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Yun Zhang, Juan Cen, Zhili Jia, Chung-Der Hsiao, Qing Xia, Xue Wang, Xiqiang Chen, Rongchun Wang, Zhenzhou Jiang, Luyong Zhang, Kechun Liu
Isoniazid (INH) is a first-line antituberculosis drug. The incidence of adverse reactions accompanied by inflammation in the liver during drug administration to tuberculosis patients is high and severely affects clinical treatment. To better understanding the mechanism of hepatotoxicity induced by INH under the inflammatory state, we compared the differences in hepatotoxicity from INH between normal and inflammatory zebrafish to elucidate the hepatotoxic mechanism using different endpoints such as mortality, malformation, inflammatory effects, liver morphology, histological changes, transaminase analysis and certain genes expression...
March 11, 2019: Antimicrobial Agents and Chemotherapy
Ming Sun, Judy L M Kotler, Shanshan Liu, Timothy O Street
Hsp70 and Hsp90 chaperones are critical for protein quality control in the cytosol, while organelle-specific Hsp70/Hsp90 paralogs provide similar protection for mitochondria and the endoplasmic reticulum (ER). Cytosolic Hsp70/Hsp90 can operate sequentially with Hsp90 selectively associating with Hsp70 after Hsp70 is bound to a client protein. This observation has long suggested that Hsp90 could have a preference for interacting with clients at their later stages of folding. However, recent work has shown that cytosolic Hsp70/Hsp90 can directly interact even in the absence of a client, which opens up an alternative possibility that the ordered interactions of Hsp70/Hsp90 with clients could be a consequence of regulated changes in the direct interactions between Hsp70 and Hsp90...
February 20, 2019: Journal of Biological Chemistry
Kentaro Oh-Hashi, Shiori Matsumoto, Takayuki Sakai, Yoko Hirata, Kensuke Okuda, Hideko Nagasawa
We recently characterized the cytotoxic action of a novel phenformin derivative, 2-(2-chlorophenyl)ethylbiguanide (2-Cl-Phen), on HT-29 cells under a serum- and glucose-deprived condition and found that 2-Cl-Phen attenuated ATF4 and GRP78, typical downstream targets of the unfolded protein response (UPR), together with c-Myc protein expression in a transcriptional and posttranscriptional manner. In the current study, we focused on the expression of ER-associated protein degradation (ERAD) components after treatment with 2-Cl-Phen under a serum- and glucose-deprived condition...
February 16, 2019: Applied Biochemistry and Biotechnology
Qun Wei, Jun Zhang, Le Su, Xuan Zhao, BaoXiang Zhao, JunYing Miao, ZhaoMin Lin
Vascular endothelial cell (VEC) apoptosis takes part in the development of various cardiovascular diseases. Heat shock protein 90 (HSP90) regulates apoptosis through various apoptosis associated client proteins. In previous study, we identified a novel HSP90 inhibitor HCP1 induced apoptosis in A549 human lung cancer cells. Here, we found that low-concentration HCP1 (1 μM, 2 μM) suppressed VEC apoptosis caused by serum and fibroblast growth factor 2 (FGF-2) deprivation. HCP1 directly bound to glucose-regulated protein 94 (Grp94), an isoform of HSP90 located in endoplasmic reticulum, and HCP1 selectively inhibited Grp94 activity via binding to site 3...
February 13, 2019: Biochemical and Biophysical Research Communications
Sebastian Sjöqvist, Taichi Ishikawa, Daisuke Shimura, Yoshiyuki Kasai, Aya Imafuku, Sophia Bou-Ghannam, Takanori Iwata, Nobuo Kanai
The oral mucosa exhibits unique regenerative properties, sometimes referred to as foetal-like wound healing. Researchers from our institute have used sheets of oral mucosa epithelial cells (OMECs) for regenerative medicine applications including cornea replacement and oesophageal epithelial regeneration for stricture prevention. Here, we have isolated exosomes from clinical-grade production of OMEC sheets from healthy human donors ( n  = 8), aiming to evaluate the clinical potential of the exosomes to stimulate epithelial regeneration and to improve understanding of the mode-of-action of the cells...
