Buyang Huanwu Decoction ameliorates ischemic stroke by modulating multiple targets with multiple components: In vitro evidences

doi:10.1016/S1875-5364(18)30047-5

Chinese Journal of Natural Medicines

Volume 16, Issue 3, March 2018, Pages 194-202

https://doi.org/10.1016/S1875-5364(18)30047-5 Get rights and content

Abstract

Buyang Huanwu Decoction (BYHWD) is a well-known traditional Chinese medicine prescription which is used to treat ischaemic stroke and stroke-induced disabilities. However, the exact mechanism underlying BYHWD's amelioration of ischaemic stroke and its effective constituents remain unclear. The present study aimed to identify the effective constituents of BYHWD and to further explore its action mechanisms in the amelioration of ischaemic stroke by testing the activities of 15 absorbable chemical constituents of BYHWD with the same methods under the same conditions. The following actions of these 15 compounds were revealed: 1) Ferulic acid, calycosin, formononetin, astrapterocarpan-3-O-β-D-glucoside, paeonol, calycosin-7-O-β-D-glucoside, astraisoflavan-7-O-β-D-glucoside, ligustrazine, and propyl gallate significantly suppressed concanavalin A (Con A)-induced T lymphocyte proliferation; 2) Propyl gallate, calycosin-7-O-β-D-glucoside, paeonol, and ferulic acid markedly inhibited LPS-induced apoptosis in RAW264.7 cells; 3) Propyl gallate and formononetin significantly inhibited LPS-induced NO release; 4) Hydroxysafflor yellow A and inosine protected PC12 cells against the injuries caused by glutamate; and 5) Formononetin, astragaloside IV, astraisoflavan-7-O-β-D-glucoside, inosine, paeoniflorin, ononin, paeonol, propyl gallate, ligustrazine, and ferulic acid significantly suppressed the constriction of the thoracic aorta induced by KCl in rats. In conclusion, the results from the present study suggest that BYHWD exerts its ischaemic stroke ameliorating activities by modulating multiple targets with multiple components.

