Molecular mechanism and research progress on pharmacology of traditional Chinese medicine in liver injury

Figures & data

Table 1. Comparison of various types of liver injury. (A summary and comparison of all kind of major models experimental models of liver injury, including type, model, key index, molecular mechanism, advantages, and disadvantages.)

Type	Model	Key index	Molecular mechanism	Advantages	Disadvantages
CCl4	40%–50% CCl4 vegetable oil solution	ALT, AST, TNF-α, TLR, TGF-β, IL, NF-κB	1. Inflammation 2. Oxidative stress 3. Hepatic fibrosis 4. Mitochondrial pathway 5. Apoptosis	1. Good repeatability 2. Economics	1. High mortality 2. Poisonous
d-GalN	d-GalN solution	ALT, AST、 GSH, TNF-α, TLR, IL, NF-κB	1. Inflammation 2. Oxidative stress 3. Metabolic disorder 4. Necrosis 5. Apoptosis	1. Does not affect other organs 2. A better model for evaluating therapeutic efficacy of viral hepatitis	Expensive
ANIT	ANIT olive oil solution	ALT, AST, SOD, GSH, IL, NADPH	1. Inflammation 2. Hepatotoxicity 3. Cholestasis Necrosis	1. Simple and easy 2. Good reproducibility	Expensive
DMN	1% DMN solution	ALT, AST, TNF-α, TLR, TGF-β, α-SMA	1. Inflammation 2. Hepatic fibrosis 3. Apoptosis	1. A good model for studying hepatic fibrosis 2. The rate of hepatic fibrosis is high and relatively stable after formation	1. More toxic 2. Volatile Excreta contain poisons and pollute the environment
TAA	TAA solution	ALT, AST, NO, SOD, TNF-α, IL, NF-κB	1. Metabolic disorder 2. Enterogenous toxicemia 3. Apoptosis 4. Necrosis	1. Low mortality 2. High success rate	Expensive
ConA	ConA solution	ALT, AST, TNF-α, IL, NF-κB, NLRP3	1. Inflammation 2. Apoptosis 3. Necrosis	1. Simple operation 2. No pre sensitization is required	There is no viral replication and sustained injury to the liver parenchyma
BCG/LPS	BCG/LPS normal saline solution	ALT, AST, NO, TNF-α, TGF-β, IL, NF-κB	1. Sensitization 2. Hepatocellular damage	1. Short molding time 2. Simple and convenient	Pre-sensitized with BCG
d-GalN/LPS	d-GalN/LPS solution	ALT, AST, NO, TNF-α, TGF-β, IL, NF-κB	1. Metabolic block 2. Protein synthesis 3. Hepatocyte DNA fracture and degradation 4. Necrosis	It is a good model for endotoxin-induced liver injury	Pre-sensitized with d-GalN
Alcoholic	White spirit	ALT, AST, SOD, TNF-α, IL, GSH, NF-κB	1. Inflammation 2. Oxidative stress 3. Hepatic fibrosis Mitochondrial 4. Pathway 5. Necrosis 6. Apoptosis	Stable and reliable	1. Long molding time 2. Frequent gastric lavage is more complicated
APAP	APAP normal saline solution	ALT, AST, NO, SOD, TNF-α, IL, GSH, NF-κB	1. Inflammation 2. JNK pathway 3. Necrosis	Very sensitive to mice	Insensitive to rats
INH/RIF	INH/RIF solution	ALT, AST, GSH, MDA	1. Inflammation 2. Cholestasis 3. Metabolic disorder 4. Necrosis	Stable	Expensive

Table 2. A summary of the effect of traditional Chinese medicine on liver injury. (This is an overview of liver injury treated by Chinese medicine by the end of May 2018, including the name of herb or compound, parts or solvent, liver injury model, mechanism of action, and reference.)

