Liver immunology and herbal treatment

Yasemin H Balaban, Ceylan Aka, Ufuk Koca-Caliskan REVIEW WJH|www.wjgnet.com 757 June 18, 2017|Volume 9|Issue 17| Liver immunology and herbal treatment Yasemin H Balaban, Gastroenterology Unit, Private Etimed Hospital, 06790 Ankara, Turkey Ceylan Aka, Ufuk Koca-Caliskan, Department of Pharmacognosy, Gazi University - Pharmacy Faculty, 06330 Ankara, Turkey Author contributions: We attest to the fact that all authors listed on the title page have contributed equally significantly to the work, have read the manuscript, and agree to its submission to the World Journal of Hepatology. Conflict-of-interest statement: This statement is to certify that all the authors have approved the manuscript being submitted. We the authors warrant that the article is our original work, which has not received prior publication in whole or in part elsewhere and is not under consideration for publication elsewhere. On behalf of all co-authors, the corresponding author shall bear full responsibility for the submission. Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/ licenses/by-nc/4.0/ Manuscript source: Invited manuscript Correspondence to: Dr. Yasemin H Balaban, Professor, Gastroenterology Unit, Private Etimed Hospital, Elvan Mah, 1934 Sok, No. 4, 06790 Ankara, Turkey. ybalaban@hacettepe.edu.tr Telephone: +90-533-2344232 Fax: +90-312-2930605 Received: March 4, 2017 Peer-review started: March 7, 2017 First decision: April 18, 2017 Revised: April 29, 2017 Accepted: May 18, 2017 Article in press: May 19, 2017 Published online: June 18, 2017 Abstract Beyond the metabolic functions, the liver recently has been defined as an organ of immune system (IS), which have central regulatory role for innate and adaptive immunity. The liver keeps a delicate balance between hepatic screening of pathogenic antigens and immune tolerance to self-antigens. Herbal treatments with immunological effects have potential to alter this hepatic immune balance towards either therapeutic side or diseases side by inducing liver injury via hepatotoxicity or initiation of autoimmune diseases. Most commonly known herbal treatments, which have therapeutic effect on liver and IS, have proven via in vitro, in vivo, and/or clinical studies were summarized in this review. Key words: Herbal treatments; Hepatic immunology; Drug induced liver injury; Adaptive immunity; Innate immunity © The Author(s) 2017. Published by Baishideng Publishing Group Inc. All rights reserved. Core tip: Herbal treatment is the mother of modern medicine. The ancient habit of treating diseases with plants still goes on as either primary or complementary to conventional medical treatment. The other side of medallion is the fact that the liver is number one target organ for herbal toxicity. Furthermore, liver has been recently defined as an active organ of immune system, which have central regulatory role on innate and adaptive immune response. The delicate homeostasis between immediate and efficient defense against threats (immune surveilance of antigens) without triggering harmful immune response towards self-structures (periferal immune tolerance to self antigens) is controled by liver. Herbal formulas are not a single plant extract, but is an interacting mixture of ingredients that determines the final clinical outcome as therapeutic and hepatotoxic effect. This review aimed to drive attention on both potentials of herbals from the point of immunology, in order to initiate a motivation for feature studies defining Submit a Manuscript: http://www.f6publishing.com DOI: 10.4254/wjh.v9.i17.757 World J Hepatol 2017 June 18; 9(17): 757-770 ISSN 1948-5182 (online) WJH|www.wjgnet.com 758 June 18, 2017|Volume 9|Issue 17| Balaban YH et al. Liver immunology and herbal treatment the mechanisms of immunological interaction between herbals and liver. Balaban YH, Aka C, Koca-Caliskan U. Liver immunology and herbal treatment. World J Hepatol 2017; 9(17): 757-770 Available from: URL: http://www.wjgnet.com/1948-5182/full/v9/i17/757. htm DOI: http://dx.doi.org/10.4254/wjh.v9.i17.757 INTRODUCTION Herbal treatment is the mother of modern medicine. Because of cultural, economical and practical reasons, the ancient habit of treating diseases with plants still goes on as either primary or complementary to conventional medical treatment. The other side of medallion is the fact that the liver is number one target organ of herbal and dietary supplements (HDS) induced toxicity. The Food and Drug Administration (FDA) under the Dietary Supplement Health and Education Act (DSHEA) regulate herbal treatments since 1994[1]. The submissions of new herbal products to FDA require the dose and list of ingredients to be written on its bottle, however, documentation of safety and efficacy is not need to be reported. Furthermore, HDS can be obtained without prescription, medical advice or monitoring. Although the actual size of the problem is not well defined, HDSinduced hepatotoxicity accounts for 20% of cases of hepatotoxicity in the United States and the rates differ from 2.5% in India to 70% in Singapore[2]. The liver is prone to drug-induced liver injury (DILI) because of its functions on metabolizing chemicals and regulating immune response. DILI can develop either by dose related direct drug toxicity, or - much more commonly - as idiosyncratic reactions due to individual susceptibility to ingredients. The complex composition of HDS eases the both direct toxicity and idiosyncratic reactions during their metabolism in liver. Idiosyncratic DILI (IDILI) is in most instances characterized by a mild injury (ALT < 3 times upper normal limit) which normalized with continuous drug treatment. This phenomenon of clinical adaptation is a biochemical adaptive response of organelles such as endoplasmic reticulum and mitochondria metabolizing chemicals. It is hypothesized that defective clinical adaptation mechanisms result in severe IDILI with jaundice and liver failure, in < 0.1% population with susceptible human leucocyte antigen (HLA) type. Microbiota is the ecological community of commensal, symbiotic and pathogenic microorganisms that literally share our body space[3]. The microbiota of gut also determinates IDILI susceptibly by regulating hepatic immune-tolerance though lipo­polysaccharides (LPS) induced T-cell response in liver. According to theory, haptens of metabolized chemicals covalently bind to proteins, and become antigenic peptides. While 70%-90% of population has immune tolerance, the rest develop adaptive immune response due to their susceptible type HLA and/or dysfunctional microbiota. If biochemical adaptation mechanisms cannot control this initiated mild injury, acute liver failure develops[4]. There are supporting evidences to this theory. The many top IDILI drugs are antibiotics changing the normal microbiota. The “immune check point therapy” for cancer treatments are FDA approved antibodies that aim to inhibit T cell immune-tolerant states, such as ipilimumab (anti-CTLA4), pembrolizumab (anti-PD-1) and nivolumab (anti-PD-1). The major side effect of these treatments is to make individuals to susceptible to haptens (so inducing IDILI) and auto-antigens (so inducing autoimmunity). This review aimed to drive attention on both therapeutic mechanisms and hepatotoxic potentials of herbal treatments from the point of immunology. After defining basic immune system (IS), we summarized the role of liver as an immune regulatory organ and then the herbal treatments with therapeutic potential on liver. IS IS has evolved to recognize and eliminate internal insults (i.e., cancer cells) or external invading pathogens (i.e., infections) by developing local or systemic response. IS composed of “classical lymphoid organs”; thymus, bone marrow, spleen, tonsils, lymph nodes and “peripheral immune organs”; skin, respiratory and gut mucosaassociated lymphoid tissues, adrenal glands. Additionally, the gut and liver are recently defined as active organs of IS. Although the primary functions of liver parenchymal cells are methabolical, they also carry out essential immune tasks. Beside all metabolic functions, liver has important role as an organ of IS. IS begins to develop during intrauterine life. However, maturation of IS depends on antigenic stimulations from environment. The gut microbiota is initiated by maternal microorganisms gained during passage through birth channel and it dynamically change according to external conditions. The gut microbiota is necessary for proper “education” of IS. Although IS completes its maturation around teenage, lifelong antigenic stimulations from microbiota is needed for normal functioning of IS. Epidemiological observations and then, experimental data from germ-free animals leads to “hygiene hypothesis” and its modern extension called “microflora hypothesis”. According to these hypotheses, the higher levels of cleanliness and decreased exposure to microorganisms (driven by factors such as antibiotic use, xenobiotics, infection, or diet) during early childhood disrupt maturation if IS. In other words, the dysbiotic gut microbiota, which arisen during critical window of IS maturation, turns the differentiation of naïve immune gut dentritic cells (DCs) from generation of Treg (regulatory) cells by tolerogenic DCs into generation of effector T cells by immunogenic DCs. This shifts TH response from Th1 type (IFN-γ mediated) to Th2 type (IL-4 mediated). As a result, the risk for autoimmune and allergic diseases increases[5,6]. By definition IS has 2 parts; the innate IS and the adaptive IS. Although this division simplifies the understanding of immune processes, IS orchestrates WJH|www.wjgnet.com 759 June 18, 2017|Volume 9|Issue 17| whole immune cells during local or systemic