Deficiency of ROS-Activated TRPM2 Channel Protects Neurons from Cerebral Ischemia-Reperfusion Injury through Upregulating Autophagy.
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ABSTRACT:
SUBMITTER: Hu X
PROVIDER: S-EPMC8337124 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:BACKGROUND:Acupuncture treatment possesses the neuroprotection potential to attenuate cerebral ischemia-reperfusion (I/R) injury. Endoplasmic reticulum (ER) stress has been suggested to be involved in the pathogenic mechanism of cerebral I/R injury. Whether acupuncture protects against cerebral I/R injury via regulating ER stress remains unclear. This study aimed to evaluate the role of ER stress in the neuroprotection of acupuncture against cerebral I/R injury and its underlying mechanisms. METHODS:Cerebral I/R injury was induced by middle cerebral artery occlusion (MCAO) in rats. Acupuncture was carried out at Baihui (GV 20), and Qubin (GB7) acupoints in rats immediately after reperfusion. The infarct volumes, neurological score, ER stress, autophagy and apoptosis were determined. RESULTS:Acupuncture treatment decreased infarct volume, neurological score and suppressed ER stress via inactivation of ATF-6, PERK, and IRE1 pathways in MCAO rats. Attributing to ER stress suppression, 4-PBA (ER stress inhibitor) promoted the beneficial effect of acupuncture against cerebral I/R injury. Whereas, ER stress activator tunicamycin significantly counteracted the neuroprotective effects of acupuncture. In addition, acupuncture restrained autophagy via regulating ER stress in MCAO rats. Finally, ER stress took part in the neuroprotective effect of acupuncture against apoptosis in cerebral I/R injury. CONCLUSIONS:Our findings suggest that acupuncture offers neuroprotection against cerebral I/R injury, which is attributed to repressing ER stress-mediated autophagy and apoptosis.
| S-EPMC7653860 | biostudies-literature
Project description:After myocardial ischemia-reperfusion, fatty acid oxidation shows fast recovery while glucose oxidation rates remain depressed. A metabolic shift aimed at increasing glucose oxidation has shown to be beneficial in models of myocardial ischemia-reperfusion. However, strategies aimed at increasing glucose consumption in the clinic have provided mixed results and have not yet reached routine clinical practice. A better understanding of the mechanisms underlying the protection afforded by increased glucose oxidation may facilitate the transfer to the clinic. The purpose of this study was to evaluate if the modulation of reactive oxygen species (ROS) was involved in the protection afforded by increased glucose oxidation. Firstly, we characterized an H9C2 cellular model in which the use of glucose or galactose as substrates can modulate glycolysis and oxidative phosphorylation pathways. In this model, there were no differences in morphology, cell number, or ATP and PCr levels. However, galactose-grown cells consumed more oxygen and had an increased Krebs cycle turnover, while cells grown in glucose had increased aerobic glycolysis rate as demonstrated by higher lactate and alanine production. Increased aerobic glycolysis was associated with reduced ROS levels and protected the cells against simulated ischemia-reperfusion injury. Furthermore, ROS scavenger N-acetyl cysteine (NAC) was able to reduce the amount of ROS and to prevent cell death. Lastly, cells grown in galactose showed higher activation of mTOR/Akt signaling pathways. In conclusion, our results provide evidence indicating that metabolic shift towards increased glycolysis reduces mitochondrial ROS production and prevents cell death during ischemia-reperfusion injury.
