Exploring the mechanism of Huangqi in treating viral myocarditis based on network pharmacology and molecular docking
Viral myocarditis (VMC) is a focal or diffuse inflammatory lesion of the myocardium caused by direct damage to the heart muscle by a virus or an autoimmune inflammatory response. Its clinical manifestations mainly include intestinal or upper respiratory tract infection symptoms before the onset of the disease. Mild patients have no symptoms, while severe cases may present with symptoms such as shock and sudden death. The incidence rate of VMC is about 10-22 per 100000 people. However, there are currently no specific clinical treatment drugs, and antiviral and nutritional cardiomyocyte drugs are mainly used to effectively control the patient’s condition.
Based on the clinical manifestations of VMC, traditional Chinese medicine believes that VMC should be classified as “warm disease”, “chest obstruction”, “palpitations” and other categories. Its illness is caused by the deficiency of human righteous qi and the external transmission of warm and pathogenic toxins; The pathogenesis is due to the invasion of heat and toxins, causing damage to the human body and yin, resulting in blood stasis obstructing the meridians and loss of nourishment for the heart. Patients often exhibit symptoms such as deficiency, stagnation, and stasis. In treatment, it is important to combine stage differentiation and type differentiation, emphasizing the importance of nourishing qi and yin, promoting blood circulation, and removing blood stasis. In recent years, numerous studies have shown that Huangqi is highly effective in treating VMC. Huangqi injection alone or in combination with other drugs is commonly used in clinical practice to treat VMC, and has been widely promoted.
Traditional Chinese medicine Huangqi contains various active ingredients such as Huangqi polysaccharides, Huangqi IV glycosides, Huangqi flavonoids, quercetin, and kaempferol. Modern medical research has shown that Huangqi and its active ingredient monomers (such as Huangqi IV glycoside, Huangqi flavonoids, Huangqi polysaccharides, etc.) have multiple potential mechanisms for treating viral myocarditis, including oxidative stress, immune regulation, inhibition of inflammatory response, regulation of cell apoptosis, etc. However, the detailed mechanism of action is still unclear. This study is based on network pharmacology and molecular docking technology to predict the active ingredients, related targets, and pathways of Astragalus membranaceus in the treatment of viral myocarditis, in order to elucidate its biological processes and mechanisms of action.

 

Huangqi, as a traditional Qi tonifying medicine, has the effects of tonifying the spleen and qi, detoxifying and promoting muscle growth. The different main active ingredients of Huangqi have different effects on the treatment of viral myocarditis, each with its own advantages. In this study, 22 active ingredients of Astragalus membranaceus were included in the discussion, resulting in a total of 505 drug targets and 1116 targets related to VMC. Among them, quercetin, 3,9-di-O-methylnisen pea rosewood phenol, kaempferol, (3R) -3- (2-hydroxy-3,4-dimethoxyphenyl) chrom-7-ol, and berberine have a large number of connected target points and play a key role in the treatment of VMC. Previous studies have shown that quercetin alleviates CVB3 induced myocardial cell injury by activating the PI3K/Akt pathway. In addition, quercetin can also inhibit inflammatory reactions, manifested by decreased levels of IL-1 β, IL-6, and iN-OS. The flavonoid compound kaempferol can inhibit apoptosis of hypoxic cardiomyocytes through the mTOR pathway. And how other components work remains to be studied.
According to the analysis of the “Astragalus membranaceus active ingredient VMC target” network and protein interaction network, there are 97 potential targets that can act on diseases, indicating that Astragalus membranaceus has the characteristics of multi-component and multi-target treatment for VMC. Important target proteins (such as ALB, TP53, AKT1, MAPK3, VEG-FA, CASP3, EGFR, etc.) have different protein types including transcription factors, signal transduction factors, enzymes, transport factors, etc. This suggests that multi-target therapy plays a synergistic role, which also reflects the overall and systemic nature of traditional Chinese medicine in treating diseases. Previous studies have shown that Astragalus membranaceus can significantly reduce the expression level of apoptosis related factor Caspase-3 in myocardial tissue and alleviate the degree of myocardial cell apoptosis. The impact of other factors can serve as a direction for future research.
