Abstract

Introduction

   Leeches are flesh-eating and bloodsucking parasitic worms. They are
   being used as a traditional Chinese medicine for centuries in
   activating blood and dissolving statis, dreging the meridims and tick.
   Hirudin, an active peptide product present in leech, has blood
   anticoagulant property and can assist in the treatment of thrombosis
   and diseases related to blood circulation. The efficacy and potential
   mechanism of action of leeches in such diseases should be further
   explored.

Materials and methods

   First, network pharmacology was used to screen the predicted potential
   targets of the active constituents of leech and AS. The common targets
   of the active constituents of leech and AS were obtained using Venn
   diagram. Further, the drug-active-constituent–target network diagram,
   protein–protein interaction, and GO and KEGG pathway enrichment
   analyses were used to construct the active-constituent–AS
   target–pathway network diagram. Subsequently, the protein–drug molecule
   docking model was drawn. Finally, the results of network pharmacology
   were validated using a mouse model of AS.

Results

   In total, 34 active constituents of leech and 1172 AS-related gene
   targets were selected, took the drug action targets and potential
   disease targets to get the common targets, and took the top 10 of
   degree value as the main active constituents for the treatment of
   atherosclerosis. There were 89 common targets and 12 core targets. The
   main targets included MAPK, EGFR, PIK3CB, etc. Potential regulatory
   pathways included cancer pathways, EGFR tyrosine kinase inhibitor
   resistance, Rap1 signaling pathway, PPAR signaling pathway, PI3K-Akt
   signaling pathway, C-type lectin receptor signaling pathway, and
   AGE-RAGE signaling pathway in diabetic complications. Animal
   experiments using mouse model of AS confirmed that AS plaques were
   smaller after treatment with leeches. SRC level was measured using
   western blotting. Expression of SRC in myocardial tissue was remarkably
   lower in the mice treated with leech than in the mice from model group
   fed on high-fat chow.

Conclusions

   To the best of our knowledge, this is the first study to explore the
   mechanism of action of the active components of leech in AS prevention.
   The active components of leeches play a coordinated role in preventing
   AS through multicomponent, multitarget, and multichannel mechanism of
   action related to inflammatory response, oxidative stress, and lipid
   metabolism. This study provided a reference for subsequent cellular and
   animal experiments.

   Keywords: Network pharmacology, Leech, Atherosclerosis, Molecular
   docking, Plaque stability

Graphical abstract

   [35]Image 1
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1. Introduction

   Leeches are flesh-eating and bloodsucking worms and are used as
   traditional Chinese medicine. They are harsh and fierce, with unique
   effects such as activating blood and dissolving statis, dreging the
   meridims and tick, etc. Leeches play a unique role in the treatment of
   atherosclerosis (AS), and their action cannot be replaced by other
   drugs [[37]1]. According to the theory of “stasis and lipid toxicity,”
   stasis toxicity is the important mechanism of action for the formation
   of vulnerable plaques in AS, and activating blood, resolving stasis and
   toxicity is the basic treatment for stabilizing vulnerable plaques
   [[38]2]. Zhang explored the medication rules of traditional Chinese
   medicine in the treatment of AS. Among the 109 selected literatures,
   almost 20.9% of the references were about drugs for activating blood