Chapter-II Review of Literature - Shodhgangashodhganga.inflibnet.ac.in/bitstream/10603/15970/6/06... · 2015-12-04 · Chapter-II Review of Literature Department of Zoology, Dr. H.S

Chapter-II Review of Literature

Department of Zoology, Dr. H.S. Gour Central University, Sagar (M.P.) 33

Plants are the invaluable, incredible and traditional sources for the

curability of various diseases in the form of medicines (Guerra et al., 2003).

Plants are the main source of drugs that being used from the ancient times

as a herbal remedies for the health care, prevention and cure of various

diseases and ailments (Kalia, 2005). Plants secondary metabolites have been

implicated for most plants therapeutic activities (Timothy et al., 2008). WHO

says that about three quarters of world population depends upon traditional

remedies (Ansari and Inamdar, 2010). Plants use as a medicine have not

been occurred recently, but its use as a traditional and folklore drug

throughout the world for the health services is a matter of tremendous

historical legacy and evidences (Hoareau and Dasilva, 1999). A large

population of India is using plants for its healing, preventive, curative and

many therapeutic properties together with immunomodulatory property

(Ranjith et al., 2008). Out of seventy thousand angiosperm plants, three

lakhs are recorded for medicinal purposes by the people of different

civilization all over the world (Pushpangadan, 2006). Apart from various

therapeutic properties of plants today the most emphasis of researchers at

present on a variety of immunomodulators which could enhance the immune

system and eventually combat the disease or infection by modulating

immune responses.

Ancient Indian literature abounds information on a large number of

plants reported to have Immunomodulatory activity some are as follows.

Abutilon indicum commonly known as "Atibala" in Sanskrit gives

excessive tonic strength. Atibala is a stronger diuretic and heart tonic. Abutilon

indicum reported in the Siddha system as a remedy for jaundice, piles, ulcer,

leprosy, rakttapitta dosha and blood purifier. Chemically it contains flavonoids

(quercetin), saponins, alkaloids and phenolic compounds. The ethanolic and

aqueous extract of leaves of Abutilon indicum was administered orally at the

dosage levels of 200 mg/kg/day and 400 mg/kg/day body weight in mice. The

assessment of immunomodulatory activity on specific and non-specific

immunity were studied by heamagglutination antibody (HA) titer, delayed type

hypersensitivity (DTH), neutrophil adhesion test and carbon clearance test. In

order to induced immunosuppression in mice by using cyclophosphamide (100

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mg/kg/day, p.o.) and levamisole (50 mg/kg/day, p.o.) used as

immunostimulating agents. The study demonstrates that A. indicum triggers

both specific and non-specific responses to a greater extent (Dashputre et al.,

2010).

Actinidia macrosperma (AM) is a medicinal plant in China and has

been well known for its activities against cancers, especially of lung, liver and

digestive system. The immunomodulatory effects of AM aqueous extract were

examined using S180-bearing mice. The immunomodulatory effect was dose-

dependent in a nonlinear fashion with the optimal dose of 100 mg/kg. The AM-

induced antitumor effects were at least partially indirect and were associated

with the modulation of immune functions (Lu Yin et al., 2007).

Aegle marmelos, belongs to family Rutaceae is generally known as bael

fruit. They were evaluated for potential immunomodulatory activity using the

in vitro Polymorphonuclear leukocyte function test. Both Methanolic and

Ethanolic extract of Aegle marmelos leaves were evaluated for their

immunomodulatory activity. The extract was tested for hypersensitivity and

hemagglutination reactions, using sheep red blood cells (SRBC) antigen

methanol extract exhibited a significant increase in the percentage phagocytosis

versus the control. The Methanolic extract was found to stimulate cell mediated

and antibody mediated immune responses in rats (Ankur et al., 2010).

The immunostimulating effect of ("Pule") Alstonia scholaris Family:

Apocynaceae) bark extracts was studied in mice. The extracts were

administered orally, once a day for 7 consecutive days. The results showed that

at the same doses (50, 100 and 200 mg/kg b.wt.) the aqueous extract had

higher phagocytic index (1.39-1.79) than the ethanolic extracts (0.81-0.93) in

normal mice. The results showed that Alstonia scholaris has a significant

immunomodulatory activity (IWO et al., 2000).

Aesculus indica belonging to the family Sapindaceae is generally

known as Bankhor. A study has shown the immunostimulatory effect of

Aesculus indica, assessment of immunostimulatory activity was carried out by

testing the humoral (antibody titer) and cellular ( foot pad swelling) immune

responses to the antigenic challenge by sheep red blood cells (SRBCs) and by



neutrophil adhesion test. The study stated that Aesculus indica could

stimulate the cell-mediated immunity and had no effects on the humoral

immunity (Chakraborthy et al., 2009).

Organosulfur compounds of Allium sativum (garlic) have been shown

to inhibit growth of tumors in animals and to modulate activity of diverse

chemical carcinogens. This effect may be related to activation of natural killer

(NK) cells, stimulation of T-lymphocytes and enhanced production of IL-2

(Tang et al., 1997).

To study the immunomodulatory activity of saline extracts of leaves of

Aloe vera Linn. (Family: Liliaceae) on the albino mice. The saline extract of

leaves of Aloe vera was administered orally according to their body weight in

mice. The assessment of immunomodulatory activity on specific and

nonspecific immunity was studied by administration of test extract. The study

demonstrates that A. vera triggers both specific and non-specific responses to a

greater extent. The study comprised the acute toxicity and preliminary

phytochemical screening of A. vera. From the results obtained and

phytochemical studies the immunostimulant effect of Aloe vera could be

attributed to the alkaloids content (Atul et al., 2011).

Ethanol extract and purified diterpene andrographolides of

Andrographis. paniculata have been shown to induce significant stimulation of

antibody and DTH response to sheep red blood cells (SRBC) in mice (Puri et al.,

1993). The stimulation was found to be both antigen specific and non-specific.

