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2.1.9 Andrographis paniculata
Andrographolide, a labdane diterpene, is the main bioactive
phytoconstituent in Andrographis paniculata. Recent clini-
cal reports have documented the utility and potential of
andrographolide as therapeutic agent in treatment of ADs
like osteoarthritis, upper respiratory diseases and MS [106–
109]. Methanolic and aqueous extracts of A. paniculata or
andrographolide are reported to exhibit antioxidant and acute
anti-inammatory effect in carrageenan-induced paw
oedema in rodents, with free radical scavenging activity by
inhibiting formation of oxygen free radicals. Suppressing the
expression of major pro-inammatory genes like COX-2,
IL-6, IL-8, IL-1β and iNOS is reported to be the underlying
mechanism of action [67].
2.1.10 Rosmarinus ocinalis
Rosmarinus ofcinalis, Family Lamiaceae, commonly
known as Rosemary, contains important active constituents
like phenolic diterpenes, triterpenes and acids. Studies have
reported that essential oil of Rosmarinus ofcinalis suppresses transcription of NF-κB and the arachidonic acid
pathway and thus exerts anti-inammatory effect [110].
Phenolic compounds including carnosic acid, carnosol, ursolic acid and rosmarinic acid are shown to exhibit strong antioxidant activity [111].
2.1.11 Coriandrum sativum
Coriandrum sativum (Coriander) is an herbaceous annual
herb belonging to the Apiaceae family. Essential oils of coriander are rich in monoterpenes, with potent anti-bacterial,
antifungal, antidiabetic, antiseptic, anxiolytic and antioxidant activity. Linalool, pinene, cymene, borneol, phellandrene and geraniol are the major constituents in seed oil and
decanal, decanol, cyclodecane and dodecena in the leaves
[112, 113]. In vitro studies were carried out by Foudah etal.
[114] to screen anti-inammatory, antimicrobial and antioxidant properties of Coriandrum sativum leaves oil. Antiinammatory activity was evaluated in terms of degree of
inhibition of egg albumin and trypsin-induced casein denaturation. C. sativum leaves oil was found to demonstrate
excellent anti-inammatory and antimicrobial activity and
poor antioxidant effect [114]. The phytoconstituents from
coriander suppress NF-κB and MAPKs signalling pathways
with consequent reduction in levels of nitrite, ROS, IL-6 and
TNF-α [112].
2.1.12 Morinda citrifolia
Noni (Morinda citrifolia), family Rubiaceae, commonly
known as beach mulberry or cheese fruit, is an evergreen
Polynesian herb. Noni seed oil (NSO) could be a preferable
option for people with excessive cholesterol and cardiovascular disorders because of its high concentrations of polyunsaturated fatty acids, phytosterols and tocopherols [115].
Bioactive substances with anti-cancer, anti-inammatory
and antimicrobial activity have been found in noni seed
extracts. Tanikawa etal. [116] have reported that M. citrifo-
lia seed extract exhibits anti-inammatory effect in LPSinduced RAW 264 cells. M. citrifolia seed extract was found
to be effective in reducing NO generation while having no
negative effect on cell viability. It was found that the M. citri-
folia seed extract produced antioxidant effect by decreasing
the expression of TNF-α and iNOS.These ndings support
the potential therapeutic application of M. citrifolia seed
extract [116]. In another study, Lee etal. [117] have reported
that noni fruit juice contains asperulosidic acid, rutin, noniosideA, (2E,4E,7Z)-deca-2,4,7-trienoate-2-O-β--
glucopyranosyl-β--glucopyranoside and tricetin that
suppress expression of NFκB p65, iNOS and COX-2 and
reduce NO levels in LPS-stimulated RAW 264.7 cells [117].
2.1.13 Cymbopogon citratus
Cymbopogon citratus, family Gramineae, commonly known
as lemongrass, contains aglycones as well as glycosides of
avonoids with anti-inammatory and antioxidant activity
[118]. C. citratus has potential as a therapeutic action for
inammatory disease, particularly at the gut. Suppressing
expression of iNOS and NO scavenging activity are reported
to be the possible mechanism of action [119]. In vivo studies
have reported antidiabetic, anxiolytic, antibacterial and antihypertensive in leaf extracts of C. citratus. Flavonoid glyco-
sides (isoorientin, cymaroside, cassiaoccidentalin B and
kurilesin A) have been reported to inhibit α-glucosidase and
exert hypoglycaemic effect [120]. Borges etal. [120] reported
in vitro inhibition of yeast-glucosidase by various extracts
and fractions of C. citratus. Molecular docking studies of the
avonoids provided proof-of-concept for the hypoglycaemic
effect; the compounds were found to interact with the active
sites of the enzyme via hydrogen bonding [120].
2.1.14 Ocimum gratissimum
Ocimum gratissimum L. belongs to family Lamiaceae and is
a widely distributed aromatic herb in management of a range
of inammatory disorders. Ajayi etal. [121] have reported
in vivo anti-inammatory activity of various phenolic
extracts and fractions of O. gratissimum leaves in carragenaninduced inammation rodent models. The effect was possibly by free radical scavenging, with rutin, quercetin, caffeic
acid, rosmarinic acid, circhoric acid, sitosterol, ursolic acid,
salvigenin and transferulic acid being the main phytoconstituents involved [121].
2.1.15 Tinospora cordifolia
Tinospora cordifolia, commonly known as Guduchi, belongs
to Family Menispermaceae, and is reported in Ayurveda to
act as an immunomodulatory agent, improving the host ability to ward off infections. The major active constituents
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include alkaloids (berberine, magnoorine), glycoside (cardifolioside A, tinocordiside), steroids (β-sitosterol) and aliphatic compounds (octacosanol, hepatocosanol) [122]. In a
study by Nandan etal. [123], immunomodulatory effect and
efcacy of T. cordifolia in Th17-linked ADs were evaluated.
Aqueous extract of T. cordifolia was shown to suppress dif-
ferentiation and proliferation of anti-CD3ε and anti-CD28stimulated naive CD4+ T cells, with reduced production of
IL-17. In silico molecular docking studies validated the ndings, with a cytokine-receptor signalling pathway reported as
the possible mechanism [123].