responses. Innate IS The innate IS initiates first defense against insults, and is characterized by its ability to distinguish self from non-self. Its members are classic immune cells such as polymorphic nuclear leukocytes (neutrophils), monocytes, macrophages and DCs, natural killer (NK) cells, and innate lymphoid cells (ILCs), beside epithelial, endothelial and mesenchymal cells which are nonimmune cells. The inflammation during innate immune response is triggered by pattern-recognition receptors (PRRs). The 3 families of PRR, according to the structure they can recognize, are Toll-like receptors (TLRs), retinoic acidinducible gene I-like receptors and nucleotide-binding oligomerization domain-like receptors. The cells expressing PRR can recognize conserved structures. For instance, miRNAs controls multiple immune processes such as regulating the innate immune responses of macrophages, dendritic cells and NK cells; involving in T-cell differentiation and function. Furthermore defective PRR function might lead to autoimmune or auto-inflammatory diseases, since nucleic acids (DNA and RNA) is commonly shared by the pathogen and host. Additionally, damage associated molecular patterns (DAMP), pathogen associated molecular patterns (PAMP), microbiome associated molecular patterns are the subtypes of PRR[6,7]. Mononuclear phagocyte system (MPS) composed by monocytes, macrophages, and DCs that have phenotypical and functional overlaping boundaries leading to uncertainty in differentiating them form each other. Antigen-presenting cells (APCs) express PRR and characterized by their ability to recognize, process and present antigens for activation of innate and adaptive immunity. The classical APCs include DC, monocytes and macrophages, although parenchymal cells can also act as APCs. MPS may be precursor of some APCs of liver, namely DCs and Kuppfer cells (KCs)[8]. ILCs are a recently identified family of heterogeneous variety of T cells and non-T cells, including NK cells, CD56+ Tcells, natural killer T cells (NKT), gamma/deltaT cells, mucosal- associated invariant T cells, lymphoid tissueinducer cells and cells that produce IL-5, IL-13, IL-17 and IL-22. ILCs not only regulate innate and adaptive immune responses by promoting DC maturation into APCs, they have function in lymphoid tissue formation and the homeostasis of tissue stromal cells remodeling the tissues[9,10]. Adaptive IS The adaptive immunity evolutionarily developed later than innate immunity in high-class vertebrates. The adaptive immune response occurs as second phase of immune response, mediated mainly by lymphocytes, and characterized by the features of antigen-specific response and memory response. It is initiated by antigen presentation lymphocytes. The main lymphoid repertoire includes T-cells, B cells. B cells produce specific antibodies in response to a specific antigen. These antibodies are crucial for T cells activation against bacterial infections and development of active immunization after vaccination[7,11]. However, the major mediator of adaptive immune response is the T cells, which control both the establishment and regulation of adaptive immunity. T cells are identified by CD3 and T cell receptors (TCRs) positivity, and have vital importance in the adaptive and innate immunity. Conventional T cells express alphabeta type TCR. Gamma-delta T cells are located in skin, genitourinary tract mucosa and gut, as well as liver. The naive T cells produced in bone barrow migrates to thymus and differentiate into 2 main subtypes are Th (helper) and Ts (supressor). The differentiated T cells are exported to periphery, where they become effector T cells upon activation by APCs or B cells. T cell activation requires binding of TCR to major histocompatibility complex (MHC), as well as binding of co-stimulatory molecule present on T cells to its co-receptor on APCs (e.g., binding of CD28 to B7). Th cells express CD4, which recognizes antigens in the context of MHC class Ⅱ, and are mainly regulatory cells. Ts are cytotoxic cells carrying CD8 receptors, which are activated by MHC class I molecules[11]. Recently, CD4+ cells have been divided into subsets according to their distinct cytokine production and function; Th1, Th2, T17, Treg, Tfh (follicular T helper). Some features of CD4+ cells are as shown on Table 1. Treg cells express CD4+CD25+ and are essential for maintaining immune homeostasis and selftolerance. Treg cells either naturally produced from CD4+ thymocytes in the thymus or iTreg cells are induced at periphery from naive CD4+ T cells in response to the lowdose stimulation of TCR, TGF-beta and IL-2. Beside all these effector T cells, there are also memory T cells. Id3 is the key transcriptional regulator for controlling T-cell differentiation into either effector T cells or memory T cells by its action though mTORC signaling[7,9,12]. DCs are professional APC, which can recognize foreign antigens by their PRR, initiate immune response and constitute a bridge between innate and adaptive immunity. They primary screen surrounding microenviron­ment by antigen sampling and direct IS towards pro- or antiinflammatory response[6]. DCs are found throughout the body as immature DCs and subdivided as plasmacytoid (or lymphoid) DCs and myeloid DCs. Plasmacytoid DCs mediate anti-viral immunity by its capability of viral recognition and type 1 interferons secretion. The myeloid DCs constitute conventional MPS derived DCs in blood, interstitial DCs in tissues, Langerhan cells in skin and monocyte-derived DCs. mDC can internalise antigens by phagocytosis, pinocytosis or receptor-mediated endocytosis. After generation of peptide by proteolytic degradation within endocytic vesicles, it complexes with newly synthesized MHC class Ⅱ molecule within endocytic compartment, and then is carried via the transGolgi network to the cell surface. The recognition and internalization of pathogens by DCs leads to maturation of them into professional APCs, which have altered adhesion molecule and chemokine receptor expression. Balaban YH et al. Liver immunology and herbal treatment WJH|www.wjgnet.com 760 June 18, 2017|Volume 9|Issue 17| After maturation DCs leave primary side of infection through lymphatic’s to carry the inter­nalized pathogen to secondary lymphoid organ. The professional APCs can be either immunogenic DCs which express high levels of MHC and co-stimulatory molecules, and secrete IL-12, IL-18, IL-21 and IL-23 or tolerogenic DCs having low expression levels, express inhibitory receptors, such as programmed death ligand-1, and releasing suppressive cytokines, such as IL-10, IL-27 and TGFbeta. Immunogenic DCs stimulate naïve CD4+ T cells to differentiation into effector cell mediating adaptive immunity against specific pathogen. On the other hand, if the antigenic peptid is presented to naïve CD4+ T cell by tolerogenic DCs, immune tolerance develops either at thymus or periphery. The consequen result in thymus is either T cell apoptosis or T cell maturation into natural Treg cells. The mechanisms for peripheral immune tolerance are anergy of T cells and exhaustion of T cells. The anergy arises when T cells are inactivated due to lack of co-stimulation. The exhaustion of T cells is characterized by expression of inhibitory receptors, namely programmed death-1 (PD-1), cytotoxic T lymphocyte antigen-4 (CTLA4) and T cell immunoglobulin mucin-3. Interestingly in mice and humans, the lipid content of DCs in liver determines the maturation type of APCs, as lipid content decreases tolerant immune response is favoured. This phenomenon might be important for progression of simple steatosis into steatohepatitis. The relationship of autoimmune diseases with infection and environmental pollution and is very well known fact. It is though that the similarity between insulting antigen and self antigens of individuals with susceptible HLA haplotypes causes a shift during APCs maturation from tolerogenic DCs towards to immuno­genic DCs, leading to differention of naive T cells into effector ratherden tolerogenic cells, and ending in loss of self-immune tolerance[1,9,11]. NK express CD56 in the absence of CD3, but NKT express both of them. NKT mediate anti-tumor effect by activating CD8+ T cells cytotoxicity or overriding the tolerogenic mechanisms through counter-regulation of Treg cells. NKT can identify glycolipid antigens and subtyped into two according to TCR expression profile. Type 1 or invariant NKT (iNKT) carry an invariant TCR alfa-chain pairing with a limited number of beta-chains, whereas type 2 NKT cells express a diverse array of TCRs that recognize CD1d which is MHC class I-like molecule. Innate T lymphocytes (ITLs) is composed of iNKT cells and gamma-delta T cells. ITLs regulate adaptive immune response through its key roles in initiation and polaration of APCs and other cells of IS. This feature of ITLs has made them target as immunomodulation for treatment of autoimmune diseases[1,9]. LIVER AS AN ORGAN OF IS In order to keep homeostasis for survival, the immune response had to continuously adopt according to age, sex, dietary antigens, hormones (i.e., pregnancy and lactation), and external stress factors such as microbiota, environmental flora or exposed chemicals[13]. Therefore IS has a dynamic nature and has a wide “range of normal”. Beyond being a metabolic organ attached to gut, liver recently has been defined as central axis in IS controlling local and systemic immune reactions and tolerance. All types of liver cells have active immune function, including both parenchymal cells (hepatocytes, cholangiocytes) and non-parenchymal cells [liver sinu­soidal endothelial cells (LSECs), hepatic satellite cells (HSCs) or ito cells, KCs, neutrophiles, mononuclear