Effects of Mdivi-1 on Neural Mitochondrial Dysfunction and Mitochondria-Mediated Apoptosis in Ischemia-Reperfusion Injury After Stroke: A Systematic Review of Preclinical Studies

This systematic review sought to determine the effects of Mitochondrial division inhibitor-1 (Mdivi-1) on neural mitochondrial dysfunction and neural mitochondria-mediated apoptosis in ischemia/reperfusion (I/R) injury after ischemic stroke. Pubmed, Web of Science, and EMBASE databases were searched through July 2021. The studies published in English language that mentioned the effects of Mdivi-1 on neural mitochondrial dysfunction and neural mitochondria-mediated apoptosis in I/R-induced brain injury were included. The CAMARADES checklist (for in vivo studies) and the TOXRTOOL checklist (for in vitro studies) were used for study quality evaluation. Twelve studies were included (median CAMARADES score = 6; TOXRTOOL scores ranging from 16 to 18). All studies investigated neural mitochondrial functions, providing that Mdivi-1 attenuated the mitochondrial membrane potential dissipation, ATP depletion, and complexes I-V abnormalities; enhanced mitochondrial biogenesis, as well as inactivated mitochondrial fission and mitophagy in I/R-induced brain injury. Ten studies analyzed neural mitochondria-mediated apoptosis, showing that Mdivi-1 decreased the levels of mitochondria-mediated proapoptotic factors (AIF, Bax, cytochrome c, caspase-9, and caspase-3) and enhanced the level of antiapoptotic factor (Bcl-2) against I/R-induced brain injury. The findings suggest that Mdivi-1 can protect neural mitochondrial functions, thereby attenuating neural mitochondria-mediated apoptosis in I/R-induced brain injury. Our review supports Mdivi-1 as a potential therapeutic compound to reduce brain damage in ischemic stroke (PROSPERO protocol registration ID: CRD42020205808).Systematic Review Registration: [https://www.crd.york.ac.uk/prospero/], identifier [CRD42020205808].

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

Oxidative Medicine and Cellular Longevity ◽

10.1155/2021/4805040 ◽

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.

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Astaxanthin Ameliorates Ischemic-Hypoxic-Induced Neurotrophin Receptor p75 Upregulation in the Endothelial Cells of Neonatal Mouse Brains

International Journal of Molecular Sciences ◽

10.3390/ijms20246168 ◽

2019 ◽

Vol 20 (24) ◽

pp. 6168

Author(s):

Min-Hsun Kuo ◽

Hung-Fu Lee ◽

Yi-Fang Tu ◽

Li-Hsuan Lin ◽

Ya-Yun Cheng ◽

...

Keyword(s):

Endothelial Cells ◽

Ischemic Stroke ◽

Reperfusion Injury ◽

Cell Injury ◽

Ischemia Reperfusion Injury ◽

Ischemia Reperfusion ◽

Neurotrophin Receptor ◽

P75 Neurotrophin Receptor

Ischemic stroke is a leading cause of human death in present times. Two phases of pathological impact occur during an ischemic stroke, namely, ischemia and reperfusion. Both periods include individual characteristic effects on cell injury and apoptosis. Moreover, these conditions can cause severe cell defects and harm the blood-brain barrier (BBB). Also, the BBB components are the major targets in ischemia-reperfusion injury. The BBB owes its enhanced protective roles to capillary endothelial cells, which maintain BBB permeability. One of the nerve growth factor (NGF) receptors initiating cell signaling, once activated, is the p75 neurotrophin receptor (p75NTR). This receptor is involved in both the survival and apoptosis of neurons. Although many studies have attempted to explain the role of p75NTR in neurons, the mechanisms in endothelial cells remain unclear. Endothelial cells are the first cells to encounter p75NTR stimuli. In this study, we found the upregulated p75NTR expression and reductive expression of tight junction proteins after in vivo and in vitro ischemia-reperfusion injury. Moreover, astaxanthin (AXT), an antioxidant drug, was utilized and was found to reduce p75NTR expression and the number of apoptotic cells. This study verified that p75NTR plays a prominent role in endothelial cell death and provides a novel downstream target for AXT.

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MiR-298 Exacerbates Ischemia/Reperfusion Injury Following Ischemic Stroke by Targeting Act1

Cellular Physiology and Biochemistry ◽

10.1159/000491810 ◽

2018 ◽

Vol 48 (2) ◽

pp. 528-539 ◽

Cited By ~ 11

Author(s):

Hongxue Sun ◽

Di Zhong ◽

Cheng Wang ◽

Yilei Sun ◽

Jiaying Zhao ◽

...

