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https://www.readbyqxmd.com/read/28097887/pseudokinases-update-on-their-functions-and-evaluation-as-new-drug-targets
#1
Dominic P Byrne, Daniel M Foulkes, Patrick A Eyers
The pseudokinase complement of the human kinase superfamily consists of approximately 60 signaling proteins, which lacks one or more of the amino acids typically required to correctly align ATP and metal ions, and phosphorylate protein substrates. Recent studies in the pseudokinase field have begun to expose the biological relevance of pseudokinases, which are now thought to perform a diverse range of physiological roles and are connected to a multitude of human diseases, including cancer. In this review, we discuss how and why members of the 'pseudokinome' represent important new targets for drug discovery, and describe how knowledge of protein structure and function provides informative clues to help guide the rational chemical design or repurposing of inhibitors to target pseudokinases...
January 18, 2017: Future Medicinal Chemistry
https://www.readbyqxmd.com/read/28097641/natural-products-diversity-of-marine-ascidians-tunicates-ascidiacea-and-successful-drugs-in-clinical-development
#2
REVIEW
Satheesh Kumar Palanisamy, N M Rajendran, Angela Marino
This present study reviewed the chemical diversity of marine ascidians and their pharmacological applications, challenges and recent developments in marine drug discovery reported during 1994-2014, highlighting the structural activity of compounds produced by these specimens. Till date only 5% of living ascidian species were studied from <3000 species, this study represented from family didemnidae (32%), polyclinidae (22%), styelidae and polycitoridae (11-12%) exhibiting the highest number of promising MNPs...
January 17, 2017: Natural Products and Bioprospecting
https://www.readbyqxmd.com/read/28096233/role-of-the-constant-region-domain-in-the-structural-diversity-of-human-antibody-light-chains
#3
Emi Hifumi, Hiroaki Taguchi, Ryuichi Kato, Taizo Uda
Issues regarding the structural diversity (heterogeneity) of an antibody molecule have been the subject of discussion along with the development of antibody drugs. Research on heterogeneity has been extensive in recent years, but no clear solution has been reached. Heterogeneity is also observed in catalytic antibody κ light chains (CLs). In this study, we investigated how the constant region domain of CLs concerns structural diversity because it is a simple and good example for elucidating heterogeneity. By means of cation-exchange chromatography, SDS-PAGE, and 2-dimensional electrophoresis for the CL, multimolecular forms consisting of different electrical charges and molecular sizes coexisted in the solution, resulting in the similar heterogeneity of the full length of CLs...
January 17, 2017: FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology
https://www.readbyqxmd.com/read/28095880/high-throughput-expression-of-animal-venom-toxins-in-escherichia-coli-to-generate-a-large-library-of-oxidized-disulphide-reticulated-peptides-for-drug-discovery
#4
Jeremy Turchetto, Ana Filipa Sequeira, Laurie Ramond, Fanny Peysson, Joana L A Brás, Natalie J Saez, Yoan Duhoo, Marilyne Blémont, Catarina I P D Guerreiro, Loic Quinton, Edwin De Pauw, Nicolas Gilles, Hervé Darbon, Carlos M G A Fontes, Renaud Vincentelli
BACKGROUND: Animal venoms are complex molecular cocktails containing a wide range of biologically active disulphide-reticulated peptides that target, with high selectivity and efficacy, a variety of membrane receptors. Disulphide-reticulated peptides have evolved to display improved specificity, low immunogenicity and to show much higher resistance to degradation than linear peptides. These properties make venom peptides attractive candidates for drug development. However, recombinant expression of reticulated peptides containing disulphide bonds is challenging, especially when associated with the production of large libraries of bioactive molecules for drug screening...
January 17, 2017: Microbial Cell Factories
https://www.readbyqxmd.com/read/28095533/neck-contouring-and-treatment-of-submental-adiposity
#5
W Walsh Thomas, Jason D Bloom
There have been many recent and significant innovations to the cosmetic physician's repertoire for addressing excess submental fat and improving patients' neck contour. These new techniques include submental cryolipolysis, injectable chemical lipolysis, percutaneous radiofrequency, laser techniques, and liposuction with or without laser or power assistance. These modalities range from completely non-invasive to surgical procedures. Each technique has its own unique advantages, and limitations and as such, aesthetic practitioners should be familiar with the various indications to use each technique...
