Notoginsenoside R1 protects against myocardial ischemia/reperfusion injury in mice via suppressing TAK1-JNK/p38 signaling

Zeng, Jingjing; Shi, Hanqing; Ren, Fangfang; Zhao, Xiao-shan; Chen, Qiao-ying; Wang, Dong-juan; Wu, Lianpin; Chu, Maoping; Lai, Teng-Fang; Li, Lei

doi:10.1038/s41401-023-01057-y

Cited by 26 publications

(8 citation statements)

References 61 publications

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“…PNS formulations, including Xuesaitong, Xueshuantong , and Lulutong injections, have been clinically validated through trials and fundamental studies. These investigations substantiate PNS’s efficacy in reducing cardiac damage, mitigating inflammation, and inhibiting platelet aggregation ( Zhou et al, 2018a ; Wang et al, 2021a ; Li et al, 2022 ; Wang et al, 2022 ; Zeng et al, 2023 ).…”

Section: Introductionsupporting

confidence: 62%

Efficacy and safety of Panax notoginseng saponin injection in the treatment of acute myocardial infarction: a systematic review and meta-analysis of randomized controlled trials

Chen,

Gao,

Guo

et al. 2024

Front. Pharmacol.

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Purpose: This study aimed to assess the efficacy and safety of Panax notoginseng saponin (PNS) injection, when combined with conventional treatment (CT), for acute myocardial infarction (AMI).Methods: Comprehensive searches were conducted in seven databases from inception until 28 September 2023. The search aimed to identify relevant randomized controlled trials (RCTs) focusing on PNS injection in the context of AMI. This meta-analysis adhered to the PRISMA 2020 guidelines, and its protocol was registered with PROSPERO (number: CRD42023480131).Result: Twenty RCTs involving 1,881 patients were included. The meta-analysis revealed that PNS injection, used adjunctively with CT, significantly improved treatment outcomes compared to CT alone, as evidenced by the following points: (1) enhanced total effective rate [OR = 3.09, p < 0.05]; (2) decreased incidence of major adverse cardiac events [OR = 0.32, p < 0.05]; (3) reduction in myocardial infarct size [MD = −6.53, p < 0.05]; (4) lower ST segment elevation amplitude [MD = −0.48, p < 0.05]; (5) mitigated myocardial injury as indicated by decreased levels of creatine kinase isoenzymes [MD = −11.19, p < 0.05], cardiac troponin T [MD = −3.01, p < 0.05], and cardiac troponin I [MD = −10.72, p < 0.05]; (6) enhanced cardiac function, reflected in improved brain natriuretic peptide [MD = −91.57, p < 0.05], left ventricular ejection fraction [MD = 5.91, p < 0.05], left ventricular end-diastolic dimension [MD = −3.08, p < 0.05], and cardiac output [MD = 0.53, p < 0.05]; (7) reduced inflammatory response, as shown by lower levels of C-reactive protein [MD = −2.99, p < 0.05], tumor necrosis factor-α [MD = −6.47, p < 0.05], interleukin-6 [MD = −24.46, p < 0.05], and pentraxin-3 [MD = −2.26, p < 0.05]; (8) improved vascular endothelial function, demonstrated by decreased endothelin-1 [MD = −20.56, p < 0.05] and increased nitric oxide [MD = 1.33, p < 0.05]; (9) alleviated oxidative stress, evidenced by increased superoxide dismutase levels [MD = 25.84, p < 0.05]; (10) no significant difference in adverse events [OR = 1.00, p = 1.00].Conclusion: This study highlighted the efficacy and safety of adjunctive PNS injections in enhancing AMI patient outcomes beyond CT alone. Future RCTs need to solidify these findings through rigorous methods.Systematic Review Registration: (https://www.crd.york.ac.uk/PROSPERO/), identifier (CRD42023480131)

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Section: Introductionsupporting

confidence: 62%

Efficacy and safety of Panax notoginseng saponin injection in the treatment of acute myocardial infarction: a systematic review and meta-analysis of randomized controlled trials

Chen,

Gao,

Guo

et al. 2024

Front. Pharmacol.

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“…The activation of MAPK signaling pathway is involved in the myocardial injury process in ischemia/reperfusion mice. Zeng et al [ 42 ] found that notoginseng saponin R1 prevented MIRI in mice by inhibiting TAK1-JNK/p38 signaling. Jin et al [ 43 ] further reported that dual-specificity protein phosphatase 1 (DUSP1) can protect mitochondrial homeostasis in mice with myocardial infarction, and its mechanism is associated with the inactivation of JNK signaling pathway.…”

Section: Discussionmentioning

confidence: 99%

Oleuropein alleviates myocardial ischemia–reperfusion injury by suppressing oxidative stress and excessive autophagy via TLR4/MAPK signaling pathway