Name of herb or compound	Parts or Solvent	Liver injury model	Experiment	Mechanism of action	Reference
Aconitum carmichaelii Debeaux	Aqueous extract	d-Gal-N	vivo	Inhibited inflammatory reaction, apoptosis and promoted liver tissue regeneration in the acute liver failure rats.	Luo J et al. 2016. Aqueous extract from Aconitum carmichaelii Debeaux reduces liver injury in rats via regulation of HMGB1/TLR4/ NF-ΚB/ caspase-3 and PCNA signaling pathways. J Ethnopharmacol.
Acremoniumterricola milleretal mycelium	Aqueous extract	CCl4	vivo	Scavenge free radicals, decrease the level of TGF-β1 and block TGF-β/Smad signaling pathway.	Tian X et al. 2011. Effects and Mechanisms of Acremoniumterricola milleretal mycelium on Liver Fibrosis Induced by Carbon Tetrachloride in Rats. The American Journal of Chinese Medicine.
Aesculus hippocastanum	Aqueous extract	ConA	vivo	Significantly protect the Con A-induced acute liver injury in mice via inhibition of ROS and JNK pathway.	Wu SJ et al. 2017. The hepatoprotective effect of Aesculus hippocastanum seed extract against concanavalin A-induced acute liver injury in mice via inhibition of ROS and JNK pathway. Chinese Pharmacological Bulletin
Antrodia camphorate Zang & Su	Methanol extract	LPS	vivo	Utilize the NF-κB and MAPKs pathways and the regulation of SOD activity to attenuate LPS-induced nonspecific pulmonary inflammation	Huang GJ et. 2014. Methanol extract of Antrodia camphorata protects against lipopolysaccharide-induced acute lung injury by suppressing NF-κB and MAPK pathways in mice. Journal of Agricultural and Food Chemistry.
Antrosterol	Antrodia camphorata synonym	CCl4	vivo	Inhibited lipid peroxidation, enhance the activities of antioxidant enzymes, decreases the TNF-α level, NO and iNOS, and COX-2 expressions.	Huang G et al. 2012. Protective effect of antrosterol from Antrodia camphorata submerged whole broth against carbon tetrachloride-induced acute liver injury in mice. Food Chemistry.
Anoectochilus formosanus Hay. and Gynostemma pentaphyllum Makino	Methanol extract and aqueous extract	APAP	vivo	Increased levels of AST and ALT	Lin C et al. 2000. Antioxidant and hepatoprotective effects of Anoectochilus formosanus and Gynostemma pentaphyllum. The American Journal of Chinese Medicine.
Arctium- lappa L.	Aqueous extract	APAP and CCl4	vivo	Decrease the GSH, MDA, and CYP450	Lin SC et al. 2000. Hepatoprotective effects of Arctium lappa on carbon tetrachloride- and acetaminophen-induced liver damage. The American Journal of Chinese Medicine.
Artemisia capillaris Thunb	Aqueous extract	CCl4	vivo	Successfully lower serum ALT and AST activities, restore the GSH level, ameliorate or restore GPx and CAT activities as well.	Yang C C et al. 2012. Potential antioxidant properties and hepatoprotective effects of an aqueous extract formula derived from three Chinese medicinal herbs against CCl4-induced liver injury in rats. International Immunopharmacology.
Chlorogenic acid	Lonicera japonica Thunb.	APAP	vitro (L-02 cells)	Reversed the decreased cell viability; reduced serum levels of ALT/AST; prevented liver oxidative stress injury.	Chun P et al. 2015. Chlorogenic acid prevents acetaminophen-induced liver injury: the involvement of CYP450 metabolic enzymes and some antioxidant signals. J Zhejiang Univ Sci B.
Cirsium setidens Nakai	n-butanol extract	CCl4	vivo	Transcript levels of genes encoding antioxidant enzymes such as GPO1, GPO3 and SOD1 were elevated.	Lee SH et al. 2008. Antioxidant and Hepatoprotective Activities of Cirsium setidens NAKAI against CCl4-Induced Liver Damage. American Journal of Chinese Medicine.
Esculentoside A	Phytolacca esculen-ta van Houtte	CCl4 and D-GalN/LPS	vivo	Attenuated CCl4 and D-GalN/LPS-induced acute liver injury in mice and its protective effects might be involved in inhibiting inflammatory response and oxidative stress.	Zhang F et al. 2014. The protective effect of esculentoside an on experimental acute liver injury in mice. PLoS ONE.
