Upregulation of CDGSH iron sulfur domain 2 attenuates cerebral ischemia/reperfusion injury

CDGSH iron sulfur domain 2 can inhibit ferroptosis,which has been associated with cerebral ischemia/reperfusion,in individuals with head and neck cancer.Therefore,CDGSH iron sulfur domain 2 may be implicated in cerebral ischemia/reperfusion injury.To validate this hypothesis in the present study,we established mouse models of occlusion of the middle cerebral artery and HT22 cell models of oxygen-glucose deprivation and reoxygenation to mimic cerebral ischemia/reperfusion injury in vivo and in vitro,respectively.We found remarkably decreased CDGSH iron sulfur domain 2 expression in the mouse brain tissue and HT22 cells.When we used adeno-associated virus and plasmid to up-regulate CDGSH iron sulfur domain 2 expression in the brain tissue and HT22 cell models separately,mouse neurological dysfunction was greatly improved;the cerebral infarct volume was reduced;the survival rate of HT22 cells was increased;HT22 cell injury was alleviated;the expression of ferroptosis-related glutathione peroxidase 4,cystine-glutamate antiporter,and glutathione was increased;the levels of malondialdehyde,iron ions,and the expression of transferrin receptor 1 were decreased;and the expression of nuclear-factor E2-related factor 2/heme oxygenase 1 was increased.Inhibition of CDGSH iron sulfur domain 2 upregulation via the nuclear-factor E2-related factor 2 inhibitor ML385 in oxygen-glucose deprived and reoxygenated HT22 cells blocked the neuroprotective effects of CDGSH iron sulfur domain 2 up-regulation and the activation of the nuclear-factor E2-related factor 2/heme oxygenase 1 pathway.Our data indicate that the up-regulation of CDGSH iron sulfur domain 2 can attenuate cerebral ischemia/reperfusion injury,thus providing theoretical support from the perspectives of cytology and experimental zoology for the use of this protein as a therapeutic target in patients with cerebral ischemia/reperfusion injury.

Correlation between Nrf2‑GPX4 signaling pathway and patients with coronary heart disease

Objective:To analyze the correlation between serum Nrf2 and GPX4 activity levels with coronary heart disease(CHD)and the severity of coronary artery disease,and to explore the role of ferroptosis mediated by its signaling pathway in the progression of CHD.Methods:A total of 540 patients suspected of CHD were selected for coronary angiography,of which 360 patients were diagnosed with CHD.The activity levels of Nrf2 and GPX4 in the serum of CHD patients were detected by ELISA,and the differences in the activities of Nrf2 and GPX4 in the presence or absence of CHD were statistically analyzed.Western blot detection of Nrf2 protein expression of peripheral blood mononuclear cells(PBMCS)in the control(CON)and CHD groups(90 cases each).The expression and significance of its signaling pathway in CHD patients were analyzed.Results:The activity levels of Nrf2 and GPX4 in the CHD group were lower than those in the CON group(P<0.05),and the expression levels of Nrf2 in PBMCs of the two groups were detected by Western blot.The protein expression level of Nrf2 in the CHD group(0.25±0.05)was down‑regulated compared with CON group(0.87±0.16)(P<0.05),indicating that Nrf2 protein expression level was low in CHD patients.Pearson correlation analysis showed that serum Nrf2 and GPX4 levels were negatively correlated with Gensini score(Nrf2:r=‑0.347,P<0.001;GPX4:r=-0.423,P=0.001).Nrf2 and GPX4 were negatively correlated with TG(Nrf2:r=-0.284,P<0.001;GPX4:r=-0.275,P=0.001),Nrf2 and GPX4 levels were negatively correlated with LDL(Nrf2:r=-0.418,P<0.001)0.05;(GPX4:r=-0.426,P<0.05),Nrf2 and GPX4 levels were positively correlated with HDL(Nrf2:r=0.318,P<0.05;GPX4:r=0.428,P<0.05),and Nrf2 was positively correlated with GPX4(r=0.456,P<0.01).Conclusion:The ferroptosis pathway mediated by the Nrf2‑GPX4 signaling pathway is closely related to the degree of coronary artery disease and the pathogenesis of CHD,and its mechanism may be related to the down‑regulation of the Nrf2‑GPX4 signaling pathway.

