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https://www.readbyqxmd.com/read/28432282/loss-of-function-myostatin-mutation-increases-insulin-sensitivity-and-browning-of-white-fat-in-meishan-pigs
#1
Chunbo Cai, Lili Qian, Shengwang Jiang, Youde Sun, Qingqing Wang, Dezun Ma, Gaojun Xiao, Biao Li, Shanshan Xie, Ting Gao, Yaoxing Chen, Jie Liu, Xiaorong An, Wentao Cui, Kui Li
Myostatin-deficient mice showed a remarkable hypertrophy of skeletal muscle, with a decreased fat mass and enhanced insulin sensitivity. Currently, it is unclear if the inhibition of myostatin could be used as an approach to treat human obesity and insulin resistance. In this study, we investigated if the inhibition of porcine myostatin has any effect on fat deposition and insulin sensitivity using genetically engineered Meishan pigs containing a myostatin loss-of-function mutation (Mstn -/- ). Our results indicated that, when compared with wild-type pigs, the amount of subcutaneous fat and leaf fat of Mstn -/- pigs were significantly decreased mainly due to the browning of subcutaneous adipose tissue...
April 4, 2017: Oncotarget
https://www.readbyqxmd.com/read/28430399/targeting-conformational-activation-of-cdk2-kinase
#2
Morgan Pellerano, Sergey Tcherniuk, Corine Perals, Thi Nhu Ngoc Van, Elsa Garcin, Florence Mahuteau-Betzer, Marie-Paule Teulade-Fichou, May C Morris
Cyclin-dependent kinases constitute attractive pharmacological targets for cancer therapeutics, yet inhibitors in clinical trials target the ATP-binding pocket of the CDK and therefore suffer from limited selectivity and emergence of resistance. The more recent development of allosteric inhibitors targeting conformational plasticity of protein kinases offers promising perspectives for therapeutics. In particular tampering with T-loop dynamics of CDK2 kinase would provide a selective means of inhibiting this kinase, by preventing its conformational activation...
April 21, 2017: Biotechnology Journal
https://www.readbyqxmd.com/read/28429928/a-dual-enzyme-hydrogen-peroxide-generation-machinery-in-hydrogels-supports-antimicrobial-wound-treatment
#3
Daniela Huber, Gregor Tegl, Anna Mensah, Bianca Beer, Martina Baumann, Nicole Borth, Christoph Sygmund, Roland Ludwig, Georg M Guebitz
The aging population and accompanying diseases like diabetes resulted in an increased occurrence of chronic wounds. Topical wound treatment with antimicrobial agents to inhibit bacterial invasion and promote wound healing is often associated with difficulties. Here, we investigated the potential of succinyl chitosan (SC) - carboxymethyl cellulose (CMC) hydrogels which constantly release clinically relevant levels of hydrogen peroxide (H2O2). CMC hydrogel matrix was in-situ converted by limited hydrolysis by a cellulase into substrates accepted by cellobiose dehydrogenase (CDH) for continuous production of H2O2 (30 µM over 24 h)...
April 21, 2017: ACS Applied Materials & Interfaces
https://www.readbyqxmd.com/read/28429838/pyrophosphate-as-substrate-for-alkaline-phosphatase-activity-a-convenient-flow-injection-chemiluminescence-assay
#4
Qingfeng Zhang, Cuiyun Zhang, Meiding Yang, Donghong Yu, Cong Yu
A sensitive and convenient flow-injection chemiluminescence (FI-CL) turn-on assay for alkaline phosphatase (ALP) activity without any label and synthesis is developed. Cu(2+) can catalyze the luminol-H2 O2 CL reaction. Pyrophosphate (PPi) can chelate Cu(2+) and therefore the Cu(2+) -mediated luminol-H2 O2 CL reaction is inhibited. The addition of ALP can catalyze the hydrolysis of PPi into phosphate ions, Cu(2+) is released and the chemiluminescence recovers. A detection limit of 1 mU/mL ALP is obtained.
