Glabridin from Yashtimadhu-Licorice (Glycyrrhiza glabra)
Glabridin
from Yashtimadhu-Licorice (Glycyrrhiza
glabra)
Dr.
Hemant Vinze M.
S.
Introduction
Glabridin displays
pleotropic pharmacological activities. It is a key phytochemical found in Yashtimadhu-Licorice
(Glycyrrhiza glabra). It can be said
that all pharmacological activities of Yashtimadhu are due glabridin. In this
article I discuss in detail the pharmacology of glabridin.
Glabridin
Molecular
formula: C20H20O4
Structural
formula:
Glabridin
is an isoflavone, a type of isoflonoid found in the roots of
yashtimadhu-licorice (Glycyrrhiza glabra).
It is a yellowish-brown powder, insoluble in water but soluble in organic solvents
such as propylene glycol. It is a hydrophobic chemical. Glabridin improves the functions
of mitochondria. Glabridin stimulates DNA synthesis in human
endothelial cells. Glabridin has bi-phasic effect on proliferation of
human vascular smooth muscle. It is a natural skin lightener having no longterm
side effects. In summary glabridin shows pleotropic pharmacological activity. I
describe pharmacology of glabridin in detail below---- [1], [2], [3], [4]
Pharmacokinetics
Studies
on five healthy male subjects showed that on oral administration, glabridin was
well absorbed in the intestine, and its maximum concentration in blood reached
in four hours and then eliminated relatively slowly in approximately ten hours
at all doses. The multiple-dose studies with healthy male and female subjects
for one week and four weeks suggested that plasma glabridin reached steady
state levels within two weeks with a daily single dose administration
of 300 to 1200 mg. No adverse effects were recorded even after repeated
administration for four weeks. [5]
In
a study on rats it was found that the systemic bioavailability of glabridin was
7.5%, but increases when combined with verapamil. The Caco-2 cell line is a
continuous cell of heterogeneous human colorectal adenocarcinoma cells, developed
by Sloan-Kettering Institute for Cancer Research. Incubation of verapamil
significantly altered the intracellular accumulation of glabridin in Caco-2
cells. [6]
Actions of
Glabridin in septic shock
Sepsis
or septic shock is a life threatening emergency. In a study on animal models,
anti-inflammatory, antioxidant, antimicrobial and cardio-respiratory-protective
activities of glabridin were found to delay/avert death of animals with
sepsis/septic shock. This suggests a possible application of glabridin for the
management of sepsis/septic shock. [7]
Anti-inflammatory/Antioxidant
activity
Glabridin
has anti-inflammatory, antioxidant and free radical scavenging, skin-whitening,
neuroprotective, anti- atherogenic, estrogenic and anti-osteoporotic
properties. Glabridin regulates food, dietary and energy metabolism. The
biological activity of glabridin results from its capacity to down-regulate
intra-cellular reactive oxygen species, bind to antioxidant effectors and act
on estrogen receptors and act as plant based Selective Estrogen Receptor
Modular (phyto SERM) [8]
Glabridin
exhibits anti-inflammatory property through the inhibition of PGE (2), TXB (2)
(COX), and LTB (4) [9]
Immunomodulatory
activity
Dietary
flavonoids like glabridin show anti-inflammatory and immunomodulatory
activities. [10]
Antibacterial
activity of glabridin
Since
1980 antibacterial activity of yashtimadhu-licorice (Glycyrrhiza glabra), especially its phytochemical glabridin has
been well documented by many researchers. (Mitscher et al, 1980, Demizu
et al 1988, Okada et al, 1989, Haraguchi et al, 1998, Fukai et al 2002).
Glabridin is active against Staphylococcus aureus, methicillin
resistant Staphylococcus
aureus, Staphylococcus epidermidis, Streptococcus mutans, Helicobacter pylori,
Bacillus subtilis, Enterococcus faecalis, Klebsiella pneumoniae,
Salmonella typhi, Yersinia enterocolitica, Enterobacter aerogens and
Escherichia coli.