2019: Journal of Extracellular Vesicles
Chien-Yu Huang, Po-Li Wei, Jin-Wun Wang, Precious Takondwa Makondi, Ming-Te Huang, Hsin-An Chen, Yu-Jia Chang
Background: Osteosarcoma (OS) is the most common and most aggressive primary solid malignant bone tumor in children and young adults and has high rates of recurrence and metastasis. The endoplasmic reticulum (ER) stress pathway is important in regulating the chemo-responsiveness of cancer. However, the role of glucose-regulated protein 94 (GRP94) in regulating the response of OS to chemotherapy has never been explored. Methods: In this study, two OS cell lines, MG63 and 143B cells, were used to evaluate the mechanism by which GRP94 modulates the response of osteosarcoma to chemotherapy...
2019: Disease Markers
Bo Li, Alison Hock, Richard Y Wu, Adam Minich, Steven R Botts, Carol Lee, Lina Antounians, Hiromu Miyake, Yuhki Koike, Yong Chen, Augusto Zani, Philip M Sherman, Agostino Pierro
Necrotizing enterocolitis (NEC) is characterized by intestinal injury and impaired mucin synthesis. We recently showed that breast milk exosomes from rodents promote intestinal cell viability, epithelial proliferation, and stem cell activity, but whether they also affect mucus production is unknown. Therefore, the aim of this study was to investigate the effects of bovine milk-derived exosomes on goblet cell expression in experimental NEC and delineate potential underlying mechanisms of action. Exosomes were isolated from bovine milk by ultracentrifugation and confirmed by Nanoparticle Tracking Analysis and through the detection of exosome membrane markers...
2019: PloS One
Seyed Mojtaba Ghiasi, Tina Dahlby, Caroline Hede Andersen, Leena Haataja, Sólrun Petersen, Muhmmad Omar-Hmeadi, Mingyu Yang, Celina Pihl, Sophie Emilie Bresson, Muhammad Saad Khilji, Kristian Klindt, Oana Cheta, Marcelo J Perone, Björn Tyrberg, Clara Prats, Sebastian Barg, Anders Tengholm, Peter Arvan, Thomas Mandrup-Poulsen, Michal Tomasz Marzec
Although endoplasmic reticulum (ER) chaperone binding to mutant proinsulin has been reported, the role of protein chaperones in the handling of wild-type proinsulin is under-investigated. Here, we have explored the importance of glucose regulated protein 94 (GRP94), a prominent ER chaperone known to fold insulin-like growth factors, in proinsulin handling within β-cells. We found that GRP94 co-immunoprecipitated with proinsulin and that inhibition of GRP94 function and/or expression reduced glucose-dependent insulin secretion, shortened proinsulin half-life and lowered intracellular proinsulin and insulin levels...
January 22, 2019: Diabetes
Dongmin Zhao, Jing Yang, Kaikai Han, Qingtao Liu, Huili Wang, Yuzhuo Liu, Xinmei Huang, Lijiao Zhang, Yin Li
BACKGROUND: Tembusu virus (TMUV), classified in the genus Flavivirus, causes reduced egg production and neurological problems in poultry. Flavivirus replication depends on the host endoplasmic reticulum (ER) and induces ER stress that leads to activation of the cellular unfolded protein response (UPR), an important signalling pathway that regulates many biological functions involved in viral pathogenesis and innate immunity. However, the mechanism of TMUV-induced UPR activation remains unclear...
January 22, 2019: BMC Veterinary Research
Limeng Dai, Gang He, Kun Zhang, Xingying Guan, Yan Wang, Bo Zhang
Trichostatin A (TSA) has been demonstrated to exhibit various anticancer effects that influence cell cycle arrest, cell proliferation and apoptosis of cancer cells. A potential association between TSA and endoplasmic reticulum (ER) function has been suggested but its anticancer mechanism involving the induction of ER stress is unknown. p53 has previously been demonstrated to regulate ER function in response to stress but its role involving TSA and ER stress in cancer cells is poorly understood. The current study identified that TSA induced ER stress in wild type (WT) HCT116 human colon cancer cells...
