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https://www.readbyqxmd.com/read/28811106/questiomycin-a-stimulates-sorafenib-induced-cell-death-via-suppression-of-glucose-regulated-protein-78
#1
Kayo Machihara, Hidenori Tanaka, Yoshihiro Hayashi, Ichiro Murakami, Takushi Namba
Hepatocellular carcinoma (HCC) is one of the most difficult cancers to treat owing to the lack of effective chemotherapeutic methods. Sorafenib, the first-line and only available treatment for HCC, extends patient overall survival by several months, with a response rate below 10%. Thus, the identification of an agent that enhances the anticancer effect of sorafenib is critical for the development of therapeutic options for HCC. Endoplasmic reticulum (ER) stress response is one of the methods of sorafenib-induced cell death...
August 12, 2017: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/28808818/first-in-human-study-of-the-epichaperome-inhibitor-pu-h71-clinical-results-and-metabolic-profile
#2
Giovanna Speranza, Larry Anderson, Alice P Chen, Khanh Do, Michelle Eugeni, Marcie Weil, Larry Rubinstein, Eva Majerova, Jerry Collins, Yvonne Horneffer, Lamin Juwara, Jennifer Zlott, Rachel Bishop, Barbara A Conley, Howard Streicher, Joseph Tomaszewski, James H Doroshow, Shivaani Kummar
Background Molecular chaperone targeting has shown promise as a therapeutic approach in human cancers of various histologies and genetic backgrounds. The purine-scaffold inhibitor PU-H71 (NSC 750424), selective for Hsp90 in epichaperome networks, has demonstrated antitumor activity in multiple preclinical cancer models. The present study was a first in-human trial of PU-H71 aimed at establishing its safety and tolerability and characterizing its pharmacokinetic (PK) profile on a weekly administration schedule in human subjects with solid tumors refractory to standard treatments...
August 12, 2017: Investigational New Drugs
https://www.readbyqxmd.com/read/28808089/bag3-mediated-proteostasis-at-a-glance
#3
REVIEW
Christina Klimek, Barbara Kathage, Judith Wördehoff, Jörg Höhfeld
Cellular and organismal survival depend on the ability to maintain the proteome, even under conditions that threaten protein integrity. BCL2-associated athanogene 3 (BAG3) is essential for protein homeostasis (proteostasis) in stressed cells. Owing to its multi-domain structure, it engages in diverse processes that are crucial for proteome maintenance. BAG3 promotes the activity of molecular chaperones, sequesters and concentrates misfolded proteins, initiates autophagic disposal, and balances transcription, translation and degradation...
August 14, 2017: Journal of Cell Science
https://www.readbyqxmd.com/read/28805849/topology-of-polymer-chains-under-nanoscale-confinement
#4
Vahid Satarifard, Maziar Heidari, Samaneh Mashaghi, Sander J Tans, Mohammad Reza Ejtehadi, Alireza Mashaghi
Spatial confinement limits the conformational space accessible to biomolecules but the implications for bimolecular topology are not yet known. Folded linear biopolymers can be seen as molecular circuits formed by intramolecular contacts. The pairwise arrangement of intra-chain contacts can be categorized as parallel, series or cross, and has been identified as a topological property. Using molecular dynamics simulations, we determine the contact order distributions and topological circuits of short semi-flexible linear and ring polymer chains with a persistence length of lp under a spherical confinement of radius Rc...
August 14, 2017: Nanoscale
https://www.readbyqxmd.com/read/28802884/astrocytes-and-endoplasmic-reticulum-stress-a-bridge-between-obesity-and-neurodegenerative-diseases
#5
REVIEW
Cynthia A Martin-Jiménez, Ángela García-Vega, Ricardo Cabezas, Gjumrakch Aliev, Valentina Echeverria, Janneth González, George E Barreto
Endoplasmic reticulum (ER) is a subcellular organelle involved in protein folding and processing. ER stress constitutes a cellular process characterized by accumulation of misfolded proteins, impaired lipid metabolism and induction of inflammatory responses. ER stress has been suggested to be involved in several human pathologies, including neurodegenerative diseases and obesity. Different studies have shown that both neurodegenerative diseases and obesity trigger similar cellular responses to ER stress. Moreover, both diseases are assessed in astrocytes as evidences suggest these cells as key regulators of brain homeostasis...