Vivek
K Gupta et al had special interest in investigating antimicrobial potential
of yashtimadhu-licorice (Glycyrrhiza
glabra) against Mycobacterium tuberculosis. They found, at a
concentration of 500g/mL, the extract of roots of yashtimadhu-licorice (Glycyrrhiza glabra) against Mycobacterium
tuberculosis. The phytochemical identified to show this activity was
glabridin. The antitubercular activity of glabridin was 20 times higher than
that of crude extract. Through BACTEC assay the antimycobacterial
activity was tested against Mycobacterium tuberculosis H37Ra and
H37RV. The ethyl acetate extract
of the plant showed antimycobacterial activity at a concentration range of 100-250
g/mL. The column fraction eluted with chloroform:ethyl acetate (96:4) was found
to be more effective against tubercular bacilli at a concentration range of
50-120 g/mL. The antitubercular activity of glabridin was found to be good at a
concentration of 29.16 g/mL against both the strains. [11]
In
an in vitro study, glabridin was tested for its antibacterial
activity at concentrations ranging from 3.12 to 25 μg /mL against
multi-drug-resistant Staphylococcus
aureus. Glabridin displayed antibacterial activity against multi-
drug-resistant Staphylococcus aureus.
This was attributed to antioxidant property of glabridin. Interestingly this
activity was observed at a much lower concentration than expected. When
combined with antibiotics such as oxacillin, norfloxacin, vancomycin etc.
glabridin reduced the minimum inhibitory concentrations (MIC) of these
antibiotics by up to four-fold, while the minimum inhibitory
concentration (MIC) of glabridin itself was found to be reduced by up to eight-
fold. Thus glabridin is suitable for combination antibacterial therapy. [12]
Antiviral
activity
Yashtimadhu-licorice
(Glycyrrhiza glabra) contains more
than 20 triterpenoids and 300 flavonoids. Of these very few show antiviral
activity. Glabridin is an important antiviral agent. It shows antiviral
activity against following viruses--------
Cerebral
capillary vessel endothelial virus, coxsackie virus A 16, coxsackie
virus B3, dehydroglyasperin C, duck hepatitis virus, enterovirus 17,
hepatitis B virus, nepatitis C virus, human immunodeficiency virus,
high-mobility-group box 1, human respiratory syncytial virus, herpes simplex
virus, herpes simplex virus type 1, varicella (chicken pox) virus and varicella-zoster
(shingles) virus.
The
mechanism of antiviral activity of glabridin can be summarized as-------
It
affects release step while viral particles are infecting cells
It
inhibits core gene expression of viruses
It
blocks the degradation of nuclear factor κB inhibitor IκB
It
activates T lymphocyte proliferation
It
suppresses virus-induced apoptosis
It
prevents viral attachment to cells and stimulates interferon secretion
It
reduces binding of virus to DNA and inhibits virus-polymerase activity
It
reduces the levels of viral proteins at a step subsequent to virus entry. [13],
[14]
Antifungal
activity
Glabridin
was found to be active against both yeast and fungi. At concentrations of 31.25
to 250 microgram/mL glabridin is active against Candida albicans and drug resistant mutant strains of fungi. [15]
The
phytochemicals glabridin and licochalcone A found in yashtimadhu-licorice (Glycyrrhiza glabra) inhibit the growth
of oral Candida albicans infection.
They are very potent anti-fungal agents. They also work in synergy with nystatin. The
phytochemical glycyrrhizic acid found in yashtimadhu-licorice (Glycyrrhiza glabra) has no
anti-fungal effect. [16]
Antiparasitic
activity
By
inducing oxidative stress in Plasmodium
falciparum parasite, glabridin inhibits in vitro, the growth
of malarial parasite. Glabridin could induce apoptosis in Plasmodium falciparum. In
erythrocytic cycle, trophozoit stage of Plasmodium
falciparum was found to be most
sensitive to glabridin. These results suggest that glabridin can be a cheap
anti-malarial drug for tomorrow. [17]
Actions on the
skin
In
humans the enzyme tyrosinase is essential for the production of melanin, the
pigment that imparts color to skin and eyes. The inflammatory reactions
are induced in the skin when it is exposed to ultraviolet rays in the sunlight.
