scholarly journals p53 Inhibition Protects against Neuronal Ischemia/Reperfusion Injury by the p53/PRAS40/mTOR Pathway

2021 ◽  
Vol 2021 ◽  
pp. 1-18
Author(s):  
Jianlan Zhao ◽  
Yinhui Dong ◽  
Xingyu Chen ◽  
Xiao Xiao ◽  
Bo Tan ◽  
...  
Keyword(s):  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Mtor Pathway ◽  
Protective Effects ◽  
Potential Mechanism ◽  
Primary Neuronal Culture ◽  
P53 Overexpression ◽  
Neuronal Autophagy

The underlying mechanisms of cerebral ischemia/reperfusion (I/R) injury are unclear. Within this study, we aimed to explore whether p53 inhibition exerts protective effects via the p53/PRAS40/mTOR pathway after stroke and its potential mechanism. Both an in vitro oxygen-glucose deprivation (OGD) model with a primary neuronal culture and in vivo stroke models (dMCAO or MCAO) were used. We found that the infarction size, neuronal apoptosis, and autophagy were less severe in p53 KO mice and p53 KO neurons after cerebral I/R or OGD/R injury. By activating the mTOR pathway, p53 knockdown alleviated cerebral I/R injury both in vitro and in vivo. When PRAS40 was knocked out, the regulatory effects of p53 overexpression or knockdown against stroke disappeared. PRAS40 knockdown could inhibit the activities of the mTOR pathway; moreover, neuronal autophagy and apoptosis were exacerbated by PRAS40 knockdown. To sum up, in this study, we showed p53 inhibition protects against neuronal I/R injury after stroke via the p53/PRAS40/mTOR pathway, which is a novel and pivotal cerebral ischemic injury signaling pathway. The induction of neuronal autophagy and apoptosis by the p53/PRAS40/mTOR pathway may be the potential mechanism of this protective effect.

scholarly journals Propofol attenuates lung ischemia/reperfusion injury though the involvement of the MALAT1/microRNA-144/GSK3β axis

2021 ◽  
Vol 27 (1) ◽  
Author(s):  
Jian-Ping Zhang ◽  
Wei-Jing Zhang ◽  
Miao Yang ◽  
Hua Fang
Keyword(s):  
Cell Apoptosis ◽  
Ischemia Reperfusion Injury ◽  
Glycogen Synthase ◽  
Ischemia Reperfusion ◽  
Inflammatory Factors ◽  
Therapeutic Effects ◽  
Protective Effects ◽  
Loss Of Function

Abstract Background Propofol, an intravenous anesthetic, was proven to protect against lung ischemia/reperfusion (I/R) injury. However, the detailed mechanism of Propofol in lung I/R injury is still elusive. This study was designed to explore the therapeutic effects of Propofol, both in vivo and in vitro, on lung I/R injury and the underlying mechanisms related to metastasis-associated lung adenocarcinoma transcript 1 (MALAT1)/microRNA-144 (miR-144)/glycogen synthase kinase-3β (GSK3β). Methods C57BL/6 mice were used to establish a lung I/R injury model while pulmonary microvascular endothelial cells (PMVECs) were constructed as hypoxia/reperfusion (H/R) cellular model, both of which were performed with Propofol treatment. Gain- or loss-of-function approaches were subsequently employed, followed by observation of cell apoptosis in lung tissues and evaluation of proliferative and apoptotic capabilities in H/R cells. Meanwhile, the inflammatory factors, autophagosomes, and autophagy-related proteins were measured. Results Our experimental data revealed that Propofol treatment could decrease the elevated expression of MALAT1 following I/R injury or H/R induction, indicating its protection against lung I/R injury. Additionally, overexpressing MALAT1 or GSK3β promoted the activation of autophagosomes, proinflammatory factor release, and cell apoptosis, suggesting that overexpressing MALAT1 or GSK3β may reverse the protective effects of Propofol against lung I/R injury. MALAT1 was identified to negatively regulate miR-144 to upregulate the GSK3β expression. Conclusion Overall, our study demonstrated that Propofol played a protective role in lung I/R injury by suppressing autophagy and decreasing release of inflammatory factors, with the possible involvement of the MALAT1/miR-144/GSK3β axis.

