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https://www.readbyqxmd.com/read/28446531/mining-exosomal-genes-for-pancreatic-cancer-targets
#1
Amy Makler, Ramaswamy Narayanan
BACKGROUND: Exosomes, cell-derived vesicles encompassing lipids, DNA, proteins coding genes and noncoding RNAs (ncRNAs) are present in diverse body fluids. They offer novel biomarker and drug therapy potential for diverse diseases, including cancer. MATERIALS AND METHODS: Using gene ontology, exosomal genes database and GeneCards metadata analysis tools, a database of cancer-associated protein coding genes and ncRNAs (n=2,777) was established. Variant analysis, expression profiling and pathway mapping were used to identify putative pancreatic cancer exosomal gene candidates...
May 2017: Cancer Genomics & Proteomics
https://www.readbyqxmd.com/read/28445938/pirfenidone-normalizes-the-tumor-microenvironment-to-improve-chemotherapy
#2
Christiana Polydorou, Fotios Mpekris, Panagiotis Papageorgis, Chrysovalantis Voutouri, Triantafyllos Stylianopoulos
Normalization of the tumor microenvironment by selectively targeting components of the tumor extracellular matrix has been recently proposed to have the potential to decompress tumor blood vessels, increase vessel perfusion and thus, improve drug delivery and the efficacy of cancer therapy. Therefore, we now need to identify safe and well tolerated pharmaceutical agents that are able to remodel the microenvironment of solid tumors and enhance chemotherapy. In this study, we repurposed Pirfenidone, a clinically approved anti-fibrotic drug for the treatment of idiopathic pulmonary fibrosis, to investigate its possible role on tumor microenvironment normalization...
April 11, 2017: Oncotarget
https://www.readbyqxmd.com/read/28438925/identification-of-mycobacterial-genes-involved-in-antibiotic-sensitivity-implications-in-the-treatment-of-tuberculosis-with-%C3%AE-lactam-containing-regimens
#3
Gopinath Viswanathan, Sangya Yadav, Tirumalai R Raghunand
In a Mycobacterium smegmatis mutant library screen, transposon mutants with insertions in fhaA, dprE2, rpsT and parA, displayed hypersusceptibility to antibiotics including the β-lactams meropenem, ampicillin, amoxicillin and cefotaxime. Sub MIC levels of octoclothepin, a psychotic drug inhibiting ParA, phenocopied the parA insertion and enhanced the bactericidal activity of meropenem against Mycobacteriumtuberculosis in combination with clavulanate. Our study identifies novel factors associated with antibiotic resistance, with implications in repurposing β-lactams for tuberculosis treatment...
April 24, 2017: Antimicrobial Agents and Chemotherapy
https://www.readbyqxmd.com/read/28433417/mechanistic-insights-into-epigenetic-modulation-of-ethanol-consumption
#4
Igor Ponomarev, Claire E Stelly, Hitoshi Morikawa, Yuri A Blednov, R Dayne Mayfield, R Adron Harris
There is growing evidence that small-molecule inhibitors of epigenetic modulators, such as histone deacetylases (HDAC) and DNA methyltransferases (DNMT), can reduce voluntary ethanol consumption in animal models, but molecular and cellular processes underlying this behavioral effect are poorly understood. We used C57BL/6J male mice to investigate the effects of two FDA-approved drugs, decitabine (a DNMT inhibitor) and SAHA (an HDAC inhibitor), on ethanol consumption using two tests: binge-like drinking in the dark (DID) and chronic intermittent every other day (EOD) drinking...
March 12, 2017: Alcohol
https://www.readbyqxmd.com/read/28430857/repurposed-drugs-targeting-eif2%C3%AE-p-mediated-translational-repression-prevent-neurodegeneration-in-mice
#5
Mark Halliday, Helois Radford, Karlijn A M Zents, Collin Molloy, Julie A Moreno, Nicholas C Verity, Ewan Smith, Catharine A Ortori, David A Barrett, Martin Bushell, Giovanna R Mallucci
Signalling through the PERK/eIF2α-P branch of the unfolded protein response plays a critical role in controlling protein synthesis rates in cells. This pathway is overactivated in brains of patients with Alzheimer's disease and related disorders and has recently emerged as a promising therapeutic target for these currently untreatable conditions. Thus, in mouse models of neurodegenerative disease, prolonged overactivation of PERK/eIF2α-P signalling causes sustained attenuation of protein synthesis, leading to memory impairment and neuronal loss...
