Abstract
BackgroundGuizhi decoction (GZD), a classical Chinese herbal formula, has been widely used to treat hypertension, but its underlying mechanisms remain elusive. The present study aimed to explore the potential mechanisms and therapeutic effects of GZD on hypertension by integrating network pharmacology and experimental validation.MethodsThe active ingredients and corresponding targets were collected from the Traditional Chinese Medicine Systems Pharmacology database and Analysis Platform (TCMSP). The targets related to hypertension were identified from the CTD, GeneCards, OMIM and Drugbank databases. Multiple networks were constructed to identify the key compounds, hub targets, and main biological processes and pathways of GZD against hypertension. The Surflex-Dock software was used to validate the binding affinity between key targets and their corresponding active compounds. The Dahl salt-sensitive rat model was used to evaluate the therapeutic effects of GZD against hypertension.ResultsA total of 112 active ingredients, 222 targets of GZD and 341 hypertension-related targets were obtained. Furthermore, 56 overlapping targets were identified, five of which were determined as the hub targets for experimental verification, including interleukin 6 (IL-6), C–C motif chemokine 2 (CCL2), IL-1β, matrix metalloproteinase 2 (MMP-2), and MMP-9. Pathway enrichment analysis results indicated that 56 overlapping targets were mainly enriched in several inflammation pathways such as the tumor necrosis factor (TNF) signaling pathway, Toll-like receptor (TLR) signaling pathway and nuclear factor kappa-B (NF-κB) signaling pathway. Molecular docking confirmed that most active compounds of GZD could bind tightly to the key targets. Experimental studies revealed that the administration of GZD improved blood pressure, reduced the area of cardiac fibrosis, and inhibited the expression of IL-6, CCL2, IL-1β, MMP-2 and MMP-9 in rats.ConclusionThe potential mechanisms and therapeutic effects of GZD on hypertension may be attributed to the regulation of cardiac inflammation and fibrosis.
Highlights
Guizhi decoction (GZD), a classical Chinese herbal formula, has been widely used to treat hypertension, but its underlying mechanisms remain elusive
222 targets of active compounds of GZD were obtained from the TCMSP database and the gene names of these targets were collected via the Uniprot database (Additional file 2)
The docking scores and the spatial structure suggested that multiple active compounds of GZD were able to bind tightly to the key targets, which further indicated that the specific therapeutic effect of GZD in the treatment of hypertension, especially for β-sitosterol, kaempferol, and quercetin, were very close to the Vina scores of furosemide and nifedipine. These results indicated that quercetin, β-sitosterol, and Guizhi decoction improves the blood pressure in rats As shown in Fig. 8, no obvious differences were observed in the systolic blood pressure (SBP) between the HS group and GZD group before administration of GZD
Summary
Guizhi decoction (GZD), a classical Chinese herbal formula, has been widely used to treat hypertension, but its underlying mechanisms remain elusive. The present study aimed to explore the potential mechanisms and therapeutic effects of GZD on hypertension by integrating network pharmacology and experimental validation. Hypertension is one of the most common cardiovascular diseases worldwide [1]. It is predicted that more than 1.5 billion people worldwide will suffer from hypertension. The pathological mechanisms of hypertension include the overactivation of the renin–angiotensin–aldosterone system (RAAS) and sympathetic nervous system (SNS), and sodium and water retention [2, 4]. The first-line treatments for hypertension primarily include diuretics, β-blockers, calcium channel blockers, angiotensin-converting enzyme inhibitors, and angiotensin II receptor blockers [5]. It is necessary to develop more feasible and safer therapeutic strategies for the management of hypertension
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