This work was supported by the Innovation Team and Talents Cultivation Program of National Administration of Traditional Chinese Medicine (grant no. ZYYCXTD-C-202006 to XL); Beijing Municipal Science & Technology Commission (grant no. 7212174 to XL); National Natural Science Foundation of China (grant no. 82004045 to XL); Beijing Nova Program of Science & Technology (grant no. Z191100001119088 to XL; grant no. Z201100006820025 to RL); and the Young Talents Promotion Project of China Association of Traditional Chinese Medicine (grant no. 2020-QNRC2-01 to XL).

About

Sections

PDF

Tools

Share a link

Email
Wechat
Bluesky

Abstract

Autoimmune hepatitis (AIH) is a chronic inflammatory liver disease occurring in individuals of all ages with a higher incidence in females and characterized by hypergammaglobulinemia, elevated serum autoantibodies and histological features of interface hepatitis. AIH pathogenesis remains obscure and still needs in-depth study, which is likely associated with genetic susceptibility and the loss of immune homeostasis. Steroids alone and in combination with other immunosuppressant agents are the primary choices of AIH treatment in the clinic, whereas, in some cases, severe adverse effects and disease relapse may occur. Chinese medicine used for the treatment of AIH has proven its merits over many years and is well tolerated. To better understand the pathogenesis of AIH and to evaluate the efficacy of novel therapies, several animal models have been generated to recapitulate the immune microenvironment of patients with AIH. In the current review, we summarize recent advances in the study of animal models for AIH and their application in pharmacological research of Chinese medicine-based therapies and also discuss current limitations. This review aims to provide novel insights into the discovery of Chinese medicine-originated therapies for AIH using cutting-edge animal models.

1 INTRODUCTION

Autoimmune hepatitis (AIH), a chronic self-perpetuating inflammatory liver disease with a female preponderance, has been characterized by moderate or severe interface hepatitis, hypergammaglobulinemia, elevated serum aminotransferase and autoantibodies, hepatocyte necrosis and even liver failure owing to immunological tolerance.¹ Comparing cases over past decades, the incidence of AIH has sharply increased in individuals of all ethnicities, regions and ages.^{2, 3} Due to the lack of specific and well-accepted biomarkers, AIH diagnosis is based on diagnostic criteria comprising a combination of multiple parameters and is distinct among different age groups.⁴ Based on numerous clinical reports, AIH is more likely to be initiated and rapidly developed in female adults and is characterized by mild fatigue, elevated levels of γ-globulins (mainly IgG), increased autoantibodies that react with intrahepatic and extrahepatic antigens or fulminant hepatitis, in some cases.⁵ Unlike in adults, AIH in children and adolescents shows a cascade of T-cell-medicated reactions that target hepatocytes, resulting in anorexia, headache, repetitive jaundice and progressive fatigue but not fulminant hepatitis.⁶ If continuously left untreated, AIH results in destruction of hepatic parenchyma and persistent hepatitis, and probably evolves into cirrhosis, hepatobiliary malignancies and even multiple organ failure in severe cases.^{5, 7, 8}

At present, AIH is recognized as two types: AIH-1, positive for anti-nuclear (ANA) and/or anti-smooth muscle (SMA) antibodies, and AIH-2, positive for anti-liver kidney microsomal antibody type 1 (anti-LKM1), anti-LKM3 and/or anti-liver cytosol antibody type 1 (anti-LC1).^{9, 10} Recent studies have revealed that the etiology and pathogenesis of AIH are correlated with genetic susceptibility, the loss of self-tolerance, molecular mimicry or non-specific activation of T lymphocytes.¹¹ Notably, the interaction between genetic susceptibility and the loss of self-tolerance caused by environmental factors is the core of pathogenesis.¹² In adults, genetic predisposition to AIH is strongly associated with the specific genes located within the human-leukocyte-antigen (HLA) region on the short arm of chromosome 6, especially with genes encoding HLA-DR4 and HLA-DR3 alleles.¹³ In patients with HLA-DRB1 cross-reactions with liver autoantigens and rapid disease progression are more likely to occur.¹⁴ In addition, several environmental factors including drugs, xenobiotics and viruses result in the loss of self-tolerance and initiate the immune response, and current studies aim to address this issue by developing animal models that mimic the liver damage caused by the immune system dysfunction in AIH patients.¹⁵ T lymphocytes control the balance of intrinsic and extrinsic peripheral tolerance in healthy individuals, alteration of which may give rise to the dysregulation of immunoregulatory networks. Support for the role of loss of self-tolerance in AIH comes from studies showing that the deletion of medullary thymic epithelial cells that regulate T cell tolerance by eliminating autoreactive T cells and expressing self-antigens caused the enrichment of anti-ANA and initiated AIH in mice.^{16, 17} Moreover, antigen-presenting cells (APCs) are involved in the process and presentation of self-antigens to T cell receptor (TCR) on naive CD4⁺ T helper (T_H0) cells and trigger immunoregulation. Exposure to self-mimicking exogenous sequences results in the production of anti-LKM1 antibodies in patients who have α1-antitrypsin deficiency and acquired hepatitis C virus after liver transplantation.^{18, 19} Cytochrome P4502D6 (CYP2D6) is reported to mainly express in endoplasmic reticulum and hepatocyte membranes and become the target of anti-LKM1 antibodies, thus leading hepatocytes to be directly attacked by humoral immunity.²⁰

At present, first-line therapeutic drugs targeting AIH and complications are glucocorticoids and azathioprine, which can be used either alone or in combination to achieve biochemical remission, defined as normal serum transaminase and IgG levels.^{21, 22} However, patients with AIH generally relapse after cessation of these drugs or suffer side effects caused by their long-term use.²³ When AIH progresses into end-stage cirrhosis or fulminant liver failure, patients are no longer sensitive to pharmacotherapy and are forced to choose the final treatment option, liver transplantation.²⁴ Therefore, exploring novel medications with high efficiency and low toxicity is of both basic science and clinical relevance. Traditional Chinese medicine (TCM) consists of different medicinal formulas and has shown success in regulating immune responses, thus exhibiting therapeutic effects against acute or chronic liver diseases.²⁵ Considering the multi-component and multi-target characters of TCM, identifying various Chinese herbal prescriptions or natural Chinese medicine extracts is potentially an efficient approach to discovery of novel therapeutics against AIH. Recently, more AIH patients have prefered to take TCM to alleviate their severe symptoms and suppress steroid-induced side effects.²⁶ Many experimental studies have illustrated the promising therapeutic effects of several natural products from TCM, including phenols, glycosides, flavonoids, polysaccharides and alkaloids, in the treatment of AIH by activating T/B lymphocytes, inducing helper T (Th2) cell development, promoting T cell proliferation and ultimately regulating T cell-mediated immunity.^{27, 28}

In the current review, we mainly focus on the hepatoprotective and immunoregulative effects of TCM and its natural products on several kinds of AIH-related animal models. This review also provides a comprehensive summary of recent studies, highlights findings that have been ignored, and indicates potential prospects of clinical application of TCM for the management of AIH and associated manifestations.

2 MURINE INJURY MODELS FOR AIH

Given that AIH pathogenesis is not yet been understood, multifarious animal models have been generated to mimic the histopathological features of AIH patients and help to identify mechanisms responsible for immunological intolerance. A variety of drugs has been associated with the induction of AIH, including concanavalin A (Con A), lipopolysaccharide/D-galactosamine (LPS/D-GalN), complete Freund's adjuvant (CFA), α-galactosylceramide (α-GalCer), carbon tetrachloride (CCl₄) and alcohol (Figure 1). However, owing to differences in the major histocompatibility complex (MHC) class I and II proteins involved in the T cell response between mouse and human, mouse models used to mimic human autoimmune diseases often don't share the same target autoantigens and have certain limitations.²⁹ Recently, Chinese herbal prescriptions, single Chinese herbs and active ingredients isolated from Chinese medicines have been shown to possess protective effects in these animal models of AIH and related diseases (Table 1).

Details are in the caption following the image — **FIGURE 1**
Open in figure viewer PowerPoint

Different mechanisms account for the impairment of immune cells in autoimmune hepatitis (AIH)

TABLE 1. Effects of Chinese medicines on the treatment for autoimmune hepatitis (AIH) diseases