Glabridin inhibits tyrosinase activity in cultured B 16 murine melanoma cells
and guinea pig skin. It has no detectable effect on their DNA synthesis.
Glabridin decreases the activities of T1 and T3 tyrosinase isozymes. Thus
glabridin inhibits the production of melanin in the skin. Glabridin also
inhibits UV-B induced erythema and skin pigmentation in guinea pig skins. The
synthetic derivatives of glabridin also show similar activities. [18], [19]
Glabridin
is poorly soluble in water. This impedes its topical application in cosmetic
products. To overcome this difficulty, by using anti-solvent
precipitation-homogenization method, a nanosuspension formulation of glabridin formulation
has been developed. This improves the skin permeation of glabridin.
The
optimum formulation consisted of:
Glabridin
0.25 %
Poloxamer
188
0.47 %
Polyvinylpyrolidone
K30 0.11 %
The
obtained nanosuspension formulation showed an average particle size of 149.2 nm
with a ploydispersity index of 0.254. The glabridin nanosuspension showed no
significant particle aggregates and the drug loss after 3 months of storage at
room temperature was 5.46%. With enhanced skin penetration, the nanosuspension
might be a more preferable formulation for topical administration of poorly
soluble glabridin. [20]
Ultra
violet (UVB) radiation is the major etiological factor in the pathogenesis of
aging and development of skin cancer. Glabridin and 18β-glycyrrhetinic acid,
potent antioxidants from the extract of yashtimadhu-licirice (Glycyrrhiza
glabra), protect the skin from UVB damage. They also prevent oxidative DNA
fragmentation and the activation of proteins associated with apoptosis in human
keratinocytes. [21]
Actions on wound
healing
The
anti-inflammatory property of glabridin reduces inflammation in wounds. At a
low concentration of 1 x 10-8 mol/L, glabridin accelerates the formation
of healthy granulation tissue and laying of fibroblasts; thus accelerating
wound healing. [22]
Actions on the
eye
Glabridin
is a strong COX-2 inhibitor. Anti-inflammatory, antioxidant and free radical
scavenging properties of glabridin alleviate retinopathy. [23]
Actions on
musculoskeletal system
To investigate
effects of glabridin on musculoskeletal system, glabridin was administered at
5, 10, 20 mg/kg body weight for consecutive 28 days to BALB/c mice. Body
mass, blood lactic acid (BLA), blood urea nitrogen (BUN), liver glycogen and
muscle glycogen concentrations in mice were determined. The results showed that
glabridin significantly increased exercise time, inhibited fatigue, delayed
elevation of blood lactic acid and increased the storage of glycogen in the
liver and muscles. Thus glabridin in yashtimadhu-licorice (Glycyrrhiza glabra)
validates the tenet of Ayurveda: "Yashtimadhu is a 'Rasaayana'
drawya" [24]
In
vitro and in vivo glabridin and glabrene demonstrate actions similar to
estradiol-17 β on osteoblasts, but differ in their extent of action and
interactions with other drugs. Both glabridin and glabrene stimulated creatine
kinase- specific activity in diaphysial bone and epiphysial cartilage of
prepubertal female rats. However glabridin demonstrated superior activity in
this regard. Pharmacological activity of glabridin also resembled to that
of estradiol-17 β in ovariectomized female rats and in post-menopausal
women. Glabrin has greater potential than glabrene, with or without vitamin
D, to modulate bone disorders in post-menopausal women. [25]
The
osteoblastic activity shows constructive bone forming activity. The
osteoclastic activity destroys bone formation leading to osteoporosis. To
evaluate the effect of glabridin, on osteoporosis, glabridin was administered
to ovariectomized rats at a dose of 5 mg/kg body weight. The results obtained
indicated that glabridin protected the animals from osteoprosis. The
anti-osteoporosis activity of glabridin was attributed to estrogen-like
activity of glabridin. Furthermore, glabridin was shown to inhibit osteoclastic
