Molecular Medicine Reports
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2020
·Vol. 22
·期 5
·3944-3954
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IF 2.1
Li Zhu,Xueying Zhou,Shanshan Li,Jianmeng Liu,Jingyan Yang,Xiangyun Fan,Shengnian Zhou
Cerebral ischemia is a common cerebrovascular disease caused by the occlusion of a cerebral blood vessel. MicroRNAs (miRNAs/miRs) are emerging regulators of various human diseases, including cerebral ischemia. Upregulation of miR‑183‑5p has been reported to alleviate liver injury induced by ischemia‑reperfusion (I/R). However, the effect of miR‑183‑5p on cerebral ischemia injury remains unknown. The present study evaluated the effects of miR‑183‑5p on ischemia injury using ischemic models of mouse brains exposed to transient middle cerebral artery occlusion and Neuro‑2A (N2A) neuroblastoma cells exposed to oxygen‑glucose‑deprivation (OGD) and subsequently reoxygenated. Ischemia was evaluated in mice using neurological function scores, cerebral edema, 2,3,5‑triphenyltetrazoliumchloride, Nissl and Fluoro‑Jade B staining assays. In addition, miR‑183‑5p expression, N2A cell viability and the expression levels of apoptosis‑associated proteins were detected by quantitative PCR, Cell Counting Kit‑8 assay, flow cytometry and western blotting. The association between miR‑183‑5p and phosphatase and tensin homolog (PTEN) was also confirmed by a luciferase reporter assay. The results revealed that miR‑183‑5p expression was decreased and brain damage was increased in ischemic mice compared with the sham group. Additionally, miR‑183‑5p levels were reduced, and apoptosis was increased in N2A cells exposed to ischemia compared with the control group. Following transfection with agomiR‑183‑5p, cerebral ischemic injury and apoptosis levels were reduced in the in vivo I/R stroke model and OGD‑induced N2A cells. In addition, PTEN was determined to be a target of miR‑183‑5p following elucidation of a direct binding site. Overexpression of PTEN reversed the miR‑183‑5p‑induced N2A cell apoptosis inhibition and survival after OGD. The results of the present study suggested that miR‑183‑5p reduced ischemic injury by negatively regulating PTEN, which may aid the development of a novel therapeutic strategy for cerebral ischemia.
研究领域:
神经科学
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分子生物学
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医学研究
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DOI
PubMed
高影响因子
PHYTOTHERAPY RESEARCH
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2025
·
IF 6.3
Anpei Wang,Yi Li,Fei Zhao,Hai Fang,Chengxue Pan,Bo Wei
Cardioprotective formulations in traditional Chinese medicine often combine cold and hot herbs, with licorice frequently included to balance their properties and reduce adverse effects. However, the independent cardioprotective mechanisms of licorice in ischemic heart disease remain unclear. This study aimed to investigate the effects of licorice extract (GC) on myocardial ischemia (MI) and ischemia/reperfusion (MI/R) injury. Myocardial injury models were established using H 2 O 2 -induced H9c2 cardiomyocytes and left anterior descending coronary artery ligation in rats. Cardioprotective effects were evaluated through electrocardiography, echocardiography, and pharmacodynamic assessments. Network pharmacology and PCR were used to explore the anti-inflammatory mechanism, followed by investigation of the upstream inflammatory pathways using Western blotting, co-immunoprecipitation, immunofluorescence, and molecular docking. Metabolomics confirmed GC's impact on terminal metabolic disturbances. Pharmacodynamic evaluations demonstrated that GC exerted significant cardioprotective effects both in vitro and in vivo. Network pharmacology suggested anti-inflammatory potential, which was confirmed by PCR showing reduced levels of IL-1β, IL-6, and TNF-α. Expression analysis of seven Sirtuin and four NOD-like receptor family members revealed that GC's anti-inflammatory effect was mediated by upregulation of Sirt3, leading to inhibition of NLRP3 inflammasome activation, decreased Caspase-1 activity, and reduced secretion of IL-1β and IL-18. Additionally, GC modulated ischemia-induced metabolic disturbances, notably restoring disrupted amino acid and unsaturated fatty acid metabolism. In conclusion, GC exerted cardioprotective effects by suppressing inflammation through the Sirt3/NLRP3 axis and restoring metabolic homeostasis. These findings supported its traditional use and suggested its potential application in cardiovascular health.