Peroxisome proliferator-activated receptor gamma coactivator-1(PGC-1)family in physiological and pathophysiological process and diseases

Peroxisome proliferator-activated receptor gamma coactivator-1(PGC-1)family(PGC-1s),consisting of three members encompassing PGC-1a,PGC-1β,and PGC-1-related coactivator(PRC),was discovered more than a quarter-century ago.PGC-1s are essential coordinators of many vital cellular events,including mitochondrial functions,oxidative stress,endoplasmic reticulum homeostasis,and inflammation.Accumulating evidence has shown that PGC-1s are implicated in many diseases,such as cancers,cardiac diseases and cardiovascular diseases,neurological disorders,kidney diseases,motor system diseases,and metabolic disorders.Examining the upstream modulators and co-activated partners of PGC-1s and identifying critical biological events modulated by downstream effectors of PGC-1s contribute to the presentation of the elaborate network of PGC-1s.Furthermore,discussing the correlation between PGC-1s and diseases as well as summarizing the therapy targeting PGC-1s helps make individualized and precise intervention methods.In this review,we summarize basic knowledge regarding the PGC-1s family as well as the molecular regulatory network,discuss the physio-pathological roles of PGc-1s in human diseases,review the application of PGC-1s,including the diagnostic and prognostic value of PGC-1s and several therapies in pre-clinical studies,and suggest several directions for future investigations.This review presents the immense potential of targeting PGC-1s in the treatment of diseases and hopefully facilitates the promotion of PGC-1s as new therapeutic targets.

Fermented Chinese formula Shuan-Tong-Ling attenuates ischemic stroke by inhibiting inflammation and apoptosis

The fermented Chinese formula Shuan-Tong-Ling is composed of radix puerariae（Gegen）,salvia miltiorrhiza（Danshen）,radix curcuma（Jianghuang）,hawthorn（Shanzha）,salvia chinensis（Shijianchuan）,sinapis alba（Baijiezi）,astragalus（Huangqi）,panax japonicas（Zhujieshen）,atractylodes macrocephala koidz（Baizhu）,radix paeoniae alba（Baishao）,bupleurum（Chaihu）,chrysanthemum（Juhua）,rhizoma cyperi（Xiangfu） and gastrodin（Tianma）,whose aqueous extract was fermented with lactobacillus,bacillus aceticus and saccharomycetes.ShuanTong-Ling is a formula used to treat brain diseases including ischemic stroke,migraine,and vascular dementia.Shuan-Tong-Ling attenuated H_2O_2-induced oxidative stress in rat microvascular endothelial cells.However,the potential mechanism involved in these effects is poorly understood.Rats were intragastrically treated with 5.7 or 17.2 m L/kg Shuan-Tong-Ling for 7 days before middle cerebral artery occlusion was induced.The results indicated Shuan-Tong-Ling had a cerebral protective effect by reducing infarct volume and increasing neurological scores.Shuan-Tong-Ling also decreased tumor necrosis factor-α and interleukin-1β levels in the hippocampus on the ischemic side.In addition,Shuan-Tong-Ling upregulated the expression of SIRT1 and Bcl-2 and downregulated the expression of acetylated-protein 53 and Bax.Injection of 5 mg/kg silent information regulator 1（SIRT1） inhibitor EX527 into the subarachnoid space once every 2 days,four times,reversed the above changes.These results demonstrate that Shuan-Tong-Ling might benefit cerebral ischemia/reperfusion injury by reducing inflammation and apoptosis through activation of the SIRT1 signaling pathway.

Buyang Huanwu Decoction(补阳还五汤)Attenuates Glial Scar by Downregulating Expression of Leukemia Inhibitory Factor in Intracerebral Hemorrhagic Rats

Objective: To evaluate the effect of Buyang Huanwu Decoction(补阳还五汤,BYHWD) on glial scar after intracerebral hemorrhage(ICH) and investigate the underlying mechanism.Methods: Collagenase type Ⅶ(0.5 U) was injected stereotaxically into right globus pallidus to induce ICH model.One hundred and twenty SpragueDawley rats were randomly divided into 3 groups according to a random number table,including normal group(n=40),ICH model group(n=40) and BYHWD group(n=40),respectively.After ICH,the rats in the BYHWD group were intragastrically administered with BYHWD(4.36 g/kg) once a day for 21 days,while the rats in ICH group were administered with equal volume of distilled water for 21 days,respectively.Double immunolabeling was performed for proliferating cell nuclear antigen(PCNA)+/glial ?brillary acidic protein(GFAP)+ nuclei.The expression of GFAP and leukemia inhibitory factor(LIF) was evaluated by immunohistochemistry and quantitative real-time reverse transcription-polymerase chain reaction(RT-PCR).Results: The astrocytes with hypertrophied morphology around the hematoma was observed on day 3 after ICH.The number of GFAP positive cells and GFAP m RNA levels increased notably on day 3 and reached the peak on day 14 post-ICH(P<0.01).PCNA+/GFAP+ nuclei were observed around the hematoma and reached the peak on day 14 post-ICH(P<0.01).In addition,LIF-positive astrocytes and LIF m RNA level in the hemorrhagic region increased signi?cantly till day 14 post-ICH(P<0.01).However,BYHWD not only reduced the number of PCNA+/GFAP+ nuclei,but also decreased GFAP and LIF levels(P<0.05).Conclusion:BYHWD could attenuate ICH-induced glial scar by downregulating the expression of LIF in the rats.