Exploring the potential mechanism of Ginkgo biloba leaves in treating hypertension based on network pharmacology and molecular docking
Hypertension is a chronic cardiovascular disease characterized by elevated systemic arterial pressure, which can cause damage to organs such as the heart, brain, and kidneys. At the same time, it will significantly increase the incidence of coronary heart disease in people; The probability of cardiovascular and cerebrovascular diseases such as atherosclerosis. With the intensification of population aging, the incidence of hypertension and its related cardiovascular and cerebrovascular diseases in China is constantly increasing, and the prevention and treatment of hypertension has become a severe challenge for public health in China. From the clinical manifestations of hypertension, traditional Chinese medicine classifies it as a disease category of “liver wind”, “headache”, “dizziness”, etc., and divides it into four syndrome types: liver fire hyperactivity, phlegm dampness stagnation, yin deficiency and yang hyperactivity, and yin and yang deficiency. Treatment is individualized and based on syndrome differentiation. As one of the medicinal parts of Ginkgo biloba, its main active ingredients include flavonoids, terpenoids, and ginkgolic acid compounds, which have various pharmacological effects such as regulating blood lipids, improving cerebral blood flow, inhibiting platelet activity, anti-aging, and anti apoptosis. At present, Ginkgo biloba leaf preparations have become one of the plant medicines for treating cardiovascular and cerebrovascular diseases, and various Ginkgo biloba leaf preparations (such as Ginkgo biloba leaves, Ginkgo biloba ketone esters, Shuxuening injection, Ginkgo biloba Damo injection, etc.) have been applied in clinical practice. At the same time, the combined use of Western medicine and Ginkgo biloba leaf preparations in clinical practice has shown that the antihypertensive effect of the two drugs is better than that of taking antihypertensive drugs alone, but the composition and mechanism of Ginkgo biloba leaf preparations for lowering blood pressure are still unclear. The network pharmacology and the holistic view of traditional Chinese medicine, as well as the principle of multi-component, multi pathway, and multi target synergistic effects of traditional Chinese medicine and its compounds, use the interaction network between drugs, targets, pathways, and diseases to reveal the mechanism of multi molecule drug synergistic effects on diseases. Therefore, this article adopts network pharmacology methods to study the potential mechanism and action network of Ginkgo biloba leaves in treating hypertension, in order to provide theoretical basis for the clinical application and research of Ginkgo biloba leaf preparations.

The risk factors for hypertension are related to various factors such as genetics, age, weight, diet, and lifestyle habits. Traditional Chinese medicine believes that the main elements of syndrome are yin deficiency, qi deficiency, phlegm deficiency, blood deficiency, etc. The liver and kidneys are the main target organs affected by hypertension. Modern medicine believes that the pathogenesis of hypertension is related to renin angiotensin aldosterone system, increased expression of adhesion molecules and cytokines, retention of water and sodium, activation and infiltration of immune cells, inflammatory reaction and formation of oxidative stress. Long term disruption of these systems or functions can disrupt the vascular homeostasis, leading to hypertrophy of vascular smooth muscle cells, dysfunction of vascular relaxation and contraction, increased peripheral resistance, and ultimately resulting in elevated blood pressure.

The research results on the network and potential mechanisms of Ginkgo biloba leaves in treating hypertension indicate that there may be 21 components in Ginkgo biloba leaves that have significant effects on treating hypertension, among which quercetin, kaempferol, luteolin, isorhamnetin, and genistein are key components, and ginkgo esters are synergistic components. Quercetin and kaempferol have significant heart related benefits, such as inhibiting LDL oxidation and acting as non endothelial dependent vasodilators; Reduce adhesion molecules and other inflammatory markers to protect nitric oxide and endothelial function under oxidative stress conditions; It can also prevent neuronal oxidation and inflammatory damage, as well as the anti aggregation effect of platelets. Previous studies have shown that oxidative stress is an important contributing factor to hypertension and plays a crucial role in hypertensive kidney damage. Ginkgolide has antioxidant stress resistance, improves the treatment effect of hypertensive intracerebral hemorrhage, and has a positive effect on the recovery of neurological function in patients with hypertensive intracerebral hemorrhage. At the same time, ginkgolide can also synergistically act with ginkgo flavonoids to effectively eliminate excess oxygen free radicals. In addition, the 190 therapeutic targets of Ginkgo biloba leaves collected in this article indicate that the treatment of hypertension with Ginkgo biloba leaves is not the result of a single component or target, but rather the result of the synergistic effect of multiple components and targets.

