterial hypertension as a side effect is rare. Case presentation We describe a melanoma patient who developed severe pulmonary arterial hypertension 30 months after initiation of adjuvant interferon alpha2b therapy. Discontinuation of interferon did not improve pulmonary arterial hypertension. This patient could be treated successfully with phosphodiesterase-5 inhibitor therapy. Conclusion This is only the 5th case of interferon-induced pulmonary arterial hypertension and the first documented case where pulmonary arterial hypertension was not reversible after termination of interferon alpha2 therapy. If interferon alpha2 treated patients develop respiratory symptoms, pulmonary arterial hypertension should be considered in the differential diagnosis. For these patients phosphodiesterase-5 inhibitors, e.g. sildenafil or vardenafil, could be an effective therapeutic approach.

  3. Daclatasvir and Asunaprevir Combination Therapy-induced Hepatitis and Cholecystitis with Coagulation Disorder due to Hypersensitivity Reactions.

    Science.gov (United States)

    Miyashima, Yuichi; Honma, Yuichi; Miyagawa, Koichiro; Oe, Shinji; Senju, Michio; Shibata, Michihiko; Hiura, Masaaki; Abe, Shintaro; Harada, Masaru

    A 70-year-old woman with chronic hepatitis C was admitted to our hospital due to liver injury, cholecystitis, and disseminated intravascular coagulation with a fever and skin rash. She had been on a combination regimen of daclatasvir and asunaprevir for 2 weeks of a 24-week regimen. Because of the symptoms, laboratory findings, results of a drug-induced lymphocyte stimulation test, and pathological findings of liver biopsy, we diagnosed her with drug-induced liver injury. Although daclatasvir and asunaprevir combination therapy is generally well-tolerated, some serious adverse effects have been reported. Our findings indicate that immunoallergic mechanisms were associated with daclatasvir and asunaprevir-induced liver injury.

  4. Dietary L-Lysine Suppresses Autophagic Proteolysis and Stimulates Akt/mTOR Signaling in the Skeletal Muscle of Rats Fed a Low-Protein Diet.

    Science.gov (United States)

    Sato, Tomonori; Ito, Yoshiaki; Nagasawa, Takashi

    2015-09-23

    Amino acids, especially L-leucine, regulate protein turnover in skeletal muscle and have attracted attention as a means of increasing muscle mass in people suffering from malnutrition, aging (sarcopenia), or a bedridden state. We previously showed that oral administration of L-lysine (Lys) by gavage suppressed proteolysis in skeletal muscles of fasted rats. However, the intake of Lys in the absence of other dietary components is unlikely in a non-experimental setting, and other dietary components may interfere with the suppressive effect of Lys on proteolysis. We supplemented Lys to a 10% casein diet and investigated the effect of Lys on proteolysis and autophagy, a major proteolytic system, in the skeletal muscle of rats. The rate of proteolysis was evaluated from 3-methylhisitidine (MeHis) released from isolated muscles, in plasma, and excreted in urine. Supplementing lysine with the 10% casein diet decreased the rate of proteolysis induced by intake of a low-protein diet. The upregulated autophagy activity [light chain 3 (LC3)-II/total LC3] caused by a low-protein diet was reduced, and the Akt/mTOR signaling pathway was activated by Lys. Importantly, continuous feeding of a Lys-rich 10% casein diet for 15 days increased the masses of the soleus and gastrocnemius muscles. Taken together, supplementation of Lys to a low-protein diet suppresses autophagic proteolysis through the Akt/mTOR signaling pathway, and continuous feeding of a Lys-rich diet may increase skeletal muscle mass.

  5. Cardiac Resynchronization Therapy Relieves Intractable Angina Due to Exercise-Induced Left Bundle Branch Block Without Left Ventricular Systolic Dysfunction: A Detailed Case Study.

    Science.gov (United States)

    Czuriga, Daniel; Lim, Pitt O

    2016-05-01

    Exercise-induced left bundle branch block is rare and can be demonstrated with exercise testing. When the heart rate reaches a certain threshold, the QRS widens into left bundle branch block. This paper describes a patient with exercise-induced left bundle branch block related angina and dyspnea, who responded to cardiac resynchronization therapy. We documented the potential benefits of cardiac resynchronization therapy with a left ventricular rapid pacing study prior to its implantation. Although exercise-induced left bundle branch block is not a current indication for cardiac resynchronization therapy in patients such as ours, it could be considered when conventional drug therapy fails. © 2016 Wiley Periodicals, Inc.

  6. A randomised controlled trial of the effect of music therapy and verbal relaxation on chemotherapy-induced anxiety.

    Science.gov (United States)

    Lin, Mei-Feng; Hsieh, Ya-Ju; Hsu, Yu-Yun; Fetzer, Susan; Hsu, Mei-Chi

    2011-04-01

    To determine the effect of music therapy and verbal relaxation on state anxiety and anxiety-induced physiological manifestations among patients with cancer before and after chemotherapy. Cancer and its treatment provoke a series of changes in the emotional sphere of the patient's anxiety. Music therapy and verbal relaxation had reported the anxiety reduction effect on patients with cancer receiving chemotherapy. Few studies have been undertaken comparing music therapy and verbal relaxation in differentiating high-normal state anxiety subsample. A randomised controlled trial and permuted block design were used. Outpatient chemotherapy clinic operated by a University medical centre in southern Taiwan. Ninety-eight patients were randomised into three groups: the music therapy group received one-hour single music session; the verbal relaxation group received 30 minutes of guided relaxation; the control group received usual care. Spielberger State-Trait Anxiety Instrument, Emotional Visual Analog Scale, three biobehavioural indicators: skin temperature, heart rate and consciousness level were measured during and after chemotherapy. Music therapy had a greater positive effect on postchemotherapy anxiety than verbal relaxation and control groups and a significantly increase in skin temperature. Patients with high state anxiety receiving music therapy had a greater drop in postchemotherapy anxiety than did the normal state anxiety subsample. Both music and verbal relaxation therapy are effective in reducing chemotherapy-induced anxiety. Thirty minutes of intervention initiates anxiety reduction. Patients with high state anxiety receiving chemotherapy obtain the most benefit from music or verbal relaxation. Prior to chemotherapy, patients with high state anxiety must be sorted from all patients as they are more responsive to interventions. Oncology nurses can offer music and verbal relaxation as adjuvant interventions to reduce chemotherapy-induced anxiety and enhance the

  7. Tyrosine kinase inhibitor therapy-induced changes in humoral immunity in patients with chronic myeloid leukemia.

    Science.gov (United States)

    Rajala, Hanna L M; Missiry, Mohamed El; Ruusila, Anniina; Koskenvesa, Perttu; Brümmendorf, Tim H; Gjertsen, Bjorn T; Janssen, Jeroen; Lotfi, Kourosh; Markevärn, Berit; Olsson-Strömberg, Ulla; Stenke, Leif; Stentoft, Jesper; Richter, Johan; Hjorth-Hansen, Henrik; Kreutzman, Anna; Mustjoki, Satu

    2017-08-01

    Tyrosine kinase inhibitors (TKIs) have well-characterized immunomodulatory effects on T and NK cells, but the effects on the humoral immunity are less well known. In this project, we studied TKI-induced changes in B cell-mediated immunity. We collected peripheral blood (PB) and bone marrow (BM) samples from chronic myeloid leukemia (CML) patients before and during first-line imatinib (n = 20), dasatinib (n = 16), nilotinib (n = 8), and bosutinib (n = 12) treatment. Plasma immunoglobulin levels were measured, and different B cell populations in PB and BM were analyzed with flow cytometry. Imatinib treatment decreased plasma IgA and IgG levels, while dasatinib reduced IgM levels. At diagnosis, the proportion of patients with IgA, IgG, and IgM levels below the lower limit of normal (LLN) was 0, 11, and 6% of all CML patients, respectively, whereas at 12 months timepoint the proportions were 6% (p = 0.13), 31% (p = 0.042) and 28% (p = 0.0078). Lower initial Ig levels predisposed to the development of hypogammaglobulinemia during TKI therapy. Decreased Ig levels in imatinib-treated patients were associated with higher percentages of immature BM B cells. The patients, who had low Ig levels during the TKI therapy, had significantly more frequent minor infections during the follow-up compared with the patients with normal Ig values (33% vs. 3%, p = 0.0016). No severe infections were reported, except recurrent upper respiratory tract infections in one imatinib-treated patient, who developed severe hypogammaglobulinemia. TKI treatment decreases plasma Ig levels, which should be measured in patients with recurrent infections.

  8. Renal replacement therapies for prevention of radiocontrast-induced nephropathy: a systematic review.

    Science.gov (United States)

    Cruz, Dinna N; Goh, Ching Yan; Marenzi, Giancarlo; Corradi, Valentina; Ronco, Claudio; Perazella, Mark A

    2012-01-01

    Radiocontrast-induced nephropathy (RCIN) is an important cause of acute kidney injury, increasing in-hospital and long-term mortality. It is controversial whether prophylactic renal replacement therapy (RRT) may reduce a patient's risk of RCIN when compared with standard medical therapy (SMT). We searched through PubMed and bibliographies of retrieved articles. Published studies of RRT for RCIN prevention in patients receiving radiocontrast were included. The primary endpoint was RCIN incidence, defined as an increase in serum creatinine ≥0.5 mg/dL. Results were combined on the risk ratio (RR) scale. Random-effects models were used. Sensitivity analyses were defined a priori to evaluate the effects of RRT modality, study design, and sample size. Nine randomized controlled and 2 nonrandomized trials were included (n = 1010 patients); 8 studies used hemodialysis (HD) and 3 used hemofiltration or hemodiafiltration. Nine studies had data for primary endpoint; RCIN incidence was 23.3% in the RRT group and 21.2% in SMT. RRT did not decrease RCIN incidence compared with SMT (risk ratio [RR] 1.02; 95% confidence interval [CI], 0.54-1.93); however, intertrial heterogeneity was high. In sensitivity analyses, limiting to only HD studies significantly reduced heterogeneity. HD appeared to increase RCIN risk (RR 1.61; 95% CI, 1.13-2.28) and had no effect on need for permanent RRT or progression to end-stage renal disease (RR 1.47; 95% CI, 0.56-3.89). In this updated meta-analysis, periprocedural RRT did not decrease the incidence of RCIN compared with SMT. HD appears to actually increase RCIN risk. Copyright © 2012 Elsevier Inc. All rights reserved.

  9. Woodchuck hepatitis virus-induced carcinoma as a relevant natural model for therapy of human hepatoma.

    Science.gov (United States)

    Gouillat, C; Manganas, D; Zoulim, F; Vitrey, D; Saguier, G; Guillaud, M; Ain, J F; Duque-Campos, R; Jamard, C; Praves, M; Trepo, C

    1997-06-01

    Eastern American woodchuck (Marmota monax), naturally infected with woodchuck hepatitis virus, a virus similar to human hepatitis B virus, develops liver cancer with a high prevalence. The aim of this work was to assess Marmota monax as a model of human hepatocellular carcinoma, especially to assess new potential adjuvant therapies after surgical resection. Forty-four woodchuck hepatitis virus-infected animals were regularly screened by ultrasound examination from the age of 18 months and for a 30-month period. One or more liver tumors were diagnosed in 31 animals (70%). Five of them with multifocal tumor or poor general status were considered unsuitable for surgery. The other 26 were operated on. At laparotomy no tumor was found in three. The 18 liver tumors studied were hepatocellular carcinomas, grossly and microscopically similar to human hepatocellular carcinoma. Peritumoral parenchyma studied in 13 specimens was always non-cirrhotic but adequate staining demonstrated patterns of fibrosis in four cases. Clear evidence of chronic active hepatitis, periportal hepatitis and steatosis were demonstrated in five, seven and one of the 13 specimens, respectively. Tumors were treated by tumorectomy in eight animals, by alcoholization in seven and by laser photocoagulation in one. A simple tumor biopsy was performed in the other seven. Ten animals died postoperatively. All the survivors in the tumorectomy group died from tumor recurrence within 10-18 months after surgery. It is concluded that woodchuck hepatitis virus-induced liver carcinoma is a natural model of human hepatocellular carcinoma with similar pathology and natural history, including early ultrasonic detection and tumor recurrence after resection. Tumor excision is feasible in this animal model, which now provides the basis for assessment of new potential adjuvant therapies for human hepatocellular carcinoma in an attempt to reduce the high recurrence rate after surgical resection in humans.