研究领域:
心血管药理学
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分子生物学
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炎症免疫学
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代谢组学
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中药药理学
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产品关联
DOI
PubMed
高影响因子
EXPERIMENTAL NEUROLOGY
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2024
·
IF 4.6
Jing Qiu,Yi-Han Wang,Xiu-Ming Wang,Hui-Sheng Chen
The pericytes (PCs) surrounding capillaries are vital regulators of capillary constriction. Persistent PC contraction results in the increased capillary constriction, therefore leading to the impaired cerebral blood flow (CBF) recovery after reperfusion and worsening the clinical outcomes in stroke patients. However, the potential determinants of PC functions during ischemia/reperfusion are poorly understood. Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit Delta (PIK3CD/PI3Kδ) is a crucial factor involved with neuronflammation during ischemic stroke. PI3Kδ has shown the expression in PCs, while its effect on PC functions has not been explored yet. In this study, a rodent ischemia/reperfusion model was established in C57BL/6 mice via transient middle cerebral artery occlusion and reperfusion (MCAO/R). The PI3Kδ expression in ischemic penumbra was remarkably upregulated following MCAO/R induction. PI3Kδ inhibitor CAL-101 improved the CBF recovery, ischemic brain injury, and suppressed capillary constriction in MCAO/R mice. Besides, the production of tumor necrosis factor alpha (TNF-α), an inducer for tissue injury, and the expression of transient receptor potential vanilloid type 2 (TRPV2), a channel protein permitting calcium (Ca 2+ ) uptake, were significantly reduced in ischemic penumbra after CAL-101 treatment. In vitro, oxygen-glucose deprivation and reoxygenation (OGD/R) enhanced the expression of PI3Kδ and TRPV2 in primary mouse PCs. CAL-101 suppressed the TNF-α-induced TRPV2 expression in OGD/R-treated PCs, thus inhibiting the Ca 2+ uptake and PC contraction. Collectively, this study suggests that PI3Kδ is a critical regulator of PC function during ischemic stroke.
研究领域:
神经科学
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药理学
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细胞生物学
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DOI
PubMed
高影响因子
MOLECULAR BIOLOGY REPORTS
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2025
·Vol. 52
·期 1
·1-14
·
IF 2.8
Liang Chen,Guo Liping,Tian Xinyan,Mu Zhidan,Chen Mingyang,Hu Yarong,Su Juan
Objective By establishing a mouse model of hepatic ischemia–reperfusion injury (HIRI), to investigate the effects of cyclooxygenase-2 (COX-2) and endoplasmic reticulum stress (ERS) on HIRI and their interaction in HIRI. Methods C57BL/6J male mice were divided into four groups: Sham operation group (Sham group), hepatic ischemia–reperfusion (HIR) group, hepatic ischemia–reperfusion + Salubrinal (ER stress inhibitor) pretreatment group (HIR + Sal group), hepatic ischemia–reperfusion + NS398 (inhibitor of COX-2) pretreatment group (HIR + NS398 group). The levels of Aspartate transaminase (AST) and Alanine transaminase (ALT) in serum, the activity of Super Oxide Dismutase (SOD) and the content of malondialdehyde (MDA) in liver tissue were detected. The mRNA and protein expression of Glucose-regulated protein 78 (GRP78), C/EBP homologous protein (CHOP), phosphorylated eukaryotic translation initiation factor 2α (p-eIF2α) and COX-2/PTGS (Prostaglandin-endoperoxide synthase) in liver tissue were detected. The morphological changes and apoptosis of liver tissue were observed. Results Compared with the Sham group, the serum ALT and AST levels of the HIR group were increased, the SOD activity in the liver tissue was decreased, the MDA content and the expression of COX-2, p-eIF2α, GRP78 and CHOP protein were increased, and the staining results showed that hepatic sinusoidal congestion, a large number of hepatocyte death, inflammatory cell infiltration and apoptotic cells were significantly increased. The levels of ALT and AST decreased after Sal or NS398 pretreatment. SOD activity was increased, MDA content, COX-2, GRP78, CHOP mRNA and protein were decreased in liver tissue, and staining showed that liver tissue injury was improved. Conclusion In mice with HIR, COX-2 interacts with ERS to cause liver injury by regulating oxidative stress and apoptosis.