Cytokines are involved in regulating cellular inflammatory responses. Multiple studies have shown that after treating VMC with Huangqi, the levels of inflammatory cytokines IL-6, IL-8, and TNF – α in the serum are significantly reduced, effectively alleviating the inflammatory response in patients. The activation of the STAT3 (transcription activator 3) signaling pathway induces endogenous protective mechanisms in the myocardium, thereby promoting myocardial vascular growth and slowing down myocardial cell apoptosis. A study has found that Astragalus membranaceus has an impact on STAT3 and its pathway during the treatment of VMC, mainly affecting virus replication, but does not affect the function of normal myocardial cells. In addition, Huangqi can downregulate the expression of Caspase-3 in myocardial tissue to alleviate the degree of myocardial cell apoptosis. The mechanisms of action of other targets are worth further exploration.
Through target GO enrichment analysis, the results suggest that key genes of Astragalus membranaceus located on cellular components such as membrane tissue, transcription factor complexes, and immune synapses may regulate biological processes such as nutrient levels, oxygen levels, cascade reactions, and stress responses by affecting the binding of potential targets to related kinases, cytokine receptors, transcription factors, etc., in order to treat viral myocarditis. The Fas receptor on the surface of target cells can bind to the FasL receptor protein on the membrane surface, which can induce apoptosis of target cells. Liu et al.’s research suggests that Huangqi may exert a protective effect on the myocardium by downregulating the transcription of FasL and Fas genes on the surface of VMC mouse myocardial tissue related cells, thereby reducing the expression of Fas and FasL. Immune synapses may also be very important. Qi et al. have demonstrated that Huangqi injection can activate the immune response of Treg cells, thereby secreting IL-10 and TNF – β, inhibiting the secretion of IL-17 and IL-21 by Th17 cells, and exerting a protective effect on the myocardium. Zhang et al.’s basic research has shown that Astragalus membranaceus saponins (AST) can significantly inhibit the levels of creatine kinase isoenzyme (CK-MB) and lactate dehydrogenase (LDH) in the peripheral blood of mice. Clinical studies have shown that Huangqi can protect the myocardium by inhibiting the activation and diffusion of oxidative stress, reducing myocardial damage. Nutritional conditions and oxygen supply are particularly important for patients with heart dysfunction, suggesting that active ingredients in Astragalus membranaceus may alleviate myocardial injury by improving and regulating the patient’s nutritional and oxygen status. Research has found that when Huangqi inhibits inflammatory response and exerts therapeutic effects on VMC, it mostly downregulates the expression of TNF – α. Zhong et al.’s basic research has shown that treatment with Astragaloside IV significantly reduces myocardial infiltration and necrosis scores in mice, and significantly reduces the apoptosis index of cells around the lesion. This proves that the treatment of VMC with Huangqi may be a multi-target and multi pathway regulatory mechanism.
Based on current research, there are many mechanisms by which Huangqi treats viral myocarditis, which may be related to oxidative stress response, inhibition of inflammatory response, cell apoptosis, immune regulation, and other factors. After KEGG pathway enrichment analysis, it suggests that these mechanisms may be related to signaling pathways such as PI3K Akt, TNF, apoptosis, and Th17 cell differentiation. In addition, there are still some biological processes and pathways not yet involved (such as AGE-RAG signaling pathway, Erb signaling pathway, MAP signaling pathway, relaxin signaling pathway, human cytomegalovirus infection in diabetes complications) to be explored and verified.
Based on network pharmacology, this study elucidated the active ingredients, potential targets, and biological pathways of traditional Chinese medicine Huangqi in treating viral myocarditis. The preliminary research results have revealed the relevant mechanism of action of Huangqi in treating VMC, providing a theoretical basis for further research on its pharmacological mechanism. However, there are still certain shortcomings in this study, as it only relies on existing validated data in the database to predict the pharmacological mechanism of Huangqi in treating VMC, which still needs to be validated through many basic and clinical studies. Therefore, this study aims to provide ideas and references for the mechanism of action of Huangqi in the treatment of viral myocarditis.