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Glycosides of Buyang Huanwu decoction inhibits inflammation associated with cerebral ischemia-reperfusion via the PINK1/Parkin mitophagy pathway
2024, Journal of Ethnopharmacology
A classic stroke formula is Buyang Huanwu Decoction (BYHWD), Glycosides are the pharmacological components found in BYHWD, which are utilized for the prevention and management of cerebral ischemia-reperfusion (CIR), as demonstrated in a previous study. Its neuroprotective properties are closely related to its ability to modulate inflammation, but its mechanism is as yet unclear.
A research was undertaken to investigate the impact of glycosides on the inflammation of CIR through the PTEN-induced putative kinase-1 (PINK1)/Parkin mitophagy pathway.
Analyzing glycosides containing serum components was performed with ultra-performance liquid chromatography-quadrupole-time of flight-mass spectrometry (UPLC-Q-TOF-MS). Glycosides were applied to rat of Middle cerebral artery occlusion/reperfusion (MCAO/R) model and primary neural cell of Oxygen glucose deprivation/reperfusion (OGD/R) model. The neuroprotective effect and the regulation of mitophagy of glycosides were evaluated through neural damage and PINK1/Parkin mitophagy activation. Moreover, the assessment of the relationship between glycosides regulation of mitophagy and its anti-inflammatory effects subsequent to mitophagy blockade was conducted by examining neural damage, PINK1/Parkin mitophagy activation, and levels of pyroptosis.
(1) It was observed that the administration of glycosides resulted in a decrease in neurological function scores, a reduction in cerebral infarction volume, an increase in mitochondrial autophagosome, and the maintenance of a high expression status of light chain 3 (LC3) II/LC3Ⅰ protein. Additionally, there was a significant inhibition of p62 protein expression and an enhancement of PINK1 and Parkin protein expression. Furthermore, it was found that the effect of glycosides at a dosage of 0.128 g · kg^-1 was significantly superior to that of glycosides at a dosage of 0.064 g · kg^-1. Notably, the neuroprotective effect and inhibition of pyroptosis protein of glycosides at a dosage of 0.128 g · kg^-1 were attenuated when mitochondrial autophagy was blocked. (2)
Glycosides repaired cellular morphological damage, enhanced cell survival, and reduced Lactate dehydrogenase (LDH) leakage, with glycosides (2.36 μg·mL^-1 and 4.72 μg·mL⁻¹) neuronal protection being the strongest. Glycosides (4.72 μg·mL⁻¹) maintained LC3II/LC3Ⅰ protein high expression state, inhibited p62 protein expression, and promoted PINK1 and Parkin protein expression, which was stronger than glycosides (2.36 μg·mL^-1). The blockade of mitophagy resulted in a reduction of neuroprotection and inhibition of pyroptosis protein exerted by glycosides.
Glycosides demonstrate the ability to hinder inflammation through the activation of the PINK1/Parkin mitophagy pathway, thereby leading to subsequent neuroprotective effects on CIR.
Optimization of green extraction process with natural deep eutectic solvent and comparative in vivo pharmacokinetics of bioactive compounds from Astragalus-Safflower pair
2023, Phytomedicine
Natural deep eutectic solvents (NaDESs) are promising not only in componential extraction, but also in drug delivery system due to their green and safe features. In this work, NaDESs were applied to extract bioactive components from Astragalus-Safflower pair, a classic traditional Chinese medicine combination. Furthermore, ready-to-use crude extracts were administrated to SD rats.
Total 9 NaDESs composed of food grade ingredients were screened for the extraction of representative 9 components (hydroxysafflor yellow A, anhydrosafflor yellow B, eleutheroside B, calycosin-7-O-glucoside, kaempferol-3-O-rutinoside, ononin, calycosin, astraganoside, and carthamin) from Astragalus-Safflower pair. Afterwards, genetic artificial neural network (GNN) was adopted for optimizing the ultrasound-assisted extraction process. After SD rats were orally administrated with the ready-to-use crude extracts extracted under the optimized conditions, the in vivo pharmacokinetic characteristics of 5 components were evaluated comprehensively from weight, gender, solvent and modeling surgery, under a well-established UPLC-MS/MS method.
Betaine-Lactic acid (Bet-Lac) was eventually determined as the optimal extraction solvent for subsequent experiments. The optimal ultrasound assisted extraction process was as follows: 90 min of extraction time, 65 °C of temperature, 80% of Bet-Lac content and 50 mg/ml of solid-liquid ratio. Bet-Lac enhanced to varying degrees the bioavailability of analytes in normal and cerebral ischemia/reperfusion injured (CI/RI) rats in contrast with corresponding rats administrated with water extract groups (p < 0.05). Besides, the bioavailability of active components in CI/RI rat plasma was significantly lower than that in normal rats (p < 0.05), indicating pathological damage of CI/R had a significant impact on pharmacokinetic profile of compounds in rats. However, gender and body weight had no significant effects on the pharmacokinetic profile of bioactive components.
NaDESs exhibited higher extraction efficiency than conventional solvents. And GNN is reliable to optimize the ultrasound assisted extraction process. This study supported the potential of non-toxic NaDESs as solvents for extraction process and drug delivery systems at the same time.
A multiomics and network pharmacological study reveals the neuroprotective efficacy of Fu-Fang-Dan-Zhi tablets against glutamate-induced oxidative cell death
