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Sample records for attractive therapeutic target

  1. Obesity, insulin resistance, adipocytokines and breast cancer: New biomarkers and attractive therapeutic targets.

    Science.gov (United States)

    Dalamaga, Maria

    2013-08-20

    Worldwide, breast cancer (BC) represents the most common type of non-skin human malignancy and the second leading cause of cancer-related deaths amid women in Western countries. Obesity and its metabolic complications have rapidly become major global health issues and are associated with increased risk for cancer, especially BC in postmenopausal women. Adipose tissue is considered as a genuine endocrine organ secreting a variety of bioactive adipokines, such as leptin, adiponectin, resistin and nicotinamide phosphoribosyl-transferase/visfatin. Recent evidence has indicated that the constellation of obesity, insulin resistance and adipokines is associated with the risk and prognosis of postmenopausal BC. Direct evidence is growing rapidly supporting the stimulating and/or inhibiting role of adipokines in the process of development and progression of BC. Adipokines could exert their effects on the normal and neoplastic mammary tissue by endocrine, paracrine and autocrine mechanisms. Recent studies support a role of adipokines as novel risk factors and potential diagnostic and prognostic biomarkers in BC. This editorial aims at providing important insights into the potential pathophysiological mechanisms linking adipokines to the etiopathogenesis of BC in the context of a dysfunctional adipose tissue and insulin resistance in obesity. A better understanding of these mechanisms may be important for the development of attractive preventive and therapeutic strategies against obesity-related breast malignancy. PMID:24520544

  2. Molecularly targeted therapeutic radiopharmaceuticals

    International Nuclear Information System (INIS)

    Full text: It is generally agreed that current focus of nuclear medicine development should be on molecular imaging and therapy. Though, the widespread use of the terminology 'molecular imaging' is quite recent, nuclear medicine has used molecular imaging techniques for more than 20 years ago. A variety of radiopharmaceuticals have been introduced for the internal therapy of malignant and inflammatory lesions in nuclear medicine. In the field of bio/medical imaging, nuclear medicine is one of the disciplines which has the privilege of organized and well developed chemistry/ pharmacy section; radio-chemistry/radiopharmacy. Fundamental principles have been developed more than 40 years ago and advanced research is going well into postgenomic era. The genomic revolution and dramatically increased insight in the molecular mechanisms underlying pathology have led to paradigm shift in drug development. Likewise does in the nuclear medicine. Here, the author will present current clinical and pre-clinical therapeutic radiopharmaceuticals based on molecular targets such as membrane-bound receptors, enzymes, nucleic acids, sodium iodide symporter, etc, in correlation with fundamentals of radiopharmacy. (author)

  3. Targeting and Therapeutic Peptides in Nanomedicine for Atherosclerosis

    OpenAIRE

    Chung, Eun Ji

    2016-01-01

    Peptides in atherosclerosis nanomedicine provide structural, targeting, and therapeutic functionality, and can assist in overcoming delivery barriers of traditional pharmaceuticals. Moreover, their inherent biocompatibility and biodegradability make them especially attractive as materials intended for use in vivo. In this review, an overview of nanoparticle-associated targeting and therapeutic peptides for atherosclerosis are provided, including peptides designed for cellular targets such as ...

  4. Therapeutic Targeting of Telomerase.

    Science.gov (United States)

    Jäger, Kathrin; Walter, Michael

    2016-01-01

    Telomere length and cell function can be preserved by the human reverse transcriptase telomerase (hTERT), which synthesizes the new telomeric DNA from a RNA template, but is normally restricted to cells needing a high proliferative capacity, such as stem cells. Consequently, telomerase-based therapies to elongate short telomeres are developed, some of which have successfully reached the stage I in clinical trials. Telomerase is also permissive for tumorigenesis and 90% of all malignant tumors use telomerase to obtain immortality. Thus, reversal of telomerase upregulation in tumor cells is a potential strategy to treat cancer. Natural and small-molecule telomerase inhibitors, immunotherapeutic approaches, oligonucleotide inhibitors, and telomerase-directed gene therapy are useful treatment strategies. Telomerase is more widely expressed than any other tumor marker. The low expression in normal tissues, together with the longer telomeres in normal stem cells versus cancer cells, provides some degree of specificity with low risk of toxicity. However, long term telomerase inhibition may elicit negative effects in highly-proliferative cells which need telomerase for survival, and it may interfere with telomere-independent physiological functions. Moreover, only a few hTERT molecules are required to overcome senescence in cancer cells, and telomerase inhibition requires proliferating cells over a sufficient number of population doublings to induce tumor suppressive senescence. These limitations may explain the moderate success rates in many clinical studies. Despite extensive studies, only one vaccine and one telomerase antagonist are routinely used in clinical work. For complete eradication of all subpopulations of cancer cells a simultaneous targeting of several mechanisms will likely be needed. Possible technical improvements have been proposed including the development of more specific inhibitors, methods to increase the efficacy of vaccination methods, and

  5. Therapeutic Targeting of Telomerase

    Science.gov (United States)

    Jäger, Kathrin; Walter, Michael

    2016-01-01

    Telomere length and cell function can be preserved by the human reverse transcriptase telomerase (hTERT), which synthesizes the new telomeric DNA from a RNA template, but is normally restricted to cells needing a high proliferative capacity, such as stem cells. Consequently, telomerase-based therapies to elongate short telomeres are developed, some of which have successfully reached the stage I in clinical trials. Telomerase is also permissive for tumorigenesis and 90% of all malignant tumors use telomerase to obtain immortality. Thus, reversal of telomerase upregulation in tumor cells is a potential strategy to treat cancer. Natural and small-molecule telomerase inhibitors, immunotherapeutic approaches, oligonucleotide inhibitors, and telomerase-directed gene therapy are useful treatment strategies. Telomerase is more widely expressed than any other tumor marker. The low expression in normal tissues, together with the longer telomeres in normal stem cells versus cancer cells, provides some degree of specificity with low risk of toxicity. However, long term telomerase inhibition may elicit negative effects in highly-proliferative cells which need telomerase for survival, and it may interfere with telomere-independent physiological functions. Moreover, only a few hTERT molecules are required to overcome senescence in cancer cells, and telomerase inhibition requires proliferating cells over a sufficient number of population doublings to induce tumor suppressive senescence. These limitations may explain the moderate success rates in many clinical studies. Despite extensive studies, only one vaccine and one telomerase antagonist are routinely used in clinical work. For complete eradication of all subpopulations of cancer cells a simultaneous targeting of several mechanisms will likely be needed. Possible technical improvements have been proposed including the development of more specific inhibitors, methods to increase the efficacy of vaccination methods, and

  6. Therapeutic Targeting of Telomerase

    Directory of Open Access Journals (Sweden)

    Kathrin Jäger

    2016-07-01

    Full Text Available Telomere length and cell function can be preserved by the human reverse transcriptase telomerase (hTERT, which synthesizes the new telomeric DNA from a RNA template, but is normally restricted to cells needing a high proliferative capacity, such as stem cells. Consequently, telomerase-based therapies to elongate short telomeres are developed, some of which have successfully reached the stage I in clinical trials. Telomerase is also permissive for tumorigenesis and 90% of all malignant tumors use telomerase to obtain immortality. Thus, reversal of telomerase upregulation in tumor cells is a potential strategy to treat cancer. Natural and small-molecule telomerase inhibitors, immunotherapeutic approaches, oligonucleotide inhibitors, and telomerase-directed gene therapy are useful treatment strategies. Telomerase is more widely expressed than any other tumor marker. The low expression in normal tissues, together with the longer telomeres in normal stem cells versus cancer cells, provides some degree of specificity with low risk of toxicity. However, long term telomerase inhibition may elicit negative effects in highly-proliferative cells which need telomerase for survival, and it may interfere with telomere-independent physiological functions. Moreover, only a few hTERT molecules are required to overcome senescence in cancer cells, and telomerase inhibition requires proliferating cells over a sufficient number of population doublings to induce tumor suppressive senescence. These limitations may explain the moderate success rates in many clinical studies. Despite extensive studies, only one vaccine and one telomerase antagonist are routinely used in clinical work. For complete eradication of all subpopulations of cancer cells a simultaneous targeting of several mechanisms will likely be needed. Possible technical improvements have been proposed including the development of more specific inhibitors, methods to increase the efficacy of vaccination

  7. Therapeutic targets in liver fibrosis.

    Science.gov (United States)

    Fallowfield, Jonathan A

    2011-05-01

    Detailed analysis of the cellular and molecular mechanisms that mediate liver fibrosis has provided a framework for therapeutic approaches to prevent, slow down, or even reverse fibrosis and cirrhosis. A pivotal event in the development of liver fibrosis is the activation of quiescent hepatic stellate cells (HSCs) to scar-forming myofibroblast-like cells. Consequently, HSCs and the factors that regulate HSC activation, proliferation, and function represent important antifibrotic targets. Drugs currently licensed in the US and Europe for other indications target HSC-related components of the fibrotic cascade. Their deployment in the near future looks likely. Ultimately, treatment strategies for liver fibrosis may vary on an individual basis according to etiology, risk of fibrosis progression, and the prevailing pathogenic milieu, meaning that a multiagent approach could be required. The field continues to develop rapidly and starts to identify exciting potential targets in proof-of-concept preclinical studies. Despite this, no antifibrotics are currently licensed for use in humans. With epidemiological predictions for the future prevalence of viral, obesity-related, and alcohol-related cirrhosis painting an increasingly gloomy picture, and a shortfall in donors for liver transplantation, the clinical urgency for new therapies is high. There is growing interest from stakeholders keen to exploit the market potential for antifibrotics. However, the design of future trials for agents in the developmental pipeline will depend on strategies that enable equal patient stratification, techniques to reliably monitor changes in fibrosis over time, and the definition of clinically meaningful end points. PMID:21233278

  8. Therapeutic targeting of replicative immortality.

    Science.gov (United States)

    Yaswen, Paul; MacKenzie, Karen L; Keith, W Nicol; Hentosh, Patricia; Rodier, Francis; Zhu, Jiyue; Firestone, Gary L; Matheu, Ander; Carnero, Amancio; Bilsland, Alan; Sundin, Tabetha; Honoki, Kanya; Fujii, Hiromasa; Georgakilas, Alexandros G; Amedei, Amedeo; Amin, Amr; Helferich, Bill; Boosani, Chandra S; Guha, Gunjan; Ciriolo, Maria Rosa; Chen, Sophie; Mohammed, Sulma I; Azmi, Asfar S; Bhakta, Dipita; Halicka, Dorota; Niccolai, Elena; Aquilano, Katia; Ashraf, S Salman; Nowsheen, Somaira; Yang, Xujuan

    2015-12-01

    One of the hallmarks of malignant cell populations is the ability to undergo continuous proliferation. This property allows clonal lineages to acquire sequential aberrations that can fuel increasingly autonomous growth, invasiveness, and therapeutic resistance. Innate cellular mechanisms have evolved to regulate replicative potential as a hedge against malignant progression. When activated in the absence of normal terminal differentiation cues, these mechanisms can result in a state of persistent cytostasis. This state, termed "senescence," can be triggered by intrinsic cellular processes such as telomere dysfunction and oncogene expression, and by exogenous factors such as DNA damaging agents or oxidative environments. Despite differences in upstream signaling, senescence often involves convergent interdependent activation of tumor suppressors p53 and p16/pRB, but can be induced, albeit with reduced sensitivity, when these suppressors are compromised. Doses of conventional genotoxic drugs required to achieve cancer cell senescence are often much lower than doses required to achieve outright cell death. Additional therapies, such as those targeting cyclin dependent kinases or components of the PI3K signaling pathway, may induce senescence specifically in cancer cells by circumventing defects in tumor suppressor pathways or exploiting cancer cells' heightened requirements for telomerase. Such treatments sufficient to induce cancer cell senescence could provide increased patient survival with fewer and less severe side effects than conventional cytotoxic regimens. This positive aspect is countered by important caveats regarding senescence reversibility, genomic instability, and paracrine effects that may increase heterogeneity and adaptive resistance of surviving cancer cells. Nevertheless, agents that effectively disrupt replicative immortality will likely be valuable components of new combinatorial approaches to cancer therapy. PMID:25869441

  9. The potential therapeutic targets for cervical cancer

    Directory of Open Access Journals (Sweden)

    L Priyanka Dwarampudi

    2013-01-01

    Full Text Available In case of invasive cervical carcinoma several molecular events were reported and these molecular events resulting in multiple genetic abnormalities. In order to control these tumors multiple molecular therapeutic targets are needed with different molecular mechanisms. Unfortunately, these molecular targets were in early stages of development. Because of less degree of success of conventional therapeutics for late stages of cervical cancer and lowering of prognosis of patients there is an increase in interest for the development of potential therapeutic targets for cervical cancer. This review article emphasizes the current molecular targeted agents; with special attention to estrogen receptors for human papilloma virus infected cervical cancer.

  10. Pathogenesis and new therapeutic targets

    OpenAIRE

    Mertens, Michael

    2010-01-01

    Acute lung injury and its pronounced form, acute respiratory distress syndrome, are life-threatening diseases with 190,000 patients and 74,500 deaths per year in the United States. Until now there have been no therapeutic approaches to lower morbidity and mortality, except for ventilation with small tidal volumes. This partially results from a lack of understanding of the underlying mechanism of ventilator induced acute lung injury on the alveolar and alveolar capillary level. In addition, ph...

  11. The potential therapeutic targets for cervical cancer

    OpenAIRE

    L Priyanka Dwarampudi; Gowthamarajan, K.; Shanmugam, R; Madhuri, K.; Nilani, P.; M N Satish Kumar

    2013-01-01

    In case of invasive cervical carcinoma several molecular events were reported and these molecular events resulting in multiple genetic abnormalities. In order to control these tumors multiple molecular therapeutic targets are needed with different molecular mechanisms. Unfortunately, these molecular targets were in early stages of development. Because of less degree of success of conventional therapeutics for late stages of cervical cancer and lowering of prognosis of patients there is an inc...

  12. Therapeutic targeting of Janus kinases

    OpenAIRE

    Pesu, Marko; Laurence, Arian; Kishore, Nandini; Zwillich, Sam; Chan, Gary; O’Shea, John J.

    2008-01-01

    Cytokines play pivotal roles in immunity and inflammation, and targeting cytokines and their receptors is an effective means of treating such disorders. Type I and II cytokine receptors associate with Janus family kinases (JAKs) to effect intracellular signaling. These structurally unique protein kinases play essential and specific roles in immune cell development and function. One JAK, JAK3, has particularly selective functions. Mutations of this kinase underlie severe combined immunodeficie...

  13. Therapeutic Targeting of Hyaluronan in the Tumor Stroma

    OpenAIRE

    H. Michael Shepard; Frost, Gregory I.; Thompson, Curtis B.; Ping Jiang; Xiaoming Li; Anne Kultti

    2012-01-01

    The tumor stroma, consisting of non-malignant cells and the extracellular matrix, undergoes significant quantitative and qualitative changes throughout malignant transformation and tumor progression. With increasing recognition of the role of the tumor microenvironment in disease progression, stromal components of the tumor have become attractive targets for therapeutic intervention. Stromal accumulation of the glycosaminoglycan hyaluronan occurs in many tumor types and is frequently associat...

  14. Conotoxins: Molecular and Therapeutic Targets

    Science.gov (United States)

    Lewis, Richard J.

    Marine molluscs known as cone snails produce beautiful shells and a complex array of over 50,000 venom peptides evolved for prey capture and defence. Many of these peptides selectively modulate ion channels and transporters, making them a valuable source of new ligands for studying the role these targets play in normal and disease physiology. A number of conopeptides reduce pain in animal models, and several are now in pre-clinical and clinical development for the treatment of severe pain often associated with diseases such as cancer. Less than 1% of cone snail venom peptides are pharmacologically characterised.

  15. BAD: a good therapeutic target?

    International Nuclear Information System (INIS)

    The major goal in cancer treatment is the eradication of tumor cells. Under stress conditions, normal cells undergo apoptosis; this property is fortunately conserved in some tumor cells, leading to their death as a result of chemotherapeutic and/or radiation-induced stress. Many malignant cells, however, have developed ways to subvert apoptosis, a characteristic that constitutes a major clinical problem. Gilmore et al. recently described the ability of ZD1839, a small-molecule inhibitor of the epidermal growth factor receptor (EGFR), to induce apoptosis of mammary cells that are dependent upon growth factors for survival. Furthermore, they showed that the major effector of the EGFR-targeted therapy is BAD, a widely expressed BCL-2 family member. These results are promising in light of the role of the EGFR in breast cancer development

  16. Critical questions in development of targeted nanoparticle therapeutics.

    Science.gov (United States)

    Korsmeyer, Richard

    2016-06-01

    One of the fourteen Grand Challenges for Engineering articulated by the US National Academy of Engineering is 'Engineer Better Medicines'. Although there are many ways that better medicines could be engineered, one of the most promising ideas is to improve our ability to deliver the therapeutic molecule more precisely to the desired target. Most conventional drug delivery methods (oral absorption, intravenous infusion etc.) result in systemic exposure to the therapeutic molecule, which places severe constraints on the types of molecules that can be used. A molecule administered by systemic delivery must be effective at low concentrations in the target tissue, yet safe everywhere else in the body. If drug carriers could be developed to deliver therapeutic molecules selectively to the desired target, it should be possible to greatly improve safety and efficacy of therapy. Nanoparticles (and related nanostructures, such as liposomes, nanoemulsions, micelles and dendrimers) are an attractive drug carrier concept because they can be made from a variety of materials engineered to have properties that allow loading and precise delivery of bound therapeutic molecules. The field of targeted nanoparticles has been extraordinarily active in the academic realm, with thousands of articles published over the last few years. Many of these publications seem to demonstrate very promising results in in vitro studies and even in animal models. In addition, a handful of human clinical trials are in progress. Yet, the biopharmaceutical industry has been relatively slow to make major investments in targeted nanoparticle development programs, despite a clear desire to introduce innovative new therapies to the market. What is the reason for such caution? Some degree of caution is no doubt due to the use of novel materials and the unproven nature of targeted nanoparticle technology, but many other unproven technologies have generated intense interest at various times. We believe that the

  17. Critical questions in development of targeted nanoparticle therapeutics

    Science.gov (United States)

    Korsmeyer, Richard

    2016-01-01

    One of the fourteen Grand Challenges for Engineering articulated by the US National Academy of Engineering is ‘Engineer Better Medicines’. Although there are many ways that better medicines could be engineered, one of the most promising ideas is to improve our ability to deliver the therapeutic molecule more precisely to the desired target. Most conventional drug delivery methods (oral absorption, intravenous infusion etc.) result in systemic exposure to the therapeutic molecule, which places severe constraints on the types of molecules that can be used. A molecule administered by systemic delivery must be effective at low concentrations in the target tissue, yet safe everywhere else in the body. If drug carriers could be developed to deliver therapeutic molecules selectively to the desired target, it should be possible to greatly improve safety and efficacy of therapy. Nanoparticles (and related nanostructures, such as liposomes, nanoemulsions, micelles and dendrimers) are an attractive drug carrier concept because they can be made from a variety of materials engineered to have properties that allow loading and precise delivery of bound therapeutic molecules. The field of targeted nanoparticles has been extraordinarily active in the academic realm, with thousands of articles published over the last few years. Many of these publications seem to demonstrate very promising results in in vitro studies and even in animal models. In addition, a handful of human clinical trials are in progress. Yet, the biopharmaceutical industry has been relatively slow to make major investments in targeted nanoparticle development programs, despite a clear desire to introduce innovative new therapies to the market. What is the reason for such caution? Some degree of caution is no doubt due to the use of novel materials and the unproven nature of targeted nanoparticle technology, but many other unproven technologies have generated intense interest at various times. We believe that

  18. Therapeutic strategies targeting cancer stem cells.

    Science.gov (United States)

    Ning, Xiaoyan; Shu, Jianchang; Du, Yiqi; Ben, Qiwen; Li, Zhaoshen

    2013-04-01

    Increasing studies have demonstrated a small proportion of cancer stem cells (CSCs) exist in the cancer cell population. CSCs have powerful self-renewal capacity and tumor-initiating ability and are resistant to chemotherapy and radiation. Conventional anticancer therapies kill the rapidly proliferating bulk cancer cells but spare the relatively quiescent CSCs, which cause cancer recurrence. So it is necessary to develop therapeutic strategies acting specifically on CSCs. In recent years, studies have shown that therapeutic agents such as metformin, salinomycin, DECA-14, rapamycin, oncostatin M (OSM), some natural compounds, oncolytic viruses, microRNAs, cell signaling pathway inhibitors, TNF-related apoptosis inducing ligand (TRAIL), interferon (IFN), telomerase inhibitors, all-trans retinoic acid (ATRA) and monoclonal antibodies can suppress the self-renewal of CSCs in vitro and in vivo. A combination of these agents and conventional chemotherapy drugs can significantly inhibit tumor growth, metastasis and recurrence. These strategies targeting CSCs may bring new hopes to cancer therapy. PMID:23358473

  19. Molecular Therapeutic Targets for Glioma Angiogenesis

    Directory of Open Access Journals (Sweden)

    Shingo Takano

    2010-01-01

    Full Text Available Due to the prominent angiogenesis that occurs in malignant glioma, antiangiogenic therapy has been attempted. There have been several molecular targets that are specific to malignant gliomas, as well as more broadly in systemic cancers. In this review, I will focus on some topics related to molecular therapeutic targets for glioma angiogenesis. First, important angiogenic factors that could be considered molecular targets are VEGF, VEGF-induced proteins on endothelial cells, tissue factor, osteopontin, v3 integrin, and thymidine phosphorylase as well as endogenous inhibitors, soluble Flt1, and thrombospondin 1. Second, hypoxic areas are also decreased by metronomic CPT11 treatment as well as temozolomide. Third, glioma-derived endothelial cells that are genetically and functionally distinct from normal endothelial cells should be targeted, for example, with SDF-1 and CXCR7 chemokine. Fourth, endothelial progenitor cells (EPCs likely contribute towards glioma angiogenesis in the brain and could be useful as a drug delivery tool. Finally, blockade of delta-like 4 (Dll4 results in a nonfunctioning vasculature and could be another important target distinct from VEGF.

  20. Reinforcing targeted therapeutics with phenotypic stability factors.

    Science.gov (United States)

    Yaswen, Paul

    2014-01-01

    Deregulated cell cycle progression can often be traced to intrinsic defects in specific regulatory proteins in cancer cells. Knowledge of these primary defects has led to targeted approaches that exploit the defects and spare normal cells. However, the success of such targeted approaches is still hit-or-miss. Genetic and epigenetic variability inherent in most tumors often results in phenotypic heterogeneity that, in turn, results in de novo or acquired resistance to therapeutic agents. The ability of cells to compensate and adapt to the inhibition of a specific cell cycle mediator is not remarkable. What is novel and of great potential importance is that the ability of cells to exhibit such adaptability varies markedly. "Phenotypic stability factors" that restrict the ability of cells to undergo epithelial-mesenchymal transitions (EMT) may dictate the success or failure of targeted therapies by interfering with compensatory changes such as deregulation of CDK2 activity. Identification of existing and new agents that induce and maintain phenotypic stability factors will inform and enable synergistic approaches to the eradication of even the most aggressive tumors. PMID:25483053

  1. Discovering Che-1/AATF: a new attractive target for cancer therapy

    Directory of Open Access Journals (Sweden)

    Simona eIezzi

    2015-04-01

    Full Text Available The transcriptional cofactor Che-1/AATF is currently emerging as an important component of the DNA damage response machinery, the complex signaling network that maintains genome integrity and prevents tumorigenesis. Moreover this protein is involved in a wide range of cellular pathways, regulating proliferation and survival in both physiological and pathological conditions. Notably, some evidence indicates that dysregulation of Che-1/AATF levels are associated with the transformation process and elevated levels of Che-1/AATF are required for tumor cell survival. It is for these reasons that Che-1/AATF has been regarded as an attractive, still theoretical, therapeutic target for cancer treatments. In this review, we will provide an updated overview of Che-1/AATF activities, from transcriptional regulation to DNA damage response.

  2. Targeting HCV Entry For Development of Therapeutics

    Directory of Open Access Journals (Sweden)

    Jeffrey F. McKelvy

    2010-08-01

    Full Text Available Recent progress in defining the molecular mechanisms of Hepatitis C Virus (HCV entry affords the opportunity to exploit new viral and host targets for therapeutic intervention. Entry inhibitors would limit the expansion of the infected cell reservoir, and would complement the many replication inhibitors now under development. The current model for the pathway of entry involves the initial docking of the virus onto the cell surface through interactions of virion envelope and associated low density lipoproteins (LDL with cell surface glycosaminoglycans and lipoprotein receptors, followed by more specific utilization with other hepatocyte membrane proteins: Scavenger Receptor Class B type 1 (SR-BI, CD81, Claudin 1 (CLDN1 and Occludin (OCLN. The use of blockers of these interactions, e.g. specific antibodies, suggests that inhibition of any one step in the entry pathway can inhibit infection. Despite this knowledge base, the tools for compound screening, HCV pseudoparticles (HCVpp and cell culture virus (HCVcc, and the ability to adapt them to industrial use are only recently available and as a result drug discovery initiatives are in their infancy. Several therapies aiming at modulating the virus envelope to prevent host cell binding are in early clinical testing. The first test case for blocking a cellular co-receptor is an SR-BI modulator. ITX 5061, an orally active small molecule, targets SR-BI and has shown potent antiviral activity against HCVpp and HCVcc. ITX 5061 has exhibited good safety in previous clinical studies, and is being evaluated in the clinic in chronic HCV patients and patients undergoing liver transplantation. Entry inhibitors promise to be valuable players in the future development of curative therapy against HCV.

  3. Ascaris lumbricoides: an overview of therapeutic targets.

    Science.gov (United States)

    Hagel, Isabel; Giusti, Tatiana

    2010-10-01

    A. lumbricoides is the largest of the common nematode parasites of man and has been associated with intestinal pathology, respiratory symptoms and malnutrition in children from endemic areas. Current anthelmintic treatments have proven to be safe. However, a reduced efficacy of single dose drugs has been reported. In veterinary practice, anthelmintic drug resistance is an irreversible problem. Thus, research and development of sensitive tools for early detection of drug resistance as well as new anthelmintic approaches are urgently needed. In this review, we summarized data providing information about current drug therapy against A. lumbricoides and other intestinal helminths, new drugs in experimental trials, future drugs perspectives and the identification of immunogenic parasite molecules that may be suitable vaccine targets. In addition to the WHO recommended drugs (albendazole, mebendazole, levamisole, and pyrantel pamoate), new anthelmintic alternatives such as tribendimidine and Nitazoxanide have proved to be safe and effective against A. lumbricoides and other soil-transmitted helminthiases in human trials. Also, some new drugs for veterinary use, monepantel and cyclooctadepsipeptides (e.g., PF1022A), will probably expand future drug spectrum for human treatments. The development of genomic technology has provided a great amount of available nematode DNA sequences, coupled with new gene function data that may lead to the identification of new drug targets through efficient mining of nematode genomic databases. On the other hand, the identification of nematode antigens involved in different parasite vital functions as well as immunomodulatory molecules in animals and humans may contribute to future studies of new therapeutic approaches. PMID:20701574

  4. GPR35 as a novel therapeutic target

    Directory of Open Access Journals (Sweden)

    GraemeMilligan

    2011-11-01

    Full Text Available G protein-coupled receptors (GPCRs remain the best studied class of cell surface receptors and the most tractable family of proteins for novel small molecule drug discovery. Despite this, a considerable number of GPCRs remain poorly characterised and in a significant number of cases, endogenous ligand(s that activate them remain undefined or of questionable physiological relevance. GPR35 was initially discovered over a decade ago but has remained an ‘orphan’ receptor. Recent publications have highlighted novel ligands, both endogenously produced and synthetic, which demonstrate significant potency at this receptor. Furthermore, evidence is accumulating which highlights potential roles for GPR35 in disease and therefore, efforts to characterise GPR35 more fully and develop it as a novel therapeutic target in conditions that range from diabetes, hypertension to asthma are increasing. Recently identified ligands have shown marked species selective properties, indicating major challenges for future drug development. As we begin to understand these issues, the continuing efforts to identify novel agonist and antagonist ligands for GPR35 will help to decipher its true physiological relevance; translating multiple assay systems in vitro, to animal disease systems in vivo and finally to man.

  5. Targeting NF-κB in glioblastoma: A therapeutic approach.

    Science.gov (United States)

    Friedmann-Morvinski, Dinorah; Narasimamurthy, Rajesh; Xia, Yifeng; Myskiw, Chad; Soda, Yasushi; Verma, Inder M

    2016-01-01

    Glioblastoma multiforme (GBM) is the most common and lethal form of intracranial tumor. We have established a lentivirus-induced mouse model of malignant gliomas, which faithfully captures the pathophysiology and molecular signature of mesenchymal human GBM. RNA-Seq analysis of these tumors revealed high nuclear factor κB (NF-κB) activation showing enrichment of known NF-κB target genes. Inhibition of NF-κB by either depletion of IκB kinase 2 (IKK2), expression of a IκBαM super repressor, or using a NEMO (NF-κB essential modifier)-binding domain (NBD) peptide in tumor-derived cell lines attenuated tumor proliferation and prolonged mouse survival. Timp1, one of the NF-κB target genes significantly up-regulated in GBM, was identified to play a role in tumor proliferation and growth. Inhibition of NF-κB activity or silencing of Timp1 resulted in slower tumor growth in both mouse and human GBM models. Our results suggest that inhibition of NF-κB activity or targeting of inducible NF-κB genes is an attractive therapeutic approach for GBM. PMID:26824076

  6. Diabetic retinopathy and inflammation: Novel therapeutic targets

    Directory of Open Access Journals (Sweden)

    Sampathkumar Rangasamy

    2012-01-01

    Full Text Available Most anti-vascular endothelial growth factor (VEGF therapies in diabetic macular edema are not as robust as in proliferative diabetic retinopathy. Although the VEGF appears to be a good target in diabetic macular edema, the anti-VEGF therapies appear to be of transient benefit as the edema recurs within a few weeks, and repeated injections are necessary. There is new evidence that indicates ′retinal inflammation′ as an important player in the pathogenesis of diabetic retinopathy. There are common sets of inflammatory cytokines that are upregulated in both the serum and vitreous and aqueous samples, in subjects with diabetic retinopathy, and these cytokines can have multiple interactions to impact the pathogenesis of the disease. The key inflammatory events involved in the blood retinal barrier (BRB alteration appear to be: (1 Increased expression of endothelial adhesion molecules such as ICAM1, VCAM1, PECAM-1, and P-selectin, (2 adhesion of leukocytes to the endothelium, (3 release of inflammatory chemokines, cytokines, and vascular permeability factors, (4 alteration of adherens and tight junctional proteins between the endothelial cells, and (5 infiltration of leukocytes into the neuro-retina, resulting in the alteration of the blood retinal barrier (diapedesis. VEGF inhibition itself may not achieve neutralization of other inflammatory molecules involved in the inflammatory cascade of the breakdown of the BRB. It is possible that the novel selective inhibitors of the inflammatory cascade (like angiopoietin-2, TNFα, and chemokines may be useful therapeutic agents in the treatment of diabetic macular edema (DME, either alone or in combination with the anti-VEGF drugs.

  7. Therapeutic Targeting of Hyaluronan in the Tumor Stroma

    Energy Technology Data Exchange (ETDEWEB)

    Kultti, Anne, E-mail: akultti@halozyme.com [Department of Research, Halozyme Therapeutics, 11388 Sorrento Valley Road, San Diego, CA 92121 (United States); Li, Xiaoming; Jiang, Ping; Thompson, Curtis B. [Department of Pharmacology and Safety Assessment, Halozyme Therapeutics, 11388 Sorrento Valley Road, San Diego, CA 92121 (United States); Frost, Gregory I. [Department of General and Administrative, Halozyme Therapeutics, 11388 Sorrento Valley Road, San Diego, CA 92121 (United States); Shepard, H. Michael [Department of Research, Halozyme Therapeutics, 11388 Sorrento Valley Road, San Diego, CA 92121 (United States)

    2012-09-06

    The tumor stroma, consisting of non-malignant cells and the extracellular matrix, undergoes significant quantitative and qualitative changes throughout malignant transformation and tumor progression. With increasing recognition of the role of the tumor microenvironment in disease progression, stromal components of the tumor have become attractive targets for therapeutic intervention. Stromal accumulation of the glycosaminoglycan hyaluronan occurs in many tumor types and is frequently associated with a negative disease prognosis. Hyaluronan interacts with other extracellular molecules as well as cellular receptors to form a complex interaction network influencing physicochemical properties, signal transduction, and biological behavior of cancer cells. In preclinical animal models, enzymatic removal of hyaluronan is associated with remodeling of the tumor stroma, reduction of tumor interstitial fluid pressure, expansion of tumor blood vessels and facilitated delivery of chemotherapy. This leads to inhibition of tumor growth and increased survival. Current evidence shows that abnormal accumulation of hyaluronan may be an important stromal target for cancer therapy. In this review we highlight the role of hyaluronan and hyaluronan-mediated interactions in cancer, and discuss historical and recent data on hyaluronidase-based therapies and the effect of hyaluronan removal on tumor growth.

  8. Therapeutic Targeting of Hyaluronan in the Tumor Stroma

    International Nuclear Information System (INIS)

    The tumor stroma, consisting of non-malignant cells and the extracellular matrix, undergoes significant quantitative and qualitative changes throughout malignant transformation and tumor progression. With increasing recognition of the role of the tumor microenvironment in disease progression, stromal components of the tumor have become attractive targets for therapeutic intervention. Stromal accumulation of the glycosaminoglycan hyaluronan occurs in many tumor types and is frequently associated with a negative disease prognosis. Hyaluronan interacts with other extracellular molecules as well as cellular receptors to form a complex interaction network influencing physicochemical properties, signal transduction, and biological behavior of cancer cells. In preclinical animal models, enzymatic removal of hyaluronan is associated with remodeling of the tumor stroma, reduction of tumor interstitial fluid pressure, expansion of tumor blood vessels and facilitated delivery of chemotherapy. This leads to inhibition of tumor growth and increased survival. Current evidence shows that abnormal accumulation of hyaluronan may be an important stromal target for cancer therapy. In this review we highlight the role of hyaluronan and hyaluronan-mediated interactions in cancer, and discuss historical and recent data on hyaluronidase-based therapies and the effect of hyaluronan removal on tumor growth

  9. Gastrointestinal stromal tumor and its targeted therapeutics

    Institute of Scientific and Technical Information of China (English)

    Jheri Dupart; Wei Zhang; Jonathan C. Trent

    2011-01-01

    Over the past 60 years, investigators of basic science, pathology, and clinical medicine have studied gastrointestinal stromal tumor (GIST) and made minor advances in patient care. Recent discoveries have led to an understanding of the biological rote of KIT and platelet-derived growth factor receptor-α in GIST and the development of the tyrosine kinase inhibitor imatinib mesylate (Gleevec, formerly STI-571), one of the most exciting examples of targeted therapy to date. The success of targeted therapy in GIST has lead to new developments in our understanding of the medical and surgical management of the disease. Intense study of GIST may lead to new paradigms in the management of cancer.

  10. Antibody therapeutics targeting ion channels:are we there yet?

    Institute of Scientific and Technical Information of China (English)

    Han SUN; Min LI

    2013-01-01

    The combination of technological advances,genomic sequences and market success is catalyzing rapid development of antibodybased therapeutics.Cell surface receptors and ion channel proteins are well known drug targets,but the latter has seen less success.The availability of crystal structures,better understanding of gating biophysics and validation of physiological roles now form an excellent foundation to pursue antibody-based therapeutics targeting ion channels to treat a variety of diseases.

  11. Antibody therapeutics targeting ion channels: are we there yet?

    Science.gov (United States)

    Sun, Han; Li, Min

    2013-01-01

    The combination of technological advances, genomic sequences and market success is catalyzing rapid development of antibody-based therapeutics. Cell surface receptors and ion channel proteins are well known drug targets, but the latter has seen less success. The availability of crystal structures, better understanding of gating biophysics and validation of physiological roles now form an excellent foundation to pursue antibody-based therapeutics targeting ion channels to treat a variety of diseases. PMID:23381110

  12. Targeting of microRNAs for therapeutics

    DEFF Research Database (Denmark)

    Stenvang, Jan; Lindow, Morten; Kauppinen, Sakari

    miRNAs (microRNAs) comprise a class of small endogenous non-coding RNAs that post-transcriptionally repress gene expression by base-pairing with their target mRNAs. Recent evidence has shown that miRNAs play important roles in a wide variety of human diseases, such as viral infections, cancer and...

  13. Novel therapeutic targets for erectile dysfunction.

    Science.gov (United States)

    Williams, Steve K; Melman, Arnold

    2012-01-01

    Erectile dysfunction (ED) is a neurovascular phenomenon modulated by hormonal, local biochemical, and biomechanical/structural factors of the penis. The success of the orally active phosphodiesterase inhibitors for the treatment of ED has boosted research activities into the physiology of the erectile mechanism. Peripheral intracellular signal transduction in the penis as well as central brain and spinal cord pathways controlling penile erection have been investigated and are now better understood. The results of this ongoing research have provided the basis for the development and introduction of several novel therapeutic modalities into the management of ED. Many novel pharmacotherapeutic approaches under development including the use of melanocortins and Rho-kinase inhibitors as well as the introduction of gene therapy and tissue engineering have demonstrated efficacy in animal as well as early human trials. This review describes the major new and evolving pharmacological advances in the field of oral pharmacotherapy for the treatment of male ED. PMID:22154078

  14. New Therapeutic Targets for Mood Disorders

    Directory of Open Access Journals (Sweden)

    Rodrigo Machado-Vieira

    2010-01-01

    Full Text Available Existing pharmacological treatments for bipolar disorder (BPD and major depressive disorder (MDD are often insufficient for many patients. Here we describe a number of targets/compounds that clinical and preclinical studies suggest could result in putative novel treatments for mood disorders. These include: (1 glycogen synthase kinase-3 (GSK-3 and protein kinase C (PKC, (2 the purinergic system, (3 histone deacetylases (HDACs, (4 the melatonergic system, (5 the tachykinin neuropeptides system, (6 the glutamatergic system, and (7 oxidative stress and bioenergetics. The paper reviews data on new compounds that have shown antimanic or antidepressant effects in subjects with mood disorders, or similar effects in preclinical animal models. Overall, an improved understanding of the neurobiological underpinnings of mood disorders is critical in order to develop targeted treatments that are more effective, act more rapidly, and are better tolerated than currently available therapies.

  15. Potential new therapeutic targets for pathological pruritus.

    Science.gov (United States)

    Kuraishi, Yasushi

    2013-01-01

    Very few approved medications are indicated for the treatment of pruritus, and drug development for pruritic diseases is awaited. During the past two decades, progress has been made in understanding the molecular basis of the physiology and pathophysiology of pruritus. Newly identified potential targets for pathological pruritus include receptors (histamine H4 receptor, leukotriene B4 receptors, interleukin-31 receptor A, bombesin BB2 receptor, toll-like receptor 3, α-adrenoceptor, and opioid μ- and κ-receptors), channels (transient receptor potential (TRP) V3 and TRPA1 channels), and enzymes (histidine decarboxylase, sphingomyelin glucosylceramide deacylase, 5-lipoxygenase, leukotriene A4 hydrolase, and autotaxin). The development of specific, effective blockers and agonists/antagonists of these targets is awaited. PMID:23902965

  16. GPCRs as potential therapeutic targets in preeclampsia

    OpenAIRE

    McGuane, JT; Conrad, KP

    2012-01-01

    Preeclampsia is an important obstetric complication that arises in 5% of women after the 20th week of gestation, for which there is no specific therapy and no cure. Although much of the recent investigation in this field has focused on soluble forms of the angiogenic membrane receptor tyrosine kinase Flt1 and the transforming growth factor β co-receptor Endoglin, there is significant clinical potential for several GPCR targets and their agonists or antagonists in preeclampsia. In this review,...

  17. New Therapeutic Targets for Mood Disorders

    OpenAIRE

    Rodrigo Machado-Vieira; Giacomo Salvadore; Nancy DiazGranados; Lobna Ibrahim; David Latov; Cristina Wheeler-Castillo; Jacqueline Baumann; Henter, Ioline D.; Carlos A. Zarate

    2010-01-01

    Existing pharmacological treatments for bipolar disorder (BPD) and major depressive disorder (MDD) are often insufficient for many patients. Here we describe a number of targets/compounds that clinical and preclinical studies suggest could result in putative novel treatments for mood disorders. These include: (1) glycogen synthase kinase-3 (GSK-3) and protein kinase C (PKC), (2) the purinergic system, (3) histone deacetylases (HDACs), (4) the melatonergic system, (5) the tachykinin neuropepti...

  18. Utility of network integrity methods in therapeutic target identification.

    Science.gov (United States)

    Peng, Qian; Schork, Nicholas J

    2014-01-01

    Analysis of the biological gene networks involved in a disease may lead to the identification of therapeutic targets. Such analysis requires exploring network properties, in particular the importance of individual network nodes (i.e., genes). There are many measures that consider the importance of nodes in a network and some may shed light on the biological significance and potential optimality of a gene or set of genes as therapeutic targets. This has been shown to be the case in cancer therapy. A dilemma exists, however, in finding the best therapeutic targets based on network analysis since the optimal targets should be nodes that are highly influential in, but not toxic to, the functioning of the entire network. In addition, cancer therapeutics targeting a single gene often result in relapse since compensatory, feedback and redundancy loops in the network may offset the activity associated with the targeted gene. Thus, multiple genes reflecting parallel functional cascades in a network should be targeted simultaneously, but require the identification of such targets. We propose a methodology that exploits centrality statistics characterizing the importance of nodes within a gene network that is constructed from the gene expression patterns in that network. We consider centrality measures based on both graph theory and spectral graph theory. We also consider the origins of a network topology, and show how different available representations yield different node importance results. We apply our techniques to tumor gene expression data and suggest that the identification of optimal therapeutic targets involving particular genes, pathways and sub-networks based on an analysis of the nodes in that network is possible and can facilitate individualized cancer treatments. The proposed methods also have the potential to identify candidate cancer therapeutic targets that are not thought to be oncogenes but nonetheless play important roles in the functioning of a cancer

  19. Sphingolipid and Ceramide Homeostasis: Potential Therapeutic Targets

    Directory of Open Access Journals (Sweden)

    Simon A. Young

    2012-01-01

    Full Text Available Sphingolipids are ubiquitous in eukaryotic cells where they have been attributed a plethora of functions from the formation of structural domains to polarized cellular trafficking and signal transduction. Recent research has identified and characterised many of the key enzymes involved in sphingolipid metabolism and this has led to a heightened interest in the possibility of targeting these processes for therapies against cancers, Alzheimer's disease, and numerous important human pathogens. In this paper we outline the major pathways in eukaryotic sphingolipid metabolism and discuss these in relation to disease and therapy for both chronic and infectious conditions.

  20. Particulate Systems for Targeting of Macrophages: Basic and Therapeutic Concepts

    DEFF Research Database (Denmark)

    Moghimi, Seyed Moien; Parhamifar, Ladan; Ahmadvand, Davoud;

    2012-01-01

    Particulate systems in the form of liposomes, polymeric micelles, polymeric nano- and microparticles, and many others offer a rational approach for selective delivery of therapeutic agents to the macrophage from different physiological portals of entry. Particulate targeting of macrophages and...... intracellular drug release processes can be optimized through modifications of the drug carrier physicochemical properties, which include hydrodynamic size, shape, composition and surface characteristics. Through such modifications together with understanding of macrophage cell biology, targeting may be aimed...... at a particular subset of macrophages. Advances in basic and therapeutic concepts of particulate targeting of macrophages and related nanotechnology approaches for immune cell modifications are discussed.Copyright © 2012 S. Karger AG, Basel...

  1. Is Estrogen a Therapeutic Target for Glaucoma?

    Science.gov (United States)

    Dewundara, Samantha S; Wiggs, Janey L; Sullivan, David A; Pasquale, Louis R

    2016-01-01

    endothelial nitric oxide synthase, a gene receptive to estrogen regulation, are associated with glaucoma. The study concluded that increasing evidence suggests that lifetime exposure to estrogen may alter the pathogenesis of glaucoma. Estrogen exposure may have a neuroprotective effect on the progression of POAG but further studies need to confirm this finding. The role of sex-specific preventive and therapeutic treatment may be on the horizon. PMID:26959139

  2. Superparamagnetic nanoparticles as targeted probes for diagnostic and therapeutic applications†

    OpenAIRE

    Xu, Chenjie; Sun, Shouheng

    2009-01-01

    Superparamagnetic nanoparticles (NPs) have been attractive for medical diagnostics and therapeutics due to their unique magnetic properties and their ability to interact with various biomolecules of interest. The solution phase based chemical synthesis provides a near precise control on NP size, and monodisperse magnetic NPs with standard deviation in diameter of less than 10% are now routinely available. Upon controlled surface functionalization and coupling with fragments of DNA strands, pr...

  3. Beta-3 adrenoceptors as new therapeutic targets for cardiovascular pathologies.

    OpenAIRE

    Gauthier, Chantal; Rozec, Bertrand; Manoury, Boris; Balligand, Jean-Luc

    2011-01-01

    Catecholamines play a key role in the regulation of cardiovascular function, classically through ß(1/2)-adrenoreceptors (AR) activation. After ß(3)-AR cloning in the late 1980s, convincing evidence for ß(3)-AR expression and function in cardiovascular tissues recently initiated a reexamination of their involvement in the pathophysiology of cardiovascular diseases. Their upregulation in diseased cardiovascular tissues and resistance to desensitization suggest they may be attractive therapeutic...

  4. Factor XI as a Therapeutic Target.

    Science.gov (United States)

    Gailani, David; Gruber, Andras

    2016-07-01

    Factor XIa is a plasma serine protease that contributes to thrombin generation primarily through proteolytic activation of factor IX. Traditionally considered part of the intrinsic pathway of coagulation, several lines of evidence now suggest that factor XIa serves as an interface between the vitamin-K-dependent thrombin generation mechanism and the proinflammatory kallikrein-kinin system, allowing the 2 systems to influence each other. Work with animal models and results from epidemiological surveys of human populations support a role for factor XIa in thromboembolic disease. These data and the clinical observation that deficiency of factor XI, the zymogen of factor XIa, produces a relatively mild bleeding disorder suggest that drugs targeting factor XI or XIa could produce an antithrombotic effect while leaving hemostasis largely intact. Results of a recent trial comparing antisense-induced factor XI reduction to standard-dose low molecular-weight heparin as prophylaxis for venous thrombosis during knee replacement are encouraging in this regard. Here, we discuss recent findings on the biochemistry, physiology, and pathology of factor XI as they relate to thromboembolic disease. PMID:27174099

  5. Molecular Targets in Alzheimer’s Disease: From Pathogenesis to Therapeutics

    Directory of Open Access Journals (Sweden)

    Xuan Cheng

    2015-01-01

    Full Text Available Alzheimer’s disease (AD is characterized by progressive cognitive decline usually beginning with impairment in the ability to form recent memories. Nonavailability of definitive therapeutic strategy urges developing pharmacological targets based on cell signaling pathways. A great revival of interest in nutraceuticals and adjuvant therapy has been put forward. Tea polyphenols for their multiple health benefits have also attracted the attention of researchers. Tea catechins showed enough potentiality to be used in future as therapeutic targets to provide neuroprotection against AD. This review attempts to present a concise map of different receptor signaling pathways associated with AD with an insight into drug designing based on the proposed signaling pathways, molecular mechanistic details of AD pathogenesis, and a scientific rationale for using tea polyphenols as proposed therapeutic agents in AD.

  6. Non-coding RNAs as therapeutic targets in hepatocellular cancer.

    Science.gov (United States)

    Braconi, Chiara; Patel, Tushar

    2012-11-01

    Hepatocellular carcinoma (HCC) is a common malignancy that affects a large number of patients worldwide, with an increasing incidence in the United States and Europe. The therapies that are currently available for patients with inoperable HCC have limited benefits. Although molecular targeted therapies against selected cell signaling pathways have shown some promising results, their impact has been minimal. There is a need to identify and explore other targets for the development of novel therapeutics. Several non-protein coding RNAs (ncRNA) have recently been implicated in hepatocarcinogenesis and tumor progression. These ncRNA genes represent promising targets for cancer. However, therapeutic targeting of ncRNA genes has not been employed for HCC. The use of antisense oligonucleotides and viral vector delivery approaches have been shown to be feasible approaches to modulate ncRNA expression. HCC is an optimal cancer to evaluate novel RNA based therapeutic approaches because of the potential of effective delivery and uptake of therapeutic agents to the liver. In this review, we discuss selected ncRNA that could function as potential targets in HCC treatment and outline approaches to target ncRNA expression. Future challenges include the need to achieve site-specific targeting with acceptable safety and efficacy. PMID:22873215

  7. The therapeutic value of targeting inflammation in gastrointestinal cancers

    OpenAIRE

    Sun, Beicheng; Karin, Michael

    2014-01-01

    Inflammation has been implicated in the initiation and progression of gastrointestinal (GI) cancers. Inflammation also plays important roles in subverting immune tolerance, escape from immune surveillance, and conferring resistance to chemotherapeutic agents. Targeting key regulators and mediators of inflammation represents an attractive strategy for GI cancer prevention and treatment. However, the targeting of inflammation in GI cancer is not straight-forward and sometimes inflammation may c...

  8. Targeted drug delivery to magnetic implants for therapeutic applications

    International Nuclear Information System (INIS)

    A new method for locally targeted drug delivery is proposed that employs magnetic implants placed directly in the cardiovascular system to attract injected magnetic carriers. Theoretical simulations and experimental results support the assumption that using magnetic implants in combination with externally applied magnetic field will optimize the delivery of magnetic drug to selected sites within a subject

  9. ENaCs and ASICs as therapeutic targets

    OpenAIRE

    Qadri, Yawar J.; Rooj, Arun K.; Fuller, Catherine M.

    2012-01-01

    The epithelial Na+ channel (ENaC) and acid-sensitive ion channel (ASIC) branches of the ENaC/degenerin superfamily of cation channels have drawn increasing attention as potential therapeutic targets in a variety of diseases and conditions. Originally thought to be solely expressed in fluid absorptive epithelia and in neurons, it has become apparent that members of this family exhibit nearly ubiquitous expression. Therapeutic opportunities range from hypertension, due to the role of ENaC in ma...

  10. Critical questions in development of targeted nanoparticle therapeutics

    OpenAIRE

    Korsmeyer, Richard

    2016-01-01

    One of the fourteen Grand Challenges for Engineering articulated by the US National Academy of Engineering is ‘Engineer Better Medicines’. Although there are many ways that better medicines could be engineered, one of the most promising ideas is to improve our ability to deliver the therapeutic molecule more precisely to the desired target. Most conventional drug delivery methods (oral absorption, intravenous infusion etc.) result in systemic exposure to the therapeutic molecule, which places...

  11. Automatic Attraction of Visual Attention by Supraletter Features of Former Target Strings

    DEFF Research Database (Denmark)

    Kyllingsbæk, Søren; Van Lommel, Sven; Sørensen, Thomas Alrik;

    2014-01-01

    Observers were trained to search for a particular horizontal string of 3 capital letters presented among similar strings consisting of exactly the same letters in different orders. The training was followed by a test in which the observers searched for a new target that was identical to one of the...... circumference of an imaginary circle around the fixation point. The training phase of Experiment 2 was similar, but in the test phase of the experiment, the strings were located in a vertical array centered on fixation, and in target-present arrays, the target always appeared at fixation. In both experiments......, performance (d’) degraded on trials in which former targets were present, suggesting that the former targets automatically drew processing resources away from the current targets. Apparently, the two experiments showed automatic attraction of visual attention by supraletter features of former target strings....

  12. Elements toward novel therapeutic targeting of the adrenergic system.

    Science.gov (United States)

    Ghanemi, Abdelaziz; Hu, Xintian

    2015-02-01

    Adrenergic receptors belong to the family of the G protein coupled receptors that represent important targets in the modern pharmacotherapies. Studies on different physiological and pathophysiological properties of the adrenergic system have led to novel evidences and theories that suggest novel possible targeting of such system in a variety of pathologies and disorders, even beyond the classical known therapeutic possibilities. Herein, those advances have been illustrated with selected concepts and different examples. Furthermore, we illustrated the applications and the therapeutic implications that such findings and advances might have in the contexts of experimental pharmacology, therapeutics and clinic. We hope that the content of this work will guide researches devoted to the adrenergic aspects that combine neurosciences with pharmacology. PMID:25481798

  13. A Current Review of Targeted Therapeutics for Ovarian Cancer

    Directory of Open Access Journals (Sweden)

    Susana M. Campos

    2010-01-01

    Full Text Available Difficult to detect, ovarian cancer typically presents at an advanced stage. Significant progress has been achieved in the treatment of ovarian cancer with therapeutics focused on DNA replication or cell division. However, despite sensitivity to induction chemotherapy the majority of patients will develop recurrent disease. Conventional agents for recurrent disease offer little in terms of long-term responses. Various targeted therapeutics have been explored in the management of ovarian cancer. These include monoclonal antibodies to epidermal growth factor receptors, small molecule tyrosine kinase inhibitors, monoclonal antibodies directed at the vascular endothelial growth factor (bevacizumab, and the small tyrosine kinase inhibitors that target the vascular endothelial growth factor receptor. Recently, several other agents have come forth as potential therapeutic agents in the management of ovarian cancer. These include monoclonal antibodies to the folate receptor, triple angiokinase inhibitors, PARP inhibitors, aurora kinase inhibitors, inhibitors of the Hedgehog pathway, folate receptor antagonists, and MTOR inhibitors.

  14. Myostatin as a therapeutic target in Amyotrophic lateral sclerosis.

    Science.gov (United States)

    Walsh, Frank S; Rutkowski, Julia Lynn

    2012-11-01

    Amyotrophic Lateral Sclerosis is a devastating neurological disease that is inevitably fatal after 3-5years duration. Treatment options are minimal and as such new therapeutic modalities are required. In this review, we discuss the role of the myostatin pathway as a modulator of skeletal muscle mass and therapeutic approaches using biological based therapies. Both monoclonal antibodies to myostatin and a soluble receptor decoy to its high affinity receptor have been used in clinical trials of neuromuscular diseases and while there have been efficacy signals with the latter approach there have also been safety issues. Our approach is to target the high affinity receptor-binding site on myostatin and to develop a next generation set of therapeutic reagents built on a novel protein scaffold. This is the natural single domain VNAR found in sharks which is extremely versatile and has the ability to develop products with superior properties compared to existing therapeutics. PMID:22841860

  15. Adenosine and its receptors as therapeutic targets: An overview

    OpenAIRE

    Sachdeva, Sakshi; Gupta, Monika

    2012-01-01

    The main goal of the authors is to present an overview of adenosine and its receptors, which are G-protein coupled receptors. The four known adenosine receptor subtypes are discussed along with the therapeutic potential indicating that these receptors can serve as targets for various dreadful diseases.

  16. AMPA Receptors as Therapeutic Targets for Neurological Disorders.

    Science.gov (United States)

    Lee, Kevin; Goodman, Lucy; Fourie, Chantelle; Schenk, Susan; Leitch, Beulah; Montgomery, Johanna M

    2016-01-01

    Almost every neurological disease directly or indirectly affects synapse function in the brain. However, these diseases alter synapses through different mechanisms, ultimately resulting in altered synaptic transmission and/or plasticity. Glutamate is the major neurotransmitter that mediates excitatory synaptic transmission in the brain through activation of alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionate (AMPA) receptors. These receptors have therefore been identified as a target for the development of therapeutic treatments for neurological disorders including epilepsy, neurodegenerative diseases, autism, and drug addiction. The fact that AMPA receptors play a dominant role throughout the brain raises the significant challenge of selectively targeting only those regions affected by disease, and clinical trials have raised doubt regarding the feasibility of specifically targeting AMPA receptors for new therapeutic options. Benzamide compounds that act as positive allosteric AMPA receptor modulators, known as AMPAkines, can act on specific brain regions and were initially proposed to revolutionize the treatment of cognitive deficits associated with neurological disorders. Their therapeutic potential has since declined due to inconsistent results in clinical trials. However, recent advances in basic biomedical research are significantly increasing our knowledge of AMPA receptor structure, binding sites, and interactions with auxiliary proteins. In particular, the large complex of postsynaptic proteins that interact with AMPA receptor subunits have been shown to control AMPA receptor insertion, location, pharmacology, synaptic transmission, and plasticity. These proteins are now being considered as alternative therapeutic target sites for modulating AMPA receptors in neurological disorders. PMID:26920691

  17. RhoC a new target for therapeutic vaccination against metastatic cancer

    DEFF Research Database (Denmark)

    Wenandy, L.; Sorensen, R.B.; Straten, P.T.;

    2008-01-01

    Most cancer deaths are due to the development of metastases. Increased expression of RhoC is linked to enhanced metastatic potential in multiple cancers. Consequently, the RhoC protein is an attractive target for drug design. The clinical application of immunotherapy against cancer is rapidly...... moving forward in multiple areas, including the adoptive transfer of anti-tumor-reactive T cells and the use of "therapeutic" vaccines. The over-expression of RhoC in cancer and the fact that immune escape by down regulation or loss of expression of this protein would reduce the morbidity and mortality...... of cancer makes RhoC a very attractive target for anti-cancer immunotherapy. Herein, we describe an HLA-A3 restricted epitope from RhoC, which is recognized by cytotoxic T cells. Moreover, RhoC-specific T cells show cytotoxic potential against HLA-matched cancer cells of different origin. Thus, Rho...

  18. Self-Microemulsifying Drug Delivery Systems: An Attractive Strategy for Enhanced Therapeutic Profile

    OpenAIRE

    Akula, Samatha; Gurram, Aravind Kumar; Devireddy, Srinivas Reddy

    2014-01-01

    Ease of administration and painless approach made oral route the most preferred. Poor oral bioavailability is pronounced with the majority of recent active ingredients because of dissolution rate limited absorption. Failure to attain intended therapeutic effect of the poor water soluble drugs by this route led to development of novel drug delivery systems which will fulfill therapeutic needs with minimum dose. Although many formulation approaches like solid dispersions, complexation, pH modif...

  19. EGFR-Targeted Therapeutics: Focus on SCCHN and NSCLC

    Directory of Open Access Journals (Sweden)

    Martin Sattler

    2008-01-01

    Full Text Available Cancers of the head and neck and of the lung are associated with high morbidity and mortality rates that have remained relatively unchanged for more than 3 decades, despite advances in radiation therapies and chemotherapies over the same time. It is generally believed that the efficacy of standard therapy regimens has reached a plateau for these cancers. The discovery of specific aberrant molecular signaling pathways in solid tumors has afforded promising new directions for newer “targeted” cancer therapeutics. Among these, the epidermal growth factor receptor (EGFR shows promise as a therapeutic target. Clinical studies have demonstrated that this targeted approach provides clinically meaningful benefit. This article reviews EGFR-targeted therapies in use and in development, with a focus on the role of EGFR in the pathophysiology of head and neck and lung cancer, and new concepts being investigated to improve outcomes with these agents.

  20. Breast cancer stem cells, EMT and therapeutic targets

    International Nuclear Information System (INIS)

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

  1. Breast cancer stem cells, EMT and therapeutic targets

    Energy Technology Data Exchange (ETDEWEB)

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

    2014-10-10

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

  2. Therapeutic Targets of Triglyceride Metabolism as Informed by Human Genetics.

    Science.gov (United States)

    Bauer, Robert C; Khetarpal, Sumeet A; Hand, Nicholas J; Rader, Daniel J

    2016-04-01

    Human genetics has contributed to the development of multiple drugs to treat hyperlipidemia and coronary artery disease (CAD), most recently including antibodies targeting PCSK9 to reduce LDL cholesterol. Despite these successes, a large burden of CAD remains. Genetic and epidemiological studies have suggested that circulating triglyceride (TG)-rich lipoproteins (TRLs) are a causal risk factor for CAD, presenting an opportunity for novel therapeutic strategies. We discuss recent unbiased human genetics testing, including genome-wide association studies (GWAS) and whole-genome or -exome sequencing, that have identified the lipoprotein lipase (LPL) and hepatic lipogenesis pathways as important mechanisms in the regulation of circulating TRLs. Further strengthening the causal relationship between TRLs and CAD, findings such as these may provide novel targets for much-needed potential therapeutic interventions. PMID:26988439

  3. Mitochondria as therapeutic targets for cancer stem cells

    Institute of Scientific and Technical Information of China (English)

    In Sung Song; Jeong Yu Jeong; Seung Hun Jeong; Hyoung Kyu Kim; Kyung Soo Ko; Byoung Doo Rhee; Nari Kim; Jin Han

    2015-01-01

    Cancer stem cells (CSCs) are maintained by theirsomatic stem cells and are responsible for tumorinitiation, chemoresistance, and metastasis. Evidencefor the CSCs existence has been reported for a numberof human cancers. The CSC mitochondria have beenshown recently to be an important target for cancertreatment, but clinical significance of CSCs and theirmitochondria properties remain unclear. Mitochondriatargetedagents are considerably more effectivecompared to other agents in triggering apoptosis ofCSCs, as well as general cancer cells, via mitochondrialdysfunction. Mitochondrial metabolism is altered incancer cells because of their reliance on glycolyticintermediates, which are normally destined for oxidativephosphorylation. Therefore, inhibiting cancer-specificmodifications in mitochondrial metabolism, increasingreactive oxygen species production, or stimulatingmitochondrial permeabilization transition could bepromising new therapeutic strategies to activate celldeath in CSCs as well, as in general cancer cells. Thisreview analyzed mitochondrial function and its potentialas a therapeutic target to induce cell death in CSCs.Furthermore, combined treatment with mitochondriatargeteddrugs will be a promising strategy for thetreatment of relapsed and refractory cancer.

  4. Autophagy as a new therapeutic target in Duchenne muscular dystrophy

    OpenAIRE

    Palma, C.; F. Morisi; Cheli, S; S. Pambianco; Cappello, V; Vezzoli, M; Rovere-Querini, P; Moggio, M; Ripolone, M.; Francolini, M; Sandri, M.; Clementi, E

    2012-01-01

    A resolutive therapy for Duchene muscular dystrophy, a severe degenerative disease of the skeletal muscle, is still lacking. Because autophagy has been shown to be crucial in clearing dysfunctional organelles and in preventing tissue damage, we investigated its pathogenic role and its suitability as a target for new therapeutic interventions in Duchenne muscular dystrophy (DMD). Here we demonstrate that autophagy is severely impaired in muscles from patients affected by DMD and mdx mice, a mo...

  5. Macrophages associated with tumors as potential targets and therapeutic intermediates

    OpenAIRE

    Vinogradov, Serguei; Warren, Galya; Wei, Xin

    2014-01-01

    Tumor-associated macrophages (TAMs) form approximately 50% of tumor mass. TAMs were shown to promote tumor growth by suppressing immunocompetent cells, inducing neovascularization and supporting cancer stem cells. TAMs retain mobility in tumor mass, which can potentially be employed for better intratumoral biodistribution of nanocarriers and effective tumor growth inhibition. Due to the importance of TAMs, they are increasingly becoming principal targets of novel therapeutic approaches. In th...

  6. Targeting Mitochondria as Therapeutic Strategy for Metabolic Disorders

    OpenAIRE

    Daniela Sorriento; Antonietta Valeria Pascale; Rosa Finelli; Anna Lisa Carillo; Roberto Annunziata; Bruno Trimarco; Guido Iaccarino

    2014-01-01

    Mitochondria are critical regulator of cell metabolism; thus, mitochondrial dysfunction is associated with many metabolic disorders. Defects in oxidative phosphorylation, ROS production, or mtDNA mutations are the main causes of mitochondrial dysfunction in many pathological conditions such as IR/diabetes, metabolic syndrome, cardiovascular diseases, and cancer. Thus, targeting mitochondria has been proposed as therapeutic approach for these conditions, leading to the development of small mol...

  7. Targeted polymeric therapeutic nanoparticles: design, development and clinical translation†

    OpenAIRE

    Kamaly, Nazila; Xiao, Zeyu; Valencia, Pedro M.; Radovic-Moreno, Aleksandar F.; Farokhzad, Omid C.

    2012-01-01

    Polymeric materials have been used in a range of pharmaceutical and biotechnology products for more than 40 years. These materials have evolved from their earlier use as biodegradable products such as resorbable sutures, orthopaedic implants, macroscale and microscale drug delivery systems such as microparticles and wafers used as controlled drug release depots, to multifunctional nanoparticles (NPs) capable of targeting, and controlled release of therapeutic and diagnostic agents. These newe...

  8. Functions of astrocytes and their potential as therapeutic targets

    OpenAIRE

    Kimelberg, Harold K.; NEDERGAARD, Maiken

    2010-01-01

    Astrocytes are often referred to, and historically have been regarded as, support cells of the mammalian CNS. Work over the last decade suggests otherwise, that astrocytes may in fact play a more active role in higher neural processing than previously recognized. Because astrocytes can potentially serve as novel therapeutic targets, it is critical to understand how astrocytes execute their diverse supportive tasks while maintaining neuronal health. To that end, this review will focus on the s...

  9. Novel therapeutic Strategies for Targeting Liver Cancer Stem Cells

    Directory of Open Access Journals (Sweden)

    Naoki Oishi, Xin Wei Wang

    2011-01-01

    Full Text Available The cancer stem cell (CSC hypothesis was first proposed over 40 years ago. Advances in CSC isolation were first achieved in hematological malignancies, with the first CSC demonstrated in acute myeloid leukemia. However, using similar strategies and technologies, and taking advantage of available surface markers, CSCs have been more recently demonstrated in a growing range of epithelial and other solid organ malignancies, suggesting that the majority of malignancies are dependent on such a compartment.Primary liver cancer consists predominantly of hepatocellular carcinoma (HCC and intrahepatic cholangiocarcinoma (ICC. It is believed that hepatic progenitor cells (HPCs could be the origin of some HCCs and ICCs. Furthermore, stem cell activators such as Wnt/β-catenin, TGF-β, Notch and Hedgehog signaling pathways also expedite tumorigenesis, and these pathways could serve as molecular targets to assist in designing cancer prevention strategies. Recent studies indicate that additional factors such as EpCAM, Lin28 or miR-181 may also contribute to HCC progression by targeting HCC CSCs. Various therapeutic drugs that directly modulate CSCs have been examined in vivo and in vitro. However, CSCs clearly have a complex pathogenesis, with a considerable crosstalk and redundancy in signaling pathways, and hence targeting single molecules or pathways may have a limited benefit for treatment. Many of the key signaling molecules are shared by both CSCs and normal stem cells, which add further challenges for designing molecularly targeted strategies specific to CSCs but sparing normal stem cells to avoid side effects. In addition to the direct control of CSCs, many other factors that are needed for the maintenance of CSCs, such as angiogenesis, vasculogenesis, invasion and migration, hypoxia, immune evasion, multiple drug resistance, and radioresistance, should be taken into consideration when designing therapeutic strategies for HCC.Here we provide a brief

  10. Superparamagnetic nanoparticles as targeted probes for diagnostic and therapeutic applications.

    Science.gov (United States)

    Xu, Chenjie; Sun, Shouheng

    2009-08-01

    Superparamagnetic nanoparticles (NPs) have been attractive for medical diagnostics and therapeutics due to their unique magnetic properties and their ability to interact with various biomolecules of interest. The solution phase based chemical synthesis provides a near precise control on NP size, and monodisperse magnetic NPs with standard deviation in diameter of less than 10% are now routinely available. Upon controlled surface functionalization and coupling with fragments of DNA strands, proteins, peptides or antibodies, these NPs can be well-dispersed in biological solutions and used for drug delivery, magnetic separation, magnetic resonance imaging contrast enhancement and magnetic fluid hyperthermia. This Perspective reviews the common syntheses and controlled surface functionalization of monodisperse Fe(3)O(4)-based superparamagnetic NPs. It further outlines the exciting application potentials of these NPs in magnetic resonance imaging and drug delivery. PMID:20449070

  11. Mesothelin as a Potential Therapeutic Target in Human Cholangiocarcinoma

    Directory of Open Access Journals (Sweden)

    Liping Yu, Mingqian Feng, Heungnam Kim, Yen Phung, David E. Kleiner, Gregory J. Gores, Min Qian, Xin Wei Wang, Mitchell Ho

    2010-01-01

    Full Text Available Background: Hepatocellular carcinoma (HCC and cholangiocarcinoma (CCA are the two most common primary liver cancers, yet there have been no significant advances in effective therapeutics. Mesothelin has been reported as a new therapeutic target in various types of cancer. Here, we investigated the expression of mesothelin in liver cancer and its potential role as a novel therapeutic target for immunotherapy.Methods: HCC and CCA specimens were examined by immunohistochemistry for mesothelin expression. Protein expression was assessed by immunoblotting and flow cytometry. The SS1P immunotoxin targeting mesothelin was evaluated in the well-established CCA cell lines HuCCT1, HuH-28, KMBC, KMCH, Mz-ChA-1 and OZ.Results: We showed strong immunochemical mesothelin staining in 33% of the surgically resected CCA specimens and 3 of 6 CCA cell lines (OZ, KMBC and KMCH. No mesothelin staining was found in HCC or normal liver tissue. Mesothelin was primarily localized to the cellular plasma membrane and the mature form (molecular weight, ~40 kDa was expressed at a high level in CCA tissues. Moreover, 22% of CCA specimens had a high mesothelin expression level which was comparable to the CCA cell line models. Interestingly, SS1P showed very high and specific growth inhibition when added to mesothelin-expressing CCA cells with IC50 values ranging from 0.5 to 11 ng/mL.Conclusions: Mesothelin is overexpressed in one-third of CCA tissues. SS1P targeting mesothelin reveals a remarkable single agent activity against CCA in vitro. These findings indicate a potential for SS1P in the immunotherapeutic treatment of CCA.

  12. Attention attraction in an ophthalmic diagnostic device using sound-modulated fixation targets.

    Science.gov (United States)

    Gramatikov, Boris I; Rangarajan, Shreya; Irsch, Kristina; Guyton, David L

    2016-08-01

    This study relates to eye fixation systems with combined optical and audio systems. Many devices for eye diagnostics and some devices for eye therapeutics require the patient to fixate on a small target for a certain period of time, during which the eyes do not move and data from substructures of one or both eyes are acquired and analyzed. With young pediatric patients, a monotonously blinking target is not sufficient to retain attention steadily. We developed a method for modulating the intensity of a point fixation target using sounds appropriate to the child's age and preference. The method was realized as a subsystem of a Pediatric Vision Screener which employs retinal birefringence scanning for detection of central fixation. Twenty-one children, age 2-18, were studied. Modulation of the fixation target using sounds ensured the eye fixated on the target, and with appropriate choice of sounds, performed significantly better than a monotonously blinking target accompanied by a plain beep. The method was particularly effective with children of ages up to 10, after which its benefit disappeared. Typical applications of target modulation would be as supplemental subsystems in pediatric ophthalmic diagnostic devices, such as scanning laser ophthalmoscopes, optical coherence tomography units, retinal birefringence scanners, fundus cameras, and perimeters. PMID:27245750

  13. Alzheimer’s disease: Risk factors and therapeutic targets

    Directory of Open Access Journals (Sweden)

    Laxman Pokhrel

    2015-09-01

    Full Text Available Alzheimer’s disease (AD, a neurodegenerative disorder, has been determined as an outcome of genetic as well as behavioral conditions. The complete understanding of its generation and progress is yet to be understood. However, there has been a significant progress in the diagnosis and identification of the associated risk factors of AD. Several of the risk factors were found connected with cholesterol. Scientists are mainly focusing on the reduction of amyloid β and stabilization of tau protein towards the development of its drugs. To modulate amyloid β, the key components of cholesterol metabolism have been attractive targets and the enzymes involved in the phosphorylation of tau have been tried to stabilize tau protein. This review article briefly highlights the symptoms, risk factors, and drug targets of AD.

  14. Alzheimer’s disease:Risk factors and therapeutic targets

    Institute of Scientific and Technical Information of China (English)

    Laxman Pokhrel

    2015-01-01

    Alzheimer’s disease (AD), a neurodegenerative disorder, has been determined as an outcome of genetic as well as behavioral conditions. The complete understanding of its generation and progress is yet to be understood. However, there has been a significant progress in the diagnosis and identification of the associated risk factors of AD. Several of the risk factors were found connected with cholesterol. Scientists are mainly focusing on the reduction of amyloid β and stabilization of tau protein towards the development of its drugs. To modulate amyloid β, the key components of cholesterol metabolism have been attractive targets and the enzymes involved in the phosphorylation of tau have been tried to stabilize tau protein. This review article briefly highlights the symptoms, risk factors, and drug targets of AD.

  15. Clinical development of cancer therapeutics that target metabolism.

    Science.gov (United States)

    Clem, B F; O'Neal, J; Klarer, A C; Telang, S; Chesney, J

    2016-06-01

    Glucose and glutamine metabolism in cancer cells are markedly elevated relative to non-transformed normal cells. This metabolic reprogramming enables the production of adenosine triphosphate and the anabolic precursors needed for survival, growth and motility. The recent observations that mutant oncogenic proteins and the loss of tumor suppressors activate key metabolic enzymes suggest that selective inhibition of these enzymes may yield effective cancer therapeutics with acceptable toxicities. In support of this concept, pre-clinical studies of small molecule antagonists of several metabolic enzymes in tumor-bearing mice have demonstrated reasonable therapeutic indices. We will review the rationale for targeting metabolic enzymes as a strategy to treat cancer and will detail the results of several recent clinical trials of metabolic inhibitors in advanced cancer patients. PMID:26428335

  16. Toll-like receptors as therapeutic targets in cystic fibrosis.

    LENUS (Irish Health Repository)

    Greene, Catherine M

    2008-12-01

    Background: Toll-like receptors (TLRs) are pattern recognition receptors that act as a first-line of defence in the innate immune response by recognising and responding to conserved molecular patterns in microbial factors and endogenous danger signals. Cystic fibrosis (CF)-affected airways represent a milieu potentially rich in TLR agonists and the chronic inflammatory phenotype evident in CF airway epithelial cells is probably due in large part to activation of TLRs. Objective\\/methods: To examine the prospects of developing novel therapies for CF by targeting TLRs. We outline the expression and function of TLRs and explore the therapeutic potential of naturally-occurring and synthetic TLR inhibitors for CF. Results\\/conclusion: Modulation of TLRs has therapeutic potential for the inflammatory lung manifestations of CF.