  10. Patients with moderate chemotherapy-induced mucositis: pain therapy using low intensity lasers.

    Science.gov (United States)

    Nes, A G; Posso, M B S

    2005-03-01

    Intensive cancer therapy normally affects malignant and normal cells with high replication rates. Cells in the gastrointestinal tract are therefore commonly affected by cytotoxins. This often results in the development of chemotherapy-induced oral mucositis (COM). COM is the inflammatory response of the oral mucous membrane to the chemotherapy drugs. Low level laser therapy (LLLT) has proved to be effective in treating and repairing biologically damaged tissue and to reduce pain. LLLT has also proven to be an efficient method for the prevention of oral mucositis. To investigate the effect of LLLT on pain relief among patients who have developed COM. The study was performed as a clinical test with a sample consisting of 13 adult patients receiving oncology treatment. The patients were treated during a 5-day period, and the pain was measured before and after each laser application. The laser used was an AsGaAl, with a wavelength of 830 nm and a potency of 250 mW. The energy given was 35 J cm(-2). The results were analysed using the Wilcoxon test. There was a significant (P = 0.007) 67% decrease in the daily average experience of pain felt before and after each treatment, confirming that LLLT can relieve pain among patients who have developed COM. The low number of COM patients at the hospital did not allow a control group to be included in the study, and therefore the results contain a potential placebo effect. IMPLICATIONS FOR NURSING CARE: The most important benefit the authors consider to be the value for the patients of better and quicker treatment with a drastic reduction in painful mucositis.

  11. Ultrasonographic assessment of the cutaneous changes induced by topical flavonoid therapy

    Directory of Open Access Journals (Sweden)

    Crisan D

    2012-01-01

    Full Text Available Diana Crisan1, Maria Crisan2, Mirela Moldovan3, Monica Lupsor4, Radu Badea41Student, Faculty of Medicine, 2Department of Histology, 3Department of Dermopharmacy and Cosmetics, 4Department of Ultrasonography, University of Medicine and Pharmacy “Iuliu Hatieganu” Cluj-Napoca, RomaniaAbstract: Ultrasonography allows the quantification of dermal density and echogenicity changes during the physiological senescence process. Some active ingredients are able to slow down the tissular degeneration and disorganization process. The purpose of this study was to assess the cutaneous changes induced by the topical use of products containing Viniferol® as active ingredient, using high-frequency ultrasound. The study was performed over 12 weeks and included 80 healthy Caucasian female subjects, aged 22–75 years, divided into two groups: the study group and the control group. The product was applied according to a predetermined protocol. The measurements performed for each subject were: the thickness of the epidermis and dermis (mm, the number of low, medium, and high echogenic pixels, and the number of low echogenic pixels in the upper dermis/number of low echogenic pixels in the lower dermis. All the parameters showed a significant improvement. Ultrasound measurements showed an increase of the mean thickness of the epidermis (P < 0.0001 and dermis (P < 0.0001 following the application of the Viniferol product as compared to the control group. The changes in the dermal echogenicity confirm the efficacy and direct action of Viniferol upon the cutaneous fibroblasts. No side effects related to the treatment were recorded. The study proves the efficacy of this active ingredient in the cutaneous senescence process as well, as the fact that anti-aging prophylaxis should be initiated in the 20–40 year critical age group. This interval involves specific changes in dermal echogenicity that quantify intense molecular, biochemical and structural changes, being

  12. Radiation Therapy Induces Macrophages to Suppress Immune Responses Against Pancreatic Tumors in Mice

    Science.gov (United States)

    Seifert, Lena; Werba, Gregor; Tiwari, Shaun; Ly, Nancy Ngoc Giao; Nguy, Susanna; Alothman, Sara; Alqunaibit, Dalia; Avanzi, Antonina; Daley, Donnele; Barilla, Rocky; Tippens, Daniel; Torres-Hernandez, Alejandro; Hundeyin, Mautin; Mani, Vishnu R.; Hajdu, Cristina; Pellicciotta, Ilenia; Oh, Philmo; Du, Kevin; Miller, George

    2016-01-01

    Background & Aims The role of radiation therapy in the treatment of patients with pancreatic ductal adenocarcinoma (PDA) is controversial. Randomized controlled trials investigating the efficacy of radiation therapy in patients with locally advanced unresectable PDA have reported mixed results, with effects ranging from modest benefit to worse outcome, compared with control therapies. We investigated whether radiation causes inflammatory cells to acquire an immune-suppressive phenotype that limits the therapeutic effects of radiation on invasive PDAs and accelerates progression of pre-invasive foci. Methods We investigated the effects of radiation in p48Cre;LSL-KrasG12D (KC) and p48Cre;LSLKrasG12D;LSL-Trp53R172H (KPC) mice, as well as in C57BL/6 mice with orthotopic tumors grown from FC1242 cells derived from KPC mice. Some mice were given neutralizing antibodies against macrophage colony stimulating factor 1 (CSF1 or MCSF) or F4/80. Pancreata were exposed to doses of radiation ranging from 2–12 Gy and analyzed by flow cytometry. Results Pancreata of KC mice exposed to radiation had a higher frequency of advanced pancreatic intraepithelial lesions and more foci of invasive cancer than pancreata of unexposed mice (controls); radiation reduced survival time by more than 6 months. A greater proportion of macrophages from invasive and pre-invasive pancreatic tumors had an immune-suppressive, M2-like phenotype, compared with control mice. Pancreata from mice exposed to radiation had fewer CD8+ T cells than controls and greater numbers of CD4+ T cells of T-helper 2 and T-regulatory cell phenotypes. Adoptive transfer of T cells from irradiated PDA to tumors of control mice accelerated tumor growth. Radiation induced production of MCSF by PDA cells. An antibody against MCSF prevented radiation from altering the phenotype of macrophages in tumors, increasing the anti-tumor T-cell response and slowing tumor growth. Conclusions Radiation exposure causes macrophages in PDAs

  13. Effects of photobiomodulation therapy, pharmacological therapy, and physical exercise as single and/or combined treatment on the inflammatory response induced by experimental osteoarthritis.

    Science.gov (United States)

    Tomazoni, Shaiane Silva; Leal-Junior, Ernesto Cesar Pinto; Pallotta, Rodney Capp; Teixeira, Simone; de Almeida, Patricia; Lopes-Martins, Rodrigo Álvaro Brandão

    2017-01-01

    Osteoarthritis (OA) triggers increased levels of inflammatory markers, including prostaglandin (PG) E2 and proinflammatory cytokines. The elevation of cytokine levels is closely associated with increased articular tissue degeneration. Thus, the use of combination therapies may presumably be able to enhance the effects on the modulation of inflammatory markers. The present study aimed to evaluate and compare the effects of photobiomodulation therapy (PBMT), physical exercise, and topical nonsteroidal anti-inflammatory drug (NSAID) use on the inflammatory process after they were applied either alone or in different combinations. OA was induced by intra-articular papain injection in the knee of rats. After 21 days, the animals began treatment with a topical NSAID and/or with physical exercise and/or PBMT. Treatments were performed three times a week for eight consecutive weeks, totaling 24 therapy sessions. Analysis of real-time polymerase chain reaction (RT-PCR) gene expression; interleukin (IL)-1β, IL-6, and tumor necrosis factor alpha (TNF-α) protein expression; and PGE2 levels by enzyme-linked immunosorbent assay (ELISA) was conducted. Our results showed that PBMT alone and Exerc + PBMT significantly reduced IL-1β gene expression (p treatment changed both IL-6 and TNF-α gene expression. Treatment with NSAID alone, PBMT alone, Exerc + PBMT, and NSAID + PBMT reduced IL-1β protein expression (p therapies significantly reduced IL-6 and TNF-α protein expression (p therapies, except Exerc, reduced the levels of PGE2 (p treatment with PBMT is more effective in modulating the inflammatory process underlying OA when compared with the other therapies tested.

  14. Screening of microbial radiation-inducible promoter and study of its expression; Development of basic technique of radiogenic therapy

    Energy Technology Data Exchange (ETDEWEB)

    Lim, Sangyong; Kim Dongho; Yang, Jaeseung

    2007-02-15

    In the search for new therapeutic modalities for cancer, gene therapy has attracted enormous interest over the last few years. Recently, the use of bacteria as a tumor specific protein transfer system has attracted interest. Attenuated Salmonella has been shown to provide selective colonization in tumors. This strategy to apply gene therapy for cancer has been defined as 'Radiogenic Therapy'. In this research, firstly, we screened a radiation inducible promoter of Salmonella responding to clinically relevant low dose of 10 Gy using microarray analysis. Of all genes showing a expression ratio of at least 2-fold changes relative to wild type, 168 genes were induced. To confirm the findings of the microarray by an alternative method, we investigated the transcriptional changes of radio-inducible genes using real time PCR analysis. To verify the ability of screened genes (fadB, narK, cyoA, STM1011, STM2617, and STM2632) to produce a downstream protein by irradiation, the reporter plasmids were constructed. Finally, we found that the promoter of fadB, cyoA, and STM2617 can be activated by irradiation within cancer cells. These results suggest that these genes may be the most probable candidate used in radiogenic therapy.

  15. Modified constraint-induced movement therapy improves fine and gross motor performance of the upper limb in Parkinson disease.

    Science.gov (United States)

    Lee, Kyoung-Suk; Lee, Wan-Hee; Hwang, Sujin

    2011-05-01

    The purpose of this study was to examine the effect of modified constraint-induced movement therapy on hand and arm functions in people with Parkinson disease. Twenty individuals with Parkinson disease participated in the study. The experimental group (ten subjects) performed modified constraint-induced movement therapy for 4 wks (3 hrs/day, 5 days/wk), whereas the control group performed general upper limb exercises on the same schedule. The outcome measures both pretest and posttest were the box and block test, Fugl-Meyer assessment, and action research arm test. The scores for the box and block test in the experimental group increased from 35.8 ± 2.6 to 44.8 ± 3.4 after training. Total scores for the Fugl-Meyer assessment in the experimental group significantly increased from 33.6 ± 1.5 to 53.7 ± 3.1 after training. Greater improvement in action research arm test scores were observed in the experimental group (from 35.1 ± 4.9 to 50.8 ± 3.6) than in the general exercise group (from 33.1 ± 2.2 to 34.8 ± 2.7). Modified constraint-induced movement therapy improves fine and gross motor performances of the upper limb in people with Parkinson disease. Therefore, the therapy would be recommended as an effective treatment for them.

  16. Cryo-thermal therapy elicits potent anti-tumor immunity by inducing extracellular Hsp70-dependent MDSC differentiation

    Science.gov (United States)

    Zhu, Jun; Zhang, Yan; Zhang, Aili; He, Kun; Liu, Ping; Xu, Lisa X.

    2016-01-01

    Achieving control of metastatic disease is a long-sought goal in cancer therapy. Treatments that encourage a patient’s own immune system are bringing new hopes in reaching such a goal. In clinic, local hyperthermia and cryoablation have been explored to induce anti-tumor immune responses against tumors. We have also developed a novel therapeutic modality of cryo-thermal treatment by alternating liquid nitrogen (LN2) cooling and radio frequency (RF) heating, and better therapeutic effect was achieved in treating metastatic cancer in animal model. In this study, we investigated the mechanism of systemic immune response elicited by cryo-thermal therapy. In the 4T1 murine mammary carcinoma model, we found that local cryo-thermal therapy resulted in a considerable reduction of distant lung metastases, and improved long-term survival. Moreover, results of tumor re-challenge experiments indicated generation of a strong tumor-specific immune memory after the local treatment of primary tumors. Our further study indicated that cryo-thermal therapy caused an elevated extracellular release of Hsp70. Subsequently, Hsp70 induced differentiation of MDSCs into mature DCs, contributing to the relief of MDSCs-mediated immunosuppression and ultimately the activation of strong anti-tumor immune response. Our findings reveal new insight into the mechanism of robust therapeutic effects of cryo-thermal therapy against metastatic cancers. PMID:27256519

  17. Effect of laser therapy on the inflammatory response induced by endodontic medications implanted into the subcutaneous tissue of rats

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    Felipe de Souza MATOS

    Full Text Available INTRODUCTION: Endodontic medications contain toxic components that cause varying degrees of inflammation.OBJECTIVE: This study evaluated the effect of laser therapy on the inflammatory response induced by intracanal medications implanted into the subcutaneous tissue of rats using a quantitative analysis of mast cells.MATERIAL AND METHOD: Polyethylene tubes containing the medications were implanted in the dorsum of 60 rats divided into six groups, including HS (P.A. calcium hydroxide paste, HL (P.A. calcium hydroxide paste and laser therapy, HPS (P.A. calcium hydroxide paste with camphorated paramonochlorophenol, HPL (P.A. calcium hydroxide paste with camphorated paramonochlorophenol and laser therapy, IS (iodoform with saline and IL (iodoform with saline and laser therapy. The animals were euthanized eight or fifteen days after surgery, and samples were removed and embedded in paraffin. Histological sections were stained with 0.2% toluidine blue for the quantification of mast cells. Analysis of variance (ANOVA and Tukey's post-hoc test were applied to determine significant differences in the number of mast cells between groups (p<0.05.RESULT: There was a decrease in mast cells for the HL, HPL and IL groups when compared with the HS, HPS and IS groups at both time points. There was no statistically significant difference between the HPS and HPL groups at the eight-day time point.CONCLUSION: Laser therapy was effective at modulating the inflammatory response induced by endodontic medications by significantly reducing the number of mast cells.