| S-EPMC7240969 | biostudies-literature
Project description:ObjectiveTo examine the effect of autophagy on cerebral damage caused by different models and test the hypothesis that its protection mechanism acts via inhibiting expression of neuroinflammatory mediators.MethodsAutophagy was induced by rapamycin treatment. Cerebral damage was induced using models of IL-6 treatment, oxygen glucose deprivation/reoxygenation (OGD/R) in vitro, and middle cerebral artery occlusion (MCAO) in vivo. The effect and mechanism of autophagy was examined and assessed in terms of cell viability, infarction size in brain tissue, neurological score, production of inflammatory mediators IL-1β and IL-6, transcription and protein expression of autophagy markers beclin-1 and LC-3II in different experimental groups.ResultsAutophagy triggered by rapamycin could protect neurons from IL-6-induced injury and astrocytes from OGD/R-induced injury in vitro and in rat brain tissue from MCAO in vivo. Autophagy significantly increased cell viability, attenuated cerebral infarction and improved neurological scores. It also inhibited production of the IL-1β and IL-6 and elevated the expression of beclin-1 and LC-3II.ConclusionsAutophagy can inhibit the inflammatory response and reduce cerebral I/R injury. There was a relationship between the extent of protection and (i) the level of the autophagic response, (ii) the stage of the cerebral I/R injury, and (iii) the time of intervention.
| S-EPMC8205746 | biostudies-literature
Project description:Background: 2-Methoxyestradiol (2ME), a natural 17-β estradiol metabolite, is a potent anti-inflammatory agent, but its effect on ischemia/reperfusion (IR)-induced acute lung inflammation remains unknown. Annexin A1 (AnxA1), a glucocorticoid-regulated protein, is effective at inhibiting neutrophil transendothelial migration by binding the formyl peptide receptors (FPRs). We aimed to investigate whether 2ME upregulates the expression of AnxA1 and protects against IR-induced lung damage. Methods: IR-mediated acute lung inflammation was induced by ischemia for 40 min followed by reperfusion for 60 min in an isolated, perfused rat lung model. The rat lungs were randomly treated with vehicle or 2ME, and the functional relevance of AnxA1 was determined using an anti-AnxA1 antibody or BOC2 (a pan-receptor antagonist of the FPR). In vitro, human primary alveolar epithelial cells (HPAECs) and rat neutrophils were pretreated with 2ME and an AnxA1 siRNA or anti-AnxA1 antibody and subjected to hypoxia-reoxygenation (HR). Results: 2ME significantly decreased all lung edema parameters, neutrophil infiltration, oxidative stress, proinflammatory cytokine production, lung cell apoptosis, tight junction protein disruption, and lung tissue injury in the IR-induced acute lung inflammation model. 2ME also increased the expression of the AnxA1 mRNA and protein and suppressed the activation of nuclear factor-κB (NF-κB). In vitro, 2ME attenuated HR-triggered NF-κB activation and interleukin-8 production in HPAECs, decreased transendothelial migration, tumor necrosis factor-α production, and increased apoptosis in neutrophils exposed to HR. These protective effects of 2ME were significantly abrogated by BOC2, the anti-AnxA1 antibody, or AnxA1 siRNA. Conclusions: 2ME ameliorates IR-induced acute lung inflammation by increasing AnxA1 expression. Based on these results, 2ME may be a promising agent for attenuating IR-induced lung injury.
| S-EPMC8007881 | biostudies-literature
Project description:Oxidative stress and mitochondrial dysfunction play critical roles in ischemia/reperfusion (I/R) injury. DJ-1 is an endogenous antioxidant that attenuates oxidative stress and maintains mitochondrial function, likely acting as a protector of I/R injury. In the present study, we explored the protective effect of a possible DJ-1 agonist, sodium phenylbutyrate (SPB), against I/R injury by protecting mitochondrial dysfunction via the upregulation of DJ-1 protein. Pretreatment with SPB upregulated the DJ-1 protein level and rescued the I/R injury-induced DJ-1 decrease about 50% both in vivo and in vitro. SPB also improved cellular viability and mitochondrial function and alleviated neuronal apoptosis both in cell and animal models; these effects of SPB were abolished by DJ-1 knockdown with siRNA. Furthermore, SPB improved the survival rate about 20% and neurological functions, as well as reduced about 50% of the infarct volume and brain edema, of middle cerebral artery occlusion mice 23?h after reperfusion. Therefore, our findings demonstrate that preconditioning of SPB possesses a neuroprotective effect against cerebral I/R injury by protecting mitochondrial function dependent on the DJ-1 upregulation, suggesting that DJ-1 is a potential therapeutic target for clinical ischemic stroke.
