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Mohammad T Mazhab-Jafari, Alexis Rohou, Carla Schmidt, Stephanie A Bueler, Samir Benlekbir, Carol V Robinson, John L Rubinstein
Vacuolar-type ATPases (V-ATPases) are ATP-powered proton pumps involved in processes such as endocytosis, lysosomal degradation, secondary transport, TOR signalling, and osteoclast and kidney function. ATP hydrolysis in the soluble catalytic V1 region drives proton translocation through the membrane-embedded VO region via rotation of a rotor subcomplex. Variability in the structure of the intact enzyme has prevented construction of an atomic model for the membrane-embedded motor of any rotary ATPase. We induced dissociation and auto-inhibition of the V1 and VO regions of the V-ATPase by starving the yeast Saccharomyces cerevisiae, allowing us to obtain a ~3...
October 24, 2016: Nature
Yu Zhang, Yifei Lu, Feng Wang, Sai An, Yujie Zhang, Tao Sun, Jianhua Zhu, Chen Jiang
Inflammation has been reported as one significant hallmark of breast cancer in relation to tumor development, metastasis, and invasion. The bradykinin receptor 1 (B1R) is highly expressed on inflammatory breast tumor cells thus providing a promising targeting site for tumor recognition and sufficient receptor mediated endocytosis. In this study, the authors evaluate the targeting efficiency of l-form and d-form [des-Arg(10) ]kallidin both in vitro and in vivo. To further improve the drug delivery efficiency, the authors establish a dandelion like nanoparticle by combining the polymeric drug conjugates and aptamer complex together...
October 24, 2016: Small
R-H Xu, B Liu, J-D Wu, Y-Y Yan, J-N Wang
OBJECTIVE: Atherosclerosis is recognized as a chronic inflammatory disease leading to hardening of the vessel wall and narrowing of arteries. Endothelial cells (ECs) exhibit highly active glycolysis, the dysfunction of which leads to accumulation of lipids in the arterial wall and formation of atherosclerotic plaque. MATERIALS AND METHODS: qRT-PCR was performed to compare the deregulated miR-143 between atherosclerotic plaque and normal vessel tissues. The direct target of miR-143 was verified by Western blot and luciferase assay...
October 2016: European Review for Medical and Pharmacological Sciences
Anusha Mishra, James P Reynolds, Yang Chen, Alexander V Gourine, Dmitri A Rusakov, David Attwell
Active neurons increase their energy supply by dilating nearby arterioles and capillaries. This neurovascular coupling underlies blood oxygen level-dependent functional imaging signals, but its mechanism is controversial. Canonically, neurons release glutamate to activate metabotropic glutamate receptor 5 (mGluR5) on astrocytes, evoking Ca(2+) release from internal stores, activating phospholipase A2 and generating vasodilatory arachidonic acid derivatives. However, adult astrocytes lack mGluR5, and knockout of the inositol 1,4,5-trisphosphate receptors that release Ca(2+) from stores does not affect neurovascular coupling...
October 24, 2016: Nature Neuroscience
Yunxiang Zang, Mingliang Jin, Huping Wang, Zhicheng Cui, Liangliang Kong, Caixuan Liu, Yao Cong
The eukaryotic chaperonin TRiC (or CCT) assists in the folding of 10% of cytosolic proteins. Here we present two cryo-EM structures of Saccharomyces cerevisiae TRiC in a newly identified nucleotide partially preloaded (NPP) state and in the ATP-bound state, at 4.7-Å and 4.6-Å resolution, respectively. Through inner-subunit eGFP tagging, we identified the subunit locations in open-state TRiC and found that the CCT2 subunit pair forms an unexpected Z shape. ATP binding induces a dramatic conformational change on the CCT2 side, thereby suggesting that CCT2 plays an essential role in TRiC allosteric cooperativity...
October 24, 2016: Nature Structural & Molecular Biology
Yi-Ju Hsu, Wen-Ching Huang, Chien-Chao Chiu, Yan-Lin Liu, Wan-Chun Chiu, Chun-Hui Chiu, Yen-Shuo Chiu, Chi-Chang Huang
Chili pepper is used as a food, seasoning and has been revered for its medicinal and health claims. It is very popular and is the most common spice worldwide. Capsaicin (CAP) is a major pungent and bioactive phytochemical in chili peppers. CAP has been shown to improve mitochondrial biogenesis and adenosine triphosphate (ATP) production. However, there is limited evidence around the effects of CAP on physical fatigue and exercise performance. The purpose of this study was to evaluate the potential beneficial effects of CAP on anti-fatigue and ergogenic functions following physiological challenge...