activity and promote osteoblastic activity. However when administered at doses smaller than
5 mg/kg body weight, glabridin failed to show beneficial effects on the
chemical composition and mechanical properties of bones in ovariectomized
animals. [26], [27]
By
inhibiting receptor activator-induced osteoclast differentiation glabridin
prevents osteoporosis. [28]
In
another study on mice glabridin at a dose of 1-10 micro M
significantly increased the function of osteoblastic cell line, caused a
significant increase in alkaline phosphatase (ALP) activity, increase in
collagen content and osteocalcin secretion in the cells. These effects were
attributed to estrogen-like activity of glabridin. [29]
Actions on the
Breast
That
glabridin shows estrogen like activity is now well established. The synthetic
derivatives of glabridin also show similar properties. However glabridin was
found to be three to four times more active than its derivatives 2'-O-
methylglabridin and 4'-O-methylglabridin. Glbridin showed biphasic activity on
breast-tumor-cells. At low concentrations (10nM-10 microM)
glabridin showed an estrogen receptor-dependent growth-promoting effect and at
high concentrations (> 15 microM) glabridin demonstrated estrogen
receptor-dependent anti-proliferative activity. [30]
In
breast cancer, the cancer stem cells (CSCs) are thought to be the main cause
for recurrence and metastasis. Therefore targeting CSCs is a new approach for
the treatment of breast cancer. Glanridin is recently used for this purpose.
It is suggested that glabridin inhibits the cancer like properties of
stem cells to arrest human breast cancer. [31]
Some
researchers suggested that glabridin displays its anti-breast cancer and
anti-metastatic property through Fokal Anti Kinase (FAK)/Reactive Oxygen
Species (ROS) pathway. The miRNA- family, which is frequently expressed at low
levels in triple negative breast cancers, inhibits metastasis by blocking the
epithelial-mesenchymal transition. In a study glabridin attenuated the
migratory and invasive capacity of breast cancer cells by activating miR-200c.
Glabridin induced the mesenchymal-epithelial transition in vitro and in vivo. Although
many mechanisms for anti-breast cancer activities of glabridin are suggested,
the exact mechanism of antitumor activity of glabridin at molecular level is
still unclear. [32]
A
study to evaluate effects of glabridin on adenocarcinoma of the breast showed
that glabridin inhibits the proliferation of breast-cancer cells, by decreasing
cell migration and invasion inhibits metastasis and decreases the angiogenesis
of breast cancer. Glabridin also decreased the active forms of focal adhesion
kinase. The study shows that, glabridin that acts in three ways: inhibition of
migration, invasion and angiogenesis; may be a novel anticancer agent for the
treatment of breast cancer. [33]
Actions on mouth
Chronic
inflammation and persistent activation of myofibroblasts leads to oral
submucous fibrosis. Oral submucous fibrosis (OSF) is a potentially malignant
disorder. Betel nut (Areca nut) chewing is implicated in this pathological fibrosis.
The chemical arecoline found in betel causes chronic inflammation and
persistent activation of myofibroblasts. Glabridin prevents inflammation and
inhibits activation of myofibroblasts. Thus glabridin is a natural
anti-fibrosis compound for oral submucous fibrosis. [34]
Actions on CNS
Neuroprotective
Effect
Stroke
is a life-threarening disease characterized by focal or global disturbance of
cerebral function. In a study on rats intraperitoneal injection of glabridin at
a dose of 25 mg/kg body weight significantly decreased the volume of infarct. The
clinical findings were supported by histological study of the infarcted area.
Furthermore there was a significant elevation of levels of endogenous
antioxidants i.e. superoxide dismutase (SOD) in the brain and reduction of glutathione.