April 19, 2017: Brain: a Journal of Neurology
https://www.readbyqxmd.com/read/28429253/modified-metformin-as-a-more-potent-anticancer-drug-mitochondrial-inhibition-redox-signaling-antiproliferative-effects-and-future-epr-studies
#6
Balaraman Kalyanaraman, Gang Cheng, Micael Hardy, Olivier Ouari, Adam Sikora, Jacek Zielonka, Michael B Dwinell
Metformin, one of the most widely prescribed antidiabetic drugs in the world, is being repurposed as a potential drug in cancer treatment. Epidemiological studies suggest that metformin exerts anticancer effects in diabetic patients with pancreatic cancer. However, at typical antidiabetic doses the bioavailability of metformin is presumably too low to exert antitumor effects. Thus, more potent analogs of metformin are needed in order to increase its anticancer efficacy. To this end, a new class of mitochondria-targeted metformin analogs (or mito-metformins) containing a positively-charged lipophilic triphenylphosphonium group was synthesized and tested for their antitumor efficacy in pancreatic cancer cells...
April 21, 2017: Cell Biochemistry and Biophysics
https://www.readbyqxmd.com/read/28427007/novel-and-revisited-approaches-in-antituberculosis-drug-discovery
#7
REVIEW
Jennifer Herrmann, Jan Rybniker, Rolf Müller
The increasing prevalence of multidrug-resistant Mycobacterium tuberculosis (Mtb) necessitates the discovery and development of novel drugs against tuberculosis. In this review, we focus on two recent approaches that led to the discovery of promising antitubercular compound classes: (I) Hits derived from large compound library screens are increasingly difficult to translate into clinical application; this in turn fostered the development of innovative screening methods. (II) An alternative strategy towards high-quality hits and leads is to evaluate chemically diverse scaffolds which can be found among natural products...
April 17, 2017: Current Opinion in Biotechnology
https://www.readbyqxmd.com/read/28424418/the-aryl-hydrocarbon-receptor-is-required-for-induction-of-p21cip1-waf1-expression-and-growth-inhibition-by-su5416-in-hepatoma-cells
#8
Edmond F O'Donnell, Hyo Sang Jang, Martin Pearce, Nancy I Kerkvliet, Siva Kumar Kolluri
The aryl hydrocarbon receptor (AhR) is a potential clinical target for cancer and autoimmune dysfunction. Identifying selective AhR modulators that produce desirable clinical outcomes represents an opportunity for developing new anti-cancer agents. Repurposing clinically-used drugs with established safety profiles that activate the AhR represents a good starting place to pursue this goal. In this study, we characterized the AhR-dependent effects of SU5416 (Semaxanib) following its identification in a small-molecule library screen...
April 11, 2017: Oncotarget
https://www.readbyqxmd.com/read/28423712/model-based-unsupervised-learning-informs-metformin-induced-cell-migration-inhibition-through-an-ampk-independent-mechanism-in-breast-cancer
#9
Arjun P Athreya, Krishna R Kalari, Junmei Cairns, Alan J Gaglio, Quin F Wills, Nifang Niu, Richard Weinshilboum, Ravishankar K Iyer, Liewei Wang
We demonstrate that model-based unsupervised learning can uniquely discriminate single-cell subpopulations by their gene expression distributions, which in turn allow us to identify specific genes for focused functional studies. This method was applied to MDA-MB-231 breast cancer cells treated with the antidiabetic drug metformin, which is being repurposed for treatment of triple-negative breast cancer. Unsupervised learning identified a cluster of metformin-treated cells characterized by a significant suppression of 230 genes (p-value < 2E-16)...
