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https://www.readbyqxmd.com/read/28092830/trpv1-antagonism-by-piperazinyl-aryl-compounds-a-topomer-comfa-study-and-its-use-in-virtual-screening-for-identification-of-novel-antagonists
#1
Rajendra Kristam, Shashidhar N Rao, Anne Sudha D'Cruz, Vijayalakshmi Mahadevan, Vellarkad N Viswanadhan
Transient Receptor Potential Vanilloid, member 1 (TRPV1), is a non-selective cation channel belonging to the transient receptor potential (TRP) family of ion channels. It occurs in the peripheral and central nervous system, activated by a variety of exogenous and endogenous stimuli, thus playing a key role in transmission of pain. This has been a target for chronic pain since more than a decade and a number of antagonists that progressed into clinical trials have failed due to the unexpected side effect of core body temperature rise, thus halting progress in this field...
January 7, 2017: Journal of Molecular Graphics & Modelling
https://www.readbyqxmd.com/read/28092695/absorption-distribution-and-excretion-of-the-anti-tuberculosis-drug-delamanid-in-rats-extensive-tissue-distribution-suggests-potential-therapeutic-value-for-extrapulmonary-tuberculosis
#2
Masakazu Shibata, Yoshihiko Shimokawa, Katsunori Sasahara, Noriaki Yoda, Hiroyuki Sasabe, Mitsunari Suzuki, Ken Umehara
Delamanid (OPC-67683, Deltyba(TM) , nitro-dihydro-imidazooxazoles derivative) is approved for the treatment of adult pulmonary multidrug-resistant tuberculosis. The absorption, distribution, and excretion of delamanid-derived radioactivity were investigated after a single oral administration of (14) C-delamanid at 3 mg/kg to rats. In both male and female rats, radioactivity in blood and all tissues reached peak levels by 8 or 24 hours postdose, and thereafter decreased slowly. Radioactivity levels were 3- to 5-fold higher in lung tissue at time to maximum concentration compared with plasma...
January 16, 2017: Biopharmaceutics & Drug Disposition
https://www.readbyqxmd.com/read/28092690/post-translational-selective-intracellular-silencing-of-acetylated-proteins-with-de-novo-selected-intrabodies
#3
Michele Chirichella, Simonetta Lisi, Marco Fantini, Martina Goracci, Mariantonietta Calvello, Rossella Brandi, Ivan Arisi, Mara D'Onofrio, Cristina Di Primio, Antonino Cattaneo
The ability to selectively interfere with post-translationally modified proteins would have many biological and therapeutic applications. However, post-translational modifications cannot be selectively targeted by nucleic-acid-based interference approaches. Here we describe post-translational intracellular silencing antibody technology (PISA), a method for selecting intrabodies against post-translationally modified proteins. We demonstrate our method by generating intrabodies against native acetylated proteins and showing functional interference in living cells...
January 16, 2017: Nature Methods
https://www.readbyqxmd.com/read/28092679/genome-wide-analysis-of-p53-regulated-transcription-in-myc-driven-lymphomas
#4
C Tonelli, M J Morelli, A Sabò, A Verrecchia, L Rotta, T Capra, S Bianchi, S Campaner, B Amati
The tumour suppressor p53 is a transcription factor that controls cellular stress responses. Here, we dissected the transcriptional programmes triggered upon restoration of p53 in Myc-driven lymphomas, based on the integrated analysis of p53 genomic occupancy and gene regulation. p53 binding sites were identified at promoters and enhancers, both characterized by the pre-existence of active chromatin marks. Only a small fraction of these sites showed the 20 base-pair p53 consensus motif, suggesting that p53 recruitment to genomic DNA was primarily mediated through protein-protein interactions in a chromatin context...
January 16, 2017: Oncogene
https://www.readbyqxmd.com/read/28092676/intracellular-il-37b-interacts-with-smad3-to-suppress-multiple-signaling-pathways-and-the-metastatic-phenotype-of-tumor-cells
#5
C Luo, Y Shu, J Luo, D Liu, D-S Huang, Y Han, C Chen, Y-C Li, J-M Zou, J Qin, Y Wang, D Li, S-S Wang, G-M Zhang, J Chen, Z-H Feng
Multiple signaling pathways that promote tumor cell metastasis are differentially activated in low/non-metastatic and metastatic tumor cells, resulting in the differential expression of metastasis-related genes. The underlying mechanism may involve the alterations of the intrinsic negative regulation in tumor cells. Here we report that the differential expression of interleukin-37b (IL-37b) in tumor cells alters the intrinsic negative regulation of signaling pathways, resulting in the difference of metastatic capacity...