3 Specic AD Conditions andHerbs
Used inTheir Management
3.1 Systemic Lupus Erythematosus
Lupus is chronic inammatory autoimmune condition with a
broad spectrum of clinical implications which eventually
lead to tissue damage and multiple organ failure. Fig.4 gives
an overview of different types of lupus such as SLE, discoid
lupus erythematosus (DLE), neonatal and drug-induced
lupus [124].
SLE: Multiple organ failure and diverse array of clinical manifestations and production of autoantibodies
against nucleic acid.
DLE: Chronic cutaneous disorder. Patients with DLE
get red, raised sores on the face or scalp.
Neonatal Lupus (NL): At birth, babies have skin
rashes, kidney problems or may have heart problems
that slows down rhythm of heart.
Drug-induced Lupus: Some drugs (such as hydralazine, procainamide and isoniazid) may induce SLElike condition although features go away when drug
administration is stopped.
Numerous immunological and cellular regulators are
deployed for managing this complicated autoimmune condition that is characterised by a dysregulated immune response.
But a complete treatment plan for this disease is not yet
available [124]. Also, the existing chemosynthetic medications, such as nonsteroidal anti-inammatory drugs
(NSAIDS) and corticosteroids, offer restricted therapeutic
benet with severe side effects like gastrointestinal reaction,
bone marrow suppression and leukopenia with recurrence or
aggravation of disease after withdrawal of therapy.
Additionally, the illness heterogeneity and multiple clinical
manifestations are highly extensive, making it difcult to
manage with a single chemical medicine [8]. Wide range of
clinical manifestations associated with this chronic autoimmune conditions are maculopapular (erythematous, elevated
buttery-shaped painful lesions on cheeks), cerebrovascular
(anxiety, headache, seizures, psychosis, demyelination of
nerve cells, ALD), hepatic (hepatitis, hepatomegaly, hepatic
aneurysm), nephron-pathological [nephritis, proteinuria,
haematuria, lupus nephritis (LN)], haematological (anaemia,
leukopenia, thrombocytopenia), cardiac (pericarditis, myocardial infarction, cardiomyopathy), pulmonary (pulmonary
embolism, pneumonitis, brosis), mucocutaneous (mouth
ulcers, sores in inner cheek, dry mouth and gum disease) and
musculoskeletal involvement (arthritis, osteoporosis, osteomyelitis, Raynaud’s disease) [125].
Pathogenesis of SLE is complex and involves multiple
cross interactions between the various elements of innate and
adaptive immunity. Various aetiological factors are involved
in clinical manifestation of SLE such as person’s genetic predisposition [inammation triggering genes such as interferon
regulatory factor (IRF), OX40L, secreted phosphoprotein 1
(SPP1), TNF alpha induced protein 3 (TNFATP3), signalling
pathway gene STAT], epigenetic (histone modication and
DNA methylation), hormonal components (oestrogen, prolactin), immunological and environmental triggers [125].
Immune tolerance to self-antigens is lost in the permissive
situation associated with pro-inammatory stimuli which
leads to unregulated differentiation and expression of B and
Fig. 4 Overview of different
types of lupus
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T cells, further inducing production of autoantibodies [126].
This overproduction of antibodies leads to DNA and ribonucleoprotein damage in healthy cells, with consequent apoptosis [124].
3.1.1 Herbs Used forManagement ofSLE
Immunomodulatory properties have been ascribed to a wide
variety of phytoconstituents and can be deployed for treatment of autoimmune disorders such as SLE.Alkaloids (berberines), lectins (tomato lectin), avonoids (quercetin),
phenolic glycosides, terpenoids (azadirachtin) and saponins
(ginsenoside) have been found to reduce inammatory
cytokines and intracellular signalling, resulting in antiinammatory and immunosuppressive effects [9]. Natural
plant-based immunotherapies and regulators of intracellular
signalling provide therapeutic alternatives with symptomatic
relief by altering the cell signalling pathways and ultimately
reducing release of proinammatory cytokines production
and B-T cell co-stimulation [9, 126, 127]. Figure5 illustrates
the phytoconstituents used as symptomatic relief providers
in SLE.
3.1.1.1 Tripterygium wilfordii Hook F
Triptolide, a diterpene triepoxide, is the principal bioactive
phytoconstituent in the plant TwHF, that is used in management of inammatory and autoimmune diseases [128].
Triptolide has been reported to suppress the production of
proinammatory cytokines, including IL-2, IFN, IL-6 and
TNF, as well as the upregulation of iNOS and COX-2 [128,
129].
Zhang etal. [130] reported a study evaluating the effect of
(5R)-5-hydroxy triptolide (LLDT-8), a triptolide derivative
on LN in MRL/lpr mouse model of SLE.LLDT-8 was found
to have therapeutic benet in LN by suppressing chemokine
expression and inhibiting immune cell inltration in kidneys
[130].
Zhang etal. [131] reported a study evaluating the neuroprotective effect of triptolide in the treatment of SLE by
using microRNA-146a in B cell TLR7 signalling pathway in
mice. Triptolide produced signicant reduction in levels of
double-stranded DNA and IgG and also improved
microRNA-146a expression, with reduced expression of
TLR7 microRNA, protein levels TLR7, MyD88, p-IRAK1
and p-NF-κBp65 [131]. Similarly, Liu etal. [132] showed
that the effectiveness of TwHF in combination with prednisone for the treatment of SLE was 87.5%, signicantly
higher than the rate for the control (prednisone in combination with Methotrexate) [132]. More extensive safety and
efcacy data for triptolide in humans needs to be generated
[128].
Artemisinin
Artemisinin, a sesquiterpene lactone, is isolated from
Artemisia annua and Artemisia apiaceae (sweet annie, quing
hao), Family Asteraceae. Both species contain active ingredient artemisinin and its congeners that are widely used as
antimalarial and immunosuppressive agents [133]. It has
been reported by Zamani et al. [134] that sesquiterpene
extracts of A. annua exerted immunosuppressive effect by
lowering levels of nitric oxide in LPS-primed J774A.1 macrophages [134]. The essential oil of the plant’s aerial parts
are reported to demonstrate appreciable antioxidant effect
[135].
The use of artemisinin therapy relieved proteinuria in LN,
restored blood urea nitrogen and creatinine levels, lessened
pathological damage to the kidneys and decreased mortality;
Fig. 5 Phytoconstituents
used as symptomatic relief
providers for SLE.