研究领域:
分子生物学
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病理学
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药理学
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细胞生物学
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DOI
PubMed
高影响因子
Genes
·
2022
·Vol. 13
·期 11
·2133
·
IF 4.141
Jiahui Lin,Xianhui Lai,Xiaoxi Fan,Bozhi Ye,Lingfeng Zhong,Yucong Zhang,Ruiyin Shao,Si Shi,Weijian Huang,Lan Su,Miaomiao Ying
Pyroptosis serves a crucial function in various types of ischemia and reperfusion injuries. Oridonin, a tetracycline diterpene derived fromRabdosia rubescens, can significantly inhibit the aggregation of NLRP3-mediated inflammasome. This experiment is aimed at investigating the effect of oridonin on pyroptosis in mice cardiomyocytes. Based on the models of myocardial ischemia/reperfusion (I/R) and hypoxia/reoxygenation (H/R), Evans Blue/TTC double staining, TUNEL staining, and Western blotting were applied to determine the effects of oridonin on myocardial damage, cellular activity and signaling pathways involved in pyroptosis. During I/R and H/R treatments, the extent of gasdermin D-N domains was upregulated in cardiomyocytes. Apart from that, oridonin improved cell survival in vitro and decreased the myocardial infarct size in vivo by also downregulating the activation of pyroptosis. Finally, the expression levels of ASC, NLRP3 and p-p65 were markedly upregulated in cardiomyocytes after H/R treatment, whereas oridonin suppressed the expression of these proteins. The present experiment revealed that myocardial I/R injury and pyroptosis can be alleviated and inhibited by oridonin pretreatment via NF-κB/NLRP3 signaling pathway, both in vivo and in vitro. Therefore, oridonin may serve as a potentially novel agent for the clinical treatment of myocardial ischemia-reperfusion injuries.Keywords:oridonin;cardiac ischemia/reperfusion injury;pyroptosis;GSDMD
研究领域:
心脏病学
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药理学
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细胞生物学
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产品关联
DOI
PubMed
高影响因子
Journal of Neuroimmune Pharmacology
·
2025
·Vol. 20
·期 1
·1-15
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IF 3.5
Xiao Lifang,Wang Mengyao,Li Jingjing,Wang Haoran,Pu Niu,Bo Xitong,Chen Fuxiang,Zhou Yilong,Cheng Qiong
The underlying pathological mechanism of ischemic stroke is complex, with oxidative stress and inflammation being two key factors that are intertwined and mutually influential. They also serve as important potential targets for the intervention of cerebral ischemia. Pyrroloquinoline quinone (PQQ) is known for its neuroprotective properties and the ability to modulate immune system function. Previous studies have demonstrated that PQQ mitigates brain infarction in rodent models of cerebral ischemia; however, the neuroprotective mechanisms underlying PQQ’s effects against ischemic brain injury are not yet fully understood. This study used an MCAO rat model, an OGD model with SH-SY5Y cells, and an LPS-activated BV2 microglia model to investigate the neuroprotective functions of PQQ on brain ischemia. Using various experimental methods, including cell viability assays, oxidative stress damage assessments, inflammatory factor expression analysis, behavioral tests in animal models, and histological evaluations, we discovered that PQQ activates the nuclear translocation of Nrf2 in neurons, thereby enhancing downstream antioxidant responses. Additionally, PQQ inhibits NF-kB activation in microglia and suppresses their M1-type polarization, leading to decreased pro-inflammatory mediators’ expression levels and reduced neural inflammatory damage. These results provide further insights into the neuroprotective mechanisms involved in PQQ’s effects against cerebral ischemia and may offer evidence for its translational application in treating brain ischemia. Graphical