Extract of Asparagus racemosus has been tested for anticancer activity

(Seena et al., 1993). The protective effect of A. racemosus against

mvelosuppression induced by single dose of cyclophosphamide has been

reported by Thatte and Dahanukar (1988).

Adhatoda vasica is a well-known in Ayurvedic and Unani medicine. It

has been used for the treatment of various diseases and disorders,

particularly for the respiratory tract ailments. Many studies have been

conducted on Adhatoda vasica and some of the reported activities of the plant

include anti-diabetic (Talib et al., 2002), anti-implantation (Prakash et al.,

1985), antiphlogistic, anti-allergic (Wagner 1989), anti-tussive (Dhuley et al.,



1999), anti-ulcer (Shrivastava et al., 2006), antioxidant, anti-genotoxicity

(Jahangir et al., 2006), anti-tubercular (Gupta et al., 2010), abortifacient

(Gupta et al., 1978), radioprotective (Kumae et al., 2005), bronchodilator

(Amin and Mehta 1959),hepatoprotective (Jayakumar et al., 2009).

An aqueous extract of roots of Baliospermum montanum was

evaluated on preliminary basis for immunostimulatory activity by studying

neutrophil phagocytic function. The different concentrations of aqueous

extract of roots of Baliospermum montanum were subjected to study their

effects on different in vitro methods of phagocytosis such as neutrophil

locomotion, chemotaxis, immunostimulant activity of phagocytosis of killed

Candida albicans and qualitative nitroblue tetrazolium test by using human

neutrophils. This preliminary study revealed that Baliospermum montanum

extract has stimulated chemotactic, phagocytic and intracellular killing

potency of human neutrophils at different concentrations. From the results

obtained, it can be observed that the aqueous extract of Baliospermum

montanum stimulate cell-mediated immune system by increasing neutrophil

function (Baral et al., 2005).

The traditional claim endowed upon the Bauhinia variegata (EBV) has

an herbal drug as a rasayana in Ayurveda. The effect of the ethanolic extract of

the stem bark of Bauhinia variegata (EBV) on the primary and secondary

antibody responses was evaluated by the humoral antibody response for a

specific immune response. The effect of EBV on the phagocytic activity was

evaluated by the carbon clearance test and neutrophil activation was evaluated

by the neutrophil adhesion test for a nonspecific immune response. On oral

administration, EBV showed a significant increase in the primary and

secondary humoral antibody responses, by increasing the heamagglutinating

antibody titer at doses of 250 and 500mg/kg/p.o. There was a significant

increase in the phagocytic index and percentage neutrophil adhesion at doses

of 250 and 500mg/kg/b wt. This study reveals that the ethanolic extract of the

stem bark of Bauhinia variegata Linn holds a promise as an

immunomodulatory agent, which acts probably by stimulating both the specific

and nonspecific arms of immunity (Ghaisas et al., 2009).

Aqueous extract of Boerhaavia diffusa roots has been shown to



induce leukocytosis with predominant neutrophilia, associated with a

stimulation of the phagocytic and bactericidal capacity of neutrophils and

macrophages. The aqueous extract also protected mice against Escherichia

coli-induced peritonitis based on its immunostimulatory activity. A study has

also shown in vivo immunostimulatory activity of Boerhaavia diffusa

without in vitro effect where alkaloidal fraction of Boerhaavia diffusa was

studied for its effect on cellular and humoral functions in mice. Oral

administration of the fraction (25 to 100 mg/kg) significantly inhibited

SRBC-induced DTH reactions in mice. A significant dose-related increase in

antibody titer was observed during pre- and post-immunization treatment

(Mugantiwar et al., 1999).

Boswellia carterii or Boswellia serrata belongs to the family

Burseraceae. This salai guggal has been shown to exhibit strong

immunostimulant activity. The active constituents are contained in the

extracted Boswellia terpenoid portion and are composed of boswellic acids

(BAs) (Chevrier et al., 2005).

Immunostimulatory activity of ethanolic and water extracts of

Capparis zeylanica leaves on cellular and humoral immune responses to the

antigenic challenge by SRBCs and by neutrophil adhesion test, phagocytic

activity and cyclophosphamide-induced myelosuppression (Ghule et al.,

2006).

The evaluation of immunomodulatory potential by oral administration

of ethanolic seed extract of Caesalpinia bonducella (200-500 mg/kg) evoked a

significant increase in percent neutrophil adhesion to nylon fibers as well as a

dose-dependent increase in antibody titer values, and potentiated the delayed-

type hypersensitivity reaction induced by sheep red blood cells. Also it

prevented myelosuppression in cyclophosphamide drug treated rats and good

response towards phagocytosis in carbon clearance assay. The results

obtained in this study indicate that Caesalpinia bonducella possesses

potential immunomodulatory activity and has therapeutic potential for the

prevention of autoimmune diseases (Shukla et al., 2009).

Centella asiatica (family Apiaceae) is a perennial creeper, growing

abundantly in moist areas and distributed widely in tropical and subtropical

countries. The reticuloendothelial stimulating activity of the alcoholic



extract of Centella asiatica (Dicarlo et al., 1964) and an increase in the

antibody titer and cell-mediated response (DTH) at 100 mg/kg body weight

of dried powder of Centella asiatica (Patil et al., 1998) have been reported.

Chlorophytum borivilianum (family Liliaceae) is a very popular herb

in traditional Indian medicine and constitutes a group of herbs used as a

rasayana or an adaptogen. Ethanol extract of the roots and its sapogenin

were evaluated for their immunostimulatory activity (Thakur et al., 2007).

The alkaloidal fraction (AFCP) of roots of Cissampelos pareira Linn.

