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Review on the Potential Role of Boerhavia diffusa

as a Medicinal Plant

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Aashis Dutta Manas Das

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 Chapter - 3
Review on the Potential Role of Boerhavia diffusa
as a Medicinal Plant

Authors
Aashis Dutta
Assistant Professor, Behali Degree College, Borgang,
Biswanath, Assam, India
Dr. Manas Das
Assistant Professor, Department of Zoology, Gauhati
University, Guwahati, Assam, India

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Page | 44
 Chapter - 3
Review on the Potential Role of Boerhavia diffusa as a
Medicinal Plant
Aashis Dutta and Dr. Manas Das

Abstract
The various side effects of the allopathic medicines have driven the
minds of scientists and researchers to shift their focus on the
pharmacological characteristics of herbal plants. The present review explores
the therapeutic potential of a perennial herb, Boerhavia diffusa that has been
used in the Ayurvedic and Unani system of medicine. Numerous medicinal
properties including anti-oxidant, anti-inflammatory, anti-hyperglycemic,
anti-nephrotoxic, cardiotonic, anti-cancer property have been found to be
present in the plant that has been primarily attributed to the presence of
phytochemical constituents like the alkaloid punarnavine. Thus, the
possession of a number of phytoconstituents isolated from primarily the
ethanolic and the methanolic extract confers the multifaceted character of
being effective against a number of ailments. However, extrapolated studies
on the medicinal characteristics of the crude extracts of the herb as well as
the isolated compounds are required that might be useful in exploiting the
curative property to a whole new extent and as such the herbal treatment of
various human diseases like diabetes, renal disease and cancer might thereby
reduce the load on allopathic medicine with lesser side effects and present a
holistic approach to life, stability of mind, body and environment and stress
on health quality instead of disease.
Keywords: Boerhavia diffusa, phytochemical constituents, punarnavine,
anti-nephrotoxic, anti-inflammatory
1. Introduction
Boerhavia diffusa, a perennial herb belonging to the Nyctaginaceae
family is used in Ayurvedic and Unani system of medicine in India and
worldwide. The herb has excellent therapeutic features as its various parts
have been demonstrated to function as appetizer, alexiteric, eye tonic and is
extensively utilized in the treatment of ailments like heart disease,

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inflammation, kidney disorders and anemia. The demonstration of various
pharmacological activities like immunomodulation, anti-cancer, anti-
diabetic, anti-inflammatory, anti-hypertrophic, cardiotonic, anti-convulsant
activities have been confirmed through the conduction of various studies and
trials on animals [1]. Besides, a number of phytoconstituents are reported to
be present that are responsible for exemplifying some of the medicinal
properties. Some of these bioactive compounds include alkaloid like
punarnavine, rotenoids like Boeravinone G, Boeravinone H, Boeravinone B,
flavonoids like kaempferol, quercetin, lignans like liriodendrin that exhibit
anti-genotoxic, anti-oxidative, cardioprotective, calcium channel antagonistic
property thereby contributing to medicinal value of the whole plant [2, 3, 4, 5].
2. Pharmacological activities of Boerhavia diffusa extracts
The different solvent extracts (ethanolic, methanolic, aqueous, n-hexane
and ethyl acetate extract) of aerial parts of B. diffusa possess anti-oxidant,
anti-hyperlipidemic and anti-hyperglycemic properties by prohibiting the
digestion of lipid and carbohydrate and abdominal glucose intake while
simultaneously increasing muscle glucose uptake. Along with the extracts,
the diverse chemical compounds or the phytoconstituents like the alkaloid
punarnavine present in the herb are of tremendous medicinal value.
Anti-oxidant activity
Free radical scavenging activity has been regarded as protective effect
against oxidative stress [6]. The 2,2-diphenyl-1-picrylhydrazyl (DPPH)
scavenging activity and the total reducing power of the ethanolic and
aqueous extracts of the aerial parts of B. diffusa display an anti-oxidant
effect that attributes the protective property against complications in Type 2
Diabetes Mellitus (T2DM) as oxidative stress is considered to be associated
with the pathogenesis of diabetes [7]. Even the free radical scavenging
property has also been exhibited by the methanolic extract and this character
might be conferred by the presence of flavonoids that belongs to the class of
polyphenols [8]. Even some researchers have argued to attribute the anti-
oxidant potential to the presence of rotenoids (Boeravinone G, H and D) [9, 10,
11, 12, 13, 14]
. The oxidative stress caused by Fe2+ in rat pancreas leads to the
production of superoxide, hydrogen peroxide and hydroxy radicals. The
levels of the anti-oxidant enzymes like superoxide dismutase (SOD) and
catalase (CAT) are assessed as the former one catalyses the dismutation of
superoxide to H2O2 while the later one catalyses the conversion of the
generated H2O2 to water and O2 [15]. The capability of the aqueous and
ethanolic extract to elevate the activities of these enzymes demonstrates their

