scholarly journals sFlt-1 (sVEGFR1) induces placental endoplasmic reticulum stress in trophoblast cell: implications for the complications in preeclampsia- an in vitro study

2017 ◽  
Author(s):  
Sankat Mochan ◽  
Manoj Kumar Dhingra ◽  
Betsy Varghese ◽  
Sunil Kumar Gupta ◽  
Shobhit saxena ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Endoplasmic Reticulum Stress ◽  
Er Stress ◽  
Sandwich Elisa ◽  
Maternal Serum ◽  
Trophoblast Cells ◽  
Maternal Circulation ◽  
Stress Markers ◽  
Apoptotic Protein

AbstractBackgroundThe concentration of sFlt-1, a major anti-angiogenic protein in maternal circulation has been seen to be raised in preeclamptic pregnancies. Endoplasmic reticulum (ER) stress represents one of the three (immunological, oxidative and ER stress) major stresses which placenta undergoes during pregnancies. The present study is designed to investigate the role of sFlt-1 in induction of ER stress in trophoblast cells.Materials and MethodsMaternal serum levels of anti-angiogenic protein sFlt-1 and central regulator of unfolded protein response GRP78 was measured using sandwich ELISA. The expression of various ER stress markers (GRP78, eIF2α, XBP1, ATF6 and apoptotic protein CHOP) were analyzed depending on various treatments given to the trophoblast cells using Immunofluorescence, western blot and q-RT PCR.ResultsIncreased expression of ER stress markers (GRP78, eIF2α, XBP1 ATF6 and apoptotic protein CHOP) was detected in the placental trophoblast cells treated with raised concentration of sFlt-1.ConclusionSignificant upregulated expression of ER stress markers in trophoblast cells exposed with increased concentration of sFlt-1 suggested that it may be one of the anti-angiogenic factors present in maternal sera which not only contributes to oxidative stress but also may cause endoplasmic reticulum stress.

scholarly journals sFlt-1 commutes unfolded protein response into endoplasmic reticulum stress in trophoblast cells in preeclamptic pregnancies

2018 ◽  
Author(s):  
Sankat Mochan ◽  
Manoj Kumar Dhingra ◽  
Sunil Kumar Gupta ◽  
Shobhit saxena ◽  
Pallavi Arora ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Endoplasmic Reticulum ◽  
Endoplasmic Reticulum Stress ◽  
Er Stress ◽  
Late Onset ◽  
Trophoblast Cells ◽  
Bewo Cells ◽  
Placental Cells

AbstractPreeclampsia (PE) and its subtypes (early and late onset) are serious concerns all across the globe affecting about 8% of total pregnancies and accounts for approximately 60,000 deaths annually with a predominance in developing under-developed and countries. The two-stage model in the progression of this disease, deficient spiral artery remodelling and an imbalance between angiogenic (VEGF) and anti-antigenic factor(s) (sFlt-1) are well established facts pertaining to this disease. The presence of increased sFlt-1, high oxidative stress and Endoplasmic reticulum stress (ER stress) have been proposed in preeclamptic pregnancies. Recently, the role of endoplasmic reticulum stress in the onset of the variant forms of PE highlighted a new window to explore further. In our previous studies, we demonstrated that sFlt-1 can induce apoptosis and oxidative stress in trophoblast cells. However the role of sFlt-1, in inducing ER stress is not known so far. In the present study, we for the first time demonstrated significant ER stress in the placental cells (BeWo Cells) (in vitro) when exposed to sera from preeclamptic pregnancies having increased concentration of sFlt-1. The expression of ER stress markers (GRP78, eIF2α, XBP1, ATF6 and CHOP) at both transcript and protein levels were compared (between preeclamptic and normotensive non-proteinuric women) at three different time points (8h, 14h and 24hrs), analyzed and found to be significant (p<0.05).ConclusionOur results suggested that sFlt-1, released from placental cells in preeclampsia may be one of the various factors having potential to induce endoplasmic reticulum stress in BeWo cells.