2022, Computers in Biology and Medicine
Citation Excerpt :
Senkyunolide I also exhibits neuroprotective effects against glutamate-induced cell death by attenuating JNK/caspase-3 activation and apoptosis [16]. 5-Ethyl-2-hexylfuran-3-sulfonic acid and ononin are capable of anticoagulation, anti-platelet aggregation, and anti-vasoconstriction [17,18]. However, the therapeutic mechanism of FFDZT in ischemic stroke is still largely unknown.
Neuroprotective therapy after ischemic stroke remains a significant need, but current measures are still insufficient. The Fu-Fang-Dan-Zhi tablet (FFDZT) is a proprietary Chinese medicine clinically employed to treat ischemic stroke in the recovery period. This work aims to systematically investigate the neuroprotective mechanism of FFDZT. A systems strategy that integrated metabolomics, transcriptomics, network pharmacology, and in vivo and in vitro experiments was used. First, middle cerebral artery occlusion (MCAO) model rats were treated with FFDZT. FFDZT treatment significantly reduced the infarct volume in the brains of middle cerebral artery occlusion (MCAO) model rats. Then, samples of serum and brain tissue were taken for metabolomics and transcriptomics studies, respectively; gene expression profiles of MCF7 cells treated with FFDZT and its 4 active compounds (senkyunolide I, formononetin, drilodefensin, and tanshinone IIA) were produced for CMAP analysis. Computational analysis of metabolomics and transcriptomics results suggested that FFDZT regulated glutamate and oxidative stress-related metabolites (2-hydroxybutanoic acid and 2-hydroxyglutaric acid), glutamate receptors (NMDAR, KA, and AMPA), glutamate involved pathways (glutamatergic synapse pathway; d-glutamine and d-glutamate metabolism; alanine, aspartate and glutamate metabolism), as well as the reactive oxygen species metabolic process. CMAP analysis indicated that two active ingredients of FFDZT (tanshinone ⅡA and senkyunolide I) could act as glutamate receptor antagonists. Next, putative therapeutic targets of FFDZT's active ingredients identified in the brain were collected from multiple resources and filtered by statistical criteria and tissue expression information. Network pharmacological analysis revealed extensive interactions between FFDZT's putative targets, anti-IS drug targets, and glutamate-related enzymes, while the resulting PPI network exhibited modular topology. The targets in two of the modules were significantly enriched in the glutamatergic synapse pathway. The interactions between FFDZT's ingredients and important targets were verified by molecular docking. Finally, in vitro experiments validated the effects of FFDZT and its ingredients in suppressing glutamate-induced PC12 cell injury and reducing the generation of reactive oxygen species. All of our findings indicated that FFDZT's efficacy for treating ischemic stroke could be due to its neuroprotection against glutamate-induced oxidative cell death.
An evidence-based evaluation of Buyang Huanwu decoction for the treatment of the sequelae of stroke: A PRISMA-compliant systematic review and meta-analysis of randomized controlled trials
2022, Phytomedicine
Citation Excerpt :
Traditional Chinese medicine (TCM), including acupuncture and Chinese herbal therapy, is widely used as a complementary treatment for the sequelae of stroke in China. Chinese herbal therapy is based on the principle of syndrome differentiation, acting on multiple pathological processes with multiple targets, levels, and pathways (Hu et al., 2018; Pei et al., 2020; Zhang et al., 2018; Zhang et al., 2015). Studies have shown that the combination of Chinese herbal therapy and CT could improve the neurological symptoms and daily activities of stroke patients (Cai et al., 2019; Gao et al., 2021; Kwon et al., 2021; Xu et al., 2015).
Buyang Huanwu decoction (BYHWD) is a famous traditional Chinese formula that has been widely prescribed for sequelae of stroke in China. However, the efficacy and safety of BYHWD in treating sequelae of stroke have never been systematically evaluated.
To evaluate the effectiveness and safety of BYHWD in the treatment of sequelae of stroke.
A Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA)-compliant systematic review and meta-analysis of randomized clinical trials (RCTs).
A systematic review and meta-analysis was performed in accordance with the PRISMA guidelines. Five common electronic databases were searched for relevant RCTs from their inception until May 20, 2022. The Cochrane risk-of-bias tool was used to evaluate the methodological quality and the risk of bias of the included RCTs. Review Manager 5.4 was used to analyse all the data obtained. The clinical effective rate (CER) was the primary outcome, and National Institutes of Health Stroke Scale (NIHSS) and Fugl-Meyer Assessment (FMA) scores were the secondary outcomes. The Grading of Recommendations, Assessment, Development and Evaluations (GRADE) system was used to evaluate the quality of evidence for each outcome.
Thirty-two clinical studies that recruited 2,527 eligible patients were included in this meta-analysis. The results of the meta-analysis suggested that compared with conventional treatment alone, the addition of BYHWD significantly improved the CER (RR = 1.24, 95% CI: 1.20-1.29, p < 0.00001), decreased the NIHSS score (MD = -5.42, 95% CI: -5.87-4.97, p < 0.00001), and increased the FMA score (MD = 17.28, 95% CI: 15.12-19.45, p < 0.00001). There were no reported adverse events in the included studies. Most results were robust, and the quality of evidence was moderate.