  18. Cryo-thermal therapy elicits potent anti-tumor immunity by inducing extracellular Hsp70-dependent MDSC differentiation

    Science.gov (United States)

    Zhu, Jun; Zhang, Yan; Zhang, Aili; He, Kun; Liu, Ping; Xu, Lisa X.

    2016-06-01

    Achieving control of metastatic disease is a long-sought goal in cancer therapy. Treatments that encourage a patient’s own immune system are bringing new hopes in reaching such a goal. In clinic, local hyperthermia and cryoablation have been explored to induce anti-tumor immune responses against tumors. We have also developed a novel therapeutic modality of cryo-thermal treatment by alternating liquid nitrogen (LN2) cooling and radio frequency (RF) heating, and better therapeutic effect was achieved in treating metastatic cancer in animal model. In this study, we investigated the mechanism of systemic immune response elicited by cryo-thermal therapy. In the 4T1 murine mammary carcinoma model, we found that local cryo-thermal therapy resulted in a considerable reduction of distant lung metastases, and improved long-term survival. Moreover, results of tumor re-challenge experiments indicated generation of a strong tumor-specific immune memory after the local treatment of primary tumors. Our further study indicated that cryo-thermal therapy caused an elevated extracellular release of Hsp70. Subsequently, Hsp70 induced differentiation of MDSCs into mature DCs, contributing to the relief of MDSCs-mediated immunosuppression and ultimately the activation of strong anti-tumor immune response. Our findings reveal new insight into the mechanism of robust therapeutic effects of cryo-thermal therapy against metastatic cancers.

  19. The Role of Endogenous Neurogenesis in Functional Recovery and Motor Map Reorganization Induced by Rehabilitative Therapy after Stroke in Rats.

    Science.gov (United States)

    Shiromoto, Takashi; Okabe, Naohiko; Lu, Feng; Maruyama-Nakamura, Emi; Himi, Naoyuki; Narita, Kazuhiko; Yagita, Yoshiki; Kimura, Kazumi; Miyamoto, Osamu

    2017-02-01

    Endogenous neurogenesis is associated with functional recovery after stroke, but the roles it plays in such recovery processes are unknown. This study aims to clarify the roles of endogenous neurogenesis in functional recovery and motor map reorganization induced by rehabilitative therapy after stroke by using a rat model of cerebral ischemia (CI). Ischemia was induced via photothrombosis in the caudal forelimb area of the rat cortex. First, we examined the effect of rehabilitative therapy on functional recovery and motor map reorganization, using the skilled forelimb reaching test and intracortical microstimulation. Next, using the same approaches, we examined how motor map reorganization changed when endogenous neurogenesis after stroke was inhibited by cytosine-β-d-arabinofuranoside (Ara-C). Rehabilitative therapy for 4 weeks after the induction of stroke significantly improved functional recovery and expanded the rostral forelimb area (RFA). Intraventricular Ara-C administration for 4-10 days after stroke significantly suppressed endogenous neurogenesis compared to vehicle, but did not appear to influence non-neural cells (e.g., microglia, astrocytes, and vascular endothelial cells). Suppressing endogenous neurogenesis via Ara-C administration significantly inhibited (~50% less than vehicle) functional recovery and RFA expansion (~33% of vehicle) induced by rehabilitative therapy after CI. After CI, inhibition of endogenous neurogenesis suppressed both the functional and anatomical markers of rehabilitative therapy. These results suggest that endogenous neurogenesis contributes to functional recovery after CI related to rehabilitative therapy, possibly through its promotion of motor map reorganization, although other additional roles cannot be ruled out. Copyright © 2017 National Stroke Association. Published by Elsevier Inc. All rights reserved.

  20. Gross motor outcomes in children with hemiparesis involved in a modified constraint-induced therapy program.

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    Gillick, Bernadette T; Koppes, Amanda

    2010-01-01

    Constraint-Induced Therapy (CIT) has been used in pediatric rehabilitation and targets upper extremity (UE) outcomes. The purpose of this study was to measure concurrent gross motor and lower extremity functional changes using the Gross Motor Function Measure (GMFM) before and after a modified UE CIT program. The Assisting Hand Assessment (AHA) was used to evaluate upper extremity outcomes. Before-after trial design of a 19-day outpatient CIT program at Seattle Children's Hospital in Seattle, WA, USA of six ambulatory children with spastic hemiparesis between the ages of 5 and 11 years with GMFCS scores of 1. GMFM Section D (Standing) and E (Walking, Running, Jumping) and AHA scores were obtained before and after a modified CIT program. Significant differences were found between pre and post-CIT AHA and GMFM section D and E scores (p children improved from baseline, yet the child with the lowest initial scores revealed the greatest improvements. Improvements in GMFM and AHA scores were noted after a modified CIT program. Such data suggests that CIT may also influence rehabilitation outcomes not only specific to the upper extremity and warrants further investigation.

  1. Dosimetric study of photobiomodulation therapy in 5-FU-induced oral mucositis in hamsters

    Science.gov (United States)

    Cotomacio, Claudia Carrara; Campos, Luana; Nesadal de Souza, Douglas; Arana-Chavez, Victor Elias; Simões, Alyne

    2017-01-01

    Oral mucositis (OM) is a debilitating consequence of cancer treatment that could be treated with photobiomodulation therapy (PBMT); however, there is no consensus about its dosimetric parameters for OM healing. The aim of this study was to compare different PBMT protocols on OM treatment, through clinical and histological analysis. Thirty hamsters were used, in an induced model of OM by 5-fluorouracil (5-FU) and superficial scratching, in seven days of follow-up. The animals were divided into five groups: control (C), which received only anesthesia and chemotherapeutic vehicle; chemotherapy (Ch), which received anesthesia, 5-FU, and scratches; laser 1 (L1), the same as Ch group, PBMT 6 J/cm2 and 0.24 J (one point); laser 2 (L2), the same as Ch group, PBMT 25 J/cm2 and 1 J (one point); and laser 3 (L3), the same as Ch group, PBMT 4 points of 0.24 J and 6 J/cm2 each. The laser used has λ=660 nm, 0.04 cm2 of spot area, and 40 mW. The best PBMT protocol to maintain lowest OM levels compared to Ch group was L1, followed by L2 and L3. Our results suggest that the application mode of PBMT and the energy delivered per area could interfere with the OM healing.

  2. Therapy-induced effects in normal tissue; Therapieinduzierte Effekte am Normalgewebe

    Energy Technology Data Exchange (ETDEWEB)

    Kaick, G. van; Delorme, S. [Deutsches Krebsforschungszentrum (DKFZ), Abteilung E010 - Radiologie, Heidelberg (Germany)

    2008-09-15

    More than 50% of cancer patients survive for more than 5 years, owing to modern and effective treatment. Therefore, long-term sequelae of treatment are more frequently seen than in the past. Such effects on normal tissue may both mimic and obscure tumor recurrences. Besides the direct consequences of surgery, tissue damage due to radiation or chemotherapy frequently cause problems in differential diagnosis. Among the numerous sequelae of radiotherapy, the most prominent are disturbance of the blood-brain barrier, radiation pneumonitis, osteodystrophy and osteoradionecrosis, fatty changes of bone marrow, or increased radiodensity of breast parenchyma. Chemotherapy may cause, e.g., diffuse abnormalities of white matter, pneumonitis and lung fibrosis, cardiomyopathy, or diffuse and patchy changes in bone marrow signals in MRI. The most devastating long-term complications are secondary cancers and leukemia induced by both radiotherapy and chemotherapy. (orig.) [German] Mehr als 50% der Tumorpatienten ueberleben dank moderner Therapie laenger als 5 Jahre, sodass die Spaetfolgen am gesunden Gewebe haeufiger und genauer erfasst werden. Diese koennen Tumorrezidive sowohl verschleiern als auch vortaeuschen. Neben den unmittelbaren Folgen operativer Eingriffe sind Auswirkungen der Chemo- und Strahlentherapie ein haeufiges differenzialdiagnostisches Problem. Wichtige Folgen einer Strahlentherapie sind z. B. Blut-Hirn-Schranken-Stoerungen, Strahlenpneumonitis, Osteodystrophie und -radionekrose, Verfettung des blutbildenden Knochenmarks oder Parenchymverdichtungen der Brust. Chemotherapie kann u. a. zur Leukenzephalopathie, Pneumonitis und Lungenfibrose, Kardiomyopathie sowie zu diffusen und fleckfoermigen Signalaenderungen des Knochenmarks in der MRT fuehren. Die schwerstwiegende Spaetkomplikation ist die Induktion solider Zweittumoren und Leukaemien sowohl nach Strahlen- als auch Chemotherapie. (orig.)

  3. Attenuation of anti-tuberculosis therapy induced hepatotoxicity by Spirulina fusiformis, a candidate food supplement.

    Science.gov (United States)

    Martin, Sherry Joseph; Baskaran, Udhaya Lavinya; Vedi, Mahima; Sabina, Evan Prince

    2014-12-01

    Therapy using Isoniazid (INH) and Rifampicin (RIF) leads to induction of hepatotoxicity in some individuals undergoing anti-tuberculosis treatment. In this study, we assessed the effect of Spirulina fusiformis on INH and RIF induced hepatotoxicity in rats compared with hepatoprotective drug Silymarin. Induction of hepatotoxicity was measured by changes in the liver marker enzymes (aspartate transaminase, alanine transaminase, and alkaline phosphatase). The antioxidant status was also analyzed in liver tissue homogenate and plasma by measurement of superoxide dismutase, catalase, glutathione-S-transferase, glutathione reductase, and lipid peroxidation levels. We also aimed to study the binding and interactions of the transcription factors Pregnane X Receptor (PXR) and Farnesoid X Receptor (FXR) with INH, RIF, and representative active compounds of Spirulina fusiformis by in silico methods. The administration of INH and RIF resulted in significant (p Spirulina fusiformis was seen to protect the parameters from significant changes upon challenge with INH and RIF in a dose-dependent manner. This was corroborated by histological examination of the liver. The results of the in silico analyses further support the wet lab results.

  4. Testosterone Replacement Therapy Prevents Alterations of Coronary Vascular Reactivity Caused by Hormone Deficiency Induced by Castration.

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    Wender Nascimento Rouver

    Full Text Available The present study aimed to determine the effects of chronic treatment with different doses of testosterone on endothelium-dependent coronary vascular reactivity in male rats. Adult male rats were divided into four experimental groups: control (SHAM, castrated (CAST, castrated and immediately treated subcutaneously with a physiological dose (0.5 mg/kg/day, PHYSIO group or supraphysiological dose (2.5 mg/kg/day, SUPRA group of testosterone for 15 days. Systolic blood pressure (SBP was assessed at the end of treatment through tail plethysmography. After euthanasia, the heart was removed and coronary vascular reactivity was assessed using the Langendorff retrograde perfusion technique. A dose-response curve for bradykinin (BK was constructed, followed by inhibition with 100 μM L-NAME, 2.8 μM indomethacin (INDO, L-NAME + INDO, or L-NAME + INDO + 0.75 μM clotrimazole (CLOT. We observed significant endothelium-dependent, BK-induced coronary vasodilation, which was abolished in the castrated group and restored in the PHYSIO and SUPRA groups. Furthermore, castration modulated the lipid and hormonal profiles and decreased body weight, and testosterone therapy restored all of these parameters. Our results revealed an increase in SBP in the SUPRA group. In addition, our data led us to conclude that physiological concentrations of testosterone may play a beneficial role in the cardiovascular system by maintaining an environment that is favourable for the activity of an endothelium-dependent vasodilator without increasing SBP.

