Curcumin attenuates palmitic acid-induced cell apoptosis by inhibiting endoplasmic reticulum stress in H9C2 cardiomyocytes

2019 ◽  
Vol 38 (6) ◽  
pp. 655-664 ◽  
Author(s):  
G Guan ◽  
L Lei ◽  
Q Lv ◽  
Y Gong ◽  
L Yang
Keyword(s):  
Endoplasmic Reticulum ◽  
Protein Expression ◽  
Cell Viability ◽  
Palmitic Acid ◽  
Er Stress ◽  
Diabetic Cardiomyopathy ◽  
Molecular Mechanisms ◽  
Caspase 3 ◽  
Protective Action ◽  
H9c2 Cardiomyocytes

Diabetic cardiomyopathy is mediated by multiple molecular mechanisms including endoplasmic reticulum (ER) stress. Curcumin, a phenolic compound, has cytoprotective properties, but its potential protective action against diabetic cardiomyopathy and the related molecular mechanisms are not fully elucidated. In this study, we evaluated the effects of curcumin on cell viability and apoptosis in palmitic acid (PA)-treated H9C2 cardiomyocytes and investigated the signaling pathways involved. Treatment with PA reduced cell viability, induced apoptosis, enhanced apoptosis-related protein expression (Caspase 3 and BCL-2 associated X protein (BAX)), and activated ER stress marker protein expression (glucose-regulated protein 78 (GRP78) and CCAAT/enhancer binding protein homologous protein (CHOP)). Curcumin attenuated PA-induced reduction in cell viability and activation of apoptosis, Caspase 3 activity, BAX, CHOP, and GRP78 expression. 4-Phenylbutyric acid (4-PBA) attenuated the PA-induced effects on cell viability and apoptosis, similar to curcumin. Both curcumin and 4-PBA also attenuated PA-induced increase in ER stress protein (CHOP and GRP78) expression. Curcumin also protected against cytotoxicity, apoptosis, and ER stress induced by thapsigargin. These findings indicate that PA triggers apoptosis in H9C2 cells via ER stress pathways and curcumin protects against this phenomenon.

scholarly journals Diverse Action of Selected Statins on Skeletal Muscle Cells—An Attempt to Explain the Protective Effect of Geranylgeraniol (GGOH) in Statin-Associated Myopathy (SAM)

2019 ◽  
Vol 8 (5) ◽  
pp. 694 ◽  
Author(s):  
Anna Jaśkiewicz ◽  
Beata Pająk ◽  
Magdalena Łabieniec-Watała ◽  
Clara De Palma ◽  
Arkadiusz Orzechowski
Keyword(s):  
Skeletal Muscle ◽  
Protein Expression ◽  
Cell Viability ◽  
Mitochondrial Respiration ◽  
Molecular Mechanisms ◽  
Caspase 3 ◽  
C2c12 Cell ◽  
Muscle Cells ◽  
C2c12 Cells ◽  
Calpain Inhibitor

The present study is centered on molecular mechanisms of the cytoprotective effect of geranylgeraniol (GGOH) in skeletal muscle harmed by statin-associated myopathy (SAM). GGOH via autophagy induction was purportedly assumed to prevent skeletal muscle viability impaired by statins, atorvastatin (ATR) or simvastatin (SIM). The C2C12 cell line was used as the ‘in vitro’ model of muscle cells at different stages of muscle formation, and the effect of ATR or SIM on the cell viability, protein expression and mitochondrial respiration were tested. Autophagy seems to be important for the differentiation of muscle cells; however, it did not participate in the observed GGOH cytoprotective effects. We showed that ATR- and SIM-dependent loss in cell viability was reversed by GGOH co-treatment, although GGOH did not reverse the ATR-induced drop in the cytochrome c oxidase protein expression level. It has been unambiguously revealed that the mitochondria of C2C12 cells are not sensitive to SIM, although ATR effectively inhibits mitochondrial respiration. GGOH restored proper mitochondria functioning. Apoptosis might, to some extent, explain the lower viability of statin-treated myotubes as the pan-caspase inhibitor, N-Benzyloxycarbonyl-Val-Ala-Asp(O-Me) fluoromethyl ketone (Z-VAD-FMK), partly reversed ATR- or SIM-induced cytotoxic effects; however, it does not do so in conjunction with caspase-3. It appears that the calpain inhibitor, N-Acetyl-L-leucyl-L-leucyl-L-norleucinal (ALLM), restored the viability that was reduced by ATR and SIM (p < 0.001). GGOH prevents SAM, in part, as a consequence of a caspase-3 independent pathway, probably by calpain system inactivation.

