Danggui-Shaoyao-San (DSS) Ameliorates Cerebral Ischemia-Reperfusion Injury via Activating SIRT1 Signaling and Inhibiting NADPH Oxidases

Luo, Yiwen; Chen, Hansen; Tsoi, Bun; Wang, Qi; Shen, Jiangang

doi:10.3389/fphar.2021.653795

Cited by 21 publications

(15 citation statements)

References 81 publications

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“…Next, we explored the underlying mechanism of TFCJ against IS. Previous studies ( Zhang et al, 2019 ; Heidari et al, 2021 ; Luo et al, 2021 ) have reported that oxidative stress and cell apoptosis may have the strongest correlation with IS. Li et al (2021) reported that miR-27A-3p reduces apoptosis and oxidative stress induced by oxygen-glucose deprivation/reoxygenation through FOXO1/p27 Kip1 signaling.…”

Section: Discussionmentioning

confidence: 85%

Total Flavonoids of Chuju Decrease Oxidative Stress and Cell Apoptosis in Ischemic Stroke Rats: Network and Experimental Analyses

et al. 2021

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Background: Pharmacological research results showed that total flavonoids of Chuju (TFCJ) could be used to treat acute myocardial ischemia and myocardial ischemia-reperfusion injury. In this study, we explored the protective effect of TFCJ on ischemic stroke (IS) in the IS rat model. We hypothesized that TFCJ might exert its neuroprotective effects by suppressing apoptosis and oxidative stress that are closely related to PI3K/Akt/mTOR signaling pathway.Method: TFCJ (10, 20, and 40 mg/kg) was administered for 7 days. Rats (260 ± 20 g) were subjected to middle cerebral artery occlusion (MCAO) for 2 h and reperfusion for 24 h. The neuroprotective effect of TFCJ was substantiated in terms of neurological deficits, oxidative stress (superoxide dismutase, glutathione peroxidase, catalase, and malondialdehyde), pathomorphological changes (HE staining and TUNEL staining), and neurobehavioral functions in the rats. Then, we employed network pharmacology to reveal the potential mechanism of TFCJ against IS. Western blot was used to determine the levels of PI3K/AKT/mTOR pathway proteins. The expression of BCL-2, BAX, and cleaved-Caspase-3 was also measured by Western blots and RT-PCR.Results: The histopathological assessment showed that TFCJ reduced MCAO-induced brain damage. Besides, TFCJ exerted a protective role in MCAO rats by alleviating cell apoptosis and oxidative stress. Network pharmacology showed that TFCJ might be used against IS through the PI3K/AKT signaling pathway. TFCJ reduced cell apoptosis and oxidative stress by increasing the level of p-AKT and p-mTOR in MCAO rats, while the effect of TFCJ was significantly reversed when applying LY294002 (PI3k inhibitor).Conclusion: These results indicated that TFCJ might decrease oxidative stress and apoptosis that are closely related to PI3K/Akt/mTOR pathway in IS. TFCJ is a promising authentic traditional Chinese medicine for the management of IS.

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Section: Discussionmentioning

confidence: 85%

Total Flavonoids of Chuju Decrease Oxidative Stress and Cell Apoptosis in Ischemic Stroke Rats: Network and Experimental Analyses

et al. 2021

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“…It has been reported that I/R decreased p47 phox /p67 phox in the cytosol and increased p47 phox /p67 phox /gp91 phox in the membrane [38]. Upregulation of all major NOX subunits (p47 phox , p67 phox , p22 phox , and gp91 phox ) has also been found to be associated with increased NOX activity post-stroke [39][40][41][42]. Our current study showcased significantly decreased ROS levels, NOX enzyme activity, and levels of p47 phox , p67 phox , p22 phox , and gp91 phox proteins after C+P therapy, consistent with the results of the NOX inhibitor group or PKC-δ inhibitor group.…”

Section: Discussionmentioning

confidence: 97%

Chlorpromazine and Promethazine (C+P) Reduce Brain Injury after Ischemic Stroke through the PKC-δ/NOX/MnSOD Pathway