Esculin	Cortex Fraxini Bark	LPS	vivo	Diminished the protein expression of NF-κB p65 in liver, which resulted in lower levels of inflammatory mediators.	Li W et al. 2016. Esculin attenuates endotoxin shock induced by lipopolysaccharide in mouse and NO production in vitro through inhibition of NF-κB activation. Eur J Pharmacol.
Ferulago campestris Besser	Essential oil	D-GalN/LPS	vivo	Decreased oxidative stress and inhibiting cytokines.	Li W et al. 2016. The Chemical Constituents and the Hepato-protective Effect of the Essential Oil of Ferulago campestris (Besser) Grecescu (Apiaceae). Journal of Essential Oil Bearing Plants.
Gallic acid	Rhus chinensis Mill.	CCl4	vivo	Protective effect of these substances on cell membranes.	Kanai S et al. Mechanism of the protective effects of sumac gall extract and gallic acid on the progression of CCl4-induced acute liver injury in rats. The American Journal of Chinese Medicine.
Gentiopicroside	Gentiana scabra Bunge	ANIT	vivo	Change bile acids metabolism which highlights its importance in mitigating cholestasis, resulting in the marked decrease of intracellular bile acid pool back toward basal levels.	Tang X et al. 2016. Target profiling analyses of bile acids in the evaluation of hepatoprotective effect of gentiopicroside on ANIT-induced cholestatic liver injury in mice. J Ethnopharmacol.
Glycyrrhiza uralensis Fisch.	Polysaccharide	CCl4	vivo	Decrease of NOS and NO levels, and reduction of the production of free radicals	Chen D et al. 2016. Study on Protective Effect of Glycyrrhiza uralensis Polysaccharide on CCl4 Induced Acute Liver Injury in Mice and Its Mechanism. China Pharmacy.
Glycyrrhiza uralensis Fisch.	Total saponins	CCl4	vivo	Decreased in serum ALT and AST	Gao XY et al. 2011. Preparation of total licorice saponin and research on its hepatoprotective effect. Pharmacology and Clinics of Chinese Materia Medica.
Homoplantaginin	Salvia plebeia R. Br	BCG/LPS	vitro (HL-7702 cells)	Decreased in serum ALT and AST, decreased the levels of TNF-α and IL-1, elevated the levels of GSH, GSH-Px and SOD.	Qu XJ et al. 2009. Protective effects of Salvia plebeia compound homoplantaginin on hepatocyte injury. Food and Chemical Toxicology.
Hypericum japonicum Thunb.	Aqueous extract	ANIT and CCl4	vivo	Had an obvious effect on the decreasing of AST, ALT and T-BIL levels in serum.	Wang N et al. 2008. Hepatoprotective effect of Hypericum japonicum extract and its fractions. Journal of Ethnopharmacology.
Isofuranodiene	Curcua zedoara Christ. Rosc	D-GalN/LPS	vivo	Significantly inhibited D-GalN/LPS-induced mRNA expression of IL-1β, IL-6, and iNOS in liver tissues.	Chen XP et al. 2015. Isofuranodiene protect D-galactosamin/lipopolysacchride induced liver injury in rats. Chin J Pharm Toxicol.
Kaerophyllin	Bupleurum chinense DC.	TAA	vivo	Suppressed hepatic inflammation and inhibiting HSC activation, possibly through upregulation of PPAR-γ expression.	Lee T et al. 2012. Protective effects of kaerophyllin against liver fibrogenesis in rats. European Journal of Clinical Investigation.
Kukoamine B	cortex Lycii	LPS	vivo	Inhibited inflammation in septic mice by reducing the concentrations of plasma LPS, decreased leukocyte sequestration and interfering with NF-κB activation, suppressed the pro-adhesive phenotype of endothelial cells.	Qin W et al. 2015. A novel role of kukoamine B: Inhibition of the inflammatory response in the livers of lipopolysaccharide-induced septic mice via its unique property of combining with lipopolysaccharide. Exp Ther Med.
Litsea coreana Levl.	total flavonoids	CCl4	vivo	Inhibited the expression of TGF-β1 and increased the expression of PPAR-γ.	Huang C et al. 2010. Potential protective effects of a traditional Chinese herb, Litsea coreana Levl., on liver fibrosis in rats. Journal of Pharmacy and Pharmacology.