April 21, 2017: Luminescence: the Journal of Biological and Chemical Luminescence
https://www.readbyqxmd.com/read/28429609/chemical-evaluation-of-the-rhynchophorus-ferrugineus-larvae-fed-on-different-substrates-as-human-food-source
#5
Annarita Cito, Santi Longo, Giuseppe Mazza, Elena Dreassi, Valeria Francardi
We investigated the chemical composition of the weevil Rhynchophorus ferrugineus larvae, traditionally used as human food in Asia and known worldwide as one of the most significant pest for palm trees. Total fat content and fatty acid composition were analyzed using standard methodologies in (1) weevil larvae reared on apple fruit slices and wild specimens collected from attacked (2) Phoenix canariensis and (3) Syagrus romanzoffiana palm trees. Total fat content was extremely high in all the specimens (ranged between 57...
January 1, 2017: Food Science and Technology International, Ciencia y Tecnología de Los Alimentos Internacional
https://www.readbyqxmd.com/read/28429285/the-organogermanium-compound-ge-132-interacts-with-nucleic-acid-components-and-inhibits-the-catalysis-of-adenosine-substrate-by-adenosine-deaminase
#6
Yasuhiro Shimada, Katsuyuki Sato, Tomoya Takeda, Yoshihiko Tokuji
Poly-trans-[(2-carboxyethyl)germasesquioxane] (Ge-132) is a water-soluble organogermanium compound that exerts various physiological effects, including anti-inflammatory activity and pain relief. In water, Ge-132 is hydrolyzed to 3-(trihydroxygermyl)propanoic acid (THGP), which in turn is capable of interacting with cis-diol compounds through its trihydroxy group, indicating that this compound could also interact with diol-containing nucleic acid constituents. In this study, we evaluated the ability of THGP to interact with nucleosides or nucleotides via nuclear magnetic resonance (NMR) analysis...
April 20, 2017: Biological Trace Element Research
https://www.readbyqxmd.com/read/28429187/curcumin-reverses-the-depressive-like-behavior-and-insulin-resistance-induced-by-chronic-mild-stress
#7
Ji-Duo Shen, Yu Wei, Yu-Jie Li, Jing-Yi Qiao, Yu-Cheng Li
Increasing evidence has demonstrated that patients with depression have a higher risk of developing type 2 diabetes. Insulin resistance has been identified as the key mechanism linking depression and diabetes. The present study established a rat model of depression complicated by insulin resistance using a 12-week exposure to chronic mild stress (CMS) and investigated the therapeutic effects of curcumin. Sucrose intake tests were used to evaluate depressive-like behaviors, and oral glucose tolerance tests (OGTT) and intraperitoneal insulin tolerance tests (IPITT) were performed to evaluate insulin sensitivity...
April 21, 2017: Metabolic Brain Disease
https://www.readbyqxmd.com/read/28428365/interaction-and-transport-of-methamphetamine-and-its-primary-metabolites-by-organic-cation-and-multidrug-and-toxin-extrusion-transporters
#8
David J Wagner, Jennifer E Sager, Haichuan Duan, Nina Isoherranen, Joanne Wang
Methamphetamine is one of the most abused illicit drugs with roughly 1.2 million users in the United States alone. A large portion of methamphetamine and its metabolites is eliminated by the kidney with renal clearance larger than glomerular filtration clearance. Yet the mechanism of active renal secretion is poorly understood. The goals of this study were to characterize the interaction of methamphetamine and its major metabolites with organic cation transporters (OCT) and multidrug and toxin extrusion (MATE) transporters and to identify the major transporters involved in the disposition of methamphetamine and its major metabolites, amphetamine and p-hydroxymethamphetamine (p-OHMA)...