scholarly journals Protective effects of ginsenoside Rg1 on intestinal ischemia/reperfusion injury-induced oxidative stress and apoptosis via activation of the Wnt/β-catenin pathway

2016 ◽  
Vol 6 (1) ◽  
Author(s):  
Guo Zu ◽  
Jing Guo ◽  
Ningwei Che ◽  
Tingting Zhou ◽  
Xiangwen Zhang
Keyword(s):  
Signaling Pathway ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Inflammatory Factors ◽  
Therapeutic Effects ◽  
Protective Effects ◽  
Ginsenoside Rg1 ◽  
Intestinal Ischemia Reperfusion

Abstract Ginsenoside Rg1 (Rg1) is one of the major bioactive ingredients in Panax ginseng, and it attenuates inflammation and apoptosis. The aims of our study were to explore the potential of Rg1 for the treatment of intestinal I/R injury and to determine whether the protective effects of Rg1 were exerted through the Wnt/β-catenin signaling pathway. In this study, Rg1 treatment ameliorated inflammatory factors, ROS and apoptosis that were induced by intestinal I/R injury. Cell viability was increased and cell apoptosis was decreased with Rg1 pretreatment following hypoxia/reoxygenation (H/R) in the in vitro study. Rg1 activated the Wnt/β-catenin signaling pathway in both the in vivo and in vitro models, and in the in vitro study, the activation was blocked by DKK1. Our study provides evidence that pretreatment with Rg1 significantly reduces ROS and apoptosis induced by intestinal I/R injury via activation of the Wnt/β-catenin pathway. Taken together, our results suggest that Rg1 could exert its therapeutic effects on intestinal I/R injury through the Wnt/β-catenin signaling pathway and provide a novel treatment modality for intestinal I/R injury.

The cardioprotection of dihydrotanshinone I against myocardial ischemia–reperfusion injury via inhibition of arachidonic acid ω-hydroxylase

2016 ◽  
Vol 94 (12) ◽  
pp. 1267-1275 ◽  
Author(s):  
Yidan Wei ◽  
Meijuan Xu ◽  
Yi Ren ◽  
Guo Lu ◽  
Yangmei Xu ◽  
...  
Keyword(s):  
Arachidonic Acid ◽  
Myocardial Ischemia ◽  
Reperfusion Injury ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Protective Effects ◽  
Myocardial Ischemia Reperfusion Injury ◽  
Myocardial Ischemia Reperfusion

Arachidonic acid (AA) is a precursor that is metabolized by several enzymes to many biological eicosanoids. Accumulating data indicate that the ω-hydroxylation metabolite of AA, 20-hydroxyeicosatetraenoic acid (20-HETE), is considered to be involved in the myocardial ischemia–reperfusion injury (MIRI). The inhibitors of AA ω-hydroxylase, however, are demonstrated to exhibit protective effects on MIRI. Dihydrotanshinone I (DI), a bioactive constituent of danshen, is proven to be a potent inhibitor of AA ω-hydroxylase by our preliminary study in vitro. The purpose of the present study was to investigate the cardioprotection of DI against MIRI and its effects on the concentrations of 20-HETE in vivo. Rats subjected to 30 min of ischemia followed by 24 h of reperfusion were assigned to intravenously receive vehicle (sham and ischemia–reperfusion), low (1 mg/kg), middle (2 mg/kg), or high (4 mg/kg) doses of DI before reperfusion. The results demonstrated that DI treatment could improve cardiac function, reduce infarct size, ameliorate the variations in myocardial zymogram and histopathological disorders, decrease 20-HETE generation, and regulate apoptosis-related protein in myocardial ischemia–reperfusion rats. These findings suggested DI could exert considerable cardioprotective action on MIRI by the attenuation of 20-HETE generation, subsequent myocardial injury, and apoptosis through inhibition on AA ω-hydroxylase.

scholarly journals Calenduloside E Ameliorates Myocardial Ischemia-Reperfusion Injury through Regulation of AMPK and Mitochondrial OPA1