These findings suggest that glabridin has a neuroprotective effect against
ischemia. [35]
On learning and
memory
Clinically
glabridin at 1, 2 and 4 mg/kg body weight is used as nootropic agent. At higher
doses (2 and 4 mg/kg body weight) glabridin significantly antagonizes the
amnesia induced by 0.5 mg mg/kg body weight of scopolamine. Furthermore
glabridin at doses 2 and 4 mg/kg body weight remarkably reduced the
cholinesterase activity in mice. Glabridin therefore appears to be a
promising phytochemical in the management of Alzheimer's disease. [36]
Recently Chakravarthi
and Avadhani have demonstrated anti-inflammatory, antioxidant activity. They
also found a remarkable cholinesterase inhibitory activity of glabridin in the
brain. Furthermore they found glabridin was useful to alleviate memory deficit.
They attributed this effect to anti-inflammatory and antioxidant activities of
glabridin. They think that glabridin can be useful in the management of
Alzheimer's Disease (AD). [37]
Beta-secretase
1 (BACE 1) also known as beta-site amyloid precursor protein cleaving enzyme 1.
In humans it is encoded by BACE1 gene. It is important in the formation of
myelin sheath. BACE 1 is required for the production of the neurotoxic β-amyloid
peptide that is widely considered to have a crucial role in the etiology of
Alzheimer's disease. [38]
Rui
Yang Li et al found that higher doses of glabridin significantly antagonized amnesia
induced by scopolamine. Glabridin also inhibits BACE 1. Rui et
al therefore think that glabridin can be used in the management of Alzheimer's
disease (AD) [39]
Antidepressant
activity
The
isoflavan glabridin and isoflavene glabrene found in yashtimadhu-licirice (Glycyrrhiza glabra) inhibit serotonin re-uptake
thus showing antidepressant activity. They may be beneficial for mild to
moderate depression in pre-menopausal and postmenopausal women. [40]
Effects on sleep
Licorice
has been traditionally used for the treatment of insomnia. Glabridin in
licorice potentiates GABA A and 5-HT (2C) receptors. This makes glabridin a
useful anxiolytic, sedative and hypnotic agent. Glabridin has been recently recommended
for the treatment of insomnia. Glabridin decreases the sleep latency and
increases the duration of sleep. [41], [42], [43]
A
study was designed to evaluate the effect of glabridin on isolated dorsal raphe
neurons of rats. It was found that glabridin potentiated GABA (gamma amino butyric
acid)-induced responses by positively modulating GABA-A. Thus glabridin
displayed sedative and hypnotic effects comparable to diazepam. The activity
was dose dependent. [44]
Actions on CVS
Recently
seven phytochemicals have been isolated from yashtimadhu-licorice (Glycyrrhiza glabra).
(A)
Isoflavans: (1) Hispaglabridin A (2) Hispaglabridin B (3)
Glabridin (4) 4'-O-Methylglabridin
(B)
Chalcones: (5) Isoprenylchalcone derivatives (6) Isoliquitrigenin
(C)
Isoflavone: Formononetin
When
tested for antioxidative capacities, flavans displayed the strongest capacity
towards β-carotene and LDL, chalcones displayed moderate and isoflavone
displayed the lowest capacity. Of isoflavans, glabrin displayed the strongest
antioxidant activity towards LDL oxidation. As LDL oxidation is a key event in
the formation of atherosclerotic lesion, glabridin may be useful in preventing
or attenuating atherosclerosis. [45]
By
preventing or attenuating the formation of atherosclerosis and by anti-inflammatory
property, glabridin displays cardio-vascular protective effect. [46]
Lycopene,
vitamin E, rosmarinic acid, carnosic acid, garlic and glabridin inhibit
oxidation of LDL. However combination of lycopene, vitamin D, rosmarinic acid,
carnosic acid, garlic and glabridin is a superior antioxidant than the
individual chemical. [47]
In
a study, pregnant female mice were fed on saturated fatty acids.
Their adult mouse offspring, when exposed to high fat
diet, developed hyperglycemia in their adult life, had lower levels
of heart paraoxonase 2 (PON2), mRNA and protein
expression. Glabridin prevented these ill effects
of hyperglycemia. These effects in mice were verified in vitro. The results indicate
that glabridin preserves the anti-atherogenic abilities of paraoxonase 2
(PON2). [48], [49]
Atherosclerosis
preceded by chronic inflammation is a great scourge to cardiovascular diseases.