Lxeris chinensis Thunb.	Aqueous extract	CCl4	vivo	Inhibited the acute elevation of serum transaminases.	Lin SC et al. 1994. Hepatoprotective effects of Taiwan folk medicine: Ixeris chinensis (Thunb.) Nak. on experimental liver injuries. The American Journal of Chinese Medicine.
Magnolol	Magnolia officinalis Rehd.	ConA	Vitro (Th17 Cells)	Inhibited Th17 cell differentiation; suppressed IL-17A generation.	Zhang H et al. 2017. Magnolol Attenuates Concanavalin A-induced Hepatic Fibrosis, Inhibits CD4+ T Helper 17 (Th17) Cell Differentiation and Suppresses Hepatic Stellate Cell Activation: Blockade of Smad3/Smad4 Signalling. Basic & Clinical Pharmacology & Toxicology.
Matrine	Sophora flavescens Ait	CCl4	vivo	Prevented monocyte infiltration into the injured livers and inhibition of MCP-1 production and activity.	Shi D. et al. 2013. Matrine Inhibits Infiltration of the Inflammatory Monocyte Subset in Injured Mouse Liver through Inhibition of Monocyte Chemoattractant Protein-1. Evidence-based Complementary and Alternative Medicine.
Oenanthe javanica Blume	total phenolics	D-Gal-N	vivo	Improve the survival of acute liver failure model significantly and prevent the elevation of the serum enzymatic markers and nonenzymatic markers levels significantly.	Guo A et al. 2016. The protective effect of total phenolics from Oenanthe javanica on acute liver failure induced by d-Galactosamine. J Ethnopharmacol.
Oridonin	Rabdosia rubescens(Hamst.) Y. wuet. Hsuan	D-Gal-N/LPS	vivo	Attenuated D-GalN/LPS-induced apoptosis in hepatocytes by reducing pro-apoptotic signals.	Deng Y et. 2017. Oridonin ameliorates lipopolysaccharide/D-galactosamine-induced acute liver injury in mice via inhibition of apoptosis. Am J Transl Res.
Orychophragmus violaceus	Aqueous extract	CCl4	vivo	Prevent CCl4-induced liver injury in mice via regulating the Nrf2 and NFκB pathways.	Huo X et al. 2017. Hepatoprotective Effect of Aqueous Extract from the Seeds of Orychophragmus violaceus against Liver Injury in Mice and HepG2 Cells. Int J Mol Sci.
Osthole	Cnidium monnieric (L.) Cuss.	APAP	vivo	Inhibited the metabolic activation of APAP and enhanced its clearance through an antioxidation mechanism.	Cai Y et al. 2018. Osthole prevents acetaminophen-induced liver injury in mice. Acta Pharmacol Sin.
Paeonialactiflora Pall. And Astragalus membranaceus Fisch.	70% aqueous ethanol	BCG/LPS	vivo	Reduced nitric oxide production and suppressed Kupffer cell activity and pro-inflammatory mediator and cytokines production.	Sun W et al. 2008. Protective effect of extract from Paeonia lactiflora and Astragalus membranaceus against liver injury induced by bacillus Calmette-Guérin and lipopolysaccharide in mice. Basic and Clinical Pharmacology and Toxicology.
Panax ginseng C. A. Mey	Aqueous extract	CCl4	vivo	Induced oxidative stress in rats	Karadeniz A et al. 2009. Protective effect of Panax ginseng on carbon tetrachloride-induced liver, heart and kidney injury in rats. Revue de Medicine Veterinaire.
Penthorum chinense Pursh	Aqueous extract	CCl4	vivo	Ameliorated CCl4-induced oxidative stress via activating Nrf2 signaling pathway.	Wang M et al. 2017. Hepatoprotective properties of Penthorum chinense Pursh against carbon tetrachloride-induced acute liver injury in mice. Chin Med.
Penthorum chinense Purs	Aqueous extract	Alcoholic	vivo	Suppressed CYP2E1-mediated oxidative stress and enhancing the oxidant defense systems via the activation of Nrf2/HO-1 pathway.	Cao Y et al. 2015. Protective effects of Penthorum chinense Pursh against chronic ethanol-induced liver injury in mice. Journal of Ethnopharmacology.
Periplocoside A	Periploca sepium Bge	ConA	vivo	Inhibited of NKT-derived inflammatory cytokine productions.	Wan J et al. 2008. Periplocoside A, a pregnane glycoside from Periploca sepium Bge, prevents concanavalin A-induced mice hepatitis through inhibiting NKT-derived inflammatory cytokine productions. International immunopharmacology.