  17. Human neutrophil elastase: mediator and therapeutic target in atherosclerosis.

    Science.gov (United States)

    Henriksen, Peter A; Sallenave, Jean-Michel

    2008-01-01

    Human neutrophil elastase (HNE) is present within atherosclerotic plaques where it contributes to matrix degradation and weakening of the vessel wall associated with the complications of aneurysm formation and plaque rupture. It is joined by other extracellular proteases in these actions but the broad range of substrates and potency of HNE coupled with the potential for rapid increases in HNE activity associated with neutrophil degranulation in acute coronary syndromes single this disruptive protease out as therapeutic target in atherosclerotic disease. This review summarises the role of HNE in neutrophil-mediated endothelial injury and the evidence for HNE as a mediator of atherosclerotic plaque development. The therapeutic potential of HNE neutralising antiproteases, alpha-1-antitrypsin and elafin, in atherosclerosis, is discussed. PMID:18289916

  18. Neuropeptide Receptors: Novel Targets for HIV/AIDS Therapeutics

    Directory of Open Access Journals (Sweden)

    Donald R. Branch

    2011-03-01

    Full Text Available The vasoactive intestinal peptide/pituitary adenylyl cyclase-activating polypepetide (VPAC receptors are important for many physiologic functions, including glucose homeostasis, neuroprotection, memory, gut function, modulation of the immune system and circadian function. In addition, VPAC receptors have been shown to function in vitro to modulate the infection of HIV by a signal transduction pathway that appears to regulate viral integration. In this article, the affects of VPAC stimulation on HIV infection will be reviewed and approaches for the development of HIV/AIDS therapeutics that target these receptors will be described. Novel HIV/AIDS therapeutics are urgently required to stem the continued spread of this disease, particularly in underdeveloped countries. Drug design to inhibit signaling through VPAC1 and stimulate signaling through VPAC2 could lead to alternative therapies for the treatment and/or prevention of HIV/AIDS.

  19. Vitamin A-aldehyde adducts: AMD risk and targeted therapeutics.

    Science.gov (United States)

    Sparrow, Janet R

    2016-04-26

    Although currently available treatment options for age-related macular degeneration (AMD) are limited, particularly for atrophic AMD, the identification of predisposing genetic variations has informed clinical studies addressing therapeutic options such as complement inhibitors and anti-inflammatory agents. To lower risk of early AMD, recommended lifestyle interventions such as the avoidance of smoking and the intake of low glycemic antioxidant-rich diets have largely followed from the identification of nongenetic modifiable factors. On the other hand, the challenge of understanding the complex relationship between aging and cumulative damage leading to AMD has fueled investigations of the visual cycle adducts that accumulate in retinal pigment epithelial (RPE) cells and are a hallmark of aging retina. These studies have revealed properties of these compounds that provide insights into processes that may compromise RPE and could contribute to disease mechanisms in AMD. This work has also led to the design of targeted therapeutics that are currently under investigation. PMID:27071115

  20. Exosomal miRNAs as cancer biomarkers and therapeutic targets.

    Science.gov (United States)

    Thind, Arron; Wilson, Clive

    2016-01-01

    Intercommunication between cancer cells and with their surrounding and distant environments is key to the survival, progression and metastasis of the tumour. Exosomes play a role in this communication process. MicroRNA (miRNA) expression is frequently dysregulated in tumour cells and can be reflected by distinct exosomal miRNA (ex-miRNA) profiles isolated from the bodily fluids of cancer patients. Here, the potential of ex-miRNA as a cancer biomarker and therapeutic target is critically analysed. Exosomes are a stable source of miRNA in bodily fluids but, despite a number of methods for exosome extraction and miRNA quantification, their suitability for diagnostics in a clinical setting is questionable. Furthermore, exosomally transferred miRNAs can alter the behaviour of recipient tumour and stromal cells to promote oncogenesis, highlighting a role in cell communication in cancer. However, our incomplete understanding of exosome biogenesis and miRNA loading mechanisms means that strategies to target exosomes or their transferred miRNAs are limited and not specific to tumour cells. Therefore, if ex-miRNA is to be employed in novel non-invasive diagnostic approaches and as a therapeutic target in cancer, two further advances are necessary: in methods to isolate and detect ex-miRNA, and a better understanding of their biogenesis and functions in tumour-cell communication. PMID:27440105

  1. Breast cancer stem cells, EMT and therapeutic targets.

    Science.gov (United States)

    Kotiyal, Srishti; Bhattacharya, Susinjan

    2014-10-10

    A small heterogeneous population of breast cancer cells acts as seeds to induce new tumor growth. These seeds or breast cancer stem cells (BCSCs) exhibit great phenotypical plasticity which allows them to undergo "epithelial to mesenchymal transition" (EMT) at the site of primary tumor and a future reverse transition. Apart from metastasis they are also responsible for maintaining the tumor and conferring it with drug and radiation resistance and a tendency for post-treatment relapse. Many of the signaling pathways involved in induction of EMT are involved in CSC generation and regulation. Here we are briefly reviewing the mechanism of TGF-β, Wnt, Notch, TNF-α, NF-κB, RTK signalling pathways which are involved in EMT as well as BCSCs maintenance. Therapeutic targeting or inhibition of the key/accessory players of these pathways could control growth of BCSCs and hence malignant cancer. Additionally several miRNAs are dysregulated in cancer stem cells indicating their roles as oncogenes or tumor suppressors. This review also lists the miRNA interactions identified in BCSCs and discusses on some newly identified targets in the BCSC regulatory pathways like SHIP2, nicastrin, Pin 1, IGF-1R, pro-inflammatory cytokines and syndecan which can be targeted for therapeutic achievements. PMID:25261721

  2. Neuroimmunotherapies Targeting T Cells: From Pathophysiology to Therapeutic Applications.

    Science.gov (United States)

    Bittner, Stefan; Wiendl, Heinz

    2016-01-01

    Therapeutic options for multiple sclerosis (MS) have significantly increased over the last few years. T lymphocytes are considered to play a central role in initiating and perpetuating the pathological immune response. Currently approved therapies for MS target T lymphocytes, either in an unspecific manner or directly by interference with specific T-cell pathways. While the concept of "T-cell-specific therapy" implies specificity and selectivity, currently approved approaches come from a general shaping of the immune system towards anti-inflammatory immune responses by non-T-cell-selective immune suppression or immune modulation (e.g., interferons-immune modulation approach) to a depletion of immune cell populations involving T cells (e.g., anti-CD52, alemtuzumab-immune selective depletion approach), or a selective inhibition of distinct molecular pathways in order to sequester leucocytes (e.g., natalizumab-leukocyte sequestration approach). This review will highlight the rationale and results of different T-cell-directed therapeutic approaches coming from basic animal experiments to clinical trials. We will first discuss the pathophysiological rationale for targeting T lymphocytes in MS leading to currently approved treatments acting on T lymphocytes. Furthermore, we will disuss previous promising concepts that have failed to show efficacy in clinical trials or were halted as a result of unexpected adverse events. Learning from the discrepancies between expectations and failures in practical outcomes helps to optimize future research approaches and clinical study designs. As our current view of MS pathogenesis and patient needs is rapidly evolving, novel therapeutic approaches targeting T lymphocytes will also be discussed, including specific molecular interventions such as cytokine-directed treatments or strategies enhancing immunoregulatory mechanisms. Based on clinical experience and novel pathophysiological approaches, T-cell-based strategies will remain a

  3. Targeted polymeric therapeutic nanoparticles: design, development and clinical translation.

    Science.gov (United States)

    Kamaly, Nazila; Xiao, Zeyu; Valencia, Pedro M; Radovic-Moreno, Aleksandar F; Farokhzad, Omid C

    2012-04-01

    Polymeric materials have been used in a range of pharmaceutical and biotechnology products for more than 40 years. These materials have evolved from their earlier use as biodegradable products such as resorbable sutures, orthopaedic implants, macroscale and microscale drug delivery systems such as microparticles and wafers used as controlled drug release depots, to multifunctional nanoparticles (NPs) capable of targeting, and controlled release of therapeutic and diagnostic agents. These newer generations of targeted and controlled release polymeric NPs are now engineered to navigate the complex in vivo environment, and incorporate functionalities for achieving target specificity, control of drug concentration and exposure kinetics at the tissue, cell, and subcellular levels. Indeed this optimization of drug pharmacology as aided by careful design of multifunctional NPs can lead to improved drug safety and efficacy, and may be complimentary to drug enhancements that are traditionally achieved by medicinal chemistry. In this regard, polymeric NPs have the potential to result in a highly differentiated new class of therapeutics, distinct from the original active drugs used in their composition, and distinct from first generation NPs that largely facilitated drug formulation. A greater flexibility in the design of drug molecules themselves may also be facilitated following their incorporation into NPs, as drug properties (solubility, metabolism, plasma binding, biodistribution, target tissue accumulation) will no longer be constrained to the same extent by drug chemical composition, but also become in-part the function of the physicochemical properties of the NP. The combination of optimally designed drugs with optimally engineered polymeric NPs opens up the possibility of improved clinical outcomes that may not be achievable with the administration of drugs in their conventional form. In this critical review, we aim to provide insights into the design and development

  4. Exosomal miRNAs as cancer biomarkers and therapeutic targets

    OpenAIRE

    Arron Thind; Clive Wilson

    2016-01-01

    Intercommunication between cancer cells and with their surrounding and distant environments is key to the survival, progression and metastasis of the tumour. Exosomes play a role in this communication process. MicroRNA (miRNA) expression is frequently dysregulated in tumour cells and can be reflected by distinct exosomal miRNA (ex-miRNA) profiles isolated from the bodily fluids of cancer patients. Here, the potential of ex-miRNA as a cancer biomarker and therapeutic target is critically analy...

  5. Cancer Stem Cells: Biological Functions and Therapeutically Targeting

    Directory of Open Access Journals (Sweden)

    Marius Eugen Ciurea

    2014-05-01

    Full Text Available Almost all tumors are composed of a heterogeneous cell population, making them difficult to treat. A small cancer stem cell population with a low proliferation rate and a high tumorigenic potential is thought to be responsible for cancer development, metastasis and resistance to therapy. Stem cells were reported to be involved in both normal development and carcinogenesis, some molecular mechanisms being common in both processes. No less controversial, stem cells are considered to be important in treatment of malignant diseases both as targets and drug carriers. The efforts to understand the role of different signalling in cancer stem cells requires in depth knowledge about the mechanisms that control their self-renewal, differentiation and malignant potential. The aim of this paper is to discuss insights into cancer stem cells historical background and to provide a brief review of the new therapeutic strategies for targeting cancer stem cells.

  6. The GABAA Receptor as a Therapeutic Target for Neurodevelopmental Disorders.

    Science.gov (United States)

    Braat, Sien; Kooy, R Frank

    2015-06-01

    Intellectual disability, autism spectrum disorder, and epilepsy are prime examples of neurodevelopmental disorders that collectively affect a significant percentage of the world population. Recent technological breakthroughs allowed the elucidation of the genetic causes of many of these disorders. As neurodevelopmental disorders are genetically heterogeneous, the development of rational therapy is extremely challenging. Fortunately, many causative genes are interconnected and cluster in specific cellular pathways. Targeting a common node in such a network would allow us to interfere with a series of related neurodevelopmental disorders at once. Here, we argue that the GABAergic system is disturbed in many neurodevelopmental disorders, including fragile X syndrome, Rett syndrome, and Dravet syndrome, and is a key candidate target for therapeutic intervention. Many drugs that modulate the GABAergic system have already been tested in animal models with encouraging outcomes and are readily available for clinical trials. PMID:26050032

  7. Therapeutic Implications of Targeting Energy Metabolism in Breast Cancer

    Directory of Open Access Journals (Sweden)

    Meena K. Sakharkar

    2013-01-01

    Full Text Available PPARs are ligand activated transcription factors. PPARγ agonists have been reported as a new and potentially efficacious treatment of inflammation, diabetes, obesity, cancer, AD, and schizophrenia. Since cancer cells show dysregulation of glycolysis they are potentially manageable through changes in metabolic environment. Interestingly, several of the genes involved in maintaining the metabolic environment and the central energy generation pathway are regulated or predicted to be regulated by PPARγ. The use of synthetic PPARγ ligands as drugs and their recent withdrawal/restricted usage highlight the lack of understanding of the molecular basis of these drugs, their off-target effects, and their network. These data further underscores the complexity of nuclear receptor signalling mechanisms. This paper will discuss the function and role of PPARγ in energy metabolism and cancer biology in general and its emergence as a promising therapeutic target in breast cancer.

  8. In Search of New Therapeutic Targets in Obesity Treatment: Sirtuins

    Science.gov (United States)

    Kurylowicz, Alina

    2016-01-01

    Most of the available non-invasive medical therapies for obesity are non-efficient in a long-term evaluation; therefore there is a constant need for new methods of treatment. Research on calorie restriction has led to the discovery of sirtuins (silent information regulators, SIRTs), enzymes regulating different cellular pathways that may constitute potential targets in the treatment of obesity. This review paper presents the role of SIRTs in the regulation of glucose and lipid metabolism as well as in the differentiation of adipocytes. How disturbances of SIRTs’ expression and activity may lead to the development of obesity and related complications is discussed. A special emphasis is placed on polymorphisms in genes encoding SIRTs and their possible association with susceptibility to obesity and metabolic complications, as well as on data regarding altered expression of SIRTs in human obesity. Finally, the therapeutic potential of SIRTs-targeted strategies in the treatment of obesity and related disorders is discussed. PMID:27104517

  9. Targeting angiogenesis-dependent calcified neoplasms using combined polymer therapeutics.

    Directory of Open Access Journals (Sweden)

    Ehud Segal

    Full Text Available BACKGROUND: There is an immense clinical need for novel therapeutics for the treatment of angiogenesis-dependent calcified neoplasms such as osteosarcomas and bone metastases. We developed a new therapeutic strategy to target bone metastases and calcified neoplasms using combined polymer-bound angiogenesis inhibitors. Using an advanced "living polymerization" technique, the reversible addition-fragmentation chain transfer (RAFT, we conjugated the aminobisphosphonate alendronate (ALN, and the potent anti-angiogenic agent TNP-470 with N-(2-hydroxypropylmethacrylamide (HPMA copolymer through a Glycine-Glycine-Proline-Norleucine linker, cleaved by cathepsin K, a cysteine protease overexpressed at resorption sites in bone tissues. In this approach, dual targeting is achieved. Passive accumulation is possible due to the increase in molecular weight following polymer conjugation of the drugs, thus extravasating from the tumor leaky vessels and not from normal healthy vessels. Active targeting to the calcified tissues is achieved by ALN's affinity to bone mineral. METHODS AND FINDING: The anti-angiogenic and antitumor potency of HPMA copolymer-ALN-TNP-470 conjugate was evaluated both in vitro and in vivo. We show that free and conjugated ALN-TNP-470 have synergistic anti-angiogenic and antitumor activity by inhibiting proliferation, migration and capillary-like tube formation of endothelial and human osteosarcoma cells in vitro. Evaluation of anti-angiogenic, antitumor activity and body distribution of HPMA copolymer-ALN-TNP-470 conjugate was performed on severe combined immunodeficiency (SCID male mice inoculated with mCherry-labeled MG-63-Ras human osteosarcoma and by modified Miles permeability assay. Our targeted bi-specific conjugate reduced VEGF-induced vascular hyperpermeability by 92% and remarkably inhibited osteosarcoma growth in mice by 96%. CONCLUSIONS: This is the first report to describe a new concept of a narrowly-dispersed combined

  10. EphB4 as a therapeutic target in mesothelioma

    International Nuclear Information System (INIS)

    Malignant pleural mesothelioma (MPM) often develops decades following exposure to asbestos. Current best therapy produces a response in only half of patients, and the median survival with this therapy remains under a year. A search for novel targets and therapeutics is underway, and recently identified targets include VEGF, Notch, and EphB4-Ephrin-B2. Each of these targets has dual activity, promoting tumor cell growth as well as tumor angiogenesis. We investigated EphB4 expression in 39 human mesothelioma tissues by immunohistochemistry. Xenograft tumors established with human mesothelioma cells were treated with an EphB4 inhibitor (monomeric soluble EphB4 fused to human serum albumin, or sEphB4-HSA). The combinatorial effect of sEphB4-HSA and biologic agent was also studied. EphB4 was overexpressed in 72% of mesothelioma tissues evaluated, with 85% of epithelioid and 38% of sarcomatoid subtypes demonstrating overexpression. The EphB4 inhibitor sEphB4-HSA was highly active as a single agent to inhibit tumor growth, accompanied by tumor cell apoptosis and inhibition of PI3K and Src signaling. Combination of sEphB4-HSA and the anti-VEGF antibody (Bevacizumab) was superior to each agent alone and led to complete tumor regression. EphB4 is a potential therapeutic target in mesothelioma. Clinical investigation of sEphB4-HSA as a single agent and in combination with VEGF inhibitors is warranted

  11. Endocannabinoid System: A Multi-Facet Therapeutic Target.

    Science.gov (United States)

    Kaur, Rimplejeet; Ambwani, Sneha R; Singh, Surjit

    2016-01-01

    the therapeutic targets for both cannabinoid receptor agonists and antagonists. One challenge is to develop drugs that target only cannabinoid receptors in a particular tissue and another is to invent drugs that act selectively on cannabinoid receptors located outside the blood brain barrier. Besides this, development of the suitable dosage forms with maximum efficacy and minimum adverse effects is also warranted. Another angle to be introspected for therapeutic abilities of this group of drugs is non-CB1 and non-CB2 receptor targets for cannabinoids. In order to successfully exploit the therapeutic potential of endocannabinoid system, it is imperative to further characterize the endocannabinoid system in terms of identification of the exact cellular location of cannabinoid receptors and their role as "protective" and "disease inducing substance", time-dependent changes in the expression of cannabinoid receptors. PMID:27086601

  12. Metformin and prostate cancer stem cells: a novel therapeutic target.

    Science.gov (United States)

    Mayer, M J; Klotz, L H; Venkateswaran, V

    2015-12-01

    Prostate cancer is the second most frequently diagnosed cancer in the world. Localized disease can be effectively treated with radiation therapy or radical prostatectomy. However, advanced prostate cancer is more difficult to treat and if metastatic, is incurable. There is a need for more effective therapy for advanced prostate cancer. One potential target is the cancer stem cell (CSC). CSCs have been described in several solid tumors, including prostate cancer, and contribute to therapeutic resistance and tumor recurrence. Metformin, a common oral biguanide used to treat type 2 diabetes, has been demonstrated to have anti-neoplastic effects. Specifically, metformin targets CSCs in breast cancer, pancreatic cancer, glioblastoma and colon cancer. Metformin acts directly on the mitochondria to inhibit oxidative phosphorylation and reduce mitochondrial ATP production. This forces tumor cells to compensate by increasing the rate of glycolysis. CSCs rely heavily on mitochondrial oxidative phosphorylation for energy production. The glycolytic switch results in an energy crisis in these cells. Metformin could be used to exploit this metabolic weakness in CSCs. This would increase CSC sensitivity to conventional cancer therapies, circumventing treatment resistance and enhancing treatment efficacy. This review will explore the characteristics of prostate CSCs, their role in tumor propagation and therapeutic resistance and the role of metformin as a potential prostate CSC sensitizer to current anticancer therapies. PMID:26215782

  13. Carcinoma-Associated Fibroblasts Are a Promising Therapeutic Target

    Energy Technology Data Exchange (ETDEWEB)

    Togo, Shinsaku, E-mail: shinsaku@juntendo.ac.jp [Department of Respiratory Medicine, Juntendo University School of Medicine, Tokyo 113-8412 (Japan); Polanska, Urszula M. [CR-UK Stromal-Tumour Interaction Group, Paterson Institute for Cancer Research, The University of Manchester, Wilmslow Road, Manchester M20 4BX (United Kingdom); Horimoto, Yoshiya [Department of Pathology and Oncology, Juntendo University School of Medicine, Tokyo 113-8412 (Japan); Atopy Research Centre, Juntendo University School of Medicine, Tokyo 113-8412 (Japan); Department of Breast Oncology, Juntendo University School of Medicine, Tokyo 113-8412 (Japan); Orimo, Akira, E-mail: shinsaku@juntendo.ac.jp [CR-UK Stromal-Tumour Interaction Group, Paterson Institute for Cancer Research, The University of Manchester, Wilmslow Road, Manchester M20 4BX (United Kingdom); Department of Pathology and Oncology, Juntendo University School of Medicine, Tokyo 113-8412 (Japan); Atopy Research Centre, Juntendo University School of Medicine, Tokyo 113-8412 (Japan)

    2013-01-31

    Human carcinomas frequently exhibit significant stromal reactions such as the so-called “desmoplastic stroma” or “reactive stroma”, which is characterised by the existence of large numbers of stromal cells and extracellular matrix proteins. Carcinoma-associated fibroblasts (CAFs), which are rich in activated fibroblast populations exemplified by myofibroblasts, are among the predominant cell types present within the tumour-associated stroma. Increased numbers of stromal myofibroblasts are often associated with high-grade malignancies with poor prognoses in humans. CAF myofibroblasts possess abilities to promote primary tumour development, growth and progression by stimulating the processes of neoangiogenesis as well as tumour cell proliferation, survival, migration and invasion. Moreover, it has been demonstrated that CAFs serve as a niche supporting the metastatic colonisation of disseminated carcinoma cells in distant organs. Their contribution to primary and secondary malignancies makes these fibroblasts a potential therapeutic target and they also appear to be relevant to the development of drug resistance and tumour recurrence. This review summarises our current knowledge of tumour-promoting CAFs and discusses the therapeutic feasibility of targeting these cells as well as disrupting heterotypic interactions with other cell types in tumours that may improve the efficacy of current anti-tumour therapies.

  14. Alveolar bone loss: mechanisms, potential therapeutic targets, and interventions.

    Science.gov (United States)

    Intini, G; Katsuragi, Y; Kirkwood, K L; Yang, S

    2014-05-01

    This article reviews recent research into mechanisms underlying bone resorption and highlights avenues of investigation that may generate new therapies to combat alveolar bone loss in periodontitis. Several proteins, signaling pathways, stem cells, and dietary supplements are discussed as they relate to periodontal bone loss and regeneration. RGS12 is a crucial protein that mediates osteoclastogenesis and bone destruction, and a potential therapeutic target. RGS12 likely regulates osteoclast differentiation through regulating calcium influx to control the calcium oscillation-NFATc1 pathway. A working model for RGS10 and RGS12 in the regulation of Ca(2+) oscillations during osteoclast differentiation is proposed. Initiation of inflammation depends on host cell-microbe interactions, including the p38 mitogen-activated protein kinase (MAPK) signaling pathway. Oral p38 inhibitors reduced lipopolysaccharide (LPS)-induced bone destruction in a rat periodontitis model but showed unsatisfactory safety profiles. The p38 substrate MK2 is a more specific therapeutic target with potentially superior tolerability. Furthermore, MKP-1 shows anti-inflammatory activity, reducing inflammatory cytokine biosynthesis and bone resorption. Multipotent skeletal stem cell (SSC) populations exist within the bone marrow and periosteum of long bones. These bone-marrow-derived SSCs and periosteum-derived SSCs have shown therapeutic potential in several applications, including bone and periodontal regeneration. The existence of craniofacial bone-specific SSCs is suggested based on existing studies. The effects of calcium, vitamin D, and soy isoflavone supplementation on alveolar and skeletal bone loss in post-menopausal women were investigated. Supplementation resulted in stabilization of forearm bone mass density and a reduced rate of alveolar bone loss over 1 yr, compared with placebo. Periodontal attachment levels were also well-maintained and alveolar bone loss suppressed during 24 wk of

  15. The histone demethylase LSD1 is a novel oncogene and therapeutic target in oral cancer.

    Science.gov (United States)

    Wang, Yanling; Zhu, Yumin; Wang, Qiong; Hu, Huijun; Li, Zhongwu; Wang, Dongmiao; Zhang, Wei; Qi, Bin; Ye, Jinhai; Wu, Heming; Jiang, Hongbing; Liu, Laikui; Yang, Jianrong; Cheng, Jie

    2016-04-28

    The histone demethylase LSD1 functions as a key pro-oncogene and attractive therapeutic target in human cancer. Here we sought to interrogate the oncogenic roles of LSD1 in OSCC tumorigenesis and therapeutic intervention by integrating chemical-induced OSCC model, genetic and pharmacological loss-of-function approaches. Our data revealed that aberrant LSD1 overexpression in OSCC was significantly associated with tumor aggressiveness and shorter overall survival. Increased abundance of LSD1 was detected along with disease progression in DMBA- or 4NQO-induced OSCC animal models. LSD1 depletion via siRNA-mediated knockdown in OSCC cells resulted in impaired cell proliferation, migration/invasion, tumorsphere formation and reduced xenograft growth while inducing cell apoptosis and enhancing chemosensitivity to 5-FU. Moreover, treatments of LSD1 chemical inhibitors (pargyline and tranylcypromine) induced its protein reduction probably via enhanced protein degradation and produced similar phenotypic changes resembling LSD1 silencing in OSCC cells. Pharmacological inhibition of LSD1 by intraperitoneal delivery of these inhibitors resulted in impaired xenograft overgrowth. Taken together, our data reveal the tumorigenic roles of LSD1 and identified LSD1 as a novel biomarker with diagnostic and prognostic significance, and also establish that targeting LSD1 by chemical inhibitors is a viable therapeutic strategy against OSCC. PMID:26872725

  16. Enhanced Delivery of Gold Nanoparticles with Therapeutic Potential for Targeting Human Brain Tumors

    Science.gov (United States)

    Etame, Arnold B.

    The blood brain barrier (BBB) remains a major challenge to the advancement and application of systemic anti-cancer therapeutics into the central nervous system. The structural and physiological delivery constraints of the BBB significantly limit the effectiveness of conventional chemotherapy, thereby making systemic administration a non-viable option for the vast majority of chemotherapy agents. Furthermore, the lack of specificity of conventional systemic chemotherapy when applied towards malignant brain tumors remains a major shortcoming. Hence novel therapeutic strategies that focus both on targeted and enhanced delivery across the BBB are warranted. In recent years nanoparticles (NPs) have emerged as attractive vehicles for efficient delivery of targeted anti-cancer therapeutics. In particular, gold nanoparticles (AuNPs) have gained prominence in several targeting applications involving systemic cancers. Their enhanced permeation and retention within permissive tumor microvasculature provide a selective advantage for targeting. Malignant brain tumors also exhibit transport-permissive microvasculature secondary to blood brain barrier disruption. Hence AuNPs may have potential relevance for brain tumor targeting. However, the permeation of AuNPs across the BBB has not been well characterized, and hence is a potential limitation for successful application of AuNP-based therapeutics within the central nervous system (CNS). In this dissertation, we designed and characterized AuNPs and assessed the role of polyethylene glycol (PEG) on the physical and biological properties of AuNPs. We established a size-dependent permeation profile with respect to core size as well as PEG length when AuNPs were assessed through a transport-permissive in-vitro BBB. This study was the first of its kind to systematically examine the influence of design on permeation of AuNPs through transport-permissive BBB. Given the significant delivery limitations through the non

  17. BONE TUMOR ENVIRONMENT AS POTENTIAL THERAPEUTIC TARGET IN EWING SARCOMA

    Directory of Open Access Journals (Sweden)

    Françoise eREDINI

    2015-12-01

    Full Text Available Ewing sarcoma is the second most common pediatric bone tumor, with three cases per million worldwide. In clinical terms, ES is an aggressive, rapidly fatal malignancy that mainly develops in osseous sites (85%, but also in extraskeletal soft tissue. It spreads naturally to the lungs, bones and bone marrow with poor prognosis in the two latter cases. Bone lesions from primary or secondary (metastases tumors are characterized by extensive bone remodeling, more often due to osteolysis. Osteoclast activation and subsequent bone resorption is responsible for the clinical features of bone tumors including pain, vertebral collapse and spinal cord compression. Based on the vicious cycle concept of tumor cells and bone resorbing cells, drugs which target osteoclasts may be promising agents as adjuvant setting for treating bone tumors, including Ewing sarcoma. There is also increasing evidence that cellular and molecular protagonists present in the bone microenvironment play a part in establishing a favorable niche for tumor initiation and progression. The purpose of this review is to discuss the potential therapeutic value of drugs targeting the bone tumor microenvironment in Ewing Sarcoma. The first part of the review will focus on targeting the bone resorbing function of osteoclasts by means of bisphosphonates (BPs or drugs blocking the pro-resorbing cytokine Receptor Activator of NF-kappa B Ligand (RANKL. Second, the role of this peculiar hypoxic microenvironment will be discussed in the context of resistance to chemotherapy, escape from the immune system, or neo-angiogenesis. Therapeutic interventions based on these specificities could be then proposed in the context of Ewing sarcoma.

  18. Frizzled-7 as a Potential Therapeutic Target in Colorectal Cancer

    Directory of Open Access Journals (Sweden)

    Koji Ueno

    2008-07-01

    Full Text Available We investigated whether one of the Wnt receptors, frizzled-7 (FZD7, functions in the canonical Wnt signaling pathway of colorectal cancer (CRC cells harboring an APC or CTNNB1 mutation and may be a potential therapeutic target for sporadic CRCs. The expression level of FZD gene family members in colon cancer cells and primary CRC tissues were determined by real-time PCR. Activation of the Wnt signaling pathway was evaluated by TOPflash assay. The expression level of Wnt target genes was determined by real-time polymerase chain reaction and/or Western blot analysis. Cell growth and cell invasion were assessed by MTS and matrigel assays, respectively. Among 10 FZD gene family members, FZD7 mRNA was predominantly expressed in six colon cancer cell lines with APC or CTNNB1 mutation. These six cell lines were transfected with FZD7 cDNA together with a TOPflash reporter plasmid, resulting in a 1.5- to 24.3-fold increase of Tcf transcriptional activity. The mRNA expression levels of seven known Wnt target genes were also increased by 1.5- to 3.4-fold after transfection of FZD7 cDNA into HCT-116 cells. The six cell lines were then cotransfected with FZD7-siRNA and a TOPflash reporter plasmid, which reduced Tcf transcriptional activity to 20% to 80%. FZD7-siRNA was shown to significantly decrease cell viability and in vitro invasion activity after transfection into HCT-116 cells. Our present data demonstrated that FZD7 activates the canonical Wnt pathway in colon cancer cells despite the presence of APC or CTNNB1 mutation and that FZD7-siRNA may be used as a therapeutic reagent for CRCs.

  19. RPS2: a novel therapeutic target in prostate cancer

    Directory of Open Access Journals (Sweden)

    Stearns Mark E

    2009-01-01

    Full Text Available Abstract Background A number of studies have previously shown that the over expression of different ribosomal proteins might play an important role in cancer (i.e. S3a, L10, L16. We have previously reported that RPS2, a 33 Kda ribosomal protein was over expressed in malignant prostate cancer cell lines and in archived tumor specimens. Thus, RPS2 or other aberrantly over-expressed ribosomal proteins might promote cancer and be excellent therapeutic targets for treatment of the disease. Methods Western blotting and RT-PCR have been used to measure and compare the levels of expression of RPS2 in a variety of malignant prostate cancer cell lines, plus normal and benign cells lines. We have developed a 'ribozyme-like' DNAZYM-1P '10–23' motif oligonucleotide and examined whether it targets RPS2 in different cell lines by RT-PCR and Western blots. Growth and apoptosis assays were carried out to measure whether DNAZYM-1P 'knock-down' of RPS2 influenced cell proliferation or survival. We have also developed a SCID mouse tumor model with PC-3ML cells to determine whether DNAZYM-1P targeting of RPS2 compromised tumor growth and mouse survival rates in vivo. Results Western blots showed that PC-3ML, LNCaP, CPTX-1532, and pBABE-cmyc stably transfected IBC-10a cells all over-expressed RPS2, whereas IBC-10a parent, NPTX-1532, and BPH-1 cells or mouse NIH-3T3 cells expressed barely detectable levels of RPS2. RT-PCR assays showed that DNAZYM-1P, which targeted RPS2, 'knocked-down' RPS2 expression in the malignant cells (i.e. PC-3ML cells in vitro. The DNAZYM-1P also inhibited cell growth and induced apoptosis in the malignant prostate cells, but had little effect on the normal IBC-10a or NPTX-1532 cell lines. Finally, SCID mouse tumor modeling studies showed that DNAZYM-1P blocked tumor growth and metastasis by PC-3ML cells and eventually eradicated tumors following localized or systemic i.v. delivery. Mouse survival studies revealed that there was a dosage

  20. Neuroendothelial NMDA receptors as therapeutic targets in experimental autoimmune encephalomyelitis.

    Science.gov (United States)

    Macrez, Richard; Ortega, Maria C; Bardou, Isabelle; Mehra, Anupriya; Fournier, Antoine; Van der Pol, Susanne M A; Haelewyn, Benoit; Maubert, Eric; Lesept, Flavie; Chevilley, Arnaud; de Castro, Fernando; De Vries, Helga E; Vivien, Denis; Clemente, Diego; Docagne, Fabian

    2016-09-01

    Multiple sclerosis is among the most common causes of neurological disability in young adults. Here we provide the preclinical proof of concept of the benefit of a novel strategy of treatment for multiple sclerosis targeting neuroendothelial N-methyl-D-aspartate glutamate receptors. We designed a monoclonal antibody against N-methyl-D-aspartate receptors, which targets a regulatory site of the GluN1 subunit of N-methyl-D-aspartate receptor sensitive to the protease tissue plasminogen activator. This antibody reverted the effect of tissue plasminogen activator on N-methyl-D-aspartate receptor function without affecting basal N-methyl-D-aspartate receptor activity (n = 21, P mouse, at the vicinity of tight junctions of the blood-spinal cord barrier. Noteworthy, it reduced human leucocyte transmigration in an in vitro model of the blood-brain barrier (n = 12, P multiple sclerosis, and highlights the therapeutic potential of strategies targeting the protease-regulated site of N-methyl-D-aspartate receptor. PMID:27435092

  1. Mast cells: new therapeutic target in helminth immune modulation.

    Science.gov (United States)

    Vukman, K V; Lalor, R; Aldridge, A; O'Neill, S M

    2016-01-01

    Helminth infection and their secreted antigens have a protective role in many immune-mediated inflammatory disorders such as inflammatory bowel disease, rheumatoid arthritis and multiple sclerosis. However, studies have focused primarily on identifying immune protective mechanisms of helminth infection and their secreted molecules on dendritic cells and macrophages. Given that mast cells have been shown to be implicated in the pathogenesis and progression of many inflammatory disorders, their role should also be examined and considered as cellular target for helminth-based therapies. As there is a dearth of studies examining the interaction of helminth-derived antigens and mast cells, this review will focus on the role of mast cells during helminth infection and examine our current understanding of the involvement of mast cells in TH 1/TH 17-mediated immune disorders. In this context, potential mechanisms by which helminths could target the TH 1/TH 17 promoting properties of mast cells can be identified to unveil novel therapeutic mast cell driven targets in combating these inflammatory disorders. PMID:26577605

  2. Autophagy as a Therapeutic Target in Cardiovascular Disease

    Science.gov (United States)

    Nemchenko, Andriy; Chiong, Mario; Turer, Aslan; Lavandero, Sergio; Hill, Joseph A.

    2011-01-01

    The epidemic of heart failure continues apace, and development of novel therapies with clinical efficacy has lagged. Now, important insights into the molecular circuitry of cardiovascular autophagy have raised the prospect that this cellular pathway of protein quality control may be a target of clinical relevance. Whereas basal levels of autophagy are required for cell survival, excessive levels – or perhaps distinct forms of autophagic flux – contribute to disease pathogenesis. Our challenge will be to distinguish mechanisms that drive adaptive versus maladaptive autophagy and to manipulate those pathways for therapeutic gain. Recent evidence suggests this may be possible. Here, we review the fundamental biology of autophagy and its role in a variety of forms of cardiovascular disease. We discuss ways in which this evolutionarily conserved catabolic mechanism can be manipulated, discuss studies presently underway in heart disease, and provide our perspective on where this exciting field may lead in the future. PMID:21723289

  3. Molecular markers as therapeutic targets in lung cancer

    Institute of Scientific and Technical Information of China (English)

    Hsin-Hui Tseng; Biao He

    2013-01-01

    Lung cancer is responsible for 29% of cancer deaths in the United States and has very low 5-year survival rates of approximately 11% in men and 15% in women.Although the early diagnosis of lung cancer may increase the survival rate with adequate treatment,advanced lung cancers are often metastasized and receive limited benefit from therapeutic regimens.As conventional treatments for lung cancer reach their limitations,researchers have attempted to discover novel drug therapies aimed at specific targets contributing to the progression of tumorigenesis.Recent advances in systems biology have enabled the molecular biology of lung carcinogenesis to be elucidated.Our understanding of the physiologic processes of tumor development provide a means to design more effective and specific drugs with less toxicity,thereby accelerating the delivery of new drug therapies to the patient's bedside.

  4. Autophagy: A new therapeutic target for liver fibrosis

    Institute of Scientific and Technical Information of China (English)

    2015-01-01

    Hepatic fibrosis is a wound-healing response to liverinjury and the result of imbalance of extracellular matrix(ECM) accumulation and degradation. The relentless production and progressive accumulation of ECM canlead to end-stage liver disease. Although significantprogress has been achieved in elucidating the mechanismsof fibrogenesis, effective anti-fibrotic strategiesare still lacking. Autophagy is an intracellular process ofself-digestion of defective organelles to provide materialrecycling or energy for cell survival. Autophagy hasbeen implicated in the pathophysiology of many humandisorders including hepatic fibrosis. However, the exactrelationships between autophagy and hepatic fibrosisare not totally clear and need further investigations.A new therapeutic target for liver fibrosis could bedeveloped with a better understanding of autophagy.

  5. Novel therapeutic approaches targeting matrix metalloproteinases in cardiovascular disease.

    Science.gov (United States)

    Briasoulis, Alexandros; Tousoulis, Dimitris; Papageorgiou, Nikolaos; Kampoli, Anna-Maria; Androulakis, Emmanuel; Antoniades, Charalambos; Tsiamis, Eleftherios; Latsios, George; Stefanadis, Christodoulos

    2012-01-01

    Matrix metalloproteinases (MMPs), are proteinases that participate in extracellular matrix remodelling and degradation. Under normal physiological conditions, the activities of MMPs are regulated at the level of transcription, of activation of the pro-MMP precursor zymogens and of inhibition by endogenous inhibitors (tissue inhibitors of metalloproteinases; TIMPs). Alteration in the regulation of MMP activity is implicated in atherosclerotic plaque development, coronary artery disease and heart failure. The pathological effects of MMPs and TIMPs in cardiovascular diseases involve vascular remodelling, atherosclerotic plaque instability and left ventricular remodelling after myocardial infarction. Since excessive tissue remodelling and increased matrix metalloproteinase activity have been demonstrated during atherosclerotic lesion progression, MMPs represent a potential target for therapeutic intervention aimed at modification of vascular pathology by restoring the physiological balance between MMPs and TIMPs. This review discusses pharmacological approaches to MMP inhibition. PMID:22519451

  6. PTP1B: a new therapeutic target for Rett syndrome.

    Science.gov (United States)

    Tautz, Lutz

    2015-08-01

    Rett syndrome (RTT) is an X-linked neurodevelopmental disorder that is characterized by successive loss of acquired cognitive, social, and motor skills and development of autistic behavior. RTT affects approximately 1 in 10,000 live female births and is the second most common cause of severe mental retardation in females, after Down syndrome. Currently, there is no cure or effective therapy for RTT. Approved treatment regimens are presently limited to supportive management of specific physical and mental disabilities. In this issue, Krishnan and colleagues reveal that the protein tyrosine phosphatase PTP1B is upregulated in patients with RTT and in murine models and provide strong evidence that targeting PTP1B has potential as a viable therapeutic strategy for the treatment of RTT. PMID:26214520

  7. Hippocampal Area CA2: An Overlooked but Promising Therapeutic Target.

    Science.gov (United States)

    Chevaleyre, Vivien; Piskorowski, Rebecca A

    2016-08-01

    While the hippocampus has long been recognized as a brain structure specialized in mapping 'space' in rodents, human studies and now recent data from rodents have shown that its function extends well beyond spatial coding. Recently, an overlooked area of the hippocampus, CA2, has emerged as a critical region for social memory. This area is also uniquely altered during several pathologies such as schizophrenia and age-related dementia. Because of its singular connectivity, we propose that area CA2 resides at the interface between emotional brain activity and higher cognitive function. Furthermore, because of the unique expression of multiple neuromodulator receptors in area CA2, we posit that this region may represent a fruitful therapeutic target for diseases where social dysfunction occurs. PMID:27372610

  8. Macrophages associated with tumors as potential targets and therapeutic intermediates.

    Science.gov (United States)

    Vinogradov, Serguei; Warren, Galya; Wei, Xin

    2014-04-01

    Tumor-associated macrophages (TAMs) form approximately 50% of tumor mass. TAMs were shown to promote tumor growth by suppressing immunocompetent cells, inducing neovascularization and supporting cancer stem cells. TAMs retain mobility in tumor mass, which can potentially be employed for better intratumoral biodistribution of nanocarriers and effective tumor growth inhibition. Due to the importance of TAMs, they are increasingly becoming principal targets of novel therapeutic approaches. In this review, we compare features of macrophages and TAMs that are essential for TAM-directed therapies, and illustrate the advantages of nanomedicine that are related to the preferential capture of nanocarriers by Mϕ in the process of drug delivery. We discuss recent efforts in reprogramming or inhibiting tumor-protecting properties of TAMs, and potential strategies to increase efficacy of conventional chemotherapy by combining with macrophage-associated delivery of nanodrugs. PMID:24827844

  9. Autophagy: A new therapeutic target for liver fibrosis.

    Science.gov (United States)

    Mao, Yu-Qing; Fan, Xiao-Ming

    2015-08-01

    Hepatic fibrosis is a wound-healing response to liver injury and the result of imbalance of extracellular matrix (ECM) accumulation and degradation. The relentless production and progressive accumulation of ECM can lead to end-stage liver disease. Although significant progress has been achieved in elucidating the mechanisms of fibrogenesis, effective anti-fibrotic strategies are still lacking. Autophagy is an intracellular process of self-digestion of defective organelles to provide material recycling or energy for cell survival. Autophagy has been implicated in the pathophysiology of many human disorders including hepatic fibrosis. However, the exact relationships between autophagy and hepatic fibrosis are not totally clear and need further investigations. A new therapeutic target for liver fibrosis could be developed with a better understanding of autophagy. PMID:26261688

  10. Inflammation as a Therapeutic Target for Diabetic Neuropathies.

    Science.gov (United States)

    Pop-Busui, Rodica; Ang, Lynn; Holmes, Crystal; Gallagher, Katherine; Feldman, Eva L

    2016-03-01

    Diabetic neuropathies (DNs) are one of the most prevalent chronic complications of diabetes and a major cause of disability, high mortality, and poor quality of life. Given the complex anatomy of the peripheral nervous system and types of fiber dysfunction, DNs have a wide spectrum of clinical manifestations. The treatment of DNs continues to be challenging, likely due to the complex pathogenesis that involves an array of systemic and cellular imbalances in glucose and lipids metabolism. These lead to the activation of various biochemical pathways, including increased oxidative/nitrosative stress, activation of the polyol and protein kinase C pathways, activation of polyADP ribosylation, and activation of genes involved in neuronal damage, cyclooxygenase-2 activation, endothelial dysfunction, altered Na(+)/K(+)-ATPase pump function, impaired C-peptide-related signaling pathways, endoplasmic reticulum stress, and low-grade inflammation. This review summarizes current evidence regarding the role of low-grade inflammation as a potential therapeutic target for DNs. PMID:26897744

  11. Sphingosine kinase-1--a potential therapeutic target in cancer.

    Science.gov (United States)

    Cuvillier, Olivier

    2007-02-01

    Sphingolipid metabolites play critical functions in the regulation of a number of fundamental biological processes including cancer. Whereas ceramide and sphingosine mediate and trigger apoptosis or cell growth arrest, sphingosine 1-phosphate promotes proliferation and cell survival. The delicate equilibrium between the intracellular levels of each of these sphingolipids is controlled by the enzymes that either produce or degrade these metabolites. Sphingosine kinase-1 is a crucial regulator of this two-pan balance, because it produces the prosurvival sphingosine 1-phosphate, and reduces the content of both ceramide and sphingosine, the proapoptotic sphingolipids. Sphingosine kinase-1 controls the levels of sphingolipids having opposite effects on cell survival/death, its gene was found to be of oncogenic nature, its mRNA is overexpressed in many solid tumors, its overexpression protects cells from apoptosis and its activity is decreased during anticancer treatments. Therefore, sphingosine kinase-1 appears to be a target of interest for therapeutic manipulation via its pharmacological inhibition. Strategies to kill tumor cells by increasing their ceramide and/or sphingosine content while blocking sphingosine 1-phosphate generation should have a favorable therapeutic index. PMID:17159597

  12. Leptin, ghrelin, and endocannabinoids: potential therapeutic targets in anorexia nervosa.

    Science.gov (United States)

    Støving, René Klinkby; Andries, Alin; Brixen, Kim; Flyvbjerg, Allan; Hørder, Kirsten; Frystyk, Jan

    2009-04-01

    Anorexia nervosa (AN) has the highest mortality rate between psychiatric disorders, and evidence for managing it is still very limited. So far, pharmacological treatment has focused on a narrow range of drugs and only a few controlled studies have been performed. Furthermore, the studies have been of short duration and included a limited number of subjects, often heterogenic with regard to stage and acute nutritive status. Thus, novel approaches are urgently needed. Body weight homeostasis is tightly regulated throughout life. With the discovery of orexigenic and anorectic signals, an array of new molecular targets to control eating behavior has emerged. This review focuses on recent advances in three important signal systems: leptin, ghrelin, and endocannabinoids toward the identification of potential therapeutical breakthroughs in AN. Our review of the current literature shows that leptin may have therapeutic potentials in promoting restoration of menstrual cycles in weight restored patients, reducing motor restlessness in severely hyperactive patients, and preventing osteoporosis in chronic patients. Ghrelin and endocannabinoids exert orexigenic effects which may facilitate nutritional restoration. Leptin and endocannabinoids may exert antidepressive and anxiolytic effects. Finally, monitoring serum concentration of leptin may be useful in order to prevent refeeding syndrome. PMID:18926548

  13. Gli as a novel therapeutic target in malignant pleural mesothelioma.

    Directory of Open Access Journals (Sweden)

    Hui Li

    Full Text Available Malignant pleural mesothelioma (MPM is a highly aggressive tumor with poor prognosis. Current treatment is rarely curative, thus novel meaningful therapies are urgently needed. Inhibition of Hedgehog (Hh signaling at the cell membrane level in several cancers has shown anti-cancer activity in recent clinical studies. Evidence of Hh-independent Gli activation suggests Gli as a more potent therapeutic target. The current study is aimed to evaluate the potential of Gli as a therapeutic target to treat MPM. The expression profiles of Gli factors and other Hh signaling components were characterized in 46 MPM patient tissue samples by RT-PCR and immunohistochemistry. Cultured cell lines were employed to investigate the requirement of Gli activation in tumor cell growth by inhibiting Gli through siRNA or a novel small molecule Gli inhibitor (Gli-I. A xenograft model was used to evaluate Gli-I in vivo. In addition, a side by side comparison between Gli and Smoothened (Smo inhibition was conducted in vitro using siRNA and small molecule inhibitors. Our study reported aberrant Gli1 and Gli2 activation in a large majority of tissues. Inhibition of Gli by siRNAs or Gli-I suppressed cell growth dramatically both in vitro and in vivo. Inhibition of Gli exhibited better cytotoxicity than that of Smo by siRNA and small molecule inhibitors vismodegib and cyclopamine. Combination of Gli-I and pemetrexed, as well as Gli-I and vismodegib demonstrated synergistic effects in suppression of MPM proliferation in vitro. In summary, Gli activation plays a critical role in MPM. Inhibition of Gli function holds strong potential to become a novel, clinically effective approach to treat MPM.

  14. Pathogenic inflammation and its therapeutic targeting in systemic lupus erythematosus

    Directory of Open Access Journals (Sweden)

    Timothy Andrew Gottschalk

    2015-10-01

    Full Text Available Systemic Lupus Erythematosus (SLE, lupus is a highly complex and heterogeneous autoimmune disease that most often afflicts women in their child-bearing years. It is characterized by circulating self-reactive antibodies that deposit in tissues including skin, kidneys and brain, and the ensuing inflammatory response can lead to irreparable tissue damage. Over many years, clinical trials in SLE have focused on agents that control B and T lymphocyte activation, and, with the single exception of an agent known as Belimumab which targets the B cell survival factor BAFF, they have been disappointing. At present, standard therapy for SLE with mild disease is the agent hydroxychloroquine. During disease flares, steroids are often used, while the more severe manifestations with major organ involvement warrant potent, broad-spectrum immuno-suppression with cyclophosphamide or mycophenolate. Current treatments have severe and dose-limiting toxicities and thus a more specific therapy targeting a causative factor or signaling pathway would be greatly beneficial in SLE treatment. Moreover, the ability to control inflammation alongside B cell activation may be a superior approach for disease control. There has been a recent focus on the innate immune system and associated inflammation, which has uncovered key players in driving the pathogenesis of SLE. Delineating some of these intricate inflammatory mechanisms has been possible with studies using spontaneous mouse mutants and genetically engineered mice. These strains, to varying degrees, exhibit hallmarks of the human disease and therefore have been utilized to model human SLE and to test new drugs. Developing a better understanding of the initiation and perpetuation of disease in SLE may uncover suitable novel targets for therapeutic intervention. Here we discuss the involvement of inflammation in SLE disease pathogenesis, with a focus on several key proinflammatory cytokines and myeloid growth factors, and

  15. Estrogen receptor beta is a novel therapeutic target for photoaging.

    Science.gov (United States)

    Chang, Ken C N; Wang, Yihe; Oh, Inn Gyung; Jenkins, Susan; Freedman, Leonard P; Thompson, Catherine C; Chung, Jin Ho; Nagpal, Sunil

    2010-05-01

    One of the many harmful factors faced by the skin is solar UV radiation, which damages skin by inducing chronic low-grade inflammation through increased expression of proinflammatory cytokines, metalloproteinases (MMPs) and cyclooxygenase-2 (COX-2). Estrogen receptors (ERs) alpha and beta are ligand-dependent transcription factors that are expressed in skin, and an ERbeta agonist has previously shown efficacy in vivo in models of pain and inflammation. Because ERbeta does not carry the breast and uterine proliferation liabilities of ERalpha, we decided to explore the possibility of using ERbeta as a target for photoaging. We show that ERbeta-selective compounds suppressed the expression of cytokines and MMPs in activated keratinocytes and fibroblast-based in vitro models of photoaging. Furthermore, in activated dermal fibroblasts, ERbeta-selective compounds also inhibited COX-2. These activities of ERbeta ligands in skin cells correlated with the expression levels of ERbeta and showed reversal by treatment with a potent synthetic ER antagonist. Furthermore, the pharmacology of ERbeta-selective compound was observed in wild-type but not in skin cells obtained from ERbeta knockout mice. Finally, we demonstrate that a synthetic ERbeta agonist inhibited UV-induced photodamage and skin wrinkle formation in a murine model of photoaging. Therefore, the potential of an ERbeta ligand to regulate multiple pathways underlying the cause of photoaging suggests ERbeta to be a novel therapeutic target for the prevention and treatment of photoaging. PMID:20110405

  16. SALL4 is a novel therapeutic target in intrahepatic cholangiocarcinoma

    Science.gov (United States)

    Deng, Gang; Zhu, Lei; Huang, Feizhou; Nie, Wanpin; Huang, Wei; Xu, Hongbo; Zheng, Shaopeng; Yi, Zhongjie; Wan, Tao

    2015-01-01

    Intrahepatic cholangiocarcinoma (ICC) is the most common and deadly disease of the biliary tree due to its poor prognosis. Sal-like protein 4 (SALL4), a stem cell marker, has been identified as a potential target for aggressive hepatocellular carcinoma (HCC). In our study, 175 ICC cases with an average age of 55 years were included, and 53% (93/175) were male. And 28 adjacent non-tumor tissues were also collected. The SALL4-positive immunoreactivity was detected in a total of 102 ICC cases (58%), whereas all 28 adjacent tissues showed negative staining. Univariate analysis, showed that the SALL4-positive ICC cases had significantly more frequent lymph nodal metastasis (P = 0.0460), vascular invasion (P < 0.0001), and nerve invasion (P < 0.0001). Furthermore, the strong SALL4-positive cases (n = 7, 5 months) had shorter overall survival, when compared to moderate SALL4-positive (n = 46, 9 months) or SALL4-negative cases (n = 73, 7 months), respectively. Our data also suggest that SALL4 may be involved in the regulation of epithelial-mesenchymal transition (EMT) in ICC. Those results for the first time indicate an oncogenic role of SALL4 in ICC. Therefore, SALL4 may serve as a promising therapeutic target for ICC. PMID:26317546

  17. Transcription Inhibition as a Therapeutic Target for Cancer

    International Nuclear Information System (INIS)

    During tumorigenesis the transformed cells lose their normal growth control mechanisms and become dependent on oncogenes' products and pathways for survival. Treatments tailored to block the expression or function of transforming genes have shown efficacy in eliminating neoplastic cells. The mRNAs of many oncogenes, as well as regulators of other key processes such as cell proliferation, angiogenesis, and apoptosis, typically have shorter half-lives. Agents that impede mRNA synthesis are expected to selectively hinder the expression of these genes and, therefore, be detrimental to neoplastic cells that are physiologically dependent on them. In addition to exploiting the tumor cells' dependency on short-lived transcripts, RNA-directed agents also take advantage of the differential sensitivity between transformed and non-transformed cells, as the cytotoxic effects of inhibiting RNA synthesis have not been seen in non-transformed cells. The abrogation of the formation of oncotranscripts provides a new concept in cancer therapeutics and numerous agents have been developed which are able to target transcription. The focus of this review is to give an overview of transcription and the different inhibitory strategies that target various aspects of the transcriptional process

  18. Cannabidiol in Humans—The Quest for Therapeutic Targets

    Directory of Open Access Journals (Sweden)

    Stéphane Potvin

    2012-05-01

    Full Text Available Cannabidiol (CBD, a major phytocannabinoid constituent of cannabis, is attracting growing attention in medicine for its anxiolytic, antipsychotic, antiemetic and anti-inflammatory properties. However, up to this point, a comprehensive literature review of the effects of CBD in humans is lacking. The aim of the present systematic review is to examine the randomized and crossover studies that administered CBD to healthy controls and to clinical patients. A systematic search was performed in the electronic databases PubMed and EMBASE using the key word “cannabidiol”. Both monotherapy and combination studies (e.g., CBD + ∆9-THC were included. A total of 34 studies were identified: 16 of these were experimental studies, conducted in healthy subjects, and 18 were conducted in clinical populations, including multiple sclerosis (six studies, schizophrenia and bipolar mania (four studies, social anxiety disorder (two studies, neuropathic and cancer pain (two studies, cancer anorexia (one study, Huntington’s disease (one study, insomnia (one study, and epilepsy (one study. Experimental studies indicate that a high-dose of inhaled/intravenous CBD is required to inhibit the effects of a lower dose of ∆9-THC. Moreover, some experimental and clinical studies suggest that oral/oromucosal CBD may prolong and/or intensify ∆9-THC-induced effects, whereas others suggest that it may inhibit ∆9-THC-induced effects. Finally, preliminary clinical trials suggest that high-dose oral CBD (150–600 mg/d may exert a therapeutic effect for social anxiety disorder, insomnia and epilepsy, but also that it may cause mental sedation. Potential pharmacokinetic and pharmacodynamic explanations for these results are discussed.

  19. Cannabidiol in humans-the quest for therapeutic targets.

    Science.gov (United States)

    Zhornitsky, Simon; Potvin, Stéphane

    2012-01-01

    Cannabidiol (CBD), a major phytocannabinoid constituent of cannabis, is attracting growing attention in medicine for its anxiolytic, antipsychotic, antiemetic and anti-inflammatory properties. However, up to this point, a comprehensive literature review of the effects of CBD in humans is lacking. The aim of the present systematic review is to examine the randomized and crossover studies that administered CBD to healthy controls and to clinical patients. A systematic search was performed in the electronic databases PubMed and EMBASE using the key word "cannabidiol". Both monotherapy and combination studies (e.g., CBD + ∆9-THC) were included. A total of 34 studies were identified: 16 of these were experimental studies, conducted in healthy subjects, and 18 were conducted in clinical populations, including multiple sclerosis (six studies), schizophrenia and bipolar mania (four studies), social anxiety disorder (two studies), neuropathic and cancer pain (two studies), cancer anorexia (one study), Huntington's disease (one study), insomnia (one study), and epilepsy (one study). Experimental studies indicate that a high-dose of inhaled/intravenous CBD is required to inhibit the effects of a lower dose of ∆9-THC. Moreover, some experimental and clinical studies suggest that oral/oromucosal CBD may prolong and/or intensify ∆9-THC-induced effects, whereas others suggest that it may inhibit ∆9-THC-induced effects. Finally, preliminary clinical trials suggest that high-dose oral CBD (150-600 mg/d) may exert a therapeutic effect for social anxiety disorder, insomnia and epilepsy, but also that it may cause mental sedation. Potential pharmacokinetic and pharmacodynamic explanations for these results are discussed. PMID:24281562

  20. Importins and exportins as therapeutic targets in cancer.

    Science.gov (United States)

    Mahipal, Amit; Malafa, Mokenge

    2016-08-01

    The nuclear transport proteins, importins and exportins (karyopherin-β proteins), may play an important role in cancer by transporting key mediators of oncogenesis across the nuclear membrane in cancer cells. During nucleocytoplasmic transport of tumor suppressor proteins and cell cycle regulators during the processing of these proteins, aberrant cellular growth signaling and inactivation of apoptosis can occur, both critical to growth and development of tumors. Karyopherin-β proteins bind to these cargo proteins and RanGTP for active transport across the nuclear membrane through the nuclear pore complex. Importins and exportins are overexpressed in multiple tumors including melanoma, pancreatic, breast, colon, gastric, prostate, esophageal, lung cancer, and lymphomas. Furthermore, some of the karyopherin-β proteins such as exportin-1 have been implicated in drug resistance in cancer. Importin and exportin inhibitors are being considered as therapeutic targets against cancer and have shown preclinical anticancer activity. Moreover, synergistic activity has been observed with various chemotherapeutic and targeted agents. However, clinical development of the exportin-1 inhibitor leptomycin B was stopped due to adverse events, including vomiting, anorexia, and dehydration. Selinexor, a selective nuclear export inhibitor, is being tested in multiple clinical trials both as a single agent and in combination with chemotherapy. Selinexor has demonstrated clinical activity in multiple cancers, especially acute myelogenous leukemia and multiple myeloma. The roles of other importin and exportin inhibitors still need to be investigated clinically. Targeting the key mediators of nucleocytoplasmic transport in cancer cells represents a novel strategy in cancer intervention with the potential to significantly affect outcomes. PMID:27113410

  1. The Paramyxovirus Polymerase Complex as a Target for Next-Generation Anti-Paramyxovirus Therapeutics

    Directory of Open Access Journals (Sweden)

    Richard K Plemper

    2015-05-01

    Full Text Available The paramyxovirus family includes major human and animal pathogens, including measles virus, mumps virus, and human respiratory syncytial virus (RSV, as well as the emerging zoonotic Hendra and Nipah viruses. In the United States, RSV is the leading cause of infant hospitalizations due to viral infectious disease. Despite their clinical significance, effective drugs for the improved management of paramyxovirus disease are lacking. The development of novel anti-paramyxovirus therapeutics is therefore urgently needed. Paramyxoviruses contain RNA genomes of negative polarity, necessitating a virus-encoded RNA-dependent RNA polymerase (RdRp complex for replication and transcription. Since an equivalent enzymatic activity is absent in host cells, the RdRp complex represents an attractive druggable target, although structure-guided drug development campaigns are hampered by the lack of high-resolution RdRp crystal structures. Here, we review the current structural and functional insight into the paramyxovirus polymerase complex in conjunction with an evaluation of the mechanism of activity and developmental status of available experimental RdRp inhibitors. Our assessment spotlights the importance of the RdRp complex as a premier target for therapeutic intervention and examines how high-resolution insight into the organization of the complex will pave the path towards the structure-guided design and optimization of much-needed next-generation paramyxovirus RdRp blockers.

  2. Matrix metalloproteinases as therapeutic targets for idiopathic pulmonary fibrosis.

    Science.gov (United States)

    Craig, Vanessa J; Zhang, Li; Hagood, James S; Owen, Caroline A

    2015-11-01

    Idiopathic pulmonary fibrosis (IPF) is a restrictive lung disease that is associated with high morbidity and mortality. Current medical therapies are not fully effective at limiting mortality in patients with IPF, and new therapies are urgently needed. Matrix metalloproteinases (MMPs) are proteinases that, together, can degrade all components of the extracellular matrix and numerous nonmatrix proteins. MMPs and their inhibitors, tissue inhibitors of MMPs (TIMPs), have been implicated in the pathogenesis of IPF based upon the results of clinical studies reporting elevated levels of MMPs (including MMP-1, MMP-7, MMP-8, and MMP-9) in IPF blood and/or lung samples. Surprisingly, studies of gene-targeted mice in murine models of pulmonary fibrosis (PF) have demonstrated that most MMPs promote (rather than inhibit) the development of PF and have identified diverse mechanisms involved. These mechanisms include MMPs: (1) promoting epithelial-to-mesenchymal transition (MMP-3 and MMP-7); (2) increasing lung levels or activity of profibrotic mediators or reducing lung levels of antifibrotic mediators (MMP-3, MMP-7, and MMP-8); (3) promoting abnormal epithelial cell migration and other aberrant repair processes (MMP-3 and MMP-9); (4) inducing the switching of lung macrophage phenotypes from M1 to M2 types (MMP-10 and MMP-28); and (5) promoting fibrocyte migration (MMP-8). Two MMPs, MMP-13 and MMP-19, have antifibrotic activities in murine models of PF, and two MMPs, MMP-1 and MMP-10, have the potential to limit fibrotic responses to injury. Herein, we review what is known about the contributions of MMPs and TIMPs to the pathogenesis of IPF and discuss their potential as therapeutic targets for IPF. PMID:26121236

  3. Pyruvate Dehydrogenase Kinase as a Novel Therapeutic Target in Oncology

    Directory of Open Access Journals (Sweden)

    Gopinath eSutendra

    2013-03-01

    Full Text Available Current drug development in oncology is non-selective as it typically focuses on pathways essential for the survival of all dividing cells. The unique metabolic profile of cancer, which is characterized by increased glycolysis and suppressed mitochondrial glucose oxidation provides cancer cells with a proliferative advantage, conducive with apoptosis resistance and even increased angiogenesis. Recent evidence suggests that targeting the cancer-specific metabolic and mitochondrial remodeling may offer selectivity in cancer treatment. Pyruvate dehydrogenase kinase (PDK is a mitochondrial enzyme that is activated in a variety of cancers and results in the selective inhibition of pyruvate dehydrogenase (PDH, a complex of enzymes that converts cytosolic pyruvate to mitochondrial acetyl-CoA, the substrate for the Krebs’ cycle. Inhibition of PDK with either small interfering RNAs or the orphan drug dichloroacetate (DCA shifts the metabolism of cancer cells from glycolysis to glucose oxidation and reverses the suppression of mitochondria-dependent apoptosis. In addition, this therapeutic strategy increases the production of diffusible Krebs’ cycle intermediates and mitochondria-derived reactive oxygen species (mROS, activating p53 or inhibiting pro-proliferative and pro-angiogenic transcription factors like nuclear factor of activated T-cells (NFAT and hypoxia-inducible factor 1α (HIF1α. These effects result in decreased tumor growth and angiogenesis in a variety of cancers with high selectivity. In a small but mechanistic clinical trial in patients with glioblastoma, a highly aggressive and vascular form of brain cancer, DCA decreased tumor angiogenesis and tumor growth, suggesting that metabolic targeting therapies can be translated directly to patients. Therefore, reversing the mitochondrial suppression with metabolic-modulating drugs, like PDK inhibitors holds promise in the rapidly expanding field of metabolic oncology.

  4. Glioblastoma: Molecular Pathways, Stem Cells and Therapeutic Targets

    International Nuclear Information System (INIS)

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

  5. Epigenetic targeting of histone deacetylase: therapeutic potential in Parkinson's disease?

    Science.gov (United States)

    Harrison, Ian F; Dexter, David T

    2013-10-01

    Parkinson's disease (PD) is the most common movement disorder affecting more than 4million people worldwide. The primary motor symptoms of the disease are due to degeneration of dopaminergic nigrostriatal neurons. Dopamine replacement therapies have therefore revolutionised disease management by partially controlling these symptoms. However these drugs can produce debilitating side effects when used long term and do not protect degenerating neurons against death. Recent evidence has highlighted a pathological imbalance in PD between the acetylation and deacetylation of the histone proteins around which deoxyribonucleic acid (DNA) is coiled, in favour of excessive histone deacetylation. This mechanism of adding/removing acetyl groups to histone lysine residues is one of many epigenetic regulatory processes which control the expression of genes, many of which will be essential for neuronal survival. Hence, such epigenetic modifications may have a pathogenic role in PD. It has therefore been hypothesised that if this pathological imbalance can be corrected with the use of histone deacetylase inhibiting agents then neurodegeneration observed in PD can be ameliorated. This article will review the current literature with regard to epigenetic changes in PD and the use of histone deacetylase inhibitors (HDACIs) in PD: examining the evidence of the neuroprotective effects of numerous HDACIs in cellular and animal models of Parkinsonian cell death. Ultimately answering the question: does epigenetic targeting of histone deacetylases hold therapeutic potential in PD? PMID:23711791

  6. [50 years of hepatology - from therapeutic nihilism to targeted therapies].

    Science.gov (United States)

    Manns, Michael P

    2013-04-01

    Over the past 50 years significant progress has been made in the whole field of hepatology. Part of this is translation of basic research (biochemistry, immunology, virology, molecular biology and others) into clinical hepatology. This enabled us to understand more about the pathogenesis of liver diseases and led to the discovery of the five major hepatotropic viruses, the identification of hepatocellular autoantigens, and to the development of specific therapies for chronic hepatitis B, C and D. In addition, the molecular basis of most genetic liver diseases has been identified. Significant progress was made in the development of medical therapies for various liver diseases with different underlying etiologies. Surgery significantly contributed to the progress in the management of liver diseases; examples are laparoscopic cholecystectomy and the development of liver transplantation. A multimodal therapeutic algorithm has been established for the therapy of hepatocelluar carcinoma (HCC); with Sorafenib "targeted therapy" has entered the area of HCC. The progress made over the last 50 years not only led to an aetiological differentiation of acute and chronic liver diseases but also to specific therapies based on the identification and understanding of the underlying etiology. PMID:23585265

  7. SOCS3: A novel therapeutic target for cardioprotection.

    Science.gov (United States)

    Yasukawa, Hideo; Nagata, Takanobu; Oba, Toyoharu; Imaizumi, Tsutomu

    2012-10-01

    The suppressors of cytokine signaling (SOCS) family of proteins are cytokine-inducible inhibitors of Janus kinase (JAK)-signal transducer and activator of the transcription (STAT) signaling pathways. Among the family, SOCS1 and SOCS3 potently suppress cytokine actions by inhibiting JAK kinase activities. The generation of mice lacking individual SOCS genes has been instrumental in defining the role of individual SOCS proteins in specific cytokine pathways in vivo; SOCS1 is an essential negative regulator of interferon-γ (IFNγ) and SOCS3 is an essential negative regulator of leukemia inhibitory factor (LIF). JAK-STAT3 activating cytokines have exhibited cardioprotective roles in the heart. The cardiac-specific deletion of SOCS3 enhances the activation of cardioprotective signaling pathways, inhibits myocardial apoptosis and fibrosis and results in the inhibition of left ventricular remodeling after myocardial infarction (MI). We propose that myocardial SOCS3 is a key determinant of left ventricular remodeling after MI, and SOCS3 may serve as a novel therapeutic target to prevent left ventricular remodeling after MI. In this review, we discuss the signaling pathways mediated by JAK-STAT and SOCS proteins and their roles in the development of myocardial injury under stress (e.g., pressure overload, viral infection and ischemia). PMID:24058778

  8. Purinergic receptors as potential therapeutic targets in Alzheimer's disease.

    Science.gov (United States)

    Woods, Lucas T; Ajit, Deepa; Camden, Jean M; Erb, Laurie; Weisman, Gary A

    2016-05-01

    Alzheimer's disease (AD) is a neurodegenerative disorder characterized by a progressive loss of memory and cognitive ability and is a serious cause of mortality. Many of the pathological characteristics associated with AD are revealed post-mortem, including amyloid-β plaque deposition, neurofibrillary tangles containing hyperphosphorylated tau proteins and neuronal loss in the hippocampus and cortex. Although several genetic mutations and risk factors have been associated with the disease, the causes remain poorly understood. Study of disease-initiating mechanisms and AD progression in humans is inherently difficult as most available tissue specimens are from late-stages of disease. Therefore, AD researchers rely on in vitro studies and the use of AD animal models where neuroinflammation has been shown to be a major characteristic of AD. Purinergic receptors are a diverse family of proteins consisting of P1 adenosine receptors and P2 nucleotide receptors for ATP, UTP and their metabolites. This family of receptors has been shown to regulate a wide range of physiological and pathophysiological processes, including neuroinflammation, and may contribute to the pathogenesis of neurodegenerative diseases like Parkinson's disease, multiple sclerosis and AD. Experimental evidence from human AD tissue has suggested that purinergic receptors may play a role in AD progression and studies using selective purinergic receptor agonists and antagonists in vitro and in AD animal models have demonstrated that purinergic receptors represent novel therapeutic targets for the treatment of AD. This article is part of the Special Issue entitled 'Purines in Neurodegeneration and Neuroregeneration'. PMID:26519903

  9. Pyruvate Dehydrogenase Kinases: Therapeutic Targets for Diabetes and Cancers

    Directory of Open Access Journals (Sweden)

    Nam Ho Jeoung

    2015-06-01

    Full Text Available Impaired glucose homeostasis is one of the risk factors for causing metabolic diseases including obesity, type 2 diabetes, and cancers. In glucose metabolism, pyruvate dehydrogenase complex (PDC mediates a major regulatory step, an irreversible reaction of oxidative decarboxylation of pyruvate to acetyl-CoA. Tight control of PDC is critical because it plays a key role in glucose disposal. PDC activity is tightly regulated using phosphorylation by pyruvate dehydrogenase kinases (PDK1 to 4 and pyruvate dehydrogenase phosphatases (PDP1 and 2. PDKs and PDPs exhibit unique tissue expression patterns, kinetic properties, and sensitivities to regulatory molecules. During the last decades, the up-regulation of PDKs has been observed in the tissues of patients and mammals with metabolic diseases, which suggests that the inhibition of these kinases may have beneficial effects for treating metabolic diseases. This review summarizes the recent advances in the role of specific PDK isoenzymes on the induction of metabolic diseases and describes the effects of PDK inhibition on the prevention of metabolic diseases using pharmacological inhibitors. Based on these reports, PDK isoenzymes are strong therapeutic targets for preventing and treating metabolic diseases.

  10. Glioblastoma: Molecular Pathways, Stem Cells and Therapeutic Targets

    Energy Technology Data Exchange (ETDEWEB)

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

    2015-03-25

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

  11. Obesity, insulin resistance, adipocytokines and breast cancer: New biomarkers and attractive therapeutic targets

    OpenAIRE

    Dalamaga, Maria

    2013-01-01

    Worldwide, breast cancer (BC) represents the most common type of non-skin human malignancy and the second leading cause of cancer-related deaths amid women in Western countries. Obesity and its metabolic complications have rapidly become major global health issues and are associated with increased risk for cancer, especially BC in postmenopausal women. Adipose tissue is considered as a genuine endocrine organ secreting a variety of bioactive adipokines, such as leptin, adiponectin, resistin a...

  12. Novel antibody-based therapeutic agents targeting CD70: a potential approach for treating Waldenström's macroglobulinemia.

    Science.gov (United States)

    Law, Che-Leung; McEarchern, Julie A; Grewal, Iqbal S

    2009-03-01

    Targeting leukocyte differentiation antigens is a validated approach to develop therapeutic agents for the treatment of cancer, autoimmunity, and inflammatory diseases. A subset of activation antigens transiently induced on leukocytes is particularly interesting because many of them are absent from normal tissues, including those of most vital organs, and therapeutic agents' targeting of such antigens is expected to impart limited toxicity. One such antigen, CD70, has recently emerged as an attractive potential drug target for the treatment of cancers. Whereas CD70 is only transiently expressed on activation T and B cells and mature dendritic cells, it is found to be aberrantly expressed on a variety of tumor cells, including Waldenström's macroglobulinemia. In this report, we discuss potential antibody-based therapeutic approaches targeting CD70 for tumor elimination where various mechanisms such as antibody effector functions, immune enhancement, blockade of paracrine growth loop, and delivery of cytotoxic payloads can be exploited to achieve efficacy. Indeed, early clinical trials with therapeutic anti-CD70 antibodies are currently in progress, and those for anti-CD70 drug conjugates will soon follow. PMID:19362984

  13. "Siglec"ting the allergic response for therapeutic targeting.