scholarly journals Endoplasmic reticulum stress regulates cell injury in lipopolysaccharide-induced nerve cells

2020 ◽  
Vol 48 (9) ◽  
pp. 030006052094976
Author(s):  
Min Li ◽  
Ying Zhang ◽  
Jixing Wang
Keyword(s):  
Endoplasmic Reticulum ◽  
Cell Viability ◽  
Er Stress ◽  
Cell Apoptosis ◽  
Caspase 3 ◽  
Cell Injury ◽  
Cell Counting ◽  
Tunel Staining ◽  
Dependent Manner ◽  
Stress Markers

Objective Sepsis-associated encephalopathy (SAE) is a common complication of sepsis, and excessive endoplasmic reticulum (ER) stress is closely correlated with the cell injury caused by sepsis. This study aimed to analyze the possible role of ER stress in SAE cell models. Methods PC12 and MES23.5 cells were treated with increasing concentrations of lipopolysaccharides (LPS). The Cell Counting Kit-8 assay was used to detect cell viability and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining was performed to assess cell apoptosis. In addition, the protein expression levels of ER stress markers [GRP78, CHOP, inositol-requiring enzyme 1 (IRE1), and PKR-like ER kinase (PERK)] and apoptosis-related proteins (Bax, Bcl-2, caspase-3, and cleaved caspase-3) were analyzed using western blotting. Results LPS treatment activated ER stress markers in both the PC12 and MES23.5 cells. The overexpression of GRP78 significantly reduced cell viability and enhanced cell apoptosis in a time-dependent manner. An ER stress inhibitor, 4-PBA, significantly enhanced cell viability and inhibited the cell apoptosis induced by LPS. Therefore, an enhanced unfolded protein response (UPR) and UPR suppression may regulate cell apoptosis. Conclusions UPR was shown to be involved in regulating LPS-induced neuron injury. UPR could be a potential therapeutic target in SAE.

scholarly journals Oxidative and endoplasmic reticulum stresses are involved in palmitic acid-induced H9c2 cell apoptosis

2019 ◽  
Vol 39 (5) ◽  
Author(s):  
Lei Yang ◽  
Gaopeng Guan ◽  
Lanjie Lei ◽  
Jianyun Liu ◽  
Lingling Cao ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Endoplasmic Reticulum ◽  
Palmitic Acid ◽  
Er Stress ◽  
Cell Apoptosis ◽  
H9c2 Cell ◽  
H9c2 Cells ◽  
Proliferation And Apoptosis ◽  
H9c2 Cardiomyocytes ◽  
Heart Muscle Cells

Abstract Palmitic acid (PA) is the most common saturated long-chain fatty acid that causes damage to heart muscle cells. However, the molecular mechanism of PA toxicity in myocardial cells is not fully understood. In the present study, we explored the effects of PA on proliferation and apoptosis of H9c2 cardiomyocytes, and uncovered the signaling pathways involved in PA toxicity. Our study revealed induction of both oxidative and endoplasmic reticulum (ER) stresses and exacerbation of apoptosis in PA-treated H9c2 cells. Inhibition of oxidative stress by N-acetylcysteine (NAC) reduced apoptosis and decreased ER stress in PA-treated H9c2 cells. Moreover, inhibition of ER stress by 4-phenyl butyric acid decreased apoptosis and attenuated oxidative stress. In summary, the present study demonstrated that oxidative stress coordinates with ER stress to play important roles in PA-induced H9c2 cell apoptosis.