(Reproduced with permission
from Acharya Balkrishna,
MDPI Cells 2020,9(4),
Published by MDPI,
Year-2020)
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these effects are produced by inhibition of NF-κB and regulation of adaptive and innate immune cells, including subsets
of CD4+ T cells (Th1/Th2/Th9/Th17/Tfh/Tfr/Treg), CD8+
memory T cells, Treg cells, B cells, dendritic cells, neutrophils, mast cells and macrophages [133].
3.2 Skin-Related Autoimmune Diseases
The body’s largest organ is the skin and accounts for about
16% of the body mass. It is essential for keeping the body
protected against various infectious agents and is considered
as a part of the immune system. Some of the autoimmune
skin disease including atopic dermatitis, vitiligo, psoriasis,
pemphigus and lupus are discussed with their respective
pathophysiology and herbal therapies for their management
and treatment.
3.2.1 Atopic Dermatitis/Eczema
Atopic dermatitis, often known as eczema, is a chronic
relapsing inammatory skin condition characterised by
impaired epidermal barrier function and hyperimmune
response [136]. The complex involvement of various immunological elements, coupled with genetic and environmental
factors, is linked to onset and progression of atopic dermatitis [137]. The three main stages of atopic dermatitis are
infantile, childhood and adulthood [138].
Filaggrin (FLG), a crucial protein in epidermis development
and claudin-1 (CLDN1) and a structural component of tight
junctions in epidermis, was found to have a genetic relationship
with atopic dermatitis. Pro-laggrin (ProFLG), a protein that
functions as a structural component of stratum corneum, is
encoded by the laggrin gene [139]. ProFLG polymers are
cleaved and dephosphorylated by proteases to generate FLG
monomers, which are linked to the accumulation of keratin laments and the development of stratum corneum. The moisture
and acidic pH of skin are both regulated by FLG metabolites,
urocanic acid and pyrrolidine carboxylic acid [137]. The homozygous mutation of laggrin gene is linked to early onset and
severe atopic dermatitis. The expression of proteins laggrin,
keratin, transglutaminase and other intracellular proteins is
downregulated, resulting in aberrant corneocyte development,
decreased skin moisture and elevated skin pH.
The compromised skin barrier allows allergens and
microbes to enter the skin and stimulate keratinocytes into
releasing IL-1β, IL-25, IL-33, macrophage-derived chemokines and thymic stromal lymphopoietin (TSLP) that further
activate dendritic and Langerhans cells [140]. Acute atopic
dermatitis is caused by response of Th2 subset; the activated
dendritic cells stimulate Th2 cells to release IL-4, IL-5,
IL-13, IL-31 and IL-33 which impairs keratinocyte development, reduces antimicrobial peptide production and produces burning sensation. The chronic atopic dermatitis is
associated with Th1, Th22 and Th17 responses which results
in aberrant keratinocyte proliferation and thickening of epidermis [141–143].
Current therapies for management of atopic dermatitis
include emollients, calcineurin inhibitors, phosphodiesterase- 4 inhibitors (Crisaborole) and biological agents (dupilumab, baricitinib) [144]. Some of the plant-based therapies
reported for atopic dermatitis are discussed below.
3.2.1.1 Herbs Used forManagement ofAtopic
Dermatitis
Aloe vera
Aloe vera is a perennial succulent xerophyte with antioxidant
and antibacterial properties [145]. Aloe vera leaf extracts
with high polysaccharide content are routinely used in cosmetics and over-the-counter medications to cure sunburn,
skin irritation and skin diseases like eczema. Studies were
performed by Na etal. [11] to investigate the oral administration of processed Aloe vera gel (PAG) containing low molecular weight aloe polysaccharides in treating ovalbumin
(OVA)-induced atopic dermatitis in BALB/c mice. The
expression of tight junction genes, including claudin-1, claudin- 8 and zonula occludens-1 (ZO-1), was downregulated in
atopic dermatitis epidermis as compared to normal epidermis. It was found that PAG administration through oral route
lowered the thickness of epidermis and suppressed both
overall and OVA-specic immunoglobulin E (IgE) production. In addition, inammatory cytokines, such as IFN-γ,
IL-4 and IL-17A, were suppressed and restored tight junctions to protect skin barrier function [11].
3.2.1.2 Pentaherbs Formula
In traditional Chinese herbal medicine, PHF, a mixture of
ve herbs is used as an alternative adjunct therapy for atopic
dermatitis. PHF contains Flos lonicerae, Herba menthae,
Cortex phellodendri, Cortex moutan and Rhizoma atractylodis in a 2:1:2:2:2 w/w ratio. Tsang etal. [12] investigated the
effectiveness of PHF using an invivo mouse model with
oxazolone (OXA)-mediated dermatitis. Additionally, the
active components of PHF water extract were isolated and
their in vitro anti-inammatory effects were evaluated on
pruritogenic cytokine IL-31 and IL-33-activated human
eosinophils and dermal broblasts. In this study, PHF therapy either orally or topically signicantly decreased ear
swelling, epidermis thickness, eosinophil inltration in epidermal and dermal layers, and the levels of serum IL-12in
mouse OXA-mediated dermatitis. The active ingredients of
PHF water extract—gallic acid, berberine and chlorogenic
acid—were reported to be effective in inhibiting release of
pro-inammatory cytokines (IL-6, CCL7) [12].
3.2.2 Vitiligo
Vitiligo is a chronic depigmentation disorder of skin, characterised by destruction and loss of melanocytes which results
in non-scaly depigmented patches on the skin [13]. Systemic
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inammation of the ears and eyes can coexist with vitiligo.
The brain, eye and hairs are affected by the rarest form of
vitiligo known as Vogt-Koyanagi-Harada syndrome [146].
Aetiology of vitiligo is unclear, but it is mainly due to the
destruction of melanocytes; about 80% of genetic and 20%
of environmental factors continue to remain the leading
causes of vitiligo [13].