(Family: Menispermaceae) was screened for immunomodulatory activity in

mice. The HPTLC finger print profile was also established for the identification

of AFCP which was found to contain 0.176 % of berberine. AFCP was found to

have significant immunosuppressive activity at lower doses (25 and 50 mg/kg)

while no activity was observed at higher doses (75 and 100 mg/kg). Humoral

antibody titer was significantly (p<0.01) lowered by AFCP at the doses of 25 and

50 mg/kg. Delayed type hypersensitivity response was also significantly

(p<0.01) suppressed by the AFCP at the dose of 75 mg/kg. Thus the present

study revealed the immunosuppressive and antioxidant activities of the

alkaloidal fraction of C. pareira roots (Anand et al., 2010).

The assessment of immunomodulatory activity of ethanolic extracts of

aerial parts of Cleome gynandra Linn. (Family: Capperdiceae) at the doses of

50, 100 and 200 mg/kg, p.o. was done by carbon clearance method for non-

specific immunity, haemagglutination antibody titer method for humoral

immunity and footpad swelling method for cell mediated immunity on wistar

albino rats. Results of present studies suggest that the ethanolic extract of

Cleome gynandra Linn. exhibited significant immune suppression effect in

dose dependent manner when compare with control group (Gaur et al., 2009).

Clerodendrum phlomidis belongs to the family Verbanaceae and its

roots are valued as tonic, diuretic, febrifuge, antidiabetic and anti-

inflammatory. A study has shown immunostimulatory potential of roots of

this plant. Oral administration of methanol extract of roots in mice prior to

immunization with SRBCs resulted in significant increase in

haemagglutinating antibody titer, plaque-forming cell (PFC) assay and DTH to

SRBCs. Clerodendrum phlomidis enhanced the non-specific immune response



in carbon clearance test and showed significant immunoprophylactic effect,

when tested on Escherichia coli-induced abdominal sepsism (Gokini et al.,

2007).

Cuminum cyminum has varied biological activities, which include anti-

diabetic, antioxidant (Jagtap et al., 2010), anti-bacterial (Iacoballis et

al.,2005), anti-fungal (Ramagnoli et al., 2010), bronchodilatory (Boskabady et

al., 2005), hepatoprotective, renoprotective (Aruna et al., 2005), anti-epileptic

(Jahanmadi et al., 2006), galactagogue (Agarwala et al., 1968),

hypolipidemic (Dhandapani et al., 2002), male anti-fertility (Gupta et al.,

2011), memory-enhancing and anti-stress (Koppula and Choi 2011). Toxicity

of Cuminum cyminum has been studied by Haroun et al., 2002.

Methanolic extract of the roots of Curculigo orchioides has been

shown to enhance phagocytic activity of macrophages and an active principle

of the extract was identified as a curculigoside, which has been reported to

possess adjuvant activity (Kubo et al., 1983). Its rhizomes had yielded a

phenolic glycoside named corchioside A~451, in addition to a few triterpene

glycosides. These glycosides were studied for their effects on macrophage

migration index (MMI) haemagglutination (HA) titer, PFC, phytohemagglutinin

(PHA)-induced blast transformation of lymphocytes (BTL) and DTH.

Significant immunostimulant activity was found in purified glycoside-rich

fraction isolated from the ethyl acetate extract (Laxmi et al., 2003).

The immunomodulatory activity of an Indian medicinal plant i.e.

ethanolic extract from Dodonaea viscosa L.F. namely DV was studied for there

phagocytic activity, cell mediated and humoral immune system on rat/mouse.

Immunomodulatory effect was assessed in carbon clearance test, delayed type

of hypersensitivity (DTH), T-cell population test, and sheep erythrocyte

agglutination test (SEAT) in animal treated with DV at doses of 200 and 400

mg/kg. In carbon clearance test, D. viscosa exhibited significantly high

phagocytic index against control group, indicating stimulation of the

reticuloendothelial system. Significant decrease in mean difference, in the foot

paw thickness in DTH indicates its anti-inflammatory activity. In SEAT D.

viscosa treated groups at 200, 400 mg/kg doses showed significant increase in

antibody titer against control in normal immune status animals while In T-cell



population test, showed significant increase in T-cell rosette formation against

control. These results confirm the immunomodulatory activity of D. viscosa

extract, which is a known immunomodulator in indigenous medicine (Jagdap

et al., 2011).

Eclepta alba (family Asteraceae) is called “Bhringraj” in India. In

traditional medicine, whole dried herb powder is used in liver disorders,

especially jaundice (Chopra et al., 1958). The herb contains wedelolactone

and dimethylwedelolactone as coumestan derivatives and recently, a triterpe-

noidal saponin named eclalbatin, has also been isolated from this plant

(Upadhyay et al., 2001). Eclipta alba increased the phagocytic index and

antibody titer significantly and the F ratios of the phagocytic index and white

blood cell (WBC) count are also significantly increased when it was tested by

using carbon clearance, antibody titer and cyclophosphamide induced

immunosuppression.

Emblica officinalis, commonly known as Amla (family Euphorbiaceae),

it shows immunostimulatory effects on lymphocyte function, particularly in

immunosuppressive conditions. Therefore, an in vitro study was undertaken

to determine the relative effects of fruit extracts of Amla with regard to

cytoprotection and immunostimulation by using rat splenocytes as the model

system. Immunostimulatory properties of Amla are determined by using

chromium (VI) as an immunosuppressive agent. Amla inhibited apoptosis and

DNA fragmentation induced by chromium. Interestingly, Amla relieved the

immunosuppressive effects of chromium on lymphocyte proliferation and

even restored the IL-2 and g-IFN production considerably (Sai Ram et al.,

2002).

