Abstract
Background Hyperlipidemia, due to the practice of unhealthy lifestyles of modern people, has been a disturbance to a large portion of population worldwide. Recently, several scholars have turned their attention to Chinese medicine (CM) to seek out a lipid-lowering approach with high efficiency and low toxicity. This study aimed to explore the mechanism of Huatan Jiangzhuo decoction (HTJZD, a prescription of CM) in the treatment of hyperlipidemia and to determine the major regulation pathways and potential key targets involved in the treatment process. Methods Data on the compounds of HTJZD, compound-related targets (C-T), and known disease-related targets (D-T) were collected from databases. The intersection targets (I-T) between C-T and D-T were filtered again to acquire the selected targets (S-T) according to the specific index. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment, as well as network construction, were applied to predict the putative mechanisms of HTJZD in treating hyperlipidemia. Thereafter, an animal experiment was conducted to validate the therapeutic effect of HTJZD. In addition, regulated differentially expressed genes (DEGs) were processed from the RNA sequencing analysis results. Common genes found between regulated DEGs and S-T were analyzed by KEGG pathway enrichment to select the key targets. Lastly, key targets were validated by real-time quantitative reverse transcription PCR (qRT-PCR) analysis. Results A total of 210 S-T were filtered out for enrichment analysis and network construction. The enrichment results showed that HTJZD may exert an effect on hyperlipidemia through the regulation of lipid metabolism and insulin resistance. The networks predict that the therapeutic effect of HTJZD may be based on the composite pharmacological action of these active compounds. The animal experiment results verify that HTJZD can inhibit dyslipidemia in rats with hyperlipidemia, suppress lipid accumulation in the liver, and reverse the expression of 202 DEGs, which presented an opposite trend in the model and HTJZD groups. Six targets were selected from the common targets between 210 S-T and 202 regulated DEGs, and the qRT-PCR results showed that HTJZD could effectively reverse Srebp-1c, Cyp3a9, and Insr mRNA expression (P < 0.01). Conclusion In brief, network pharmacology predicted that HTJZD exerts a therapeutic effect on hyperlipidemia. The animal experimental results confirmed that HTJZD suppressed the pathological process induced by hyperlipidemia by regulating the expression of targets involved in lipid metabolism and insulin resistance.
Highlights
Hyperlipidemia is a condition wherein lipid-glucose metabolic disruption occurs, and it is mainly characterized by the derangements of lipoproteins circulating in the blood, such as high levels of total cholesterol (TC), triglyceride (TG) and/ or low-density lipoprotein cholesterol (LDL-c), or aberrant declined level of low-density lipoprotein cholesterol (HDLc) [1, 2]
282 intersection targets (I-T) (Supplemental Table 2) were found in compound-related targets (C-T) and diseaserelated targets (D-T) after the intersection performed. en, 282 I-T were put into STRING to determine the interaction relationship among the targets, and lastly 210 selected targets (S-T) (Supplemental Table 2) were identified according to the criteria of combined score of ≥0.95 in the node interaction index
We found that Gene ontology (GO) annotations and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichments showed a better view of the connections between targets and the underlying therapeutic mechanisms of Huatan Jiangzhuo decoction (HTJZD)
Summary
Hyperlipidemia is a condition wherein lipid-glucose metabolic disruption occurs, and it is mainly characterized by the derangements of lipoproteins circulating in the blood, such as high levels of total cholesterol (TC), triglyceride (TG) and/ or low-density lipoprotein cholesterol (LDL-c), or aberrant declined level of low-density lipoprotein cholesterol (HDLc) [1, 2]. Accompanying the favorable effects of reducing cholesterol biosynthesis, statins cause adverse effects, such as myalgia, hepatic and renal toxicity, and cognitive disorder [8] It seems that the Pcsk inhibitor, a new agent, is beneficial as it lowers the LDL levels [9]. E enrichment results showed that HTJZD may exert an effect on hyperlipidemia through the regulation of lipid metabolism and insulin resistance. Six targets were selected from the common targets between 210 S-Tand 202 regulated DEGs, and the qRT-PCR results showed that HTJZD could effectively reverse Srebp-1c, Cyp3a9, and Insr mRNA expression (P < 0.01). E animal experimental results confirmed that HTJZD suppressed the pathological process induced by hyperlipidemia by regulating the expression of targets involved in lipid metabolism and insulin resistance Network pharmacology predicted that HTJZD exerts a therapeutic effect on hyperlipidemia. e animal experimental results confirmed that HTJZD suppressed the pathological process induced by hyperlipidemia by regulating the expression of targets involved in lipid metabolism and insulin resistance
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