scholarly journals EGFRvIII Promotes Cell Survival during Endoplasmic Reticulum Stress through a Reticulocalbin 1-Dependent Mechanism

Cancers ◽  
2021 ◽  
Vol 13 (6) ◽  
pp. 1198
Author(s):  
Juliana Gomez ◽  
Zammam Areeb ◽  
Sarah F. Stuart ◽  
Hong P. T. Nguyen ◽  
Lucia Paradiso ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Cell Viability ◽  
Er Stress ◽  
Cell Survival ◽  
Glioblastoma Cells ◽  
Over Expression ◽  
Stress Markers ◽  
Apoptotic Protein ◽  
Novel Association ◽  
Reduced Activity

Reticulocalbin 1 (RCN1) is an endoplasmic reticulum (ER)-residing protein, involved in promoting cell survival during pathophysiological conditions that lead to ER stress. However, the key upstream receptor tyrosine kinase that regulates RCN1 expression and its potential role in cell survival in the glioblastoma setting have not been determined. Here, we demonstrate that RCN1 expression significantly correlates with poor glioblastoma patient survival. We also demonstrate that glioblastoma cells with expression of EGFRvIII receptor also have high RCN1 expression. Over-expression of wildtype EGFR also correlated with high RCN1 expression, suggesting that EGFR and EGFRvIII regulate RCN1 expression. Importantly, cells that expressed EGFRvIII and subsequently showed high RCN1 expression displayed greater cell viability under ER stress compared to EGFRvIII negative glioblastoma cells. Consistently, we also demonstrated that RCN1 knockdown reduced cell viability and exogenous introduction of RCN1 enhanced cell viability following induction of ER stress. Mechanistically, we demonstrate that the EGFRvIII-RCN1-driven increase in cell survival is due to the inactivation of the ER stress markers ATF4 and ATF6, maintained expression of the anti-apoptotic protein Bcl-2 and reduced activity of caspase 3/7. Our current findings identify that EGFRvIII regulates RCN1 expression and that this novel association promotes cell survival in glioblastoma cells during ER stress.

114 ENDOPLASMIC RETICULUM (ER) STRESS IN HYPOXIA-INDUCED DIABETES MELLITUS MODEL

2016 ◽  
Vol 28 (2) ◽  
pp. 187
Author(s):  
C. Ahn ◽  
D. Lee ◽  
K. P. Kim ◽  
M. H. Lee ◽  
E.-B. Jeung
Keyword(s):  
Endoplasmic Reticulum ◽  
Endoplasmic Reticulum Stress ◽  
Er Stress ◽  
Pancreatic Beta Cells ◽  
Hypoxic Condition ◽  
Protein Translation ◽  
Ion Concentration ◽  
Cellular Stress Response ◽  
Stress Markers ◽  
Calbindin D9k

Endoplasmic reticulum (ER) regulates calcium ion concentration as a reservoir in the cell. ER stress is a cellular stress response related to the endoplasmic reticulum. At the initial stage of ER stress, ER tries to restore normal function by halting protein translation, degrading misfolded proteins, and increasing production of chaperones involved in protein folding. If ER fails to restore ER stress, ER stress can lead cells to apoptosis. To study the signaling between ER stress and calcium channels under ER-stressed circumstances, we designed a hypoxia-induced diabetic model. Nine-week-old male mice were chosen, maintained under hypoxic condition under 10% O2, 5% CO2 for 10 days, and the expression of ER stress markers and calcium channel gene expression were examined by real-time PCR. By maintaining hypoxic condition, the mice showed high glucose levels. Under this diabetic condition, in pancreatic beta cells, ER stress markers were elevated. This tendency showed an increase in calbindin-D9k KO mice. Chaperones such as calreticulin and calnexin were decreased, but in calbindin-D9k KO mice chaperone calnexin was not decreased. Interestingly, the calbindin-D9k KO normoxia mice showed increased glucose level compared with wild-type normoxia mice. Also, calnexin expression of pancreas was decreased in calbindin-D9k KO normoxia mice. This result indicates that pancreas cells were under endoplasmic reticulum stress. Taken together, calbindin may play an important role in endoplasmic reticulum stress in pancreas. This work was supported by the National Research Foundation of Korea (NRF) grant of Korean government (MEST) (No. 2013-010514).