Epilobium angustifolium (family Onagraceae) has been traditionally

used in the treatment of a number of diseases; however, not much is known

regarding its effect on innate immune cells. In a recent study, it has reported

that extracts of Epilobium angustifolium activated functional responses in

neutrophils and monocyte/macrophages. Activity-guided fractionation,

followed by mass spectroscopy and nuclear magnetic resonance analysis,

resulted in the identification of oenothein B as the primary component

responsible for phagocyte activation. Oenothein B, a dimeric hydrolysable



tannin, dose-dependently induced a number of phagocyte functions in vitro,

including intracellular Ca2+ flux, production of reactive oxygen species,

chemotaxis, nuclear factor (NF)-KB activation, and proinflammatory cytokine

production. Furthermore, oenothein B was active in vivo, inducing

keratinocyte chemoattractant production and neutrophil recruitment to the

peritoneum after intraperitoneal administration. The ability of oenothein B to

modulate phagocyte functions in vitro and in vivo suggested that this

compound was responsible for at least part of the therapeutic properties of

Epilobium angustifolium extracts (Schepetkin et al., 2009).

Various extracts of the aerial roots of Ficus benghalensis (Family

Moraceae) were evaluated for potential immunomodulatory activity, using the

in vitro polymorphonuclear leucocyte (human neutrophils) function test. The

methanol extract was evaluated for immunomodulatory activity in in vivo

studies, using rats as the animal model. The extracts were tested for

hypersensitivity and haemagglutination reactions, using sheep red blood cells

(SRBG) as the antigen. Distilled water served as a control in all the tests. The

successive methanol and water extracts exhibited a significant increase in the

percentage phagocytosis versus the control. In the in vivo studies, the

successive methanol extract was found to exhibit a dose related increase in the

hypersensitivity reaction, to the SRBG antigen, at concentrations of 100 and

200 mg/kg. It also resulted in a significant increase in the antibody titer value, to

SRBG, at doses of 100 and 200 mg/kg in animal studies. The successive

methanol extract was found to stimulate cell mediated and antibody mediated

immune responses in rats. It also enhanced the phagocytic function of the

human neutrophils, in vitro (Gabhe et al., 2006).

The Immunomodulatory effect of ethanolic extract of the leaves of Ficus

carica (Family: Moraceae) was investigated in mice. The study was carried out

by various hematological and serological tests. Administration of extract

remarkably ameliorated both cellular and humoral antibody response. The

present study show that Ficus carica leaves ethanolic extract (100mg/kg/i.p.,

daily) produces stimulatory effect on the humoral and cells mediated immune

response in the experimental animals and suggest its therapeutic usefulness

in disorders of immunological origin. Further studies using in vivo and in vitro



models of immunomodulation are needed to confirm the Immunomodulatory

activity of Ficus carica leaves and its mechanism of action (Vikas et al.,

2010).

Glycyrrhiza glabra has been studied for its biological actions,

including hypocholesterolaemic (Visavadiya and Narsimhacharya 2006), anti-

cancer (Rafi, 2004), anti-diabetic: PPAR-γ ligand binding (Kuroda et

al., 2010), anti-allergic (Shin et al., 2007), anti-depressive (Dhingra and

Sharma 2006), anti-arthritic (Gujral et al., 1959), anti-ulcer: inhibit adhesion

of Helicobacter pylori (Wittschier et al., 2009), antioxidant, anti-genotoxic,

anti-inflammatory (Siracusa et al., 2011), anti-viral: encephalitis (Badam

1997), anti-microbial (Mitscher et al., 1980), anti-nephritis (Fukai et al.,

2003), antithrombotic (Francischetti et al., 1997), anti-atopic dermatitis

(Saeedi et al., 2003), radioprotective (shetty et al., 2002), memory enhancing

(Dhingra et al., 2006). The herbal formulation DHC-1 has been studied for its

cardio and renoprotective activities (Bafna and Balaraman, 2005).

Gymnema sylvestre (family: Asclepiadaceae) leaves, commonly known

as Gudmar. Tannins are the main chemical constituents present in

Gymnema sylvestre and are known to possess anti-inflammatory and

immunomodulatory properties (Trease and Evan, 1983). The aqueous

extract of Gymnema sylvestre leaves was investigated for

immunostimulatory activity by assessing neutrophil locomotion and

chemotaxis test, phagocytosis of killed Candida albicans and nitroblue

tetrazolium tests. The extract was given at 10, 25, 50, 100 and 1000 ug/mL.

Results of in vitro immunostimulatory activity lead to the conclusion that

the aqueous extract of Gymnema sylvestre showed predominantly

significant activity on in vitro human neutrophils in all parameters as

compared with the standard (Gupta et al., 2010).

Various effects of Hemidesmus indicus, such as hypoglycemic,

hypolipidemic (Murshed et al., 2005), antioxidant, antithrombotic (Mary et

al., 2003), anti-inflammatory, anti-pyretic (Laxman et al., 2006),

antiulcerogenic (Anup and Jagdeesan 2003), cardioprotective (Khandelwal et

al., 2010), hepatoprotective (Baheti et al., 2006), renoprotective (Kotnis et al.,

2004), genotoxic and anti-genotoxic (Ananthi et al., 2010), radioprotective



(Shetty et al., 2005), neutralization of vipervenom (Alam et al., 1996), anti-

bacterial and larvicidal (Josheph et al., 2011), have been reported.

Heracleum persicum Desf. (Family: Apiaceae), a medicinal plant native

to Iran, was studied for its immunomodulatory activity. Immunomodulatory

activity of different doses of an aqueous extract of H. persicum, was

evaluated in female Swiss albino mice. Mice were treated with three doses (50,

100 and 200 mg/kg body weight) for 5 days. Body weight, relative organ

weight, delayed type hypersensitivity (DTH) response and haemagglutination

titer (HT) were studied in various groups of animals. No significant body weight

gain differences were recorded in various groups of animals. The results

obtained showed a significant stimulatory effect on both humoral and cellular

immune functions in mice (Farifa et al., 2009).