October 20, 2016: Nutrients
Yana K Rennie, Patrick J McIntyre, Tito Akindele, Richard Bayliss, Andrew G Jamieson
Inhibition of protein kinases using ATP-competitive compounds is an important strategy in drug discovery. In contrast, the allosteric regulation of kinases through the disruption of protein-protein interactions has not been widely adopted, despite the potential for selective targeting. Aurora-A kinase regulates mitotic entry and mitotic spindle assembly, and is a promising target for anti-cancer therapy. The microtubule-associated protein TPX2 activates Aurora-A through binding to two sites. Aurora-A recognition is mediated by two motifs within the first 43 residues of TPX2, connected by a flexible linker...
October 24, 2016: ACS Chemical Biology
María-Victoria Hinckelmann, Amandine Virlogeux, Christian Niehage, Christel Poujol, Daniel Choquet, Bernard Hoflack, Diana Zala, Frédéric Saudou
The glycolytic enzyme glyceraldehyde-3-phosphate dehydrogenase (GAPDH) facilitates fast axonal transport in neurons. However, given that GAPDH does not produce ATP, it is unclear whether glycolysis per se is sufficient to propel vesicles. Although many proteins regulating transport have been identified, the molecular composition of transported vesicles in neurons has yet to be fully elucidated. Here we selectively enrich motile vesicles and perform quantitative proteomic analysis. In addition to the expected molecular motors and vesicular proteins, we find an enrichment of all the glycolytic enzymes...
October 24, 2016: Nature Communications
Hattan A Alharbi, Jane Alcorn, Ahmed Al-Mousa, John P Giesy, Steve B Wiseman
Oil sands process-affected water (OSPW) is generated during extraction of bitumen in the surface mining oil sands industry in Alberta, Canada. Studies were performed in vitro by use of Caco-2 cells, and in vivo with larvae of Japanese medaka (Oryzias latipes) to determine if organic compounds from the aqueous phase of OSPW inhibit ATP binding cassette protein ABCB1 (permeability-glycoprotein, P-gp). Neutral and basic fractions of OSPW inhibited activity of P-gp in Caco-2 cells by 1.9- and 2.0-fold, respectively, while the acidic fraction had the least effect...
October 24, 2016: Journal of Applied Toxicology: JAT
Zhao Li, Guanghui Hu, Xiangfeng Liu, Yao Zhou, Yu Li, Xu Zhang, Xiaohui Yuan, Qian Zhang, Deguang Yang, Tianyu Wang, Zhiwu Zhang
Originating in a tropical climate, maize has faced great challenges as cultivation has expanded to the majority of the world's temperate zones. In these zones, frost and cold temperatures are major factors that prevent maize from reaching its full yield potential. Among 30 elite maize inbred lines adapted to northern China, we identified two lines of extreme, but opposite, freezing tolerance levels-highly tolerant and highly sensitive. During the seedling stage of these two lines, we used RNA-seq to measure changes in maize whole genome transcriptome before and after freezing treatment...
2016: Frontiers in Plant Science
Liliana F Iannucci, Jingfeng Sun, Brijesh K Singh, Jin Zhou, Vincent A Kaddai, Antonia Lanni, Paul M Yen, Rohit A Sinha
Short-chain fatty acids (SCFAs) are gut microbial fermentation products derived from dietary fiber sources. Although depletion of gut microflora has been linked to the development of liver disease, the direct effects of SCFAs on intracellular hepatic processes are not well understood. In this study, we demonstrated that the SCFAs, propionate and butyrate, regulated autophagic flux in hepatic cells in a cell-autonomous manner. Induction of autophagy by SCFAs required PPARγ stimulation of Uncoupling Protein 2 (UCP2) expression that was associated with reduced intracellular ATP levels and activation of PRKAA1/AMPK (protein kinase, AMP-activated, alpha 1 catalytic subunit)...
October 20, 2016: Biochemical and Biophysical Research Communications
Hema Negi, Aparna Shukla, Feroz Khan, Rakesh Pandey
Remarkably the c-Jun-NH2-terminal kinase (JNK) pathway is all evolutionarily conserved across species. In view of the hypothesis that increased stress resistance subdue aging, we investigated the role of ursolic acid (3β-Hydroxy-urs-12-en-28-oic acid; UA) in the pioneering aging model Caenorhabditis elegans with an increase in mean and maximum lifespan by up to 30%. Our genetic study unravelled the underlying pathway where JNK-1 is acting independently of insulin-IGF-1 signalling (IIS) pathway to modulate longevity...
October 20, 2016: Biochemical and Biophysical Research Communications
Xueting Wang, Jie Ding, Zou Xiang, Peipei Jiang, Jing Du, Xiaodong Han
Microcystin-LR (MC-LR), which generates strong reproductive toxicity, reduces serum testosterone level without directly damaging Leydig cells. The purpose of this study was to identify the target cells of MC-LR in the rat hypothalamic-pituitary axis and to investigate the underlying mechanisms. We found that the gonadotropin-releasing hormone (GnRH) neurons were the direct target of MC-LR. In vivo results showed that upon exposure to rats, cells around the third ventricle of hypothalamus underwent apoptosis...