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 Downregulation of ceramide synthase 1 promotes oral cancer through endoplasmic reticulum stress

2020 ◽  
Author(s):  
WEN CHEN ◽  
ZHE LIU ◽  
CHENZHOU WU ◽  
YAFEI CHEN ◽  
LING QIU ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Oral Cancer ◽  
Endoplasmic Reticulum Stress ◽  
Er Stress ◽  
Cell Counting ◽  
Luciferase Assay ◽  
Migration And Invasion ◽  
Ceramide Synthase ◽  
Rt Pcr

Abstract Background C18 ceramide (CER) plays an important role in the occurrence and development of oral squamous cell carcinoma (OSCC). However, the function of ceramide synthase 1 (CERS1), a key enzyme in C18 CER synthesis, in OSCC is still unclear. The aim of our study was to investigate the relationship between CERS1 and oral cancer. Methods The expression of CERS1 on 48 pairs of matching OSCC patients’ cancer and normal tissues was determined by quantitative real-time PCR (RT-PCR). A mouse OSCC model induced by 4-nitroquinolin-1-oxide (4NQO) was established on CERS1+/+ and CERS1-/- C57BL/N6 mice. The functions of CERS1 downregulated were accessed by cell counting kit-8 method, colony formation assay, EdU DNA Proliferation in vitro Detection, wound healing test and Annexin V/PI double staining. RT-PCR, Western blot and luciferase assay were performed to explore the molecular mechanisms of CERS1. Results In this study, we found that the expression of CERS1 was downregulated in oral cancer tissues and cell lines. In the mouse OSCC model, CERS1 knockout was associated with the severity of oral malignant transformation. Immunohistochemical studies showed significant upregulation of PCNA, MMP2, MMP9, and BCL2 expression and downregulation of BAX expression in the pathological hyperplastic area. In addition, CERS1 knockdown promoted cell proliferation, migration and invasion in vitro. CERS1 knockdown caused endoplasmic reticulum stress (ER stress) and induced the activating transcription factor 4 (ATF4) pathway. ATF4 upregulated VEGFA transcription to promote tumor growth and metastasis. In addition, mild ER stress caused by CERS1 knockdown could induce cisplatin resistance. Conclusions Our study suggests that CERS1 is downregulated in oral cancer. The downregulation of CERS1 promotes the aggressiveness of OSCC and chemotherapeutic drug resistance by inducing mild ER stress.

3-O-Hydroxytyrosol glucuronide and 4-O-hydroxytyrosol glucuronide reduce endoplasmic reticulum stress in vitro

2015 ◽  
Vol 6 (10) ◽  
pp. 3275-3281 ◽  
Author(s):  
Elena Giordano ◽  
Olivier Dangles ◽  
Njara Rakotomanomana ◽  
Silvia Baracchini ◽  
Francesco Visioli
Keyword(s):  
Endoplasmic Reticulum ◽  
Endoplasmic Reticulum Stress ◽  
Er Stress ◽  
Unfolded Protein Response ◽  
Unfolded Protein ◽  
Atherosclerosis Development ◽  
The Unfolded Protein Response ◽  
Protein Response

Endoplasmic reticulum (ER) stress is important for atherosclerosis development and is mediated by the unfolded protein response (UPR).

scholarly journals Plant Bioactive Molecules Reduces Endoplasmic Reticulum Stress in Liver and Adipose Tissue of Obese Mice

2020 ◽  
Vol 4 (Supplement_2) ◽  
pp. 482-482
Author(s):  
Ivan Torre-Villalvazo ◽  
Armando Tovar ◽  
Claudia Tovar-Palacio ◽  
Nimbe Torres ◽  
Erik Alejandro Torre ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Adipose Tissue ◽  
Endoplasmic Reticulum Stress ◽  
Er Stress ◽  
Low Dose ◽  
Control Diet ◽  
Bioactive Molecules ◽  
Obese Mice ◽  
Funding Sources ◽  
Stress Markers