    Science.gov (United States)

    Bochner, Bruce S

    2016-06-01

    As a physician-scientist, I have pursued research related to translational immunology with the goal of improving our ability to diagnose and treat allergic, immunologic and other diseases involving eosinophils, basophils and mast cells. We have tried to delineate novel mechanisms of human disease, working whenever possible with primary human cells and tissues, attempting to identify targets that might be amenable to the development of new therapies. As a general strategy, we have compared eosinophils, basophils, mast cells and neutrophils to look for pathways in inflammation that were unique to distinct subsets of these cells. In doing so, the concepts of glycobiology did not enter my mind until we began noticing some intriguing functional differences involving selectins and their ligands among these cell types. One simple observation, that neutrophils were coated with a glycan that allowed them to interact with an endothelial adhesion molecule while eosinophils lacked this structure, pried open the glyco-door for me. Fruitful collaborations with card-carrying glycobiologists soon followed that have forever positively influenced our science, and have enhanced our hypotheses, experimental design, research opportunities and discoveries. Within a few years, we helped to discover Siglec-8, an I-type lectin expressed only on human eosinophils, basophils, mast cells. This receptor, together with its closest mouse counterpart Siglec-F, has been the primary focus of our work now for over a decade. If not for those in the fields of glycobiology and glycoimmunology, my lab would not have made much progress toward the goal of leveraging Siglec-8 for therapeutic purposes. PMID:26911285

  14. RhoA: A therapeutic target for chronic myeloid leukemia

    Directory of Open Access Journals (Sweden)

    Molli Poonam R

    2012-03-01

    therapeutic target in CML.

  15. MYC as therapeutic target in leukemia and lymphoma

    Directory of Open Access Journals (Sweden)

    Cortiguera MG

    2015-07-01

    Full Text Available Maria G Cortiguera,1 Ana Batlle-López,1,2 Marta Albajar,1,2 M Dolores Delgado,1,3 Javier León1,3 1Institute of Biomedicine and Biotechnology of Cantabria (IBBTEC, CSIC-University of Cantabria, 2Department of Hemathology, Hospital Universitario Marqués de Valdecilla, 3Department of Molecular Biology, University of Cantabria, Santander, Spain Abstract: MYC is a transcription factor that is involved in the expression of many genes. Deregulated MYC is found in about half of human tumors, being more prevalent in hematological neoplasms. Deregulation mechanisms include chromosomal translocation (particularly in lymphoma, amplification, and hyperactivation of MYC transcription. Here we review MYC involvement in the major types of leukemia and lymphoma. MYC rearrangements appear in all Burkitt lymphomas and are common in other lymphoma types, whereas in acute lymphoblastic leukemia, acute myeloid leukemia, lymphoproliferative, and myeloproferative diseases, they are less frequent. However, MYC overexpression is present in all types of hematological malignancies and often correlates with a worse prognosis. Data in leukemia-derived cells and in animal models of lymphomagenesis and leukemogenesis suggest that MYC would be a good therapeutic target. Several MYC-directed therapies have been assayed in preclinical settings and even in clinical trials. First, peptides and small molecules that interrupt the MYC–MAX interaction impair MYC-mediated tumorogenesis in several mouse models of solid tumors, although not yet in lymphoma and leukemia models. Second, there are a number of small molecules inhibiting the interaction of MYC–MAX heterodimers with DNA, still in the preclinical research phase. Third, inhibitors of MYC expression via the inhibition of BRD4 (a reader of acetylated histones have been shown to control the growth of MYC-transformed leukemia and lymphoma cells and are being used in clinic trials. Finally, we review a number of promising MYC

  16. THE TRPV1 RECEPTOR: TARGET OF TOXICANTS AND THERAPEUTICS

    Science.gov (United States)

    Understanding the structural and functional complexities of the TRPV1 is essential to the therapeutic modulation of inflammation and pain. Because of its central role in initiating inflammatory processes and integrating painful stimuli, there is an understandable interest...

  17. Periostin: a promising target of therapeutical intervention for prostate cancer

    Directory of Open Access Journals (Sweden)

    Ding Weihong

    2011-06-01

    RNA-Periostin LNCap cells growed slowly in vitro and in vivo. The tissues of xenografts as PCa were verificated by HE staining. Additionally, the weak positive Periostin expressed tumor cells could be seen in the tissues of 6 xenografts from the group of down-regulated Periostin LNCap cells which had a significant decrease of the amount of Periostin compared to the other two group. Furthermore, our results demonstrated that sliencing Periostin could inhibit migration of LNCap cells in vitro. Conclusions Our data indicates that Periostin as an up-regulated protein in PCa may be a promising target of therapeutical intervention for PCa in future.

  18. Therapeutic opportunities in Ewing sarcoma: EWS-FLI inhibition via LSD1 targeting.

    Science.gov (United States)

    Theisen, Emily R; Pishas, Kathleen I; Saund, Ranajeet S; Lessnick, Stephen L

    2016-04-01

    Ewing sarcoma is an aggressive primary pediatric bone tumor, often diagnosed in adolescents and young adults. A pathognomonic reciprocal chromosomal translocation results in a fusion gene coding for a protein which derives its N-terminus from a FUS/EWS/TAF15 (FET) protein family member, commonly EWS, and C-terminus containing the DNA-binding domain of an ETS transcription factor, commonly FLI1. Nearly 85% of cases express the EWS-FLI protein which functions as a transcription factor and drives oncogenesis. As the primary genomic lesion and a protein which is not expressed in normal cells, disrupting EWS-FLI function is an attractive therapeutic strategy for Ewing sarcoma. However, transcription factors are notoriously difficult targets for the development of small molecules. Improved understanding of the oncogenic mechanisms employed by EWS-FLI to hijack normal cellular programming has uncovered potential novel approaches to pharmacologically block EWS-FLI function. In this review we examine targeting the chromatin regulatory enzymes recruited to conspire in oncogenesis with a focus on the histone lysine specific demethylase 1 (LSD1). LSD1 inhibitors are being aggressively investigated in acute myeloid leukemia and the results of early clinical trials will help inform the future use of LSD1 inhibitors in sarcoma. High LSD1 expression is observed in Ewing sarcoma patient samples and mechanistic and preclinical data suggest LSD1 inhibition globally disrupts the function of EWS-ETS proteins. PMID:26848860

  19. Targeted Tumor Therapy with "Magnetic Drug Targeting": Therapeutic Efficacy of Ferrofluid Bound Mitoxantrone

    Science.gov (United States)

    Alexiou, Ch.; Schmid, R.; Jurgons, R.; Bergemann, Ch.; Arnold, W.; Parak, F.G.

    The difference between success or failure of chemotherapy depends not only on the drug itself but also on how it is delivered to its target. Biocompatible ferrofluids (FF) are paramagnetic nanoparticles, that may be used as a delivery system for anticancer agents in locoregional tumor therapy, called "magnetic drug targeting". Bound to medical drugs, such magnetic nanoparticles can be enriched in a desired body compartment (tumor) using an external magnetic field, which is focused on the area of the tumor. Through this form of target directed drug application, one attempts to concentrate a pharmacological agent at its site of action in order to minimize unwanted side effects in the organism and to increase its locoregional effectiveness. Tumor bearing rabbits (VX2 squamous cell carcinoma) in the area of the hind limb, were treated by a single intra-arterial injection (A. femoralis) of mitoxantrone bound ferrofluids (FF-MTX), while focusing an external magnetic field (1.7 Tesla) onto the tumor for 60 minutes. Complete tumor remissions could be achieved in these animals in a dose related manner (20% and 50% of the systemic dose of mitoxantrone), without any negative side effects, like e.g. leucocytopenia, alopecia or gastrointestinal disorders. The strong and specific therapeutic efficacy in tumor treatment with mitoxantrone bound ferrofluids may indicate that this system could be used as a delivery system for anticancer agents, like radionuclids, cancer-specific antibodies, anti-angiogenetic factors, genes etc.

  20. The effect of target's physical attractiveness and dominance on STD-risk perceptions

    NARCIS (Netherlands)

    Dijkstra, P; Buunk, BP; Blanton, H

    2000-01-01

    Utilizing a 2 x 2 design, the present study examined the effect of a female's physical attractiveness and dominance on men's sexual motivation and sexually transmitted disease (STD) risk perceptions in a sample of 72 heterosexual male college students. As predicted, participants a ere more motivated

  1. Prioritization of Eco-tourism Attractions (The target villages of Charmahal O Bakhtiar province

    Directory of Open Access Journals (Sweden)

    D. Rahimi

    2012-01-01

    Full Text Available Extended abstract1-IntroductionIn today’s world tourism is one of the essential revenue generating industries that serves as a means for cultural exchange among nation as well. Rural-tourism is a branch of tourism that is limited to the rural environment with respect to the culture and traditional customs that include their hand-craft, behavior, hospitality, green-tours, farm-tours, hunting, their cooking manners etc. Any country that intends to attract tourists in this field should be equipped with the following two characteristics: the potential that is the natural resources and the ability to provide services and facilities for rural-tourism that is the accommodation.2- Theoretical basesThis idea was first established during the 19th century in the western civilization when due to industrialization and urban-dwelling, transportation and welfare; people had more leisure time to visit rural areas in vast numbers.In the 20 year forecast program of development in the realm of tourism a national approach is adopted to promote the deprived regions’ potentials through manipulation of their natural/rural capacities and abilities. In order to finance the fundamental aspects of such programs, the authorities would face numerous problems.One of the measures that could overcome these problems to a certain degree is to prioritize the villages in a province based on their potentials then categorizes them as the village-tourism centers. For this purpose, an attempt is made to prioritize the potential villages by applying AHP, which is to validate them for investment, which will include all that is needed for Village Tourism. This issue has been of concern in different countries where putting the available natural resources at the National Tourist Industry’s services would be beneficial.- The study zoneCharmahal o Bakhtiar is a province with an area of 16,532 Km2. The geographic and demographic features of this province are presented in Table 1: RowTarget

  2. Cannabidiol in Humans—The Quest for Therapeutic Targets

    OpenAIRE

    Stéphane Potvin; Simon Zhornitsky

    2012-01-01

    Cannabidiol (CBD), a major phytocannabinoid constituent of cannabis, is attracting growing attention in medicine for its anxiolytic, antipsychotic, antiemetic and anti-inflammatory properties. However, up to this point, a comprehensive literature review of the effects of CBD in humans is lacking. The aim of the present systematic review is to examine the randomized and crossover studies that administered CBD to healthy controls and to clinical patients. A systematic search was performed in th...

  3. Targeting PARP-1 allosteric regulation offers therapeutic potential against cancer

    OpenAIRE

    Steffen, Jamin D.; Tholey, Renee M.; Langelier, Marie-France; Planck, Jamie L.; Schiewer, Matthew J.; Lal, Shruti; Bildzukewicz, Nikolai A.; Yeo, Charles J.; Knudsen, Karen E.; Brody, Jonathan R; Pascal, John M.

    2013-01-01

    PARP-1 is a nuclear protein that has important roles in maintenance of genomic integrity. During genotoxic stress, PARP-1 recruits to sites of DNA damage where PARP-1 domain architecture initiates catalytic activation and subsequent poly(ADP-ribose)-dependent DNA repair. PARP-1 inhibition is a promising new way to selectively target cancers harboring DNA repair deficiencies. However, current inhibitors target other PARPs raising important questions concerning long-term off-target effects. Her...

  4. Galectins as therapeutic targets for hematological malignancies: a hopeful sweetness.

    Science.gov (United States)

    Pena, Camilo; Mirandola, Leonardo; Figueroa, Jose A; Hosiriluck, Nattamol; Suvorava, Natallia; Trotter, Kayley; Reidy, Adair; Rakhshanda, Rahman; Payne, Drew; Jenkins, Marjorie; Grizzi, Fabio; Littlefield, Lauren; Chiriva-Internati, Maurizio; Cobos, Everardo

    2014-09-01

    Galectins are family of galactose-binding proteins known to play critical roles in inflammation and neoplastic progression. Galectins facilitate the growth and survival of neoplastic cells by regulating their cross-talk with the extracellular microenvironment and hampering anti-neoplastic immunity. Here, we review the role of galectins in the biology of hematological malignancies and their promise as potential therapeutic agents in these diseases. PMID:25405162

  5. Antioxidants Meet Molecular Targets for Cancer Prevention and Therapeutics

    OpenAIRE

    Ahmad, Nihal; Mukhtar, Hasan

    2013-01-01

    A fine balance between oxidants and antioxidants is required for the normal functioning of living systems. A deregulation of this balance has been implicated in many adverse effects and diseases, including cancer. Extensive research has been done in the area of cancer prevention and therapeutics by a wide range of antioxidants, especially naturally occurring and diet-based agents. However, additional efforts are still needed toward clinical development of the most promising antioxidant agents...

  6. Cell migration in paediatric glioma; characterisation and potential therapeutic targeting

    OpenAIRE

    Cockle, J V; Picton, S; Levesley, J.; Ilett, E; Carcaboso, A M; Short, S.(Queen Mary University of London, School of Physics and Astronomy, London, United Kingdom); Steel, L P; Melcher, A.; Lawler, S. E.; Brüning-Richardson, A

    2015-01-01

    Background: Paediatric high grade glioma (pHGG) and diffuse intrinsic pontine glioma (DIPG) are highly aggressive brain tumours. Their invasive phenotype contributes to their limited therapeutic response, and novel treatments that block brain tumour invasion are needed. Methods: Here, we examine the migratory characteristics and treatment effect of small molecule glycogen synthase kinase-3 inhibitors, lithium chloride (LiCl) and the indirubin derivative 6-bromoindirubin-oxime (BIO), previousl...

  7. Reverse cholesterol transport: a potential therapeutic target for atherosclerosis

    OpenAIRE

    Ying ZHAO

    2011-01-01

    Atherosclerosis is the major cause of death in the Western society due to the development of acute clinical events such as myocardial infarction and cerebral stroke. Currently, lowering plasma LDL cholesterol (LDL-C) levels using statins, inhibitors of de-novo cholesterol synthesis, is the main therapeutic strategy to prevent the progression of atherosclerosis. The remaining high incidence of cardiovascular disease indicates a clear need for new therapies. Numerous epidemiological studies hav...

  8. MicroRNA as therapeutic targets for treatment of depression

    OpenAIRE

    Hansen KF; Obrietan K

    2013-01-01

    Katelin F Hansen, Karl Obrietan Department of Neuroscience, Ohio State University, Columbus, OH, USA Abstract: Depression is a potentially life-threatening mental disorder affecting approximately 300 million people worldwide. Despite much effort, the molecular underpinnings of clinical depression remain poorly defined, and current treatments carry limited therapeutic efficacy and potentially burdensome side effects. Recently, small noncoding RNA molecules known as microRNA (miRNA) have gaine...

  9. Molecular markers as therapeutic targets in lung cancer

    OpenAIRE

    Hsin-Hui Tseng; Biao He

    2013-01-01

    Lung cancer is responsible for 29% of cancer deaths in the United States and has very low 5-year survival rates of approximately 11% in men and 15% in women. Although the early diagnosis of lung cancer may increase the survival rate with adequate treatment, advanced lung cancers are often metastasized and receive limited benefit from therapeutic regimens. As conventional treatments for lung cancer reach their limitations, researchers have attempted to discover novel drug therapies aimed at sp...

  10. ROCK as a Therapeutic Target of Diabetic Retinopathy

    OpenAIRE

    Tatsuro Ishibashi; Yasuaki Hata; Ryoichi Arita

    2010-01-01

    The increasing global prevalence of diabetes is a critical problem for public health. In particular, diabetic retinopathy, a prevalent ocular complication of diabetes mellitus, causes severe vision loss in working population. A better understanding of the pathogenesis and the development of new pharmacologic treatments are needed. This paper describes the relevance between Rho/ROCK pathway and the pathogenesis of diabetic retinopathy from its early to late stages. Moreover, the therapeutic po...

  11. Attractive target wave patterns in complex networks consisting of excitable nodes

    International Nuclear Information System (INIS)

    This review describes the investigations of oscillatory complex networks consisting of excitable nodes, focusing on the target wave patterns or say the target wave attractors. A method of dominant phase advanced driving (DPAD) is introduced to reveal the dynamic structures in the networks supporting oscillations, such as the oscillation sources and the main excitation propagation paths from the sources to the whole networks. The target center nodes and their drivers are regarded as the key nodes which can completely determine the corresponding target wave patterns. Therefore, the center (say node A) and its driver (say node B) of a target wave can be used as a label, (A,B), of the given target pattern. The label can give a clue to conveniently retrieve, suppress, and control the target waves. Statistical investigations, both theoretically from the label analysis and numerically from direct simulations of network dynamics, show that there exist huge numbers of target wave attractors in excitable complex networks if the system size is large, and all these attractors can be labeled and easily controlled based on the information given by the labels. The possible applications of the physical ideas and the mathematical methods about multiplicity and labelability of attractors to memory problems of neural networks are briefly discussed. (topical review - statistical physics and complex systems)

  12. Assessing the therapeutic efficacy of VEGFR-1-targeted polymer drug conjugates in mouse tumor models.

    Science.gov (United States)

    Shamay, Yosi; Golan, Moran; Tyomkin, Dalia; David, Ayelet

    2016-05-10

    Polymer-drug conjugates that can actively target the tumor vasculature have emerged as an attractive technology for improving the therapeutic efficacy of cytotoxic drugs. We have recently provided, for the first time, in vivo evidence showing the significant advantage of the E-selectin-targeted N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer-doxorubicin conjugate, P-(Esbp)-DOX, in inhibiting primary tumor growth and preventing the formation and development of cancer metastases. Here, we describe the design of a vascular endothelial growth factor receptor (VEGFR)-1-targeted HPMA copolymer-DOX conjugate (P-(F56)-DOX) that can actively and simultaneously target different cell types in the tumor microenvironment, such as endothelial cells (ECs), bone marrow-derived cells and many human cancer cells of diverse tumor origin. The VEGFR-1-targeted copolymer was tested for its binding, internalization and in vitro cytotoxicity in ECs (bEnd.3 and cEND cells) and cancer cells (B16-F10, 3LL and HT29). The in vivo anti-cancer activity of P-(F56)-DOX was then tested in two tumor-bearing mice (TBM) models (i.e., primary Lewis lung carcinoma (3LL) tumors and B16-F10 melanoma pulmonary metastases), relative to that of the E-selectin-targeted system (P-(Esbp)-DOX) that solely targets ECs. Our results indicate that the binding and internalization profiles of the VEGFR-1-targeted copolymer were superior towards ECs as compared to cancer cells and correlated well to the level of VEGFR-1 expression in cells. Accordingly, the VEGFR-1-targeted copolymer (P-(F56)-DOX) was more toxic towards bEnd.3 cells than to cancer cells, and exhibited significantly higher cytotoxicity than did the non-targeted control copolymer. P-(F56)-DOX inhibited 3LL tumor growth and significantly prolonged the survival of mice with B16-F10 pulmonary metastases. When compared to a system that actively targets only tumor vascular ECs, P-(F56)-DOX and P-(Esbp)-DOX exhibited comparable efficacy in slowing the

  13. Non-Coding RNAs as Therapeutic Targets in Hepatocellular Cancer

    OpenAIRE

    Braconi, Chiara; Patel, Tushar

    2012-01-01

    Hepatocellular carcinoma (HCC) is a common malignancy that affects a large number of patients worldwide, with an increasing incidence in the United States and Europe. The therapies that are currently available for patients with inoperable HCC have limited benefits. Although molecular targeted therapies against selected cell signaling pathways have shown some promising results, their impact has been minimal. There is a need to identify and explore other targets for the development of novel the...

  14. ABCC4/MRP4: a MYCN-regulated transporter and potential therapeutic target in neuroblastoma.

    Directory of Open Access Journals (Sweden)

    Tony eHuynh

    2012-12-01

    Full Text Available Resistance to cytotoxic drugs is thought to be a major cause of treatment failure in childhood neuroblastoma, and members of the ATP-binding cassette (ABC transporter superfamily may contribute to this phenomenon by active efflux of chemotherapeutic agents from cancer cells. As a member of the C subfamily of ABC transporters, multidrug resistance-associated protein MRP4/ABCC4 has the ability to export a variety of endogenous and exogenous substances across the plasma membrane. In light of its capacity for chemotherapeutic drug efflux, MRP4 has been studied in the context of drug resistance in a number of cancer cell types. However, MRP4 also influences cancer cell biology independently of chemotherapeutic drug exposure, which highlights the potential importance of endogenous MRP4 substrates in cancer biology. Furthermore, MRP4 is a direct transcriptional target of Myc family oncoproteins and expression of this transporter is a powerful independent predictor of clinical outcome in neuroblastoma. Together these features suggest that inhibition of MRP4 may be an attractive therapeutic approach for neuroblastoma and other cancers that rely on MRP4. In this respect, existing options for MRP4 inhibition are relatively non-selective and thus development of more specific anti-MRP4 compounds should be a major focus of future work in this area.

  15. Prioritization of Eco-tourism Attractions (The target villages of Charmahal O Bakhtiar province)

    OpenAIRE

    D. Rahimi; M. Ranjbar Dashtestani

    2012-01-01

    Extended abstract1-IntroductionIn today’s world tourism is one of the essential revenue generating industries that serves as a means for cultural exchange among nation as well. Rural-tourism is a branch of tourism that is limited to the rural environment with respect to the culture and traditional customs that include their hand-craft, behavior, hospitality, green-tours, farm-tours, hunting, their cooking manners etc. Any country that intends to attract tourists in this field should be equipp...

  16. Targeting histone deacetylases: A novel therapeutic strategy for atrial fibrillation.

    Science.gov (United States)

    Lkhagva, Baigalmaa; Kao, Yu-Hsun; Chen, Yao-Chang; Chao, Tze-Fan; Chen, Shih-Ann; Chen, Yi-Jen

    2016-06-15

    Atrial fibrillation (AF) is a common cardiac arrhythmia associated with high mortality and morbidity. Current treatments of AF have limited efficacy and considerable side effects. Histone deacetylases (HDACs) play critical roles in the pathophysiology of cardiovascular diseases and contribute to the genesis of AF. Therefore, HDAC inhibition may prove a novel therapeutic strategy for AF through upstream therapy and modifications of AF electrical and structural remodeling. In this review, we provide an update of the knowledge of the effects of HDACs and HDAC inhibitors on AF, and dissect potential underlying mechanisms. PMID:27089819

  17. Gene therapy of cancer and development of therapeutic target gene

    International Nuclear Information System (INIS)

    We applied HSV-tk/GCV strategy to orthotopic rat hepatoma model and showed anticancer effects of hepatoma. The increased expression of Lac Z gene after adenovirus-mediated gene delivery throughout hepatic artery was thought that is increased the possibility of gene therapy for curing hepatoma. With the construction of kGLP-laboratory, it is possible to produce a good quantity and quality of adenovirus in lage-scale production and purification of adenovirus vector. Also, the analysis of hepatoma related genes by PCR-LOH could be used for the diagnosis of patients and the development of therapeutic gene

  18. Tumor angiogenesis--a new therapeutic target in gliomas

    DEFF Research Database (Denmark)

    Lund, E L; Spang-Thomsen, M; Skovgaard-Poulsen, H; Kristjansen, P E

    1998-01-01

    Tumor growth is critically dependent on angiogenesis, which is sprouting of new vessels from pre-existing vasculature. This process is regulated by inducers and inhibitors released from tumor cells, endothelial cells, and macrophages. Brain tumors, especially glioblastoma multiforme, have...... significant angiogenic activity primarily by the expression of the angiogenic factor VEGF Anti-angiogenic therapy represents a new promising therapeutic modality in solid tumors. Several agents are currently under evaluation in clinical trials. The present review describes the principal inducers and...... inhibitors of angiogenesis in tumors and summarizes what is known about their mechanisms of action in relation to CNS tumors. Potential areas for clinical use are also discussed....

  19. Is tau a suitable therapeutical target in tauopathies?

    Institute of Scientific and Technical Information of China (English)

    Elena; Gomez; de; Barreda; Jesús; Avila

    2010-01-01

    Tau is an intracellular protein,found mainly in neurons,but it can also be found in the extracellular space in pathological situations.Here we discuss whether intracellular tau,in aggregated form or modified by phosphorylation,could be toxic inside a neuron.On the other hand,it has been proposed that extracellular tau could be toxic.In this review,we address the question if the elimination of tau would be a possible therapeutic method to avoid tauopathy disorder and we suggest ways to eliminate intracellular and extracellular tau as treatment.

  20. The Natural Flavonoid Pinocembrin: Molecular Targets and Potential Therapeutic Applications.

    Science.gov (United States)

    Lan, Xi; Wang, Wenzhu; Li, Qiang; Wang, Jian

    2016-04-01

    Pinocembrin is a natural flavonoid compound extracted from honey, propolis, ginger roots, wild marjoram, and other plants. In preclinical studies, it has shown anti-inflammatory and neuroprotective effects as well as the ability to reduce reactive oxygen species, protect the blood-brain barrier, modulate mitochondrial function, and regulate apoptosis. Considering these pharmaceutical characteristics, pinocembrin has potential as a drug to treat ischemic stroke and other clinical conditions. In this review, we summarize its pharmacologic characteristics and discuss its mechanisms of action and potential therapeutic applications. PMID:25744566

  1. Gene therapy of cancer and development of therapeutic target gene

    Energy Technology Data Exchange (ETDEWEB)

    Kim, Chang Min; Kwon, Hee Chung

    1998-04-01

    We applied HSV-tk/GCV strategy to orthotopic rat hepatoma model and showed anticancer effects of hepatoma. The increased expression of Lac Z gene after adenovirus-mediated gene delivery throughout hepatic artery was thought that is increased the possibility of gene therapy for curing hepatoma. With the construction of kGLP-laboratory, it is possible to produce a good quantity and quality of adenovirus in lage-scale production and purification of adenovirus vector. Also, the analysis of hepatoma related genes by PCR-LOH could be used for the diagnosis of patients and the development of therapeutic gene.

  2. Development of new estrogen receptor-targeting therapeutic agents for tamoxifen-resistant breast cancer

    OpenAIRE

    Jiang, Quan; Zheng, Shilong; Wang, Guangdi

    2013-01-01

    Despite our deepening understanding of the mechanisms of resistance and intensive efforts to develop therapeutic solutions to combat resistance, de novo and acquired tamoxifen resistance remains a clinical challenge, and few effective regimens exist to treat tamoxifen-resistant breast cancer. The complexity of tamoxifen resistance calls for diverse therapeutic approaches. This review presents several therapeutic strategies and lead compounds targeting the estrogen receptor signaling pathways ...

  3. Emerging therapeutic targets and strategies in Crohn's disease.

    Science.gov (United States)

    Furfaro, Federica; Fiorino, Gionata; Allocca, Mariangela; Gilardi, Daniela; Danese, Silvio

    2016-06-01

    Crohn's disease (CD) is an immune-mediated inflammatory bowel disease, in which inflammation is driven by a complex interaction between the microbiota, immune cells, genes and mediators. New mechanisms of action and several cytokines have been identified as factors involved in the inflammatory process in CD, and many new molecules have been developed to treat this complex disease. New agents have been developed that target leukocyte trafficking, block or adhesion molecules for example, as well as the development of antibodies against classic inflammatory cytokines or therapies directed against IL-12/23 and Janus kinases. The development of selective mechanisms of action and targeting of different cytokines or inflammatory mediators for each patient presents the biggest challenge for the future in CD therapy. Such agents are currently at different phases of development. We aim to review the current literature data on a targeted approach in CD, which could be promising alternative approach for CD patients in the near future. PMID:26766496

  4. Therapeutic approaches targeting intestinal microflora in inflammatory bowel disease

    Institute of Scientific and Technical Information of China (English)

    Akira Andoh; Yoshihide Fujiyama

    2006-01-01

    Inflammatory bowel diseases, ulcerative colitis, and Crohn's disease, are chronic intestinal disorders of unknown etiology in which in genetically susceptible individuals, the mucosal immune system shows an aberrant response towards commensal bacteria.The gastrointestinal tract has developed ingenious mechanisms to coexist with its autologous microflora,but rapidly responds to invading pathogens and then returns to homeostasis with its commensal bacteria after the pathogenic infection is cleared. In case of disruption of this tightly-regulated homeostasis, chronic intestinal inflammation may be induced. Previous studies showed that some commensal bacteria are detrimental while others have either no influence or have a protective action. In addition, each host has a genetically determined response to detrimental and protective bacterial species. These suggest that therapeutic manipulation of imbalance of microflora can influence health and disease. This review focuses on new insights into the role of commensal bacteria in gut health and disease, and presents recent findings in innate and adaptive immune interactions. Therapeutic approaches to modulate balance of intestinal microflora and their potential mechanisms of action are also discussed.

  5. Bone biology, signaling pathways, and therapeutic targets for osteoporosis.

    Science.gov (United States)

    Iñiguez-Ariza, Nicole M; Clarke, Bart L

    2015-10-01

    Major advances have occurred recently in the treatment of osteoporosis in recent years. Most patients are currently treated with bisphosphonates, denosumab, raloxifene, or teriparatide, and in some countries, strontium ranelate. Strontium ranelate and calcitonin have recently had their use restricted due to cardiovascular concerns and malignancy, respectively. The available agents have generally provided excellent options that effectively reduce fracture risk. New targets are being sought based on appreciation of the bone biology and signaling pathways involved in bone formation and resorption. These agents will directly target these signaling pathways, and further expand the options available for treatment of osteoporosis. PMID:26255682

  6. 1st Joint European Conference on Therapeutic Targets and Medicinal Chemistry (TTMC 2015).

    Science.gov (United States)

    Le Borgne, Marc; Haidar, Samer; Duval, Olivier; Wünsch, Bernhard; Jose, Joachim

    2015-01-01

    The European Conference on Therapeutic Targets and Medicinal Chemistry is a new two-day meeting on drug discovery that is focused on therapeutic targets and the use of tools to explore all fields of drug discovery and drug design such as molecular modelling, bioorganic chemistry, NMR studies, fragment screening, in vitro assays, in vivo assays, structure activity relationships, autodisplay. Abstracts of keynote lectures, plenary lectures, junior lectures, flash presentations, and posters presented during the meeting are collected in this report. PMID:26712767

  7. Identification of attractive drug targets in neglected-disease pathogens using an in silico approach.

    Directory of Open Access Journals (Sweden)

    Gregory J Crowther

    Full Text Available BACKGROUND: The increased sequencing of pathogen genomes and the subsequent availability of genome-scale functional datasets are expected to guide the experimental work necessary for target-based drug discovery. However, a major bottleneck in this has been the difficulty of capturing and integrating relevant information in an easily accessible format for identifying and prioritizing potential targets. The open-access resource TDRtargets.org facilitates drug target prioritization for major tropical disease pathogens such as the mycobacteria Mycobacterium leprae and Mycobacterium tuberculosis; the kinetoplastid protozoans Leishmania major, Trypanosoma brucei, and Trypanosoma cruzi; the apicomplexan protozoans Plasmodium falciparum, Plasmodium vivax, and Toxoplasma gondii; and the helminths Brugia malayi and Schistosoma mansoni. METHODOLOGY/PRINCIPAL FINDINGS: Here we present strategies to prioritize pathogen proteins based on whether their properties meet criteria considered desirable in a drug target. These criteria are based upon both sequence-derived information (e.g., molecular mass and functional data on expression, essentiality, phenotypes, metabolic pathways, assayability, and druggability. This approach also highlights the fact that data for many relevant criteria are lacking in less-studied pathogens (e.g., helminths, and we demonstrate how this can be partially overcome by mapping data from homologous genes in well-studied organisms. We also show how individual users can easily upload external datasets and integrate them with existing data in TDRtargets.org to generate highly customized ranked lists of potential targets. CONCLUSIONS/SIGNIFICANCE: Using the datasets and the tools available in TDRtargets.org, we have generated illustrative lists of potential drug targets in seven tropical disease pathogens. While these lists are broadly consistent with the research community's current interest in certain specific proteins, and suggest

  8. Therapeutic strategies targeting B-cells in multiple sclerosis.

    Science.gov (United States)

    Milo, Ron

    2016-07-01

    Multiple sclerosis (MS) is a chronic inflammatory and demyelinating disease of the central nervous system (CNS) that traditionally has been considered to be mediated primarily by T-cells. Increasing evidence, however, suggests the fundamental role of B-cells in the pathogenesis of the disease. Recent strategies targeting B-cells in MS have demonstrated impressive and sometimes surprising results: B-cell depletion by monoclonal antibodies targeting the B-cell surface antigen CD20 (e.g. rituximab, ocrelizumab, ofatumumab) was shown to exert profound anti-inflammatory effect in MS with favorable risk-benefit ratio, with ocrelizumab demonstrating efficacy in both relapsing-remitting (RR) and primary-progressive (PP) MS in phase III clinical trials. Depletion of CD52 expressing T- and B-cells and monocytes by alemtuzumab resulted in impressive and durable suppression of disease activity in RRMS patients. On the other hand, strategies targeting B-cell cytokines such as atacicept resulted in increased disease activity. As our understanding of the biology of B-cells in MS is increasing, new compounds that target B-cells continue to be developed which promise to further expand the armamentarium of MS therapies and allow for more individualized therapy for patients with this complex disease. PMID:26970489

  9. Novel drugs that target the estrogen-related receptor alpha: their therapeutic potential in breast cancer

    International Nuclear Information System (INIS)

    The incidence of breast cancer continues to rise: 1.7 million women were diagnosed with and 521,000 women died from breast cancer in 2012. This review considers first current treatment options: surgery; radiotherapy; and systemic endocrine, anti-biological, and cytotoxic therapies. Clinical management includes prevention, early detection by screening, treatment with curative intent, management of chronic disease, and palliative control of advanced breast cancer. Next, the potential of novel drugs that target DNA repair, growth factor dependence, intracellular and intercellular signal transduction, and cell cycle are considered. Estrogen-related receptor alpha has attracted attention as a therapeutic target in triple-negative breast cancers with de novo resistance to, and in breast cancers with acquired resistance to, endocrine therapies such as antiestrogens and aromatase inhibitors. Estrogen-related receptor alpha is an orphan receptor and transcription factor. Its activity is regulated by coregulator proteins and posttranslational modification. It is an energy sensor that controls adaptation to energy demand and may facilitate glycolytic metabolism and mitochondrial oxidative respiration in breast cancer cells. Estrogen-related receptor alpha increases breast cancer cell migration, proliferation, and tumor development. It is expressed at high levels in estrogen receptor-negative tumors, and is proposed to activate estrogen-responsive genes in endocrine-resistant tumors. The structures and functions of the ligand-binding domains of estrogen receptor alpha and estrogen-related receptor alpha, their ability to bind estrogens, phytoestrogens, and synthetic ligands, and the effects of ligand agonists, antagonists, and inverse agonists on biological activity, are evaluated. Synthetic ligands of estrogen-related receptor alpha have activity in preclinical models of metabolic disorders, diabetes, osteoporosis, and oncology. The clinical settings in which these novel

  10. Overview of Nrf2 as Therapeutic Target in Epilepsy

    Directory of Open Access Journals (Sweden)

    Liliana Carmona-Aparicio

    2015-08-01

    Full Text Available Oxidative stress is a biochemical state of imbalance in the production of reactive oxygen and nitrogen species and antioxidant defenses. It is involved in the physiopathology of degenerative and chronic neuronal disorders, such as epilepsy. Experimental evidence in humans and animals support the involvement of oxidative stress before and after seizures. In the past few years, research has increasingly focused on the molecular pathways of this process, such as that involving transcription factor nuclear factor E2-related factor 2 (Nrf2, which plays a central role in the regulation of antioxidant response elements (ARE and modulates cellular redox status. The aim of this review is to present experimental evidence on the role of Nrf2 in this neurological disorder and to further determine the therapeutic impact of Nrf2 in epilepsy.

  11. Targeting the Fanconi Anemia Pathway to Identify Tailored Anticancer Therapeutics

    Directory of Open Access Journals (Sweden)

    Chelsea Jenkins

    2012-01-01

    Full Text Available The Fanconi Anemia (FA pathway consists of proteins involved in repairing DNA damage, including interstrand cross-links (ICLs. The pathway contains an upstream multiprotein core complex that mediates the monoubiquitylation of the FANCD2 and FANCI heterodimer, and a downstream pathway that converges with a larger network of proteins with roles in homologous recombination and other DNA repair pathways. Selective killing of cancer cells with an intact FA pathway but deficient in certain other DNA repair pathways is an emerging approach to tailored cancer therapy. Inhibiting the FA pathway becomes selectively lethal when certain repair genes are defective, such as the checkpoint kinase ATM. Inhibiting the FA pathway in ATM deficient cells can be achieved with small molecule inhibitors, suggesting that new cancer therapeutics could be developed by identifying FA pathway inhibitors to treat cancers that contain defects that are synthetic lethal with FA.

  12. Targeting Notch degradation system provides promise for breast cancer therapeutics.

    Science.gov (United States)

    Liu, Jing; Shen, Jia-Xin; Wen, Xiao-Fen; Guo, Yu-Xian; Zhang, Guo-Jun

    2016-08-01

    Notch receptor signaling pathways play an important role, not only in normal breast development but also in breast cancer development and progression. As a group of ligand-induced proteins, different subtypes of mammalian Notch (Notch1-4) are sensitive to subtle changes in protein levels. Thus, a clear understanding of mechanisms of Notch protein turnover is essential for understanding normal and pathological mechanisms of Notch functions. It has been suggested that there is a close relationship between the carcinogenesis and the dysregulation of Notch degradation. However, this relationship remains mostly undefined in the context of breast cancer, as protein degradation is mediated by numerous signaling pathways as well as certain molecule modulators (activators/inhibitors). In this review, we summarize the published data regarding the regulation of Notch family member degradation in breast cancer, while emphasizing areas that are likely to provide new therapeutic modalities for mechanism-based anti-cancer drugs. PMID:27263934

  13. Mesenchymal Migration as a Therapeutic Target in Glioblastoma

    Directory of Open Access Journals (Sweden)

    Jessie Zhong

    2010-01-01

    Full Text Available Extensive infiltration of the surrounding healthy brain tissue is a cardinal feature of glioblastomas, highly lethal brain tumors. Deep infiltration by the glioblastoma cells renders complete surgical excision difficult and contemporary adjuvant therapies have had little impact on long-term survival. Thus, deep infiltration and resistance to irradiation and chemotherapy remain a major cause of patient mortality. Modern therapies specifically targeted to this unique aspect of glioblastoma cell biology hold significant promise to substantially improve survival rates for glioblastoma patients. In the present paper, we focus on the role of adhesion signaling molecules and the actin cytoskeleton in the mesenchymal mode of motility that characterizes invading glioblastoma cells. We then review current approaches to targeting these elements of the glioblastoma cell migration machinery and discuss other aspects of cell migration that may improve the treatment of infiltrating glioblastoma.

  14. Nucleic Acid Aptamers for Target Validation and Therapeutic Applications

    OpenAIRE

    Pendergrast, P. Shannon; Marsh, H Nicholas; Grate, Dilara; Healy, Judith M.; Stanton, Martin

    2005-01-01

    In the simplest view, aptamers can be thought of as nucleic acid analogs to antibodies. They are able to bind specifically to proteins, and, in many cases, that binding leads to a modulation of protein activity. New aptamers are rapidly generated through the SELEX (Systematic Evolution of Ligands by Exponential enrichment) process and have a very high target affinity and specificity (picomoles to nanomoles). Furthermore, aptamers composed of modified nucleotides have a long in vivo half-life ...

  15. Novel HIV-1 Therapeutics through Targeting Altered Host Cell Pathways

    OpenAIRE

    Coley, William; Kehn-Hall, Kylene; Van Duyne, Rachel; KASHANCHI, FATAH

    2009-01-01

    The emergence of drug-resistant human immunodeficiency virus type I (HIV-1) strains presents a challenge for the design of new drugs. Anti-HIV compounds currently in use are the subject of advanced clinical trials using either HIV-1 reverse-transcriptase, viral protease, or integrase inhibitors. Recent studies show an increase in the number of HIV-1 variants resistant to anti-retroviral agents in newly infected individuals. Targeting host cell factors involved in the regulation of HIV-1 repli...

  16. MicroRNAs as potential therapeutic targets in kidney disease

    OpenAIRE

    Gomez, Ivan G.; Grafals, Monica; Portilla, Didier; Duffield, Jeremy S.

    2013-01-01

    One cornerstone of Chronic Kidney Disease (CKD) is fibrosis, as kidneys are susceptible due to their high vascularity and predisposition to ischemia. Presently, only therapies targeting the angiotensin receptor are used in clinical practice to retard the progression of CKD. Thus, there is a pressing need for new therapies designed to treat the damaged kidney. Several independent laboratories have identified a number of microRNAs that are dysregulated in human and animal models of CKD. We will...

  17. Contemporary Therapeutic Approaches Targeting Bone Complications in Prostate Cancer

    OpenAIRE

    Lee, Richard J.; Saylor, Philip J.; Smith, Matthew R.

    2010-01-01

    Skeletal complications are major causes of morbidity in patients with prostate cancer. Despite the osteoblastic appearance of prostate cancer bone metastases, elevated serum and urinary markers of bone resorption are indicative of high osteoclast activity. Increased osteoclast activity is independently associated with subsequent skeletal complications, disease progression, and death. Osteoclast-targeted therapies aim to reduce the risk for disease-related skeletal complications, bone metastas...

  18. Plasmacytoid Dendritic Cells in the Tumor Microenvironment: Immune Targets for Glioma Therapeutics

    Directory of Open Access Journals (Sweden)

    Marianela Candolfi

    2012-08-01

    Full Text Available Adenovirus-mediated delivery of the immune-stimulatory cytokine Flt3L and the conditionally cytotoxic thymidine kinase (TK induces tumor regression and long-term survival in preclinical glioma (glioblastoma multiforme [GBM] models. Flt3L induces expansion and recruitment of plasmacytoid dendritic cells (pDCs into the brain. Although pDCs can present antigen and produce powerful inflammatory cytokines, that is, interferon α (IFN-α, their role in tumor immunology remains debated. Thus, we studied the role of pDCs and IFN-α in Ad.TK/GCV+ Ad.Flt3L-mediated anti-GBM therapeutic efficacy. Our data indicate that the combined gene therapy induced recruitment of plasmacytoid DCs (pDCs into the tumor mass; which were capable of in vivo phagocytosis, IFN-α release, and T-cell priming. Thus, we next used either pDCs or an Ad vector encoding IFN-α delivered within the tumor microenvironment. When rats were treated with Ad.TK/GCV in combination with pDCs or Ad-IFN-α, they exhibited 35% and 50% survival, respectively. However, whereas intracranial administration of Ad.TK/GCV + Ad.Flt3L exhibited a high safety profile, Ad-IFN-α led to severe local inflammation, with neurologic and systemic adverse effects. To elucidate whether the efficacy of the immunotherapy was dependent on IFN-α-secreting pDCs, we administered an Ad vector encoding B18R, an IFN-α antagonist, which abrogated the antitumoral effect of Ad.TK/GCV + Ad.Flt3L. Our data suggest that IFN-α release by activated pDCs plays a critical role in the antitumor effect mediated by Ad.TK/GCV + Ad.Flt3L. In summary, taken together, our results demonstrate that pDCs mediate anti-GBM therapeutic efficacy through the production of IFN-α, thus manipulation of pDCs constitutes an attractive new therapeutic target for the treatment of GBM.

  19. Emerging targets for addiction neuropharmacology: From mechanisms to therapeutics.

    Science.gov (United States)

    Ubaldi, Massimo; Cannella, Nazzareno; Ciccocioppo, Roberto

    2016-01-01

    Drug abuse represents a considerable burden of disease and has enormous economic impacts on societies. Over the years, few medications have been developed for clinical use. Their utilization is endowed with several limitations, including partial efficacy or significant side effects. On the other hand, the successful advancement of these compounds provides an important proof of concept for the feasibility of drug development programs in addiction. In recent years, a wealth of information has been generated on the psychological mechanisms, genetic or epigenetic predisposing factors, and neurobiological adaptations induced by drug consumption that interact with each other to contribute to disease progression. It is now clear that addiction develops through phases, from initial recreational use to excessive consumption and compulsive drug seeking, with a shift from positive to negative reinforcement driving motivated behaviors. A greater understanding of these mechanisms has opened new vistas in drug development programs. Researchers' attention has been shifted from investigation of classical targets associated with reward to biological substrates responsible for negative reinforcement, impulse loss of control, and maladaptive mechanisms resulting from protracted drug use. From this research, several new biological targets for the development of innovative therapies have started to emerge. This chapter offers an overview of targets currently under scrutiny for the development of new medications for addiction. This work is not exhaustive but rather it provides a few examples of how this research has advanced in recent years by virtue of studies carried out in our laboratory. PMID:26822362

  20. Therapeutic antibodies: market considerations, disease targets and bioprocessing.

    Science.gov (United States)

    Elvin, John G; Couston, Ruairidh G; van der Walle, Christopher F

    2013-01-01

    Antibodies are well established in mainstream clinical practice and present an exciting area for collaborative research and development in industry and academia alike. In this review, we will provide an overview of the current market and an outlook to 2015, focussing on whole antibody molecules while acknowledging the next generation scaffolds containing variable fragments. The market will be discussed in the context of disease targets, particularly in the areas of oncology and immune disorders which generate the greatest revenue by a wide margin. Emerging targets include central nervous system disorders which will also stimulate new delivery strategies. It is becoming increasingly apparent that a better understanding of bioprocessing is required in order to optimize the steps involved in the preparation of a protein prior to formulation. The latter is outside the scope of this review and nor is it our intention to discuss protein delivery and pharmacokinetics. The challenges that lie ahead include the discovery of new disease targets and the development of robust bioprocessing operations. PMID:22227342

  1. MicroRNAs: a novel therapeutic target for schizophrenia.

    LENUS (Irish Health Repository)

    Bravo, Javier A

    2011-01-01

    Schizophrenia is one of the most disabling psychiatric conditions. Current treatments target monoamine receptors but this approach does not address the full complexity of the disorder. Here we explore the possibility of developing new anti-psychotics by targeting microRNAs (miRNAs), single stranded RNA molecules, 21-23 nucleotides in length that are not translated into proteins and regulate gene expression. The present review reveals that research involving schizophrenia and miRNA is very recent (the earliest report from 2007) and miRNAs add a significant layer of complexity to the pathophysiology of the disorder. However, miRNAs offer an exciting potential not only to understand the underlying mechanisms of schizophrenia, but also for the future development of antipsychotics, as the human miRNA system provides a rich and diverse opportunity for pharmacological targeting. However, technology is still developing in order to produce effective strategies to modulate specific and localized changes in miRNA, particularly in relation to the central nervous system and schizophrenia.

  2. Molecular target based combinational therapeutic approaches in thyroid cancer

    Directory of Open Access Journals (Sweden)

    Rajoria Shilpi

    2012-05-01

    Full Text Available Abstract Background Thyroid cancer, as with other types of cancer, is dependent on angiogenesis for its continued growth and development. Interestingly, estrogen has been shown to contribute to thyroid cancer aggressiveness in vitro, which is in full support of the observed increased incidence of thyroid cancer in women over men. Provided that estrogen has been observed to contribute to increased angiogenesis of estrogen responsive breast cancer, it is conceivable to speculate that estrogen also contributes to angiogenesis of estrogen responsive thyroid cancer. Methods In this study, three human thyroid cancer cells (B-CPAP, CGTH-W-1, ML-1 were treated with estrogen alone or estrogen and anti-estrogens (fulvestrant and 3,3′-diindolylmethane, a natural dietary compound for 24 hours. The cell culture media was then added to human umbilical vein endothelial cell (HUVECs and assayed for angiogenesis associated events. Vascular endothelial growth factor (VEGF levels were also quantified in the conditioned media so as to evaluate if it is a key player involved in these observations. Results Conditioned medium from estrogen treated thyroid cancer cells enhanced phenotypical changes (proliferation, migration and tubulogenesis of endothelial cells typically observed during angiogenesis. These phenotypic changes observed in HUVECs were determined to be modulated by estrogen induced secretion of VEGF by the cancer cells. Lastly, we show that VEGF secretion was inhibited by the anti-estrogens, fulvestrant and 3,3′-diindolylmethane, which resulted in diminished angiogenesis associated events in HUVECs. Conclusion Our data establishes estrogen as being a key regulator of VEGF secretion/expression in thyroid cells which enhances the process of angiogenesis in thyroid cancer. These findings also suggest the clinical utility of anti-estrogens as anti-angiogenic compounds to be used as a therapeutic means to treat thyroid cancer. We also observed that 3,3

  3. V-ATPase as an effective therapeutic target for sarcomas

    International Nuclear Information System (INIS)

    Malignant tumors show intense glycolysis and, as a consequence, high lactate production and proton efflux activity. We investigated proton dynamics in osteosarcoma, rhabdomyosarcoma, and chondrosarcoma, and evaluated the effects of esomeprazole as a therapeutic agent interfering with tumor acidic microenvironment. All sarcomas were able to survive in an acidic microenvironment (up to 5.9–6.0 pH) and abundant acidic lysosomes were found in all sarcoma subtypes. V-ATPase, a proton pump that acidifies intracellular compartments and transports protons across the plasma membrane, was detected in all cell types with a histotype-specific expression pattern. Esomeprazole administration interfered with proton compartmentalization in acidic organelles and induced a significant dose-dependent toxicity. Among the different histotypes, rhabdomyosarcoma, expressing the highest levels of V-ATPase and whose lysosomes are most acidic, was mostly susceptible to ESOM treatment. - Highlights: • Osteosarcoma, rhabdomyosarcoma, and chondrosarcoma survive in acidic microenvironment. • At acidic extracellular pH, sarcoma survival is dependent on V-ATPase expression. • Esomeprazole administration induce a significant dose-dependent toxicity

  4. V-ATPase as an effective therapeutic target for sarcomas

    Energy Technology Data Exchange (ETDEWEB)

    Perut, Francesca, E-mail: francesca.perut@ior.it [Laboratory for Orthopaedic Pathophysiology and Regenerative Medicine, Istituto Ortopedico Rizzoli, Bologna (Italy); Avnet, Sofia; Fotia, Caterina; Baglìo, Serena Rubina; Salerno, Manuela [Laboratory for Orthopaedic Pathophysiology and Regenerative Medicine, Istituto Ortopedico Rizzoli, Bologna (Italy); Hosogi, Shigekuni [Laboratory for Orthopaedic Pathophysiology and Regenerative Medicine, Istituto Ortopedico Rizzoli, Bologna (Italy); Department of Molecular Cell Physiology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto (Japan); Kusuzaki, Katsuyuki [Department of Molecular Cell Physiology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto (Japan); Baldini, Nicola [Laboratory for Orthopaedic Pathophysiology and Regenerative Medicine, Istituto Ortopedico Rizzoli, Bologna (Italy); Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna (Italy)

    2014-01-01

    Malignant tumors show intense glycolysis and, as a consequence, high lactate production and proton efflux activity. We investigated proton dynamics in osteosarcoma, rhabdomyosarcoma, and chondrosarcoma, and evaluated the effects of esomeprazole as a therapeutic agent interfering with tumor acidic microenvironment. All sarcomas were able to survive in an acidic microenvironment (up to 5.9–6.0 pH) and abundant acidic lysosomes were found in all sarcoma subtypes. V-ATPase, a proton pump that acidifies intracellular compartments and transports protons across the plasma membrane, was detected in all cell types with a histotype-specific expression pattern. Esomeprazole administration interfered with proton compartmentalization in acidic organelles and induced a significant dose-dependent toxicity. Among the different histotypes, rhabdomyosarcoma, expressing the highest levels of V-ATPase and whose lysosomes are most acidic, was mostly susceptible to ESOM treatment. - Highlights: • Osteosarcoma, rhabdomyosarcoma, and chondrosarcoma survive in acidic microenvironment. • At acidic extracellular pH, sarcoma survival is dependent on V-ATPase expression. • Esomeprazole administration induce a significant dose-dependent toxicity.

  5. Cardiovascular disorders in anorexia nervosa and potential therapeutic targets.

    Science.gov (United States)

    Di Cola, Giovanni; Jacoangeli, Francesca; Jacoangeli, Fabrizio; Lombardo, Mauro; Iellamo, Ferdinando

    2014-10-01

    Anorexia nervosa (AN) is an eating disorder in which a distorted self-perception of body image and an excessive fear of gaining weight result in extreme restrictions in eating habits. AN may be divided into two types: a "binge-eating/purging type" during which the individual regularly engages in overeating and then purging behavior, and a "restricting type", in which she does not. AN is a serious medical problem in young people in Western societies. It is widely reported that patients with AN exhibit an enhanced mortality rate as compared with age-matched healthy subjects, which has been mainly ascribed to cardiac complications. At least one-third of all deaths in patients with anorexia nervosa are estimated to be due to cardiac causes, mainly sudden death. Cardiovascular complications of AN can be present in up to 80% of cases, and among them alterations in cardiac electrical activity, structure and hemodynamics have been reported as causes of morbidity and mortality. The objective of this brief review is to summarize current knowledge on the main cardiovascular complications of AN, their underlying mechanisms and the possible therapeutic approaches. PMID:25056404

  6. Therapeutics targeting inflammation in the immune reconstitution inflammatory syndrome.

    Science.gov (United States)

    Shahani, Lokesh; Hamill, Richard J

    2016-01-01

    Immune reconstitution inflammatory syndrome (IRIS) is characterized by improvement in a previously incompetent human immune system manifesting as worsening of clinical symptoms secondary to the ability of the immune system to now mount a vigorous inflammatory response. IRIS was first recognized in the setting of human immunodeficiency virus, and this clinical setting continues to be where it is most frequently encountered. Hallmarks of the pathogenesis of IRIS, independent of the clinical presentation and the underlying pathogen, include excessive activation of the immune system, with increased circulating effector memory T cells, and elevated levels of serum cytokines and inflammatory markers. Patients with undiagnosed opportunistic infections remain at risk for unmasking IRIS at the time of active antiretroviral therapy (ART) initiation. Systematic screening for opportunistic infections before starting ART is a key element to prevent this phenomenon. Appropriate management of IRIS requires prompt recognition of the syndrome and exclusion of alternative diagnoses, particularly underlying infections and drug resistance. Controlled studies supporting the use of pharmacologic interventions in IRIS are scare, and recommendations are based on case series and expert opinions. The only controlled trial published to date, showed reduction in morbidity in patients with paradoxical tuberculosis-related IRIS with the use of oral corticosteroids. There are currently limited data to recommend other anti-inflammatory or immunomodulatory therapies that are discussed in this review, and further research is needed. Ongoing research regarding the immune pathogenesis of IRIS will likely direct future rational therapeutic approaches and clinical trials. PMID:26303886

  7. Therapeutic Targets in Sepsis: Past, Present, and Future.

    Science.gov (United States)

    Seeley, Eric J; Bernard, Gordon R

    2016-06-01

    Antibiotics and fluids have been standard treatment for sepsis since World War II. Many molecular mediators of septic shock have since been identified. In models of sepsis, blocking these mediators improved organ injury and decreased mortality. Clinical trials, however, have failed. The absence of new therapies has been vexing to clinicians, clinical researchers, basic scientists, and the pharmaceutical industry. This article examines the evolution of sepsis therapy and theorizes about why so many well-reasoned therapies have not worked in human trials. We review new molecular targets for sepsis and examine trial designs that might lead to successful treatments for sepsis. PMID:27229636

  8. Axonal degeneration in multiple sclerosis: defining therapeutic targets by identifying the causes of pathology.

    Science.gov (United States)

    Lee, Jae Young; Biemond, Melissa; Petratos, Steven

    2015-12-01

    Current therapeutics in multiple sclerosis (MS) target the putative inflammation and immune attack on CNS myelin. Despite their effectiveness in blunting the relapse rate in MS patients, such therapeutics do not prevent MS disease progression. Importantly, specific clinical dilemma arises through inability to predict MS progression and thereby therapeutically target axonal injury during MS, limiting permanent disability. The current review identifies immune and neurobiological principles that govern the sequelae of axonal degeneration during MS disease progression. Defining the specific disease arbiters, inflammatory and autoimmune, oligodendrocyte dystrophy and degenerative myelin, we discuss a basis for a molecular mechanism in axons that may be targeted therapeutically, in spatial and temporal manner to limit axonal degeneration and thereby halt progression of MS. PMID:26619755

  9. Targeting hydrogen sulfide as a promising therapeutic strategy for atherosclerosis.

    Science.gov (United States)

    Xu, Suowen; Liu, Zhiping; Liu, Peiqing

    2014-03-15

    Physiological concentrations of nitric oxide (NO) and carbon monoxide (CO) have multiple protective effects in the cardiovascular system. Recent studies have implicated hydrogen sulfide (H2S) as a new member of vasculoprotective gasotransmitter family, behaving similarly to NO and CO. H2S has been demonstrated to inhibit multiple key aspects of atherosclerosis, including atherogenic modification of LDL, monocytes adhesion to the endothelial cells, macrophage-derived foam cell formation and inflammation, smooth muscle cell proliferation, neointimal hyperplasia, vascular calcification, and thrombogenesis. H2S also decreases plasma homocysteine levels in experimental animal models. In the human body, H2S production is predominantly catalyzed by cystathionine-β-synthase (CBS) and cystathionine γ-lyase (CSE). CSE is the primary H2S-producing enzyme in the vasculature. Growing evidence suggests that atherosclerosis is associated with vascular CSE/H2S deficiency and that H2S supplementation by exogenous H2S donors (such as NaHS and GYY4137) attenuates, and H2S synthesis suppression by inhibitors (such as D, L-propargylglycine) aggravates the development of atherosclerotic plaques. However, it remains elusive whether CSE deficiency plays a causative role in atherosclerosis. A recent study (Circulation. 2013; 127: 2523-2534) demonstrates that decreased endogenous H2S production by CSE genetic deletion accelerates atherosclerosis in athero-prone ApoE-/- mice, pinpointing that endogenously produced H2S by CSE activation may be of benefit in the prevention and treatment of atherosclerosis. This study will facilitate the development of H2S-based pharmaceuticals with therapeutic applications in atherosclerosis-related cardiovascular diseases. PMID:24491853

  10. MOGAT2: A New Therapeutic Target for Metabolic Syndrome

    Directory of Open Access Journals (Sweden)

    Muhua Yang

    2015-08-01

    Full Text Available Metabolic syndrome is an ever-increasing health problem among the world’s population. It is a group of intertwined maladies that includes obesity, hypertriglyceridemia, hypertension, nonalcoholic fatty liver disease (NAFLD, and diabetes mellitus type II (T2D. There is a direct correlation between high triacylglycerol (triglyceride; TAG level and severity of metabolic syndrome. Thus, controlling the synthesis of TAG will have a great impact on overall systemic lipid metabolism and thus metabolic syndrome progression. The Acyl-CoA: monoacylglycerolacyltransferase (MGAT family has three members (MGAT1, -2, and -3 that catalyze the first step in TAG production, conversion of monoacylglycerol (MAG to diacylglycerol (DAG. TAG is then directly synthesized from DAG by a Acyl-CoA: diacylglycerolacyltransferase (DGAT. The conversion of MAG → DAG → TAG is the major pathway for the production of TAG in the small intestine, and produces TAG to a lesser extent in the liver. Transgenic and pharmacological studies in mice have demonstrated the beneficial effects of MGAT inhibition as a therapy for treating several metabolic diseases, including obesity, insulin resistance, T2D, and NAFLD. In this review, the significance of several properties of MGAT physiology, including tissue expression pattern and its relationship to overall TAG metabolism, enzymatic biochemical properties and their effects on drug discovery, and finally what is the current knowledge about MGAT small molecule inhibitors and their efficacy will be discussed. Overall, this review highlights the therapeutic potential of inhibiting MGAT for lowering TAG synthesis and whether this avenue of drug discovery warrants further clinical investigation.

  11. Endocannabinoid signaling in female reproductive events: a potential therapeutic target?

    Science.gov (United States)

    Maccarrone, Mauro

    2015-01-01

    Nearly 30 years after the discovery in 1964 of the psychoactive ingredient of cannabis (Cannabis sativa), Δ(9)-tetrahydrocannabinol, its endogenous counterparts were discovered and collectively termed endocannabinoids (eCBs): N-arachidonoylethanolamine (anandamide) in 1992 and 2-arachidonoylglycerol in 1995. Since then, intense research has identified additional eCBs and an ensemble of proteins that bind, synthesize and degrade them, the so-called eCB system. Altogether, these new compounds have been recognized as key mediators of several aspects of human pathophysiology, and in particular of female fertility. Here, the main features of the eCB system are presented, in order to put in a better perspective the relevance of eCB signaling in virtually all steps of human reproduction and to highlight emerging hopes that elements of this system might indeed become novel targets to combat fertility problems. PMID:26126134

  12. Skp2 is a promising therapeutic target in breast cancer

    Directory of Open Access Journals (Sweden)

    Zhiwei eWang

    2012-01-01

    Full Text Available Breast cancer is the most common type of cancer among American women, and remains the second leading cause of cancer-related death for female in the United States. It has been known that several signaling pathways and various factors play critical roles in the development and progression of breast cancer, such as estrogen receptor, Notch, PTEN, Her2, PI3K/Akt, BRCA1 and BRCA2. Emerging evidence has shown that the F-box protein Skp2 (S-phase kinase associated protein 2 also plays an important role in the pathogenesis of breast cancer. Therefore, in this brief review, we summarize the novel functions of Skp2 in the pathogenesis of breast cancer. Moreover, we provide further evidence regarding the state of our knowledge toward the development of novel Skp2 inhibitors especially natural chemopreventive agents as targeted approach for the prevention and/or treatment of breast cancer.

  13. Targeting nicotine addiction: the possibility of a therapeutic vaccine

    Directory of Open Access Journals (Sweden)

    Escobar-Chávez JJ

    2011-04-01

    Full Text Available José Juan Escobar-Chávez1, Clara Luisa Domínguez-Delgado2, Isabel Marlen Rodríguez-Cruz21Unidad de Investigación Multidisciplinaria, Facultad de Estudios Superiores Cuautitlán-Universidad Nacional Autónoma de México, Cuautitlán Izcalli, Estado de México, México; 2División de Estudios de Posgrado (Tecnología Farmacéutica, Facultad de Estudios Superiores Cuautitlán-Universidad Nacional Autónoma de México, Cuautitlán Izcalli, Estado de México, MéxicoAbstract: Cigarette smoking is the primary cause of lung cancer, cardiovascular diseases, reproductive disorders, and delayed wound healing all over the world. The goals of smoking cessation are both to reduce health risks and to improve quality of life. The development of novel and more effective medications for smoking cessation is crucial in the treatment of nicotine dependence. Currently, first-line smoking cessation therapies include nicotine replacement products and bupropion. The partial nicotinic receptor agonist, varenicline, has recently been approved by the US Food and Drug Administration (FDA for smoking cessation. Clonidine and nortriptyline have demonstrated some efficacy, but side effects may limit their use to second-line treatment products. Other therapeutic drugs that are under development include rimonabant, mecamylamine, monoamine oxidase inhibitors, and dopamine D3 receptor antagonists. Nicotine vaccines are among newer products seeking approval from the FDA. Antidrug vaccines are irreversible, provide protection over years and need booster injections far beyond the critical phase of acute withdrawal symptoms. Interacting with the drug in the blood rather than with a receptor in the brain, the vaccines are free of side effects due to central interaction. For drugs like nicotine, which interacts with different types of receptors in many organs, this is a further advantage. Three anti-nicotine vaccines are today in an advanced stage of clinical evaluation. Results

  14. Hippocampal neurogenesis, neurotrophic factors and depression: possible therapeutic targets?

    Science.gov (United States)

    Serafini, Gianluca; Hayley, Shawn; Pompili, Maurizio; Dwivedi, Yogesh; Brahmachari, Goutam; Girardi, Paolo; Amore, Mario

    2014-01-01

    Major depression is one of the leading causes of disability and psychosocial impairment worldwide. Although many advances have been made in the neurobiology of this complex disorder, the pathophysiological mechanisms are still unclear. Among the proposed theories, impaired neuroplasticity and hippocampal neurogenesis have received considerable attention. The possible association between hippocampal neurogenesis, neurotrophic factors, major depression, and antidepressant responses was critically analyzed using a comprehensive search of articles/book chapters in English language between 1980 and 2014. One common emerging theme was that chronic stress and major depression are associated with structural brain changes such as a loss of dendritic spines and synapses, as well as reduced dendritic arborisation, together with diminished glial cells in the hippocampus. Both central monoamines and neurotrophic factors were associated with a modulation of hippocampal progenitor proliferation and cell survival. Accordingly, antidepressants are generally suggested to reverse stress-induced structural changes augmenting dendritic arborisation and synaptogenesis. Such antidepressant consequences are supposed to stem from their stimulatory effects on neurotrophic factors, and possibly modulation of glial cells. Of course, accumulating evidence also suggested that glutamatergic systems are implicated in not only basic neuroplastic processes, but also in the core features of depression. Hence, it is critical that antidepressant strategies focus on links between the various neurotransmitter systems, neurotrophic processes of hippocampal neurogenesis, and neurotrophic factors with regards to depressive symptomology. The identification of novel alternative antidepressant medications that target these systems is discussed in this review. PMID:25470403

  15. Neuroprotection as a Therapeutic Target for Diabetic Retinopathy

    Directory of Open Access Journals (Sweden)

    Cristina Hernández

    2016-01-01

    Full Text Available Diabetic retinopathy (DR is a multifactorial progressive disease of the retina and a leading cause of vision loss. DR has long been regarded as a vascular disorder, although neuronal death and visual impairment appear before vascular lesions, suggesting an important role played by neurodegeneration in DR and the appropriateness of neuroprotective strategies. Upregulation of vascular endothelial growth factor (VEGF, the main target of current therapies, is likely to be one of the first responses to retinal hyperglycemic stress and VEGF may represent an important survival factor in early phases of DR. Of central importance for clinical trials is the detection of retinal neurodegeneration in the clinical setting, and spectral domain optical coherence tomography seems the most indicated technique. Many substances have been tested in animal studies for their neuroprotective properties and for possible use in humans. Perhaps, the most intriguing perspective is the use of endogenous neuroprotective substances or nutraceuticals. Together, the data point to the central role of neurodegeneration in the pathogenesis of DR and indicate neuroprotection as an effective strategy for treating this disease. However, clinical trials to determine not only the effectiveness and safety but also the compliance of a noninvasive route of drug administration are needed.

  16. Adhesion receptors as therapeutic targets for circulating tumor cells

    Directory of Open Access Journals (Sweden)

    MichaelR.King

    2012-07-01

    Full Text Available Metastasis contributes to >90% of cancer-associated mortality. Though primary tumors can be removed by surgical resection or chemo/radiotherapy, metastatic disease is a great challenge to treatment due to its systemic nature. As metastatic “seeds”, circulating tumor cells (CTCs are believed to be responsible for dissemination from a primary tumor to anatomically distant organs. Despite the possibility of physical trapping of CTCs in microvessels, recent advances have provided insights into the involvement of a variety of adhesion molecules on CTCs. Such adhesion molecules facilitate direct interaction with the endothelium in specific tissues or indirectly through leukocytes. Importantly, significant progress has been made in understanding how these receptors confer enhanced invasion and survival advantage during hematogenous circulation of CTCs through recruitment of macrophages, neutrophils, platelets, and other cells. This review highlights the identification of novel adhesion molecules and how blocking their function can compromise successful seeding and colonization of CTCs in new microenvironment. Encouraged by existing diagnostic tools to identify and isolate CTCs, strategic targeting of these adhesion molecules to deliver conventional chemotherapeutics or novel apoptotic signals is discussed for the neutralization of CTCs in the circulation.

  17. Mitochondrial Respiration - An Important Therapeutic Target in Melanoma

    Science.gov (United States)

    Barbi de Moura, Michelle; Vincent, Garret; Fayewicz, Shelley L.; Bateman, Nicholas W.; Hood, Brian L.; Sun, Mai; Suhan, Joseph; Duensing, Stefan; Yin, Yan; Sander, Cindy; Kirkwood, John M.; Becker, Dorothea; Conrads, Thomas P.; Van Houten, Bennett; Moschos, Stergios J.

    2012-01-01

    The importance of mitochondria as oxygen sensors as well as producers of ATP and reactive oxygen species (ROS) has recently become a focal point of cancer research. However, in the case of melanoma, little information is available to what extent cellular bioenergetics processes contribute to the progression of the disease and related to it, whether oxidative phosphorylation (OXPHOS) has a prominent role in advanced melanoma. In this study we demonstrate that compared to melanocytes, metastatic melanoma cells have elevated levels of OXPHOS. Furthermore, treating metastatic melanoma cells with the drug, Elesclomol, which induces cancer cell apoptosis through oxidative stress, we document by way of stable isotope labeling with amino acids in cell culture (SILAC) that proteins participating in OXPHOS are downregulated. We also provide evidence that melanoma cells with high levels of glycolysis are more resistant to Elesclomol. We further show that Elesclomol upregulates hypoxia inducible factor 1-α (HIF-1α), and that prolonged exposure of melanoma cells to this drug leads to selection of melanoma cells with high levels of glycolysis. Taken together, our findings suggest that molecular targeting of OXPHOS may have efficacy for advanced melanoma. PMID:22912665

  18. Mitochondrial respiration--an important therapeutic target in melanoma.

    Directory of Open Access Journals (Sweden)

    Michelle Barbi de Moura

    Full Text Available The importance of mitochondria as oxygen sensors as well as producers of ATP and reactive oxygen species (ROS has recently become a focal point of cancer research. However, in the case of melanoma, little information is available to what extent cellular bioenergetics processes contribute to the progression of the disease and related to it, whether oxidative phosphorylation (OXPHOS has a prominent role in advanced melanoma. In this study we demonstrate that compared to melanocytes, metastatic melanoma cells have elevated levels of OXPHOS. Furthermore, treating metastatic melanoma cells with the drug, Elesclomol, which induces cancer cell apoptosis through oxidative stress, we document by way of stable isotope labeling with amino acids in cell culture (SILAC that proteins participating in OXPHOS are downregulated. We also provide evidence that melanoma cells with high levels of glycolysis are more resistant to Elesclomol. We further show that Elesclomol upregulates hypoxia inducible factor 1-α (HIF-1α, and that prolonged exposure of melanoma cells to this drug leads to selection of melanoma cells with high levels of glycolysis. Taken together, our findings suggest that molecular targeting of OXPHOS may have efficacy for advanced melanoma.

  19. Ion Channels in Obesity: Pathophysiology and Potential Therapeutic Targets.

    Science.gov (United States)

    Vasconcelos, Luiz H C; Souza, Iara L L; Pinheiro, Lílian S; Silva, Bagnólia A

    2016-01-01

    Obesity is a multifactorial disease related to metabolic disorders and associated with genetic determinants. Currently, ion channels activity has been linked to many of these disorders, in addition to the central regulation of food intake, energetic balance, hormone release and response, as well as the adipocyte cell proliferation. Therefore, the objective of this work is to review the current knowledge about the influence of ion channels in obesity development. This review used different sources of literature (Google Scholar, PubMed, Scopus, and Web of Science) to assess the role of ion channels in the pathophysiology of obesity. Ion channels present diverse key functions, such as the maintenance of physiological homeostasis and cell proliferation. Cell biology and pharmacological experimental evidences demonstrate that proliferating cells exhibit ion channel expression, conductance, and electrical properties different from the resting cells. Thereby, a large variety of ion channels has been identified in the pathogenesis of obesity such as potassium, sodium, calcium and chloride channels, nicotinic acetylcholine receptor and transient receptor potential channels. The fundamental involvement of these channels on the generation of obesity leads to the progress in the knowledge about the mechanisms responsible for the obesity pathophysiology, consequently emerging as new targets for pharmacological modulation. PMID:27065858

  20. Ion Channels in Obesity: Pathophysiology and Potential Therapeutic Targets

    Directory of Open Access Journals (Sweden)

    LUIZ HENRIQUE CÉSAR VASCONCELOS

    2016-03-01

    Full Text Available Obesity is a multifactorial disease related to metabolic disorders and associated with genetic determinants. Currently, ion channels activity has been linked to many of these disorders, in addition to the central regulation of food intake, energetic balance, hormone release and response, as well as the adipocyte cell proliferation. Therefore, the objective of this work is to review the current knowledge about the influence of ion channels in obesity development. This review used different sources of literature (Google Scholar, PubMed, Scopus and Web of Science to assess the role of ion channels in the pathophysiology of obesity. Ion channels present diverse key functions, such as the maintenance of physiological homeostasis and cell proliferation. Cell biology and pharmacological experimental evidences demonstrate that proliferating cells exhibit ion channel expression, conductance and electrical properties different from the resting cells. Thereby, a large variety of ion channels has been identified in the pathogenesis of obesity such as potassium, sodium, calcium and chloride channels, nicotinic acetylcholine receptor and transient receptor potential channels. The fundamental involvement of these channels on the generation of obesity leads to the progress in the knowledge about the mechanisms responsible for the obesity pathophysiology, consequently emerging as new targets for pharmacological modulation.