January 16, 2017: Oncogene
https://www.readbyqxmd.com/read/28092674/a-targetable-hb-egf-cited4-axis-controls-oncogenesis-in-lung-cancer
#6
C-H Hsieh, Y-T Chou, M-H Kuo, H-P Tsai, J-L Chang, C-W Wu
Aberrant epidermal growth factor (EGF) receptor (EGFR) signaling contributes to neoplastic initiation and progression in lung. Mutated EGFR has become as an important therapeutic target in lung cancer, whereas targeted treatment is not available for wild-type EGFR or its ligands. In this study, we found that heparin-binding (HB)-EGF, a member of the EGF family, was highly expressed in a subset of lung cancer, proliferation of which was dependent on HB-EGF signaling. Silencing of HB-EGF with RNA interference inhibited cell cycle progression in lung cancer cells...
January 16, 2017: Oncogene
https://www.readbyqxmd.com/read/28092669/interplay-between-epigenetics-and-metabolism-in-oncogenesis-mechanisms-and-therapeutic-approaches
#7
REVIEW
C C Wong, Y Qian, J Yu
Epigenetic and metabolic alterations in cancer cells are highly intertwined. Oncogene-driven metabolic rewiring modifies the epigenetic landscape via modulating the activities of DNA and histone modification enzymes at the metabolite level. Conversely, epigenetic mechanisms regulate the expression of metabolic genes, thereby altering the metabolome. Epigenetic-metabolomic interplay has a critical role in tumourigenesis by coordinately sustaining cell proliferation, metastasis and pluripotency. Understanding the link between epigenetics and metabolism could unravel novel molecular targets, whose intervention may lead to improvements in cancer treatment...
January 16, 2017: Oncogene
https://www.readbyqxmd.com/read/28092667/oncogenic-braf-fusions-in-mucosal-melanomas-activate-the-mapk-pathway-and-are-sensitive-to-mek-pi3k-inhibition-or-mek-cdk4-6-inhibition
#8
H S Kim, M Jung, H N Kang, H Kim, C-W Park, S-M Kim, S J Shin, S H Kim, S G Kim, E K Kim, M R Yun, Z Zheng, K Y Chung, J Greenbowe, S M Ali, T-M Kim, B C Cho
Despite remarkable progress in cutaneous melanoma genomic profiling, the mutational landscape of primary mucosal melanomas (PMM) remains unclear. Forty-six PMMs underwent targeted exome sequencing of 111 cancer-associated genes. Seventy-six somatic nonsynonymous mutations in 42 genes were observed, and recurrent mutations were noted on eight genes, including TP53 (13%), NRAS (13%), SNX31 (9%), NF1 (9%), KIT (7%) and APC (7%). Mitogen-activated protein kinase (MAPK; 37%), cell cycle (20%) and phosphatidylinositol 3-kinase (PI3K)-mTOR (15%) pathways were frequently mutated...
January 16, 2017: Oncogene
https://www.readbyqxmd.com/read/28092616/generation-and-characterization-of-a-monoclonal-antibody-against-duck-tembusu-virus-envelope-protein
#9
K Han, D Zhao, Y Liu, Q Liu, X Huang, J Yang, K Bi, T Xu, Y Li
Duck Tembusu virus (DTMUV) is a newly emerging pathogenic flavivirus that has caused massive economic losses to the duck industry in China. Envelope (E) protein of DTMUV is an important structural protein, which is able to induce protective immune response in target animals and can be used as specific serological diagnosis tool. In this study, a novel monoclonal antibody, designated mAb 3E9, was generated against DTMUV E protein. It is positive in indirect ELISA against both His-E protein and the purified whole viral antigen...
December 1, 2016: Polish Journal of Veterinary Sciences
https://www.readbyqxmd.com/read/28092499/nanoparticles-for-sirna-based-gene-silencing-in-tumor-therapy
#10
Anish Babu, Ranganayaki Muralidharan, Narsireddy Amreddy, Meghna Mehta, Anupama Munshi, Rajagopal Ramesh
Gene silencing through RNA interference (RNAi) has emerged as a potential strategy in manipulating cancer causing genes by complementary base-pairing mechanism. Small interfering RNA (siRNA) is an important RNAi tool that has found significant application in cancer therapy. However due to lack of stability, poor cellular uptake and high probability of loss-of-function due to degradation, siRNA therapeutic strategies seek safe and efficient delivery vehicles for in vivo applications. The current review discusses various nanoparticle systems currently used for siRNA delivery for cancer therapy, with emphasis on liposome based gene delivery systems...
