摘要
OBJECTIVE:To examine Hedan tablet(HDT,荷丹片)'s potential mechanisms in hyperlipidemic rats induced by a high-fat diet(HFD),as well as its regulatory effects and primary active constituents.METHODS:By using ultra-performance liquid chromatography(UPLC)-quadrupole-time-of-flight(QTOF)-tandem mass spectrometry(MS/MS),the components of HDT that can enter the circulatory system were found,aiming to investigate its active constituents with pharmacological effects.Based on network pharmacology approaches,the relevant HDT targets in the therapy of hyperlipidemia were anticipated.The possible mechanism of HDT for hyperlipidemia treatment was verified by in-vivo experiments,and the main active components of HDT for hyperlipidemia treatment were analyzed via in-vitro experiments.RESULTS:UPLC-QTOF-MS/MS identified 30 components of HDT entering the circulatory system,primarily consisting of flavonoids,diterpenoids and alkaloids.The results of a network pharmacology study revealed that 30 active components mostly target 74 genes associated with hyperlipidemia.The primary active ingredients may include quercetin,kaempferol,and epicatechin,and the main gene targets may be tumor necrosis factor(TNF),interleukin-6(IL-6),interleukin 1 beta(IL-1β),etc.The results of animal experiments demonstrated that HDT can significantly regulate the blood lipid level in rats with HFD,improve the degree of inflammatory infiltration in rat liver cells,lower TNF-α,Creactive protein(CRP),IL-6,matrix metalloproteinase 9(MMP9) and malondialdehyde(MDA) levels while raising total superoxide dismutase(T-SOD) level.Meanwhile,HDT can considerably lower the expression of sterol regulatory element-binding transcription factor 2(SREBF2),3-hydroxy-3-methylglutaryl-CoA reductase(HMGCR),and MMP9 while significantly increasing the expression of peroxisome proliferator-activated receptor alpha(PPAR-α) and PPAR-γ.In vitro study confirmed that quercetin and kaempferol could reduce the levels of IL-6,IL1B,MMP9 and HMGCR in the high-fat model of hepatoma G2 cells.CONCLUSIONS:The mechanism by which HDT treats hyperlipidemia involves modification of the lipid metabolism targets such as downregulating SREBF2,HMGCR and MMP9,and upregulating PPAR-α and PPAR-γ,as well as anti-inflammatory and antioxidant actions.This study provides a pharmacological and biological rationale for the use of HDT in clinical hyperlipidemia management.
基金
the National Natural Science Foundation of China:Effects of Hawthorn Leaves Flavonoids on Atherosclerosis Unstable Plaques based on the Mechanism of Liver-gut axis Liver X Receptor (LXR-a)-mediated Iron and Lipid Metabolism Disorders (No.82260794)
the Natural Science Foundation of Jiangxi Province:based on Secreted Phospholipase A2 TypeⅡA (sPLA2-ⅡA) Regulating Lipid Mediated Foam Cell Formation to Explore the Effect and Molecular Mechanism of Hawthorn Leaf Flavonoids on Antiatherosclerosis (No.20212BAB206013)
the Key R&D Program of Jiangxi Province:Research on the Quality Enhancement and Industrialization Technology Improvement of the Lipid-Lowering Traditional Chinese Medicine"Hedan Tablet"(No.20201BBG71005)
Science and Technology Project of Jiangxi Provincial Department of Education:based on the"Phlegm-Stasis"Theory to Explore the Effects and Molecular Mechanisms of Hawthorn Leaves Flavonoids on Improving Iron and Lipid Metabolism Disorders in Atherosclerosis (No.GJJ2203502)。