The inheritance of vitiligo is polygenic, including various
alleles and gene loci. The HLA involved in vitiligo patients
were found to be A2, DR4, DR7 and DQB1*0303. The candidate genes involved in vitiligo are transporters linked to
antigen processing protein-1 (TAP1) gene, angiotensinconverting enzyme (ACE) gene, CTLA-4 and catalase (CAT)
gene [147]. The innate immune response is mediated by the
genes CASP7, NLRP1 and TICAM1, while the adaptive
immune response is mediated by the genes CTLA4, CD80,
HLA and Foxp3; majority of the genes are immune genes,
that emphasise the key role of immune system in the pathogenesis of vitiligo. A small subset of risk alleles tyrosine
(TYR), Oculocutaneous albinism (OCA2) and melanocortin
1 receptor(MC1R) are solely expressed in melanocytes,
implying a role for melanocytes in the onset of disease [146].
The rate-limiting steps of melanin production are catalysed
by the enzyme tyrosinase, which is encoded by the TYR
gene [148].
Environmental risk factors associated with vitiligo include
phenolic compounds that are tyrosine analogues and interfere with tyrosinase enzyme and synthesis of melanin.
Chemically induced depigmentation was found in skinlightening products, hair dyes, paints, adhesives and industrial oil which may contain the phenolic compounds such as
rhododendrol, monobenzyl ether of hydroquinone (MBEH),
4-tert-butylcatechol (4-TBC) and 4-tert-butylphenol (4-TBP)
[149].
Hereditary factors, autoimmune reactions, oxidative
stress and production of inammatory mediators have been
linked to pathophysiology of vitiligo [148]. Melanogenesis
is an energy-demanding process carried out by melanocytes
that results in a pro-oxidant condition in the skin. The synthesis of melanin requires essential protein tyrosine-related
protein 1. Tyrosine-related protein 1 interacts with the calnexin complex in response to oxidative stress, which
reduces its stability and induces the formation of hazardous
melanin intermediates. Individuals with vitiligo demonstrate modied functionality of mitochondria, that seem to
be the main source of ROS [146, 148]. Overproduction of
ROS triggers the unfolded protein response (UPR), which
causes melanocytes to produce exosomes that carry molecular protein patterns associated with damage, as well as
melanocyte-specic antigens, miRNAs and heat shock proteins [150]. Exosomes aid in their development into efcient antigen-presenting cells by transferring vitiligo target
antigens to nearby dendritic cells. Stressed melanocytes
release CXCL12 and CCL5, which are also implicated in T
cell localisation to the skin. In vitiligo lesions, CD8+ T cells
release IFN-γ; IFN-γ binds to its receptor and activates the
JAK/STAT pathway, as a result CXCL9 and CXCL10 are
secreted in the skin. The melanocyte-specic CD8+ T cells
are recruited through cognate receptors CXCR3, CXCL9
into the skin and CXCL10 increases their localisation
within the epidermis which results in acceleration of
inammation through a positive feedback mechanism.
Melanocyte-reactive resident memory T cells are responsible for maintaining established vitiligo in skin through
IL-15-dependent signalling [13, 151].
The current therapies for management of vitiligo include
topical corticosteroids, mini pulse oral corticosteroids, narrow band UVB phototherapy and methotrexate, that need to
be used over extended periods of time with resultant skin
atrophy, acne and contact allergy. Some of the herbal therapies for management of vitiligo with least adverse events are
discussed here.
3.2.2.1 Herbs Used forManagement ofVitiligo
Piper nigrum
Piper nigrum fruit belongs to the family Piperaceae, with
reported bioactivities including antioxidant, antiinammatory and immunomodulatory [15]. Melanocyte proliferation stimulants are of interest as potential treatment for
vitiligo. The amides such as piperine, guineesine and pipericide found in P. nigrum have the ability to promote the
growth of melanocytes [14, 152]. In a study by Shaee etal.
[153], patients with facial vitiligo were given topical piperine, along with narrowband UVB (NB-UVB) irradiation
which appreciably increased the incidence of re- pigmentation
at 1, 2 and 3 months compared to the untreated control group
[153]. Another clinical trial was performed on human subjects affected by vitiligo in which ointments containing pure
piperine and P. nigrum fruit extract were tested and found to
repigment the affected skin areas. Crude extract produced
results more quickly and effectively compared to pure piperine [14].
Nigella sativa
Nigella sativa, family Ranunculaceae, is commonly known
as black seed or black cumin [16]. N. sativa contains natural
bioactive substances like alkaloids, saponins, alpha-hederin
and thymoquinone, which are responsible for its wide list of
therapeutic activities including analgesic, anti-inammatory,
antioxidant and immunomodulatory activity. N. sativa inhibits the enzymes elastase and myeloperoxidase and also lipid
peroxidation, raising the defence against free radicals with
consequent exertion of antioxidant effect [154]. Clinical trials were carried out by Sarac etal. [17] to examine the effectiveness of topical N. sativa seed oil in vitiligo patients. N.
sativa-containing cream was used topically on commonly
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affected areas of face, hands and genital region twice a day
for 6 months. The studies reported noteworthy hyperpigmentation with no adverse effects [17].
strated superior activity of Oryza sativa extract in substantially reducing severity of psoriasis as compared to untreated
skin specimens. In this study, Oryza sativa extract has been
found to increase expression of anti-inammatory cytokines
3.2.3 Psoriasis
Psoriasis is a chronic inammatory autoimmune skin condition that affects individuals of all age groups, involving interaction of immune cells and epidermal keratinocytes and is
characterised by excessive proliferation and inltration of
immune cells [155]. The most common clinical symptoms
(IL-10 and TGF-β) and downregulation of proinammatory
cytokines (IL-6, IL-8, IL-20, IL-22 and TNF-α). It was
reported to decrease inammation of epidermis and extent of
apoptosis through induction of caspase-3. Anthocyanins
being antioxidant and anti-inammatory in nature, reduce
keratinocyte proliferation [19].
include recurrent are ups of thick patches of red and
inamed skin covered by aky and silver scales on the surface of skin, dry itchy skin, pruritis, swelling of joints and
discoloration of skin. Clinically, psoriasis is divided into two
groups: psoriasis with pustular and non-pustular lesions. The
non-pustular type of psoriasis involves plaque, arthritis, vulgaris, inverse, guttate and erythrodermic, whereas pustular
psoriasis involves impetigo herpetiformis, palmoplantar and
acrodermatitis continua of hallopeau [156, 157]. Aetiology
of psoriasis is not clear; interplay of genetic, epigenetic and
environmental factors triggers the onset of disease. With
involvement of myeloid dendritic cells, cytokines stimulate
Perilla frutescens
Various portions of Perilla frutescens have been reported to
contain a diverse range of phytoconstituents like volatile oil,
fatty acids, policosanols, tocopherols, phytosterols and
hydrophilic compounds like phenols, avonoids and triterpenes. Xu etal. [163] analysed the effectiveness of the essential oil isolated from P. frutescens stem and leaves using
IMQ-induced psoriasis-like lesions in the BALB/c mice
model. It has been observed that essential oil is able to reduce
the levels of pro-inammatory cytokines IL-6, IL-17, IL-23
and NF-B [163].