October 20, 2016: Toxicon: Official Journal of the International Society on Toxinology
Wei Cui, Anhe Wang, Jie Zhao, Junbai Li
Polyelectrolyte multilayer capsules have become a novel and promising class of hybrid materials with great potential since they can be applied in various areas, such as pharmaceutical sciences, biotechnology, and biomedicine. The concept of using such carriers for biology application is diagnosis and treatment of diseases for convenience, safety and specific targeting. Therefore, the development of biocompatible, biodegradable and specific characteristic nanostructure material is highly desirable. Much effort has been devoted to exploring innovative and effective techniques to fabricate such materials...
October 6, 2016: Advances in Colloid and Interface Science
Xinlai Cheng, Karl-Heinz Merz
Indirubin is the major active component of an herbal recipe 'Dangui Luhui Wan' () in traditional Chinese medicine (TCM). It is widely used in China for the treatment of inflammation, cancer, and other chronic diseases and is known for good efficiency and very low side effects. Primary studies on the mechanism of action revealed that indirubin and derivatives are potent ATP-competitive inhibitors of CDKs and GSK3ß achieving IC50 values down to the low nanomolar range. However, the clinical application of indirubins is limited by the extremely poor water solubility (<1 mg/L in general) and consequently the insufficient bioavailability originating from strong binding forces in the crystal lattice...
2016: Advances in Experimental Medicine and Biology
Dmitry M Korzhnev, Dante Neculai, Sirano Dhe-Paganon, Cheryl H Arrowsmith, Irina Bezsonova
HLTF is a SWI2/SNF2-family ATP-dependent chromatin remodeling enzyme that acts in the error-free branch of DNA damage tolerance (DDT), a cellular mechanism that enables replication of damaged DNA while leaving damage repair for a later time. Human HLTF and a closely related protein SHPRH, as well as their yeast homologue Rad5, are multi-functional enzymes that share E3 ubiquitin-ligase activity required for activation of the error-free DDT. HLTF and Rad5 also function as ATP-dependent dsDNA translocases and possess replication fork reversal activities...
October 22, 2016: Journal of Biomolecular NMR
Gabriele Picco, Consalvo Petti, Francesco Sassi, Katia Grillone, Giorgia Migliardi, Teresa Rossi, Claudio Isella, Federica Di Nicolantonio, Ivana Sarotto, Anna Sapino, Alberto Bardelli, Livio Trusolino, Andrea Bertotti, Enzo Medico
BACKGROUND: The NEDD8 conjugation pathway modulates the ubiquitination and activity of a wide range of intracellular proteins, and its blockade by pevonedistat is emerging as a promising therapeutic approach in various cancer settings. However, systematic characterization of pevonedistat efficacy in specific tumor types and definition of response predictors are still missing. METHODS: We investigated in vitro sensitivity to pevonedistat in 122 colorectal cancer (CRC) cell lines by an ATP-based proliferation assay and evaluated apoptosis and DNA content by flow cytometry...
February 2017: Journal of the National Cancer Institute
Samir S Roy, Manju Kapoor
Hsp90 contains two distinct Nucleotide Binding Sites (NBS), in its N-terminal domain (NTD) and C-terminal domain (CTD), respectively. The NTD site belongs to the GHKL super-family of ATPases and has been the subject of extensive characterization. However, a structure of the nucleotide-bound form of CTD is still unavailable. In this study molecular modeling was employed to incorporate experimental data using partial constructs of the CTD, from work published by many research groups, onto existing structural models of its apo- form...
October 3, 2016: Journal of Molecular Graphics & Modelling
Jie Sun, Jing Wang, Rui Zhang, Dongyang Wei, Qin Long, Yu Huang, Xianchuan Xie, Aimin Li
In this study, secondary effluent from the Wulongkou (WLK) municipal wastewater plant (Zhengzhou, China) was tested for its toxicity effects before and after five advanced treatment processes (ATPs, i.e. coagulation sedimentation, nan da magnetic polyacrylic anion exchange resin (NDMP) resin adsorption, activated carbon adsorption, ozonation and electro-adsorption). Results showed that estrogen disruption effects (EDEs) were particularly significant for the raw secondary effluent among the studied dioxin-like toxicity effect, androgenic/anti-androgenic response effect, EDEs, and genotoxicity effect...
October 20, 2016: Chemosphere
Akos A Gerencser, Shona A Mookerjee, Martin Jastroch, Martin D Brand
Analysis of the cellular mechanisms of metabolic disorders, including type 2 diabetes mellitus, is complicated by the large number of reactions and interactions in metabolic networks. Metabolic control analysis with appropriate modularization is a powerful method for simplifying and analyzing these networks. To analyze control of cellular energy metabolism in adherent cell cultures of the INS-1832/13 pancreatic β-cell model we adapted our microscopy assay of absolute mitochondrial membrane potential (ΔψM) to a fluorescence microplate reader format, and applied it in conjunction with cell respirometry...
October 20, 2016: Biochimica et Biophysica Acta
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