| S-EPMC5465296 | biostudies-literature
Project description:The current study aimed to evaluate the neuroprotective effect of Ginkgo biloba extract (GbE) on the progression of acute cerebral ischemia?reperfusion injury in diabetic rats, and to determine the molecular mechanism associated with this effect. Streptozotocin (STZ) induced diabetic rats were pretreated with GbE (50, 100 and 200 mg/kg/day; intragastric) for 3 weeks. During this period, body weight changes and fasting blood glucose levels were assessed each week. Following pretreatment, rats were subjected to suture occlusion of the middle cerebral artery for 30 min, which was followed by 24 h of reperfusion. Neurological deficits were subsequently evaluated at 2 and 24 h following reperfusion. Rats were sacrificed after 24 h reperfusion, and infarct volume and S100B content were measured to evaluate the neuroprotective effect of GbE. The results of the present study demonstrated that GbE pretreatment improved neurological scores, and reduced cerebral infarct volume and S100B content. Oxidative stress markers, including glutathione (GSH) and superoxide dismutase (SOD) were increased, and malondialdehyde (MDA) contents were reduced following GbE treatment. The levels of p?Akt, p?mTOR and glutamate transporter 1 (GLT1) were observed to be increased in GbE?pretreated rats. These results indicated that GbE pretreatment may serve a protective role against cerebral ischemia?reperfusion injury in diabetic rats by inhibiting oxidative stress reaction, upregulating the expression of Akt/mTOR and promoting GLT1 expression. In conclusion, the current study revealed the protective role and molecular mechanisms of GbE in diabetic rats with cerebral ischemia?reperfusion injury, and may provide novel insight into the future clinical treatment of this condition.
| S-EPMC7057817 | biostudies-literature
Project description:This study aimed to investigate whether ischemic postconditioning (IpostC) alleviates cerebral ischemia/reperfusion (I/R) injury involved in autophagy. Adult Sprague-Dawley rats were divided into five groups: sham (sham surgery), I/R (middle cerebral artery occlusion [MCAO] for 100 min, then reperfusion), IpostC (MCAO for 100 min, reperfusion for 10 min, MCAO for 10 min, then reperfusion), IpostC+3MA (3-methyladenine, an autophagy inhibitor, administered 30 min before first reperfusion), and IpostC+Veh (vehicle control for IpostC+3MA group). Infarct volume was measured using cresyl violet staining. Autophagy-related proteins were detected by western blot and immunohistochemistry. Autophagosomes, autophagolysosomes, and mitochondrial damage were identified by transmission electron microscopy. Cortical cell apoptosis was detected by the TUNEL assay. Neurologic function was assessed using the modified Neurologic Severity Score. IpostC improved neurological function and reduced infarct volume after I/R (P?<?0.05). These effects of IpostC were inhibited by 3MA (P?<?0.05). Autophagosome formation was increased in the I/R and IpostC+Veh groups (P?<?0.05), but not in the IpostC+3MA group. The I/R group showed enhanced LC3-II/LC3-I ratio, p62, and Cathepsin B levels and decreased LAMP-2 level (all P?<?0.05 vs. sham), indicating dysfunction of autophagic clearance. IpostC reduced p62 and Cathepsin B levels and increased the LC3-II/LC3-I ratio, and nuclear translocation of transcription factor EB (all P?<?0.05); these effects of IpostC were reversed by 3MA, suggesting IpostC enhanced autophagic flux. Furthermore, IpostC attenuated I/R-induced mitochondrial translocation of Bax and mitochondrial cytochrome-c release (all P?<?0.05); 3MA inhibited these effects of IpostC (P?<?0.05). In conclusion, IpostC may alleviate cerebral I/R injury by activating autophagy during early reperfusion.
