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Li Chen, Chao Huang, Zhuo Chen
Depression is a mental disease that causes severe economic and social burdens. The mechanism for the onset of depression remains largely unknown. Recently, more and more attention is being given to the role of neuroinflammation and oxidative stress in depression. Tauroursodeoxycholic acid (TUDCA), a clinically available agent used to treat cholesterol gallstone and protect neurons against neurodegeneration, has been reported to prevent neuroinflammation and oxidative stress. In this study, we investigated the effect of TUDCA on lipopolysaccharide (LPS)-induced depression-like behavior, neuroinflammation, and oxido-nitrosative stress in mice...
December 5, 2018: Pharmacology
C De Miguel, R Sedaka, M Kasztan, J M Lever, M Sonnenberger, A Abad, C Jin, P K Carmines, D M Pollock, J S Pollock
AIM: Chronic high salt intake exaggerates renal injury and inflammation, especially with the loss of functional ETB receptors. Tauroursodeoxycholic acid (TUDCA) is a chemical chaperone and bile salt that is approved for the treatment of hepatic diseases. Our aim was to determine whether TUDCA is reno-protective in a model of ETB receptor deficiency with chronic high salt-induced renal injury and inflammation. METHODS: ETB -deficient and transgenic control rats were placed on normal (0...
November 30, 2018: Acta Physiologica
David Peter Obert, Alexander Karl Wolpert, Sebastian Korff
BACKGROUND: Impaired function of the endoplasmic reticulum (ER) results in ER stress, an accumulation of proteins in the ER lumen. ER stress is a major contributor to inflammatory diseases and is part of the pathomechanism of ischemia-reperfusion injury (IRI). Since severe traumatic injury is often accompanied by remote organ damage and immune cell dysfunction, we investigated the influence of ER stress modulation on the systemic inflammatory response and liver damage after hemorrhagic shock and reperfusion (HS/R)...
November 28, 2018: Shock
Sevtap Han, Nur Banu Bal, Gökhan Sadi, Suzan Emel Usanmaz, Merve Matilda Tuglu, Mecit Orhan Uludag, Emine Demirel-Yilmaz
Hypertension has complex vascular pathogenesis and therefore the molecular etiology remains poorly elucidated. Endoplasmic reticulum stress (ERS), which is a condition of the unfolded/misfolded protein accumulation in the endoplasmic reticulum, has been defined as a potential target for cardiovascular disease. In the present study, the effects of ERS inhibition on hypertension-induced alterations in the vessels were investigated. In male Wistar albino rats, hypertension was induced through unilateral nephrectomy, deoxycorticosterone-acetate (DOCA) injection (20 mg/kg, twice a week) and 1% NaCl with 0...
November 17, 2018: Vascular Pharmacology
Sebastian Thams, Emily Rhodes Lowry, Marie-Hélène Larraufie, Krista J Spiller, Hai Li, Damian J Williams, Phuong Hoang, Elise Jiang, Luis A Williams, Jackson Sandoe, Kevin Eggan, Ivo Lieberam, Kevin C Kanning, Brent R Stockwell, Christopher E Henderson, Hynek Wichterle
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease selectively targeting motor neurons in the brain and spinal cord. The reasons for differential motor neuron susceptibility remain elusive. We developed a stem cell-based motor neuron assay to study cell-autonomous mechanisms causing motor neuron degeneration, with implications for ALS. A small-molecule screen identified cyclopiazonic acid (CPA) as a stressor to which stem cell-derived motor neurons were more sensitive than interneurons. CPA induced endoplasmic reticulum stress and the unfolded protein response...
October 19, 2018: Molecular Therapy: the Journal of the American Society of Gene Therapy
Jerilee M K Azhary, Miyuki Harada, Nozomi Takahashi, Emi Nose, Chisato Kunitomi, Hiroshi Koike, Tetsuya Hirata, Yasushi Hirota, Kaori Koga, Osamu Wada-Hiraike, Tomoyuki Fujii, Yutaka Osuga
Polycystic ovary syndrome (PCOS) is associated with hyperandrogenism and growth arrest of antral follicles. Previously, we found that endoplasmic reticulum (ER) stress is activated in granulosa cells of antral follicles in PCOS, evidenced by activation of unfolded protein response (UPR) genes. Based on this observation, we hypothesized that ER stress is activated by androgens in granulosa cells of antral follicles, and that activated ER stress promotes apoptosis via induction of the UPR transcription factor C/EBP homologous protein (CHOP) and subsequent activation of death receptor (DR) 5...