Heracleum nepalense (family Apiaceae) exhibited stimulant property

and increased the rate of respiration and blood pressure in goats (Council of

Scientific and Industrial Research.The wealth of India: A dictionary of Indian

raw material and industrial products. New Delhi: Publication and

Information Directorate, Council of Scientific and Industrial Research). An

investigation was undertaken to evaluate the immunostimulatory potential of

Heracleum nepalense roots by using in vitro and in vivo models. The

immunostimulatory potential of this plant was investigated by in vitro

phagocytic index and lymphocyte viability tests, using IFN-a-2b, a known

immunostimulant drug, as the standard. Other tests such as carbon

clearance, antibody titer and DTH were studied in mice by using levimasole

as the standard. The dried root extract (1000 iig/mL) and isolated quercetin

glycoside (50 tig/mL) significantly increased the in vitro phagocytic index

and lymphocyte viability in all assays. They also showed a significant

increase in antibody titer, carbon clearance and DTH in mice. Thus

Heracleum nepalense exhibited a dose-dependent immunostimulant effect,

which could be attributed to the flavonoid content or due to the combination

with other components (Dash et al., 2006).

Janakia arayalpathra (family Periplocaceae) is a perennial woody

laticiferous shrub (Joseph and Chandrasekaran, 1978). Recent

pharmacological investigations of the root extract of the plant revealed



immunostimulatory and anticancer properties. It stimulated an increase in

humoral antibody titers and also of antibody-secreting spleen cells in the

PFC assay following immunization with sheep erythrocytes. It also increased

the number of peritoneal macrophages and produced an increase in DTH

reaction in mice (Subromanium et al., 1996).

Mangifera indica (family Anacardiaceae) is commonly known as

mango. It has been reported for its in vitro immunostimulatory activity. The

alcoholic extract of the stem bark containing 2.6% of mangiferin had

promising in vivo immunostimulatory effect. Further it was confirmed that

the immunostimulatory effect was due to cell- and humoral antibody-

mediated activation of T and B cells (Makare et al., 2001).

Morinda citrifolia Linn (Family: Rubiaceae) is a traditional medicinal

herb that has been purported to be beneficial in the treatment of infections

due to its immune enhancing properties. However, detailed studies

highlighting the effect of different compounds isolated from the plant on the

immune system are lacking. In this study, the stimulatory effects of the extracts

and fractions of M. citrifolia fruits on important components of the adaptive

immune system such as T lymphocytes and B lymphocytes were studied. The

effects of the plant extracts on lymphocytes were assessed by in vitro (MTT

assay) and in vivo (cell mediated immune response) techniques. The results of

this study confirm the cellular and humoral immunostimulant properties of M.

citrifolia fruits and justify its usage in traditional medicine (Nayak and Mengi,

2010).

The present study was to investigate the immunomodulatory action of

methanolic extract of Moringa oleifera (MEMO) in an experimental model of

immunity. The cellular immunity was evaluated using neutrophil adhesion

test, cyclophosphamide induced neutropenia and carbon clearance assay,

whereas, humoral immunity was tested by mice lethality test, serum

immunoglobulin estimation and indirect haemagglutination assay in animals.

Administration of MEMO (250 and 750 mg/kg, po) and Ocimum sanctum (100

mg/kg, po) significantly increased the levels of serum immunoglobulins and

also prevented the mortality induced by bovine Pasteurella multocida in mice.

They also increased significantly the circulating antibody titer in indirect



haemagglunation test. Moreover, MEMO produced significant increase in

adhesion of neutrophils, attenuation of cyclophosphamide induced

neutropenia and an increase in phagocytic index in carbon clearance assay.

From the results, it can be concluded that MEMO stimulate both cellular and

humoral immune response. However, low dose of MEMO was found to be more

effective than the high dose (Sudha et al., 2010).

Some of the reported activities in Mucana pruriens include

hypoglycemic(Bhaskar et al., 2008), hypocholesterolemic (Ratnawati and

Widowati 2011), antioxidant (Tripathiana upadhyay 2002), aphrodisiac

(Suresh etal., 2009), neuroprotective (Manyam et al., 2004), anti-Asiatic cobra

venom (Tan et al., 2009), inhibition of hyperprolactinemia in man (Vaidhya et

al., 1978), management of Parkinson’s disease (Katzenschlager et al., 2004).

Adverse effects like acute toxic psychosis (Infant et al., 1990), pruritus

(Shelley and Arthur, 1955), has been reported.

Nyctanthes arbortristis (family Oleaceae) is used in tribal herbal

medicine for the treatment of many kinds of acute or chronic inflammatory

diseases. The recent phytochemical analysis of Nyctanthes arbortristis

revealed the presence of tertiary alkaloids, represented mainly by 7-(alpha-

anilino-p-nitrobenzyl)-8-quinolinol and quaternary alkaloids, belonging to

protoberberines and aporphines. These substances may influence the

immuno-bioactivities of Nyctanthes arbortristis. An ethanolic extract of

Nyctanthes arbortristis ( NAEE ) was screened in rats for humoral and cell-

mediated immune responses. Oral administration of the NAEE to rats at 50,

100, 150 and 200 mg/kg significantly enhanced the circulating antibody

titer when challenged with SRBCs and heat-killed Salmonella antigens. The

chronic administration of NAEE increased the total counts of WBCs and

potentiated the DTH reactions. The present study confirmed the strong

immuno-bioactivities in the extracts of Nyctanthes arbortristis (Khanna et

al., 2007).

Extract of Ocimum sanctum was tested for anticancer activity (Seena et

al., 1993). Though this plant extract did not completely inhibit the

development of solid tumor, it induced significant lag in tumor development.

