Endoplasmic Reticulum Stress PERK-ATF4-CHOP Pathway Is Associated with Hypothalamic Neuronal Injury in Different Durations of Stress in Rats

Yi, Shanyong; Shi, Wanying; Wang, He; Ma, Chunling; Zhang, Xiaojing; Wang, Songjun; Cong, Bin; Li, Yingmin

doi:10.3389/fnins.2017.00152

Cited by 17 publications

(24 citation statements)

References 38 publications

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“…The hypothalamus can be activated by various internal and external stimulating factors via a variety of signaling pathways, promoting the adrenal cortex to synthesize, and release glucocorticoids through the HPA axis; this process can establish good body adaptability (Kadmiel et al, 2016). It has also been reported that stress can cause dysfunction of the HPA axis, leading to negative effects (Yi et al, 2017; Starr et al, 2019). In the present experiment, the result of thionine staining revealed that stress exposure led to reduced Nissl bodies in hypothalamic and pyknotic neurons.…”

Section: Discussionmentioning

confidence: 99%

“…Tissue Preparation was performed as described previously (Yi et al, 2017). Tissue used for staining was harvested and fixed immediately in 10% formalin.…”

Section: Methodsmentioning

confidence: 99%

“…Immunohistochemistry was performed as described previously (Yi et al, 2017) Deparaffinized sections were pretreated using microwave antigen retrieval, followed by incubation in 3% H 2 O 2 in cold methanol for 30 min and goat serum for 30 min. Next, the tissues were incubated overnight at 4°C with antibodies against GRP78 (Cat.No.…”

Section: Methodsmentioning

confidence: 99%

“…Cell counting was performed as described previously (Yi et al, 2017). Six rats from each group were used for morphological observation and data analysis.…”

Section: Methodsmentioning

confidence: 99%

“…The hypothalamus is activated when the body is stimulated by internal or external risk factors, which then promotes adrenal cortex synthesis, and the release of glucocorticoids through the HPA axis; Glucocorticoids can enhance the body’s resistance to risk factors by mobilizing energy and regulating metabolism, while long-term stress exposure or excessive stress can also lead to varying degrees of damage, and dysfunction (McLaughlin et al, 2007; Vegas et al, 2018). In a previous study, we observed that serum glucocorticoid levels significantly increased in stressed rats and stress led to pathological damage in the hypothalamus (Yi et al, 2017). However, there is no detailed report on the damage related to this mechanism.…”

Section: Introductionmentioning

confidence: 93%

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Endoplasmic Reticulum Stress Is Involved in Stress-Induced Hypothalamic Neuronal Injury in Rats via the PERK-ATF4-CHOP and IRE1-ASK1-JNK Pathways

Chen

Zhang

et al. 2019

Front. Cell. Neurosci.

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Objective As a high-level nerve center that regulates visceral and endocrine activity, the hypothalamus plays an important role in regulating the body’s stress response. Previous studies have shown that stress can cause damage to hypothalamic neurons. The present study aimed to further clarify the mechanism of endoplasmic reticulum stress (ERS) involvement in hypothalamic neuronal injury. Methods A 7-day stressed rat model was established with daily restraining for 8 h and forced ice-water swimming for 5 min. The rats were randomly divided into control, stress, stress + GSK2606414 (PERK phosphorylation inhibitor), stress + KIRA6 (IRE1 phosphokinase activity inhibitor), GSK2606414, and KIRA6 groups. The pathological changes of hypothalamic neurons were observed by thionine staining. Expression of ERS proteins GRP78, ATF4, ASK1, JNK, and CHOP in the hypothalamic neurons were observed by immunohistochemical staining. The expression of JNK and CHOP mRNA in the hypothalamic neurons were observed by RNA in situ hybridization (RNA Scope) and the expression of related proteins and mRNA was semiquantitatively analyzed by microscopy-based multicolor tissue cytometry (MMTC). Results Thionine staining revealed that stress exposure resulted in edema, a lack of Nissl bodies, and pyknosis in hypothalamic neurons. Immunohistochemistry and RNA Scope showed that stress exposure significantly increased the expression of GRP78, ATF4, ASK1, CHOP, JNK, JNK mRNA, and CHOP mRNA. Treatment with PERK and IRE1 inhibitors attenuated pathological damage and downregulated the expression of ATF4, ASK1, JNK, CHOP, JNK mRNA, and CHOP mRNA. Conclusion Stress caused pathological changes in rat hypothalamic neurons. ERS PERK-ATF4-CHOP and IRE1-ASK1-JNK pathways were involved in the injury process.

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Section: Discussionmentioning

confidence: 99%

“…Tissue Preparation was performed as described previously (Yi et al, 2017). Tissue used for staining was harvested and fixed immediately in 10% formalin.…”

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

“…Cell counting was performed as described previously (Yi et al, 2017). Six rats from each group were used for morphological observation and data analysis.…”

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 93%

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Endoplasmic Reticulum Stress Is Involved in Stress-Induced Hypothalamic Neuronal Injury in Rats via the PERK-ATF4-CHOP and IRE1-ASK1-JNK Pathways

Chen

Zhang

et al. 2019

Front. Cell. Neurosci.