  1. Therapeutic challenges for systemic sclerosis: facts and future targets.

    Science.gov (United States)

    Cerinic Matucci, M; Del Rosso, Angela; Federico, Perfetto; Livi, Riccardo; Fiori, Ginevra; Bartoli, Francesca; Blagojevic, Jelena; Tempestini, Alessio; Pignone, Alberto

    2007-09-01

    Pulmonary arterial hypertension (PAH) is an important cause of death in systemic sclerosis (SSc), despite the improvement of therapies. An early diagnosis and the use of drugs interfering with the main pathogenic pathways of PAH is pivotal for the improvement of prognosis in primary PAH and PAH secondary to autoimmune rheumatic diseases, mainly SSc. Lately, new specific therapies have been developed targeting prostacyclin, endothelin, and nitric oxide pathways, the major pathogenic pathways leading to endothelial dysfunction in PAH. Epoprostenol improved life expectancy of patients with primary and secondary PAH, but its continuous intravenous administration requires experienced centers. More stable analogues of prostacyclin, administrated by intravenous (iloprost, treprostinil), subcutaneous, inhalatory (treprostinil, iloprost), and oral route (Beraprost) have shown efficacy in PAH. Bosentan, the first oral endothelin receptor antagonist (with affinity for endothelin A and B receptors) improves exercise function and survival in PAH, both primary and secondary to autoimmune rheumatic diseases. This is confirmed also for Sitaxsentan and Ambrisentan, selective A receptor antagonists. Because of its short half-life and systemic side effects, short-term NO inhalation is used only in short-term management of PAH in critically ill adults. Inhibitors of NO degradation, such as sildenafil, a phosphodiesterase (PDE) type 5 inhibitor, improved functional and hemodynamic parameters without significant side effects. Vardenafil and taladafil, longer-acting PDE inhibitors, also have vascular pulmonary selectivity. All these drugs may be used in combination, to maximize their clinical benefit not only in patients unresponsive to single drugs, but also potentially as initial therapy of PAH. PMID:17911460

  2. Pathophysiological mechanisms involved in non-alcoholicsteatohepatitis and novel potential therapeutic targets

    Institute of Scientific and Technical Information of China (English)

    2015-01-01

    Non-alcoholic fatty liver disease (NAFLD) is a major healthcare problem and represents the hepatic expression ofthe metabolic syndrome. NAFLD is classified as nonalcoholicfatty liver (NAFL) or simple steatosis, and nonalcoholicsteatohepatitis (NASH). NASH is characterizedby the presence of steatosis and inflammation withor without fibrosis. The physiopathology of NAFL andNASH and their progression to cirrhosis involve severalparallel and interrelated mechanisms, such as, insulinresistance (IR), lipotoxicity, inflammation, oxidativestress, and recently the gut-liver axis interaction has beendescribed. Incretin-based therapies could play a role inthe treatment of NAFLD. Glucagon-like peptide-1 (GLP-1)is an intestinal mucosa-derived hormone which is secretedinto the bloodstream in response to nutrient ingestion;it favors glucose-stimulated insulin secretion, inhibitionof postprandial glucagon secretion and delayed gastricemptying. It also promotes weight loss and is involvedin lipid metabolism. Once secreted, GLP-1 is quicklydegraded by dipeptidyl peptidase-4 (DPP-4). Therefore,DPP-4 inhibitors are able to extend the activity of GLP-1.Currently, GLP-1 agonists and DPP-4 inhibitors representattractive options for the treatment of NAFLD andNASH. The modulation of lipid and glucose metabolismthrough nuclear receptors, such as the farsenoid Xreceptor, also constitutes an attractive therapeutic target.Obeticholic acid is a potent activator of the farnesoidX nuclear receptor and reduces liver fat content andfibrosis in animal models. Ursodeoxycholic acid (UDCA)is a hydrophilic bile acid with immunomodulatory, antiinflammatory,antiapoptotic, antioxidant and antifibroticproperties. UDCA can improve IR and modulatelipid metabolism through its interaction with nuclearreceptors such as, TGR5, farnesoid X receptor-a, orthe small heterodimeric partner. Finally, pharmacologicmodulation of the gut microbiota could have a role in thetherapy of NAFLD and

  3. N-α-PGP and PGP, potential biomarkers and therapeutic targets for COPD

    OpenAIRE

    Gaggar Amit; Dransfield Mark; Parker Suzanne; Noerager Brett; Jackson Patricia L; O'Reilly Philip; Blalock J Edwin

    2009-01-01

    Abstract Background Chronic obstructive pulmonary disease (COPD) is a common respiratory disorder for which new diagnostic and therapeutic approaches are required. Hallmarks of COPD are matrix destruction and neutrophilic airway inflammation in the lung. We have previously described two tri-peptides, N-α-PGP and PGP, which are collagen fragments and neutrophil chemoattractants. In this study, we investigate if N-α-PGP and PGP are biomarkers and potential therapeutic targets for COPD. Methods ...

  4. P2RX7 purinoceptor: a therapeutic target for ameliorating the symptoms of duchenne muscular dystrophy.

    Directory of Open Access Journals (Sweden)

    Anthony Sinadinos

    2015-10-01

    Full Text Available Duchenne muscular dystrophy (DMD is the most common inherited muscle disease, leading to severe disability and death in young men. Death is caused by the progressive degeneration of striated muscles aggravated by sterile inflammation. The pleiotropic effects of the mutant gene also include cognitive and behavioral impairments and low bone density. Current interventions in DMD are palliative only as no treatment improves the long-term outcome. Therefore, approaches with a translational potential should be investigated, and key abnormalities downstream from the absence of the DMD product, dystrophin, appear to be strong therapeutic targets. We and others have demonstrated that DMD mutations alter ATP signaling and have identified P2RX7 purinoceptor up-regulation as being responsible for the death of muscles in the mdx mouse model of DMD and human DMD lymphoblasts. Moreover, the ATP-P2RX7 axis, being a crucial activator of innate immune responses, can contribute to DMD pathology by stimulating chronic inflammation. We investigated whether ablation of P2RX7 attenuates the DMD model mouse phenotype to assess receptor suitability as a therapeutic target.Using a combination of molecular, histological, and biochemical methods and behavioral analyses in vivo we demonstrate, to our knowledge for the first time, that genetic ablation of P2RX7 in the DMD model mouse produces a widespread functional attenuation of both muscle and non-muscle symptoms. In dystrophic muscles at 4 wk there was an evident recovery in key functional and molecular parameters such as improved muscle structure (minimum Feret diameter, p < 0.001, increased muscle strength in vitro (p < 0.001 and in vivo (p = 0.012, and pro-fibrotic molecular signatures. Serum creatine kinase (CK levels were lower (p = 0.025, and reduced cognitive impairment (p = 0.006 and bone structure alterations (p < 0.001 were also apparent. Reduction of inflammation and fibrosis persisted at 20 mo in leg (p = 0

  5. Heat shock proteins 27, 40, and 70 as combinational and dual therapeutic cancer targets

    OpenAIRE

    McConnell, Jeanette R.; McAlpine, Shelli R.

    2013-01-01

    The heat shock proteins are essential players in the development of cancer and they are prime therapeutic targets. Targeting multiple hsps in dual therapies decreases the likelihood of drug resistance compared to utilizing mono-therapies. Further, employing an hsp inhibitor in combination with another therapy has proven clinically successful. Examples of efficacious strategies include the inhibition of hsp27, which prevents protein aggregation, controlling hsp40’s role as an ATPase modulator,...

  6. Integrative omics analysis of rheumatoid arthritis identifies non-obvious therapeutic targets.

    Directory of Open Access Journals (Sweden)

    John W Whitaker

    Full Text Available Identifying novel therapeutic targets for the treatment of disease is challenging. To this end, we developed a genome-wide approach of candidate gene prioritization. We independently collocated sets of genes that were implicated in rheumatoid arthritis (RA pathogenicity through three genome-wide assays: (i genome-wide association studies (GWAS, (ii differentially expression in RA fibroblast-like synoviocytes (FLS, and (iii differentially methylation in RA FLS. Integrated analysis of these complementary data sets identified a significant enrichment of multi-evidence genes (MEGs within pathways relating to RA pathogenicity. One MEG is Engulfment and Cell Motility Protein-1 (ELMO1, a gene not previously considered as a therapeutic target in RA FLS. We demonstrated in RA FLS that ELMO1 is: (i expressed, (ii promotes cell migration and invasion, and (iii regulates Rac1 activity. Thus, we created links between ELMO1 and RA pathogenicity, which in turn validates ELMO1 as a potential RA therapeutic target. This study illustrated the power of MEG-based approaches for therapeutic target identification.

  7. Integrative omics analysis of rheumatoid arthritis identifies non-obvious therapeutic targets.

    Science.gov (United States)

    Whitaker, John W; Boyle, David L; Bartok, Beatrix; Ball, Scott T; Gay, Steffen; Wang, Wei; Firestein, Gary S

    2015-01-01

    Identifying novel therapeutic targets for the treatment of disease is challenging. To this end, we developed a genome-wide approach of candidate gene prioritization. We independently collocated sets of genes that were implicated in rheumatoid arthritis (RA) pathogenicity through three genome-wide assays: (i) genome-wide association studies (GWAS), (ii) differentially expression in RA fibroblast-like synoviocytes (FLS), and (iii) differentially methylation in RA FLS. Integrated analysis of these complementary data sets identified a significant enrichment of multi-evidence genes (MEGs) within pathways relating to RA pathogenicity. One MEG is Engulfment and Cell Motility Protein-1 (ELMO1), a gene not previously considered as a therapeutic target in RA FLS. We demonstrated in RA FLS that ELMO1 is: (i) expressed, (ii) promotes cell migration and invasion, and (iii) regulates Rac1 activity. Thus, we created links between ELMO1 and RA pathogenicity, which in turn validates ELMO1 as a potential RA therapeutic target. This study illustrated the power of MEG-based approaches for therapeutic target identification. PMID:25901943

  8. Insights into orphan nuclear receptors as prognostic markers and novel therapeutic targets for breast cancer

    OpenAIRE

    Reidun eAesoy; Colin D Clyne; Ashwini eChand

    2015-01-01

    The roles of orphan nuclear receptors in breast cancer development and progression are not well understood. In this review, we correlate orphan nuclear receptor expression in breast cancer tumour subtypes with patient outcomes and provide an overview of functional evidence that identifies candidate orphan nuclear receptors as prognostic markers or as therapeutic targets in breast cancer.

  9. Multi-target screening mines hesperidin as a multi-potent inhibitor: Implication in Alzheimer's disease therapeutics.

    Science.gov (United States)

    Chakraborty, Sandipan; Bandyopadhyay, Jaya; Chakraborty, Sourav; Basu, Soumalee

    2016-10-01

    Alzheimer's disease (AD) is the most frequent form of neurodegenerative disorder in elderly people. Involvement of several pathogenic events and their interconnections make this disease a complex disorder. Therefore, designing compounds that can inhibit multiple toxic pathways is the most attractive therapeutic strategy in complex disorders like AD. Here, we have designed a multi-tier screening protocol combining ensemble docking to mine BACE1 inhibitor, as well as 2-D QSAR models for anti-amyloidogenic and antioxidant activities. An in house developed phytochemical library of 200 phytochemicals has been screened through this multi-target procedure which mine hesperidin, a flavanone glycoside commonly found in citrus food items, as a multi-potent phytochemical in AD therapeutics. Steady-state and time-resolved fluorescence spectroscopy reveal that binding of hesperidin to the active site of BACE1 induces a conformational transition of the protein from open to closed form. Hesperidin docks close to the catalytic aspartate residues and orients itself in a way that blocks the cavity opening thereby precluding substrate binding. Hesperidin is a high affinity BACE1 inhibitor and only 500 nM of the compound shows complete inhibition of the enzyme activity. Furthermore, ANS and Thioflavin-T binding assay show that hesperidin completely inhibits the amyloid fibril formation which is further supported by atomic force microscopy. Hesperidin exhibits moderate ABTS(+) radical scavenging assay but strong hydroxyl radical scavenging ability, as evident from DNA nicking assay. Present study demonstrates the applicability of a novel multi-target screening procedure to mine multi-potent agents from natural origin for AD therapeutics. PMID:27068363

  10. Phytochemical-mediated Protein Expression Profiling and the Potential Applications in Therapeutic Drug Target Identifications.

    Science.gov (United States)

    Wong, Fai-Chu; Tan, Siok-Thing; Chai, Tsun-Thai

    2016-07-29

    Many phytochemicals derived from edible medicinal plants have been investigated intensively for their various bioactivities. However, the detailed mechanism and their corresponding molecular targets frequently remain elusive. In this review, we present a summary of the research works done on phytochemical-mediated molecular targets, identified via proteomic approach. Concurrently, we also highlighted some pharmaceutical drugs which could be traced back to their origins in phytochemicals. For ease of presentation, these identified protein targets were categorized into two important healthcare-related fields, namely anti-bacterial and anti-cancer research. Through this review, we hope to highlight the usefulness of comparative proteomic as a powerful tool in phytochemical-mediated protein target identifications. Likewise, we wish to inspire further investigations on some of these protein targets identified over the last few years. With contributions from all researchers, the accumulative efforts could eventually lead to the discovery of some target-specific, low-toxicity therapeutic agents. PMID:26193174

  11. Steroid hormone receptors and prostate cancer: role of structural dynamics in therapeutic targeting

    Science.gov (United States)

    Kumar, Raj

    2016-01-01

    Steroid hormone receptors (SHRs) act in cell type- and gene-specific manner through interactions with coregulatory proteins to regulate numerous physiological and pathological processes at the level of gene regulation. Binding of steroid receptor modulator (SRM) ligand leads to allosteric changes in SHR to exert positive or negative effects on the expression of target genes. Due, in part, to the fact that current SRMs generally target ligand binding domain (LBD)/AF2 and neglect intrinsically disordered (ID) N-terminal domain (NTD)/AF1, clinically relevant SRMs lack selectivity and are also prone to the development of resistance over time. Therefore, to maximize the efficacy of SHR-based therapeutics, the possibility of developing unique modulators that act to control AF1 activity must be considered. Recent studies targeting androgen receptor's (AR's) ID AF1 domain for the castration-resistant prostate cancer has provided the possibility of therapeutically targeting ID NTD/AF1 surfaces by allosteric modulations to achieve desired effects. In this review article, we discuss how inter- and intra- molecular allosteric regulations controlled by AR's structural flexibility and dynamics particularly the ID NTD/AF1 is an emerging area of investigation, which could be exploited for drug development and therapeutic targeting of prostate cancer. PMID:27364545

  12. Chemokines as Therapeutic Targets to Improve Healing Efficiency of Chronic Wounds

    OpenAIRE

    Satish, Latha

    2015-01-01

    Significance: Impaired wound healing leading to chronic wounds is an important clinical problem that needs immediate attention to develop new effective therapies. Members of the chemokine family seem to be attractive and amenable to stimulate the healing process in chronic wounds. Targeting specific chemokines and/or their receptors has the potential to modify chronic inflammation to acute inflammation, which will hasten the healing process.

  13. Complement therapeutics in inflammatory diseases: promising drug candidates for C3-targeted intervention.

    Science.gov (United States)

    Mastellos, D C; Ricklin, D; Hajishengallis, E; Hajishengallis, G; Lambris, J D

    2016-02-01

    There is increasing appreciation that complement dysregulation lies at the heart of numerous immune-mediated and inflammatory disorders. Complement inhibitors are therefore being evaluated as new therapeutic options in various clinical translation programs and the first clinically approved complement-targeted drugs have profoundly impacted the management of certain complement-mediated diseases. Among the many members of the intricate protein network of complement, the central component C3 represents a 'hot-spot' for complement-targeted therapeutic intervention. C3 modulates both innate and adaptive immune responses and is linked to diverse immunomodulatory systems and biological processes that affect human pathophysiology. Compelling evidence from preclinical disease models has shown that C3 interception may offer multiple benefits over existing therapies or even reveal novel therapeutic avenues in disorders that are not commonly regarded as complement-driven, such as periodontal disease. Using the clinically developed compstatin family of C3 inhibitors and periodontitis as illustrative examples, this review highlights emerging therapeutic concepts and developments in the design of C3-targeted drug candidates as novel immunotherapeutics for oral and systemic inflammatory diseases. PMID:26332138

  14. Combined analgesics in (headache pain therapy: shotgun approach or precise multi-target therapeutics?

    Directory of Open Access Journals (Sweden)

    Fiebich Bernd L

    2011-03-01

    Full Text Available Abstract Background Pain in general and headache in particular are characterized by a change in activity in brain areas involved in pain processing. The therapeutic challenge is to identify drugs with molecular targets that restore the healthy state, resulting in meaningful pain relief or even freedom from pain. Different aspects of pain perception, i.e. sensory and affective components, also explain why there is not just one single target structure for therapeutic approaches to pain. A network of brain areas ("pain matrix" are involved in pain perception and pain control. This diversification of the pain system explains why a wide range of molecularly different substances can be used in the treatment of different pain states and why in recent years more and more studies have described a superior efficacy of a precise multi-target combination therapy compared to therapy with monotherapeutics. Discussion In this article, we discuss the available literature on the effects of several fixed-dose combinations in the treatment of headaches and discuss the evidence in support of the role of combination therapy in the pharmacotherapy of pain, particularly of headaches. The scientific rationale behind multi-target combinations is the therapeutic benefit that could not be achieved by the individual constituents and that the single substances of the combinations act together additively or even multiplicatively and cooperate to achieve a completeness of the desired therapeutic effect. As an example the fixesd-dose combination of acetylsalicylic acid (ASA, paracetamol (acetaminophen and caffeine is reviewed in detail. The major advantage of using such a fixed combination is that the active ingredients act on different but distinct molecular targets and thus are able to act on more signalling cascades involved in pain than most single analgesics without adding more side effects to the therapy. Summary Multitarget therapeutics like combined analgesics broaden

  15. Advances in the proteomic discovery of novel therapeutic targets in cancer

    Directory of Open Access Journals (Sweden)

    Guo S

    2013-10-01

    Full Text Available Shanchun Guo,1 Jin Zou,2 Guangdi Wang3 1Department of Microbiology, Biochemistry, and Immunology, Morehouse School of Medicine, 2Center for Cancer Research and Therapeutic Development, Clark Atlanta University, Atlanta, GA, USA; 3Research Centers in Minority Institutions Cancer Research Program, Xavier University of Louisiana, New Orleans, LA, USA Abstract: Proteomic approaches are continuing to make headways in cancer research by helping to elucidate complex signaling networks that underlie tumorigenesis and disease progression. This review describes recent advances made in the proteomic discovery of drug targets for therapeutic development. A variety of technical and methodological advances are overviewed with a critical assessment of challenges and potentials. A number of potential drug targets, such as baculoviral inhibitor of apoptosis protein repeat-containing protein 6, macrophage inhibitory cytokine 1, phosphoglycerate mutase 1, prohibitin 1, fascin, and pyruvate kinase isozyme 2 were identified in the proteomic analysis of drug-resistant cancer cells, drug action, and differential disease state tissues. Future directions for proteomics-based target identification and validation to be more translation efficient are also discussed. Keywords: proteomics, cancer, therapeutic target, signaling network, tumorigenesis

  16. Identification of the YES1 Kinase as a Therapeutic Target in Basal-Like Breast Cancers.

    Science.gov (United States)

    Bilal, Erhan; Alexe, Gabriela; Yao, Ming; Cong, Lei; Kulkarni, Atul; Ginjala, Vasudeva; Toppmeyer, Deborah; Ganesan, Shridar; Bhanot, Gyan

    2010-10-01

    Normal cellular behavior can be described as a complex, regulated network of interaction between genes and proteins. Targeted cancer therapies aim to neutralize specific proteins that are necessary for the cancer cell to remain viable in vivo. Ideally, the proteins targeted should be such that their downregulation has a major impact on the survival/fitness of the tumor cells and, at the same time, has a smaller effect on normal cells. It is difficult to use standard analysis methods on gene or protein expression levels to identify these targets because the level thresholds for tumorigenic behavior are different for different genes/proteins. We have developed a novel methodology to identify therapeutic targets by using a new paradigm called "gene centrality." The main idea is that, in addition to being overexpressed, good therapeutic targets should have a high degree of connectivity in the tumor network because one expects that suppression of its expression would affect many other genes. We propose a mathematical quantity called "centrality," which measures the degree of connectivity of genes in a network in which each edge is weighted by the expression level of the target gene. Using our method, we found that several SRC proto-oncogenes LYN, YES1, HCK, FYN, and LCK have high centrality in identifiable subsets of basal-like and HER2+ breast cancers. To experimentally validate the clinical value of this finding, we evaluated the effect of YES1 knockdown in basal-like breast cancer cell lines that overexpress this gene. We found that YES1 downregulation has a significant effect on the survival of these cell lines. Our results identify YES1 as a target for therapeutics in a subset of basal-like breast cancers. PMID:21779430

  17. Identification of the YES1 Kinase as a Therapeutic Target in Basal-Like Breast Cancers

    Science.gov (United States)

    Bilal, Erhan; Alexe, Gabriela; Yao, Ming; Cong, Lei; Kulkarni, Atul; Ginjala, Vasudeva; Toppmeyer, Deborah; Ganesan, Shridar; Bhanot, Gyan

    2010-01-01

    Normal cellular behavior can be described as a complex, regulated network of interaction between genes and proteins. Targeted cancer therapies aim to neutralize specific proteins that are necessary for the cancer cell to remain viable in vivo. Ideally, the proteins targeted should be such that their downregulation has a major impact on the survival/fitness of the tumor cells and, at the same time, has a smaller effect on normal cells. It is difficult to use standard analysis methods on gene or protein expression levels to identify these targets because the level thresholds for tumorigenic behavior are different for different genes/proteins. We have developed a novel methodology to identify therapeutic targets by using a new paradigm called “gene centrality.” The main idea is that, in addition to being overexpressed, good therapeutic targets should have a high degree of connectivity in the tumor network because one expects that suppression of its expression would affect many other genes. We propose a mathematical quantity called “centrality,” which measures the degree of connectivity of genes in a network in which each edge is weighted by the expression level of the target gene. Using our method, we found that several SRC proto-oncogenes LYN, YES1, HCK, FYN, and LCK have high centrality in identifiable subsets of basal-like and HER2+ breast cancers. To experimentally validate the clinical value of this finding, we evaluated the effect of YES1 knockdown in basal-like breast cancer cell lines that overexpress this gene. We found that YES1 downregulation has a significant effect on the survival of these cell lines. Our results identify YES1 as a target for therapeutics in a subset of basal-like breast cancers. PMID:21779430

  18. Aurora kinases as druggable targets in pediatric leukemia: heterogeneity in target modulation activities and cytotoxicity by diverse novel therapeutic agents.

    Directory of Open Access Journals (Sweden)

    Aarthi Jayanthan

    Full Text Available Leukemia is the most common pediatric malignancy, constituting more than 30% of all childhood cancers. Although cure rates have improved greatly, approximately one in five children relapse and poor survival rates post relapse remain a challenge. Given this, more effective and innovative therapeutic strategies are needed in order to improve prognosis. Aurora kinases, a family of serine/threonine kinases essential for the regulation of several mitotic processes, have been identified as potential targets for cancer therapeutics. Elevated expression of Aurora kinases has been demonstrated in several malignancies and is associated with aberrant mitotic activity, aneuploidy and alterations in chromosomal structure and genome instability. Based on this rationale, a number of small molecule inhibitors have been formulated and advanced to human studies in the recent past. A comparative analysis of these agents in cytotoxicity and target modulation analyses against a panel of leukemia cells provides novel insights into the unique mechanisms and codependent activity pathways involved in targeting Aurora kinases, constituting a distinctive preclinical experimental framework to identify appropriate agents and combinations in future clinical studies.

  19. The p53 network as therapeutic target in gastroenteropancreatic neuroendocrine neoplasms.

    Science.gov (United States)

    Briest, Franziska; Grabowski, Patricia

    2015-05-01

    Gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs) are heterogeneous and especially the midgut tumors currently lack effective therapy options. Actionable driver mutations as therapeutic targets are rare. Subtype specific data concerning regulatory mechanisms or epigenetic aberrations are necessary for novel clinical trials. Although the p53 protein itself is rarely mutated in GEP-NENs, epigenetic and regulatory aberrations interfere with the p53 network activity and might function as s target for novel therapeutic approaches. In this review we analyze the current knowledge about the p53 network in GEP-NENs and discuss three possible strategies that include recovering p53 function, enforcing apoptosis by genotoxic stress induction and restoring silenced gene function, based on in vitro, in vivo and clinical data. PMID:25837868

  20. The cytoskeleton as a novel therapeutic target for old neurodegenerative disorders.

    Science.gov (United States)

    Eira, Jessica; Silva, Catarina Santos; Sousa, Mónica Mendes; Liz, Márcia Almeida

    2016-06-01

    Cytoskeleton defects, including alterations in microtubule stability, in axonal transport as well as in actin dynamics, have been characterized in several unrelated neurodegenerative conditions. These observations suggest that defects of cytoskeleton organization may be a common feature contributing to neurodegeneration. In line with this hypothesis, drugs targeting the cytoskeleton are currently being tested in animal models and in human clinical trials, showing promising effects. Drugs that modulate microtubule stability, inhibitors of posttranslational modifications of cytoskeletal components, specifically compounds affecting the levels of tubulin acetylation, and compounds targeting signaling molecules which regulate cytoskeleton dynamics, constitute the mostly addressed therapeutic interventions aiming at preventing cytoskeleton damage in neurodegenerative disorders. In this review, we will discuss in a critical perspective the current knowledge on cytoskeleton damage pathways as well as therapeutic strategies designed to revert cytoskeleton-related defects mainly focusing on the following neurodegenerative disorders: Alzheimer's Disease, Parkinson's Disease, Huntington's Disease, Amyotrophic Lateral Sclerosis and Charcot-Marie-Tooth Disease. PMID:27095262

  1. Immunohistochemical detection of a potential molecular therapeutic target for canine hemangiosarcoma.

    Science.gov (United States)

    Adachi, Mami; Hoshino, Yuki; Izumi, Yusuke; Takagi, Satoshi

    2016-05-01

    Canine hemangiosarcoma (HSA) is a progressive malignant neoplasm of dogs for which there is currently no effective treatment. A recent study suggested that receptor tyrosine kinases (RTKs), the PI3K/Akt/m-TOR and MAPK pathways are all activated in canine and human HSA. The aim of the present study was to investigate the overexpression of these proteins by immunohistochemistry in canine splenic HSA to identify potential molecular therapeutic targets. A total of 10 splenic HSAs and two normal splenic samples surgically resected from dogs were sectioned and stained with hematoxylin and eosin for histological diagnosis or analyzed using immunohistochemistry. The expression of RTKs, c-kit, VEGFR-2 and PDGFR-2, as well as PI3K/Akt/m-TOR and MEK was higher in canine splenic HSAs compared to normal spleens. These proteins may therefore be potential therapeutic targets in canine splenic HSA. PMID:26685984

  2. Gene Body Methylation can alter Gene Expression and is a Therapeutic Target in Cancer

    Science.gov (United States)

    Yang, Xiaojing; Han, Han; De Carvalho, Daniel D.; Lay, Fides D.; Jones, Peter A.; Liang, Gangning

    2014-01-01

    SUMMARY DNA methylation in promoters is well known to silence genes and is the presumed therapeutic target of methylation inhibitors. Gene body methylation is positively correlated with expression yet its function is unknown. We show that 5-aza-2'-deoxycytidine treatment not only reactivates genes but decreases the over-expression of genes, many of which are involved in metabolic processes regulated by c-MYC. Down-regulation is caused by DNA demethylation of the gene bodies and restoration of high levels of expression requires remethylation by DNMT3B. Gene body methylation may therefore be an unexpected therapeutic target for DNA methylation inhibitors, resulting in the normalization of gene over-expression induced during carcinogenesis. Our results provide direct evidence for a causal relationship between gene body methylation and transcription. PMID:25263941

  3. Targeting reactive nitrogen species: a promising therapeutic strategy for cerebral ischemia-reperfusion injury

    Institute of Scientific and Technical Information of China (English)

    Xing-miao CHEN; Han-sen CHEN; Ming-jing XU; Jian-gang SHEN

    2013-01-01

    Ischemic stroke accounts for nearly 80% of stroke cases.Recanalization with thrombolysis is a currently crucial therapeutic strategy for re-building blood supply,but the thrombolytic therapy often companies with cerebral ischemia-reperfusion injury,which are mediated by free radicals.As an important component of free radicals,reactive nitrogen species (RNS),including nitric oxide (NO) and peroxynitrite (ONO0ˉ),play important roles in the process of cerebral ischemia-reperfusion injury.Ischemia-reperfusion results in the production of nitric oxide (NO) and peroxynitrite (ONOOˉ) in ischemic brain,which trigger numerous molecular cascades and lead to disruption of the blood brain barrier and exacerbate brain damage.There are few therapeutic strategies available for saving ischemic brains and preventing the subsequent brain damage.Recent evidence suggests that RNS could be a therapeutic target for the treatment of cerebral ischemia-reperfusion injury.Herein,we reviewed the recent progress regarding the roles of RNS in the process of cerebral ischemic-reperfusion injury and discussed the potentials of drug development that target NO and ONO0ˉ to treat ischemic stroke.We conclude that modulation for RNS level could be an important therapeutic strategy for preventing cerebral ischemiareperfusion injury.

  4. Molecular pathways: novel approaches for improved therapeutic targeting of Hedgehog signaling in cancer stem cells.

    Science.gov (United States)

    Justilien, Verline; Fields, Alan P

    2015-02-01

    The Hedgehog (Hh) signaling pathway is critical for embryonic development. In adult tissues, Hh signaling is relatively quiescent with the exception of roles in tissue maintenance and repair. Aberrant activation of Hh signaling is implicated in multiple aspects of transformation, including the maintenance of the cancer stem cell (CSC) phenotype. Preclinical studies indicate that CSCs from many tumor types are sensitive to Hh pathway inhibition and that Hh-targeted therapeutics block many aspects of transformation attributed to CSCs, including drug resistance, relapse, and metastasis. However, to date, Hh inhibitors, specifically those targeting Smoothened [such as vismodegib, BMS-833923, saridegib (IPI-926), sonidegib/erismodegib (LDE225), PF-04449913, LY2940680, LEQ 506, and TAK-441], have demonstrated good efficacy as monotherapy in patients with basal cell carcinoma and medulloblastoma, but have shown limited activity in other tumor types. This lack of success is likely due to many factors, including a lack of patient stratification in early trials, cross-talk between Hh and other oncogenic signaling pathways that can modulate therapeutic response, and a limited knowledge of Hh pathway activation mechanisms in CSCs from most tumor types. Here, we discuss Hh signaling mechanisms in the context of human cancer, particularly in the maintenance of the CSC phenotype, and consider new therapeutic strategies that hold the potential to expand considerably the scope and therapeutic efficacy of Hh-directed anticancer therapy. PMID:25646180

  5. Cornering metastases: therapeutic targeting of circulating tumor cells and stem cells.

    Directory of Open Access Journals (Sweden)

    Bishoy eFaltas

    2012-07-01

    Full Text Available The last decade has witnessed an evolution of our understanding of the biology of the metastatic cascade. Recent insights into the metastatic process show that it is complex, dynamic and multi-directional. This process starts at a very early stage in the natural history of solid tumor growth leading to early development of metastases that grow in parallel with the primary tumor. The role of stem cells in perpetuating cancer metastases is increasingly becoming more evident. At the same time, there is a growing recognition of the crucial role circulating tumor cells (CTCs play in the development of metastases. These insights have laid the biological foundations for therapeutic targeting of CTCs, a promising area of research that aims to reduce cancer morbidity and mortality by preventing the development of metastases at a very early stage. The hematogenous transport phase of the metastatic cascade provides critical access to CTCs for therapeutic targeting aiming to interrupt the metastatic process. Recent advances in the fields of nanotechnology and micro-fluidics have led to the development of several devices for in-vivo targeting of CTC during transit in the circulation. Selectin-coated tubes that target cell adhesion molecules, immuno-magnetic separators and in-vivo photoacoustic flow cytometers are currently being developed for this purpose. On the pharmacological front, several pharmacological and immunological agents targeting cancer stem cells are currently being developed. Such agents may ultimately prove to be effective against circulating tumor stem cells (CTSCs. Although still in its infancy, therapeutic targeting of CTCs and CTSCs offers an unprecedented opportunity to prevent the development of metastasis and potentially alter the natural history of cancer. By rendering cancer a local disease, these approaches could lead to major reductions in metastasis-related morbidity and mortality.

  6. Female resistance to pneumonia identifies lung macrophage nitric oxide synthase-3 as a therapeutic target

    DEFF Research Database (Denmark)

    Yang, Zhiping; Huang, Yuh-Chin T; Koziel, Henry;

    2014-01-01

    ). Epidemiologic data show decreased hospitalization for pneumonia in women receiving estrogen or statins (known to activate NOS3). Pharmacologic targeting of NOS3 with statins or another small-molecule compound (AVE3085) enhanced macrophage bacterial killing, improved bacterial clearance, and increased host...... survival in both primary and secondary (post-influenza) pneumonia. The data identify a novel mechanism for host defense via NOS3 and suggest a potential therapeutic strategy to reduce secondary bacterial pneumonia after influenza....

  7. MicroRNAs are potential therapeutic targets in fibrosing kidney disease: lessons from animal models

    OpenAIRE

    Duffield, Jeremy S.; Grafals, Monica; Portilla, Didier

    2012-01-01

    Chronic disease of the kidneys has reached epidemic proportions in industrialized nations. New therapies are urgently sought. Using a combination of animal models of kidney disease and human biopsy samples, a pattern of dysregulated microRNA expression has emerged which is common to chronic diseases. A number of these dysregulated microRNA have recently been shown to have functional consequences for the disease process and therefore may be potential therapeutic targets. We highlight microRNA-...

  8. DD-07A KINOME RNA INTERFERENCE SCREEN IDENTIFIES NOVEL THERAPEUTIC TARGETS FOR GLIOBLASTOMA

    OpenAIRE

    Pham, Lily; Liang, Yanping; Guo, Sujuan; Murphy, Susan; Sheng, Zhi

    2014-01-01

    Glioblastoma (GBM) is the most common primary central nervous system tumor. Despite aggressive therapies such as surgical resection, chemo- and radiotherapies, the life expectancy and survival rates for GBM patients are still low. There is an urgent need for more effective therapies. We here hypothesized that certain kinases that are essential for GBM cell survival and thereby the better therapeutic targets for GBM remain to be defined. To identify these kinases, we designed and performed a d...

  9. HIV Capsid is a Tractable Target for Small Molecule Therapeutic Intervention

    OpenAIRE

    Blair, Wade S.; Pickford, Chris; Irving, Stephen L.; Brown, David G.; Anderson, Marie; Bazin, Richard; Cao, Joan; Ciaramella, Giuseppe; Isaacson, Jason; Jackson, Lynn; Hunt, Rachael; Kjerrstrom, Anne; Nieman, James A.; Patick, Amy K.; Perros, Manos

    2010-01-01

    Despite a high current standard of care in antiretroviral therapy for HIV, multidrug-resistant strains continue to emerge, underscoring the need for additional novel mechanism inhibitors that will offer expanded therapeutic options in the clinic. We report a new class of small molecule antiretroviral compounds that directly target HIV-1 capsid (CA) via a novel mechanism of action. The compounds exhibit potent antiviral activity against HIV-1 laboratory strains, clinical isolates, and HIV-2, a...

  10. Targeting the Glutamatergic System to Develop Novel, Improved Therapeutics for Mood Disorders

    OpenAIRE

    Sanacora, Gerard; Zarate, Carlos A.; Krystal, John; Manji, Husseini K.

    2008-01-01

    Mood disorders are common, chronic, recurrent mental illnesses that affect the lives of millions of individuals worldwide. To date, the monoaminergic systems (serotonergic, noradrenergic and dopaminergic) in the brain have received the greatest attention in neurobiological studies of mood disorders, and most therapeutics target these systems. However, there is growing evidence that the glutamatergic system is central to the neurobiology and treatment of these disorders. Here, we review data s...

  11. From DNA to Targeted Therapeutics: Bringing Synthetic Biology to the Clinic

    OpenAIRE

    Chen, Yvonne Y; Smolke, Christina D.

    2011-01-01

    Synthetic biology aims to make biological engineering more scalable and predictable, lowering the cost and facilitating the translation of synthetic biological systems to practical applications. Increasingly sophisticated, rationally designed synthetic systems that are capable of complex functions pave the way to translational applications, including disease diagnostics and targeted therapeutics. Here, we provide an overview of recent developments in synthetic biology in the context of transl...

  12. Integrative Omics Analysis of Rheumatoid Arthritis Identifies Non-Obvious Therapeutic Targets

    OpenAIRE

    Whitaker, John W.; Boyle, David L.; Bartok, Beatrix; Ball, Scott T.; Gay, Steffen; Wang, Wei; Firestein, Gary S.

    2015-01-01

    Identifying novel therapeutic targets for the treatment of disease is challenging. To this end, we developed a genome-wide approach of candidate gene prioritization. We independently collocated sets of genes that were implicated in rheumatoid arthritis (RA) pathogenicity through three genome-wide assays: (i) genome-wide association studies (GWAS), (ii) differentially expression in RA fibroblast-like synoviocytes (FLS), and (iii) differentially methylation in RA FLS. Integrated analysis of the...

  13. Integrative omics analysis of rheumatoid arthritis identifies non-obvious therapeutic targets

    OpenAIRE

    Whitaker, John W.; Boyle, David L.; Bartok, Beatrix; Ball, Scott T.; Gay, Steffen; Wang, Wei; Firestein, Gary S.

    2015-01-01

    Identifying novel therapeutic targets for the treatment of disease is challenging. To this end, we developed a genome-wide approach of candidate gene prioritization. We independently collocated sets of genes that were implicated in rheumatoid arthritis (RA) pathogenicity through three genome-wide assays: (i) genome-wide association studies (GWAS), (ii) differentially expression in RA fibroblast-like synoviocytes (FLS), and (iii) differentially methylation in RA FLS. Integrated analysis of the...

  14. Glycolysis in the African Trypanosome: Targeting Enzymes and Their Subcellular Compartments for Therapeutic Development

    OpenAIRE

    James C. Morris; Morris, Meredith T.; Dodson, Heidi C.; Coley, April F.

    2011-01-01

    Subspecies of the African trypanosome, Trypanosoma brucei, which cause human African trypanosomiasis, are transmitted by the tsetse fly, with transmission-essential lifecycle stages occurring in both the insect vector and human host. During infection of the human host, the parasite is limited to using glycolysis of host sugar for ATP production. This dependence on glucose breakdown presents a series of targets for potential therapeutic development, many of which have been explored and validat...

  15. Cytogenomic profiling of breast cancer brain metastases reveals potential for repurposing targeted therapeutics

    OpenAIRE

    Bollig-Fischer, Aliccia; Michelhaugh, Sharon K.; Wijesinghe, Priyanga; Dyson, Greg; Kruger, Adele; Palanisamy, Nallasivam; Choi, Lydia; Alosh, Baraa; Ali-Fehmi, Rouba; Mittal, Sandeep

    2015-01-01

    Breast cancer brain metastases remain a significant clinical problem. Chemotherapy is ineffective and a lack of treatment options result in poor patient outcomes. Targeted therapeutics have proven to be highly effective in primary breast cancer, but lack of molecular genomic characterization of metastatic brain tumors is hindering the development of new treatment regimens. Here we contribute to fill this void by reporting on gene copy number variation (CNV) in 10 breast cancer metastatic brai...

  16. Mitochondrial fusion and fission proteins: Novel therapeutic targets for combating cardiovascular disease.

    OpenAIRE

    Hall, A.; Burke, N; Dongworth, R.; Hausenloy, D.

    2014-01-01

    Mitochondria are no longer considered to be solely the static powerhouses of the cell. While they are undoubtedly essential to sustaining life and meeting the energy requirements of the cell through oxidative phosphorylation, they are now regarded as highly dynamic organelles with multiple funtions, playing key roles in cell survival and death. In this review, we discuss the emerging role of mitochondrial fusion and fission proteins, as novel therapeutic targets for treating a wide range of c...

  17. Mitochondrial Oxidative Damage in Aging and Alzheimer's Disease: Implications for Mitochondrially Targeted Antioxidant Therapeutics

    OpenAIRE

    Reddy, P. Hemachandra

    2006-01-01

    The overall aim of this article is to review current therapeutic strategies for treating AD, with a focus on mitochondrially targeted antioxidant treatments. Recent advances in molecular, cellular, and animal model studies of AD have revealed that amyloid precursor protein derivatives, including amyloid beta (Aβ) monomers and oligomers, are likely key factors in tau hyperphosphorylation, mitochondrial oxidative damage, inflammatory changes, and synaptic failure in the brain tissue of AD patie...

  18. Targeting leukemic fusion proteins with small interfering RNAs: recent advances and therapeutic potentials

    Institute of Scientific and Technical Information of China (English)

    Maria THOMAS; Johann GREIL; Olaf HEIDENREICH

    2006-01-01

    RNA interference has become an indispensable research tool to study gene functions in a wide variety of organisms.Because of their high efficacy and specificity,RNA interference-based approaches may also translate into new therapeutic strategies to treat human diseases.In particular,oncogenes such as leukemic fusion proteins,which arise from chromosomal translocations,are promising targets for such gene silencing approaches,because they are exclusively expressed in precancerous and cancerous tissues,and because they are frequently indispensable for maintaining the malignant phenotype.This review summarizes recent developments in targeting leukemia-specific genes and discusses problems and approaches for possible clinical applications.

  19. HIV-1 TAT and IMMUNE DYSREGULATION in AIDS PATHOGENESIS: a THERAPEUTIC TARGET.

    Science.gov (United States)

    Chiozzini, Chiara; Toschi, Elena

    2016-01-01

    The HIV-1 transactivator Tat protein plays a key role in AIDS pathogenesis. Besides the Tat role as activator of HIV-1 transcription, it exerts several important functions on infected and uninfected cells. In fact, HIV-1 Tat is released by infected cells and is taken up by neighboring cells. In this way it regulates expression of viral and cellular genes and it modulates several cellular pathways leading to HIV-1 infection spreading and immune dysregulation. So far, Tat protein and the cellular pathways targeted by Tat may represent potential targets for new anti-HIV therapeutic approaches and vaccine development against AIDS. PMID:26302810

  20. Hypoxia-Inducible Factors: Mediators of Cancer Progression; Prognostic and Therapeutic Targets in Soft Tissue Sarcomas

    Energy Technology Data Exchange (ETDEWEB)

    Sadri, Navid; Zhang, Paul J., E-mail: pjz@mail.med.upenn.edu [Anatomic Pathology, Department of Pathology and Laboratory Medicine, Hospital of the University of Pennsylvania, 3400 Spruce Street, 6th Floor Founders Building, Philadelphia, PA 19104 (United States)

    2013-04-02

    Soft-tissue sarcomas remain aggressive tumors that result in death in greater than a third of patients due to either loco-regional recurrence or distant metastasis. Surgical resection remains the main choice of treatment for soft tissue sarcomas with pre- and/or post-operational radiation and neoadjuvant chemotherapy employed in more advanced stage disease. However, in recent decades, there has been little progress in the average five-year survival for the majority of patients with high-grade soft tissue sarcomas, highlighting the need for improved targeted therapeutic agents. Clinical and preclinical studies demonstrate that tumor hypoxia and up-regulation of hypoxia-inducible factors (HIFs) is associated with decreased survival, increased metastasis, and resistance to therapy in soft tissue sarcomas. HIF-mediated gene expression regulates many critical aspects of tumor biology, including cell survival, metabolic programming, angiogenesis, metastasis, and therapy resistance. In this review, we discuss HIFs and HIF-mediated genes as potential prognostic markers and therapeutic targets in sarcomas. Many pharmacological agents targeting hypoxia-related pathways are in development that may hold therapeutic potential for treating both primary and metastatic sarcomas that demonstrate increased HIF expression.

  1. Engineering novel targeted nanoparticle formulations to increase the therapeutic efficacy of conventional chemotherapeutics against multiple myeloma

    Science.gov (United States)

    Ashley, Jonathan D.

    Multiple myeloma (MM) is a hematological malignancy which results from the uncontrolled clonal expansion of plasma cells within the body. Despite recent medical advances, this disease remains largely incurable, with a median survival of ˜7 years, owing to the development of drug resistance. This dissertation will explore new advances in nanotechnology that will combine the cytotoxic effects of small molecule chemotherapeutics with the tumor targeting capabilities of nanoparticles to create novel nanoparticle formulations that exhibit enhanced therapeutic indices in the treatment of MM. First, doxorubicin was surfaced conjugated onto micellar nanoparticles via an acid labile hydrazone bond to increase the drug accumulation at the tumor. The cell surface receptor Very Late Antigen-4 (VLA-4; alpha4beta1) is expressed on cancers of hematopoietic origin and plays a vital role in the cell adhesion mediated drug resistance (CAM-DR) in MM. Therefore, VLA-4 antagonist peptides were conjugated onto the nanoparticles via a multifaceted procedure to actively target MM cells and simultaneously inhibit CAM-DR. The micellar doxorubicin nanoparticles were able to overcome CAM-DR and demonstrated improved therapeutic index relative to free doxorubicin. In addition to doxorubicin, other classes of therapeutic agents, such as proteasome inhibitors, can be incorporated in nanoparticles for improved therapeutic outcomes. Utilizing boronic acid chemistry, bortezomib prodrugs were synthesized using a reversible boronic ester bond and then incorporated into liposomes. The different boronic ester bonds that could be potentially used in the synthesis of bortezomib prodrugs were screened based on stability using isobutylboronic acid. The liposomal bortezomib nanoparticles demonstrated significant proteasome inhibition and cytotoxicity in MM cells in vitro, and dramatically reduced the non-specific toxicities associated with free bortezomib while maintaining significant tumor growth

  2. Engineering Multi-Walled Carbon Nanotube Therapeutic Bionanofluids to Selectively Target Papillary Thyroid Cancer Cells.

    Directory of Open Access Journals (Sweden)

    Idit Dotan

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

  3. Engineering Multi-Walled Carbon Nanotube Therapeutic Bionanofluids to Selectively Target Papillary Thyroid Cancer Cells

    Science.gov (United States)

    Paliouras, Miltiadis; Mitmaker, Elliot J.; Trifiro, Mark A.

    2016-01-01

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

  4. Advances in Antisense Oligonucleotide Development for Target Identification, Validation, and as Novel Therapeutics

    Directory of Open Access Journals (Sweden)

    Moizza Mansoor

    2008-01-01

    Full Text Available Antisense oligonucleotides (As-ODNs are single stranded, synthetically prepared strands of deoxynucleotide sequences, usually 18–21 nucleotides in length, complementary to the mRNA sequence of the target gene. As-ODNs are able to selectively bind cognate mRNA sequences by sequence-specific hybridization. This results in cleavage or disablement of the mRNA and, thus, inhibits the expression of the target gene. The specificity of the As approach is based on the probability that, in the human genome, any sequence longer than a minimal number of nucleotides (nt, 13 for RNA and 17 for DNA, normally occurs only once. The potential applications of As-ODNs are numerous because mRNA is ubiquitous and is more accessible to manipulation than DNA. With the publication of the human genome sequence, it has become theoretically possible to inhibit mRNA of almost any gene by As-ODNs, in order to get a better understanding of gene function, investigate its role in disease pathology and to study novel therapeutic targets for the diseases caused by dysregulated gene expression. The conceptual simplicity, the availability of gene sequence information from the human genome, the inexpensive availability of synthetic oligonucleotides and the possibility of rational drug design makes As-ODNs powerful tools for target identification, validation and therapeutic intervention. In this review we discuss the latest developments in antisense oligonucleotide design, delivery, pharmacokinetics and potential side effects, as well as its uses in target identification and validation, and finally focus on the current developments of antisense oligonucleotides in therapeutic intervention in various diseases.

  5. Recent Advancements in Targeted Delivery of Therapeutic Molecules in Neurodegenerative Disease - Spinocerebellar Ataxia - Opportunities and Challenges

    Directory of Open Access Journals (Sweden)

    Satya Prakash

    2008-01-01

    Full Text Available Drug discovery and its methodologies have been very effective in terms of treating cancers and immunological disorders but have not been able to stop genetic diseases as most of the drugs target at the protein level. They merely mitigate the symptoms of the disease. Spinocerebellar ataxia is a neurological genetic disorder that is caused by the formation of an abnormal protein. There have been several reports on ataxic drug development but actual clinical treatment is yet to be achieved. Oligonucleotide therapy called sequence specific siRNA mediated gene silencing has evolved with promising results. This approach emphasizes on suppressing the expression of the diseased gene at mRNA level. However, there is a limitation in delivery of siRNA to the target site. Several methods have been developed over the last decade to enhance the target specific delivery of DNA, siRNA, protein and small drug molecules for therapeutic purpose with less or no side effects. This review discusses the latest upcoming technologies in the field that focus on a number of nonviral nanocarriers for targeted delivery. In this review, we explore the promise and potential of novel therapeutics with interest on ataxia therapy.

  6. Radiolabelled multifunctional nanoparticles for targeted diagnostic and therapeutic applications in oncology

    International Nuclear Information System (INIS)

    Nanoparticles, liposomes in particular, have gained great attention as easily engineerable nanoscale systems with distinct properties, offering an ideal platform for a variety of diagnostic and therapeutic applications. The aim of this PhD thesis was the design, synthesis as well as the in vitro and in vivo evaluation of several radiolabelled multifunctional liposomal nanoparticles for the targeted imaging of tumour cells and tumour-induced angiogenesis. Radiolabelling methods for different radionuclides were developed and the liposomes were functionalised with polyethylene glycol (PEG) to improve the pharmacokinetic profile. Targeting sequences such as the tripeptide Arg-Gly-Asp (RGD), the neuropeptide substance P (SP), the somatostatin analogue tyrosine-3-octreotide (TOC), and the vasoactive intestinal peptide (VIP) were tested for their applicability as tools for the targeted delivery of imaging agents. Finally, by the combination of two targeting sequences, namely RGD and SP, on one liposome multireceptor-targeting (hybrid-targeting) was investigated. These multifunctional vehicles were also functionalized with imaging labels for the detection and imaging of tumours by single photon emission computed tomography (SPECT), fluorescence microscopy as well as magnetic resonance (MR) imaging. The liposomes developed in this thesis showed multifunctional properties combining several imaging approaches with specific targeting for oncological applications. In vitro behaviour, e.g., receptor binding could be improved, resulting in optimised targeting shown both by the radiolabel and fluorescent label. However, the in vivo properties, especially the tumour targeting characteristics remained suboptimal, revealing the challenges of targeting approaches in nanoscience. Nonetheless, these results brought important insights for the development and optimisation of multifunctional nanocarriers. (author)

  7. CD19-targeted CAR T-cell therapeutics for hematologic malignancies: interpreting clinical outcomes to date.

    Science.gov (United States)

    Park, Jae H; Geyer, Mark B; Brentjens, Renier J

    2016-06-30

    Adoptive transfer of T cells genetically modified to express chimeric antigen receptors (CARs) targeting CD19 has produced impressive results in treating patients with B-cell malignancies. Although these CAR-modified T cells target the same antigen, the designs of CARs vary as well as several key aspects of the clinical trials in which these CARs have been studied. It is unclear whether these differences have any impact on clinical outcome and treatment-related toxicities. Herein, we review clinical results reflecting the investigational use of CD19-targeted CAR T-cell therapeutics in patients with B-cell hematologic malignancies, in light of differences in CAR design and production, and outline the limitations inherent in comparing outcomes between studies. PMID:27207800

  8. Fatty acid oxidation and carnitine palmitoyltransferase I: emerging therapeutic targets in cancer.

    Science.gov (United States)

    Qu, Q; Zeng, F; Liu, X; Wang, Q J; Deng, F

    2016-01-01

    Tumor cells exhibit unique metabolic adaptations that are increasingly viewed as potential targets for novel and specific cancer therapies. Among these targets, the carnitine palmitoyltransferase system is responsible for delivering the long-chain fatty acid (FA) from cytoplasm into mitochondria for oxidation, where carnitine palmitoyltransferase I (CPTI) catalyzes the rate-limiting step of fatty acid oxidation (FAO). With increasing understanding of the crucial role had by fatty acid oxidation in cancer, CPTI has received renewed attention as a pivotal mediator in cancer metabolic mechanism. CPTI activates FAO and fuels cancer growth via ATP and NADPH production, constituting an essential part of cancer metabolism adaptation. Moreover, CPTI also functionally intertwines with other key pathways and factors to regulate gene expression and apoptosis of cancer cell. Here, we summarize recent findings and update the current understanding of FAO and CPTI in cancer and provide theoretical basis for this enzyme as an emerging potential molecular target in cancer therapeutic intervention. PMID:27195673

  9. Pharmacological targeting of PI3K isoforms as a therapeutic strategy in chronic lymphocytic leukaemia

    Science.gov (United States)

    Blunt, Matthew D.; Steele, Andrew J.

    2015-01-01

    PI3Kδ inhibitors such as idelalisib are providing improved therapeutic options for the treatment of chronic lymphocytic leukaemia (CLL). However under certain conditions, inhibition of a single PI3K isoform can be compensated by the other PI3K isoforms, therefore PI3K inhibitors which target multiple PI3K isoforms may provide greater efficacy. The development of compounds targeting multiple PI3K isoforms (α, β, δ, and γ) in CLL cells, in vitro, resulted in sustained inhibition of BCR signalling but with enhanced cytotoxicity and the potential for improve clinical responses. This review summarises the progress of PI3K inhibitor development and describes the rationale and potential for targeting multiple PI3K isoforms. PMID:26500849

  10. Pharmacological targeting of PI3K isoforms as a therapeutic strategy in chronic lymphocytic leukaemia

    Directory of Open Access Journals (Sweden)

    Matthew D. Blunt

    2015-01-01

    Full Text Available PI3Kδ inhibitors such as idelalisib are providing improved therapeutic options for the treatment of chronic lymphocytic leukaemia (CLL. However under certain conditions, inhibition of a single PI3K isoform can be compensated by the other PI3K isoforms, therefore PI3K inhibitors which target multiple PI3K isoforms may provide greater efficacy. The development of compounds targeting multiple PI3K isoforms (α, β, δ, and γ in CLL cells, in vitro, resulted in sustained inhibition of BCR signalling but with enhanced cytotoxicity and the potential for improve clinical responses. This review summarises the progress of PI3K inhibitor development and describes the rationale and potential for targeting multiple PI3K isoforms.

  11. MicroRNAs are potential therapeutic targets in fibrosing kidney disease: lessons from animal models

    Science.gov (United States)

    Duffield, Jeremy S; Grafals, Monica; Portilla, Didier

    2012-01-01

    Chronic disease of the kidneys has reached epidemic proportions in industrialized nations. New therapies are urgently sought. Using a combination of animal models of kidney disease and human biopsy samples, a pattern of dysregulated microRNA expression has emerged which is common to chronic diseases. A number of these dysregulated microRNA have recently been shown to have functional consequences for the disease process and therefore may be potential therapeutic targets. We highlight microRNA-21, the most comprehensively studied microRNA in the kidney so far. MicroRNA-21 is expressed widely in healthy kidney but studies from knockout mice indicate it is largely inert. Although microRNA-21 is upregulated in many cell compartments including leukocytes, epithelial cells and myofibroblasts, the inert microRNA-21 also appears to become activated, by unclear mechanisms. Mice lacking microRNA-21 are protected from kidney injury and fibrosis in several distinct models of kidney disease, and systemically administered oligonucleotides that specifically bind to the active site in microRNA-21, inhibiting its function, recapitulate the genetic deletion of microRNA-21, suggesting inhibitory oligonucleotides may have therapeutic potential. Recent studies of microRNA-21 targets in kidney indicate that it normally functions to silence metabolic pathways including fatty acid metabolism and pathways that prevent Reactive Oxygen Species generation in peroxisomes and mitochondria in epithelial cells and myofibroblasts. Targeting specific pathogenic microRNAs in a specific manner is feasible in vivo and may be a new therapeutic target in disease of the kidney PMID:25018773

  12. Sensitivity of chronic lymphocytic leukemia cells to small targeted therapeutic molecules: An in vitro comparative study.

    Science.gov (United States)

    Sylvan, Sandra Eketorp; Skribek, Henriette; Norin, Stefan; Muhari, Orsolya; Österborg, Anders; Szekely, Laszlo

    2016-01-01

    New drugs targeting important cellular signaling pathways are currently being developed for chronic lymphocytic leukemia (CLL). It is therefore of interest to analyze their in vitro killing capacity in manufacturer-independent, comparative experiments. We here report on the sensitivity of CLL cells to a panel of emerging targeted therapeutics using high-throughput screening based on an automated fluorescence digital scanning system. Fresh CLL cells from 42 patients with indolent or progressive CLL were cultured for 72 hours on microtiter plates in a unique primary cell culture medium. Antitumor effects of 31 small therapeutic molecules (and, as controls, 29 cytostatic agents) at equimolar concentration were compared in a fluorescence survival assay. In vitro sensitivity to each drug exhibited considerable interpatient variability. The highest mean direct killing was observed for one survivin inhibitor (YM-155), two bcl-2 inhibitors (ABT-199, ABT-737), and one selective CDK inhibitor (dinaciclib). Their killing capacity was, in contrast to most cytostatic agents, similarly high in refractory versus untreated CLL patients and was significantly higher on cells with the 17p deletion/TP53 mutation than on cells with other cytogenetic abnormalities (p = 0.02). Sensitivity of bone marrow and lymph node cells was highly correlated with that of blood cells. Even though direct killing may not be the only therapeutic effector function in vivo, results from this head-to-head comparison may help to identify drugs of particular interest for intensified clinical development. PMID:26325331

  13. Pathophysiological significance and therapeutic targeting of germinal center kinase in diffuse large B-cell lymphoma.

    Science.gov (United States)

    Matthews, Julie Marie; Bhatt, Shruti; Patricelli, Matthew P; Nomanbhoy, Tyzoon K; Jiang, Xiaoyu; Natkunam, Yasodha; Gentles, Andrew J; Martinez, Ezequiel; Zhu, Daxing; Chapman, Jennifer Rose; Cortizas, Elena; Shyam, Ragini; Chinichian, Shideh; Advani, Ranjana; Tan, Li; Zhang, Jianming; Choi, Hwan Geun; Tibshirani, Robert; Buhrlage, Sara J; Gratzinger, Dita; Verdun, Ramiro; Gray, Nathanael S; Lossos, Izidore S

    2016-07-14

    Diffuse large B-cell lymphoma (DLBCL) is the most common subtype of non-Hodgkin lymphoma, yet 40% to 50% of patients will eventually succumb to their disease, demonstrating a pressing need for novel therapeutic options. Gene expression profiling has identified messenger RNAs that lead to transformation, but critical events transforming cells are normally executed by kinases. Therefore, we hypothesized that previously unrecognized kinases may contribute to DLBCL pathogenesis. We performed the first comprehensive analysis of global kinase activity in DLBCL, to identify novel therapeutic targets, and discovered that germinal center kinase (GCK) was extensively activated. GCK RNA interference and small molecule inhibition induced cell-cycle arrest and apoptosis in DLBCL cell lines and primary tumors in vitro and decreased the tumor growth rate in vivo, resulting in a significantly extended lifespan of mice bearing DLBCL xenografts. GCK expression was also linked to adverse clinical outcome in a cohort of 151 primary DLBCL patients. These studies demonstrate, for the first time, that GCK is a molecular therapeutic target in DLBCL tumors and that inhibiting GCK may significantly extend DLBCL patient survival. Because the majority of DLBCL tumors (∼80%) exhibit activation of GCK, this therapy may be applicable to most patients. PMID:27151888

  14. The endothelin system as a therapeutic target in cardiovascular disease: great expectations or bleak house?

    Science.gov (United States)

    Kirkby, N S; Hadoke, P W F; Bagnall, A J; Webb, D J

    2008-03-01

    There is considerable evidence that the potent vasoconstrictor endothelin-1 (ET-1) contributes to the pathogenesis of a variety of cardiovascular diseases. As such, pharmacological manipulation of the ET system might represent a promising therapeutic goal. Many clinical trials have assessed the potential of ET receptor antagonists in cardiovascular disease, the most positive of which have resulted in the licensing of the mixed ET receptor antagonist bosentan, and the selective ET(A) receptor antagonists, sitaxsentan and ambrisentan, for the treatment of pulmonary arterial hypertension (PAH). In contrast, despite encouraging data from in vitro and animal studies, outcomes in human heart failure have been disappointing, perhaps illustrating the risk of extrapolating preclinical work to man. Many further potential applications of these compounds, including resistant hypertension, chronic kidney disease, connective tissue disease and sub-arachnoid haemorrhage are currently being investigated in the clinic. Furthermore, experience from previous studies should enable improved trial design and scope remains for development of improved compounds and alternative therapeutic strategies. Although ET-converting enzyme inhibitors may represent one such alternative, there have been relatively few suitable compounds developed, and consequently, clinical experience with these agents remains extremely limited. Recent advances, together with an increased understanding of the biology of the ET system provided by improved experimental tools (including cell-specific transgenic deletion of ET receptors), should allow further targeting of clinical trials to diseases in which ET is involved and allow the therapeutic potential for targeting the ET system in cardiovascular disease to be fully realized. PMID:17965745

  15. Targeting the endocannabinoid system with cannabinoid receptor agonists: pharmacological strategies and therapeutic possibilities.

    Science.gov (United States)

    Pertwee, Roger G

    2012-12-01

    Human tissues express cannabinoid CB(1) and CB(2) receptors that can be activated by endogenously released 'endocannabinoids' or exogenously administered compounds in a manner that reduces the symptoms or opposes the underlying causes of several disorders in need of effective therapy. Three medicines that activate cannabinoid CB(1)/CB(2) receptors are now in the clinic: Cesamet (nabilone), Marinol (dronabinol; Δ(9)-tetrahydrocannabinol (Δ(9)-THC)) and Sativex (Δ(9)-THC with cannabidiol). These can be prescribed for the amelioration of chemotherapy-induced nausea and vomiting (Cesamet and Marinol), stimulation of appetite (Marinol) and symptomatic relief of cancer pain and/or management of neuropathic pain and spasticity in adults with multiple sclerosis (Sativex). This review mentions several possible additional therapeutic targets for cannabinoid receptor agonists. These include other kinds of pain, epilepsy, anxiety, depression, Parkinson's and Huntington's diseases, amyotrophic lateral sclerosis, stroke, cancer, drug dependence, glaucoma, autoimmune uveitis, osteoporosis, sepsis, and hepatic, renal, intestinal and cardiovascular disorders. It also describes potential strategies for improving the efficacy and/or benefit-to-risk ratio of these agonists in the clinic. These are strategies that involve (i) targeting cannabinoid receptors located outside the blood-brain barrier, (ii) targeting cannabinoid receptors expressed by a particular tissue, (iii) targeting upregulated cannabinoid receptors, (iv) selectively targeting cannabinoid CB(2) receptors, and/or (v) adjunctive 'multi-targeting'. PMID:23108552

  16. Plasma-derived Extracellular Vesicles Contain Predictive Biomarkers and Potential Therapeutic Targets for Myocardial Ischemic (MI) Injury.

    Science.gov (United States)

    Cheow, Esther Sok Hwee; Cheng, Woo Chin; Lee, Chuen Neng; de Kleijn, Dominique; Sorokin, Vitaly; Sze, Siu Kwan

    2016-08-01

    Myocardial infarction (MI) triggers a potent inflammatory response via the release of circulatory mediators, including extracellular vesicles (EVs) by damaged cardiac cells, necessary for myocardial healing. Timely repression of inflammatory response are critical to prevent and minimize cardiac tissue injuries, nonetheless, progression in this aspect remains challenging. The ability of EVs to trigger a functional response upon delivery of carried bioactive cargos, have made them clinically attractive diagnostic biomarkers and vectors for therapeutic interventions. Using label-free quantitative proteomics approach, we compared the protein cargo of plasma EVs between patients with MI and from patients with stable angina (NMI). We report, for the first time, the proteomics profiling on 252 EV proteins that were modulated with >1.2-fold after MI. We identified six up-regulated biomarkers with potential for clinical applications; these reflected post-infarct pathways of complement activation (Complement C1q subcomponent subunit A (C1QA), 3.23-fold change, p = 0.012; Complement C5 (C5), 1.27-fold change, p = 0.087), lipoprotein metabolism (Apoliporotein D (APOD), 1.86-fold change, p = 0.033; Apolipoprotein C-III (APOCC3), 2.63-fold change, p = 0.029) and platelet activation (Platelet glycoprotein Ib alpha chain (GP1BA), 9.18-fold change, p p = 0.027). The data have been deposited to the ProteomeXchange with identifier PXD002950. This novel biomarker panel was validated in 43 patients using antibody-based assays (C1QA (p = 0.005); C5 (p = 0.0047), APOD (p = 0.0267); APOC3 (p = 0.0064); GP1BA (p = 0.0031); PPBP (p = 0.0465)). We further present that EV-derived fibrinogen components were paradoxically down-regulated in MI, suggesting that a compensatory mechanism may suppress post-infarct coagulation pathways, indicating potential for therapeutic targeting of this mechanism in MI. Taken together, these data demonstrated that plasma EVs contain novel diagnostic biomarkers

  17. Possible molecular targets for therapeutic applications of caffeic acid phenethyl ester in inflammation and cancer

    Directory of Open Access Journals (Sweden)

    Ghulam Murtaza

    2015-03-01

    Full Text Available Of the various derivatives of caffeic acid, caffeic acid phenethyl ester (CAPE is a hydrophobic, bioactive polyphenolic ester obtained from propolis extract. The objective in writing this review article was to summarize all published studies on therapeutics of CAPE in inflammation and cancer to extract direction for future research. The possible molecular targets for the action of CAPE, include various transcription factors such as nuclear factor-κB, tissue necrosis factor-α, interleukin-6, cyclooxygenase-2, Nrf2, inducible nitric oxide synthase, nuclear factor of activated T cells, hypoxia-inducible factor-1α, and signal transducers and activators of transcription. Based on the valuable data on its therapeutics in inflammation and cancer, clinical studies of CAPE should also be conducted to explore its toxicities, if any.

  18. Potential prospects of nanomedicine for targeted therapeutics in inflammatory bowel diseases

    Institute of Scientific and Technical Information of China (English)

    Madharasi VA Pichai; Lynnette R Ferguson

    2012-01-01

    Inflammatory bowel diseases (IBDs) such as Crohn's disease are highly debilitating.There are inconsistencies in response to and side effects in the current conventional medications,failures in adequate drug delivery,and the lack of therapeutics to offer complete remission in the presently available treatments of IBD.This suggests the need to explore beyond the horizons of conventional approaches in IBD therapeutics.This review examines the arena of the evolving IBD nanomedicine,studied so far in animal andin vitro models,before comprehensive clinical testing in humans.The investigations carried out so far in IBD models have provided substantial evidence of the nanotherapeutic approach as having the potential to overcome some of the current drawbacks to conventional IBD therapy.We analyze the pros and cons of nanotechnology in IBD therapies studied in different models,aimed at different targets and mechanisms of IBD pathogenesis,in an attempt to predict its possible impact in humans.

  19. Macrophage migration inhibitory factor: a potential therapeutic target for rheumatoid arthritis.

    Science.gov (United States)

    Kim, Kyoung-Woon; Kim, Hae-Rim

    2016-07-01

    Macrophage migration inhibitory factor (MIF) is originally identified in the culture medium of activated T lymphocytes as a soluble factor that inhibits the random migration of macrophages. MIF is now recognized as a multipotent cytokine involved in the regulation of immune and inf lammatory responses. In rheumatoid arthritis (RA), MIF promotes inf lammatory responses by inducing proinflammatory cytokines and tissue-degrading molecules, promoting the proliferation and survival of synovial fibroblasts, stimulating neutrophil chemotaxis, and regulating angiogenesis and osteoclast differentiation. Expression of MIF in synovial tissue and synovial fluid levels of MIF are elevated in RA patients. Specifically, MIF levels correlate with RA disease activity and high levels are associated with bone erosion. In animal models of RA, the genetic and therapeutic inhibition of MIF has been shown to control inflammation and bone destruction. Based on the role of MIF in RA pathogenesis, small molecular inhibitors targeting it or its receptor pathways could provide a new therapeutic option for RA patients. PMID:27169879

  20. Sjögren's syndrome: from pathogenesis to novel therapeutic targets.

    Science.gov (United States)

    Barone, Francesca; Colafrancesco, Serena

    2016-01-01

    Primary Sjögren's syndrome (pSS) is a chronic inflammatory autoimmune disease, characterised by a chronic infiltration of exocrine glands, mainly salivary glands, with the histological features of focal lymphocytic sialoadenitis. Disease spectrum is broad and the occurrence of several extra-glandular manifestations, and in rare cases lymphoma development, is well known. A specific approved treatment for pSS is still lacking and the detection of novel therapeutic biologic target is ongoing. The identification of biological fingerprints seems essential in order to stratify patients both in clinical trials and in real life. Discovery of new components of the inflammatory response will be the key in the future for the identification of novel additional therapeutic options. PMID:27586806

  1. Potential prospects of nanomedicine for targeted therapeutics in inflammatory bowel diseases.

    Science.gov (United States)

    Pichai, Madharasi V A; Ferguson, Lynnette R

    2012-06-21

    Inflammatory bowel diseases (IBDs) such as Crohn's disease are highly debilitating. There are inconsistencies in response to and side effects in the current conventional medications, failures in adequate drug delivery, and the lack of therapeutics to offer complete remission in the presently available treatments of IBD. This suggests the need to explore beyond the horizons of conventional approaches in IBD therapeutics. This review examines the arena of the evolving IBD nanomedicine, studied so far in animal and in vitro models, before comprehensive clinical testing in humans. The investigations carried out so far in IBD models have provided substantial evidence of the nanotherapeutic approach as having the potential to overcome some of the current drawbacks to conventional IBD therapy. We analyze the pros and cons of nanotechnology in IBD therapies studied in different models, aimed at different targets and mechanisms of IBD pathogenesis, in an attempt to predict its possible impact in humans. PMID:22736912

  2. Network science for the identification of novel therapeutic targets in epilepsy

    Science.gov (United States)

    Scott, Rod C.

    2016-01-01

    The quality of life of children with epilepsy is a function of seizures and associated cognitive and behavioral comorbidities. Current treatments are not successful at stopping seizures in approximately 30% of patients despite the introduction of multiple new antiepileptic drugs over the last decade. In addition, modification of seizures has only a modest impact on the comorbidities. Therefore, novel approaches to identify therapeutic targets that improve seizures and comorbidities are urgently required. The potential of network science as applied to genetic, local neural network, and global brain data is reviewed. Several examples of possible new therapeutic approaches defined using novel network tools are highlighted. Further study to translate the findings into clinical practice is now required. PMID:27239287

  3. Macrophage migration inhibitory factor: a potential therapeutic target for rheumatoid arthritis

    Science.gov (United States)

    Kim, Kyoung-Woon; Kim, Hae-Rim

    2016-01-01

    Macrophage migration inhibitory factor (MIF) is originally identified in the culture medium of activated T lymphocytes as a soluble factor that inhibits the random migration of macrophages. MIF is now recognized as a multipotent cytokine involved in the regulation of immune and inf lammatory responses. In rheumatoid arthritis (RA), MIF promotes inf lammatory responses by inducing proinflammatory cytokines and tissue-degrading molecules, promoting the proliferation and survival of synovial fibroblasts, stimulating neutrophil chemotaxis, and regulating angiogenesis and osteoclast differentiation. Expression of MIF in synovial tissue and synovial fluid levels of MIF are elevated in RA patients. Specifically, MIF levels correlate with RA disease activity and high levels are associated with bone erosion. In animal models of RA, the genetic and therapeutic inhibition of MIF has been shown to control inflammation and bone destruction. Based on the role of MIF in RA pathogenesis, small molecular inhibitors targeting it or its receptor pathways could provide a new therapeutic option for RA patients. PMID:27169879

  4. Long non-coding RNAs as novel therapeutic targets in cancer.

    Science.gov (United States)

    Lavorgna, Giovanni; Vago, Riccardo; Sarmini, Mohamad; Montorsi, Francesco; Salonia, Andrea; Bellone, Matteo

    2016-08-01

    Thanks to impressive technology advancements, pervasive expression of non-coding RNAs (ncRNAs) has been recently identified in the genome of numerous cancers. Long ncRNAs (lncRNAs) belong to a new class of ncRNAs including tens of thousands different species. A fraction of these molecules shows a striking cancer-enriched expression pattern, suggesting an essential role in tumor cells and, possibly, a utility in therapeutic terms. This review aims at summarizing current knowledge for the identification and validation of lncRNAs as therapeutics targets in tumors. Both in-silico and wet-biology resources are presented in relation to the many challenges that the scientific community still needs to address in terms of lncRNA identification, stratification, patient personalization, drug delivery and toxicity. PMID:27210721

  5. ErbB polymorphisms: insights and implications for response to targeted cancer therapeutics.

    Science.gov (United States)

    Alaoui-Jamali, Moulay A; Morand, Grégoire B; da Silva, Sabrina Daniela

    2015-01-01

    Advances in high-throughput genomic-scanning have expanded the repertory of genetic variations in DNA sequences encoding ErbB tyrosine kinase receptors in humans, including single nucleotide polymorphisms (SNPs), polymorphic repetitive elements, microsatellite variations, small-scale insertions and deletions. The ErbB family members: EGFR, ErbB2, ErbB3, and ErbB4 receptors are established as drivers of many aspects of tumor initiation and progression to metastasis. This knowledge has provided rationales for the development of an arsenal of anti-ErbB therapeutics, ranging from small molecule kinase inhibitors to monoclonal antibodies. Anti-ErbB agents are becoming the cornerstone therapeutics for the management of cancers that overexpress hyperactive variants of ErbB receptors, in particular ErbB2-positive breast cancer and non-small cell lung carcinomas. However, their clinical benefit has been limited to a subset of patients due to a wide heterogeneity in drug response despite the expression of the ErbB targets, attributed to intrinsic (primary) and to acquired (secondary) resistance. Somatic mutations in ErbB tyrosine kinase domains have been extensively investigated in preclinical and clinical setting as determinants for either high sensitivity or resistance to anti-ErbB therapeutics. In contrast, only scant information is available on the impact of SNPs, which are widespread in genes encoding ErbB receptors, on receptor structure and activity, and their predictive values for drug susceptibility. This review aims to briefly update polymorphic variations in genes encoding ErbB receptors based on recent advances in deep sequencing technologies, and to address challenging issues for a better understanding of the functional impact of single versus combined SNPs in ErbB genes to receptor topology, receptor-drug interaction, and drug susceptibility. The potential of exploiting SNPs in the era of stratified targeted therapeutics is discussed. PMID:25699077

  6. The molecular phenotype of endocapillary proliferation: novel therapeutic targets for IgA nephropathy.

    Directory of Open Access Journals (Sweden)

    Jeffrey B Hodgin

    Full Text Available IgA nephropathy (IgAN is a clinically and pathologically heterogeneous disease. Endocapillary proliferation is associated with higher risk of progressive disease, and clinical studies suggest that corticosteroids mitigate this risk. However, corticosteroids are associated with protean cellular effects and significant toxicity. Furthermore the precise mechanism by which they modulate kidney injury in IgAN is not well delineated. To better understand molecular pathways involved in the development of endocapillary proliferation and to identify novel specific therapeutic targets, we evaluated the glomerular transcriptome of microdissected kidney biopsies from 22 patients with IgAN. Endocapillary proliferation was defined according to the Oxford scoring system independently by 3 nephropathologists. We analyzed mRNA expression using microarrays and identified transcripts differentially expressed in patients with endocapillary proliferation compared to IgAN without endocapillary lesions. Next, we employed both transcription factor analysis and in silico drug screening and confirmed that the endocapillary proliferation transcriptome is significantly enriched with pathways that can be impacted by corticosteroids. With this approach we also identified novel therapeutic targets and bioactive small molecules that may be considered for therapeutic trials for the treatment of IgAN, including resveratrol and hydroquinine. In summary, we have defined the distinct molecular profile of a pathologic phenotype associated with progressive renal insufficiency in IgAN. Exploration of the pathways associated with endocapillary proliferation confirms a molecular basis for the clinical effectiveness of corticosteroids in this subgroup of IgAN, and elucidates new therapeutic strategies for IgAN.