April 20, 2017: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/28428248/new-insights-into-the-tetraspanin-tspan5-using-novel-monoclonal-antibodies
#9
Julien Saint-Pol, Martine Billard, Emmanuel Dornier, Etienne Eschenbrenner, Lydia Danglot, Claude Boucheix, Stéphanie Charrin, Eric Rubinstein
Tspan5 is a member of a subgroup of tetraspanins referred to as TspanC8. These tetraspanins directly interact with the metalloprotease ADAM10, regulate its exit from the endoplasmic reticulum and subsequent trafficking, and differentially regulate its ability to cleave various substrates and activate Notch signaling. The study of Tspan5 has been limited by the lack of good antibodies. This study provides new insights into Tspan5 using new monoclonal antibodies (mAbs), including two mAbs recognizing both Tspan5 and the highly similar tetraspanin Tspan17...
April 20, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28427993/washout-and-non-washout-solutions-of-a-system-describing-microbial-fermentation-process-under-the-influence-of-growth-inhibitions-and-maximal-concentration-of-yeast-cells
#10
Kasbawati, A Y Gunawan, K A Sidarto
An unstructured model for the growth of yeast cell on glucose due to growth inhibitions by substrate, products, and cell density is discussed. The proposed model describes the dynamical behavior of fermentation system that shows multiple steady states for a certain regime of operating parameters such as inlet glucose and dilution rate. Two types of steady state solutions are found, namely washout and non-washout solutions. Furthermore, different numerical impositions to the two parameters put in evidence three results regarding non-washout solution: a unique locally stable non-washout solution, a unique locally stable non-washout solution towards which other nearby solutions exhibit damped oscillations, and multiple non-washout solutions where one is locally stable while the other is unstable...
April 18, 2017: Mathematical Biosciences
https://www.readbyqxmd.com/read/28427921/enhancement-of-ethyl-s-4-chloro-3-hydroxybutanoate-production-at-high-substrate-concentration-by-in-situ-resin-adsorption
#11
Li-Feng Chen, Hai-Yang Fan, Yi-Ping Zhang, Wei Wei, Jin-Ping Lin, Dong-Zhi Wei, Hua-Lei Wang
Asymmetric reduction of ethyl 4-chloro-3-oxobutyrate (COBE) by carbonyl reductases presents an efficient way to produce Ethyl (S)-4-chloro-3-hydroxybutanoate ((S)-CHBE), an important chiral intermediate for the synthesis of hydroxymethylglutaryl-CoA reductase inhibitors such as Lipitor(®). In this study, an NADPH-dependent carbonyl reductase (SrCR) from Synechocystis sp. was characterized to demonstrate a broad substrate spectrum, and the highest activity (53.1U/mg protein) with COBE. To regenerate the cofactor NADPH, Bacillus subtilis glucose dehydrogenase was successfully coexpressed with SrCR...
April 17, 2017: Journal of Biotechnology
https://www.readbyqxmd.com/read/28427004/enzymatic-activity-of-the-cam-pde1-system-upon-addition-of-actinyl-ions
#12
Florian Brulfert, Samir Safi, Aurélie Jeanson, Harald Foerstendorf, Stephan Weiss, Catherine Berthomieu, Sandrine Sauge-Merle, Éric Simoni
The threat of a dirty bomb which could cause internal contamination has been of major concern for the past decades. Because of their high chemical toxicity and their presence in the nuclear fuel cycle, uranium and neptunium are two actinides of high interest. Calmodulin (CaM) which is a ubiquitous protein present in all eukaryotic cells and is involved in calcium-dependent signaling pathways has a known affinity for uranyl and neptunyl ions. The impact of the complexation of these actinides on the physiological response of the protein remains, however, largely unknown...