2020 ◽  
Vol 2020 ◽  
pp. 1-12
Author(s):  
Min Wang ◽  
Rui-ying Wang ◽  
Jia-hui Zhou ◽  
Xue-heng Xie ◽  
Gui-bo Sun ◽  
...  
Keyword(s):  
Myocardial Ischemia ◽  
Reperfusion Injury ◽  
Ischemia Reperfusion Injury ◽  
Mitochondrial Dynamics ◽  
Ischemia Reperfusion ◽  
Protective Effects ◽  
Myocardial Ischemia Reperfusion Injury ◽  
Myocardial Ischemia Reperfusion

Calenduloside E (CE) is a natural triterpenoid saponin isolated from Aralia elata (Miq.) Seem., a well-known traditional Chinese medicine. Our previous studies have shown that CE exerts cardiovascular protective effects both in vivo and in vitro. However, its role in myocardial ischemia/reperfusion injury (MIRI) and the mechanism involved are currently unknown. Mitochondrial dynamics play a key role in MIRI. This study investigated the effects of CE on mitochondrial dynamics and the signaling pathways involved in myocardial ischemia/reperfusion (MI/R). The MI/R rat model and the hypoxia/reoxygenation (H/R) cardiomyocyte model were established in this study. CE exerted significant cardioprotective effects in vivo and in vitro by improving cardiac function, decreasing myocardial infarct size, increasing cardiomyocyte viability, and inhibiting cardiomyocyte apoptosis associated with MI/R. Mechanistically, CE restored mitochondrial homeostasis against MI/R injury through improved mitochondrial ultrastructure, enhanced ATP content and mitochondrial membrane potential, and reduced mitochondrial permeability transition pore (MPTP) opening, while promoting mitochondrial fusion and preventing mitochondrial fission. However, genetic silencing of OPA1 by siRNA abolished the beneficial effects of CE on cardiomyocyte survival and mitochondrial dynamics. Moreover, we demonstrated that CE activated AMP-activated protein kinase (AMPK) and treatment with the AMPK inhibitor, compound C, abolished the protective effects of CE on OPA1 expression and mitochondrial function. Overall, this study demonstrates that CE is effective in mitigating MIRI by modulating AMPK activation-mediated OPA1-related mitochondrial fusion.

scholarly journals Involvement of GPR30 in protection effect of Dexmedetomidine against myocardial ischemia/reperfusion injury in rat via AKT pathway

2021 ◽  
Author(s):  
Zheming Shao ◽  
Qihong Shen ◽  
Min Kong ◽  
Huadong Ni ◽  
Xiaomin Hou
Keyword(s):  
Protective Effect ◽  
Molecular Mechanism ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Cardioprotective Effect ◽  
Mechanism Analysis ◽  
Protective Effects ◽  
Akt Inhibitor

Acute myocardial infarction (AMI) is a heart disease that seriously threatens human health. Dexmedetomidine (DEX) has a certain protective effect on cardiac injury. This study investigated the cardioprotective effect of DEX and its potential molecular mechanism in vivo and in vitro. The results showed that DEX could significantly increase the viability of hypoxia/reoxygenation (H/R) treated cardiomyocytes and reduce oxidative damage and apoptosis. Further molecular mechanism analysis showed that the above cardiac protective effects may be related to Akt signaling pathway. In addition, the expression of G-Protein Receptor 30 (GPR30) was promoted after H/R treatment. However, knockdown of GPR30 by shRNA significantly counteracted the cardioprotective effect of DEX. Meanwhile, we constructed a rat model of AMI to investigate the role of GPR30 in vivo. The results showed that DEX significantly reduced the infarct size, and GPR30 agonist G1 enhanced the protective effect of DEX on heart. On the contrary, protein kinase B (AKT) inhibitor LY294002 counteracted the protective effect of DEX on heart, suggesting that GPR30 enhanced the protective effect of DEX on ischemia-reperfusion induced heart injury by regulating AKT related pathways. In conclusion, our study provides a potential target for the clinical treatment of AMI.

scholarly journals Schizandrin Protects against OGD/R-Induced Neuronal Injury by Suppressing Autophagy: Involvement of the AMPK/mTOR Pathway