March 10, 2017: Oncotarget
https://www.readbyqxmd.com/read/28422756/%C3%AE-catenin-and-pi3k%C3%AE-inhibition-expands-precursor-th17-cells-with-heightened-stemness-and-antitumor-activity
#10
Kinga Majchrzak, Michelle H Nelson, Jacob S Bowers, Stefanie R Bailey, Megan M Wyatt, John M Wrangle, Mark P Rubinstein, Juan C Varela, Zihai Li, Richard A Himes, Sherine S L Chan, Chrystal M Paulos
ICOS costimulation generates Th17 cells with durable memory responses to tumor. Herein, we found that ICOS induces PI3K/p110δ/Akt and Wnt/β-catenin pathways in Th17 cells. Coinhibiting PI3Kδ and β-catenin altered the biological fate of Th17 cells. Th17 cells inhibited of both pathways expressed less RORγt, which, in turn, reduced their ability to secrete IL-17. Unexpectedly, these cells were more effective (than uninhibited cells) at regressing tumor when infused into mice, leading to long-term curative responses...
April 20, 2017: JCI Insight
https://www.readbyqxmd.com/read/28418694/drug-repurposing-patent-applications-october-december-2016
#11
Hermann A M Mucke
No abstract text is available yet for this article.
April 2017: Assay and Drug Development Technologies
https://www.readbyqxmd.com/read/28418693/validating-the-predicted-effect-of-astemizole-and-ketoconazole-using-a-drosophila-model-of-parkinson-s-disease
#12
Katarzyna Styczyńska-Soczka, Luigi Zechini, Lysimachos Zografos
Parkinson's disease is a growing threat to an ever-ageing population. Despite progress in our understanding of the molecular and cellular mechanisms underlying the disease, all therapeutics currently available only act to improve symptoms and do not stop the disease process. It is therefore imperative that more effective drug discovery methods and approaches are developed, validated, and used for the discovery of disease-modifying treatments for Parkinson's. Drug repurposing has been recognized as being equally as promising as de novo drug discovery in the field of neurodegeneration and Parkinson's disease specifically...
April 2017: Assay and Drug Development Technologies
https://www.readbyqxmd.com/read/28418692/drug-repurposing-patent-applications-january-march-2017
#13
Hermann A M Mucke
No abstract text is available yet for this article.
April 2017: Assay and Drug Development Technologies
https://www.readbyqxmd.com/read/28417261/neutrophil-infiltration-and-matrix-metalloproteinase-9-in-lacunar-infarction
#14
Wolfgang Walz, Francisco S Cayabyab
We use the modified pial vessel disruption rat model to elucidate the cellular and molecular mechanisms of cavitation as it plays a role in lacunar infarction. Here we discuss the similarities between the genesis of pulmonary cavitation in various animal models and lacunar infarction in the cerebral cortex of rats. Both pathological processes involve the creation of a cavity surrounded by fibroblasts or reactive astrocytes. A crucial step in both, the lung and the cerebral cortex, appears to be the migration of neutrophils across the endothelial barrier into the parenchyma...
April 18, 2017: Neurochemical Research
https://www.readbyqxmd.com/read/28415586/promoting-oligodendroglial-oriented-differentiation-of-glioma-stem-cell-a-repurposing-of-quetiapine-for-the-treatment-of-malignant-glioma
#15
Yun Wang, Nanxin Huang, Hongli Li, Shubao Liu, Xianjun Chen, Shichang Yu, Nan Wu, Xiu-Wu Bian, Hai-Ying Shen, Chengren Li, Lan Xiao
As a major contributor of chemotherapy resistance and malignant recurrence, glioma stem cells (GSCs) have been proposed as a target for the treatment of gliomas. To evaluate the therapeutic potential of quetiapine (QUE), an atypical antipsychotic, for the treatment of malignant glioma, we established mouse models with GSCs-initiated orthotopic xenograft gliomas and subcutaneous xenograft tumors, using GSCs purified from glioblastoma cell line GL261. We investigated antitumor effects of QUE on xenograft gliomas and its underlying mechanisms on GSCs...
