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https://www.readbyqxmd.com/read/29452240/the-effect-of-non-anti-tnf-targeting-biologics-and-small-molecules-on-insulin-resistance-in-inflammatory-arthritis
#1
REVIEW
Francesco Ursini, Emilio Russo, Piero Ruscitti, Roberto Giacomelli, Giovambattista De Sarro
Inflammatory arthritides are chronic diseases characterised by an increase in cardiovascular risk, largely attributable to the synergy between high-grade systemic inflammation and an elevated prevalence of traditional cardiovascular risk factors. Amongst the latter, insulin resistance and type 2 diabetes (T2D) play a key position. Previous studies demonstrated a potential insulin-sensiting effect of anti-TNF biologic medications. For converse, less is known about the role of newer biologics or small molecules...
February 13, 2018: Autoimmunity Reviews
https://www.readbyqxmd.com/read/29452121/an-open-label-pilot-study-to-evaluate-the-efficacy-of-tofacitinib-in-moderate-to-severe-patch-type-alopecia-areata-totalis-and-universalis
#2
A Jabbari, F Sansaricq, J Cerise, J C Chen, A Bitterman, G Ulerio, J Borbon, R Clynes, A M Christiano, J Mackay-Wiggan
Alopecia areata (AA) is a common autoimmune disease, with a lifetime risk of ∼2%. In AA, the immune systems targets the hair follicle, resulting in clinical hair loss. AA prognosis is unpredictable, and currently there is no definitive treatment. Our previous whole genome expression studies identified active immune circuits in AA lesions, including common γ-chain cytokine and IFN pathways. Since these pathways are mediated through JAK kinases, we prioritized clinical exploration of small molecule JAK inhibitors...
February 13, 2018: Journal of Investigative Dermatology
https://www.readbyqxmd.com/read/29451852/delta-opioids-neuroprotective-roles-in-preclinical-studies
#3
Shahid Husain
Since ancient times, opioids have been used clinically and abused recreationally. In the early stages (about 1,000 AD) of opium history, an Arab physician, Avicenna, administered opioids to control diarrhea and eye diseases. 1 Opioids have very strong pain relieving properties and they also regulate numerous cellular responses. Opioid receptors are expressed throughout the body, including the nervous system, heart, lungs, liver, gastrointestinal tract, and retina. 2-6 Delta opioid receptors (DORs) are a very attractive target from the perspective of both receptor function and their therapeutic potential...
January 2018: Journal of Ocular Pharmacology and Therapeutics
https://www.readbyqxmd.com/read/29451780/using-i-in-vitro-i-evolution-and-whole-genome-analysis-iviewga-to-discover-next-generation-targets-for-antimalarial-drug-discovery
#4
Madeline R Luth, Purva Gupta, Sabine Ottilie, Elizabeth A Winzeler
Although many new anti-infectives have been discovered and developed solely using phenotypic cellular screening and assay optimization, most researchers recognize that structure-guided drug design is more practical and less costly. In addition, a greater chemical space can be interrogated with structure-guided drug design. The practicality of structure-guided drug design has launched a search for the targets of compounds discovered in phenotypic screens. One method that has been used extensively in malaria parasites for target discovery and chemical validation is in vitro evolution and whole genome analysis (IVIEWGA)...
February 16, 2018: ACS Infectious Diseases
https://www.readbyqxmd.com/read/29450992/assessment-of-fragmentation-strategies-for-large-proteins-using-the-multilayer-molecules-in-molecules-approach
#5
Bishnu Thapa, Daniel Beckett, K V Jovan Jose, Krishnan Raghavachari
We present a rigorous evaluation of the potential for the multilayer Molecules-in-Molecules (MIM) fragmentation method to be applied to large biomolecules. Density functional total energies of a test set of 8 peptides, sizes ranging from 107 to 721 atoms, were evaluated with MIM and compared to unfragmented energies to help develop a protocol for the treatment of large proteins. Fragmentation schemes involving subsystems of 4 to 5 covalently bonded fragments (tetramer or pentamer schemes) were tested with a single level of theory (MIM1) and produced errors on the order of 100 kcal/mol due to the relatively small size of the subsystems and the neglect of nonbonded interactions...
