scholarly journals Melatonin Relieves Busulfan-Induced Spermatogonial Stem Cell Apoptosis of Mouse Testis by Inhibiting Endoplasmic Reticulum Stress

2017 ◽  
Vol 44 (6) ◽  
pp. 2407-2421 ◽  
Author(s):  
Yanhua Cui ◽  
Lipeng Ren ◽  
Bo Li ◽  
Jia Fang ◽  
Yuanxin Zhai ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Endoplasmic Reticulum Stress ◽  
Caspase 3 ◽  
Survival Rates ◽  
Underlying Mechanism ◽  
Pcr Analysis ◽  
Caspase 12 ◽  
Apoptosis Proteins

Background/Aims: Busulfan is commonly used for cancer chemotherapy. Although it has the advantage of increasing the survival rate of patients, it can cause male infertility via damaging the testes and reducing sperm counts. Therefore, the underlying mechanism should be explored, and new agents should be developed to protect the male reproductive system from busulfan-induced damage. Endoplasmic reticulum stress (ERS) is considered a key contributor to numerous pathologies. Despite several studies linking ERS to toxicants, studies have yet to determine whether ERS is a contributing factor to busulfan-induced testicular damage. Melatonin is a well-known broad-spectrum antioxidant, anti-inflammatory and antitumour agent, but the effects of melatonin on busulfan-induced ERS in mouse testes damage are less documented. Methods: The effects of melatonin were measured by immunofluorescence staining, Western blot, qRT-PCR analysis and flow cytometry assay. The underlying mechanism was investigated by measuring ERS. Results: We found that ERS was strongly activated in mouse testes (in vivo) and the C18-4 cell line (in vitro) after busulfan administration. ERS-related apoptosis proteins such as caspase-12, CHOP and caspase-3 were activated, and the expression of apoptotic proteins such as P53 and PUMA were upregulated. Furthermore, we investigated whether melatonin reduced the extent of damage to mouse testes and improved the survival rates of busulfan-treated mice. When exploring the underlying mechanisms, we found melatonin could counteract ERS by decreasing the expression levels of the ERS markers GRP78, ATF6, pIRE1 and XBP1 in mouse testes and mouse SSCs (C18-4 cells). Moreover, it blocked the activation of ERS-related apoptosis proteins caspase-12, CHOP and caspase-3 and suppressed P53 and PUMA expression stimulated by busulfan both in vivo and in vitro. Conclusion: Our results demonstrate that ERS is an important mediator for busulfan-induced apoptosis. The attenuation of ERS by melatonin can prevent busulfan-treated SSCs apoptosis and protect busulfan-treated testes from damage. Thus, this study suggests that melatonin may alleviate the side effects of busulfan for male patients during clinical treatment.

scholarly journals Effect of Berberine from Coptis chinensis on Apoptosis of Intestinal Epithelial Cells in a Mouse Model of Ulcerative Colitis: Role of Endoplasmic Reticulum Stress

2020 ◽  
Vol 2020 ◽  
pp. 1-7 ◽  
Author(s):  
Shen Yan ◽  
Liu Yingchao ◽  
Wang Zhangliu ◽  
Ruan Xianli ◽  
Li Si ◽  
...  
Keyword(s):  
Ulcerative Colitis ◽  
Endoplasmic Reticulum ◽  
Epithelial Cells ◽  
Endoplasmic Reticulum Stress ◽  
Caspase 3 ◽  
Intestinal Epithelial Cells ◽  
High Dose ◽  
Intestinal Epithelial ◽  
Model Group ◽  
Caspase 12

