scholarly journals Glycoursodeoxycholic Acid Ameliorates Diet-induced Metabolic Disorders with Inhibiting Endoplasmic Reticulum Stress

2021 ◽  
Author(s):  
Lele Cheng ◽  
Tao Chen ◽  
Manyun Guo ◽  
Peining Liu ◽  
Xiangrui Qiao ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Endoplasmic Reticulum ◽  
Bile Acid ◽  
Er Stress ◽  
Hepatic Steatosis ◽  
Metabolic Disorders ◽  
Stool Samples ◽  
Glycoursodeoxycholic Acid

Recent studies reveal that bile acid metabolite composition and its metabolism are changed in metabolic disorders, such as obesity, type 2 diabetes and metabolic associated fatty liver disease (MAFLD), yet its role and the mechanism remain largely unknown. In the present study, metabolomic analysis of 163 serum and stool samples of our metabolic disease cohort was performed and we identified glycoursodeoxycholic acid (GUDCA), glycine-conjugated bile acid produced from intestinal bacteria, were decreased in both serum and stool samples from patients with hyperglycemia. RNA-sequencing and quantitative PCR results indicated that GUDCA alleviated endoplasmic reticulum (ER) stress in livers of high fat diet (HFD)-fed mice without alteration of liver metabolism. In vitro, GUDCA reduced palmitic acid induced-ER stress and -apoptosis, as well as stabilized calcium homeostasis. In vivo, GUDCA exerted effects on amelioration of HFD-induced insulin resistance and hepatic steatosis. In parallel, ER stress and apoptosis were decreased in GUDCA-treated mice as compared to vehicle-treated mice in liver. These findings demonstrate that reduced GUDCA is an indicator of hyperglycemia. Supplementation of GUDCA could be an option for the treatment of diet-induced metabolic disorders, including insulin resistance and hepatic steatosis, with inhibiting ER stress.

scholarly journals Dehydrodiisoeugenol inhibits colorectal cancer growth by endoplasmic reticulum stress-induced autophagic pathways

2021 ◽  
Vol 40 (1) ◽  
Author(s):  
Changhong Li ◽  
Kui Zhang ◽  
Guangzhao Pan ◽  
Haoyan Ji ◽  
Chongyang Li ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Endoplasmic Reticulum ◽  
Cell Growth ◽  
Er Stress ◽  
Cancer Cells ◽  
Tumor Xenograft ◽  
Anticancer Activities ◽  
Colorectal Cancer Cells

Abstract Background Dehydrodiisoeugenol (DEH), a novel lignan component extracted from nutmeg, which is the seed of Myristica fragrans Houtt, displays noticeable anti-inflammatory and anti-allergic effects in digestive system diseases. However, the mechanism of its anticancer activity in gastrointestinal cancer remains to be investigated. Methods In this study, the anticancer effect of DEH on human colorectal cancer and its underlying mechanism were evaluated. Assays including MTT, EdU, Plate clone formation, Soft agar, Flow cytometry, Electron microscopy, Immunofluorescence and Western blotting were used in vitro. The CDX and PDX tumor xenograft models were used in vivo. Results Our findings indicated that treatment with DEH arrested the cell cycle of colorectal cancer cells at the G1/S phase, leading to significant inhibition in cell growth. Moreover, DEH induced strong cellular autophagy, which could be inhibited through autophagic inhibitors, with a rction in the DEH-induced inhibition of cell growth in colorectal cancer cells. Further analysis indicated that DEH also induced endoplasmic reticulum (ER) stress and subsequently stimulated autophagy through the activation of PERK/eIF2α and IRE1α/XBP-1 s/CHOP pathways. Knockdown of PERK or IRE1α significantly decreased DEH-induced autophagy and retrieved cell viability in cells treated with DEH. Furthermore, DEH also exhibited significant anticancer activities in the CDX- and PDX-models. Conclusions Collectively, our studies strongly suggest that DEH might be a potential anticancer agent against colorectal cancer by activating ER stress-induced inhibition of autophagy.

scholarly journals Biochanin A Alleviates Cerebral Ischemia/Reperfusion Injury by Suppressing Endoplasmic Reticulum Stress-Induced Apoptosis and p38MAPK Signaling Pathway In Vivo and In Vitro