cells, lymphocytes (B cells, T cells, NK cells, NKT cells, ITL)]. Parenchymal cells occupy most of liver volume (78%-80%). Nonparenchymal cells and extracellular space represent the remaining 5%-6% and 14%-17%, respectively[11,14]. The unique anatomical and histological features of liver are important for its immune functions. The liver is located at the junction between systemic and portal circulation. It is supplied by approximately 1.5 L of blood every minute; 2/3 via the portal vein and 1/3 via the hepatic artery. The double blood supply carries a massive antigenic load from the gastrointestinal tract and systemic circulation to liver. The blood, coming from these two sources mixes within sinusoids, and then flows through hepatic lobule from peri-portal area towards central vein. The fenestrated structures of sinusoids enable intimate interaction of antigens and blood immune cells with hepatocytes, KCs and HSCs at space of Disse. The abundant cells of the innate and adaptive ISs are located in hepatic sinusoids, and have ability for pathogen sensing, phagocytosis, cytotoxicity, cytokine release and antigen presentation to T cells. Th1 Th2 T17 Treg Tfh Produced Cytokines IFN-gama, TNF-alpha, IL-2 IL-4, IL-5, IL-9, IL-10, IL-13 IL-17A, IL-17F, IL-21, IL-22, IL-26 TGF-beta, IL-10 CXCR5, IL-21 Immune response mediated aginst Intracellular pathogens Extracellular parasites, allergy, humoral response Extracellular bacteria and fungi, autoimmunity IgA secretion, selftolerance Differentiation of B cells Master transcription factors for differentiation T-bet GATA-3 RORct Foxp3 Bcl6 Effected cells Macrophages, cytotoxic cells activated Eosinophils, mast cells activated Neutrophils activated B cells activated Th1, Th2, Th17 supressed B cells activated Table 1 Features of CD4+ cell subsets IFN: Interferons; IL: Interleukin; TGF: transforming growth factor; TNF: Tumor necrosis factor. Balaban YH et al. Liver immunology and herbal treatment WJH|www.wjgnet.com 761 June 18, 2017|Volume 9|Issue 17| The antigen-rich blood passing through the liver sinusoids is “scanned” by IS, which is tightly regulated between activation and tolerance. The liver remains tolerant to harmless dietary antigens, products of commensal gut microbiota and auto-antigens, while responds to exogen toxins, a variety of blood-borne or gut originated viruses, bacteria and parasites, as well as to metastatic cells, which try to home to the liver. Therefore, immune roles of liver can be divided into 2 groups; immune surveillance and induction of peripheral immune tolerance[3,15]. Indeed, the hepatic IS plays predominantly tolerogenic role. This can clinically be observed in liver transplant patients, e.g., liver allograft from major MHC or even ABO mismatched donors can be transplanted; if combined transplantation is done with organs from the same donor, non-liver allografts are more likely to be accepted; “operational tolerance”, which describes a patient with clinically normal graft function without needing immunosuppression, developments in up to 50% of hepatic transplantations[16]. Immune surveillance function of liver The liver relies on its strong immunity for its immediate and efficiend defense against potentially toxic agents without triggering harmful immune response towards self-structures. Liver, primarily hepatocytes, synthesizes the major amount of proteins involved in local and systemic immune responses. These proteins are called acute phase reactants such as fibrinogen, proteinase inhibitors, complement proteins, PRRs [e.g., C reactive protein, lipopolysaccharide (LPS)-binding protein, peptidoglycan-recognition protein, soluble CD14], opsonizing proteins (e.g., mannose-binding lectin, serum amyloids), cytokines [e.g., IL-6, tumor necrosis factor-alpha (TNFalpha) and transforming growth factor-beta (TGF-beta)], and hepcidin. The acute phase reactants function during innate immune response, mediate inflammation as well as tissue repair and regeneration. Their expression in hepatocytes is controlled by liver-enriched transcription factors (e.g., HNFs, C/EBPs), pro-inflammatory cytokines (e.g., IL-6, IL-22, IL-1β, TNF-α), and downstream signaling pathways (e.g., STAT3, NF-kappa B)[7,15]. Neutrophils are short-lived, circulating, phagocytic cells, which are recruited to site of infection by cytokines and chemokines, mainly IL-1 and IL-8. They are the first responders to infections and act by three main mechanisms; phagocytosis (requiring opsonization), generation of reactive oxygen species and degranulation (releasing enzymes and antimicrobial peptides), and formation of neutrophil extracellular traps (NETs). NETs are another mechanism of microbe killing. Nuclear DNA ligated with various microbicidal proteins released by activated neutrophils forms these webs. Under normal conditions the liver have few neutrophils, but they rapidly accumulate following necrosis. Neutrophils can rapidly shift their adhesive mechanisms in order to reqrude and form NETs in liver as a response to both endotoxin and bacteria[14]. Macrophages have been classified as classically activated macrophages (M1, secretes TNF-α, IL-1, IL-6, IL-8 and IL-12) or alternatively activated macro­phages (M2, secretes IL-10 and TGF-β) based on their cytokine secretory patterns and proinflammatory vs immunoregulatory activity which however, are inter­changeable functional states depending on the micro­environment the macrophages encounter[6,11]. KCs are fixed macrophages specialized at eliminating insoluble waste by phagocytosis and capable of processing and presenting antigens to T cells and participate in the regulation of the adaptive immune response. KCs reside on intravascular side of LSECs, and capture bacteria and able to bind component 3b under shear conditions while flowing through sinusoids. The role of KCs in microbial killing depends on the nature of the pathogen and on the recruited immune cells to the inflammation side. The characteristic feature of PRRs expression in liver is their constitutive expression and continuous low-level stimulation by endotoxins from gut. TLR4 is an PRRS expressed on all liver cells and it binds and clears endotoxins, and so initiates secretion of pro-inflammatory and anti-inflammatory cytokines[7]. Although, more than 80% of the CD3+ T cells are alpha-betaT-cells, the liver is also enrichmented by NKs and unconventional lymphocytes (NKT and gammadelta T cells). The gamma-deltaT cells is 5 times higher in the liver (15%) then the periphery[4]. Hepatocytes, which constitutively express intercellular adhesion molecule-1, can directly interact with T cells through the fenestrations of LSECs. IFN-gamma primes hepatocytes to APCs by dose dependently enhancing HLA expression; from moderate HLA class I expression to enhanced HLA class Ⅱ expression at low to high IFNgamma levels. Hepatocyte primed naïve T cells either become effector T cells or undergoes apoptosis in the absence of co-stimulatory signals. On the other hand, cholangiocytes are relatively spared form antigenic stimulation from blood, but not from those one secreted into bile. Cholangiocytes can express TLRs, HLA class I at a low frequency and co-stimulatory molecules. Hepatotropic viruses (i.e., CMV) enhances HLA class I expression without inducing HLA class Ⅱ. In pathological conditions such as that of PBC, cholangiocytes act as APC by overexpress HLA class Ⅱ, as well as CD80 and CD86 co-stimulatory molecules. The limited experimental data supports that HSCs have capacity to act as APCs. The presentation of lipids to T-cells and NKT cells by HSCs can cause activation or tolerance in IS depending on costimulation[4,7]. Liver mediated peripheral immune tolerance Besides conferring strong local innate immunity, the liver regulates immune homeostasis as being a major site for induction of T cell mediated local and systemic adaptive immune response. Both resident and transiting T and B cells scattered throughout the parenchyma and the portal tracts become important effector cells of defensive adaptive immune in liver after activation by APCs. Both hepatic parenchymal and non-parenchymal cells can act as APCs depending on the stimulus and special cytokine milieu. The classical hepatic APCs are Balaban YH et al. Liver immunology and herbal treatment WJH|www.wjgnet.com 762 June 18, 2017|Volume 9|Issue 17| DCs and reticulo-endothelial system (including KCs and LSECs). However, hepatocytes and cholangiocytes become non-conventional APCs by expressing MHC Ⅱ, if there is under pathological insult or persistent inflammation. Classical hepatic APCs constitutively express MHC classⅠ-Ⅱ, co-stimulatory receptors and molecules that promote antigen uptake (e.g., mannose and scavenger receptors). Under the physiological liver conditions, DCs are at immature developmental status and there is high production an anti-inflammatory cytokine (IL-10, TGF-b, TNF-a and prostaglandins) from reticulo-endothelial cells. This reduces capacity of APCs to activate effector T cells and lead to generation of anergic T cells and Treg cells. In other words, the tolerogenic nature of the liver by preferentially suppressing adaptive immunity is created by APCs, which kill or suppress effector CD4+ and CD8+ T cells and induce maturation of naïve T cells into Treg cells. Since diversion of portal flow results in the loss of immune-tolerance, it is hypothesized that physiological concentration of endotoxin is essential for maintain hepatic immune tolerance. LPS from gut microbiota drained to the liver by portal vein, modulates LSECs mediated CD4+ T cell activation by inducing secretion of IL-10 from LSECs and by down-regulating expression of MHC class Ⅱ, CD80 and CD86 on LSEC. Another proposed mechanism for hepatic induction of peripheral