scholarly journals Autophagy protein NRBF2 attenuates endoplasmic reticulum stress-associated neuroinflammation and oxidative stress via promoting autophagosome maturation by interacting with Rab7 after SAH

2021 ◽  
Vol 18 (1) ◽  
Author(s):  
Hanhai Zeng ◽  
Huaijun Chen ◽  
Min Li ◽  
Jianfeng Zhuang ◽  
Yucong Peng ◽  
...  

Abstract Background Neuroinflammation and oxidative stress plays an important role in the pathogenesis of early brain injury (EBI) after subarachnoid hemorrhage (SAH). This study is the first to show that activation of autophagy protein nuclear receptor binding factor 2 (NRBF2) could reduce endoplasmic reticulum stress (ERS)-associated inflammation and oxidative stress after SAH. Methods Male C57BL/6J mice were subjected to endovascular perforation to establish a model of SAH. NRBF2 overexpression adeno-associated virus (AAV), NRBF2 small interfering RNAs (siRNA), lysosomal inhibitor-chloroquine (CQ), and late endosome GTPase Rab7 receptor antagonist-CID1067700 (CID) were used to investigate the role of NRBF2 in EBI after SAH. Neurological tests, brain water content, western blotting and immunofluorescence staining were evaluated. Results Our study found that the level of NRBF2 was increased after SAH and peaked at 24 h after SAH. In addition, we found that the overexpression of NRBF2 significantly improved neurobehavioral scores and reduced ERS, oxidative stress, and neuroinflammation in SAH, whereas the inhibition of NRBF2 exacerbated these phenotypes. In terms of mechanism, NRBF2 overexpression significantly promoted autophagosome maturation, with the downregulation of CHOP, Romo-1, TXNIP, NLRP3, TNF-α, and IL-1β expression through interaction with Rab7. The protective effect of NRBF2 on ERS-associated neuroinflammation and oxidative stress after SAH was eliminated by treatment with CQ. Meanwhile, it was also reversed by intraperitoneal injection of CID. Moreover, the MIT domain of NRBF2 was identified as a critical binding site that interacts with Rab7 and thereby promotes autophagosome maturation. Conclusion Our data provide evidence that the autophagy protein NRBF2 has a protective effect on endoplasmic reticulum stress-associated neuroinflammation and oxidative stress by promoting autophagosome maturation through interactions with Rab7 after SAH.

2019 ◽  
Vol 19 (5) ◽  
pp. 665-675 ◽  
Author(s):  
Wenjiao Shi ◽  
Zhixin Guo ◽  
Ruixia Yuan

Background and Objective: This study investigated whether rapamycin has a protective effect on the testis of diabetic rats by regulating autophagy, endoplasmic reticulum stress, and oxidative stress. Methods: Thirty male Sprague-Dawley rats were randomly divided into three groups: control, diabetic, and diabetic treated with rapamycin, which received gavage of rapamycin (2mg.kg-1.d-1) after induction of diabetes. Diabetic rats were induced by intraperitoneal injection of streptozotocin (STZ, 65mg.Kg-1). All rats were sacrificed at the termination after 8 weeks of rapamycin treatment. The testicular pathological changes were determined by hematoxylin and eosin staining. The protein or mRNA expression of autophagy-related proteins (Beclin1, microtubule-associated protein light chain 3 (LC3), p62), ER stress marked proteins (CCAAT/enhancer-binding protein (C/EBP) homologous protein (CHOP), caspase-12), oxidative stress-related proteins (p22phox, nuclear factor erythroid2-related factor 2 (Nrf2)) and apoptosis-related proteins (Bax, B cell lymphoma-2 (Bcl-2)) were assayed by western blot or real-time fluorescence quantitative PCR. Results: There were significant pathological changes in the testes of diabetic rats. The expression of Beclin1, LC3, Nrf2, Bcl-2 were significantly decreased and p62, CHOP, caspase12, p22phox, and Bax were notably increased in the testis of diabetic rats (P <0.05). However, rapamycin treatment for 8 weeks significantly reversed the above changes in the testis of diabetic rats (P <0.05). Conclusion: Rapamycin appears to produce a protective effect on the testes of diabetic rats by inducing the expression of autophagy and inhibiting the expression of ER-stress, oxidative stress, and apoptosis.


Author(s):  
Matshediso Zachariah ◽  
Hatem Maamoun ◽  
Larissa Milano ◽  
Margaret P. Rayman ◽  
Lisiane B. Meira ◽  
...  

2015 ◽  
Vol 2015 ◽  
pp. 1-7 ◽  
Author(s):  
Yanfen Zhou ◽  
Lianyou Zhao ◽  
Zhimin Zhang ◽  
Xuanhao Lu

In the present study, we investigated the effect of methionine-enriched diet (MED) on blood pressure in rats and examined the protective effect of enalapril, a widely used angiotensin converting enzyme inhibitors (ACEi) class antihypertensive drug. The results showed that MED induced significant increase of SBP and Ang II-induced contractile response in aortae of rats. MED significantly increased plasma levels of homocysteine (Hcy) and ACE. In addition, MED increased the phosphorylation of protein kinase R-like endoplasmic reticulum kinase (PERK) and eukaryotic initiation factor 2 (eIF2α) and expression of activating transcription factor 3 (ATF3) and ATF6 in aortae of rats, indicating the occurrence of endoplasmic reticulum (ER) stress. Moreover, MED resulted in oxidative stress as evidenced by significant increase of TBARS level and decrease of superoxide dismutase and catalase activities. Administration of enalapril could effectively inhibit these pathological changes induced by MED in rats. These results demonstrated that ACE-mediated ER stress and oxidative stress played an important role in high Hcy-induced hypertension and MED may exert a positive loop between the activation of ACE and accumulation of Hcy, aggravating the pathological condition of hypertension. The data provide novel insights into the mechanism of high Hcy-associated hypertension and the therapeutic efficiency of enalapril.


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