January 1, 2017: Journal of Drugs in Dermatology: JDD
https://www.readbyqxmd.com/read/28095528/the-role-of-cutaneous-microbiota-harmony-in-maintaining-a-functional-skin-barrier
#6
Hilary E Baldwin, Neal D Bhatia, Adam Friedman, Richard Martin Eng, Sophie Seite
The skin is constantly exposed to various endogenous and exogenous factors that may impact its barrier function at the physical, mechanical, immunological, and microbial levels. These factors have the potential to initiate or exacerbate a variety of inflammatory skin conditions, especially those associated with barrier dysfunction. The barrier function of the skin depends upon a symbiotic relationship between resident microbial communities and host tissue. This symbiosis results from complex signals involved in both the innate and adaptive immune responses...
January 1, 2017: Journal of Drugs in Dermatology: JDD
https://www.readbyqxmd.com/read/28094846/chronic-drug-induced-effects-on-contractile-motion-properties-and-cardiac-biomarkers-in-human-induced-pluripotent-stem-cell-derived-cardiomyocytes
#7
Ivan Kopljar, An De Bondt, Petra Vinken, Ard Teisman, Bruce Damiano, Nick Goeminne, Ilse Van den Wyngaert, David J Gallacher, Hua Rong Lu
BACKGROUND AND PURPOSE: Risk assessment of chronic cardiac safety liabilities within the pharmaceutical industry is mostly performed during late stages of pre-clinical drug development using in vivo animal models. Here, we explored the potential of human induced pluripotent stem cell-derived cardiomyocytes (hiPS-CMs) to detect chronic cardiac risks such as drug-induced cardiomyocyte toxicity. EXPERIMENTAL APPROACH: Video microscopy-based motion field imaging was applied to evaluate chronic effect (over 72 h) of cardiotoxic drugs on the contractile motion of hiPS-CMs...
January 17, 2017: British Journal of Pharmacology
https://www.readbyqxmd.com/read/28094765/selective-antagonism-of-muscarinic-receptors-is-neuroprotective-in-peripheral-neuropathy
#8
Nigel A Calcutt, Darrell R Smith, Katie Frizzi, Mohammad Golam Sabbir, Subir K Roy Chowdhury, Teresa Mixcoatl-Zecuatl, Ali Saleh, Nabeel Muttalib, Randy Van der Ploeg, Joseline Ochoa, Allison Gopaul, Lori Tessler, Jürgen Wess, Corinne G Jolivalt, Paul Fernyhough
Sensory neurons have the capacity to produce, release, and respond to acetylcholine (ACh), but the functional role of cholinergic systems in adult mammalian peripheral sensory nerves has not been established. Here, we have reported that neurite outgrowth from adult sensory neurons that were maintained under subsaturating neurotrophic factor conditions operates under cholinergic constraint that is mediated by muscarinic receptor-dependent regulation of mitochondrial function via AMPK. Sensory neurons from mice lacking the muscarinic ACh type 1 receptor (M1R) exhibited enhanced neurite outgrowth, confirming the role of M1R in tonic suppression of axonal plasticity...
January 17, 2017: Journal of Clinical Investigation
https://www.readbyqxmd.com/read/28093085/gene-design-fusion-technology-and-tev-cleavage-conditions-influence-the-purification-of-oxidized-disulphide-rich-venom-peptides-in-escherichia-coli
#9
Ana Filipa Sequeira, Jeremy Turchetto, Natalie J Saez, Fanny Peysson, Laurie Ramond, Yoan Duhoo, Marilyne Blémont, Vânia O Fernandes, Luís T Gama, Luís M A Ferreira, Catarina I P I Guerreiro, Nicolas Gilles, Hervé Darbon, Carlos M G A Fontes, Renaud Vincentelli
BACKGROUND: Animal venoms are large, complex libraries of bioactive, disulphide-rich peptides. These peptides, and their novel biological activities, are of increasing pharmacological and therapeutic importance. However, recombinant expression of venom peptides in Escherichia coli remains difficult due to the significant number of cysteine residues requiring effective post-translational processing. There is also an urgent need to develop high-throughput recombinant protocols applicable to the production of reticulated peptides to enable efficient screening of their drug potential...
