Quercetin and aconitine synergistically induces the human cervical carcinoma HeLa cell apoptosis via endoplasmic reticulum (ER) stress pathway

Objective: Macrophage apoptosis contributes to atherosclerotic plaque necrosis, inflammation, development and rupture. Scavenger receptor class B type I (SR-BI) is a key regulator of HDL metabolism and cellular cholesterol homeostasis. Here we examined the hypothesis that macrophage SR-BI modulates lipid-associated cellular stress and apoptosis. Methods and Results: In vitro cell apoptosis assays were performed in primary macrophages, and for in vivo evidence, we examined TUNEL staining of atherosclerotic lesions of LDLR -/- mice that were reconstituted with SR-BI -/- or WT bone marrow after 16 weeks on a Western diet. We found that SR-BI deficiency led to ~64.3% more apoptotic cells induced by oxidized LDL or free cholesterol in primary macrophages, and 6-fold more lesional apoptotic cells in SR-BI -/- →LDLR -/- mice compared to WT recipient mice. In macrophages, SR-BI deficiency caused significant accumulations of cellular free cholesterol and elevated markers of endoplasmic reticulum (ER) stress. These were exacerbated by feeding mice a high-cholesterol diet or inactivating the apolipoprotein E gene. Peroxidation of lipoproteins and cell membranes leads to modification of phosphatidylethanolamine by lipid aldehydes including isolevuglandins (IsoLG-PE). Treatment of macrophages with IsoLG-PE induced 52.6% more apoptotic cells in SR-BI -/- macrophages compared to WT. Transgenic expression of SR-BI by transfection of SR-BI -/- macrophages rescued oxidative stress-induced ER stress and cell apoptosis. SR-BI deficiency inhibited the Akt pathway compromising macrophage survival and increasing lesion necrosis. Moreover, Akt Activator was able to rescue SR-BI deficiency associated apoptosis in macrophages. Apolipoprotein E interacts with SR-BI in macrophages, co-operating for cellular lipid homeostasis and cell survival signaling. Conclusion: SR-BI protects against cell apoptosis induced by lipid stress in macrophages and atherosclerotic lesions. The underlying mechanisms are, at least in part, through reducing lipid-associated ER stress and promoting Akt activity in macrophages. Thus, we identify macrophage SR-BI-mediated apoptosis pathways as molecular targets for the prevention of atherosclerotic cardiovascular events.

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Enteroids Derived From Inflammatory Bowel Disease Patients Display Dysregulated Endoplasmic Reticulum Stress Pathways, Leading to Differential Inflammatory Responses and Dendritic Cell Maturation

Journal of Crohn s and Colitis ◽

10.1093/ecco-jcc/jjz194 ◽

2019 ◽

Vol 14 (7) ◽

pp. 948-961 ◽

Cited By ~ 4

Author(s):

William D Rees ◽

Martin Stahl ◽

Kevan Jacobson ◽

Brian Bressler ◽

Laura M Sly ◽

...

Keyword(s):