immune-tolerance is clonal deletion/apoptosis of antigen-specific T cell at liver. HSCs may have a role in creation of tolerogenic microenvironment. HSCs have a capacity to serve as APCs, expand Treg cells, and promote T cell apoptosis (via B7-H1, PDL-1) or inhibit cytotoxic CD8+ T cells[4,9,15]. The local and systemic self-tolerance can be overridden and so autoimmune diseases can be initiated by several pathological immune mechanisms developed in liver. First of all, pathological antigen presentation might generate of auto reactive T cells and B cells due to defective clonal deletion (apoptosis of antigen-specific T cells). Similarly ILCs also switch on the autoimmunity by promoting antigen presentation with classical APCs, by releasing cytokines that polarize immune response towards effector T cells. ILCs may also be important mediators autoimmune liver injury by killing hepatocytes and/or bile duct epithelial cells. Pathological endotoxemia caused by dysbiotic microbiota may switch immune response from Th2 to Th1 predominance. Treg cells regulate both innate and adaptive immunity through regulation of CD4+ cells, KCs and LSECs. Therefore, defective function of Treg cells impairs hepatic immune tolerance leading to autoimmune hepatitis[4,7]. SPECTRUM OF IMMUNE HOMEOSTASIS IN LIVER Hepatic IS is always active, regardless the overall response outcome. The nature of insult to liver and spectrum of activated cells determines the clinical picture. Healthy individuals have balanced immune surveillance of pathogens together with immune tolerance towards self-antigens. The over immune tolerance in liver leads to chronic infections with viruses or hepatic metastasis of cancer cells. In contrast the over activation of hepatic immune response causes fulminant hepatitis, allograft rejection or autoimmune diseases. Hepatic immune hemoastasis is continuously rebalanced during clinical courses of cirrhosis. Patients with compensated cirrhosis have hyperactivated IS depending on underlying etiology of the liver diseases. Hepatic decompensation is associated with increased intestinal permeability. The episodic translocation of gut microbiota and their endotoxins into portal circulation triggers systemic and hepatic inflammation. PAMRs recognizing LPS, lipopeptides, glycopolymers, flagellin and bacterial DNA/RNA, activate innate and adaptive immunity. The released pro-inflammatory cytokines and chemokines cause hepatic injury and activation of DAMP. The viscous cycle between members of PRR, namely PAMP and DAMP exhausts IS and so, switches immune response from a predominantly ‘‘pro-inflammatory’’ to wards ‘‘immunodeficient’’ status. This very late stage of cirrhosis is clinically defined as acute- on-chronic liver failure (ACLF). The immune deficient state in ACLF patients is called cirrhosis associated immune deficiency[15]. HERBAL TREATMENTS WITH POTENTIAL THERAPEUTIC EFFECT ON LIVER Herbal treatments are very often multifaceted blends of slightly processed medicinal plants, parts of the plants or products of the medicinal plants, which are traditionally accepted, comparatively low side-effects, and naturally compatible with the human body. Herbal remedies are applied for the treatment of a variety of indications and disorders, including hepatic as well as immunological problems (Table 2). Since scientific studies on herbal treatments have shown that they might effect cytokine and immunoglobulin secretion, cellular co-receptor expression, histamine release, lymphocyte proliferation, and cytotoxic activity, thus, herbal preparations might modify immune functions. In this study, literature was surveyed based on in vitro, in vivo and clinical studies on hepatoprotective, as well as immunostimulant and/or immunomodulator effective medicinal plants, which are lead by ethnopharmacological data. Table 2 was established, which covers common name, scientific name, effective part, known phytochemical content of the plant, ethnopharmacological/clinical effects, and medicinal preparation with their corresponding references. Due to complexity of the herbal treatments, the complete scientific data on mechanism of action is lacking, although clinical outcomes of herbal treatment are promising and leading the researchers to take on demanding scientific studies on the immune activity of herbal remedies (Table 3). The most applied medical plants in herbal treatments were selected and their mechanism of action on liver diseases and on immun system were searched to establish the Table 3. Flavonoid Balaban YH et al. Liver immunology and herbal treatment WJH|www.wjgnet.com 763 June 18, 2017|Volume 9|Issue 17| Common name Scientıfic name Effectıve part Phytochemıcal content Preparatıon on lıver dısorders1 Ref. Chaff-flower Achyranthes aspera L. Whole plant Ecdysterone, achyranthine, betaine, pentatriaontane, 6-pentatriacontanone, hexatriacontane and tritriacontane Natrossil natiris [28-30] Fennel Foeniculum vulgare Mill. Root Coumarins (bergapten, ısopimpinellin, anthotoxin), flavonoids (quercetin, rutin) Presselin dyspeptikum presselin, bupleurum compound phytomedicine, epagest lampugnani [18,25,31] Korean Ginseng, Chinese Red Ginseng Panax ginseng Mey. Root Polysaccharides, saponins, ginsenoside Tripid teguhsindo [32-34] Yarrow Achillea sp. Flower Volatile oils, flavonoids, terpenoids, alkaloids, saponins, sesquiterpenlactones Liv-52 drops, cheiranthol klein [35-38] Carqueja Baccharis trimera (Less) DC Epigeous part Flavonoids, diterpenoids Boldina Plata [39-41] Chicory Cichorium intybus L. Aerial part, root, leaf Saccharides, methoxycoumarin cichorine, flavonoids, essential oils, anthocyanins Natusor hepavesical soria natural, Liv-52 drops [42-46] Globe artichoke Cynara cardunculus var. scolymus L. Leaf Sesquiterpenes lactones (cynaropicrin), flavonoids (cynaropicrin), phenolic acids (mainly caffeic acid derivatives) Livstim mediherb, livton complex mediherb, lorbihepatic bioquimico, olocynan makros, rapacholin C herbapol wroclaw, farmasa, sylicynar herbapol poznan, alcafelol luper, bagohepat bago, armstrong, benevolus schwabe, boldina plata, cinarepa cristalfarma, colachofra EMS, cynarex roux-ocefa, herbapol wroclaw, cynarzym N altana, digestron loprofar, epagest lampugnani, figatil catarinense, salus, hecrosine B12 ortoquimica, hepatofalk falk, jurubileno ıbefar [47,48] Pale purple coneflower Echinacea pallida (Nutt.) Nutt. Echinacea angustifolia (DC.) Hell. Echinacea purpurea (L.) Moench Whole plant Alkamides, polysaccharides, glycoproteins, cichoric acid (a derivate of caffeic acid) Andrographis complex mediherb, kalbe, hepatin lapi, ımudator pyridam, herbal cleanse vitaplex [49-52] Faise daisy Eclipta alba (syn E. prostrata L.) Aerial part Tannins, flavonoids, coumestans, saponins, alkaloids Dipana promed [53,54] Chamomile Matricaria chamomilla L. Flower Coumarin (herniarin and umbelliferone), phenylpropanoids (chlorogenic acid and caffeic acid), flavonoids (apigenin, apigenin-7- o-glucoside, luteolin, luteolin-7-oglucoside, quercetin, rutin, naringenin), blue essential oils Presselin dyspeptikum presselin, cholesol herbapol wroclaw, gotas digestivas bunker [42,55-57] Milk thisle Silybum marianum (L.) Gaertn. Seed Polyphenolic flavonoids(silymarin, isosilyins, silibinins, silydianin silychristin) Liverine cardinal, livermin korean ginseng, liverton sıffra, livosil-b centaur, livstim mediherb, livton complex mediherb, lomacholan lomapharm, phytohepar steigerwald, poikicholan lomapharm, prol procare, samarin berlin pharm, schwohepan S schworer, silegon teva, silibene merckle, silicur hexal, silimalon nikkho, silimarin benedetti, silimarit bionorica, silimax filofarm, silirex lampugnani, siliver farmasa, silliver abbott, silmar hennig, silvaysan sanum-kehlbeck, silybon micro, silygal ıvax, silyhexal hexal, sily-sabona sabona, mepha, sivylar ranbaxy, sylicaps herbapol lublin, sylicynar herbapol poznan, sylimarol herbapol pruszkow [18,19,58,59] Table 2 Plants are effective on liver disorders and immune system Balaban YH et al. Liver immunology and herbal treatment WJH|www.wjgnet.com 764 June 18, 2017|Volume 9|Issue 17| Syliverin aflofarm, sylivit herbapol poznan, solas, vionin nf tempo scan pacific, alepa duopharm, apihepar madaus, vıa tris, aptivium liver support cynergen, ardeyhepan emonta, ardeypharm, bibol leloup hexa, bilisan duo repha Bioglan liver-vite bioglan, bupleurum complex mediherb, bupleurum compound phytomedicine, carsil sopharma, cefasliymarin cefak, cheiranthol klein, soho capsule/syrup, depatox progen, durasilymarin merck dura, eleparon sankyo, epagest lampugnani, flavobion zentiva, hegrimarin strathmann, strathmann, hepabene ratiopharm, merckle, ratiopharm, hepabesch strathmann, hepadigenor baliarda, hepaduran v otw, loges Capsule, hepamax dankos, hepa-merz sil merz, hepar-pasc pascoe, heparsyx n syxyl, heparviton bode, tempo scan pacific, hepatin lapi, kalbe, falk, daryavaria, hepatos, Yung shin, heplant spitzner, herbal liver formula faulding, worwag, legalon-madaus, laragon roemmers, ıfet, leveron vesco, limarin serum ınstitute, herbal cleanse vitaplex Dandelion Taraxacum officinale G. Root Sesquiterpenes, saponins, phenolic compounds, flavonoids, sugars Naturica DFM ıkapharmindo, livstim mediherb, livton complex mediherb, berberis complex blackmores, cholesol herbapol wroclaw, cinarepa cristalfarma, hepatofalk falk, herbal cleanse vitaplex [60-63] Radish Raphanus sativus L. Leaf, root Flavanoids, terpenoids, alkaloids, saponins, sterols Rapacholin AC herbapol wroclaw, rapacholin c herbapol wroclaw [64-67] Caper Capparis spinosa L. Root bark Sugars (glucose, arabinose, mannose, galactose), lipid, volatile oils Liv-52 drops [68-71] Kinkéliba Combretum micranthum G. Don Leaf catechins, glycosylflavones, flavans, galloylated c-glycosylflavone derivatives, flavan-piperidine alkaloid Tisane mediflor N°5 hepatique [72-74] Arjuna Terminalia arjuna (Roxb.) Wight and Arn. Bark Arjunolic acid, tomentosic acid, arjunin, β-sitosterol, ellagic acid, leucodelphinidin, tannins Liv-52 drops [75-77] Coffee senna Cassia occidentalis L.