February 16, 2018: Journal of Chemical Theory and Computation
https://www.readbyqxmd.com/read/29450657/in-silico-identification-of-small-molecules-as-novel-lxr-agonists-for-the-treatment-of-cardiovascular-disease-and-cancer
#6
Xin Wang, Kaimin Lu, Hao Luo, Danfeng Liang, Xin Long, Yuan Yuan, Chuanfang Wu, Jinku Bao
Liver X receptor (LXR), a member of the nuclear receptor superfamily, mainly serves as a reverse cholesterol transporter in lipid metabolism. It has been demonstrated that LXR is a promising target for the treatment of cardiovascular diseases. LXR is also involved in cancer metabolism, glucose homeostasis, immunity, and various physiological processes. The antitumor function of LXR has become of great interest to researchers in recent years. However, while it is believed that activating LXR with small molecules could be a promising approach to cancer treatment, effective drugs that target LXR are yet to be reported...
February 15, 2018: Journal of Molecular Modeling
https://www.readbyqxmd.com/read/29448954/new-therapeutic-strategies-to-treat-human-cancers-expressing-mutant-p53-proteins
#7
REVIEW
Giovanni Blandino, Silvia Di Agostino
The tumor suppressor p53 plays a critical role to preserve DNA fidelity from diverse insults through the regulation of cell-cycle checkpoints, DNA repair, senescence and apoptosis. The TP53 is the most frequently inactivated gene in human cancers. This leads to the production of mutant p53 proteins that loose wild-type p53 tumor suppression functions and concomitantly acquire new oncogenic properties among which deregulated cell proliferation, increased chemoresistance, disruption of tissue architecture, promotion of migration, invasion and metastasis and several other pro-oncogenic activities...
February 15, 2018: Journal of Experimental & Clinical Cancer Research: CR
https://www.readbyqxmd.com/read/29448911/investigation-of-the-selectivity-of-one-type-of-small-molecule-inhibitor-for-three-na-v-channel-isoforms-based-on-the-method-of-computer-simulation
#8
Fan Zhao, Wei Jin, Lin Ma, Jian-Ye Zhang, Jin-Long Wang, Jing-Hai Zhang, Yong-Bo Song
Voltage-gated sodium (Na v ) channels play a pivotal role for the changes in membrane potential and belong to large membrane proteins that compose four voltage sensor domains (VSD1-4). In this study we describe the binding mode and selectivity of one of the aryl sulfonamide sodium channel inhibitors, PF-04856264, for the VSD4s in Na v 1.4, Na v 1.5 and Na v 1.7, respectively, through molecular dynamics simulation and enhanced post-dynamics analyses. Our results show that there are three binding site regions (BSR1-3) in the combination of the ligand and receptors, of which BSR1 and BSR3 contribute to the selectivity and affinity of the ligand to the receptor...
February 15, 2018: Journal of Biomolecular Structure & Dynamics
https://www.readbyqxmd.com/read/29448849/development-of-small-molecule-immune-checkpoint-inhibitors-of-pd-1-pd-l1-as-a-new-therapeutic-strategy-for-tumour-immunotherapy
#9
Kui Li, Tian Hongqi
Cancer immunotherapy has been increasingly utilized to treat advanced malignancies. The signalling network of immune checkpoints has attracted considerable attention. Immune checkpoint inhibitors are revolutionizing the treatment options and expectations for patients with cancer. The reported clinical success of targeting the T-cell immune checkpoint receptors PD-1/PD-L1 has demonstrated the importance of immune modulation. Indeed, antibodies binding to PD-1 or PD-L1 have shown remarkable efficacy. However, antibody drugs have many disadvantages, such as their production cost, stability, and immunogenicity, and therefore, small-molecule inhibitors of PD-1 and its ligand PD-L1 are being introduced...