研究领域:
神经科学
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药理学
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生物化学
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细胞生物学
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免疫学
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产品关联
DOI
PubMed
高影响因子
EXPERIMENTAL NEUROLOGY
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2024
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IF 4.6
Kai Wang,Wentao Zhou,Lijun Wen,Xiangyu Jin,Tingting Meng,Sufen Li,Yiling Hong,Yichong Xu,Hong Yuan,Fuqiang Hu
Background and purpose The pathophysiological features of acute ischemic stroke (AIS) often involve dysfunction of the blood-brain barrier (BBB), characterized by the degradation of tight junction proteins (Tjs) leading to increased permeability. This dysfunction can exacerbate cerebral injury and contribute to severe complications. The permeability of the BBB fluctuates during different stages of AIS and is influenced by various factors. Developing effective therapies to restore BBB function remains a significant challenge in AIS treatment. High levels of vascular endothelial growth factor (VEGF) in the early stages of AIS have been shown to worsen BBB breakdown and stroke progression. Our study aimed to investigate the protective effects of the VEGF receptor inhibitor Axitinib on BBB dysfunction and cerebral ischemia/reperfusion-induced injury. Methods BEnd3 cell exposed to oxygen–glucose deprivation (OGD) model was constructed to estimate pharmacological activity of Axitinib (400 ng/ml) on anti-apoptosis and pathological barrier function recovery. In vivo, rats were subjected to a 1 h transient middle cerebral artery occlusion and 23 h reperfusion (tMCAO/R) to investigate the permeability of BBB and cerebral tissue damage. Axitinib was administered through the tail vein at the beginning of reperfusion. BBB integrity was assessed by Evans blue leakage and the expression levels of Tjs claudin-5 and occludin. Results Our research revealed that co-incubation with Axitinib enhanced the cell viability of OGD-insulted bEnd3 cells, decreased LDH leakage rate, and suppressed the expression of apoptosis-related proteins cytochrome C and Bax. Axitinib also mitigated the damage to Tjs and facilitated the restoration of transepithelial electrical resistance in OGD-insulted bEnd.3 cells. In vivo, Axitinib administration reduced intracerebral Evans blue leakage and up-regulated the expression of Tjs in the penumbra brain tissue in tMCAO/R rats. Notably, 10 mg/kg Axitinib exerted a significant anti-ischemic effect by decreasing cerebral infarct volume and brain edema volume, improving neurological function, and reducing pro-inflammatory cytokines IL-6 and TNF-α in the brain. Conclusions Our study highlights Axitinib as a potent protectant of blood-brain barrier function, capable of promoting pathological blood-brain barrier recovery through VEGF inhibition and increased expression of tight junction proteins in AIS. This suggests that VEGF antagonism within the first 24 h post-stroke could be a novel therapeutic approach to enhance blood-brain barrier function and mitigate ischemia-reperfusion injury.