The efficacy of its crude extract was compared with steroids (dexamethasone)



in the treatment of patients with acute viral encephalitis (Das et al., 1983).

The survival in the O. sanctum treated group was significantly higher (p <

0.05).

Panax ginseng and P. pseudoginseng is a Korean plant which is widely

used as general health tonic. A number of steroidal saponins and glycosides

from this plant have been shown to possess adaptogenic activity. The crude

extract and saponins of Indian P. pseudoginseng also possess similar activity.

Saponins from Indian pseudoginseng were also found to be potent

immunostimulant (macrophage migration, antibody plaque forming cells and

haemagglutinating antibody titer against sheep red blood cells). We have

evaluated the extract of P. ginseng root obtained from Pharmaton,

Switzerland. It was found to significantly potentiate the protection afforded by

an IFN inducer (6-MFA) when ginseng extract was administered orally for 7

days prior to challenge with 100 X LD50 of the Semliki forest encephalitis

virus (Singh et al., 1983a). The production of IFN was also enhanced, with

change in the ratio of acid labile to acid stable varieties of IFNs (Singh et al.,

1984). In another experiment circulating antibody titers and antibody plaque

forming cells in response to SRBC, as well as macrophage migration inhibition

factor against Semliki forest virus antigen were also enhanced by this extract

(Singh et al., 1984). However, these results could not be reproduced with

another batch of P ginseng root extract obtained from Ginseng Research

Institute, Daejeon, South Korea (unpublished observation). The reason for

this variation is not known. Further supplies of the ginseng preparation from

Pharmaton, Switzerland could not be obtained.

The known activities of Phyllanthus niruri are anti-babesial, anti-

plasmodial (Subeki et al., 2005), antihyperuricemic (Murugaiyah et al., 2009),

anti-nociceptive (Santos et al., 1995), anti-HIV (Naik and Juvekar 2003),

antioxidant, hepatoprotective (Chatarjee et al.,2006), vasorelaxant (Lizuka et

al., 2006)and lipid lowering (Khanna et al., 2002). It is also used for inhibition

of platelet aggregation (Lizuka et al., 2006), urolithiasis (Sampaio, 2007),

hepatitis B virus, Woodchuck hepatitis virus (Venkteswaran et al., 1987).

Piper longum (family Piperaceae) as an important medicinal plant, is

used in traditional medicines by many people in Asia and Pacific islands



especially in Indian medicine. Alcoholic extract of the fruits of Piper longum

and its component piperine were studied for their immunostimulatory

activity. Administration of Piper longum extract and piperine increased the

total WBC count to 142.8% and 138.9%, respectively, in BALB/c mice. The

number of PFC was also enhanced significantly by the administration of the

extract (100.3%) and piperine (71.4%) on the 5th day after immunization.

Bone marrow cellularity and esterase positive cells were also increased by

the administration of Piper longum extract and piperine (Sunila and Kuttan,

2004).

Plumbago zeylanica, commonly known as Doctorbush, is a species of

plumbago with a pantropical distribution (Family: Plumbaginaceae). Effects of

seselin identified from Plumbago zeylanica on phytohemagglutinin (PHA)-

stimulated cell proliferation were studied in human peripheral blood

mononuclear cells (PBMC). The data demonstrated that seselin inhibited

PBMC proliferation-activated with PHA with an IC (50) of 53.87+/-0.74

microM. Cell viability test indicated that inhibitory effects of seselin on PBMC

proliferation were not through direct cytotoxicity. The action mechanisms of

seselin may involve the regulation of cell cycle progression, interleukin-2 (IL-2)

and interferon-gamma (IFN-gamma) production in PBMC. Since cell cycle

analysis indicated that seselin arrested the cell cycle progression of activated

PBMC from the G(1) transition to the S phase. Seselin suppressed IL-2 and

IFN-gamma production in a concentration-dependent manner. Furthermore,

seselin significantly decreased the IL-2 and IFN-gamma gene expression in

PHA-activated PBMC. Therefore, results elucidated for the first time that

seselin is likely an immunomodulatory agent for PBMC (Tasai et al., 2008).

Picrorhiza kurroa has been reported by (Atal et al., 1986) to be a

promising immunomodulatory agent. Its ethanol extract has been observed to

enhance DTH response by 80%, and also antibody production and phagocytic

activity. The plant extract has been shown to hasten skin graft rejection. The

effect of P. kurroa on macrophages obtained from mice treated with carcinogen

ochratoxin A has been investigated by Dhuley (1997). It significantly inhibited

ochratoxininduced suppression of chemotactic activity and production of IL-1

and TNF-a.



Randia dumetorum Lamk. (Family: Rubiaceae) a plant widely used in

the traditional medicinal systems of India, has been reported to possess

antiviral, antibacterial and anti-inflammatory activities. In present study, the

attempt was made to screen immunomodulatory activity of methanol extract

and its petroleum ether, chloroform, ethyl acetate and methanol fraction of

fruits of R. dumetorum. The effects of R. dumetorum on cell mediated and

humoral components of the immune system in mice were observed.

Administration of chloroform fraction at dose 100 mg/kg produced statistically

significant results as evidenced by increase in humoral antibody (HA) titer (p <

0.05), delayed type hypersensitivity (DTH) response (p < 0.001).This fraction

also enhanced the total WBC level in cyclophosphamide induced

mylosuppression model (p < 0.001) at dose 100 mg/kg. Petroleum ether

fraction and methanol fraction affected only cell mediated immunity. Present

study, therefore reveals that drug holds promise as immunomodulatory agent

(Satpute et al., 2009).

Saraca indica is a genus is the family Fabaceae (legume family).