aberrant keratinocyte growth and induction of various
inammatory mediators. IL-17-producing Th cells, with
innate lymphoid cells 3 (ILC3), apparently induce psoriasis
3.3 Autoimmune Addison’s Disease
rashes without T-cell/antigen interaction, in response to antimicrobial peptides secreted by activated keratinocytes and
inammatory cytokines [18]. Cell signalling pathways play a
major role in aetiology of psoriasis; the key regulatory pathways involve STAT, NF-κB and MAPK signalling [158].
AAD, usually referred as primary adrenocortical insufciency, is characterised by inefcacy of the adrenal cortex in
synthesis of adequate amount of mineralocorticoids and vital
steroidal hormones-glucocorticoids. Effective management
of AAD requires continuous hormone replacement therapy.
3.2.3.1 Herbs Used forManagement ofPsoriasis
Number of medicinal plants have been reported in literature,
for management and therapeutic interventions of psoriasis
including Silybum marianum, Wrightia tinctoria, Curcuma
longa, Aloe vera, Angelica sinesis, Cassia tora, Capsicum
annum, Smilax china and many more [159–161]. Some of
the more commonly used herbs are discussed with their
respective molecular mechanisms of action.
Depending on whether the condition is acute or chronic, several clinical manifestations may occur; the most frequent
symptoms are exhaustion, weight loss, anorexia, nausea,
vomiting, diarrhoea and salt craving. The most specic
symptom is hyperpigmentation of the surfaces of the skin
and mucosa, and is related to elevated levels of adrenocorticotropic hormone (ACTH) and melanocyte stimulating hormone (MSH) [164]. Melanin production is catalysed by the
enzyme tyrosinase, that converts amino acid tyrosine into
Oryza sativa
Oryza sativa L. is commonly known as black rice. It has
been reported by Thepthanee et al. [162] that n-butanolic
L-3,4-DOPA, which is further oxidised to form DOPA quinine and leads to production of melanin by free radical coupling pathway.
(n-BuOH) extract of Oryza sativa enriched with total avonoids, phenolics and anthocyanins, possesses strong antimicrobial and immunomodulatory effects. It was also shown to
have strong antioxidant properties as determined by
2,2′-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid)
(ABTS) and α,α-diphenyl-β-picryl hydrazyl (DPPH) radicalscavenging tests [162]. In vitro and invivo studies were per-
formed by Ampawong etal. [19] on human psoriatic articial
skin and imiquimod (IMQ)-induced rat psoriasis model,
respectively. Both in vitro and invivo models have demon-
destruction of adrenal tissues and failure of adrenal cortex; it
may occur in combination with APS1 and autoimmune polyglandular syndrome type 2 (APS2) or isolated AADs [165].
Mutation in AIRE is thought to be the major causative factor
for monogenetic autoimmune disorder APS-1 [166].
Aetiology of primary adrenocortical insufciency includes
destruction of adrenal cortex, deciency of steroidogenic
enzyme, impaired steroidogenesis pathway and infectious
agents [167]. Congenital adrenal hyperplasia is the most fre-
Common cause of primary adrenocortical insufciency is
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quent hereditary form of primary adrenocortical insufciency caused by deciency of steroidogenic enzyme. The
immune system targets enzyme 21-hydroxylase which is
located in smooth endoplasmic reticulum (ER) of adrenocortical cells, resulting in autoimmune destruction of the adrenal cortex, which is a hallmark of autoimmune primary
adrenal insufciency. The gene CYP21A2 encodes the
enzyme 21-hydroxylase, which is essential for biosynthesis
of the steroidal hormones cortisol and aldosterone. Mutation
of gene CYP21A2 is associated with congenital adrenal
hyperplasia [168]. Patients with AAD develop autoantibodies against self-antigen 21-hydroxylase, which is a key indicator in clinical diagnosis [164]. Autoantibodies against
21-hydroxylase attack the carboxy terminal of the enzyme
and consist of IgG1 isotype which can cross the placenta
[169]. Studies have reported that 21-hydroxylase autoantibodies inhibit the activity of 21-hydroxylase enzyme invitro,
but do not show inhibitory effect invivo. Though these autoantibodies can cross the placenta, they do not cause hypoadrenalism in newborns. The pathophysiology of AAD may not
be inuenced by steroidal 21-hydroxylase autoantibodies.
[170].
AAD is mediated by 21-hydroxylase-specic CD8+ T
cells; the cells of adrenal cortex respond to inammatory and
stressful events by releasing proinammatory cytokines
IL-6, IL-8, IL-18, IL-1 and TNF-α. The infections caused by
Mycobacterium tuberculosis lead to cytotoxic T lymphocyte
inltration that reaches adrenal glands through blood circulation leading to initiation of AAD. The specic epitope
HLA-A2 (21-hydroxylase 342–350 amino acid) binds with
specic CD8+ T lymphocytes and stimulates production of
IFN-γ. The CD8+ T lymphocytes lyse the cells that express
21-hydroxylase through the production of granzyme B [170].
Hormone replacement therapy with glucocorticoids forms
the mainstay for current AAD management. However,
chronic administration of this therapy is linked to severe toxicity and drug-induced autoimmunity. In AAD, hyperpigmentation of skin is associated with stimulation of
melanocyte receptors by ACTH [170]. Herbs like Curcuma
longa, Glycyrrhiza glabra, Emblica ofcinalis, Trigonella
foenum graecum (fenugreek), Boswellia serrata and many
more commonly used for management of AAD are discussed
below.
3.3.1 Herbs Used forManagement ofAddison’s
Disease
3.3.1.1 Glycyrrhiza glabra
Glycyrrhiza glabra, Family Fabaceae, has been used in treatment of mild-to-moderate adrenal insufciency. Glycyrrhizin
increases the cortisol level by inhibiting the enzyme 11betahydroxysteroid dehydrogenase (11-HSD) which is responsible for oxidation of cortisol to its inactive form cortisone
[23]. Long-term use of glycysrrhizin is associated with hyper
mineralocorticoid-like effect in humans and animals.
