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Herbs forAutoimmune Diseases

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A.Mukne, S.Dangat, P.Shirodkar, andK.Sawate

Abstract

The incidence of autoimmune diseases worldwide is on the rise, with extensive impact on lifestyle of individuals and spiralling healthcare costs. Phytotherapies are increasingly being deployed in management and treatment of various autoimmune diseases, primarily due to the restricted therapeutic benet and serious side effects and toxicities associated with the long-term use of biologicals and other immunosuppressant drugs that currently form the mainstay of autoimmune disease management. This chapter focuses on providing an update on herbs reported in management and treatment of autoimmune diseases, with detailed, in-depth understanding of their molecular-level mechanism of action and modulation of various cell signalling pathways including NF-κB, STAT/JAK, MAPK and iNOS.Insights into the aetiology and pathogenesis of some of the major autoimmune diseases help in guring out the arsenal of herbs that can be developed as effective therapeutic agents against these difcult-to-manage disease conditions. We take a look at phytotherapies reported for treatment and management of organ- specic and systemic autoimmune conditions including systemic lupus erythematosus, skin-related autoimmune conditions (atopic dermatitis, vitiligo and psoriasis), Addison’s disease and neurodegenerative diseases (multiple sclerosis, Alzheimer’s disease and Parkinson’s disease).

Keywords

Autoimmune diseases · Phytotherapies · Systemic lupus erythematosus · Addison’s disease · Neurodegenerative diseases · Autoimmune skin conditions

A. Mukne (*) · S. Dangat · P. Shirodkar · K. Sawate Department of Pharmacognosy and Phytochemistry, Bombay College of Pharmacy, Mumbai, Maharashtra, India

Abbreviations

(NF-κB) Nuclear factor kappa light of activation

B cell 11-HSD 11 beta-hydroxysteroid dehydrogenase 4-TBC 4-tert-Butylcatechol 4-TBP 4-tert-Butylphenol 6-OHDA 6-Hydroxydopamine AAD Autoimmune Addison’s disease ABTS 2,2′-Azino-bis(3-ethylbenzothiazoline-6-

sulfonic acid) ACE Angiotensin-converting enzyme ACTH Adrenocorticotropic hormone ADCC Antibody-dependent cell-mediated

cytotoxicity ADs Autoimmune diseases AIRE Autoimmune regulator ALD Alzheimer’s disease AP-1 Activator protein-1 APCs Antigen-presenting cells APECED Autoimmune polyendocrinopathy

candidiasis ectodermal dystrophy APP Amyloid precursor protein APS1 Autoimmune polyglandular syndrome

type 1 APS2 Autoimmune polyglandular syndrome

type 2 AR Aldose reductase AS-IV Astragaloside IV B cells Bursa-derived cell BBB Blood brain barrier CAT Catalase CCL Chemokine ligand CD Clusters of differentiation cell CFA Complete Ferund’s adjuvant CLDN1 Claudin-1 CNS Central nervous system COX-2 Cyclooxygenase-2

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CTLA-4 Cytotoxic T Lymphocyte Antigen-4 CTLs Cytotoxic T lymphocytes CXCL CXC chemokine ligand DA Dopamine DAD Diallyl disulde DAT Diallyl trisulde DCs Dendritic cells DJ-1 Protein deglycase DLE Discoid lupus erythematosus DPPH α,α-Diphenyl-β-picryl hydrazyl EAE Experimental autoimmune encephalitis EBV Epstein-Barr virus EC Epicatechin ECG Epicatechin gallate EGC Epigallocatechin EGCG Epigallocatechin gallate ER Endoplasmic reticulum ERK Extracellular-signal-regulated kinase FLG Filaggrin Foxp3 Forkhead box protein 3 gene GluR3 Glutamate receptor GM-CSF Granulocyte macrophage colony

stimulating factor GR Glucocorticoid receptor HBD-2 Human beta-defensin HD Huntington’s disease HHV6 Human herpes virus-6 HLA Human lymphocyte antigen HLA Human lymphocyte antigen-27 IB kinase I-kappa B kinase IBD Inammatory bowel disease IFNs Type 1 interferons IFN-β Interferon-β IFN-γ Interferon-gamma IgE Immunoglobulin E IL Interleukin ILC3 Innate lymphoid cells 3 IMQ Imiquimod iNOS Inducible nitric oxide synthase IPEX syndrome Immune polyendocrinopathy X-linked

syndrome IRF Interferon regulatory factor JAK/STAT Janus kinase/signal transducer and

activators of transcription LN Lupus nephritis LPS Lipopolysaccharide MAPK Mitogen-activated protein kinase MBEH Monobenzyl ether of hydroquinone MC1R Melanocortin 1 receptor MEOg Methanol extraction of O. gratissimum

leaves MHC Major histocompatibility complex

MMP Matrix metalloproteinase MOG Myelin oligodendrocyte glycoprotein MPP+ 1-Methyl-4-phenylpyridinium ion MPTP

