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

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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Maslinic Acid Attenuates Ischemia/Reperfusion Injury-Induced Myocardial Inflammation and Apoptosis by Regulating HMGB1-TLR4 Axis

Frontiers in Cardiovascular Medicine ◽

10.3389/fcvm.2021.768947 ◽

2021 ◽

Vol 8 ◽

Author(s):

Qi Li ◽

Mengping Xu ◽

Zhuqing Li ◽

Tingting Li ◽

Yilin Wang ◽

...

Keyword(s):

Reperfusion Injury ◽

Ischemia Reperfusion Injury ◽

Ischemia Reperfusion ◽

Myocardial Inflammation ◽

Dependent Manner ◽

H9c2 Cells ◽

Maslinic Acid ◽

Dose Dependent

Aims: The inflammatory response and apoptosis are the major pathological features of myocardial ischemia/reperfusion injury (MI/RI). Maslinic acid (MA), a natural pentacyclic triterpene with various bioactivities, plays critical roles in the multiple cellular biological processes, but its protective effects on the pathophysiological processes of MI/RI have not been extensively investigated. Our study aimed to determine whether MA treatment alleviate ischemia/reperfusion (I/R)-induced myocardial inflammation and apoptosis both in vitro and in vivo, and further reveal the underlying mechanisms.Methods and results: An MI/RI rat model was successfully established by ligating the left anterior descending coronary artery and H9c2 cells were exposed to hypoxia/reoxygenation (H/R) to mimic I/R injury. In addition, prior to H/R stimulation or myocardial I/R operation, the H9c2 cells or rats were treated with varying concentrations of MA or vehicle for 24 h and two consecutive days, respectively. In this study, our results showed that MA could obviously increase the cell viability and decrease the cardiac enzymes release after H/R in vitro. MA could significantly improve the H/R-induced cardiomyocyte injury and I/R-induced myocardial injury in a dose-dependent manner. Moreover, MA suppressed the expression of inflammatory cytokines (tumor necrosis factor alpha [TNF-α, interleukin-1β [IL-1β and interleukin-6 [IL-6]) and the expressions of apoptosis-related proteins (cleaved caspase-3 and Bax) as well as increased the levels of anti-apoptotic protein Bcl-2 expression both in vitro and in vivo. Mechanistically, MA significantly inhibited nuclear translocation of nuclear factor-κB (NF-κB) p65 after H/R via regulating high mobility group box 1 (HMGB1)/toll-like receptor 4 (TLR4) axis.Conclusion: Taken together, MA treatment may alleviate MI/RI by suppressing both the inflammation and apoptosis in a dose-dependent manner, and the cardioprotective effect of MA may be partly attributable to the inactivation of HMGB1/TLR4/NF-κB pathway, which offers a new therapeutic strategy for MI/RI.

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

Scientific Reports ◽

10.1038/srep38480 ◽

2016 ◽

Vol 6 (1) ◽

Cited By ~ 27

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.

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Histidine–Tryptophan-–Ketoglutarate Solution as a Neuroprotective Against Ischemia/Reperfusion Injury

10.20944/preprints201810.0105.v1 ◽

2018 ◽

Author(s):

Jiun Hsu ◽

Chih-Hsien Wang ◽

Shu-Chien Huang ◽

Yung-Wei Chen ◽

Shengpin Yu ◽

...

Keyword(s):

Cortical Neurons ◽

Ischemia Reperfusion Injury ◽

Ischemia Reperfusion ◽

In Vitro Study ◽

Dependent Manner ◽

Sterile Saline ◽

Nadph Oxidase 4 ◽

H2o2 Level

Ischemic neuron loss contributes to brain dysfunction in patients with cardiac arrest (CA). Histidine–tryptophan–ketoglutarate (HTK) solution is a preservative used during organ transplantation. Can HTK also protect neurons from severe hypoxia (SH) following CA? We isolated rat primary cortical neurons and induced SH with or without HTK. Changes in caspase-3, hypoxia-inducible factor 1-alpha (HIF-1α), and NADPH oxidase-4 (NOX4) expression were evaluated at different time points till 72 h. Using a rat asphyxia model, we induced CA-mediated brain damage and then completed resuscitation. HTK or sterile saline was administered into the left carotid artery. Neurological deficit scoring and mortality were evaluated for 3 days. Then the rats were sacrificed for evaluating NOX4 and H2O2 level in blood and brain. In the in vitro study, HTK attenuated SH- and H2O2-mediated cytotoxicity in a volume- and time-dependent manner, associated with persisted HIF-1α expression, reductions in procaspase-3 activation and NOX4 expression. The inhibition of HIF-1α abrogated HTK’s effect on NOX4. In the in vivo study, neurological scores were significantly improved by HTK. H2O2 level, NOX4 activity and NOX4 gene expression were all decreased in the brain specimen of HTK-treated rats. Our results suggest that HTK acts as an effective neuroprotective solution.