Saracin, a seed integument lectin from Saraca indica is highly specific for

binding N-acetyl-neuraminyl-N-acetyllactosamine [Neu5Ac-alpha-(2-6)/(2-3)-

D-Gal-beta-(1-4)-D-G1cNAc]. This lectin has been found to be mitogenic for

human lymphocytes, and this mitogenic activity could be inhibited in presence

of fetuin. Further, treatment with saracin could induce secretion of IL-2 in a

cultureof resting human peripheral blood mononuclear cells (PBMC) after 48 h.

Saracin has a higher affinity for the CD8(+) than CD4(+) T cells as revealed by

FAGS analysis. Agarose gel electrophoresis of DNA isolated from lymphocytes

cultured under different conditions has shown that this lectin could induce

apoptosis in activated T-lymphocytes, as also confirmed by flow cytometric

studies. Phenotypic analysis of the apoptotic cells reveals that they belong to

GD8 (+) T cells lineage. Four surface glycoproteins of PBMG have been found to

interact with saracin in a trisaccharide [Neu5Acalpha-(2-6)/ (2-3)-D-Gal-beta-

(1-4)-D-G1cNAc]-sequence specific manner. Saracin seems to be an interesting

immunomodulator for the mammalian immune system (Ghosh et al., 1999).

The effect of Solanurn torvurn (Family: Solanaceae) on delayed type



hypersensitivity (DTH) response, haemagglutinating antibody (HA) titer, white

blood cells (WBG), red blood cells (RBG) and hemoglobin concentration was

investigated in Sprague-Dawley rats to establish immune modulatory and

erythropoietic activity. Sheep red blood cells (SRBG)-immunized and challenged

rats were treated with Solanurn torvurn extract, levamisole and

dexamethasone. Phenylhydrazine (PHZ)-induced anemia in rats was treated

with the extract. The aqueous Solanum torvurn extract and levamisole

significantly enhanced DTH response, increased HA titer and WBG count, while

dexamethasone significantly decreased DTH response, did not increase HA

titer, and did not enhance WBG profile. The extract and Feroglobin, the

reference heamatinic, were able to reverse PHZ-induced anemia, and increase

the RBGs and Hb concentration above baseline values within 24 days.

Solanurn torvurn extract showed a concentration-dependent immunostimulant

and erythropoietic activity (George et al., 2011).

The immunomodulatory effect of clove, Syzygiurn arornaticurn (Family:

Myrtaceae) essential oils was evaluated by studying humor- and cell-mediated

immune responses. Essential oils were administered to mice (once a day, orally,

for a week) previously immunized with sheep red blood cells (SRBG5). Glove

essential oil increased the total white blood cell (WBG) count and enhanced the

delayed-type hypersensitivity (DTH) response in mice. Moreover, it restored

cellular and humoral immune responses in cyclophosphamide-

immunosuppressed mice in a dose-dependent manner. The findings were

established that the immunostimulatory activity found in mice treated with

clove essential oil is due to improvement in humor- and cell-mediated immune

response mechanisms (Carrasco et al., 2009).

Tinospora cordifolia is a large, glabrous and deciduous climbing

shrub belonging to the family Menispermaceae. This plant is reported to

benefit the immune system in a variety of ways (Kapil and Sharma 1997). The

alcoholic and aqueous extracts of Tinospora cordifolia have been tested

successfully for immunostimulatory activity. It helped increasing the

effectiveness of WBC and building up the body's immune system. TC-1

(clerodane furanoditerpene glycoside), TC-2 (cordioside), TC-4 (syringin), TC-5

(cordifolioside A), TC-6 (cordifolioside B ) and TC-7 (cordiol) isolated from



Tinospora cordifolia were found to have anticomplement and

immunostimulating activities. TC-4 and TC-7 inhibited the in vitro immuno-

haemolysis of antibody-coated sheep erythrocytes by guinea pig serum. The

reduced immunohaemolysis was found to be due to the inhibition of the C3-

convertase of the classical complement pathway. The compounds also gave rise

to a significant increase in IgG antibodies in serum. Both humoral immunity

and cell-mediated immunity were also dose-dependently enhanced.

Macrophage activation was reported for TC-2, TC-5 and TC-7 and this

activation was more pronounced with increasing incubation time (Wazir et al.,

1995).

Tridax procumbens (family Compositae) has been extensively used in

Ayurvedic system of medicine for various ailments. Earlier studies on the

extracts of Tridax procumbens revealed remarkable immunostimulatory

activity of the Tridax procumbens ethanol-insoluble fraction extract. The in

vitro (phagocytosis) and in vivo (haemagglutination and DTH) tests were used

to study the effect of the extract and fractions on the cellular and humoral

immunity. Alcoholic extract revealed significant immunostimulation by in

vitro phagocytosis, DTH and haemagglutination model (Agarwal et al.,

2010).

Withania coagulans (Family Solanaceae) contain six new withanolides,

withacoagulins A-F (1-6, resp.), together with ten known withanolides, 7-16,

were isolated from the aerial parts of Withania coagulans. These compounds,

including the crude extracts of this herb, exhibited strong inhibitory activities on

the T- and B-cell proliferation. From, that the results showed Withania

coagulans has a immunosuppressive activity (Huang et al., 2009).

Withania somnifera has been an important herb in the Ayurvedic and

indigenous medical systems for over 3 000 years. It is a small, woody shrub of

the Solanaceae family. Administration of an extract from the powdered roots

of the plant Withania somnifera was found to stimulate immunological

activity in BALB/c mice. Treatment with five doses of Withania somnifera

root extract was found to enhance the total WBC count on the 10th day.

Bone marrow cellularity as well as a-esterase-positive cell number also

increased significantly after the administration of the extract. Treatment with



the extract along with the antigen (SRBC) produced enhancements in the

circulating antibody titer and the number of PFC in the spleen. Maximum

number of PFC (985 PFC/106 spleen cells) was obtained on the 4th day.

Withania somnifera extract inhibited DTH reaction in mice (Mantoux test).