Inflammatory Bowel Disease ◽

Endoplasmic Reticulum ◽

Er Stress ◽

Bowel Disease ◽

Inflammatory Responses ◽

Human Colon ◽

Intestinal Epithelial ◽

Stress Changes ◽

Inflammatory Bowel ◽

Stress Pathway

Abstract Background and Aims Endoplasmic reticulum [ER] stress in intestinal epithelial cells [IECs] contributes to the pathogenesis of inflammatory bowel disease [IBD]. We hypothesized that ER stress changes innate signalling in human IECs, augmenting toll-like receptor [TLR] responses and inducing pro-inflammatory changes in underlying dendritic cells [DCs]. Methods Caco-2 cells and primary human colon-derived enteroid monolayers were exposed to ATP [control stressor] or thapsigargin [Tg] [ER stress inducer], and were stimulated with the TLR5 agonist flagellin. Cytokine release was measured by an enzyme immunoassay. ER stress markers CHOP, GRP78 and XBP1s/u were measured via quantitative PCR and Western blot. Monocyte-derived DCs [moDCs] were cultured with the IEC supernatants and their activation state was measured. Responses from enteroids derived from IBD patients and healthy control participants were compared. Results ER stress enhanced flagellin-induced IL-8 release from Caco-2 cells and enteroids. Moreover, conditioned media activated DCs to become pro-inflammatory, with increased expression of CD80, CD86, MHCII, IL-6, IL-15 and IL-12p70 and decreased expression of CD103 and IL-10. Flagellin-induced IL-8 production correlated with DC activation, suggesting a common stress pathway. Moreover, there were distinct differences in cytokine expression and basal ER stress between IBD and healthy subject-derived enteroid monolayers, suggesting a dysregulated ER stress pathway in IBD-derived enteroids. Conclusions Cellular stress enhances TLR5 responses in IECs, leading to increased DC activation, indicating a previously unknown mechanistic link between epithelial ER stress and immune activation in IBD. Furthermore, dysregulated ER stress may be propagated from the intestinal epithelial stem cell niche in IBD patients.

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

Journal of International Medical Research ◽

10.1177/0300060520949762 ◽

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.

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Human ether‑�‑go‑go‑related gene mutation L539fs/47‑hERG leads to cell apoptosis through the endoplasmic reticulum stress pathway

International Journal of Molecular Medicine ◽

10.3892/ijmm.2019.4049 ◽

2019 ◽

Author(s):

Shuting Ma ◽

Yun Zhao ◽

Miaomiao Cao ◽

Chaofeng Sun

Keyword(s):

Endoplasmic Reticulum ◽

Endoplasmic Reticulum Stress ◽

Gene Mutation ◽

Cell Apoptosis ◽

Related Gene ◽

Endoplasmic Reticulum Stress Pathway ◽

Stress Pathway

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Novel targets for endoplasmic reticulum stress-induced apoptosis in B-CLL

Blood ◽

10.1182/blood-2010-03-275628 ◽

2010 ◽

Vol 116 (15) ◽

pp. 2713-2723 ◽

Cited By ~ 53

Author(s):

Emanuela Rosati ◽

Rita Sabatini ◽

Giuliana Rampino ◽

Filomena De Falco ◽

Mauro Di Ianni ◽

...

Keyword(s):

Endoplasmic Reticulum ◽

Er Stress ◽

Cell Apoptosis ◽

Ex Vivo ◽

Lymphocytic Leukemia ◽

Minor Role ◽

Caspase 8 ◽

Caspase 9 ◽

Cytochrome C Release ◽

Induced Apoptosis

Abstract A better understanding of apoptotic signaling in B-chronic lymphocytic leukemia (B-CLL) cells may help to define new therapeutic strategies. This study investigated endoplasmic reticulum (ER) stress signaling in spontaneous apoptosis of B-CLL cells and whether manipulating ER stress increases their apoptosis. Results show that a novel ER stress-triggered caspase cascade, initiated by caspase-4 and involving caspase-8 and -3, plays an important role in spontaneous B-CLL cell apoptosis. ER stress-induced apoptosis in B-CLL cells also involves CHOP/GADD153 up-regulation, increased JNK1/2 phosphorylation, and caspase-8–mediated cleavage of Bap31 to Bap20, known to propagate apoptotic signals from ER to mitochondria. In ex vivo B-CLL cells, some apoptotic events associated with mitochondrial pathway also occur, including mitochondrial cytochrome c release and caspase-9 processing. However, pharmacologic inhibition studies show that caspase-9 plays a minor role in B-CLL cell apoptosis. ER stress also triggers survival signals in B-CLL cells by increasing BiP/GRP78 expression. Manipulating ER signaling by siRNA down-regulation of BiP/GRP78 or treating B-CLL cells with 2 well-known ER stress-inducers, tunicamycin and thapsigargin, increases their apoptosis. Overall, our findings show that ER triggers an essential pathway for B-CLL cell apoptosis and suggest that genetic and pharmacologic manipulation of ER signaling could represent an important therapeutic strategy.

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