  5. Hyperpolarized Helium-3 MRI of exercise-induced bronchoconstriction during challenge and therapy.

    Science.gov (United States)

    Kruger, Stanley J; Niles, David J; Dardzinski, Bernard; Harman, Amy; Jarjour, Nizar N; Ruddy, Marcella; Nagle, Scott K; Francois, Christopher J; Sorkness, Ronald L; Burton, Ryan M; Munoz del Rio, Alejandro; Fain, Sean B

    2014-05-01

    To investigate the utility of hyperpolarized He-3 MRI for detecting regional lung ventilated volume (VV) changes in response to exercise challenge and leukotriene inhibitor montelukast, human subjects with exercise induced bronchoconstriction (EIB) were recruited. This condition is described by airway constriction following exercise leading to reduced forced expiratory volume in 1 second (FEV1) coinciding with ventilation defects on hyperpolarized He-3 MRI. Thirteen EIB subjects underwent spirometry and He-3 MRI at baseline, postexercise, and postrecovery at multiple visits. On one visit montelukast was given and on two visits placebo was given. Regional VV was calculated in the apical/basilar dimension, in the anterior/posterior dimension, and for the entire lung volume. The whole lung VV was used as an end-point and compared with spirometry. Postchallenge FEV1 dropped with placebo but not with treatment, while postchallenge VV dropped more with placebo than treatment. Sources of variability for VV included region (anterior/posterior), scan, and treatment. VV correlated with FEV1/ forced vital capacity (FVC) and forced expiratory flow between 25 and 75% of FVC and showed gravitational dependence after exercise challenge. A paradigm testing the response of ventilation to montelukast revealed both a whole-lung and regional response to exercise challenge and therapy in EIB subjects. Copyright © 2013 Wiley Periodicals, Inc.

  6. Induced pluripotent stem cell technology for modelling and therapy of cerebellar ataxia.

    Science.gov (United States)

    Watson, Lauren M; Wong, Maggie M K; Becker, Esther B E

    2015-07-01

    Induced pluripotent stem cell (iPSC) technology has emerged as an important tool in understanding, and potentially reversing, disease pathology. This is particularly true in the case of neurodegenerative diseases, in which the affected cell types are not readily accessible for study. Since the first descriptions of iPSC-based disease modelling, considerable advances have been made in understanding the aetiology and progression of a diverse array of neurodegenerative conditions, including Parkinson's disease and Alzheimer's disease. To date, however, relatively few studies have succeeded in using iPSCs to model the neurodegeneration observed in cerebellar ataxia. Given the distinct neurodevelopmental phenotypes associated with certain types of ataxia, iPSC-based models are likely to provide significant insights, not only into disease progression, but also to the development of early-intervention therapies. In this review, we describe the existing iPSC-based disease models of this heterogeneous group of conditions and explore the challenges associated with generating cerebellar neurons from iPSCs, which have thus far hindered the expansion of this research.

  7. Studies on the mechanism of photodynamic-therapy-induced tumor destruction

    Science.gov (United States)

    Fingar, Victor H.; Wieman, Thomas J.

    1990-07-01

    There exists little doubt that profound changes occur to both tumor and normal tissue microvasculature during photodynamic therapy, and that these changes are important in the process of tumor destruction. We hypothesize that singlet oxygen, produced during light activation of photosensitizer, interacts with cellular membranes and induces the release of arachidonic acid metabolites, notably thromboxane, into the intravascular environment. This leads to vasoconstriction, platelet aggregation, and hemostasis. To test this hypothesis, we have measured the release of thromboxane into serum as a function of porphyrin and light doses used in phototherapy. Sprague Dawley rats bearing chondrosarcoma in the right hind limb were injected with 0-25 mg/kg Photofrin IP'. A catheter was implanted in the carotid artery 24 h later, and the hind limb exposed to 0-135 J/cm2 630 nm light. Immediately after treatment, serum was collected and thromboxane levels were measured by radioimmunoassay. We found significant increases in systemic thromboxane concentrations following phototherapy at the highest porphyrin and light doses, compared to drug and light controls. The administration of indomethacin (10 mg/kg i.p.) prior to treatment suppressed the release of thromboxane from tumor and normal tissues and inhibited hemostasis and tumor response to phototherapy. These studies have reinforced the important role of arachidonic acid metabolites in producing vascular damage during phototherapy.

  8. Constraint-induced aphasia therapy stimulates language recovery in patients with chronic aphasia after ischemic stroke.

    Science.gov (United States)

    Szaflarski, Jerzy P; Ball, Angel; Grether, Sandra; Al-Fwaress, Firas; Griffith, Nathan M; Neils-Strunjas, Jean; Newmeyer, Amy; Reichhardt, Robert

    2008-05-01

    Constraint-induced aphasia therapy (CIAT) offers potential benefits to individuals with history of aphasia-producing ischemic stroke. The goals of this pilot study were to implement the original German CIAT protocol, refine the treatment program, and confirm its efficacy in patients with chronic aphasia. We translated and modified the original CIAT protocol to include a hierarchy of individual skill levels for semantic, syntactic, and phonological language production, while constraining non-use behaviors. Three male participants with moderate to severe post-stroke aphasia received CIAT 3-4 hours/day for 5 consecutive days. Pre and post-testing included formal language evaluation, linguistic analysis of story retell, and mini-Communication Activity Log (mini-CAL). Substantial improvements in comprehension and verbal skills were noted in 2 patients with an increase in the total number of words (31% and 95%) and in number of utterances for story-retell task (57% and 75%). All participants demonstrated an improvement on at least one linguistic measure. No subjective improvements on mini-CAL were noted by any of the participants. Given that the duration of treatment was only 1 week, these linguistic improvements in post stroke aphasia participants were remarkable. The results indicate that the CIAT protocol used in this study may be a useful tool in language restoration after stroke. These initial findings should be confirmed in a larger, randomized study.

  9. Speech production gains following constraint-induced movement therapy in children with hemiparesis.

    Science.gov (United States)

    Allison, Kristen M; Reidy, Teressa Garcia; Boyle, Mary; Naber, Erin; Carney, Joan; Pidcock, Frank S

    2017-01-01

    The purpose of this study was to investigate changes in speech skills of children who have hemiparesis and speech impairment after participation in a constraint-induced movement therapy (CIMT) program. While case studies have reported collateral speech gains following CIMT, the effect of CIMT on speech production has not previously been directly investigated to the knowledge of these investigators. Eighteen children with hemiparesis and co-occurring speech impairment participated in a 21-day clinical CIMT program. The Goldman-Fristoe Test of Articulation-2 (GFTA-2) was used to assess children's articulation of speech sounds before and after the intervention. Changes in percent of consonants correct (PCC) on the GFTA-2 were used as a measure of change in speech production. Children made significant gains in PCC following CIMT. Gains were similar in children with left and right-sided hemiparesis, and across age groups. This study reports significant collateral gains in speech production following CIMT and suggests benefits of CIMT may also spread to speech motor domains.

  10. In vivo optical imaging to visualize photodynamic therapy-induced immune responses

    Science.gov (United States)

    Mitra, Soumya; Foster, Thomas H.

    2009-02-01

    Motivated by recent successes in growing intradermal tumors in the ears of mice and establishing the feasibility of in vivo confocal imaging of anatomic vessels in these tumors using fluorophore-conjugated antibodies to CD31, we are exploring a number of applications of optical fluorescence imaging in superficial murine tumor models in vivo. Immune responses induced by photodynamic therapy (PDT) are dynamic processes that occur in a spatially and temporally specific manner. To visualize these processes noninvasively, we have made progress in developing optical molecular imaging strategies that take advantage of intradermal injection of fluorophore-conjugated-antibodies against surface antigens on immune cells. This enables confocal imaging of the fluorescently labeled host cells to depths of at least 100 microns, and using this technique we have achieved in vivo imaging of granulocyte (GR-1)- and major histocompatibility complex class II (MHC-II)-positive cell trafficking in tumors in response to PDT. The latter include macrophages and dendritic cells. Data from tumors that were subjected to PDT with the photosensitizer, HPPH, reveals a significantly enhanced level of GR-1+ cell infiltration compared to untreated control tumor. The temporal kinetics of GR-1+ and MHC-II+ cells at different time intervals post-PDT are being examined. The ability to image host responses in vivo without excising or perturbing the tissue has opened up opportunities to explore means of optimizing them to therapeutic advantage.

  11. Bu-Shen-Jian-Pi-Yi-Qi Therapy Prevents Alcohol-Induced Osteoporosis in Rats.

    Science.gov (United States)

    Ren, Shu-Jun; Xing, Guo-Li; Hu, Nai-Wu; Xu, Wei-Ming; Wang, Yong-Qi; Dong, Qing-Ping; Jiang, Yi-Chang

    2016-01-01

    Bu-Shen-Jian-Pi-Yi-Qi therapy, which refers to reinforcing kidney, regulating qi, and invigorating spleen, is a traditional Chinese medicine, and we investigated its efficacy in treatment of alcohol-induced osteoporosis and its underlying mechanism. Forty adult male Sprague-Dawley rats were randomly assigned into alcohol-supplemented group, JIAN-GU-LING (JGL) group, calcium D3 + alfacalcidol group, and sham-treated group. Bone mineral density (BMD), bone mineral content (BMC), and bone biomechanical properties were assessed. Biochemical analyses of serum and urine specimens were detected. Reverse transcription-polymerase chain reaction was used to detect the mRNA level of vitamin D receptor (VDR). There were markedly lower bone metabolic markers and biomechanical properties in alcohol-supplemented group compared with sham-treated group (all P alcohol + calcium D3 + alfacalcidol group (P alcoholic osteoporosis. The disease reversal is evidenced by increased BMD and BMC, improved biomechanical properties, elevated VDR mRNA level, enhanced response sensitivity of 1, 25(OH)2D3, and reduced S-Ca/P.

  12. Photoprotective Effect of the Plant Collaea argentina against Adverse Effects Induced by Photodynamic Therapy

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    Leandro Mamone

    2014-01-01

    Full Text Available Photodynamic therapy (PDT is a treatment modality for tumours and other accessible lesions based on the combination of light and a photosensitizer (PS accumulated in the target tissue. The main disadvantage of PDT is PS retention after treatment during long time periods that conduces to cutaneous damage. It is believed that singlet oxygen is responsible for that skin photosensitization. The aim of this work was to evaluate the photoprotective activity of the methanolic extract of the Argentinian plant Collaea argentina against PDT under several treatments and employing different PSs. C. argentina exhibited photoprotective activity against aminolevulinic acid- (ALA- PDT in the LM2 murine adenocarcinoma cell line. The photoprotection was dependant on the extract concentration and the incubation time, being detectable from 40 μg/mL onwards and at least after 3 h exposure of the cells. C. argentina extract protects these mammalian tumor cells against PDT effects, and it interferes with the oxygen singlet production from PSs during PDT treatment. We propose that it will be a promising agent to protect cells against PDT-induced skin sensitivity.

  13. Contrast water therapy and exercise induced muscle damage: a systematic review and meta-analysis.

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    François Bieuzen

    Full Text Available The aim of this systematic review was to examine the effect of Contrast Water Therapy (CWT on recovery following exercise induced muscle damage. Controlled trials were identified from computerized literature searching and citation tracking performed up to February 2013. Eighteen trials met the inclusion criteria; all had a high risk of bias. Pooled data from 13 studies showed that CWT resulted in significantly greater improvements in muscle soreness at the five follow-up time points (<6, 24, 48, 72 and 96 hours in comparison to passive recovery. Pooled data also showed that CWT significantly reduced muscle strength loss at each follow-up time (<6, 24, 48, 72 and 96 hours in comparison to passive recovery. Despite comparing CWT to a large number of other recovery interventions, including cold water immersion, warm water immersion, compression, active recovery and stretching, there was little evidence for a superior treatment intervention. The current evidence base shows that CWT is superior to using passive recovery or rest after exercise; the magnitudes of these effects may be most relevant to an elite sporting population. There seems to be little difference in recovery outcome between CWT and other popular recovery interventions.

  14. Stem Cell Therapies for the Treatment of Radiation-Induced Normal Tissue Side Effects

    NARCIS (Netherlands)

    Benderitter, Marc; Caviggioli, Fabio; Chapel, Alain; Coppes, Robert P.; Guha, Chandan; Klinger, Marco; Malard, Olivier; Stewart, Fiona; Tamarat, Radia; Van Luijk, Peter; Limoli, Charles L.