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anti-oxidant property. Besides, reduced glutathione (GSH) is considered to
be a direct marker of oxidative stress at the cellular level whose levels get
lowered at the time of β-cell dysfunction. The treatment with the aerial
extracts causes their level to shoot up (Table I) [16]. When the polyphenol
rich ethanolic extract of B. diffusa was tested against quinolinic acid, 3-
nitropropionic acid, sodium nitroprusside and Fe2+/EDTA stimulated
oxidative stress in rat brain homogenates, it was found that the generation of
thiobarbituric acid reactive substances that was elevated by the different
neurotoxic agents was reduced by the extract. Likewise the activities of anti-
oxidant enzymes like SOD, CAT and also the non-enzymatic anti-oxidant
GSH was also enhanced by the ethanolic extract. Lipid peroxidation was
prohibited in the cerebral cortex. The inhibitory property of the B. diffusa
ethanolic extract (BDEE) against deoxyribose degradation (IC50 value
38.91±0.12 µg/mL) demonstrated the capability of the extract to retard the
hydroxyl radical stimulated DNA damage. Thus the herb has alarmingly
high anti-oxidant capacity that could prohibit oxidative stress brought about
by various neurotoxic agents in brain (Table I) [17].
Anti-inflammatory activity
Inflammation is an essential requirement for the healing of wounded
tissue and is normally associated with all the disease processes like
immunity, vascular pathology, trauma and sepsis 18. But on the other hand, it
is also regarded as a necessary evil with ill effects like systemic shock and
damage to the circulatory system and if untreated can lead to localized tissue
damage in different organs [19, 20]. The secretory phospholipase A2 (sPLA2) is
a major enzyme in the generation of pro-inflammatory mediators in various
chronic inflammatory diseases like rheumatoid arthritis, coronary heart
disease, diabetes and asthma and also causes neuroinflammatory diseases
like Parkinson's, Alzheimer's and Crohn's disease. The crude extracts of the
B. diffusa exhibited anti-sPLA2 activity as the ethanolic extract was reported
to be more potent in this case followed by aqueous and methanolic extract.
Thus, B. diffusa has more of hydrophilic inhibitors than hydrophobic ones.
The ethanolic extract inhibits the sPLA2 enzyme from human synovial fluid
(HSF), human pleural fluid (HPF) and V. russelli snake venom (VRV-PL-V)
which belongs to Group IIA sPLA2. When tested for their ability to inhibit
Group IA sPLA2 enzymes, it was found that these extracts have more
inhibition potency against Group IIA sPLA2 than Group IA sPLA2 enzymes.
The differential extent of inhibition might be due to the variable binding
affinities of the active site [21]. It has been found that even when the substrate
concentration was doubled, the B. diffusa extracts (aqueous, methanolic and

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ethanolic) exhibited the sPLA2 inhibition that led to the conclusion that these
crude extracts don't compete for the binding site of the substrate and might
function by interacting with a different site and the inhibition is independent
of the substrate concentration. However, there is a controversy surrounding
the binding site of the constituents of the extract as substantial evidence is in
favor of binding of the constituents to the substrate binding site as it is
witnessed in the inhibition of the in vitro sPLA2 inhibition and in direct
hemolytic assay in which the substrate nature is completely different [21]. It
has been found that some of the inhibitors of sPLA2 control inhibition by the
shift of catalytically essential Ca2+ ions from the enzyme and the inhibition
depends upon the Ca2+ ions in one way or the other. Since the inhibition of
sPLA2 enzyme by the B. diffusa extract was around 50% even in presence of
four times the Ca2+ ion concentration, the proposition that the constituents of
the extract function by binding to Ca2+ ions during inhibition is completely
invalid. The crude extract components directly interact with the enzyme to
bring about irreversible inhibition. This type of inhibition is reported to be
directly proportional to the anti-oxidant and anti-peroxidative activity. The
simultaneous injection of B. diffusa extract along with VRV-PL-V reduced
the edema-stimulating capacity in a dose dependant pattern. Furthermore, the
ethanolic and aqueous extracts of B. diffusa decreased the sPLA2-induced
paw edema [21].
Wound healing is a mechanism based on complicated restructuring
process of cells and tissue layers in an impaired tissue to make it achieve the
normal physiological condition and start the fibroblastic stage where the
wounded area has shrunken [22]. The process involves three phases-
inflammatory, proliferative and remodeling phase which are distinguished by
haemostasis and inflammation, cell multiplication and movement and
angiogenesis and collagen accumulation respectively. The shrinkage of the
wound begins during the remodeling phase. The stimulation of a number of
cells such as keratinocytes, fibroblasts, epithelial cells and macrophages is
correlated with wound healing [23]. A successful interaction between healthy
keratinocytes and cell types involved in wound healing is necessary [24].
When both the methanolic extract and chloroform leaf extract were tested for
their efficacy in increasing the viability of human keratinocytes in vitro, the
methanolic extract was capable of causing prominently higher activation of
keratinocytes as the total phenolics, flavonoids and anti-oxidant properties
were present in greater amount as revealed through the in-vitro scratch assay.
The higher wound healing capability of the methanolic extract might be due
to the accelerated anti-oxidant potential that can be attributed to the high
concentration of phenolics and flavonoids. Furthermore it was also