Keyword(s):

Ischemic Stroke ◽

Ischemia Reperfusion Injury ◽

Ischemia Reperfusion ◽

Artery Occlusion ◽

Neurological Deficits ◽

Luciferase Assay ◽

Regulatory Relationship

Background/Aims: This study investigated the role of the microRNA miR-298 and its target Act1 in ischemic stroke. Methods: Cell viability was assessed with the 3-(4,5-dimethythiazol-2- yl)-2,5-diphenyl tetrazolium bromide assay. Apoptotic cells were detected by flow cytometry, and mRNA and protein expression were assessed by quantitative real-time PCR and western blotting, respectively. The regulatory relationship between miR-298 and Act1 was evaluated with the luciferase assay. To clarify the role of Act1 following ischemic stroke, the transcript was knocked down by short interfering RNA. The in vitro findings were validated in a mouse model of middle cerebral artery occlusion by administration of miR-298 mimic. Results: Act1 was upregulated whereas miR-298 was downregulated in ischemic stroke. miR-298 overexpression by transfection of a mimic suppressed Act1 protein levels in vitro and in vivo, and the luciferase assay showed that miR-298 directly binds to the 3’ untranslated region of the Act1 transcript. miR-298 overexpression enhanced cell apoptosis and autophagy and exacerbated ischemic infarction and neurological deficits, effects that were exerted via negative regulation of Act1/c-Jun N-terminal kinase (JNK)/nuclear factor (NF)-κB signaling and downstream autophagy pathways. Conclusions: Upregulation of miR-298 following ischemic stroke promotes brain injury in vitro and vivo by inhibiting the Act1/JNK/NF-κB signaling cascade and the downstream autophagy pathway. Therapeutic strategies that target miR-298 could be beneficial for the treatment of ischemic stroke.

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Osthole prevents cerebral ischemia–reperfusion injury via the Notch signaling pathway

Biochemistry and Cell Biology ◽

10.1139/bcb-2016-0233 ◽

2017 ◽

Vol 95 (4) ◽

pp. 459-467 ◽

Cited By ~ 10

Author(s):

Junhong Guan ◽

Xiangtai Wei ◽

Shengtao Qu ◽

Tao Lv ◽

Qiang Fu ◽

...

Keyword(s):

Ischemic Stroke ◽

Cerebral Infarction ◽

Signaling Pathway ◽

Ischemia Reperfusion Injury ◽

Ischemia Reperfusion ◽

Dependent Manner ◽

Notch 1 ◽

Dose Dependent

Stroke is a common cerebrovascular disease in aging populations, and constitutes the second highest principle cause of mortality and the principle cause of permanent disability, and ischemic stroke is the primary form. Osthole is a coumarin derivative extracted from the fruits of Cnidium monnieri (L.) Cusson. In this study, we established a rat model of middle cerebral artery occlusion/reperfusion (MCAO/R) in vivo and found that MCAO/R caused cerebral infarction, hippocampus neuronal injury and apoptosis, and also activated the Notch 1 signaling pathway. However, treatment with osthole further enhanced the activity of Notch 1 signaling and reduced the cerebral infarction as well as the hippocampus neuronal injury and apoptosis induced by MCAO/R in a dose-dependent manner. The same results were observed in a primary neuronal oxygen glucose deficiency/reperfusion (OGD/R) model in vitro, and the effect of osthole could be blocked by an inhibitor of Notch 1 signaling, N-[N-(3,5-difluorophenacetyl)-l-alanyl]-S-phenylglycine tert-butyl ester (DAPT). Therefore, we demonstrated that osthole injection prevented rat ischemia–reperfusion injury via activating the Notch 1 signaling pathway in vivo and in vitro in a dose-dependent manner, which may be significant for clinical treatment of ischemic stroke.

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Long noncoding RNA ANRIL Knockdown Attenuates Neuroinflammation Following Ischemic Stroke via Suppressing the Expression of NF-κB In Vitro and In Vivo

10.21203/rs.3.rs-181506/v1 ◽

2021 ◽

Author(s):

Zhi Dong ◽

Ling Deng ◽

Yi Guo ◽

Jingdong Liu ◽

Sha Chen ◽

...

