Exploration of the potential mechanism of Banxia Xiexin Decoction for the effects on TNBS-induced ulcerative colitis rats with the assistance of network pharmacology analysis
Graphical abstract
Introduction
Ulcerative colitis (UC), an inflammatory bowel disease with unknown etiology, mainly invades the rectum and colon mucosa and submucosa. Traditionally, UC has been viewed as a Western disease. The incidence and prevalence of UC has stabilized in Western Europe and North America (affecting 0.2% of the population), and the incidence continues to rise in newly industrialized countries. The highest incidence of ulcerative colitis is in Northern Europe (24.3 per 100,000), Canada (19.2 per 100,000) and Australia (17.4 per 100,000). The countries with the highest prevalence rates are Europe (505 per 100,000), Canada (248 per 100,000) and the United States (214 per 100,000) (Ungaro et al., 2017). In addition, epidemiological data from the last four decades have shown 1.5-fold to almost 20-fold increases in the incidence and prevalence of UC in some Asian countries, although prevalence remains generally lower than in the West (Wei et al., 2021). Apart from affecting the quality of life and work efficiency, UC also has the risk of causing colorectal cancer. And there are many risks that could be induced in the drug treatment on moderate to severe UC which may lead to serious opportunistic infections and malignant tumors. Surgical treatment may cause serious complications as well (Singh et al., 2020).
The main clinical manifestation of UC is gastrointestinal symptoms, such as diarrhea, abdominal pain, and mucopurulent bloody stool. Long-term inflammation can cause many complications, and colorectal cancer entails the most serious consequences. Therefore, UC is considered to be one of the precancerous lesions of colon cancer (Yashiro, 2014). The current treatment of UC mainly includes drug and surgical treatments (Xue et al., 2017). In the clinical treatment of UC, aminosalicylic acid and glucocorticoid drugs, such as mesalazine (Yorulmaz et al., 2019), budesonide (Abdalla and Herfarth, 2016) are mostly used. Many new drugs have been developed and applied to treat UC (Alasmary et al., 2018), but most of them can hardly cure the disease. As the mechanism of the disease remains unclear and no cure has been determined for UC, this disease has been listed by WHO as one of the “refractory diseases in the world.” As a matter of fact, although chemical medicines have a quick effect on UC, more side effects and incomplete treatments are rampant (Gilca et al., 2017; Huang et al., 2018).
In recent years, an increasing number of traditional Chinese medicines (TCMs) have been proven to offer various benefits, such as anti-inflammatory, anti-oxidant, and anti-tumor effects, with relatively high safety and less side effects. A large number of studies have involved the treatment of UC with TCM, in which Pinelliae Decoction for Purging Stomach-Fire (called Banxia Xiexin Decoction in Chinese), is a typical example. Banxia Xiexin Decoction (BXD), originally recorded in “Treatise on Febrile Diseases” (Shang Han Lun), is a classical TCM prescription composed of seven medicinal herbs, including Pinelliae Rhizoma (Ban Xia), Coptidis Rhizoma (Huang Lian), Scutellariae Radix (Huang Qin), Zingiberis Rhizoma (Gan Jiang), Ginseng Radix (Ren Shen), Jujubae Fructus (Da Zao) and Glycyrrhizae Radix (Gan Cao). In TCM theory, the composition of BXD represents the harmony between acrid-opening and bitter down-bearing features. Previous studies have shown that BXD has anti-inflammatory and antioxidant effects (Chen et al., 2015), and has a protective effect on mice with UC (Wang et al., 2014). Clinically, BXD has also been widely used in treating patients with UC (Zhang, 2016; Zhu et al., 2016), with positive effects and high safety, suggesting that BXD can relieve the pain of UC patients and effectively improve their physical and mental conditions. However, the decoction method in modern clinical practice has commonly been used differently from the ancient ones recorded in the original document (Shang Han Lun). Thus, investigating the difference in the pharmacological effects brought by different decoction methods is an interesting endeavor, which could provide a reference for the modern application of traditional TCM classical prescription.
Network pharmacology is a novel method for exploring the therapeutic effects, targets of Chinese medicines (medicinal herbs or compound prescriptions) and bioactive compounds. Its concept of “multi-targets, multi-components” is most suitable for exploring the therapeutic effects of Chinese medicines at the molecular level (Lv et al., 2020; Wang et al., 2020). Network pharmacology has facilitated the development of evidence-based medicine and herbal-based drug discovery, which differs greatly from the traditional research approach. In recent years, network pharmacology analyses have been increasingly employed to reveal the potential action mechanism of single-component or compounds of Chinese medicinal preparations, including Ganghuo Kanggan Decoction (Lai et al., 2020), Toujie Quwen Granules (Ye et al., 2020), and even the effective prescriptions against COVID-19, such as Maxing Shigan Decoction (Li et al., 2020) and Lianhua Qingwen capsule (Xia et al., 2020).
On the basis of the clinical practice in China, we investigated BXD's in-vivo pharmacological effects on experimental TNBS-induced UC rats, with the extracts prepared using the ancient extraction method and modern extraction method. Then, network pharmacology analysis was used to investigate the interaction between the active components of BXD, their potential targets and UC targets. The results of the combined in-vivo experiments and virtual network pharmacology analysis were used as basis to determine the key components and possible mechanisms related to UC.
Section snippets
Drugs and reagents
Salicylazosulfapyridine (SASP, purity: 97%, lot: A0322A) was purchased from Dalian Meilun Biological Technology Co., Ltd. (Dalian, China). Pentobarbital sodium and TNBS were purchased from Sigma-Aldrich Co., Ltd. (Shanghai, China). The cytokine enzyme-linked immunosorbent assay kits for interleukin IL-4, IL-10, IL-1β, IL-6, and TNF-α were purchased from Raybiotech (USA) and Biolegend (USA). The prepared slices of crude herbs used in BXD, including Pinelliae Rhizoma [Ban Xia, Pinellia ternate
DAI and colon weight index
With respect to the DAI score of the control group, the DAI score of the model group was significantly increased (P < 0.01) after TNBS modeling. The colon weight index of the rats in model group also increased (P < 0.05) relative to that in the control group. The findings indicated that the TNBS-induced models had been successfully established, with an increase in both DAI and colon weight index. The DAI scores of all treatment groups decreased significantly with respect to the model group (P
Discussion
In clinical practice, many TCM compounds are used to treat UC, including Huangkui Lianchang Decoction, Jianpi Qingchang Decoction (He et al., 2019; Zheng et al., 2017), and BXD. In particular, BXD is also used to treat various gastrointestinal diseases, including chronic atrophic gastritis (Ji et al., 2020), peptic ulcers (Chen et al., 2018), diarrhea (Lu, H. et al., 2018), and colon cancer (Li et al., 2019), yielding remarkable effects. The recent studies (Cui et al., 2018; Liang et al., 2019)
Conclusions
This study evaluated the effects of two BXD extracts on TNBS-induced rats, prepared with the ancient and modern decoction methods. The results showed that both BXD-AED (-L, -M, –H groups) and BXD-MED (-L, -M, –H groups) might alleviate the severity of UC with different degrees, indicated by the evaluations of DAI, colon weight index, macroscopic and histological evaluation of colon damage, or the inflammatory cytokine levels. BXD-AED (-L group) performed better compared with BXD-MED (-H group)
Declaration of competing interest
The authors report no conflicts of interest in this work.
Acknowledgements
The study was financially supported by grants from National Natural Science Foundation of China (82003962) and Science and Technology Commission of Shanghai Municipality (18401931400).
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