1-Methyl-4-phenyl-1,2,3,6-

tetrahydropyridine MS Multiple sclerosis MSH Melanocyte stimulating hormone n-BuOH n-Butanolic NBUVB Narrowband UVB NGF Nerve growth factor NL Neonatal lupus NMDA N-methyl--aspartate NO Nitric oxide NSAID Nonsteroidal anti-inammatory drugs NSO Noni seed oil OCA2 Oculocutaneous albinism OVA Ovalbumin OXA Oxazolone PAG Processed Aloe vera gel PD Parkinson’s disease PGE2 Prostaglandin E2 PHF Pentaherbs formula PINK1 PTEN induced putative kinase 1 PPMS Primary progressive MS ProFLG Pro-laggrin PSEN1 Presenilin 1 PSEN2 Presenilin 2 PTS Propyl-propane thiosulnate PTSO Propyl-propane thiosulfonate RA Rheumatoid arthritis ROS Reactive oxygen species RRMS Relapsing remitting MS SAC S-allyl-cysteine SLE Systemic lupus erythematosus SPMS Secondary progressive MS SPP1 Secreted phosphoprotein 1 SS Sjogren’s syndrome STAT-3 Signal transducer and activator of

transcription 3 T CELLS T lymphocytes TAP1 Transporters associated with antigen

processing protein-1 T-bet T-box expressed in T cells TCR T-cell receptor T

Effector T cells

EFF

Tfh T follicular helper TGF-β Transforming growth factor beta Th T helper cell TH Tyrosine hydroxylase TLRs Toll-like receptors TNFATP3 TNF alpha induced protein 3

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TNF-α Tumor necrosis factor-α T

Regulatory T cells

reg

TSLP Lymphopoietin TSN Tanshione IIA TwHF Tripterygium wilfordii hook f. TYR Tyrosine UCH-L1 Ubiquitin carboxyl-terminal hydrolase

L1 UPR Unfolded protein response UPS Ubiquitin-proteasome system WS Withania somnifera ZO1 Zonula occludens-1

1 Introduction

Autoimmunity is a disease state in which the body is unable to distinguish between self and foreign antigens. At the beginning of twentieth Century, Paul Ehrlich brought in the concept of “horror autotoxicus” and emphasised on the ability of the immune system to distinguish between self and foreign antigens [1]. The immune system exhibits tolerance to the molecules identied as “self” under normal conditions; the mechanism of self-tolerance involves central and peripheral tolerance. Aetiology of autoimmune diseases is complex; it involves a combination of environmental triggers and genetic factors which lead to failure of immune tolerance mechanisms [2]. The failure of immune tolerance mechanisms is thus the characteristic feature of autoimmune diseases (ADs). It has been reported that an overall global prevalence of autoimmune diseases are increasing annually at rates of 19.1% and 12.5%, respectively [3]. Autoimmune diseases are chronic and clinically multifactorial, primarily caused by dysregulation of the cell-mediated and antibodymediated immune response. Autoantibodies and major histocompatibility complex (MHC) are the main predictors in the development of autoimmune diseases. In humans, MHC also known as human lymphocyte antigen (HLA) accounts for almost 50% of genetic predisposition in ADs [4, 5].

Current pharmacological therapies for the management and control of ADs include calcineurin inhibitors (cyclosporine, tacrolimus), cytotoxic drugs (cyclophosphamide), glucocorticoids (prednisolone, methylprednisolone) and biological agents (rituximab, iniximab) that suppress inammation. However, long-term use of these drugs often leads to serious drug-induced toxicity and decline of organ function [6]. Phytotherapies with major active constituents including avonoids, terpenoids, alkaloids and phenolic acids have been reported to produce signicant antiinammatory effect, without the attendant toxicities and side effects. Here, we look at recent advances in developing such therapies as effective medicinal agents in treatment and management of ADs. Table1 gives an overview of various organ-

specic and systemic autoimmune diseases along with common herbs used in treatment and management of these ADs.

Organ-specic autoimmune diseases: The antibodies and T lymphocytes (T cells) react with self-antigens in targeted organs. Non-organ-specic (multiple organ)/systemic autoimmune diseases: The antibodies and T cells attack antigens spread throughout tissues and organs.

1.1 Aetiology ofADs

1.1.1 Dysregulation ofInnate andAdaptive Immunity

Environmental triggers and genetic factors cause failure of immune tolerance mechanisms that leads to a disturbance in numbers and outputs of regulatory T cells (T T cells (T

). In order to maintain immunological homeosta-

EFF

) and effector

reg

sis, regulatory and pathogenic effector T cell subsets must coexist in proportion [31]. Figure1 gives a schematic illustration of overview of dysregulation of immune homeostasis.