January 2019: Oncology Letters
Lynne Cassimeris, Julie B Engiles, Hannah Galantino-Homer
BACKGROUND: Laminitis is often associated with endocrinopathies that cause hyperinsulinemia and is also induced experimentally by hyperinsulinemia, suggesting that insulin initiates laminitis pathogenesis. Hyperinsulinemia is expected to activate pro-growth and anabolic signaling pathways. We hypothesize that chronic over-stimulation of these pathways in lamellar tissue results in endoplasmic reticulum stress, contributing to tissue pathology, as it does in human metabolic diseases. We tested this hypothesis by asking whether lamellar tissue from horses with naturally-occurring endocrinopathic laminitis showed expression of protein markers of endoplasmic reticulum stress...
January 10, 2019: BMC Veterinary Research
Erawan Borkham-Kamphorst, Eddy Van de Leur, Ute Haas, Ralf Weiskirchen
Unfolded protein response (UPR) is an adaptive mechanism allowing the endoplasmic reticulum (ER) to react to an accumulation of unfolded proteins in its lumen, also known as ER stress. The UPR is interconnected with inflammation through several pathways such as reactive oxygen species (ROS) production resulting from the protein folding or alternatively, activation of nuclear factor-κB (NF-κB) and c-Jun N-terminal kinase (JNK) via IRE1, or induction of acute phase response (APR). Lipocalin 2 (LCN2) is one of the APR proteins induced under inflammatory conditions and up-regulated during ER stress...
January 4, 2019: Cellular Signalling
Wei Liu, Tianyao Yang, Zhaofa Xu, Bin Xu, Yu Deng
Methyl-mercury (MeHg) is a dangerous environmental contamination biotransformed from mercury or inorganic mercury compounds in waterways, which induces severe toxic effects in central nervous system. Oxidative stress is involved in various ways of intracellular physiological or pathological processes including neuronal apoptosis. For understanding the ways that oxidative stress participating in MeHg-induced apoptosis, the current study attempted to explore the effects of oxidative stress on endoplasmic reticulum (ER) and mitochondria function, especially focussing on ER stress followed by unfold protein response (UPR), as well as mitochondrial apoptosis pathways activation in primary cultured cortical neurons...
December 4, 2018: Free Radical Research
Jing Fang, Zhixiang Zheng, Zhuangzhi Yang, Xi Peng, Zhicai Zuo, Hengmin Cui, Ping Ouyang, Gang Shu, Zhengli Chen, Chao Huang
Aflatoxin B1 (AFB1 ), one of most potent and common mycotoxins in human food and animal feed, has hepatotoxic and carcinogenic effects on humans and poultry. Recent studies indicated that selenium (Se) has a protective effect on apoptosis induced by toxin poisoning. The present study was designed to reveal the ameliorative effects of selenium on the expression of apoptosis related molecules in the jejunum of broilers exposed to an AFB1 diet for 3 weeks. A total of 216 one-day-old healthy Cobb broilers were randomly divided into the control group (0 mg kg-1 AFB1 ), AFB1 group (0...
November 1, 2018: Toxicology Research
Yong Zhang, Liangsheng Miao, Huijuan Zhang, Gang Wu, Zhenni Zhang, Jianrui Lv
BACKGROUND: We demonstrated growing evidence supports a protective role of chlorogenic acid of rat hepatocytes elicited by two compounds, i.e. thapsigargin and palmitic acid. Nevertheless, little is known about the mechanisms of palmitic acid induced endoplasmic reticulum (ER) stress and cell death. METHODS: The proliferation of primary rat hepatocytes was detected by MTT assay. The expression of GRP78, CHOP and GRP94 was detected by Western blot analyses. Caspase-3 activity was detected by a Caspase-3 substrate kit...