    2014-01-01

    Significance: Targeted irradiation is an effective cancer therapy but damage inflicted to normal tissues surrounding the tumor may cause severe complications. While certain pharmacologic strategies can temper the adverse effects of irradiation, stem cell therapies provide unique opportunities for

  15. A Founder Mutation in VPS11 Causes an Autosomal Recessive Leukoencephalopathy Linked to Autophagic Defects.

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    Jinglan Zhang

    2016-04-01

    Full Text Available Genetic leukoencephalopathies (gLEs are a group of heterogeneous disorders with white matter abnormalities affecting the central nervous system (CNS. The causative mutation in ~50% of gLEs is unknown. Using whole exome sequencing (WES, we identified homozygosity for a missense variant, VPS11: c.2536T>G (p.C846G, as the genetic cause of a leukoencephalopathy syndrome in five individuals from three unrelated Ashkenazi Jewish (AJ families. All five patients exhibited highly concordant disease progression characterized by infantile onset leukoencephalopathy with brain white matter abnormalities, severe motor impairment, cortical blindness, intellectual disability, and seizures. The carrier frequency of the VPS11: c.2536T>G variant is 1:250 in the AJ population (n = 2,026. VPS11 protein is a core component of HOPS (homotypic fusion and protein sorting and CORVET (class C core vacuole/endosome tethering protein complexes involved in membrane trafficking and fusion of the lysosomes and endosomes. The cysteine 846 resides in an evolutionarily conserved cysteine-rich RING-H2 domain in carboxyl terminal regions of VPS11 proteins. Our data shows that the C846G mutation causes aberrant ubiquitination and accelerated turnover of VPS11 protein as well as compromised VPS11-VPS18 complex assembly, suggesting a loss of function in the mutant protein. Reduced VPS11 expression leads to an impaired autophagic activity in human cells. Importantly, zebrafish harboring a vps11 mutation with truncated RING-H2 domain demonstrated a significant reduction in CNS myelination following extensive neuronal death in the hindbrain and midbrain. Thus, our study reveals a defect in VPS11 as the underlying etiology for an autosomal recessive leukoencephalopathy disorder associated with a dysfunctional autophagy-lysosome trafficking pathway.

  16. Aging and Autophagic Function Influences the Progressive Decline of Adult Drosophila Behaviors.

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    Eric P Ratliff

    Full Text Available Multiple neurological disorders are characterized by the abnormal accumulation of protein aggregates and the progressive impairment of complex behaviors. Our Drosophila studies demonstrate that middle-aged wild-type flies (WT, ~4-weeks exhibit a marked accumulation of neural aggregates that is commensurate with the decline of the autophagy pathway. However, enhancing autophagy via neuronal over-expression of Atg8a (Atg8a-OE reduces the age-dependent accumulation of aggregates. Here we assess basal locomotor activity profiles for single- and group-housed male and female WT flies and observed that only modest behavioral changes occurred by 4-weeks of age, with the noted exception of group-housed male flies. Male flies in same-sex social groups exhibit a progressive increase in nighttime activity. Infrared videos show aged group-housed males (4-weeks are engaged in extensive bouts of courtship during periods of darkness, which is partly repressed during lighted conditions. Together, these nighttime courtship behaviors were nearly absent in young WT flies and aged Atg8a-OE flies. Previous studies have indicated a regulatory role for olfaction in male courtship partner choice. Coincidently, the mRNA expression profiles of several olfactory genes decline with age in WT flies; however, they are maintained in age-matched Atg8a-OE flies. Together, these results suggest that middle-aged male flies develop impairments in olfaction, which could contribute to the dysregulation of courtship behaviors during dark time periods. Combined, our results demonstrate that as Drosophila age, they develop early behavior defects that are coordinate with protein aggregate accumulation in the nervous system. In addition, the nighttime activity behavior is preserved when neuronal autophagy is maintained (Atg8a-OE flies. Thus, environmental or genetic factors that modify autophagic capacity could have a positive impact on neuronal aging and complex behaviors.

  17. Chrysin Protects Rat Kidney from Paracetamol-Induced Oxidative Stress, Inflammation, Apoptosis, and Autophagy: A Multi-Biomarker Approach

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    Fatih Mehmet Kandemir

    2017-01-01

    Full Text Available Paracetamol (PC is a safe analgesic and antipyretic drug at therapeutic doses, and it is widely used in clinics. However, at high doses, it can induce hepatotoxicity and nephrotoxicity. Chrysin (CR is a natural flavonoid that has biological activities that include being an antioxidant, an anti-inflammatory, and an anti-cancer agent. The main objective of this study was to investigate the efficacy of CR against PC-induced nephrotoxicity in rats. CR was given orally via feeding needle to male Sprague Dawley rats as a single daily dose of 25 or 50 mg/kg for six days. PC was administered orally via feeding needle as a single dose on the sixth day. PC caused significant glutathione depletion, lipid peroxidation, increased serum toxicity markers (serum urea and creatinine, and reductions in activities of antioxidant enzymes (superoxide dismutase — SOD, catalase — CAT, and glutathione peroxidase — GPx. The renal protective effect of CR was associated with decreasing the regulation of serum renal toxicity markers and increasing the regulation of antioxidant enzyme activities. Additionally, PC led to significant increases in the levels of inflammatory markers including tumour necrosis factor-alpha (TNF-α, interleukin-1β (IL-1β and interleukin-33 (IL-33. Furthermore, PC induced apoptotic tissue damage by increasing cysteine aspartate-specific protease-3 (caspase-3 activity and autophagic tissue damage by increasing the expression of light chain 3B (LC3B. CR therapy significantly decreased these values in rats. This study demonstrated that CR has antioxidant, anti-apoptotic, anti-inflammatory and anti-autophagic effects on PC-induced kidney toxicity in rats.

  18. Combination therapies in adjuvant with topical ALA-mediated photodynamic therapy for DMBA-induced hamster buccal pouch premalignant lesions

    Science.gov (United States)

    Yang, Deng-Fu; Hsu, Yih-Chih

    2012-03-01

    In Taiwan, oral cancer has becomes the fastest growth male cancer disease due to the betel nut chewing habit combing with smoking and alcohol-drinking lifestyle of people. In order to eliminate the systemic phototoxic effect of 5-aminolevulinic acid (ALA), this study was designed to use a topical ALA-mediated PDT for treatment of DMBA-induced hamster buccal pouch precancerous lesions. DMBA was applied to one of the buccal pouches of hamsters thrice a week for 10 to 12 weeks. Cancerous lesions were induced and proven by histological examination. These DMBA-induced cancerous lesions were used for testing the efficacy of topical ALA-mediated PDT. Before PDT, fluorescence spectroscopy was used to determine when ALA reached its peak level in the lesional epithelial cells after topical application of ALA gel. We found that ALA reached its peak level in precancerous lesions about 2.5 hrs after topical application of ALA gel. The cancerous lesions in hamsters were then treated with topical ALA -mediated PDT with light exposure dose of 150 J/cm2 using LED 635 nm fiber-guided light device. Visual examination demonstrated that adjuvant topical ALA -mediated PDT group has shown better therapeutic results in compared to those of non-adjuvant topical ALA-mediated PDT group for DMBA-induced hamster buccal pouch precancerous lesions.

  19. A prospective study on chemotherapy-induced hepatitis B virus reactivation in chronic HBs Ag carriers with hematologic malignancies and pre-emptive therapy with nucleoside analogues.

    Science.gov (United States)

    Yağci, Münci; Yağci, Müncý; Acar, Kadir; Acar, Kadýr; Sucak, Gülsan Türköz; Aki, Zeynep; Bozdayi, Gülendam; Haznedar, Rauf

    2006-08-01

    Chemotherapy-induced hepatitis B virus (HBV) reactivation is a serious problem in chronic HBV carriers with hematologic malignancies. In 12 patients with hematologic malignancies, we performed a prospective study to determine the effectiveness of nucleoside analogues in the pre-emptive therapy of chemotherapy-induced HBV reactivation. HBV reactivation occurred in seven patients (58.3%) whereas five of the seven patients (71%) responded to nucleoside analogue therapy. HBV reactivation-related acute liver failure and death was not observed in the present study. All five patients with chronic lymphocytic leukemia (CLL) experienced chemotherapy-induced HBV reactivation regardless of the chemotherapy regimen. Therefore, we suggest that CLL carries a significant risk of chemotherapy-induced HBV reactivation. The pre-emptive therapy of chemotherapy-induced HBV reactivation appears to be safe, based on the results of this pilot study. Pre-emptive therapy enables the definition of high-risk patients who cannot be identified by primary prophylaxis.

  20. Interference with the Autophagic Process as a Viral Strategy to Escape from the Immune Control: Lesson from Gamma Herpesviruses

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    Roberta Santarelli

    2015-01-01

    Full Text Available We summarized the most recent findings on the role of autophagy in antiviral immune response. We described how viruses have developed strategies to subvert the autophagic process. A particular attention has been given to Epstein-Barr and Kaposi’s sarcoma associated Herpesvirus, viruses studied for many years in our laboratory. These two viruses belong to γ-Herpesvirus subfamily and are associated with several human cancers. Besides the effects on the immune response, we have described how autophagy subversion by viruses may also concur to the enhancement of their replication and to viral tumorigenesis.

  1. Drug-induced lung injury associated with combination therapy of daclatasvir and asunaprevir: The first case report.

    Science.gov (United States)

    Kamada, Takahiro; Furuta, Kenjiro; Tomioka, Hiromi

    2016-05-01

    Combination therapy with direct acting antiviral agents (DAAs) without interferon (IFN) has emerged as a treatment for chronic hepatitis C because of its high overall sustained virologic response rates and favorable side effect profile as compared to that with interferon. We report the first case of drug-induced lung injury (DLI) associated with IFN-free therapy with the DAAs, daclatasvir (NS5A inhibitor) and asunaprevir (NS3/4A protease inhibitor). Although this combination therapy of DAAs has been considered to have fewer side effects than IFN, more attention should be paid to DLI as an important side effect. Copyright © 2016 The Japanese Respiratory Society. Published by Elsevier B.V. All rights reserved.

  2. Induced Pluripotent Stem Cell-Derived Neural Stem Cell Therapy Enhances Recovery in an Ischemic Stroke Pig Model.

    Science.gov (United States)

    Baker, Emily W; Platt, Simon R; Lau, Vivian W; Grace, Harrison E; Holmes, Shannon P; Wang, Liya; Duberstein, Kylee Jo; Howerth, Elizabeth W; Kinder, Holly A; Stice, Steve L; Hess, David C; Mao, Hui; West, Franklin D

    2017-08-30

    Induced pluripotent stem cell-derived neural stem cells (iNSCs) have significant potential as an autologous, multifunctional cell therapy for stroke, which is the primary cause of long term disability in the United States and the second leading cause of death worldwide. Here we show that iNSC transplantation improves recovery through neuroprotective, regenerative, and cell replacement mechanisms in a novel ischemic pig stroke model. Longitudinal multiparametric magnetic resonance imaging (MRI) following iNSC therapy demonstrated reduced changes in white matter integrity, cerebral blood perfusion, and brain metabolism in the infarcted tissue. The observed tissue level recovery strongly correlated with decreased immune response, enhanced neuronal protection, and increased neurogenesis. iNSCs differentiated into neurons and oligodendrocytes with indication of long term integration. The robust recovery response to iNSC therapy in a translational pig stroke model with increased predictive potential strongly supports that iNSCs may be the critically needed therapeutic for human stroke patients.

  3. TO STUDY THE EFFECT OF PLAY THERAPY AND CHILD FRIENDLY CONSTRAINT INDUCED MOMEMENT THERAPY TO IMPROVE HAND FUNCTION IN SPASTIC HEMIPLEGIC CEREBRAL PALSY CHILDREN: A COMPARATIVE STUDY

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    Anjuman Nahar

    2015-12-01

    Full Text Available Background: Cerebral Palsy (CP is a neurodevelopmental disorder caused by nonprogressive lesion in the developing brain. The early central nervous system (CNS damage results in chronic physical disabilities and often includes sensory impairments. In addition CP is often associated with epilepsy and abnormalities of speech, vision, and intellect; it is the selective vulnerability of the brains motor systems that defines the disorder. Child friendly CIMT involves intensive targeted practice with the involved extremity coordination above and beyond their unilateral impairments. Ply Therapy is designed for active involvement of child in performing various tasks. The aim of the study is to evaluate the effectiveness of constraint induced movement therapy and play therapy to improve hand function in spastic hemiplegic cerebral palsy children. Methods: A sample of 30 patients was divided in two groups, each group having 15 children. Convenient sampling was done on the basis of base line assessment and diagnosis of their condition. Duration of the study was 3 months and data collection started at day 0 and at the end of 90 days. Children in group A wore a bivalve plaster cast on the non-involved upper extremity from shoulder to finger tips for the entire time during the session lasting for 2 hours and the plaster cast was removed at the end of the session. B group consists of 15 subjects who received play therapy. The treatment program was conducted individually and adjusted to current needs and abilities of each of the patients. Outcomes: Box and Block test, QOM scale and AOU scale. Results: It was found that there is an improvement in the hand function on application of child friendly CIMT in the patients with spastic hemiplegic cerebral palsy which was found significant using the Mann-Whitney U test (p≤0.005. Conclusion: In this study it has been found that the use of Child friendly CIMT and PLAY THERAPY produces significant improvement in hand

  4. Cell Therapy Using Human Induced Pluripotent Stem Cell-Derived Renal Progenitors Ameliorates Acute Kidney Injury in Mice

    OpenAIRE

    Toyohara, Takafumi; Mae, Shin-Ichi; Sueta, Shin-Ichi; Inoue, Tatsuyuki; Yamagishi, Yukiko; Kawamoto, Tatsuya; Kasahara, Tomoko; Hoshina, Azusa; Toyoda, Taro; Tanaka, Hiromi; Araoka, Toshikazu; Sato-Otsubo, Aiko; Takahashi, Kazutoshi; Sato, Yasunori; Yamaji, Noboru

    2015-01-01

    Acute kidney injury (AKI) is defined as a rapid loss of renal function resulting from various etiologies, with a mortality rate exceeding 60% among intensive care patients. Because conventional treatments have failed to alleviate this condition, the development of regenerative therapies using human induced pluripotent stem cells (hiPSCs) presents a promising new therapeutic option for AKI. We describe our methodology for generating renal progenitors from hiPSCs that show potential in ameliora...