January 17, 2017: Microbial Cell Factories
https://www.readbyqxmd.com/read/28092681/genomic-analysis-of-globally-diverse-mycobacterium-tuberculosis-strains-provides-insights-into-the-emergence-and-spread-of-multidrug-resistance
#10
Abigail L Manson, Keira A Cohen, Thomas Abeel, Christopher A Desjardins, Derek T Armstrong, Clifton E Barry, Jeannette Brand, Sinéad B Chapman, Sang-Nae Cho, Andrei Gabrielian, James Gomez, Andreea M Jodals, Moses Joloba, Pontus Jureen, Jong Seok Lee, Lesibana Malinga, Mamoudou Maiga, Dale Nordenberg, Ecaterina Noroc, Elena Romancenco, Alex Salazar, Willy Ssengooba, A A Velayati, Kathryn Winglee, Aksana Zalutskaya, Laura E Via, Gail H Cassell, Susan E Dorman, Jerrold Ellner, Parissa Farnia, James E Galagan, Alex Rosenthal, Valeriu Crudu, Daniela Homorodean, Po-Ren Hsueh, Sujatha Narayanan, Alexander S Pym, Alena Skrahina, Soumya Swaminathan, Martie Van der Walt, David Alland, William R Bishai, Ted Cohen, Sven Hoffner, Bruce W Birren, Ashlee M Earl
Multidrug-resistant tuberculosis (MDR-TB), caused by drug-resistant strains of Mycobacterium tuberculosis, is an increasingly serious problem worldwide. Here we examined a data set of whole-genome sequences from 5,310 M. tuberculosis isolates from five continents. Despite the great diversity of these isolates with respect to geographical point of isolation, genetic background and drug resistance, the patterns for the emergence of drug resistance were conserved globally. We have identified harbinger mutations that often precede multidrug resistance...
January 16, 2017: Nature Genetics
https://www.readbyqxmd.com/read/28092266/tgf-%C3%AE-reduces-dna-ds-break-repair-mechanisms-to-heighten-genetic-diversity-and-adaptability-of-cd44-cd24-cancer-cells
#11
Debjani Pal, Anja Pertot, Nitin H Shirole, Zhan Yao, Naishitha Anaparthy, Tyler Garvin, Hilary Cox, Kenneth Chang, Fred Rollins, Jude Kendall, Leyla Edwards, Vijay A Singh, Gary C Stone, Michael C Schatz, James Hicks, Gregory Hannon, Raffaella Sordella
Many lines of evidence have indicated that both genetic and non-genetic determinants can contribute to intra-tumor heterogeneity and influence cancer outcomes. Among the best described sub-population of cancer cells generated by non-genetic mechanisms are cells characterized by a CD44+/CD24- cell surface marker profile. Here, we report that human CD44+/CD24- cancer cells are genetically highly unstable due to intrinsic defects in their DNA repair capabilities. In fact, in CD44+/CD24- cells constitutive activation of the TGF-beta axis was both necessary and sufficient to reduce the expression of genes that are critical in coordinating DNA damage repair mechanisms...
January 16, 2017: ELife
https://www.readbyqxmd.com/read/28092168/associations-between-at-risk-alcohol-use-substance-use-and-smoking-with-lipohypertrophy-and-lipoatrophy-among-patients-living-with-hiv
#12
Marisela Noorhasan, Daniel Drozd, Carl Grunfeld, Joe Merrill, Greer Burkholder, Michael J Mugavero, James H Willig, Amanda Willig, Karen L Cropsey, Kenneth Mayer, Aaron Blashill, Matthew Mimiaga, Mary E McCaul, Heidi Hutton, Geetanjali Chander, William C Matthews, Sonia Napravnik, Joseph J Eron, Katerina Christopoulos, Rob Fredericksen, Robin Nance, Joseph Chris Delaney, Paul Crane, Michael Saag, Mari M Kitahata, Heidi Crane
OBJECTIVE: To examine associations between lipohypertrophy and lipoatrophy and illicit drug use, smoking, and at-risk alcohol use among a large diverse cohort of persons living with HIV (PLWH) in clinical care. METHODS: 7,931 PLWH at 6 sites across the US completed 21,279 clinical assessments including lipohypertrophy and lipoatrophy, drug/alcohol use, physical activity level, and smoking. Lipohypertrophy and lipoatrophy were measured using the FRAM body morphology instrument and associations were assessed with generalized estimating equations...