(Senna occidentalis) Leaf Anthraquinones, saponins, sterols, triterpenes, quinines, tannins, flavonoids Tisane mediflor N°5 hepatıque, Liv-52 drops [78-80] Liquorice, Licorice Glycyrrhiza glabra L. Root Triterpene saponins, flavonoids, isoflavonoids and chalcones, glycyrrhizic acid Tisane mediflor N°5 hepatıque, neominophagen C dexa, torii, curliv soho, soho capsule/syrup [18,26,81] Holy basil Ocimum sanctum Linn. Leaf Volatile oils (eugenol, euginal, urosolic acid, carvacrol, linalool, limatrol, caryophyllene, methyl carvicol), anthocyans, alkaloids, flavonoids, tannins, carbohydrates,xylose, polysaccharides Andrographis complex mediherb [22,82-85] Rosemary Rosmarinus officinalis L. Leaf Diterpenoids, triterpenoids, phenolic acids, and flavonoids, carnosic acid, carnosol, rosmarinic acid Tisane mediflor N°5 hepatıque, natusor hepavesical soria natural, cinarepa cristalfarma [86-88] Red sage, Danshen Salvia miltiorrhiza Bunge. Root Tanshinones (tanshinone ı, tanshinoneıı, cryptotanshinone) miltirone and salvianolic acid a, b Bupleurum complex mediherb [18,89,90] Common mallow Malva sylvestris L. Leaf Amino acids/protein derivatives, flavonoids, mucilages, terpenoids, phenol derivatives, coumarin Tisane mediflor N°5 hepatıque [91-93] Tinospora, Guduchi, Giloya Tinospora cordifolia (Willd.) Hook. f. and Thoms. (Guduchi) Root, stem Flavonoids, alkaloids, sesquiterpenes, diterpenes arabinogalactan, syringine, cordiol, cordioside, cordifoliosides (a and b), berberine, tinosporine, giloin, giloinin Dipana promed [22,33,94-96] Balaban YH et al. Liver immunology and herbal treatment WJH|www.wjgnet.com 765 June 18, 2017|Volume 9|Issue 17| derivatives such as silybin, silymarin, obtained from milk-thistle [Silybum marianum (L.) Gaertn.] decreased alkaline phosphatase (completely) and gamma-glutamyl transpeptidase (partially) in CCl4 induced liver damage[17]. Moreover, it has been claimed that Silymarine containing preparations are the principal therapeutic of choice in liver diseases caused by oxidative stress. Many studies have proven that plant phyto compound Silymarin has medical applications to cure (alcoholic and non-alcoholic) fatty liver, cirrhosis, ischaemic injury, drug and chemicallyinduced hepatic toxicity, radiation toxicity, viral and toxic hepatitis by means of its anti-oxidative, antilipidperoxidative, anti-fibrotic, anti-inflammatory, liver regenerating and immunomodulating effects. Several studies have identified that continuous usage of Silymarin has significantly proved to increase the survival period of patients with alcohol-caused liver cirrhosis and primary liver cancer[18] (Figure 1). Scientific studies also Boldo, Boldu, Boldus Peumus boldus Molina Leaf Alkaloids (isoquinoline-boldine, isoboldine, 6a,7-dehydroboldine, isocorydine, isocorydine-n-oxide, norisocorydine, laurolitsine, laurotetanine, n-methyllaurotetanine, reticuline, (-)-pronuciferine, sinoacutine), flavonoids, volatile oil, coumarin, resin, tannin) Tisane mediflor N°5 hepatıque, natrossil natiris, natusor hepavesical soria natural, prinachol zurita, farmasa, alcafelol luper, berberis complex blackmores, boldina plata, boldopeptan neo quimica, colachofra ems, cynarzym N altana, eparema nycomed, figatil catarinense, gotas digestivas bunker, jurubileno ıbefar [97-99] Greater celandine Chelidonium majus L. Aerial parts Isoquinoline alkaloids, such as sanguinarine, chelidonine, chelerythrine, berberine and coptisine, (-)-turkiyenine) Livstim mediherb, livton complex mediherb, natusor hepavesical soria natural, schwohepan S schworer, berberis complex blackmores, chelicur hasco-lek, cynarzym N altana, hepatofalk falk, falk, darya-varia [100-105] Gale of the wind Phyllanthus niruri L. Whole plant Flavonoids, alkaloids, terpenoids, lignans, polyphenols, tannins, coumarins and saponins Natrossil natiris, meprofarm, dipana promed, gramuno graha, hepimun landson, ımudator pyridam [106-108] Kutki Picrorhiza kurroa Royle ex Benth. Rhizome, root Iridoid glycoside (picrovil) Dipana promed [109,110] Rhubarb Rheum emodi Rhizome Anthraquinone (rhein, chrysophanol, aloe-emodin, emodin, physcion, and their glycosides) and stilbene (picetannol, resveratrol and their glycosides), flavonoids, glycosides, tannins, volatile oils, saponins Natrossil natiris, boldopeptan neo quimica, eparema nycomed, SIT, hepatofalk falk [111] Magnolia-vine, Schisandra Schisandra chinensis (Turcz.) Baill. Fruit Dibenzocyclooctadiene derivative lignans (or schisandra lignans), organic acids (citric, malic, fumaric and tartaric acid), sugars, vitamic C, vitamin E, phenolic acids, tannins, phytosterols, essential oil Curliv soho, soho capsule/syrup, hepacell medikon, hepamax dankos [31,112,113] European black nightshade Solanum nigrum L. Whole plant Glycoalkaloids, glycoproteins, polysaccharides, polyphenolic compounds (gallic acid, catechin, protocatechuic acid (pca), caffeic acid, epicatechin, rutin, naringenin) Liv-52 drops, dipana promed [114-117] French tamaris Tamarix gallica L. Aerial parts Tannin, tamarixin, tamauxetin, troupin, 4-methylcoumarin and 3,3’-di-o-methylellagic acid, tannic acid, 4-methylcoumarin and 3,3’-di-omethylellagic acid Liv-52 drops [118,119] Turmeric Curcuma longa L. Rhizome Curcuminoid Meprofarm, tripid teguhsindo, turmerik knop, aptivium liver support cynergen, chelicur hasco-lek, galena, ıvax, cinarepa cristalfarma, depatox progen, heparviton bode, tempo scan pacific, kalbe, hepatin lapi, falk [22,31,120] Ginger Zingiber officinale Roscoe Rhizome Volatile oils, pungent phenol compounds [sesquiterpenoids,betasitosterol palmitate, isovanillin, glycol monopalmitate, hexacosanoic acid 2,3-dihydroxypropyl ester, maleimide5-oxime, p-hydroxybenzaldehyde adenine, 6-gingerol, 6-shogaol, 1-(omega-ferulyloxyceratyl) glycerols] Presselin dyspeptikum presselin, dipana promed, herbal cleanse vitaplex [121-127] 1 Martindale W, Sweetman SC. Martindale: The complete drug reference. Pharmaceutical press, 2007. Balaban YH et al. Liver immunology and herbal treatment WJH|www.wjgnet.com 766 June 18, 2017|Volume 9|Issue 17| have shown that, both silybin and silymarin normalized immunoregulatory failures by restoration of the cellular thiol status, T-cell activation (CD69), together with a substantial decrease in TNF[18,19]. Effects of the selected herbal medicines on immune and liver were summarized in Figure 1. Another study demonstrated that an edible plant Artichoke (Cynara scolymus L.) prevented CCl4 and oxidative stress-induced hepatotoxicity and it protected the liver[20]. Inulin, obtained from artichoke, stimulates components of the IS[21]. The extract of the rhizome Turmeric (Curcuma longa L.), which has hepatoprotective plant, amplified both Th1 (IL-2 and IFN gamma) and Th2 (IL-10) cytokines signifying its dual immune roles. Polysaccharide fraction of this rhizome showed potent immunostimulatory action in the direction of proliferation of splenocytes cell number and IL-10 secretion. Polysaccharides of the plant extract might be causative of these proliferative and cytokine release assets in murine splenocytes. In different studies have been shown that the cytokine productions (TGF-β, TNF-α, GM-CSF, IL-1α, IL-5, IL-6, IL-8, IL-10, IL-13, etc.) have been modulated by polysaccharide-enriched fractions[18,22-24]. Fennel (Foeniculum vulgare Mill.) and liquorice (Glycyrrhiza glabra L.) have also shown immuno­modulatory and hepatoprotective effects[18,25-27]. Herbal drugs are composed of complex mixtures of phytochemicals, unlike conventional and plant originated single compound drugs, which are composed of known chemical constituents and are precisely quantified. For that reasons studying the clinical effects of individual chemical constituents separately will not be accurate, due to various reasons, such as the synergistic or inhibiting effects of phytochemicals on each other and neutralization of harmful chemicals in the mixture by other compounds, which provides a flawless combination for therapeutic purposes. Aspects such as, absorption, distribution intrinsic concentration and metabolism of the drug should be known precisely to determine the dosage, safety margin and length of treatment. Moreover, future research should include characterization of multifactorial mechanisms of action, elucidation of adverse effects and well-designed clinical trials in pediatrics and geriatrics as well. CONCLUSION Scientists as well as immunologists, who study herbal treatments in hepatic diseases most be ready to face challenges and opportunities. In vivo and clinical molecular researches on immunomodulatory, immunoenhancing, immunostimulant effects of herbal treatments will offer novel perceptions into IS and immunotherapy. Not only single plant extract, but the interactions of the ingredients in a given herbal treatment formula determines the final clinical picture by finely tuning the balance between therapeutic effect and hepatotoxicity. Feature studies Scientific name Effect/mechanism on liver Effect/mechanısm on immun system Ref. Curcuma longa L. Acute liver damage by chemicals, e.g., ethanol, CCl4, Dimethylnitrosamines Immunostimulant, immunomodulatory [18,22-24] The extract of the rhizome C. longa increased both Th1 (IL-2 and IFN gamma) and Th2 (IL-10) cytokines indicating its dual immune functions. NR-INF-02 significantly increased the IL-2 and IFN gamma levels in Con A stimulated splenic lymphocytes. The above results indicated that NR-INF-02 showed a specific immunity response by