Pogostone	Pogostemon cablin (Blanco) Benth	LPS	vivo	Suppressed the production of the proinflammatory mediators in serum, and attenuate liver injury.	Lia Y. 2014. Pogostone suppresses proinflammatory mediator production and protects against endotoxic shock in mice. Journal of Ethnopharmacology.
Polygonatum sibiricum	Polysaccharides	CCl4	vivo	Reduce the activities of ALT, AST, ALP and the contents of DBIL, TBIL in serum of rats.	Han CY et al. 2018. Study on extraction of Polygonatum sibiricum polysaccharides and its protective effect on CCl4-induced acute liver injury in rats. Acta Agriculturae Zhejiangensis
puerarin	Radix Puerariae Lobatae	Alcoholic and CCl4	vivo	Mediates hepatoprotection by the inhibition of inflammatory response and downregulation of the TNFα/NFκB pathway	Zhu P L et al. 2015, Effects of combined dietary supplementation with fenofibrate and Schisandrae Fructus pulp on lipid and glucose levels and liver function in normal and hypercholesterolemic mice. Drug Design, Development and Therapy
puerarin	Radix Puerariae Lobatae	D-Gal-N/LPS	vivo	Increase autophagy and suppress of apoptosis	Li L et al. 2018. Protective role of puerarin on LPS/D-Gal induced acute liver injury via restoring autophagy. Am J Transl Res.
Radix Polygoni Multiflori	Methanol extract	DMN	vivo	Reverse the pathogenic progression of the disease, decrease the hydroxyproline content and increases the expression of HGF messenger RNA in liver tissue	Huang C et al. 2007. Chinese herb Radix Polygoni Multiflori as a therapeutic drug for liver cirrhosis in mice. Journal of Ethnopharmacology.
Rheum Palmatum L.	total extract; 90% ethanol	CCl4	vivo	Liver toxicity of High dose, liver preservation of low dose.	Wang JB et al. 2011. Hepatotoxicity or Hepatoprotection? Pattern Recognition for the Paradoxical Effect of the Chinese Herb Rheum palmatum L. in Treating Rat Liver Injury. PLoS ONE.
Rhus chinensis Mill.	Aqueous extract	CCl4	vivo	Protective effect of these substances on cell membranes.	Kanai S et al. Mechanism of the protective effects of sumac gall extract and gallic acid on the progression of CCl4-induced acute liver injury in rats. The American Journal of Chinese Medicine.
Saikosaponin-d	Bupleurum chinense DC.	DMN	vivo	Reduced collagen I deposition in the liver and ALT level in the serum; decreased the content of TGF-1 in the liver.	Fan J et al. 2007. Saikosaponin-d attenuates the development of liver fibrosis by preventing hepatocyte injury. Biochemistry and Cell Biology.
Saikosaponin-d	Bupleurum chinense DC.	CCl4	vivo	Alleviated hepatocyte injury from oxidative stress.	Fan J et al. 2007. Saikosaponin-d attenuates the development of liver fibrosis by preventing hepatocyte injury. Biochemistry and Cell Biology.
Saikosaponin-d	Bupleurum chinense DC.	APAP	vivo	Down-regulating NF-κB- and STAT3-mediated inflammatory signaling.	Aiming L et al. 2014. Saikosaponin d protects against acetaminophen-induced hepatotoxicity by inhibiting NF-κB and STAT3 signaling. Chemico-Biological Interactions.
Salvia miltiorrhiza Bge.	Polysaccharide	BCG/LPS	vivo	Effectively improved the liver index, spleen index and thymus index; reduced the serum levels of ALT, AST and NO; restored liver homogenate contents of TNF-α and IL-1β.	Song YH et al. 2008. Protection of a polysaccharide from Salvia miltiorrhiza, a Chinese medicinal herb, against immunological liver injury in mice. International Journal of Biological Macromolecules.
Salvia miltiorrhiza Bunge.	Aqueous extract	CCl4	vivo	Reduced levels of transforming growth factor-beta1, procollagens I and III and tissue inhibitor of metalloproteinase-1 transcripts and an increased level of matrix metalloproteinase-13 transcript.	Wasser S et al. 1998. Salvia miltiorrhiza reduces experimentally-induced hepatic fibrosis in rats. Journal of Hepatology.
Salvianolic acid-A	Salvia miltiorrhiza Bge.	CCl4	vivo	Have protective effects against liver injury and fibrosis in rats.	Hu Y Y et al. 2000. Protective actions of salvianolic acid A on hepatocyte injured by peroxidation in vitro. World Journal of Gastroenterology.