| S-EPMC6096887 | biostudies-other
Project description:Autophagy of mitochondria, termed mitophagy, plays an important role in cerebral ischemia-reperfusion (IR) injury, but the mechanism is not yet clear. Tissue-type plasminogen activator (tPA) is the most important thrombolytic drug in the clinical treatment of ischemic stroke and has neuroprotective effects. Here, we explored the effects of tPA on neuronal apoptosis and mitophagy following IR. We found that knocking out the tPA gene significantly aggravated brain injury and increased neuronal apoptosis and mitochondrial damage. Exposure of neurons to tPA reduced injury severity and protected mitochondria. Further studies demonstrated that this protective effect of tPA was achieved via regulation of FUNDC1-mediated mitophagy. Furthermore, we found that tPA enhanced the expression level of FUNDC1 by activating the phosphorylation of AMPK. In summary, our results confirm that tPA exerts neuroprotective effects by increasing the phosphorylation of AMPK and the expression of FUNDC1, thereby inhibiting apoptosis and improving mitochondrial function.
| S-EPMC7679257 | biostudies-literature
Project description:We investigated the function of microRNA (miR)-532-5p in cerebral ischemia-reperfusion injury (CI/RI) and the underlying mechanisms using oxygen-glucose deprivation and reperfusion (OGD/R)-treated SH-SY5Y cells and middle cerebral artery occlusion (MCAO) model rats. MiR-532-5p levels were significantly downregulated in OGD/R-treated SH-SY5Y cells and the brain tissues of MCAO model rats. MiR-532-5p overexpression significantly reduced apoptosis, reactive oxygen species (ROS), and inflammation in the OGD/R-induced SH-SY5Y cells. Bioinformatics analysis using the targetscan and miRDB databases as well as dual luciferase reporter assays confirmed that miR-532-5p directly binds to the 3'UTR of C-X-C Motif Ligand 1 (CXCL1). Methylation-specific PCR (MSP) analysis showed that miR-532-5p expression was reduced in OGD/R-treated SH-SY5Y cells because of miR-532-5p promoter hypermethylation. Moreover, 5-azacytidine, a methylation inhibitor, restored miR-532-5p expression in OGD/R-treated SH-SY5Y cells. Brain tissues of MCAO model rats showed significantly increased cerebral infarction areas, cerebral water, neuronal apoptosis, and activated CXCL1/CXCR2/NF-κB signaling, but these effects were alleviated by intraventricular injection of miR-532-5p agomir. These findings demonstrate that miR-532-5p overexpression significantly reduces in vitro and in vivo CI/RI by targeting CXCL1. Thus, miR-532-5p is a potential therapeutic target for patients with CI/RI.
| S-EPMC8109118 | biostudies-literature
Project description:Glutathione (GSH) is an endogenous antioxidant found in plants, animals, fungi, and some microorganisms that protects cells by neutralizing hydrogen peroxide. Honokiol, an active ingredient of Magnolia officinalis, is known for antioxidant, anti-inflammatory, and anti-bacterial properties. We investigated the protective mechanism of honokiol through regulating cellular GSH in renal proximal tubules against acute kidney injury (AKI). First, we measured cellular GSH levels and correlated them with the expression of GSH biosynthetic enzymes after honokiol treatment in human kidney-2 (HK-2) cells. Second, we used pharmacological inhibitors or siRNA-mediated gene silencing approach to determine the signaling pathway induced by honokiol. Third, the protective effect of honokiol via de novo GSH biosynthesis was investigated in renal ischemia-reperfusion (IR) mice. Honokiol significantly increased cellular GSH levels by upregulating the subunits of glutamate-cysteine ligase (Gcl)-Gclc and Gclm. These increases were mediated by activation of nuclear factor erythroid 2-related factor 2, via PI3K/Akt and protein kinase C signaling. Consistently, honokiol treatment reduced the plasma creatinine, tubular cell death, neutrophil infiltration and lipid peroxidation in IR mice and the effect was correlated with upregulation of Gclc and Gclm. Conclusively, honokiol may benefit to patients with AKI by increasing antioxidant GSH via transcriptional activation of the biosynthetic enzymes.
| S-EPMC7555803 | biostudies-literature