November 12, 2018: Endocrinology
Jun Lou, Lei Huang, Aimei Wang, Yueyang Liu, Ruiping Cai, Weihong Li, Ming-Sheng Zhou
Background: Endoplasmic reticulum (ER) stress plays an important role in the pathogenesis of obesity, insulin resistance and cardiovascular diseases (CVDs). Impairment of insulin vascular action may represent a mechanism linking insulin resistance and CVDs. The present study tested the hypothesis that adipocyte-derived resistin inhibits insulin-stimulated endothelial NO production through the induction of ER stress. Methods and Results: Human umbilical vein endothelial cells (HUVC) were incubated with tunicamycin (an inducer of ER stress, 1-20 μg/mL) or resistin (10-100 ng/mL) for 1 h...
2018: Frontiers in Pharmacology
Jonas Maczewsky, Julia Kaiser, Anne Gresch, Felicia Gerst, Martina Düfer, Peter Krippeit-Drews, Gisela Drews
The Takeda-G-protein-receptor-5 (TGR5) mediates physiological actions of bile acids. Since it was shown that TGR5 is expressed in pancreatic tissue, a direct TGR5 activation in beta-cells is currently postulated and discussed. The present study reveals that oleanolic acid (OLA) affects murine beta-cell function by TGR5 activation. Both, a Gαs inhibitor and an inhibitor of adenylyl cyclase (AC) prevented stimulating effects of OLA. Accordingly, OLA augmented the intracellular cAMP concentration. OLA and two well-established TGR5 agonists, RG239 and tauroursodeoxycholic acid (TUDCA), acutely promoted stimulus-secretion coupling (SSC)...
November 8, 2018: Diabetes
Stewart F Graham, Nolwen L Rey, Zafer Ugur, Ali Yilmaz, Eric Sherman, Michael Maddens, Ray O Bahado-Singh, Katelyn Becker, Emily Schulz, Lindsay K Meyerdirk, Jennifer A Steiner, Jiyan Ma, Patrik Brundin
For people with Parkinson's disease (PD), considered the most common neurodegenerative disease behind Alzheimer's disease, accurate diagnosis is dependent on many factors; however, misdiagnosis is extremely common in the prodromal phases of the disease, when treatment is thought to be most effective. Currently, there are no robust biomarkers that aid in the early diagnosis of PD. Following previously reported work by our group, we accurately measured the concentrations of 18 bile acids in the serum of a prodromal mouse model of PD...
October 31, 2018: Metabolites
Seung Un Seo, Kyoung-Jin Min, Seon Min Woo, Ji Hae Seo, Taeg Kyu Kwon
We previously reported that PP242 (dual inhibitor of mTORC1/2) plus curcumin induced apoptotic cell death through lysosomal membrane permeabilization (LMP)-mediated autophagy. However, the relationship between ER stress and apoptotic cell death by combined PP242 and curcumin treatment remains unknown. In the present study, we found that combined PP242 and curcumin treatment induced cytosolic Ca2+ release and ER stress. Interestingly, pretreatment with the chemical chaperones (TUDCA and 4-PBA) and knockdown of CHOP and ATF4 by siRNA did not abolish combined treatment-induced apoptosis in renal carcinoma cells...
October 24, 2018: Molecules: a Journal of Synthetic Chemistry and Natural Product 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
Huimin Hu, Changyuan Wang, Yue Jin, Qiang Meng, Qi Liu, Zhihao Liu, Kexin Liu, Xiaoyu Liu, Huijun Sun
Hyperhomocysteinemia (HHCY) has been recognized as an independent risk factor for atherosclerosis and plays a vital role in the development of atherosclerosis. Catalpol, an iridoid glucoside extracted from the root of Rehmannia glutinosa, can produce anti-inflammatory, anti-oxidant, anti-tumor, and dopaminergic neurons protecting effects. This study aimed to determine the protecting effects of catalpol against homocysteine (HCY)-induced injuries in human aortic endothelial cells (HAECs) and uncover the underlying mechanisms: 1...
October 12, 2018: Inflammation
Shaoqun Shu, Jiefu Zhu, Zhiwen Liu, Chengyuan Tang, Juan Cai, Zheng Dong
BACKGROUND: Acute kidney injury (AKI) may lead to the development of chronic kidney disease (CKD), i.e. AKI-CKD transition, but the underlying mechanism remains largely unclear. Endoplasmic reticulum (ER) stress is characterized by the accumulation of unfolded or misfolded proteins in ER resulting in a cellular stress response. The role of ER stress in AKI-CKD transition remains unknown. METHODS: In this study, we examined ER stress in the mouse model of AKI-CKD transition after unilateral renal ischemia-reperfusion injury (uIR)...
October 9, 2018: EBioMedicine
Qingqing Song, Wenjing Liu, Xiaojia Chen, Jun Li, Peng Li, Fengqing Yang, Yitao Wang, Yuelin Song, Pengfei Tu
The acquisition of high-quality quantitative dataset is the prerequisite for large-scale targeted metabolomics. However, the goal is usually dampened by the complexity of the biological matrices in terms of structural diversity, concentration span, and polarity range. We attempted herein to propose an analytical approach being able to circumvent these technical obstacles, and medicinal bile was employed as a proof of concept. In the liquid chromatography (LC) domain, reversed phase LC and hydrophilic liquid interaction chromatography were coupled in series, namely RPLC-HILIC, to yield appropriate chromatographic behavior for each component regardless of the polarity...