stimulating both Th1 and Th2 cells Polysaccharide fraction of the rhizome showed potent immunostimulatory activity towards proliferation of splenocytes cell number and IL-10 secretion. Polysaccharides might be contributing to this proliferative and cytokine release property in murine splenocytes Hot water extracts of the rhizome showed that the high polarity fraction exhibited stimulatory effects on PBMC. The cytokine productions (TGF-beta, TNF-alpha, GM-CSF, IL-1alpha, IL-5, IL-6, IL-8, IL-10, IL-13, etc.) have been modulated by a polysaccharide-enriched fraction.The proportion of CD14 positive stained PBMC was increased by the fraction Anti-HIV-1 and HIV-2 Foeniculum vulgare Mill. Oxidative stress of the liver bacterial and viral infections antiinflammatory, acute hepatotoxicity Immunomodulatory [18,25] Antimicrobial, antifungal Glycyrrhiza glabra L. Cirrhosis fibrosis chronic viral hepatitis B and C Immunomodulatory [18,26,27] Leukocyte count and phagocytic index (carbon clearance) was increased significantly with the treatment of water extract of G. glabra root. Zinc (45 mg/ kg) in combination with ALE (0.75 g/kg) showed highly significant increase of leukocyte count and phagocytic index Silybum marianum (L.) Gaertn. Oxidative stress inflammation and fibrosis alcohol-induced cirrhosis mushroom poisoning viral hepatitis Immunomodulatory [18,19] Flavonoids from S. marianum normalize immunoregulatory defects via restoration of the cellular thiol status. T-cell activation (CD69), along with a significant decrease in TNF Table 3 Commonly used plants on liver disorders and their effect mechanisms IFN: Interferons; TNF: Tumor necrosis factor; IL: Interleukin; TGF: transforming growth factor; HIV: Human immunodeficiency virus; PBMC: Peripheral blood mononuclear cells; GM-CSF: Granulocyte-macrophage colony-stimulating factor; ALE: Aqueous liquorice extract. Balaban YH et al. Liver immunology and herbal treatment WJH|www.wjgnet.com 767 June 18, 2017|Volume 9|Issue 17| must pricely define the interaction between the liver as an organ regulating local and systemic immune response and complex action mechanisms of herbal treatment. REFERENCES 1 Doherty DG. Immunity, tolerance and autoimmunity in the liver: A comprehensive review. J Autoimmun 2016; 66: 60-75 [PMID: 26358406 DOI: 10.1016/j.jaut.2015.08.020] 2 Liu J, Liu S, Cao X. Highlights of the advances in basic immunology in 2011. Cell Mol Immunol 2012; 9: 197-207 [PMID: 22522654 DOI: 10.1038/cmi.2012.12] 3 Navarro VJ, Khan I, Björnsson E, Seeff LB, Serrano J, Hoofnagle JH. Liver injury from herbal and dietary supplements. Hepatology 2017; 65: 363-373 [PMID: 27677775 DOI: 10.1002/hep.28813] 4 Dara L, Liu ZX, Kaplowitz N. Mechanisms of adaptation and progression in idiosyncratic drug induced liver injury, clinical implications. Liver Int 2016; 36: 158-165 [PMID: 26484420 DOI: 10.1111/liv.12988] 5 Elmore SA. Enhanced histopathology of the immune system: a review and update. Toxicol Pathol 2012; 40: 148-156 [PMID: 22089843 DOI: 10.1177/0192623311427571] 6 Marques PE, Oliveira AG, Chang L, Paula-Neto HA, Menezes GB. Understanding liver immunology using intravital microscopy. J Hepatol 2015; 63: 733-742 [PMID: 26055800 DOI: 10.1016/ j.jhep.2015.05.027] 7 Strauss O, Dunbar PR, Bartlett A, Phillips A. The immunophenotype of antigen presenting cells of the mononuclear phagocyte system in normal human liver--a systematic review. J Hepatol 2015; 62: 458-468 [PMID: 25315649 DOI: 10.1016/j.jhep.2014.10.006] 8 Invernizzi P. Liver auto-immunology: the paradox of autoimmunity in a tolerogenic organ. J Autoimmun 2013; 46: 1-6 [PMID: 24012346 DOI: 10.1016/j.jaut.2013.08.006] 9 Levine J. The impact of immune dysregulation on the development of autoimmune gastrointestinal and liver disease. Curr Probl Pediatr Adolesc Health Care 2014; 44: 322-323 [PMID: 25466501 DOI: 10.1016/j.cppeds.2014.10.001] 10 Castelo-Branco C, Soveral I. The immune system and aging: a review. Gynecol Endocrinol 2014; 30: 16-22 [PMID: 24219599 DOI: 10.3109/09513590.2013.852531] 11 Albillos A, Lario M, Álvarez-Mon M. Cirrhosis-associated immune dysfunction: distinctive features and clinical relevance. J Hepatol 2014; 61: 1385-1396 [PMID: 25135860 DOI: 10.1016/ j.jhep.2014.08.010] 12 Food and Drug Administration. Dietary Supplements. 21 January 2016. Accessed: February 15, 2017. Available from: URL: http:// www.fda.gov/Food/DietarySupplements/default.htm 13 Stiemsma LT, Reynolds LA, Turvey SE, Finlay BB. The hygiene hypothesis: current perspectives and future therapies. Immunotargets Ther 2015; 4: 143-157 [PMID: 27471720 DOI: 10.2147/ ITT.S61528] 14 de Souza HS, Fiocchi C. Immunopathogenesis of IBD: current state of the art. Nat Rev Gastroenterol Hepatol 2016; 13: 13-27 [PMID: 26627550 DOI: 10.1038/nrgastro.2015.186] 15 Lederberg J, Mc Cray AT. ‘Ome Sweet ‘Omics-a genealogical treasury of words. Scientist 2001; 15: 8 16 Emond JC, Griesemer AD. Tolerance in clinical liver transplantation: The long road ahead. Hepatology 2017; 65: 411-413 [PMID: 27718261 DOI: 10.1002/hep.28862] 17 Muriel P, Mourelle M. Prevention by silymarin of membrane alterations in acute CCl4 liver damage. J Appl Toxicol 1990; 10: 275-279 [PMID: 1975258 DOI: 10.1002/jat.2550100408] 18 Rajaratnam M, Prystupa A, Lachowska-Kotowska P, Zaluska W, Filip R. Herbal medicine for treatment and prevention of liver diseases. JPCCR 2014; 8: 55-60 [DOI: 10.5604/18982395.1135650] 19 Tamayo C, Diamond S. Review of clinical trials evaluating safety and efficacy of milk thistle (Silybum marianum [L.] Gaertn.). Integr Cancer Ther 2007; 6: 146-157 [PMID: 17548793 DOI: 10.1177/1534735407301942] Silybum marianum (silymarin) Oxidative stress Inflammation and fibrosis Alcohol induced cirrhosis Mushroom poisoning Viral hepatitis Induced acut liver damages Ethanol CCl4 Dimethylnitrosamines Curcuma longa (curcumin) Th1 cytokines (IL-2, IFN-γ) ↑ Th2 cytokines (IL-10) ↑ Proliferation of splenocytes ↑ Modulating of “TGF-β, TNF-α, GM-CSF, IL1-α, IL-5, IL-6, IL-8, IL-13” Cirrhosis Fibrosis Chronic viral hepatitis B Chronic viral hepatitis C Glycyrrhiza glabra (glycyrrhizic acid) Leucocytes ↑ TNF ↓ Figure 1 Immunological action mechanismes of some herbals on the liver. IFN: Interferons; TNF: Tumor necrosis factor; IL: Interleukin; TGF: Transforming growth factor. Balaban YH et al. Liver immunology and herbal treatment WJH|www.wjgnet.com 768 June 18, 2017|Volume 9|Issue 17| 20 Mehmetçik G, Ozdemirler G, Koçak-Toker N, Cevikbaş U, Uysal M. Effect of pretreatment with artichoke extract on carbon tetrachloride-induced liver injury and oxidative stress. Exp Toxicol Pathol 2008; 60: 475-480 [PMID: 18583118 DOI: 10.1016/j.etp. 2008.04.014] 21 López-Molina D, Navarro-Martínez MD, Rojas Melgarejo F, Hiner AN, Chazarra S, Rodríguez-López JN. Molecular properties and prebiotic effect of inulin obtained from artichoke (Cynara scolymus L.). Phytochemistry 2005; 66: 1476-1484 [PMID: 15960982 DOI: 10.1016/j.phytochem.2005.04.003] 22 Adhvaryu MR, Reddy N, Parabia MH. Effects of four Indian medicinal herbs on Isoniazid-, Rifampicin- and Pyrazinamideinduced hepatic injury and immunosuppression in guinea pigs. World J Gastroenterol 2007; 13: 3199-3205 [PMID: 17589898 DOI: 10.3748/wjg.v13.i23.3199] 23 Chandrasekaran CV, Sundarajan K, Edwin JR, Gururaja GM, Mundkinajeddu D, Agarwal A. Immune-stimulatory and antiinflammatory activities of Curcuma longa extract and its polysaccharide fraction. Pharmacognosy Res 2013; 5: 71-79 [PMID: 23798880 DOI: 10.4103/0974-8490.110527] 24 Yue GG, Chan BC, Hon PM, Kennelly EJ, Yeung SK, Cassileth BR, Fung KP, Leung PC, Lau CB. Immunostimulatory activities of polysaccharide extract isolated from Curcuma longa. Int J Biol Macromol 2010; 47: 342-347 [PMID: 20609432 DOI: 10.1016/ j.ijbiomac.2010.05.019] 25 He W, Huang B. A review of chemistry and bioactivities of a medicinal spice: Foeniculum vulgare. J Med Plant Res 2011; 5: 3595-3600 26 Asl MN, Hosseinzadeh H. Review of pharmacological effects of Glycyrrhiza sp. and its bioactive compounds. Phytother Res 2008; 22: 709-724 [PMID: 18446848 DOI: 10.1002/ptr.2362] 27 Mazumder PM, Pattnayak S, Parvani H, Sasmal D, Rathi­navelusamy P. Evaluation of immunomodulatory activity of Glycyrhiza glabra l roots in combination with zing. Asian Pac J Trop Biomed 2012; 2: 15-20 [DOI: 10.1016/S2221-1691(12)60122-1] 28 Bafna AR, Mishra S. Effect of methanol extract of Achyranthes aspera linn. on rifampicin-induced hepatotoxicity in rats. Ars Pharmaceutica 2004; 45: 343-351 29 Chakrabarti R, Vasudeva RY. Achyranthes aspera stimulates the immunity and enhances the antigen clearance in Catla catla. Int Immunopharmacol 2006; 6: 782-790 [PMID: 16546709 DOI: 10.1016/j.intimp.2005.11.020] 30 Srivastav S, Singh P, Mishra G, Jha KK, Khosa RL. Achyranthes aspera-An important medicinal plant: A review. J Nat Prod Plant Resour 2011; 1: 1-14 31 Duke JA. Handbook of phytochemical constituent grass, herbs and other economic plants. CRC press. Boca Raton, FL, 1992: 54-59, 197-199, 224-229, 257-259, 438-441 32 Coon JT, Ernst E. Panax ginseng: a systematic review of adverse effects and drug interactions. Drug Saf 2002; 25: 323-344 [PMID: 12020172 DOI: 10.2165/00002018-200225050-00003] 33 Govind P. Some important anticancer herbs: a review. IRJP 2011; 2: 45-53 34 Tang W, Eisenbrand G. Panax ginseng CA Mey. In Chinese drugs of plant origin Springer Berlin Heidelberg, 1992: 711-737 35 Nemeth E, Bernath J. Biological activities of yarrow species (Achillea spp.). Curr Pharm Des 2008; 14: 3151-3167 [PMID: 19075697 DOI: 10.2174/138161208786404281] 36 Saeidnia S, Gohari A, Mokhber-Dezfuli N, Kiuchi F. A review on phytochemistry and medicinal properties of the genus Achillea. Daru 2011; 19: 173-186 [PMID: 22615655] 37 Sharififar F, Pournourmohammadi S, Arabnejad