Oxidation of low density lipoprotein (LDL) is the beginning of the end. In
vitro and in vivo studies showed that glabridin and glabridin derivatives exhibit
protective effect on cardiovascular system. The mechanisms of this
protection can be summarized thus-----
1.
They are strong anti-inflammatory agents
2.
They prevent the oxidation of low density lipoprotein (LDL) and
apolipoprotein E. They prevent the oxidation of LDL by inhibiting the formation
of lipid peroxides and oxysterols.
3.
They prevent consumption of beta-carotene and lycopene (but do not protect
vitamin E)
4.
They prevent the activation of macrophages and dendritic cells.
5.
They prevent the adhesion of molecules to endothelial cells.
They
can be used as therapeutic agents for the treatment of cardiovascular diseases
in future. [There are many research papers on cardiovascular-protective effects
and anti-atherosclerotic effects of glabridin and glabridin derivatives. Here I
have compiled them in short.] [50], [51], [52]
Pre-menopausal
women being protected by estrogen are protected from cardio-vascular disease.
Post menopausal women having lost estrogen protection have higher incidence of
heart disease. Glabridin has estrogen-like activity. Glabridin protects
post-menopausal women from the risk of cardio-vascular disease. Aberrant
proliferation of vascular smooth muscle cells (VSMCs) promotes plaque
formation. This leads to atherosclerosis. At high doses glabridin inhibits
the proliferation of vascular smooth muscle cells (VSMCs) and arrests
the formation of atherosclerosis. [53]
A
group of researchers examined the effect of glabridin on mesenteric artery of
rat using isometric myography. The results showed that glabridin induced
vasorelaxation that was dependent on the opening of potassium (K+) channels.
[54]
Delirium
is a major, serious and dreadful complication of coronary artery bypass (CABG)
surgery. This happens due to acute inflammation of the nervous system and
reduced neurotransmitter serotonin. Neuroprotecctive activity of propofol can
prevent delirium after CABG surgery. Recently anti-inflammatory, antioxidant
and neuroprotective activity of glabridin has been shown to prevent post CABG
delirium. Furthermore glabridin can also protect myocardium against
ischemia-reperfusion injury. [55], [56], [57], [58]
Actions on RS
Yashtimadhu-licorice
(Glycyrrhiza glabra) has been used as
an antitussive and expectorant for centuries. Of many phytochemicals isolated
from Yashtimadhu-licorice (Glycyrrhiza
glabra) fourteen major compounds were evaluated on animal models
for antitussive and expectorant activity. Glabridin was one of them. The
results showed that most of them displayed strong antitussive and
expectorant activity. Their antitussive effects depend on both peripheral and central
mechanisms. [59]
Actions on GI
system
Glabridin
significantly increases gastric emptying time. Glabridin is a potent prokinetic
agent comparable to domperidone. Glabridin relieves functional dyspepsia. [60]
Yashtimadhu-licorice
(Glycyrrhiza glabra) has been used
for acid peptic disease in India, China and Japan for centuries. Glabridin
reduces gastric secretion and inhibits ulcer formation. Compounds such as
glabridin, glycyrrhizin and aglycone glycyrrhetinic
acid protect the gastric mucosa from erosion by increasing secretion of mucus
and by preventing the inflammation of gastric mucosa. This anti-ulcer
activity is due to flavones contained in it. Glabridin is one of them. Recently
flavones have been shown to inhibit the growth of Helicobacter
pylori that is responsible for acid peptic disease. Furthermore flavonoids
also inhibit the growth of Helicobacter pylori resistant to
clarithromycin and amoxycillin. [61], [62]
Acute
colitis was induced in BALB/c mice by oral administration of 5 % dextran
sodium sulphate (DDS) for seven days. To evaluate the efficacy of
glabridin for the treatment of inflammatory bowel disease, the animals were
then treated with glabridin at doses 10 and 50 mg/kg body weight per day for
seven days. Treatment with glabridin significantly attenuated mortality, loss
of body weight and severity of clinical symptoms. Glabridin reduced the
inflammation of the colon, improved the architecture and histology of the
colon. Glabridin reduced the production of inflammatory mediators such as
nitric oxide (NO), prostaglandin (PG) E2 and inflammatory cytokines. Thus
glabridin may be useful for the treatment of inflammatory bowel disease. [63]
Actions on the
liver
Hepatoprotective
Flavonoids
of yashtimadhu-licorice (Glycyrrhiza
glabra) are reported to display hepatoprotective activity against CCl4 (Carbon
tetrachloride) and acetaminophen. Glabridin is one such flavonoid. [64]
Viral hepatitis
For
actions of glabridin on viral hepatitis see above.