2021 ◽  
Vol 12 ◽  
Author(s):  
Min-min Guo ◽  
Sheng-biao Qu ◽  
Hui-ling Lu ◽  
Wen-bo Wang ◽  
Mu-Liang He ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Er Stress ◽  
P38 Mapk ◽  
Ischemia Reperfusion ◽  
Biochanin A ◽  
Neurological Deficits ◽  
Mapk Phosphorylation ◽  
Cerebral Ischemia Reperfusion

We have previously shown that biochanin A exhibits neuroprotective properties in the context of cerebral ischemia/reperfusion (I/R) injury. The mechanistic basis for such properties, however, remains poorly understood. This study was therefore designed to explore the manner whereby biochanin A controls endoplasmic reticulum (ER) stress, apoptosis, and inflammation within fetal rat primary cortical neurons in response to oxygen-glucose deprivation/reoxygenation (OGD/R) injury, and in a rat model of middle cerebral artery occlusion and reperfusion (MCAO/R) injury. For the OGD/R in vitro model system, cells were evaluated after a 2 h OGD following a 24 h reoxygenation period, whereas in vivo neurological deficits were evaluated following 2 h of ischemia and 24 h of reperfusion. The expression of proteins associated with apoptosis, ER stress (ERS), and p38 MAPK phosphorylation was evaluated in these samples. Rats treated with biochanin A exhibited reduced neurological deficits relative to control rats following MCAO/R injury. Additionally, GRP78 and CHOP levels rose following I/R modeling both in vitro and in vivo, whereas biochanin A treatment was associated with reductions in CHOP levels but further increases in GRP78 levels. In addition, OGD/R or MCAO/R were associated with markedly enhanced p38 MAPK phosphorylation that was alleviated by biochanin A treatment. Similarly, OGD/R or MCAO/R injury resulted in increases in caspase-3, caspase-12, and Bax levels as well as decreases in Bcl-2 levels, whereas biochanin A treatment was sufficient to reverse these phenotypes. Together, these findings thus demonstrate that biochanin A can alleviate cerebral I/R-induced damage at least in part via suppressing apoptosis, ER stress, and p38 MAPK signaling, thereby serving as a potent neuroprotective agent.

scholarly journals Regulation of Adipsin Expression by Endoplasmic Reticulum Stress in Adipocytes

Biomolecules ◽  
2020 ◽  
Vol 10 (2) ◽  
pp. 314
Author(s):  
Ka-Young Ryu ◽  
Eon Ju Jeon ◽  
Jaechan Leem ◽  
Jae-Hyung Park ◽  
Hochan Cho
Keyword(s):  
Endoplasmic Reticulum ◽  
Er Stress ◽  
Peroxisome Proliferator ◽  
Adipose Tissues ◽  
Peroxisome Proliferator Activated Receptor ◽  
Er Stress Response ◽  
Stress Markers ◽  
Transcriptional Reprogramming

Adpsin is an adipokine that stimulates insulin secretion from β-cells and improves glucose tolerance. Its expression has been found to be markedly reduced in obese animals. However, it remains unclear what factors lead to downregulation of adipsin in the context of obesity. Endoplasmic reticulum (ER) stress response is activated in various tissues under obesity-related conditions and can induce transcriptional reprogramming. Therefore, we aimed to investigate the relationship between adipsin expression and ER stress in adipose tissues during obesity. We observed that obese mice exhibited decreased levels of adipsin in adipose tissues and serum and increased ER stress markers in adipose tissues compared to lean mice. We also found that ER stress suppressed adipsin expression via adipocytes-intrinsic mechanisms. Moreover, the ER stress-mediated downregulation of adipsin was at least partially attributed to decreased expression of peroxisome proliferator-activated receptor γ (PPARγ), a key transcription factor in the regulation of adipocyte function. Finally, treatment with chemical chaperones recovered the ER stress-mediated downregulation of adipsin and PPARγ in vivo and in vitro. Our findings suggest that activated ER stress in adipose tissues is an important cause of the suppression of adipsin expression in the context of obesity.

scholarly journals A Novel Transcription Factor, ERD15 (Early Responsive to Dehydration 15), Connects Endoplasmic Reticulum Stress with an Osmotic Stress-induced Cell Death Signal