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demonstrated that the wound healing process was increased in animals
treated with methanolic extract. The GC-MS analysis revealed that the
methanolic extract had higher content of plant metabolites like D-pinitol, an
insulinomimetic plant metabolite as compared to chloroform extract [25]. The
molecule had free radical scavenging activity that has rendered it effective
against oxidative stress [26]. Topical insulin ameliorated diabetic wound
healing by modulating wound inflammatory cells and reinstating cellular
functions [27]. The bioactive insulin is found to stimulate the activation of the
Insulin Receptor/Insulin Receptor Substrate/Phosphoinositide 3-
kinases/Protein Kinase B (IR/IRS/PI3K/AKT) pathways associated with
cutaneous wound healing that leads to tissue regeneration and growth,
multiplication and movement of keratinocytes and fibroblasts [28]. These
studies reveal a strong association between insulinomimetic D-pinitol and
PI3K/AKT pathway in wound healing.
Anti-hyperglycemic activity
Diabetes mellitus is a heterogeneous group of conditions characterized
by resultant chronic hyperglycemia affecting both children and adult alike [29,
30]
. Amongst the various manifestations of this metabolic disorder in the
body, Type 2 diabetes (Non-insulin dependent diabetes mellitus) accounts
for 90-95% of the cases. The aqueous leaf extract of B. diffusa causes
significant decrease in blood glucose in normal and alloxan diabetic rats. The
anti-diabetic property might be caused by the elevated secretion of insulin
from β-cells [31]. In case of improperly controlled diabetes, elevated level of
glycosylated haemoglobin (Hb) is witnessed and the level of increase was
found to be directly proportional to the fasting blood glucose level [32].
During diabetes, the excessive blood glucose reacts with haemoglobin and as
such, it leads to a decrease in total Hb level in alloxan diabetic rats [33]. It has
been found that the aqueous leaf extract of B. diffusa treatment for a stretch
of about 30 days prohibits an increase in glycosylated Hb, thus increasing
the total blood Hb level of diabetic rats. This might be due to the effect of
amelioration of hyperglycemia by the leaf extract treatment of B. diffusa. It
has also been able to restore the body weight in alloxan induced diabetic rats
that might be attributed to its anti-hyperglycemic property 31. It is often
argued that the leaf extract leads to improved glucose utilization in the body
which is due to its ability to restore delayed insulin response or suppress the
intestinal glucose absorption [31]. The endocrine disorder is characterized by
marked alterations in the level of enzymes involved in glucose metabolism.
One such enzyme is hexokinase, the rate limiting enzyme of glycolysis
whose activity decreases in alloxan induced diabetic rats while the leaf

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extract administration causes elevated hexokinase activity. The enhanced
activity might cause increased glycolysis and elevates glucose utilization for
energy production as it has been reported that blood glucose level decreases
in B. diffusa leaf extract treated mice. Moreover the activities of
gluconeogenic enzymes, glucose-6-phosphatase and fructose-1,6-
bisphosphatase are reported to be significantly inhibited in diabetic rats
(Table I) [31]. The substantial suppression of the enzymes like lipase and α-
glucosidase can regulate the post-prandial blood glucose level and can even
limit the aggregation of fats in obese T2DM patients [34, 35]. The inhibitory
capacity of the aerial extracts of B. diffusa causes delayed digestion of
carbohydrates and lipids in the intestine. Thus, the blood glucose and the
fatty acid level in the blood stream decreases [7]. The anti-hyperglycemic
property is shown in the blockage of glucose absorption in the isolated
intestine treated with the ethanolic extract. The absorption or the uptake of
glucose by the muscles irrespective of the insulin level decreases blood
glucose concentration. The muscles treated with the ethanolic extract
exhibits elevated glucose uptake that confers it anti-hyperglycemic property
[16]
.
Anti-hypertrophic activity
Cardiac hypertrophy refers to the enhancement of the heart with an
elevation in the volume of cardiomyocytes. Sustained hypertrophy is
considered to be linked with the ailing heart function, the occurrence of heart
failure and sudden collapse [36]. It is one of the principal factors responsible
for cardiac morbidity and mortality [37]. A signaling mechanism that causes
cardiac hypertrophy is the excessive generation of Reactive Oxygen Species
(ROS) [38]. Overproduction of ROS provokes cell dysfunction, lipid
peroxidation, DNA mutation and can cause permanent cellular damage or
even death [39]. The octapeptide angiotensin II is significant for developing
cardiomyocyte hypertrophy [40]. The reduction in cell size, protein content,
leakage of lactate dehydrogenase (LDH) and decreased expression of anti-
natriuretic peptide (ANP) and B-type natriuretic peptide (BNP) upon
(BDEE) treatment explains the protective nature of B. diffusa against cardiac
hypertrophy. The elevated concentration of cellular ROS hinders cardiac
function by impairing ion channels, suppressing contractility and destroying
the structure of ion channels by causing lipid peroxidation inside the cell [41].
The ROS production gets depleted upon BDEE treatment. The increased
ROS production is mainly because of faulty endogenous anti-oxidant system
[42]
. The defective system fails to remove the different free radicals and
causes cellular oxidative stress. Besides, elevated levels of ROS stimulates