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Maternal obesity during pregnancy leads to adipose tissue ER stress in mice via miR-126-mediated reduction in Lunapark

et al. 2021

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Aims/hypothesis Levels of the microRNA (miRNA) miR-126-3p are programmed cell-autonomously in visceral adipose tissue of adult offspring born to obese female C57BL/6J mice. The spectrum of miR-126-3p targets and thus the consequences of its dysregulation for adipocyte metabolism are unknown. Therefore, the aim of the current study was to identify novel targets of miR-126-3p in vitro and then establish the outcomes of their dysregulation on adipocyte metabolism in vivo using a well-established maternal obesity mouse model. Methods miR-126-3p overexpression in 3T3-L1 pre-adipocytes followed by pulsed stable isotope labelling by amino acids in culture (pSILAC) was performed to identify novel targets of the miRNA. Well-established bioinformatics algorithms and luciferase assays were then employed to confirm those that were direct targets of miR-126-3p. Selected knockdown experiments were performed in vitro to define the consequences of target dysregulation. Quantitative real-time PCR, immunoblotting, histology, euglycaemic–hyperinsulinaemic clamps and glucose tolerance tests were performed to determine the phenotypic and functional outcomes of maternal programmed miR-126-3p levels in offspring adipose tissue. Results The proteomic approach confirmed the identity of known targets of miR-126-3p (including IRS-1) and identified Lunapark, an endoplasmic reticulum (ER) protein, as a novel one. We confirmed by luciferase assay that Lunapark was a direct target of miR-126-3p. Overexpression of miR-126-3p in vitro led to a reduction in Lunapark protein levels and increased Perk (also known as Eif2ak3) mRNA levels and small interference-RNA mediated knockdown of Lunapark led to increased Xbp1, spliced Xbp1, Chop (also known as Ddit3) and Perk mRNA levels and an ER stress transcriptional response in 3T3-L1 pre-adipocytes. Consistent with the results found in vitro, increased miR-126-3p expression in adipose tissue from adult mouse offspring born to obese dams was accompanied by decreased Lunapark and IRS-1 protein levels and increased markers of ER stress. At the whole-body level the animals displayed glucose intolerance. Conclusions/interpretation Concurrently targeting IRS-1 and Lunapark, a nutritionally programmed increase in miR-126-3p causes adipose tissue insulin resistance and an ER stress response, both of which may contribute to impaired glucose tolerance. These findings provide a novel mechanism by which obesity during pregnancy leads to increased risk of type 2 diabetes in the offspring and therefore identify miR-126-3p as a potential therapeutic target. Graphical abstract

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CHOP/caspase-3 signal pathway involves in mitigative effect of selenium on lead-induced apoptosis via endoplasmic reticulum pathway in chicken testes

Huang

Jiao

et al. 2018

Environ Sci Pollut Res

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Lead (Pb) is an environmental pollutant. Selenium (Se) has alleviative effect on Pb poisoning. However, mitigative effect of Se on Pb-induced apoptosis has not been unclear via endoplasmic reticulum (ER) pathway in chicken testes. The aim of this study was to investigate mitigative effect of Se on apoptosis induced by Pb poisoning via ER pathway in chicken testes. Sixty male chickens (7-day-old) were randomly divided into the control group offered drinking water (DW) and basic diet (BD) (0.49 mg/kg Se), the Se group offered DW and BD containing NaSeO (SeBD) (1.00 mg/kg Se), the Pb group offered DW containing (CHOO)Pb (PbDW) (350.00 mg/L Pb) and BD, and the Pb + Se group offered PbDW and SeBD; and were fed for 90 days. The following contents were performed as follows: histology; antioxidant indexes (reduced glutathione (GSH), malondialdehyde (MDA), glutathione peroxidase (GPx), glutathione S-transferase (GST), and superoxide dismutase (SOD)); mRNA expressions of ER-related genes (glucose-related protein 78 (GRP78), protein kinase-like ER kinase (PERK), eukaryotic initiation factor 2α (eIF2α), activating transcription factor 4 (ATF4), and enhancer-binding protein homologous protein (CHOP)); and apoptosis-related genes (cysteine-aspartic protease (caspase)-3 and caspase-12) in chicken testes. The results indicated that Pb poisoning caused histological changes; increased MDA content; decreased the content of GSH and the activities of GPx, GST, and SOD; and upregulated mRNA expressions of the above five ER-related genes and two apoptosis-related genes in the chicken testes. Se alleviated Pb-induced oxidative stress, ER stress, and apoptosis via CHOP/caspase-3 signal pathway in the chicken testes.

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Endoplasmic Reticulum Stress PERK-ATF4-CHOP Pathway Is Associated with Hypothalamic Neuronal Injury in Different Durations of Stress in Rats

Cited by 17 publications

References 38 publications

Endoplasmic Reticulum Stress Is Involved in Stress-Induced Hypothalamic Neuronal Injury in Rats via the PERK-ATF4-CHOP and IRE1-ASK1-JNK Pathways

Endoplasmic Reticulum Stress Is Involved in Stress-Induced Hypothalamic Neuronal Injury in Rats via the PERK-ATF4-CHOP and IRE1-ASK1-JNK Pathways

Maternal obesity during pregnancy leads to adipose tissue ER stress in mice via miR-126-mediated reduction in Lunapark

CHOP/caspase-3 signal pathway involves in mitigative effect of selenium on lead-induced apoptosis via endoplasmic reticulum pathway in chicken testes

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