2011 ◽  
Vol 286 (22) ◽  
pp. 20020-20030 ◽  
Author(s):  
Murilo S. Alves ◽  
Pedro A. B. Reis ◽  
Silvana P. Dadalto ◽  
Jerusa A. Q. A. Faria ◽  
Elizabeth P. B. Fontes ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Cell Death ◽  
Transcription Factor ◽  
Osmotic Stress ◽  
Er Stress ◽  
Unfolded Protein ◽  
Eukaryotic Organisms ◽  
Protein Response

As in all other eukaryotic organisms, endoplasmic reticulum (ER) stress triggers the evolutionarily conserved unfolded protein response in soybean, but it also communicates with other adaptive signaling responses, such as osmotic stress-induced and ER stress-induced programmed cell death. These two signaling pathways converge at the level of gene transcription to activate an integrated cascade that is mediated by N-rich proteins (NRPs). Here, we describe a novel transcription factor, GmERD15 (Glycine max Early Responsive to Dehydration 15), which is induced by ER stress and osmotic stress to activate the expression of NRP genes. GmERD15 was isolated because of its capacity to stably associate with the NRP-B promoter in yeast. It specifically binds to a 187-bp fragment of the NRP-B promoter in vitro and activates the transcription of a reporter gene in yeast. Furthermore, GmERD15 was found in both the cytoplasm and the nucleus, and a ChIP assay revealed that it binds to the NRP-B promoter in vivo. Expression of GmERD15 in soybean protoplasts activated the NRP-B promoter and induced expression of the NRP-B gene. Collectively, these results support the interpretation that GmERD15 functions as an upstream component of stress-induced NRP-B-mediated signaling to connect stress in the ER to an osmotic stress-induced cell death signal.

scholarly journals Exogenous acylated ghrelin promotes but un-acylated ghrelin prevents hepatic steatosis by modulating peripheral insulin resistance and hepatic oxidative and endoplasmic reticulum stress

2021 ◽  
Vol 7 (3) ◽  
Keyword(s):  
Insulin Resistance ◽  
Endoplasmic Reticulum ◽  
Endoplasmic Reticulum Stress ◽  
Er Stress ◽  
Hepatic Steatosis ◽  
Fatty Acid Synthase ◽  
Lipid Synthesis ◽  
Acylated Ghrelin ◽  
Mrna Levels ◽  
Protein Levels

Objectives: This study tested the effects of acylated (AG and un-acylated ghrelin (UAG) on hepatic lipid synthesis and insulin resistance (IR) from prospective to their effect on endoplasmic reticulum stress and investigated the possible underlying mechanisms. Methods: Healthy rats were divided as 4 groups (n=12/each) as control, control + AG, control + UAG, and control + AG + UAG (1:1). GA or UAG were given subcutaneously (200 ng/kg/each) for 8 weeks. Results: AG increased fasting levels of glucose and insulin resistance, increased hepatic glucose production, and impaired glucose and insulin tolerance. Besides, it increased serum levels of free fatty acids (FFAs), enhanced serum and hepatic levels of triglycerides and cholesterol, and increased lipid deposition in the livers of rats. Concomitantly, it stimulated the mRNA levels of SREBP1/2, fatty acid synthase, and protein levels of all arms of ER stress including Xbp-1, CHOP, ATF-6, and p-eIF2α, thus activating lipid synthesis and ER stress. It also reduced protein levels of p-IRS (Tyr612), p-Akt (Ser307), and increased levels of ROS, TNF-α, IL-6, and protein levels of cleaved caspase-12, p-IRS (Ser307), and p-JNK (The183/Tyr186) in rats’ livers. Administration of UAG alone or in combination with AG produced contradictory effects. However, both AG and UAG significantly increased mRNA levels of AMPK and PPARα suggesting FAs oxidation. Conclusion: AG induces hepatic steatosis and suppresses hepatic insulin signaling mainly by inducing peripheral IR that is associated with hepatic oxidative stress, inflammation, and ER stress. However, UAG alone or in combination exerts opposite effects.

scholarly journals Docosahexaenoic Acid Lessens Hepatic Lipid Accumulation and Inflammation via the AMP-Activated Protein Kinase and Endoplasmic Reticulum Stress Signaling Pathway in Grass Carp (Ctenopharyngodon Idella)

2021 ◽  
Author(s):  
Xiaocheng Huang ◽  
Jian Sun ◽  
Chenchen Bian ◽  
Shanghong Ji ◽  
Hong ji
Keyword(s):  
Endoplasmic Reticulum ◽  
Protein Kinase ◽  
Hepatic Steatosis ◽  
Grass Carp ◽  
Lipid Accumulation ◽  
Ctenopharyngodon Idella ◽  
Hepatic Inflammation ◽  
Amp Activated Protein Kinase

