Hypertension is a clinical syndrome characterized by increased systemic arterial blood pressure, which may be accompanied by functional or organic damage of the heart, brain, kidney, and other organs [Hypertension was defined as systolic blood pressure (SBP) ≥ 140 mmHg or diastolic blood pressure (DBP) ≥ 90 mmHg] (Messerli et al., 2007). Hypertension is the leading preventable risk factor for cardiovascular disease and all-cause mortality worldwide (Mills et al., 2020). The prevalence of hypertension will gradually increase with urbanization, population aging, and related lifestyle changes such as unhealthy diets and physical inactivity. In China, the prevalence of hypertension among people over 18 years old is 23.2%, which is about 240 million (Zhao et al., 2019). A 2019 study found that only 30% of people with hypertension were treated with medications, and only 10% had their blood pressure controlled below threshold levels for hypertension. High-income countries generally do better, but most have lower treatment and control rates than developed countries (Geldsetzer et al., 2019). Therefore, prevention and treatment of hypertension are urgent.

Over the past half-century, tremendous progress has been made in the pharmacological treatment of hypertension, but some shortcomings remain (adverse effects, drug resistance, long-term use, economic burden, etc.) (Bramlage and Hasford, 2009; Albasri et al., 2021). Hypertension belongs to the category of headache and vertigo in traditional Chinese medicine (TCM). TCM has a long history in the treatment of hypertension and has accumulated a lot of experience in pre-hypertension, hypertension, obese hypertension, and resistant hypertension (Xiong et al., 2013; Xiong et al., 2015; Zhang et al., 2020). Banxia Baizhu Tianma Decoction (BXD) is a TCM formula that originated from the Qing Dynasty. BXD is composed of 6 types of botanical drugs, including Pinellia ternata (Thunb.) Makino [Araceae] (Banxia), Atractylodes macrocephala Koidz. [Asteraceae] (Baizhu), Citrus × aurantium L. [Rutaceae] (Chenpi), Glycyrrhiza uralensis Fisch. ex DC. [Fabaceae] (Gancao), Gastrodia elata Blume [Orchidaceae] (Tianma), Wolfiporia cocos (F.A. Wolf) Ryvarden & Gilb. 1984 (Fulin). BXD has the effects of eliminating dampness and phlegm, dispelling pathogenic wind and eliminating phlegm and is widely used in hypertension and its complications (Xiong et al., 2012), however, there is a lack of high-quality, high-level evidence to further confirm its clinical efficacy. Currently, the active ingredients from BXD have been shown to have anti-inflammatory, antioxidant, vasodilator, and calcium ion regulation effects (Tan et al., 2018; Xu et al., 2022), however, the mechanism of BXD in improving hypertension has not been clarified. Network pharmacology is a new subject based on systems biology and bioinformatics, which can elucidate the mechanism of drug action at the molecular level (Xiao et al., 2021). TCM network pharmacology approach provides a new research paradigm for translating TCM from an experience-based medicine to an evidence-based medicine system, which will accelerate botanical drug discovery, and improve current drug discovery strategies (Luo et al., 2020). In this study, we aimed to validate the efficacy of BXD in hypertensive patients and to explore the underlying molecular and cellular mechanisms from network pharmacology perspective.

This study was conducted and reported according to the guidelines of Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) (Liberati et al., 2009). The study protocol (CRD42022353666) was registered in the PROSPERO (https://www.crd.york.ac.uk/prospero/).

To the best of our knowledge, this is the first article that integrates meta-analysis and network pharmacology to evaluate the efficacy and potential pharmacological mechanisms of BXD in the treatment of hypertension. This article reviews 23 intervention studies of BXD combined with conventional treatment in patients with hypertension, aiming to reveal the clinical effects of BXD. The meta-analysis found that compared with conventional treatment, combined BXD treatment was beneficial to improve clinical efficacy rate, blood pressure, blood lipids, Hcy, endothelial function, and inflammation. Notably, the combined treatment with BXD was effective in improving TCM symptoms which were important for improving the quality of life of patients. The treatment of hypertension should not only lower blood pressure but also improve the patient’s symptoms. According to TCM theory, the appearance of symptoms is a response to the imbalance of the internal environment of the body. Through the treatment of BXD, the internal environment of the body can be changed to improve the disease. In addition, BXD is safe and has no obvious adverse reactions. In general, BXD can be used as a complementary and alternative therapy for patients with hypertension on the premise of TCM syndrome differentiation.

Unfortunately, the overall quality of this study was not high. The methodological quality of RCTs was low, and the blinding, selective reporting of results and other biases were not described. In addition, the sample size of these RCTs was small, and they were all Chinese studies, and they were positive publications, which suggested a significant publication bias.