However, these effects are reversible upon withdrawal of
glycyrrhizin [24]. Methlie et al. reported increased serum
cortisol levels for 2.6h after consumption of G. glabra in 17
AAD patients, selected from Haukeland University
Hospital’s outpatient clinic [171]. Kumari etal. [172] studied
invitro tyrosinase-inhibitory activity of different concentrations of glabridin on B16 melanoma cells and reported
concentration- dependent reduction in melanin [172].
3.3.1.2 Boswellia serrata
Boswellia serrata, Burseraceae, commonly known as Salai/
Salai guggul, has been in use for a long time in folk medicine to combat a variety of chronic inammatory diseases as
well as in ceremonial and religious events as incense. It contains oleo gum resin obtained from incision made on the
trunk of Boswellia tree and consists of 30–60% resin,
5–10% essential oils, and polysaccharides. These extracts
contain 4 major pentacyclic triterpenic acids—11-keto-β-
boswellic acid, acetyl-β-boswellic acid, β-boswellic acid
and acetyl-11- keto-β-boswellic acid—and monoterpenes,
diterpenes, triterpenes and tetracyclic triterpenic acids, that
are reported to be responsible for inhibition of pro-inammatory enzymes [173, 174]. Morsy etal. [173], reported a
study comparing the efcacy of a host of plant steroids in
interacting with glucocorticoid receptor (GR) by in silico
techniques and further validation of their in vivo antiinammatory activity in the classical cotton pellet-induced
granuloma models in rats. Boswellic acid demonstrated
superior interaction with GR, comparable to uticasone as
well as brought in a signicant decrease in serum levels of
IL-6 and TNF-α [173].
3.3.1.3 Fenugreek
Trigonella foenum graecum Linn, Fabaceae, used as dietary
supplement and spice in India contains steroidal sapognins
diosgenin along with lecithin, phosphates, trimethylamine,
trigonelline, choline and iron and has antioxidant, hypolipidemic, hypoglycaemic and immunomodulatory activity. Its
potential role in managing various neurological disorders
such as cognitive impairment, depression and neurodegenerative disorders (PD, ALD and Huntington’s disease (HD))
is being examined [175]. Aylanc etal. [176] evaluated invitro
tyrosinase-inhibitory activity of various phenolic extracts of
Trigonella spruneriana BOISS and reported that its methanolic, ethanolic and ethyl acetate extracts showed appreciable tyrosinase-inhibitory activity when compared with kojic
acid [176]. Prema etal. [177], reported that fenugreek seed
extract was able to inhibit the action of AChE, a crucial
enzyme involved in the progression of ALD, when tested in
aluminium chloride-induced experimental AD model in
male albino Wistar rats [177].
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3.4 Neurological Diseases
Progressive destruction and malfunction of the neurons or
nerve cells are characteristics of neurodegenerative disorders
with protein deterioration, oxidative stress, inammation,
environmental factors, mitochondrial deciencies, family
history and aberrant protein build-up in neurons listed as
some of the most extensively researched causes. Neurological
autoimmune diseases that cause inammation and neurodegeneration of central nervous system (CNS) include MS,
ALD and PD.
3.4.1 Commonly Used Herbs
forNeurodegenerative Diseases
Medicinal plants and products such as Baccopa monnieri,
Withania somnifera (ashwagandha), curcumin, ginseng, jata-
mansi, Shankhpushpi, guduchi, resveratrol, Ginkgo biloba,
Centella asiatica and Triphala have been used to prevent or
treat neurological illnesses [178]. Some of these are discussed below.
3.4.1.1 Bacopa monnieri
Bacopa monnieri, family Scrophulariaceae, commonly
known as Brahmi has been applied in Ayurveda as a nervine
tonic since the sixteenth Century. Brahmi contains betullic
acid, bacoside A (64.28%), bacoside B (27.11%), - mannitol,
stigmastanol and β-sitosterol. Bacopa monnieri contains
pharmacologically active saponins (bacosides A and B,
bacopide or bacopasaponins), which have sedative, antiamnesic, anti-epileptic, anti-anxiety, anti-depressant and
neuroprotective activities [179]. Its potential as antiParkinsonian drug is reported to be, by reducing alpha synuclein aggregation, preventing dopaminergic
neurodegeneration and restoring the lipid content in nematodes on pharmacological Caenorhabditis elegans models of
Parkinson’s [180]. Kishore etal. [181] evaluated two marketed drugs of Bacopa monnieri for their nootropic effect in
treatment of dementia in scopolamine-induced amnesic
Swiss mice models. Both the products, after 14 days of
administration, were able to decrease the effect of scopolamine and restore memory [181].
3.4.1.2 Ginkgo biloba
Ginkgo biloba, commonly referred as Living fossil [182], is
well known for enhancing cerebral function [183]. Yu etal.
[184] reported a study evaluating the neuroprotective effect
of Ginkgo biloba extract and formulation in in vitro and
invivo PD models. The extract and formulations provided
neuroprotective effect in 1-methyl-4-phenyl-1,2,3,6tetrahydropyridine (MPTP)-induced damage in human neuroblastoma SH-SY5Y cells by blocking the apoptotic cycle.
Similar results were observed in MPTP-induced PD mice
models, with reduced neuronal damage and improved motor
coordination. Improved locomotion in 6-hydroxydopamine
(6-OHDA)-induced PD in zebra sh was reported, possibly
due to inhibition of dopaminergic loss, as demonstrated by
Tyrosine hydroxylase (TH) immunostaining [184]. In a pilot
study reported by Rapp etal. [185], 189 patients suffering
from ALD were divided into groups that received either G.
biloba extracts or donepezil, over a period of 12 months. The
patients who received G. biloba extracts showed comparable
effect on cognitive symptoms, as those that were administered donepezil, but with much fewer adverse events and
improved safety prole [185].