M. Immunomodulatory activity of aqueous extract of Achillea wilhelmsii C. Koch in mice. Indian J Exp Biol 2009; 47: 668-671 [PMID: 19775073] 38 Yaeesh S, Jamal Q, Khan AU, Gilani AH. Studies on hepatoprotective, antispasmodic and calcium antagonist activities of the aqueous-methanol extract of Achillea millefolium. Phytother Res 2006; 20: 546-551 [PMID: 16619341 DOI: 10.1002/ptr.1897] 39 Paul EL, Lunardelli A, Caberlon E, de Oliveira CB, Santos RC, Biolchi V, Bastos CM, Moreira KB, Nunes FB, Gosmann G, de Oliveira JR. Anti-inflammatory and immunomodulatory effects of Baccharis trimera aqueous extract on induced pleurisy in rats and lymphoproliferation in vitro. Inflammation 2009; 32: 419-425 [PMID: 19756999 DOI: 10.1007/s10753-009-9151-1] 40 Soicke H, Leng-Peschlow E. Characterisation of flavonoids from Baccharis trimera and their antihepatotoxic properties. Planta Med 1987; 53: 37-39 [PMID: 3575511 DOI: 10.1055/s-2006-962613] 41 Torres LM, Gamberini MT, Roque NF, Lima-Landman MT, Souccar C, Lapa AJ. Diterpene from Baccharis trimera with a relaxant effect on rat vascular smooth muscle. Phytochemistry 2000; 55: 617-619 [PMID: 11130673 DOI: 10.1016/S0031- 9422(00)00223-5] 42 Amirghofran Z, Azadbakht M, Karimi MH. Evaluation of the immunomodulatory effects of five herbal plants. J Ethnopharmacol 2000; 72: 167-172 [PMID: 10967468 DOI: 10.1016/S0378- 8741(00)00234-8] 43 Gadgoli C, Mishra SH. Antihepatotoxic activity of Cichorium intybus. J Ethnopharmacol 1997; 58: 131-134 [PMID: 9406902 DOI: 10.1016/S0378-8741(97)00090-1] 44 Gilani AH, Janbaz KH. Evaluation of the liver protective potential of Cichorium intybus seed extract on Acetaminophen and CCl(4)- induced damage. Phytomedicine 1994; 1: 193-197 [PMID: 23195938 DOI: 10.1016/S0944-7113(11)80064-4] 45 Heibatollah S, Reza NM, Izadpanah G, Sohailla S. Hepatoprotective effect of Cichorium intybus on CCl4-induced liver damage in rats. Afr J Biochem Res 2008; 2: 141-144 46 Street RA, Sidana J, Prinsloo G. Cichorium intybus: Traditional Uses, Phytochemistry, Pharmacology, and Toxicology. Evid Based Complement Alternat Med 2013; 2013: 579319 [PMID: 24379887 DOI: 10.1155/2013/579319] 47 Braun L, Cohen M. Herbs & Natural Supplements: An Evidencebased guide (3rd ed.). Chatswood, NWS: Churchill Livingstone/ Elsevier, 2010: 207, 532 48 Menin B, Moglia A, Comino C, Hakkert JC, Lanteri S, Beekwilder J. In vitro callus-induction in globe artichoke (Cynara cardunculus L. var. scolymus) as a system for the production of caffeoylquinic acids. J Hortic Sci Biotech 2013; 88: 537-542 [DOI: 10.1080/1462 0316.2013.11513003] 49 Barnes J, Anderson LA, Gibbons S, Phillipson JD. Echinacea species (Echinacea angustifolia (DC.) Hell., Echinacea pallida (Nutt.) Nutt.,Echinacea purpurea (L.) Moench): a review of their chemistry, pharmacology and clinical properties. J Pharm Pharmacol 2005; 57: 929-954 [PMID: 16102249 DOI: 10.1211/00 22357056127] 50 Block KI, Mead MN. Immune system effects of echinacea, ginseng, and astragalus: a review. Integr Cancer Ther 2003; 2: 247-267 [PMID: 15035888 DOI: 10.1177/1534735403256419] 51 Binns SE, Livesey JF, Arnason JT, Baum BR. Phytochemical variation in echinacea from roots and flowerheads of wild and cultivated populations. J Agric Food Chem 2002; 50: 3673-3687 [PMID: 12059142 DOI: 10.1021/jf011439t] 52 Rusu MA, Tamas M, Puica C, Roman I, Sabadas M. The hepatoprotective action of ten herbal extracts in CCl4 intoxicated liver. Phytother Res 2005; 19: 744-749 [PMID: 16220565 DOI: 10.1002/ ptr.1625] 53 Dalal S, Kataria SK, Sastry KV, Rana SVS. Phytochemical screening of methanolic extract and antibacterial activity of active principles of hepatoprotective herb, Eclipta alba. Ethnobot Leaflets 2010; 2010: 3 54 Mithun NM, Shashidhara S, Vivek Kumar R. Eclipta alba (L.) A review on its phytochemical and pharmacological profile. Pharmacologyonline 2011; 1: 345-357 55 Salamon I. Chamomile a medicinal plant. J Herbs Spices Med Plants 1992; 10: 1-4 56 Singh O, Khanam Z, Misra N, Srivastava MK. Chamomile (Matricaria chamomilla L.): An overview. Pharmacogn Rev 2011; 5: 82-95 [PMID: 22096322 DOI: 10.4103/0973-7847.79103] 57 Tavakol HS, Farzad K, Fariba M, Abdolkarim C, Hassan G, Seyed-Mostafa HZ, Akram R. Hepatoprotective effect of Matricaria chamomilla.L in paraquat induced rat liver injury. Drug Res (Stuttg) 2015; 65: 61-64 [PMID: 24696426 DOI: 10.1055/s-0033-1363999] Balaban YH et al. Liver immunology and herbal treatment WJH|www.wjgnet.com 769 June 18, 2017|Volume 9|Issue 17| 58 Flora K, Hahn M, Rosen H, Benner K. Milk thistle (Silybum marianum) for the therapy of liver disease. Am J Gastroenterol 1998; 93: 139-143 [PMID: 9468229 DOI: 10.1111/j.1572-0241. 1998.00139.x] 59 Madani H, Talebolhosseini M, Asgary S, Nader GH. Hepatoprotective activity of Silybum marianum and Cichorium intybus against thioacetamide in rat. Pak J Nutr 2008; 7: 1726 [DOI: 10.3923/pjn.2008.172.176] 60 Martinez M, Poirrier P, Chamy R, Prüfer D, Schulze-Gronover C, Jorquera L, Ruiz G. Taraxacum officinale and related speciesAn ethnopharmacological review and its potential as a commercial medicinal plant. J Ethnopharmacol 2015; 169: 244-262 [PMID: 25858507 DOI: 10.1016/j.jep.2015.03.067] 61 Schütz K, Carle R, Schieber A. Taraxacum--a review on its phytochemical and pharmacological profile. J Ethnopharmacol 2006; 107: 313-323 [PMID: 16950583 DOI: 10.1016/j.jep. 2006. 07.021] 62 Yoon TJ. Effect of water extracts from root of Taraxacum officinale on innate and adaptive immune responses in mice. Korean J Food Nutr 2008; 21: 275-282 63 You Y, Yoo S, Yoon HG, Park J, Lee YH, Kim S, Oh KT, Lee J, Cho HY, Jun W. In vitro and in vivo hepatoprotective effects of the aqueous extract from Taraxacum officinale (dandelion) root against alcohol-induced oxidative stress. Food Chem Toxicol 2010; 48: 1632-1637 [PMID: 20347918 DOI: 10.1016/j.fct.2010.03.037] 64 Baek SH, Park M, Suh JH, Choi HS. Protective effects of an extract of young radish (Raphanus sativus L) cultivated with sulfur (sulfur-radish extract) and of sulforaphane on carbon tetrachlorideinduced hepatotoxicity. Biosci Biotechnol Biochem 2008; 72: 1176-1182 [PMID: 18460814 DOI: 10.1271/bbb.70545] 65 Chaturvedi P, George S, Machacha CN. Protective role of Raphanus sativus root extract on paracetamol-induced hepato­toxicity in albino rats. Int J Vitam Nutr Res 2007; 77: 41-45 [PMID: 17685094 DOI: 10.1024/0300-9831.77.1.41] 66 Popovic M, Lukie V, Jakovljevie V, Mikov M. The effect of the radish juice on liver function. Fitoterapia 1993; 64: 229-231 67 Syed SN, Rizvi W, Kumar A, Khan AA, Moin S, Ahsan A. In Vitro Antioxidant and In Vivo Hepatoprotective Activity of Leave Extract of Raphanus sativus in Rats Using CCL 4 Model. Afr J Tradit Complement Altern Med 2014; 11: 102-106 68 Aghel N, Rashidi I, Mombeini A. Hepatoprotective activity of Capparis spinosa root bark against CCl4 induced hepatic damage in mice. Iran J Pharm Res 2010: 285-290 69 Arena A, Bisignano G, Pavone B, Tomaino A, Bonina FP, Saija A, Cristani M, D’Arrigo M, Trombetta D. Antiviral and immunomodulatory effect of a lyophilized extract of Capparis spinosa L. buds. Phytother Res 2008; 22: 313-317 [PMID: 18058988 DOI: 10.1002/ptr.2313] 70 Sher H, Alyemeni MN. Ethnobotanical and pharmaceutical evaluation of Capparis spinosa L, validity of local folk and Unani system of medicine. J Med Plant Res 2010; 4: 1751-1756 [DOI: 10.5897/JMPR10.380] 71 Tlili N, Elfalleh W, Saadaoui E, Khaldi A, Triki S, Nasri N. The caper (Capparis L.): ethnopharmacology, phytochemical and pharmacological properties. Fitoterapia 2011; 82: 93-101 [PMID: 20851750 DOI: 10.1016/j.fitote.2010.09.006] 72 Bitsindou M, Lejoly J. Plants used in hepatoprotective remedies in traditional African medicine. In WOCMAP I-Medicinal and Aromatic Plants Conference: part 2 of 4. 1992; 332: 73-80 73 Dicarlo FJ, Haynes LJ, Sliver NJ, Phillips GE. Reticuloendothelial system stimulants of botanical origin. J Reticuloendothel Soc 1964; 1: 224-232 [PMID: 14192585] 74 Welch CR. Chemistry and pharmacology of Kinkéliba (Combretum micranthum), a West African medicinal plant. Doctoral dissertation, Rutgers University-Graduate School-New Brunswick, 2010 75 Halder S, Bharal N, Mediratta PK, Kaur I, Sharma KK. Antiinflammatory, immunomodulatory and antinociceptive activity of Terminalia arjuna Roxb bark powder in mice and rats. Indian J Exp Biol 2009; 47: 577-583 [PMID: 19761042] 76 Manna P, Sinha M, Sil PC. Aqueous extract of Terminalia arjuna prevents carbon tetrachloride induced hepatic and renal disorders. BMC Complement Altern Med 2006; 6: 33 [PMID: 17010209 DOI: 10.1186/1472-6882-6-33] 77 Paarakh PM. Terminalia arjuna (Roxb.) Wt. and arn: A review. Int J Pharmacol 2010; 6: 515-534 [DOI: 10.3923/ijp.2010.515.534] 78 Abongwa M, Rageh GA, Arowolo O, Dawurung C, Oladipo O, Atiku A. Efficacy of Senna occidentalis in the amelioration of tetracycline induced hepatoand nephro-toxicities in rabbits. Toxicol Lett 2010; 196S: S207: P206-009 79 Bin-Hafeez B, Ahmad I, Haque R, Raisuddin S. Protective effect of Cassia occidentalis L. on cyclophosphamide-induced suppression of humoral immunity in mice. J Ethnopharmacol 2001; 75: 13-18 [PMID: 11282437 DOI: 10.1016/S0378-8741(00)00382-2] 80 Yadav JP, Arya V, Yadav S, Panghal M, Kumar S, Dhankhar S. Cassia occidentalis L.: a review on its ethnobotany, phytochemical and pharmacological profile. Fitoterapia 2010; 81: 223-230 [PMID: 19796670 DOI: 10.1016/j.fitote.2009.09.008] 81 Kaur R, Kaur H, Dhindsa AS. Glycyrrhiza glabra: a phytopharmacological review. IJPSR 2013; 4: 2470 [DOI: 10.13040/ IJPSR. 