  5. PELATIHAN MIRROR NEURON SYSTEM SAMA DENGAN PELATIHAN CONSTRAINT INDUCED MOVEMENT THERAPY DALAM MENINGKATKAN KEMAMPUAN FUNGSIONAL ANGGOTA GERAK ATAS PASIEN STROKE

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    Abdul chalik meidian

    2014-03-01

    Full Text Available Stroke is an interruption of blood vasculature system in the brain that causes suddenly neurological dysfunction, resulted in clinically brain tissue damage in a relatively long time period, decreased physical mobility and functional ability impaired of upper limb. The purpose of this study is to know an increasing in upper limb functional ability among stroke patients after mirror neuron system exercise and constraint induced movement therapy exercise and to know the comparison of both exercise. This study uses an experimental research with pre-test and post-test control group design. Number of samples of the first group is 13 patients given mirror neuron system exercise for 30-60 minutes , while the second group 13 patients were given constraint induced movement therapy exercise for 30-60 minutes. The research was conducted in 2 month period time. Each patient is taught a variety of upper limb functional ability in accordance with the operational concept guidance and patients were asked to repeat the exercise independently at home as directed. Measuring test of upper limb functional ability is using the wolf motor function test instruments. The result is an increase the upper limb functional ability of 21.7% in the mirror neuron system exercise group and proved a significant difference (p<0.05 and an increase in the upper limb functional ability of 17.1% in the constraint induced movement therapy exercise group and proved a significant difference (p<0.05 while the difference of increasing of upper limb functional ability of the two groups showed no significant difference (p>0,05. It was concluded that the mirror neuron system exercise is similar with constraint induced movement therapy exercise in increasing the upper limb functional ability among stroke patients.

  6. Potential predictors of functional outcomes after home-based constraint-induced therapy for children with cerebral palsy.

    Science.gov (United States)

    Chen, Chia-ling; Lin, Keh-chung; Kang, Lin-ju; Wu, Ching-yi; Chen, Hsieh-ching; Hsieh, Yu-wei

    2014-01-01

    OBJECTIVE. Our objective was to identify predictors for treatment outcomes after home-based constraint-induced therapy (CIT) in children with cerebral palsy (CP). METHOD. Forty-three children (aged 4-12 yr) with CP were treated with individualized CIT at home for 4 wk. Potential predictors were age, sex, affected hand, and upper-extremity motor capacity measured by the Peabody Developmental Motor Scale, 2nd edition (PDMS-2). Outcomes were the Pediatric Motor Activity Log (PMAL) Amount of Hand Use and Quality of Hand Use subscales and the Functional Independence Measure for Children (WeeFIM). RESULTS. A higher PDMS-2 Visual-Motor Integration subscale score predicted a better WeeFIM score after home-based CIT (adjusted R² = .35). Younger age predicted better performance on the PMAL Amount of Hand Use and Quality of Hand Use subscales (adjusted R² = .06-.08) after home-based CIT. CONCLUSION. The potential predictors may allow occupational therapy practitioners to target those children who will benefit most after home-based constraint-induced therapy. Copyright © 2014 by the American Occupational Therapy Association, Inc.

  7. The effect of spinal manipulative therapy on experimentally induced pain: a systematic literature review

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    Millan Mario

    2012-08-01

    Full Text Available Abstract Background Although there is evidence that spinal manipulative therapy (SMT can reduce pain, the mechanisms involved are not well established. There is a need to review the scientific literature to establish the evidence-base for the reduction of pain following SMT. Objectives To determine if SMT can reduce experimentally induced pain, and if so, if the effect is i only at the level of the treated spinal segment, ii broader but in the same general region as SMT is performed, or iii systemic. Design A systematic critical literature review. Methods A systematic search was performed for experimental studies on healthy volunteers and people without chronic syndromes, in which the immediate effect of SMT was tested. Articles selected were reviewed blindly by two authors. A summary quality score was calculated to indicate level of manuscript quality. Outcome was considered positive if the pain-reducing effect was statistically significant. Separate evidence tables were constructed with information relevant to each research question. Results were interpreted taking into account their manuscript quality. Results Twenty-two articles were included, describing 43 experiments, primarily on pain produced by pressure (n = 27 or temperature (n = 9. Their quality was generally moderate. A hypoalgesic effect was shown in 19/27 experiments on pressure pain, produced by pressure in 3/9 on pain produced by temperature and in 6/7 tests on pain induced by other measures. Second pain provoked by temperature seems to respond to SMT but not first pain. Most studies revealed a local or regional hypoalgesic effect whereas a systematic effect was unclear. Manipulation of a “restricted motion segment” (“manipulable lesion” seemed not to be essential to analgesia. In relation to outcome, there was no discernible difference between studies with higher vs. lower quality scores. Conclusions These results indicate that SMT has a direct local

  8. Contribution of mitochondria and lysosomes to photodynamic therapy-induced death in cancer cells

    Science.gov (United States)

    Nieminen, Anna-Liisa; Azizuddin, Kashif; Zhang, Ping; Kenney, Malcolm E.; Pediaditakis, Peter; Lemasters, John J.; Oleinick, Nancy L.

    2008-02-01

    In photodynamic therapy (PDT), visible light activates a photosensitizing drug added to a tissue, resulting in singlet oxygen formation and cell death. Employing confocal microscopy, we previously found that the phthalocyanine Pc 4 localized primarily to mitochondrial membranes in various cancer cell lines, resulting in mitochondrial reactive oxygen species (ROS) production, followed by inner membrane permeabilization (mitochondrial permeability transition) with mitochondrial depolarization and swelling, which in turn led to cytochrome c release and apoptotic death. Recently, derivatives of Pc 4 with OH groups added to one of the axial ligands were synthesized. These derivatives appeared to be taken up more avidly by cells and caused more cytotoxicity than the parent compound Pc 4. Using organelle-specific fluorophores, we found that one of these derivatives, Pc 181, accumulated into lysosomes and that PDT with Pc 181 caused rapid disintegration of lysosomes. We hypothesized that chelatable iron released from lysosomes during PDT contributes to mitochondrial damage and subsequent cell death. We monitored cytosolic Fe2+ concentrations after PDT with calcein. Fe2+ binds to calcein causing quenching of calcein fluorescence. After bafilomycin, an inhibitor of the vacuolar proton-translocating ATPase, calcein fluorescence became quenched, an effect prevented by starch desferal s-DFO, an iron chelator that enters cells by endocytosis. After Pc 181-PDT, cytosolic calcein fluorescence also decreased, indicating increased chelatable Fe2+ in the cytosol, and apoptosis occurred. s-DFO decreased Pc 181-PDT-induced apoptosis as measured by a decrease of caspase-3 activation. In isolated mitochondria preparations, Fe2+ induced mitochondrial swelling, which was prevented by Ru360, an inhibitor of the mitochondrial Ca2+ uniporter. The data support a hypothesis of oxidative injury in which Pc 181-PDT disintegrates lysosomes and releases constituents that synergistically promote

  9. The effect of spinal manipulative therapy on experimentally induced pain: a systematic literature review

    Science.gov (United States)

    2012-01-01

    Background Although there is evidence that spinal manipulative therapy (SMT) can reduce pain, the mechanisms involved are not well established. There is a need to review the scientific literature to establish the evidence-base for the reduction of pain following SMT. Objectives To determine if SMT can reduce experimentally induced pain, and if so, if the effect is i) only at the level of the treated spinal segment, ii) broader but in the same general region as SMT is performed, or iii) systemic. Design A systematic critical literature review. Methods A systematic search was performed for experimental studies on healthy volunteers and people without chronic syndromes, in which the immediate effect of SMT was tested. Articles selected were reviewed blindly by two authors. A summary quality score was calculated to indicate level of manuscript quality. Outcome was considered positive if the pain-reducing effect was statistically significant. Separate evidence tables were constructed with information relevant to each research question. Results were interpreted taking into account their manuscript quality. Results Twenty-two articles were included, describing 43 experiments, primarily on pain produced by pressure (n = 27) or temperature (n = 9). Their quality was generally moderate. A hypoalgesic effect was shown in 19/27 experiments on pressure pain, produced by pressure in 3/9 on pain produced by temperature and in 6/7 tests on pain induced by other measures. Second pain provoked by temperature seems to respond to SMT but not first pain. Most studies revealed a local or regional hypoalgesic effect whereas a systematic effect was unclear. Manipulation of a “restricted motion segment” (“manipulable lesion”) seemed not to be essential to analgesia. In relation to outcome, there was no discernible difference between studies with higher vs. lower quality scores. Conclusions These results indicate that SMT has a direct local/regional hypoalgesic effect on

  10. 5-Aminolevulinic Acid-Based Sonodynamic Therapy Induces the Apoptosis of Osteosarcoma in Mice.

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    Yongning Li

    Full Text Available Sonodynamic therapy (SDT is promising for treatment of cancer, but its effect on osteosarcoma is unclear. This study examined the effect of 5-Aminolevulinic Acid (5-ALA-based SDT on the growth of implanted osteosarcoma and their potential mechanisms in vivo and in vitro.The dose and metabolism of 5-ALA and ultrasound periods were optimized in a mouse model of induced osteosarcoma and in UMR-106 cells. The effects of ALA-SDT on the proliferation and apoptosis of UMR-106 cells and the growth of implanted osteosarcoma were examined. The levels of mitochondrial membrane potential (ΔψM, ROS production, BcL-2, Bax, p53 and caspase 3 expression in UMR-106 cells were determined.Treatment with 5-ALA for eight hours was optimal for ALA-SDT in the mouse tumor model and treatment with 2 mM 5-ALA for 6 hours and ultrasound (1.0 MHz 2.0 W/cm2 for 7 min were optimal for UMR-106 cells. SDT, but not 5-ALA, alone inhibited the growth of implanted osteosarcoma in mice (P<0.01 and reduced the viability of UMR-106 cells (p<0.05. ALA-SDT further reduced the tumor volumes and viability of UMR-106 cells (p<0.01 for both. Pre-treatment with 5-ALA significantly enhanced the SDT-mediated apoptosis (p<0.01 and morphological changes. Furthermore, ALA-SDT significantly reduced the levels of ΔψM, but increased levels of ROS in UMR-106 cells (p<0.05 or p<0.01 vs. the Control or the Ultrasound. Moreover, ALA-SDT inhibited the proliferation of osteosarcoma cells and BcL-2 expression, but increased levels of Bax, p53 and caspase 3 expression in the implanted osteosarcoma tissues (p<0.05 or p<0.01 vs. the Control or the Ultrasound.The ALA-SDT significantly inhibited osteosarcoma growth in vivo and reduced UMR-106 cell survival by inducing osteosarcoma cell apoptosis through the ROS-related mitochondrial pathway.

  11. A model of radiation-induced cell killing: insights into mechanisms and applications for hadron therapy.

    Science.gov (United States)

    Ballarini, Francesca; Altieri, Saverio; Bortolussi, Silva; Giroletti, Elio; Protti, Nicoletta

    2013-09-01

    A mechanism-based, two-parameter biophysical model of cell killing was developed with the aim of elucidating the mechanisms underlying radiation-induced cell death and predicting cell killing by different radiation types, including protons and carbon ions at energies and doses of interest for cancer therapy. The model assumed that certain chromosome aberrations (dicentrics, rings and large deletions, called "lethal aberrations") lead to clonogenic inactivation, and that aberrations derive from μm-scale misrejoining of chromatin fragments, which in turn are produced by "dirty" double-strand breaks called "cluster lesions" (CLs). The average numbers of CLs per Gy per cell were left as a semi-free parameter and the threshold distance for chromatin-fragment rejoining was defined the second parameter. The model was "translated" into Monte Carlo code and provided simulated survival curves, which were compared with survival data on V79 cells exposed to protons, carbon ions and X rays. The agreement was good between simulations and survival data and supported the assumptions of the model at least for doses up to a few Gy. Dicentrics, rings and large deletions were found to be lethal not only for AG1522 cells exposed to X rays, as already reported by others, but also for V79 cells exposed to protons and carbon ions of different energies. Furthermore, the derived CL yields suggest that the critical DNA lesions leading to clonogenic inactivation are more complex than "clean" DSBs. After initial validation, the model was applied to characterize the particle and LET dependence of proton and carbon cell killing. Consistent with the proton data, the predicted fraction of inactivated cells after 2 Gy protons was 40-50% below 7.7 keV/μm, increased by a factor ∼1.6 between 7.7-30.5 keV/μm, and decreased by a factor ∼1.1 between 30.5-34.6 keV/μm. These LET values correspond to proton energies below a few MeV, which are always present in the distal region of hadron therapy

  12. Application of cationic propyl gallate as inducer of thrombocyte aggregation for evaluation of effectiveness of antiaggregation therapy.