3.4.1.3 Centella asiatica
Centella asiatica (Gotu kola) is a conventional herb widely
used in Ayurveda for memory and cognitive function
improvement. Centella contains several pentacyclic triterpenoids, including asiaticoside, brahmoside and madecassic
acid that shows anti-inammatory, neuroprotective and
mitoprotective effects [186–188]. Haz etal. [188] reported
a comprehensive study evaluating the neuroprotective effect
of ethanolic extract of C. asiatica by a series of invitro and
in vivo tests. The extract produced signicant reduction in
acetylcholinesterase activity in SH-SY5Y cells. A similar
concentration-dependent reduction in levels of ROS and
GSH and the pro-inammatory cytokines—PGE2 and
TNF-α—were observed in LPS-stimulated RAW 264.7 cells.
These invitro ndings were validated in vivo in the LPSinduced Sprague Dawley rats model for neuroinammation
[188]. Fujimori etal. reported a study evaluating the neuroprotective effect of Centella asiatica and its component ara-
liadiol against damage induced by ER stressors—glutamate
and tunicamycin—in murine hippocampal cells (HT22).
Suppression of cell death by inhibiting ROS production and
phosphorylation of PERK (one of the main transducers of
ER stress), respectively, was found to be the mechanism
involved. They further validated this invivo, in mice with
scopolamine-induced amnesia, with improved cognitive
function in treated mice [189]. Gray etal. [190] reported the
physiological mechanism for the improved cognitive function demonstrated by C. asiatica. They evaluated the neuroprotective effect of C. asiatica on amyloid-β (Aβ) exposure
in the mouse model of ALD.Water extract of C. asiatica
increased arborisation in the dendrites and spine densities in
the neurons and prevented loss of spines caused by Aβ expo-
sure [190].
3.4.1.4 Nardostachys jatamansi
Nardostachys jatamansi is a blooming, rare and most ancient
species within the family Valerianaceae. It has antiinammatory, antioxidative, cardioprotective, hepatoprotective, hypolipidemic and antifungal activity. The major
chemical constituents include crystalline acid, jatamansic
acid, hydrocarbons, a poly-oxygenated crystalline solid
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together with A-endesmol, B-eudesmol, ethanol, angelicin
and 4-hydroxy thymol dimethyl ether [191]. Liu etal. [192]
studied the neuroprotective effect of N. jatamansi root ethanolic extract in both invitro cell culture system and invivo
Drosophila ALD model. It was observed that N. jatamansi
extract suppressed Aβ-induced cell death in SH-SY5Y cells
and also reduced Aβ42-induced cell death in the brain in
ies. Intake of N. jatamansi extract reduced ROS level, NO
level in Aβ42-expressing ies and extracellular-signalregulated kinase (ERK) phosphorylation. It was reported by
Liu et al. that N. jatamansi exhibits neuroprotective effect
against Aβ42 neurotoxicity both invivo and invitro, due to
its anti-inammatory, antioxidative and ERK signalling
inhibitory action [192].
Shankhpushpi
In Ayurveda, the plant Shankhpushpi (Convolvulus pluricaulis), which is categorised under Medhya Rasayana, is utilised
as the greatest brain tonic medication. The major bioactive
components of C. pluricaulis are the glycosides, steroids
(stigmasterol and betulinic acid), avonoids (β-carotene and
chlorogenic acid), alkaloids and coumarins (scopoletin). C.
pluricaulis possesses anti-inammatory, anti-oxidative,
analgesic and tranquilising properties. Since ancient times, it
has been used to treat chronic bronchitis, asthma, hypertension and for fever reduction [193, 194]. In Indian traditional
medicine, four sources of Shankhpushpi reported are
Canscora decussata Schult., Clitorea ternatea Linn.,
Convolvulus pluricaulis and Evolvulus alsinoides Linn. In
vitro and invivo studies on β-amyloid-induced neurotoxicity
in neuroblastoma cell lines, Neuro-2a and scopolamineinduced amnesia in male Sprague Dawley rats, respectively,
were conducted by Sethiya etal. [195] to examine the neuropharmacological effects of methanolic extracts of all four
species of Shankhpushpi. Inhibition of the enzymes acetylcholinesterase and 5-lipoxygenase and antioxidant activity
were the other invitro studies conducted by them. Evolvulus
alsinoides Linn. demonstrated superior invitro and invivo
neuropharmacological effects in comparison to the other
three varieties of Shankhpushpi suggesting that it had the
potential to be developed as therapeutic agents against neurodegenerative diseases [195].
Triphala
Triphala is a widely used and extremely effective polyherbal
Ayurvedic medication classied as Tridoshaic rasayana
made from the fruits of the plants Terminalia bellerica
(Bibhitaki), Terminalia chebula (Haritaki) and Emblica of-
cinalis (Amalaki). It is a key component of digestive system
and other rejuvenative therapies. In streptozotocin-induced
diabetes rat models, triphala treatment was reported to suppress the progression of associated neuropathy, with signicantly increased motor nerve conduction velocity and
decreased thermal and mechanical hyperalgesia as well as
mechanical allodynia, possibly due to elevated levels of
Nerve growth factor (NGF), particularly in the sciatic nerves.
TGF-1, TNF and IL-1 levels in the circulation were markedly reduced by this therapy. Histopathological investigation
conrmed Triphala churna’s neuroprotective properties
[196]. In another study, it has been reported that triphala has
potential as a neuroprotective agent, with activity against
oxidative stress, both in SH-SY5Y cells and zebra shes
[197].
3.4.2 Multiple Sclerosis
MS is a chronic inammatory disease of the CNS, categorised by demyelination, degeneration of neurons and loss of
axons, giving rise to localised lesions in the grey and white
matter of the brain. Aetiology of MS is not clear and includes
immunological, genetic and environmental factors. The factors that trigger onset of MS include gut microbiota, smoking, deciency of vitamin D, obesity, infections and heavy
metals (cadmium, lead) in food [198]. The clinical symptoms associated with MS include dysarthria, nystagmus,
tremor, disturbance of vision, sensory and motor neurons.
Individuals with genetic predisposition to environmental factors and variables are at greater risk of developing
MS.Infections associated with human herpes virus-6 (HHV-
6), Epstein-Barr virus (EBV) and Chlamydia pneumoniae
are responsible for increasing risk of developing MS [199].