February 16, 2018: Journal of Drug Targeting
https://www.readbyqxmd.com/read/29448130/optimized-slice-selective-1-h-nmr-experiments-combined-with-highly-accurate-quantitative-13-c-nmr-using-an-internal-reference-method
#10
Tangi Jézéquel, Virginie Silvestre, Katy Dinis, Patrick Giraudeau, Serge Akoka
Isotope ratio monitoring by 13 C NMR spectrometry (irm- 13 C NMR) provides the complete 13 C intramolecular position-specific composition at natural abundance. It represents a powerful tool to track the (bio)chemical pathway which has led to the synthesis of targeted molecules, since it allows Position-specific Isotope Analysis (PSIA). Due to the very small composition range (which represents the range of variation of the isotopic composition of a given nuclei) of 13 C natural abundance values (50‰), irm- 13 C NMR requires a 1‰ accuracy and thus highly quantitative analysis by 13 C NMR...
February 6, 2018: Journal of Magnetic Resonance
https://www.readbyqxmd.com/read/29447131/dna-repair-deficiency-sensitizes-lung-cancer-cells-to-nad-biosynthesis-blockade
#11
Mehdi Touat, Tony Sourisseau, Nicolas Dorvault, Roman M Chabanon, Marlène Garrido, Daphné Morel, Dragomir B Krastev, Ludovic Bigot, Julien Adam, Jessica Frankum, Sylvère Durand, Clement Pontoizeau, Sylvie Souquère, Mei-Shiue Kuo, Sylvie Sauvaigo, Faraz Mardakheh, Alain Sarasin, Ken A Olaussen, Luc Friboulet, Frédéric Bouillaud, Gérard Pierron, Alan Ashworth, Anne Lombès, Christopher J Lord, Jean-Charles Soria, Sophie Postel-Vinay
Synthetic lethality is an efficient mechanism-based approach to selectively target DNA repair defects. ERCC1 deficiency is frequently found in non-small cell lung cancers, making this DNA repair protein an attractive target for exploiting synthetic lethal approaches in this disease. Using unbiased proteomic and metabolic high-throughput profiling on a unique in-house generated isogenic model of ERCC1 deficiency, we found marked metabolic rewiring of ERCC1-deficient populations, including decreased levels of the metabolite NAD+ and reduced expression of the rate-limiting NAD+ biosynthetic enzyme nicotinamide phosphoribosyltransferase (NAMPT)...
February 15, 2018: Journal of Clinical Investigation
https://www.readbyqxmd.com/read/29446853/preclinical-characterization-of-anlotinib-a-highly-potent-and-selective-vascular-endothelial-growth-factor-receptor-2-inhibitor
#12
Chengying Xie, Xiaozhe Wan, Haitian Quan, Mingyue Zheng, Li Fu, Yun Li, Liguang Lou
Abrogating tumor angiogenesis by inhibiting vascular endothelial growth factor receptor-2 (VEGFR2) has been established as a therapeutic strategy for treating cancer. However, because of their low selectivity, most small molecule inhibitors of VEGFR2 tyrosine kinase exhibit unexpected adverse effects and limited anti-cancer efficacy. In this study, we detailed the pharmacologic properties of anlotinib, a highly potent and selective VEGFR2 inhibitor, in preclinical models. Anlotinib occupied the ATP-binding pocket of the VEGFR2 tyrosine kinase and showed high selectivity and inhibitory potency (IC 50 < 1 nM) for VEGFR2 relative to other tyrosine kinases...
February 15, 2018: Cancer Science
https://www.readbyqxmd.com/read/29446717/activators-of-sirtuin-1-and-their-involvement-in-cardioprotection
#13
Carlotta Granchi, Filippo Minutolo
SIRT1 is a nicotinamide adenosine dinucleotide (NAD+)-dependent deacetylase, which removes acetyl groups from many target proteins, such as histone proteins, transcription factors and cofactors. SIRT1-catalyzed deacetylation of these factors modulates the activity of downstream proteins, thus influencing many biological processes. SIRT1 is involved in the regulation of metabolism, inflammation, and tumor growth. The activity of this enzyme is related to the beneficial health effects of calorie restriction, such as lifespan extension and, in particular, the activation of SIRT1 has a positive impact on the cardiovascular system...