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lipid peroxidation in cellular, mitochondrial and nuclear membranes along
with protein oxidation [43]. The in vitro chemical assays reveal xanthine
oxidase (XO) and angiotensin convertin enzyme (ACE) inhibitory ability.
The XO activity was reportedly higher at the time of cardiac dysfunction [41].
The BDEE has XO inhibitory capacity which is ascertained by its ability to
remove superoxide anions and thus protects the myocardium from cardiac
hypertrophy. Similarly, ACE inhibition by BDEE is linked with a significant
betterment of cardiac hypertrophy (Table I) [44, 45]. The effect of cardiac
hypertrophy induced by angiotensin II on the transcription factors, nuclear
factor kappa B (NF-κB) and Tumor Growth Factor-β1 (TGF-β1) were
analysed in H9c2 cells. NF-κβ is a stimulating transcription factor that is
induced by various inflammatory stimuli and growth factors and it is also
known to be correlated with the occurrence of inflammation, immune
response and cell survival [46]. Its activation is intimately connected with
cardiac hypertrophy while ROS functions as a powerful stimuli for its
activation [47, 48, 49, 50]. The decrease in the transcriptional product of NF-κβ in
BDEE treated cells depicts that BDEE can lower the expression of NF-κβ by
reducing the ROS production. Similar results were evident in case of TGF-
β1, a significant mediator of the hypertrophic growth of heart (Table I) [45, 51].
Rats administered with Ang II developed cardiac hypertrophy and
demonstrated the presence of enhanced cardiac collagen level and also
developed fibrosis by overexpressing TGF-β1. The capability of the
ethanolic extract in lowering the enhanced collagen content in the heart and
cardiac fibrosis might be due to its ability of downregulating the expression
of TGF-β1 (Table I) [52, 53]. The cell viability assays using BDEE and
angiotensin II revealed that BDEE protected the cells from Ang II stimulated
cell death in a dose dependant pattern and the action of the extract was found
to be maximum at a concentration of 75 µg/mL (Table I) [45]. The
hypertrophied wistar rats displayed a marked reduction in the action of Na+-
K+ ATPase and Ca2+-ATPase while the extract elevated the functioning of
these membrane bound ATPases. Substantial evidence suggests that the
increased activities of Na+-K+ ATPase causes hyperpolarization followed by
decline in intracellular calcium that is effective in lowering the occurrence of
myocardial hypertrophy [54]. Nuclear factor erythroid 2-related factor 2
(Nrf2) is regarded as one of the primary regulatory elements correlated with
oxidative stress and commences the transcription of various anti-oxidative
genes responsible for primary defense mechanism against ROS mediated
cardiac injury inside the nucleus [55]. The ethanolic extract treatment caused
the nuclear translocation of Nrf2 in hypertrophied rats. This elevated Nrf2
translocation might be causing the amelioration in the anti-oxidant status in