Molecules ◽  
2019 ◽  
Vol 24 (19) ◽  
pp. 3624 ◽  
Author(s):  
Guangyun Wang ◽  
Tiezheng Wang ◽  
Yuanyuan Zhang ◽  
Fang Li ◽  
Boyang Yu ◽  
...  
Keyword(s):  
Cerebral Ischemia ◽  
Pc12 Cells ◽  
Cell Damage ◽  
Ischemia Reperfusion ◽  
Glucose Deprivation ◽  
Mtor Pathway ◽  
Protective Effects ◽  
Compound C

The neuroprotective role of schizandrin (SA) in cerebral ischemia-reperfusion (I/R) was recently highlighted. However, whether SA plays a regulatory role on autophagy in cerebral I/R injury is still unclear. This study aimed to explore whether the neuroprotective mechanisms of SA were linked to its regulation of AMP-activated protein kinase (AMPK)/mammalian target of rapamycin (mTOR)/autophagy pathway in vivo and in vitro. The present study confirmed that SA significantly improved oxygen-glucose deprivation/re-oxygenation (OGD/R)-induced PC12 cells injury. The results of immunoblotting and confocal microscope showed that SA decreased autophagy in OGD/R-injured PC12 cells, which was reflected by the decreased Beclin-1 and LC3-II expression, autophagy flux level, and LC3 puncta formation. In addition, the autophagy inducer rapamycin partially prevented the effects of SA on cell viability and autophagy after OGD/R, whereas the autophagy inhibitor 3-methyladenine (3-MA) exerted the opposite effect. The results of Western blotting showed that SA markedly decreased the phosphorylation of AMPK (p-AMPK), whereas the phosphor-mTOR (p-mTOR) levels increased in the presence of OGD/R insult. Furthermore, pretreatment with the AMPK inducer AICAR partially reversed the protective effects and autophagy inhibition of SA. However, AMPK inhibitor Compound C pretreatment further promoted the inhibition of SA on autophagy induction and cell damage induced by OGD/R. Taken together, these findings demonstrate that SA protects against OGD/R insult by inhibiting autophagy through the regulation of the AMPK-mTOR pathway and that SA may have therapeutic value for protecting neurons from cerebral ischemia.

scholarly journals Microglia-derived FGF21 as a modulator of astrocytic phenotype and cerebral ischemia injury

2020 ◽  
Author(s):  
Fei Liu ◽  
Dongxue Wang ◽  
Liyun Zhu ◽  
Jingting Du ◽  
Ping Lin ◽  
...  
Keyword(s):  
Cerebral Ischemia ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Glucose Deprivation ◽  
Cell Counting ◽  
Fibroblast Growth Factor 21 ◽  
Protective Effects ◽  
Triphenyltetrazolium Chloride

Abstract Background: Fibroblast growth factor 21 (FGF21) is an important neuroprotective factor in the central nervous system (CNS), and it has been reported that FGF21 can protect against cerebral ischemia during the acute phase. However, the possible effects of FGF21 on ischemic brains and the interactions between FGF21 and nonneuronal cells have not been examined. Thus, the aim of this study was to elucidate the protective effects of endogenous FGF21 in ischemic brains.Methods: In this study, in vivo ischemia/reperfusion injury mouse model established by transient middle cerebral artery occlusion (MCAO)/reperfusion and in vitro cell models of oxygen/glucose deprivation (OGD)/reoxygenation (R) were used. Western blot analysis, RT-PCR, double immunofluorescence staining, immunohistochemistry, 2,3,5-triphenyltetrazolium chloride (TTC) staining, hematoxylin-eosin (H&E) staining, neurobehavioral tests, cell counting kit-8 (CCK-8) assay and high-throughput gene sequencing were employed to explore the mechanism by which FGF21 unleash neuroprotective effort of astrocyte phenotype shifts in ischemic stroke.Results: We found that cortical FGF21 expression significantly increased after MCAO/reperfusion, peaking at 7 d. Ischemia-activated microglia were the main sources of endogenous FGF21 in brain tissue. However, FGF21 deficiency aggravated brain injury and slowed neurological functional recovery in FGF21 knockout mice. The in vitro and vivo studies revealed that FGF21 could activate astrocytes and mediate astrocytic phenotype. FGF21-activated astrocytes contributed to neuronal survival and synaptic protein upregulation after ischemia.Conclusion: Collectively, our data indicate that FGF21 plays vital roles in alleviating ischemic brain by mediating the manifestation of potentially pro-recovery astrocytic phenotypes. Therefore, modulation of FGF21 is a potential target strategy for stroke.

