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Resveratrol alleviates FFA and CCl4 induced apoptosis in HepG2 cells via restoring endoplasmic reticulum stress.

ABSTRACT: Cell apoptosis often induces inflammation and injury in the liver, with endoplasmic reticulum (ER) stress as the most possible reason. Resveratrol (RSV) has been shown to prevent hepatic steatosis and alleviate apoptosis, however, the exact mechanisms underlying the effects still need to be explored. Here we co-cultured HepG2 cells with free fatty acid (FFA) solution (oleic acid: palmitic acid = 2:1) and then exposed to a carbon tetrachloride (CCl4) solution to induce apoptosis. To evaluate the therapeutic effects, RSV (2.5 μM, 5 μM, 10 μM) was added to the cells. Results showed that HepG2 cells co-cultured with FFA exhibited lipid infiltration and were susceptible to apoptosis upon exposure to the CCl4 solution. The expression of molecules related to apoptosis (Caspases, Bcl-2/Bax) and ER stress (GRP78, IRE1, ATF6, PERK, et al.) was all significantly decreased upon RSV treatment. We further inhibited GRP78 by siRNA, results showed that the anti-apoptotic effect of RSV still maintained under GRP78 siRNA condition. Our data demonstrated that lipid accumulated HepG2 cells were susceptible to injury, and RSV could improve apoptosis in FFA and CCl4 stressed cells, which partially via restoring ER function.

SUBMITTER: Li F

PROVIDER: S-EPMC5546441 | biostudies-other | 2017 Jul

REPOSITORIES: biostudies-other

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Tetramethylpyrazine alleviates endoplasmic reticulum stress-activated apoptosis and related inflammation in chondrocytes

Project description:Excessive apoptosis of chondrocytes and degradation of the extracellular matrix (ECM) contribute to the typical pathological characteristics of osteoarthritis (OA). Various studies have reported that tetramethylpyrazine (TMP) protects against multiple disorders by inhibiting inflammation and oxidative stress. The present study investigated the effects of TMP on chondrocytes and evaluated the associated mechanisms. To determine the effect of TMP on OA and the underlying mechanisms, chondrocytes were incubated with TMP and IL-1β or thapsigargin (TG) Western blotting assays were performed to examine the expression levels of endoplasmic reticulum (ER) stress proteins, and TUNEL staining, fluorescence immunostaining and reverse transcription-quantitative PCR were used to determine the apoptosis levels, and catabolic and inflammatory factors. It was found that TMP protected chondrocytes by suppressing IL-1β-induced expression of glucose-regulated protein 78 (GRP78) and CHOP (an apoptotic protein). TMP regulated the TG-mediated upregulated expression of GRP78 and CHOP in the chondrocytes of rats, as well as markedly suppressed levels of ER stress-triggered inflammatory cytokines (TNF-α and IL-6). Furthermore, TMP modulated TG-induced changes in ECM catabolic metabolism in rat chondrocytes. Collectively, TMP alleviated ER-stress-activated apoptosis and related inflammation in chondrocytes, indicating that it has therapeutic potential for the treatment of OA.

| S-EPMC8600404 | biostudies-literature

Resolvin D1 alleviates apoptosis triggered by endoplasmic reticulum stress in IPEC-J2 cells.

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| S-EPMC10983747 | biostudies-literature

Sestrin2 Overexpression Ameliorates Endoplasmic Reticulum Stress-Induced Apoptosis via Inhibiting mTOR Pathway in HepG2 Cells.

Project description:Sestrin2 is a highly conserved stress-inducible protein, acting as a crucial part in regulating homeostasis in response to various stress conditions in the cell. However, the role of Sestrin2 in regulating cell apoptosis related to endoplasmic reticulum (ER) has not been fully investigated. Our study presented here aims to reveal the effect of Sestrin2 in tunicamycin (TM)-induced cell apoptosis related to ER stress and its underlying molecular mechanisms. The results demonstrated that Sestrin2 expression was significantly upregulated correlated with ER stress responses in TM treated HepG2 cells. Sestrin2 overexpression obviously alleviated ER stress with the determination of ER stress-related proteins expression. In addition, Sestrin2 overexpression inhibited cell apoptosis with the examination of apoptosis-related proteins and TUNEL assay. However, Sestrin2 knockdown further promoted the ER stress-mediated cell apoptosis. The further mechanistic study revealed that Sestrin2 overexpression inhibited TM-induced mTOR pathway activation. Taken together, our current study indicated that Sestrin2 overexpression ameliorates ER stress-induced apoptosis via inhibiting mTOR pathway in HepG2 cells.

| S-EPMC9759384 | biostudies-literature

IL-33/ST2L signaling alleviates diabetic nephropathy by regulating endoplasmic reticulum stress and apoptosis.