January 16, 2017: AIDS Research and Human Retroviruses
https://www.readbyqxmd.com/read/28092098/evaluation-the-ethnopharmacological-studies-in-iran-during-2004-2016-a-systematic-review
#13
REVIEW
Zahra Sadeghi, Maryam Akaberi, Seyed Ahmad Emami, Alireza Sobhkhizi, Amirhossein Sahebkar
Although Iran has a deep history in herbal medicine and great heritage of ancient medical scholars, few efforts have been made to evaluate ethnopharmacological aspects of medicinal plants in this country. In the present study, the authors have reviewed all important literature about the ethnopharmacological investigations on medicinal plants used in the last decade in Iran. All provinces of Iran were categorized according to a phytogeographical division. Information was collected through bibliographic investigations from scientific journals and books...
January 16, 2017: Journal of Cellular Physiology
https://www.readbyqxmd.com/read/28091672/a-rapid-way-to-discover-nonstandard-macrocyclic-peptide-modulators-of-drug-targets
#14
Toby Passioura, Hiroaki Suga
Studies of the fundamental nature of RNA catalysis and the potential mechanism of a shift from the "RNA world" to proteinaceous life lead us to identify a set of ribozymes (flexizymes) capable of promiscuous tRNA acylation. Whilst theoretically and mechanistically interesting in their own right, flexizymes have turned out to have immense practical value for the simple synthesis of tRNAs acylated with unusual amino acids, which in turn can be used for the ribosomal synthesis of peptides containing non-canonical residues...
January 16, 2017: Chemical Communications: Chem Comm
https://www.readbyqxmd.com/read/28090719/diversity-oriented-synthesis-of-cyclic-azapeptides-by-a-3-macrocyclization-provides-high-affinity-cd36-modulating-peptidomimetics
#15
Jinqiang Zhang, Mukandila Mulumba, Huy Ong, William D Lubell
Macrocyclization has enabled the use of peptides in drug discovery creating a need for methods to synthesize diverse peptide macrocycles. Azapeptides have advanced to clinically used drugs, however, few cyclic azapeptides have been studied. A multiple component "A(3) -macrocyclization" strategy is described for the preparation of diverse cyclic azapeptides and is demonstrated by the synthesis of 15 growth hormone releasing hormone-6 (GHRP-6) analogs. Certain cyclic aza-GHRP-6 analogs exhibited unprecedented affinity for the CD36 receptor, and capacity to modulate Toll-like receptor agonist-induced overproduction of nitric oxide, and reduce pro-inflammatory cytokine and chemokine production in macrophages...
January 16, 2017: Angewandte Chemie
https://www.readbyqxmd.com/read/28090649/-the-pharmacogenomics-research-network-translational-pharmacogenetics-program-outcomes-and-metrics-of-pharmacogenetic-implementations-across-diverse-healthcare-systems
#16
Jasmine A Luzum, Ruth E Pakyz, Amanda R Elsey, Cyrine E Haidar, Josh F Peterson, Michelle Whirl-Carrillo, Samuel K Handelman, Kathleen Palmer, Jill M Pulley, Marc Beller, Jonathan S Schildcrout, Julie R Field, Kristin W Weitzel, Rhonda M Cooper-DeHoff, Larisa H Cavallari, Peter H O'Donnell, Russ B Altman, Naveen Pereira, Mark J Ratain, Dan M Roden, Peter J Embi, Wolfgang Sadee, Teri E Klein, Julie A Johnson, Mary V Relling, Liewei Wang, Richard M Weinshilboum, Alan R Shuldiner, Robert R Freimuth
Numerous pharmacogenetic clinical guidelines and recommendations have been published, but barriers have hindered the clinical implementation of pharmacogenetics. The Translational Pharmacogenetics Program (TPP) of the NIH Pharmacogenomics Research Network was established in 2011 to catalog and contribute to the development of pharmacogenetic implementations at eight US healthcare systems, with the goal to disseminate real-world solutions for the barriers to clinical pharmacogenetic implementation. The TPP collected and normalized pharmacogenetic implementation metrics through June 2015, including gene-drug pairs implemented, interpretations of alleles and diplotypes, numbers of tests performed and actionable results, and workflow diagrams...
