Pharmacological effects of bioactive agents in earthworm extract: A comprehensive review

Abstract

This review compiles information from the literature on the chemical composition, pharmacological effects, and molecular mechanisms of earthworm extract (EE) and suggests possibilities for clinical translation of EE. We also consider future trends and concerns in this domain. We summarize the bioactive components of EE, including G-90, lysenin, lumbrokinase, antimicrobial peptides, earthworm serine protease (ESP), and polyphenols, and detail the antitumor, antithrombotic, antiviral, antibacterial, anti-inflammatory, analgesic, antioxidant, wound-healing, antifibrotic, and hypoglycemic activities and mechanisms of action of EE based on existing in vitro and in vivo studies. We further propose the potential of EE for clinical translation in anticancer and lipid-modifying therapies, and its promise as source of a novel agent for wound healing and resistance to antibiotic tolerance. The earthworm enzyme lumbrokinase embodies highly effective anticoagulant and thrombolytic properties and has the advantage of not causing bleeding phenomena due to hyperfibrinolysis. Its antifibrotic properties can reduce the excessive accumulation of extracellular matrix. The glycolipoprotein extract G-90 can effectively scavenge reactive oxygen groups and protect cellular tissues from oxidative damage. Earthworms have evolved a well-developed defense mechanism to fight against microbial infections, and the bioactive agents in EE have shown good antibacterial, fungal, and viral properties in in vitro and in vivo experiments and can alleviate inflammatory responses caused by infections, effectively reducing pain. Recent studies have also highlighted the role of EE in lowering blood glucose. EE shows high medicinal value and is expected to be a source of many bioactive compounds.

Keywords: antithrombotic; antitumor; bioactive agent; earthworm extract; pharmacological effects.

FIGURE 1

Bioactive components and classification of EE.

FIGURE 2

Mechanism of platelet‐induced thrombosis. (A) Under physiological conditions, vascular endothelial cells synthesize and release PGI2, NO, and ADPase to inhibit platelet adhesion. When the vascular endothelium is injured, subendothelial collagen is exposed, which mediates the binding of subendothelial collagen to platelets via vWF. Vascular endothelial cell injury also releases tissue factor (TF), which initiates the exogenous coagulation process and activates thrombinogen to thrombin. (B) Activated platelets further release ADP and TXA2 to promote more platelet aggregation, and fibrinogen is hydrolyzed to fibrin monomer by thrombin. (C) Fibrin nets platelets and red blood cells to form platelet thrombi.

FIGURE 3

EE blocks platelet adhesion and activation at the site of vascular injury. After vascular injury, many subendothelial matrix proteins are exposed to blood, including von Willebrand factor (vWF), fibrillar collagens, fibronectin and laminin, which facilitate platelet adhesion by binding to specific receptors on platelets; vWF binds the platelet GPIb‐V‐IX complex, and collagens bind the glycoprotein receptor GPVI and integrin α2β1. Once firmly adhered, platelets undergo a series of morphological and biochemical changes that induce activation of integrin αIIbβ3, leading to high‐affinity interactions with adhesion proteins, including vWF, fibrinogen, and fibronectin, and these adhesion interactions are essential for platelets to form stable aggregates with other activated platelets and promote thrombus growth. Activated platelets release or locally produce soluble agonists, including ADP, TXA2, and thrombin, which activate specific G protein‐coupled receptors on the platelet surface, stimulate intracellular signaling events, induce cytosolic calcium mobilization, and trigger further platelet activation as well as thrombus formation via autocrine or paracrine secretion. A variety of substances in EE can inhibit the aggregation of malignant platelets by blocking PAR‐1/PAR‐4, P2Y12, COX‐1, vWF, calcium mobilization, etc., thereby achieving antiplatelet aggregation effect.

FIGURE 4

Antibacterial mechanisms of EE. The antibacterial mechanisms of active substances in EE, including lumbricin‐1, OEP3121, PP‐1, lumbricin‐PG, lysenin, and AAF, are classified into five main categories. Target the bacterial cell wall and change the cell morphology. Target the cell membrane to increase membrane permeability. For example, lysenin specifically binds to sphingomyelin (SM) on the cell membrane to form oligomers which subsequently form pores, which in turn lyses the cell. Inhibition of DNA replication. Inhibition of bacterial transcription. Inhibition of bacterial translation. Interference with bacterial metabolic processes, such as affecting enzymes necessary for bacterial growth and damaging protein structure.

FIGURE 5

Anti‐inflammatory mechanism of protein‐free Guang‐Pheretima decoction (PF‐GPD). PF‐GPD significantly inhibits IκB degradation and NF‐κB translocation in LPS‐stimulated macrophages, downregulates iNOS and COX‐2, reduces the production of inflammatory mediators (NO, PGE2 and TNF‐α) and various inflammatory cytokines, and attenuates the infiltration of inflammatory factors.