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| S-EPMC10698915 | biostudies-literature

DsbA-L alleviates endoplasmic reticulum stress-induced adiponectin downregulation.

Project description:ObjectiveObesity impairs adiponectin expression, assembly, and secretion, yet the underlying mechanisms remain elusive. The aims of this study were 1) to determine the molecular mechanisms by which obesity impairs adiponectin multimerization and stability, and 2) to determine the potential role of disulfide-bond-A oxidoreductase-like protein (DsbA-L), a recently identified adiponectin interactive protein that promotes adiponectin multimerization and stability in obesity-induced endoplasmic reticulum (ER) stress and adiponectin downregulation.Research design and methodsTauroursodeoxycholic acid (TUDCA), a chemical chaperone that alleviates ER stress, was used to study the mechanism underlying obesity-induced adiponectin downregulation in db/db mice, high-fat diet-induced obese mice, and in ER-stressed 3T3-L1 adipocytes. The cellular levels of DsbA-L were altered by RNAi-mediated suppression or adenovirus-mediated overexpression. The protective role of DsbA-L in obesity- and ER stress-induced adiponectin downregulation was characterized.ResultsTreating db/db mice and diet-induced obese mice with TUDCA increased the cellular and serum levels of adiponectin. In addition, inducing ER stress is sufficient to downregulate adiponectin levels in 3T3-L1 adipocytes, which could be protected by treating cells with the autophagy inhibitor 3-methyladenine or by overexpression of DsbA-L.ConclusionsER stress plays a key role in obesity-induced adiponectin downregulation. In addition, DsbA-L facilitates adiponectin folding and assembly and provides a protective effect against ER stress-mediated adiponectin downregulation in obesity.

| S-EPMC2963539 | biostudies-literature

Inhibition of Brd4 alleviates renal ischemia/reperfusion injury-induced apoptosis and endoplasmic reticulum stress by blocking FoxO4-mediated oxidative stress.

Project description:Ischemia/reperfusion injury (I/R) is one of the leading causes of acute kidney injury (AKI) that typically occurs in renal surgeries. However, renal I/R still currently lacks effective therapeutic targets. In this study, we proved that inhibition of Brd4 with its selective inhibitor, JQ1, could exert a protective role in renal I/R injury in mice. Inhibiting Brd4 with either JQ1 or genetic knockdown resulted in reduction of endoplasmic reticulum stress (ERS)-associated protein and proapoptotic protein expression both in I/R-induced injury and hypoxia/reoxygenation (H/R) stimulation in HK-2 cells. H/R-induced apoptosis and ERS depended on oxidative stress in vitro. Moreover, FoxO4, which is involved in the generation of hydrogen peroxide, was up-regulated during H/R stimulation-mediated apoptosis and ERS, and this upregulation could be abolished by Brd4 inhibition. Consistently, FoxO4-mediated ROS generation was attenuated upon inhibition of Brd4 with JQ1 or siRNA against Brd4. Further, the transcriptional activity of FoxO4 was suppressed by PI3K and AKT phosphorylation, which are upstream signals of FoxO4 expression, and were enhanced by Brd4 both in vivo and in vitro. In conclusion, our results proved that Brd4 inhibition blocked renal apoptotic and ERS protein expression by preventing FoxO4-dependent ROS generation through the PI3K/AKT pathway, indicating that Brd4 could be a potential therapeutic target for renal I/R injury.

| S-EPMC6475721 | biostudies-literature

IRE1α siRNA relieves endoplasmic reticulum stress-induced apoptosis and alleviates diabetic peripheral neuropathy in vivo and in vitro.

Project description:Diabetic peripheral neuropathy (DPN) is mainly characterized by demyelination resulted from the apoptosis of the Schwann cell (SCs). Although the exact mechanisms underlying DPN remain unclear, endoplasmic reticulum (ER) stress is strongly implicated in the apoptosis. Under ER stress, activated inositol-requiring kinase 1α (IRE1α) unregulated CHOP, phosphorylated JNK and Caspase-12 to aggravate apoptosis-mediated damage of DPN. Therefore, we tested the hypothesis that inhibition of IRE1α could reduce the ER stress-related apoptosis to relieve DPN. Here, we show that IRE1α siRNA improved the neurological morphology and function of DPN rats and rescued ER stress-related apoptosis in the sciatic nerve. Additionally, RSC96 cells transfected with IRE1α siRNA were used as in vitro model of DPN. It was found that IRE1α siRNA also decreased high glucose-induced apoptosis and inhibited ER stress-related apoptosis in the cells. Altogether, our results suggest that IRE1α should be considered a potential therapeutic agent for DPN.

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Sodium formononetin-3'-sulphonate alleviates cerebral ischemia-reperfusion injury in rats via suppressing endoplasmic reticulum stress-mediated apoptosis.