Keyword(s):

Ischemic Stroke ◽

Cell Viability ◽

Long Noncoding Rna ◽

Noncoding Rna ◽

Ischemia Reperfusion Injury ◽

Ischemia Reperfusion ◽

Immunofluorescent Staining ◽

Neuroprotective Effects

Abstract Increasing evidence suggests that long noncoding RNAs can exert neuroprotective effects in cerebral ischemia-reperfusion injury. Levels of the long noncoding RNA ANRIL (ANRIL) are reportedly altered in ischemic stroke (IS) patients, but its role in IS requires further clarification. This study was designed to explore the mechanistic function of ANRIL in IS. In vitro, HT22 cells was treated with an oxygen-glucose deprivation/reperfusion (OGD/R). In vivo, brain ischemia/reperfusion was induced by 60-minute transient middle cerebral artery occlusion/ reperfusion (MCAO/R) IS model in C57/BL6 mice. Additionally, cells were transfected with si-ANRIL, pcDNA3.1-ANRIL, pcDNA3.1-NF-κB, or appropriate negative controls, and si-ANRIL and pcDNA3.1-NF-κB were administered into the lateral ventricles in MCAO/R model mice. Cell viability and apoptosis were detected via MTT and flow cytometry assays. mRNA and protein expression of NF-κB were detected via qRT-PCR and Western blotting. IL-1β, IL-6, TNF-a, and iNOS levels were detected via ELISA. In addition, infarcted area and neuronal injury were evaluated via TTC, Nissl, and immunofluorescent staining. We found that ANRIL knockdown increased cell viability and reduced apoptosis in vitro. Additionally, we found that ANRIL knockdown decreased p-P65, P65, IL-1β, IL-6, TNF-a, and iNOS levels, whereas these effects were reversed by NF-κB overexpression both in vitro and in vivo. Our results suggest that ANRIL knockdown attenuates neuroinflammation by suppressing the expression of NF-κB both in vitro and vivo model of IS, sugguesting that ANRIL might be a potentially viable therapeutictarget to diminish neuroinflammation in IS patients.

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TRAP1 Provides Protection Against Myocardial Ischemia-Reperfusion Injury by Ameliorating Mitochondrial Dysfunction

Cellular Physiology and Biochemistry ◽

10.1159/000430174 ◽

2015 ◽

Vol 36 (5) ◽

pp. 2072-2082 ◽

Cited By ~ 21

Author(s):

Peng Zhang ◽

Yong Lu ◽

Dong Yu ◽

Dadong Zhang ◽

Wei Hu

Keyword(s):

Cell Death ◽

Mitochondrial Dysfunction ◽

Mitochondrial Function ◽

Ischemia Reperfusion Injury ◽

Ischemia Reperfusion ◽

Ros Generation ◽

Complex Activity ◽

Atp Production

Background: Tumor necrosis factor receptor-associated protein 1 (TRAP1), an essential mitochondrial chaperone is induced in rat hearts following ischemia/reperfusion (I/R), but its role in myocardial I/R injury is unclear. The present study examined the function of TRAP1 in cardiomyocyte hypoxia/reoxygenation injury in vitro and myocardial I/R injury in vivo. Methods: HL-1 cardiomyocytes transfected with TRAP1 or vector were subjected to simulated I/R (SI/R) in vitro. Cell death and mitochondrial function were assessed. Wild type (WT) and TRAP1 knockout (TRAP1 KO) mice were subjected to cardiac I/R in vivo. The infarct size and myocardial apoptosis were determined. WT and TRAP1 KO cardiomyocytes were subjected to SI/R in vitro. Mitochondrial function was assessed. Results: TRAP1 overexpression protects HL-1 cardiomyocytes from SI/R-induced cell death in vitro. The reduced cell death was associated with decreased ROS generation, better-preserved mitochondrial ETC complex activity, membrane potential, and ATP production, as well as delayed mPTP opening. Loss of TRAP1 aggravates SI/R-induced mitochondrial damage in cardiomyocytes in vitro and myocardial I/R injury and apoptosis in vivo. Conclusion: The results of the present study show that TRAP1 provides cardioprotection against myocardial I/R by ameliorating mitochondrial dysfunction.

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CTRP1 Attenuates Cerebral Ischemia/Reperfusion Injury via the PERK Signaling Pathway

Frontiers in Cell and Developmental Biology ◽

10.3389/fcell.2021.700854 ◽

2021 ◽

Vol 9 ◽

Author(s):

Huizhi Fei ◽

Pu Xiang ◽

Wen Luo ◽

Xiaodan Tan ◽

Chao Gu ◽

...