Animal models	TCM	Category	Effector immune cells	Target/signal pathways	References
Con A	PoPx	Punica granatum	NKT/CD4+/CD⁸⁺ T cells, neutrophils, macrophage	ALT, AST, TNF-α, IFN-γ and IL-6	30
	Abietoquinones A	Prunella vulgarisis	CD3⁺ T cells, neutrophils, macrophage, splenocytes	IFN-γ, TNF-α, IL-2, IL-4, IL-6, IL-10, IL-17	31
	Betulin	Hedyotis hedyotidea	NKT/CD4⁺/CD8⁺ T cells, neutrophils, macrophages and, splenocyte	CD69, TNF-α, IFN-γ, IL-6	32
	PSA	Periploca sepium Bge	NKT/CD4⁺/CD8⁺ T cells, neutrophils, macrophage	ALT, IL-4 and IFN-γ	33
	YST	Decoction of herbal medicine	NKT/CD4⁺/CD8⁺ T cells, neutrophils, macrophage	a-SMA, cola1(I), IL-6, IL-17, TGF-β1, caspase-3/8/9, Bax	34
	L-THP	Corydalis yanhusuo	NKT/CD4⁺/CD8⁺ T cells, neutrophils, macrophages	TNF-α, IL-6, Bcl-2, Bax, caspase 3/9, Beclin-1, LC3-II, TNF/TNFR, TRAF6/JNK signaling	35
	SCG	Decoction of herbal medicine	NKT/CD4⁺/CD8⁺ T cells, neutrophils, macrophage	ALT, AST, IL-2/4/5, cytochrome P450, Bax, FAS, TRAIL, FASL, Caspase-3/8/9	36, 37
	Resveratrol	P. cuspidatum	NKT/CD4⁺/CD8⁺ T cells, neutrophils, macrophage	TNF-α, IFN-γ, IL-4, IL-6, MCP-1, SIRT1, Ki67, PCNA, Cyclin D1, Cdk2, p66^shc	38
	RA	Dracocephalum heterophyllum	NKT/CD4⁺/CD8⁺ T cells, neutrophils, macrophages, leukocytes	ALT, AST, IFN-γ, IL-2, IL-1β,IL-10, AMPK, ACC	39
	Berberine	Coptis chinensis	NKT/CD4⁺/CD8⁺ T cells, neutrophils, macrophage	TNF-α, IFN-γ, IL-6, IL-10, STAT1, AMPK	40
	ERA	Rabdosia amethystoides	NKT/CD4⁺/CD8⁺ T cells, neutrophils, macrophage	IκB, p65, NF-κB, TLR4	41
	ARS	Derivative	NKT/CD4⁺/CD8⁺ T cells, neutrophils, macrophage	IFN-γ, IL-17, IL-1β, TNF-α, ERK, JNK, p38, NF-κB p65, IκBα	42
	ARC	Arctium lappa L.	NKT/CD4⁺/CD8⁺ T cells, neutrophils, macrophage	IL-6, IL-10, IFN-γ, Atg7, Beclin1, LC3-II, P62, Pkr, STAT1, Bnip3	43
LPS/D-GalN	Scoparone	Artemisia capillaris	NKT/CD4⁺/CD8⁺ T cells, neutrophils, macrophage	TNF-α, IL-6, IFN-β, TRIF, MyD88, IRF3, ERK, p38, JNK, I-κB, TLR4	44
	Lupeol	Adenophora triphylla var. japonica	Monocytes, macrophages, hepatic Kupffer cells	TNF-α, IL-6, IRAK-M, TRIF, TLR4 signaling	45
	Acacetin	Agastache rugosa	Monocytes, macrophages, hepatic Kupffer cells	TNF-α, IL-6, Atg5, Atg7, LC3-II, p62, autophagic flux, TLR4 signaling pathways	46
	CTN	Salvia miltiorrhiza Bunge	Monocytes, macrophages, hepatic Kupffer cells	TAK1, JNK, ERK, p38,NF-κb, caspase 3/8/9, cyto C	47
	HRP	Sea buckthorn (Hippophae rhamnoides L.)	Monocytes, macrophages, hepatic Kupffer cells	ALT, AST, MDA, SOD, GSH-PX, TNF-α, IL-1β, MAPKs, NF-κB/TLR4 signaling	48
	MA	Dry olive-pomace oil	Monocytes, macrophages, hepatic Kupffer cells	MPO, TNF-α, IL-6, NF-κB, Nrf2, HO-1	49
	Alpinetin	Alpinia katsumadai Hayata	Monocytes, macrophages, hepatic Kupffer cells	MPO, MDA, TNF-α, IL-1β, NF-κB, Nrf2, HO-1	50
	Esculin	Aesculus hippocastanum L.	Monocytes, macrophages, hepatic Kupffer cells	MPO, MDA, TNF-α, IL-1β, NF-κB, Nrf2, HO-1	51
	CSS	Acanthopanax sessiliflorus	Monocytes, macrophages, hepatic Kupffer cells	ALT, AST, CAT, GSH, SOD, MDA, NF-κB, Nrf2, HO-1	52
	ADH	Andrographis paniculata	Monocytes, macrophages, hepatic Kupffer cells	ALT, AST, MDA, MPO, ROS, TNF-α, IL-1β, NF-κB, Nrf2, HO-1	53
	Isovitexin	Oryza sativa	Monocytes, macrophages, hepatic Kupffer cells	TNF-α, ALT, AST, MPO, MDA, NF-κB, Nrf2 signaling pathway	54
	SPG	Panax ginseng	Monocytes, macrophages, hepatic Kupffer cells	ALT, AST, MDA, SOD, CAT, GSH, TNF-α, IL-1β, P65, IκB, HO-1, SIRT1/Nrf2/NF-κB	55
	Biochanin A	Red clover and peanuts	Monocytes, macrophages, hepatic Kupffer cells	ALT, AST, IL-1β, TNF-α, MDA, Nrf2, HO-1, NLRP3, TXNIP, ASC, caspase-1	56
	TEN	Polygala tenuifolia root	Monocytes, macrophages, hepatic Kupffer cells	TNF-α, IL-1β, ALT, AST, MDA, MPO, ASK1, NF-κB, MAPKs, Nrf2, HO-1	57
	Linarin	Chrysanthemum indicum L.	Monocytes, macrophages, hepatic Kupffer cells	TNF-α, IL-1, IL-6, FADD, caspase3/8, cyto C, STAT3, Bcl-xL	58
	Garcinol	Garcinia indica	Monocytes, macrophages, hepatic Kupffer cells	MDA, NFκ-B, Bax, caspase 3/8/9	59
CFA	PKRE	Picrorhiza Kurroar hizome	CD4⁺/CD8⁺ T cells, macrophage	TNF-α, IL-1β, IL-6, IL-10, COX-2, TNFR1, iNOS, NF-κB	60
	PRAP	Paeoniae radix alba polysaccharides	CD4⁺/CD8⁺ T cells, macrophage	NF-κB, IL-2, IL-6 and IL-10	61
	Prunella vulgarisis	Prunella vulgarisis	CD4⁺/CD8⁺ T cells, macrophage	IFN-γ, IL-17A, TGF-β, BAX and caspase 3	62
α-GalCer	Bu Xu Hua Yu recipe	Decoction of herbal medicine	NKT/Treg/Th17 cells	Foxp3, RORγt, IL-10, IL-17, TGF-β	63
CCl₄	LPCE	Launaea procumbens methanolice	Neutrophils	SOD, GST, GSR, GSH-Px, GSH	64
	NPME	Nicotiana plumbignifolia	Neutrophils	TBARS	65
	TFs	Cichorium intybus L.	Macrophages, neutrophils	ALT, ALP, AST, GGT	66
	Ginsenoside Rg2	Ginseng	Neutrophils	AST, ALT, ALP, GSH, MDA	67
	Ucche	Momordica charantia L. var. muricata Willd.	Neutrophils, Kupffer cells	ROS, LPO, AST, ALT, TBARS, GPx, iron-mediated signaling pathways	68
	TFs	Cichorium glandulosum seeds	Neutrophils	LPO, AST, ALT, ALP, TB, LDH, MDA, GSH, TBARs	69
	SP	Hippophaerhamnoides L.	Macrophages, neutrophils	ALT, AST, SOD, MAD, GSH, GSHpx, TNF-α, IL-1β, NO, iNOS, TLR4, NF-κB, MAPKs	70
	Apocynin	Picrorhiza kurroa	Neutrophils	ALT, AST, ROS, MPO, MDA, SOD, NO, APOP	71
	SME	Sonchus arvensis	Neutrophils	CAT, SOD, GST, GSR, GSHpx, TBARS, DNA	72
Alcohol	PG	platycodon grandiflorum	Lymphocytes, macrophages	CAT, SOD, GPx, GR, GOT, GPT, TG, ROS.	73
	Cii	Cichorium intybus	Lymphocytes, macrophages	GOT, GPT, TG, CYP2E1, ADH, ALDH	74
	PCP	Penthorum chinense Pursh	Lymphocytes, macrophages	TNF-α, IL-6, MDA, SOD, GSH, ROS, GPx, HO-1, CYP2E1, TG, Nrf2	75
	Taraxasterol	Taraxacum	Lymphocytes, macrophages	ALT, AST, MDA, GSH, SOD, TG, TNF-α, IL-6, CYP2E1/Nrf2/HO-1, NF-κB signaling pathways	76
	PCP	Cichorium intybus	Lymphocytes, macrophages	ALT, AST, MDA, GSH, SOD, CAT, WAT, CYP2E1, CD36, ATGL	77
	Gastrodin	Gastrodia elata Bl.	Lymphocytes, macrophages	ALT, AST, MDA, SOD, GPx, CAT, CYP2E1, TNF-α, IFN-γ, IL6, CXCL-1, VCAM-1, NF-κB, AMPK/Nrf2 pathway	78
	TASP	Triticum aestivum	Lymphocytes, macrophages	ALT, AST, GSH, SOD, CYP2E1, HO-1, Bcl-2/Bax, PI3K/Akt/Nrf2 signaling pathway	79
	AC	Cinnamomea mycelia	Lymphocytes, macrophages	Akt/NF-κB signaling pathway, caspase 3/8/9	80
	ME	Morchella esculenta	Lymphocytes, macrophages	YKL-40, IL-7, PAI-1, RBP4, Keap-1, Nrf2, NF-κB signaling	81

2.1 Effects of TCM on the treatment of immune cell-mediated murine hepatic models

2.1.1 TCM and Con A-induced liver injury models

Con A, a lectin isolated from jack beans, is a T cell mitogen for inducing antigen non-specific T cell activation and severe acute hepatitis with cytokine storm.⁸² Recent studies report that Con A can stimulate CD4⁺ T cells, natural killer T (NKT) cells, macrophages and APCs, and cause the secretion of proinflammatory cytokines including interleukins (IL-6, IL-12, IL-18), tumor necrosis factor-α (TNF-α), interferon-γ (IFN-γ) and several chemokines in mice.⁸³ Although Con A represents a model of non-specific and T cell-mediated acute liver injury rather than a typical AIH model, Con A-induced hepatitis has been extensively used to investigate the immune system-mediated liver injury and evaluate possible therapies for human AIH.

According to their different biological functions in the immune response, T cells are further divided into three subgroups: cytotoxic T cells (CTLs), namely CD8⁺ T cells, which release granzyme and perforin to induce the apoptosis of target cells; CD4⁺ helper T cells (Th cells), which secrete a variety of cytokines such as interleukins, TNF-α and IFN-γ and activate B cells to differentiate and produce antibodies; regulatory T cells (Tregs), which inhibit the immune response by secreting forkhead box p3 (Foxp3), transforming growth factor-β (TGF-β), IL-4, and IL-10.^84-86 It has been well-established that aberrant activation of CTLs, cytokines released by Th1 cells and macrophages, and adhesion of NKT cells to hepatocytes coated with autoantibodies contribute to hepatocyte destruction in Con A-induced animal models.⁸⁷ Wang et al.³⁰ obtained pomegranate peel extract (PoPx) from Punica granatumand and demonstrated that pretreatment in a Con A-induced AIH murine model with PoPx obviously reduced the level of cytokines (TNF-α, IFN-γ and IL-6), serum transaminases and the murine mortality rate, and played a protective role by decreasing the liver damage caused by ROS. It also remarkably reduced the hepatic infiltration of activated CD4⁺/CD8⁺ T cells. Yunfang Cao isolated abietoquinones A from Prunella vulgarisis and found that it decreased the serum level of aminotransferases, inhibited the production of proinflammatory cytokines and alleviated the proliferation and infiltration of CD3⁺ T cells in a Con A-induced hepatitis mouse model.³¹ NKT cells, a T cell subset expressing surface markers of both NKT cells and T lymphocytes, are crucial first responders against multiple infectious diseases. Once stimulated, NKT cells secrete a large number of cytokines and chemokines, especially IL-4 and IFN-γ, and simultaneously inhibit the differentiation of Th1/Th2 cells.⁸⁸ It has also been reported that betulin, extracted from Hedyotis hedyotidea, inhibited the activation of NKT and conventional T cells by decreasing the enhanced expression of CD69, prevented the production of pro-inflammatory cytokines, particularly Th1-type cytokines, in these two cell populations, and subsequently ameliorated liver injury.³² Additionally, betulin abolished NKT cell death in mice, and dose-dependently attenuated splenocyte proliferation stimulated by Con A in vitro.³² Researchers from the same lab further extracted periplocoside A (PSA) from Periploca sepium Bge and investigated whether this ingredient also alleviated Con A-induced hepatitis in mice. As expected, PSA inhibited the proliferation of primary T cells and the production of NKT-derived inflammatory cytokines (IL-4 and IFN-γ), reduced the necrosis and infiltration of leukocytes and protected mice from Con A-induced AIH damage.³³