Innate immunity has a key role in concert with adaptive immune-mediated tissue damage in aetiology of ADs [32]. Figure2 illustrates the pathways of tissue damage and malfunctioning of innate and adaptive immunity in cell- mediated and autoantibody-mediated ADs. Antigen-presenting cells (APCs) identify antigens and trigger the activation of innate immunity cells (dendritic cells (DCs), macrophages, B cells and natural killer cells) by toll-like receptors (TLRs). Activation of innate immune cells triggers release of proinammatory cytokines such as granulocyte macrophage colony stimulating factor (GM-CSF), type 1 interferons (IFNs) and interleukins((IL) like IL-12, IL-1β, IL-10, IL-6 that are associated with tissue damage in autoimmune conditions [33, 34]. Further, it stimulates the activation of adaptive immune response through maturation of T cells into clusters of differentiation cells (CD)—CD4+ and CD8+. Immature (CD8+) and (CD4+) T lymphocytes are exposed to MHC I and MHC II peptides, respectively, on the surface of the APCs. Thus, immature CD8+ and CD4+ T cells get activated and differentiated into effector T helper cell (Th) subsets, namely T follicular helper (Tfh), Th1, Th2, Th17 and Treg cells; each of them exhibits a distinct phenotypic prole and triggers release of unique sets of cytokines that exert different functions in the immune response. These subsets of T cells negatively control both innate and adaptive immunity and their reduction causes failure of tolerance mechanisms, as seen in various autoimmune diseases [33].

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Table 1 Organ-specic and systemic ADs along with common herbs reported in their management

Types of diseases Disease name Epidemiology Clinical manifestation Herbs used for treatment References

Non-organ specic disease

Skin-related diseases

Adrenal gland-related disease

Neurological autoimmune diseases

Systemic lupus erythematosus (SLE)

Atopic Dermatitis/ Eczema

Vitiligo 0.2–2% population

Psoriasis 2% population

Autoimmune Addison’s Disease (AAD)

Multiple Sclerosis (MS)

Alzheimer’s Disease (ALD)

Parkinson’s Disease (PD)

13–7713.5 per 100,000 individuals found to be affected globally [7]

10–20% and 1–3% of children and adults, respectively, found to be affected globally [10]

affected worldwide [13]

affected worldwide [18]

1/5000 to 1/7000 individuals are affected [22]

2.8 million people are affected worldwide [25]

44 million people affected worldwide [27]

1–3% of the population over 60 years of age found to be affected globally [29]

Maculopapular, mucocutaneous, musculoskeletal, cerebrovascular, hepatic, renal, pancreatic, pulmonary, cardiopulmonary, haemolytic, ocular, oesophageal, gynaecological furthermore, multiple organ failure

Red dry, patches of skin, rashes, swollen discoloured skin

Non-scaly, chalky macules Piper nigrum, Nigella

Dry itchy skin, silver scaly patches, pruritus, swelling of joints, discoloration of skin

Weight loss, anorexia, nausea, vomiting, diarrhoea, salt craving and hyperpigmentation of skin and mucosal membranes

Disturbance of sensory and motor neurons

Cognitive impairment, loss of memory, dementia

Bradykinesia, tremor, muscle rigidity, postural instability, cognitive impairment, dementia, hallucination and autonomic dysfunction

Tripterygium wilfordii, Artemisia annua, Artemisia apiaceae

Aloe vera, Pentaherbs formula (Flos lonicerae, Herba menthae, Cortex phellodendri, Cortex moutan and Rhizoma atractyodis)

sativa, Ammi visnaga, Picrorhiza kurroa, Angelica sinesis

Oryza sativa L., Curcuma longa

Glycyrrhiza glabra, Curcuma longa, Emblica ofcinalis

Artemisia dracunculus, Curcuma longa

Withania somnifera, Bacopa monnieri, Ginkgo biloba, Crocus sativus

Citrus sinensis, Hypericum perforatum, Ginkgo biloba, Panax ginseng

A. Mukne et al.

[8, 9]

[11, 12]

[14–17]

[19–21]

[23, 24]

[26]

[28]

[30]

Fig. 1 Outline of dysregulation of immune homeostasis

The transcription factor T-bet (T-box expressed in T cells) and the cytokines (Type 1 IFN and IL-12) are activated to promote differentiation of CD8+ and CD4+ naïve helper T cells. Activated CD8+ T cells are differentiated into Th1 cells, through activation of signal transducer and activator of

transcription 3 (STAT-3) in T cells. Th1 cells aid in the production of cytotoxic T lymphocytes (CTLs) with release of IL-12 and IL-27. Further, autoreactive CTLs produce cytotoxic granules, activate Fas-Fas ligand and release cytokines tumor necrosis factor-α (TNF-α) and interferon-gamma

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Fig. 2 Pathways of tissue damage and malfunctioning of innate and adaptive immunity in cell-mediated and autoantibody-mediated autoimmune diseases. (Reproduced with permission from Lifeng Wang,

(IFN-γ), IL-2 which leads to apoptosis. Similarly, activation of the transcription factors STAT3 by release of cytokines IL-21, IL-1β, IL-6 are essential for the differentiation of naïve CD4+ helper T cells into Th17 cells. Elevated levels of Th17 have been associated with the development of most of autoimmune diseases such as SLE, rheumatoid arthritis (RA), Sjogren’s syndrome (SS), inammatory bowel disease (IBD) and MS and crucial for both host defence against external pathogens and inammatory ADs [35]. Th2 and Tfh cells promote the production of autoantibodies by stimulating B-cell activation, maturation, plasma cell differentiation and autoantibody production which eventually leads to tissue damage through antibody-dependent cell-mediated cytotoxicity (ADCC), release of reactive oxygen species (ROS) and binding to cell surface receptors which aid in tissue damage, as in SLE, MS and SS, in which large proportion of host antibodies are directed against own cellular structural components and receptors. A common example of immune complex impairment-mediated disease is SLE.Synovial injury in RA is mediated via rheumatoid factor-IgG complexes. Autoantibodies may also interact with cell surface receptors, which can both upregulate (antithyroid hormone for Graves’ disease) and inhibit certain processes (anti-acetylcholine receptor for myasthenia gravis). The insufcient clearance of cellular debris, enriched with DNA and RNA ligands, can activate the TLR7, TLR8 and TLR9 [36], resulting in forma-