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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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Aescin Protects Neuron from Ischemia-Reperfusion Injury via Regulating the PRAS40/mTOR Signaling Pathway

Oxidative Medicine and Cellular Longevity ◽

10.1155/2020/7815325 ◽

2020 ◽

Vol 2020 ◽

pp. 1-11

Author(s):

Xinjie Gao ◽

Heng Yang ◽

Jiabin Su ◽

Weiping Xiao ◽

Wei Ni ◽

...

Keyword(s):

Reperfusion Injury ◽

Signaling Pathway ◽

Ischemia Reperfusion Injury ◽

Ischemia Reperfusion ◽

Intravenous Thrombolysis ◽

Mtor Signaling ◽

Dependent Manner ◽

Protective Effects ◽

Mtor Signaling Pathway

Ischemic stroke is one of the major causes of disability; widely use of endovascular thrombectomy or intravenous thrombolysis leads to more attention on ischemia-reperfusion injury (I/R injury). Aescin, a natural compound isolated from the seed of the horse chestnut, has been demonstrated anti-inflammatory and antiedematous effects previously. This study was aimed at determining whether aescin could induce protective effects against ischemia-reperfusion injury and exploring the underlying mechanisms in vitro. Primary cultured neurons were subjected to 2 hours of oxygen-glucose deprivation (OGD) followed by 24 hours of simulated reperfusion. Aescin, which worked in a dose-dependent manner, could significantly attenuate neuronal death and reduce lactate dehydrogenase (LDH) release after OGD and simulated reperfusion. Aescin treatment at a concentration of 50 μg/ml provided protection with fewer side effects. Results showed that aescin upregulated the phosphorylation level of PRAS40 and proteins in the mTOR signaling pathway, including S6K and 4E-BP1. However, PRAS40 knockdown or rapamycin treatment was able to undermine and even abolish the protective effects of aescin; meanwhile, the levels of phosphorylation PRAS40 and proteins in the mTOR signaling pathway were obviously decreased. Hence, our study demonstrated that aescin provided neuronal protective effects against I/R injury through the PRAS40/mTOR signaling pathway in vitro. These results might contribute to the potential clinical application of aescin and provide a therapeutic target on subsequent cerebral I/R injury.

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Hydroxychloroquine Inhibits Macrophage Activation and Attenuates Renal Fibrosis After Ischemia-Reperfusion Injury

Frontiers in Immunology ◽

10.3389/fimmu.2021.645100 ◽

2021 ◽

Vol 12 ◽

Author(s):

Haofeng Zheng ◽

Yannan Zhang ◽

Jiannan He ◽

Zhe Yang ◽

Rui Zhang ◽

...

Keyword(s):

Reperfusion Injury ◽

Renal Fibrosis ◽

Ischemia Reperfusion Injury ◽

Ischemia Reperfusion ◽

Tubulointerstitial Fibrosis ◽

Health Concern ◽

Dependent Manner ◽

Renal Tubulointerstitial Fibrosis

Chronic kidney disease (CKD), which is associated with high morbidity, remains a worldwide health concern, while effective therapies remain limited. Hydroxychloroquine (HCQ), which mainly targets toll-like receptor-7 (TLR-7) and TLR-9, is associated with a lower risk of incident CKD. Taking into account that TLR-9 is involved in the development of renal fibrosis and serves as a potential therapy target for CKD, we investigated whether HCQ could attenuate CKD via TLR-9 signal pathway. The effects of HCQ on renal tubulointerstitial fibrosis were further explored using a mouse model of renal tubulointerstitial fibrosis after ischemia/reperfusion injury. Bone marrow-derived macrophages were isolated to explore the effects of HCQ in vitro. Judicious use of HCQ efficiently inhibited the activation of macrophages and MAPK signaling pathways, thereby attenuating renal fibrosis in vivo. In an in vitro model, results showed that HCQ promoted apoptosis of macrophages and inhibited activation of macrophages, especially M2 macrophages, in a dose-dependent manner. Because TLR-7 is not involved in the development of CKD post-injury, a TLR-9 knockout mouse was used to explore the mechanisms of HCQ. The effects of HCQ on renal fibrosis and macrophages decreased after depletion of TLR-9 in vivo and in vitro. Taken together, this study indicated that proper use of HCQ could be a new strategy for anti-fibrotic therapy and that TLR-9 could be a potential therapeutic target for CKD following acute kidney injury.