scholarly journals Interactions between Endoplasmic Reticulum Stress and Autophagy: Implications for Apoptosis and Neuroplasticity-Related Proteins in Palmitic Acid-Treated Prefrontal Cells

2021 ◽  
Vol 2021 ◽  
pp. 1-14
Author(s):  
Xiangli Xue ◽  
Feng Li ◽  
Ming Cai ◽  
Jingyun Hu ◽  
Qian Wang ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Palmitic Acid ◽  
Er Stress ◽  
Molecular Mechanisms ◽  
Apoptotic Cell ◽  
Critical Role ◽  
Sprague Dawley ◽  
Related Proteins ◽  
Phenylbutyric Acid

Lipotoxicity of palmitic acid (PA) or high-fat diets has been reported to increase endoplasmic reticulum (ER) stress and autophagy in peripheral tissue as well as apoptotic cell death. It also can lead to an AD-like pathological pattern. However, it has been unknown that PA-induced ER stress and autophagy are involved in the regulation of neuroplastic abnormalities. Here, we investigated the roles of ER stress and autophagy in apoptosis and neuroplasticity-related protein expression in PA-treated prefrontal cells. Prefrontal cells dissected from newborn Sprague-Dawley rats were treated with PA compound with ER stress inhibitor 4-phenylbutyric acid (4-PBA) and autophagy inhibitor 3-methyladenine (3-MA) or PA alone. PA promoted ER stress and autophagy and also cause apoptosis as well as a decline in the expression of neuroplasticity-related proteins. Inhibition of ER stress decreased the expressions of neuroplasticity-related proteins and reduced autophagy activation and apoptosis in PA-treated prefrontal cells. Inhibition of autophagy exacerbated apoptosis and enhanced ER stress in PA-treated prefrontal cells. The present study illustrated that both ER stress and autophagy could be involved in apoptosis and decreased neuroplasticity-related proteins, and the interaction between ER stress and autophagy may play a critical role in apoptosis in PA-treated prefrontal cells. Our results provide new insights into the molecular mechanisms in vitro of lipotoxicity in obesity-related cognitive dysfunction.

scholarly journals Endoplasmic Reticulum Stress and Diabetic Cardiomyopathy

2012 ◽  
Vol 2012 ◽  
pp. 1-12 ◽  
Author(s):  
Jiancheng Xu ◽  
Qi Zhou ◽  
Wei Xu ◽  
Lu Cai
Keyword(s):  
Endoplasmic Reticulum ◽  
Cell Death ◽  
Er Stress ◽  
Diabetic Cardiomyopathy ◽  
Molecular Mechanisms ◽  
Critical Role ◽  
Lipid Synthesis ◽  
The Unfolded Protein Response ◽  
Cell Stress Response

The endoplasmic reticulum (ER) is an organelle entrusted with lipid synthesis, calcium homeostasis, protein folding, and maturation. Perturbation of ER-associated functions results in an evolutionarily conserved cell stress response, the unfolded protein response (UPR) that is also called ER stress. ER stress is aimed initially at compensating for damage but can eventually trigger cell death if ER stress is excessive or prolonged. Now the ER stress has been associated with numerous diseases. For instance, our recent studies have demonstrated the important role of ER stress in diabetes-induced cardiac cell death. It is known that apoptosis has been considered to play a critical role in diabetic cardiomyopathy. Therefore, this paper will summarize the information from the literature and our own studies to focus on the pathological role of ER stress in the development of diabetic cardiomyopathy. Improved understanding of the molecular mechanisms underlying UPR activation and ER-initiated apoptosis in diabetic cardiomyopathy will provide us with new targets for drug discovery and therapeutic intervention.

scholarly journals Selenium Attenuates Chronic Heat Stress-Induced Apoptosis via the Inhibition of Endoplasmic Reticulum Stress in Mouse Granulosa Cells

