Ginsenosides: potential therapeutic source for fibrosis-associated human diseases

Abstract

Tissue fibrosis is an eventual pathologic change of numerous chronic illnesses, which is characterized by resident fibroblasts differentiation into myofibroblasts during inflammation, coupled with excessive extracellular matrix deposition in tissues, ultimately leading to failure of normal organ function. Now, there are many mechanistic insights into the pathogenesis of tissue fibrosis, which facilitate the discovery of effective antifibrotic drugs. Moreover, many chronic diseases remain a significant clinical unmet need. For the past five years, many research works have undoubtedly addressed the functional dependency of ginsenosides in different types of fibrosis and the successful remission in various animal models treated with ginsenosides. Caveolin-1, interleukin, thrombospondin-1 (TSP-1), liver X receptors (LXRs), Nrf2, microRNA-27b, PPARδ-STAT3, liver kinase B1 (LKB1)-AMPK, and TGF-β1/Smads are potential therapy targeting using ginsenosides. Ginsenosides can play a targeting role and suppress chronic inflammatory response, collagen deposition, and epithelial-mesenchymal transition (EMT), as well as myofibroblast activation to attenuate fibrosis. In this report, our aim was to focus on the therapeutic prospects of ginsenosides in fibrosis-related human diseases making use of results acquired from various animal models. These findings should provide important therapeutic clues and strategies for the exploration of new drugs for fibrosis treatment.

Keywords: Chinese herb medicines; Fibrosis; Ginseng; Ginsenosides; Therapeutics.

Fig. 1

The cellular and molecular mechanisms of fibrosis and anti-fibrotic property of ginsenosides. Once an injury occurs in an organ, impaired epithelial and/or endothelial cells secrete chemokines and growth factors. Macrophages and monocytes are recruited and activated, which further result in the release of cytokines and chemokines, and further induce fibroblast activation. Activated fibroblasts transform into myofibroblasts and actively synthesize ECM. Once chronic injury, inflammation, and necrosis occur, myofibroblasts are persistently activated and excessive ECM is deposited, finally leading to fibrosis formation. Ginsenosides negatively regulate fibrosis. Red blunted line: an inhibitory effect of ginsenosides on secretion of proinflammatory cytokines from immune cells or injured tissue; blue blunted line: an inhibitory effect of ginsenosides on myofibroblast differentiation, proliferation, and activation; green blunted line: an inhibitory effect of ginsenosides on excessive ECM accumulation and fibrosis formation. Abbreviation: EMT, epithelial–mesenchymal transition; ECM, extracellular matrix.

Fig. 2

Summary and functional network target analysis of ginsenosides, which exert significant anti-fibrotic effects on heart, liver, kidney, and lung via multiple links across regulatory mechanisms and multi-target effects. Abbreviation: VEGF, vascular endothelial growth factor; HIF-1, hypoxia inducible factor-1; MAPK, mitogen-activated protein kinase; GLUT4, glucose transporter type 4; TGF-β1, transforming growth factor beta 1; ERK, extracellular signal-regulated kinase; PPARδ, peroxisome proliferator-activated receptor δ; STAT3, signal transducer and activator of transcription 3; CCN2, connective tissue growth factor; FN, fibronectin; ER, endoplasmic reticulum; JNK, c-Jun N-terminal kinase; EndoMT, endothelial–mesenchymal transition; PI3K, phosphoinositide 3-kinase; EMT, epithelial–mesenchymal transition; SIRT1, sirtuin-1; NF-κB, nuclear factor kappa-light-chain-enhancer of activated B cells; GRP78, glucose-regulated protein 78; CHOP, CCAAT/enhancer-binding protein homologous protein; TSP-1, thrombospondin-1; HO-1, heme oxygenase; TGF-β1R, transforming growth factor beta 1 receptor; TNF-α, tumor necrosis factor α; IL-6, interleukin 6; HSC, hepatic stellate cell; PDGF, platelet-derived growth factor; ECM, extracellular matrix; ROS, reactive oxygen species; LX25Rs, liver X 25 receptors; FXR, farnesoid X receptor; P2X7R, P2X7 receptor; NLRP3, NOD-, LRR- and pyrin domain-containing protein 3; Nrf2, nuclear respiratory factor 2; AMPK, AMP-activated protein kinase; LKB1, liver kinase B1. (↓), downregulation or inhibition; (↑), upregulation or activation.

Fig. 3

Overall protection of ginsenosides against fibrosis in various organs and tissues. Collectively, ginsenosides exert comprehensive protective effects against fibrosis in various organs and tissues, including heart, liver, lung, kidney, etc. These findings demonstrate that ginsenosides may contribute to protection and recovery of multiple organs and tissues after injury. CCl4, carbon tetrachloride; COPD: chronic obstructive pulmonary disease; TGF-β1: transforming growth factor beta 1.