November 28, 2018: Lipids in Health and Disease
Laetitia Allais, Chao Zhao, Mingjun Fu, Jing Hu, Jian G Qin, Lihua Qiu, Zhenhua Ma
Understanding fish larval development is of a great interest for aquaculture production efficiency. Identifying possible indicators of fish larvae stress could improve the production and limit the mortality rate that larval stage is subjected to. Heat-shock proteins (HSPs) and heat-shock factors (HSFs) are well known as indicators of response to many kinds of stressor (e.g., environmental, morphological, or pathological changes). In this study, golden pompano larvae were raised at different temperatures (23 °C, 26 °C, and 29 °C), as well as three different diets (Artemia nauplii unenriched, Artemia nauplii enriched with Nannochloropsis sp...
November 5, 2018: Fish Physiology and Biochemistry
Fen Jiang, An-Ping Guo, Jia-Chen Xu, Qi-Dong You, Xiao-Li Xu
As the endoplasmic reticulum paralogue of Hsp90, Grp94 chaperones a small set of client proteins associated with some diseases, including cancer, primary open-angle glaucoma, and inflammatory disorders. Grp94-selective inhibition has been a potential therapeutic strategy for these diseases. In this study, inspired by the conclusion that ligand-induced "Phe199 shift" effect is the structural basis of Grp94-selective inhibition, a series of novel Grp94 selective inhibitors incorporating "benzamide" moiety were developed, among which compound 54 manifested the most potent Grp94 inhibitory activity with an IC50 value of 2 nM and over 1000-fold selectivity to Grp94 against Hsp90α...
October 26, 2018: Journal of Medicinal Chemistry
Hye-Bin Park, Mi-Jeong Kim, Bae-Dong Jung, Seunghyung Lee, Choon-Keun Park, Boo-Keun Yang, Hee-Tae Cheong
We investigate the effect of endoplasmic reticulum (ER) stress inhibitor treatment during parthenogenetic activation of oocytes on the ER stress generation, apoptosis, and in vitro development of parthenogenetic porcine embryos. Porcine in vitro matured oocytes were activated by 1) electric stimulus (E) or 2) E+10 μM Ca-ionophore (A23187) treatment (EC). Oocytes were then treated by ER stress inhibitors such as salubrinal (200 nM) and tauroursodeoxychloic acid (TUDCA, 100 μM) for 3 h prior to in vitro culture...
September 2018: Balsaeng'gwa Saengsig
Ying Zhang, Xue Liu, Lu Zhang, Xuelian Li, Zhongqiu Zhou, Lei Jiao, Yingchun Shao, Mengmeng Li, Bing Leng, Yuhong Zhou, Tianyi Liu, Qiushuang Liu, Hongli Shan, Zhimin Du
Ischemia-reperfusion (I/R) injury is a major side effect of the reperfusion treatment of the ischemic heart. Few therapies are available for the effective prevention of this injury caused by the oxidative stress-induced cardiomyocyte apoptosis. Metformin was shown to have a potential cardiac protective effect and ability to reduce cardiac events, but the exact mechanism remains unclear. Here, we aimed to confirm and investigate the mechanisms underlying potential metformin activity against I/R injury in response to oxidative stress...
September 6, 2018: Molecular Therapy. Nucleic Acids
Virginia Andreani, Senthilkumar Ramamoorthy, Abhinav Pandey, Ekaterina Lupar, Stephen L Nutt, Tim Lämmermann, Rudolf Grosschedl
Plasma cell differentiation involves coordinated changes in gene expression and functional properties of B cells. Here, we study the role of Mzb1, a Grp94 cochaperone that is expressed in marginal zone (MZ) B cells and during the terminal differentiation of B cells to antibody-secreting cells. By analyzing Mzb1 -/- Prdm1 +/gfp mice, we find that Mzb1 is specifically required for the differentiation and function of antibody-secreting cells in a T cell-independent immune response. We find that Mzb1-deficiency mimics, in part, the phenotype of Blimp1 deficiency, including the impaired secretion of IgM and the deregulation of Blimp1 target genes...
October 9, 2018: Proceedings of the National Academy of Sciences of the United States of America
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