March 21, 2017: Oncotarget
https://www.readbyqxmd.com/read/28411843/the-molecular-revolution-in-cutaneous-biology-emerging-landscape-in-genomic-dermatology-new-mechanistic-ideas-gene-editing-and-therapeutic-breakthroughs
#16
REVIEW
Matthias Titeux, Araksya Izmiryan, Alain Hovnanian
Stunning technological advances in genomics have led to spectacular breakthroughs in the understanding of the underlying defects, biological pathways and therapeutic targets of skin diseases leading to new therapeutic interventions. Next-generation sequencing has revolutionized the identification of disease-causing genes and has a profound impact in deciphering gene and protein signatures in rare and frequent skin diseases. Gene addition strategies have shown efficacy in junctional EB and in recessive dystrophic EB (RDEB)...
May 2017: Journal of Investigative Dermatology
https://www.readbyqxmd.com/read/28411509/direct-acting-antivirals-and-host-targeting-strategies-to-combat-enterovirus-infections
#17
REVIEW
Lisa Bauer, Heyrhyoung Lyoo, Hilde M van der Schaar, Jeroen Rpm Strating, Frank Jm van Kuppeveld
Enteroviruses (e.g., poliovirus, enterovirus-A71, coxsackievirus, enterovirus-D68, rhinovirus) include many human pathogens causative of various mild and more severe diseases, especially in young children. Unfortunately, antiviral drugs to treat enterovirus infections have not been approved yet. Over the past decades, several direct-acting inhibitors have been developed, including capsid binders, which block virus entry, and inhibitors of viral enzymes required for genome replication. Capsid binders and protease inhibitors have been clinically evaluated, but failed due to limited efficacy or toxicity issues...
April 12, 2017: Current Opinion in Virology
https://www.readbyqxmd.com/read/28410237/combination-therapy-in-combating-cancer
#18
REVIEW
Reza Bayat Mokhtari, Tina S Homayouni, Narges Baluch, Evgeniya Morgatskaya, Sushil Kumar, Bikul Das, Herman Yeger
Combination therapy, a treatment modality that combines two or more therapeutic agents, is a cornerstone of cancer therapy. The amalgamation of anti-cancer drugs enhances efficacy compared to the monotherapy approach because it characteristically targets key pathways with a synergistic or an additive effect. This approach potentially reduces drug-resistance, while simultaneously producing therapeutic anti-cancer benefits, such as reducing tumor growth and metastatic potential, arresting cells in cell cycle, reducing cancer stem cell populations, and inducing apoptosis...
March 30, 2017: Oncotarget
https://www.readbyqxmd.com/read/28408471/genomes-structural-biology-and-drug-discovery-combating-the-impacts-of-mutations-in-genetic-disease-and-antibiotic-resistance
#19
REVIEW
Arun Prasad Pandurangan, David B Ascher, Sherine E Thomas, Tom L Blundell
For over four decades structural biology has been used to understand the mechanisms of disease, and structure-guided approaches have demonstrated clearly that they can contribute to many aspects of early drug discovery, both computationally and experimentally. Structure can also inform our understanding of impacts of mutations in human genetic diseases and drug resistance in cancers and infectious diseases. We discuss the ways that structural insights might be useful in both repurposing off-licence drugs and guide the design of new molecules that might be less susceptible to drug resistance in the future...
April 15, 2017: Biochemical Society Transactions
https://www.readbyqxmd.com/read/28408344/repurposing-bacterial-toxins-for-intracellular-delivery-of-therapeutic-proteins
#20
REVIEW
Greg L Beilhartz, Seiji N Sugiman-Marangos, Roman A Melnyk
Despite enormous efforts, achieving efficacious levels of proteins inside mammalian cells remains one of the greatest challenges in biologics-based drug discovery and development. The inability of proteins to readily cross biological membranes precludes access to the wealth of intracellular targets and applications that lie within mammalian cells. Existing methods of delivery commonly suffer from an inability to target specific cells and tissues, poor endosomal escape, and limited in vivo efficacy. The aim of the present commentary is to highlight the potential of certain classes of bacterial toxins, which naturally deliver a large protein into the cytosolic compartment of target cells after binding a host cell-surface receptor with high affinity, as robust protein delivery platforms...
April 10, 2017: Biochemical Pharmacology
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