    Science.gov (United States)

    Stejskal, D; Prosková, J; Petrzelová, A; Bartek, J; Oral, I; Lacnák, B; Horalík, D; Sekaninová, S

    2001-12-01

    Acetylsalicylic acid (ASA) is one of basic preparations used in the therapy of cardiovascular diseases. Application of ASA leads to irreversible reduction of platelet aggregation. The aim of the present study was to verify monitoring of effectiveness of ASA therapy using the measurement of platelet aggregability in vitro after induction by cationic propyl gallate (CPG), which is considered to be a highly potent inducer of aggregation. We examined a group of 27 healthy volunteers, divided into two subgroups (n = 19, n = 8). The first subgroup was examined for thrombocyte aggregation before and 24 hours after administration of 400 mg of ASA after induction by ADP, collagen, adrenalin and CPG. The second subgroup was examined for thrombocyte aggregation before and after a three-day administration of ASA in a dose of 100 mg/day. In the group of 27 healthy volunteers we determined normal values of aggregability for individual inducers. Low stability of the used methods was proved (weak or insignificant correlation of results of the same method before and after administration of ASA). The most advantageous parameter for monitoring of effectiveness of 400 and 100 mg of ASA was CPG slope (paired t test, p measurement of thrombocyte aggregation after CPG induction reveals a significantly lower percentage of ASA non-responders ASA than after other inducers. Measurement of thrombocyte aggregation after CPG induction is predicted to be highly promising for monitoring the effectiveness of anti-aggregation therapy.

  13. [Profiles of irregular bleeding induced by low-dose hormone therapy and Chinese formulated herbs products].

    Science.gov (United States)

    Wang, Shao-hai; Lin, Shou-qing; Gui, Qi-fang; Jin, Min-juan; Jiang, Ying

    2006-04-01

    To compare profiles and related factors of irregular bleeding induced by different types of low-dose hormone therapy (HT) and a Chinese formulated herbs products. Applied with open-labeled, randomized, and clinical trial design, 136 postmenopausal women were assigned into four groups: group A: estradiol valerate (E2 V) 1 mg/d + medroxyprogesterone acetate (MPA) 2 mg/d; group B: conjugated equine estrogen 0.45 mg/d + MPA 2 mg/d; group C: tibolone 1.25 mg/d; group D: a Chinese formulated herbs product (Kuntai) 4# tid. Each subject took element calcium 400 mg/d and vitamin D 200 IU/d concomitantly. Modified Kupperman scores were assessed on baseline and every 3 months thereafter and irregular bleeding was recorded on menopausal diary every day. The duration of this study was 1 year. Results The efficacies were similar in three HT-managed groups, but was better than in group D, although the latter was also effective in alleviating menopausal symptoms. Hazard ratio (HR) of irregular bleeding was 1.00 in group C, 2.43 in group A (95% CI: 1.08-5.46), 3.12 in group B (95% CI: 1.42-6.88), and 0.73 in group D (95% CI: 0.26-2.04). Most cases initially experienced bleeding in the first 3 months but such initiation was a bit later in group C. Endometrium, as detected by B-mode ultrasound, increased approximately 1 mm in HT groups, while it was a bit thicker in group C. Long periods in reproductive age and short time since menopause were high risk factors for irregular bleeding. Profiles of irregular bleeding in 3 commonly used types of low-dose HT are different and some factors such as long period in reproductive age and short time since menopause may contribute to bleeding initiation.

  14. Ultrasonographic assessment of the cutaneous changes induced by topical flavonoid therapy.

    Science.gov (United States)

    Crisan, Diana; Crisan, Maria; Moldovan, Mirela; Lupsor, Monica; Badea, Radu

    2012-01-01

    Ultrasonography allows the quantification of dermal density and echogenicity changes during the physiological senescence process. Some active ingredients are able to slow down the tissular degeneration and disorganization process. The purpose of this study was to assess the cutaneous changes induced by the topical use of products containing Viniferol(®) as active ingredient, using high-frequency ultrasound. The study was performed over 12 weeks and included 80 healthy Caucasian female subjects, aged 22-75 years, divided into two groups: the study group and the control group. The product was applied according to a predetermined protocol. The measurements performed for each subject were: the thickness of the epidermis and dermis (mm), the number of low, medium, and high echogenic pixels, and the number of low echogenic pixels in the upper dermis/number of low echogenic pixels in the lower dermis. All the parameters showed a significant improvement. Ultrasound measurements showed an increase of the mean thickness of the epidermis (P < 0.0001) and dermis (P < 0.0001) following the application of the Viniferol product as compared to the control group. The changes in the dermal echogenicity confirm the efficacy and direct action of Viniferol upon the cutaneous fibroblasts. No side effects related to the treatment were recorded. The study proves the efficacy of this active ingredient in the cutaneous senescence process as well, as the fact that anti-aging prophylaxis should be initiated in the 20-40 year critical age group. This interval involves specific changes in dermal echogenicity that quantify intense molecular, biochemical and structural changes, being thus mostly and highly responsive to the anti-aging therapy.

  15. Radioiodine therapy in patients with type II amiodarone-induced thyrotoxicosis.

    Science.gov (United States)

    Czarnywojtek, Agata; Warmuz-Stangierska, Izabela; Woliński, Kosma; Płazińska, Maria; Kobylecka, Małgorzata; Kunikowska, Jolanta; Stangierski, Adam; Miechowicz, Izabela; Waligórska-Stachura, Joanna; Rewers, Amanda; Królicki, Leszek; Ruchała, Marek

    2014-01-01

    The treatment of amiodarone-induced thyrotoxicosis (AIT) still remains a clinical challenge, requiring the cooperation of both endocrinologists and cardiologists. Unfortunately, even today AIT is related to significantly increased mortality. The aim of this study was to compare the efficacy of radioidine therapy for type II AIT in 2 groups of patients: with high or normal radioiodine uptake and treated by amiodarone (AM) in the past (AM- group) and with low radioiodine uptake and currently treated with AM (AM+ group). The AM- group included 57 patients and the AM+ group, 49. All patients received iodine-131 at a dose of 22mCi~800. Patient data were collected for over 2 years. After radioiodine administration, serum thyroid-stimulating hormone levels in the AM- group and AM+ group were 0.0 ±0.0 and 0.0 ±0.0, respectively, at 1 month; 1.2 ±3.3 and 0.6 ±1.2, respectively, at 12 months; and 4.2 ±3.6 and 1.9 ±0.8, respectively, at 2 years. All differences between the groups were statistically significant (P death occurred in 22 patients in the AM+ group and 6 patients in the AM- group. Radioiodine treatment is a safe and effective therapeutic modality for patients with type II AIT despite low radioiodine uptake, especially for patients with contraindications to other types of treatment (eg, thyroidectomy). Moreover, since thyrotoxicosis in patients with AIT is a significant risk factor for increased mortality, and since there are no alternative antiarrythmic treatments, radioiodine administration seems to be the only effective therapeutic modality.

  16. Heavy metal induced oxidative stress & its possible reversal by chelation therapy.

    Science.gov (United States)

    Flora, S J S; Mittal, Megha; Mehta, Ashish

    2008-10-01

    Exposure to heavy metals is a common phenomenon due to their environmental pervasiveness. Metal intoxication particularly neurotoxicity, genotoxicity, or carcinogenicity is widely known. This review summarizes our current understanding about the mechanism by which metalloids or heavy metals (particularly arsenic, lead, cadmium and mercury) induce their toxic effects. The unifying factor in determining toxicity and carcinogenicity for all these metals is the generation of reactive oxygen and nitrogen species. The toxic manifestations of these metals are caused primarily due to imbalance between pro-oxidant and antioxidant homeostasis which is termed as oxidative stress. Besides these metals have high affinity for thiol groups containing enzymes and proteins, which are responsible for normal cellular defense mechanism. Long term exposure to these metals could lead to apoptosis. Signaling components affected by metals include growth factor receptors, G-proteins, MAP kinases and transcription factors. Chelation therapy with chelating agents like calcium disodium ethylenediamine tetra acetic acid (CaNa(2)EDTA), British Anti Lewisite (BAL), sodium 2,3-dimercaptopropane 1-sulfonate (DMPS), meso 2,3-dimercaptosuccinic acid (DMSA) etc., is considered to be the best known treatment against metal poisoning. Despite many years of research we are still far away from effective treatment against toxicity caused due to exposure to heavy metals/metalloids. The treatment with these chelating agents is compromised with number of serious side-effects. Studies show that supplementation of antioxidants along-with a chelating agent prove to be a better treatment regimen than monotherapy with chelating agents. This review attempts a comprehensive account of recent developments in the research on heavy metal poisoning particularly the role of oxidative stress/free radicals in the toxic manifestation, an update about the recent strategies for the treatment with chelating agents and a

  17. Photodynamic therapy has antifungal effect and reduces inflammatory signals in Candida albicans-induced murine vaginitis.

    Science.gov (United States)

    Machado-de-Sena, R M; Corrêa, L; Kato, I T; Prates, R A; Senna, A M; Santos, C C; Picanço, D A; Ribeiro, M S

    2014-09-01

    Vaginal candidiasis (VC) is a disease that affects thousands of women of childbearing age, mainly caused by Candida albicans fungus. Photodynamic therapy (PDT) uses photosensitizing substances that are nontoxic in the dark, but able to produce reactive oxygen species when they are subjected to a light source. In this work our purpose was to investigate PDT effects on fungal burden and inflammatory cells in a murine model of C. albicans-induced vaginal candidiasis. Female BALB/c mice 6-10 weeks were estrogenized and maintained in this state during all experiment. After 72h, mices were inoculated intravaginally (IV) with 20μL of 2×10(5)C. albicans cells suspension. Mice were separated into 5 groups after five days: H (healthy), PBS (control), laser, MB (methylene blue) and PDT. PDT and MB groups received IV 20μL solution with 1mM of MB, others received PBS. PDT and laser groups were irradiated with a red laser (100mW, 660nm) in one (36J, 6min) or two sessions (18J, 3min). After the end of treatment, mice were submitted to microbiological and histomorphometric analysis with ImageJ software. Data were plotted by mean values and standard deviations of CFU/mL and percentage of inflammatory cells area. ANOVA and Bonferroni post-test were used and data were considered significant when psignals associated with VC in a murine model of vaginitis. Copyright © 2014 Elsevier B.V. All rights reserved.

  18. Ultrasonographic assessment of the cutaneous changes induced by topical flavonoid therapy

    Science.gov (United States)

    Crisan, Diana; Crisan, Maria; Moldovan, Mirela; Lupsor, Monica; Badea, Radu

    2012-01-01

    Ultrasonography allows the quantification of dermal density and echogenicity changes during the physiological senescence process. Some active ingredients are able to slow down the tissular degeneration and disorganization process. The purpose of this study was to assess the cutaneous changes induced by the topical use of products containing Viniferol® as active ingredient, using high-frequency ultrasound. The study was performed over 12 weeks and included 80 healthy Caucasian female subjects, aged 22–75 years, divided into two groups: the study group and the control group. The product was applied according to a predetermined protocol. The measurements performed for each subject were: the thickness of the epidermis and dermis (mm), the number of low, medium, and high echogenic pixels, and the number of low echogenic pixels in the upper dermis/number of low echogenic pixels in the lower dermis. All the parameters showed a significant improvement. Ultrasound measurements showed an increase of the mean thickness of the epidermis (P < 0.0001) and dermis (P < 0.0001) following the application of the Viniferol product as compared to the control group. The changes in the dermal echogenicity confirm the efficacy and direct action of Viniferol upon the cutaneous fibroblasts. No side effects related to the treatment were recorded. The study proves the efficacy of this active ingredient in the cutaneous senescence process as well, as the fact that anti-aging prophylaxis should be initiated in the 20–40 year critical age group. This interval involves specific changes in dermal echogenicity that quantify intense molecular, biochemical and structural changes, being thus mostly and highly responsive to the anti-aging therapy. PMID:22291475

  19. Liposuction Normalizes - in Contrast to Other Therapies - Lymphedema-Induced Adipose Tissue Hypertrophy

    OpenAIRE

    Brorson, Håkan

    2012-01-01

    The various types of treatment of lymphedema are under discussion and there has been some controversy regarding liposuction for lymphedema. Although it is clear that conservative therapies such as complex decongestive therapy (CDT) and controlled compression therapy (CCT) should be tried in the first instance, options for the treatment of late-stage lymphedema that is not responding to such treatment is not so clear. Improvements in technique, patient preparation, and patient follow-up have l...