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the heart that is sustained by increased action of anti-oxidant enzymes and
decreased oxidation of lipids and proteins. Nrf2 maintains the structural and
functional integrity of abnormally stressed heart and the upregulated Nrf2 is
regarded as responsible for prohibiting the hypertrophy mediated ROS
generation and related pathology in both cardiomyocyte and cardiac
fibroblasts [55].
Anti-estrogenic activity
The estrogen level is a crucial factor in human physiology as it affects
the development, sexual differentiation, fertility, control of female
reproductive tract, organ responsiveness and female diseases due to
hormonal imbalance. Estrogens like 17-β estradiol possesses a number of
effects on targets including breast, uterus, bone and cardiovascular tissues.
Their activities are modulated via the estrogen receptor (ER) that occurs in
two different forms i.e. ERα and ERβ that are present inside the target cell's
nucleus [56]. Even phytoestrogens exert estrogenic effects on skeleton, impact
the cardiac functions and menopausal symptoms and anti-estrogenic effect
on breast and prostate tissue [57, 58]. Estrogens are known as inducers of breast
cancer growth [59]. The anti-proliferative property of the methanolic extract
of B. diffusa was evaluated using MTT assay, that is dependant on the
reduction of tetrazolium salt by mitochondria of cells to generate a blue
colored formazan compound [60]. The extract also prohibited E2 stimulated
proliferation in MCF-7 cells demonstrating its plausible anti-estrogenic
property. Competitive radioactive binding studies demonstrate the binding of
B. diffusa methanolic extract (BDME) to the ER in a dose dependant manner
(Table I) [61]. Furthermore estrogen also stimulates transcription of various
genes including c-fos, c-erb-b2, ER, PR, pS2. The transcription of pS2 gene
is a significant response to E2 in human breast cancer cell line MCF-7 [62].
pS2 is found to be upregulated by estrogen while it is suppressed by
antiestrogen [63]. As BDME is found to downregulate pS2 gene transcription,
it was hypothesized that BDME might contain some useful compounds that
might have decreased ER-modulated transcription and generate anti-estrogen
effect in breast tissues. The same extract could cause G0-G1 cell cycle arrest
by elevating the population of MCF-7 cells in G0-G1 phase from 69.1% to
75.8%. This suggests that the extract could inhibit MCF-7 proliferation
through cell cycle arrest by prohibiting the occurrence of ER-mediated
pathways [61]. The presence of alkaloids, flavonoids, phenols and saponins in
the methanolic extract might be responsible for this anti-estrogenic property.

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Anti-nephrotoxic property
Nephrotoxicity is the condition which occurs when the detoxification
and excretion don't function properly due to renal injury by exogenous and
endogenous toxicants [64]. Cisplatin, gentamicin and other non-steroidal anti-
inflammatory drugs replicate the renal failure that occurs due to
administration of these drugs upon clinical prescription [65]. Cisplatin induces
renal injury but the underlying mechanism has not been completely
deciphered although some studies reveal inflammation, oxidative stress
damage and apoptosis as the prime factors that are responsible for the
occurrence of nephrotoxicity [66]. The oxidative stress and the
conglomeration of ROS stimulates inflammation, mitochondrial
malfunctioning, prohibition of protein synthesis, DNA damage and
ultimately leads to cell death in proximal tubule epithelium [67]. Cisplatin
modulates its own absorption into the tubular cells by organic cation
transporter 2 and is associated with the development of acute kidney injury
and kidney failure [68, 69]. Cisplatin dosage causes decline in the level of anti-
oxidant enzymes like GSH and SOD which ultimately leads to the building
up of ROS and oxidative stress inside the cells [70, 71]. Administration of B.
diffusa hydroalcoholic root extract (200 mg/kg orally) was capable of
preventing the depletion in anti-oxidant enzymes like SOD and GSH while
simultaneously prohibited the increase in malondialdehyde level (MDA), a
parameter of lipid peroxidation (Table I) [72]. The serum creatinine, Blood
Urea Nitrogen (BUN) levels in the cisplatin treated group were reported to
be elevated followed by their decline in the B. diffusa hydroalcoholic extract
treated group [66, 72]. Even in case of gentamicin sulphate induced
nephrotoxicity, creatinine and BUN levels increased and B. diffusa lowered
their levels [73]. Similarly, a 4 fold and an 8 fold enhancement in the levels of
Tumor Necrosis Factor-α (TNF-α) and Interleukin (IL-1β) respectively was
noted in the cisplatin administered group [74]. Moreover, B. diffusa root
extract curbs the elevated levels of pro-inflammatory cytokines like TNF-α,
IL-1 and IL-6 which renders its anti-inflammatory property (Table I) [72, 75].
Histopathological reports concluded that cisplatin stimulates renal tissue
apoptosis and cause kidney damage while B. diffusa treatment exerted its
anti-apoptotic effect. Thus B. diffusa exhibited its renoprotective behavior by
lowering the pro-inflammatory and apoptotic mediators and ameliorating
anti-oxidant property in the renal tissues of cisplatin administered rat (Table
I) [72]. Similar histopathological aberrations were also reported in the
gentamicin induced renal tissue damage which is characterized by tubular
desquamation and necrosis with engorged epithelium which was corrected
by aqueous root extract of B. diffusa [73]. The mercuric chloride stimulated

