scholarly journals Metformin Protects against Oxidative Stress Injury Induced by Ischemia/Reperfusion via Regulation of the lncRNA-H19/miR-148a-3p/Rock2 Axis

2019 ◽  
Vol 2019 ◽  
pp. 1-18 ◽  
Author(s):  
Jing Zeng ◽  
Long Zhu ◽  
Jing Liu ◽  
Tao Zhu ◽  
Zhaohui Xie ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Ischemic Stroke ◽  
Cerebral Ischemia ◽  
Ischemia Reperfusion ◽  
Luciferase Reporter ◽  
Neuroprotective Effects ◽  
Stress Injury ◽  
Oxidative Stress Injury

Previous studies have shown that metformin not only is a hypoglycemic agent but also has neuroprotective effects. However, the mechanism of action of metformin in ischemic stroke is unclear. Oxidative stress is an important factor in the pathogenesis of cerebral ischemia-reperfusion injury. It has been reported that metformin is associated with stroke risk in the clinical population. This study is aimed at investigating the effect and mechanism of metformin in an experimental model of oxidative stress induced by ischemia/reperfusion (I/R) in vivo and oxygen glucose deprivation/reperfusion (OGD/R) in vitro. Metformin (100, 200, and 300 mg/kg) was administered intraperitoneally immediately after induction of cerebral ischemia. The indicators of oxidative stress selected were antioxidant enzyme activities of catalase, malondialdehyde (MDA), nitric oxide (NO), superoxide dismutase (SOD), and glutathione peroxidation enzyme (GSHPx). First, we demonstrated that metformin can significantly alleviate acute and chronic cerebral I/R injury and it has a strong regulatory effect on stroke-induced oxidative stress. It can reduce the elevated activities of MDA and NO and increase the levels of GSHPx and SOD in the cerebrum of mice and N2a cells exposed to I/R. Furthermore, real-time PCR and western blot were used to detect the expression of long noncoding RNA H19 (lncRNA-H19), microRNA-148a-3p (miR-148a-3p), and Rho-associated protein kinase 2 (Rock2). The direct interaction of lncRNA-H19, miR-148a-3p, and Rock2 was tested using a dual luciferase reporter assay. lncRNA-H19 altered OGD/R-induced oxidative stress by modulating miR-148a-3p to increase Rock2 expression. The expression of lncRNA-H19 and Rock2 could be downregulated with metformin in vivo and in vitro. In conclusion, our study confirmed that metformin exerts neuroprotective effects by regulating ischemic stroke-induced oxidative stress injury via the lncRNA-H19/miR-148a-3p/Rock2 axis. These results provide new evidence that metformin may represent a potential treatment for stroke-related brain injury.

scholarly journals Scutellarin acts on the AR-NOX Axis to Remediate Oxidative Stress Injury in a Mouse Model of Cerebral Ischemia/Reperfusion Injury

2021 ◽  
Author(s):  
Llin Peng ◽  
Minzhen Deng ◽  
Yan Huang ◽  
Shuang Wu ◽  
Yucheng Cao ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Ischemic Stroke ◽  
Cerebral Ischemia ◽  
Brain Damage ◽  
Ischemia Reperfusion ◽  
Ischemic Injury ◽  
Neurological Function ◽  
Enzyme Linked Immunosorbent Assay ◽  
Stress Injury ◽  
Oxidative Stress Injury

Abstract BackbroundOxidative stress plays an important role in the ischemic stroke induced brain damage. Our previous study showed that Scutellarin protects against ischemic injury in vitro and in vivo induced oxidative damage in rats, and we also reported that the involvement of Aldose reductase (AR) in oxidative stress and cerebral ischemic injury, in this study we furtherly explicit whether the antioxidant effect of Scutellarin on cerebral ischemia injury is related to AR gene regulation and its specific mechanism.MethodsC57BL/6N mice (Wild-type, WT) and AR knockout (AR-/-) mice were subjected to transient middle cerebral artery occlusion (tMCAO) model with 1h occlusion followed by 3d reperfusion, and Scutellarin was administered from 2h before surgery to 3 days after surgery. Subsequently, Neurological function were assessed by the modified Longa score method, the histopathological morphology observed with 2,3,5-triphenyltetrazolium chloride and hematoxylin-eosin staining. Enzyme-linked immunosorbent assay was used to detect the levels of ROS, 4-hydroxynonenal (4-HNE), 8-hydroxydeoxyguanosine (8-OHDG), Neurotrophin-3 (NT-3), poly ADP-ribose polymerase-1 (PARP1) and 3-nitrotyrosine (3-NT) in the ischemic penumbra regions. Quantitative proteomics profiling using quantitative nano-HPLC-MS/MS were performed to compare the protein expression difference between AR-/- and WT mice with or without tMCAO injury. The expression of AR, NOX1, NOX2 and NOX4 in the ipsilateral side of ischemic brain were detected by Real time-PCR, Western blot and immunofluorescence co-staining with NeuN.ResultsScutellarin treatment alleviated brain damage suffered from tMCAO injury such as improved neurological function deficit, brain infarct area and neuronal injury and reduced the expression of oxidation-related products, moreover, also down-regulated tMCAO induced AR mRNA and protein expression.ConclusionsScutellarin would be a potential drug for the treatment of ischemic stroke through regulating AR-NOX Axis modulate oxidative stress injury to play the protective role of cerebral ischemia injury.