April 8, 2017: Journal of Inorganic Biochemistry
https://www.readbyqxmd.com/read/28426233/investigation-of-classical-organic-and-ionic-liquid-cosolvents-for-early-stage-screening-in-fragment-based-inhibitor-design-with-unrelated-bacterial-and-human-dihydrofolate-reductases
#13
Jacynthe L Toulouse, Sarah M J Abraham, Natalia Kadnikova, Dominic Bastien, Vincent Gauchot, Andreea R Schmitzer, Joelle N Pelletier
Drug design by methods such as fragment screening requires effective solubilization of millimolar concentrations of small organic compounds while maintaining the properties of the biological target. We investigate four organic solvents and three 1-butyl-3-methylimidazolium (BMIm)-based ionic liquids (ILs) as cosolvents to establish conditions for screening two structurally unrelated dihydrofolate reductases (DHFRs) that are prime drug targets. Moderate concentrations (10%-15%) of cosolvents had little effect on inhibition of the microbial type II R67 DHFR and of human DHFR (hDHFR), while higher concentrations of organic cosolvents generally decreased activity of both DHFRs...
April 20, 2017: Assay and Drug Development Technologies
https://www.readbyqxmd.com/read/28426203/tyrosine-kinase-activation-and-conformational-flexibility-lessons-from-src-family-tyrosine-kinases
#14
Yilin Meng, Matthew P Pond, Benoît Roux
Protein kinases are enzymes that catalyze the covalent transfer of the γ-phosphate of an adenosine triphosphate (ATP) molecule onto a tyrosine, serine, threonine, or histidine residue in the substrate and thus send a chemical signal to networks of downstream proteins. They are important cellular signaling enzymes that regulate cell growth, proliferation, metabolism, differentiation, and migration. Unregulated protein kinase activity is often associated with a wide range of diseases, therefore making protein kinases major therapeutic targets...
April 20, 2017: Accounts of Chemical Research
https://www.readbyqxmd.com/read/28425142/signaling-complexes-control-the-chemotaxis-kinase-by-altering-its-apparent-rate-constant-of-autophosphorylation
#15
Wenlin Pan, Frederick W Dahlquist, Gerald L Hazelbauer
Autophosphorylating histidine kinase CheA is central to signaling in bacterial chemotaxis. The kinase donates its phosphoryl group to two response regulators, CheY that controls flagellar rotation and thus motility and CheB, crucial for sensory adaptation. As measured by coupled CheY phosphorylation, incorporation into signaling complexes activates the kinase ∼1,000-fold and places it under control of chemoreceptors. By the same assay, receptors modulate kinase activity ∼100-fold as a function of receptor ligand occupancy and adaptational modification...
April 20, 2017: Protein Science: a Publication of the Protein Society
https://www.readbyqxmd.com/read/28425104/inactivation-kinetics-and-residual-activity-of-cyp3a4-after-treatment-with-erythromycin
#16
Yuko Ishikawa, Takeshi Akiyoshi, Ayuko Imaoka, Hisakazu Ohtani
This study aimed to characterize the inactivation kinetics of cytochrome P450 3A4 (CYP3A4) by erythromycin, which involves mechanism-based inhibition (MBI), in detail. In addition to an MBI assay based on the conventional method in which erythromycin and recombinant CYP3A4 were pre-incubated for 15 min, we also evaluated the long-term MBI kinetics of this reaction by pre-incubating for 120 min. MBI profiles were obtained using three typical substrates, testosterone, midazolam, and nifedipine. In the long-term assay, erythromycin evoked a time-dependent biphasic reduction in enzyme activity, but some residual activity (α) was detected in the terminal phase...
April 20, 2017: Biopharmaceutics & Drug Disposition
https://www.readbyqxmd.com/read/28424540/mc-ppea-as-a-new-and-more-potent-inhibitor-of-clp-induced-sepsis-and-pulmonary-inflammation-than-fk866
#17
Peixin Huang, Mark W Lee, Keivan Sadrerafi, Daniel P Heruth, Li Q Zhang, Dev Maulik, Shui Qing Ye
Our previous study indicated that overexpression of nicotinamide phosphoribosyltransferase (NAMPT) aggravated acute lung injury, while knockdown of NAMPT expression attenuated ventilator-induced lung injury. Recently, we found that meta-carborane-butyl-3-(3-pyridinyl)-2E-propenamide (MC-PPEA, MC4), in which the benzoylpiperidine moiety of FK866 has been replaced by a carborane, displayed a 100-fold increase in NAMPT inhibition over FK866. Here, we determined the effects of MC4 and FK866 on cecal ligation and puncture (CLP) surgery-induced sepsis in C57BL/6J mice...