Anti-hepatic
tumor activity
A
study showed that glabridin inhibited the proliferation of human hepatoma
cells. Huh7 is a type of human liver cell that may be grown in the laboratory
for research purposes. Depending upon dose glabridin induced apoptosis in
Huh7 cells. Furthermore, autophagy was detected as early as 12 hours after
exposure to low dose of glabridin. [65]
In
an experimental study glabridin significantly inhibited the migration/invasion
capacities of hepatocellular carcinoma (HCC) cells. Furthermore administration
of glabridin also effectively suppressed the tumor formation in the hepatoma
xenograft model in vivo. Thus glabridin may have potential as a
chemopreventive agent against hepatocellular carcinoma and liver cancer
metastasis. [66]
Actions on
Pancreas
The
ileum and pancreas display numerous morphological and functional changes in
streptozotocin (STZ)-induced diabetes. A study on male albino rats showed that
the treatment with glabridin significantly reduced the morphological and
histological changes in the ileum and β cells of the pancreas. [67]
Actions on
metabolism
A
supercritical fluid (SCF) is any substance at a temperature and pressure above
its critical point, where distinct liquid and gas phases do not exist.
Supercritical fluids are suitable as a substitute for organic solvents in a
range of industrial and laboratory processes. Carbon dioxide and water are the
most commonly used supercritical fluids. [68]
To
evaluate the anti-obesity effect of glabridin, mice were fed with high fat diet
and glabridin-rich supercritical fluid extract of licorice. Glabridin showed
inhibitory effect on adepogenesis in a dose-dependent manner. This effect
resulted from binding protein alpha and peroxisome proliferator-activated
receptor gamma. These studies suggest that glabridin and glabridin-rich
licorice extract would be effective anti-obesity agent. [69]
Cytochrome
P450 is the major drug metabolizing enzyme in humans. Glabridin inactivates the
activities of cytochrome P450 by various mechanisms [70]
A
study was carried out on several rodents to evaluate the effect of glabridin on
obesity. The results showed that glabridin decreased the weight of rodents and
adiposity with concomitant reduction in the size of fat cells, ameliorated
fatty liver and decreased the levels of cholesterol and triglyceride in blood.
Glabridin suppressed the expression of lipogenic genes such as sterol
regulatory binding transcription factor (SREBP)-1, fatty acid synthase (FAS),
acetyl-Co-A carboxylase (ACC), stearoyl-Co A desaturase (SCD)-1 in white adipose
tissue and liver. Glabridin also elevated the expression of fatty acid
oxidation genes such as carnitine
palmitoyl transferase (CPT) 1, aceyl-CoA oxidase (ACO) and peroxisome
proliferator- activated receptor (PPAR)-α in muscle. Moreover, glabridin enhanced
phosphorylation of activated protein kinase (5'-AMP) or adenosine
monophosphate-activated protein kinase (5' AMPK) in muscle and liver and
promoted fatty acid xidation by modulating mitochondrial activity. This
suggests that glabridin can be a novel molecule useful for the treatment of
obesity. [71]
Actions in
diabetes
In
diabetic females, hyperglycemia abolishes cardiovascular and vascular
protection offered by estrogen, leading to oxidative stress and inflammation.