Project description:BackgroundSodium formononetin-3'-sulphonate (Sul-F) may alleviate I/R injury in vivo with uncertain mechanism. Endoplasmic reticulum (ER) stress-mediated apoptosis participates in the process of cerebral ischemia-reperfusion (I/R) injury. Our aim is to figure out the effect of Sul-F on cerebral I/R injury and to verify whether it works through suppressing ER stress-mediated apoptosis.ResultsThe cerebral lesions of middle cerebral artery occlusion (MCAO) model in SD rats were aggravated after 24 h of reperfusion, including impaired neurological function, increased infarct volume, intensified inflammatory response and poor cell morphology. After intervention, the edaravone (EDA, 3 mg/kg) group and Sul-F high-dose (Sul-F-H, 80 mg/kg) group significantly alleviated I/R injury via decreasing neurological score, infarct volume and the serum levels of inflammatory factors (TNF-α, IL-1β and IL-6), as well as alleviating pathological injury. Furthermore, the ER stress level and apoptosis rate were elevated in the ischemic penumbra of MCAO group, and were significantly blocked by EDA and Sul-F-H. In addition, EDA and Sul-F-H significantly down-regulated the ER stress related PERK/eIF2α/ATF4 and IRE1 signal pathways, which led to reduced cell apoptosis rate compared with the MCAO group. Furthermore, there was no difference between the EDA and Sul-F-H group in terms of therapeutic effect on cerebral I/R injury, indicating a therapeutic potential of Sul-F for ischemic stroke.ConclusionsSul-F-H can significantly protects against cerebral I/R injury through inhibiting ER stress-mediated apoptosis in the ischemic penumbra, which might be a novel therapeutic target for ischemic stroke.

| S-EPMC9733209 | biostudies-literature

Taurine Supplementation Alleviates Puromycin Aminonucleoside Damage by Modulating Endoplasmic Reticulum Stress and Mitochondrial-Related Apoptosis in Rat Kidney.

Project description:Taurine (TAU) is a sulfur-containing beta amino acid that is not involved in protein composition and anabolism, conditionally essential in mammals provided through diet. Growing evidence supports a protective role of TAU supply in osmoregulation, calcium flux, and reduction of inflammation and oxidant damage in renal diseases like diabetes. Endoplasmic reticulum (ER) stress, due to abnormal proteostasis, is a contributor to nephrotic syndrome and related renal damage. Here, we investigated the effect of dietary TAU (1.5% in drinking water for 15 days) in an established rat model that mimics human minimal change nephrosis, consisting of a single puromycin aminonucleoside (PAN) injection (intraperitoneally 15 mg/100 g body weight), with sacrifice after eight days. TAU limited proteinuria and podocytes foot processes effacement, and balanced slit diaphragm nephrin and glomerular claudin 1 expressions. In cortical proximal tubules, TAU improved lysosomal density, ER perimeter, restored proper ER-mitochondria tethering and mitochondrial cristae, and decreased inflammation. Remarkably, TAU downregulated glomerular ER stress markers (GRP78, GRP94), pro-apoptotic C/EBP homologous protein, activated caspase 3, tubular caspase1, and mitochondrial chaperone GRP75, but maintained anti-apoptotic HSP25. In conclusion, TAU, by targeting upstream ER stress separate from mitochondria dysfunctions at crucial renal sites, might be a promising dietary supplement in the treatment of the drug-resistant nephrotic syndrome.

| S-EPMC6024760 | biostudies-literature

Endoplasmic reticulum stress-induced cell death in dopaminergic cells: effect of resveratrol.

Project description:Resveratrol, a naturally occurring polyphenol, exhibits antioxidant, antiaging, and anticancer activity. Resveratrol has also been shown to inhibit tumor initiation, promotion, and progression in a variety of cell culture systems. Earlier, we showed that paraquat, a bipyridyl herbicide, triggers endoplasmic reticulum stress, cell dysfunction, and dopaminergic cell death. Due to its antioxidant activity, we assessed the ability of resveratrol to rescue cells from the toxic effects of paraquat. While resveratrol did not have any protective effect at low concentrations, it triggered endoplasmic reticulum (ER) stress-induced cell death at higher concentrations (50-250 microM). The present study was carried out to determine the mechanism by which resveratrol triggers ER stress and cell death in dopaminergic N27 cells. Our studies demonstrate that resveratrol triggers ER stress and cell dysfunction, caspase activation, p23 cleavage and inhibition of proteasomal activity in dopaminergic N27 cells. While over expression of uncleavable p23 was associated with decreased cell death, downregulation of p23 protein expression by siRNA resulted in enhancement of ER stress-induced cell death triggered by resveratrol indicating a protective role for the small co-chaperone p23 in dopaminergic cell death.

| S-EPMC2745484 | biostudies-literature

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