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QKI 6 ameliorates CIRI through promoting synthesis of triglyceride in neuron and inhibiting neuronal apoptosis associated with SIRT1-PPARγ-PGC-1α axis

10.1101/2020.12.23.424095 ◽

2020 ◽

Author(s):

Rui Liu ◽

Hongzeng Li ◽

Jingyuan Deng ◽

Qunqiang Wu ◽

Chunhua Liao ◽

...

Keyword(s):

Signaling Pathway ◽

Rat Model ◽

Neuronal Apoptosis ◽

Rna Binding ◽

Ischemia Reperfusion Injury ◽

Ischemia Reperfusion ◽

Artery Occlusion ◽

Post Transcriptional Regulation

AbstractThe stroke induced by ischemia of brain remains high incidence and death rate. The study wanted to confirm the effects of QKI 6 on the protection role in neurons of rat model of cerebral ischemia/reperfusion injury (CIRI). The rat model with CIRI induced by MCAO (middle cerebral artery occlusion) was well established and rat neurons were isolated to characterize the effects of QKI 6 mediated by SIRT1 on synthesis of triglyceride in neuron and neuronal apoptosis via activation of SIRT1-PPARγ-PGC-1α signaling pathway. The expression levels of SIRT1 or QKI 6, and acetylation level of QKI 6 was decreased in neurons of rat model with CIRI. QKI 6 deacetylated and mediated by SIRT1 that contributed to suppressing the progression of neuronal apoptosis in rat through promoting synthesis of triglyceride in vivo and in vitro via SIRT1-PPARγ-PGC-1α signaling pathway, then inhibiting CIRI. In conclusion, our results demonstrated SIRT1 deacetylates QKI 6, the RNA-binding protein, that affects significantly the synthesis of triglyceride in neurons of CIRI rat model. Moreover, it activated transcription factor PGC-1α through post-transcriptional regulation of the expression of PPARγ, and further enhanced synthesis of triglyceride, thereby restrained the progression of neural apoptosis and CIRI.

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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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Renalase as a Novel Biomarker for Evaluating the Severity of Hepatic Ischemia-Reperfusion Injury

Oxidative Medicine and Cellular Longevity ◽

10.1155/2016/3178562 ◽

2016 ◽

Vol 2016 ◽

pp. 1-11 ◽

Cited By ~ 5

Author(s):

Huili Li ◽

Jianrong Guo ◽

Hongli Liu ◽

Yanfeng Niu ◽

Lixia Wang ◽

...

Keyword(s):

Oxidative Stress ◽

Mouse Models ◽

Ischemia Reperfusion Injury ◽

Ischemia Reperfusion ◽

Dependent Manner ◽

Hepatic Ischemia ◽

Hepatic Ischemia Reperfusion ◽

R Process

Hepatic ischemia-reperfusion (I/R) injury is a serious complication in clinical practice. However, no efficient biomarkers are available for the evaluation of the severity of I/R injury. Recently, renalase has been reported to be implicated in the I/R injury of various organs. This protein is secreted into the blood in response to increased oxidative stress. To investigate the responsiveness of renalase to oxidative stress, we examined the changes of renalase in cell and mouse models. We observed a significant increase of renalase expression in HepG2 cells in a time- and dose-dependent manner when treated with H2O2. Renalase expression also increased significantly in liver tissues that underwent the hepatic I/R process. The increased renalase levels could be efficiently suppressed by antioxidantsin vitroandin vivo. Furthermore, serum renalase levels were significantly increased in the mouse models and also efficiently suppressed by antioxidants treatment. The variation trends are consistent between renalase and liver enzymes in the mouse models. In conclusion, renalase is highly sensitive and responsive to oxidative stressin vitroandin vivo. Moreover, renalase can be detected in the blood. These properties make renalase a highly promising biomarker for the evaluation of the severity of hepatic I/R injury.

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