August 9, 2017: Progress in Neurobiology
https://www.readbyqxmd.com/read/28801701/the-overexpression-of-hsp90b1-is-associated-with-tumorigenesis-of-canine-mammary-glands
#6
B V Sunil Kumar, Rabia Bhardwaj, Kanika Mahajan, Neeraj Kashyap, Ashwani Kumar, Ramneek Verma
Heat shock proteins (Hsp) are molecular chaperones that are responsible for protein folding and maintenance of cellular homeostasis. Hsp90, an important member of HSP family, has an important role in breast cancer. Glucose-regulated protein 94 (Grp94) is the endoplasmic reticulum paralog of Hsp90 encoded by Hsp90B1 gene. To test if this protein is overexpressed in dogs with mammary tumor, we estimated and compared its serum levels in healthy dogs and that of dogs with mammary tumors. Hsp90B1 mRNA expression was measured in tumorous and healthy mammary tissues (from age- and breed-matched dogs) by real-time PCR...
August 12, 2017: Molecular and Cellular Biochemistry
https://www.readbyqxmd.com/read/28801645/chronic-intermittent-hypobaric-hypoxia-improves-cardiac-function-through-inhibition-of-endoplasmic-reticulum-stress
#7
Fang Yuan, Li Zhang, Yan-Qing Li, Xu Teng, Si-Yu Tian, Xiao-Ran Wang, Yi Zhang
We investigated the role of endoplasmic reticulum stress (ERS) in chronic intermittent hypobaric hypoxia (CIHH)-induced cardiac protection. Adult male Sprague-Dawley rats were exposed to CIHH treatment simulating 5000 m altitude for 28 days, 6 hours per day. The heart was isolated and perfused with Langendorff apparatus and subjected to 30-min ischemia followed by 60-min reperfusion. Cardiac function, infarct size, and lactate dehydrogenase (LDH) activity were assessed. Expression of ERS molecular chaperones (GRP78, CHOP and caspase-12) was assayed by western blot analysis...
August 11, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28795723/intracellular-iron-and-heme-trafficking-and-metabolism-in-developing-erythroblasts
#8
Martin D Kafina, Barry H Paw
Vertebrate red blood cells (RBCs) arise from erythroblasts in the human bone marrow through a process known as erythropoiesis. Iron uptake is a crucial hallmark, essential for heme biosynthesis in the differentiating erythroblasts, which are dedicated to producing hemoglobin. Erythropoiesis is facilitated by a network of intracellular transport proteins, chaperones, and circulating hormones. Intracellular iron is targeted to the mitochondria for incorporation into a porphyrin ring to form heme and cytosolic iron-sulfur proteins, including Iron Regulatory Protein 1 (IRP1)...
August 10, 2017: Metallomics: Integrated Biometal Science
https://www.readbyqxmd.com/read/28794932/screening-of-neem-extracts-for-microbial-anti-chaperone-activity-by-employing-in-vitro-enzyme-refolding-assay
#9
Jyoti M Patki, Priyanka Shah
Microbial heat shock proteins (Hsps) play an important role in pathogenesis and development of resistance to existing drugs. New compounds that target microbial molecular chaperones have the potential of combating the challenge of anti-microbial resistance. The present study was aimed at assessing the employment of in vitro enzyme refolding assay to detect anti-chaperone activity of Neem (Azadirachta indica) extracts. Protein extracts of thermotolerant Escherichia coli cells were used as a source of Hsps or chaperones...
October 2017: 3 Biotech
https://www.readbyqxmd.com/read/28794819/upregulation-of-autophagy-genes-and-the-unfolded-protein-response-in-human-heart-failure
#10
Brian C Jensen, Scott J Bultman, Darcy Holley, Wei Tang, Gustaaf de Ridder, Salvatore Pizzo, Dawn Bowles, Monte S Willis
The cellular environment of the mammalian heart constantly is challenged with environmental and intrinsic pathological insults, which affect the proper folding of proteins in heart failure. The effects of damaged or misfolded proteins on the cell can be profound and result in a process termed "proteotoxicity". While proteotoxicity is best known for its role in mediating the pathogenesis of neurodegenerative diseases such as Alzheimer's disease, its role in human heart failure also has been recognized. The UPR involves three branches, including PERK, ATF6, and IRE1...
2017: International Journal of Clinical and Experimental Medicine
https://www.readbyqxmd.com/read/28793882/rpon2-and-flia-regulated-flitx-is-indispensible-for-flagellar-motility-and-virulence-in-xanthomonas-oryzae-pv-oryzae
#11
Chao Yu, Huamin Chen, Fang Tian, Fenghuan Yang, Chenyang He
BACKGROUND: Bacterial blight of rice caused by Xanthomonas oryzae pv. oryzae (Xoo) is one of the most important crop diseases in the world. More insights into the mechanistic regulation of bacterial pathogenesis will help us identify novel molecular targets for developing effective disease control strategies. A large flagellar gene cluster is regulated under a three-tiered hierarchy by σ(54) factor RpoN2 and its activator FleQ, and σ(28) factor FliA. A hypothetical protein gene fliTX is located upstream of rpoN2, however, how it is regulated and how it is related to bacterial behaviors remain to be elucidated...