Fu-Sheng Wang, M. Eric Gershwin, Journal of Internal Medicine, Human autoimmune diseases, Published by John Wiley and Sons, Year-2015)

tion of immune complexes with pre-existing autoantibodies [2].

IL-1β is involved in differentiation of immature CD4+ T

cells into Treg cells. Treg cells express transcription factor forkhead box protein 3 gene (Foxp3) that plays a crucial role in the control and suppression of immune response by inhibiting activation of helper T and bursa-derived cell (B cells) [37, 38]. Treg cells also secrete transforming growth factor beta (TGF-β) and IL-10 that regulate immunological responses [39]. Treg cells with decient transcription factor Foxp3 are unable to suppress production of Th1 and Th17 cells, leading to inammation, antibody production and tissue injury [31].

1.1.2 Failure ofCentral andPeripheral Tolerance

Central tolerance is conferred in the thymus and bone marrow by way of negative selection wherein, in the dendritic and medullary epithelial cells, immature lymphocytes with strong afnity for auto-antigens are removed via apoptosis [40]. The lymphocytes with low afnity for auto-antigens are positively selected for survival and differentiate into mature single lymphocytes (CD4+ or CD8+) in the cortex region of thymus [41]. Despite the strictness of the central tolerance mechanism, few autoreactive lymphocytes (CD4+ or CD8+ lymphocytes) manage to escape the process [37].

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Peripheral tolerance occurs in the spleen and lymph nodes and can be prevented by mechanism of energy (T cells remain unresponsive to self-peptides) and clonal ignorance (autoreactive T cells ignore the self- peptides).

Molecular mimicry, epitope spreading and bystander activation mechanisms are involved in loss of immune tolerance.

1.1.2.1 Molecular Mimicry

Pathogens including the microorganisms and chemical agents induce autoimmunity by molecular mimicry mechanism. The hypothesis of molecular mimicry relies on the structural similarity of the peptides of host and pathogen, which activates autoreactive T or B cells [42]. The other factors that may induce molecular mimicry and development of autoimmune disease include chemicals, cosmetics and food additives [43]. Rheumatic fever, a typical example of molecular mimicry, is an outcome of cross reaction between infective microorganism Streptococcus pyogenes and antigens of the heart of the human host leading to damage of heart muscles [44].

1.1.2.2 Epitope Spreading

Epitope spreading is the broadening of immune response induced by an antigen to T or B cells in the process of development of autoimmune disease [45]. Though epitope spreading is one of the contributing factors in the progression or onset of chronic disease, it is also protective in function [46]. The rst step in epitope spreading is molecular mimicry. The diversication of immune response may take place for the same antigen or for separate antigens, which are referred to as intramolecular spreading and intermolecular spreading, respectively. Epitope spreading is triggered by interaction with T cells, somatic hypermutation and endocytic processing in B cell and can be the cause of RA, SLE and MS. Epstein-Barr virus (EBV) are reported to diversify other auto-antigens through B-cell epitope spreading [47, 48].

1.2 Genetic andEpigenetic Factors Contributing toFailure ofImmune Tolerance

1.2.1 Genetic Factors

Most autoimmune diseases are suspected to be polygenic, in which mutation or alteration of more than one gene occurs. However, some rare monogenic autoimmune diseases are also reported.

1.2.1.1 Gene Autoimmune Regulator (AIRE)

The gene autoimmune regulator (AIRE), which encodes 545 amino acids and consists of 14 exons is found on chromosome 21q22.3, and is crucial for the development of T cells in thymus that present tissue-specic antigen. It also regulates the expression of self-antigen by medullary thymic epithelial cells, which is crucial for the development of tolerance and positive and negative selection of autoreactive T cells [52]. The failure of the tolerance mechanism is brought on by mutation or lack of the gene AIRE, which prevents the deletion of autoreactive T cells and allows them to invade the periphery. The AIRE gene has more than 100 known variants, and each mutation exhibits a particular pattern, such as missense/nonsense, splicing and deletion.

AIRE gene encodes a transcription factor that plays a role in the presentation of tissue-restricted antigens during T-cell maturation in the thymus. AIRE’s participation in the negative selection of autoreactive T cells has a signicant impact on the development of the T-cell repertoire. The mutation of gene AIRE was identied in patients with autoimmune polyglandular syndrome type 1 (APS1); it is also referred to as ‘autoimmune polyendocrinopathy candidiasis ectodermal dystrophy’ (APECED). It is a rare, multiple organ autosomal recessive autoimmune disease, characterised by variable autoimmune reactions affecting endocrine and non- endocrine organs. Two of the following diseases, hypoparathyroidism, AAD or chronic mucocutaneous candidiasis, are typically found in coexistence with APECED [53].