Schisandra chinensi-s （Turcz.）Baill	Aqueous extract	CCl4	vivo and clinical	Induced liver cytochrome P-450 and promote certain anabolic metabolism such as serum protein biosynthesis and glycogenesis.	Liu GT. 1989. Pharmacological actions and clinical use of fructus schizandrae. Chin Med J (Engl).
Schisandrin B	Schisandra chinensis Baill	d-Gal-N	vivo	Proteins 27 and 70 were involved in the protective effect.	Gao Z et al. 2016. Heat shock proteins 27 and 70 contribute to the protection of Schisandrin B against d-galactosamine-induced liver injury in mice. Canadian Journal of Physiology and Pharmacology.
Scutellarin	Scutellaria baicalensis Georgi	Con A	vivo	Inhibited the NF-kappaB-TNF-α-iNOS transduction pathway.	Zheng H et al. 2007. The protective action of scutellarin against immunological liver injury induced by concanavalin A and its effect on pro-inflammatory cytokines in mice. Journal of Pharmacy and Pharmacology.
Semen Persicae and Flos Carthami	Aqueous extract	CCl4	vivo	Inhibited pathological angiogenesis and hepatic fibrogenesis may be through affecting the angiogenesis-associated VEGF and its upstream and downstream signaling pathways.	Xi S et al. 2016. The Effects of Taoren-Honghua Herb Pair on Pathological Microvessel and Angiogenesis-Associated Signaling Pathway in Mice Model of CCl4-Induced Chronic Liver Disease. Evidence-Based Complementary and Alternative Medicine.
Shikonin	Lithospermum erythrorhizon Sieb.	d-Gal-N/LPS	vivo	Inhibited TLR4 signaling pathway	Lin MX et al. 2017. Shikonin protects against D-Galactosamine and lipopolysaccharide-induced acute hepatic injury by inhibiting TLR4 signaling pathway. Oncotarget.
Silymarin	Silybum marianum (L.) Gaertn.	CCl4	vivo	Reduce ALT elevation in animals exposed to CCl4.	Li Y et al. 2003. Traditional Chinese Medicine Prevents Inflammation in CCI4-Related Liver Injury in Mice. American Journal of Chinese Medicine.
Sparstolonin B	Scirpus yagara Ohwi	LPS	vivo	Suppressed LPS-induced increase of TNF-α and IL-6 in serum and livers.	Liang QL et al. 2015. Protective effects of Sparstolonin B, a selective TLR2, and TLR4 antagonist, on mouse endotoxin shock. Cytokine.
Stephania tetrandra Moore. and Salvia miltiorrhiza Bge.	Aqueous extract	CCl4	vivo	Safely and effectively prevents and reverses hepatic fibrosis through activating HSC apoptosis in rats	Josette S Y et. 2009. Stephania tetrandra prevents and regresses liver fibrosis induced by carbon tetrachloride in rats. Journal of gastroenterology and hepatology.
Tannins	Toxicodendron vernicifluum (S-tokes)	CCl4	vivo	The mechanism for this prevention might be due mainly to the protective effect of these substances on cell membranes.	Kanai S et al. 1998. Mechanism of the protective effects of sumac gall extract and gallic acid on the progression of CCl4-induced acute liver injury in rats. The American Journal of Chinese Medicine.
Thaliporphine	Thalictrum aquilegifolium L.	LPS	vivo	Suppressed TNF-α, NO, and O^2- production.	Chiao C et al. 2005. Thaliporphine increases survival rate and attenuates multiple organ injury in LPS-induced endotoxaemia. Naunyn Schmiedeberg's Archives of Pharmacology.
Tetrandrine	Tephania tetrandra S. Moore	ConA	vivo	Suppressed the production of various inflammatory mediators in the liver through inhibited of NF-κB activation.	Feng D et al. 2008. Tetrandrine protects mice from concanavalin A-induced hepatitis through inhibiting NF-κB activation. Immunology Letters.
Wedelia chinensis (Osbeck) Merr.	Aqueous extract	CCl4, APAP, D-Gal-N	vivo and clinical	Improve the general damage condition and suppress enzyme leakage from cellular membranes.	Lin SC et al. 1994. Hepatoprotective effects of Taiwan folk medicine: wedelia chinensis on three hepatotoxin-induced hepatotoxicity. The American Journal of Chinese Medicine.