The purpose of this study was to verify the effect of berberine (BBR) on endoplasmic reticulum stress (ERS) and apoptosis of intestinal epithelial cells (IECs) in mice with ulcerative colitis (UC). BALB/c mice were randomly divided into five groups as follows: blank control, model, and low-, medium-, and high-dose BBR. A dextran sodium sulfate- (DSS-) induced model of UC was prepared, and the low-, medium-, and high-dose BBR groups were simultaneously gavaged with a BBR suspension for 7 d. Disease activity index (DAI) was assessed, and tissue damage index (TDI) was assessed from colon samples after the last administration. TUNEL assays were used to detect apoptosis of IECs. Immunohistochemistry and/or real-time PCR were applied to determine the expression of GRP78, caspase-12, and caspase-3. In all BBR treatment groups, clinical symptoms of colitis and histopathological damage were significantly reduced. The high-dose BBR group exhibited particularly pronounced decrease (p<0.01) in both DAI (0.48 ± 0.36) and TDI (1.62 ± 0.64) relative to the model group (1.50 ± 0.65 and 3.88 ± 0.04, respectively). In colon tissues of the model group, the number of apoptotic IECs was significantly increased; the expression of GRP78, caspase-12, and caspase-3 proteins was significantly increased; and the expression of the GRP78 mRNA was upregulated. In low-, medium-, and high-dose BBR groups, the number of apoptotic IECs was significantly reduced. Moreover, GRP78 and caspase-3 expression levels were significantly decreased in the medium- and high-dose BBR groups, caspase-12 expression was significantly decreased in the high-dose BBR group, and the GRP78 mRNA expression level was significantly decreased in the high-dose BBR group. BBR can effectively reduce the rate of IEC apoptosis in UC mice and alleviate the inflammatory response in the colon. The underlying mechanism seems to involve ERS modulation and inhibition of ERS-mediated activation of the caspase-12/caspase-3 apoptosis signaling pathway.

scholarly journals Lidocaine Induces Endoplasmic Reticulum Stress-Associated Apoptosis in Vitro and in Vivo

2011 ◽  
Vol 12 (11) ◽  
pp. 7652-7661 ◽  
Author(s):  
Dae Young Hong ◽  
Kisang Kwon ◽  
Kyeong Ryong Lee ◽  
Young Jin Choi ◽  
Tae-Won Goo ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Endoplasmic Reticulum Stress

scholarly journals HIF-1α Protects Granulosa Cells From Hypoxia-Induced Apoptosis During Follicular Development by Inducing Autophagy

2021 ◽  
Vol 9 ◽  
Author(s):  
Zonghao Tang ◽  
Renfeng Xu ◽  
Zhenghong Zhang ◽  
Congjian Shi ◽  
Yan Zhang ◽  
...  
Keyword(s):  
Granulosa Cells ◽  
Mammalian Cells ◽  
Caspase 3 ◽  
Ovarian Follicle ◽  
Hypoxia Inducible Factor ◽  
Follicular Development ◽  
B Cell Lymphoma ◽  
Underlying Mechanism

Owing to the avascular structure of the ovarian follicle, proliferation of granulosa cells (GCs) and development of follicles occur under hypoxia, which is obviously different from the cell survival requirements of most mammalian cells. We hypothesized that autophagy may exert an inhibitory effect on GC apoptosis. To decipher the underlying mechanism, we constructed a rat follicular development model using pregnant mare serum gonadotropin and a cell culture experiment in hypoxic conditions (3% O2). The present results showed that the autophagy level was obviously increased and was accompanied by the concomitant elevation of hypoxia inducible factor (HIF)-1α and BNIP3 (Bcl-2/adenovirus E1B 19kDa-interacting protein 3) in GCs during follicular development. The levels of Bax (Bcl2-associated X) and Bcl-2 (B-cell lymphoma-2) were increased, while the activation of caspase-3 exhibited no obvious changes during follicular development. However, inhibition of HIF-1α attenuated the increase in Bcl-2 and promoted the increase in Bax and cleaved caspase-3. Furthermore, we observed the downregulation of BNIP3 and the decrease in autophagy after treatment with a specific HIF-1α activity inhibitor (echinomycin), indicating that HIF-1α/BNIP3 was involved in autophagy regulation in GCs in vivo. In an in vitro study, we also found that hypoxia did not obviously promote GC apoptosis, while it significantly enhanced the activation of HIF-1α/BNIP3 and the induction of autophagy. Expectedly, this effect could be reversed by 3-methyladenine (3-MA) treatment. Taken together, these findings demonstrated that hypoxia drives the activation of HIF-1α/BNIP3 signaling, which induces an increase in autophagy, protecting GC from apoptosis during follicular development.

scholarly journals High Doses of Dexamethasone Induce Endoplasmic Reticulum Stress-Mediated Apoptosis by Promoting Calcium Ion Influx-Dependent CHOP Expression in Osteoblasts

2021 ◽  
Author(s):  
Yunshan Guo ◽  
Dingjun Hao
Keyword(s):  
Endoplasmic Reticulum ◽  
Endoplasmic Reticulum Stress ◽  
Cell Apoptosis ◽  
Calcium Ion ◽  
Caspase 3 ◽  
Combined Treatment ◽  
Caspase 12 ◽  
Ion Influx ◽  
High Doses ◽  
In Cells