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nephrotoxicity also inferred similar results as the anti-oxidant enzymes like
ascorbic acid, catalase and glutathione peroxidase were enhanced by
mercuric chloride but the condition was reported back to somewhat normal
by the aqueous leaf extract of B. diffusa [76]. The altered expression pattern of
the aquaporin genes primarily aqp1, aqp3, aqp4 and aqp7 due to the
induction of chronic kidney disease in rats was reinstated to the normal
condition by treatment with BDEE. Even aberrations in serum urea and
creatinine levels and the histopathological damage was normalized to a
significant extent by the treatment [77].
Cardiotonic activity
B. diffusa possesses significant cardiotonic property as its extracts are
capable of reverting the damage induced by cardiotoxic substances. Arsenic
trioxide (ATO) happens to be a chemotherapeutic agent because of its anti-
neoplastic property. The underlying mechanism of the anti-neoplastic
activity might be due to the stimulation of apoptotic pathway and abundant
intracellular calcium ion trafficking [78, 79, 80]. Its therapeutic use is however
limited due to its cardiotoxic property. 3-[4,5-dimethylthiazole-2-yl]-2,5-
diphenyltetrazolium bromide (MTT), Lactate dehydrogenase (LDH) and
Neural Red (NR) assays were utilized to figure out the cytotoxic effects of
ATO on H9c2 clonal myoblastic cell line that has many characteristics of
adult human cardiomyocyte. Vacuolation, blebbing and granulation were
observed in ATO treated cells which was lessened by the administration of
BDEE. The ROS production produces alteration in cell signaling including
induction of transcription factors, alteration of gene expression that results in
damage to DNA, lipids and proteins causing apoptotic death [81, 82]. A dose
dependant suppression of anti-oxidant enzymes like SOD and CAT was
observed in case of ATO treated cells while BDEE due to its anti-oxidant
nature was capable of protecting the enzymes from declining [83]. The
membrane depolarization produced by ATO was stabilized by the ethanolic
extract except in case of 10 µM concentration of ATO. The ATO is capable
of causing Ca2+ ions overload by activating L-type calcium channel activity
and increasing the duration of action potential at 20% repolarization [84]. This
calcium surcharge is capable of causing mitochondrial damage because it
functions on different inner mitochondrial membrane proteins. The ethanolic
extract is capable of inhibiting the accumulation of Ca2+ only at low and
medium doses of ATO treated cells [83]. Another bioactive octapeptide of
RAAS, Angiotensin II (Ang II) stimulates cardiac hypertrophy and apoptosis
by switching on the ROS dependant molecular signaling pathways [55]. ROS
functions as intracellular signaling molecules that regulate cardiac

Page | 54
hypertrophy. Apoptotic cell death is considered a crucial event in the
development of Ang II induced cardiac diseases and apoptosis in
cardiomyocyte induces malfunctioning of cardiac muscle [85, 86].
Enhancement in cellular viability and lowering of hypertrophic markers (cell
volume, protein content, ANP, BNP) with B. diffusa treatment in Ang II
induced cells demonstrates the anti-hypertrophic nature of the plant.
Hypertrophic cardiac modeling is characterized by increased concentration
of β-MHC and decreased concentration of α-MHC isoforms while the
ethanolic extract treatment reciprocated these alterations [87]. The extract
prohibited the occurrence of apoptosis in H9c2 cells and this inhibition
might be brought about by an elevation in anti-apoptotic Bcl-2 protein,
decrease in Bax, suppression of cytochrome c release and switching on of
caspase-3. The gene expression of Bcl-2 is regarded as a significant marker
of cell survival in myocardium and the apoptosis in cardiomyocyte leads to
pathological cardiac hypertrophy causing heart failure with decreased
expression of Bcl-2, causing cardiomyocyte to undergoing apoptosis [88].
Enhanced Bcl-2 levels in the cardiomyocyte prohibit the marked changes of
mitochondrial electrochemical gradient preventing the release of inter-
membrane proteins like Cytochrome c (cyt c). The stressful stimuli switches
on the Bax protein that further provokes its movement to outer mitochondrial
membrane that in turn causes Cyt c discharge from inter-membrane space.
Cyt c brings about the apoptosome generation in cytosol and activates
downstream executioner caspases causing apoptosis [89, 90]. Significant
lowering of the ratio between Bcl-2 and Bax protein and lowered cyt-c in
cytosol by the ethanolic extract proves that the extract can prohibit the
intrinsic pathway of apoptosis in cardiomyocyte. Even the level of TNF-α
and IL-10 which was reported to be elevated by Ang II was significantly
lowered by BDEE. Besides, p38 MAPK that play a significant role in
cellular processes like inflammation, apoptosis, cell growth, cell contraction
and also in the occurrence of cardiovascular diseases like cardiac
hypertrophy was activated by Ang II but the ethanolic extract was capable of
decreasing the phosphorylated p38 MAPK levels stimulated by Ang II
(Table I) [87].
Anti-cancer activity
Unlimited cell multiplication and metastasis are the two distinguishing
characteristics of neoplastic cells. In a study in which B16F10 melanoma
cells induced metastases in C57BL/6 mice, treatment with aqueous
methanolic extract (3:7) extract of B. diffusa was capable of inhibiting
metastasis by about 95% (in case of prophylactic pre-treatment) and by