Figure 1. CCl₄-induced liver injury. CCl₄ trigger the continuous development of hepatocyte injury by inducing cell stress via inflammation, macrophages activation, mitochondrion path, and oxidative stress, resulting in apoptosis, hepatic fibrosis, and liver injury. COX-2: epoxide hydrolase; PGs: prostaglandins; HSC: hepatic stellate cells; CYP450: cytochrome P450; TNF-α: tumor necrosis factor α; IL: interleukin; NF-κB: nuclear factor κB; AP-1: activated protein transcription factor 1; PLA₂: phosphatase A2; TGF-β: transforming growth factor β; Cyt-C: cytochrome C.

Figure 2. d-GalN-induced liver injury. d-GalN trigger the continuous development of hepatocyte injury by inducing cell stress via inflammation, metabolic disorder, and oxidative stress, resulting in necrosis, apoptosis, autophagy, and liver injury. UDP: uridine diphosphate; UTP: uridine triphosphate; UDPase: UDP-glucose pyrophosphorylase; GSH: glutathione; TNF-α: tumor necrosis factor α.

Figure 3. ANIT-induced liver injury. ANIT trigger the continuous development of hepatocyte injury by inducing cell stress via inflammation, hepatotoxicity, cholestatic jaundice, and hyperbilirubinemia, resulting in apoptosis, autophagy, cholestasis, and liver injury. GSH: glutathione; IL: interleukin; MIP-2: macrophage inflammatory protein-2; NADPH: nicotinamide adenine dinucleotide phosphate.