He,

Huang,

Sun

et al. 2024

Chin Med

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Background Myocardial ischemia/reperfusion injury (MIRI) is an important complication of reperfusion therapy, and has a lack of effective prevention and treatment methods. Oleuropein (OP) is a natural strong antioxidant with many protective effects on cardiovascular diseases, but its protective effect on MIRI has not yet been studied in depth. Methods Tert-Butyl hydroperoxide (tBHP) was used to establish an in vitro oxidative stress model. Cell viability was detected by 3-(4,5)-dimethylthiahiazo (-z-y1)-3,5-di-phenytetrazoliumromide (MTT) and lactate dehydrogenase (LDH). Flow cytometry and fluorescence assays were performed for evaluating the ROS levels and mitochondrial membrane potential (MMP). Immunofluorescence analysis detected the NRF2 nuclear translocation and autophagy indicators. Further, Western blotting and quantitative real-time PCR were performed to evaluate the expression levels of proteins and mRNAs. Molecular docking, CETSA, and molecular interaction analysis explored the binding between OP and TLR4. The protective effects of OP in vivo were determined using a preclinical MIRI rat model. Results OP protected against tBHP-treated injury, reduced ROS levels and reversed the damaged MMP. Mechanistically, OP activated NRF2-related antioxidant pathways, inhibited autophagy and attenuated the TLR4/MAPK signaling pathway in tBHP-treated H9C2 cells with a high binding affinity to TLR4 (KD = 37.5 µM). The TLR4 inhibitor TAK242 showed a similar effect as OP. In vivo, OP could alleviate cardiac ischemia/reperfusion injury and it ameliorated adverse cardiac remodeling. Consistent with in vitro studies, OP inhibited TLR4/MAPK and autophagy pathway and activated NRF2-dependent antioxidant pathways in vivo. Conclusion This study shows that OP binds to TLR4 to regulate oxidative stress and autophagy for protecting damaged cardiomyocytes, supporting that OP can be a potential therapeutic agent for MIRI.

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“…Rats were randomly divided into seven groups: sham; MCAO; MCAO + dexmedetomidine (Hengrui Pharmaceutical Co., Ltd.) (injected intravenously with 9 μg/kg dexmedetomidine 30 min after MCAO) [ 38 , 39 ]; MCAO + SB203580 (Shanghai Baililai Biotech) (injected intraperitoneally with 200 μg/kg SB203580 30 min before MCAO) [ 40 , 41 ]; MCAO + dexmedetomidine + anisomycin (Beyotime) (injected intravenously with 9 μg/kg dexmedetomidine plus intraperitoneally with 100 μg/kg anisomycin 30 min after MCAO) [ 42 , 43 ]; MCAO + dexmedetomidine + P79350 (Acmec) (injected intravenously with 9 μg/kg dexmedetomidine plus intraperitoneally with 100 μg/kg P79350 30 min after MCAO) [ 44 ]; MCAO + dexmedetomidine + EGF (Peprotech) (injected intravenously with 9 μg/kg dexmedetomidine plus intraperitoneally with 250 μg/kg EGF 30 min after MCAO) [ 45 ].…”

Section: Methodsmentioning

confidence: 99%

Dexmedetomidine alleviates blood-brain barrier disruption in rats after cerebral ischemia-reperfusion by suppressing JNK and p38 MAPK signaling

Zhu,

Wang,

Chang

et al. 2024

Korean J Physiol Pharmacol

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Dexmedetomidine displays multiple mechanisms of neuroprotection in ameliorating ischemic brain injury. In this study, we explored the beneficial effects of dexmedetomidine on blood-brain barrier (BBB) integrity and neuroinflammation in cerebral ischemia/reperfusion injury. Sprague-Dawley rats were subjected to middle cerebral artery occlusion (MCAO) for 1.5 h and reperfusion for 24 h to establish a rat model of cerebral ischemia/reperfusion injury. Dexmedetomidine (9 μg/kg) was administered to rats 30 min after MCAO through intravenous injection, and SB203580 (a p38 MAPK inhibitor, 200 μg/kg) was injected intraperitoneally 30 min before MCAO. Brain damages were evaluated by 2,3,5-triphenyltetrazolium chloride staining, hematoxylin-eosin staining, Nissl staining, and brain water content assessment. BBB permeability was examined by Evans blue staining. Expression levels of claudin-5, zonula occludens-1, occludin, and matrix metalloproteinase-9 (MMP-9) as well as M1/M2 phenotypes-associated markers were assessed using immunofluorescence, RT-qPCR, Western blotting, and gelatin zymography. Enzyme-linked immunosorbent assay was used to examine inflammatory cytokine levels. We found that dexmedetomidine or SB203580 attenuated infarct volume, brain edema, BBB permeability, and neuroinflammation, and promoted M2 microglial polarization after cerebral ischemia/reperfusion injury. Increased MMP-9 activity by ischemia/reperfusion injury was inhibited by dexmedetomidine or SB203580. Dexmedetomidine inhibited the activation of the ERK, JNK, and p38 MAPK pathways. Moreover, activation of JNK or p38 MAPK reversed the protective effects of dexmedetomidine against ischemic brain injury. Overall, dexmedetomidine ameliorated brain injury by alleviating BBB permeability and promoting M2 polarization in experimental cerebral ischemia/reperfusion injury model by inhibiting the activation of JNK and p38 MAPK pathways.

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Notoginsenoside R1 protects against myocardial ischemia/reperfusion injury in mice via suppressing TAK1-JNK/p38 signaling

Cited by 26 publications

References 61 publications

Efficacy and safety of Panax notoginseng saponin injection in the treatment of acute myocardial infarction: a systematic review and meta-analysis of randomized controlled trials

Efficacy and safety of Panax notoginseng saponin injection in the treatment of acute myocardial infarction: a systematic review and meta-analysis of randomized controlled trials

Oleuropein alleviates myocardial ischemia–reperfusion injury by suppressing oxidative stress and excessive autophagy via TLR4/MAPK signaling pathway

Dexmedetomidine alleviates blood-brain barrier disruption in rats after cerebral ischemia-reperfusion by suppressing JNK and p38 MAPK signaling

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