Apoptosis is programmed cell death including internal and external apoptosis pathways and is of great importance in resisting pathogen invasion and regulating the immune response. In addition to its role in stimulating T cells, Con A can cause AIH injury by directly triggering hepatic parenchymal cell death. The intrinsic pathway includes endoplasmic reticulum (ER) stress or mitochondrial dysfunction. After the destruction of Ca²⁺ balance or the aberrant accumulation of ER protein, endoplasmic reticulum stress (ERS) triggers the apoptosis signals and promotes cell apoptosis by activating caspase 3/7/12.⁸⁹ Under the stimulation of various apoptotic signals, B-cell lymphoma-2 (Bcl-2) and Bcl-2-associated X protein (Bax) form a heteromer and migrate to the outer membrane of mitochondria, causing the release of cyto C and a cascade reaction of downstream caspases.⁹⁰ Yongdamsagan-tang (YST) extracts markedly inhibited the apoptosis of hepatocytes and prevented the Con A-induced AIH injury in mice via the suppression of caspase-3/8/9 and Bax.³⁴ In addition, YST also suppressed IL-6 expression and lipid accumulation caused by IL-17 in hepatocytes. Levo-tetrahydropalmatine (L-THP), an active ingredient from Corydalis yanhusuo, was reported to inhibit T lymphocyte proliferation and cytokine production, upregulate Bcl-2 expression, downregulate Bax and caspase 3/9 through the inhibition of TNF-α-mediated TNF receptor associated factor 6/c-Jun N-terminal kinase (TRAF6/JNK) signaling pathway, thereby reducing Con A-induced hepatocyte apoptosis.³⁵ Sancao granule (SCG), a traditional Chinese formula, has long been used for treating AIH in the clinic. There is renewed interest in SCG-induced protective effects, which decrease pro-inflammatory cytokines and inhibit hepatocyte death. Using metabolomics profiling, SCG was found to ameliorate Con A-induced liver injury in mice by inhibiting cytoplasmic vacuolization, hepatocyte apoptosis and neutrophil infiltration in livers, and the metabolites related to the efficacy of SCG in treating AIH were clarified.³⁶ An increasing number of studies have recently implied that external factors promote the combination of death ligand and its receptor to form an apoptosis-inducing complex on the cell membrane, which causes the cascade reaction leading to apoptosis. Other research has shown that oral administration of SCG in Con A-induced mouse model regulated the balance of pro- and anti-inflammatory cytokines and dose-dependently inhibited the activation of apoptotic mediators (Bax, Caspase-3/8/9) by interrupting the tumor necrosis factor-related apoptosis inducing ligand (TRAIL)- and first apoptosis signal ligand (FASL)-mediated apoptosis pathway, which subsequently decreased the pathological changes in liver tissue.³⁷ Furthermore, SCG was reported to restrain neutrophil infiltration of liver tissues by adjusting the level of cytokines (IFN-γ, TNF-α, IL-2, IL-4, IL-5 and IL-33), decreasing the high expression of cytochrome P450, and increasing the low expression of FAS in a Con A-induced liver injury of mice.³⁷

Oxidative stress was reported to result in the dysregulation of the immune system, abnormal activation of cell-death signals and the production of autoantibodies.⁹¹ P66^shc acts as a dual player in cell survival and the interplay between p66^shc and oxidative stress is implicated in the pathogenesis of various liver diseases, including AIH.⁹² Silent information regulator 1 (SIRT1) is an NAD⁺-dependent histone deacetylase and regulates cell apoptosis, inflammation and oxidative stress, which also influences the function of multiple biological targets such as p66^shc. Resveratrol, a well-known polyphenol phytoalexin, has been isolated in the roots of multitudinous Chinese herbal medicines, such as Polygonum cuspidatum, Magnolia officinalis Rehd. and Morus alba L. and acts as a hepatoprotective agent against multiple xenobiotics-induced liver injury. Recent studies have shown that resveratrol functions as an activator of S1RT1.⁹³ Recently, resveratrol was reported to dramatically reduce the infiltration of macrophages, neutrophils, and T lymphocytes in the liver caused by Con A. Furthermore, it inhibited Con A-induced reactive oxygen species (ROS) production and hepatocyte apoptosis in mice by decreasing the level of p66^shc and increasing the expression of SIRT1.³⁸ SIRT1 also exerts its anti-inflammatory, immunosuppressive and other biological activities by regulating a series of survival-related signaling pathways, such as adenosine 5′-monophosphate (AMP) activated protein kinase (AMPK). It has been demonstrated that rosmarinic acid (RA) reduced hepatocyte swelling and death, infiltration of leukocytes and serum levels of IFN-γ, IL-2 and IL-1β, and elevated the serum level of IL-10 by inducing AMPK activation and subsequent acetyl-CoA carboxylase (ACC) phosphorylation, thereby protecting mice against Con A-induced AIH.³⁹ In addition, berberine decreased the production of TNF-α, IFN-γ, IL-2, IL-1β, increased the level of IL-10 and alleviated hepatitis by blocking the transcriptional activity of signal transducer and activator of transcription 1 (STAT1), which was largely dependent on activating AMPK.⁴⁰

The transcription factor nuclear factor-kappa B (NF-κB) is considered a central mediator of the immune response and exists as an inhibitor of nuclear factor kappa B (IκB) kinase (IKK) complex with its inhibitory protein α (IκBα) in the cytoplasm in a quiescent condition. Once activated, NF-κB is translocated from the cytoplasm to the nucleus, driving the expression of target genes involved in immune and inflammation responses.⁹⁴ It was reported that SIRT1 negatively regulated the transcriptional activity of NF-κB/P65 and thus controlled the immune response of macrophages.³⁸ Interestingly, the higher level of NF-κB/P65, lower expression of SIRT1, accumulated macrophages and hepatocyte apoptosis that appeared in the livers of aged mice following long-term administration of Con A were all completely reversed by resveratrol pretreatment.⁹⁵ An extract of Rabdosia amethystoides (Benth) Hara (ERA) was reported to significantly inhibit the release of pro-inflammatory cytokines, attenuate the activation of the NF-κB pathway by reducing the expression of Toll-like receptors (TLRs) and inhibit the phosphorylation of IκB and P65 in Con A-induced mouse liver injury.⁴¹ In addition, mitogen-activated protein kinases (MAPKs) pathways including the extracellular signal-related proteins kinase (ERK), JNK and mitogen-activated protein kinase38 (p38) play a striking role in the regulation of pro-inflammatory cytokine production and the immune system.⁹⁶ It was reported that artesunate (ARS), a derivative of artemisinin, possesses a higher solubility, shorter half-life and better anti-inflammatory activity than artemisinin itself. Lijingui et al.⁴² reported that ARS reduced the excess production of pro-inflammatory cytokines (IFN-γ, IL-17 and TNF-α), increased the production of IL-10, suppressed the level of serum aminotransferases and protected mice from Con A-induced autoimmune hepatitis by inhibiting the phosphorylation of ERK, JNK and p38, NF-κB p65 and IκBα signaling in a dose-dependent manner.

Autophagy is a cannibalistic catabolic process involving the degradation of cytoplasmic constituents in lysosomes, and contributes to most biological processes from cell apoptosis and aging to immune reactions.⁹⁷ Conserved factors called autophagy-related gene (ATG) proteins and light chain 3 (LC3), as well as Beclin-1 and autophagy substrate p62 are required for autophagosome formation. IFN-γ was demonstrated to upregulate the expression of many autophagy-related proteins such as double-stranded RNA-dependent protein kinase (Pkr), Atg7, LC3-II, p62 through the Janus Kinase 1(JAK1)/STAT1 signaling pathway in Con A-induced hepatitis.⁹⁸ After induction by IL-6/JAK/STAT3 signaling, bnip3, a pro-apoptotic protein, activated Bcl-2-antagonist/killer (BAK)/BAX and initiated mitochondrial apoptosis in Con A-induced hepatitis.⁹⁹ Arctigenin (ARC), a biologically active lignan extracted from the seeds of Arctium lappa L, inhibited autophagy by downregulating Atg7, Beclin-1, LC3-II and p62, and prevented hepatocyte apoptosis by decreasing the expression of Bnip3 and Beclin-1 in Con A-induced AIH injury. In addition, ARC significantly inhibited the release of cytokines and portal inflammation, via a possible molecular mechanism inhibiting IFN-γ/IL-6/Stat1 and IL6/Bnip3 signaling pathways.⁴³

2.1.2 TCM and LPS/D-GalN-induced liver injury models

Recently, a variety of studies have shown a strong correlation between endotoxin LPS and liver failure. LPS stimulates the excessive secretion of inflammatory cytokines through the activation of TLR4 and NF-κB signaling, thereby leading to systemic inflammation and multiple organ failure.¹⁰⁰ D-GalN, a hepatocyte-specific macromolecule synthesis inhibitor, significantly aggravated LPS-induced liver inflammation in mice. LPS/D-GalN-induced hepatotoxicity is related to the upregulation of pro-inflammatory cytokines and the generation of free radicals that readily elicit a distinct DNA damage response and cause significant cytotoxicity. Although acute co-injection of LPS/D-GalN is a widely used experimental method for mimicking acute liver injury, there are still several studies that apply this animal model to investigate the therapeutic effects and molecular mechanism of herbal medicines on AIH.

TLR4 activates MAPK and NF-KB signaling by interacting with the connector protein myeloid differentiation factor (MyD88), or induces the phosphorylation of interferon regulatory factor 3 (IRF3) and the expression of IFN-β by activating TIR-domain-containing adapter-inducing IFN-β (TRIF) and TRAF3. LPS/D-GalN was observed to induce the activation of MyD88 and TRIF-dependent signaling pathways, which further increased serum ALT activity and inflammatory cell infiltration and caused fulminant hepatic failure in mice. However, most of the above symptoms caused by LPS/D-GalN were improved after scoparone treatment, a major component of A. Capillaris, accompanied by inhibition of the expression of IFN-β, TNF-α, IL-6, TRIF, MyD88 and the phosphorylation of IRF3, ERK, p38, JNK and I-κB.⁴⁴ Interleukin-1 receptor-associated kinase M (IRAK-M) is a member of the IRAK family that acts as a negative regulator of TLR signal transduction. Researchers have suggested that lupeol, a major active triterpenoid isolated from Adenophora triphylla var. japonica, plays an important role in restraining TLR4/MyD88 inflammatory signaling through the augmentation of increased IRAK-M, thus further alleviating LPS/D-GalN-mediated liver injury.⁴⁵ A previous study demonstrated that acacetin, a flavonoid isolated from Agastache rugosa, not only inhibited TLR4-mediated inflammatory responses and hepatocellular necrosis, but also enhanced autophagic flux to protect against LPS/D-GalN-induced liver injury⁴⁶. TAK1, together with its coactivator TAB1, facilitates the expression of inflammatory cytokines by simultaneously triggering the NF-κB and MAPK pathways.¹⁰¹ Cryptotanshinone (CTN) inhibited LPS/D-GalN-induced activation of NF-κB and the release of inflammatory cytokines (IL-1α and IL-β) by suppressing the phosphorylation of TAK1 and MAPK pathways, and attenuated apoptosis by blocking the activation of caspase 3/8/9 as well as the release of cyto C from the mitochondria.⁴⁷