1.1.2.3 Bystander Activation

Bystander activation is characterised by non-specic lymphocyte activation and stimulation of T and B cell receptors regardless of their specicity. Bystander T cell activation is independent of T-cell receptor (TCR) signalling and responds rapidly to the inammatory mediators (cytokines and TLR signalling) [49]. Bystander activation of CD8+ memory T cells is mediated by cytokines; studies demonstrated that lipopolysaccharide (LPS) injection stimulates IFN-1 production, which enhances proliferation of CD8+ T cells irrespective of TCR and antigen specicity [50]. Bystander activation and diverse pathogens (viruses, bacteria and parasites) are associated with onset and relapse of several autoimmune diseases including SLE, autoimmune hepatitis and type I diabetes [49, 51].

1.2.1.2 Forkhead Box P3 (Foxp3)

Foxp3, which is encoded with 431 amino acids on the X chromosome, is the main gene controlling the growth and function of Treg cells. Immune polyendocrinopathy X-linked syndrome (IPEX syndrome) is an example of mutation of Foxp3 with consequent immune dysregulation [54].

1.2.1.3 Cytotoxic T Lymphocyte Antigen-4 (CTLA-4)

The negative regulation of the T cell immune response and self-tolerance is facilitated by the CTLA-4. CD28 and CTLA-4, which share the ligands B7.1 (CD80) and B7.2 (CD86) on the APCs are essential for up- and downregulation of T cell activation, respectively. By competing with CD28 receptor for binding to their common ligand B7.2, CTLA-4 inhibits T cell activation [55].

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1.2.1.4 Human Lymphocyte Antigen (HLA)

HLA gene encodes for cell surface proteins and are thought to make up the MHC in humans. Mutations in HLA is strongly associated with different autoimmune conditions such asRA (RA: HLA-DR4), SLE (SLE: HLA-DR2, DR3), type 1 diabetes mellitus (T1D: HLA-II-DR3, DR4), MS (MS: HLA-DR2), celiac disease (CD: DQA1), SS (SS: HLA-DR2) and psoriasis (HLA-B-13,16,17). Whereas, individuals with HLA-B27 have greater predisposition to ankylosing spondylitis as compared to the individuals who are B27 negative. Individuals with DQ6 gene are more likely to develop MS and narcolepsy [5].

1.2.2 Epigenetic andEnvironmental Factors

Epigenetics is dened as the heritable and stable change in gene expression without alteration in DNA sequence, and is linked to environmental triggers [56]. The last few decades have witnessed signicant increase in development of autoimmune diseases due to increase in exposure to environmental pollutants and other agents [57]. The environmental factors associated with autoimmunity include nutrition, xenobiotics, hormones, diet, stress, smoking, biological agents and infectious agents.

1.2.2.1 Stress

The immune system is dysregulated by stress-triggered neuroendocrine hormones which results in development of autoimmune diseases. Studies suggest that stress management intervention is necessary in the treatment of autoimmune diseases in order to prevent immunological imbalance triggered by stress [58]. The development of type 1 diabetes, SLE, and MS is aided by the elevated levels of IL-17, IFN-γ, and interferon-β (IFN-β), also seen in psychological stressinduced abnormalities in gastrointestinal barriers and systemic immune response [59].

1.2.2.2 Hormones

Women are more predisposed to development of autoimmune diseases as compared to men, as oestrogen is reported to be one of the more potent stimulators of autoimmunity whereas androgen is protective in function. The sex bias is mainly seen in autoimmune thyroid diseases, SLE and SS [60]. SLE is associated with early menarche where there is increased exposure to endogenous and exogenous sex hormones (contraceptive pills or hormone relapse therapy) which affects gene expression in women.

1.2.2.3 Diet/Nutrition

In vitro study by Lerner etal. (2015) demonstrated that commonly used food additives disrupt intestinal mucosal barrier function leading to leaky gut syndrome, that is, to say, the fountainhead of autoimmune conditions via molecular mimicry [61, 62]. Dietary iodine, a crucial element of thyroid hormone, is a major environmental risk factor in ADs [63].

2 Phytoconstituents/Herbs

asImmunosuppressive andImmunomodulatory Agents

Numerous plant-derived phytoconstituents hold promise as immunoregulatory therapeutic options. Their principal mechanism of action in maintaining normal immune homeostasis is by either regulating the release of inammatory cytokines and/or moderating functions of immune cells. Phytoconstituents exert immunosuppressive effects by antagonistic action on oxidative stressors. Various plants have been found to exert immunomodulatory effects, including Acacia farnesiana, Allium sativum, Andrographis panic-

ulata, Angelica glauca, Arundo donax, Camellia sinensis, Cymbopogon citratus, Dracocephalum rupestre and Malus domestica [9]. Phytochemicals with anti-inammatory and

immunoregulatory effect include alkaloids (berberine), lectins (tomato lectin), avonoids (quercetin), phenolic glycosides (curcumin), terpenoids (azadirachtin) and saponins (ginsenoside). These have been shown to suppress inammatory cytokines such as IL-6, IL-10, IL-12, IL-17, IL-21, IL-23 and preserve immunological homeostasis and intracellular signalling. Adaptogenic herbs like amla, ashwagandha, ginseng, licorice and brahmi used in stress management have a key role to play in treatment and management of ADs [64]. Figure3 illustrates the biomolecular mechanism of action of prominent indigenous herbs that are commonly used in Ayurveda and other traditional Indian systems of medicine for treatment and management of ADs. Overview of herbs used for management of autoimmune diseases with their molecular targets is elucidated in Table2.