The fundamental mechanisms behind MS remain largely
unknown, which has resulted in disease classications based
on natural history and an insufcient knowledge of the processes responsible for its origin and progression. MS is classied in major types, namely relapsing remitting MS
(RRMS) type in which exacerbation occurs recurrently with
partial or complete recovery. About 85% of MS patients are
found to be affected with RRMS [200]. Secondary progressive MS (SPMS) is the type in which there is gradual worsening of clinical disability; about 50% of patients with
RRMS enter SPMS.Primary progressive MS (PPMS) is a
type in which there is gradual worsening of neurologic function. Microorganisms have the ability to elicit antiinammatory and proinammatory responses, activate the
innate immune system and mimic myelin proteins in the
CNS.Gene responsible for higher risk of developing MS is
human lymphocyte antigen DRB1*15:01 allele (HLADRB1*15:01) [200].
Pathogenesis of MS involves interaction between immune
cells and neurons. It is believed that failure of central and
peripheral immune tolerance mechanisms triggers autoimmune activation of T cells [201]; the presence of T cells in
CNS plays an important role in pathogenesis of MS. The
activated autoreactive T cells enter CNS through impaired
blood brain barrier (BBB) and create an inammatory environment that leads to death of oligodendrocytes which ulti-
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mately leads to degeneration of myelin sheath and loss of
neuron. The subsets of helper T cells, Th1 and Th17 release
proinammatory cytokines IFN-γ and IL-17, respectively.
The oligodendrocytes are directly killed by cytokine IFN-γ
whereas IL-17 expresses TNF-α and IL-6 [202–204].
Granzyme B can be released by CD4+ and CD8+ T cells that
express IL-17 and destroy neurons by binding to the glutamate receptor (GluR3). The inammatory response triggered
by IL-17 and TNF-α is associated with degeneration of neurons by activation of transcriptional factors STAT-1 and
NF-κB [205]. The inammatory response is triggered when
IL-17 produces inducible NO synthase, which eventually
results in an increase in NO in various cells [206]. Alteration
of gut microbiota, and increased exosomal protein and intracellular miRNA prole are the factors responsible for alteration in function of Treg cell in MS [207]. Activation of
microglia with involvement of T and B cells, release ROS
and nitrogen species which leads to mitochondrial damage
and gene deletion in MS lesions with persistent demyelination or neurodegeneration [207, 208].
Currently, there are no treatments to treat MS completely;
however, a number of therapeutic options are available to
moderate the disease progression and provide characteristic
mitigation. There are a number of phytoconstituents that are
reported to decrease demyelination, these include avonoids
(quercetin, hesperidin, luteolin and icariin) [209]. Some of
the herbs with potential to manage MS are discussed below.
3.4.2.1 Artemisia dracunculus
Artemisia dracunculus L., family Asteraceae, is an everlasting herb containing essential oils, avonoids, coumarins,
phenylpropanoids and tannins which are attributed with antiinammatory and antioxidant properties [26]. Since aetiology of MS is unclear, therapies focus on reducing
inammation and restoring myelin through the repair of
damaged tissue. The inhibition of Th1 and Th17 cell cytokines by the aqueous extract of A. dracunculus was studied
in the experimental autoimmune encephalitis (EAE) model
by Safari etal. [210]. Immunisation with myelin oligodendrocyte glycoprotein (MOG35-55) and Complete Ferund’s
adjuvant (CFA) was done to induce EAE in C57BL/6 mice.
A. dracunculus was found to markedly reduce expression of
pro-inammatory cytokines IL-1, TNF-α, IL-6 and IFN-γ
through inhibition of NF-κB signalling pathway. A. dracun-
culus extracts in EAE mice appear to modify immunological
responses and raise serum antioxidant levels, which reduces
demyelination [210].
3.4.2.2 Silybum marianum
Silybum marianum belongs to the family Asteraceae and is
commonly known as milk thistle. Silymarin, a complex mixture of avonolignans, avonoids (taxifolin, quercetin) and
polyphenolic compounds, is reported to have excellent
hepato- protective and antioxidant properties [211]. In vitro
study performed by Shariati etal. [212] suggested that silymarin might present a potential therapeutic option for MS.In
this study, the effect of silymarin on the proliferation and
activation of Treg cells isolated from newly diagnosed MS
patients was investigated. Expression of STAT5, JAK3 and
Foxp3 genes and release of IL-10in IFN-β treated RRMS
patients were also examined. Silymarin promoted proliferation of Treg cells and the expression of genes STAT5, JAK3
and Foxp3 was improved by silymarin [212].
3.4.3 Alzheimer’s Disease
ALD is the most common reason for memory loss in older
adults. It is a slowly progressing, complex neurodegenerative
disorder that impacts numerous regions of the cerebral cortex and hippocampus, and is characterised by neuritic
plaques and neurobrillary tangles due to accumulation of
insoluble forms of amyloid-beta peptide (Aβ) in the extracellular spaces and blood vessels of the affected areas of the
brain [213, 214]. The major clinical manifestations are cognitive impairment, behavioural changes, depression, hallucination and dementia. The basic aetiology of ALD is
destruction of nerves, especially cholinergic nerves. The risk
factors associated with ALD include genetic predisposition
to environmental triggers such as smoking, infectious agents
and toxins. ALD is classied into two types based on the age
groups: affected-sporadic and familial ALD.Sporadic ALD
affects individuals above 65 years of age and familial ALD
affects individuals between 30 and 65 years age group. The
risk factors associated with sporadic ALD include the presence of the epsilon-4 (ε4) allele of the APOE gene (APOEε4)
and the mutations in the APP or presenilin 1 (PSEN1); presenilin 2 (PSEN2) genes are the causative factors for familial
ALD [214–217].
APP exists as a transmembrane protein which helps in
growth and repair of neurons, and commonly occurs in neuronal synapses. In normal non-amyloidogenic processing,
APP is degraded by enzyme α-secretase followed by
β-secretase that forms soluble fragments and is cleared from
the brain. The enzymes α-secretase and β-secretase cleave
APP during aberrant amyloidogenic processing, producing
insoluble amyloid beta 42 fragments. Extracellular plaques
build up as a result of impaired removal of the insoluble fragments from interstices of the brain. In neural axons, the tau
protein serves as a stabilising protein for microtubules.
Evidence suggests that elevated levels of ferrous (Fe2+) chloride in neurons leads to aberrant phosphorylation of tau protein causing microtubule instability and formation of
neurobrillary tangles eventually inducing neurodegeneration changes [218]. Accumulation of these pathogenic proteins and free radicals causes mitochondrial damage,
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