December 2016: IEEE Transactions on Nanobioscience
https://www.readbyqxmd.com/read/28092486/use-of-polyclonal-monoclonal-antibody-therapies-in-transplantation
#11
Melissa Y Yeung, Steven Gabardi, Mohamed H Sayegh
For over thirty years, antibody (mAb)-based therapies have been a standard component of transplant immunosuppression, and yet much remains to be learned in order for us to truly harness their therapeutic capabilities. Current mAbs used in transplant directly target and destroy graft-destructive immune cells, interrupt cytokine and costimulation-dependent T and B cell activation, and prevent down-stream complement activation. Areas covered: This review summarizes our current approaches to using antibody-based therapies to prevent and treat allograft rejection...
January 16, 2017: Expert Opinion on Biological Therapy
https://www.readbyqxmd.com/read/28092369/context-dependent-role-for-chromatin-remodeling-component-pbrm1-baf180-in-clear-cell-renal-cell-carcinoma
#12
A Murakami, L Wang, S Kalhorn, P Schraml, W K Rathmell, A C Tan, R Nemenoff, K Stenmark, B-H Jiang, M E Reyland, L Heasley, C-J Hu
A subset of clear cell renal cell carcinoma (ccRCC) tumors exhibit a HIF1A gene mutation, yielding two ccRCC tumor types, H1H2 type expressing both HIF1α and HIF2α, and H2 type expressing HIF2α, but not functional HIF1α protein. However, it is unclear how the H1H2 type ccRCC tumors escape HIF1's tumor-suppressive activity. The polybromo-1 (PBRM1) gene coding for the BAF180 protein, a component of the SWItch/Sucrose Non-Fermentable (SWI/SNF) chromatin remodeling complex, is inactivated in 40% ccRCCs, the function and mechanism of BAF180 mutation is unknown...
January 16, 2017: Oncogenesis
https://www.readbyqxmd.com/read/28092358/recurrent-rna-motifs-as-scaffolds-for-genetically-encodable-small-molecule-biosensors
#13
Ely B Porter, Jacob T Polaski, Makenna M Morck, Robert T Batey
Allosteric RNA devices are increasingly being viewed as important tools capable of monitoring enzyme evolution, optimizing engineered metabolic pathways, facilitating gene discovery and regulators of nucleic acid-based therapeutics. A key bottleneck in the development of these platforms is the availability of small-molecule-binding RNA aptamers that robustly function in the cellular environment. Although aptamers can be raised against nearly any desired target through in vitro selection, many cannot easily be integrated into devices or do not reliably function in a cellular context...
January 16, 2017: Nature Chemical Biology
https://www.readbyqxmd.com/read/28092309/microbiota-targeted-therapies-on-the-intensive-care-unit
#14
Bastiaan W Haak, Marcel Levi, W Joost Wiersinga
PURPOSE OF REVIEW: The composition and diversity of the microbiota of the human gut, skin, and several other sites is severely deranged in critically ill patients on the ICU, and it is likely that these disruptions can negatively affect outcome. We here review new and ongoing studies that investigate the use of microbiota-targeted therapeutics in the ICU, and provide recommendations for future research. RECENT FINDINGS: Practically every intervention in the ICU as well as the physiological effects of critical illness itself can have a profound impact on the gut microbiota...
January 13, 2017: Current Opinion in Critical Care
https://www.readbyqxmd.com/read/28092276/asialoglycoprotein-receptors-as-important-mediators-of-plasma-lipids-and-atherosclerosis
#15
Suleiman A Igdoura
PURPOSE OF REVIEW: This review seeks to describe the role of the asialoglycoprotein receptor (ASGR) in modulating non-HDL lipoprotein levels, platelet numbers and atherosclerosis. RECENT FINDINGS: Genetics studies have revealed that ASGR haplodeficiency provides protection from atherosclerosis. The potential interactions of ASGR with LDL receptor may regulate the rate of LDL uptake and as a result may lower plasma non-HDL cholesterol. ASGR clears senescent platelets and induces the expression of hepatic thrombopoietin...