Page | 55
about 87% (in case of simultaneous administration). Besides, the elevated
levels of hydroxyproline, the major building block of collagen results in
fibrosis. With the administration of aqueous methanolic extract (3:7), the
treated animals had decreased lung collagen hydroxyproline content that in
turn means reduced fibrosis and a smooth alveolar function. Demonstration
of reduced lung tumor nodules correlates well with these findings (Table I)
[91]
. Hyaluronic acid, a glycosaminoglycan consisting of repeated units of D-
glucuronic acid and N-acetyl glucosamine when degraded by hyaluronidase
releases disaccharide units that are capable of regulating the multiplication,
adhesion and trafficking of endothelial cells and as such are excellent
promoters of angiogenesis [92, 93, 94, 95]. Enhanced levels of these structural
carbohydrates of hyaluronic acid is witnessed in metastatic animals with the
probability that these compounds might stimulate metastasis and tumour
directed angiogenesis. B. diffusa treatment markedly lowered the
concentration of these monosaccharides thereby causing a decrease in the
metastatic potential of B16F10 melanoma. The markers of neoplastic
multiplication like serum sialic acids and γ-glutamyl transpeptidase were
lowered by the extract treatment in metastatic animals (Table I) [91].
Immunomodulatory activity
The hexane, chloroform and ethanolic leaf extracts of B. diffusa and the
compounds Bd-I (5,4'-Dihydroxy 6,7-dimethoxy-flavonol-3-O-β-D-
galactoside) and Bd-II (3,5,4'-trihydroxy-6,7-dimethoxyflavone) isolated
from the ethanolic extract have immunosuppressive features. The
immunomodulatory property has been experimented by the capacity to
regulate the in vitro multiplication of peripheral blood mononuclear cells
(PBMCs) and the generation of nitric oxide (NO) in mouse macrophage cell
RAW 264.7 [96]. All the extracts and the compounds were able to suppress
the mitogen (PHA-phytohaemagglutinin)-stimulated multiplication of
PBMCs but the chloroform, ethanolic extract and Bd-I exhibited the
maximum potency followed by the hexane extract and Bd-II. Similar results
were also demonstrated by the chloroform and ethanolic extract (100 and
500 µg/mL concentration) and Bd-I in prohibiting the NO accumulation
while the other extracts including Bd-II did not exert any effect [96, 97]. The
chloroform and the hexane extract also inhibited allogenic response of
lymphocyte as assessed by Mixed Lymphocyte Reaction (MLR). The MLR
assay also revealed the capability of Bd-I in suppressing the lymphocyte
proliferation and the level of suppression was found to be equivalent to that
of the ethanolic extract. PHA induced IL-2 and LPS stimulated TNF-α
generation in human PBMC culture was prohibited at a concentration of 10

Page | 56
µg/mL by the ethanolic extract [96]. Surprisingly, the compound Bd-I isolated
from the ethanolic extract also exhibits the inhibition of LPS-induced TNF-α
generation and this action was reported to be higher than the ethanolic
extract indicating that the compound might be the primary
immunomodulatory one present in the extract (Table I) [97]. Moreover the
chloroform and the ethanolic leaf and root extracts of B. diffusa
demonstrated natural killer (NK) cells cytotoxicity in vitro and the root
extract treatment was viable at 500 µg/mL concentration and the inhibition
was visible both at 40:1 and 20:1 effector/target ratios [96, 97]. The pure
compounds, Bd-I and Bd-II did not exert any effect on the NK cell
cytotoxicity but was capable of prohibiting the macrophage/monocyte
lineage of cells and thus the fact that Bd-I was effective against lymphocyte
and macrophage/monocyte lineage cells but not against neutrophils and NK
cells proves that the action of these compounds is cell type specific (Table I)
[97]
. When the analysis of the effect of the ethanolic extract on the PHA
stimulated Th1 and Th2 was done, it was found that the extract prohibited
the stimulation of both the Th1 and Th2 cytokines (RNA transcript analysis
by Ribonuclease protection assay) and the effect was more pronounced in
case of IL-2, IL-3, IL-5 and Interferon-γ (IFN-γ) that is supportive of the
observation of decline in mitogen stimulated lymphoproliferative response
and decreased NK cell cytotoxicity [96].
Anti-depression activity
Depression is a recurring, deadly heterogeneous disease with a variety
of psychological, behavioral and physiological symptoms. The implication
of the same is 50% more in females than in males 98. The different doses of
the aqueous root extract of B. diffusa exerted prominent anti-depressant
behavior in Tail Swim Test (TST) and Forced Swim Test (FST). As this
activity was reverted significantly by pre-treatment with prazosin (α1-
adrenoreceptor agonist), sulpiride (dopamine D2 receptor antagonist), p-CPA
(serotonin synthesis inhibitor) and baclofen (GABAB agonist), the aqueous
extract might exert its effect by interacting with α1-adrenoreceptors,
dopamine D2 receptors, serotonergic and GABAB receptors, thereby
enhancing the brain noradrenaline, dopamine and serotonin levels while
lowering the γ-amino butyric acid (GABA). B. diffusa caused marked
inhibition of brain monoamine oxidase-A (MAO-A), indicating that reduced
metabolism of monoamines like serotonin, dopamine and noradrenaline
might be responsible for its anti-depressant behaviour (Table I) [99].