August 9, 2017: BMC Microbiology
https://www.readbyqxmd.com/read/28792733/crohn-s-disease-variants-of-nod2-are-stabilized-by-critical-contact-region-of-hsp70
#12
Amy K Schaefer, Hannah Wastyk, Vishnu Mohanan, Ching-Wen Hou, Mackenzie L Lauro, James E Melnyk, Catherine Leimkuhler Grimes
Nod2 is a cytosolic, innate immune receptor responsible for binding to bacterial cell wall fragments such as muramyl dipeptide (MDP). Upon binding, subsequent downstream activation of the NF-κB pathway leads to an immune response. Nod2 mutations are correlated with an increased susceptibility for Crohn's disease (CD) and ultimately results in a misregulated immune response. Previous work had demonstrated that Nod2 interacts with and is stabilized by the molecular chaperone Hsp70. In this work it is shown using purified protein and in vitro bio-chemical assays that the critical Nod2 CD mutations (G908R, R702W, 1007fs) retain the ability to bind bacterial ligands...
August 9, 2017: Biochemistry
https://www.readbyqxmd.com/read/28791545/microbial-cyclophilins-specialized-functions-in-virulence-and-beyond
#13
REVIEW
Maria Dimou, Anastasia Venieraki, Panagiotis Katinakis
Cyclophilins belong to the superfamily of peptidyl-prolyl cis/trans isomerases (PPIases, EC: 5.2.1.8), the enzymes that catalyze the cis/trans isomerization of peptidyl-prolyl peptide bonds in unfolded and partially folded polypeptide chains and native state proteins. Cyclophilins have been extensively studied, since they are involved in multiple cellular processes related to human pathologies, such as neurodegenerative disorders, infectious diseases, and cancer. However, the presence of cyclophilins in all domains of life indicates a broader biological importance...
August 8, 2017: World Journal of Microbiology & Biotechnology
https://www.readbyqxmd.com/read/28780408/an-essential-role-of-n-terminal-domain-of-copper-chaperone-in-the-enzymatic-activation-of-cu-zn-superoxide-dismutase
#14
Mami Fukuoka, Eiichi Tokuda, Kenta Nakagome, Zhiliang Wu, Isao Nagano, Yoshiaki Furukawa
Cu/Zn-superoxide dismutase (SOD1) is an enzyme that disproportionates superoxide anion into hydrogen peroxide and molecular oxygen. The enzymatic activity of SOD1 requires the binding of copper and zinc ions and also the formation of a conserved intramolecular disulfide bond. In a eukaryotic cell, a copper chaperone for SOD1 (CCS) has been known to supply a copper ion and also introduce the disulfide bond into SOD1; however, a mechanism controlling the CCS-dependent activation of SOD1 remains obscure. Here, we characterized CCS isolated from a human liver fluke, Clonorchis sinensis, and found that an N-terminal domain of CCS was essential in supplying a copper ion in SOD1...
July 31, 2017: Journal of Inorganic Biochemistry
https://www.readbyqxmd.com/read/28778081/multiple-regulatory-aspects-of-histone-methyltransferase-ezh2-in-pb-induced-neurotoxicity
#15
Wei-Zhen Xue, Xiaozhen Gu, Yulan Wu, Danyang Li, Yi Xu, Hui-Li Wang
Pb is a pervasive environmental threat to human health. Although remarkable progress has been made in its neurotoxicity, the precise molecular mechanisms underlying this widespread toxicant still remain elusive. In this study, the detailed roles of EZH2, a transcriptional repressor, in the regulation of Pb-led neurotoxicity were investigated, highlighting its sub-functionalization, compartmentalization, functional chaperones and downstream partners. Based on the findings, EZH2's protein levels were significantly reduced in response to Pb treatment; EZH2's gain-of-function trials recovered the dampened neurite outgrowth; EZH2' recruitment to ploycomb complex, as well as its interaction with cytosolic Vav1, was altered in a distinct manner, suggesting that EZH2's multiple roles were markedly redistributed in this context; EZH2's cytosolic and nuclear presence differed in their respective response towards Pb treatment; EZH2 directly occupied the promoters of EGR2, NGFR and CaMKK2, genes responsible for various nerve functions and repair mechanisms, and essentially contributed to their aberrant expression...