Guo

Ding

Wills

et al. 2022

Mediators of Inflammation

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Cerebral ischemia-reperfusion (I/R) incites neurologic damage through a myriad of complex pathophysiological mechanisms, most notably, inflammation and oxidative stress. In I/R injury, nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (NOX) produces reactive oxygen species (ROS), which promote inflammatory and apoptotic pathways, augmenting ROS production and promoting cell death. Inhibiting ischemia-induced oxidative stress would be beneficial for reducing neuroinflammation and promoting neuronal cell survival. Studies have demonstrated that chlorpromazine and promethazine (C+P) induce neuroprotection. This study investigated how C+P minimizes oxidative stress triggered by ischemic injury. Adult male Sprague-Dawley rats were subject to middle cerebral artery occlusion (MCAO) and subsequent reperfusion. 8 mg/kg of C+P was injected into the rats when reperfusion was initiated. Neurologic damage was evaluated using infarct volumes, neurological deficit scoring, and TUNEL assays. NOX enzymatic activity, ROS production, protein expression of NOX subunits, manganese superoxide dismutase (MnSOD), and phosphorylation of PKC-δ were assessed. Neural SHSY5Y cells underwent oxygen-glucose deprivation (OGD) and subsequent reoxygenation and C+P treatment. We also evaluated ROS levels and NOX protein subunit expression, MnSOD, and p-PKC-δ/PKC-δ. Additionally, we measured PKC-δ membrane translocation and the level of interaction between NOX subunit (p47phox) and PKC-δ via coimmunoprecipitation. As hypothesized, treatment with C+P therapy decreased levels of neurologic damage. ROS production, NOX subunit expression, NOX activity, and p-PKC-δ/PKC-δ were all significantly decreased in subjects treated with C+P. C+P decreased membrane translocation of PKC-δ and lowered the level of interaction between p47phox and PKC-δ. This study suggests that C+P induces neuroprotective effects in ischemic stroke through inhibiting oxidative stress. Our findings also indicate that PKC-δ, NOX, and MnSOD are vital regulators of oxidative processes, suggesting that C+P may serve as an antioxidant.

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“…Caspase-3 is considered to play an executing role at the final step of apoptosis-producing DNA fragmentation [ 31 ]. The report showed that DSS reduced the expression of caspase-3 and upregulated the expression of Bcl-2 at the MCAO rat model [ 11 ]. In this study, the Western blot results revealed that DSS significantly regulated the expression of p-ERK1/2, p-AKT, and Bcl-2.…”

Section: Discussionmentioning

confidence: 99%

“…Several studies have demonstrated that PPARA-mediated reduction in oxidative stress correlates with improved outcomes in rodent stroke models [ 40 ]. Recently, the study showed that DSS could attenuate oxidative stress against cerebral ischemic-reperfusion injury via SIRT1-dependent manner [ 11 ].…”

Section: Discussionmentioning

confidence: 99%

“…It is reported that DSS not only prevents cognitive impairment from Alzheimer's disease (AD) but also improves microcirculation in patients with asymptomatic cerebral infarction [ 10 ]. A number of studies indicate the potentials of DSS for improving neurological functions in poststroke treatment [ 11 , 12 ]. DSS treatment also promotes focal angiogenesis and neurogenesis, attenuates neurological deficit scores, and improves memory functions in experimental rat models of cerebral ischemic-reperfusion injury [ 13 , 14 ].…”

Section: Introductionmentioning

confidence: 99%

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Systematic Understanding of Mechanism of Danggui Shaoyao San against Ischemic Stroke Using a Network Pharmacology Approach

Yang

Zhang

et al. 2022

Evidence-Based Complementary and Alternative Medicine

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Purpose. Danggui Shaoyao San (DSS) was developed to treat the ischemic stroke (IS) in patients and animal models. The purpose of this study was to explore its active compounds and demonstrate its mechanism against IS through network pharmacology, molecular docking, and animal experiment. Methods. All the components of DSS were retrieved from the pharmacology database of TCM system. The genes corresponding to the targets were retrieved using OMIM, CTD database, and TTD database. The herb-compound-target network was constructed by Cytoscape software. The target protein-protein interaction network was built using the STRING database. The core targets of DSS were analyzed by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG). Then, we achieved molecular docking between the hub proteins and the key active compounds. Finally, animal experiments were performed to verify the core targets. Triphenyltetrazolium chloride (TTC) staining was used to calculate the infarct size in mice. The protein expression was determined using the Western blot. Results. Compound-target network mainly contained 51 compounds and 315 corresponding targets. Key targets contained MAPK1, SRC, PIK3R1, HRAS, AKT1, RHOA, RAC1, HSP90AA1, and RXRA FN1. There were 417 GO items in GO enrichment analysis ( p < 0.05 ) and 119 signaling pathways ( p < 0.05 ) in KEGG, mainly including negative regulation of apoptosis, steroid hormone-mediated signaling pathway, neutrophil activation, cellular response to oxidative stress, and VEGF signaling pathway. MAPK1, SRC, and PIK3R1 docked with small molecule compounds. According to the Western blot, the expression of p-MAPK 1, p-AKT, and p-SRC was regulated by DSS. Conclusions. This study showed that DSS can treat IS through multiple targets and routes and provided new insights to explore the mechanisms of DSS against IS.

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Danggui-Shaoyao-San (DSS) Ameliorates Cerebral Ischemia-Reperfusion Injury via Activating SIRT1 Signaling and Inhibiting NADPH Oxidases

Cited by 21 publications

References 81 publications

Total Flavonoids of Chuju Decrease Oxidative Stress and Cell Apoptosis in Ischemic Stroke Rats: Network and Experimental Analyses

Total Flavonoids of Chuju Decrease Oxidative Stress and Cell Apoptosis in Ischemic Stroke Rats: Network and Experimental Analyses

Chlorpromazine and Promethazine (C+P) Reduce Brain Injury after Ischemic Stroke through the PKC-δ/NOX/MnSOD Pathway

Systematic Understanding of Mechanism of Danggui Shaoyao San against Ischemic Stroke Using a Network Pharmacology Approach

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