Administration of Withania somnifera extract also showed an enhancement

in phagocytic activity of peritoneal macrophages (76.5 pigmented cells/200)

compared with the control (31.5 pigmented cells/200) in mice. These results

confirmed the immunomodulatory activity of Withania somnifera extract,

which is a known immunomodulator in indigenous medicine (Davis and Kuttan,

2000, Baral et al., 2005).

Zingiber officinale is widely used by pregnant women for nausea and

vomiting. It has been studied for various activities like cardioprotective

(Ansari et al., 2006), anti-convulsant, anxiolytic, anti-emetic (Vishwakarma et

al., 2002), anti-diabetic, hypolipidaemic (Al-Amin et al., 2007), anti-

inflammatory, anti-tumor (Sang et al., 2009), anti-thrombotic (Thomson et

al., 2002), anti-obesity (Goyal and Kadnur, 2006), antioxidant (Masuda,

2004), anti-atherosclerotic (Fhurman et al., 2000), radioprotective (Haksar et

al., 2006), hypotensive (Ghayur and Gilani, 2005), renoprotective (Ajith et al.,

2007), anti-reproductive toxicity (Amin and Hamza, 2006), anti-ulcer

(Siddaraju and Dharmesh, 2007), hepatoprotective (Yemitan and Izegbu,

2006), androgenic Kamtchouing et al., 2002), anti-fouling (Etoh et al., 2002),

prokinetic (Ghayur and Gilani, 2006). inhibition of angiogenesis (Kim et al.,

2005), increasing insulin sensitivity (Sekiya, 2004), molluscicidal, anti-

schistosomal (Adewumni et al., 1990), nootropic (Joshi and Parle, 2005), for

treatment of gastrointestinal disorders (Ghayur and Gilani, 2005), migraine

(Mustafa and Shrivastava 1990), morning sickness (Willetts et al.,

2003). Ginger is also non teratogenic (Weidner and Sigwart, 2001).



Table: 2.1 Summary of immunostimulatory plants reviewed.

S. No.

Plants name Part used

Extracts/ Phyto-constituents

Model used

1. Actinidia macrosperma

Fruit

Aqueous Lymphocyte proliferation, natural killer cell, cytotoxicity, phagocytic activity

2. Aesculus indica Leaves

Aqueous, Alcoholic

Delayed type hypersensitivity response, Neutrophil adhesion test

3. Allium sativum Bulb

Proteins Contact hypersensitivity test

4. Aloe vera Gel Aqueous Macrophage activation

5. Andrographis paniculata

Leaves

Ethanolic

Delayed type hypersensitivity response

6. Asparagus racemosus

Roots

Alcoholic Sepsis inducement test

7. Azadirachta indica

Leaves

Aqueous Delayed type hypersensitivity response

8. Baliospermum montanum

Roots

Aqueous Neutrophilic phagocytic test

9. Boerhaavia diffusa

Roots


10.

Boswellia carterii

Bark

Triterpenoids T-lymphocyte proliferation

11.

Capparis zeylanica

Leaves

Ethanolic

Delayed type hypersensitivity response, Neutrophil adhesion test

12.

Caesalpinia bonducella

Seed

Ethanolic

Delayed type hypersensitivity response, Neutrophil adhesion test,

carbon clearance test

13.

Centella asiatica

Leaves

Ethanolic

Delayed type hypersensitivity response,reticuloendothelial stimulatina test,phagocytosis

14.

Chlorella vulgaris

Whole part

Proteins hydrolysate


15.

Chlorophytum borivilianum

Roots

Ethanolic

Delayed type hypersensitivity response, Neutrophil adhesion test, carbon clearance test

16 Clerodendrum Roo Methanolic Delayed type



S. No.



Model used

. phlonidis ts hypersensitivity response, carbon clearance test

17.

Curculigo orchioides

Roots

Methanolic

Delayed type hypersensitivity response, plaque-forming test, macrophage migration index

18.

Curcuma longa Whole part

Curcumin Concalavalin A-induced proliferation test

19.

Eclipta alba Eclalbatin cyclophosphamide induced myelosuppression, carbon clearance test

20 Emblica officinalis

Fruit

Ethanolic Rat splenocyte test

21.

Epilobium angusti folium

Roots

Oenothein B Phagocyte activation

22.

Ficus benghalensis

Leaves


23.

Gymnema sylvestre

Leaves

Aqueous Nitroblue tetrazolium test, neutrophil locomotion test

24.

Heracleum nepalense

Roots

Quercetin glycoside

Delayed type hypersensitivity response, carbon clearance test

25.

Janakia arayalpathra

Roots

Extracts Delayed type hypersensitivity response

26.

Mangifera indica

Bark

Alcoholic Ativation of T and B cells

27.

Morinda citrifolia

Fruit

Phagocytosis

28.

Nyctanthes arbortristis

Leaves

Ethanolic


29.

Ocimum sanctum

Leaves

Steam distilled extracts


30.

Panax ginseng Roots

Polysaccharide Increases in number of bone marrow cells, splenocytes, and hematopoietic stem cells and Cytokine production

31.

Picrorhiza kurrua

Leaves

Ethanolic

Delayed type hypersensitivity response, Increases total white blood cell count



S. No.



Model used

32.

Piper longum Fruit

Alcoholic

33.

Randia dumetorum

Fruit

Methanolic

Delayed type hypersensitivity response, cyclophosphamide induced myelosuppression

34.

Randia dumetorum

Whole part

Polysaccharide Delayed type hypersensitivity response, Cytokine production,

35.

Tinospora cordifolia

Fruit

Alcoholic Delayed type hypersensitivity response,

36.

Tridax procumben

Arial part

Ethanolic

Delayed type hypersensitivity response,

37.

Withania somnifera

Roots

Extracts Delayed type hypersensitivity response

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