Abstract Background: The liver is the primary organ for frontline immune defense and lipid metabolism. Excessive lipid accumulation in the liver severely affects its metabolic homeostasis and causes metabolic diseases. Docosahexaenoic acid (DHA) is known for its beneficial effects on lipid metabolism and anti-inflammation, but its molecular mechanism remains unknown, especially in fish. In this study, we evaluated the protective effects of DHA on hepatic steatosis of grass carp (Ctenopharyngodon idella) in vivo and in vitro and mainly focused on lipogenesis and inflammation. Grass carp were fed with purified diets supplemented with 0%, 0.5% and 1% DHA for 8 weeks in vivo. Hepatocytes were treated with palmitic acid (PA) (200 μM) with or without DHA (50 or 100 μM) for 24 h in vitro. In addition, Compound C (CC, the inhibitor of AMP-activated protein kinase) was used to examine the mechanism of DHA on hepatic steatosis in vitro.Results: In this study, 1% DHA significantly decreased the liver triglyceride (TG), malondialdehyde (MDA), serum tumor necrosis factor α (TNFα) and nuclear factor kappa B (NFκB) contents. DHA (100 μM) effectively attenuated PA-induced lipid accumulation (P<0.05). Furthermore, DHA significantly inhibited endoplasmic reticulum (ER) stress and stimulated the expression of AMP-activated protein kinase (AMPK) and its downstream factors related to hepatic inflammation and lipogenesis in vivo and in vitro. However, the effects of DHA could be abrogated by CC in vitro.Conclusions: DHA exerted a protective effect on hepatic steatosis by inhibiting ER stress, improving antioxidant ability, relieving hepatic inflammation and inhibiting hepatic lipogenesis in an AMPK-dependent manner. Our findings give a theoretical foundation for further elucidation of the beneficial role of DHA in vertebrates.

Abstract 13: Targeting the PERK Pathway of ER Stress Response for Endothelium Protection and Restenosis Prevention: A Paradigm for Developing Anti-thrombogenic Stents

2016 ◽  
Vol 36 (suppl_1) ◽  
Author(s):  
Bowen Wang ◽  
Mengxue Zhang ◽  
Xudong Shi ◽  
Lian-Wang Guo ◽  
Michael Hoffmann ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Er Stress ◽  
Selective Inhibition ◽  
Post Injury ◽  
Mortality And Morbidity ◽  
Lumen Narrowing ◽  
Potential Strategy ◽  
Differentiation And Proliferation

Introduction: Cardiovascular disease is the leading cause of mortality and morbidity in the US. Reconstructions often fail due to the recurrent lumen narrowing, or restenosis. Stents eluting rapamycin or paclitaxel are deployed to inhibit the excessive proliferation of smooth muscle cells (SMCs), which is the core component of restenosis. However, these drugs cause collateral damage to endothelial cells (ECs) leading to stent thrombosis. To address this, our group initiated the first campaign of drug screening for compounds that selectively inhibit SMC proliferation without causing EC dysfunction. We recently identified lead compounds as such, which are inhibitors for protein kinase RNA-like endoplasmic reticulum kinase (PERK), an endoplasmic reticulum (ER) stress sensor. Here we evaluated PERK as a target for intervention of both SMC pathophysiology and EC dysfunction. Methods: Rat carotid artery balloon angioplasty was performed as a restenosis model. PDGF-BB and TNF-a were applied to primary human aortic SMCs and ECs, respectively, to mimic the in vivo pathogenic stimuli. Results: In balloon-injured arteries, both PERK phosphorylation and the expression of its downstream transcription factor ATF4 were increased compared to sham control. PERK activation was also observed in vitro in both SMCs and ECs stimulated with PDGF-BB and TNF-a, respectively. In SMCs, either selective inhibition (1μM GSK2606414) or siRNA knockdown of PERK abolished PDGF-BB induced de-differentiation and proliferation. In ECs, PERK antagonism abrogated TNF-a induced growth impairment and EC secretion of Tissue Factor (TF), which is the key initiator of thrombogenesis. Finally, in a pilot experiment, peri-adventitial application of GSK2606414 (25mg/kg, n=2 rats) reduced intima/media ratio by 80% and increased lumen area by ~ 2 fold compared to vehicle control (n=2) at 4 weeks post injury. Conclusion: Our results indicate an important role of PERK activation in promoting SMC phenotype switching and EC dysfunction in vitro as well as restenosis in vivo . Thus, PERK targeting represents a potential strategy to simultaneously achieve restenosis prevention and endothelium protection, with a long-term goal of developing anti-thrombogenic drug-eluting stents.