Figure 4. DMN-induced liver injury. DMN trigger the continuous development of hepatocyte injury by inducing cell stress via inflammation, and activation of HSC, resulting in apoptosis, autophagy, sedimentation of ECM, hepatic fibrosis, and liver injury. CYP2EI: cytochrome P2EI; TNF-α: tumor necrosis factor α; IL: interleukin; α-SMA: α smooth muscle actin; TGF-β: transforming growth factor β; CTGF: connective tissue growth factor; TIMP1: tissue inhibitor of metalloproteinases 1; Smad: drosophila mothers against decapentaplegic protein; ECM: extracellular matrix.

Figure 5. TAA-induced liver injury. TAA trigger the continuous development of hepatocyte injury by inducing cell stress via inflammation, metabolic disorder, enterogenous toxicemia, and oxidative stress, resulting in hepatic necrosis, apoptosis, and liver injury. CYP450: cytochrome P450; IETM: intestinal endotoxemia; iNOS: inducible nitric oxide synthase; eNOS: endothelial nitric oxide synthase; TXA₂: thromboxane A₂; ROS: reactive oxygen species.

Figure 6. ConA-induced liver injury. ConA triggers the continuous development of hepatocyte injury by inducing cell stress via inflammation and macrophages activation, resulting in hepatic necrosis and liver injury. NF-κB: nuclear factor κB; Irf-3: Interferon regulatory factor -3; NLRP3: NACHT, LRR and PYD domains-containing protein 3; TNF-α: tumor necrosis factor α; IFN-γ: Interferon-γ; IL: interleukin.

Figure 7. BCG/LPS-induced liver injury. BCG/LPS trigger the continuous development of hepatocyte injury by inducing cell stress via inflammation and sensitization, resulting in hepatic necrosis and liver injury. TNF-α: tumor necrosis factor α; IL: interleukin.

Figure 8. d-GalN/LPS-induced liver injury. d-GalN/LPS triggers the continuous development of hepatocyte injury by inducing cell stress via inflammation, metabolic block, protein synthesis decrease, and hepatocyte DNA fracture and degradation, resulting in hepatic necrosis and liver injury. UDP: uridine diphosphate; UTP: uridine triphosphate; TLR: toll-like receptor; TNF-α: tumor necrosis factor α; IL: interleukin.

Figure 9. Alcoholic-induced liver injury. Alcohol triggers the continuous development of hepatocyte injury by inducing cell stress via inflammation, oxidative stress, protein synthesis decrease, and hepatocyte DNA fracture and degradation, resulting in hepatic necrosis, apoptosis, hepatic fibrosis, and liver injury. ADH: alcohol dehydrogenase; ALDH: aldehyde dehydrogenase; CYP2EI: cytochrome P2EI; ROS: reactive oxygen species; Cyt-C: cytochrome C; RIP: receptor-interacting protein; TRADD: tumor necrosis factor receptor-related domain death protein; FADD: fas-associating protein with a novel death domain; TNF-α: tumor necrosis factor α; IL: interleukin; NF-κB: nuclear factor κB.

Figure 10. APAP-induced liver injury. APAP trigger the continuous development of hepatocyte injury by inducing cell stress via inflammation, oxidative stress, and JNK pathway, resulting in hepatic necrosis, apoptosis, hepatic fibrosis, and liver injury. CYP450: cytochrome P450; NAPQI: N-acetyl-p-benzoquinonimine; GSH: glutathione; ROS: reactive oxygen species; iNOS: inducible nitric oxide synthase; NF-κB: nuclear factor κB; TNF-α: tumor necrosis factor α.

Figure 11. INH/RIF-induced liver injury. INH/RIF trigger the continuous development of hepatocyte injury by inducing cell stress via inflammation, cholestasis, and metabolic disorder, resulting in hepatic necrosis, apoptosis, and liver injury. CYP450: cytochrome P450; PPAR: peroxisome proliferator-activated receptors.