scholarly journals Hydroxysafflor Yellow A and Anhydrosafflor Yellow B Protect Against Cerebral Ischemia/Reperfusion Injury by Attenuating Oxidative Stress and Apoptosis via the Silent Information Regulator 1 Signaling Pathway

2021 ◽  
Vol 12 ◽  
Author(s):  
Yijia Fangma ◽  
Huifen Zhou ◽  
Chongyu Shao ◽  
Li Yu ◽  
Jiehong Yang ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Cerebral Ischemia ◽  
Ischemia Reperfusion ◽  
Water Soluble ◽  
Hydroxysafflor Yellow A ◽  
Neuroprotective Effects ◽  
Cerebral Ischemia Reperfusion ◽  
Silent Information Regulator 1

Hydroxysafflor yellow A (HSYA) and anhydrosafflor yellow B (AHSYB) are the main water-soluble compounds in Carthamus tinctorius L. However, studies on the effect of AHSYB on cerebral ischemia/reperfusion (I/R) injury and the therapeutic effect of HSYA by regulating silent information regulator 1 (SIRT1) pathway remain obscure. In this study, we investigated whether the neuroprotective effects of HSYA and AHSYB on oxygen-glucose deprivation/reoxygenation in primary-cultured hippocampal neuronal cells and the middle cerebral artery occlusion and reperfusion model in rats are associated with the regulation of the SIRT1 pathway. In vitro, HSYA and AHSYB increased cell viability, depressed oxidation properties, and reduced neuronal cell apoptosis. In vivo results showed that HSYA and AHSYB effectively reduced infarct volume, improved neurological function, suppressed apoptosis, and decreased the oxidative stress reaction. Besides, RT-PCR and Western blot analysis showed that HSYA and AHSYB increased the mRNA and protein expressions of the main factors in the SIRT1 pathway, including SIRT1, forkhead box O (FOXO) 1, and peroxisome proliferator–activated receptor coactivator 1α (PGC1α), decreased the expression of Bax, and increased the expression of Bcl-2. The results from immunohistochemistry also showed that the expressions of SIRT1, FOXO1, and PGC1α were increased after treatment with HSYA and AHSYB. Furthermore, the neuroprotective effects of HSYA and AHSYB were abolished by EX527 (SIRT1–specific inhibitor). These results indicated that HSYA and AHSYB should be developed into potential drugs for treating cerebral I/R injury via the SIRT1 pathway. Although HSYA and AHSYB have different chemical structures, both of them exert similar neuroprotective properties against I/R injury in vitro and in vivo, which means that AHSYB is also a non-negligible component in safflower.

scholarly journals The Neuroprotective Effects of Carvacrol on Ethanol-Induced Hippocampal Neurons Impairment via the Antioxidative and Antiapoptotic Pathways

2017 ◽  
Vol 2017 ◽  
pp. 1-17 ◽  
Author(s):  
Peng Wang ◽  
Qian Luo ◽  
Hui Qiao ◽  
Hui Ding ◽  
Yonggang Cao ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Western Blot ◽  
Cognitive Dysfunction ◽  
Hippocampal Neurons ◽  
Morris Water Maze Test ◽  
Oxidative Stress Biomarkers ◽  
Neuroprotective Effects ◽  
Stress Injury