February 13, 2018: Current Medicinal Chemistry
https://www.readbyqxmd.com/read/29446631/mechanistic-investigation-and-multiplexing-of-liposome-assisted-metabolic-glycan-labeling
#14
Yuting Sun, Senlian Hong, Ran Xie, Rongbing Huang, Ruoxing Lei, Bo Cheng, Deen Sun, Yifei Du, Corwin M Nycholat, James C Paulson, Xing Chen
Metabolic labeling of glycans with bioorthogonal reporters has been widely used for glycan imaging and glycoproteomic profiling. One of the intrinsic limitations of metabolic glycan labeling is the lack of cell-type selectivity. The recently developed liposome-assisted bioorthogonal reporter (LABOR) strategy provides a promising means to overcome this limitation, but the mechanism of LABOR has not been investigated in detail. In this work, we performed a mechanistic study on LABOR and explored its multiplexing capability...
February 15, 2018: Journal of the American Chemical Society
https://www.readbyqxmd.com/read/29446053/systems-pharmacological-analysis-of-mitochondrial-cardiotoxicity-induced-by-selected-tyrosine-kinase-inhibitors
#15
Tanaya Vaidya, Jeff Kamta, Maher Chaar, Anusha Ande, Sihem Ait-Oudhia
Tyrosine kinase inhibitors (TKIs) are targeted therapies rapidly becoming favored over conventional cytotoxic chemotherapeutics. Our study investigates two FDA approved TKIs, DASATINIB; indicated for IMATINIB-refractory chronic myeloid leukemia, and SORAFENIB; indicated for hepatocellular carcinoma and advanced renal cell carcinoma. Limited but crucial evidence suggests that these agents can have cardiotoxic side effects ranging from hypertension to heart failure. A greater understanding of the underlying mechanisms of this cardiotoxicity are needed as concerns grow and the capacity to anticipate them is lacking...
February 14, 2018: Journal of Pharmacokinetics and Pharmacodynamics
https://www.readbyqxmd.com/read/29444985/molecular-pharmacodynamics-guided-scheduling-of-biologically-effective-doses-a-drug-development-paradigm-applied-to-met-tyrosine-kinase-inhibitors
#16
Apurva K Srivastava, Melinda G Hollingshead, Jeevan P Govindharajulu, Joseph M Covey, Dane Liston, Melanie A Simpson, James O Peggins, Donald P Bottaro, John J Wright, Robert J Kinders, James H Doroshow, Ralph E Parchment
The development of molecularly targeted agents has benefited from use of pharmacodynamic (PD) markers to identify "biologically effective doses" (BEDs) below maximum tolerable doses, yet this knowledge remains underutilized in selecting dosage regimens and in comparing the effectiveness of targeted agents within a class. We sought to establish preclinical proof-of-concept for such PD-based BED regimens and effectiveness comparisons using MET kinase small molecule inhibitors. Utilizing PD biomarker measurements of MET signaling (tumor pY 1234/1235 MET/total MET ratio) in a Phase 0-like preclinical setting, we developed optimal dosage regimens for several MET kinase inhibitors and compared their antitumor efficacy in a MET-amplified gastric cancer xenograft model (SNU-5)...