scholarly journals β-Sitosterol Protects against Myocardial Ischemia/Reperfusion Injury via Targeting PPARγ/NF-κB Signalling

2020 ◽  
Vol 2020 ◽  
pp. 1-9
Author(s):  
Fengxia Lin ◽  
Luhua Xu ◽  
Meizhu Huang ◽  
Bin Deng ◽  
Weiwei Zhang ◽  
...  
Keyword(s):  
Myocardial Ischemia ◽  
Molecular Mechanisms ◽  
Caspase 3 ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Peroxisome Proliferator ◽  
Protective Effects ◽  
Myocardial Ischemia Reperfusion

Myocardial ischemia/reperfusion (I/R) injury is a clinically severe complication, which can cause high rates of disability and mortality particularly in patients with myocardial infarction, yet the molecular mechanisms underlying this process remain unclear. This study aimed to explore the protective effects of β-sitosterol against myocardial I/R injury and to elucidate the underlying molecular mechanisms. Our results showed that hypoxia/reoxygenation (H/R) treatment suppressed cell viability, induced cell apoptosis and reactive oxygen species production, increased caspase-3 and -9 activities, upregulated caspase-3 and -9 protein expressions, downregulated the Bcl-2 protein expression, and reduced the mitochondrial membrane potential. β-Sitosterol treatment attenuated H/R-induced cardiomyocyte injury. Moreover, β-sitosterol treatment counteracted the inhibitory effects of H/R treatment on the peroxisome proliferator-activated receptor gamma (PPARγ) expression and enhanced effects of H/R treatment on the NF-κB expression in cardiomyocytes. Furthermore, inhibition of PPARγ impaired the protective actions of β-sitosterol against H/R-induced cardiomyocyte injury. In the I/R rats, β-sitosterol treatment reduced the myocardial infarcted size and apoptosis, which was attenuated by the inhibition of PPARγ. In conclusion, our results demonstrate that β-sitosterol protected against in vitro H/R-induced cardiomyocyte injury and in vivo myocardial I/R injury. The β-sitosterol-mediated cardioprotective effects may involve the modulation of PPARγ/NF-κB signalling during myocardial I/R injury. Further studies are required to further explore the clinical application of β-sitosterol in the myocardial I/R injury.

scholarly journals N6-methyladenosine demethylase FTO impairs hepatic ischemia–reperfusion injury via inhibiting Drp1-mediated mitochondrial fragmentation

2021 ◽  
Vol 12 (5) ◽  
Author(s):  
Ying Dong Du ◽  
Wen Yuan Guo ◽  
Cong Hui Han ◽  
Ying Wang ◽  
Xiao Song Chen ◽  
...  
Keyword(s):  
Reperfusion Injury ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Mitochondrial Fragmentation ◽  
Hepatic Ischemia ◽  
Adeno Associated Virus ◽  
Downstream Target ◽  
Hepatic Ischemia Reperfusion

AbstractDespite N6-methyladenosine (m6A) is functionally important in various biological processes, its role and the underlying regulatory mechanism in the liver remain largely unexplored. In the present study, we showed that fat mass and obesity-associated protein (FTO, an m6A demethylase) was involved in mitochondrial function during hepatic ischemia–reperfusion injury (HIRI). We found that the expression of m6A demethylase FTO was decreased during HIRI. In contrast, the level of m6A methylated RNA was enhanced. Adeno-associated virus-mediated liver-specific overexpression of FTO (AAV8-TBG-FTO) ameliorated the HIRI, repressed the elevated level of m6A methylated RNA, and alleviated liver oxidative stress and mitochondrial fragmentation in vivo and in vitro. Moreover, dynamin-related protein 1 (Drp1) was a downstream target of FTO in the progression of HIRI. FTO contributed to the hepatic protective effect via demethylating the mRNA of Drp1 and impairing the Drp1-mediated mitochondrial fragmentation. Collectively, our findings demonstrated the functional importance of FTO-dependent hepatic m6A methylation during HIRI and provided valuable insights into the therapeutic mechanisms of FTO.

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