Chronic alcohol consumption causes hippocampal neuronal impairment, which is associated with oxidative stress and apoptosis. Carvacrol is a major monoterpenic phenol found in essential oils from the family Labiatae and has antioxidative stress and antiapoptosis actions. However, the protective effects of carvacrol in ethanol-induced hippocampal neuronal impairment have not been fully understood. We explored the neuroprotective effects of carvacrol in vivo and in vitro. Male C57BL/6 mice were exposed to 35% ethanol for 4 weeks to establish ethanol model in vivo, and hippocampal neuron injury was simulated by 200 mM ethanol in vitro. Morris water maze test was performed to evaluate the cognitive dysfunction. The oxidative stress injury of hippocampal neurons was evaluated by measuring the levels of oxidative stress biomarkers. Histopathological examinations and western blot were performed to evaluate the apoptosis of neurons. The results showed that carvacrol attenuates the cognitive dysfunction, oxidative stress, and apoptosis of the mice treated with ethanol and decreases hippocampal neurons apoptosis induced by ethanol in vitro. In addition, western blot analysis revealed that carvacrol modulates the protein expression of Bcl-2, Bax, caspase-3, and p-ERK, without influence of p-JNK and p-p38. Our results suggest that carvacrol alleviates ethanol-mediated hippocampal neuronal impairment by antioxidative and antiapoptotic effects.

scholarly journals OM-MSCs Alleviate the Golgi Apparatus Stress Response following Cerebral Ischemia/Reperfusion Injury via the PEDF-PI3K/Akt/mTOR Signaling Pathway

2021 ◽  
Vol 2021 ◽  
pp. 1-19
Author(s):  
Jialin He ◽  
Jianyang Liu ◽  
Yan Huang ◽  
Xiangqi Tang ◽  
Han Xiao ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Stress Response ◽  
Cerebral Ischemia ◽  
Stress Responses ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Cerebral Ischemia Reperfusion ◽  
Cerebral Ischemia Reperfusion Injury

The mechanism of Golgi apparatus (GA) stress responses mediated by GOLPH3 has been widely studied in ischemic stroke, and the neuroprotection effect of olfactory mucosa mesenchymal stem cells (OM-MSCs) against cerebral ischemia/reperfusion injury (IRI) has been preliminarily presented. However, the exact role of OM-MSCs in the GA stress response following cerebral IRI remains to be elucidated. In the present study, we used an oxygen-glucose deprivation/reoxygenation (OGD/R) model and reversible middle cerebral artery occlusion (MCAO) model to simulate cerebral IRI in vitro and in vivo. Our results showed that the level of GOLPH3 protein, reactive oxygen species (ROS), and Ca2+ was upregulated, SPCA1 level was downregulated, and GA fragmentation was increased in ischemic stroke models, and OM-MSC treatment clearly ameliorated these GA stress responses in vitro and in vivo. Subsequently, the knockdown of PEDF in OM-MSCs using PEDF-specific siRNA further demonstrated that secretion of PEDF in OM-MSCs protected OGD/R-treated N2a cells and MCAO rats from GA stress response. Additionally, rescue experiment using specific pathway inhibitors suggested that OM-MSCs could promote the phosphorylation of the PI3K/Akt/mTOR pathway, thereby mitigating OGD/R-induced GA stress response and excessive autophagy. In conclusion, OM-MSCs minimized the GA stress response following cerebral IRI, at least partially, through the PEDF-PI3K/Akt/mTOR pathway.

scholarly journals Neuroprotective Effects of Ginsenosides against Cerebral Ischemia

Molecules ◽  
2019 ◽  
Vol 24 (6) ◽  
pp. 1102 ◽  
Author(s):  
Zhekang Cheng ◽  
Meng Zhang ◽  
Chengli Ling ◽  
Ying Zhu ◽  
Hongwei Ren ◽  
...  
Keyword(s):  
Cerebral Ischemia ◽  
Ischemia Reperfusion ◽  
Ischemic Injury ◽  
Neurological Dysfunction ◽  
Control Group ◽  
Protective Effects ◽  
Ginsenoside Rb1 ◽  
Neuroprotective Effects