  7. ErbB polymorphisms: Insights and implications for response to targeted cancer therapeutics

    Directory of Open Access Journals (Sweden)

    Moulay A Alaoui-Jamali

    2015-02-01

    Full Text Available Advances in high-throughput genomic-scanning have expanded the repertory of genetic variations in DNA sequences encoding ErbB tyrosine kinase receptors in humans, including single nucleotide polymorphisms (SNPs, polymorphic repetitive elements, microsatellite variations, small-scale insertions and deletions. The ErbB family members: EGFR, ErbB2, ErbB3 and ErbB4 receptors are established as drivers of many aspects of tumor initiation and progression to metastasis. This knowledge has provided rationales for the development of an arsenal of anti-ErbB therapeutics, ranging from small molecule kinase inhibitors to monoclonal antibodies. Anti-ErbB agents are becoming the cornerstone therapeutics for the management of cancers that overexpress hyperactive variants of ErbB receptors, in particular ErbB2-positive breast cancer and non-small cell lung carcinomas. However, their clinical benefit has been limited to a subset of patients due to a wide heterogeneity in drug response despite the expression of the ErbB targets, attributed to intrinsic (primary and to acquired (secondary resistance. Somatic mutations in ErbB tyrosine kinase domains have been extensively investigated in preclinical and clinical setting as determinants for either high sensitivity or resistance to anti-ErbB therapeutics. In contrast, only scant information is available on the impact of SNPs, which are widespread in genes encoding ErbB receptors, on receptor structure and activity, and their predictive values for drug susceptibility. This review aims to briefly update polymorphic variations in genes encoding ErbB receptors based on recent advances in deep sequencing technologies, and to address challenging issues for a better understanding of the functional impact of single versus combined SNPs in ErbB genes to receptor topology, receptor-drug interaction, and drug susceptibility. The potential of exploiting SNPs in the era of stratified targeted therapeutics is discussed.

  8. DISC1 pathway in brain development: exploring therapeutic targets for major psychiatric disorders

    Directory of Open Access Journals (Sweden)

    AtsushiKamiya

    2012-03-01

    Full Text Available Genetic risk factors for major psychiatric disorders play key roles in neurodevelopment. Thus, exploring the molecular pathways of risk genes is important not only for understanding the molecular mechanisms underlying brain development, but also to decipher how genetic disturbances affect brain maturation and functioning relevant to major mental illnesses. During the last decade, there has been significant progress in determining the mechanisms whereby risk genes impact brain development. Nonetheless, given that the majority of psychiatric disorders have etiological complexities encompassing multiple risk genes and environmental factors, the biological mechanisms of these diseases remain poorly understood. How can we move forward in our research for discovery of the biological markers and novel therapeutic targets for major mental disorders? Here we review recent progress in the neurobiology of Disrupted in schizophrenia 1 (DISC1, a major risk gene for major mental disorders, with a particular focus on its roles in cerebral cortex development. Convergent findings implicate DISC1 as part of a large, multi-step pathway implicated in various cellular processes and signal transduction. We discuss links between the DISC1 pathway and environmental factors, such as immune/inflammatory responses, which may suggest novel therapeutic targets. Existing treatments for major mental disorders are hampered by a limited number of pharmacological targets. Consequently, elucidation of the DISC1 pathway, and its association with neuropsychiatric disorders, may offer hope for novel treatment interventions.

  9. Nrf2 as molecular target for polyphenols: A novel therapeutic strategy in diabetic retinopathy.

    Science.gov (United States)

    Nabavi, Seyed Fazel; Barber, Alistair J; Spagnuolo, Carmela; Russo, Gian Luigi; Daglia, Maria; Nabavi, Seyed Mohammad; Sobarzo-Sánchez, Eduardo

    2016-10-01

    Diabetic retinopathy is a microvascular complication of diabetes that is considered one of the leading causes of blindness among adults. More than 4.4 million people suffer from this disorder throughout the world. Growing evidence suggests that oxidative stress plays a crucial role in the pathophysiology of diabetic retinopathy. Nuclear factor erythroid 2-related factor 2 (Nrf2), a redox sensitive transcription factor, plays an essential protective role in regulating the physiological response to oxidative and electrophilic stress via regulation of multiple genes encoding antioxidant proteins and phase II detoxifying enzymes. Many studies suggest that dozens of natural compounds, including polyphenols, can supress oxidative stress and inflammation through targeting Nrf2 and consequently activating the antioxidant response element-related cytoprotective genes. Therefore, Nrf2 may provide a new therapeutic target for treatment of diabetic retinopathy. In the present article, we will focus on the role of Nrf2 in diabetic retinopathy and the ability of polyphenols to target Nrf2 as a therapeutic strategy. PMID:26926494

  10. Fetal Alcohol Spectrum Disorder (FASD Associated Neural Defects: Complex Mechanisms and Potential Therapeutic Targets

    Directory of Open Access Journals (Sweden)

    James A. Marrs

    2013-06-01

    Full Text Available Fetal alcohol spectrum disorder (FASD, caused by prenatal alcohol exposure, can result in craniofacial dysmorphism, cognitive impairment, sensory and motor disabilities among other defects. FASD incidences are as high as 2% to 5 % children born in the US, and prevalence is higher in low socioeconomic populations. Despite various mechanisms being proposed to explain the etiology of FASD, the molecular targets of ethanol toxicity during development are unknown. Proposed mechanisms include cell death, cell signaling defects and gene expression changes. More recently, the involvement of several other molecular pathways was explored, including non-coding RNA, epigenetic changes and specific vitamin deficiencies. These various pathways may interact, producing a wide spectrum of consequences. Detailed understanding of these various pathways and their interactions will facilitate the therapeutic target identification, leading to new clinical intervention, which may reduce the incidence and severity of these highly prevalent preventable birth defects. This review discusses manifestations of alcohol exposure on the developing central nervous system, including the neural crest cells and sensory neural placodes, focusing on molecular neurodevelopmental pathways as possible therapeutic targets for prevention or protection.

  11. Exosome targeting of tumor antigens expressed by cancer vaccines can improve antigen immunogenicity and therapeutic efficacy.

    Science.gov (United States)

    Rountree, Ryan B; Mandl, Stefanie J; Nachtwey, James M; Dalpozzo, Katie; Do, Lisa; Lombardo, John R; Schoonmaker, Peter L; Brinkmann, Kay; Dirmeier, Ulrike; Laus, Reiner; Delcayre, Alain

    2011-08-01

    MVA-BN-PRO (BN ImmunoTherapeutics) is a candidate immunotherapy product for the treatment of prostate cancer. It encodes 2 tumor-associated antigens, prostate-specific antigen (PSA), and prostatic acid phosphatase (PAP), and is derived from the highly attenuated modified vaccinia Ankara (MVA) virus stock known as MVA-BN. Past work has shown that the immunogenicity of antigens can be improved by targeting their localization to exosomes, which are small, 50- to 100-nm diameter vesicles secreted by most cell types. Exosome targeting is achieved by fusing the antigen to the C1C2 domain of the lactadherin protein. To test whether exosome targeting would improve the immunogenicity of PSA and PAP, 2 additional versions of MVA-BN-PRO were produced, targeting either PSA (MVA-BN-PSA-C1C2) or PAP (MVA-BN-PAP-C1C2) to exosomes, while leaving the second transgene untargeted. Treatment of mice with MVA-BN-PAP-C1C2 led to a striking increase in the immune response against PAP. Anti-PAP antibody titers developed more rapidly and reached levels that were 10- to 100-fold higher than those for mice treated with MVA-BN-PRO. Furthermore, treatment with MVA-BN-PAP-C1C2 increased the frequency of PAP-specific T cells 5-fold compared with mice treated with MVA-BN-PRO. These improvements translated into a greater frequency of tumor rejection in a PAP-expressing solid tumor model. Likewise, treatment with MVA-BN-PSA-C1C2 increased the antigenicity of PSA compared with treatment with MVA-BN-PRO and resulted in a trend of improved antitumor efficacy in a PSA-expressing tumor model. These experiments confirm that targeting antigen localization to exosomes is a viable approach for improving the therapeutic potential of MVA-BN-PRO in humans. PMID:21670078

  12. Modulation of heat shock transcription factor 1 as a therapeutic target for small molecule intervention in neurodegenerative disease.

    Directory of Open Access Journals (Sweden)

    Daniel W Neef

    2010-01-01

    Full Text Available Neurodegenerative diseases such as Huntington disease are devastating disorders with no therapeutic approaches to ameliorate the underlying protein misfolding defect inherent to poly-glutamine (polyQ proteins. Given the mounting evidence that elevated levels of protein chaperones suppress polyQ protein misfolding, the master regulator of protein chaperone gene transcription, HSF1, is an attractive target for small molecule intervention. We describe a humanized yeast-based high-throughput screen to identify small molecule activators of human HSF1. This screen is insensitive to previously characterized activators of the heat shock response that have undesirable proteotoxic activity or that inhibit Hsp90, the central chaperone for cellular signaling and proliferation. A molecule identified in this screen, HSF1A, is structurally distinct from other characterized small molecule human HSF1 activators, activates HSF1 in mammalian and fly cells, elevates protein chaperone expression, ameliorates protein misfolding and cell death in polyQ-expressing neuronal precursor cells and protects against cytotoxicity in a fly model of polyQ-mediated neurodegeneration. In addition, we show that HSF1A interacts with components of the TRiC/CCT complex, suggesting a potentially novel regulatory role for this complex in modulating HSF1 activity. These studies describe a novel approach for the identification of new classes of pharmacological interventions for protein misfolding that underlies devastating neurodegenerative disease.

  13. Musashi1 as a potential therapeutic target and diagnostic marker for lung cancer

    OpenAIRE

    Wang, Xiao-Yang; Yu, Huina; Linnoila, R. Ilona; Li, Laodong; Li, Dangyu; Mo, Biwen; Okano, Hideyuki; Luiz O. F. Penalva; Glazer, Robert I.

    2013-01-01

    Lung cancer remains one of the leading causes of cancer-related deaths worldwide with a 5-year survival rate of less than 20%. One approach to improving survival is the identification of biomarkers to detect early stage disease. In this study, we investigated the potential of the stem cell and progenitor cell marker, Musashi1 (Msi1), as a diagnostic marker and potential therapeutic target for lung cancer. Functional studies in A549 bronchioalveolar carcinoma and NCI-H520 squamous cell carcino...

  14. Progress in the development of therapeutic antibodies targeting prion proteins and β-amyloid peptides

    Institute of Scientific and Technical Information of China (English)

    2010-01-01

    Prion diseases and Alzheimer’s disease (AD) are characterized by protein misfolding, and can lead to dementia. However, prion diseases are infectious and transmissible, while AD is not. The similarities and differences between these diseases have led researchers to perform comparative studies. In the last 2 decades, progress has been made in immunotherapy using anti-prion protein and anti-β-amyloid antibodies. In this study, we review new ideas and strategies for therapeutic antibodies targeting prion diseases and AD through conformation dependence.

  15. Therapeutic Targets for Neurodevelopmental Disorders Emerging from Animal Models with Perinatal Immune Activation

    Directory of Open Access Journals (Sweden)

    Daisuke Ibi

    2015-11-01

    Full Text Available Increasing epidemiological evidence indicates that perinatal infection with various viral pathogens enhances the risk for several psychiatric disorders. The pathophysiological significance of astrocyte interactions with neurons and/or gut microbiomes has been reported in neurodevelopmental disorders triggered by pre- and postnatal immune insults. Recent studies with the maternal immune activation or neonatal polyriboinosinic polyribocytidylic acid models of neurodevelopmental disorders have identified various candidate molecules that could be responsible for brain dysfunction. Here, we review the functions of several candidate molecules in neurodevelopment and brain function and discuss their potential as therapeutic targets for psychiatric disorders.

  16. Toll-like receptors are potential therapeutic targets in rheumatoid arthritis

    Institute of Scientific and Technical Information of China (English)

    Siamak; Sandoghchian; Shotorbani

    2011-01-01

    Toll-like receptors (TLRs) are found on the membranes of pattern recognition receptors and not only play important roles in activating immune responses but are also involved in the pathogenesis of inflammatory disease, injury and cancer. Furthermore, TLRs are also able to recognize endogenous alarmins released by damaged tissue and necrosis and/or apoptotic cells and are present in numerous autoimmune diseases. Therefore, the release of endogenous TLR ligands plays an important role in initiating and driving inflammatory diseases. Increasing data suggest a role for TLR signaling in rheumatoid arthritis, which is an autoimmune disease. Although their involvement is not comprehensively understood, the TLRs signaling transducers may provide potential therapeutic targets.

  17. Visceral hypersensitivity and electromechanical dysfunction as therapeutic targets in pediatric functional dyspepsia

    Institute of Scientific and Technical Information of China (English)

    John; M; Rosen; Jose; T; Cocjin; Jennifer; V; Schurman; Jennifer; M; Colombo; Craig; A; Friesen

    2014-01-01

    Functional gastrointestinal disorders(FGID) are common clinical syndromes diagnosed in the absence of biochemical,structural,or metabolic abnormalities. They account for significant morbidity and health care expenditures and are identifiable across variable age,geography,and culture. Etiology of abdominal pain associated FGIDs,including functional dyspepsia(FD),remains incompletely understood,but growing evidence implicates the importance of visceral hypersensitivity and electromechanical dysfunction. This manuscript explores data supporting the role of visceral hypersensitivity and electromechanical dysfunction in FD,with focus on pediatric data when available,and provides a summary of potential therapeutic targets.

  18. Targeted anti-inflammatory therapeutics in asthma and chronic obstructive lung disease.

    Science.gov (United States)

    Durham, Andrew L; Caramori, Gaetano; Chung, Kian F; Adcock, Ian M

    2016-01-01

    Asthma and chronic obstructive pulmonary disease (COPD) are chronic inflammatory diseases of the airway, although the drivers and site of the inflammation differ between diseases. Asthmatics with a neutrophilic airway inflammation are associated with a poor response to corticosteroids, whereas asthmatics with eosinophilic inflammation respond better to corticosteroids. Biologicals targeting the Th2-eosinophil nexus such as anti-interleukin (IL)-4, anti-IL-5, and anti-IL-13 are ineffective in asthma as a whole but are more effective if patients are selected using cellular (eg, eosinophils) or molecular (eg, periostin) biomarkers. This highlights the key role of individual inflammatory mediators in driving the inflammatory response and for accurate disease phenotyping to allow greater understanding of disease and development of patient-oriented antiasthma therapies. In contrast to asthmatic patients, corticosteroids are relatively ineffective in COPD patients. Despite stratification of COPD patients, the results of targeted therapy have proved disappointing with the exception of recent studies using CXC chemokine receptor (CXCR)2 antagonists. Currently, several other novel mediator-targeted drugs are undergoing clinical trials. As with asthma specifically targeted treatments may be of most benefit in specific COPD patient endotypes. The use of novel inflammatory mediator-targeted therapeutic agents in selected patients with asthma or COPD and the detection of markers of responsiveness or nonresponsiveness will allow a link between clinical phenotypes and pathophysiological mechanisms to be delineated reaching the goal of endotyping patients. PMID:26334389

  19. Integrated nanotechnology platform for tumor-targeted multimodal imaging and therapeutic cargo release.

    Science.gov (United States)

    Hosoya, Hitomi; Dobroff, Andrey S; Driessen, Wouter H P; Cristini, Vittorio; Brinker, Lina M; Staquicini, Fernanda I; Cardó-Vila, Marina; D'Angelo, Sara; Ferrara, Fortunato; Proneth, Bettina; Lin, Yu-Shen; Dunphy, Darren R; Dogra, Prashant; Melancon, Marites P; Stafford, R Jason; Miyazono, Kohei; Gelovani, Juri G; Kataoka, Kazunori; Brinker, C Jeffrey; Sidman, Richard L; Arap, Wadih; Pasqualini, Renata

    2016-02-16

    A major challenge of targeted molecular imaging and drug delivery in cancer is establishing a functional combination of ligand-directed cargo with a triggered release system. Here we develop a hydrogel-based nanotechnology platform that integrates tumor targeting, photon-to-heat conversion, and triggered drug delivery within a single nanostructure to enable multimodal imaging and controlled release of therapeutic cargo. In proof-of-concept experiments, we show a broad range of ligand peptide-based applications with phage particles, heat-sensitive liposomes, or mesoporous silica nanoparticles that self-assemble into a hydrogel for tumor-targeted drug delivery. Because nanoparticles pack densely within the nanocarrier, their surface plasmon resonance shifts to near-infrared, thereby enabling a laser-mediated photothermal mechanism of cargo release. We demonstrate both noninvasive imaging and targeted drug delivery in preclinical mouse models of breast and prostate cancer. Finally, we applied mathematical modeling to predict and confirm tumor targeting and drug delivery. These results are meaningful steps toward the design and initial translation of an enabling nanotechnology platform with potential for broad clinical applications. PMID:26839407

  20. Integrated Genomic Characterization Reveals Novel, Therapeutically Relevant Drug Targets in FGFR and EGFR Pathways in Sporadic Intrahepatic Cholangiocarcinoma

    OpenAIRE

    Borad, Mitesh J.; Champion, Mia D.; Egan, Jan B.; Liang, Winnie S.; Rafael Fonseca; Bryce, Alan H.; Ann E McCullough; Barrett, Michael T.; Katherine Hunt; Maitray D Patel; Young, Scott W.; Collins, Joseph M.; Silva, Alvin C; Condjella, Rachel M.; Matthew Block

    2014-01-01

    Advanced cholangiocarcinoma continues to harbor a difficult prognosis and therapeutic options have been limited. During the course of a clinical trial of whole genomic sequencing seeking druggable targets, we examined six patients with advanced cholangiocarcinoma. Integrated genome-wide and whole transcriptome sequence analyses were performed on tumors from six patients with advanced, sporadic intrahepatic cholangiocarcinoma (SIC) to identify potential therapeutically actionable events. Among...

  1. Critical analysis of the potential for therapeutic targeting of mammalian target of rapamycin (mTOR in gastric cancer

    Directory of Open Access Journals (Sweden)

    Inokuchi M

    2014-04-01

    Full Text Available Mikito Inokuchi,1 Keiji Kato,1 Kazuyuki Kojima,2 Kenichi Sugihara1 1Department of Surgical Oncology, 2Department of Minimally Invasive Surgery, Tokyo Medical and Dental University, Tokyo, Japan Abstract: Multidisciplinary treatment including chemotherapy has become the global standard of care for patients with metastatic gastric cancer (mGC; nonetheless, survival remains poor. Although many molecular-targeted therapies have been developed for various cancers, only anti-HER2 treatment has produced promising results in patients with mGC. Mammalian target of rapamycin (mTOR plays a key role in cell proliferation, antiapoptosis, and metastasis in signaling pathways from the tyrosine kinase receptor, and its activation has been demonstrated in gastric cancer (GC cells. This review discusses the clinical relevance of mTOR in GC and examines its potential as a therapeutic target in patients with mGC. Preclinical studies in animal models suggest that suppression of the mTOR pathway inhibits the proliferation of GC cells and delays tumor progression. The mTOR inhibitor everolimus has been evaluated as second- or third-line treatment in clinical trials. Adverse events were well tolerated although the effectiveness of everolimus alone was limited. Everolimus is now being evaluated in combination with chemotherapy in Phase III clinical studies in this subgroup of patients. Two Phase III studies include exploratory biomarker research designed to evaluate the predictive value of the expression or mutation of molecules related to the Akt/mTOR signaling pathway. These biomarker studies may lead to the realization of targeted therapy for selected patients with mGC in the future. Keywords: gastric cancer, mTOR, everolimus

  2. New therapeutic targets in the management of urothelial carcinoma of the bladder

    Directory of Open Access Journals (Sweden)

    Sverrisson EF

    2013-03-01

    Full Text Available Einar F Sverrisson, Patrick N Espiritu, Philippe E SpiessDepartment of Genitourinary Oncology, H Lee Moffitt Cancer Center, Tampa, FL, USAAbstract: Urothelial carcinoma of the bladder, despite the myriad of treatment approaches and our progressively increasing knowledge into its disease processes, remains one of the most clinically challenging problems in modern urological clinical practice. New therapies target biomolecular pathways and cellular mediators responsible for regulating cell growth and metabolism, both of which are frequently overexpressed in malignant urothelial cells, with the intent of inducing cell death by limiting cellular metabolism and growth, creating an immune response, or selectively delivering or activating a cytotoxic agent. These new and novel therapies may offer a potential for reduced toxicity and an encouraging hope for better treatment outcomes, particularly for a disease often refractory or not amenable to the current therapeutic approaches.Keywords: targeted therapy, intravesical agents, systemic therapies

  3. A peptide for targeted, systemic delivery of imaging and therapeutic compounds into acute brain injuries

    Science.gov (United States)

    Mann, Aman P.; Scodeller, Pablo; Hussain, Sazid; Joo, Jinmyoung; Kwon, Ester; Braun, Gary B.; Mölder, Tarmo; She, Zhi-Gang; Kotamraju, Venkata Ramana; Ranscht, Barbara; Krajewski, Stan; Teesalu, Tambet; Bhatia, Sangeeta; Sailor, Michael J.; Ruoslahti, Erkki

    2016-06-01

    Traumatic brain injury (TBI) is a major health and socio-economic problem, but no pharmacological agent is currently approved for the treatment of acute TBI. Thus, there is a great need for advances in this field. Here, we describe a short peptide (sequence CAQK) identified by in vivo phage display screening in mice with acute brain injury. The CAQK peptide selectively binds to injured mouse and human brain, and systemically injected CAQK specifically homes to sites of brain injury in mouse models. The CAQK target is a proteoglycan complex upregulated in brain injuries. Coupling to CAQK increased injury site accumulation of systemically administered molecules ranging from a drug-sized molecule to nanoparticles. CAQK-coated nanoparticles containing silencing oligonucleotides provided the first evidence of gene silencing in injured brain parenchyma by systemically administered siRNA. These findings present an effective targeting strategy for the delivery of therapeutics in clinical management of acute brain injuries.

  4. Insulin Resistance and Endothelial Dysfunction Constitute a Common Therapeutic Target in Cardiometabolic Disorders

    Directory of Open Access Journals (Sweden)

    A. Janus

    2016-01-01

    Full Text Available Insulin resistance and other risk factors for atherosclerosis, such as hypertension and hypercholesterolemia, promote endothelial dysfunction and lead to development of metabolic syndrome which constitutes an introduction to cardiovascular disease. The insulin resistance and endothelial dysfunction cross talk between each other by numerous metabolic pathways. Hence, targeting one of these pathologies with pleiotropic treatment exerts beneficial effect on another one. Combined and expletive treatment of hypertension, lipid disorders, and insulin resistance with nonpharmacological interventions and conventional pharmacotherapy may inhibit the transformation of metabolic disturbances to fully developed cardiovascular disease. This paper summarises the common therapeutic targets for insulin resistance, endothelial dysfunction, and vascular inflammatory reaction at molecular level and analyses the potential pleiotropic effects of drugs used currently in management of cardiovascular disease, metabolic syndrome, and diabetes.

  5. Expression and therapeutic targeting of dopamine receptor-1 (D1R) in breast cancer.

    Science.gov (United States)

    Borcherding, D C; Tong, W; Hugo, E R; Barnard, D F; Fox, S; LaSance, K; Shaughnessy, E; Ben-Jonathan, N

    2016-06-16

    Patients with advanced breast cancer often fail to respond to treatment, creating a need to develop novel biomarkers and effective therapeutics. Dopamine (DA) is a catecholamine that binds to five G protein-coupled receptors. We discovered expression of DA type-1 receptors (D1Rs) in breast cancer, thereby identifying these receptors as novel therapeutic targets in this disease. Strong to moderate immunoreactive D1R expression was found in 30% of 751 primary breast carcinomas, and was associated with larger tumors, higher tumor grades, node metastasis and shorter patient survival. DA and D1R agonists, signaling through the cGMP/protein kinase G (PKG) pathway, suppressed cell viability, inhibited invasion and induced apoptosis in multiple breast cancer cell lines. Fenoldopam, a peripheral D1R agonist that does not penetrate the brain, dramatically suppressed tumor growth in two mouse models with D1R-expressing xenografts by increasing both necrosis and apoptosis. D1R-expressing primary tumors and metastases in mice were detected by fluorescence imaging. In conclusion, D1R overexpression is associated with advanced breast cancer and poor prognosis. Activation of the D1R/cGMP/PKG pathway induces apoptosis in vitro and causes tumor shrinkage in vivo. Fenoldopam, which is FDA (Food and Drug Administration) approved to treat renal hypertension, could be repurposed as a novel therapeutic agent for patients with D1R-expressing tumors. PMID:26477316

  6. Cell to cell spreading of misfolded proteins as a therapeutic target in motor neuron disease.

    Science.gov (United States)

    Pasquali, Livia; Lenzi, Paola; Biagioni, Francesca; Siciliano, Gabriele; Fornai, Francesco

    2014-01-01

    Despite a number of genetic mutations and molecular mechanisms are recognized to participate in amyotrophic lateral sclerosis (ALS), such a devastating neurological disorder still lacks a substantial cure. The present manuscript rather than a general overview of potential therapeutic approaches focuses on novel research findings detailing novel molecular mechanisms which appear to be promising for developing future ALS therapeutics. A special emphasis is given to the abnormal autophagy status and to those autophagy substrates which aggregate in the form of misfolded proteins. In fact, as reviewed in the first part of the manuscript, altered autophagy pathway is present in most genetic mutations responsible for familial ALS. These mutations impair clearance of autophagy substrates, which determines accumulation of giant altered mitochondria and misfolded proteins. Therefore, a considerable piece of the review is dedicated to unconventional processing of misfolded proteins leading to unconventional protein secretions which may underlie a prionoid cellto- cell spreading of ALS neuropathology. The intimate mechanisms regulating these steps are analyzed in order to comprehend which potential therapeutic targets might be considered in future studies. At the same time, negative findings concerning recent trials are explained in light of novel disease mechanisms. In the final part of the review the replacement therapy with focal stem cells implantation is discussed in relationship with toxic mechanisms operating in the intercellular space of the spinal cord and motor-related areas. PMID:24934358

  7. Quantitative Phosphoproteomics Reveals Wee1 Kinase as a Therapeutic Target in a Model of Proneural Glioblastoma.

    Science.gov (United States)

    Lescarbeau, Rebecca S; Lei, Liang; Bakken, Katrina K; Sims, Peter A; Sarkaria, Jann N; Canoll, Peter; White, Forest M

    2016-06-01

    Glioblastoma (GBM) is the most common malignant primary brain cancer. With a median survival of about a year, new approaches to treating this disease are necessary. To identify signaling molecules regulating GBM progression in a genetically engineered murine model of proneural GBM, we quantified phosphotyrosine-mediated signaling using mass spectrometry. Oncogenic signals, including phosphorylated ERK MAPK, PI3K, and PDGFR, were found to be increased in the murine tumors relative to brain. Phosphorylation of CDK1 pY15, associated with the G2 arrest checkpoint, was identified as the most differentially phosphorylated site, with a 14-fold increase in phosphorylation in the tumors. To assess the role of this checkpoint as a potential therapeutic target, syngeneic primary cell lines derived from these tumors were treated with MK-1775, an inhibitor of Wee1, the kinase responsible for CDK1 Y15 phosphorylation. MK-1775 treatment led to mitotic catastrophe, as defined by increased DNA damage and cell death by apoptosis. To assess the extensibility of targeting Wee1/CDK1 in GBM, patient-derived xenograft (PDX) cell lines were also treated with MK-1775. Although the response was more heterogeneous, on-target Wee1 inhibition led to decreased CDK1 Y15 phosphorylation and increased DNA damage and apoptosis in each line. These results were also validated in vivo, where single-agent MK-1775 demonstrated an antitumor effect on a flank PDX tumor model, increasing mouse survival by 1.74-fold. This study highlights the ability of unbiased quantitative phosphoproteomics to reveal therapeutic targets in tumor models, and the potential for Wee1 inhibition as a treatment approach in preclinical models of GBM. Mol Cancer Ther; 15(6); 1332-43. ©2016 AACR. PMID:27196784

  8. Providing a Basin of Attraction to a Target Region of Polynomial Systems by Computation of Lyapunov-Like Functions

    Czech Academy of Sciences Publication Activity Database

    Ratschan, Stefan; She, Z.

    2010-01-01

    Roč. 48, č. 7 (2010), s. 4377-4394. ISSN 0363-0129 R&D Projects: GA ČR GC201/08/J020 Institutional research plan: CEZ:AV0Z10300504 Keywords : basin of attraction * stability * constraint solving * interval computation * algorithms Subject RIV: IN - Informatics, Computer Science Impact factor: 1.297, year: 2010

  9. Nuclear Export as a Novel Therapeutic Target: The CRM1 Connection.

    Science.gov (United States)

    Lu, Chuanwen; Figueroa, Jose A; Liu, Zhongwei; Konala, Venu; Aulakh, Amardeep; Verma, Rashmi; Cobos, Everardo; Chiriva-Internati, Maurizio; Gao, Weimin

    2015-01-01

    The integrity of eukaryotic cellular function depends on molecular and biochemical compartmentalization. The transport of macromolecules between compartments requires specific and energydriven mechanisms. It occurs through a class of transport proteins known as karyopherins, which are divided in three different groups (exportins, importins, and transportins). The ubiquitous exportin Chromosome Region Maintenance 1 (CRM1) is involved in the transport of many proteins and RNA molecules from nucleus to cytoplasm. We have reviewed the available evidence supporting the relevance of CRM1 in the biology of several human neoplasms, its potential role in drug resistance, and its promise as a therapeutic target. Here we discuss different cancer related proteins (tumor suppressor genes, oncogenes, and enzymatic therapeutic targets), their function, and their association with CRM1, as well as agents that specifically inhibit CRM1, their mechanism of action, and their clinical relevance in certain human neoplasms. The directionality of nuclear transport and the specific molecular cargo in question are of paramount importance when examining the effects that CRM1 inhibition may have on cellular pathophysiology. The available data point out the potential role of CRM1-dependent nuclear export of regulatory proteins in the biology of certain human malignancies. Further studies should expand and clarify the importance of this mechanism in the pathobiology of human neoplasia. PMID:26324128

  10. Evidence for the endothelin system as an emerging therapeutic target for the treatment of chronic pain

    Directory of Open Access Journals (Sweden)

    Smith TP

    2014-08-01

    Full Text Available Terika P Smith,1 Tami Haymond,1 Sherika N Smith,1 Sarah M Sweitzer1,2 1Department of Pharmacology, Physiology and Neuroscience, University of South Carolina, Columbia, SC, USA; 2Department of Pharmaceutical and Administrative Sciences, Presbyterian College School of Pharmacy, Clinton, SC, USA Abstract: Many people worldwide suffer from pain and a portion of these sufferers are diagnosed with a chronic pain condition. The management of chronic pain continues to be a challenge, and despite taking prescribed medication for pain, patients continue to have pain of moderate severity. Current pain therapies are often inadequate, with side effects that limit medication adherence. There is a need to identify novel therapeutic targets for the management of chronic pain. One potential candidate for the treatment of chronic pain is therapies aimed at modulating the vasoactive peptide endothelin-1. In addition to vasoactive properties, endothelin-1 has been implicated in pain transmission in both humans and animal models of nociception. Endothelin-1 directly activates nociceptors and potentiates the effect of other algogens, including capsaicin, formalin, and arachidonic acid. In addition, endothelin-1 has been shown to be involved in inflammatory pain, cancer pain, neuropathic pain, diabetic neuropathy, and pain associated with sickle cell disease. Therefore, endothelin-1 may prove a novel therapeutic target for the relief of many types of chronic pain. Keywords: endothelin-1, acute pain, chronic pain, endothelin receptor antagonists

  11. Immune system of the inner ear as a novel therapeutic target for sensorineural hearing loss

    Directory of Open Access Journals (Sweden)

    Takayuki eOkano

    2014-09-01

    Full Text Available Sensorineural hearing loss (SNHL is a common clinical condition resulting from dysfunction in one or more parts in the auditory pathway between the inner ear and auditory cortex. Despite the prevalence of SNHL, little is known about its etiopathology, although several mechanisms have been postulated including ischemia, viral infection or reactivation, and microtrauma. Immune-mediated inner ear disease has been introduced and accepted as one SNHL pathophysiology; it responds to immunosuppressive therapy and is one of the few reversible forms of bilateral SNHL. The concept of immune-mediated inner ear disease is straightforward and comprehensible, but criteria for clinical diagnosis and the precise mechanism of hearing loss have not been determined. Moreover, the therapeutic mechanisms of corticosteroids are unclear, leading to several misconceptions by both clinicians and investigators concerning corticosteroid therapy. This review addresses our current understanding of the immune system in the inner ear and its involvement in the pathophysiology in SNHL. Treatment of SNHL, including immune-mediated inner ear disorder, will be discussed with a focus on the immune mechanism and immunocompetent cells as therapeutic targets. Finally, possible interventions modulating the immune system in the inner ear to repair the tissue organization and improve hearing in patients with SNHL will be discussed. Tissue macrophages in the inner ear appear to be a potential target for modulating the immune response in the inner ear in the pathophysiology of SNHL.

  12. sFRP-mediated Wnt sequestration as a potential therapeutic target for Alzheimer's disease.

    Science.gov (United States)

    Warrier, Sudha; Marimuthu, Raja; Sekhar, Sreeja; Bhuvanalakshmi, G; Arfuso, Frank; Das, Anjan Kumar; Bhonde, Ramesh; Martins, Ralph; Dharmarajan, Arun

    2016-06-01

    The extracellular ligand, Wnt, and its receptors are involved in sign al transduction and play an important role in axis formation and neural development. In neurodegenerative disorders such as Alzheimer's disease (AD), a decrease of the intracellular Wnt effector, β-catenin, has been linked to amyloid-β-peptide-induced neurotoxicity. Despite this knowledge, targeting Wnt inhibitors as potential biomarkers has not been explored, and harnessing Wnt activators as therapeutic candidates remains largely not investigated. A wide acting family of Wnt mediators, secreted frizzled-related proteins (sFRPs), has not been probed so far as molecular indicators of disease occurrence and progression of Alzheimer's. Unlike the effect of the Dickkopf (DKK) family of Wnt antagonists on AD, the sFRP molecules have a more pleiotropic impact on the Wnt signaling cascade and probably have a far-reaching involvement in neurodegeneration. The role of sFRPs has been poorly described in AD, and in this review, we analyze the present status of the role of sFRPs on neurodegeneration, their likely involvement, and potential implications in treatment modalities of AD. This information would provide valuable clues for the development of potential therapeutic targets for aberrant neurodegenerative disorders. PMID:27063405

  13. Adenosine Monophosphate-Activated Protein Kinase (AMPK) as a Diverse Therapeutic Target: A Computational Perspective.

    Science.gov (United States)

    Ramesh, M; Vepuri, Suresh B; Oosthuizen, Frasia; Soliman, Mahmoud E

    2016-02-01

    Adenosine monophosphate-activated protein kinase (AMPK) is viewed as a privileged therapeutic target for several diseases such as cancer, diabetes, inflammation, obesity, etc. In addition, AMPK has entered the limelight of current drug discovery with its evolution as a key metabolic regulator. AMPK also plays a key role in the maintenance of cellular energy homeostasis. Structurally, AMPK is a heterotrimeric protein, which consists of three protein subunits (α, β, and γ). The crystal structure of AMPK was solved, and several computational studies including homology modeling, molecular docking, molecular dynamics, and QSAR have been reported in order to explore the structure and function of this diverse therapeutic target. In this review, we present a comprehensive up-to-date overview on the computational and molecular modeling approaches that have been carried out on AMPK in order to understand its structure, function, dynamics, and its drug binding landscape. Information provided in this review would be of great interest to a wide pool of researchers involved in the design of new molecules against various diseases where AMPK plays a predominant role. Graphical Abstract ᅟ. PMID:26541160

  14. Targeting Nicotinamide Phosphoribosyltransferase as a Potential Therapeutic Strategy to Restore Adult Neurogenesis.

    Science.gov (United States)

    Wang, Shu-Na; Xu, Tian-Ying; Li, Wen-Lin; Miao, Chao-Yu

    2016-06-01

    Adult neurogenesis is the process of generating new neurons throughout life in the olfactory bulb and hippocampus of most mammalian species, which is closely related to aging and disease. Nicotinamide phosphoribosyltransferase (NAMPT), also an adipokine known as visfatin, is the rate-limiting enzyme for mammalian nicotinamide adenine dinucleotide (NAD) salvage synthesis by generating nicotinamide mononucleotide (NMN) from nicotinamide. Recent findings from our laboratory and other laboratories have provided much evidence that NAMPT might serve as a therapeutic target to restore adult neurogenesis. NAMPT-mediated NAD biosynthesis in neural stem/progenitor cells is important for their proliferation, self-renewal, and formation of oligodendrocytes in vivo and in vitro. Therapeutic interventions by the administration of NMN, NAD, or recombinant NAMPT are effective for restoring adult neurogenesis in several neurological diseases. We summarize adult neurogenesis in aging, ischemic stroke, traumatic brain injury, and neurodegenerative disease and review the advances of targeting NAMPT in restoring neurogenesis. Specifically, we provide emphasis on the P7C3 family, a class of proneurogenic compounds that are potential NAMPT activators, which might shed light on future drug development in neurogenesis restoration. PMID:27018006

  15. Medicinal plants growing in the Judea region: network approach for searching potential therapeutic targets

    Directory of Open Access Journals (Sweden)

    Arie Budovsky

    2012-09-01

    Full Text Available Plants growing in the Judea region are widely used in traditional medicine of the Levant region. Nevertheless, they have not so far been sufficiently analyzed and their medicinal potential has not been evaluated. This study is the first attempt to fill the gap in the knowledge of the plants growing in the region. Comprehensive data mining of online botanical databases and peer-reviewed scientific literature including ethno-pharmacological surveys from the Levant region was applied to compile a full list of plants growing in the Judea region, with the focus on their medicinal applications. Around 1300 plants growing in the Judea region were identified. Of them, 25% have medicinal applications which were analyzed in this study. Screening for chemical-protein interactions, together with the network-based analysis of potential targets, will facilitate discovery and therapeutic applications of the Judea region plants. Such an approach could also be applied as an integrative platform for further searching the potential therapeutic targets of plants growing in other regions of the world.

  16. Nonmuscle myosin IIB as a therapeutic target for the prevention of relapse to methamphetamine use.

    Science.gov (United States)

    Young, E J; Blouin, A M; Briggs, S B; Sillivan, S E; Lin, L; Cameron, M D; Rumbaugh, G; Miller, C A

    2016-05-01

    Memories associated with drug use increase vulnerability to relapse in substance use disorder (SUD), and there are no pharmacotherapies for the prevention of relapse. Previously, we reported a promising finding that storage of memories associated with methamphetamine (METH), but not memories for fear or food reward, is vulnerable to disruption by actin depolymerization in the basolateral amygdala complex (BLC). However, actin is not a viable therapeutic target because of its numerous functions throughout the body. Here we report the discovery of a viable therapeutic target, nonmuscle myosin IIB (NMIIB), a molecular motor that supports memory by directly driving synaptic actin polymerization. A single intra-BLC treatment with Blebbistatin (Blebb), a small-molecule inhibitor of class II myosin isoforms, including NMIIB, produced a long-lasting disruption of context-induced drug seeking (at least 30 days). Further, postconsolidation genetic knockdown of Myh10, the heavy chain of the most highly expressed NMII in the BLC, was sufficient to produce METH-associated memory loss. Blebb was found to be highly brain penetrant. A single systemic injection of the compound selectively disrupted the storage of METH-associated memory and reversed the accompanying increase in BLC spine density. This effect was specific to METH-associated memory, as it had no effect on an auditory fear memory. The effect was also independent of retrieval, as METH-associated memory was disrupted 24 h after a single systemic injection of Blebb delivered in the home cage. Together, these results argue for the further development of small-molecule inhibitors of NMII as potential therapeutics for the prevention of SUD relapse triggered by drug associations. PMID:26239291

  17. Potential Diagnostic, Prognostic and Therapeutic Targets of MicroRNAs in Human Gastric Cancer

    Directory of Open Access Journals (Sweden)

    Ming-Ming Tsai

    2016-06-01

    Full Text Available Human gastric cancer (GC is characterized by a high incidence and mortality rate, largely because it is normally not identified until a relatively advanced stage owing to a lack of early diagnostic biomarkers. Gastroscopy with biopsy is the routine method for screening, and gastrectomy is the major therapeutic strategy for GC. However, in more than 30% of GC surgical patients, cancer has progressed too far for effective medical resection. Thus, useful biomarkers for early screening or detection of GC are essential for improving patients’ survival rate. MicroRNAs (miRNAs play an important role in tumorigenesis. They contribute to gastric carcinogenesis by altering the expression of oncogenes and tumor suppressors. Because of their stability in tissues, serum/plasma and other body fluids, miRNAs have been suggested as novel tumor biomarkers with suitable clinical potential. Recently, aberrantly expressed miRNAs have been identified and tested for clinical application in the management of GC. Aberrant miRNA expression profiles determined with miRNA microarrays, quantitative reverse transcription-polymerase chain reaction and next-generation sequencing approaches could be used to establish sample specificity and to identify tumor type. Here, we provide an up-to-date summary of tissue-based GC-associated miRNAs, describing their involvement and that of their downstream targets in tumorigenic and biological processes. We examine correlations among significant clinical parameters and prognostic indicators, and discuss recurrence monitoring and therapeutic options in GC. We also review plasma/serum-based, GC-associated, circulating miRNAs and their clinical applications, focusing especially on early diagnosis. By providing insights into the mechanisms of miRNA-related tumor progression, this review will hopefully aid in the identification of novel potential therapeutic targets.

  18. Identification of unique expression signatures and therapeutic targets in esophageal squamous cell carcinoma

    Directory of Open Access Journals (Sweden)

    Yan Wusheng

    2012-01-01

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

  19. Recent insights into the molecular pathogenesis of Crohn's disease: a review of emerging therapeutic targets.

    Science.gov (United States)

    Manuc, Teodora-Ecaterina M; Manuc, Mircea M; Diculescu, Mircea M

    2016-01-01

    Chronic inflammatory bowel diseases (IBDs) are a subject of great interest in gastroenterology, due to a pathological mechanism that is difficult to explain and an optimal therapeutic approach still undiscovered. Crohn's disease (CD) is one of the main entities in IBD, characterized by clinical polymorphism and great variability in the treatment response. Modern theories on the pathogenesis of CD have proven that gut microbiome and environmental factors lead to an abnormal immune response in a genetically predisposed patient. Genome-wide association studies in patients with CD worldwide revealed several genetic mutations that increase the risk of IBD and that predispose to a more severe course of disease. Gut microbiota is considered a compulsory and an essential part in the pathogenesis of CD. Intestinal dysmicrobism with excessive amounts of different bacterial strains can be found in all patients with IBD. The discovery of Escherichia coli entero-invasive on resection pieces in patients with CD now increases the likelihood of antimicrobial or vaccine-type treatments. Recent studies targeting intestinal immunology and its molecular activation pathways provide new possibilities for therapeutics. In addition to antitumor necrosis factor molecules, which were a breakthrough in IBD, improving mucosal healing and resection-free survival rate, other classes of therapeutic agents come to focus. Leukocyte adhesion inhibitors block the leukocyte homing mechanism and prevent cellular immune response. In addition to anti-integrin antibodies, chemokine receptor antagonists and SMAD7 antisense oligonucleotides have shown encouraging results in clinical trials. Micro-RNAs have demonstrated their role as disease biomarkers but it could also become useful for the treatment of IBD. Moreover, cellular therapy is another therapeutic approach under development, aimed for severe refractory CD. Other experimental treatments include intravenous immunoglobulins, exclusive enteral

  20. HIV capsid is a tractable target for small molecule therapeutic intervention.

    Science.gov (United States)

    Blair, Wade S; Pickford, Chris; Irving, Stephen L; Brown, David G; Anderson, Marie; Bazin, Richard; Cao, Joan; Ciaramella, Giuseppe; Isaacson, Jason; Jackson, Lynn; Hunt, Rachael; Kjerrstrom, Anne; Nieman, James A; Patick, Amy K; Perros, Manos; Scott, Andrew D; Whitby, Kevin; Wu, Hua; Butler, Scott L

    2010-01-01

    Despite a high current standard of care in antiretroviral therapy for HIV, multidrug-resistant strains continue to emerge, underscoring the need for additional novel mechanism inhibitors that will offer expanded therapeutic options in the clinic. We report a new class of small molecule antiretroviral compounds that directly target HIV-1 capsid (CA) via a novel mechanism of action. The compounds exhibit potent antiviral activity against HIV-1 laboratory strains, clinical isolates, and HIV-2, and inhibit both early and late events in the viral replication cycle. We present mechanistic studies indicating that these early and late activities result from the compound affecting viral uncoating and assembly, respectively. We show that amino acid substitutions in the N-terminal domain of HIV-1 CA are sufficient to confer resistance to this class of compounds, identifying CA as the target in infected cells. A high-resolution co-crystal structure of the compound bound to HIV-1 CA reveals a novel binding pocket in the N-terminal domain of the protein. Our data demonstrate that broad-spectrum antiviral activity can be achieved by targeting this new binding site and reveal HIV CA as a tractable drug target for HIV therapy. PMID:21170360

  1. Kinesin family members KIF11 and KIF23 as potential therapeutic targets in malignant pleural mesothelioma.

    Science.gov (United States)

    Kato, Tatsuya; Lee, Daiyoon; Wu, Licun; Patel, Priya; Young, Ahn Jin; Wada, Hironobu; Hu, Hsin-Pei; Ujiie, Hideki; Kaji, Mitsuhito; Kano, Satoshi; Matsuge, Shinichi; Domen, Hiromitsu; Kaga, Kichizo; Matsui, Yoshiro; Kanno, Hiromi; Hatanaka, Yutaka; Hatanaka, Kanako C; Matsuno, Yoshihiro; de Perrot, Marc; Yasufuku, Kazuhiro

    2016-08-01

    Malignant pleural mesothelioma (MPM) is a rare and aggressive form of cancer commonly associated with asbestos exposure that stems from the thoracic mesothelium with high mortality rate. Currently, treatment options for MPM are limited, and new molecular targets for treatments are urgently needed. Using quantitative reverse transcription-polymerase chain reaction (RT-PCR) and an RNA interference-based screening, we screened two kinesin family members as potential therapeutic targets for MPM. Following in vitro investigation of the target silencing effects on MPM cells, a total of 53 MPMs were analyzed immunohistochemically with tissue microarray. KIF11 and KIF23 transcripts were found to be overexpressed in the majority of clinical MPM samples as well as human MPM cell lines as determined by quantitative RT-PCR. Gene knockdown in MPM cell lines identified growth inhibition following knockdown of KIF11 and KIF23. High expression of KIF11 (KIF11-H) and KIF23 (KIF23-H) were found in 43.4 and 50.9% of all the MPM cases, respectively. Patients who received curative resection with tumors displaying KIF23-H showed shorter overall survival (P=0.0194). These results provide that inhibition of KIF11 and KIF23 may hold promise for treatment of MPMs, raising the possibility that kinesin-based drug targets may be developed in the future. PMID:27279560

  2. Novel anti-HIV therapeutics targeting chemokine receptors and actin regulatory pathways.

    Science.gov (United States)

    Spear, Mark; Guo, Jia; Wu, Yuntao

    2013-11-01

    The human immunodeficiency virus-1 (HIV-1) infects helper CD4(+) T cells, and causes CD4(+) T-cell depletion and immunodeficiency. In the past 30 years, significant progress has been made in antiretroviral therapy, and the disease has become manageable. Nevertheless, an effective vaccine is still nowhere in sight, and a cure or a functional cure awaits discovery. Among possible curative therapies, traditional antiretroviral therapy, mostly targeting viral proteins, has been proven ineffective. It is possible that targeting HIV-dependent host cofactors may offer alternatives, both for preventing HIV transmission and for forestalling disease progression. Recently, the actin cytoskeleton and its regulators in blood CD4(+) T cells have emerged as major host cofactors that could be targeted. The novel concept that the cortical actin is a barrier to viral entry and early post-entry migration has led to the nascent model of virus-host interaction at the cortical actin layer. Deciphering the cellular regulatory pathways has manifested exciting prospects for future therapeutics. In this review, we describe the study of HIV interactions with actin cytoskeleton. We also examine potential pharmacological targets that emerge from this interaction. In addition, we briefly discuss several actin pathway-based anti-HIV drugs that are currently in development or testing. PMID:24117829

  3. Identification of CD90 as Putative Cancer Stem Cell Marker and Therapeutic Target in Insulinomas.

    Science.gov (United States)

    Buishand, Floryne O; Arkesteijn, Ger J A; Feenstra, Laurien R; Oorsprong, Claire W D; Mestemaker, Margiet; Starke, Achim; Speel, Ernst-Jan M; Kirpensteijn, Jolle; Mol, Jan A

    2016-06-01

    The long-term prognosis after surgical resection of malignant insulinoma (INS) is poor. Novel adjuvant therapies, specifically targeting cancer stem cells (CSCs), are warranted. Therefore, the goal of this study was to characterize and target putative INS CSCs. Using fluorescence-activated cell sorting, human INS cell line CM and pancreatic carcinoid cell line BON1 were screened for the presence of stem cell-associated markers. CD90, CD166, and GD2 were identified as potential CSC markers. Only CD90(+) INS cells had an increased tumor-initiating potential in athymic nude mice. Anti-CD90 monoclonal antibodies decreased the viability and metastatic potential of injected cells in a zebrafish embryo INS xenograft model. Primary INS stained positive for CD90 by immunohistochemistry, however also intratumoral fibroblasts and vascular endothelium showed positive staining. The results of this study suggest that anti-CD90 monoclonals form a potential novel adjuvant therapeutic modality by targeting either INS cells directly, or by targeting the INS microenvironment. PMID:27049037

  4. Control of Aedes albopictus with attractive toxic sugar baits (ATSB) and potential impact on non-target organisms in St. Augustine, Florida

    OpenAIRE

    Revay, Edita E.; Müller, Gunter C.; Qualls, Whitney A; Kline, Daniel; Naranjo, Diana P.; Arheart, Kristopher L; Kravchenko, Vasiliy D; Yfremova, Zoya; Hausmann, Axel; Beier, John C.; Schlein, Yosef; Xue, Rui-De

    2014-01-01

    The purpose of this study was to test the efficacy of bait stations and foliar applications containing attractive toxic sugar baits (ATSB) and eugenol to control Aedes albopictus. At the same time the potential impact of these control methods was evaluated on non-target organisms. The study was conducted at five tire sites in St. Augustine, Florida. Aedes albopictus populations were significantly reduced with ATSB-eugenol applications applied directly to non-flowering vegetation and as bait s...

  5. Targeting Importin-α7 as a Therapeutic Approach against Pandemic Influenza Viruses.

    Science.gov (United States)

    Resa-Infante, Patricia; Paterson, Duncan; Bonet, Jaume; Otte, Anna; Oliva, Baldo; Fodor, Ervin; Gabriel, Gülsah

    2015-09-01

    Viral drug resistance is believed to be less likely to occur if compounds are directed against cellular rather than viral proteins. In this study, we analyzed the feasibility of a crucial viral replication factor, namely, importin-α7, as a cellular drug target to combat pandemic influenza viruses. Surprisingly, only five viral lung-to-lung passages were required to achieve 100% lethality in importin-α7⁻/⁻ mice that otherwise are resistant. Viral escape from importin-α7 requirement was mediated by five mutations in the viral ribonucleoprotein complex and the surface glycoproteins. Moreover, the importin-α7⁻/⁻ mouse-adapted strain became even more virulent for wild-type mice than the parental strain. These studies show that targeting host proteins may still result in viral escape by alternative pathways, eventually giving rise to even more virulent virus strains. Thus, therapeutic intervention strategies should consider a multitarget approach to reduce viral drug resistance. IMPORTANCE Here, we investigated the long-standing hypothesis based on in vitro studies that viral drug resistance occurrence is less likely if compounds are directed against cellular rather than viral proteins. Here, we challenged this hypothesis by analyzing, in an in vivo animal model, the feasibility of targeting the cellular factor importin-α7, which is crucial for human influenza virus replication and pathogenesis, as an efficient antiviral strategy against pandemic influenza viruses. In summary, our studies suggest that resistance against cellular factors is possible in vivo, and the emergence of even more virulent viral escape variants calls for particular caution. Thus, therapeutic intervention strategies should consider a multitarget approach using compounds against viral as well as cellular factors to reduce the risk of viral drug resistance and potentially increased virulence. PMID:26085167

  6. Injectable actarit-loaded solid lipid nanoparticles as passive targeting therapeutic agents for rheumatoid arthritis.

    Science.gov (United States)

    Ye, Jiesheng; Wang, Qun; Zhou, Xuefeng; Zhang, Na

    2008-03-20

    This work systematically studied the intravenous injection formulation of solid lipid nanoparticles (SLNs) loaded with actarit, a poor water soluble anti-rheumatic drug. The goal of this study was to design passive targeting nanoparticles which could improve therapeutic efficacy and reduce side-effects such as nephrotoxicity and gastrointestinal disorders commonly associated with oral formulations of actarit. Based on the optimized results of single-factor and orthogonal design, actarit-loaded SLNs were prepared by a modified solvent diffusion-evaporation method. The formulated SLNs were found to be relatively uniform in size (241+/-23 nm) with a negative zeta potential (-17.14+/-1.6 mV). The average drug entrapment efficiency and loading were (50.87+/-0.25)% and (8.48+/-0.14)%, respectively. The actarit-loaded SLNs exhibited a longer mean retention time in vivo (t(1/2(beta)), 9.373 h; MRT, 13.53 h) compared with the actarit 50% propylene glycol solution (t(1/2(ke)), 0.917 h; MRT, 1.323 h) after intravenous injection to New Zealand rabbits. The area under curve of plasma concentration-time (AUC) of actarit-loaded SLNs was 1.88 times greater than that of the actarit in 50% propylene glycol solution. The overall targeting efficiency (TE(C)) of the actarit-loaded SLNs was enhanced from 6.31% to 16.29% in spleen while the renal distribution of actarit was significantly reduced as compared to that of the actarit solution after intravenous administration to mice. These results indicated that injectable actarit-loaded solid lipid nanoparticles were promising passive targeting therapeutic agents for rheumatoid arthritis. PMID:18054182

  7. MicroRNAs as novel therapeutic targets to treat kidney injury and fibrosis.

    Science.gov (United States)

    Gomez, Ivan G; Nakagawa, Naoki; Duffield, Jeremy S

    2016-05-01

    MicroRNAs (miRs), a class of small noncoding RNAs that act as post-transcriptional regulators of gene expression, have attracted increasing attention as critical regulators of organogenesis, cancer, and disease. Interest has been spurred by development of a novel class of synthetic RNA oligonucleotides with excellent drug-like properties that hybridize to a specific miR, preventing its action. In kidney disease, a small number of miRs are dysregulated. These overlap with regulated miRs in nephrogenesis and kidney cancers. Several dysregulated miRs have been identified in fibrotic diseases of other organs, representing a "fibrotic signature," and some of these fibrotic miRs contribute remarkably to the pathogenesis of kidney disease. Chronic kidney disease, affecting ∼10% of the population, leads to kidney failure, with few treatment options. Here, we will explore the pathological mechanism of miR-21, whose pre-eminent role in amplifying kidney disease and fibrosis by suppressing mitochondrial biogenesis and function is established. Evolving roles for miR-214, -199, -200, -155, -29, -223, and -126 in kidney disease will be discussed, and we will demonstrate how studying functions of distinct miRs has led to new mechanistic insights for kidney disease progression. Finally, the utility of anti-miR oligonucleotides as potential novel therapeutics to treat chronic disease will be highlighted. PMID:26911854

  8. Evaluation of LMP1 of Epstein-Barr virus as a therapeutic target by its inhibition

    Directory of Open Access Journals (Sweden)

    Wilson Joanna B

    2010-07-01

    Full Text Available Abstract Background The latent membrane protein-1 (LMP1 encoded by Epstein-Barr virus (EBV is an oncoprotein which acts by constitutive activation of various signalling pathways, including NF-κB. In so doing it leads to deregulated cell growth intrinsic to the cancer cell as well as having extrinsic affects upon the tumour microenvironment. These properties and that it is a foreign antigen, lead to the proposition that LMP1 may be a good therapeutic target in the treatment of EBV associated disease. LMP1 is expressed in several EBV-associated malignancies, notably in Hodgkin's lymphoma and nasopharyngeal carcinoma (NPC. However, the viral protein is only detected in approximately 30%-50% of NPC samples, as such its role in carcinogenesis and tumour maintenance can be questioned and thus its relevance as a therapeutic target. Results In order to explore if LMP1 has a continuous function in established tumours, its activity was inhibited through expression of a dominant negative LMP1 mutant in tumour cell lines derived from transgenic mice. LMP1 is the tumour predisposing oncogene in two different series of transgenic mice which separately give rise to either B-cell lymphomas or carcinomas. Inhibition of LMP1 activity in the carcinoma cell lines lead to a reduction in clonagenicity and clone viability in all of the cell lines tested, even those with low or below detection levels of LMP1. Inhibition of LMP1 activity in the transgenic B-cell lines was incompatible with growth and survival of the cells and no clones expressing the dominant negative LMP1 mutant could be established. Conclusions LMP1 continues to provide a tumour cell growth function in cell lines established from LMP1 transgenic mouse tumours, of both B-cell and epithelial cell origin. LMP1 can perform this function, even when expressed at such low levels as to be undetectable, whereby evidence of its expression can only be inferred by its inhibition being detrimental to the growth

  9. Molecular pathogenesis and targeted therapeutics in Ewing sarcoma/primitive neuroectodermal tumours

    Directory of Open Access Journals (Sweden)

    Kelleher Fergal C

    2012-02-01

    Full Text Available Abstract Background Ewing sarcoma/PNET is managed with treatment paradigms involving combinations of chemotherapy, surgery, and sometimes radiation. Although the 5-year survival rate of non-metastatic disease approaches 70%, those cases that are metastatic and those that recur have 5-year survival rates of less than 20%. Molecularly targeted treatments offer the potential to further improve treatment outcomes. Methods A PUBMED search was performed from 1997 to 2011. Published literature that included the topic of the Ewing sarcoma/PNET was also referenced. Results Insulin-like growth factor-1 receptor (IGF-1R antagonists have demonstrated modest single agent efficacy in phase I/II clinical trials in Ewing sarcoma/PNET, but have a strong preclinical rationale. Based on in vitro and animal data, treatment using antisense RNA and cDNA oligonucleotides directed at silencing the EWS-FLI chimera that occurs in most Ewing sarcoma/PNET may have potential therapeutic importance. However drug delivery and degradation problems may limit this therapeutic approach. Protein-protein interactions can be targeted by inhibition of RNA helicase A, which binds to EWS/FLI as part of the transcriptional complex. Tumour necrosis factor related apoptosis inducing ligand induction using interferon has been used in preclinical models. Interferons may be incorporated into future chemotherapeutic treatment paradigms. Histone deacetylase inhibitors can restore TGF-β receptor II allowing TFF-β signalling, which appears to inhibit growth of Ewing sarcoma/PNET cell lines in vitro. Immunotherapy using allogeneic natural killer cells has activity in Ewing sarcoma/PNET cell lines and xenograft models. Finally, cyclin dependent kinase inhibitors such as flavopiridol may be clinically efficacious in relapsed Ewing sarcoma/PNET. Conclusion Preclinical evidence exists that targeted therapeutics may be efficacious in the ESFT. IGF-1R antagonists have demonstrated efficacy in phase I

  10. NADPH Oxidase as a Therapeutic Target for Neuroprotection against Ischaemic Stroke: Future Perspectives

    Directory of Open Access Journals (Sweden)

    Carli L. Roulston

    2013-04-01

    Full Text Available Oxidative stress caused by an excess of reactive oxygen species (ROS is known to contribute to stroke injury, particularly during reperfusion, and antioxidants targeting this process have resulted in improved outcomes experimentally. Unfortunately these improvements have not been successfully translated to the clinical setting. Targeting the source of oxidative stress may provide a superior therapeutic approach. The NADPH oxidases are a family of enzymes dedicated solely to ROS production and pre-clinical animal studies targeting NADPH oxidases have shown promising results. However there are multiple factors that need to be considered for future drug development: There are several homologues of the catalytic subunit of NADPH oxidase. All have differing physiological roles and may contribute differentially to oxidative damage after stroke. Additionally, the role of ROS in brain repair is largely unexplored, which should be taken into consideration when developing drugs that inhibit specific NADPH oxidases after injury. This article focuses on the current knowledge regarding NADPH oxidase after stroke including in vivo genetic and inhibitor studies. The caution required when interpreting reports of positive outcomes after NADPH oxidase inhibition is also discussed, as effects on long term recovery are yet to be investigated and are likely to affect successful clinical translation.

  11. Neuromuscular therapeutics by RNA-targeted suppression of ACHE gene expression.

    Science.gov (United States)

    Dori, Amir; Soreq, Hermona

    2006-10-01

    RNA-targeted therapeutics offers inherent advantages over small molecule drugs wherever one out of several splice variant enzymes should be inhibited. Here, we report the use of Monarsen, a 20-mer acetylcholinesterase-targeted antisense agent with three 3'-2'o-methyl-protected nucleotides, for selectively attenuating the stress-induced accumulation of the normally rare, soluble "readthrough" acetylcholinesterase variant AChE-R. Acetylcholine hydrolysis by AChE-R may cause muscle fatigue and moreover, limit the cholinergic anti-inflammatory blockade, yielding inflammation-associated pathology. Specific AChE-R targeting by Monarsen was achieved in cultured cells, experimental animals, and patient volunteers. In rats with experimental autoimmune myasthenia gravis, oral delivery of Monarsen improved muscle action potential in a lower dose regimen (nanomolar versus micromolar), rapid and prolonged manner (up to 72 h versus 2-4 h) as compared with the currently used small molecule anticholinesterases. In central nervous system neurons of both rats and cynomolgus monkeys, systematic Monarsen treatment further suppressed the levels of the proinflammatory cytokines interleukin-1 (IL-1) and IL-6. Toxicology testing and ongoing clinical trials support the notion that Monarsen treatment would offer considerable advantages over conventional cholinesterase inhibitors with respect to dosing, specificity, side effects profile, and duration of efficacy, while raising some open questions regarding its detailed mechanism of action. PMID:17145929

  12. Targeting hepatitis B virus and human papillomavirus induced carcinogenesis: novel patented therapeutics.

    Science.gov (United States)

    Kanwar, Rupinder K; Singh, Neha; Gurudevan, Sneha; Kanwar, Jagat R

    2011-05-01

    Viral infections leading to carcinogenesis tops the risk factors list for the development of human cancer. The decades of research has provided ample scientific evidence that directly links 10-15% of the worldwide incidence of human cancers to the infections with seven human viruses. Moreover, the insights gained into the molecular pathogenetic and immune mechanisms of hepatitis B virus (HBV) and human papillomavirus (HPV) viral transmission to tumour progression, and the identification of their viral surface antigens as well as oncoproteins have provided the scientific community with opportunities to target these virus infections through the development of prophylactic vaccines and antiviral therapeutics. The preventive vaccination programmes targeting HBV and high risk HPV infections, linked to hepatocellular carcinoma (HCC) and cervical cancer respectively have been recently reported to alter age-old cancer patterns on an international scale. In this review, with an emphasis on HBV and HPV mediated carcinogenesis because of the similarities and differences in their global incidence patterns, viral transmission, mortality, molecular pathogenesis and prevention, we focus on the development of recently identified HBV and HPV targeting innovative strategies resulting in several patents and patent applications. PMID:21517743

  13. The Actin Cytoskeleton as a Therapeutic Target for the Prevention of Relapse to Methamphetamine Use.

    Science.gov (United States)

    Young, Erica J; Briggs, Sherri B; Miller, Courtney A

    2015-01-01

    A high rate of relapse is a defining characteristic of substance use disorder for which few treatments are available. Exposure to environmental cues associated with previous drug use can elicit relapse by causing the involuntary retrieval of deeply engrained associative memories that trigger a strong motivation to seek out drugs. Our lab is focused on identifying and disrupting mechanisms that support these powerful consolidated memories, with the goal of developing therapeutics. A particularly promising mechanism is regulation of synaptic dynamics by actin polymerization within dendritic spines. Emerging evidence indicates that memory is supported by structural and functional plasticity dendritic spines, for which actin polymerization is critical, and that prior drug use increases both spine and actin dynamics. Indeed we have found that inhibiting amygdala (AMY) actin polymerization immediately or twenty-four hours prior to testing disrupted methamphetamine (METH)-associated memories, but not food reward or fear memories. Furthermore, METH training increased AMY spine density which was reversed by actin depolymerization treatment. Actin dynamics were also shifted to a more dynamic state by METH training. While promising, actin polymerization inhibitors are not a viable therapeutic, as a multitude of peripheral process (e.g. cardiac function) rely on dynamic actin. For this reason, we have shifted our focus upstream of actin polymerization to nonmuscle myosin II. We and others have demonstrated that myosin IIb imparts a mechanical force that triggers spine actin polymerization in response to synaptic stimulation. Similar to an actin depolymerizing compound, pre-test inhibition of myosin II ATPase activity in the AMY produced a rapid and lasting disruption of drug-seeking behavior. While many questions remain, these findings indicate that myosin II represents a potential therapeutic avenue to target the actin cytoskeleton and disrupt the powerful, extinction

  14. Therapeutic hypothermia and targeted temperature management in traumatic brain injury: Clinical challenges for successful translation.

    Science.gov (United States)

    Dietrich, W Dalton; Bramlett, Helen M

    2016-06-01

    The use of therapeutic hypothermia (TH) and targeted temperature management (TTM) for severe traumatic brain injury (TBI) has been tested in a variety of preclinical and clinical situations. Early preclinical studies showed that mild reductions in brain temperature after moderate to severe TBI improved histopathological outcomes and reduced neurological deficits. Investigative studies have also reported that reductions in post-traumatic temperature attenuated multiple secondary injury mechanisms including excitotoxicity, free radical generation, apoptotic cell death, and inflammation. In addition, while elevations in post-traumatic temperature heightened secondary injury mechanisms, the successful implementation of TTM strategies in injured patients to reduce fever burden appear to be beneficial. While TH has been successfully tested in a number of single institutional clinical TBI studies, larger randomized multicenter trials have failed to demonstrate the benefits of therapeutic hypothermia. The use of TH and TTM for treating TBI continues to evolve and a number of factors including patient selection and the timing of the TH appear to be critical in successful trial design. Based on available data, it is apparent that TH and TTM strategies for treating severely injured patients is an important therapeutic consideration that requires more basic and clinical research. Current research involves the evaluation of alternative cooling strategies including pharmacologically-induced hypothermia and the combination of TH or TTM approaches with more selective neuroprotective or reparative treatments. This manuscript summarizes the preclinical and clinical literature emphasizing the importance of brain temperature in modifying secondary injury mechanisms and in improving traumatic outcomes in severely injured patients. This article is part of a Special Issue entitled SI:Brain injury and recovery. PMID:26746342

  15. Targeting Specific HATs for Neurodegenerative Disease Treatment: Translating Basic Biology to Therapeutic Possibilities

    Directory of Open Access Journals (Sweden)

    Sheila K. Pirooznia

    2013-03-01

    Full Text Available Dynamic epigenetic regulation of neurons is emerging as a fundamental mechanism by which neurons adapt their transcriptional responses to specific developmental and environmental cues. While defects within the neural epigenome have traditionally been studied in the context of early developmental and heritable cognitive disorders, recent studies point to aberrant histone acetylation status as a key mechanism underlying acquired inappropriate alterations of genome structure and function in post-mitotic neurons during the aging process. Indeed, it is becoming increasingly evident that chromatin acetylation status can be impaired during the lifetime of neurons through mechanisms related to loss of function of histone acetyltransferase (HATs activity. Several HATs have been shown to participate in vital neuronal functions such as regulation of neuronal plasticity and memory formation. As such, dysregulation of such HATs has been implicated in the pathogenesis associated with age-associated neurodegenerative diseases and cognitive decline. In order to counteract the loss of HAT function in neurodegenerative diseases, the current therapeutic strategies involve the use of small molecules called histone deacetylase (HDAC inhibitors that antagonize HDAC activity and thus enhance acetylation levels. Although this strategy has displayed promising therapeutic effects, currently used HDAC inhibitors lack target specificity, raising concerns about their applicability. With rapidly evolving literature on HATs and their respective functions in mediating neuronal survival and higher order brain function such as learning and memory, modulating the function of specific HATs holds new promises as a therapeutic tool in neurodegenerative diseases. In this review, we focus on the recent progress in research regarding epigenetic histone acetylation mechanisms underlying neuronal activity and cognitive function. We discuss the current understanding of specific HDACs and

  16. Receptor tyrosine kinase (c-Kit) inhibitors: a potential therapeutic target in cancer cells

    Science.gov (United States)

    Abbaspour Babaei, Maryam; Kamalidehghan, Behnam; Saleem, Mohammad; Huri, Hasniza Zaman; Ahmadipour, Fatemeh

    2016-01-01

    c-Kit, a receptor tyrosine kinase, is involved in intracellular signaling, and the mutated form of c-Kit plays a crucial role in occurrence of some cancers. The function of c-Kit has led to the concept that inhibiting c-Kit kinase activity can be a target for cancer therapy. The promising results of inhibition of c-Kit for treatment of cancers have been observed in some cancers such as gastrointestinal stromal tumor, acute myeloid leukemia, melanoma, and other tumors, and these results have encouraged attempts toward improvement of using c-Kit as a capable target for cancer therapy. This paper presents the findings of previous studies regarding c-Kit as a receptor tyrosine kinase and an oncogene, as well as its gene targets and signaling pathways in normal and cancer cells. The c-Kit gene location, protein structure, and the role of c-Kit in normal cell have been discussed. Comprehending the molecular mechanism underlying c-Kit-mediated tumorogenesis is consequently essential and may lead to the identification of future novel drug targets. The potential mechanisms by which c-Kit induces cellular transformation have been described. This study aims to elucidate the function of c-Kit for future cancer therapy. In addition, it has c-Kit inhibitor drug properties and their functions have been listed in tables and demonstrated in schematic pictures. This review also has collected previous studies that targeted c-Kit as a novel strategy for cancer therapy. This paper further emphasizes the advantages of this approach, as well as the limitations that must be addressed in the future. Finally, although c-Kit is an attractive target for cancer therapy, based on the outcomes of treatment of patients with c-Kit inhibitors, it is unlikely that Kit inhibitors alone can lead to cure. It seems that c-Kit mutations alone are not sufficient for tumorogenesis, but do play a crucial role in cancer occurrence. PMID:27536065

  17. PGC-1{alpha}, A Potential Therapeutic Target for Early Intervention in Parkinson's Disease

    DEFF Research Database (Denmark)

    Zheng, B.; Liao, Z.; Locascio, J.J.; Lesniak, K.A.; Roderick, S.S.; Watt, M.L.; Eklund, Aron Charles; Zhang-James, Y.; Kim, P.D.; Hauser, M.A.; Grünblatt, E.; Moran, L.B.; Mandel, S.A.; Riederer, P.; Miller, R.M.; Federoff, H.J.; Wüllner, U.; Papapetropoulos, S.; Youdim, M.B.; Cantuti-Castelvetri, I.; Young, A.B.; Vance, J.M.; Davis, R.L.; Hedreen, J.C.; Adler, S.H.; Beach, T.G.; Graeber, M.B.; Middleton, F.A.; Rochet, J.C.; Scherzer, C.R.

    2010-01-01

    Parkinson's disease affects 5 million people worldwide, but the molecular mechanisms underlying its pathogenesis are still unclear. Here, we report a genome-wide meta-analysis of gene sets (groups of genes that encode the same biological pathway or process) in 410 samples from patients with...... symptomatic Parkinson's and subclinical disease and healthy controls. We analyzed 6.8 million raw data points from nine genome-wide expression studies, and 185 laser-captured human dopaminergic neuron and substantia nigra transcriptomes, followed by two-stage replication on three platforms. We found 10 gene...... mutant α-synuclein or the pesticide rotenone in cellular disease models. Our systems biology analysis of Parkinson's disease identifies PGC-1α as a potential therapeutic target for early intervention....

  18. Bromodomain and extra-terminal (BET) family proteins: New therapeutic targets in major diseases

    Indian Academy of Sciences (India)

    Balasundaram Padmanabhan; Shruti Mathur; Manjula Ramu; Shailesh Tripathi

    2016-06-01

    The bromodomains and extra-terminal domain (BET) family proteins recognize acetylated chromatin through their bromodomains (BDs) and helps in regulating gene expression. BDs are chromatin ‘readers’; by interacting with acetylated lysines on the histone tails, they recruit chromatin-regulating proteins on the promoter region to regulate gene expression and repression. Extensive efforts have been employed by the scientific communities worldwide, to identify and develop potential inhibitors of BET family BDs to regulate protein expression by inhibiting acetylated histone (H3/H4) interactions. Several small molecule inhibitors have been reported, which not only have high affinity, but also have high specificity to BET BDs. These developments make BET family proteins to be an important therapeutic targets, for major diseases such as cancer, neurological disorders, obesity and inflammation. Here, we review and discuss the structural biology of BET family BDs and their applications in major diseases.

  19. Therapeutic potential of mGluR5 targeting in Alzheimer's disease

    Directory of Open Access Journals (Sweden)

    Anil eKumar

    2015-06-01

    Full Text Available Decades of research dedicated towards Alzheimer's disease (AD has culminated in much of the current understanding of the neurodegeneration associated with disease. However, delineating the pathophysiology and finding a possible cure for the disease is still wanting. This is in part due to the lack of knowledge pertaining to the connecting link between neurodegenerative and neuroinflammatory pathways. Consequently, the inefficacy and ill-effects of the drugs currently available for AD encourage the need for alternative and safe therapeutic intervention. In this review we highlight the potential of mGluR5, a metabotropic glutamatergic receptor, in understanding the mechanism underlying the neuronal death and neuroinflammation in AD. We also discuss the role of mGlu5 receptor in mediating the neuron-glia interaction in the disease. Finally, we discuss the potential of mGluR5 as target for treating AD.