2.1 Anti-inammatory Herbs Commonly

Used inManagement ofVarious Autoimmune Diseases

2.1.1 Curcuma longa

Curcumin, a naturally occurring avonoid, is isolated from the rhizome of Curcuma longa, family Zingiberaceae. It exhibits strong anti-inammatory, antioxidant and antibacterial properties. Curcumin suppresses activation of NF-κB, mitogen-activated protein kinase (MAPK), activator protein 1 (AP-1), Janus kinase/signal transducer and activators of transcription (JAK/STAT) and other signalling pathways and proinammatory transcriptional factor that control the expression of genes involved in the early stages of inammatory response; suppression of NF-κB results in downregulation of COX-2 and in iNOS [81], eventually leading to inhibition of pro-inammatory cytokines IL-6, IL-23, IL-12, IL-8, IL-1, IL-17, IFN-γ, TNF-α, monocyte chemoattractant proteins (also known as CCL2) and NO release [87]. Curcumin can be used in the treatment of IBD, arthritis, psoriasis, depression and atherosclerosis and other inamma-

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Fig. 3 Bimolecular mechanism of action of herbs used in treatment and management of ADs. (Reproduced with permission from Acharya Balkrishna, MDPI Cells 2020, 9(4) Published by MDPI, year-2020). (a) Immunomodulatory action: 1. iNOS inhibitors: Alizarin, asperuloside, α-amyrin, β-amyrin, andrographolide, angelic acid, Cadinol, isophytol, β-phellandrene, gallic acid, kaempferol, 2. Inhibitors of autoantibody production: linalool acetate, α-terpinyl acetate 3. PEG2

tory diseases, in which curcumin reduces inammatory response, providing effective symptomatic relief as well as disease treatment.

The antioxidant property of curcumin protects vital organs such as heart, liver, kidney and brain from oxidative stressors, thus protecting from inammatory damage. Curcumin increases the activity and differentiation of oligodendrocytes, improves myelin genesis, reduces astrocyte proliferation and thus plays an important role in management of neurodegenerative conditions [88].

Curcumin is also used as a golden nutraceutical both topically and orally to alleviate and cure a variety of skin-related disorders (psoriasis, skin inammation, acne and skin cancer) and metabolic diseases [87]. Studies have demonstrated the protective effect of curcumin against H2O2-induced skin injury to keratinocytes. In vitro studies carried out by Kang etal. on transgenic mouse model show that curcumin inhibits release of proinammatory cytokines IL-17, IL-22, IFN-γ, IL-2, IL-8 and TNF-α in mice with psoriasis-like condition [89]. Curcumin treatment has been found to be effective in alleviating psoriasis symptoms in a number of clinical trials [87, 90].

The poor absorption, fast metabolism and rapid systemic clearance of curcumin may be the main causes of its limited

inhibitors: Andrographolide, isophytol, farnesene, cadinol, eugenol, troptolide. (b) Intracellular signalling regulators: 4. NF-κB inhibi- tors: Allicin, alliin-γ-glutamyl-S-allyl--cysteine, andrographolide, saikosaponin, epigallocatechin gallate, lupeol, taraxerol, friedelin, betulinic acid, linalool, pinene, terpinene, limonene, curcumin 5. STAT3 inhibitors: Berbamine, curcumin 6. ROCK inhibitors: Curcumin

bioavailability in both plasma and tissue [87]. Novel drug delivery platforms for curcuminoid phytomolecules have been developed for circumventing these issues and improving bioavailability [91, 92].

2.1.2 Allium sativum

Garlic (Allium sativum L.) is an herbaceous plant, belongs to Amarillidaceae family and contains a number of biologically active compounds, including alkaloids, phenolic compounds, saponins, polysaccharides, as well as organosulfur compounds namely—diallyl thiosulfonate (allicin), diallyl sulde (DAS), DADS, DATS, E/Z-ajoene, S-allyl-cysteine (SAC), as well as S-allylcysteine sulfoxide (alliin) [93]. Studies conducted by Zhu etal. (2022) reported that garlic- derived preparation containing two organosulfur metabolites, propyl-propane thiosulfonate (PTSO) and propyl-propane thiosulnate (PTS), could reduce inammation primarily by inhibiting a number of inammatory biomarkers, such as NO, TNF and IL-1, that regulate the expression of IL-6, IL-10, TNF-α and IFN-γ in RAW 264.7 murine macrophages that were previously treated with LPS [83]. Due to its minimal or complete lack of toxicity, garlic has a signicant potential to heal a variety of inammatory disorders.