Abstract Objectives To determine if diferent plant bioactive compounds can ammelirate endoplasmic reticulum stress markers in liver and adipose tissue of obese mice and mice administered with a low dose of tunicamicin. Methods C57BL6 mice were fed a control diet (7% fat) or a high-fat diet (21% fat) with and without genistein or resveratrol supplementation (0.1%) for 12 weeks. Pharmacologic ER stress was induced in mice fed the control diet by an ip injection of a low dose of tunicamycin and euthanized 8 or 24 h after tunicamycin administration. Adipose tissues and liver were harvested to determine the abundance of ER stress markers by western blot and real time PCR. Results Genistein and resveratrol reduced the abundance of phospho JNK and phospho PERK in liver and subcutaneous adipose tissue of obese mice and lean mice administered with tunicamycin. Both polyphenols increased the mRNA abundance of XBP1s and BiP and reduced that of CHOP in both organs. These changes in proten phosphorylation and gene expression were accompanied with reduced hepatic steatosis and adipocyte hypertrophy. Conclusions The supplementation with plant polyphenols such as genistein or resveratrol reduced ER stress markers in liver and adipose tissue of obese mice and lean mice administerd with tunicamycin. Funding Sources This work is supported by a grant from CONACYT, Mexico to ITV Grant No. A1-S-41,077.

scholarly journals Metformin inhibits testosterone-induced endoplasmic reticulum stress in ovarian granulosa cells via inactivation of p38 MAPK

2020 ◽  
Vol 35 (5) ◽  
pp. 1145-1158 ◽  
Author(s):  
Jiamin Jin ◽  
Yerong Ma ◽  
Xiaomei Tong ◽  
Weijie Yang ◽  
Yongdong Dai ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Western Blot ◽  
Er Stress ◽  
P38 Mapk ◽  
Cumulus Cells ◽  
Mapk Phosphorylation ◽  
Stress Markers ◽  
Sensor Proteins ◽  
Stress Activation