Molecules ◽  
2020 ◽  
Vol 25 (3) ◽  
pp. 557 ◽  
Author(s):  
Yongjie Xiong ◽  
Qirun Yin ◽  
Erhui Jin ◽  
Huatao Chen ◽  
Shaojun He
Keyword(s):  
Heat Stress ◽  
Er Stress ◽  
Granulosa Cells ◽  
Molecular Mechanisms ◽  
Caspase 3 ◽  
Protective Action ◽  
Protective Effects ◽  
Expression Levels ◽  
Induced Apoptosis

Heat stress induces apoptosis in various cells. Selenium, an essential micronutrient, has beneficial effects in maintaining the cellular physiological functions. However, its potential protective action against chronic heat stress (CHS)-induced apoptosis in granulosa cells and the related molecular mechanisms are not fully elucidated. In this study, we investigated the roles of selenium in CHS-induced apoptosis in mouse granulosa cells and explored its underlying mechanism. The heat treatment for 6–48 h induced apoptosis, potentiated caspase 3 activity, increased the expression levels of apoptosis-related gene BAX and ER stress markers, glucose-regulated protein 78 (GRP78), and CCAAT/enhancer binding protein homologous protein (CHOP) in mouse granulosa cells. The treatment with ER stress inhibitor 4-PBA significantly attenuated the adverse effects caused by CHS. Selenium treatment significantly attenuated the CHS- or thapsigargin (Tg, an ER stress activator)-induced apoptosis, potentiation of caspase 3 activity, and the increased protein expression levels of BAX, GRP78, and CHOP. Additionally, treatment of the cells with 5 ng/mL selenium significantly ameliorated the levels of estradiol, which were decreased in response to heat exposure. Consistently, administering selenium supplement alleviated the hyperthermia-caused reduction in the serum estradiol levels in vivo. Together, our findings indicate that selenium has protective effects on CHS-induced apoptosis via inhibition of the ER stress pathway. The current study provides new insights in understanding the role of selenium during the process of heat-induced cell apoptosis.

scholarly journals High-glucose environment accelerates annulus fibrosus cell apoptosis by regulating endoplasmic reticulum stress

2020 ◽  
Vol 40 (7) ◽  
Author(s):  
Lianglong Pang ◽  
Keshi Yang ◽  
Zhi Zhang
Keyword(s):  
Endoplasmic Reticulum ◽  
Protein Expression ◽  
Er Stress ◽  
Disc Degeneration ◽  
High Glucose ◽  
Cell Apoptosis ◽  
Annulus Fibrosus ◽  
Culture Medium ◽  
Caspase 3 ◽  
Apoptosis Ratio

Abstract Diabetes mellitus (DM) is an important risk factor of intervertebral disc degeneration. However, how DM affects annulus fibrosus (AF) biology remains unclear. The present study was aimed to investigate the effects and mechanism of high glucose on AF cell biology. Rat AF cells were cultured in baseline medium and culture medium with 0.2 M glucose. The inhibitor 4-PBA was added along with the high glucose culture medium to study the role of endoplasmic reticulum (ER) stress in this process. Compared with the control cells, high glucose significantly increased cell apoptosis ratio and caspase-3/9 activity, up-regulated mRNA/protein expression of Bax and caspase-3/cleaved caspase-3, but down-regulated mRNA/protein expression of Bcl-2. Moreover, high glucose increased mRNA and protein expression of CHOP, ATF-6 and GRP78. However, once ER stress was inhibited by the inhibitor 4-PBA in the high glucose group, cell apoptosis ratio and caspase-3/9 activity were decreased, mRNA/protein expression of Bax and caspase-3/cleaved caspase-3 was down-regulated, but mRNA/protein expression of Bcl-2 was up-regulated. In conclusion, high glucose condition can promote AF cell apoptosis through inducing ER stress. The present study helps us understand the mechanism of disc degeneration in DM patients.