  20. Targeting autophagy as a potential therapeutic approach for immune thrombocytopenia therapy.

    Science.gov (United States)

    Shan, Ning-Ning; Dong, Li-Li; Zhang, Xiao-Mei; Liu, Xin; Li, Ying

    2016-04-01

    Autophagy involves the sequestration and lysosomal degradation of various cytoplasmic structures, including damaged organelles and invading microorganisms. Autophagy is not only an essential cell-intrinsic mechanism for protecting against internal and external stress conditions but is also key in the cellular response against microbes, in antigen processing for major histocompatibility complex (MHC) presentation, and in lymphocyte development, survival, and proliferation. In recent years, perturbations in autophagy have been implicated in a number of diseases, including autoimmune diseases, such as systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), and multiple sclerosis (MS). Immune thrombocytopenia (ITP) is a multifactorial disease characterized by autoimmune responses to self-platelet membrane proteins. Recently, our unpublished original data demonstrated aberrant expression of molecules in the autophagy pathway in ITP patients compared with controls, and we found a close correlation between the pathogenesis of ITP and the autophagy pathway. The potential of targeting the autophagy pathway in ITP as a novel therapeutic approach has been discussed. PMID:26830007

  1. Activation of sphingosine kinase-1 in cancer: implications for therapeutic targeting.

    Science.gov (United States)

    Cuvillier, Olivier; Ader, Isabelle; Bouquerel, Pierre; Brizuela, Leyre; Malavaud, Bernard; Mazerolles, Catherine; Rischmann, Pascal

    2010-06-01

    Sphingolipid metabolites are critical to the regulation of a number of fundamental biological processes including cancer. Whereas ceramide and sphingosine mediate and trigger apoptosis or cell growth arrest, sphingosine 1-phosphate promotes proliferation, cell survival and angiogenesis. The delicate equilibrium between the intracellular levels of each of these sphingolipids is controlled by the enzymes that either produce or degrade these metabolites. Sphingosine kinase-1 is a crucial regulator of this two-pan balance, because its produces the pro-survival and pro-angiogenic sphingosine 1-phosphate and decreases the amount of both ceramide and sphingosine, the pro-apoptotic sphingolipids. Moreover, its gene is oncogenic, its mRNA is overproduced in several solid tumors, its overexpression protects cells from apoptosis, and its activity is down-regulated by anti-cancer treatments. Therefore, the sphingosine kinase-1/sphingosine 1-phosphate signaling pathway appears to be a target of interest for therapeutic manipulation. PMID:20302564

  2. Targeting therapeutic liabilities engendered by PIK3R1 mutations for cancer treatment.

    Science.gov (United States)

    Cheung, Lydia Wt; Mills, Gordon B

    2016-02-01

    The regulatory subunit of PI3K, p85α (encoded by PIK3R1), binds, stabilizes and inhibits the PI3K p110 catalytic subunit. Functional characterization of PIK3R1 mutations has identified not only hypomorphs with reduced inhibition of p110, but also hypomorphs and dominant negative mutants that disrupt a novel regulatory role of p85α on PTEN or neomorphs that activate unexpected signaling pathways. The diverse phenotypic spectrum of these PIK3R1 driver mutations underscores the need for different treatment strategies targeting tumors harboring these mutations. This article describes the functional consequences of the spectrum of PIK3R1 driver mutations and therapeutic liabilities they may engender. PMID:26807692

  3. Dysfunction of two lysosome degradation pathways of α-synuclein in Parkinson's disease: potential therapeutic targets?

    Institute of Scientific and Technical Information of China (English)

    Tian-Fang Jiang; Sheng-Di Chen

    2012-01-01

    Parkinson's disease (PD) is pathologically characterized by the presence of α-synuclein (α-syn)-positive intracytoplasmic inclusions named Lewy bodies in the dopaminergic neurons of the substantia nigra.A series of morbid consequences are caused by pathologically high amounts or mutant forms of α-syn,such as defects of membrane trafficking and lipid metabolism.In this review,we consider evidence that both point mutation and overexpression of α-syn result in aberrant degradation in neurons and microglia,and this is associated with the autophagy-lysosome pathway and endosomelysosome system,leading directly to pathological intracellular aggregation,abnormal externalization and re-internalization cycling (and,in turn,internalization and re-externalization),and exocytosis.Based on these pathological changes,an increasing number of researchers have focused on these new therapeutic targets,aiming at alleviating the pathological accumulation of α-syn and re-establishing normal degradation.

  4. Apelin and APJ, a novel critical factor and therapeutic target for atherosclerosis

    Institute of Scientific and Technical Information of China (English)

    Deguan Lv; Hening Li; Linxi Chen

    2013-01-01

    Apelin is a bioactive peptide discovered recently that has been proved to be an endogenous ligand of the APJ receptor.Apelin and APJ are widely distributed in the central nervous system and peripheral tissues.Researches have confirmed that apelin/APJ involved in a wide range of physiological and pathological functions in the cardiovascular system.Investigations indicated that apelin is a novel critical factor in the development of atherosclerosis (AS).In this review,we discuss the roles of apelin in the vascular smooth muscle cell proliferation,monocytes-endothelial cell adhesion,and angiogenesis that potentially reveals a new cellular mechanism of AS.Considering these roles,apelin and APJ may be novel therapeutic targets of AS.

  5. Biomolecular self-defense and futility of high-specificity therapeutic targeting.

    Science.gov (United States)

    Rosenfeld, Simon

    2011-01-01

    Robustness has been long recognized to be a distinctive property of living entities. While a reasonably wide consensus has been achieved regarding the conceptual meaning of robustness, the biomolecular mechanisms underlying this systemic property are still open to many unresolved questions. The goal of this paper is to provide an overview of existing approaches to characterization of robustness in mathematically sound terms. The concept of robustness is discussed in various contexts including network vulnerability, nonlinear dynamic stability, and self-organization. The second goal is to discuss the implications of biological robustness for individual-target therapeutics and possible strategies for outsmarting drug resistance arising from it. Special attention is paid to the concept of swarm intelligence, a well studied mechanism of self-organization in natural, societal and artificial systems. It is hypothesized that swarm intelligence is the key to understanding the emergent property of chemoresistance. PMID:22272063

  6. p53, SKP2 and DKK3 as MYCN target genes and their potential therapeutic significance

    Directory of Open Access Journals (Sweden)

    LindiChen

    2012-11-01

    Full Text Available Neuroblastoma is the most common extracranial solid tumour of childhood. Despite significant advances, it currently still remains one of the most difficult childhood cancers to cure, with less than 40% of patients with high-risk disease being long-term survivors. MYCN is a proto-oncogene implicated to be directly involved in neuroblastoma development. Amplification of MYCN is associated with rapid tumour progression and poor prognosis. Novel therapeutic strategies which can improve the survival rates whilst reducing the toxicity in these patients are therefore required. Here we discuss genes regulated by MYCN in neuroblastoma, with particular reference to p53, SKP2 and DKK3 and strategies that may be employed to target them.

  7. Demyelination as a rational therapeutic target for ischemic or traumatic brain injury.

    Science.gov (United States)

    Shi, Hong; Hu, Xiaoming; Leak, Rehana K; Shi, Yejie; An, Chengrui; Suenaga, Jun; Chen, Jun; Gao, Yanqin

    2015-10-01

    Previous research on stroke and traumatic brain injury (TBI) heavily emphasized pathological alterations in neuronal cells within gray matter. However, recent studies have highlighted the equal importance of white matter integrity in long-term recovery from these conditions. Demyelination is a major component of white matter injury and is characterized by loss of the myelin sheath and oligodendrocyte cell death. Demyelination contributes significantly to long-term sensorimotor and cognitive deficits because the adult brain only has limited capacity for oligodendrocyte regeneration and axonal remyelination. In the current review, we will provide an overview of the major causes of demyelination and oligodendrocyte cell death following acute brain injuries, and discuss the crosstalk between myelin, axons, microglia, and astrocytes during the process of demyelination. Recent discoveries of molecules that regulate the processes of remyelination may provide novel therapeutic targets to restore white matter integrity and improve long-term neurological recovery in stroke or TBI patients. PMID:25819104

  8. Circulating microRNAs as Biomarkers, Therapeutic Targets, and Signaling Molecules

    Directory of Open Access Journals (Sweden)

    Seena K. Ajit

    2012-03-01

    Full Text Available Small noncoding microRNAs (miRNAs are important regulators of post-transcriptional gene regulation and have altered the prevailing view of a linear relationship between gene and protein expression. Aberrant miRNA expression is an emerging theme for a wide variety of diseases, highlighting the fundamental role played by miRNAs in both physiological and pathological states. The identification of stable miRNAs in bodily fluids paved the way for their use as novel biomarkers amenable to clinical diagnosis in translational medicine. Identification of miRNAs in exosomes that are functional upon delivery to the recipient cells has highlighted a novel method of intercellular communication. Delivery of miRNAs to recipient cells via blood, with functional gene regulatory consequences, opens up novel avenues for target intervention. Exosomes thus offer a novel strategy for delivering drugs or RNA therapeutic agents. Though much work lies ahead, circulating miRNAs are unequivocally ushering in a new era of novel biomarker discovery, intercellular communication mechanisms, and therapeutic intervention strategies.

  9. Lipoprotein-associated phospholipase A2: a novel marker of cardiovascular risk and potential therapeutic target.

    Science.gov (United States)

    Macphee, Colin; Benson, G Martin; Shi, Yi; Zalewski, Andrew

    2005-06-01

    Although the clinical benefit of statins is well established, these agents reduce the risk of cardiovascular events by only 20 - 40%, and the residual risk for high-risk patients is considerable. The recognition of atherosclerosis as an inflammatory disease has opened the door to numerous complementary therapeutic approaches to further reduce risk and the overall burden of cardiovascular disease. Lipoprotein-associated phospholipase A(2) (Lp-PLA(2)) is a novel inflammatory marker of cardiovascular risk that is being evaluated as a potential therapeutic target. The biological function of this enzyme in atherosclerosis has been controversial but recent evidence supports its pro-atherogenic role. The enzyme is predominantly bound to low-density lipoprotein cholesterol particles in humans, and its activity produces bioactive lipid mediators that promote inflammatory processes present at every stage of atherogenesis, from atheroma initiation to plaque destabilisation and rupture. Initial clinical studies suggest that the inhibitors of Lp-PLA(2) can block enzyme activity in plasma and within atherosclerotic plaques. However, more studies are needed to determine the potential clinical benefits of inhibiting Lp-PLA(2). PMID:16004595

  10. The Emerging Role of HMGB1 in Neuropathic Pain: A Potential Therapeutic Target for Neuroinflammation

    Directory of Open Access Journals (Sweden)

    Wenbin Wan

    2016-01-01

    Full Text Available Neuropathic pain (NPP is intolerable, persistent, and specific type of long-term pain. It is considered to be a direct consequence of pathological changes affecting the somatosensory system and can be debilitating for affected patients. Despite recent progress and growing interest in understanding the pathogenesis of the disease, NPP still presents a major diagnostic and therapeutic challenge. High mobility group box 1 (HMGB1 mediates inflammatory and immune reactions in nervous system and emerging evidence reveals that HMGB1 plays an essential role in neuroinflammation through receptors such as Toll-like receptors (TLR, receptor for advanced glycation end products (RAGE, C-X-X motif chemokines receptor 4 (CXCR4, and N-methyl-D-aspartate (NMDA receptor. In this review, we present evidence from studies that address the role of HMGB1 in NPP. First, we review studies aimed at determining the role of HMGB1 in NPP and discuss the possible mechanisms underlying HMGB1-mediated NPP progression where receptors for HMGB1 are involved. Then we review studies that address HMGB1 as a potential therapeutic target for NPP.

  11. Innate immune receptors in heart failure: Side effect or potential therapeutic target?

    Institute of Scientific and Technical Information of China (English)

    Katharina; B; Wagner; Stephan; B; Felix; Alexander; Riad

    2014-01-01

    Heart failure(HF) is a leading cause of mortality and morbidity in western countries and occasions major expenses for public health systems. Although optimal medical treatment is widely available according to current guidelines, the prognosis of patients with HF is still poor. Despite the etiology of the disease, increased systemic or cardiac activation of the innate immune system is well documented in several types of HF. In some cases there is evidence of an association between innate immune activation and clinical outcome of patients with this disease. However, the few large trials conducted with the use of anti-inflammatory medication in HF have not revealed its benefits. Thus, greater understanding of the relationship between alteration in the immune system and development and progression of HF is urgently necessary: prior to designing therapeutic interventions that target pathological inflammatory processes in preventing harmful cardiac effects of immune modulatory therapy. In this regard, relatively recently discovered receptors of the innate immune system, i.e., namely toll-like receptors(TLRs) and nodlike receptors(NLRs)-are the focus of intense cardiovascular research. These receptors are main up-stream regulators of cytokine activation. This review will focus on current knowledge of the role of TLRs and NLRs, as well as on downstream cytokine activation, and will discuss potential therapeutic implications.

  12. Functional amyloid signaling via the inflammasome, necrosome, and signalosome: New therapeutic targets in heart failure

    Directory of Open Access Journals (Sweden)

    Traci L Parry

    2015-05-01

    Full Text Available As the most common cause of death and disability globally, heart disease remains an incompletely understood enigma. A growing number of cardiac diseases are being characterized by the presence of misfolded proteins underlying their pathophysiology, including cardiac amyloidosis and dilated cardiomyopathy (DCM. At least nine precursor proteins have been implicated in the development of cardiac amyloidosis, most commonly caused by multiple myeloma (MM light chain disease and disease-causing mutant or wildtype transthyretin (TTR. Similarly aggregates with PSEN1 and COFILIN-2 have been identified in up to 1/3 of idiopathic DCM cases studied indicating the potential predominance of misfolded proteins in heart failure. In this review, we present recent evidence linking misfolded proteins mechanistically with heart failure and present multiple lines of new therapeutic approaches that target the prevention of misfolded proteins in cardiac TTR amyloid disease. These include multiple small molecule pharmacological chaperones now in clinical trials designed specifically to support TTR folding by rational design, such as tafamidis, and chaperones previously developed for other purposes, such as doxycycline and tauroursodeoxycholic acid. Lastly, we present newly discovered non-pathological functional amyloid structures, such as the inflammasome and necrosome signaling complexes, which can be activated directly by amyloid. These may represent future targets to successfully attenuate amyloid-induced proteotoxicity in heart failure as the inflammasome, for example, is being therapeutically inhibited experimentally in autoimmune disease. Together, these studies demonstrate multiple novel points in which new therapies may be used to primarily prevent misfolded proteins or to inhibit their downstream amyloid-mediated effectors, such as the inflammasome, to prevent proteotoxicity in heart failure.

  13. Functional Amyloid Signaling via the Inflammasome, Necrosome, and Signalosome: New Therapeutic Targets in Heart Failure.

    Science.gov (United States)

    Parry, Traci L; Melehani, Jason H; Ranek, Mark J; Willis, Monte S

    2015-01-01

    As the most common cause of death and disability, globally, heart disease remains an incompletely understood enigma. A growing number of cardiac diseases are being characterized by the presence of misfolded proteins underlying their pathophysiology, including cardiac amyloidosis and dilated cardiomyopathy (DCM). At least nine precursor proteins have been implicated in the development of cardiac amyloidosis, most commonly caused by multiple myeloma light chain disease and disease-causing mutant or wildtype transthyretin (TTR). Similarly, aggregates with PSEN1 and COFILIN-2 have been identified in up to one-third of idiopathic DCM cases studied, indicating the potential predominance of misfolded proteins in heart failure. In this review, we present recent evidence linking misfolded proteins mechanistically with heart failure and present multiple lines of new therapeutic approaches that target the prevention of misfolded proteins in cardiac TTR amyloid disease. These include multiple small molecule pharmacological chaperones now in clinical trials designed specifically to support TTR folding by rational design, such as tafamidis, and chaperones previously developed for other purposes, such as doxycycline and tauroursodeoxycholic acid. Last, we present newly discovered non-pathological "functional" amyloid structures, such as the inflammasome and necrosome signaling complexes, which can be activated directly by amyloid. These may represent future targets to successfully attenuate amyloid-induced proteotoxicity in heart failure, as the inflammasome, for example, is being therapeutically inhibited experimentally in autoimmune disease. Together, these studies demonstrate multiple novel points in which new therapies may be used to primarily prevent misfolded proteins or to inhibit their downstream amyloid-mediated effectors, such as the inflammasome, to prevent proteotoxicity in heart failure. PMID:26664897

  14. ATP synthase ecto-α-subunit: a novel therapeutic target for breast cancer

    Directory of Open Access Journals (Sweden)

    Pan Jian

    2011-12-01

    Full Text Available Abstract Background Treatment failure for breast cancer is frequently due to lymph node metastasis and invasion to neighboring organs. The aim of the present study was to investigate invasion- and metastasis-related genes in breast cancer cells in vitro and in vivo. Identification of new targets will facilitate the developmental pace of new techniques in screening and early diagnosis. Improved abilities to predict progression and metastasis, therapeutic response and toxicity will help to increase survival of breast cancer patients. Methods Differential protein expression in two breast cancer cell lines, one with high and the other with low metastatic potential, was analyzed using two-dimensional liquid phase chromatographic fractionation (Proteome Lab PF 2D system followed by matrix-assisted laser desorption/time-of-flight mass spectrometry (MALDI-TOF/MS. Results Up regulation of α-subunit of ATP synthase was identified in high metastatic cells compared with low metastatic cells. Immunohistochemical analysis of 168 human breast cancer specimens on tissue microarrays revealed a high frequency of ATP synthase α-subunit expression in breast cancer (94.6% compared to normal (21.2% and atypical hyperplasia (23% breast tissues. Levels of ATP synthase expression levels strongly correlated with large tumor size, poor tumor differentiation and advanced tumor stages (P Conclusions Over-expression of ATP synthase α-subunit may be involved in the progression and metastasis of breast cancer, perhaps representing a potential biomarker for diagnosis, prognosis and a therapeutic target for breast cancer. This finding of this study will help us to better understand the molecular mechanism of tumor metastasis and to improve the screening, diagnosis, as well as prognosis and/or prediction of responses to therapy for breast cancer.

  15. Animal models and therapeutic molecular targets of cancer: utility and limitations

    Directory of Open Access Journals (Sweden)

    Cekanova M

    2014-10-01

    Full Text Available Maria Cekanova, Kusum Rathore Department of Small Animal Clinical Sciences, College of Veterinary Medicine, The University of Tennessee, Knoxville, TN, USA Abstract: Cancer is the term used to describe over 100 diseases that share several common hallmarks. Despite prevention, early detection, and novel therapies, cancer is still the second leading cause of death in the USA. Successful bench-to-bedside translation of basic scientific findings about cancer into therapeutic interventions for patients depends on the selection of appropriate animal experimental models. Cancer research uses animal and human cancer cell lines in vitro to study biochemical pathways in these cancer cells. In this review, we summarize the important animal models of cancer with focus on their advantages and limitations. Mouse cancer models are well known, and are frequently used for cancer research. Rodent models have revolutionized our ability to study gene and protein functions in vivo and to better understand their molecular pathways and mechanisms. Xenograft and chemically or genetically induced mouse cancers are the most commonly used rodent cancer models. Companion animals with spontaneous neoplasms are still an underexploited tool for making rapid advances in human and veterinary cancer therapies by testing new drugs and delivery systems that have shown promise in vitro and in vivo in mouse models. Companion animals have a relatively high incidence of cancers, with biological behavior, response to therapy, and response to cytotoxic agents similar to those in humans. Shorter overall lifespan and more rapid disease progression are factors contributing to the advantages of a companion animal model. In addition, the current focus is on discovering molecular targets for new therapeutic drugs to improve survival and quality of life in cancer patients. Keywords: mouse cancer model, companion animal cancer model, dogs, cats, molecular targets

  16. Keap1-Nrf2 pathway: A promising target towards lung cancer prevention and therapeutics

    Institute of Scientific and Technical Information of China (English)

    Ying-Hui Tong; Bo Zhang; Yun Fan; Neng-Ming Lin

    2015-01-01

    Objectives: Drugs for targeted therapy have become a new strategy of adjuvant therapy for treatment of lung cancer.The Keapl (kelch-like ECH-associated protein 1)-Nrf2 (nuclear factor erythroid 2-related factor 2) pathway is recognized to be critical in regulating genes related to the cellular protective response and protecting cells from oxidative damages and toxic insult.Methods: Pubmed, Embase, OVID, and the Cochrane Library databases were searched from the beginning of each database without any limitations to the date of publication.Search terms were "Nrf2" or "Keap1" and "Lung cancer".Results: The upregulation of Nrf2 had been closely related to tumor protection and drug resistance.The aberrant state of Keap 1 or Nrf2 that were frequently found in lung cancer conferred a poor prognosis.Nrf2 could prevent cells from undergoing oncogenesis as a tumor suppressor, while it could also promote cancer progression and resistance to chemotherapeutic drugs as an oncogene,depending on the different stages of tumor progression.Target Nrf2 signaling by specific chemicals showed it could prevent tumor growth or combat chemoresistance.Conclusions: Increasing evidence has demonstrated the dual roles of the Keap1-Nrf2 pathway in tumor initiation and progression.In this paper, we provide a comprehensive overview of the potency of the Keap 1-Nrf2 pathway as an antitumor target, and the current status of Nrf2 activators or inhibitors for therapeutic approaches.Further studies are required to clarify the role of Nrf2 in lung cancer at different tumor stages, in order to maximize the efficacy of Keap1-Nrf2 targeting agents.Copyright 2015, Chinese Medical Association Production.Production and hosting by Elsevier B.V.on behalf of KeAi Communications Co., Ltd.This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/ by-nc-nd/4.0/).

  17. CXCL8 as a Potential Therapeutic Target for HIV-Associated Neurocognitive Disorders.

    Science.gov (United States)

    Mamik, Manmeet K; Ghorpade, Anuja

    2016-01-01

    Chemokine CXCL8 is a low molecular weight neutrophil chemoattractant implicated in various neurodegenerative disorders including Alzheimer's disease and stroke. Increased expression of CXCL8 has been reported in serum, plasma and brain of human immunodeficiency virus (HIV)-1 infected individuals with neurocognitive impairment, indicating its role in neuroinflammation associated with HIV-1 infection of the brain. Since chemokines are critical in eliciting immune responses in the central nervous system (CNS), CXCL8 is of particular importance for being one of the first chemokines described in the brain. Activation of astrocytes and microglia by HIV-1 and virus associated proteins results in production of this chemokine in the brain microenvironment. Consequently, CXCL8 exerts its effect on target cells via Gprotein coupled receptors CXCR1 and CXCR2. Neutrophils are the main target cells for CXCL8; however, microglia and neurons also express CXCR1/CXCR2 and therefore are important targets for CXCL8-mediated crosstalk. The objective of this review is to focus on CXCL8 production, signaling and regulation in neuronal and glial cells in response to HIV-1 infection. We highlight the role of HIV-1 secreted proteins such as trans-activator of transcription, envelope glycoprotein, negative regulatory factor and viral protein r in the regulation of CXCL8. We discuss dual role of CXCL8 in neurodegeneration as well as neuroprotection in the CNS. Thus, targeting CXCL8 through the development of CXCR1/CXCR2-based therapeutic strategies to either selectively agonize or antagonize receptors may be able to selectively promote neuroprotective and anti-inflammatory outcomes, leading to significant clinical applications in many neuroinflammatory CNS diseases, including HIV-associated neurocognitive disorders. PMID:26112047

  18. Recent insights into the molecular pathogenesis of Crohn's disease: a review of emerging therapeutic targets

    Directory of Open Access Journals (Sweden)

    Manuc TE

    2016-03-01

    Full Text Available Teodora-Ecaterina M Manuc,1 Mircea M Manuc,2 Mircea M Diculescu2 1Fundeni Clinical Institute, 2University of Medicine and Pharmacy "Carol Davila", Bucharest, Romania Abstract: Chronic inflammatory bowel diseases (IBDs are a subject of great interest in gastroenterology, due to a pathological mechanism that is difficult to explain and an optimal therapeutic approach still undiscovered. Crohn's disease (CD is one of the main entities in IBD, characterized by clinical polymorphism and great variability in the treatment response. Modern theories on the pathogenesis of CD have proven that gut microbiome and environmental factors lead to an abnormal immune response in a genetically predisposed patient. Genome-wide association studies in patients with CD worldwide revealed several genetic mutations that increase the risk of IBD and that predispose to a more severe course of disease. Gut microbiota is considered a compulsory and an essential part in the pathogenesis of CD. Intestinal dysmicrobism with excessive amounts of different bacterial strains can be found in all patients with IBD. The discovery of Escherichia coli entero-invasive on resection pieces in patients with CD now increases the likelihood of antimicrobial or vaccine-type treatments. Recent studies targeting intestinal immunology and its molecular activation pathways provide new possibilities for therapeutics. In addition to antitumor necrosis factor molecules, which were a breakthrough in IBD, improving mucosal healing and resection-free survival rate, other classes of therapeutic agents come to focus. Leukocyte adhesion inhibitors block the leukocyte homing mechanism and prevent cellular immune response. In addition to anti-integrin antibodies, chemokine receptor antagonists and SMAD7 antisense oligonucleotides have shown encouraging results in clinical trials. Micro-RNAs have demonstrated their role as disease biomarkers but it could also become useful for the treatment of IBD

  19. Fatal attraction

    DEFF Research Database (Denmark)

    Jensen, Kim Ebensgaard

    2012-01-01

    of the use of the Danish ihjel-construction which accounts for patterns of attraction of construction-verb attraction, patterns of productivity, and various types of subconstructions, including item- and item-class-based ones and metaphorical extensions. The description of the ihjel...

  20. Targeted localized use of therapeutic antibodies: a review of non-systemic, topical and oral applications.

    Science.gov (United States)

    Jones, Russell G A; Martino, Angela

    2016-06-01

    Therapeutic antibodies provide important tools in the "medicine chest" of today's clinician for the treatment of a range of disorders. Typically monoclonal or polyclonal antibodies are administered in large doses, either directly or indirectly into the circulation, via a systemic route which is well suited for disseminated ailments. Diseases confined within a specific localized tissue, however, may be treated more effectively and at reduced cost by a delivery system which targets directly the affected area. To explore the advantages of the local administration of antibodies, we reviewed current alternative, non-systemic delivery approaches which are in clinical use, being trialed or developed. These less conventional approaches comprise: (a) local injections, (b) topical and (c) peroral administration routes. Local delivery includes intra-ocular injections into the vitreal humor (i.e. Ranibizumab for age-related macular degeneration), subconjunctival injections (e.g. Bevacizumab for corneal neovascularization), intra-articular joint injections (i.e. anti-TNF alpha antibody for persistent inflammatory monoarthritis) and intratumoral or peritumoral injections (e.g. Ipilimumab for cancer). A range of other strategies, such as the local use of antibacterial antibodies, are also presented. Local injections of antibodies utilize doses which range from 1/10th to 1/100th of the required systemic dose therefore reducing both side-effects and treatment costs. In addition, any therapeutic antibody escaping from the local site of disease into the systemic circulation is immediately diluted within the large blood volume, further lowering the potential for unwanted effects. Needle-free topical application routes become an option when the condition is restricted locally to an external surface. The topical route may potentially be utilized in the form of eye drops for infections or corneal neovascularization or be applied to diseased skin for psoriasis, dermatitis, pyoderma

  1. Vascular endothelial growth factor:an attractive target in the treatment of hypoxic/ischemic brain injury

    Institute of Scientific and Technical Information of China (English)

    Hui Guo; Hui Zhou; Jie Lu; Yi Qu; Dan Yu; Yu Tong

    2016-01-01

    Cerebral hypoxia or ischemia results in cell death and cerebral edema, as well as other cellular reactions such as angiogenesis and the reestablishment of functional microvasculature to promote recovery from brain injury. Vascular endothelial growth factor is expressed in the central nervous system after hypoxic/ischemic brain injury, and is involved in the process of brain repairvia the regulation of angiogenesis, neurogenesis, neurite outgrowth, and cerebral edema, which all require vascular endothelial growth factor signaling. In this review, we focus on the role of the vascular endothelial growth factor signaling pathway in the response to hypoxic/ischemic brain injury, and discuss potential therapeutic interventions.

  2. Current understanding of BRAF alterations in diagnosis, prognosis and therapeutic targeting in paediatric low grade gliomas

    Directory of Open Access Journals (Sweden)

    Catherine Louise Penman

    2015-03-01

    Full Text Available The mitogen-activated protein kinase (MAPK pathway is known to play a key role in the initiation and maintenance of many tumours as well as normal development. This often occurs through mutation of the genes encoding RAS and RAF proteins which are involved in signal transduction in this pathway. BRAF is one of three RAF kinases which act as downstream effectors of growth factor signalling leading to cell cycle progression, proliferation and survival. Initially reported as a point mutation (V600E in the majority of metastatic melanomas, other alterations in the BRAF gene have now been reported in a variety of human cancers including papillary thyroid cancer, colon carcinomas, hairy cell leukaemia and more recently in gliomas. The identification of oncogenic mutations in the BRAF gene have led to a revolution in the treatment of metastatic melanoma using targeted molecular therapies that affect the MAPK pathway either directly through BRAF inhibition or downstream through inhibition of MEK. This review describes the molecular biology of BRAF in the context of paediatric low grade gliomas, the role of BRAF as a diagnostic marker, the prognostic implications of BRAF and evidence for therapeutic targeting of BRAF.

  3. Therapeutic efficacy by targeting correction of Notch1-induced aberrants in uveal tumors.

    Directory of Open Access Journals (Sweden)

    Xiaolin Huang

    Full Text Available There is a need for more effective treatments for uveal melanoma. The recombinant oncolytic adenovirus H101 replicates specifically in p53-depleted tumor cells, and has been approved for use by the Chinese State Food and Drug Administration. However, this treatment is associated with subsequent remission. Transfection of uveal melanoma cells with a small interfering RNA against Notch1 (siNotch1 effectively suppressed Notch1 expression, resulting in significant cell growth inhibition when combined with H101 treatment. Combined treatment with siNotch1 and H101 (H101-Notch1-siRNA greatly enhanced apoptosis and cell cycle arrest in vitro as compared to treatment with H101 or siNotch1 alone. For in vivo treatments, the combined treatment of siNotch1 and H101 showed remarkable tumor growth inhibition and prolonged mouse survival in the OCM1 xenograft model. We predict that Notch pathway deregulation could be a feature of uveal melanoma, and could be a therapeutic target, especially if p53 is concurrently targeted.

  4. Histone deacetylase 3 (HDAC3) as a novel therapeutic target in multiple myeloma

    Science.gov (United States)

    Minami, Jiro; Suzuki, Rikio; Mazitschek, Ralph; Gorgun, Gullu; Ghosh, Balaram; Cirstea, Diana; Hu, Yiguo; Mimura, Naoya; Ohguchi, Hiroto; Cottini, Francesca; Jakubikova, Jana; Munshi, Nikhil C.; Haggarty, Stephen J.; Richardson, Paul G.; Hideshima, Teru; Anderson, Kenneth C.

    2014-01-01

    Histone deacetylases (HDACs) represent novel molecular targets for the treatment of various types of cancers, including multiple myeloma (MM). Many HDAC inhibitors have already shown remarkable anti-tumor activities in the preclinical setting; however, their clinical utility is limited due to unfavorable toxicities associated with their broad range HDAC inhibitory effects. Isoform-selective HDAC inhibition may allow for MM cytotoxicity without attendant side effects. In this study, we demonstrated that HDAC3 knockdown and a small molecule HDAC3 inhibitor BG45 trigger significant MM cell growth inhibition via apoptosis, evidenced by caspase and PARP cleavage. Importantly, HDAC3 inhibition downregulates phosphorylation (tyrosine 705 and serine 727) of STAT3. Neither IL-6 nor bone marrow stromal cells overcome this inhibitory effect of HDAC3 inhibition on p-STAT3 and MM cell growth. Moreover, HDAC3 inhibition also triggers hyperacetylation of STAT3, suggesting crosstalk signaling between phosphorylation and acetylation of STAT3. Importantly, inhibition of HDAC3, but not HDAC1 or HDAC2, significantly enhances bortezomib-induced cytotoxicity. Finally, we confirm that BG45 alone and in combination with bortezomib trigger significant tumor growth inhibition in vivo in a murine xenograft model of human MM. Our results indicate that HDAC3 represents a promising therapeutic target, and validate a prototype novel HDAC3 inhibitor BG45 in MM. PMID:23913134

  5. NADPH oxidase enzymes in skin fibrosis: molecular targets and therapeutic agents.

    Science.gov (United States)

    Babalola, Olubukola; Mamalis, Andrew; Lev-Tov, Hadar; Jagdeo, Jared

    2014-05-01

    Fibrosis is characterized by the excessive deposition of extracellular matrix components eventually resulting in organ dysfunction and failure. In dermatology, fibrosis is the hallmark component of many skin diseases, including systemic sclerosis, graft-versus-host disease, hypertrophic scars, keloids, nephrogenic systemic fibrosis, porphyria cutanea tarda, restrictive dermopathy and other conditions. Fibrotic skin disorders may be debilitating and impair quality of life. There are few FDA-approved anti-fibrotic drugs; thus, research in this area is crucial in addressing this deficiency. Recent investigations elucidating the pathogenesis of skin fibrosis have implicated endogenous reactive oxygen species produced by the multicomponent nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (Nox) enzyme complex. In this review, we discuss Nox enzymes and their role in skin fibrosis. An overview of the Nox enzyme family is presented and their role in the pathogenesis of skin fibrosis is discussed. The mechanisms by which Nox enzymes influence specific fibrotic skin disorders are also reviewed. Finally, we describe the therapeutic approaches to ameliorate skin fibrosis by directly targeting Nox enzymes with the use of statins, p47phox subunit modulators, or GKT137831, a competitive inhibitor of Nox enzymes. Nox enzymes can also be targeted indirectly via scavenging ROS with antioxidants. We believe that Nox modulators are worthy of further investigation and have the potential to transform the management of skin fibrosis by dermatologists. PMID:24155025

  6. Therapeutic Modulation of Apoptosis: Targeting the BCL-2 Family at the Interface of the Mitochondrial Membrane

    Science.gov (United States)

    Nemec, Kathleen N.

    2008-01-01

    A vast portion of human disease results when the process of apoptosis is defective. Disorders resulting from inappropriate cell death range from autoimmune and neurodegenerative conditions to heart disease. Conversely, prevention of apoptosis is the hallmark of cancer and confounds the efficacy of cancer therapeutics. In the search for optimal targets that would enable the control of apoptosis, members of the BCL-2 family of anti- and pro-apoptotic factors have figured prominently. Development of BCL-2 antisense approaches, small molecules, and BH3 peptidomimetics has met with both success and failure. Success-because BCL-2 proteins play essential roles in apoptosis. Failure-because single targets for drug development have limited scope. By examining the activity of the BCL-2 proteins in relation to the mitochondrial landscape and drawing attention to the significant mitochondrial membrane alterations that ensue during apoptosis, we demonstrate the need for a broader based multi-disciplinary approach for the design of novel apoptosis-modulating compounds in the treatment of human disease. PMID:18972587

  7. Lamin B1 Is a Novel Therapeutic Target of Betulinic Acid in Pancreatic Cancer

    Science.gov (United States)

    Li, Lei; Du, Yiqi; Kong, Xiangyu; Li, Zhaoshen; Jia, Zhiliang; Cui, Jiujie; Gao, Jun; Wang, Guokun; Xie, Keping

    2013-01-01

    Purpose Betulinic acid (BA), a naturally occurring pentacyclic triterpenoid, exhibits potent anti-tumor activities, whereas the underlying mechanisms remain unclear. In current study, we sought to determine the role and regulation of lamin B1 expression in human pancreatic cancer pathogenesis and BA-based therapy. Experimental Design We used cDNA microarray to identify BA target genes and used tissue microarray to determine the expression levels of lamin B1 in pancreatic cancer tissues and to define their relationship with the clinicopathologic characteristics of pancreatic cancer. We also used in vitro and in vivo models to determine the biological impacts of altered lamin B1 expression on and mechanisms underlying lamin B1 overexpression in human pancreatic cancer. Results We found that lamin B1 was significantly downregulated by BA treatment in pancreatic cancer in both in vitro culture and xenograft models. Overexpression of lamin B1 was pronounced in human pancreatic cancer and increased lamin B1 expression was directly associated with low grade differentiation, increased incidence of distant metastasis and poor prognosis of pancreatic cancer patients. Furthermore, knockdown of lamin B1 significantly attenuated the proliferation, invasion and tumorigenicity of pancreatic cancer cells. Conclusions Lamin B1 plays an important role in pancreatic cancer pathogenesis and is a novel therapeutic target of BA treatment. PMID:23857605

  8. Dynamic Regulation of APE1/Ref-1 as a Therapeutic Target Protein

    Science.gov (United States)

    Choi, Sunga; Joo, Hee Kyoung

    2016-01-01

    Apurinic/apyrimidinic endonuclease 1/redox factor-1 (APE1/Ref-1) is a multifunctional protein that plays a central role in the cellular response to DNA damage and redox regulation against oxidative stress. APE1/Ref-1 functions in the DNA base excision repair pathway, the redox regulation of several transcription factors, and the control of intracellular redox status through the inhibition of reactive oxygen species (ROS) production. APE1/Ref-1 is predominantly localized in the nucleus; however, its subcellular localization is dynamically regulated and it may be found in the mitochondria or elsewhere in the cytoplasm. Studies have identified a nuclear localization signal and a mitochondrial target sequence in APE1/Ref-1, as well as the involvement of the nuclear export system, as determinants of APE1/Ref-1 subcellular distribution. Recently, it was shown that APE1/Ref-1 is secreted in response to hyperacetylation at specific lysine residues. Additionally, post-translational modifications such as phosphorylation, S-nitrosation, and ubiquitination appear to play a role in fine-tuning the activities and subcellular localization of APE1/Ref-1. In this review, we will introduce the multifunctional role of APE1/Ref-1 and its potential usefulness as a therapeutic target in cancer and cardiovascular disease. PMID:27231670

  9. New strategies to direct therapeutic targeting of PML to treat cancers

    Directory of Open Access Journals (Sweden)

    KamilWolyniec

    2013-05-01

    Full Text Available The tumor suppressor function of the promyelocytic leukemia (PML protein was first identified as a result of its dysregulation in acute promyelocytic leukemia (APL, however, its importance is now emerging far beyond hematological neoplasms, to an extensive range of malignancies, including solid tumours. In response to stress signals, PML coordinates the regulation of numerous proteins, which activate fundamental cellular processes that suppress tumorigenesis. Importantly, PML itself is the subject of specific post-translational modifications, including ubiquitination, phosphorylation, acetylation and SUMOylation, which in turn control PML activity and stability and ultimately dictate cellular fate. Improved understanding of the regulation of this key tumor suppressor is uncovering potential opportunities for therapeutic intervention. Targeting the key negative regulators of PML in cancer cells such as CK2, BMK1 and E6AP, with specific inhibitors that are becoming available, provides unique and exciting avenues for restoring tumor suppression through the induction of apoptosis and senescence. These approaches could be combined with DNA damaging drugs and cytokines that are known to activate PML. Depending on the cellular context, reactivation or enhancement of tumor suppressive PML functions, or targeted elimination of aberrantly functioning PML, may provide clinical benefit.

  10. Magnetic resonance monitoring of focused ultrasound/magnetic nanoparticle targeting delivery of therapeutic agents to the brain

    OpenAIRE

    Liu, Hao-Li; Hua, Mu-Yi; Yang, Hung-Wei; Huang, Chiung-Yin; Chu, Po-Chun; Wu, Jia-Shin; Tseng, I-Chou; Wang, Jiun-Jie; Yen, Tzu-Chen; Chen, Pin-Yuan; Wei, Kuo-Chen

    2010-01-01

    The superparamagnetic properties of magnetic nanoparticles (MNPs) allow them to be guided by an externally positioned magnet and also provide contrast for MRI. However, their therapeutic use in treating CNS pathologies in vivo is limited by insufficient local accumulation and retention resulting from their inability to traverse biological barriers. The combined use of focused ultrasound and magnetic targeting synergistically delivers therapeutic MNPs across the blood–brain barrier to enter th...

  11. Delivery of Therapeutics Targeting the mRNA-Binding Protein HuR Using 3DNA Nanocarriers Suppresses Ovarian Tumor Growth.

    Science.gov (United States)

    Huang, Yu-Hung; Peng, Weidan; Furuuchi, Narumi; Gerhart, Jacquelyn; Rhodes, Kelly; Mukherjee, Neelanjan; Jimbo, Masaya; Gonye, Gregory E; Brody, Jonathan R; Getts, Robert C; Sawicki, Janet A

    2016-03-15

    Growing evidence shows that cancer cells use mRNA-binding proteins and miRNAs to posttranscriptionally regulate signaling pathways to adapt to harsh tumor microenvironments. In ovarian cancer, cytoplasmic accumulation of mRNA-binding protein HuR (ELAVL1) is associated with poor prognosis. In this study, we observed high HuR expression in ovarian cancer cells compared with ovarian primary cells, providing a rationale for targeting HuR. RNAi-mediated silencing of HuR in ovarian cancer cells significantly decreased cell proliferation and anchorage-independent growth, and impaired migration and invasion. In addition, HuR-depleted human ovarian xenografts were smaller than control tumors. A biodistribution study showed effective tumor-targeting by a novel Cy3-labeled folic acid (FA)-derivatized DNA dendrimer nanocarrier (3DNA). We combined siRNAs against HuR with FA-3DNA and found that systemic administration of the resultant FA-3DNA-siHuR conjugates to ovarian tumor-bearing mice suppressed tumor growth and ascites development, significantly prolonging lifespan. NanoString gene expression analysis identified multiple HuR-regulated genes that function in many essential cellular and molecular pathways, an attractive feature of candidate therapeutic targets. Taken together, these results are the first to demonstrate the versatility of the 3DNA nanocarrier for in vivo-targeted delivery of a cancer therapeutic and support further preclinical investigation of this system adapted to siHuR-targeted therapy for ovarian cancer. PMID:26921342

  12. Asthma phenotyping: a necessity for improved therapeutic precision and new targeted therapies.

    Science.gov (United States)

    Chung, Kian Fan

    2016-02-01

    Asthma is a common heterogeneous disease with a complex pathophysiology that carries a significant mortality rate and high morbidity. Current therapies based on inhaled corticosteroids and long-acting β-agonists remain effective in a large proportion of patients with asthma, but ~10% (considered to have 'severe asthma') do not respond to these treatments even at high doses or with the use of oral corticosteroids. Analytical clustering methods have revealed phenotypes that include dependence on high-dose corticosteroid treatment, severe airflow obstruction and recurrent exacerbations associated with an allergic background and late onset of disease. One severe phenotype is eosinophilic inflammation-predominant asthma, with late-onset disease, rhinosinusitis, aspirin sensitivity and exacerbations. Blood and sputum eosinophilia have been used to distinguish patients with high Th2 inflammation and to predict therapeutic response to treatments targeted towards Th2-associated cytokines. New therapies in the form of humanized antibodies against Th2 targets, such as anti-IgE, anti-IL4Rα, anti-IL-5 and anti-IL-13 antibodies, have shown encouraging results in terms of reduction in exacerbations and improvement in airflow in patients with a 'Th2-high' expression profile and blood eosinophilia. Research efforts are now focusing on elucidating the phenotypes underlying the non-Th2-high (or Th2-low) group, which constitutes ~50% of severe asthma cases. There is an increasing need to use biomarkers to indicate the group of patients who will respond to a specifically targeted treatment. The use of improved tools to measure activity of disease, a better definition of severe asthma and the delineation of inflammatory pathways with omics analyses using computational tools, will lead to better-defined phenotypes for specific therapies. PMID:26076339

  13. Use of macrophages to target therapeutic adenovirus to human prostate tumors.

    Science.gov (United States)

    Muthana, Munitta; Giannoudis, Athina; Scott, Simon D; Fang, Hsin-Yu; Coffelt, Seth B; Morrow, Fiona J; Murdoch, Craig; Burton, Julian; Cross, Neil; Burke, Bernard; Mistry, Roshna; Hamdy, Freddie; Brown, Nicola J; Georgopoulos, Lindsay; Hoskin, Peter; Essand, Magnus; Lewis, Claire E; Maitland, Norman J

    2011-03-01

    New therapies are required to target hypoxic areas of tumors as these sites are highly resistant to conventional cancer therapies. Monocytes continuously extravasate from the bloodstream into tumors where they differentiate into macrophages and accumulate in hypoxic areas, thereby opening up the possibility of using these cells as vehicles to deliver gene therapy to these otherwise inaccessible sites. We describe a new cell-based method that selectively targets an oncolytic adenovirus to hypoxic areas of prostate tumors. In this approach, macrophages were cotransduced with a hypoxia-regulated E1A/B construct and an E1A-dependent oncolytic adenovirus, whose proliferation is restricted to prostate tumor cells using prostate-specific promoter elements from the TARP, PSA, and PMSA genes. When such cotransduced cells reach an area of extreme hypoxia, the E1A/B proteins are expressed, thereby activating replication of the adenovirus. The virus is subsequently released by the host macrophage and infects neighboring tumor cells. Following systemic injection into mice bearing subcutaneous or orthotopic prostate tumors, cotransduced macrophages migrated into hypoxic tumor areas, upregulated E1A protein, and released multiple copies of adenovirus. The virus then infected neighboring cells but only proliferated and was cytotoxic in prostate tumor cells, resulting in the marked inhibition of tumor growth and reduction of pulmonary metastases. This novel delivery system employs 3 levels of tumor specificity: the natural "homing" of macrophages to hypoxic tumor areas, hypoxia-induced proliferation of the therapeutic adenovirus in host macrophages, and targeted replication of oncolytic virus in prostate tumor cells. PMID:21233334

  14. RGS6 as a Novel Therapeutic Target in CNS Diseases and Cancer.

    Science.gov (United States)

    Ahlers, Katelin E; Chakravarti, Bandana; Fisher, Rory A

    2016-05-01

    Regulator of G protein signaling (RGS) proteins are gatekeepers regulating the cellular responses induced by G protein-coupled receptor (GPCR)-mediated activation of heterotrimeric G proteins. Specifically, RGS proteins determine the magnitude and duration of GPCR signaling by acting as a GTPase-activating protein for Gα subunits, an activity facilitated by their semiconserved RGS domain. The R7 subfamily of RGS proteins is distinguished by two unique domains, DEP/DHEX and GGL, which mediate membrane targeting and stability of these proteins. RGS6, a member of the R7 subfamily, has been shown to specifically modulate Gαi/o protein activity which is critically important in the central nervous system (CNS) for neuronal responses to a wide array of neurotransmitters. As such, RGS6 has been implicated in several CNS pathologies associated with altered neurotransmission, including the following: alcoholism, anxiety/depression, and Parkinson's disease. In addition, unlike other members of the R7 subfamily, RGS6 has been shown to regulate G protein-independent signaling mechanisms which appear to promote both apoptotic and growth-suppressive pathways that are important in its tumor suppressor function in breast and possibly other tissues. Further highlighting the importance of RGS6 as a target in cancer, RGS6 mediates the chemotherapeutic actions of doxorubicin and blocks reticular activating system (Ras)-induced cellular transformation by promoting degradation of DNA (cytosine-5)-methyltransferase 1 (DNMT1) to prevent its silencing of pro-apoptotic and tumor suppressor genes. Together, these findings demonstrate the critical role of RGS6 in regulating both G protein-dependent CNS pathology and G protein-independent cancer pathology implicating RGS6 as a novel therapeutic target. PMID:27002730

  15. Tumor Progression Locus 2 (Tpl2 Kinase as a Novel Therapeutic Target for Cancer: Double-Sided Effects of Tpl2 on Cancer

    Directory of Open Access Journals (Sweden)

    Hye Won Lee

    2015-02-01

    Full Text Available Tumor progression locus 2 (Tpl2 is a mitogen-activated protein kinase (MAPK kinase kinase (MAP3K that conveys various intra- and extra-cellular stimuli to effector proteins of cells provoking adequate adoptive responses. Recent studies have elucidated that Tpl2 is an indispensable signal transducer as an MAP3K family member in diverse signaling pathways that regulate cell proliferation, survival, and death. Since tumorigenesis results from dysregulation of cellular proliferation, differentiation, and apoptosis, Tpl2 participates in many decisive molecular processes of tumor development and progression. Moreover, Tpl2 is closely associated with cytokine release of inflammatory cells, which has crucial effects on not only tumor cells but also tumor microenvironments. These critical roles of Tpl2 in human cancers make it an attractive anti-cancer therapeutic target. However, Tpl2 contradictorily works as a tumor suppressor in some cancers. The double-sided effects of Tpl2 originate from the specific upstream and downstream signaling environment of each tumor, since Tpl2 interacts with various signaling components. This review summarizes recent studies concerning the possible roles of Tpl2 in human cancers and considers its possibility as a therapeutic target, against which novel anti-cancer agents could be developed.

  16. DUBbing Cancer: Deubiquitylating Enzymes Involved in Epigenetics, DNA Damage and the Cell Cycle As Therapeutic Targets

    Science.gov (United States)

    Pinto-Fernandez, Adan; Kessler, Benedikt M.

    2016-01-01

    Controlling cell proliferation is one of the hallmarks of cancer. A number of critical checkpoints ascertain progression through the different stages of the cell cycle, which can be aborted when perturbed, for instance by errors in DNA replication and repair. These molecular checkpoints are regulated by a number of proteins that need to be present at the right time and quantity. The ubiquitin system has emerged as a central player controlling the fate and function of such molecules such as cyclins, oncogenes and components of the DNA repair machinery. In particular, proteases that cleave ubiquitin chains, referred to as deubiquitylating enzymes (DUBs), have attracted recent attention due to their accessibility to modulation by small molecules. In this review, we describe recent evidence of the critical role of DUBs in aspects of cell cycle checkpoint control, associated DNA repair mechanisms and regulation of transcription, representing pathways altered in cancer. Therefore, DUBs involved in these processes emerge as potentially critical targets for the treatment of not only hematological, but potentially also solid tumors.

  17. Glo1 genetic amplification as a potential therapeutic target in hepatocellular carcinoma

    Science.gov (United States)

    Zhang, Shirong; Liang, Xiaodong; Zheng, Xiaoliang; Huang, Haixiu; Chen, Xufeng; Wu, Kan; Wang, Bing; Ma, Shenglin

    2014-01-01

    Glyoxalase 1 (Glo1) gene aberrations is associated with tumorigenesis and progression in numerous cancers. In this study, we explored the role of Glo1 genetic amplification and expression in Chinese patients with hepatocellular carcinoma (HCC), and Glo1 genetic amplification as potential therapeutic target for HCC. We used fluorescence in situ hybridization (FISH) analysis and qRT-PCR to examine Glo1 genetic aberrations and Glo1 mRNA expression in paired tumor samples obtained from HCC patients. Glo1 genetic amplification was identified in a subset of HCC patient (6%, 3/50), and up-regulation of Glo1 expression was found in 48% (24/50) of tumor tissues compared with adjacent non-tumorous tissues. Statistic analysis showed that Glo1-upregulation significantly correlated with high serum level of alpha-fetoprotein (AFP). Interfering Glo1 expression with shRNA knocking-down led to significant inhibition of cell growth and induced apoptosis in primarily cultured HCC cells carrying genetic amplified Glo1 gene, while no inhibitory effects on cell proliferation were observed in HCC cells with normal copies of Glo1 gene. Glo1 knockdown also inhibited tumor growth and induced apoptosis in xenograft tumors established from primarily cultured HCC cells with Glo1 gene amplification. In addition, Glo1 knocking-down with shRNA interfering caused cellular accumulation of methylglyoxal, a Glo1 cytotoxic substrate. Our data suggested Glo1 pathway activation is required for cell proliferation and cell survival of HCC cells carrying Glo1 genetic amplification. Intervention of Glo1 activation could be a potential therapeutic option for patients with HCC carrying Glo1 gene amplification. PMID:24966916

  18. New Strategies for the Next Generation of Matrix-Metalloproteinase Inhibitors: Selectively Targeting Membrane-Anchored MMPs with Therapeutic Antibodies

    Directory of Open Access Journals (Sweden)

    Laetitia Devy

    2011-01-01

    Full Text Available MMP intervention strategies have met with limited clinical success due to severe toxicities. In particular, treatment with broad-spectrum MMP-inhibitors (MMPIs caused musculoskeletal pain and inflammation. Selectivity may be essential for realizing the clinical potential of MMPIs. Here we review discoveries pinpointing membrane-bound MMPs as mediators of mechanisms underlying cancer and inflammation and as possible therapeutic targets for prevention/treatment of these diseases. We discuss strategies to target these therapeutic proteases using highly selective inhibitory agents (i.e., human blocking antibodies against individual membrane-bound MMPs.

  19. Identification of cell surface targets for HIV-1 therapeutics using genetic screens

    International Nuclear Information System (INIS)

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

  20. Choline Kinase Alpha as an Androgen Receptor Chaperone and Prostate Cancer Therapeutic Target

    Science.gov (United States)

    Asim, Mohammad; Massie, Charles E.; Orafidiya, Folake; Pértega-Gomes, Nelma; Warren, Anne Y.; Esmaeili, Mohsen; Selth, Luke A.; Zecchini, Heather I.; Luko, Katarina; Qureshi, Arham; Baridi, Ajoeb; Menon, Suraj; Madhu, Basetti; Escriu, Carlos; Lyons, Scott; Vowler, Sarah L.; Zecchini, Vincent R.; Shaw, Greg; Hessenkemper, Wiebke; Russell, Roslin; Mohammed, Hisham; Stefanos, Niki; Lynch, Andy G.; Grigorenko, Elena; D’Santos, Clive; Taylor, Chris; Lamb, Alastair; Sriranjan, Rouchelle; Yang, Jiali; Stark, Rory; Dehm, Scott M.; Rennie, Paul S.; Carroll, Jason S.; Griffiths, John R.; Tavaré, Simon; Mills, Ian G.; McEwan, Iain J.; Baniahmad, Aria; Tilley, Wayne D.; Neal, David E.

    2016-01-01

    Background: The androgen receptor (AR) is a major drug target in prostate cancer (PCa). We profiled the AR-regulated kinome to identify clinically relevant and druggable effectors of AR signaling. Methods: Using genome-wide approaches, we interrogated all AR regulated kinases. Among these, choline kinase alpha (CHKA) expression was evaluated in benign (n = 195), prostatic intraepithelial neoplasia (PIN) (n = 153) and prostate cancer (PCa) lesions (n = 359). We interrogated how CHKA regulates AR signaling using biochemical assays and investigated androgen regulation of CHKA expression in men with PCa, both untreated (n = 20) and treated with an androgen biosynthesis inhibitor degarelix (n = 27). We studied the effect of CHKA inhibition on the PCa transcriptome using RNA sequencing and tested the effect of CHKA inhibition on cell growth, clonogenic survival and invasion. Tumor xenografts (n = 6 per group) were generated in mice using genetically engineered prostate cancer cells with inducible CHKA knockdown. Data were analyzed with χ2 tests, Cox regression analysis, and Kaplan-Meier methods. All statistical tests were two-sided. Results: CHKA expression was shown to be androgen regulated in cell lines, xenografts, and human tissue (log fold change from 6.75 to 6.59, P = .002) and was positively associated with tumor stage. CHKA binds directly to the ligand-binding domain (LBD) of AR, enhancing its stability. As such, CHKA is the first kinase identified as an AR chaperone. Inhibition of CHKA repressed the AR transcriptional program including pathways enriched for regulation of protein folding, decreased AR protein levels, and inhibited the growth of PCa cell lines, human PCa explants, and tumor xenografts. Conclusions: CHKA can act as an AR chaperone, providing, to our knowledge, the first evidence for kinases as molecular chaperones, making CHKA both a marker of tumor progression and a potential therapeutic target for PCa. PMID:26657335

  1. Therapeutic Targeting of miR-29b/HDAC4 Epigenetic Loop in Multiple Myeloma.

    Science.gov (United States)

    Amodio, Nicola; Stamato, Maria Angelica; Gullà, Anna Maria; Morelli, Eugenio; Romeo, Enrica; Raimondi, Lavinia; Pitari, Maria Rita; Ferrandino, Ida; Misso, Gabriella; Caraglia, Michele; Perrotta, Ida; Neri, Antonino; Fulciniti, Mariateresa; Rolfo, Christian; Anderson, Kenneth C; Munshi, Nikhil C; Tagliaferri, Pierosandro; Tassone, Pierfrancesco

    2016-06-01

    Epigenetic abnormalities are common in hematologic malignancies, including multiple myeloma, and their effects can be efficiently counteracted by a class of tumor suppressor miRNAs, named epi-miRNAs. Given the oncogenic role of histone deacetylases (HDAC) in multiple myeloma, we investigated whether their activity could be antagonized by miR-29b, a well-established epi-miRNA. We demonstrated here that miR-29b specifically targets HDAC4 and highlighted that both molecules are involved in a functional loop. In fact, silencing of HDAC4 by shRNAs inhibited multiple myeloma cell survival and migration and triggered apoptosis and autophagy, along with the induction of miR-29b expression by promoter hyperacetylation, leading to the downregulation of prosurvival miR-29b targets (SP1, MCL-1). Moreover, treatment with the pan-HDAC inhibitor SAHA upregulated miR-29b, overcoming the negative control exerted by HDAC4. Importantly, overexpression or inhibition of miR-29b, respectively, potentiated or antagonized SAHA activity on multiple myeloma cells, as also shown in vivo by a strong synergism between miR-29b synthetic mimics and SAHA in a murine xenograft model of human multiple myeloma. Altogether, our results shed light on a novel epigenetic circuitry regulating multiple myeloma cell growth and survival and open new avenues for miR-29b-based epi-therapeutic approaches in the treatment of this malignancy. Mol Cancer Ther; 15(6); 1364-75. ©2016 AACR. PMID:27196750

  2. Magnetically Targeted Delivery of Therapeutic Agents to Injured Blood Vessels for Prevention of In-Stent Stenosis

    OpenAIRE

    Chorny, Michael; Fishbein, Ilia; Adamo, Richard F.; Forbes, Scott P.; Folchman-Wagner, Zoë; Alferiev, Ivan S.

    2012-01-01

    Magnetic guidance is a physical targeting strategy with the potential to improve the safety and efficacy of a variety of therapeutic agents — including small-molecule pharmaceuticals, proteins, gene vectors, and cells — by enabling their site-specific delivery. The application of magnetic targeting for in-stent restenosis can address the need for safer and more efficient treatment strategies. However, its translation to humans may not be possible without revising the traditional magnetic targ...

  3. [Revision of therapeutic index for targeted treatment in kidney cancer: What if toxicity could predict efficacy?].

    Science.gov (United States)

    Grellety, Thomas; Brugères-Chakiba, Camille; Chaminade, Axel; Roubaud, Guilhem; Ravaud, Alain; Gross-Goupil, Marine

    2014-06-01

    Since 2006, new treatments as targeted therapies (anti angiogenic and mTOR inhibitors) are prescribed in renal cell cancer. Toxicity of these treatments is well known by clinicians. Occurrence of these side effects has been associated with anti tumoral efficacy. High blood pressure, hypothyroïdie and hand foot syndrome were reported to be predictive of anti tumoral response. Fatigue and hyponatremia are still largely discussed. Moreover, non infectious pneumonia, which frequently occurs with mTOR inhibitors, is associated with clinical benefit. The main objective of treatment of advanced kidney cancer, specially renal cell cancer, is obtaining clinical benefit (stabilization and response) with a chronic evolution of the disease. This prolong exposure to drugs, according to their toxicity profile, often contributes to dose reduction, moreover interruption of treatment, potentially associated with a loss of control of disease. Thus, the adverse effects, described hereby, may be considered as « positive events », predicting efficacy, and thus looked for… Moreover, the sequential approach, with new drugs, emphasizes the need of defining the optimal sequence. Thus, because of the lack of molecular biomarkers to date, this predictives secondary effects may help for selecting the therapeutic strategy. PMID:24977449

  4. Sonic Hedgehog Signaling Drives Proliferation of Synoviocytes in Rheumatoid Arthritis: A Possible Novel Therapeutic Target

    Directory of Open Access Journals (Sweden)

    Mingxia Wang

    2014-01-01

    Full Text Available Sonic hedgehog (Shh signaling controls many aspects of human development, regulates cell growth and differentiation in adult tissues, and is activated in a number of malignancies. Rheumatoid arthritis (RA is characterized by chronic synovitis and pannus formation associated with activation of fibroblast-like synoviocytes (FLS. We investigated whether Shh signaling plays a role in the proliferation of FLS in RA. Expression of Shh signaling related components (Shh, Ptch1, Smo, and Gli1 in RA synovial tissues was examined by immunohistochemistry (IHC and in FLS by IHC, immunofluorescence (IF, quantitative RT-PCR, and western blotting. Expression of Shh, Smo, and Gli1 in RA synovial tissue was higher than that in control tissue (P<0.05. Cyclopamine (a specific inhibitor of Shh signaling decreased mRNA expression of Shh, Ptch1, Smo, and Gli1 in cultured RA FLS, Shh, and Smo protein expression, and significantly decreased FLS proliferation. Flow cytometry analysis suggested that cyclopamine treatment resulted in cell cycle arrest of FLS in G1 phase. Our data show that Shh signaling is activated in synovium of RA patients in vivo and in cultured FLS form RA patients in vitro, suggesting a role in the proliferation of FLS in RA. It may therefore be a novel therapeutic target in RA.

  5. Cell Cycle Abnormality in Metabolic Syndrome and Nuclear Receptors as an Emerging Therapeutic Target

    Directory of Open Access Journals (Sweden)

    Nakatsuka,Atsuko

    2013-06-01

    Full Text Available In recent years, many researchers have emphasized the importance of metabolic syndrome based on its increasing prevalence and its adverse prognosis due to associated chronic vascular complications. Upstream of a cluster of metabolic and vascular disorders is the accumulation of visceral adipose tissue, which plays a central role in the pathophysiology. In the accumulation of adipose tissues, cell cycle regulation is tightly linked to cellular processes such as proliferation, hypertrophy and apoptosis. In addition, various cell cycle abnormalities have also been observed in other tissues, such as kidneys and the cardiovascular system, and they are critically involved in the progression of disease. Here, we discuss cell cycle abnormalities in metabolic syndrome in various tissues. Furthermore, we describe the role of nuclear receptors in cell growth and survival, and glucose and lipid metabolism in the whole body. Therapeutic strategies for modulating various cell cycles in metabolic disorders by targeting nuclear receptors may overcome obesity and its chronic vascular complications in the future.

  6. Targeting of beta adrenergic receptors results in therapeutic efficacy against models of hemangioendothelioma and angiosarcoma.

    Directory of Open Access Journals (Sweden)

    Jessica M Stiles

    Full Text Available Therapeutic targeting of the beta-adrenergic receptors has recently shown remarkable efficacy in the treatment of benign vascular tumors such as infantile hemangiomas. As infantile hemangiomas are reported to express high levels of beta adrenergic receptors, we examined the expression of these receptors on more aggressive vascular tumors such as hemangioendotheliomas and angiosarcomas, revealing beta 1, 2, and 3 receptors were indeed present and therefore aggressive vascular tumors may similarly show increased susceptibility to the inhibitory effects of beta blockade. Using a panel of hemangioendothelioma and angiosarcoma cell lines, we demonstrate that beta adrenergic inhibition blocks cell proliferation and induces apoptosis in a dose dependent manner. Beta blockade is selective for vascular tumor cells over normal endothelial cells and synergistically effective when combined with standard chemotherapeutic or cytotoxic agents. We demonstrate that inhibition of beta adrenergic signaling induces large scale changes in the global gene expression patterns of vascular tumors, including alterations in the expression of established cell cycle and apoptotic regulators. Using in vivo tumor models we demonstrate that beta blockade shows remarkable efficacy as a single agent in reducing the growth of angiosarcoma tumors. In summary, these experiments demonstrate the selective cytotoxicity and tumor suppressive ability of beta adrenergic inhibition on malignant vascular tumors and have laid the groundwork for a promising treatment of angiosarcomas in humans.

  7. Targeting developmental regulators of zebrafish exocrine pancreas as a therapeutic approach in human pancreatic cancer

    Directory of Open Access Journals (Sweden)

    Nelson S. Yee

    2012-02-01

    Histone deacetylases (HDACs and RNA polymerase III (POLR3 play vital roles in fundamental cellular processes, and deregulation of these enzymes has been implicated in malignant transformation. Hdacs and Polr3 are required for exocrine pancreatic epithelial proliferation during morphogenesis in zebrafish. We aim to test the hypothesis that Hdacs and Polr3 cooperatively control exocrine pancreatic growth, and combined inhibition of HDACs and POLR3 produces enhanced growth suppression in pancreatic cancer. In zebrafish larvae, combination of a Hdac inhibitor (Trichostatin A and an inhibitor of Polr3 (ML-60218 synergistically prohibited the expansion of exocrine pancreas. In human pancreatic adenocarcinoma cells, combination of the HDAC inhibitor suberoylanilide hydroxamic acid (SAHA and ML-60218 produced augmented suppression of colony formation and proliferation, and induction of cell cycle arrest and apoptotic cell death. The enhanced cytotoxicity was associated with supra-additive upregulation of the pro-apoptotic regulator BAX and the cyclin-dependent kinase inhibitor p21CDKN1A. tRNAs have been shown to have pro-proliferative and anti-apoptotic roles, and SAHA-stimulated expression of tRNAs was reversed by ML-60218. These findings demonstrate that chemically targeting developmental regulators of exocrine pancreas can be translated into an approach with potential impact on therapeutic response in pancreatic cancer, and suggest that counteracting the pro-malignant side effect of HDAC inhibitors can enhance their anti-tumor activity.

  8. Mer receptor tyrosine kinase is a therapeutic target in pre–B-cell acute lymphoblastic leukemia

    Science.gov (United States)

    Linger, Rachel M. A.; Lee-Sherick, Alisa B.; DeRyckere, Deborah; Cohen, Rebecca A.; Jacobsen, Kristen M.; McGranahan, Amy; Brandão, Luis N.; Winges, Amanda; Sawczyn, Kelly K.; Liang, Xiayuan; Keating, Amy K.; Tan, Aik Choon; Earp, H. Shelton

    2013-01-01

    Acute lymphoblastic leukemia (ALL) is currently treated with an intense regimen of chemotherapy yielding cure rates near 85%. However, alterations to treatment strategies using available drugs are unlikely to provide significant improvement in survival or decrease therapy-associated toxicities. Here, we report ectopic expression of the Mer receptor tyrosine kinase in pre–B-cell ALL (B-ALL) cell lines and pediatric patient samples. Inhibition of Mer in B-ALL cell lines decreased activation of AKT and MAPKs and led to transcriptional changes, including decreased expression of antiapoptotic PRKCB gene and increase in proapoptotic BAX and BBC3 genes. Further, Mer inhibition promoted chemosensitization, decreased colony-forming potential in clonogenic assays, and delayed disease onset in a mouse xenograft model of leukemia. Our results identify Mer as a potential therapeutic target in B-ALL and suggest that inhibitors of Mer may potentiate lymphoblast killing when used in combination with chemotherapy. This strategy could reduce minimal residual disease and/or allow for chemotherapy dose reduction, thereby leading to improved event-free survival and reduced therapy-associated toxicity for patients with B-ALL. Additionally, Mer is aberrantly expressed in numerous other malignancies suggesting that this approach may have broad applications. PMID:23861246

  9. Mer receptor tyrosine kinase is a therapeutic target in pre-B-cell acute lymphoblastic leukemia.

    Science.gov (United States)

    Linger, Rachel M A; Lee-Sherick, Alisa B; DeRyckere, Deborah; Cohen, Rebecca A; Jacobsen, Kristen M; McGranahan, Amy; Brandão, Luis N; Winges, Amanda; Sawczyn, Kelly K; Liang, Xiayuan; Keating, Amy K; Tan, Aik Choon; Earp, H Shelton; Graham, Douglas K

    2013-08-29

    Acute lymphoblastic leukemia (ALL) is currently treated with an intense regimen of chemotherapy yielding cure rates near 85%. However, alterations to treatment strategies using available drugs are unlikely to provide significant improvement in survival or decrease therapy-associated toxicities. Here, we report ectopic expression of the Mer receptor tyrosine kinase in pre-B-cell ALL (B-ALL) cell lines and pediatric patient samples. Inhibition of Mer in B-ALL cell lines decreased activation of AKT and MAPKs and led to transcriptional changes, including decreased expression of antiapoptotic PRKCB gene and increase in proapoptotic BAX and BBC3 genes. Further, Mer inhibition promoted chemosensitization, decreased colony-forming potential in clonogenic assays, and delayed disease onset in a mouse xenograft model of leukemia. Our results identify Mer as a potential therapeutic target in B-ALL and suggest that inhibitors of Mer may potentiate lymphoblast killing when used in combination with chemotherapy. This strategy could reduce minimal residual disease and/or allow for chemotherapy dose reduction, thereby leading to improved event-free survival and reduced therapy-associated toxicity for patients with B-ALL. Additionally, Mer is aberrantly expressed in numerous other malignancies suggesting that this approach may have broad applications. PMID:23861246

  10. Arginine-Glycine-Aspartate-Binding Integrins as Therapeutic and Diagnostic Targets.

    Science.gov (United States)

    Sun, Cui-Cui; Qu, Xian-Jun; Gao, Zu-Hua

    2016-01-01

    Arginine-glycine-aspartate (RGD)-binding integrins, including αvβ1, αvβ3, αvβ5, αvβ6, αvβ8, α5β1, αIIbβ3, and α8β1, recognize the tripeptide motif RGD in their ligands. RGD-binding integrins are involved in various cell functions, including cell proliferation, survival, differentiation, and motility that are critically important to both health and disease. The diagnostic and therapeutic value of some RGD-binding integrin inhibitors are either clinically proven or at different stages of development. In this review, we first summarized the structure and signaling characteristics of RGD-binding integrins. We then discussed the functions of RGD-binding integrins and their association with human disease. Finally, we recapitulated the research efforts and clinical trials of targeting RGD-binding integrins for the diagnosis and treatment of human disease. This comprehensive review of the current advances in RGD-binding integrins could assist scientists and clinicians in gaining a complete understanding of this group of molecules. It can also contribute to the design of new projects to further advance this field of research and to better apply the research results to benefit patients in clinical practice. PMID:24621642

  11. Targeting NK-1 Receptors to Prevent and Treat Pancreatic Cancer: A New Therapeutic Approach

    International Nuclear Information System (INIS)

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

  12. Inflammatory and immune responses in the cochlea: potential therapeutic targets for sensorineural hearing loss

    Directory of Open Access Journals (Sweden)

    Masato eFujioka

    2014-12-01

    Full Text Available The inner ear was previously assumed to be an immune-privileged organ due to the existence of its tight junction-based blood-labyrinth barrier. However, studies performed during the past decade revealed that the mesenchymal region of the cochlea, including its lateral wall, is a common site of inflammation. Neutrophils do not enter this region, which is consistent with the old dogma; however, bone marrow-derived resident macrophages are always present in the spiral ligament of the lateral wall and are activated in response to various types of insults, including noise exposure, ischemia, mitochondrial damage and surgical stress. Recent studies have also revealed another type of immune cell, called perivascular melanocyte-like macrophages (PVM/Ms, in the stria vascularis. These dedicated antigen-presenting cells also control vascular contraction and permeability. This review discusses a series of reports regarding inflammatory/immune cells in the cochlear lateral wall, the pathways involved in cochlear damage and their potential as therapeutic targets.

  13. Potential therapeutic target for malignant paragangliomas: ATP synthase on the surface of paraganglioma cells

    Science.gov (United States)

    Fliedner, Stephanie MJ; Yang, Chunzhang; Thompson, Eli; Abu-Asab, Mones; Hsu, Chang-Mei; Lampert, Gary; Eiden, Lee; Tischler, Arthur S; Wesley, Robert; Zhuang, Zhengping; Lehnert, Hendrik; Pacak, Karel

    2015-01-01

    F1FoATP synthase (ATP synthase) is a ubiquitous enzyme complex in eukaryotes. In general it is localized to the mitochondrial inner membrane and serves as the last step in the mitochondrial oxidative phosphorylation of ADP to ATP, utilizing a proton gradient across the inner mitochondrial membrane built by the complexes of the electron transfer chain. However some cell types, including tumors, carry ATP synthase on the cell surface. It was suggested that cell surface ATP synthase helps tumor cells thriving on glycolysis to survive their high acid generation. Angiostatin, aurovertin, resveratrol, and antibodies against the α and β subunits of ATP synthase were shown to bind and selectively inhibit cell surface ATP synthase, promoting tumor cell death. Here we show that ATP synthase β (ATP5B) is present on the cell surface of mouse pheochromocytoma cells as well as tumor cells of human SDHB-derived paragangliomas (PGLs), while being virtually absent on chromaffin primary cells from bovine adrenal medulla by confocal microscopy. The cell surface location of ATP5B was verified in the tissue of an SDHB-derived PGL by immunoelectron microscopy. Treatment of mouse pheochromocytoma cells with resveratrol as well as ATP5B antibody led to statistically significant proliferation inhibition. Our data suggest that PGLs carry ATP synthase on their surface that promotes cell survival or proliferation. Thus, cell surface ATP synthase may present a novel therapeutic target in treating metastatic or inoperable PGLs. PMID:26101719

  14. Calcium/calmodulin-dependent protein kinase IV: A multifunctional enzyme and potential therapeutic target.

    Science.gov (United States)

    Naz, Huma; Islam, Asimul; Ahmad, Faizan; Hassan, Md Imtaiyaz

    2016-05-01

    The calcium/calmodulin-dependent protein kinase IV (CAMKIV) belongs to the serine/threonine protein kinase family, and is primarily involved in transcriptional regulation in lymphocytes, neurons and male germ cells. CAMKIV operates the signaling cascade and regulates activity of several transcription activators by phosphorylation, which in turn plays pivotal roles in immune response, inflammation and memory consolidation. In this review, we tried to focus on different aspects of CAMKIV to understand the significance of this protein in the biological system. This enzyme is associated with varieties of disorders such as cerebral hypoxia, azoospermia, endometrial and ovarian cancer, systemic lupus, etc., and hence it is considered as a potential therapeutic target. Structure of CAMKIV is comprised of five distinct domains in which kinase domain is responsible for enzyme activity. CAMKIV is involved in varieties of cellular functions such as regulation of gene expression, T-cell maturation, regulation of survival phase of dendritic cells, bone growth and metabolism, memory consolidation, sperm motility, regulation of microtubule dynamics, cell-cycle progression and apoptosis. In this review, we performed an extensive analysis on structure, function and regulation of CAMKIV and associated diseases. PMID:26773169

  15. HDAC4 reduction: a novel therapeutic strategy to target cytoplasmic huntingtin and ameliorate neurodegeneration.

    Directory of Open Access Journals (Sweden)

    Michal Mielcarek

    2013-11-01

    Full Text Available Histone deacetylase (HDAC 4 is a transcriptional repressor that contains a glutamine-rich domain. We hypothesised that it may be involved in the molecular pathogenesis of Huntington's disease (HD, a protein-folding neurodegenerative disorder caused by an aggregation-prone polyglutamine expansion in the huntingtin protein. We found that HDAC4 associates with huntingtin in a polyglutamine-length-dependent manner and co-localises with cytoplasmic inclusions. We show that HDAC4 reduction delayed cytoplasmic aggregate formation, restored Bdnf transcript levels, and rescued neuronal and cortico-striatal synaptic function in HD mouse models. This was accompanied by an improvement in motor coordination, neurological phenotypes, and increased lifespan. Surprisingly, HDAC4 reduction had no effect on global transcriptional dysfunction and did not modulate nuclear huntingtin aggregation. Our results define a crucial role for the cytoplasmic aggregation process in the molecular pathology of HD. HDAC4 reduction presents a novel strategy for targeting huntingtin aggregation, which may be amenable to small-molecule therapeutics.