December 11, 2018: Analytica Chimica Acta
Fan Xiong, Shan-Gong Wu, Jing Zhang, Ivan Jakovlić, Wen-Xiang Li, Hong Zou, Ming Li, Gui-Tang Wang
Lipid metabolism can influence host's health. There is increasing evidence for interplay between two key regulating factors in lipid metabolism: bile acids (BAs) and gut microbiota. However, very little is known about how types of different diet-supplemented bile salts (BS) influence this interaction in vivo . We sought to explore these relationships using grass carp ( Ctenopharyngodon idellus ), which often suffers functional disorder of liver and gallbladder. We studied fluctuations of BAs in the gall and changes of microbial communities in the gut in response to seven different diets: five different BS, chelating BS agent, and control...
2018: Frontiers in Microbiology
Xian Yu, Lu-Ping Ren, Chao Wang, Ya-Jun Zhu, Han-Ying Xing, Jing Zhao, Guang-Yao Song
Background: A high consumption of fructose leads to hepatic steatosis. About 20-30% of triglycerides are synthesized via de novo lipogenesis. Some studies showed that endoplasmic reticulum stress (ERS) is involved in this process, while others showed that a lipotoxic environment directly influences ER homeostasis. Here, our aim was to investigate the causal relationship between ERS and fatty acid synthesis and the effect of X-box binding protein-1 (XBP-1), one marker of ERS, on hepatic lipid accumulation stimulated by high fructose...
October 5, 2018: Chinese Medical Journal
Xinxin Pang, Yage Zhang, Xiujie Shi, Dongyang Li, Jiarui Han
Diabetic nephropathy (DN) is a major complication of diabetes, and the dysfunction of endoplasmic reticulum (ER) plays an important role in its pathogenesis. ERp44, an ER resident chaperone protein, has been implicated in the modulation of ER stress, however, its role and mechanism in DN are not determined. Here, we show that ERp44 expression is upregulated in the glomeruli of db/db mice, a rodent model of type 2 diabetes. When ERp44 is depleted by in vivo shRNA-mediated knockdown, the features associated with DN including albuminuria level and glomerular basement membrane (GBM) thickness are aggravated, therefore suggesting a detrimental role of ERp44 depletion in DN progression...
October 12, 2018: Biochemical and Biophysical Research Communications
Carol L Ladner-Keay, Li Ross, Rolando Perez-Pineiro, Lun Zhang, Trent C Bjorndahl, Neil Cashman, David S Wishart
Prion diseases are caused by the conversion of normal cellular prion proteins (PrP) into lethal prion aggregates. These prion aggregates are composed of proteinase K (PK) resistant fibrils and comparatively PK-sensitive oligomers. Currently there are no anti-prion pharmaceuticals available to treat or prevent prion disease. Methods of discovering anti-prion molecules rely primarily on relatively complex cell-based, tissue slice or animal-model assays that measure the effects of small molecules on the formation of PK-resistant prion fibrils...
September 18, 2018: Prion
Xin Tong, Qifan Zhang, Lu Wang, Yizhong Ji, Lei Zhang, Liwei Xie, Wei Chen, Huabing Zhang
RING finger 186 (RNF186) is involved in the process of endoplasmic reticulum (ER)-stress-mediated apoptosis and inflammation of different cell types, such as HeLa cells and colon epithelial cells. However, the physiological and functional roles of RNF186 in peripheral tissues remain largely unknown. In the current study, we investigate the physiological function of RNF186 in the regulation of ER stress with respect to its biological roles in regulating insulin sensitivity in mouse primary hepatocytes. RNF186 expression is induced in the livers of diabetic, obese and diet-induced obese (DIO) mice...
September 14, 2018: Cellular Signalling
Merve Aksoz, Esra Albayrak, Galip Servet Aslan, Raife Dilek Turan, Lamia Yazgi Alyazici, Pinar Siyah, Emre Can Tusuz, Serli Canikyan, Dogacan Yucel, Neslihan Meric, Zafer Gulbas, Fikrettin Sahin, Fatih Kocabas
c-Myc plays a major role in the maintenance of glycolytic metabolism and hematopoietic stem cell (HSC) quiescence. Targeting modulators of HSC quiescence and metabolism could lead to HSC cell cycle entry with concomitant expansion. Here we show that c-Myc inhibitor 10074-G5 treatment leads to 2-fold increase in murine LSKCD34low HSC compartment post 7 days. In addition, c-Myc inhibition increases CD34+ and CD133+ human HSC number. c-Myc inhibition leads to downregulation of glycolytic and cyclin-dependent kinase inhibitor (CDKI) gene expression ex vivo and in vivo...
September 4, 2018: Current Cancer Drug Targets
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