Tetramethylpyrazine: A promising drug for the treatment of pulmonary hypertension

Chen, Yuqin; Lu, Wenju; Yang, Kai; Duan, Xuefei; Li, Mengxi; Chen, Xiuqing; Zhang, Jie; Kuang, Meidan; Liu, Shiyun; Wu, Xiongting; Zou, Guofa; Liu, Chunli; Hong, Cheng; He, Wenjun; Liao, Jing; Hou, Chi; Zhang, Zhe; Zheng, Qiuyu; Chen, Jiyuan; Zhang, Nuofu; Tang, Haiyang; Vanderpool, Rebecca; Desai, Ankit A.; Rischard, Franz; Black, Stephen M.; Garcia, Joe G.N.; Makino, Ayako; Yuan, Jason X.‐J.; Zhong, Nanshan; Jian, Wang

doi:10.1111/bph.15000

Cited by 41 publications

(28 citation statements)

References 57 publications

(71 reference statements)

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“…Tetramethylpyrazine, extracted from the traditional herbal medicine Ligusticum , effectively prevents and reverses PAH in different animal models such as chronic hypoxia-induced PAH, sugen/hypoxia-induced PAH, and MCT-induced PAH in rodents ( Chen et al, 2020c ). In hypoxia-induced PAH, tetramethylpyrazine improved pulmonary vascular leakage and attenuated the elevation of ROS, HIF1α, and VEGF protein levels ( Zhang et al, 2011 ).…”

Section: Preclinical Studies Of Traditional Herbal Medicine For Pulmonary Arterial Hypertension Treatmentmentioning

confidence: 99%

“…Nowadays, the clinical trial of tetramethylpyrazine in PAH treatment is ongoing (registered with www.chictr.org.cn as ChiCTR-IPR-14005379). Therefore, tetramethylpyrazine has the potential to be a novel and inexpensive medication for PAH ( Chen et al, 2020c ).…”

Section: Preclinical Studies Of Traditional Herbal Medicine For Pulmonary Arterial Hypertension Treatmentmentioning

confidence: 99%

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Traditional Herbal Medicine Discovery for the Treatment and Prevention of Pulmonary Arterial Hypertension

Xue

Zhou

et al. 2021

Front. Pharmacol.

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Pulmonary arterial hypertension (PAH) is characterized by pulmonary artery remodeling that may subsequently culminate in right heart failure and premature death. Although there are currently both non-pharmacological (lung transplantation, etc.) and pharmacological (Sildenafil, Bosentan, and new oral drugs on trial) therapies available, PAH remains a serious and fatal pulmonary disease. As a unique medical treatment, traditional herbal medicine (THM) treatment has gradually exerted its advantages in treating PAH worldwide through a multi-level and multi-target approach. Additionally, the potential mechanisms of THM were deciphered, including suppression of proliferation and apoptosis of pulmonary artery smooth muscle cells, controlling the processes of inflammation and oxidative stress, and regulating vasoconstriction and ion channels. In this review, the effects and mechanisms of the frequently studied compound THM, single herbal preparations, and multiple active components from THM are comprehensively summarized, as well as their related mechanisms on several classical preclinical PAH models. It is worth mentioning that sodium tanshinone IIA sulfonate sodium and tetramethylpyrazine are under clinical trials and are considered the most promoting medicines for PAH treatment. Last, reverse pharmacology, a strategy to discover THM or THM-derived components, has also been proposed here for PAH. This review discusses the current state of THM, their working mechanisms against PAH, and prospects of reverse pharmacology, which are expected to facilitate the natural anti-PAH medicine discovery and development and its bench-to-bedside transformation.

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Section: Preclinical Studies Of Traditional Herbal Medicine For Pulmonary Arterial Hypertension Treatmentmentioning

confidence: 99%

Section: Preclinical Studies Of Traditional Herbal Medicine For Pulmonary Arterial Hypertension Treatmentmentioning

confidence: 99%

Traditional Herbal Medicine Discovery for the Treatment and Prevention of Pulmonary Arterial Hypertension

Xue

Zhou

et al. 2021

Front. Pharmacol.