Emerging evidence increasingly suggests the critical role of dysregulation of oxidative stress played in LPS/D-GalN-induced AIH. Pretreatment of the polysaccharide extracts of Sea buckthorn (HRP) significantly inhibited the activation of NF-κB, reduced the numbers of p65 positive cells and improved abundant inflammatory cell infiltration in livers through the TLR4-MyD88 signaling pathway, and restored the activity of antioxidant enzymes and prevented the necrosis of hepatocytes, thereby inhibiting LPS/D-GalN-induced liver injury in mice.⁴⁸ Nuclear factor-E2 related factor 2 (Nrf2) is generally induced by accumulated ROS in oxidative stress, followed by translocation to the nucleus and binding to antioxidant response elements (ARE) to promote the transcription of antioxidant genes including heme oxygenase-1 (HO-1) and inhibit NF-κB activity in hepatocytes. A variety of drugs including alpinetin/esculin/andrographolide/maslinic acid/isovitexin/chiisanoside were reported to alleviate LPS/D-GalN-induced histopathological changes and reduce liver inflammation by inhibiting NF-κB and activating Nrf2 signaling pathway.^{49-54, 102} Another study further suggested that SIRT1 was associated with the regulation of the inflammatory response and oxidative stress by deacetylating Nrf2 and NF-κB.¹⁰³ Sesquiterpenoids from Panax ginseng (SPG) dose-dependently attenuated neutrophil enrichment, inhibited the phosphorylation of P65 and IκB, as well as levels of TNF-α and IL-1β, which further promoted the nuclear translocation of Nrf2 and expression of HO-1 by activating the SIRT1 signaling pathway in the LPS/GalN-induced AIH mouse model.⁵⁵ Furthermore, Nrf2 has been reported to inhibit the activation of NOD-like receptor protein 3 (NLRP3) inflammasome, caspase-1 cleavage and IL-1β production,¹⁰⁴ which are activated under the stimulation of LPS/D-GalN. Recent reports suggest that the inhibition of NLRP3 inflammasome suppressed liver hepatitis in the LPS/D-GalN-induced mouse model. Notably, biochanin A was found to inhibit LPS/GalN-induced extensive hemorrhage, inflammatory cytokines and neutrophil infiltration by dose-dependently up-regulating the expression of Nrf2 and HO-1 in mice. Although it didn't directly inhibit the expression of NLRP3, biochanin A markedly inhibited the upregulation of thioredoxin interacting protein (TXNIP), the interaction of NLRP3 with apoptosis associated speck-like protein (ASC) and caspase-1, as well as the interaction between TXNIP and NLRP3.¹⁰⁵

Apoptotic signal-regulated kinase 1 (ASK1) is activated in response to various stresses and regulates inflammation and apoptosis by activating MAPK pathways. Tenuigenin (TEN), a major active component of polygala tenuifolia root, protected against LPS/GalN-induced extensive hemorrhage, necrosis and neutrophil infiltration by upregulating Nrf2 and HO-1 and inhibiting ASK1, NF-κB and MAPKs signaling.⁵⁷ On the one hand, LPS/GalN promoted the binding of apoptotic signaling sensor (TNF-α/TNFR1 complex) to FADD, which triggers caspase 8 and leads to the cascade reaction of caspase, such as caspase 3.¹⁰⁶ Seok-joo Kim reported that linarin, isolated from Chrysanthemum indicum L., inhibited the expression of Fas-related death domains and caspase 8, further reduced the release of cytochrome, and alleviated extensive areas of necrosis and portal inflammation caused by LPS/GalN.⁵⁸ Co-administration of LPS and GalN was also reported to increase the cytosolic release of cyto C as well as the activity of caspase 3/8/9. Garcinol, a polyisoprenylated benzophenone derivative of Garcinia indica, significantly reduced the level of the acetylated p65 subunit of NF-κB, restrained the cleavage of caspase 3, and decreased the activity of caspase 3/9 and the expression of Bax and Bax/Bcl-2 ratio in liver tissue, thereby resulting in the inhibition of LPS/D-Gal induced hepatocyte apoptosis and the inflammatory response.⁵⁹

2.1.3 TCM and CFA-induced liver injury models

Stimulation of the immune system with CFA results in altered leukocyte proliferation and differentiation, antibody production and inflammatory responses through the continuous release of immunogen. The use of CFA is necessary for the induction of several experimental mouse models of autoimmune diseases, including but not limited to autoimmune neuritis, uveitis and encephalomyelitis.¹⁰⁷ CFA has also been applied to establish mouse models mimicking the pathological features of patients with AIH, owing to its capacity to elicit immune responses. However, CFA-induced multiple organ damage further limits its application in experimental research. Therefore, most recent studies tend to combine recombinant CYP2D6, a hepatic protein target of anti-LKM1 antibodies, with CFA to induce an experimental AIH model.

It is reported that CFA-immune responses depend on the function of various cells such as macrophages, which phagocytose and digest cell fragments and pathogens and regulate the release of TNF-α, IL-1β, IL-6, and cyclooxygenase-2 (COX-2) to activate other immune cells and maintain immune homeostasis. Recently, Picrorhiza Kurroar hizome extract (PKRE) was noted to inhibit the production of proinflammatory factors TNF-α, IL-1β, IL-6, TNFR1 and COX-2 in CFA-induced peritoneal macrophages. Moreover, it markedly inhibited nitric oxide synthase (iNOS) and the phosphorylation of NF-κB by blocking the activation of IκB in activated macrophages.⁶⁰ IL-2 and IL-6/IL-10 are produced by CD4⁺ Th1 cells and CD4⁺ Th2 cells, respectively, expression of which reflects the severity of immune inflammatory reaction-caused hepatocyte damage. Wang et al. found that Paeoniae radix alba polysaccharides (PRAP) significantly alleviated cellular fatty degeneration, and improved cellular hydropic degeneration and hepatocyte regeneration. It also reduced the infiltration of CD4/8⁺ T cells and inhibited the upregulation of inflammatory cytokines IL-2 and IL-6, and the downregulation of IL-10 in a CFA-treated mouse model, which was dependent on the downregulation of NF-κB signaling pathway.⁶¹ Similar to other AIH experimental models, the pathogenesis of CFA-induced immune hepatitis is associated with hepatic parenchymal cell apoptosis. Recently, Prunella vulgarisis was reported to improve the CFA-induced hepatic inflammation and hepatocyte necrosis by reducing the infiltration of inflammatory cells, decreasing the level of pro-inflammatory cytokines IFN-γ and IL-17A and increasing the production of anti-inflammatory cells, Treg cells, and cytokines, TGF-β. On the other hand, it protected hepatocytes from CFA-caused apoptosis by directly inhibiting BAX and caspase 3.⁶²

2.1.4 TCM and α-GalCer-induced liver injury models

α-GalCer is a glycolipid isolated from a marine sponge, which specifically activates iNKT cells, secretes cytokines such as IFN-γ, TNF-α, IL-6, and IL-10, and thus results in AIH injury in vivo. The α-GalCer-induced AIH mouse model is associated with increased levels of pro-inflammatory cytokines produced by NKT cells, the infiltration of inflammatory cells and the necrosis of local hepatocytes. Furthermore, pretreatment with α-GalCer aggravated D-GalN-mediated AIH in mice. After induction by IL-6 and retinoic acid receptor-related orphan receptor gamma-t (RORγt), Th17 cells produce IL-17 and promote it attached to its receptor and further trigger inflammation through the MAPK and NF-κB pathway. On the other hand, IL-10 and Foxp3 induce the proliferation of Tregs, which modulates the immune system, maintains tolerance to self-antigens and thus alleviates AIH damage caused by secretion of TGF-β. The inhibition of IL-17 enhances the immunosuppressive activity of Treg cells, thus promoting its differentiation. Wang et al. proved that the Bu Xu Hua Yu recipe positively up-regulated the secretion of IL-10 and Foxp3, downregulated the secretion of IL-17, regulated the development and proliferation of Treg/Th17 cells, and subsequently improved α-GalCer-induced hepatitis in mice.⁶³

2.2 Effects of TCM on the treatment of hepatotoxicity-mediated murine hepatic models

2.2.1 TCM and CCl₄-induced liver injury models

CCl₄ is a well-known hepatotoxin and induces either acute or chronic hepatitis. Oral administration of CCl₄ results in the activation of leukocyte and immune-mediated liver damage, and is thus regarded as an experimental model of AIH. Although CCl₄ efficiently stimulates the production of pro-inflammatory cytokines, disrupts liver tolerance and even triggers autoimmune responses in livers, a few studies have pointed out that CCl₄ may induce a non-specific liver inflammation rather than a typical AIH.⁵⁶ Previous studies reported the hepatoprotective role in the CCl₄-induced hepatitis mouse model of total flavonoids (TFs) from Cichorium glandulosum seeds, chloroform extract of Launaea procumbens (LPCE), Nicotiana plumbignifolia methanolice extract (NPME), and ginsenoside Rg2.^64-67 With prolonged CCl₄ treatment, lipid peroxidation (LPO) in response to excessive accumulation of free radicals results in severe damage to the cell membrane and eventually necrosis. Due to a deficiency of heme oxygenase, Kupffer cells and hepatocytes are not capable of clearing iron deposition, which then results in oxidative damage and hepatitis by the Fenton reaction and aggravates LPO. Ucche (Momordica charantia L. var. muricata (Willd.) Chakravarty) reduced the infiltration of inflammatory cells and LPO by inhibiting iron-mediated signaling pathways and activating hematopoietic stem cells in a CCl₄-induced AIH rat model.⁶⁸

Nitric oxide (NO), produced by iNOS, is another critical mediator of hepatic inflammation, acting by regulating macrophages and neutrophils.¹⁰⁸ TFs markedly inhibited the levels of advanced protein oxidation products (APOP) and NO, as well as the activities of LPO and pancreatic lipase, which protected the liver from CCl₄-induced toxicity and inflammation.⁶⁹ Similarly, seabuckthorn berry polysaccharide pretreatment also prevented CCl₄-induced hepatitis damage by decreasing the expression of NO, iNOS and TLR4, and inhibiting the production of cytokines by macrophages and the phosphorylation of NF-κB and MAPK signaling.⁷⁰ After recruitment and activation of phagocytes, myeloperoxidase (MPO), a neutrophil marker, is highly expressed in neutrophils, participating in the generation of ROS. Apocynin, from the plant Picrorhiza kurroa, was demonstrated to significantly restore the activity of SOD, reduce the level of malondialdehyde (MDA), MPO, NO, and APOP, and inhibit vacuolar degeneration and massive infiltration of neutrophils and other immune cells in a CCl₄-induced AIH mouse model.⁷¹

Emerging evidence also highlights the potential interaction between AIH and drug-induced DNA damage. Innate immune receptors (TLRs and non-TLRs) recognize the immunogenicity of oxidized DNA in ROS-induced damage.⁹¹ The radical of CCl₄ was reported to directly contribute to the fragmentation and oxidative damage of DNA and hepatic inflammation, which were significantly restored towards normal levels with the administration of Sonchus arvensis (SME).⁷²

2.2.2 TCM and alcohol-induced liver injury models

Considering its increased clinical incidence, alcohol is regarded as another potential trigger of liver autoimmunity.¹⁰⁹ Excessive alcohol and its metabolites such as acetaldehyde and malondialdehyde (MAA) give rise to the production of autoantibodies and cause inflammatory responses. Emerging evidence demonstrates that MAA synergistically forms an adduct with soluble proteins, which promotes the release of cytokines, the proliferation of T cells and the production of antibodies.¹¹⁰ However, the mechanisms by which MAA adduction disrupts immune tolerance and induce autoimmune responses remain unclear.