July 27, 2017: Oncotarget
https://www.readbyqxmd.com/read/28774858/a-comparative-intracellular-proteomic-profiling-of-pseudomonas-aeruginosa-strain-asp-53-grown-on-pyrene-or-glucose-as-sole-source-of-carbon-and-identification-of-some-key-enzymes-of-pyrene-biodegradation-pathway
#16
Ashis K Mukherjee, Pabitra Bhagowati, Bhim Bahadur Biswa, Abhishek Chanda, Bhargab Kalita
Pseudomonas aeruginosa strain ASP-53, isolated from a petroleum oil-contaminated soil sample, was found to be an efficient degrader of pyrene. PCR amplification of selected hydrocarbon catabolic genes (alkB gene, which encodes for monooxygenase, and the C12O, C23O, and PAH-RHDα genes encoding for the dioxygenase enzyme) from the genomic DNA of P. aeruginosa strain ASP-53 suggested its hydrocarbon degradation potential. The GC-MS analysis demonstrated 30.1% pyrene degradation by P. aeruginosa strain ASP-53 after 144h of incubation at pH6...
July 31, 2017: Journal of Proteomics
https://www.readbyqxmd.com/read/28774748/investigation-on-different-chemical-stability-of-mitochondrial-hsp60-and-its-precursor
#17
Caterina Ricci, Rita Carrotta, Giacoma Cinzia Rappa, Maria Rosalia Mangione, Fabio Librizzi, Pier Luigi San Biagio, Heinz Amenitsch, Maria Grazia Ortore, Silvia Vilasi
In the large class of molecules that maintain protein homeostasis, called molecular chaperones, chaperonins constitute a subclass that specifically assist the correct folding of newly synthesized proteins. Among them, Hsp60 is composed of a double heptameric ring structure with a large central cavity where the unfolded protein binds via hydrophobic interactions and is supported, in this function, by the co-chaperonin Hsp10. Hsp60 is typically located in the mitochondria, but in some pathological situations, such as cancers and chronic inflammatory diseases, Hsp60 accumulates in the cytoplasm...
July 26, 2017: Biophysical Chemistry
https://www.readbyqxmd.com/read/28774593/inhibiton-of-fkbp10-attenuates-hypertrophic-scarring-through-suppressing-fibroblast-activity-and-extracellualr-matrix-deposition
#18
Xiao Liang, Bangda Chai, Ran Duan, Yiwen Zhou, Xiaolu Huang, Qingfeng Li
Hypertrophic scar (HS) is a pathogenic form of scar formation with no recognized treatment to date. Its molecular mechanism is related to the abnormal proliferation and transition of fibroblasts and overproduction of extracellular matrix (ECM). FK506-binding protein 10 (FKBP10) is a molecular chaperone able of regulating α-SMA expression and pro-collagen maturation in fibroblasts. However, no research has investigated the biological function of FKBP10 in scar formation to date. In this study, we aim to assess the expression and function of FKBP10 in hypertrophic scarring...
July 31, 2017: Journal of Investigative Dermatology
https://www.readbyqxmd.com/read/28771395/the-type-iii-secretion-chaperone-hpab-controls-the-translocation-of-effector-and-non-effector-proteins-from-xanthomonas-campestris-pv-vesicatoria
#19
Felix Scheibner, Nadine Hartmann, Jens Hausner, Christian Lorenz, Anne-Katrin Hoffmeister, Daniela Buettner
Pathogenicity of the Gram-negative bacterium Xanthomonas campestris pv. vesicatoria depends on a type III secretion (T3S) system, which translocates effector proteins into plant cells. Effector proteins contain N-terminal T3S and translocation signals and interact with the T3S chaperone HpaB, which presumably escorts effectors to the secretion apparatus. The molecular mechanisms underlying the recognition of effectors by the T3S system are not yet understood. In the present study, we analysed T3S and translocation signals in the type III effectors XopE2 and XopJ from X...
August 3, 2017: Molecular Plant-microbe Interactions: MPMI
https://www.readbyqxmd.com/read/28770209/aaa-machines-of-protein-destruction-in-mycobacteria
#20
REVIEW
Adnan Ali H Alhuwaider, David A Dougan
The bacterial cytosol is a complex mixture of macromolecules (proteins, DNA, and RNA), which collectively are responsible for an enormous array of cellular tasks. Proteins are central to most, if not all, of these tasks and as such their maintenance (commonly referred to as protein homeostasis or proteostasis) is vital for cell survival during normal and stressful conditions. The two key aspects of protein homeostasis are, (i) the correct folding and assembly of proteins (coupled with their delivery to the correct cellular location) and (ii) the timely removal of unwanted or damaged proteins from the cell, which are performed by molecular chaperones and proteases, respectively...
2017: Frontiers in Molecular Biosciences
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