  20. Estimating the excess lifetime risk of radiation induced secondary malignancy (SMN) in pediatric patients treated with craniospinal irradiation (CSI): Conventional radiation therapy versus helical intensity modulated radiation therapy.

    Science.gov (United States)

    Holmes, Jordan A; Chera, Bhishamjit S; Brenner, David J; Shuryak, Igor; Wilson, Adam K; Lehman-Davis, Misty; Fried, David V; Somasundaram, Vivek; Lian, Jun; Cullip, Tim; Marks, Lawrence B

    To quantify the risk of radiation-induced second malignancies (SMN) in pediatric patients receiving craniospinal irradiation (CSI) either with 3-dimensional conformal radiation therapy (Conv CSI) or tomotherapy helical intensity modulated radiation therapy (Tomo CSI). A novel predictive model that accounts for short- and long-term carcinogenesis was incorporated into our institutional treatment planning system to quantify the lifetime risk of SMN in incidentally irradiated organs. Five pediatric patients previously treated with CSI were studied. For each case, Conv CSI and Tomo CSI plans were computed. The excess absolute number of SMN was computed for each plan for each patient. For female patients, age was varied to assess its impact. Tomo CSI has a much higher risk than Conv CSI for breast cancer. Tomo has a slightly increased risk for the lung, and conventional has a slightly higher risk for the thyroid. Both techniques have intermediate risks to the pancreas and stomach, and lesser risks to the bladder and rectum. For the breast, the magnitude of the absolute risks varied with age: 14.2% versus 7.4% (Tomo vs Conv) age 5; 16.9% versus 7.6% age 10, and 18.6% versus 8.0% age 15. Tomo has a higher risk for inducing breast and lung second cancers, and when using Tomo-based intensity modulated radiation therapy, care should be taken to avoid incidental radiation to the breast. When planning CSI, one needs to balance these cancer risks against other normal tissue effects. Copyright © 2016. Published by Elsevier Inc.

  1. Antiproliferative, Apoptotic, and Autophagic Activity of Ranibizumab, Bevacizumab, Pegaptanib, and Aflibercept on Fibroblasts: Implication for Choroidal Neovascularization

    Directory of Open Access Journals (Sweden)

    Lyubomyr Lytvynchuk

    2015-01-01

    Full Text Available Purpose. Choroidal neovascularization (CNV is one of the most common complications of retinal diseases accompanied by elevated secretion of vascular endothelial growth factor (VEGF. Intravitreal anti-VEGFs (ranibizumab, bevacizumab, pegaptanib, and aflibercept can suppress neovascularization, decrease vascular permeability and CNV size, and, thereby, improve visual function. The antiproliferative, apoptotic, and autophagic effect of anti-VEGF drugs on fibroblasts found in CNVs has not been yet explored. Methods. Concentration-dependent cellular effects of the four anti-VEGFs were examined in L929 fibroblasts over a 5-day period. The cell survival, mitotic and polykaryocytic indices, the level of apoptosis and autophagy, and the cellular growth kinetics were all assessed. Results. The anti-VEGFs could inhibit the survival, mitotic activity, and proliferation as well as increase the cellular heterogeneity, apoptosis, and autophagy of the fibroblasts in a dose-dependent manner. Cellular growth kinetics showed ranibizumab to be less aggressive, but three other anti-VEGFs showed higher antiproliferative and apoptotic activity and expressed negative cellular growth kinetics. Conclusions. The antiproliferative, apoptotic, and autophagic activity of anti-VEGFs upon fibroblasts may explain the cellular response and the etiology of CNV involution in vivo and serve as a good study model for CNV in vitro.

  2. Acute high-caffeine exposure increases autophagic flux and reduces protein synthesis in C2C12 skeletal myotubes.

    Science.gov (United States)

    Hughes, M A; Downs, R M; Webb, G W; Crocker, C L; Kinsey, S T; Baumgarner, Bradley L

    2017-04-01

    Caffeine is a highly catabolic dietary stimulant. High caffeine concentrations (1-10 mM) have previously been shown to inhibit protein synthesis and increase protein degradation in various mammalian cell lines. The purpose of this study was to examine the effect of short-term caffeine exposure on cell signaling pathways that regulate protein metabolism in mammalian skeletal muscle cells. Fully differentiated C2C12 skeletal myotubes either received vehicle (DMSO) or 5 mM caffeine for 6 h. Our analysis revealed that caffeine promoted a 40% increase in autolysosome formation and a 25% increase in autophagic flux. In contrast, caffeine treatment did not significantly increase the expression of the skeletal muscle specific ubiquitin ligases MAFbx and MuRF1 or 20S proteasome activity. Caffeine treatment significantly reduced mTORC1 signaling, total protein synthesis and myotube diameter in a CaMKKβ/AMPK-dependent manner. Further, caffeine promoted a CaMKII-dependent increase in myostatin mRNA expression that did not significantly contribute to the caffeine-dependent reduction in protein synthesis. Our results indicate that short-term caffeine exposure significantly reduced skeletal myotube diameter by increasing autophagic flux and promoting a CaMKKβ/AMPK-dependent reduction in protein synthesis.

  3. Phospholipase C-related catalytically inactive protein participates in the autophagic elimination of Staphylococcus aureus infecting mouse embryonic fibroblasts.

    Directory of Open Access Journals (Sweden)

    Kae Harada-Hada

    Full Text Available Autophagy is an intrinsic host defense system that recognizes and eliminates invading bacterial pathogens. We have identified microtubule-associated protein 1 light chain 3 (LC3, a hallmark of autophagy, as a binding partner of phospholipase C-related catalytically inactive protein (PRIP that was originally identified as an inositol trisphosphate-binding protein. Here, we investigated the involvement of PRIP in the autophagic elimination of Staphylococcus aureus in infected mouse embryonic fibroblasts (MEFs. We observed significantly more LC3-positive autophagosome-like vacuoles enclosing an increased number of S. aureus cells in PRIP-deficient MEFs than control MEFs, 3 h and 4.5 h post infection, suggesting that S. aureus proliferates in LC3-positive autophagosome-like vacuoles in PRIP-deficient MEFs. We performed autophagic flux analysis using an mRFP-GFP-tagged LC3 plasmid and found that autophagosome maturation is significantly inhibited in PRIP-deficient MEFs. Furthermore, acidification of autophagosomes was significantly inhibited in PRIP-deficient MEFs compared to the wild-type MEFs, as determined by LysoTracker staining and time-lapse image analysis performed using mRFP-GFP-tagged LC3. Taken together, our data show that PRIP is required for the fusion of S. aureus-containing autophagosome-like vacuoles with lysosomes, indicating that PRIP is a novel modulator in the regulation of the innate immune system in non-professional phagocytic host cells.

  4. Thrombopoietin protects H9C2 cells from excessive autophagy and apoptosis in doxorubicin-induced cardiotoxicity

    Science.gov (United States)

    Wang, Han; Wang, Hua; Liang, En-Yu; Zhou, Li-Xia; Dong, Zhan-Ling; Liang, Ping; Weng, Qi-Fang; Yang, Mo

    2018-01-01

    Cardiac toxicity has been the major concern when using doxorubicin (DOX) in cancer therapy. Thrombopoietin (TPO) protects cardiac cells from DOX-induced cell damage; however, its molecular mechanism remains exclusive. The anti-autophagic and anti-apoptotic effects of TPO upon DOX treatment were studied in the cardiac H9C2 cell line, with bafilomycin A1 treatment as a positive control for autophagy inhibition. Cell viability was measured by Cell Counting Kit-8 assay in different treatment groups. The mRNA and/or protein levels of apoptotic markers and autophagy-associated factors were detected. The mean number of microtubule-associated protein 1A/1B-light chain 3 (LC3) puncta per cell was quantified to indicate autophagosomes and autolysosomes, of which the ones co-stained with lysosomal-associated membrane protein 1 were considered as autolysosomes. DOX treatment (5 µg/ml, 24 h) significantly impaired H9C2 cell viability compared with the control, while TPO pretreatment (10 ng/ml, 36 h) improved cell viability upon DOX treatment. DOX exposure markedly increased LC3 puncta in H9C2 cells, and TPO pretreatment reduced the number of autophagosomes, but showed no significant inhibitory effect on autolysosome formation. The autophagy inhibition by TPO upon DOX treatment was confirmed according to protein quantification of LC3-II and nucleoporin 62. TPO also suppressed autophagy-promoting protein Beclin-1, and elevated the anti-autophagic factors GATA-binding protein-4 and B cell lymphoma-2. Furthermore, TPO reduced DOX-induced apoptosis in H9C2 cells, as reflected by the amount changes of caspase-3. Taken together, these results revealed that TPO has a protective role in H9C2 cells from DOX-induced autophagy as well as apoptosis, and indicated that TPO may act as a cardioprotective drug in DOX-treated patients. PMID:29403560

  5. Multiphoton versus single-photon excitation of photosensitizers for laser-induced fluorescence diagnosis and photodynamic therapy of cancer cells

    Science.gov (United States)

    Roelofs, Theo A.; Graschew, Georgi; Schneider, Marc; Rakowsky, Stefan; Sinn, Hanns-joerg; Schlag, Peter M.

    2001-04-01

    In laser-induced fluorescence diagnosis and photodynamic therapy of cancer the applied photosensitizers (PS) are often covalently derivatized with macromolecules to improve their selective accumulation in the cancerous tissue, while maintaining its single-photon excited photophysical properties. In this contribution methoxy-polyethylene glycol (MPEG, MW ~5 kDa) and human serum albumin (HSA, MW ~60 kDa) are used as PS carriers. Multiphoton (MP) excitation of the PS is favorable as compared to single-photon excitation because the penetration depth of the laser light is improved (>5 mm) due to the longer wavelength of the ~200 fs laser pulses used in this case (700-1050 nm). In this study cotton fibers and silica gel beads (quinone) do not exhibit multiphoton-induced fluorescence. Some derivatized PS (sulforhodamine B, erythrosin B, purpurin) exhibit MP-induced fluorescence, although no single-photon absorption band exists in the spectral region around half the excitation wavelength

  6. Photofrin-mediated photodynamic therapy of chemically-induced premalignant lesions and squamous cell carcinoma of the palatal mucosa in rats

    NARCIS (Netherlands)

    Nauta, JM; vanLeengoed, HLLM; Witjes, MJH; Nikkels, PGJ; Vermey, A; Roodenburg, JLN

    Photodynamic therapy (PDT), an experimental cancer therapy, was studied in an animal model of chemically-induced epithelial dysplasia and squamous cell carcinoma. PDT was performed 24 hours after i.v. injection of 2.5 mg/kg bw Photofrin, and using 100 J/cm(2) incident light at two activation

  7. The necrosis-avid small molecule HQ4-DTPA as a multimodal imaging agent for monitoring radiation therapy-induced tumor cell death

    NARCIS (Netherlands)

    M.A. Stammes (Marieke A.); Maeda, A. (Azusa); Bu, J. (Jiachuan); Scolard, D.A. (Deborah A.); Kulbatski, I. (Iris); Medeiros, P.J. (Philip J.); Sinisi, R. (Riccardo); Dubikovskaya, E.A. (Elena A.); T.J.A. Snoeks (thomas); E.R. van Beek (Ermond); A. Chan (Albert); C.W.G.M. Löwik (Clemens); DaCosta, R.S. (Ralph S.)

    2016-01-01

    textabstractPurpose: Most effective antitumor therapies induce tumor cell death. Non-invasive, rapid and accurate quantitative imaging of cell death is essential for monitoring early response to antitumor therapies. To facilitate this, we previously developed a biocompatible necrosis-avid

  8. SU-E-J-161: Inverse Problems for Optical Parameters in Laser Induced Thermal Therapy

    Energy Technology Data Exchange (ETDEWEB)

    Fahrenholtz, SJ; Stafford, RJ; Fuentes, DT [UT MD Anderson Cancer Center, Houston, TX (United States); UT Graduate School of Biomedical Sciences, Houston, TX (United States)

    2014-06-01

    Purpose: Magnetic resonance-guided laser-induced thermal therapy (MRgLITT) is investigated as a neurosurgical intervention for oncological applications throughout the body by active post market studies. Real