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.

scholarly journals Targeted inhibition of GRP78 by HA15 promotes apoptosis of lung cancer cells accompanied by ER stress and autophagy

Biology Open ◽  
2020 ◽  
Vol 9 (11) ◽  
pp. bio053298
Author(s):  
Jingjing Wu ◽  
Youqile Wu ◽  
Xuemei Lian
Keyword(s):  
Lung Cancer ◽  
Protein Expression ◽  
Cell Viability ◽  
Er Stress ◽  
Cancer Cells ◽  
Lung Tumor ◽  
Lung Cancer Cells ◽  
Dependent Manner ◽  
Mice Model ◽  
Targeted Inhibition

ABSTRACTThis study investigated the pathophysiological role of GRP78 in the survival of lung cancer cells. Lung cancer patient data from public databases were used to analyze the expression of GRP78 and its influence on prognoses. In vivo, GRP78 protein expression was analyzed in an established urethane-induced lung tumor mouse model. In vitro, the effects of targeted inhibition of GRP78 by HA15 in lung cancer cells were assessed, with cell viability analyzed using a CCK-8 assay, cell proliferation using an EdU assay, apoptosis and cell cycle using flow cytometry, subcellular structure using electron microscopy, and relative mRNA and protein expression using RT-PCR, western blotting or immunofluorescence assays. The results showed that GRP78 was highly expressed in the lung tissue of lung cancer mice model or patients, and was associated with a poor prognosis. After inhibition of GRP78 in lung cancer cells by HA15, cell viability was decreased in a dose- and time-dependent manner, proliferation was suppressed and apoptosis promoted. Unfolded protein response signaling pathway proteins were activated, and the autophagy-related proteins and mRNAs were upregulated. Therefore, targeted inhibition of GRP78 by HA15 promotes apoptosis of lung cancer cells accompanied by ER stress and autophagy.

scholarly journals Ganoderic Acid A Protects Rat H9c2 Cardiomyocytes from Hypoxia-Induced Injury via Up-Regulating miR-182-5p

2018 ◽  
Vol 50 (6) ◽  
pp. 2086-2096 ◽  
Author(s):  
Xiaohong  Zhang ◽  
Can Xiao ◽  
Hong Liu
Keyword(s):  
Cell Viability ◽  
Molecular Mechanisms ◽  
Akt Pathway ◽  
H9c2 Cell ◽  
H9c2 Cells ◽  
Ganoderic Acid ◽  
Expression Levels ◽  
Protein Levels ◽  
Viability Loss ◽  
H9c2 Cardiomyocytes

Background/Aims: Ganoderic acid A (GAA) isolated from Ganoderma lucidum, shows various benefit activities, such as anti-tumor activity, anti-HIV activity and hepatoprotective activity. However, the potential effects of GAA on hypoxia-induced injury of cardiomyocytes are still unclear. In this study, we aimed to reveal the effects of GAA on hypoxic-induced H9c2 cell injury, as well as potential underlying molecular mechanisms. Methods: Rat H9c2 cardiomyocytes were cultured in hypoxia condition with different doses of GAA. Cell viability and apoptosis were detected by CCK-8 assay and flow cytometry, respectively. qRT-PCR was performed to assess the expression levels of microRNA-182-5p (miR-182-5p) and phosphatase and tensin homologue (PTEN). Cell transfection was conducted to change the expression levels of miR-182-5p and PTEN in H9c2 cells. Finally, protein levels of key factors involved in cell proliferation, cell apoptosis and PTEN/PI3K/AKT pathway were evaluated using western blotting. Results: Hypoxia treatment significantly induced H9c2 cell viability loss and apoptosis. GAA incubation remarkably protected H9c2 cells from hypoxia-induced viability loss, proliferation inhibition and apoptosis. In addition, GAA obviously enhanced the expression level of miR-182-5p in H9c2 cells. Suppression of miR-182-5p notably alleviated the protective effects of GAA on hypoxia-treated H9c2 cells. Furthermore, miR-182-5p negatively regulated the mRNA and protein levels of PTEN in H9c2 cells. GAA attenuated hypoxia-induced inactivation of PI3K/AKT pathway in H9c2 cells by up-regulating miR-182-5p and then down-regulating PTEN. Conclusion: GAA protected rat H9c2 cardiomyocytes from hypoxia-induced injury might via up-regulating miR-182-5p, down-regulating PTEN and then activating PI3K/AKT signaling pathway.

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