Our study is the first meta-analysis of RCTs evaluating the effects of BYHWD on sequelae of stroke. The addition of BYHWD to conventional treatment for sequelae of stroke significantly improved the CER and promoted neurological rehabilitation in patients, and there were no reported adverse events associated with this combination therapy. The findings of our study support the use of BYHWD as an adjunct treatment to conventional treatment in this clinical population. However, due to the limitations of the included clinical trials, high-quality clinical trials with longer follow-ups are needed to assess the long-term effectiveness and safety of BYHWD for treating the sequelae of stroke.
Hydroxysafflor yellows alleviate thrombosis and acetaminophen-induced toxicity in vivo by enhancing blood circulation and poison excretion
2021, Phytomedicine
Citation Excerpt :
The florets of Carthamus tinctorius L. (Safflower) is an important herbal drug that is renowned for its efficacy in promoting blood circulation and removing blood stasis and is frequently found in traditional medicine prescriptions for coronary heart disease, liver diseases, cough, asthma, indigestion, and stroke (Chinese Pharmacopoeia Committee, 2020; Zhang et al., 2018).
Hydroxysafflor yellow A (HSYA) from the flower of Carthamus tinctorius (Safflower) has been reported to have various pharmacological effects. However, little is known about the bioactivities of other chemical constituents in Safflower and the relationship between enhancement of blood circulation and hepatoprotection by HSYA.
The present research was to evaluate the antithrombotic and hepatoprotective activities of HSYA and C, examine their mechanisms of actions, including influence on the excretion velocity of acetaminophen, and the relationship between the antithrombotic, hepatoprotective, and other bioactivities.
The hepatoprotective activities were examined by acetaminophen (APAP)-induced zebrafish toxicity and carbon tetrachloride (CCl₄)-induced mouse liver injury. The concentrations of APAP in zebrafish and APAP that was excreted to the culture media were quantified by UHPLC-MS. The anti-thrombosis effect of HSYA and C were examined by the phenylhydrazine (PHZ)-induced zebrafish thrombosis.
HSYA and HSYC showed robust protection on APAP-induced toxicity and PHZ-induced thrombosis. The hepatoprotective effects of HSYA and C were more potent than that of the positive control, acetylcysteine (61.7% and 58.0%, respectively, vs. 56.9% at 100 µM) and their antithrombosis effects were more robust than aspirin (95.1% and 86.2% vs. 52.7% at 100 µM). HSYA and C enhanced blood circulation, rescued APAP-treated zebrafish from morphological abnormalities, and mitigated APAP-induced toxicity in liver development in liver-specific RFP-expressing transgenic zebrafish. HSYC attenuated CCl₄-induced mouse liver injury and regulated the levels of HIF-1α, iNOS, TNF-α, α-SMA, and NFκB in liver tissues. HSYA was also protective in a dual thrombotic and liver toxicity zebrafish model. By UHPLC-MS, HSYA accelerated the excretion of APAP.
HSYA and C are the bioactive constituents of Safflower that are responsible for the herbal drug's traditional use in promoting blood circulation to remove blood stasis. Safflower and its chalcone constituents may protect from damage due to exogenous or disease-induced endogenous toxins by enhancing the excretion velocity of toxins.
Compound Dan Zhi tablet attenuates experimental ischemic stroke via inhibiting platelet activation and thrombus formation
2020, Phytomedicine
Compound Dan Zhi tablet (DZT) is a commonly used traditional Chinese medicine formula. It has been used for the treatment of ischemic stroke for many years in clinical. However, its pharmacological mechanism is unclear.
The aim of the current study was to understand the protective effects and underlying mechanisms of DZT on ischemic stroke.
Fifteen representative chemical markers in DZT were determined by ultra-performance liquid chromatography coupled with tandem quadrupole time-of-flight mass spectrometry (UPLC-QTOF-MS). The protective effect of DZT against ischemic stroke was studied in a rat model of middle cerebral artery occlusion (MCAO), and the mechanism was further explored through a combination of network pharmacology and experimental verification.
Quantitative analysis showed that the contents of phenolic acids, furan sulfonic acids, tanshinones, flavonoids, saponins and phthalides in DZT were calculated as 7.47, 0.788, 0.627, 0.531 and 0.256 mg/g, respectively. Phenolic acids were the most abundant constituents. Orally administered DZT (1.701 g kg⁻¹) significantly alleviated the infarct size and neurological scores in MCAO rats. The network analysis predicted that 53 absorbed active compounds in DZT-treated plasma targeted 189 proteins and 47 pathways. Ten pathways were associated with anti-platelet activity. In further experiments, DZT (0.4 and 0.8 mg mL⁻¹) markedly inhibited in vitro prostaglandin G/H synthase 1 (PTGS1) activity. DZT (0.4 and 0.8 mg mL⁻¹) significantly inhibited in vitro platelet aggregation in response to ADP or AA. DZT (113 and 226 mg kg⁻¹, p.o.) also produced a marked inhibition of ADP- or AA-induced ex vivo platelet aggregation with a short duration of action. DZT decreased the level of thromboxane A₂ (TXA₂) in MCAO rats. In the carrageenan-induced tail thrombosis model and ADP-induced acute pulmonary thromboembolism mice model, DZT (113 and 226 mg kg⁻¹, p.o.) prevented thrombus formation. Importantly, DZT (113 and 226 mg kg⁻¹, p.o.) exhibited a low bleeding liability.
DZT protected against cerebral ischemic injury. The inhibition of TXA₂ level, platelet aggregation and thrombosis formation might involve in the protective mechanism.