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“…Multiple studies showed that activators of K + channels [ 7 , 99 ] and inhibitors of both Cl - channels [ 98 ] and TRPC channels [ 100 ] can prevent and/or reverse PAH in animal models. Optimising the selectivity, potency and lung-specific delivery of these compounds will therefore be paramount to the development of new PAH therapies.…”

Section: Summary and Implications For Therapymentioning

confidence: 99%

Ion channels as convergence points in the pathology of pulmonary arterial hypertension

Jouen-Tachoire

Tucker

Tammaro

2021

Biochemical Society Transactions

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Pulmonary arterial hypertension (PAH) is a fatal disease of the cardiopulmonary system that lacks curative treatments. The main pathological event in PAH is elevated vascular resistance in the pulmonary circulation, caused by abnormal vasoconstriction and vascular remodelling. Ion channels are key determinants of vascular smooth muscle tone and homeostasis, and four PAH channelopathies (KCNK3, ABCC8, KCNA5, TRPC6) have been identified so far. However, the contribution of ion channels in other forms of PAH, which account for the majority of PAH patients, has been less well characterised. Here we reason that a variety of triggers of PAH (e.g. BMPR2 mutations, hypoxia, anorectic drugs) that impact channel function may contribute to the onset of the disease. We review the molecular mechanisms by which these ‘extrinsic’ factors converge on ion channels and provoke their dysregulation to promote the development of PAH. Ion channels of the pulmonary vasculature are therefore promising therapeutic targets because of the modulation they provide to both vasomotor tone and proliferation of arterial smooth muscle cells.

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“…We recently documented that the combination of RAS and RLC effectively ameliorated fibrotic liver injury by decreasing BA accumulation and repressing the production of inflammatory cytokines [ 16 ]. Bioactive ingredients of RPA and RRP exhibited hepatoprotective effects as well [ 17 ]. However, the underlying mechanism of SWT in treating fibrotic liver injury remains elusive yet and demands urgent clarification.…”

Section: Introductionmentioning

confidence: 99%

Si-Wu-Tang ameliorates fibrotic liver injury via modulating intestinal microbiota and bile acid homeostasis

Xue

Ding

et al. 2021

Chin Med

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Background Fibrotic liver injury is a progressive scarring event, which may permanently affect liver function and progress into devastating end-stage liver diseases due to the absence of effective therapies. Si-Wu-Tang (SWT), a traditional Chinese medicine formula used in clinic to treat gynecological disorders for centuries, has been investigated in recent preliminary findings for its role in alleviating chronic liver diseases. Here we aim to elucidate the therapeutic effects and possible mechanisms of SWT against fibrotic liver injury. Methods UHPLC-MS/MS was performed to investigate the chemical characterization of SWT. After intragastrically administered with carbon tetrachloride (CCl4) every 3 days for 1-week, C57BL/6 mice were orally administered with SWT (5.2, 10.4 and 20.8 g/kg) once daily for 3 weeks along with CCl4 challenge. Liver function was determined by the measurement of serum biomarkers, hematoxylin and eosin (H&E) and Masson’s trichrome staining. Intestinal inflammatory infiltration and the disruption of intestinal barrier were examined by H&E and E-cadherin immunohistochemical staining. The microbial composition of intestinal content was determined by 16S rRNA sequencing. Serum bile acids (BAs) profiling was analyzed by LC–MS/MS. Simultaneously, the expression of genes of interest was determined by qPCR and western blot. Results SWT exhibited remarkable therapeutic effects on CCl4-induced liver fibrosis, as indicated by improved collagen accumulation in livers, intestinal barrier injury and hepatic and intestinal inflammatory response. Results of 16S rRNA sequencing revealed that SWT treatment strikingly restructured intestinal microbiota in fibrotic mice by increasing the relative abundances of Bacteroides and Lachnoclostridium and decreasing the relative abundances of Alistipes and Rikenellaceae. UHPLC-MS/MS data suggested that SWT altered the composition of BAs in circulation as evidenced by increased unconjugated BAs like cholic acid and chenodeoxycholic acid but decreased conjugated BAs including taurocholic acid and taurodeoxycholic acid, compared to that in CCl4 mice. Notably, SWT efficiently improved the imbalance of BA homeostasis in livers caused by CCl4 via activating farnesoid X receptor (FXR)-fibroblast growth factor 15 enterohepatic and FXR-small heterodimer partner hepatic pathways. Conclusion SWT decreased inflammatory response, reconstructed gut microbiota-mediated BA homeostasis as well as activated FXR pathways, which eventually protected against CCl4-induced fibrotic liver injury.

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Tetramethylpyrazine: A promising drug for the treatment of pulmonary hypertension

Cited by 41 publications

References 57 publications

Traditional Herbal Medicine Discovery for the Treatment and Prevention of Pulmonary Arterial Hypertension

Traditional Herbal Medicine Discovery for the Treatment and Prevention of Pulmonary Arterial Hypertension

Ion channels as convergence points in the pathology of pulmonary arterial hypertension

Si-Wu-Tang ameliorates fibrotic liver injury via modulating intestinal microbiota and bile acid homeostasis

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