  16. RhoA/Rho-kinase signaling: a therapeutic target in pulmonary hypertension

    Directory of Open Access Journals (Sweden)

    Scott A Barman

    2009-08-01

    Full Text Available Scott A Barman, Shu Zhu, Richard E WhiteDepartment of Pharmacology and Toxicology, Medical College of Georgia, Augusta, Georgia, USAAbstract: Pulmonary arterial hypertension (PAH is a devastating disease characterized by progressive elevation of pulmonary arterial pressure and vascular resistance due to pulmonary vasoconstriction and vessel remodeling as well as inflammation. Rho-kinases (ROCKs are one of the best-described effectors of the small G-protein RhoA, and ROCKs are involved in a variety of cellular functions including muscle cell contraction, proliferation and vascular inflammation through inhibition of myosin light chain phosphatase and activation of downstream mediators. A plethora of evidence in animal models suggests that heightened RhoA/ROCK signaling is important in the pathogenesis of pulmonary hypertension by causing enhanced constriction and remodeling of the pulmonary vasculature. Both animal and clinical studies suggest that ROCK inhibitors are effective for treatment of severe PAH with minimal risk, which supports the premise that ROCKs are important therapeutic targets in pulmonary hypertension and that ROCK inhibitors are a promising new class of drugs for this devastating disease.Keywords: pulmonary arterial hypertension, Rho-kinase, vasoconstriction, fasudil

  17. pH-Sensitive stimulus-responsive nanocarriers for targeted delivery of therapeutic agents.

    Science.gov (United States)

    Karimi, Mahdi; Eslami, Masoud; Sahandi-Zangabad, Parham; Mirab, Fereshteh; Farajisafiloo, Negar; Shafaei, Zahra; Ghosh, Deepanjan; Bozorgomid, Mahnaz; Dashkhaneh, Fariba; Hamblin, Michael R

    2016-09-01

    In recent years miscellaneous smart micro/nanosystems that respond to various exogenous/endogenous stimuli including temperature, magnetic/electric field, mechanical force, ultrasound/light irradiation, redox potentials, and biomolecule concentration have been developed for targeted delivery and release of encapsulated therapeutic agents such as drugs, genes, proteins, and metal ions specifically at their required site of action. Owing to physiological differences between malignant and normal cells, or between tumors and normal tissues, pH-sensitive nanosystems represent promising smart delivery vehicles for transport and delivery of anticancer agents. Furthermore, pH-sensitive systems possess applications in delivery of metal ions and biomolecules such as proteins, insulin, etc., as well as co-delivery of cargos, dual pH-sensitive nanocarriers, dual/multi stimuli-responsive nanosystems, and even in the search for new solutions for therapy of diseases such as Alzheimer's. In order to design an optimized system, it is necessary to understand the various pH-responsive micro/nanoparticles and the different mechanisms of pH-sensitive drug release. This should be accompanied by an assessment of the theoretical and practical challenges in the design and use of these carriers. WIREs Nanomed Nanobiotechnol 2016, 8:696-716. doi: 10.1002/wnan.1389 For further resources related to this article, please visit the WIREs website. PMID:26762467

  18. Targeting NK-1 Receptors to Prevent and Treat Pancreatic Cancer: A New Therapeutic Approach

    Energy Technology Data Exchange (ETDEWEB)

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

    2015-07-06

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

  19. Therapeutic potential of targeting protein for Xklp2 silencing for pancreatic cancer

    International Nuclear Information System (INIS)

    The targeting protein for Xklp2 (TPX2) is a microtubule- and, cell cycle-associated protein who’s overexpression has been reported in various malignancies. In this study, we verified the overexpression of TPX2 in both surgically resected specimens of pancreatic cancer and multiple pancreatic cancer cell lines. Subsequently, we found that TPX2 siRNA effectively suppressed the proliferation of pancreatic cancer cells in culture, and the direct injection of TPX2 siRNA into subcutaneously implanted pancreatic cancer cells in nude mice revealed antiproliferative effects. These results implied a therapeutic potential of TPX2 siRNA in pancreatic cancer. Among 56 angiogenesis-related factors examined using angiogenesis arrays, the average protein levels of insulin-like growth factor-binding protein-3 (IGFBP-3) were significantly higher in TPX2 siRNA-treated tumors than in the Control siRNA-treated tumors. Moreover, we demonstrated that CD34-positive microvessels were significantly reduced in tumors treated with TPX2 siRNA compared to tumors that treated with Control siRNA. The attenuated expression of CD34 in TPX2 siRNA-treated tumors coincided with the overexpression of IGFBP-3. These results indicated that TPX2 has an impact on tumor angiogenesis in pancreatic cancer. The results also implied that the antiangiogenic effect observed in TPX2 siRNA-treated pancreatic cancer cells may be partly explained by the upregulation of IGFBP-3

  20. Nrf2/ARE Signaling Pathway: Key Mediator in Oxidative Stress and Potential Therapeutic Target in ALS

    Directory of Open Access Journals (Sweden)

    Susanne Petri

    2012-01-01

    Full Text Available Nrf2 (nuclear erythroid 2-related factor 2 is a basic region leucine-zipper transcription factor which binds to the antioxidant response element (ARE and thereby regulates the expression of a large battery of genes involved in the cellular antioxidant and anti-inflammatory defence as well as mitochondrial protection. As oxidative stress, inflammation and mitochondrial dysfunctions have been identified as important pathomechanisms in amyotrophic lateral sclerosis (ALS, this signaling cascade has gained interest both with respect to ALS pathogenesis and therapy. Nrf2 and Keap1 expressions are reduced in motor neurons in postmortem ALS tissue. Nrf2-activating compounds have shown therapeutic efficacy in the ALS mouse model and other neurodegenerative disease models. Alterations in Nrf2 and Keap1 expression and dysregulation of the Nrf2/ARE signalling program could contribute to the chronic motor neuron degeneration in ALS and other neurodegenerative diseases. Therefore, Nrf2 emerges as a key neuroprotective molecule in neurodegenerative diseases. Our recent studies strongly support that the Nrf2/ARE signalling pathway is an important mediator of neuroprotection and therefore represents a promising target for development of novel therapies against ALS, Parkinson’s disease (PD, Huntington’s disease (HD, and Alzheimer’s disease (AD.

  1. Redox Signaling as a Therapeutic Target to Inhibit Myofibroblast Activation in Degenerative Fibrotic Disease

    Directory of Open Access Journals (Sweden)

    Natalie Sampson

    2014-01-01

    Full Text Available Degenerative fibrotic diseases encompass numerous systemic and organ-specific disorders. Despite their associated significant morbidity and mortality, there is currently no effective antifibrotic treatment. Fibrosis is characterized by the development and persistence of myofibroblasts, whose unregulated deposition of extracellular matrix components disrupts signaling cascades and normal tissue architecture leading to organ failure and death. The profibrotic cytokine transforming growth factor beta (TGFβ is considered the foremost inducer of fibrosis, driving myofibroblast differentiation in diverse tissues. This review summarizes recent in vitro and in vivo data demonstrating that TGFβ-induced myofibroblast differentiation is driven by a prooxidant shift in redox homeostasis. Elevated NADPH oxidase 4 (NOX4-derived hydrogen peroxide (H2O2 supported by concomitant decreases in nitric oxide (NO signaling and reactive oxygen species scavengers are central factors in the molecular pathogenesis of fibrosis in numerous tissues and organs. Moreover, complex interplay between NOX4-derived H2O2 and NO signaling regulates myofibroblast differentiation. Restoring redox homeostasis via antioxidants or NOX4 inactivation as well as by enhancing NO signaling via activation of soluble guanylyl cyclases or inhibition of phosphodiesterases can inhibit and reverse myofibroblast differentiation. Thus, dysregulated redox signaling represents a potential therapeutic target for the treatment of wide variety of different degenerative fibrotic disorders.

  2. Identification of tumorigenic cells and therapeutic targets in pancreatic neuroendocrine tumors.

    Science.gov (United States)

    Krampitz, Geoffrey Wayne; George, Benson M; Willingham, Stephen B; Volkmer, Jens-Peter; Weiskopf, Kipp; Jahchan, Nadine; Newman, Aaron M; Sahoo, Debashis; Zemek, Allison J; Yanovsky, Rebecca L; Nguyen, Julia K; Schnorr, Peter J; Mazur, Pawel K; Sage, Julien; Longacre, Teri A; Visser, Brendan C; Poultsides, George A; Norton, Jeffrey A; Weissman, Irving L

    2016-04-19

    Pancreatic neuroendocrine tumors (PanNETs) are a type of pancreatic cancer with limited therapeutic options. Consequently, most patients with advanced disease die from tumor progression. Current evidence indicates that a subset of cancer cells is responsible for tumor development, metastasis, and recurrence, and targeting these tumor-initiating cells is necessary to eradicate tumors. However, tumor-initiating cells and the biological processes that promote pathogenesis remain largely uncharacterized in PanNETs. Here we profile primary and metastatic tumors from an index patient and demonstrate that MET proto-oncogene activation is important for tumor growth in PanNET xenograft models. We identify a highly tumorigenic cell population within several independent surgically acquired PanNETs characterized by increased cell-surface protein CD90 expression and aldehyde dehydrogenase A1 (ALDHA1) activity, and provide in vitro and in vivo evidence for their stem-like properties. We performed proteomic profiling of 332 antigens in two cell lines and four primary tumors, and showed that CD47, a cell-surface protein that acts as a "don't eat me" signal co-opted by cancers to evade innate immune surveillance, is ubiquitously expressed. Moreover, CD47 coexpresses with MET and is enriched in CD90(hi)cells. Furthermore, blocking CD47 signaling promotes engulfment of tumor cells by macrophages in vitro and inhibits xenograft tumor growth, prevents metastases, and prolongs survival in vivo. PMID:27035983

  3. Quantitative proteomics approach to screening of potential diagnostic and therapeutic targets for laryngeal carcinoma.

    Directory of Open Access Journals (Sweden)

    Li Li

    Full Text Available To discover candidate biomarkers for diagnosis and detection of human laryngeal carcinoma and explore possible mechanisms of this cancer carcinogenesis, two-dimensional strong cation-exchange/reversed-phase nano-scale liquid chromatography/mass spectrometry analysis was used to identify differentially expressed proteins between the laryngeal carcinoma tissue and the adjacent normal tissue. As a result, 281 proteins with significant difference in expression were identified, and four differential proteins, Profilin-1 (PFN1, Nucleolin (NCL, Cytosolic non-specific dipeptidase (CNDP2 and Mimecan (OGN with different subcellular localization were selectively validated. Semiquantitative RT-PCR and Western blotting were performed to detect the expression of the four proteins employing a large collection of human laryngeal carcinoma tissues, and the results validated the differentially expressed proteins identified by the proteomics. Furthermore, we knocked down PFN1 in immortalized human laryngeal squamous cell line Hep-2 cells and then the proliferation and metastasis of these transfected cells were measured. The results showed that PFN1 silencing inhibited the proliferation and affected the migration ability of Hep-2 cells, providing some new insights into the pathogenesis of PFN1 in laryngeal carcinoma. Altogether, our present data first time show that PFN1, NCL, CNDP2 and OGN are novel potential biomarkers for diagnosis and therapeutic targets for laryngeal carcinoma, and PFN1 is involved in the metastasis of laryngeal carcinoma.

  4. Molecular pathogenesis of myocardial remodeling and new potential therapeutic targets in chronic heart failure

    Directory of Open Access Journals (Sweden)

    Distefano Giuseppe

    2012-09-01

    Full Text Available Abstract It is well known that the natural history of chronic heart failure (CHF,regardless of age and aetiology,is characterized by progressive cardiac dysfunction refractory to conventional cardiokinetic, diuretic and peripheral vasodilator therapy. Several previous studies, both in animals and humans, showed that the key pathogenetic element of CHF negative clinical evolution is constituted by myocardial remodeling. This is a complex pathologic process of ultrastructural rearrangement of the heart induced by various neuro-humoral factors released by cardiac fibrocells in response to biomechanical stress connected to chronic haemodynamic overload. Typical features of myocardial remodeling are represented by cardiomyocytes hypertrophy and apoptosis, extracellular matrix alterations, mesenchymal fibrotic and phlogistic processes and by cardiac gene expression modifications with fetal genetic program reactivation. In the last years, increasing knowledge of subtle molecular and cellular mechanisms involved in myocardial remodeling has led to the discovery of some new potential therapeutic targets capable of inducing its regression. In this paper our attention is focused on the possible use of antiapoptotic and antifibrotic agents, and on the fascinating perspectives offered by the development of myocardial gene therapy and, in particular, by myocardial regenerative therapy.

  5. G protein-coupled receptors as therapeutic targets for multiple sclerosis

    Institute of Scientific and Technical Information of China (English)

    Changsheng Du; Xin Xie

    2012-01-01

    G protein-coupled receptors (GPCRs) mediate most of our physiological responses to hormones,neurotransmitters and environmental stimulants.They are considered as the most successful therapeutic targets for a broad spectrum of diseases.Multiple sclerosis (MS) is an inflammatory disease that is characterized by immune-mediated demyelination and degeneration of the central nervous system (CNS).It is the leading cause of non-traumatic disability in young adults.Great progress has been made over the past few decades in understanding the pathogenesis of MS.Numerous data from animal and clinical studies indicate that many GPCRs are critically involved in various aspects of MS pathogenesis,including antigen presentation,cytokine production,T-cell differentiation,T-cell proliferation,T-cell invasion,etc.In this review,we summarize the recent findings regarding the expression or functional changes of GPCRs in MS patients or animal models,and the influences of GPCRs on disease severity upon genetic or pharmacological manipulations.Hopefully some of these findings will lead to the development of novel therapies for MS in the near future.

  6. Insulin and Insulin-Sensitizing Drugs in Neurodegeneration: Mitochondria as Therapeutic Targets

    Directory of Open Access Journals (Sweden)

    Paula I. Moreira

    2009-12-01

    Full Text Available Insulin, besides its glucose lowering effects, is involved in the modulation of lifespan, aging and memory and learning processes. As the population ages, neurodegenerative disorders become epidemic and a connection between insulin signaling dysregulation, cognitive decline and dementia has been established. Mitochondria are intracellular organelles that despite playing a critical role in cellular metabolism are also one of the major sources of reactive oxygen species. Mitochondrial dysfunction, oxidative stress and neuroinflammation, hallmarks of neurodegeneration, can result from impaired insulin signaling. Insulin-sensitizing drugs such as the thiazolidinediones are a new class of synthetic compounds that potentiate insulin action in the target tissues and act as specific agonists of the peroxisome proliferator-activated receptor gamma (PPAR-γ. Recently, several PPAR agonists have been proposed as novel and possible therapeutic agents for neurodegenerative disorders. Indeed, the literature shows that these agents are able to protect against mitochondrial dysfunction, oxidative damage, inflammation and apoptosis. This review discusses the role of mitochondria and insulin signaling in normal brain function and in neurodegeneration. Furthermore, the potential protective role of insulin and insulin sensitizers in Alzheimer´s, Parkinson´s and Huntington´s diseases and amyotrophic lateral sclerosis will be also discussed.

  7. Serotonin as a New Therapeutic Target for Diabetes Mellitus and Obesity.

    Science.gov (United States)

    Oh, Chang Myung; Park, Sangkyu; Kim, Hail

    2016-04-01

    Serotonin (5-hydroxytryptamine [5-HT]) is a monoamine that has various functions in both neuronal and non-neuronal systems. In the central nervous system, 5-HT regulates mood and feeding behaviors as a neurotransmitter. Thus, there have been many trials aimed at increasing the activity of 5-HT in the central nervous system, and some of the developed methods are already used in the clinical setting as anti-obesity drugs. Unfortunately, some drugs were withdrawn due to the development of unwanted peripheral side effects, such as valvular heart disease and pulmonary hypertension. Recent studies revealed that peripheral 5-HT plays an important role in metabolic regulation in peripheral tissues, where it suppresses adaptive thermogenesis in brown adipose tissue. Inhibition of 5-HT synthesis reduced the weight gain and improved the metabolic dysfunction in a diet-induced obesity mouse model. Genome-wide association studies also revealed genetic associations between the serotonergic system and obesity. Several genetic polymorphisms in tryptophan hydroxylase and 5-HT receptors were shown to have strong associations with obesity. These results support the clinical significance of the peripheral serotonergic system as a therapeutic target for obesity and diabetes. PMID:27126880

  8. KIFC1 is a novel potential therapeutic target for breast cancer.

    Science.gov (United States)

    Li, Yonghe; Lu, Wenyan; Chen, Dongquan; Boohaker, Rebecca J; Zhai, Ling; Padmalayam, Indira; Wennerberg, Krister; Xu, Bo; Zhang, Wei

    2015-01-01

    Kinesin-like protein KIFC1, a normally nonessential kinesin motor, plays a critical role in centrosome clustering in cancer cells and is essential for the survival of cancer cells. Herein, we reported that KIFC1 expression is up-regulated in breast cancer, particularly in estrogen receptor negative, progesterone receptor negative and triple negative breast cancer, and is not associated with epidermal growth factor receptor 2 status. In addition, KIFC1 is highly expressed in all 8 tested human breast cancer cell lines, but is absent in normal human mammary epithelial cells and weakly expressed in 2 human lung fibroblast lines. Moreover, KIFC1 silencing significantly reduced breast cancer cell viability. Finally, we found that PJ34, a potent small molecule inhibitor of poly(ADP-ribose) polymerase, suppressed KIFC1 expression and induced multipolar spindle formation in breast cancer cells, and inhibited cell viability and colony formation within the same concentration range, suggesting that KIFC1 suppression by PJ34 contributes to its anti-breast cancer activity. Together, these results suggest that KIFC1 is a novel promising therapeutic target for breast cancer. PMID:26177331

  9. Tuberculosis therapeutics: Engineering of nanomedicinal systems for local delivery of targeted drug cocktails

    Science.gov (United States)

    D'Addio, Suzanne M.

    In this thesis, a multifunctional nanocarrier drug delivery system was investigated and optimized to improve tuberculosis therapy by promoting the intracellular delivery of high payloads of antibiotics. To meet the needs of a patient population which continues to grow by close to 10 million people a year, innovative therapeutics must be formulated by robust and scalable processes. We use Flash NanoPrecipitation for the continuous precipitation of nanocarriers by block copolymer directed assembly, which enables the development of nanocarriers with tunable properties. Stable nanocarriers of Rifampicin and a hydrophobic Rifampicin prodrug have efficacy against tuberculosis in vitro that is equivalent to the soluble Rifampicin. To overcome poor in vivo efficacy of the recently discovered antitubercular drug SQ641, we co-encapsulate SQ641 and Cyclosporine A in a stable aqueous nanocarrier suspension, which enables drug administration and also enhances intracellular accumulation and antitubercular efficacy relative to SQ641 in solution. Since the mannose receptor is involved in the phagocytosis of tuberculosis bacilli, we modify the surface of nanocarriers with mannoside residues to target specific intracellular accumulation in macrophages. The surface density of mannoside terminated polyethylene glycol chains was controlled between 0 and 75% and in vitro cellular association reveals a 9% surface density is optimal for internalization mediated by the mannose receptor. We explore the preparation of large, porous aerosol carrier particles of with tunable deposition characteristics by spray freeze drying with ultrasonic atomization for direct dosing to the lungs. Nanocarriers are loaded at 3 - 50 wt% in mannitol particles with constant size, limited nanocarrier aggregation, and 63% dose delivered to the lungs, as determined by in vitro cascade impaction. There has been a lag in the development of new technologies to facilitate development and commercialization of

  10. Blood Outgrowth Endothelial Cells Increase Tumor Growth Rates and Modify Tumor Physiology: Relevance for Therapeutic Targeting

    Energy Technology Data Exchange (ETDEWEB)

    Pagan, Jonathan, E-mail: jdpagan@uams.edu; Przybyla, Beata; Jamshidi-Parsian, Azemat [Department of Radiation Oncology, University of Arkansas for Medical Sciences, 4301 West Markham Street, Little Rock, AR 72205 (United States); Gupta, Kalpna [Vascular Biology Center and Division of Hematology-Oncology Transplantation, Department of Medicine, University of Minnesota Medical School, MN 72223 (United States); Griffin, Robert J. [Department of Radiation Oncology, University of Arkansas for Medical Sciences, 4301 West Markham Street, Little Rock, AR 72205 (United States)

    2013-02-18

    Endothelial cell precursors from human peripheral blood have been shown to home to areas of neovascularization and may assist tumor growth by increasing or fortifying blood vessel growth. In the present study, the influence of these cells on tumor growth and physiology was investigated and the role of these cells as a therapeutic target or in determining treatment sensitivity was tested. After isolation from human blood and expansion in vitro, actively growing cells with verified endothelial phenotype (Blood Outgrowth Endothelial Cell, BOEC) were injected i.v. into tumor bearing mice for three consecutive days. The growth rate was significantly enhanced in relatively small RERF human lung tumors (i.e., less than 150 mm{sup 3}) grown in immunocompromised mice by an average of 1.5-fold while it had no effect when injections were given to animals bearing larger tumors. There were no signs of toxicity or unwanted systemic effects. We also observed evidence of increased perfusion, vessel number, response to 15 Gy radiation and oxygenation in RERF tumors of animals injected with BOECs compared to control tumors. In addition, FSaII murine fibrosarcoma tumors were found to grow faster upon injection of BOECs. When FSaII tumors were subjected to a partial thermal ablation treatment using high intensity focused ultrasound (HIFU) there was consistently elevated detection of fluorescently labeled and i.v. injected endothelial precursors in the tumor when analyzed with optical imaging and/or histological preparations. Importantly, we also observed that BOECs treated with the novel anti-angiogenic peptide anginex in-vitro, show decreased proliferation and increased sensitivity to radiation. In vivo, the normal increase in FSaII tumor growth induced by injected BOECs was blunted by the addition of anginex treatment. It appears that endothelial precursors may significantly contribute to tumor vessel growth, tumor progression and/or repair of tumor damage and may improve the

  11. Blood Outgrowth Endothelial Cells Increase Tumor Growth Rates and Modify Tumor Physiology: Relevance for Therapeutic Targeting

    Directory of Open Access Journals (Sweden)

    Kalpna Gupta

    2013-02-01

    Full Text Available Endothelial cell precursors from human peripheral blood have been shown to home to areas of neovascularization and may assist tumor growth by increasing or fortifying blood vessel growth. In the present study, the influence of these cells on tumor growth and physiology was investigated and the role of these cells as a therapeutic target or in determining treatment sensitivity was tested. After isolation from human blood and expansion in vitro, actively growing cells with verified endothelial phenotype (Blood Outgrowth Endothelial Cell, BOEC were injected i.v. into tumor bearing mice for three consecutive days. The growth rate was significantly enhanced in relatively small RERF human lung tumors (i.e., less than 150 mm3 grown in immunocompromised mice by an average of 1.5-fold while it had no effect when injections were given to animals bearing larger tumors. There were no signs of toxicity or unwanted systemic effects. We also observed evidence of increased perfusion, vessel number, response to 15 Gy radiation and oxygenation in RERF tumors of animals injected with BOECs compared to control tumors. In addition, FSaII murine fibrosarcoma tumors were found to grow faster upon injection of BOECs. When FSaII tumors were subjected to a partial thermal ablation treatment using high intensity focused ultrasound (HIFU there was consistently elevated detection of fluorescently labeled and i.v. injected endothelial precursors in the tumor when analyzed with optical imaging and/or histological preparations. Importantly, we also observed that BOECs treated with the novel anti-angiogenic peptide anginex in-vitro, show decreased proliferation and increased sensitivity to radiation. In vivo, the normal increase in FSaII tumor growth induced by injected BOECs was blunted by the addition of anginex treatment. It appears that endothelial precursors may significantly contribute to tumor vessel growth, tumor progression and/or repair of tumor damage and may improve

  12. Blood Outgrowth Endothelial Cells Increase Tumor Growth Rates and Modify Tumor Physiology: Relevance for Therapeutic Targeting

    International Nuclear Information System (INIS)

    Endothelial cell precursors from human peripheral blood have been shown to home to areas of neovascularization and may assist tumor growth by increasing or fortifying blood vessel growth. In the present study, the influence of these cells on tumor growth and physiology was investigated and the role of these cells as a therapeutic target or in determining treatment sensitivity was tested. After isolation from human blood and expansion in vitro, actively growing cells with verified endothelial phenotype (Blood Outgrowth Endothelial Cell, BOEC) were injected i.v. into tumor bearing mice for three consecutive days. The growth rate was significantly enhanced in relatively small RERF human lung tumors (i.e., less than 150 mm3) grown in immunocompromised mice by an average of 1.5-fold while it had no effect when injections were given to animals bearing larger tumors. There were no signs of toxicity or unwanted systemic effects. We also observed evidence of increased perfusion, vessel number, response to 15 Gy radiation and oxygenation in RERF tumors of animals injected with BOECs compared to control tumors. In addition, FSaII murine fibrosarcoma tumors were found to grow faster upon injection of BOECs. When FSaII tumors were subjected to a partial thermal ablation treatment using high intensity focused ultrasound (HIFU) there was consistently elevated detection of fluorescently labeled and i.v. injected endothelial precursors in the tumor when analyzed with optical imaging and/or histological preparations. Importantly, we also observed that BOECs treated with the novel anti-angiogenic peptide anginex in-vitro, show decreased proliferation and increased sensitivity to radiation. In vivo, the normal increase in FSaII tumor growth induced by injected BOECs was blunted by the addition of anginex treatment. It appears that endothelial precursors may significantly contribute to tumor vessel growth, tumor progression and/or repair of tumor damage and may improve the oxygenation

  13. Eigenvalue Attraction

    Science.gov (United States)

    Movassagh, Ramis

    2016-02-01

    We prove that the complex conjugate (c.c.) eigenvalues of a smoothly varying real matrix attract (Eq. 15). We offer a dynamical perspective on the motion and interaction of the eigenvalues in the complex plane, derive their governing equations and discuss applications. C.c. pairs closest to the real axis, or those that are ill-conditioned, attract most strongly and can collide to become exactly real. As an application we consider random perturbations of a fixed matrix M. If M is Normal, the total expected force on any eigenvalue is shown to be only the attraction of its c.c. (Eq. 24) and when M is circulant the strength of interaction can be related to the power spectrum of white noise. We extend this by calculating the expected force (Eq. 41) for real stochastic processes with zero-mean and independent intervals. To quantify the dominance of the c.c. attraction, we calculate the variance of other forces. We apply the results to the Hatano-Nelson model and provide other numerical illustrations. It is our hope that the simple dynamical perspective herein might help better understanding of the aggregation and low density of the eigenvalues of real random matrices on and near the real line respectively. In the appendix we provide a Matlab code for plotting the trajectories of the eigenvalues.

  14. Judging attractiveness: Biases due to raters’ own attractiveness and intelligence

    OpenAIRE

    Stacy Yen-Lin Sim; Jenna Saperia; Jill Anne Brown; Frank John Bernieri

    2015-01-01

    Tennis and Dabbs (1975) reported that physically attractive males showed a positivity bias when rating the attractiveness of others. The opposite pattern was observed for females. We attempted to replicate and extend these findings by: (1) using self-assessed attractiveness rather than the experimentally derived attractiveness measure used in previous research, (2) using face-to-face interactions with targets as opposed to using photographs, and (3) examining the effect of another ego-involvi...

  15. Controlling the angiogenic switch in developing atherosclerotic plaques: Possible targets for therapeutic intervention

    Directory of Open Access Journals (Sweden)

    Slevin Mark

    2009-09-01

    Full Text Available Abstract Plaque angiogenesis may have an important role in the development of atherosclerosis. Vasa vasorum angiogenesis and medial infiltration provides nutrients to the developing and expanding intima and therefore, may prevent cellular death and contribute to plaque growth and stabilization in early lesions. However in more advanced plaques, inflammatory cell infiltration, and concomitant production of numerous pro-angiogenic cytokines may be responsible for induction of uncontrolled neointimal microvessel proliferation resulting in production of immature and fragile neovessels similar to that seen in tumour development. These could contribute to development of an unstable haemorrhagic rupture-prone environment. Increasing evidence has suggested that the expression of intimal neovessels is directly related to the stage of plaque development, the risk of plaque rupture, and subsequently, the presence of symptomatic disease, the timing of ischemic neurological events and myocardial/cerebral infarction. Despite this, there is conflicting evidence regarding the causal relationship between neovessel expression and plaque thrombosis with some in vivo experimental models suggesting the contrary and as yet, few direct mediators of angiogenesis have been identified and associated with plaque instability in vivo. In recent years, an increasing number of angiogenic therapeutic targets have been proposed in order to facilitate modulation of neovascularization and its consequences in diseases such as cancer and macular degeneration. A complete knowledge of the mechanisms responsible for initiation of adventitial vessel proliferation, their extension into the intimal regions and possible de-novo synthesis of neovessels following differentiation of bone-marrow-derived stem cells is required in order to contemplate potential single or combinational anti-angiogenic therapies. In this review, we will examine the importance of angiogenesis in complicated plaque

  16. Experimental evidence of Migfilin as a new therapeutic target of hepatocellular carcinoma metastasis

    Energy Technology Data Exchange (ETDEWEB)

    Gkretsi, Vasiliki, E-mail: vasso.gkretsi@gmail.com [Department of Biomedical Research and Technology, Institute for Research and Technology-Thessaly, Centre for Research and Technology-Hellas (CE.R.T.H.), Larissa 41222 (Greece); Bogdanos, Dimitrios P. [Department of Biomedical Research and Technology, Institute for Research and Technology-Thessaly, Centre for Research and Technology-Hellas (CE.R.T.H.), Larissa 41222 (Greece); Department of Rheumatology, School of Medicine, University of Thessaly, University Hospital of Larissa, 41110 Larissa (Greece); Institute of Liver Studies, King' s College Hospital, Denmark Hill, London SE5 9RS (United Kingdom)

    2015-06-10

    Migfilin is a novel cell–matrix adhesion protein known to interact with Vasodilator Stimulated Phosphoprotein (VASP) and be localized both at cell–matrix and cell–cell adhesions. To date there is nothing known about its role in hepatocellular carcinoma (HCC). As matrix is important in metastasis, we aimed to investigate the Migfilin's role in HCC metastasis using two human HCC cell lines that differ in their metastatic potential; non-invasive Alexander cells and the highly invasive HepG2 cells. We silenced Migfilin by siRNA and studied its effect on signaling and metastasis-related cellular properties. We show that Migfilin's expression is elevated in HepG2 cells and its silencing leads to upregulation of actin reorganization-related proteins, namely phosphor-VASP (Ser157 and Ser239), Fascin-1 and Rho-kinase-1, promoting actin polymerization and inhibiting cell invasion. Phosphor-Akt (Ser473) is decreased contributing to the upregulation of free and phosphor-β-catenin (Ser33/37Thr41) and inducing proliferation. Migfilin elimination upregulates Extracellular Signal–regulated kinase, which increases cell adhesion in HepG2 and reduces invasiveness. This is the first study to reveal that Migfilin inhibition can halt HCC metastasis in vitro, providing the molecular mechanism involved and presenting Migfilin as potential therapeutic target against HCC metastasis. - Highlights: • Migfilin is a cell–matrix and cell–cell adhesion protein known to interact with VASP. • Nothing is known about Migfilin's role in hepatocellular carcinoma (HCC). • We eliminated Migfilin from 2 HCC cell lines and studied in vitro metastasis. • Its silencing inhibits cell invasion and promotes adhesion in HepG2 invasive cells. • We provide molecular mechanism by which Migfilin elimination halts HCC metastasis.

  17. Ectopic ATP synthase in endothelial cells: a novel cardiovascular therapeutic target.

    Science.gov (United States)

    Fu, Yi; Zhu, Yi

    2010-01-01

    Adenosine triphosphate (ATP) synthase produces ATP in cells and is found on the inner membrane of mitochondria or the cell plasma membrane (ectopic ATP synthase). Here, we summarize the functions of ectopic ATP synthase in vascular endothelial cells (ECs). Ectopic ATP synthase is involved in adenosine metabolism on the cell surface through its ATP generation or hydrolysis activity. The ATP/ADP generated by the enzyme on the plasma membrane can bind to P2X/P2Y receptors and activate the related signalling pathways to regulate endothelial function. The β-chain of ectopic ATP synthase on the EC surface can recruit inflammatory cells and activate cytotoxic activity to damage ECs and induce vascular inflammation. Angiostatin and other angiogenesis inhibitors can have anti-angiogenic functions by inhibiting ectopic ATP synthase on ECs. Moreover, ectopic ATP synthase on ECs is a receptor for apoA-I, the acceptor of cholesterol efflux, which implies that endothelial ectopic ATP synthase is involved in cholesterol metabolism. Coupling factor 6 (CF6), a part of ectopic ATP synthase, is released from ECs and can inhibit prostacyclin synthesis and promote nitric oxide (NO) degradation to enhance NO bioactivity. Because ATP/ADP generated by ectopic ATP synthase can induce NO production, substances such as CF6 can inhibit NO generation by inhibiting surface ATP/ADP production. Thus, the components of ectopic ATP synthase are associated with regulation of vascular tone. Through these functions, ectopic ATP synthase on ECs is considered a potential and novel therapeutic target for atherosclerosis, hypertension and lipid disorders. PMID:21247400

  18. Experimental evidence of Migfilin as a new therapeutic target of hepatocellular carcinoma metastasis

    International Nuclear Information System (INIS)

    Migfilin is a novel cell–matrix adhesion protein known to interact with Vasodilator Stimulated Phosphoprotein (VASP) and be localized both at cell–matrix and cell–cell adhesions. To date there is nothing known about its role in hepatocellular carcinoma (HCC). As matrix is important in metastasis, we aimed to investigate the Migfilin's role in HCC metastasis using two human HCC cell lines that differ in their metastatic potential; non-invasive Alexander cells and the highly invasive HepG2 cells. We silenced Migfilin by siRNA and studied its effect on signaling and metastasis-related cellular properties. We show that Migfilin's expression is elevated in HepG2 cells and its silencing leads to upregulation of actin reorganization-related proteins, namely phosphor-VASP (Ser157 and Ser239), Fascin-1 and Rho-kinase-1, promoting actin polymerization and inhibiting cell invasion. Phosphor-Akt (Ser473) is decreased contributing to the upregulation of free and phosphor-β-catenin (Ser33/37Thr41) and inducing proliferation. Migfilin elimination upregulates Extracellular Signal–regulated kinase, which increases cell adhesion in HepG2 and reduces invasiveness. This is the first study to reveal that Migfilin inhibition can halt HCC metastasis in vitro, providing the molecular mechanism involved and presenting Migfilin as potential therapeutic target against HCC metastasis. - Highlights: • Migfilin is a cell–matrix and cell–cell adhesion protein known to interact with VASP. • Nothing is known about Migfilin's role in hepatocellular carcinoma (HCC). • We eliminated Migfilin from 2 HCC cell lines and studied in vitro metastasis. • Its silencing inhibits cell invasion and promotes adhesion in HepG2 invasive cells. • We provide molecular mechanism by which Migfilin elimination halts HCC metastasis

  19. Molecular Expression Profile Reveals Potential Biomarkers and Therapeutic Targets in Canine Endometrial Lesions.

    Directory of Open Access Journals (Sweden)

    Fabiana Azevedo Voorwald

    Full Text Available Cystic endometrial hyperplasia (CEH, mucometra, and pyometra are common uterine diseases in intact dogs, with pyometra being a life threatening disease. This study aimed to determine the gene expression profile of these lesions and potential biomarkers for closed-cervix pyometra, the most severe condition. Total RNA was extracted from 69 fresh endometrium samples collected from 21 healthy female dogs during diestrus, 16 CEH, 15 mucometra and 17 pyometra (eight open and nine closed-cervixes. Global gene expression was detected using the Affymetrix Canine Gene 1.0 ST Array. Unsupervised analysis revealed two clusters, one mainly composed of diestrus and CEH samples and the other by 12/15 mucometra and all pyometra samples. When comparing pyometra with other groups, 189 differentially expressed genes were detected. SLPI, PTGS2/COX2, MMP1, S100A8, S100A9 and IL8 were among the top up-regulated genes detected in pyometra, further confirmed by external expression data. Notably, a particular molecular profile in pyometra from animals previously treated with exogenous progesterone compounds was observed in comparison with pyometra from untreated dogs as well as with other groups irrespective of exogenous hormone treatment status. In addition to S100A8 and S100A9 genes, overexpression of the inflammatory cytokines IL1B, TNF and IL6 as well as LTF were detected in the pyometra from treated animals. Interestingly, closed pyometra was more frequently detected in treated dogs (64% versus 33%, with IL1B, TNF, LBP and CXCL10 among the most relevant overexpressed genes. This molecular signature associated with potential biomarkers and therapeutic targets, such as CXCL10 and COX2, should guide future clinical studies. Based on the gene expression profile we suggested that pyometra from progesterone treated dogs is a distinct molecular entity.

  20. Molecular Expression Profile Reveals Potential Biomarkers and Therapeutic Targets in Canine Endometrial Lesions.

    Science.gov (United States)

    Voorwald, Fabiana Azevedo; Marchi, Fabio Albuquerque; Villacis, Rolando Andre Rios; Alves, Carlos Eduardo Fonseca; Toniollo, Gilson Hélio; Amorim, Renee Laufer; Drigo, Sandra Aparecida; Rogatto, Silvia Regina

    2015-01-01

    Cystic endometrial hyperplasia (CEH), mucometra, and pyometra are common uterine diseases in intact dogs, with pyometra being a life threatening disease. This study aimed to determine the gene expression profile of these lesions and potential biomarkers for closed-cervix pyometra, the most severe condition. Total RNA was extracted from 69 fresh endometrium samples collected from 21 healthy female dogs during diestrus, 16 CEH, 15 mucometra and 17 pyometra (eight open and nine closed-cervixes). Global gene expression was detected using the Affymetrix Canine Gene 1.0 ST Array. Unsupervised analysis revealed two clusters, one mainly composed of diestrus and CEH samples and the other by 12/15 mucometra and all pyometra samples. When comparing pyometra with other groups, 189 differentially expressed genes were detected. SLPI, PTGS2/COX2, MMP1, S100A8, S100A9 and IL8 were among the top up-regulated genes detected in pyometra, further confirmed by external expression data. Notably, a particular molecular profile in pyometra from animals previously treated with exogenous progesterone compounds was observed in comparison with pyometra from untreated dogs as well as with other groups irrespective of exogenous hormone treatment status. In addition to S100A8 and S100A9 genes, overexpression of the inflammatory cytokines IL1B, TNF and IL6 as well as LTF were detected in the pyometra from treated animals. Interestingly, closed pyometra was more frequently detected in treated dogs (64% versus 33%), with IL1B, TNF, LBP and CXCL10 among the most relevant overexpressed genes. This molecular signature associated with potential biomarkers and therapeutic targets, such as CXCL10 and COX2, should guide future clinical studies. Based on the gene expression profile we suggested that pyometra from progesterone treated dogs is a distinct molecular entity. PMID:26222498

  1. Pericyst may be a new pharmacological and therapeutic target for hydatid disease

    Institute of Scientific and Technical Information of China (English)

    WU Xiang-wei; CHEN Xue-ling; ZHANG Shi-jie; ZHANG Xi; SUN Hong; PENG Xin-yu

    2011-01-01

    Background Most hydatid cysts with calcified walls are biologically and clinically silent and inactive. Transforming growth factor-beta 1 (TGF-β1) plays a critical role in the calcification process of cells. The aim of this study was to assess the effect of modulating TGF-β1 signaling on the calcification of hydatid cysts.Methods Pericyst cells isolated from hepatic hydatid cysts were cultured with osteogenic media. These cells were assessed for alkaline phosphatase activity and mineralization capacity using Alizarin Red staining. Cells were also treated with recombinant human TGF-β1 and TGF-β inhibitor, and the expression profiles of osteoblast markers (RUNX2,osterix, and osteocalcin) were analyzed using Western blotting. The effects of inhibiting TGF-β1 signaling on calcification of pericyst walls were assessed using different doses of TGF-β inhibitor for 7 weeks in a preclinical disease model of liver cystic echinococcosis.Results Cells within the pericyst displayed high levels of alkaline phosphatase activity and mineralized nodule formation, as induced by osteogenic media. These activities, as well as expression profiles of osteoblast markers (RUNX2, osterix, and osteocalcin) could be inhibited by addition of recombinant human TGF-β1 (rhTGF-β1) and enhanced by TGF-β inhibitor. In the animal model of cystic echinococcosis, inhibition of TGF-β1 signaling increased calcification of the pericyst wall, which was associated with decreased cyst load index and lower viability of protoscoleces.Conclusions Cells within the pericysts adopt an osteoblast-like phenotype and have osteogenic potential. Inhibition of TGF-β1 signaling increases hydatid cyst calcification. Pharmacological modulation of calcification in pericysts may be a new therapeutic target in the treatment of hydatid disease.

  2. S100B as a Potential Biomarker and Therapeutic Target in Multiple Sclerosis.

    Science.gov (United States)

    Barateiro, Andreia; Afonso, Vera; Santos, Gisela; Cerqueira, João José; Brites, Dora; van Horssen, Jack; Fernandes, Adelaide

    2016-08-01

    Multiple sclerosis (MS) pathology is characterized by neuroinflammation and demyelination. Recently, the inflammatory molecule S100B was identified in cerebrospinal fluid (CSF) and serum of MS patients. Although seen as an astrogliosis marker, lower/physiological levels of S100B are involved in oligodendrocyte differentiation/maturation. Nevertheless, increased S100B levels released upon injury may induce glial reactivity and oligodendrocyte demise, exacerbating tissue damage during an MS episode or delaying the following remyelination. Here, we aimed to unravel the functional role of S100B in the pathogenesis of MS. Elevated S100B levels were detected in the CSF of relapsing-remitting MS patients at diagnosis. Active demyelinating MS lesions showed increased expression of S100B and its receptor, the receptor for advanced glycation end products (RAGE), in the lesion area, while chronic active lesions displayed increased S100B in demyelinated areas with lower expression of RAGE in the rim. Interestingly, reactive astrocytes were identified as the predominant cellular source of S100B, whereas RAGE was expressed by activated microglia/macrophages. Using an ex vivo demyelinating model, cerebral organotypic slice cultures treated with lysophosphatidylcholine (LPC), we observed a marked elevation of S100B upon demyelination, which co-localized mostly with astrocytes. Inhibition of S100B action using a directed antibody reduced LPC-induced demyelination, prevented astrocyte reactivity and abrogated the expression of inflammatory and inflammasome-related molecules. Overall, high S100B expression in MS patient samples suggests its usefulness as a diagnostic biomarker for MS, while the beneficial outcome of its inhibition in our demyelinating model indicates S100B as an emerging therapeutic target in MS. PMID:26184632

  3. Targeting CD47-SIRPα interactions for potentiating therapeutic antibody-mediated tumor cell destruction by phagocytes

    OpenAIRE

    Zhao, X.W.

    2014-01-01

    The primary aim of the studies described in this thesis was to investigate the role of CD47-SIRPα interactions in therapeutic antibody-dependent tumor cell destruction by human phagocytes and also explore the killing mechanism(s) by which human phagocytes, and in particular human neutrophils, mediate therapeutic antibody-dependent cytotoxicity towards cancer cells.

  4. CO2-free hydrogen as a substitute to fossil fuels: What are the targets? Prospective assessment of the hydrogen market attractiveness

    International Nuclear Information System (INIS)

    Hydrogen is usually presented as a promising energy carrier that has a major role to play in low carbon mobility, through the use of fuel cells. However, such a market is not expected in the short term. In the meantime, hydrogen may also contribute to reduce carbon emissions in diverse sectors: oil refining, low carbon mobility through the industrial deployment of advanced bio-fuels, natural gas consumption, and methanol production. According to the targeted market, objective costs are rather different; and so is the reachable mitigated CO2 amount. This paper assesses the dynamics of these markets' attractiveness, in order to provide target costs for CO2-free hydrogen production. The potential of the markets of hydrogen as a fuel and hydrogen for the biomass-to-liquid production is highlighted, as they could represent significant volumes by 2050, as well as interesting perspectives for CO2 emission reduction. However the targets are very sensitive to the CO2 price, thus highlighting the requirement for economic instruments in order to facilitate the penetration of such technologies. Hydrogen is then highlighted as a key player of the energy system in the years to come, as the connection of the energy and mobility sectors. (authors)

  5. Fatal attraction

    DEFF Research Database (Denmark)

    Jensen, Kim Ebensgaard

    2012-01-01

    The purpose of this paper is two-fold. Firstly, it presents an argument for usage-based inheritance models over complete inheritance models in construction grammar. It is argued that, with the principle of inductive language learning as their foundation, usage-based inheritance models allow for...... redundancies and incongruities in construction networks which enables linguists to take into account details of language use, which would otherwise not be facilitated in complete inheritance models. Secondly, making use of the method of collostructional analysis, the article offers a corpus-based description...... of the use of the Danish ihjel-construction which accounts for patterns of attraction of construction-verb attraction, patterns of productivity, and various types of subconstructions, including item- and item-class-based ones and metaphorical extensions. The description of the ihjel...

  6. Acoustic Attraction

    Science.gov (United States)

    Oviatt, Eric; Patsiaouris, Konstantinos; Denardo, Bruce

    2009-11-01

    A sound source of finite size produces a diverging traveling wave in an unbounded fluid. A rigid body that is small compared to the wavelength experiences an attractive radiation force (toward the source). An attractive force is also exerted on the fluid itself. The effect can be demonstrated with a styrofoam ball suspended near a loudspeaker that is producing sound of high amplitude and low frequency (for example, 100 Hz). The behavior can be understood and roughly calculated as a time-averaged Bernoulli effect. A rigorous scattering calculation yields a radiation force that is within a factor of two of the Bernoulli result. For a spherical wave, the force decreases as the inverse fifth power of the distance from the source. Applications of the phenomenon include ultrasonic filtration of liquids and the growth of supermassive black holes that emit sound waves in a surrounding plasma. An experiment is being conducted in an anechoic chamber with a 1-inch diameter aluminum ball that is suspended from an analytical balance. Directly below the ball is a baffled loudspeaker that exerts an attractive force that is measured by the balance.

  7. RON (MST1R) is a novel prognostic marker and therapeutic target for gastroesophageal adenocarcinoma

    Science.gov (United States)

    Catenacci, Daniel VT; Cervantes, Gustavo; Yala, Soheil; Nelson, Erik A; El-Hashani, Essam; Kanteti, Rajani; El Dinali, Mohamed; Hasina, Rifat; Brägelmann, Johannes; Seiwert, Tanguy; Sanicola, Michele; Henderson, Les; Grushko, Tatyana A; Olopade, Olufunmilayo; Karrison, Theodore; Bang, Yung-Jue; Ho Kim, Woo; Tretiakova, Maria; Vokes, Everett; Frank, David A; Kindler, Hedy L; Huet, Heather

    2011-01-01

    RON (MST1R) is one of two members of the MET receptor tyrosine kinase family, along with parent receptor MET. RON has a putative role in several cancers, but its expression and function is poorly characterized in gastroesophageal adenocarcinoma. A recognized functional role of MET tyrosine kinase in gastroesophageal cancer has led to early phase clinical trials using MET inhibitors, with unimpressive results. Therefore, the role of RON in gastroesophageal cancer, as well as its role in cooperative signaling with MET and as a mechanism of resistance to MET inhibition, was studied in gastroesophageal tissues and cell lines. By IHC, RON was highly overexpressed in 74% of gastroesophageal samples (n = 94) and overexpression was prognostic of poor survival (p = 0.008); RON and MET co-expression occurred in 43% of samples and was prognostic of worst survival (p = 0.03). High MST1R gene copy number by quantitative polymerase chain reaction and confirmed by fluorescence in situ hybridization and/or array comparative genomic hybridization, was seen in 35.5% (16/45) of cases. High MST1R gene copy number correlated with poor survival (p = 0.01), and was associated with high MET and ERBB2 gene copy number. a novel somatic MST1R juxtamembrane mutation R1018G was found in 11% of samples. RON signaling was functional in cell lines, activating downstream effector STAT3, and resulted in increased viability over controls. RON and MET co-stimulation assays led to enhanced malignant phenotypes over stimulation of either receptor alone. Growth inhibition as evidenced by viability and apoptosis assays was optimal using novel blocking monoclonal antibodies to both ROn and MET, versus either alone. SU11274, a classic MET small molecule tyrosine kinase inhibitor, blocked signaling of both receptors and proved synergistic when combined with STAT3 inhibition (combination index <1). These preclinical studies define RON as an important novel prognostic marker and therapeutic target for

  8. Potential prospects of nanomedicine for targeted therapeutics in inflammatory bowel diseases

    OpenAIRE

    Pichai, Madharasi VA; Lynnette R. Ferguson

    2012-01-01

    Inflammatory bowel diseases (IBDs) such as Crohn’s disease are highly debilitating. There are inconsistencies in response to and side effects in the current conventional medications, failures in adequate drug delivery, and the lack of therapeutics to offer complete remission in the presently available treatments of IBD. This suggests the need to explore beyond the horizons of conventional approaches in IBD therapeutics. This review examines the arena of the evolving IBD nanomedicine, studied ...

  9. Small-Nucleic-Acid-Based Therapeutic Strategy Targeting the Transcription Factors Regulating the Vascular Inflammation, Remodeling and Fibrosis in Atherosclerosis

    Directory of Open Access Journals (Sweden)

    Sung Won Youn

    2015-05-01

    Full Text Available Atherosclerosis arises when injury to the arterial wall induces an inflammatory cascade that is sustained by a complex network of cytokines, together with accumulation of lipids and fibrous material. Inflammatory cascades involve leukocyte adherence and chemotaxis, which are coordinated by the local secretion of adhesion molecules, chemotactic factors, and cytokines. Transcription factors are critical to the integration of the various steps of the cascade response to mediators of vascular injury, and are induced in a stimulus-dependent and cell-type-specific manner. Several small-nucleic-acid-based therapeutic strategies have recently been developed to target transcription factors: antisense oligodeoxynucleotides, RNA interference, microRNA, and decoy oligodeoxynucleotides. The aim of this review was to provide an overview of these particular targeted therapeutic strategies, toward regulation of the vascular inflammation, remodeling and fibrosis associated with atherosclerosis.

  10. Mouse model of intrahepatic cholangiocarcinoma validates FIG–ROS as a potent fusion oncogene and therapeutic target

    OpenAIRE

    Saborowski, Anna; Saborowski, Michael; Davare, Monika A.; Druker, Brian J.; Klimstra, David S.; Lowe, Scott W.

    2013-01-01

    Intrahepatic cholangiocarcinoma (ICC) is a fatal yet understudied primary liver malignancy. To accelerate the functional annotation of cancer genes and therapeutic targets in this disease, we generate a highly flexible orthotopic allograft mouse model of ICC that can be easily modified in vitro to mimic either oncogene expression by retrovirus-mediated gene transfer or tumor-suppressor gene loss by using RNA interference technology. We use this model to demonstrate that the fused-in-glioblast...

  11. PDX-1 Is a Therapeutic Target for Pancreatic Cancer, Insulinoma and Islet Neoplasia Using a Novel RNA Interference Platform

    OpenAIRE

    Liu, Shi-He; Rao, Donald D; Nemunaitis, John; Senzer, Neil; Zhou, Guisheng; Dawson, David; Gingras, Marie-Claude; Wang, Zhaohui; Gibbs, Richard,; Norman, Michael; Nancy S Templeton; DeMayo, Francesco J; O'Malley, Bert; Sanchez, Robbi; Fisher, William E.

    2012-01-01

    Pancreatic and duodenal homeobox-1 (PDX-1) is a transcription factor that regulates insulin expression and islet maintenance in the adult pancreas. Our recent studies demonstrate that PDX-1 is an oncogene for pancreatic cancer and is overexpressed in pancreatic cancer. The purpose of this study was to demonstrate that PDX-1 is a therapeutic target for both hormonal symptoms and tumor volume in mouse models of pancreatic cancer, insulinoma and islet neoplasia. Immunohistochemistry of human pan...

  12. Model‐Based Assessment of Plasma Citrate Flux Into the Liver: Implications for NaCT as a Therapeutic Target

    OpenAIRE

    Z. Li; Erion, DM; Maurer, TS

    2016-01-01

    Cytoplasmic citrate serves as an important regulator of gluconeogenesis and carbon source for de novo lipogenesis in the liver. For this reason, the sodium‐coupled citrate transporter (NaCT), a plasma membrane transporter that governs hepatic influx of plasma citrate in human, is being explored as a potential therapeutic target for metabolic disorders. As cytoplasmic citrate also originates from intracellular mitochondria, the relative contribution of these two pathways represents critical in...

  13. Potential therapeutic targets for oral cancer: ADM, TP53, EGFR, LYN, CTLA4, SKIL, CTGF, CD70.

    Directory of Open Access Journals (Sweden)

    Saurabh Bundela

    Full Text Available In India, oral cancer has consistently ranked among top three causes of cancer-related deaths, and it has emerged as a top cause for the cancer-related deaths among men. Lack of effective therapeutic options is one of the main challenges in clinical management of oral cancer patients. We interrogated large pool of samples from oral cancer gene expression studies to identify potential therapeutic targets that are involved in multiple cancer hallmark events. Therapeutic strategies directed towards such targets can be expected to effectively control cancer cells. Datasets from different gene expression studies were integrated by removing batch-effects and was used for downstream analyses, including differential expression analysis. Dependency network analysis was done to identify genes that undergo marked topological changes in oral cancer samples when compared with control samples. Causal reasoning analysis was carried out to identify significant hypotheses, which can explain gene expression profiles observed in oral cancer samples. Text-mining based approach was used to detect cancer hallmarks associated with genes significantly expressed in oral cancer. In all, 2365 genes were detected to be differentially expressed genes, which includes some of the highly differentially expressed genes like matrix metalloproteinases (MMP-1/3/10/13, chemokine (C-X-C motif ligands (IL8, CXCL-10/-11, PTHLH, SERPINE1, NELL2, S100A7A, MAL, CRNN, TGM3, CLCA4, keratins (KRT-3/4/13/76/78, SERPINB11 and serine peptidase inhibitors (SPINK-5/7. XIST, TCEAL2, NRAS and FGFR2 are some of the important genes detected by dependency and causal network analysis. Literature mining analysis annotated 1014 genes, out of which 841 genes were statistically significantly annotated. The integration of output of various analyses, resulted in the list of potential therapeutic targets for oral cancer, which included targets such as ADM, TP53, EGFR, LYN, CTLA4, SKIL, CTGF and CD70.

  14. Combined therapeutic benefit of mitochondria-targeted antioxidant, MitoQ10, and angiotensin receptor blocker, losartan, on cardiovascular function

    OpenAIRE

    McLachlan, Jennifer; Beattie, Elisabeth; Murphy, Michael P; Koh-Tan, Caline H.H.; Olson, Erin; Beattie, Wendy; Dominiczak, Anna F.; Nicklin, Stuart A.; Graham, Delyth

    2014-01-01

    Objective: Mitochondria-derived reactive oxygen species (ROS) play important roles in the development of cardiovascular disease highlighting the need for novel targeted therapies. This study assessed the potential therapeutic benefit of combining the mitochondria-specific antioxidant, MitoQ10, with the low-dose angiotensin receptor blocker (ARB), losartan, on attenuation of hypertension and left ventricular hypertrophy. In parallel, we investigated the impact of MitoQ10 on cardiac hypertro...

  15. βMolecular Pathways: Novel Approaches for Improved Therapeutic Targeting of Hedgehog Signaling in Cancer Stem Cells

    OpenAIRE

    Justilien, Verline; Fields, Alan P.

    2015-01-01

    The Hedgehog (Hh) signaling pathway is critical for embryonic development. In adult tissues, Hh signaling is relatively quiescent with the exception of roles in tissue maintenance and repair. Aberrant activation of Hh signaling is implicated in multiple aspects of transformation including the maintenance of the cancer stem cell (CSC) phenotype. Pre-clinical studies indicate that CSCs from many tumor types are sensitive to Hh pathway inhibition and that Hh-targeted therapeutics block many aspe...

  16. Sulfadiazine resistance in Toxoplasma gondii: no involvement of overexpression or polymorphisms in genes of therapeutic targets and ABC transporters

    OpenAIRE

    Doliwa, Christelle; Escotte-Binet, Sandie; Aubert, Dominique; Sauvage, Virginie; Velard, Frédéric; Schmid, Aline; Villena, Isabelle

    2013-01-01

    Several treatment failures have been reported for the treatment of toxoplasmic encephalitis, chorioretinitis, and congenital toxoplasmosis. Recently we found three Toxoplasma gondii strains naturally resistant to sulfadiazine and we developed in vitro two sulfadiazine resistant strains, RH-RSDZ and ME-49-RSDZ, by gradual pressure. In Plasmodium, common mechanisms of drug resistance involve, among others, mutations and/or amplification within genes encoding the therapeutic targets dhps and dhf...

  17. The CXCR3 targeting chemokine CXCL11 has potent antitumor activity in vivo involving attraction of CD8+ T lymphocytes but not inhibition of angiogenesis.

    Science.gov (United States)

    Hensbergen, Paul J; Wijnands, Pepijn G J T B; Schreurs, Marco W J; Scheper, Rik J; Willemze, Rein; Tensen, Cornelis P

    2005-01-01

    The IFN-gamma-inducible and CXCR3-targeting human CXC chemokines CXCL9 (Mig) and CXCL10 (IP10) have potent antitumor activity through attraction of cytotoxic T lymphocytes and inhibition of angiogenesis. The more recently identified CXCR3-targeting chemokine CXCL11 (I-TAC/IP9) proved to be a more potent chemokine than CXCL9 and CXCL10 in vitro, both in chemotaxis assays with CXCR3+ T lymphocytes and in calcium mobilization experiments. However, its antitumor activity in vivo has not been shown so far. To investigate this, mice were challenged with EL4 T-cell lymphoma cells, genetically modified to produce murine CXCL11. Tumor growth curves showed complete rejection of CXCL11-producing tumors but not of control tumors. Tumor infiltrate analysis by flow cytometry showed a clear correlation between rejection of CXCL11-producing tumors and an increase of tumor-infiltrating CD8+CXCR3+ as well as CD8+CXCR3- T lymphocytes. In vivo CD8 T-cell depletion completely abrogated the antitumor effect. No difference in angiogenesis between control and CXCL11-producing tumors was observed. In survivors, rechallenge experiments with wild-type tumor cells suggested development of protective antitumor immunity involving tumor-specific IFN-gamma production by CD8+ T lymphocytes. These experiments show, for the first time, antitumor activity of CXCL11 in vivo, which warrants exploration for its potential role in anticancer immunotherapy. PMID:16000952

  18. Treponema pallidum putative novel drug target identification and validation: rethinking syphilis therapeutics with plant-derived terpenoids.

    Science.gov (United States)

    Dwivedi, Upendra N; Tiwari, Sameeksha; Singh, Priyanka; Singh, Swati; Awasthi, Manika; Pandey, Veda P

    2015-02-01

    Syphilis, a slow progressive and the third most common sexually transmitted disease found worldwide, is caused by a spirochete gram negative bacteria Treponema pallidum. Emergence of antibiotic resistant T. pallidum has led to a search for novel drugs and their targets. Subtractive genomics analyses of pathogen T. pallidum and host Homo sapiens resulted in identification of 126 proteins essential for survival and viability of the pathogen. Metabolic pathway analyses of these essential proteins led to discovery of nineteen proteins distributed among six metabolic pathways unique to T. pallidum. One hundred plant-derived terpenoids, as potential therapeutic molecules against T. pallidum, were screened for their drug likeness and ADMET (absorption, distribution, metabolism, and toxicity) properties. Subsequently the resulting nine terpenoids were docked with five unique T. pallidum targets through molecular modeling approaches. Out of five targets analyzed, D-alanine:D-alanine ligase was found to be the most promising target, while terpenoid salvicine was the most potent inhibitor. A comparison of the inhibitory potential of the best docked readily available natural compound, namely pomiferin (flavonoid) with that of the best docked terpenoid salvicine, revealed that salvicine was a more potent inhibitor than that of pomiferin. To the best of our knowledge, this is the first report of a terpenoid as a potential therapeutic molecule against T. pallidum with D-alanine:D-alanine ligase as a novel target. Further studies are warranted to evaluate and explore the potential clinical ramifications of these findings in relation to syphilis that has public health importance worldwide. PMID:25683888

  19. The epigenetic regulators CBP and p300 facilitate leukemogenesis and represent therapeutic targets in acute myeloid leukemia.

    Science.gov (United States)

    Giotopoulos, G; Chan, W-I; Horton, S J; Ruau, D; Gallipoli, P; Fowler, A; Crawley, C; Papaemmanuil, E; Campbell, P J; Göttgens, B; Van Deursen, J M; Cole, P A; Huntly, B J P

    2016-01-21

    Growing evidence links abnormal epigenetic control to the development of hematological malignancies. Accordingly, inhibition of epigenetic regulators is emerging as a promising therapeutic strategy. The acetylation status of lysine residues in histone tails is one of a number of epigenetic post-translational modifications that alter DNA-templated processes, such as transcription, to facilitate malignant transformation. Although histone deacetylases are already being clinically targeted, the role of histone lysine acetyltransferases (KAT) in malignancy is less well characterized. We chose to study this question in the context of acute myeloid leukemia (AML), where, using in vitro and in vivo genetic ablation and knockdown experiments in murine models, we demonstrate a role for the epigenetic regulators CBP and p300 in the induction and maintenance of AML. Furthermore, using selective small molecule inhibitors of their lysine acetyltransferase activity, we validate CBP/p300 as therapeutic targets in vitro across a wide range of human AML subtypes. We proceed to show that growth retardation occurs through the induction of transcriptional changes that induce apoptosis and cell-cycle arrest in leukemia cells and finally demonstrate the efficacy of the KAT inhibitors in decreasing clonogenic growth of primary AML patient samples. Taken together, these data suggest that CBP/p300 are promising therapeutic targets across multiple subtypes in AML. PMID:25893291

  20. Essential proteins and possible therapeutic targets of Wolbachia endosymbiont and development of FiloBase--a comprehensive drug target database for Lymphatic filariasis.

    Science.gov (United States)

    Sharma, Om Prakash; Kumar, Muthuvel Suresh

    2016-01-01

    Lymphatic filariasis (Lf) is one of the oldest and most debilitating tropical diseases. Millions of people are suffering from this prevalent disease. It is estimated to infect over 120 million people in at least 80 nations of the world through the tropical and subtropical regions. More than one billion people are in danger of getting affected with this life-threatening disease. Several studies were suggested its emerging limitations and resistance towards the available drugs and therapeutic targets for Lf. Therefore, better medicine and drug targets are in demand. We took an initiative to identify the essential proteins of Wolbachia endosymbiont of Brugia malayi, which are indispensable for their survival and non-homologous to human host proteins. In this current study, we have used proteome subtractive approach to screen the possible therapeutic targets for wBm. In addition, numerous literatures were mined in the hunt for potential drug targets, drugs, epitopes, crystal structures, and expressed sequence tag (EST) sequences for filarial causing nematodes. Data obtained from our study were presented in a user friendly database named FiloBase. We hope that information stored in this database may be used for further research and drug development process against filariasis. URL: http://filobase.bicpu.edu.in. PMID:26806463

  1. Essential proteins and possible therapeutic targets of Wolbachia endosymbiont and development of FiloBase-a comprehensive drug target database for Lymphatic filariasis

    Science.gov (United States)

    Sharma, Om Prakash; Kumar, Muthuvel Suresh

    2016-01-01

    Lymphatic filariasis (Lf) is one of the oldest and most debilitating tropical diseases. Millions of people are suffering from this prevalent disease. It is estimated to infect over 120 million people in at least 80 nations of the world through the tropical and subtropical regions. More than one billion people are in danger of getting affected with this life-threatening disease. Several studies were suggested its emerging limitations and resistance towards the available drugs and therapeutic targets for Lf. Therefore, better medicine and drug targets are in demand. We took an initiative to identify the essential proteins of Wolbachia endosymbiont of Brugia malayi, which are indispensable for their survival and non-homologous to human host proteins. In this current study, we have used proteome subtractive approach to screen the possible therapeutic targets for wBm. In addition, numerous literatures were mined in the hunt for potential drug targets, drugs, epitopes, crystal structures, and expressed sequence tag (EST) sequences for filarial causing nematodes. Data obtained from our study were presented in a user friendly database named FiloBase. We hope that information stored in this database may be used for further research and drug development process against filariasis. URL: http://filobase.bicpu.edu.in. PMID:26806463

  2. Non-Clear Cell Renal Cell Carcinoma: Does the Mammalian Target of Rapamycin Represent a Rational Therapeutic Target?

    OpenAIRE

    Albiges, Laurence; Molinie, Vincent; Escudier, Bernard

    2012-01-01

    The disparate subtypes of non-clear cell renal cell carcinoma, the criteria for diagnosis, and the prognoses associated with each subtype, in addition to evaluating the potential use of mammalian target of rapamycin inhibitors in treating patients with this type of cancer are reviewed.

  3. Design and conduct of early-phase radiotherapy trials with targeted therapeutics: Lessons from the PRAVO experience

    International Nuclear Information System (INIS)

    New strategies to facilitate the improvement of physical and integrated biological optimization of high-precision treatment protocols are an important priority for modern radiation oncology. From a clinical perspective, as knowledge accumulates from molecular radiobiology, there is a complex and exciting opportunity to investigate novel approaches to rational patient treatment stratification based on actionable tumor targets, together with the appropriate design of next-generation early-phase radiotherapy trials utilizing targeted therapeutics, to formally evaluate relevant clinical and biomarker endpoints. A unique aspect in the development pathway of systemic agents with presumed radiosensitizing activity will also be the need for special attention on patient eligibility and the rigorous definition of radiation dose–volume relationships and potential dose-limiting toxicities. Based on recent experience from systematically investigating histone deacetylase inhibitors as radiosensitizing agents, from initial studies in preclinical tumor models through the conduct of a phase I clinical study to evaluate tumor activity of the targeted agent as well as patient safety and tumor response to the combined treatment modality, this communication will summarize principles relating to early clinical evaluation of combining radiotherapy and targeted therapeutics

  4. Gap junctions and hemichannels composed of connexins: potential therapeutic targets for neurodegenerative diseases

    Directory of Open Access Journals (Sweden)

    Hideyuki Takeuchi

    2014-09-01

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

  5. Patterns of histone acetylation as targets for novel therapeutic approaches in neurological diseases

    OpenAIRE

    Ebrahimi, Azadeh

    2013-01-01

    Neurological diseases, in particular brain tumors and neurodegenerative disorders, cause significant socio-economic burdens on societies. Exploring epigenetic mechanisms in neurological disorders in recent decades has been an emerging tool for describing the pathogenesis of neurological diseases as well as developing new therapeutics. Global histone acetylation is an epigenetic entity whose alternating patterns in various neurological diseases have recently raised special attention concer...

  6. Monoclonal Antibody Fragments for Targeting Therapeutics to Growth Plate Cartilage | NCI Technology Transfer Center | TTC

    Science.gov (United States)

    The NICHD seeks statements of capability or interest from parties interested in collaborative research to co-develop, evaluate, or commercialize treatment of skeletal disorders using targeting antibodies.

  7. TiPs: a database of therapeutic targets in pathogens and associated tools.

    KAUST Repository

    Lepore, Rosalba

    2013-05-21

    MOTIVATION: The need for new drugs and new targets is particularly compelling in an era that is witnessing an alarming increase of drug resistance in human pathogens. The identification of new targets of known drugs is a promising approach, which has proven successful in several cases. Here, we describe a database that includes information on 5153 putative drug-target pairs for 150 human pathogens derived from available drug-target crystallographic complexes. AVAILABILITY AND IMPLEMENTATION: The TiPs database is freely available at http://biocomputing.it/tips. CONTACT: anna.tramontano@uniroma1.it or allegra.via@uniroma1.it.

  8. First meeting on the CRP 'standardized high current solid targets for cyclotron production of diagnostic and therapeutic radionuclides'

    International Nuclear Information System (INIS)

    The Cyclotron Department of the VUB has three groups performing research in the field of target development, production of radionuclides and their application in nuclear medicine. 1. The Physics Group is busy on the optimization of beam parameters, on the determination of cross sections and on neutron spectrometry. 2. The Inorganic Radiochemistry Group performs research on solid target electroplating (Tl, Zn, Cd, Rh ... ), on optimisation of target carrier geometry and cooling and on automated PC-controlled radiochemistry (Tl-201, Ga-67, In-111) and recovery systems and the associated software written in Modula-2 and Visual Basic. 3. The Organic Radiochemistry Group develops new techniques for radiolabelling of organic molecules (fatty acids, neuroleptics, synthetic polypeptides...) useful in diagnostic and therapeutic nuclear medicine. All three groups take part in bulk productions of radionuclides

  9. Proteomic analysis of imatinib-resistant CML-T1 cells reveals calcium homeostasis as a potential therapeutic target

    Science.gov (United States)

    Toman, O.; Kabickova, T.; Vit, O.; Fiser, R.; Polakova, K. Machova; Zach, J.; Linhartova, J.; Vyoral, D.; Petrak, J.

    2016-01-01

    Chronic myeloid leukemia (CML) therapy has markedly improved patient prognosis after introduction of imatinib mesylate for clinical use. However, a subset of patients develops resistance to imatinib and other tyrosine kinase inhibitors (TKIs), mainly due to point mutations in the region encoding the kinase domain of the fused BCR-ABL oncogene. To identify potential therapeutic targets in imatinib-resistant CML cells, we derived imatinib-resistant CML-T1 human cell line clone (CML-T1/IR) by prolonged exposure to imatinib in growth media. Mutational analysis revealed that the Y235H mutation in BCR-ABL is probably the main cause of CML-T1/IR resistance to imatinib. To identify alternative therapeutic targets for selective elimination of imatinib-resistant cells, we compared the proteome profiles of CML-T1 and CML-T1/IR cells using 2-DE-MS. We identified eight differentially expressed proteins, with strongly upregulated Na+/H+ exchanger regulatory factor 1 (NHERF1) in the resistant cells, suggesting that this protein may influence cytosolic pH, Ca2+ concentration or signaling pathways such as Wnt in CML-T1/IR cells. We tested several compounds including drugs in clinical use that interfere with the aforementioned processes and tested their relative toxicity to CML-T1 and CML-T1/IR cells. Calcium channel blockers, calcium signaling antagonists and modulators of calcium homeostasis, namely thapsigargin, ionomycin, verapamil, carboxyamidotriazole and immunosuppressive drugs cyclosporine A and tacrolimus (FK-506) were selectively toxic to CML-T1/IR cells. The putative cellular targets of these compounds in CML-T1/IR cells are postulated in this study. We propose that Ca2+ homeostasis can be a potential therapeutic target in CML cells resistant to TKIs. We demonstrate that a proteomic approach may be used to characterize a TKI-resistant population of CML cells enabling future individualized treatment options for patients. PMID:27430982

  10. Therapeutic aptamers: developmental potential as anticancer drugs

    OpenAIRE

    Lee, Ji Won; Kim, Hyun Jung; Heo, Kyun

    2015-01-01

    Aptamers, composed of single-stranded DNA or RNA oligonucleotides that interact with target molecules through a specific three-dimensional structure, are selected from pools of combinatorial oligonucleotide libraries. With their high specificity and affinity for target proteins, ease of synthesis and modification, and low immunogenicity and toxicity, aptamers are considered to be attractive molecules for development as anticancer therapeutics. Two aptamers - one targeting nucleolin and a seco...

  11. Challenges and Opportunities in the Discovery of New Therapeutics Targeting the Kynurenine Pathway.

    Science.gov (United States)

    Dounay, Amy B; Tuttle, Jamison B; Verhoest, Patrick R

    2015-11-25

    The kynurenine pathway is responsible for the metabolism of more than 95% of dietary tryptophan (TRP) and produces numerous bioactive metabolites. Recent studies have focused on three enzymes in this pathway: indoleamine dioxygenase (IDO1), kynurenine monooxygenase (KMO), and kynurenine aminotransferase II (KAT II). IDO1 inhibitors are currently in clinical trials for the treatment of cancer, and these agents may also have therapeutic utility in neurological disorders, including multiple sclerosis. KMO inhibitors are being investigated as potential treatments for neurodegenerative diseases, such as Huntington's and Alzheimer's diseases. KAT II inhibitors have been proposed in new therapeutic approaches toward psychiatric and cognitive disorders, including cognitive impairment associated with schizophrenia. Numerous medicinal chemistry studies are currently aimed at the design of novel, potent, and selective inhibitors for each of these enzymes. The emerging opportunities and significant challenges associated with pharmacological modulation of these enzymes will be explored in this review. PMID:26207924

  12. Cannabinoid receptor 2 as a potential therapeutic target in rheumatoid arthritis

    OpenAIRE

    Fukuda, Shin; Kohsaka, Hitoshi; Takayasu, Aiko; Yokoyama, Waka; Miyabe, Chie; Miyabe, Yoshishige; Harigai, Masayoshi; Miyasaka, Nobuyuki; Nanki, Toshihiro

    2014-01-01

    Background Some of cannabinoids, which are chemical compounds contained in marijuana, are immunosuppressive. One of the receptors, CB receptor 1 (CB1), is expressed predominantly by the cells in the central nervous system, whereas CB receptor 2 (CB2) is expressed primarily by immune cells. Theoretically, selective CB2 agonists should be devoid of psychoactive effects. In this study, we investigated therapeutic effects of a selective CB2 agonist on arthritis. Methods The expression of CB2 was ...