Cytochrome P450 (CYP) 2E1-mediated alcohol metabolism leads to excessive production of ROS (·OH, H₂O₂, $O_{2}^{-}$ ), oxidative stress, LPO and hepatocyte apoptosis.¹¹¹ It has been reported that platycodon grandiflorum inhibited the activity of SOD and CAT, restrained the production of MDA, alleviated a high accumulation of microvesicular-type fat in the hepatocyte cytoplasm and prevented alcohol-induced oxidative stress and acute hepatitis.⁷³ It was also reported that Cichorium intybus root extract reduced lipid accumulation and alleviated alcohol-induced liver injury by upregulating alternative alcohol metabolism pathways mediated by ADH and ALDH and inhibiting the levels of GOT, GPT, TG and CYP2E1.⁷⁴ Under the stimulation of alcohol, excessive accumulation of fatty acids resulted in activation of lymphocytes, infiltration of macrophages and hepatic inflammation.¹¹² Penthorum chinense Pursh (PCP) reduced oxidative stress, improved inflammation and protected the liver from acute alcohol-induced hepatitis by activating the Nrf2/HO-1 pathway and downregulating the expression of CYP2E1 and hepatic TG levels.⁷⁵ A previous study showed that taraxasterol effectively improved hepatocyte steatosis and prevented the development of fatty liver by significantly reducing TG content, and inhibiting the secretion of pro-inflammatory cytokines (TNF-α and IL-6) via CYP2E1/Nrf2/HO-1 and NF-κB signaling pathways in alcohol-induced liver injury in mice.⁷⁶ Notably, pretreatment with PCP inhibited the upregulation of fatty acid translocation enzyme (CD36) expression, and ameliorated dysfunctional white adipose tissue derived-fatty acid influx to the liver, thereby protecting the liver from acute alcohol-induced hepatitis.⁷⁷

Inflammatory infiltration and hepatocyte apoptosis are widely observed in the alcohol-induced AIH mouse model. It is well established that alcohol and its metabolites promote the release of cytokines and experimental hepatitis, which are closely related to the activation of NF-κB signaling. Gastrodin ameliorated histopathological lesions of hepatocytes, alleviated liver inflammation and reduced the level of cytokines and chemokines, such as TNF-α, IFN-γ and IL-6, chemokine (C-X-C motif) ligand 1 (CXCL-1), vascular cell adhesion molecule 1 (VCAM-1) in a dose-dependent manner by regulating the NF-κB and AMPK/Nrf2 pathways in alcohol-induced AIH.⁷⁸ Akt acts as a critical upstream activator in the inflammatory reaction involving Nrf2 nuclear translocation, NF-κB activation and ROS generation.¹¹³ Triticum aestivum sprout-derived polysaccharide protected against alcohol-induced hepatitis by inhibiting the phosphatidylinositol 3-kinase (PI3K)/phosphor-protein kinase B (Akt) signaling pathway and regulating Nrf2 nuclear translocation.⁷⁹ Another study reported that cinnamomea mycelia (AC) strongly reduced lipid droplet formation, hepatocyte apoptosis and inflammatory infiltration in livers by suppressing the increased levels of TNF-α, inhibiting the phosphorylation of Akt and NF-κB and suppressing caspase 3/8/9 signaling in an alcohol-exposed rat model.⁸⁰ Under physiological conditions, excessive alcohol downregulates the production of retinol-binding protein 4 (RBP4), upregulated the expression of inflammatory factors including chitinase-3-like protein 1 (YKL 40) and plasminogen activator inhibitor type 1 (PAI-1) in the liver.¹¹⁴ A recent study further reported that Morchella esculenta prevented inflammatory cell infiltration, inhibited the production of YKL-40, IL-7, PAI-1 and RBP4 and improved the alcohol-induced imbalance in pro-oxidative and anti-oxidative signaling by altering Nrf2 and NF-κB pathways in the liver.^{81, 115}

3 CONCLUSION AND PROSPECT

AIH is a chronic inflammatory disorder characterized by interface hepatitis, increased serum autoantibodies and hypergammaglobulinemia, representing a major health burden without any available cure. Many animal models for human AIH have been generated to either provide an appropriate approach to investigate regulatory immune mechanisms or evaluate possible therapeutics. However, based on all the evidence summarized above, almost all these animal models of AIH have obvious limitations that raise the difficulty of exploring AIH pathogenesis. Although the Con A-related hepatic injury is an extensively used model mimicking the histopathological changes of human AIH, it is more suitable for studying the underlying mechanisms of immune activation and/or regulation. Moreover, while chemicals such as CCl₄ are capable of triggering liver inflammation and disrupting immune tolerance, they are more likely to induce a non-specific immune response. In addition, there is controversy about whether a liver injury model induced by MAA with soluble proteins can be widely applied to reflect the AIH injury in humans, due to the loss of immunogenicity and lack of detailed mechanisms. Furthermore, the feasibility of several established AIH animal models is still questionable. Collectively, several phenotypic characteristics need to be fulfilled in generating any novel AIH models in the future: firstly, inducing the production of autoantibodies against liver antigens; secondly, regulating the serum levels of inflammatory factors such as cytokines and chemokines; finally, altering the levels of T-cell subtypes or triggering the disorder of the immune system.

Emerging evidence shows that Chinese medicine prescriptions and natural products isolated from TCM provide additional benefits in the prevention of chronic liver diseases, including AIH, and represent a critical source of drug screening and development. In the current review, we comprehensively reviewed these researches. However, most of the above studies only investigated the regulatory effects of TCM on the typical inflammatory signaling pathways (especially those for NF-κB/MAPKs) and inflammatory factors (like IFN-γ/TNF-α/IL-6), without detecting the changes of lgG/autoantibodies and T cell subsets in the respective AIH animal models. Therefore, the precise mechanism of the protective effects of the above-reported TCM components against AIH still requires extensive research. Considering the existing deficiencies in the current AIH animal models, researchers should test combinations of different drugs or construct new animal models. For example, the NTxPD-1^−/− mouse model is an inducible AIH model that lacks the programmed cell death 1 (PD-1) gene and a sufficient number of regulatory T cells to maintain the immune T cell balance.¹¹⁶ Another novel AIH model is the CYP2D6 mouse model, which is generated by the infection of an adenovirus encoding for human CYP2D6, the best-characterized autoantigen recognized by T cells and antibodies of AIH-2 patients.¹¹⁷ These novel animal models have not been summarized in this review, because, to date, no research has yet investigated the hepatoprotective effects of TCM on these models. Further comprehensive evaluations of the effects and mechanisms of TCM on AIH-related animal models and identification of specific molecular targets are urgently needed.

CONFLICT OF INTEREST

The authors have declared no conflict of interest.

AUTHORS’ CONTRIBUTIONS

XL conceived the original idea and supervised the study. XL, JL, ZM and Han Li prepared the manuscript and figures. All authors have approved the final manuscript.