Administration of glabdrin abolished the oxidative stress induced by
hyperglycemia, protected the cardiovascular and vascular system in diabetics
under hyperglycemic state. This suggests that glabridin serves as an
anti-inflammatory agent in diabetes related vascular dysfunction. [72]
In
diabetic women the risk of death from cardiovascular disease is high. This is
due to exacerbated oxidative stress. Even under high glucose stress
the phytoestrogen glabridin displays antioxidant activity. It
up-regulates the expression of manganese superoxide dismutase and prevents
atherosclerosis in diabetic women. [73]
Cognitive
impairment occurs in diabetes mellitus. Glabridin at 5, 25 and 50 mg/kg body
weight given orally (P.O.) to streptozotocin-induced diabetic rats, partially
improved cognitive function. The dose of 5 mg/kg body weight did not improve
cognitive function but higher doses i. e. 25 and 50 mg/kg body weight did. The
combination of antioxidant, antidiabetic, neuroprotective and
anticholinesterase properties of glabridin may be responsible for these
effects. [74]
High
glucose concentration in blood leads to glycosylation of amino groups of lysine
residue in proteins. The glycosylation of proteins is an oxidation process.
Addition of reducing agent not only prevents this process but also reverses it.
The flavonoids found in plants show antioxidant properties. The plant
flavonoids have long been used to prevent glycosylation.
The flavonoid glabridin is a potent antioxidant. There is no much
work on the use of glabridin for the prevention of glycosylation. In my opinion
research should be carried out on the use of glabridin to prevent
glycosylation.
Actions on
Urinary System
Oral
administration of glabridin at 30 mg/kg body weight per day for 10 days to mice
suffering from glomerular nephritis significantly lowered ESR, reduced urinary
excretion of protein and restored levels of serum creatinine and cholesterol to
near normal. The anti-nephritic activity of glabridin was attributed to
anti-inflammatory, antioxidant, radical scavenging and immunomodulatory
properties of glabridin. [75]
Actions on male
reproductive system
Estrogen-like
actions of glabridin are antagonistic to androgen. Glabrin may reduce male
fertility. Glabridin can also be useful for the treatment of cancer of the
prostate.
Actions of
glabridin on female reproductive system
A
study showed that glabridin was able to reduce the estrogenic response of E(2)
by approximately 80 percent. Glabridin displayed ERα-selective antagonism,
similar to the ERα-selective antagonist RU 58668. [76], [77]
Polycystic
ovarian syndrome is characterized by anovulation, hyperandrogenism,
hyperinsulinemia and insulin resistance. Young women with polycystic
ovarian syndrome suffer from adverse coronary artery disease. A study on 32 women
with polycystic ovarian syndrome treated with glabridin 10 μM
daily for 12 months revealed a significant reduction in serum testosterone,
fasting insulin and glucose. They displayed a significant reduction in insulin resistance
and hirsutism. All women reverted to regular menstrual cycles. [78]
Ishikawa
cell line is human endometrial adenocarcinoma cell line developed for cancer
research. A study showed that the combination of 1 x 10 (-5) M tamoxifen and 1
x 10 (-6) M glabridin exhibited
estrogenic activity and suppressed cell growth in Ishikawa cell line. This
suggests that the combination therapy has potential to be used as estrogen
Antitumor
activity
Peroxisome
proliferator-activated receptor-γ (PPAR-γ or PPAR) is a type II nuclear
receptor that in humans is encoded by the PPARG gene. PPARG is
mainly present in adipose tissue, colon and
macrophages. PPARG regulate glucose metabolism and fatty acid storage.
Glabridin was shown to bind and activate PPAR-γ which inhibits the growth
of cultured human breast, gastric, hepatic, lung, prostate and other cancer
cells. [81], [82]
Glabridin
is a chemoprotective agent. It protects against neurotoxic side effects caused
by doxorubicin. This protection is attributed to antioxidant activity of
glabridin. [83]
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