Ginseng has been used worldwide as traditional medicine for thousands of years, and ginsenosides have been proved to be the main active components for their various pharmacological activities. Based on their structures, ginsenosides can be divided into ginseng diol-type A and ginseng triol-type B with different pharmacological effects. In this study, six ginsenosides, namely ginsenoside Rb1, Rh2, Rg3, Rg5 as diol-type ginseng saponins, and Rg1 and Re as triol-type ginseng saponins, which were reported to be effective for ischemia-reperfusion (I/R) treatment, were chosen to compare their protective effects on cerebral I/R injury, and their mechanisms were studied by in vitro and in vivo experiments. It was found that all ginsenosides could reduce reactive oxygen species (ROS), inhibit apoptosis and increase mitochondrial membrane potential in cobalt chloride-induced (CoCl2-induced) PC12 cells injury model, and they could reduce cerebral infarction volume, brain neurological dysfunction of I/R rats in vivo. The results of immunohistochemistry and western blot showed that the expression of Toll-like receptor 4 (TLR4), myeloid differentiation factor 88 (MyD88), silencing information regulator (SIRT1) and nuclear transcription factor P65 (NF-κB) in hippocampal CA1 region of some ginsenoside groups were also reduced. In general, the effect on cerebral ischemia of Rb1 and Rg3 was significantly improved compared with the control group, and was the strongest among all the ginsenosides. The effect on SIRT1 activation of ginsenoside Rb1 and the inhibition effect of TLR4/MyD88 protein expression of ginsenoside Rb1 and Rg3 were significantly stronger than that of other groups. The results indicated that ginsenoside Rg1, Rb1, Rh2, Rg3, Rg5 and Re were effective in protecting the brain against ischemic injury, and ginsenoside Rb1 and Rg3 have the strongest therapeutic activities in all the tested ginsenosides. Their neuroprotective mechanism is associated with TLR4/MyD88 and SIRT1 activation signaling pathways, and they can reduce cerebral ischemic injury by inhibiting NF-κB transcriptional activity and the expression of proinflammatory cytokines, including interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6).

scholarly journals Overexpression of miR-506-3p Aggravates DBP-Induced Testicular Oxidative Stress in Rats by Downregulating ANXA5 via Nrf2/HO-1 Signaling Pathway

2020 ◽  
Vol 2020 ◽  
pp. 1-13
Author(s):  
Min Tang ◽  
Lei Zhang ◽  
Zheng Zhu ◽  
Ran Li ◽  
Shangqian Wang ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Signaling Pathway ◽  
Male Rats ◽  
Adolescent Male ◽  
Seminiferous Tubules ◽  
Stress Injury ◽  
Oxidative Stress Injury ◽  
Testicular Injury

Background. Di-N-butylphthalate (DBP) is a kind of unique endocrine toxicity linked to hormonal disruptions that affects the male reproductive system and has given rise to more and more attention. However, the mechanism of DBP-induced testicular injury remains unclear. Here, the objective of this study was to investigate the potential molecular mechanism of miR-506-3p in DBP-induced rat testicular oxidative stress injury via ANXA5 (Annexin A5)/Nrf2/HO-1 signaling pathway. Methods. In vivo, a total of 40 adolescent male rats were treated from 2 weeks with 800 mg/kg/day of DBP in 1 mL/kg corn oil administered daily by oral gavage. Among them, some rats were also injected subcutaneously with 2 nmol agomir-506-3p and/or 10 nmol recombinant rat ANXA5. The pathomorphological changes of testicular tissue were assessed by histological examination, and the antioxidant factors were evaluated. Subsequently, ANXA5, Nrf2, and its dependent antioxidant enzymes, such as HO-1, NQO1, and GST, were detected by Western blotting or immunohistochemical staining. In vitro, TM3 cells (Leydig cells) were used to detect the cell activity by CCK-8 and the transfection in the DBP-treated group. Results. Differentially expressed miRNAs between the DBP-treated and normal rats were analyzed, and qRT-PCR showed miR-506-3p was highly expressed in testicular tissues of the DBP-treated rats. DBP-treated rats presented severe inflammatory infiltration, increased abnormal germ cells, and missed cell layers frequently existed in seminiferous tubules, resulted in oxidative stress and decreased testicular function. Meanwhile, upregulation of miR-506-3p aggravated the above changes. In addition, miR-506-3p directly bound to ANXA5, and overexpression of miR-506-3p could reduce the ANXA5 expression and also decrease the protein levels of Nrf2/HO-1 signaling pathway. Additionally, we found that recombinant rat ANXA5 reversed the DBP-treated testicular oxidative stress promoting injury of miR-506-3p in rats. In vivo results were reproduced in in vitro experiments. Conclusions. This study provided evidence that miR-506-3p could aggravate the DBP-treated testicular oxidative stress injury in vivo and in vitro by inhibiting ANXA5 expression and downregulating Nrf2/HO-1 signaling pathway, which might provide novel understanding in DBP-induced testicular injury therapy.

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