Abstract Background: The molecular mechanisms by which dexamethasone (Dex) induces apoptosis in osteoblasts remain unclear.Materials and Methods: MC3T3-E1 cells were treated with 0, 10-8, 10-6, and 10-4 M Dex for 24 h. The expression of ATF6, and phosphorylated PERK and IRE1, cell apoptosis, and the activity of caspase-12 and caspase-3 were measured. The expression of CHOP and the rate of influx of calcium ions were also measured in cells treated with 0 and 10-4 M Dex for 24 h. The effect of 2-APB treatment was assessed in cells treated with 0 or 10-4 M Dex.Results: The levels of ATF6 and phosphorylated PERK and IRE1 increased in a dose-dependent manner in MC3T3-E1 cells treated with 10-8, 10-6, and 10-4 M Dex, compared to in cells treated with 0 M Dex (P <0.05). Cells treated with 10-6 and 10-4 M Dex had significantly increased cell apoptosis rates and caspase-12 and caspase-3 activity compared to the control (P <0.05). Cells treated with 10-4 M Dex had significantly increased levels of CHOP and calcium ion influx rates compared to in the control (P <0.05). Combined treatment with 10-4 M Dex and 2-APB abrogated the observed increases in cell apoptosis and the activity of caspase-12 and caspase-3 (P>0.05). Conclusion: High doses of Dex induce endoplasmic reticulum stress-mediated apoptosis by promoting calcium ion influx-dependent expression of CHOP, and the activation of caspase-12 and caspase-3 in osteoblasts. Combined treatment with 2-APB protects the cells from the effects of Dex, preventing endoplasmic reticulum stress-mediated apoptosis.

scholarly journals Chemical chaperon 4-phenylbutyrate protects against the endoplasmic reticulum stress-mediated renal fibrosis in vivo and in vitro

Oncotarget ◽  
2016 ◽  
Vol 7 (16) ◽  
pp. 22116-22127 ◽  
Author(s):  
Shing-Hwa Liu ◽  
Ching-Chin Yang ◽  
Ding-Cheng Chan ◽  
Cheng-Tien Wu ◽  
Li-Ping Chen ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Endoplasmic Reticulum Stress ◽  
Renal Fibrosis

REG4 as a novel biomarker of lung adenocarcinoma with mutated KRAS and TTF-1 low expression.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e14541-e14541
Author(s):  
Hui Yu ◽  
Si Sun
Keyword(s):  
Lung Adenocarcinoma ◽  
Rna Sequencing ◽  
Underlying Mechanism ◽  
Clinical Samples ◽  
Cancer Center ◽  
Pcr Analysis ◽  
Cancer Pathogenesis ◽  
Low Expression

e14541 Background: Recent research has classified lung adenocarcinoma patients with KRAS mutation into three subtypes by co-occurring genetic events in TP53 (KP subgroup), STK11/LKB1 (KL subgroup) and CDKN2A/B inactivation coupled with low expression of the TTF-1 (KC subgroup). The aim of this study was to identify novel biomarkers through searching the candidate molecules that contributing to lung adenocarcinoma pathogenesis, especially KC subtype. Methods: We analyzed the publicly available database and identified the candidate REG4 using the E-GEOD-31210 dataset, and then confirmed by TCGA dataset. In addition, an independent cohort of 55 clinical samples was analyzed by quantitative real-time PCR analysis. Functional studies and RNA sequencing were performed after the silencing REG4 expression. Results: REG4, an important regulator of gastro-intestinal carcinogenesis, was highly expressed in KRAS mutated lung adenocarcinoma with low expression of TTF-1 (KC subtype). The results were validated both by gene expression analysis and immunohistochemistry study in an independent 55 clinical samples from Fudan University Shanghai Cancer Center. Further in vitro and in vivo functional assays revealed silencing REG4 expression significantly reduce cancer cell proliferation and tumorigenesis. Moreover, RNA sequencing and GSEA analysis displayed that REG4 knockdown might induce the cell cycle arrest by regulating G2/M checkpoint and E2F targets. Conclusions: Our results indicate that REG4 plays an important role in KRAS-driven lung cancer pathogenesis and is a novel biomarker of lung adenocarcinoma subtype. Future studies are required to clarify the underlying mechanism of REG4 in the division and proliferation of KC tumors and its potential therapeutic value.

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