Page | 57
Pro-reproductive and developmental activity
The exposure to the environmental toxicants make organisms highly
susceptible to possess reproductive and developmental chronic toxicity.
Toluene is a widespread industrial substance exposure to which might induce
reproductive and developmental toxicity. When such a toluene toxicity study
was conducted in D. melanogaster, the model fly suffered a lot of
reproductive and developmental stresses like the larval length and width,
mean pupal length and width, average chest width, length and width of eggs,
egg to adult survival, life span and egg production were all lessened while B.
diffusa aqueous extract was capable of reversing all these effects thereby
trying to reinstate the normal condition. Toxic substances like toluene might
commence molecular mechanisms associated with life span shortening like
deacetylation of Sirtuin (SIR2) and RPD3 while B. diffusa could
significantly lengthen the life span of flies treated with toluene [100, 101]. Even
the enhanced levels of anti-oxidant enzymes like GST, SOD and CAT were
brought down by the B. diffusa aqueous extract treatment [101].
Anti-spasmolytic activity
The methanolic root extract of B. diffusa demonstrated a concentration
dependant inhibition of exogenous spasmogens like acetyl choline, histamine
and barium chloride and also the electric field stimulation evoked
contractions in isolated pig ileum. The ileum contraction was induced by
stimulants through different processes-acetyl choline and histamine through
the induction of post-junctional receptors, electric field stimulation through
the release of acetyl choline from enteric nerves and barium chloride through
a post junctional non-receptor mediated mechanism. As no significant
difference was noticeable in the B. diffusa inhibition curves, the spasmolytic
effect is probably due to the direct effect on smooth muscles. The results
obtained in presence of Ca2+ ion blockers is supportive of the fact that the
aforementioned property of the perennial herb might partly involve
extracellular calcium while intracellular calcium seems to negatively
regulate the inhibitory effect of B. diffusa on intestinal motility (Table I) [102].
Table I: The different extracts of the various parts of Boerhavia diffusa and their
reported therapeutic activities

SL. No. Extract Plant part Reported Activity References

[31]
1. Aqueous extract Leaf Anti-diabetic
[99]
2. Aqueous extract Root Anti-depressant
[101]
3. Aqueous extract Root Anti-toxic (reproductive)
[103]
4. Hydroalcoholic extract Whole plant Radioprotective
[104]
5. Hydroalcoholic extract Root Anti-hyperplasia

Page | 58
 [72]
6. Hydroalcoholic extract Root Anti-nephrotoxic
[91]
7. Methanolic extract Whole plant Anti-metastatic
[102]
8. Methanolic extract Root Anti-spasmolytic
[105]
9. Methanolic extract Root Anti-convulsant
[61]
10. Methanolic extract Whole plant Anti-estrogenic
Anti-lymphoproliferative [75, 96]
11. Ethanolic extract Root
Immunosuppressive
Anti-diabetic; [106]
12. Ethanolic extract Leaf
Renoprotective
[83]
13. Ethanolic extract Whole plant Anti-cardiotoxic
Anti-hypertrophic; [45]
14. Ethanolic extract Whole plant
Cardiotonic
[107]
15. Ethanolic extract Whole plant Anti-hypertrophic
[17]
16. Ethanolic extract Whole plant Anti-oxidative
Anti-hypertrophic; [53]
17. Ethanolic extract Whole plant
Anti-fibrotic
Anti-lipidemic; [16]
18. Ethanolic extract Aerial part
Anti-hyperglycemic
[87]
19. Ethanolic extract Whole plant Cardiotonic
[97]
20. Ethanolic extract Leaf Immunomodulatory
[97]
21. Chloroform extract Leaf Immunomodulatory
[97]
22. Hexane extract Leaf Immunomodulatory

3. Conclusion
The perennial herb, B. diffusa have been used since long time and has
proved to be of utmost significance in the traditional system of medicine
worldwide. Presence of many signature bioactive compounds in different
solvent extracts make it a potent therapeutic agent which is exemplified in its
anti-oxidant, anti-inflammatory, anti-hyperglycemic, anti-cancer and
immunomodulatory properties. However, tapping its medicinal value holds
the key and promise towards a better herbal plant in complementary and
alternative medicine (CAM) practice, the products of which will be
environment friendly with lesser side effects and with higher health benefits.
Incorporation of B. diffusa based herbal formulation will definitely pave new
roads for designing novel drugs for treating the indications of numerous
disorders.
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