  13. Potential Diagnostic, Prognostic and Therapeutic Targets of MicroRNAs in Human Gastric Cancer

    OpenAIRE

    Ming-Ming Tsai; Chia-Siu Wang; Chung-Ying Tsai; Hsiang-Wei Huang; Hsiang-Cheng Chi; Yang-Hsiang Lin; Pei-Hsuan Lu; Kwang-Huei Lin

    2016-01-01

    Human gastric cancer (GC) is characterized by a high incidence and mortality rate, largely because it is normally not identified until a relatively advanced stage owing to a lack of early diagnostic biomarkers. Gastroscopy with biopsy is the routine method for screening, and gastrectomy is the major therapeutic strategy for GC. However, in more than 30% of GC surgical patients, cancer has progressed too far for effective medical resection. Thus, useful biomarkers for early screening or detect...

  14. Cell Survival and Apoptosis Signaling as Therapeutic Target for Cancer: Marine Bioactive Compounds

    OpenAIRE

    Kim Se-Kwon; Senthilkumar Kalimuthu

    2013-01-01

    Inhibition of apoptosis leads to activation of cell survival factors (e.g., AKT) causes continuous cell proliferation in cancer. Apoptosis, the major form of cellular suicide, is central to various physiological processes and the maintenance of homeostasis in multicellular organisms. A number of discoveries have clarified the molecular mechanism of apoptosis, thus clarifying the link between apoptosis and cell survival factors, which has a therapeutic outcome. Induction of apoptosis and inhib...

  15. Bacterial Heat-Stable Enterotoxins: Translation of Pathogenic Peptides into Novel Targeted Diagnostics and Therapeutics

    OpenAIRE

    Chang Chang; Stoecker, Brian A.; Snook, Adam E.; Peng Li; Magee, Michael S; Glen Marszalowicz; Michael Valentino; Lin, Jieru E.; Waldman, Scott A

    2010-01-01

    Heat-stable toxins (STs) produced by enterotoxigenic bacteria cause endemic and traveler’s diarrhea by binding to and activating the intestinal receptor guanylyl cyclase C (GC-C). Advances in understanding the biology of GC-C have extended ST from a diarrheagenic peptide to a novel therapeutic agent. Here, we summarize the physiological and pathophysiological role of GC-C in fluid-electrolyte regulation and intestinal crypt-villus homeostasis, as well as describe translational opportunities o...

  16. GSK-3 is a viable potential target for therapeutic intervention in bipolar disorder

    OpenAIRE

    Rowe, Michael K.; Wiest, Charlotte; Chuang, De-Maw

    2007-01-01

    Bipolar disorder is a serious psychiatric condition that has been treated for over fifty years with lithium. Lithium is a well established glycogen synthase kinase-3 (GSK-3) inhibitor, suggesting that manipulating GSK-3 may have therapeutic value in treating bipolar disorder. GSK-3 is regulated by a wide variety of mechanisms including phosphorylation, binding with protein complexes, phosphorylation state of its substrates, cellular localization and autoregulation, thus providing a wide numbe...

  17. Glucagon antagonism as a potential therapeutic target in type 2 diabetes

    DEFF Research Database (Denmark)

    Bagger, J I; Knop, F K; Holst, Jens Juul; Vilsbøll, T

    2011-01-01

    has been implicated in the development of fasting and postprandial hyperglycaemia. Therefore, new therapeutic agents based on antagonizing glucagon action, and hence blockade of glucagon-induced HGP, could be effective in lowering both fasting and postprandial hyperglycaemia in patients with T2DM....... This review focuses on the mechanism of action, safety and efficacy of glucagon antagonists in the treatment of T2DM and discusses the challenges associated with this new potential antidiabetic treatment modality....

  18. GABAB receptor as therapeutic target for drug addiction: from baclofen to positive allosteric modulators

    OpenAIRE

    Roberta Agabio; Giancarlo Colombo

    2015-01-01

    The present paper summarizes experimental and clinical data indicating the therapeutic potential of the GABAB receptor agonist, baclofen, in the treatment of alcohol use disorder (AUD) and substance use disorder (SUD). Multiple preclinical studies have demonstrated the ability of baclofen to suppress alcohol drinking (including binge- and relapse-like drinking), oral alcohol self-administration, and intravenous self-administration of cocaine, nicotine, amphetamine, methamphetamine, morphine, ...

  19. Targeting reactive nitrogen species: a promising therapeutic strategy for cerebral ischemia-reperfusion injury

    OpenAIRE

    Chen, Xing-miao; Chen, Han-sen; Xu, Ming-jing; Shen, Jian-gang

    2012-01-01

    Ischemic stroke accounts for nearly 80% of stroke cases. Recanalization with thrombolysis is a currently crucial therapeutic strategy for re-building blood supply, but the thrombolytic therapy often companies with cerebral ischemia-reperfusion injury, which are mediated by free radicals. As an important component of free radicals, reactive nitrogen species (RNS), including nitric oxide (NO) and peroxynitrite (ONOO(-)), play important roles in the process of cerebral ischemia-reperfusion injur...

  20. S100A1: A Multifaceted Therapeutic Target in Cardiovascular Disease

    OpenAIRE

    Rohde, David; Ritterhoff, Julia; Voelkers, Mirko; Hugo A. Katus; Parker, Thomas G.; Most, Patrick

    2010-01-01

    Cardiovascular disease is the leading cause of death worldwide, showing a dramatically growing prevalence. It is still associated with a poor clinical prognosis, indicating insufficient long-term treatment success of currently available therapeutic strategies. Investigations of the pathomechanisms underlying cardiovascular disorders uncovered the Ca2+ binding protein S100A1 as a critical regulator of both cardiac performance and vascular biology. In cardiomyocytes, S100A1 was found to interac...

  1. Animal models and therapeutic molecular targets of cancer: utility and limitations

    OpenAIRE

    Cekanova M; Rathore K

    2014-01-01

    Maria Cekanova, Kusum Rathore Department of Small Animal Clinical Sciences, College of Veterinary Medicine, The University of Tennessee, Knoxville, TN, USA Abstract: Cancer is the term used to describe over 100 diseases that share several common hallmarks. Despite prevention, early detection, and novel therapies, cancer is still the second leading cause of death in the USA. Successful bench-to-bedside translation of basic scientific findings about cancer into therapeutic interventions for pa...

  2. Novel Therapeutic Targets in Depression and Anxiety: Antioxidants as a Candidate Treatment

    OpenAIRE

    Xu, Ying; Wang, Chuang; Klabnik, Jonathan J; O’Donnell, James M

    2014-01-01

    There is growing evidence that the imbalance between oxidative stress and the antioxidant defense system may be associated with the development neuropsychiatric disorders, such as depression and anxiety. Major depression and anxiety are presently correlated with a lowered total antioxidant state and by an activated oxidative stress (OS) pathway. The classical antidepressants may produce therapeutic effects other than regulation of monoamines by increasing the antioxidant levels and normalizin...

  3. The endothelin system as a therapeutic target in cardiovascular disease: great expectations or bleak house?

    OpenAIRE

    Kirkby, N S; Hadoke, P.W.F.; Bagnall, A J; Webb, D J

    2007-01-01

    There is considerable evidence that the potent vasoconstrictor endothelin-1 (ET-1) contributes to the pathogenesis of a variety of cardiovascular diseases. As such, pharmacological manipulation of the ET system might represent a promising therapeutic goal. Many clinical trials have assessed the potential of ET receptor antagonists in cardiovascular disease, the most positive of which have resulted in the licensing of the mixed ET receptor antagonist bosentan, and the selective ETA receptor an...

  4. Combined MYC and P53 defects emerge at medulloblastoma relapse and define rapidly progressive, therapeutically targetable disease.

    Science.gov (United States)

    Hill, Rebecca M; Kuijper, Sanne; Lindsey, Janet C; Petrie, Kevin; Schwalbe, Ed C; Barker, Karen; Boult, Jessica K R; Williamson, Daniel; Ahmad, Zai; Hallsworth, Albert; Ryan, Sarra L; Poon, Evon; Robinson, Simon P; Ruddle, Ruth; Raynaud, Florence I; Howell, Louise; Kwok, Colin; Joshi, Abhijit; Nicholson, Sarah Leigh; Crosier, Stephen; Ellison, David W; Wharton, Stephen B; Robson, Keith; Michalski, Antony; Hargrave, Darren; Jacques, Thomas S; Pizer, Barry; Bailey, Simon; Swartling, Fredrik J; Weiss, William A; Chesler, Louis; Clifford, Steven C

    2015-01-12

    We undertook a comprehensive clinical and biological investigation of serial medulloblastoma biopsies obtained at diagnosis and relapse. Combined MYC family amplifications and P53 pathway defects commonly emerged at relapse, and all patients in this group died of rapidly progressive disease postrelapse. To study this interaction, we investigated a transgenic model of MYCN-driven medulloblastoma and found spontaneous development of Trp53 inactivating mutations. Abrogation of p53 function in this model produced aggressive tumors that mimicked characteristics of relapsed human tumors with combined P53-MYC dysfunction. Restoration of p53 activity and genetic and therapeutic suppression of MYCN all reduced tumor growth and prolonged survival. Our findings identify P53-MYC interactions at medulloblastoma relapse as biomarkers of clinically aggressive disease that may be targeted therapeutically. PMID:25533335

  5. Cell Survival and Apoptosis Signaling as Therapeutic Target for Cancer: Marine Bioactive Compounds

    Directory of Open Access Journals (Sweden)

    Kim Se-Kwon

    2013-01-01

    Full Text Available Inhibition of apoptosis leads to activation of cell survival factors (e.g., AKT causes continuous cell proliferation in cancer. Apoptosis, the major form of cellular suicide, is central to various physiological processes and the maintenance of homeostasis in multicellular organisms. A number of discoveries have clarified the molecular mechanism of apoptosis, thus clarifying the link between apoptosis and cell survival factors, which has a therapeutic outcome. Induction of apoptosis and inhibition of cell survival by anticancer agents has been shown to correlate with tumor response. Cellular damage induces growth arrest and tumor suppression by inducing apoptosis, necrosis and senescence; the mechanism of cell death depends on the magnitude of DNA damage following exposure to various anticancer agents. Apoptosis is mainly regulated by cell survival and proliferating signaling molecules. As a new therapeutic strategy, alternative types of cell death might be exploited to control and eradicate cancer cells. This review discusses the signaling of apoptosis and cell survival, as well as the potential contribution of marine bioactive compounds, suggesting that new therapeutic strategies might follow.

  6. Glycogen synthase kinase-3: A promising therapeutic target for Fragile X Syndrome

    Directory of Open Access Journals (Sweden)

    Marjelo M. Mines

    2011-11-01

    Full Text Available Recent advances in understanding the pathophysiological mechanisms contributing to Fragile X Syndrome (FXS have increased optimism that drug interventions can provide significant therapeutic benefits. FXS results from inadequate expression of functional fragile X mental retardation protein (FMRP. FMRP may have several functions, but it is most well-established as an RNA-binding protein that regulates translation, and it is by this mechanism that FMRP is capable of affecting numerous cellular processes by selectively regulating protein levels. The multiple cellular functions regulated by FMRP suggest that multiple interventions may be required for reversing the effects of deficient FMRP. Evidence that inhibitors of glycogen synthase kinase-3 (GSK3 may contribute to the therapeutic treatment of FXS is reviewed here. In the mouse model of FXS, which lacks FMRP expression (FX mice, GSK3 is hyperactive in several brain regions. Furthermore, significant improvements in several FX-related phenotypes have been obtained in FX mice following the administration of lithium, and in some case other GSK3 inhibitors. These responses include normalization of heightened audiogenic seizure susceptibility and of hyperactive locomotor behavior, enhancement of passive avoidance learning retention and of sociability behaviors, and corrections of macroorchidism, neuronal spine density, and neural plasticity measured electrophysiologically as long term depression. A pilot clinical trial of lithium in FXS patients also found improvements in several measures of behavior. Taken together, these findings indicate that lithium and other inhibitors of GSK3 are promising candidate therapeutic agents for treating FXS.

  7. Targeting childhood, adolescent and young adult non-Hodgkin lymphoma: therapeutic horizons.

    Science.gov (United States)

    Galardy, Paul J; Bedekovics, Tibor; Hermiston, Michelle L

    2016-05-01

    Non-Hodgkin lymphoma (NHL) is the third most common malignancy in children, adolescents and young adults (CAYA). NHL is a diverse set of diseases that arise at key regulatory checkpoints during B or T cell development in the bone marrow, germinal centre or thymus. While advances in the use of conventional cytotoxic agents have led to dramatic improvements in survival, these cures are associated with significant acute and long-term toxicities. Moreover, the prognosis for CAYA patients with relapsed or refractory NHL remains dismal, with the vast majority dying of their disease. Thanks to a large number of candidate-based biological studies, together with large-scale sequencing efforts, there has been an explosion of knowledge regarding the molecular pathophysiology of B- and T-NHL. This has ushered development of a flurry of novel therapeutic approaches that may simultaneously provide new hope for relapsed patients and an opportunity to reduce the therapeutic burden in newly diagnosed CAYA. Here we review a selection of the most promising new therapeutic approaches to these diseases. While the vast majority of these agents are untested in children, on-going work from many cooperative groups will soon explore their use in paediatric disease, in hope of further improving outcomes while maximizing quality of life. PMID:27019108

  8. Targeting caspase-3 as dual therapeutic benefits by RNAi facilitating brain-targeted nanoparticles in a rat model of Parkinson's disease.

    Science.gov (United States)

    Liu, Yang; Guo, Yubo; An, Sai; Kuang, Yuyang; He, Xi; Ma, Haojun; Li, Jianfeng; Lu, Jing; Lv, Jing; Zhang, Ning; Jiang, Chen

    2013-01-01

    The activation of caspase-3 is an important hallmark in Parkinson's disease. It could induce neuron death by apoptosis and microglia activation by inflammation. As a result, inhibition the activation of caspase-3 would exert synergistic dual effect in brain in order to prevent the progress of Parkinson's disease. Silencing caspase-3 genes by RNA interference could inhibit the activation of caspase-3. We developed a brain-targeted gene delivery system based on non-viral gene vector, dendrigraft poly-L-lysines. A rabies virus glycoprotein peptide with 29 amino-acid linked to dendrigraft poly-L-lysines could render gene vectors the ability to get across the blood brain barrier by specific receptor mediated transcytosis. The resultant brain-targeted vector was complexed with caspase-3 short hairpin RNA coding plasmid DNA, yielding nanoparticles. In vivo imaging analysis indicated the targeted nanoparticles could accumulate in brain more efficiently than non-targeted ones. A multiple dosing regimen by weekly intravenous administration of the nanoparticles could reduce activated casapse-3 levels, significantly improve locomotor activity and rescue dopaminergic neuronal loss and in Parkinson's disease rats' brain. These results indicated the rabies virus glycoprotein peptide modified brain-targeted nanoparticles were promising gene delivery system for RNA interference to achieve anti-apoptotic and anti-inflammation synergistic therapeutic effects by down-regulation the expression and activation of caspase-3. PMID:23675438

  9. Physical Attractiveness Stereotypes about Marriage: Attractiveness Matching Is Good.

    Science.gov (United States)

    Sussman, Steve; And Others

    Previous research on physical attractiveness stereotypes about marriage have used stimulus individuals in isolation. To examine these attractiveness stereotypes using couples as targets, 72 college students (36 females, 36 males) rated eight photographs of four male-female couple types. Members of each couple were either matched (attractive…

  10. Helping Eve Overcome ADAM: G-Quadruplexes in the ADAM-15 Promoter as New Molecular Targets for Breast Cancer Therapeutics

    Directory of Open Access Journals (Sweden)

    Robert V. Brown

    2013-12-01

    Full Text Available ADAM-15, with known zymogen, secretase, and disintegrin activities, is a catalytically active member of the ADAM family normally expressed in early embryonic development and aberrantly expressed in various cancers, including breast, prostate and lung. ADAM-15 promotes extracellular shedding of E-cadherin, a soluble ligand for the HER2/neu receptor, leading to activation, increased motility, and proliferation. Targeted downregulation of both ADAM-15 and HER2/neu function synergistically kills breast cancer cells, but to date there are no therapeutic options for decreasing ADAM-15 function or expression. In this vein, we have examined a unique string of guanine-rich DNA within the critical core promoter of ADAM-15. This region of DNA consists of seven contiguous runs of three or more consecutive guanines, which, under superhelical stress, can relax from duplex DNA to form an intrastrand secondary G-quadruplex (G4 structure. Using biophysical and biological techniques, we have examined the G4 formation within the entire and various truncated regions of the ADAM-15 promoter, and demonstrate strong intrastrand G4 formation serving to function as a biological silencer element. Characterization of the predominant G4 species formed within the ADAM-15 promoter will allow for specific drug targeting and stabilization, and the further development of novel, targeted therapeutics.

  11. Improved targeting of JAK2 leads to increased therapeutic efficacy in myeloproliferative neoplasms

    OpenAIRE

    Bhagwat, Neha; Koppikar, Priya; Keller, Matthew; Marubayashi, Sachie; Shank, Kaitlyn; Rampal, Raajit; Qi, Jun; Kleppe, Maria; Patel, Hardik J.; Shah, Smit K.; Taldone, Tony; James E Bradner; Chiosis, Gabriela; Levine, Ross L.

    2014-01-01

    Genetic deletion of JAK2 in vivo shows that MPN cells remain fully dependent on JAK2 signaling for survival.Dual JAK2 targeting with JAK and HSP90 inhibitors offers increased efficacy in murine models and primary samples.

  12. Magnetic nanoparticles for targeted therapeutic gene delivery and magnetic-inducing heating on hepatoma

    International Nuclear Information System (INIS)

    Gene therapy holds great promise for treating cancers, but their clinical applications are being hampered due to uncontrolled gene delivery and expression. To develop a targeted, safe and efficient tumor therapy system, we constructed a tissue-specific suicide gene delivery system by using magnetic nanoparticles (MNPs) as carriers for the combination of gene therapy and hyperthermia on hepatoma. The suicide gene was hepatoma-targeted and hypoxia-enhanced, and the MNPs possessed the ability to elevate temperature to the effective range for tumor hyperthermia as imposed on an alternating magnetic field (AMF). The tumoricidal effects of targeted gene therapy associated with hyperthermia were evaluated in vitro and in vivo. The experiment demonstrated that hyperthermia combined with a targeted gene therapy system proffer an effective tool for tumor therapy with high selectivity and the synergistic effect of hepatoma suppression. (paper)

  13. Cysteine proteases as therapeutic targets: does selectivity matter? A systematic review of calpain and cathepsin inhibitors

    OpenAIRE

    Marton Siklos; Manel BenAissa; Thatcher, Gregory R.J.

    2015-01-01

    Cysteine proteases continue to provide validated targets for treatment of human diseases. In neurodegenerative disorders, multiple cysteine proteases provide targets for enzyme inhibitors, notably caspases, calpains, and cathepsins. The reactive, active-site cysteine provides specificity for many inhibitor designs over other families of proteases, such as aspartate and serine; however, a) inhibitor strategies often use covalent enzyme modification, and b) obtaining selectivity within families...

  14. Identification of the YES1 Kinase as a Therapeutic Target in Basal-Like Breast Cancers

    OpenAIRE

    Bilal, Erhan; Alexe, Gabriela; Yao, Ming; Cong, Lei; Kulkarni, Atul; Ginjala, Vasudeva; Toppmeyer, Deborah; Ganesan, Shridar; Bhanot, Gyan

    2010-01-01

    Normal cellular behavior can be described as a complex, regulated network of interaction between genes and proteins. Targeted cancer therapies aim to neutralize specific proteins that are necessary for the cancer cell to remain viable in vivo. Ideally, the proteins targeted should be such that their downregulation has a major impact on the survival/fitness of the tumor cells and, at the same time, has a smaller effect on normal cells. It is difficult to use standard analysis methods on gene o...

  15. Targeting Bruton's tyrosine kinase signaling as an emerging therapeutic agent of B-cell malignancies

    OpenAIRE

    Xia, Bing; QU, FULIAN; Yuan, Tian; Zhang, Yizhuo

    2015-01-01

    It is becoming increasingly evident that B-cell receptor (BCR) signaling is central to the development and function of B cells. BCR signaling has emerged as a pivotal pathway and a key driver of numerous B-cell lymphomas. Disruption of BCR signaling can be lethal to malignant B cells. Recently, kinase inhibitors that target BCR signaling have induced notable clinical responses. These inhibitors include spleen tyrosine kinase, mammalian target of rapamycin, phosphoinositide 3′-kinase and Bruto...

  16. A novel targeted inhibitor of the alternative pathway of complement and its therapeutic application in ischemia/reperfusion injury.

    Science.gov (United States)

    Huang, Yuxiang; Qiao, Fei; Atkinson, Carl; Holers, V Michael; Tomlinson, Stephen

    2008-12-01

    Bioavailability and therapeutic efficacy of soluble Crry, a mouse inhibitor of all complement activation pathways, is significantly enhanced when linked to a fragment of complement receptor 2 (CR2), a receptor that targets C3 activation products. In this study, we characterize alternative pathway-specific inhibitors consisting of a single or dimeric N-terminal region of mouse factor H (fH; short consensus repeats 1-5) linked to the same CR2 fragment (CR2-fH and CR2-fHfH). Both CR2-fH and CR2-fHfH were highly effective at inhibiting the alternative pathway in vitro and demonstrated a higher specific activity than CR2-Crry. CR2-fH was also more effective than endogenous serum fH in blocking target deposition of C3. Target binding and complement inhibitory activity of CR2-fH/CR2-fHfH was dependent on CR2- and C3-mediated interactions. The alternative pathway of complement plays a role in intestine ischemia/reperfusion injury. However, serum fH fails to provide protection against intestine ischemia/reperfusion injury although it can bind to and provide cell surfaces with protection from complement and is present in plasma at a high concentration. In a mouse model, CR2-fH and CR2-fHfH provided complete protection from local (intestine) and remote (lung) injury. CR2-fH targeted to the site of local injury and greatly reduced levels of tissue C3 deposition. Thus, the targeting mechanism significantly enhances alternative pathway-specific complement inhibitory activity of the N-terminal domain of fH and has the potential to reduce side effects that may be associated with systemic complement blockade. The data further indicate alternative pathway dependence for local and remote injury following intestinal ischemia/reperfusion in a clinically relevant therapeutic paradigm. PMID:19017999

  17. A Novel Targeted Inhibitor of the Alternative Pathway of Complement and Its Therapeutic Application in Ischemia/Reperfusion Injury1

    Science.gov (United States)

    Huang, Yuxiang; Qiao, Fei; Atkinson, Carl; Holers, V. Michael; Tomlinson, Stephen

    2009-01-01

    Bioavailability and therapeutic efficacy of soluble Crry, a mouse inhibitor of all complement activation pathways, is significantly enhanced when linked to a fragment of complement receptor 2 (CR2), a receptor that targets C3 activation products. In this study, we characterize alternative pathway-specific inhibitors consisting of a single or dimeric N-terminal region of mouse factor H (fH; short consensus repeats 1–5) linked to the same CR2 fragment (CR2-fH and CR2-fHfH). Both CR2-fH and CR2-fHfH were highly effective at inhibiting the alternative pathway in vitro and demonstrated a higher specific activity than CR2-Crry. CR2-fH was also more effective than endogenous serum fH in blocking target deposition of C3. Target binding and complement inhibitory activity of CR2-fH/CR2-fHfH was dependent on CR2- and C3-mediated interactions. The alternative pathway of complement plays a role in intestine ischemia/reperfusion injury. However, serum fH fails to provide protection against intestine ischemia/reperfusion injury although it can bind to and provide cell surfaces with protection from complement and is present in plasma at a high concentration. In a mouse model, CR2-fH and CR2-fHfH provided complete protection from local (intestine) and remote (lung) injury. CR2-fH targeted to the site of local injury and greatly reduced levels of tissue C3 deposition. Thus, the targeting mechanism significantly enhances alternative pathway-specific complement inhibitory activity of the N-terminal domain of fH and has the potential to reduce side effects that may be associated with systemic complement blockade. The data further indicate alternative pathway dependence for local and remote injury following intestinal ischemia/reperfusion in a clinically relevant therapeutic paradigm. PMID:19017999

  18. Nanomedicine: nanoparticles, molecular biosensors, and targeted gene/drug delivery for combined single-cell diagnostics and therapeutics

    Science.gov (United States)

    Prow, Tarl W.; Salazar, Jose H.; Rose, William A.; Smith, Jacob N.; Reece, Lisa; Fontenot, Andrea A.; Wang, Nan A.; Lloyd, R. Stephen; Leary, James F.

    2004-07-01

    Next generation nanomedicine technologies are being developed to provide for continuous and linked molecular diagnostics and therapeutics. Research is being performed to develop "sentinel nanoparticles" which will seek out diseased (e.g. cancerous) cells, enter those living cells, and either perform repairs or induce those cells to die through apoptosis. These nanoparticles are envisioned as multifunctional "smart drug delivery systems". The nanosystems are being developed as multilayered nanoparticles (nanocrystals, nanocapsules) containing cell targeting molecules, intracellular re-targeting molecules, molecular biosensor molecules, and drugs/enzymes/gene therapy. These "nanomedicine systems" are being constructed to be autonomous, much like present-day vaccines, but will have sophisticated targeting, sensing, and feedback control systems-much more sophisticated than conventional antibody-based therapies. The fundamental concept of nanomedicine is to not to just kill all aberrant cells by surgery, radiation therapy, or chemotherapy. Rather it is to fix cells, when appropriate, one cell-at-a-time, to preserve and re-build organ systems. When cells should not be fixed, such as in cases where an improperly repaired cell might give rise to cancer cells, the nanomedical therapy would be to induce apoptosis in those cells to eliminate them without the damagin bystander effects of the inflammatory immune response system reacting to necrotic cells or those which have died from trauma or injury. The ultimate aim of nanomedicine is to combine diagnostics and therapeutics into "real-time medicine", using where possible in-vivo cytometry techniques for diagnostics and therapeutics. A number of individual components of these multi-component nanoparticles are already working in in-vitro and ex-vivo cell and tissue systems. Work has begun on construction of integrated nanomedical systems.

  19. Therapeutic effects of lentivirus-mediated shRNA targeting of cyclin D1 in human gastric cancer

    International Nuclear Information System (INIS)

    Gastric cancer is the second most common cause of cancer-related death in males and the fourth in females. Traditional treatment has poor prognosis because of recurrence and systemic side effects. Therefore, the development of new therapeutic strategies is an important issue. Lentivirus-mediated shRNA stably inhibits target genes and can efficiently transduce most cells. Since overexpressed cyclin D1 is closely related to human gastric cancer progression, inhibition of cyclin D1 using specific targeting could be an effective treatment method of human gastric cancer. The therapeutic effect of lentivirus-mediated shRNA targeting of cyclin D1 (ShCCND1) was analyzed both in vitro and in vivo experiments. In vitro, NCI-N87 cells with downregulation of cyclin D1 by ShCCND1 showed significant inhibition of cell proliferation, cell motility, and clonogenicity. Downregulation of cyclin D1 in NCI-N87 cells also resulted in significantly increased G1 arrest and apoptosis. In vivo, stable NCI-N87 cells expressing ShCCND1 were engrafted into nude mice. Then, the cancer-growth inhibition effect of lentivirus was confirmed. To assess lentivirus including ShCCND1 as a therapeutic agent, intratumoral injection was conducted. Tumor growth of the lentivirus-treated group was significantly inhibited compared to growth of the control group. These results are in accordance with the in vitro data and lend support to the mitotic figure count and apoptosis analysis of the tumor mass. The lentivirus-mediated ShCCND1 was constructed, which effectively inhibited growth of NCI-N87-derived cancer both in vitro and in vivo. The efficiency of shRNA knockdown and variation in the degree of inhibition is mediated by different shRNA sequences and cancer cell lines. These experimental results suggest the possibility of developing new gastric cancer therapies using lentivirus-mediated shRNA

  20. A Novel Targeted Inhibitor of the Alternative Pathway of Complement and Its Therapeutic Application in Ischemia/Reperfusion Injury1

    OpenAIRE

    Huang, Yuxiang; Qiao, Fei; Atkinson, Carl; Holers, V. Michael; Tomlinson, Stephen

    2008-01-01

    Bioavailability and therapeutic efficacy of soluble Crry, a mouse inhibitor of all complement activation pathways, is significantly enhanced when linked to a fragment of complement receptor 2 (CR2), a receptor that targets C3 activation products. In this study, we characterize alternative pathway-specific inhibitors consisting of a single or dimeric N-terminal region of mouse factor H (fH; short consensus repeats 1–5) linked to the same CR2 fragment (CR2-fH and CR2-fHfH). Both CR2-fH and CR2-...

  1. Myofibrillogenesis regulator 1 (MR-1 is a novel biomarker and potential therapeutic target for human ovarian cancer

    Directory of Open Access Journals (Sweden)

    Feng Jingjing

    2011-06-01

    Full Text Available Abstract Background Myofibrillogenesis regulator 1 (MR-1 is overexpressed in human cancer cells and plays an essential role in cancer cell growth. However, the significance of MR-1 in human ovarian cancer has not yet been explored. The aim of this study was to examine whether MR-1 is a predictor of ovarian cancer and its value as a therapeutic target in ovarian cancer patients. Methods Reverse-transcription polymerase chain reaction (PCR and quantitative real-time PCR were used to detect MR-1 mRNA levels in tissue samples from 26 ovarian cancer patients and 25 controls with benign ovarian disease. Anti-MR-1 polyclonal antibodies were prepared, tested by ELISA and western blotting, and then used for immunohistochemical analysis of the tissue samples. Adhesion and invasion of 292T cells was also examined after transfection of a pMX-MR-1 plasmid. Knockdown of MR-1 expression was achieved after stable transfection of SKOV3 cells with a short hairpin DNA pGPU6/GFP/Neo plasmid against the MR-1 gene. In addition, SKOV3 cells were treated with paclitaxel and carboplatin, and a potential role for MR-1 as a therapeutic target was evaluated. Results MR-1 was overexpressed in ovarian cancer tissues and SKOV3 cells. 293T cells overexpressed MR-1, and cellular spread and invasion were enhanced after transfection of the pMX-MR-1 plasmid, suggesting that MR-1 is critical for ovarian cancer cell growth. Knockdown of MR-1 expression inhibited cell adhesion and invasion, and treatment with anti-cancer drugs decreased its expression in cancer cells. Taken together, these results provide the first evidence of the cellular and molecular mechanisms by which MR-1 might serve as a novel biological marker and potential therapeutic target for ovarian cancer. Conclusions MR-1 may be a biomarker for diagnosis of ovarian cancer. It may also be useful for monitoring of the effects of anti-cancer therapies. Further studies are needed to clarify whether MR-1 is an early

  2. Synapses as therapeutic targets for Autism Spectrum Disorders: an International Symposium held in Pavia on July 4th, 2014

    Directory of Open Access Journals (Sweden)

    Paolo Curatolo

    2014-09-01

    Full Text Available New progresses into the molecular and cellular mechanisms of Autism Spectrum Disorders (ASDs have been discussed in one day International Symposium held in Pavia (Italy on July 4th, 2014 entitled "Synapses as therapeutic targets for Autism Spectrum Disorders" (satellite of the FENS Forum for Neuroscience, Milan 2014. In particular, world experts in the field have highlighted how animal models of ASDs have greatly advanced our understanding of the molecular pathways involved in synaptic dysfunction leading sometimes to "synaptic clinical trials" in children.

  3. Developmental origins of metabolic disorders: The need for biomarker candidates and therapeutic targets from adequate preclinical models

    Directory of Open Access Journals (Sweden)

    Antonio Gonzalez-Bulnes

    2016-03-01

    Full Text Available The investigation on obesity and associated disorders have changed from an scenario in which genome drove the phenotype to a dynamic setup in which prenatal and early-postnatal conditions are determinant. However, research in human beings is difficult due to confounding factors (lifestyle and socioeconomic heterogeneity plus ethical issues. Hence, there is currently an intensive effort for developing adequate preclinical models, aiming for an adequate combination of basic studies in rodent models and specific preclinical studies in large animals. The results of these research strategies may increase the identification and development of contrasted biomarkers and therapeutic targets.

  4. Bacterial Heat-Stable Enterotoxins: Translation of Pathogenic Peptides into Novel Targeted Diagnostics and Therapeutics

    Directory of Open Access Journals (Sweden)

    Chang Chang

    2010-08-01

    Full Text Available Heat-stable toxins (STs produced by enterotoxigenic bacteria cause endemic and traveler’s diarrhea by binding to and activating the intestinal receptor guanylyl cyclase C (GC-C. Advances in understanding the biology of GC-C have extended ST from a diarrheagenic peptide to a novel therapeutic agent. Here, we summarize the physiological and pathophysiological role of GC-C in fluid-electrolyte regulation and intestinal crypt-villus homeostasis, as well as describe translational opportunities offered by STs, reflecting the unique characteristics of GC-C, in treating irritable bowel syndrome and chronic constipation, and in preventing and treating colorectal cancer.

  5. Targeting ferritin receptors for the selective delivery of imaging and therapeutic agents to breast cancer cells

    Science.gov (United States)

    Geninatti Crich, S.; Cadenazzi, M.; Lanzardo, S.; Conti, L.; Ruiu, R.; Alberti, D.; Cavallo, F.; Cutrin, J. C.; Aime, S.

    2015-04-01

    In this work the selective uptake of native horse spleen ferritin and apoferritin loaded with MRI contrast agents has been assessed in human breast cancer cells (MCF-7 and MDA-MB-231). The higher expression of L-ferritin receptors (SCARA5) led to an enhanced uptake in MCF-7 as shown in T2 and T1 weighted MR images, respectively. The high efficiency of ferritin internalization in MCF-7 has been exploited for the simultaneous delivery of curcumin, a natural therapeutic molecule endowed with antineoplastic and anti-inflammatory action, and the MRI contrast agent Gd-HPDO3A. This theranostic system is able to treat selectively breast cancer cells over-expressing ferritin receptors. By entrapping in apoferritin both Gd-HPDO3A and curcumin, it was possible to deliver a therapeutic dose of 167 μg ml-1 (as calculated by MRI) of this natural drug to MCF-7 cells, thus obtaining a significant reduction of cell proliferation.In this work the selective uptake of native horse spleen ferritin and apoferritin loaded with MRI contrast agents has been assessed in human breast cancer cells (MCF-7 and MDA-MB-231). The higher expression of L-ferritin receptors (SCARA5) led to an enhanced uptake in MCF-7 as shown in T2 and T1 weighted MR images, respectively. The high efficiency of ferritin internalization in MCF-7 has been exploited for the simultaneous delivery of curcumin, a natural therapeutic molecule endowed with antineoplastic and anti-inflammatory action, and the MRI contrast agent Gd-HPDO3A. This theranostic system is able to treat selectively breast cancer cells over-expressing ferritin receptors. By entrapping in apoferritin both Gd-HPDO3A and curcumin, it was possible to deliver a therapeutic dose of 167 μg ml-1 (as calculated by MRI) of this natural drug to MCF-7 cells, thus obtaining a significant reduction of cell proliferation. Electronic supplementary information (ESI) available: Competition studies with free apoferritin, Fig. S1; APO-FITC intracellular distribution by

  6. Polymer therapeutics with a coiled coil motif targeted against murine BCL1 leukemia

    Czech Academy of Sciences Publication Activity Database

    Pola, Robert; Laga, Richard; Ulbrich, Karel; Sieglová, Irena; Král, Vlastimil; Fábry, Milan; Kabešová, Martina; Kovář, Marek; Pechar, Michal

    2013-01-01

    Roč. 14, č. 3 (2013), s. 881-889. ISSN 1525-7797 R&D Projects: GA ČR GAP301/11/0325; GA AV ČR IAAX00500803 Institutional research plan: CEZ:AV0Z50520514 Institutional support: RVO:61389013 ; RVO:61388971 ; RVO:68378050 Keywords : coiled coil * polymer therapeutics * scFv Subject RIV: CD - Macromolecular Chemistry; EC - Immunology (MBU-M); EB - Genetics ; Molecular Biology (UMG-J) Impact factor: 5.788, year: 2013

  7. Is phosphoadenosine phosphate phosphatase a target of lithium’s therapeutic effect?

    OpenAIRE

    Shaltiel, G.; Deutsch, J.; Rapoport, S I; Basselin, M.; Belmaker, R. H.; Agam, G.

    2009-01-01

    Lithium, which is approved for treating patients with bipolar disorder, is reported to inhibit 3′(2′)-phosphoadenosine-5′-phosphate (PAP) phosphatase activity. In yeast, deletion of PAP phosphatase results in elevated PAP levels and in inhibition of sulfation and of growth. The effect of lithium on PAP phosphatase is remarkable for the low Ki (~0.2 mM), suggesting that this system would be almost completely shut down in vivo with therapeutic levels of 1 mM lithium, thereby elevating PAP level...

  8. Mitochondria and nuclei dual-targeted heterogeneous hydroxyapatite nanoparticles for enhancing therapeutic efficacy of doxorubicin.

    Science.gov (United States)

    Xiong, Hui; Du, Shi; Ni, Jiang; Zhou, Jianping; Yao, Jing

    2016-07-01

    Dual-targeted nanoparticles have been increasingly used to realize greater anti-proliferation effect by attacking double key sites of tumor cells. In order to retain nuclei inhibition effect and enhance DOX-induced apoptosis by mitochondrial pathway simultaneously, hyaluronic acid (HA) modified hydroxyapatite (HAP) nanoparticles (HAP-HA), the functional calcium-based tumor targeting nanoparticles, have been developed. In this nanosystem, HA acts as an active tumor-targeting ligand to bind the CD44 receptors which are overexpressed on the surface of tumor cells while HAP can load and deliver DOX to both nuclei and mitochondria of tumor cells. In this study, DOX-loaded HAP-HA nanoparticles (DOX/HAP-HA) exhibited satisfactory drug loading efficiency which was up to 214.55 ± 51.05 μg mg(-1) and showed a uniform nano-scaled particle size. The mitochondrial and nuclei targetability of DOX/HAP-HA was confirmed by confocal laser scanning microscopy analyses. Besides, western blot assay demonstrated that DOX/HAP-HA could markedly enhance mitochondrial cytochrome C leakage and thereby activate apoptotic cascade associated with it. In addition, in vivo anti-tumor efficacy and toxicity evaluation of DOX/HAP-HA indicated that DOX/HAP-HA was more effective and less harmful compared to other groups. DOX/HAP-HA might be a new promising targeted delivery system for effective cancer therapy. PMID:27105438

  9. Development of Quorum-Based Anti-Virulence Therapeutics Targeting Gram-Negative Bacterial Pathogens

    Directory of Open Access Journals (Sweden)

    Wen Shan Yew

    2013-08-01

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

  10. HER3/ErbB3, an emerging cancer therapeutic target.

    Science.gov (United States)

    Zhang, Ningyan; Chang, Yujun; Rios, Adan; An, Zhiqiang

    2016-01-01

    HER3 is a member of the HER (EGFR/ErbB) receptor family consisting of four closely related type 1 transmembrane receptors (EGFR, HER2, HER3, and HER4). HER receptors are part of a complex signaling network intertwined with the Ras/Raf/MAPK, PI3K/AKT, JAK/STAT, and PKC signaling pathways. Aberrant activation of the HER receptors and downstream signaling molecules tips the balance on cellular events, leading to various types of cancers. Monoclonal antibodies (mAbs) and small molecule inhibitors targeting EGFR and HER2 tyrosine kinase activities exhibit clinical benefits in the treatment of several types of cancers, but their clinical efficacy is limited by the occurrence of drug resistance. HER3 is the preferred dimerization partner of HER2 and it is well established that HER3 plays an important role in drug resistance to EGFR- and HER2-targeting therapies. Since HER3 has limited kinase activity, mAbs are being explored to target HER3 for cancer therapy. Currently, approximately a dozen of anti-HER3 mAbs are at different stages of clinical development. However, the lack of established biomarkers has made it more challenging to stratify cancer patients to whom HER3-targeting therapies can be more effective. In this review, we focus on the validation of HER3 as a cancer drug target, the recent development in biomarker discovery for anti-HER3 therapies, and the progress made in the clinical development of HER3-targeting mAbs. PMID:26496898

  11. Therapeutics formulated to target cancer stem cells: Is it in our future?

    Directory of Open Access Journals (Sweden)

    Mousa Shaker A

    2011-03-01

    Full Text Available Abstract With the political, social and financial drives for cancer research, many advances have been made in the treatment of many different cancer types. For example, given the increase in awareness, early detection, and treatment of breast and prostate cancers, we have seen substantial increases in survival rates. Unfortunately there are some realms of cancer that have not seen these substantial advancements, largely due to their rapid progression and the inability to specifically target therapy. The hypothesis that cancers arise from a small population of cells, called cancer stem cells (CSCs, is gaining more popularity amongst researchers. There are, however, still many skeptics who bring into question the validity of this theory. Many skeptics believe that there is not a specific subset of cells that originate with these characteristics, but that they develop certain features over time making them more resistant to conventional therapy. It is theorized that many of the relapses occurring after remission are due to our inability to destroy the self-renewing CSCs. This central idea, that CSCs are biologically different from all other cancer cells, has directed research towards the development of therapy to target CSCs directly. The major dilemma in targeting therapy in myeloproliferative disorders, malignancies of the central nervous system or malignancies in general, is the inability to target CSCs as opposed to normal stem cells. However, with the recent advances in the identifications of unique molecular signatures for CSCs along with ongoing clinical trials targeting CSCs, it is possible to use targeted nanotechnology-based strategies in the management of different types of cancers.

  12. Model‐Based Assessment of Plasma Citrate Flux Into the Liver: Implications for NaCT as a Therapeutic Target

    Science.gov (United States)

    Erion, DM; Maurer, TS

    2016-01-01

    Cytoplasmic citrate serves as an important regulator of gluconeogenesis and carbon source for de novo lipogenesis in the liver. For this reason, the sodium‐coupled citrate transporter (NaCT), a plasma membrane transporter that governs hepatic influx of plasma citrate in human, is being explored as a potential therapeutic target for metabolic disorders. As cytoplasmic citrate also originates from intracellular mitochondria, the relative contribution of these two pathways represents critical information necessary to underwrite confidence in this target. In this work, hepatic influx of plasma citrate was quantified via pharmacokinetic modeling of published clinical data. The influx was then compared to independent literature estimates of intracellular citrate flux in human liver. The results indicate that, under normal conditions, NaCT inhibition will have a limited impact on hepatic citrate concentrations across species. PMID:27069776

  13. Model-Based Assessment of Plasma Citrate Flux Into the Liver: Implications for NaCT as a Therapeutic Target.

    Science.gov (United States)

    Li, Z; Erion, D M; Maurer, T S

    2016-03-01

    Cytoplasmic citrate serves as an important regulator of gluconeogenesis and carbon source for de novo lipogenesis in the liver. For this reason, the sodium-coupled citrate transporter (NaCT), a plasma membrane transporter that governs hepatic influx of plasma citrate in human, is being explored as a potential therapeutic target for metabolic disorders. As cytoplasmic citrate also originates from intracellular mitochondria, the relative contribution of these two pathways represents critical information necessary to underwrite confidence in this target. In this work, hepatic influx of plasma citrate was quantified via pharmacokinetic modeling of published clinical data. The influx was then compared to independent literature estimates of intracellular citrate flux in human liver. The results indicate that, under normal conditions, NaCT inhibition will have a limited impact on hepatic citrate concentrations across species. PMID:27069776

  14. Method for Targeted Therapeutic Delivery of Proteins into Cells | NCI Technology Transfer Center | TTC

    Science.gov (United States)

    The Protein Expression Laboratory at the National Cancer Institute in Frederick, MD is seeking statements of capability or interest from parties interested in collaborative research to further develop a platform technology for the targeted intra-cellular delivery of proteins using virus-like particles (VLPs).

  15. ADAM-17: a novel therapeutic target for triple negative breast cancer.

    LENUS (Irish Health Repository)

    McGowan, P M

    2013-02-01

    Validated targeted therapy is currently unavailable for patients with invasive breast cancer negative for oestrogen receptors, progesterone receptors and HER2 [i.e., those with triple-negative (TN) disease]. ADAM-17 is a protease involved in the activations of several ligands that bind to and promotes intracellular signalling from the EGFR\\/HER family of receptors.

  16. Do current therapeutic anti-Aβ antibodies for Alzheimer's disease engage the target?

    Science.gov (United States)

    Watt, Andrew D; Crespi, Gabriela A N; Down, Russell A; Ascher, David B; Gunn, Adam; Perez, Keyla A; McLean, Catriona A; Villemagne, Victor L; Parker, Michael W; Barnham, Kevin J; Miles, Luke A

    2014-01-01

    Reducing amyloid-β peptide (Aβ) burden at the pre-symptomatic stages of Alzheimer's disease (AD) is currently the advocated clinical strategy for treating this disease. The most developed method for targeting Aβ is the use of monoclonal antibodies including bapineuzumab, solanezumab and crenezumab. We have synthesized these antibodies and used surface plasmon resonance (SPR) and mass spectrometry to characterize and compare the ability of these antibodies to target Aβ in transgenic mouse tissue as well as human AD tissue. SPR analysis showed that the antibodies were able to bind Aβ with high affinity. All of the antibodies were able to bind Aβ in mouse tissue. However, significant differences were observed in human brain tissue. While bapineuzumab was able to capture a variety of N-terminally truncated Aβ species, the Aβ detected using solanezumab was barely above detection limits while crenezumab did not detect any Aβ. None of the antibodies were able to detect any Aβ species in human blood. Immunoprecipitation experiments using plasma from AD subjects showed that both solanezumab and crenezumab have extensive cross-reactivity with non-Aβ related proteins. Bapineuzumab demonstrated target engagement with brain Aβ, consistent with published clinical data. Solanezumab and crenezumab did not, most likely as a result of a lack of specificity due to cross-reactivity with other proteins containing epitope overlap. This lack of target engagement raises questions as to whether solanezumab and crenezumab are suitable drug candidates for the preventative clinical trials for AD. PMID:24803227

  17. Therapeutic Target Achievement in Type 2 Diabetic Patients after Hyperglycemia, Hypertension, Dyslipidemia Management

    Directory of Open Access Journals (Sweden)

    Ah Young Kang

    2011-06-01

    Full Text Available BackgroundOur study group established "3H care" in 2002. The meaning of "3H care" attain and maintain adequate controls over hypertension, hyperlipidemia, and hyperglycemia in type 2 diabetic patients. This study evaluated the achievement of target goals after one year or more of "3H care" by specialists in our diabetic clinic.MethodsThis was a retrospective study of 200 type 2 diabetic patients who received "3H care" for one year or more in our diabetic clinic. We evaluated achievement of target goals for metabolic controls as suggested by the American Diabetes Association.ResultsOverall, 200 type 2 diabetes patients were enrolled, of whom 106 were males (53% and 94 were females (47%. After one year of "3H care," the mean HbA1c was 7.2±1.5% and the percentage of patients achieving glycemic control (HbA1c <7% was 51.8%. However only 32.2% of hypertensive patients achieved the recommended target. After one year of "3H care," the percentages of those who achieved the target value for dyslipidemia were 80.0% for total cholesterol, 66.3% for low density lipoprotein cholesterol, 57.9% for triglyceride, and 51.8% for high density lipoprotein cholesterol. The percentage that achieved all three targets level was only 4.4% after one year and 14.8% after two years.ConclusionThe results of this study demonstrate that only a minor proportion of patients with type 2 diabetes achieved the recommended goals despite the implementation of "3H care." It is our suggestion that better treatment strategies and methods should be used to control hypertension, hyperlipidemia and hyperglycemia.

  18. Neddylation pathway is up-regulated in human intrahepatic cholangiocarcinoma and serves as a potential therapeutic target

    Science.gov (United States)

    Zhang, Wen-Juan; Wang, Zhi-Chao; Yang, Liu-Xiao; Duan, Meng; Zhao, Hu; Wang, Xiao-Ying; Zhou, Jian; Qiu, Shuang-Jian; Jeong, Lak Shin; Jia, Li-Jun; Fan, Jia

    2014-01-01

    Therapeutic intervention in neddylation pathway is an emerging area for cancer treatment. Herein, we evaluated the clinical relevance and therapeutic potential of targeting this pathway in intrahepatic cholangiocarcinoma (ICC). Immunohistochemistry of neddylation pathway components in a cohort of 322 cases showed that E1 (NAE1 and UBA3) and E2 (UBC12) enzymes, as well as global NEDD8 conjugation, were upregulated in over 2/3 of human ICC. Notably, NAE1 was identified as an independent prognosticator for postoperative recurrence (P=0.009) and a combination of NEDD8 and NAE1 provided a better power for predicting patient clinical outcomes. In vitro treatment with MLN4924, a small-molecule NEDD8-activating enzyme inhibitor, led to a dose-dependent decrease of viability in both established and primary cholangiocarcinoma cell lines. Additionally, MLN4924 exhibited at least additive effect when combined with cisplatin. By blocking cullins neddylation, MLN4924 inactivated Cullin-Ring ligase (CRL) and caused the accumulation of CRL substrates that triggered cell cycle arrest, senescence or apoptosis. Meanwhile, MLN4924 was well-tolerated and significantly inhibited tumor growth in xenograft model of cholangiocarcinoma. Taken together, our findings indicated that upregulated neddylation pathway was involved in ICC progression and interference in this pathway could be a promising target for ICC therapy. PMID:25229838

  19. Implication of Caspase-3 as a Common Therapeutic Target for Multineurodegenerative Disorders and Its Inhibition Using Nonpeptidyl Natural Compounds

    Directory of Open Access Journals (Sweden)

    Saif Khan

    2015-01-01

    Full Text Available Caspase-3 has been identified as a key mediator of neuronal apoptosis. The present study identifies caspase-3 as a common player involved in the regulation of multineurodegenerative disorders, namely, Alzheimer’s disease (AD, Parkinson’s disease (PD, Huntington’s disease (HD, and amyotrophic lateral sclerosis (ALS. The protein interaction network prepared using STRING database provides a strong evidence of caspase-3 interactions with the metabolic cascade of the said multineurodegenerative disorders, thus characterizing it as a potential therapeutic target for multiple neurodegenerative disorders. In silico molecular docking of selected nonpeptidyl natural compounds against caspase-3 exposed potent leads against this common therapeutic target. Rosmarinic acid and curcumin proved to be the most promising ligands (leads mimicking the inhibitory action of peptidyl inhibitors with the highest Gold fitness scores 57.38 and 53.51, respectively. These results were in close agreement with the fitness score predicted using X-score, a consensus based scoring function to calculate the binding affinity. Nonpeptidyl inhibitors of caspase-3 identified in the present study expeditiously mimic the inhibitory action of the previously identified peptidyl inhibitors. Since, nonpeptidyl inhibitors are preferred drug candidates, hence, discovery of natural compounds as nonpeptidyl inhibitors is a significant transition towards feasible drug development for neurodegenerative disorders.

  20. PTTG1 Over-expression in Adrenocortical Cancer is Associated with Poor Survival and Represents a Potential Therapeutic Target

    Science.gov (United States)

    Demeure, Michael J.; Coan, Kathryn E.; Grant, Clive S.; Komorowski, Richard A.; Stephan, Elizabeth; Sinari, Shripad; Mount, David; Bussey, Kimberly J.

    2014-01-01

    Background Adrenocortical carcinoma (ACC) is associated with poor survival rates. The objective of the study was to analyze ACC gene expression profiling data for prognostic biomarkers and therapeutic targets. Methods 44 ACC and 4 normal adrenals were profiled on Affymetrix U133 Plus 2 expression microarrays. Pathway and transcriptional enrichment analysis was performed. Protein levels were determined by western blot. Drug efficacy was assessed against ACC cell lines. Previously published expression datasets were analyzed for validation. Results Pathway enrichment analysis identified marked dysregulation of cyclin-dependent kinases and mitosis. Over-expression of PTTG1, which encodes securin, a negative regulator of p53, was identified as a marker of poor survival. Median survival for patients with tumors expressing high PTTG1 levels (log2 ratio of PTTG1 to average beta-actin <-3.04 ) was 1.8 years compared to 9.0 years if tumors expressed lower levels of PTTG1 (P<0.0001). Analysis of a previously published data set confirmed the association of high PTTG1 expression with a poor prognosis. Treatment of two ACC cell lines with vorinostat decreased securin levels and inhibited cell growth (IC50s of 1.69 uM and 0.891 uM, for SW-13 and H295R, respectively). Conclusion Over-expression of PTTG1 is correlated with poor survival in ACC. PTTG1/securin is a prognostic biomarker and warrants investigation as a therapeutic target. PMID:24238056

  1. A role for plasma cell targeting agents in immune tolerance induction in autoimmune disease and antibody responses to therapeutic proteins.

    Science.gov (United States)

    Rosenberg, A S; Pariser, A R; Diamond, B; Yao, L; Turka, L A; Lacana, E; Kishnani, P S

    2016-04-01

    Antibody responses to life saving therapeutic protein products, such as enzyme replacement therapies (ERT) in the setting of lysosomal storage diseases, have nullified product efficacy and caused clinical deterioration and death despite treatment with immune-suppressive therapies. Moreover, in some autoimmune diseases, pathology is mediated by a robust antibody response to endogenous proteins such as is the case in pulmonary alveolar proteinosis, mediated by antibodies to Granulocyte Macrophage-Colony Stimulating Factor (GM-CSF). In this work, we make the case that in such settings, when the antibody response is high titered, sustained, and refractory to immune suppressive treatments, the antibody response is mediated by long-lived plasma cells which are relatively unperturbed by immune suppressants including rituximab. However, long-lived plasma cells can be targeted by proteasome inhibitors such as bortezomib. Recent reports of successful reversal of antibody responses with bortezomib in the settings of ERT and Thrombotic Thrombocytopenic Purpura (TTP) argue that the safety and efficacy of such plasma cell targeting agents should be evaluated in larger scale clinical trials to delineate the risks and benefits of such therapies in the settings of antibody-mediated adverse effects to therapeutic proteins and autoantibody mediated pathology. PMID:26928739

  2. Respiratory virus modulation of host nucleocytoplasmic transport; target for therapeutic intervention?

    Directory of Open Access Journals (Sweden)

    Leon eCaly

    2015-08-01

    Full Text Available The respiratory diseases caused by Rhinovirus, Respiratory Syncytial Virus and Influenza virus represent a large social and financial burden on healthcare worldwide. Although all three viruses have distinctly unique properties in terms of infection and replication, they share the ability to exploit/manipulate the host-cell nucleocytoplasmic transport system in order to replicate effectively and efficiently. This review outlines the various ways in which infection by these viruses impacts on the host nucleocytoplasmic transport system, and examples where inhibition thereof in turn decreases viral replication. The highly conserved nature of the nucleocytoplasmic transport system and the viral proteins that interact with it make this virus-host interface a prime candidate for the development of specific antiviral therapeutics in the future.

  3. Invadopodia Are Required for Cancer Cell Extravasation and Are a Therapeutic Target for Metastasis

    Directory of Open Access Journals (Sweden)

    Hon S. Leong

    2014-09-01

    Full Text Available Tumor cell extravasation is a key step during cancer metastasis, yet the precise mechanisms that regulate this dynamic process are unclear. We utilized a high-resolution time-lapse intravital imaging approach to visualize the dynamics of cancer cell extravasation in vivo. During intravascular migration, cancer cells form protrusive structures identified as invadopodia by their enrichment of MT1-MMP, cortactin, Tks4, and importantly Tks5, which localizes exclusively to invadopodia. Cancer cells extend invadopodia through the endothelium into the extravascular stroma prior to their extravasation at endothelial junctions. Genetic or pharmacological inhibition of invadopodia initiation (cortactin, maturation (Tks5, or function (Tks4 resulted in an abrogation of cancer cell extravasation and metastatic colony formation in an experimental mouse lung metastasis model. This provides direct evidence of a functional role for invadopodia during cancer cell extravasation and distant metastasis and reveals an opportunity for therapeutic intervention in this clinically important process.

  4. Mucosal targeting of therapeutic molecules using genetically modified lactic acid bacteria: an update.

    Science.gov (United States)

    LeBlanc, Jean Guy; Aubry, Camille; Cortes-Perez, Naima G; de Moreno de LeBlanc, Alejandra; Vergnolle, Nathalie; Langella, Philippe; Azevedo, Vasco; Chatel, Jean-Marc; Miyoshi, Anderson; Bermúdez-Humarán, Luis G

    2013-07-01

    Lactic acid bacteria (LAB) represent a heterogeneous group of microorganisms naturally present in many foods and those have proved to be effective mucosal delivery vectors. Moreover, some specific strains of LAB exert beneficial properties (known as probiotic effect) on both human and animal health. Although probiotic effects are strain-specific traits, it is theoretically possible, using genetic engineering techniques, to design strains that can exert a variety of beneficial properties. During the two past decades, a large variety of therapeutic molecules has been successfully expressed in LAB, and although this field has been largely reviewed in recent years, approximately 20 new publications appear each year. Thus, the aim of this minireview is not to extensively assess the entire literature but to update progress made within the last 2 years regarding the use of the model LAB Lactococcus lactis and certain species of lactobacilli as live recombinant vectors for the development of new safe mucosal vaccines. PMID:23600579

  5. Chemokines in Chronic Liver Allograft Dysfunction Pathogenesis and Potential Therapeutic Targets

    Directory of Open Access Journals (Sweden)

    Bin Liu

    2013-01-01

    Full Text Available Despite advances in immunosuppressive drugs, long-term success of liver transplantation is still limited by the development of chronic liver allograft dysfunction. Although the exact pathogenesis of chronic liver allograft dysfunction remains to be established, there is strong evidence that chemokines are involved in organ damage induced by inflammatory and immune responses after liver surgery. Chemokines are a group of low-molecular-weight molecules whose function includes angiogenesis, haematopoiesis, mitogenesis, organ fibrogenesis, tumour growth and metastasis, and participating in the development of the immune system and in inflammatory and immune responses. The purpose of this review is to collect all the research that has been done so far concerning chemokines and the pathogenesis of chronic liver allograft dysfunction and helpfully, to pave the way for designing therapeutic strategies and pharmaceutical agents to ameliorate chronic allograft dysfunction after liver transplantation.

  6. Circulating endothelial progenitor cells in traumatic brain injury: an emerging therapeutic target?

    Institute of Scientific and Technical Information of China (English)

    WEI Hui-jie; JIANG Rong-cai; LIU Li; ZHANG Jian-ning

    2010-01-01

    Traumatic brain injury (TBI) is a major cause ofmortality and morbidity in the world. Recent clinical investigations and basic researches suggest that strategies to improve angiogenesis following TBI may provide promising opportunities to improve clinical outcomes and brain functional recovery. More and more evidences show that circulating endothelial progenitor cells (EPCs), which have been identified in the peripheral blood, may play an important role in the pathologic and physiological angiogenesis in adults. Moreover, impressive data demonstrate that EPCs are mobilized from bone marrow to blood circulation in response to traumatic or inflammatory stimulations.In this review, we discussed the role of EPCs in the repair of brain injury and the possible therapeutic implication for functional recovery of TBl in the future.

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

    Directory of Open Access Journals (Sweden)

    Koji eYoshimoto

    2012-12-01

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

  8. Apolipoprotein J: A New Predictor and Therapeutic Target in Cardiovascular Disease?

    Directory of Open Access Journals (Sweden)

    Ning Yang

    2015-01-01

    Full Text Available Objective: To review the functional mechanism of apolipoprotein J (apoJ in the process of atherosclerosis and the feasibility of apoJ as a therapeutic endpoint. Data Sources: Relevant articles published in English from 1983 to present were selected from PubMed. The terms of "atherosclerosis, apolipoprotein J, clusterin (CLU, oxidative stress, and inflammation" were used for searching. Study Selection: Articles studying the role of apoJ with atherosclerosis and restenosis after injury were reviewed. Articles focusing on the intrinsic determinants of atherosclerosis were selected. The exclusion criteria of articles were that the studies on immunologic vasculitis. Results: ApoJ, involved in numerous physiological process important for lipid transportation and vascular smooth muscle cell differentiation, including apoptotic cell death, cell-cycle regulation, cell adhesion, tissue remodeling, immune system regulation, and oxidative stress, plays a role in the development of clinical atherosclerosis. In the process of relieving atherosclerosis, apoJ can promote cholesterol and phospholipid export from macrophage-foam cells, and exhibit cytoprotective and anti-inflammatory actions by interacting with lots of known inflammatory proteins which may predict the onset of clinical cardiovascular events and may actually play a causal role in mediating atherosclerotic disease such as C-reactive protein, paraoxonase, and leptin. As known as CLU, apoJ has been identified to play central roles in the process of vascular smooth cells migration, adhesion, and proliferation, which can contribute significantly to restenosis after vascular injury. Conclusions: Intense effort and substantial progress have been made to identify the apoJ that relieves atherosclerosis and vascular restenosis after percutaneous coronary intervention. More work is needed to elucidate the exact mechanisms of and the interrelationship between the actions of apoJ and to successfully achieve

  9. Integrated genomic characterization reveals novel, therapeutically relevant drug targets in FGFR and EGFR pathways in sporadic intrahepatic cholangiocarcinoma.

    Directory of Open Access Journals (Sweden)

    Mitesh J Borad

    2014-02-01

    Full Text Available Advanced cholangiocarcinoma continues to harbor a difficult prognosis and therapeutic options have been limited. During the course of a clinical trial of whole genomic sequencing seeking druggable targets, we examined six patients with advanced cholangiocarcinoma. Integrated genome-wide and whole transcriptome sequence analyses were performed on tumors from six patients with advanced, sporadic intrahepatic cholangiocarcinoma (SIC to identify potential therapeutically actionable events. Among the somatic events captured in our analysis, we uncovered two novel therapeutically relevant genomic contexts that when acted upon, resulted in preliminary evidence of anti-tumor activity. Genome-wide structural analysis of sequence data revealed recurrent translocation events involving the FGFR2 locus in three of six assessed patients. These observations and supporting evidence triggered the use of FGFR inhibitors in these patients. In one example, preliminary anti-tumor activity of pazopanib (in vitro FGFR2 IC50≈350 nM was noted in a patient with an FGFR2-TACC3 fusion. After progression on pazopanib, the same patient also had stable disease on ponatinib, a pan-FGFR inhibitor (in vitro, FGFR2 IC50≈8 nM. In an independent non-FGFR2 translocation patient, exome and transcriptome analysis revealed an allele specific somatic nonsense mutation (E384X in ERRFI1, a direct negative regulator of EGFR activation. Rapid and robust disease regression was noted in this ERRFI1 inactivated tumor when treated with erlotinib, an EGFR kinase inhibitor. FGFR2 fusions and ERRFI mutations may represent novel targets in sporadic intrahepatic cholangiocarcinoma and trials should be characterized in larger cohorts of patients with these aberrations.

  10. Remote magnetic targeting of iron oxide nanoparticles for cardiovascular diagnosis and therapeutic drug delivery: where are we now?

    Science.gov (United States)

    Bietenbeck, Michael; Florian, Anca; Faber, Cornelius; Sechtem, Udo; Yilmaz, Ali

    2016-01-01

    Magnetic resonance imaging (MRI) allows for an accurate assessment of both functional and structural cardiac parameters, and thereby appropriate diagnosis and validation of cardiovascular diseases. The diagnostic yield of cardiovascular MRI examinations is often increased by the use of contrast agents that are almost exclusively based on gadolinium compounds. Another clinically approved contrast medium is composed of superparamagnetic iron oxide nanoparticles (IONs). These particles may expand the field of contrast-enhanced cardiovascular MRI as recently shown in clinical studies focusing on acute myocardial infarction (AMI) and atherosclerosis. Furthermore, IONs open up new research opportunities such as remote magnetic drug targeting (MDT). The approach of MDT relies on the coupling of bioactive molecules and magnetic nanoparticles to form an injectable complex. This complex, in turn, can be attracted to and retained at a desired target inside the body with the help of applied magnetic fields. In comparison to common systemic drug applications, MDT techniques promise both higher concentrations at the target site and lower concentrations elsewhere in the body. Moreover, concurrent or subsequent MRI can be used for noninvasive monitoring of drug distribution and successful delivery to the desired organ in vivo. This review does not only illustrate the basic conceptual and biophysical principles of IONs, but also focuses on new research activities and achievements in the cardiovascular field, mainly in the management of AMI. Based on the presentation of successful MDT applications in preclinical models of AMI, novel approaches and the translational potential of MDT are discussed. PMID:27486321

  11. HDL Cholesterol Efflux Capacity: Cardiovascular Risk Factor and Potential Therapeutic Target.

    Science.gov (United States)

    Bhatt, Anish; Rohatgi, Anand

    2016-01-01

    Low high-density lipoprotein cholesterol (HDL-C) levels are associated with incident cardiovascular events; however, many therapies targeting increases in HDL-C have failed to show consistent clinical benefit. Thus, focus has recently shifted toward measuring high-density lipoprotein (HDL) function. HDL is the key mediator of reverse cholesterol transport, the process of cholesterol extraction from foam cells, and eventual excretion into the biliary system. Cholesterol efflux from peripheral macrophages to HDL particles has been associated with atherosclerosis in both animals and humans. We review the mechanism of cholesterol efflux and the emerging evidence on the association between cholesterol efflux capacity and cardiovascular disease in human studies. We also focus on the completed and ongoing trials of novel therapies targeting different aspects of HDL cholesterol efflux. PMID:26710794

  12. Eosinophils and mast cells as therapeutic targets in pediatric functional dyspepsia

    Institute of Scientific and Technical Information of China (English)

    Craig; A; Friesen; Jennifer; V; Schurman; Jennifer; M; Colombo; Susan; M; Abdel-Rahman

    2013-01-01

    There is an increasing appreciation for the importance of inflammation as a pathophysiologic entity that contributes to functional gastrointestinal disorders including functional dyspepsia(FD).Importantly,inflammation may serve as a mediator between psychologic and physiologic functions.This manuscript reviews the literature implicating two inflammatory cell types,mast cells and eosinophils,in the generation of dyspeptic symptoms and explores their potential as targets for the treatment of FD.There are a number of inciting events which may initiate an inflammatory response,and the subsequent recruitment and activation of mast cells and eosinophils.These include internal triggers such as stress and anxiety,as well as external triggers such as microbes and allergens.Previous studies suggest that there may be efficacy in utilizing medications directed at mast cells and eosinophils.Evidence exists to suggest that combining "anti-inflammatory" medications with other treatments targeting stress can improve the rate of symptom resolution in pediatric FD.

  13. Targeted anti-inflammatory therapeutics in asthma and chronic obstructive lung disease

    OpenAIRE

    Durham, Andrew L.; Caramori, Gaetano; Chung, Kian F; Adcock, Ian M.

    2016-01-01

    Asthma and chronic obstructive pulmonary disease (COPD) are chronic inflammatory diseases of the airway, although the drivers and site of the inflammation differ between diseases. Asthmatics with a neutrophilic airway inflammation are associated with a poor response to corticosteroids, whereas asthmatics with eosinophilic inflammation respond better to corticosteroids. Biologicals targeting the Th2-eosinophil nexus such as anti–interleukin (IL)-4, anti–IL-5, and anti–IL-13 are ineffective in ...

  14. PD-1 as an emerging therapeutic target in renal cell carcinoma: current evidence

    Directory of Open Access Journals (Sweden)

    Tykodi SS

    2014-07-01

    Full Text Available Scott S Tykodi Department of Medicine, Division of Medical Oncology, University of Washington, Seattle, WA, USA Abstract: Renal cell carcinoma (RCC is the most common primary malignant tumor of the kidney in adults, representing approximately 4% of all adult cancers in the United States. Metastatic RCC is poorly responsive to conventional cytotoxic chemotherapies but can be sensitive to T-cell-directed immunotherapies such as interferon-α or interleukin-2. Despite recent progress in the application of antiangiogenic “targeted therapies” for metastatic RCC, high-dose interleukin-2 remains an appropriate first-line therapy for select patients and is associated with durable complete remissions in a small fraction of treated patients. Thus, advanced RCC provides a unique opportunity to investigate the requirements for effective antitumor immunotherapy. Accumulating evidence suggests that resistance mechanisms exploited by RCC and other tumor types may play a dominant role in limiting the effectiveness of tumor-reactive adaptive immune responses. Expression of the inhibitory coreceptor programmed cell death-1 (PD-1 on tumor-infiltrating lymphocytes within RCC tumors, as well as the expression of the PD-1 ligand (PD-L1 on RCC tumor cells, are strong negative prognostic markers for disease-specific death in RCC patients. Monoclonal antibodies targeting either PD-1 or PD-L1 have now entered clinic trials and have demonstrated promising antitumor effects for refractory metastatic RCC. This review summarizes the results of published and reported studies of PD-1- and PD-L1-targeted therapies enrolling patients with advanced RCC, focusing on key safety, toxicity, and efficacy end points. Prospects for advanced phase clinical testing and novel therapy combinations with PD-1- and PD-L1-targeted agents are discussed. Keywords: renal cell carcinoma, immune checkpoint, immunotherapy, T-lymphocyte, PD-1, PD-L1

  15. Researchers Use a Kinome Screen to Identify New Therapeutic Targets | Office of Cancer Genomics

    Science.gov (United States)

    The tumor suppressor p53 is mutated in over 50% of head and neck squamous cell carcinomas (HNSCC), yet there are currently no available therapies to target it. CTD2 researchers at the Fred Hutchison Cancer Research Center hypothesized that HNSCC cancer cells with p53 mutations are dependent on particular kinases for survival. In a study published in Clinical Cancer Research, they sought to identify these kinases using RNAi against known kinase genes in mouse and human cell lines.

  16. CD13 is a therapeutic target in human liver cancer stem cells

    OpenAIRE

    HARAGUCHI, NAOTSUGU; Ishii, Hideshi; Mimori, Koshi; Tanaka, Fumiaki; OHKUMA, MASAHISA; Kim, Ho Min; Akita, Hirofumi; Takiuchi, Daisuke; Hatano, Hisanori; Nagano, Hiroaki; Barnard, Graham F.; Doki, Yuichiro; Mori, Masaki

    2010-01-01

    Cancer stem cells (CSCs) are generally dormant or slowly cycling tumor cells that have the ability to reconstitute tumors. They are thought to be involved in tumor resistance to chemo/radiation therapy and tumor relapse and progression. However, neither their existence nor their identity within many cancers has been well defined. Here, we have demonstrated that CD13 is a marker for semiquiescent CSCs in human liver cancer cell lines and clinical samples and that targeting these cells might pr...

  17. Anti-HIV-1 Therapeutics: From FDA-approved Drugs to Hypothetical Future Targets

    OpenAIRE

    Adamson, Catherine S; Freed, Eric O.

    2009-01-01

    More than twenty-five years after its discovery, HIV-1 remains one of the world’s most formidable and destructive pathogens. Several classes of anti-HIV-1 agents are currently in widespread clinical use in developed nations; however, viral resistance to these drugs limits their effectiveness in a growing number of patients. It is therefore imperative that novel drugs be developed. Recent advances in the fields of HIV-1 molecular virology and cell biology have revealed possible new targets for...

  18. Hampering the Immune Suppressors: Therapeutic Targeting of Myeloid-Derived Suppressor Cells (MDSC) in Cancer

    OpenAIRE

    Albeituni, Sabrin Husein; Ding, Chuanlin; Yan, Jun

    2013-01-01

    Myeloid-derived suppressor cells (MDSC) are a heterogeneous population of immature myeloid cells with suppressive properties that preferentially expand in cancer. MDSC mainly suppress T cell proliferation and cytotoxicity, inhibit NK cell activation, and induce the differentiation and expansion of regulatory T cells (Tregs). The wide spectrum of MDSC suppressive activity in cancer and its role in tumor progression have rendered these cells a promising target for effective cancer immunotherapy...

  19. Integrated nanotechnology platform for tumor-targeted multimodal imaging and therapeutic cargo release

    OpenAIRE

    Hosoya, Hitomi; Andrey S Dobroff; Driessen, Wouter H. P.; Cristini, Vittorio; Brinker, Lina M.; Staquicini, Fernanda I.; Cardó-Vila, Marina; D’Angelo, Sara; Ferrara, Fortunato; Proneth, Bettina; Lin, Yu-Shen; Dunphy, Darren R.; Dogra, Prashant; Melancon, Marites P.; Stafford, R. Jason

    2016-01-01

    The main goal in the emerging field of cancer nanomedicine is to generate, standardize, and produce multifunctional carriers designed to improve the response of drugs against tumors. Here we report the design, development, and preclinical validation of a ligand-directed bioinorganic platform that integrates tumor targeting, receptor-mediated cell internalization, photon-to-heat conversion, and drug delivery. This enabling hydrogel-based technology can accommodate a broad variety of ligands, n...

  20. Insights into Orphan Nuclear Receptors as Prognostic Markers and Novel Therapeutic Targets for Breast Cancer

    OpenAIRE

    Aesoy, Reidun; Colin D Clyne; Chand, Ashwini L.

    2015-01-01

    There is emerging evidence asserting the importance of orphan nuclear receptors (ONRs) in cancer initiation and progression. In breast cancer, there is a lot unknown about ONRs in terms of their expression profile and their transcriptional targets in the various stages of tumor progression. With the classification of breast tumors into distinct molecular subtypes, we assess ONR expression in the different breast cancer subtypes and with patient outcomes. Complementing this, we review evidence...