February 14, 2018: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/29444979/irreversible-inhibition-of-cytosolic-thioredoxin-reductase-1-as-a-mechanistic-basis-for-anticancer-therapy
#17
William C Stafford, Xiaoxiao Peng, Maria Hägg Olofsson, Xiaonan Zhang, Diane K Luci, Li Lu, Qing Cheng, Lionel Trésaugues, Thomas S Dexheimer, Nathan P Coussens, Martin Augsten, Hanna-Stina Martinsson Ahlzén, Owe Orwar, Arne Östman, Sharon Stone-Elander, David J Maloney, Ajit Jadhav, Anton Simeonov, Stig Linder, Elias S J Arnér
Cancer cells adapt to their inherently increased oxidative stress through activation of the glutathione (GSH) and thioredoxin (TXN) systems. Inhibition of both of these systems effectively kills cancer cells, but such broad inhibition of antioxidant activity also kills normal cells, which is highly unwanted in a clinical setting. We therefore evaluated targeting of the TXN pathway alone and, more specifically, selective inhibition of the cytosolic selenocysteine-containing enzyme TXN reductase 1 (TXNRD1). TXNRD1 inhibitors were discovered in a large screening effort and displayed increased specificity compared to pan-TXNRD inhibitors, such as auranofin, that also inhibit the mitochondrial enzyme TXNRD2 and additional targets...
February 14, 2018: Science Translational Medicine
https://www.readbyqxmd.com/read/29444978/an-off-target-effect-of-bx795-blocks-herpes-simplex-virus-type-1-infection-of-the-eye
#18
Dinesh Jaishankar, Abraam M Yakoub, Tejabhiram Yadavalli, Alex Agelidis, Neel Thakkar, Satvik Hadigal, Joshua Ames, Deepak Shukla
Herpes simplex virus type 1 (HSV-1) causes recurrent mucocutaneous lesions in the eye that may advance to corneal blindness. Nucleoside analogs exemplified by acyclovir (ACV) form the primary class of antiherpetic drugs, but this class suffers limitations due to the emergence of viral resistance and other side effects. While studying the molecular basis of ocular HSV-1 infection, we observed that BX795, a commonly used inhibitor of TANK-binding kinase 1 (TBK1), strongly suppressed infection by multiple strains of HSV-1 in transformed and primary human cells, cultured human and animal corneas, and a murine model of ocular infection...
February 14, 2018: Science Translational Medicine
https://www.readbyqxmd.com/read/29444641/oasis-2-improved-online-analysis-of-small-rna-seq-data
#19
Raza-Ur Rahman, Abhivyakti Gautam, Jörn Bethune, Abdul Sattar, Maksims Fiosins, Daniel Sumner Magruder, Vincenzo Capece, Orr Shomroni, Stefan Bonn
BACKGROUND: Small RNA molecules play important roles in many biological processes and their dysregulation or dysfunction can cause disease. The current method of choice for genome-wide sRNA expression profiling is deep sequencing. RESULTS: Here we present Oasis 2, which is a new main release of the Oasis web application for the detection, differential expression, and classification of small RNAs in deep sequencing data. Compared to its predecessor Oasis, Oasis 2 features a novel and speed-optimized sRNA detection module that supports the identification of small RNAs in any organism with higher accuracy...
February 14, 2018: BMC Bioinformatics
https://www.readbyqxmd.com/read/29444450/high-throughput-screening-identifies-small-molecules-that-bind-to-the-ras-sos-ras-complex-and-perturb-ras-signaling
#20
Michael C Burns, Jennifer E Howes, Qi Sun, Andrew J Little, DeMarco V Camper, Jason R Abbott, Jason Phan, Taekyu Lee, Alex G Waterson, Olivia W Rossanese, Stephen W Fesik
K-RAS is mutated in approximately 30% of human cancers, resulting in increased RAS signaling and tumor growth. Thus, RAS is a highly validated therapeutic target, especially in tumors of the pancreas, lung and colon. Although directly targeting RAS has proven to be challenging, it may be possible to target other proteins involved in RAS signaling, such as the guanine nucleotide exchange factor Son of Sevenless (SOS). We have previously reported on the discovery of small molecules that bind to SOS1, activate SOS-mediated nucleotide exchange on RAS, and paradoxically inhibit ERK phosphorylation (Burns et al...
February 11, 2018: Analytical Biochemistry
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