0975-8232.4(7).2470-77] 82 Jeba CR, Vaidyanathan R, Rameshkumar G. Immunomodulatory activity of aqueous extract of Ocimum sanctum in rat. Int J Pharm Biomed Res 2011; 2: 33-38 83 Kelm MA, Nair MG, Strasburg GM, DeWitt DL. Antioxidant and cyclooxygenase inhibitory phenolic compounds from Ocimum sanctum Linn. Phytomedicine 2000; 7: 7-13 [PMID: 10782484 DOI: 10.1016/S0944-7113(00)80015-X] 84 Kumar A, Rahal A, Chakraborty S, Tiwari R, Latheef SK, Dhama K. Ocimum sanctum (Tulsi): a miracle herb and boon to medical science-A Review. Int J Agron Plant Prod 2013; 4: 589 85 Prakash P, Gupta N. Therapeutic uses of Ocimum sanctum Linn (Tulsi) with a note on eugenol and its pharmacological actions: a short review. Indian J Physiol Pharmacol 2005; 49: 125-131 [PMID: 16170979] 86 al-Sereiti MR, Abu-Amer KM, Sen P. Pharmacology of rosemary (Rosmarinus officinalis Linn.) and its therapeutic potentials. Indian J Exp Biol 1999; 37: 124-130 [PMID: 10641130] 87 Kontogianni VG, Tomic G, Nikolic I, Nerantzaki AA, Sayyad N, Stosic-Grujicic S, Stojanovic I, Gerothanassis IP, Tzakos AG. Phytochemical profile of Rosmarinus officinalis and Salvia officinalis extracts and correlation to their antioxidant and antiproliferative activity. Food Chem 2013; 136: 120-129 [PMID: 23017402 DOI: 10.1016/j.foodchem.2012.07.091] 88 Sakr SA, Lamfon HA. Protective effect of rosemary (Rosmarinus officinalis) leaves extract on carbon tetrachloride-induced nephrotoxicity in albino rats. Life Sci J 2012; 9: 779-785 89 Lee TY, Mai LM, Wang GJ, Chiu JH, Lin YL, Lin HC. Protective mechanism of salvia miltiorrhiza on carbon tetrachloride-induced acute hepatotoxicity in rats. J Pharmacol Sci 2003; 91: 202-210 [PMID: 12686743 DOI: 10.1254/jphs.91.202] 90 Wang BQ. Salvia miltiorrhiza: Chemical and pharmacological review of a medicinal plant. J Med Plant Res 2010; 4: 2813-2820 91 Gasparetto JC, Martins CA, Hayashi SS, Otuky MF, Pontarolo R. Ethnobotanical and scientific aspects of Malva sylvestris L.: a millennial herbal medicine. J Pharm Pharmacol 2012; 64: 172-189 [PMID: 22221093 DOI: 10.1111/j.2042-7158.2011.01383.x] 92 El Ghaoui WB, Ghanem EB, Chedid LA, Abdelnoor AM. The effects of Alcea rosea L., Malva sylvestris L. and Salvia libanotica L. water extracts on the production of anti-egg albumin antibodies, interleukin-4, gamma interferon and interleukin-12 in BALB/c mice. Phytother Res 2008; 22: 1599-1604 [PMID: 18688815 DOI: 10.1002/ptr.2530] 93 Hussain L, Ikram J, Rehman K, Tariq M, Ibrahim M, Akash MSH. Hepatoprotective effects of Malva sylvestris L. against paracetamol-induced hepatotoxicity. Turk J Biol 2014; 38: 396-402 [DOI: 10.3906/biy-1312-32] 94 Bishayi B, Roychowdhury S, Ghosh S, Sengupta M. Hepatoprotective and immunomodulatory properties of Tinospora cordifolia in CCl4 intoxicated mature albino rats. J Toxicol Sci 2002; 27: 139-146 [PMID: 12238138 DOI: 10.2131/jts.27.139] 95 Kavitha BT, Shruthi SD, Rai SP, Ramachandra YL. Phytochemical analysis and hepatoprotective properties of Tinospora cordifolia Balaban YH et al. Liver immunology and herbal treatment WJH|www.wjgnet.com 770 June 18, 2017|Volume 9|Issue 17| against carbon tetrachloride-induced hepatic damage in rats. J Basic Clin Pharm 2011; 2: 139-142 [PMID: 24826014] 96 Sinha K, Mishra NP, Singh J, Khanuja SPS. Tinospora cordifolia (Guduchi), a reservoir plant for therapeutic applications: A Review. Indian J Tradit Know 2004; 3: 257-270 97 EMEA - European Medical Agency-Committee on Herbal Medicinal Products, List of References Supporting the Assessment Report on: Peumus boldus, London: European Medicines Agency Evaluation of Medicines for Human Use, 2009 98 González-Cabello R, Speisky H, Bannach R, Valenzuela A, Fehér J, Gergely P. Effects of boldine on cellular immune functions in vitro. J Investig Allergol Clin Immunol 1993; 4: 139-145 [PMID: 7981884] 99 Lanhers MC, Joyeux M, Soulimani R, Fleurentin J, Sayag M, Mortier F, Younos C, Pelt JM. Hepatoprotective and antiinflammatory effects of a traditional medicinal plant of Chile, Peumus boldus. Planta Med 1991; 57: 110-115 [PMID: 1891491 DOI: 10.1055/s-2006-960043] 100 Gilca M, Gaman L, Panait E, Stoian I, Atanasiu V. Chelidonium majus--an integrative review: traditional knowledge versus modern findings. Forsch Komplementmed 2010; 17: 241-248 [PMID: 20980763 DOI: 10.1159/000321397] 101 Kadan G, Gözler T, Shamma M. (-)-Turkiyenine, a new alkaloid from Chelidonium majus. J Nat Prod 1990; 53: 531-532 [DOI: 10.1021/np50068a046] 102 Küpeli E, Koşar M, Yeşilada E, Hüsnü K, Başer C. A comparative study on the anti-inflammatory, antinociceptive and antipyretic effects of isoquinoline alkaloids from the roots of Turkish Berberis species. Life Sci 2002; 72: 645-657 [PMID: 12467905 DOI: 10.1016/S0024-3205(02)02200-2] 103 Mehta VB, Sathaye SS, Amin PD. Hepatoprotective potental of Chelidonium majus and Myrica cerifera in drug induced hepatotoxicity. Drug Manufact 2006; 43: 12 104 Mitra S, Gole M, Samajdar K, Sur RK, Chakraborty BN. Antihepatotoxic activity of Chelidonium majus. Int J Pharmacogn 1992; 30: 125-128 [DOI: 10.3109/13880209209053974] 105 Song JY, Yang HO, Pyo SN, Jung IS, Yi SY, Yun YS. Immunomodulatory activity of protein-bound polysaccharide extracted from Chelidonium majus. Arch Pharm Res 2002; 25: 158-164 [PMID: 12009029 DOI: 10.1007/BF02976557] 106 Amin ZA, Abdulla MA, Ali HM, Alshawsh MA, Qadir SW. Assessment of in vitro antioxidant, antibacterial and immune activation potentials of aqueous and ethanol extracts of Phyllanthus niruri. J Sci Food Agric 2012; 92: 1874-1877 [PMID: 22231455 DOI: 10.1002/jsfa.5554] 107 Bagalkotkar G, Sagineedu SR, Saad MS, Stanslas J. Phytochemicals from Phyllanthus niruri Linn. and their pharmacological properties: a review. J Pharm Pharmacol 2006; 58: 1559-1570 [PMID: 17331318 DOI: 10.1211/jpp.58.12.0001] 108 Harish R, Shivanandappa T. Antioxidant activity and hepatoprotective potential of Phyllanthus niruri. Food Chem 2006; 95: 180-185 [DOI: 10.1016/j.foodchem.2004.11.049] 109 Sharma ML, Rao CS, Duda PL. Immunostimulatory activity of Picrorhiza kurroa leaf extract. J Ethnopharmacol 1994; 41: 185-192 [PMID: 8176958 DOI: 10.1016/0378-8741(94)90031-0] 110 Verma PC, Basu V, Gupta V, Saxena G, Rahman LU. Pharmacology and chemistry of a potent hepatoprotective compound Picroliv isolated from the roots and rhizomes of Picrorhiza kurroa royle ex benth. (kutki). Curr Pharm Biotechnol 2009; 10: 641-649 [PMID: 19619118 DOI: 10.2174/138920109789069314] 111 Rehman H, Begum W, AnjumF, Tabasum H. Rheum emodi (Rhubarb): A fascinating herb. J Pharmacogn Phytochem 2014; 3: 89-94 112 Chan SW. Panax ginseng, Rhodiola rosea and Schisandra chinensis. Int J Food Sci Nutr 2012; 63 Suppl 1: 75-81 [PMID: 22039930 DOI: 10.3109/09637486.2011.627840] 113 Ekiert R, Szopa A, Ekiert H, Krzek J, Dzik E. Analysis of lignans in Schisandra chinensis fruits, leaves, biomasses from in vitro cultures and food supplements. J Funct Foods 2013; 5: 1576–1581 [DOI: 10.1016/j.jff.2013.06.008] 114 Atanu FO, Ebiloma UG, Ajayi EI. A review of the pharmacological aspects of Solanum nigrum Linn. Biotechnol Mol Biol Rev 2011; 6: 1-8 115 Jain R, Sharma A, Gupta S, Sarethy IP, Gabrani R. Solanum nigrum: current perspectives on therapeutic properties. Altern Med Rev 2011; 16: 78-85 [PMID: 21438649] 116 Li J, Li QW, Gao DW, Han ZS, Lu WZ. Antitumor and immunomodulating effects of polysaccharides isolated from Solanum nigrum Linne. Phytother Res 2009; 23: 1524-1530 [PMID: 19449342 DOI: 10.1002/ptr.2769] 117 Lin HM, Tseng HC, Wang CJ, Lin JJ, Lo CW, Chou FP. Hepatoprotective effects of Solanum nigrum Linn extract against CCl(4)-induced oxidative damage in rats. Chem Biol Interact 2008; 171: 283-293 [PMID: 18045581 DOI: 10.1016/j.cbi.2007.08.008] 118 Huseini HF, Alavian SM, Heshmat R, Heydari MR, Abolmaali K. The efficacy of Liv-52 on liver cirrhotic patients: a randomized, double-blind, placebo-controlled first approach. Phytomedicine 2005; 12: 619-624 [PMID: 16194047 DOI: 10.1016/j.phymed. 2004.10.003] 119 Sehrawat A, Sultana S. Tamarix gallica ameliorates thioacetamideinduced hepatic oxidative stress and hyperproliferative response in Wistar rats. J Enzyme Inhib Med Chem 2006; 21: 215-223 [PMID: 16789436 DOI: 10.1080/14756360500480673] 120 Araújo CC, Leon LL. Biological activities of Curcuma longa L. Mem Inst Oswaldo Cruz 2001; 96: 723-728 [PMID: 11500779 DOI: 10.1590/S0074-02762001000500026] 121 Abdel-Azeem AS, Hegazy AM, Ibrahim KS, Farrag AR, ElSayed EM. Hepatoprotective, antioxidant, and ameliorative effects of ginger (Zingiber officinale Roscoe) and vitamin E in acetaminophen treated rats. J Diet Suppl 2013; 10: 195-209 [PMID: 23927622 DOI: 10.3109/19390211.2013.822450] 122 Abdullah N, Saat NZM, Hasan HA, Budin SB, Kamaralzaman S. Protective effect of the ethanol extract of Zingiber officinale Roscoe on paracetamol induced hepatotoxicity in rats. Jurnal Sains Kesihatan Malaysia 2004; 2: 85-95 123 Ali BH, Blunden G, Tanira MO, Nemmar A. Some phytochemical, pharmacological and toxicological properties of ginger (Zingiber officinale Roscoe): a review of recent research. Food Chem Toxicol 2008; 46: 409-420 [PMID: 17950516 DOI: 10.1016/j.fct. 2007.09.085] 124 Bao L, Deng A, Li Z, Du G, Qin H. [Chemical constituents of rhizomes of Zingiber officinale]. Zhongguo Zhongyao Zazhi 2010; 35: 598-601 [PMID: 20506819] 125 Carrasco FR, Schmidt G, Romero AL, Sartoretto JL, CaparrozAssef SM, Bersani-Amado CA, Cuman RK. Immunomodulatory activity of Zingiber officinale Roscoe, Salvia officinalis L. and Syzygium aromaticum L. essential oils: evidence for humor- and cell-mediated responses. J Pharm Pharmacol 2009; 61: 961-967 [PMID: 19589240 DOI: 10.1211/jpp/61.07.0017] 126 Ezeonu CS, Egbuna PAC, Ezeanyika LUS, Nkwonta CG, Idoko ND. Antihepatotoxicity studies of crude extract of Zingiber officinale on CCl 4 inducedtoxicity and comparison of the extract’s fraction D hepatoprotective capacity. Res J Med Sci 2011; 5: 102-107 [DOI: 10.3923/rjmsci.2011.102.107] 127 Kumar G, Karthik L, Rao KB. A review on pharmacolo