研究领域:
神经科学
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药理学
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中风研究
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脑血管疾病
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产品关联
DOI
PubMed
高影响因子
INTERNATIONAL IMMUNOPHARMACOLOGY
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2024
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IF 4.8
Yuxin Zhang,Lixuan Yang,Yonghui Gan,Chenchen Zhao,Chao Zhou,Jian Chen,Yanping Yin,Shengnan Xia,Haiyan Yang,Xinyu Bao,Meijuan Zhang,Yun Xu,Jingwei Li
Microglia, the primary immune cells of the central nervous system, play a crucial role in the neuroinflammatory processes following ischemic stroke. Targeting neuroinflammation is a promising strategy to enhance the outcomes of ischemic stroke. Benzydamine (BA), a well-known non-steroidal anti-inflammatory drug, has demonstrated potential in inhibiting pro-inflammatory cytokines across various disease models. However, the potential role of BA in microglial activation and post-stroke neuroinflammation remains unclear. Our study reveals that BA effectively suppresses the lipopolysaccharide (LPS)-stimulated pro-inflammatory responses of primary microglia, with high-dose BA (10 μM) suppressing LPS-induced inflammatory markers by up to 59.1 % in the mRNA levels of IL-1β. Furthermore, BA mitigated ischemic brain injury in experimental stroke mice. BA treatment also significantly attenuated neuroinflammatory responses and attenuates ischemic brain injury in experimental stroke mice. Further investigation revealed that BA reduces the release of the LPS-stimulated pro-inflammatory factors and activation of primary microglia by directly binding to and inhibiting the activity of cathepsin S (CTSS). In conclusion, our study identifies BA as a promising CTSS inhibitor with potential to suppress neuroinflammation following ischemic stroke. Our findings provide a theoretical basis for developing new neuroprotective strategies.
研究领域:
神经科学
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药理学
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免疫学
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神经病学
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产品关联
DOI
PubMed
高影响因子
ANALYTICAL CHEMISTRY
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2025
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IF 6.7
Wendi Wang,Qing Han,Tianwei Wang,Jian Liu,Qingbin Ni,Jingyi Sun,Ying Wang,Baoliang Sun
Ischemic stroke (IS) has a high mortality rate. Multiplexed detection of IS core biomarkers is of great significance to early diagnosis and personalized treatment of IS patients. Whether pericytes, a key component of the neurovascular unit and blood-brain barrier located on the capillary wall, could serve as a promising biomarker for IS is to be explored. Herein, we observed a significant upregulation of inflammatory and apoptotic factors, such as MMP9, in pericytes subjected to in vitro ischemia. By transfecting pericytes with ASK1-shRNA to inhibit ASK1 expression, we noted reduced levels of inflammatory and apoptotic markers, including MMP9, as well as enhanced pericyte contraction and migration, thereby preserving the integrity of the blood-brain barrier. Additionally, ELISA assays conducted using plasma samples from patients with varying NIHSS scores revealed statistically significant concentrations of PDGFRβ and MMP9. Furthermore, we developed a highly sensitive and specific quantitative detection method for PDGFRβ and MMP9 based on fluorescence sensor technology. This novel detector exhibits high sensitivity, repeatability, and stability, enabling precise dual detection. Thus, the results suggest the great potential of the detection of PDGFRβ and MMP9 for early diagnosis of IS and prognosis prediction of the disease.
研究领域:
神经科学
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医学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
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2025
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IF 3.8
Jin Feng,Qian Yang,Ming Chen,Long Ning,Yan Wang,Dan Luo,Dongxiong Hu,Qing Lin,Fangyan He
Background The active ingredient of Gastrodia elata , 4-hydroxybenzaldehyde (4-HBd), can rapidly enter the brain and undergo massive oxidation to produce the metabolite 4-hydroxybenzoic acid (4-HBA), which has no significant activity after equal dose gavage. It is crucial to clarify the metabolic pathway of 4-HBd and its correlation with the anti IS mechanism. Objective To explore the possible mechanism of 4-HBd in clearing ROS and protecting BBB from oxidative stress damage during brain metabolism from the perspective of ROS response. Method A rat model of cerebral ischemia-reperfusion injury and a cellular oxidative stress response model were replicated to simulate the accumulation process of ROS in the brain. The changes in ROS and peroxidation products before and after 4-HBd intervention were detected, and the changes in oxidative metabolism were also measured to confirm the correlation between antioxidant stress damage and ROS capture/clearance in oxidative metabolism. Result 4-HBd has significant antioxidant stress resistance both in vitro and in vivo, and can reduce the levels of MDA and 4-HNE in ischemic brain tissue. It can capture O2·- and ·OH in vitro and use the captured ROS to oxidize and metabolize 4-HBA. Conclusion The oxidative metabolism process of 4-HBd in the brain is one of its mechanisms for exerting antioxidant stress damage and protecting BBB.