The pathological mechanism of hypertension is associated with endothelial dysfunction, increased vasoconstriction, and vascular changes characterized by arterial remodeling. The sympathetic nervous system, the renin-angiotensin-aldosterone system, and the immune system are all involved in the pathogenesis of hypertension (Coffman, 2011; Touyz et al., 2018). Using network pharmacology, we predicted the molecular mechanism of BXD against hypertension. The results showed that the key of BXD active ingredients including naringenin, 16 alpha-Hydroxydehydrotrametenolic acid, poricoic acid C, eburicoic acid, and licochalcone B. Naringenin is a flavanone, aglycone of naringin, exhibits a plethora of pharmacological properties. Studies have shown that naringenin exerts antihypertensive effects by attenuating the MCR/ACE/KIM-1 pathway (Oyagbemi et al., 2020). Recently, Liu et al. found that naringenin can reduce weight, fat, and blood pressure in obesity-associated hypertension rats, and the mechanism is related to the regulation of lipid disorders and oxidative stress (Liu et al., 2022). Eburicoic acid is present in the polyporus. Eburicoic acid has therapeutic potential for hyperlipidemia because it reduces adipose expression levels of lipogenic FAS and PPARγ, resulting in reduced lipolipid accumulation (Lin et al., 2017). Licochalcone B is a flavonoid active ingredient found in Glycyrrhiza uralensis Fisch. ex DC. [Fabaceae], which has a strong anti-inflammatory, antioxidant capacity, and can inhibit the production of NO, IL-6, and PGE2 in LPS-induced macrophage cells (Fu et al., 2013). Recent studies have shown that licochalcone B is also a specific NLRP3 (Li X et al., 2022). In conclusion, the active ingredients of BXD have potential pharmacological effects, and the beneficial effects of the active ingredients of BXD will be gradually explored with the development of technology.

In addition, we also found that the key antihypertensive targets of BXD were AKT1, NOS3, ACE, PPARG, TNF, and PTGS2. AKT regulates cell proliferation and growth and is involved in cellular processes including apoptosis and glucose metabolism. A study showed that AKT regulated endothelial function in SHR rats (Iaccarino et al., 2004). Cid-Soto et al. investigated the association of the eighth single nucleotide polymorphism in the AKT1 gene with different metabolic traits and found that AKT1 was associated with hypertension in Mestizos (Cid-Soto et al., 2018). NOS3 is important for vasodilation and heart rate (eNOS encoded by the NOS3), and eNOS knockout causes an increase in blood pressure (Shesely et al., 1996). Targeted disruption of the NOS gene in mice has become a useful tool to study cardiovascular endothelial dysfunction, response to vascular injury, and ischemia-reperfusion or atherosclerosis (Rochette et al., 2013). PPARG is a transcription factor that plays an important role in adipocyte differentiation, which is closely related to cardiometabolic diseases. A meta-analysis suggested that PPARG gene polymorphisms may be associated with the risk of hypertension (Cai et al., 2017). Similarly, Li et al. found that PPARG may also be involved in folic acid treatment of H-type hypertension (Liang et al., 2022). Subsequently, we performed validation by molecular docking and the results showed good affinity of the ligand and receptor. In addition, the possibility of combining targets and ingredients was further demonstrated by the literature review. For example, Liao et al. (2014) found demonstrated that naringenin could act by down-regulating AKT, and similarly, Zhang et al. (2015) found that naringenin inhibited the PI3K/AKT pathway, which in turn improved left ventricular function in pressure overload mice. Furthermore, it has been shown that naringenin treatment restored the impaired endothelium-dependent vasodilation by significantly increasing eNOS activity and NO levels. It is undeniable that the results of molecular docking still need to be verified by more experiments (Qin et al., 2016).

Finally, we also performed gene enrichment analysis for these targets. We found that these genes were mainly enriched in HIF-1 signaling pathway, fluid shear stress and atherosclerosis, calcium signaling pathway, cGMP-PKG signaling pathway. HIF-1 signaling pathway regulates oxygen homeostasis and plays an important role in the circulatory system. Evidence suggested that transcriptional changes in HIFs are an important molecular mechanism of hypertension (Semenza, 2014). Studies from Cowburn et al. found that the balance between HIF-1α and HIF-2α expression is a potential mechanism for the body to control blood pressure. They found that HIFs modulate macrophage production of NO via iNOS/NOS2 and arginase 1 (Takeda et al., 2010; Cowburn et al., 2013). Intracellular calcium signaling plays a crucial role in cardiovascular activity. The production of endothelium-derived vasoactive factors and the activation of endothelial potassium channels require elevated intracellular Ca²⁺levels. Disruption of Ca²⁺signaling circuits may contribute to endothelial dysfunction in hypertension (Sonkusare et al., 2014; Wilson et al., 2019). In summary, the above evidence suggested that BXD has the characteristics of regulating multiple pathways and multiple targets.

In conclusion, meta-analysis indicated that BXD combined with conventional treatment for hypertension is effective and safe. BXD has the characteristics of multi-pathway, multi-component, and multi-target in the treatment of hypertension. The antihypertensive targets of BXD may be AKT1, NOS3, ACE, and PPARG. The antihypertensive active ingredients of BXD may be naringenin, poricoic acid C, eburicoic acid, and licochalcone B. However, the evidence of BXD for hypertension should be carefully interpreted due to the low methodological quality, small sample size, limited number of trials, and other unidentified risks of bias. The efficacy and safety of BXD for hypertension still need to be further proved by high-quality clinical and basic studies.