REFERENCES

1Wang QX, Yan L, Ma X. Autoimmune hepatitis in the Asia-Pacific area. J Clin Transl Hepatol. 2018; 6(1): 48-56.
10.14218/JCTH.2017.00032
PubMed Web of Science® Google Scholar
2Sahebjam F, Vierling JM. Autoimmune hepatitis. Front Med. 2015; 9(2): 187-219.
10.1007/s11684-015-0386-y
PubMed Web of Science® Google Scholar
3Liberal R, Krawitt EL, Vierling JM, Manns MP, Mieli-Vergani G, Vergani D. Cutting edge issues in autoimmune hepatitis. J Autoimmun. 2016; 75: 6-19.
10.1016/j.jaut.2016.07.005
CAS PubMed Web of Science® Google Scholar
4Burak KW, Swain MG, Santodomingo-Garzon T, et al. Rituximab for the treatment of patients with autoimmune hepatitis who are refractory or intolerant to standard therapy. Can J Gastroenterol. 2013; 27(5): 273-280.
10.1155/2013/512624
PubMed Google Scholar
5Mieli-Vergani G, Vergani D, Czaja AJ, et al. Autoimmune hepatitis. Nat Rev Dis Primers. 2018; 4:18017.
10.1038/nrdp.2018.17
PubMed Web of Science® Google Scholar
6Adiga A, Nugent K. Lupus hepatitis and autoimmune hepatitis (Lupoid Hepatitis). Am J Med Sci. 2017; 353(4): 329-335.
10.1016/j.amjms.2016.10.014
PubMed Web of Science® Google Scholar
7Manns MP, Lohse AW, Vergani D. Autoimmune hepatitis–update 2015. J Hepatol. 2015; 62(1 Suppl): S100-S111.
10.1016/j.jhep.2015.03.005
PubMed Web of Science® Google Scholar
8Vierling JM. Autoimmune hepatitis and overlap syndromes: diagnosis and management. Clin Gastroenterol Hepatol. 2015; 13(12): 2088-2108.
10.1016/j.cgh.2015.08.012
PubMed Web of Science® Google Scholar
9de Boer YS, van Gerven NM, Zwiers A, et al. Genome-wide association study identifies variants associated with autoimmune hepatitis type 1. Gastroenterology. 2014; 147(2): 443-452 e445.
10.1053/j.gastro.2014.04.022
PubMed Web of Science® Google Scholar
10Xiao ZX, Miller JS, Zheng SG. An updated advance of autoantibodies in autoimmune diseases. Autoimmun Rev. 2021; 20(2):102743.
10.1016/j.autrev.2020.102743
CAS PubMed Web of Science® Google Scholar
11Brahim I, Brahim I, Hazime R, Admou B. Autoimmune hepatitis: immunological diagnosis. Presse Med. 2017; 46(11): 1008-1019.
10.1016/j.lpm.2017.08.012
PubMed Web of Science® Google Scholar
12Miyakawa H, Kitazawa E, Kikuchi K, et al. Immunoreactivity to various human cytochrome P450 proteins of sera from patients with autoimmune hepatitis, chronic hepatitis B, and chronic hepatitis C. Autoimmunity. 2000; 33(1): 23-32.
10.3109/08916930108994106
CAS PubMed Web of Science® Google Scholar
13Bjornsson E, Talwalkar J, Treeprasertsuk S, et al. Drug-induced autoimmune hepatitis: clinical characteristics and prognosis. Hepatology. 2010; 51(6): 2040-2048.
10.1002/hep.23588
CAS PubMed Web of Science® Google Scholar
14Chi G, Feng XX, Ru YX, et al. TLR2/4 ligand-amplified liver inflammation promotes initiation of autoimmune hepatitis due to sustained IL-6/IL-12/IL-4/IL-25 expression. Mol Immunol. 2018; 99: 171-181.
10.1016/j.molimm.2018.05.005
CAS PubMed Web of Science® Google Scholar
15Behairy BE, El-Araby HA, Abd El Kader HH, et al. Assessment of intrahepatic regulatory T cells in children with autoimmune hepatitis. Ann Hepatol. 2016; 15(5): 682-690.
CAS PubMed Web of Science® Google Scholar
16Hardtke-Wolenski M, Fischer K, Noyan F, et al. Genetic predisposition and environmental danger signals initiate chronic autoimmune hepatitis driven by CD4+ T cells. Hepatology. 2013; 58(2): 718-728.
10.1002/hep.26380
CAS PubMed Web of Science® Google Scholar
17Nomura M, Hodgkinson SJ, Tran GT, et al. Cytokines affecting CD4(+)T regulatory cells in transplant tolerance. II. Interferon gamma (IFN-gamma) promotes survival of alloantigen-specific CD4(+)T regulatory cells. Transpl Immunol. 2017; 42: 24-33.
10.1016/j.trim.2017.05.002
CAS PubMed Web of Science® Google Scholar
18Fallahi P, Ferrari SM, Colaci M, et al. Hepatitis C virus infection and type 2 diabetes. Clin Ter. 2013; 164(5): e393-a404.
CAS PubMed Web of Science® Google Scholar
19Bonito AJ, Aloman C, Fiel MI, et al. Medullary thymic epithelial cell depletion leads to autoimmune hepatitis. J Clin Invest. 2013; 123(8): 3510-3524.
10.1172/JCI65414
CAS PubMed Web of Science® Google Scholar
20Muratori L, Parola M, Ripalti A, et al. Liver/kidney microsomal antibody type 1 targets CYP2D6 on hepatocyte plasma membrane. Gut. 2000; 46(4): 553-561.
10.1136/gut.46.4.553
CAS PubMed Web of Science® Google Scholar
21Gleeson D, Heneghan MA. British Society of Gastroenterology (BSG) guidelines for management of autoimmune hepatitis. Gut. 2011; 60(12): 1611-1629.
10.1136/gut.2010.235259
CAS PubMed Web of Science® Google Scholar
22Halliday N, Dyson JK, Thorburn D, Lohse AW, Heneghan MA. Review article: experimental therapies in autoimmune hepatitis. Aliment Pharmacol Ther. 2020; 52(7): 1134-1149.
10.1111/apt.16035
PubMed Web of Science® Google Scholar
23Liberal R, Longhi MS, Mieli-Vergani G, Vergani D. Pathogenesis of autoimmune hepatitis. Best Pract Res Clin Gastroenterol. 2011; 25(6): 653-664.
10.1016/j.bpg.2011.09.009
CAS PubMed Web of Science® Google Scholar
24He C, Yang Y, Zheng K, et al. Mesenchymal stem cell-based treatment in autoimmune liver diseases: underlying roles, advantages and challenges. Ther Adv Chronic Dis. 2021; 12:2040622321993442.
10.1177/2040622321993442
Web of Science® Google Scholar
25Ma HD, Deng YR, Tian Z, Lian ZX. Traditional Chinese medicine and immune regulation. Clin Rev Allergy Immunol. 2013; 44(3): 229-241.
10.1007/s12016-012-8332-0
PubMed Web of Science® Google Scholar
26Chi XL, Xiao HM, Xie YB, et al. Protocol of a prospective study for the combination treatment of Shu-Gan-jian-Pi decoction and steroid standard therapy in autoimmune hepatitis patients. BMC Complement Altern Med. 2016; 16(1): 505.
10.1186/s12906-016-1486-1
PubMed Web of Science® Google Scholar
27Zhao C-Q, Zhou Y, Ping J, Xu L-M. Traditional Chinese medicine for treatment of liver diseases: progress, challenges and opportunities. J Integr Med. 2014; 12(5): 401-408.
10.1016/S2095-4964(14)60039-X
PubMed Google Scholar
28Lee EJ, Ko E, Lee J, et al. Ginsenoside Rg1 enhances CD4(+) T-cell activities and modulates Th1/Th2 differentiation. Int Immunopharmacol. 2004; 4(2): 235-244.
10.1016/j.intimp.2003.12.007
CAS PubMed Web of Science® Google Scholar
29Christen U. Animal models of autoimmune hepatitis. Biochim Biophys Acta Mol Basis Dis. 2019; 1865(5): 970-981.
10.1016/j.bbadis.2018.05.017
CAS PubMed Web of Science® Google Scholar
30Wang T, Men R, Hu M, et al. Protective effects of Punica granatum (pomegranate) peel extract on concanavalin A-induced autoimmune hepatitis in mice. Biomed Pharmacother. 2018; 100: 213-220.
10.1016/j.biopha.2017.12.110
PubMed Web of Science® Google Scholar
31Cao Y, Tan X, Al Chnani AA, et al. Bioassay-guided isolation of an abetiane-type diterpenoid from prunella vulgaris that protects against concanavalin a-induced autoimmune hepatitis. J Nat Prod. 2021; 84(8): 2189-2199.
10.1021/acs.jnatprod.1c00247
CAS PubMed Web of Science® Google Scholar
32Zhou YQ, Weng XF, Dou R, et al. Betulin from Hedyotis hedyotidea ameliorates concanavalin A-induced and T cell-mediated autoimmune hepatitis in mice. Acta Pharmacol Sin. 2017; 38(2): 201-210.
10.1038/aps.2016.102
CAS PubMed Web of Science® Google Scholar
33Wan J, Zhu YN, Feng JQ, et al. Periplocoside A, a pregnane glycoside from Periploca sepium Bge, prevents concanavalin A-induced mice hepatitis through inhibiting NKT-derived inflammatory cytokine productions. Int Immunopharmacol. 2008; 8(9): 1248-1256.
10.1016/j.intimp.2008.05.001
CAS PubMed Web of Science® Google Scholar
34Park J, Kim H, Lee IS, et al. The therapeutic effects of Yongdamsagan-tang on autoimmune hepatitis models. Biomed Pharmacother. 2017; 94: 244-255.
10.1016/j.biopha.2017.07.015
PubMed Web of Science® Google Scholar
35Yu Q, Liu T, Li S, et al. The protective effects of levo-tetrahydropalmatine on ConA-induced liver injury are via TRAF6/JNK signaling. Mediators Inflamm. 2018; 2018:4032484.
10.1155/2018/4032484
PubMed Web of Science® Google Scholar
36Yang Y, Li F, Wei S, et al. Metabolomics profiling in a mouse model reveals protective effect of Sancao granule on Con A-Induced liver injury. J Ethnopharmacol. 2019; 238:111838.
10.1016/j.jep.2019.111838
CAS PubMed Web of Science® Google Scholar
37Yang Y, Zhang P, Wang Y, et al. Hepatoprotective effect of san-cao granule on con a-induced liver injury in mice and mechanisms of action exploration. Front Pharmacol. 2018; 9: 624.
10.3389/fphar.2018.00624
PubMed Web of Science® Google Scholar
38Huang TH, Chen CC, Liu HM, Lee TY, Shieh SH. Resveratrol pretreatment attenuates concanavalin a-induced hepatitis through reverse of aberration in the immune response and regenerative capacity in aged mice. Sci Rep. 2017; 7(1): 2705.
10.1038/s41598-017-02881-z
PubMed Web of Science® Google Scholar
39Wang Y, Meng J, Men L, et al. Rosmarinic acid protects mice from concanavalin A-induced hepatic injury through AMPK signaling. Biol Pharm Bull. 2020; 43(11): 1749-1759.
10.1248/bpb.b20-00477
CAS PubMed Web of Science® Google Scholar
40Wang Y, Zhou L, Li Y, et al. The effects of berberine on concanavalin A-induced autoimmune hepatitis (AIH) in mice and the adenosine 5'-monophosphate (AMP)-activated protein kinase (AMPK) pathway. Med Sci Monit. 2017; 23: 6150-6161.
10.12659/MSM.907377
CAS PubMed Web of Science® Google Scholar
41Zhai KF, Duan H, Cao WG, et al. Protective effect of Rabdosia amethystoides (Benth) Hara extract on acute liver injury induced by Concanavalin A in mice through inhibition of TLR4-NF-kappaB signaling pathway. J Pharmacol Sci. 2016; 130(2): 94-100.
10.1016/j.jphs.2015.12.006
CAS PubMed Web of Science® Google Scholar
42Zhao X, Liu M, Li J, Yin S, Wu Y, Wang A. Antimalarial agent artesunate protects Concanavalin A-induced autoimmune hepatitis in mice by inhibiting inflammatory responses. Chem Biol Interact. 2017; 274: 116-123.
10.1016/j.cbi.2017.07.012
CAS PubMed Web of Science® Google Scholar
43Feng Q, Yao J, Zhou G, et al. Quantitative proteomic analysis reveals that arctigenin alleviates concanavalin A-induced hepatitis through suppressing immune system and regulating autophagy. Front Immunol. 2018; 9:1881.
10.3389/fimmu.2018.01881
PubMed Web of Science® Google Scholar
44Kang JW, Kim DW, Choi JS, Kim YS, Lee SM. Scoparone attenuates D-galactosamine/lipopolysaccharide-induced fulminant hepatic failure through inhibition of toll-like receptor 4 signaling in mice. Food Chem Toxicol. 2013; 57: 132-139.
10.1016/j.fct.2013.03.016
CAS PubMed Web of Science® Google Scholar
45Kim SJ, Cho HI, Kim SJ, et al. Protective effects of lupeol against D-galactosamine and lipopolysaccharide-induced fulminant hepatic failure in mice. J Nat Prod. 2014; 77(11): 2383-2388.
10.1021/np500296b
CAS PubMed Web of Science® Google Scholar
46Cho HI, Park JH, Choi HS, et al. Protective mechanisms of acacetin against D-galactosamine and lipopolysaccharide-induced fulminant hepatic failure in mice. J Nat Prod. 2014; 77(11): 2497-2503.
10.1021/np500537x
CAS PubMed Web of Science® Google Scholar
47Jin Q, Jiang S, Wu YL, et al. Hepatoprotective effect of cryptotanshinone from Salvia miltiorrhiza in D-galactosamine/lipopolysaccharide-induced fulminant hepatic failure. Phytomedicine. 2014; 21(2): 141-147.
10.1016/j.phymed.2013.07.016
CAS PubMed Web of Science® Google Scholar
48Liu H, Zhang W, Dong S, et al. Protective effects of sea buckthorn polysaccharide extracts against LPS/d-GalN-induced acute liver failure in mice via suppressing TLR4-NF-kappaB signaling. J Ethnopharmacol. 2015; 176: 69-78.
10.1016/j.jep.2015.10.029
CAS PubMed Web of Science® Google Scholar
49Wang YY, Diao BZ, Zhong LH, et al. Maslinic acid protects against lipopolysaccharide/d-galactosamine-induced acute liver injury in mice. Microb Pathog. 2018; 119: 49-53.
10.1016/j.micpath.2018.04.002
CAS PubMed Web of Science® Google Scholar
50Liu TG, Sha KH, Zhang LG, Liu XX, Yang F, Cheng JY. Protective effects of alpinetin on lipopolysaccharide/D-Galactosamine-induced liver injury through inhibiting inflammatory and oxidative responses. Microb Pathog. 2019; 126: 239-244.
10.1016/j.micpath.2018.11.007
CAS PubMed Web of Science® Google Scholar
51Liu A, Shen Y, Du Y, et al. Esculin prevents lipopolysaccharide/D-galactosamine-induced acute liver injury in mice. Microb Pathog. 2018; 125: 418-422.
10.1016/j.micpath.2018.10.003
CAS PubMed Web of Science® Google Scholar
52Bian X, Liu X, Liu J, et al. Hepatoprotective effect of chiisanoside from Acanthopanax sessiliflorus against LPS/D-GalN-induced acute liver injury by inhibiting NF-kappaB and activating Nrf2/HO-1 signaling pathways. J Sci Food Agric. 2019; 99(7): 3283-3290.
10.1002/jsfa.9541
CAS PubMed Web of Science® Google Scholar
53Pan CW, Yang SX, Pan ZZ, et al. Andrographolide ameliorates d-galactosamine/lipopolysaccharide-induced acute liver injury by activating Nrf2 signaling pathway. Oncotarget. 2017; 8(25): 41202-41210.
10.18632/oncotarget.17149
PubMed Google Scholar
54Hu JJ, Wang H, Pan CW, Lin MX. Isovitexin alleviates liver injury induced by lipopolysaccharide/d-galactosamine by activating Nrf2 and inhibiting NF-kappaB activation. Microb Pathog. 2018; 119: 86-92.
10.1016/j.micpath.2018.03.053
CAS PubMed Web of Science® Google Scholar
55Wang W, Zhang Y, Li H, et al. Protective effects of sesquiterpenoids from the root of panax ginseng on fulminant liver injury induced by lipopolysaccharide/D-galactosamine. J Agric Food Chem. 2018; 66(29): 7758-7763.
10.1021/acs.jafc.8b02627
CAS PubMed Web of Science® Google Scholar
56Chi G, Pei JH, Ma QY, Ru YX, Feng ZH. Chemical induced inflammation of the liver breaks tolerance and results in autoimmune hepatitis in Balb/C mice. Immunol Lett. 2020; 218: 44-50.
10.1016/j.imlet.2019.11.010
CAS PubMed Web of Science® Google Scholar
57Jia R, Zhang H, Zhang W, Zhao H, Zha C, Liu Y. Protective effects of tenuigenin on lipopolysaccharide and d-galactosamine-induced acute liver injury. Microb Pathog. 2017; 112: 83-88.
10.1016/j.micpath.2017.09.051
CAS PubMed Web of Science® Google Scholar
58Kim SJ, Cho HI, Kim SJ, et al. Protective effect of linarin against D-galactosamine and lipopolysaccharide-induced fulminant hepatic failure. Eur J Pharmacol. 2014; 738: 66-73.
10.1016/j.ejphar.2014.05.024
CAS PubMed Web of Science® Google Scholar
59Jing Y, Ai Q, Lin L, et al. Protective effects of garcinol in mice with lipopolysaccharide/D-galactosamine-induced apoptotic liver injury. Int Immunopharmacol. 2014; 19(2): 373-380.
10.1016/j.intimp.2014.02.012
CAS PubMed Web of Science® Google Scholar