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Table 2 Molecular targets for herbs used in management of autoimmune diseases

Sr. no Plant source with active metabolite Mechanism of action Therapeutic effect References

1 Machaerium acutifolium; Lectin

2 Glycine max (Vegetable soyabean);

quercetin, kaempferol

3 Andrographis paniculata; (Kalmegh)

Andrographolide (Diterpene)

4 Uncaria tomentosa; Mitraphylline Inhibit LPS stimulated inducible nitric oxide

5 Phyllanthus emblica; gallic acid

Ellagic acid

6 Citrus sinensis; hesperidin methyl chalcone

7 Sarsaparilla; Steroids: sarsapogenin

similagenin, sitosterol Saponins: smilasaponin, sarsaparilloside

8 Veratrum grandiorum; Resveratrol

9 Pentaherbs formula (PHF): Flos lonicerae,

Herba menthae, Cortex moutan, Rhizoma atractylodis and Cortex phellodendri at a

w/w ratio of 2:1:2:2:2 Active metabolites: gallic acid, berberine, chlorogenic acid

10 Mentha spicata; gallic acid Suppress inammation, inhibit proliferation and

11 Camellia sinensis; polyphenolic

compounds: catechin-epicatechin, epigallocatechin and EGC gallate

12 Tripterygium wilfordii hook f (TWHF)

Active metabolites: TWHF Triptolide, Celastrol

13 Artemisia annua; artemisinin Suppresses proinammatory genes (TNF-gene)

14 Andrographis paniculata (Kalmegh);

andrographolide (diterpene) 15 Stephania tetrandra; Tetrandine 16 Berberis aristata; Berberine Inhibition of prostaglandin E2 (PGE2) and

17 Curcuma longa; Curcumin

(Diferuloylmethane)

18 Salvia miltiorrhiza; Tanshione IIA (TSN) 19 Allium sativum; polyphenols, diallyl

disulde (DAD) diallyl trisulde (DAT)

allicin, (Z, E)-ajoene 20 Withania somnifera; Alkaloids:

Isopelletierineanaferine

Steroids: Withanolides and withaferins

Saponins: Sitoindoside VII, VIII and

withanolides

Decrease proinammatory cytokines, TNF-α and increase level of anti-inammatory cytokine IL-10

Reduced TNF-α, IL-6 and IL-1β production, inhibition of nitric oxide (NO) synthesis

Free radical scavenging activity by inhibiting formation of oxygen-derived free radicals

synthase (iNOS) by suppressing the action of nuclear factor kappa light of activation B cell (NF-κB), inhibit release of cytokines IL-1, IL-6, IL-8, IL-17 and TNF-α

Inhibit cyclooxygenase-2 (COX-2), iNOS and NF-κB

Inhibition of pro-inammatory cytokines TNF-α, IL-6, IL-1β and IL-33

TNF-α-induced β activation

Inhibition of TNF-α, IL-17, IL-6 and IL-1β and antioxidant property by neutralising ROS

Suppression of pro-inammatory cytokine IL-6 and chemokine ligand (CCL) i.e. CCL2, CCL7 and CXC chemokine ligand (CXCL) i.e. (CXCL8)

pro-inammatory cytokines such as TNF-α, IL-6, IL-1, IL-17 and inhibition of COX-2 and NO

Proliferation of proinammatory cytokines leads to increased expression of IL-8, IL-17A and human beta-defensin (HBD-2)

TWHF suppresses proliferation of inammatory cytokines such as TNF-α, IL-6, IL-17 and downregulation of T cells and macrophages

and stimulate anti-inammatory and antioxidant genes

Inhibition of COX-2 and suppression of NF-κB

Inhibition of TNF-α

INF-γ Decreases level of cytokines TNF-α, IL-1, IL-6,

IL-8, IL-12, MCP-1 and IL-1β and various inammatory enzymes and transcription factors PGE2 and INF-γ

Cytokines IL-2, IL-4 and TNF-α are inhibited T cell activation is prevented by modulating the

concentration of NF-κB, iNOS, COX-2, IL-6, TNF and IL-1

Induction of IGg2a, downregulation of B and T cells in hyper immune states

Anti-inammatory [65]

Antioxidant, anti-inammatory

Anti-inammatory, antioxidant

Immunomodulatory and anti-inammatory activity

Antioxidant, anti-inammatory

Anti-inammatory [68]

Antioxidant, anti-inammatory

Anti-inammatory and reduce allergic inammation

Immunosuppressive, anti-inammatory

Immunomodulatory, anti-inammatory

Immunosuppressive, anti-inammatory

Immunosuppressive [79]

Anti-inammatory [80]

Anti-inammatory [68] Anti-inammatory [68, 69]

Antioxidant, anti-inammatory

Immunosuppressive [69] Immunomodulatory,

antioxidant, anti-inammatory

Antioxidant, immunosuppressive

[66]

[67–69]

[70–72]

[73]

[74]

[75]

[12]

[76]

[77]

[78]

[81]

[82–84]

[85, 86]

369

370

https://t.me/medicina_free

A. Mukne et al.

2.1.3 Zingiber ocinale

Zingiber ofcinale Roscoe belonging to family Zingiberaceae is native to India and Southeast Asia [94]. Both fresh and dried ginger rhizomes are used worldwide as a spice and condiment. Ginger contains gingerols, paradol and shogoal which have potent antioxidant, anti-inammatory and anticancer properties. Previous studies reported that ginger extract was able to block the elevated expression of NF-κB and inhibit TNF-α in male Wistar rats with induced liver cancer [95]. In a study reported by Hwang etal. [96], antiinammatory activity of ginger extract in collagen-induced arthritic male DBA/1J mice was evaluated. Ginger was found to inhibit progression of RA by inhibiting the release of Th1/ Th2 and Th17 cytokines and matrix metalloproteinase (MMPs) [96].