From the constructed PPI network, it can be seen that Ginkgo biloba leaves have close interactions with hypertension targets, with 20 core targets mainly related to PTGS2, AKT1, EGFR, TNF, MMP9, MAPK1, STAT3, EGFR, MMP2, IL6, etc. Research has shown that the pathophysiology of cardiovascular disease and the occurrence of hypertension inflammation mechanisms are closely related to the infiltration of immune cells in blood vessels, kidneys, and perivascular adipose tissue. Among them, JUN is one of the components of AP2 (activator protein 2), and AP-1 can induce the expression of inflammatory factors such as interleukin-6 (IL6), interleukin-10 (IL10), tumor necrosis factor (TNF), etc., causing proliferation of vascular endothelial cells and inflammatory cells, increasing vascular resistance and leading to elevated blood pressure. Prostaglandin endogenous peroxidase synthase (PTGS2) can activate the prostacyclin receptor G protein distributed on platelets and endothelial cells, thereby relaxing vascular smooth muscle and inhibiting platelet aggregation, lowering blood pressure. VEGFA is a vascular endothelial growth factor that can induce neovascularization, regulate vascular tension, and play a central role in regulating pathological angiogenesis. Genes related to endothelial dysfunction, such as MAPK1 and AKT1, are involved in the MAPK signaling pathway, promoting endothelial cell proliferation and angiogenesis, and are closely related to the occurrence of hypertension. Flavonoids can effectively inhibit the production of inflammatory factors TNF – α, IL-6, IL-1 β, and VCAM-1, and enhance antioxidant capacity. At the same time, ginkgolides in ginkgo leaves can also reduce the levels of inflammatory factors such as IL-6, TNF – α, MMP9, and improve the inflammatory response. So, Ginkgo biloba leaves are highly likely to have therapeutic effects by controlling inflammatory reactions and improving endothelial dysfunction.

Further GO analysis and KEGG pathway analysis were conducted, and GO enrichment analysis showed that Ginkgo biloba leaves mainly exert their effects on hypertension by positively regulating biological processes such as nitric oxide biosynthesis and smooth muscle cell proliferation, as well as angiogenesis. The KEGG pathway enrichment results showed that hepatitis B, TNF signaling pathway, Toll like receptor signaling pathway, HIL-1 pathway, MAPK signaling pathway, etc. are the main pathways for Ginkgo biloba leaf blood pressure reduction. Research has shown that the HIL-1 α and VEGF signaling pathways are considered important targets for treating diseases related to angiogenesis; HIL can also activate genes that control cellular oxygen homeostasis, including genes related to oxygen consumption, erythropoiesis, angiogenesis, and mitochondrial metabolism. This precisely confirms the impact of GO enrichment analysis on biological processes such as NO biosynthesis and angiogenesis. Meanwhile, corticosteroids can significantly inhibit the TLR4-NF-KB pathway, reduce the release of inflammatory factors, and thus improve ventricular remodeling; Osmanthus extract reduces the release of cytokines induced by cerebral hemorrhage by activating Toll like receptor 4 (TLR4), TNF receptor associated factor 6 (TRAF6), and nuclear transcription factor KB (NF-KB) signaling pathways; Ginkgolide can control inflammation, inhibit endothelial cell apoptosis, and improve tissue blood flow by inhibiting signaling pathways such as IL-1 β and TNF.

In summary, this article systematically analyzes the mechanism of action of Ginkgo biloba leaves in treating hypertension, revealing the potential active ingredients, action networks, and potential mechanisms of action of Ginkgo biloba leaves in treating hypertension. It proves that Ginkgo biloba leaves have the characteristics of multi-component, multi-target, and multi pathway synergistic effects in treating hypertension, providing direction for further analysis of the pharmacological substance basis and mechanism of action research. Further experiments are needed to verify the relationships between relevant pathways in the future.