60Kumar R, Gupta YK, Singh S, Raj A. Anti-inflammatory effect of Picrorhiza kurroa in experimental models of inflammation. Planta Med. 2016; 82(16): 1403-1409.
10.1055/s-0042-106304
CAS PubMed Web of Science® Google Scholar
61Wang S, Xu J, Wang C, et al. Paeoniae radix alba polysaccharides obtained via optimized extraction treat experimental autoimmune hepatitis effectively. Int J Biol Macromol. 2020; 164: 1554-1564.
10.1016/j.ijbiomac.2020.07.214
CAS PubMed Web of Science® Google Scholar
62Tian H, Liu Q, Kang X, Tian Y, Fan W. Molecular mechanism of Prunella vulgaris in alleviating autoimmune hepatitis in mice. Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi. 2020; 36(7): 590-595.
PubMed Google Scholar
63Wang L, Du H, Liu Y, Wang L, Ma X, Zhang W. Chinese medicine bu xu hua yu recipe for the regulation of treg/th17 ratio imbalance in autoimmune hepatitis. Evid Based Complement Alternat Med. 2015; 2015:461294.
10.1155/2015/461294
PubMed Web of Science® Google Scholar
64Khan RA, Khan MR, Ahmed M, et al. Hepatoprotection with a chloroform extract of Launaea procumbens against CCl4-induced injuries in rats. BMC Complement Altern Med. 2012; 12: 114.
10.1186/1472-6882-12-114
PubMed Web of Science® Google Scholar
65Shah AS, Khan RA, Ahmed M, Muhammad N. Hepatoprotective role of Nicotiana plumbaginifolia Linn. against carbon tetrachloride-induced injuries. Toxicol Ind Health. 2016; 32(2): 292-298.
10.1177/0748233713498448
CAS PubMed Web of Science® Google Scholar
66Elgengaihi S, Mossa AT, Refaie AA, Aboubaker D. Hepatoprotective efficacy of Cichorium intybus L. extract against carbon tetrachloride-induced liver damage in rats. J Diet Suppl. 2016; 13(5): 570-584.
10.3109/19390211.2016.1144230
PubMed Google Scholar
67Hsu YJ, Wang CY, Lee MC, Huang CC. Hepatoprotection by traditional essence of ginseng against carbon tetrachloride-induced liver damage. Nutrients. 2020; 12(10):3214.
10.3390/nu12103214
CAS Web of Science® Google Scholar
68Sagor AT, Chowdhury MR, Tabassum N, Hossain H, Rahman MM, Alam MA. Supplementation of fresh ucche (Momordica charantia L. var. muricata Willd) prevented oxidative stress, fibrosis and hepatic damage in CCl4 treated rats. BMC Complement Altern Med. 2015; 15: 115.
10.1186/s12906-015-0636-1
PubMed Web of Science® Google Scholar
69Tong J, Yao X, Zeng H, et al. Hepatoprotective activity of flavonoids from Cichorium glandulosum seeds in vitro and in vivo carbon tetrachloride-induced hepatotoxicity. J Ethnopharmacol. 2015; 174: 355-363.
10.1016/j.jep.2015.08.045
CAS PubMed Web of Science® Google Scholar
70Zhang W, Zhang X, Zou K, et al. Seabuckthorn berry polysaccharide protects against carbon tetrachloride-induced hepatotoxicity in mice via anti-oxidative and anti-inflammatory activities. Food Funct. 2017; 8(9): 3130-3138.
10.1039/C7FO00399D
CAS PubMed Web of Science® Google Scholar
71Rahman MM, Muse AY, Khan D, et al. Apocynin prevented inflammation and oxidative stress in carbon tetra chloride induced hepatic dysfunction in rats. Biomed Pharmacother. 2017; 92: 421-428.
10.1016/j.biopha.2017.05.101
CAS PubMed Web of Science® Google Scholar
72Alkreathy HM, Khan RA, Khan MR, Sahreen S. CCl4 induced genotoxicity and DNA oxidative damages in rats: hepatoprotective effect of Sonchus arvensis. BMC Complement Altern Med. 2014; 14: 452.
10.1186/1472-6882-14-452
PubMed Web of Science® Google Scholar
73Noh JR, Kim YH, Gang GT, et al. Hepatoprotective effect of Platycodon grandiflorum against chronic ethanol-induced oxidative stress in C57BL/6 mice. Ann Nutr Metab. 2011; 58(3): 224-231.
10.1159/000330117
CAS PubMed Web of Science® Google Scholar
74Kim J, Kim MJ, Lee JH, Woo K, Kim M, Kim TJ. Hepatoprotective effects of the Cichorium intybus Root extract against alcohol-induced liver injury in experimental rats. Evid Based Complement Alternat Med. 2021; 2021:6643345.
10.1155/2021/6643345
PubMed Web of Science® Google Scholar
75Cao Y-W, Jiang Y, Zhang D-Y, et al. Protective effects of Penthorum chinense Pursh against chronic ethanol-induced liver injury in mice. J Ethnopharmacol. 2015; 161: 92-98.
10.1016/j.jep.2014.12.013
PubMed Web of Science® Google Scholar
76Xu L, Yu Y, Sang R, Li J, Ge B, Zhang X. Protective effects of taraxasterol against ethanol-induced liver injury by regulating CYP2E1/Nrf2/HO-1 and NF-kappaB signaling pathways in mice. Oxid Med Cell Longev. 2018; 2018:8284107.
10.1155/2018/8284107
PubMed Web of Science® Google Scholar
77Cao YW, Jiang Y, Zhang DY, et al. The hepatoprotective effect of aqueous extracts of Penthorum chinense Pursh against acute alcohol-induced liver injury is associated with ameliorating hepatic steatosis and reducing oxidative stress. Food Funct. 2015; 6(5): 1510-1517.
10.1039/C5FO00098J
CAS PubMed Web of Science® Google Scholar
78Qu LL, Yu B, Li Z, Jiang WX, Jiang JD, Kong WJ. Gastrodin ameliorates oxidative stress and proinflammatory response in nonalcoholic fatty liver disease through the AMPK/Nrf2 pathway. Phytother Res. 2016; 30(3): 402-411.
10.1002/ptr.5541
CAS PubMed Web of Science® Google Scholar
79Nepali S, Ki HH, Lee JH, Cha JY, Lee YM, Kim DK. Triticum aestivum sprout-derived polysaccharide exerts hepatoprotective effects against ethanol-induced liver damage by enhancing the antioxidant system in mice. Int J Mol Med. 2017; 40(4): 1243-1252.
10.3892/ijmm.2017.3095
CAS PubMed Web of Science® Google Scholar
80Liu Y, Wang J, Li L, et al. Hepatoprotective effects of Antrodia cinnamomea: The modulation of oxidative stress signaling in a mouse model of alcohol-induced acute liver injury. Oxid Med Cell Longev. 2017; 2017:7841823.
10.1155/2017/7841823
PubMed Web of Science® Google Scholar
81Meng B, Zhang Y, Wang Z, Ding Q, Song J, Wang D. Hepatoprotective effects of morchella esculenta against alcohol-induced acute liver injury in the C57BL/6 mouse related to Nrf-2 and NF-kappaB signaling. Oxid Med Cell Longev. 2019; 2019:6029876.
10.1155/2019/6029876
PubMed Web of Science® Google Scholar
82Tiegs G, Hentschel J, Wendel A. A T cell-dependent experimental liver injury in mice inducible by concanavalin A. J Clin Invest. 1992; 90(1): 196-203.
10.1172/JCI115836
CAS PubMed Web of Science® Google Scholar
83Khan HA, Ahmad MZ, Khan JA, Arshad MI. Crosstalk of liver immune cells and cell death mechanisms in different murine models of liver injury and its clinical relevance. Hepatobiliary Pancreat Dis Int. 2017; 16(3): 245-256.
10.1016/S1499-3872(17)60014-6
PubMed Web of Science® Google Scholar
84Maggi E, Cosmi L, Liotta F, Romagnani P, Romagnani S, Annunziato F. Thymic regulatory T cells. Autoimmun Rev. 2005; 4(8): 579-586.
10.1016/j.autrev.2005.04.010
CAS PubMed Web of Science® Google Scholar
85Chapman NM, Boothby MR, Chi H. Metabolic coordination of T cell quiescence and activation. Nat Rev Immunol. 2020; 20(1): 55-70.
10.1038/s41577-019-0203-y
CAS PubMed Web of Science® Google Scholar
86LeBien TW, Tedder TF. B lymphocytes: how they develop and function. Blood. 2008; 112(5): 1570-1580.
10.1182/blood-2008-02-078071
CAS PubMed Web of Science® Google Scholar
87Kaneko Y, Harada M, Kawano T, et al. Augmentation of Valpha14 NKT cell-mediated cytotoxicity by interleukin 4 in an autocrine mechanism resulting in the development of concanavalin A-induced hepatitis. J Exp Med. 2000; 191(1): 105-114.
10.1084/jem.191.1.105
CAS PubMed Web of Science® Google Scholar
88Takeda K, Hayakawa Y, Van Kaer L, Matsuda H, Yagita H, Okumura K. Critical contribution of liver natural killer T cells to a murine model of hepatitis. Proc Natl Acad Sci USA. 2000; 97(10): 5498-5503.
10.1073/pnas.040566697
CAS PubMed Web of Science® Google Scholar
89Bock FJ, Tait SWG. Mitochondria as multifaceted regulators of cell death. Nat Rev Mol Cell Biol. 2020; 21(2): 85-100.
10.1038/s41580-019-0173-8
CAS PubMed Web of Science® Google Scholar
90Ow YP, Green DR, Hao Z, Mak TW. Cytochrome c: functions beyond respiration. Nat Rev Mol Cell Biol. 2008; 9(7): 532-542.
10.1038/nrm2434
CAS PubMed Web of Science® Google Scholar
91Souliotis VL, Vlachogiannis NI, Pappa M, Argyriou A, Ntouros PA, Sfikakis PP. DNA damage response and oxidative stress in systemic autoimmunity. Int J Mol Sci. 2019; 21(1):55.
10.3390/ijms21010055
PubMed Web of Science® Google Scholar
92Koch OR, Fusco S, Ranieri SC, et al. Role of the life span determinant P66(shcA) in ethanol-induced liver damage. Lab Invest. 2008; 88(7): 750-760.
10.1038/labinvest.2008.44
CAS PubMed Web of Science® Google Scholar
93Ma BN, Li XJ. Resveratrol extracted from Chinese herbal medicines: a novel therapeutic strategy for lung diseases. Chin Herb Med. 2020; 12(4): 349-358.
10.1016/j.chmed.2020.07.003
Web of Science® Google Scholar
94Yeung F, Hoberg JE, Ramsey CS, et al. Modulation of NF-kappaB-dependent transcription and cell survival by the SIRT1 deacetylase. EMBO J. 2004; 23(12): 2369-2380.
10.1038/sj.emboj.7600244
CAS PubMed Web of Science® Google Scholar
95Li X, Li Y, States VA, Li S, Zhang X, Martin RC. The effect of black raspberry extracts on MnSOD activity in protection against concanavalin A induced liver injury. Nutr Cancer. 2014; 66(6): 930-937.
10.1080/01635581.2014.922201
PubMed Web of Science® Google Scholar
96Ma X, Jia YT, Qiu DK. Inhibition of p38 mitogen-activated protein kinase attenuates experimental autoimmune hepatitis: involvement of nuclear factor kappa B. World J Gastroenterol. 2007; 13(31): 4249-4254.
10.3748/wjg.v13.i31.4249
CAS PubMed Web of Science® Google Scholar
97Cui B, Lin H, Yu J, Yu J, Hu Z. Autophagy and the immune response. Adv Exp Med Biol. 2019; 1206: 595-634.
10.1007/978-981-15-0602-4_27
CAS PubMed Web of Science® Google Scholar
98Wang Y, Ren Z, Tao D, Tilwalli S, Goswami R, Balabanov R. STAT1/IRF-1 signaling pathway mediates the injurious effect of interferon-gamma on oligodendrocyte progenitor cells. Glia. 2010; 58(2): 195-208.
10.1002/glia.20912
PubMed Web of Science® Google Scholar
99Kubli DA, Ycaza JE, Gustafsson AB. Bnip3 mediates mitochondrial dysfunction and cell death through Bax and Bak. Biochem J. 2007; 405(3): 407-415.
10.1042/BJ20070319
CAS PubMed Web of Science® Google Scholar
100Jiang W, Sun R, Wei H, Tian Z. Toll-like receptor 3 ligand attenuates LPS-induced liver injury by down-regulation of toll-like receptor 4 expression on macrophages. Proc Natl Acad Sci USA. 2005; 102(47): 17077-17082.
10.1073/pnas.0504570102
CAS PubMed Web of Science® Google Scholar
101Holtmann H, Enninga J, Kalble S, et al. The MAPK kinase kinase TAK1 plays a central role in coupling the interleukin-1 receptor to both transcriptional and RNA-targeted mechanisms of gene regulation. J Biol Chem. 2001; 276(5): 3508-3516.
10.1074/jbc.M004376200
CAS PubMed Web of Science® Google Scholar
102Munro CA, Selvaggini S, de Bruijn I, et al. The PKC, HOG and Ca²⁺ signalling pathways co-ordinately regulate chitin synthesis in Candida albicans. Mol Microbiol. 2007; 63(5): 1399-1413.
10.1111/j.1365-2958.2007.05588.x
CAS PubMed Web of Science® Google Scholar
103Kemelo MK, Wojnarova L, Kutinova Canova N, Farghali H. D-galactosamine/lipopolysaccharide-induced hepatotoxicity downregulates sirtuin 1 in rat liver: role of sirtuin 1 modulation in hepatoprotection. Physiol Res. 2014; 63(5): 615-623.
10.33549/physiolres.932761
CAS PubMed Web of Science® Google Scholar
104Liu X, Zhang X, Ding Y, et al. Nuclear factor E2-related factor-2 negatively regulates NLRP3 inflammasome activity by inhibiting reactive oxygen species-induced NLRP3 priming. Antioxid Redox Signal. 2017; 26(1): 28-43.
10.1089/ars.2015.6615
CAS PubMed Web of Science® Google Scholar
105Liu X, Wang T, Liu X, et al. Biochanin A protects lipopolysaccharide/D-galactosamine-induced acute liver injury in mice by activating the Nrf2 pathway and inhibiting NLRP3 inflammasome activation. Int Immunopharmacol. 2016; 38: 324-331.
10.1016/j.intimp.2016.06.009
CAS PubMed Web of Science® Google Scholar
106Hatano E. Tumor necrosis factor signaling in hepatocyte apoptosis. J Gastroenterol Hepatol. 2007; 22(Suppl 1): S43-44.
10.1111/j.1440-1746.2006.04645.x
CAS PubMed Web of Science® Google Scholar
107Dube JY, McIntosh F, Zarruk JG, David S, Nigou J, Behr MA. Synthetic mycobacterial molecular patterns partially complete Freund's adjuvant. Sci Rep. 2020; 10(1):5874.
10.1038/s41598-020-62543-5
CAS PubMed Web of Science® Google Scholar
108Tripathi P. Nitric oxide and immune response. Indian J Biochem Biophys. 2007; 44(5): 310-319.
CAS PubMed Web of Science® Google Scholar
109Zachou K, Arvaniti P, Lyberopoulou A, Dalekos GN. Impact of genetic and environmental factors on autoimmune hepatitis. J Transl Autoimmun. 2021; 4:100125.
10.1016/j.jtauto.2021.100125
CAS PubMed Google Scholar
110Thiele GM, Duryee MJ, Willis MS, et al. Autoimmune hepatitis induced by syngeneic liver cytosolic proteins biotransformed by alcohol metabolites. Alcohol Clin Exp Res. 2010; 34(12): 2126-2136.
10.1111/j.1530-0277.2010.01309.x
CAS PubMed Web of Science® Google Scholar
111Neve EP, Ingelman-Sundberg M. Molecular basis for the transport of cytochrome P450 2E1 to the plasma membrane. J Biol Chem. 2000; 275(22): 17130-17135.
10.1074/jbc.M000957200
CAS PubMed Web of Science® Google Scholar
112Romero-Zerbo SY, Garcia-Fernandez M, Espinosa-Jimenez V, et al. The atypical cannabinoid Abn-CBD reduces inflammation and protects liver, pancreas, and adipose tissue in a mouse model of prediabetes and non-alcoholic fatty liver disease. Front Endocrinol (Lausanne). 2020; 11: 103.
10.3389/fendo.2020.00103
PubMed Web of Science® Google Scholar
113Li XX, Jiang ZH, Zhou B, Chen C, Zhang XY. Hepatoprotective effect of gastrodin against alcohol-induced liver injury in mice. J Physiol Biochem. 2019; 75(1): 29-37.
10.1007/s13105-018-0647-8
PubMed Web of Science® Google Scholar
114Swiatkowska M, Szemraj J, Al-Nedawi KN, Pawlowska Z. Reactive oxygen species upregulate expression of PAI-1 in endothelial cells. Cell Mol Biol Lett. 2002; 7(4): 1065-1071.
CAS PubMed Web of Science® Google Scholar
115Zhou W, Ye S, Li J. Expression of retinol binding protein 4 and nuclear factor-kappaB in diabetic rats with atherosclerosis and the intervention effect of pioglitazone. Exp Ther Med. 2016; 12(2): 1000-1006.
10.3892/etm.2016.3340
CAS PubMed Web of Science® Google Scholar
116Maruoka R, Aoki N, Kido M, et al. Splenectomy prolongs the effects of corticosteroids in mouse models of autoimmune hepatitis. Gastroenterology. 2013; 145(1): 209-220.e209.
10.1053/j.gastro.2013.03.011
CAS PubMed Web of Science® Google Scholar
117Hintermann E, Ehser J, Christen U. The CYP2D6 animal model: how to induce autoimmune hepatitis in mice. J Vis Exp. 2012; 60.
Google Scholar