scholarly journals Protection of pancreatic β-cells by exendin-4 may involve the reduction of endoplasmic reticulum stress; in vivo and in vitro studies

2007 ◽  
Vol 193 (1) ◽  
pp. 65-74 ◽  
Author(s):  
Shin Tsunekawa ◽  
Naoki Yamamoto ◽  
Katsura Tsukamoto ◽  
Yuji Itoh ◽  
Yukiko Kaneko ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Cell Death ◽  
Er Stress ◽  
Islet Cells ◽  
Binding Protein ◽  
Β Cells ◽  
Β Cell ◽  
Pancreatic Β Cells

The aim of this study was to investigate the in vivo and in vitro effects of exendin-4, a potent glucagon-like peptide 1 agonist, on the protection of the pancreatic β-cells against their cell death. In in vivo experiments, we used β-cell-specific calmodulin-overexpressing mice where massive apoptosis takes place in their β-cells, and we examined the effects of chronic treatment with exendin-4. Chronic and s.c. administration of exendin-4 reduced hyperglycemia. The treatment caused significant increases of the insulin contents of the pancreas and islets, and retained the insulin-positive area. Dispersed transgenic islet cells lived only shortly, and several endoplasmic reticulum (ER) stress-related molecules such as immunoglobulin-binding protein (Bip), inositol-requiring enzyme-1α, X-box-binding protein-1 (XBP-1), RNA-activated protein kinase-like endoplasmic reticulum kinase, activating transcription factor-4, and C/EBP-homologous protein (CHOP) were more expressed in the transgenic islets. We also found that the spliced form of XBP-1, a marker of ER stress, was also increased in β-cell-specific calmodulin-overexpressing transgenic islets. In the quantitative real-time PCR analyses, the expression levels of Bip and CHOP were reduced in the islets from the transgenic mice treated with exendin-4. These findings suggest that excess of ER stress occurs in the transgenic β-cells, and the suppression of ER stress and resultant protection against cell death may be involved in the anti-diabetic effects of exendin-4.

scholarly journals The Canine Papillomavirus E5 Protein Signals from the Endoplasmic Reticulum

2009 ◽  
Vol 83 (24) ◽  
pp. 12833-12841 ◽  
Author(s):  
Rachel Condjella ◽  
Xuefeng Liu ◽  
Frank Suprynowicz ◽  
Hang Yuan ◽  
Sawali Sudarshan ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Growth Inhibition ◽  
Er Stress ◽  
Protein A ◽  
Keratinocyte Differentiation ◽  
Keratinocyte Proliferation ◽  
Reading Frame ◽  
E5 Protein

ABSTRACT The recently discovered Canis familiaris papillomavirus (PV) type 2 (CfPV2) provides a unique opportunity to study PV gene functions in vitro and in vivo. Unlike the previously characterized canine oral PV, CfPV2 contains an E5 open reading frame and is associated with progression to squamous cell carcinoma. In the current study, we have expressed and characterized the CfPV2-encoded E5 protein, a small, hydrophobic, 41-amino-acid polypeptide. We demonstrate that, similar to the E5 protein from high-risk human PV type 16, the CfPV2 E5 protein is localized in the endoplasmic reticulum (ER) and that its expression decreases keratinocyte proliferation and cell life span. E5 expression also increases the percentage of cells in the G1 phase of the cell cycle, with a concomitant decrease in the percentage of cells in S phase. To identify a potential mechanism for E5-mediated growth inhibition from the ER, we developed a real-time PCR method to quantify the splicing of XBP1 mRNA as a measure of ER stress. We found that the CfPV2 E5 protein induced ER stress and that this, as well as the observed growth inhibition, is tempered significantly by coexpression of the CfPV2 E6 and E7 genes. It is possible that the spatial/temporal regulation of E6/E7 gene expression during keratinocyte differentiation might therefore modulate E5 activity and ER stress.

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