Abstract STUDY QUESTION Does metformin inhibit excessive androgen-induced endoplasmic reticulum (ER) stress in mouse granulosa cells (GCs) in vivo and in vitro? SUMMARY ANSWER Metformin inhibits testosterone-induced ER stress and unfolded protein response (UPR) activation by suppressing p38 MAPK phosphorylation in ovarian GCs. WHAT IS KNOWN ALREADY Polycystic ovary syndrome (PCOS) is associated with hyperandrogenism. Excessive testosterone induces ER stress and UPR activation in human cumulus cells, leading to cell apoptosis. Metformin has potential inhibitory effects on ER stress and UPR activation, as demonstrated in human pancreatic beta cells and obese mice. STUDY DESIGN, SIZE, DURATION Cumulus cells and follicular fluid were collected from 25 women with PCOS and 25 controls at our IVF centre. A dihydrotestosterone (DHT)-induced PCOS mouse model was constructed and treated with or without metformin. Primary mouse GCs and cumulus-oocyte complexes (COCs) were cultured with testosterone, metformin, a p38 MAPK inhibitor, or p38 MAPK small interfering RNA. PARTICIPANTS/MATERIALS, SETTING, METHODS The levels of UPR sensor proteins and UPR-related genes were measured in cumulus cells from PCOS and control patients by real-time quantitative PCR (qPCR) and western blot. The ovaries, oocytes, GCs and COCs were collected from PCOS mice treated with metformin and controls. The expressions of ER stress markers and p38 MAPK phosphorylation were assessed by qPCR, western blot and immunofluorescence. A subsequent in vitro analysis with primary cultured GCs and COCs was used to confirm the influence of metformin on ER stress activation by qPCR and western blot. Finally, the effects of ER stress activation on GCs and COCs in relation to LH responsiveness were examined by qPCR and COC expansion. MAIN RESULTS AND THE ROLE OF CHANCE The expression of the ER stress markers GRP78, CHOP and XBP1s in the cumulus cells was higher in PCOS patients than in control patients, as were the levels of the UPR sensor proteins p-IRE1α, p-EIF2α and GRP78. Compared to those of control mice, the ovaries, GCs and COCs of DHT-treated PCOS mice showed increased levels of ER stress marker genes and proteins. Hyperandrogenism in PCOS mouse ovaries also induced p38 MAPK phosphorylation in COCs and GCs. Metformin inhibited ER stress activation was associated with decreased p-p38 MAPK levels. In vitro experiments, testosterone-induced ER stress was mitigated by metformin or p38 MAPK inhibition in primary cultured GCs and COCs. COCs expanded rapidly in the presence of testosterone during LH administration, and ovulation-related genes, namely, Areg, Ereg, Ptgs2, Sult1e1, Ptx3 and Tnfaip6, were strongly expressed in the COCs and GCs. These effects were reversed by treatment with metformin, an ER stress inhibitor or by knockdown of p38 MAPK. LIMITATIONS, REASONS FOR CAUTION The number of PCOS patients in this study was small. WIDER IMPLICATIONS OF THE FINDINGS This study provides further evidence for metformin as a PCOS treatment. STUDY FUNDING/COMPETING INTEREST(S) This study was funded by the National Key Research and Developmental Program of China (2018YFC1004800), the Key Research and Development Program of Zhejiang Province (2017C03022), the Zhejiang Province Medical Science and Technology Plan Project (2017KY085, 2018KY457), the National Natural Science Foundation of China (31701260, 81401264, 81701514), and the Special Funds for Clinical Medical Research of the Chinese Medical Association (16020320648). The authors report no conflict of interest in this work and have nothing to disclose. TRIAL REGISTRATION NUMBER N/A.

scholarly journals Rapamycin Improves Palmitate-Induced ER Stress/NFκB Pathways Associated with Stimulating Autophagy in Adipocytes

2015 ◽  
Vol 2015 ◽  
pp. 1-12 ◽  
Author(s):  
Jiajing Yin ◽  
Liping Gu ◽  
Yufan Wang ◽  
Nengguang Fan ◽  
Yuhang Ma ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Er Stress ◽  
Nuclear Translocation ◽  
Kinase Inhibitor ◽  
Autophagy Flux ◽  
Protein Levels ◽  
Stress Effects ◽  
Stress Markers

Obesity-induced endoplasmic reticulum (ER) stress and inflammation lead to adipocytes dysfunction. Autophagy helps to adapt to cellular stress and involves in regulating innate inflammatory response. In present study, we examined the activity of rapamycin, a mTOR kinase inhibitor, against endoplasmic reticulum stress and inflammation in adipocytes. Anin vitromodel was used in which 3T3-L1 adipocytes were preloaded with palmitate (PA) to generate artificial hypertrophy mature adipocytes. Elevated autophagy flux and increased number of autophagosomes were observed in response to PA and rapamycin treatment. Rapamycin attenuated PA-induced PERK and IRE1-associated UPR pathways, evidenced by decreased protein levels of eIF2αphosphorylation, ATF4, CHOP, and JNK phosphorylation. Inhibiting autophagy with chloroquine (CQ) exacerbated these ER stress markers, indicating the role of autophagy in ameliorating ER stress. In addition, cotreatment of CQ abolished the anti-ER stress effects of rapamycin, which confirms the effect of rapamycin on ERs is autophagy-dependent. Furthermore, rapamycin decreased PA-induced nuclear translocation of NFκB P65 subunit, thereby NFκB-dependent inflammatory cytokines MCP-1 and IL-6 expression and secretion. In conclusion, rapamycin attenuated PA-induced ER stress/NFκB pathways to counterbalance adipocytes stress and inflammation. The beneficial of rapamycin in this context partly depends on autophagy. Stimulating autophagy may become a way to attenuate adipocytes dysfunction.

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