January 16, 2017: Clinical Pharmacology and Therapeutics
https://www.readbyqxmd.com/read/28090599/mas-related-g-protein-coupled-receptor-x2-a-potential-new-target-for-modulating-mast-cell-mediated-allergic-and-inflammatory-diseases
#17
Hydar Ali
Mast cells (MCs) are tissue resident immune cells that are best known for their roles in allergic and inflammatory diseases. In addition to the high affinity IgE receptor (FcεRI), MCs express numerous G protein coupled receptors (GPCRs), which are the most common targets of drug therapy. Neurokinin 1 receptor (NK-1R) is expressed on MCs and contributes to IgE and non-IgE-mediated responses in mice. Although NK-1R antagonists are highly effective in modulating experimental allergic and inflammatory responses in mice they lack efficacy in humans...
December 2016: Journal of Immunobiology
https://www.readbyqxmd.com/read/28088782/pde5-inhibitors-enhance-the-lethality-of-pemetrexed-sorafenib
#18
Laurence Booth, Jane L Roberts, Andrew Poklepovic, Paul Dent
The combination of pemetrexed and sorafenib has significant clinical activity against a wide variety of tumor types in patients and the present studies were performed to determine whether sildenafil enhances the killing potential of [pemetrexed + sorafenib]. In multiple genetically diverse lung cancer cell lines, sildenafil enhanced the lethality of [pemetrexed + sorafenib]. The three-drug combination reduced the activities of AKT, mTOR and STAT transcription factors; increased the activities of eIF2α and ULK-1; lowered the expression of MCL-1, BCL-XL, thioredoxin and SOD2; and increased the expression of Beclin1...
January 9, 2017: Oncotarget
https://www.readbyqxmd.com/read/28088739/the-effects-of-rurality-on-substance-use-disorder-diagnosis-a-multiple-groups-latent-class-analysis
#19
Billy Brooks, Matthew McBee, Robert Pack, Arsham Alamian
BACKGROUND: Rates of accidental overdose mortality from substance use disorder (SUD) have risen dramatically in the United States since 1990. Between 1999 and 2004 alone rates increased 62% nationwide, with rural overdose mortality increasing at a rate 3 times that seen in urban populations. Cultural differences between rural and urban populations (e.g., educational attainment, unemployment rates, social characteristics, etc.) affect the nature of SUD, leading to disparate risk of overdose across these communities...
January 6, 2017: Addictive Behaviors
https://www.readbyqxmd.com/read/28088197/production-of-human-pro-relaxin-h2-in-the-yeast-pichia-pastoris
#20
D Cimini, K Della Corte, R Finamore, L Andreozzi, A Stellavato, A V A Pirozzi, F Ferrara, R Formisano, M De Rosa, M Chino, L Lista, A Lombardi, V Pavone, C Schiraldi
BACKGROUND: Initially known as the reproductive hormone, relaxin was shown to possess other therapeutically useful properties that include extracellular matrix remodeling, anti-inflammatory, anti-ischemic and angiogenic effects. All these findings make relaxin a potential drug for diverse medical applications. Its precursor, pro-relaxin, is an 18 kDa protein, that shows activity in in vitro assays. Since extraction of relaxin from animal tissues raises several issues, prokaryotes and eukaryotes were both used as expression systems for recombinant relaxin production...
January 14, 2017: BMC Biotechnology
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