Citing Literature

Volume5, Issue2

Themed Issue: Traditional Chinese Medicines and Natural Medicines Research

April 2022

Pages 95-107

This article also appears in:

Chinese medicine in the treatment of autoimmune hepatitis: Progress and future opportunities

Abstract

1 INTRODUCTION

2 MURINE INJURY MODELS FOR AIH

2.1 Effects of TCM on the treatment of immune cell-mediated murine hepatic models

2.1.1 TCM and Con A-induced liver injury models

2.1.2 TCM and LPS/D-GalN-induced liver injury models

2.1.3 TCM and CFA-induced liver injury models

2.1.4 TCM and α-GalCer-induced liver injury models

2.2 Effects of TCM on the treatment of hepatotoxicity-mediated murine hepatic models

2.2.1 TCM and CCl₄-induced liver injury models

2.2.2 TCM and alcohol-induced liver injury models

3 CONCLUSION AND PROSPECT

CONFLICT OF INTEREST

AUTHORS’ CONTRIBUTIONS

REFERENCES

Citing Literature

Figures

References

Information

About Wiley Online Library

Help & Support

Opportunities

Connect with Wiley

Chinese medicine in the treatment of autoimmune hepatitis: Progress and future opportunities

Abstract

1 INTRODUCTION

2 MURINE INJURY MODELS FOR AIH

2.1 Effects of TCM on the treatment of immune cell-mediated murine hepatic models

2.1.1 TCM and Con A-induced liver injury models

2.1.2 TCM and LPS/D-GalN-induced liver injury models

2.1.3 TCM and CFA-induced liver injury models

2.1.4 TCM and α-GalCer-induced liver injury models

2.2 Effects of TCM on the treatment of hepatotoxicity-mediated murine hepatic models

2.2.1 TCM and CCl4-induced liver injury models

2.2.2 TCM and alcohol-induced liver injury models

3 CONCLUSION AND PROSPECT

CONFLICT OF INTEREST

AUTHORS’ CONTRIBUTIONS

REFERENCES

Citing Literature

Figures

References

Related

Information

2.2.1 TCM and CCl₄-induced liver injury models