研究领域:
药理学
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神经科学
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药物化学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
Oxidative Medicine and Cellular Longevity
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2020
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IF 5.076
Dengwen Zhang,Li Mei,Ruichun Long,Can Cui,Yi Sun,Sheng Wang,Zhengyuan Xia
Background. Cerebral ischemic stroke is a refractory disease which seriously endangers human health. Remote ischemic perconditioning (RiPerC) by which the sublethal ischemic stimulus is administered during the ischemic event is beneficial after an acute stroke. However, the regulatory mechanism of RiPerC that relieves cerebral ischemic injury is still not completely clear. Methods. In the present study, we investigated the regulatory mechanism of RiPerC in a rat model of ischemia induced by the middle cerebral artery occlusion (MCAO). Forty-eight adult male Sprague-Dawley (SD) rats were injected intracerebroventricularly with miR-98 agomir, miR-98 antagomir, or their negative controls (agomir-NC, antagomir-NC) 2 h before MCAO or MCAO+RiPerC followed by animal behavior tests and infraction volume measurement at 24 h after MCAO. The expression of miR-98, PIK3IP1, and tight junction proteins in rat hippocampus and cerebral cortex tissues was detected by quantitative polymerase chain reaction (qPCR) and Western blot (WB). Enzyme-linked immunosorbent assay (ELISA) was used to assess the IL-1β, IL-6, and TNF-α levels in the rat serum. Results. The results showed that in MCAO group, the expression of PIK3IP1 was upregulated, but decreased after RiPerC treatment. Then, we found that PIK3IP1 was a potential target of miR-98. Treatment with miR-98 agomir decreased the infraction volume, reduced brain edema, and improved neurological functions compared to control rats. But treating with miR-98 antagomir in RiPerC group, the protective effect on cerebral ischemia injury was canceled. Conclusion. Our finding indicated that RiPerC inhibited the MCAO-induced expression of PIK3IP1 through upregulated miR-98, thereby reducing the apoptosis induced by PIK3IP1 through the PI3K/AKT signaling pathway, thus reducing the cerebral ischemia-reperfusion injury.
研究领域:
神经科学
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分子生物学
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中风研究
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神经保护
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产品关联
DOI
PubMed
高影响因子
BRAIN RESEARCH BULLETIN
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2024
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IF 3.5
Yuqian Zhang,Shenghan Gao,Shengnan Xia,Haiyan Yang,Xinyu Bao,Qingxiu Zhang,Yun Xu
Due to various factors, there is still a lack of effective neuroprotective agents for ischemic stroke in clinical practice. Neuroinflammation and neuronal apoptosis mediated by endoplasmic reticulum stress are some of the important pathological mechanisms in ischemic stroke. Linarin has been reported to have anti-inflammation, antioxidant, and anti-apoptotic effects in myocardial ischemia, osteoarthritis, and kidney disease. Whether it exerts neuroprotective functions in ischemic stroke has not been investigated. The results showed that linarin could reduce the infarct volume in cerebral ischemia animal models, improve the neurological function scores and suppress the expression of inflammatory factors mediating the NF-κB. Meanwhile, it could protect the neurons from OGD/R-induced-apoptosis, which was related to the PERK-eIF2α pathway. Our results suggested linarin could inhibit neuronal inflammation and apoptosis induced by endoplasmic reticulum stress. Furthermore, the neuroprotective effect of linarin may be related to the inhibition of AKR1B1. Our study offers new insight into protecting against ischemia-reperfusion injury by linarin treatment in stroke.
研究领域:
神经科学
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药理学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
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