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Available online 20 Mar., 2018

[Research funding] This work was supported by National Natural Science Foundation of China (No. 81470050) and Beijing Natural Science Foundation (No. 7122097).

These authors have no conflict of interest to declare.

^Δ: These authors contributed equally to this work.

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Buyang Huanwu Decoction ameliorates ischemic stroke by modulating multiple targets with multiple components: In vitro evidences

Abstract

Lancet

Pathophysiology

Neuroscience letters

J Ethnopharmacol

J Ethnopharmacol

J Tradit Chin Med

J Pharm Biomed Anal

J Pharm Biomed Anal

J Pharm Biomed Anal

J Chromatogr B

Life Sci

Eur J Pharmacol

Neuron

Cell Signal

Cerebral blood flow and histopathological changes following permanent bilateral carotid artery ligation in Wistar rats [J]

Exp Brain Res

Guidelines for the early management of patients with acute ischemic stroke: a guideline for healthcare professionals from the American Heart Association/American Stroke Association [J]

Stroke

Clinical efficacy and safety of buyang huanwu decoction for acute ischemic stroke: a systematic review and meta-analysis of 19 randomized controlled trials [J]

Evid Based Complement Alternat Med

Buyang huanwu decoction for healthcare: evidence-based theoretical interpretations of treating different diseases with the same method and target of vascularity [J]

Evid Based Complement Alternat Med

A systematic review and meta-analysis of buyang huanwu decoction in animal model of focal cerebral ischemia [J]

Evid Based Complement Alternat Med

Study on the effective substances of Buyang Huanwu Decoction-Absorption of seven crude drugs [D]