2.1.4 Berberis aristata

Berberis aristata, an Indian medicinal plant belonging to family Berberidaceae, has been traditionally used in Ayurveda for a host of medicinal uses. It is a herb used since ancient times. It is commonly known as Indian berberi “Daaru haridra” [97]. The isoquinoline alkaloid berberine found in Berberis aristata is reported to inhibit differentiation of proinammatory Th1 and Th17 cells. Th cellmediated inammation is further downregulated by suppressing T

, DCs, macrophages and other immune cells

regs

that mediate autoreactive inammation [98]. In vitro studies carried out by Yue et al. [99] on collagen-induced arthritis female Wistar rats report that by encouraging the production of cortistatin in the stomach, berberine alleviated symptoms in female Wistar rats with collagen-induced arthritis. The systemic Th17 cell response was inhibited, the upregulated cortistatin entered the bloodstream and arthritis symptoms were diminished [99].

hypocortisolism (ADD) [173] and inhibiting neurodegeneration in paraquad-induced rat model of PD [22, 101].

2.1.6 Camellia sinensis

Commonly known as green tea is obtained from Camellia sinensis. Fiver major avonoids found in green tea are the

catechins, epicatechin (EC), epigallocatechin (EGC), epicatechin gallate (ECG) and epigallocatechin gallate (EGCG). It was found that green tea leaves extract inhibited the arachidonic acid-induced paw oedema in rats [102, 103]. It has been reported that anti-inammatory and antioxidant properties of green tea have potential therapeutic benets in xerostomia associated with SS.It has been reported that EGCG can inhibit proinammatory IL-8 in human lung alveolar epithelial cells [104]. In addition, there are numerous applications for green tea in the treatment of diabetes, IBD, skin conditions and tness enhancement. Green tea has a position in both the mainstream and alternative medical circles, despite the fact that there is not sufcient clinical data to support this.

2.1.7 Uncaria tomentosa

Uncaria tomentosa is commonly referred to as cat’s claw. It is a tropical medicinal vine from the Rubiaceae family [70]. Mitraphylline is the major active constituent found in U. tomentosa which shows immunomodulatory and antiinammatory properties. Additionally, it is reported as an antioxidant, antibacterial, anti-inammatory, and immune system booster and most effective complementary herb for treating parasites [72]. When given orally to mice at a dose of 30 mg/kg for 3 days, it was able to reduce the liberation of TNF-α by 50% and that of IL-1α, IL-1β and IL-17 by about 70% [72], demonstrating the therapeutic importance of this phytomolecule.

2.1.5 Withania somnifera

Withania somnifera (WS), commonly referred to as Ashwagandha, Indian ginseng, member of Solanaceae family, is a widely used adaptogen, with reported use in the treatment of host of ADs including psoriasis, AAD, arthritis and rheumatism [85]. The major chemical constituents present in Ashwagandha are alkaloids (iso pelletierine anaferine), steroidal lactones (withanolides, withaferins), saponins (sitoindoside VII and VIII) and withanolides. It has been reported that WS extract inactivates NF-κB and thus suppress inammation. Similar studies show that withaferin A, a key component of WS leaf extract, effectively inhibits NF-κB activation by inhibiting TNF-induced activation of IB kinase (I-kappa B kinase) enzyme which is responsible for antiproliferative, proapoptotic, anti-invasive, antiosteoclastogenic, antiangiogenic, antimetastatic, radio sensitising, antiarthritic and cardioprotective effects [100]. WS also helps to balance hormones in the body; it has been found to be effective in

2.1.8 Glycine max

It is also known as “Vegetable soybean”, mostly consumed in East Asia. It consists of a multitude of benecial phytochemicals, including phytic acid, isoavones and other phenolic compounds, saponins [66]. Glycine species is reported to strongly inhibit the protein expression of COX-2 and iNOS in LPS-stimulated RAW 264.7 macrophages [105] and thus shows signicant anti-inammatory and antioxidant activity. Huang etal. [105] studied invitro antioxidant, antiinammatory and antidiabetic activities of the three Glycine species in LPS-stimulated RAW 264.7 macrophage and by using α-glucosidase and aldose reductase (AR) methods. Maximum antioxidant activity was demonstrated by aqueous extract of Glycine tabacina as compared to other species. Also, bioactive compounds, genistein and daidzein, were found to demonstrate antioxidant and anti-inammatory effects with appreciable inhibition of α-glucosidase and AR [105].

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