January 13, 2017: Current Opinion in Lipidology
https://www.readbyqxmd.com/read/28092182/an-estrogen-receptor-%C3%AE-selective-agonist-inhibits-non-alcoholic-steatohepatitis-in-preclinical-models-by-regulating-bile-acid-and-xenobiotic-receptors
#16
Suriyan Ponnusamy, Quynh T Tran, Thirumagal Thiyagarajan, Duane D Miller, Dave Bridges, Ramesh Narayanan
Non-alcoholic steatohepatitis (NASH) affects 8-10 million people in the US and up to 75% of obese individuals. Despite this, there are no approved oral therapeutics to treat NASH and therefore the need for novel approaches exists. The estrogen receptor β (ER-β)-selective agonist, β-LGND2, inhibits body weight and white adipose tissue, and increases metabolism, resulting in higher energy expenditure and thermogenesis. Due to favorable effects of β-LGND2 on obesity, we hypothesized that β-LGND2 will prevent NASH directly by reducing lipid accumulation in the liver or indirectly by favorably changing body composition...
January 1, 2017: Experimental Biology and Medicine
https://www.readbyqxmd.com/read/28092171/a-pangenotypic-single-tablet-regimen-of-sofosbuvir-velpatasvir-for-the-treatment-of-chronic-hepatitis-c-infection
#17
Ilan S Weisberg, Ira M Jacobson
Hepatitis C virus (HCV) infects nearly 170 million people worldwide and is a leading cause of progressive liver damage, cirrhosis, and hepatocellular carcinoma. Curative therapies have historically relied on interferon-based treatments and were limited by significant toxicity and poor response rates, particularly among patients with prior treatment failure and advanced hepatic fibrosis. The recent advent of direct acting antiviral (DAA) agents which target key steps in the HCV viral life cycle has transformed the landscape of HCV treatment by offering highly effective and well tolerated interferon-free treatments...
January 16, 2017: Expert Opinion on Pharmacotherapy
https://www.readbyqxmd.com/read/28092102/micrornas-potential-candidates-for-diagnosis-and-treatment-of-colorectal-cancer
#18
REVIEW
Abdullah Moridikia, Hamed Mirzaei, Amirhossein Sahebkar, Jafar Salimian
Colorectal cancer (CRC) is known as the third common cancer worldwide and an important public health problem in different populations. Several genetics and environmental risk factors are involved in the development and progression of CRC including chromosomal abnormalities, epigenetic alterations, and unhealthy lifestyle. Identification of risk factors and biomarkers could lead to a better understanding of molecular pathways involved in CRC pathogenesis. MicroRNAs (miRNAs) are important regulatory molecules which could affect a variety of cellular and molecular targets in CRC...
January 16, 2017: Journal of Cellular Physiology
https://www.readbyqxmd.com/read/28092085/evidence-that-nf-%C3%AE%C2%BAb-and-mapk-signaling-promotes-nlrp-inflammasome-activation-in-neurons-following-ischemic-stroke
#19
David Yang-Wei Fann, Yun-An Lim, Yi-Lin Cheng, Ker-Zhing Lok, Prasad Chunduri, Sang-Ha Baik, Grant R Drummond, S Thameem Dheen, Christopher G Sobey, Dong-Gyu Jo, Christopher Li-Hsian Chen, Thiruma V Arumugam
Multi-protein complexes, termed "inflammasomes," are known to contribute to neuronal cell death and brain injury following ischemic stroke. Ischemic stroke increases the expression and activation of nucleotide-binding oligomerization domain (NOD)-like receptor (NLR) Pyrin domain containing 1 and 3 (NLRP1 and NLRP3) inflammasome proteins and both interleukin (IL)-1β and IL-18 in neurons. In this study, we provide evidence that activation of either the NF-κB and MAPK signaling pathways was partly responsible for inducing the expression and activation of NLRP1 and NLRP3 inflammasome proteins and that these effects can be attenuated using pharmacological inhibitors of these two pathways in neurons and brain tissue under in vitro and in vivo ischemic conditions, respectively...
January 14, 2017: Molecular Neurobiology
https://www.readbyqxmd.com/read/28091624/paracrine-cross-talk-between-skeletal-muscle-and-macrophages-in-exercise-by-pgc-1%C3%AE-controlled-bnp
#20
Regula Furrer, Petra S Eisele, Alexander Schmidt, Markus Beer, Christoph Handschin
Activation of resident and infiltrating immune cells is a central event in training adaptation and other contexts of skeletal muscle repair and regeneration. A precise orchestration of inflammatory events in muscle fibers and immune cells is required after recurrent contraction-relaxation cycles. However, the mechanistic aspects of this important regulation remain largely unknown. We now demonstrate that besides a dominant role in controlling cellular metabolism, the peroxisome proliferator-activated receptor γ co-activator 1α (PGC-1α) also has a profound effect on cytokine expression in muscle tissue...
January 16, 2017: Scientific Reports
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