Keyword(s):

Ischemic Stroke ◽

Signaling Pathway ◽

Ischemia Reperfusion Injury ◽

Ischemia Reperfusion ◽

Cerebral Ischemia Reperfusion ◽

Cerebral Ischemia Reperfusion Injury ◽

Cerebral Ischemic Stroke ◽

Cerebral Ischemic

Cerebral ischemic stroke is one of the leading causes of death worldwide. Previous studies have shown that circulating levels of CTRP1 are upregulated in patients with acute ischemic stroke. However, the function of CTRP1 in neurons remains unclear. The purpose of this study was to explore the role of CTRP1 in cerebral ischemia reperfusion injury (CIRI) and to elucidate the underlying mechanism. Middle cerebral artery occlusion/reperfusion (MCAO/R) and oxygen–glucose deprivation/reoxygenation (OGD/R) models were used to simulate cerebral ischemic stroke in vivo and in vitro, respectively. CTRP1 overexpression lentivirus and CTRP1 siRNA were used to observe the effect of CTRP1 expression, and the PERK selective activator CCT020312 was used to activate the PERK signaling pathway. We found the decreased expression of CTRP1 in the cortex of MCAO/R-treated rats and OGD/R-treated primary cortical neurons. CTRP1 overexpression attenuated CIRI, accompanied by the reduction of apoptosis and suppression of the PERK signaling pathway. Interference with CTRP1 expression in vitro aggravated apoptotic activity and increased the expression of proteins involved in the PERK signaling pathway. Moreover, activating the PERK signaling pathway abolished the protective effects of CTRP1 on neuron injury induced by CIRI in vivo and in vitro. In conclusion, CTRP1 protects against CIRI by reducing apoptosis and endoplasmic reticulum stress (ERS) through inhibiting the PERK-dependent signaling pathway, suggesting that CTRP1 plays a crucial role in the pathogenesis of CIRI.

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Expression and modulation of translocator protein and its partners by hypoxia reoxygenation or ischemia and reperfusion in porcine renal models

AJP Renal Physiology ◽

10.1152/ajprenal.90422.2008 ◽

2009 ◽

Vol 297 (1) ◽

pp. F177-F190 ◽

Cited By ~ 15

Author(s):

Frederic Favreau ◽

Ludivine Rossard ◽

Keqiang Zhang ◽

Thibault Desurmont ◽

Emilie Manguy ◽

...

Keyword(s):

Proximal Tubule ◽

Ischemia Reperfusion Injury ◽

Ischemia Reperfusion ◽

Regulatory Protein ◽

Translocator Protein ◽

Mitochondrial Functions ◽

The Impact ◽

Tspo Expression

Translocator protein (TSPO), formerly known as the peripheral-type benzodiazepine receptor, is an 18-kDa drug- and cholesterol-binding protein localized to the outer mitochondrial membrane and implicated in a variety of cell and mitochondrial functions. To determine the role of TSPO in ischemia-reperfusion injury (IRI), we used both in vivo and in vitro porcine models: an in vivo renal ischemia model where different conservation modalities were tested and an in vitro model where TSPO-transfected porcine proximal tubule LLC-PK1cells were exposed to hypoxia and oxidative stress. The expression of TSPO and its partners in steroidogenic cells, steroidogenic acute regulatory protein (StAR) and cytochrome P-450 side chain cleavage CYP11A1, as well as the impact of TSPO overexpression and exposure to TSPO ligands in vitro in hypoxia-ischemia conditions were investigated. Hypoxia induced caspase activation, reduction of ATP content, and LLC-PK1cell death. Transfection and overexpression of TSPO rescued the cells from the detrimental effects of hypoxia and reoxygenation. Moreover, TSPO overexpression was accompanied by a reduction of H2O2-induced necrosis. TSPO drug ligands did not affect TSPO-mediated functions. In vivo, TSPO expression was modulated by IRI and during regeneration particularly in proximal tubule cells, which do not express this protein at the basal level. Under the same conditions, StAR and CYP11A1 protein and gene expression was reduced without apparent relation to TSPO changes. Pregnenolone was identified and measured in the pig kidney. Pregnenolone synthesis was not affected by the experimental conditions used. Taken together, these results indicate that changes in TSPO expression in kidney regenerating tissue could be important for renal protection and maintenance of kidney function.

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

Cell Death and Disease ◽

10.1038/s41419-021-03622-x ◽

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

Molecular Medicine ◽

10.1186/s10020-021-00332-0 ◽

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.

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