2017: Drug Design, Development and Therapy
https://www.readbyqxmd.com/read/28424360/intermittent-hypoxia-in-obstructive-sleep-apnoea-mediates-insulin-resistance-through-adipose-tissue-inflammation
#18
Aoife M Murphy, Amandine Thomas, Sophie J Crinion, Brian D Kent, Murtaza M Tambuwala, Aurelie Fabre, Jean-Louis Pepin, Helen M Roche, Claire Arnaud, Silke Ryan
Obstructive sleep apnoea (OSA) is increasingly associated with insulin resistance. The underlying pathophysiology remains unclear but intermittent hypoxia (IH)-mediated inflammation and subsequent dysfunction of the adipose tissue has been hypothesised to play a key role.We tested this hypothesis employing a comprehensive translational approach using a murine IH model of lean and diet-induced obese mice, an innovative IH system for cell cultures and a tightly controlled patient cohort.IH led to the development of insulin resistance in mice, corrected for the degree of obesity, and reduced insulin-mediated glucose uptake in 3T3-L1 adipocytes, associated with inhibition of the insulin-signalling pathway and downregulation of insulin-receptor substrate-1 mRNA...
April 2017: European Respiratory Journal: Official Journal of the European Society for Clinical Respiratory Physiology
https://www.readbyqxmd.com/read/28424159/prolonged-elimination-of-negative-feedback-control-mechanisms-along-the-insulin-signalling-pathway-impairs-%C3%AE-cell-function-in-vivo
#19
Roi Isaac, Yaron Vinik, Sigalit Boura-Halfon, Lydia Farack, Sarina Streim, Eytan Elhanany, Zvi Kam, Yehiel Zick
Cellular stress and pro-inflammatory cytokines induce phosphorylation of insulin receptor substrate (IRS) proteins at Ser sites that inhibit insulin and IGF-1 signalling. We therefore examined the effects of mutation of five 'inhibitory' Ser phosphorylation sites on IRS2 function in transgenic mice that overexpress, selectively in pancreatic β cells, either wild-type (WT) or a mutated IRS2 protein (IRS2(5A)). Islets size, number, and mRNA levels of catalase and superoxide dismutase, were increased, while those of nitric oxide synthase were decreased in 7-10 weeks old IRS2(5A)-β mice compared to IRS2(WT)-β mice...
April 19, 2017: Diabetes
https://www.readbyqxmd.com/read/28423521/therapeutic-sensitivity-to-rac-gtpase-inhibition-requires-consequential-suppression-of-mtorc1-akt-and-mek-signaling-in-breast-cancer
#20
Riley A Hampsch, Kevin Shee, Darcy Bates, Lionel D Lewis, Laurent Désiré, Bertrand Leblond, Eugene Demidenko, Kurtis Stefan, Yina H Huang, Todd W Miller
Rac GTPases have oncogenic roles in cell growth, survival, and migration. We tested response to the Rac inhibitor EHT1864 in a panel of breast cancer cell lines. EHT1864-induced growth inhibition was associated with dual inhibition of the PI3K/AKT/mTORC1 and MEK/ERK pathways. Breast cancer cells harboring PIK3CA mutations or HER2 overexpression were most sensitive to Rac inhibition, suggesting that such oncogenic alterations link Rac activation with PI3K/AKT/mTORC1 and MEK/ERK signaling. Interestingly, EHT1864 decreased activation of the mTORC1 substrate p70S6K earlier than AKT inhibition, suggesting that Rac may activate mTORC1/p70S6K independently of AKT...
March 28, 2017: Oncotarget
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