Aardraka (Ginger)-Shunthee (Zingiber officinale) Part 2
Aardraka
(Ginger)-Shunthee (Zingiber officinale)
Part 2
Gingerol is a pungent
pharmacologically active phytochemical found in Ginger (Zingiber officinale)
Gingerol
Molecular
formula: C17H26O4
Structural
formula:
Gingerol, properly as [6]-gingerol,
chemically a relative of capsaicin and piperine is found in fresh Ginger (Zingiber officinale), black pepper (Piper nigrum) and chilli peppers (Capsicum annuum). Normally it is found
as pungent yellow oil but also can form low-melting crystalline solid.
Cooking transforms it
into zingerone which is less pungent and has a spicy-sweet aroma. When Ginger (Zingiber officinale) is dried (Shunthee)
gingerol undergoes dehydration reaction forming shogaol which is twice as
pungent as gingerol. [37]
Pharmacology
of Gingerol
Pharmacokinetics of Gingerol
A study on human volunteers showed that after oral
administration of a single dose from 100 mg to 1.0 gram of 6-, 8- and 10-
gingerol, 6-gingerol sulfate conjugate was detected above the dose of 1.0 but
the other two were not detectable.
In another study by the same researcher, Ginger (Zingiber officinale) was admistered
orally to human volunteers at doses of 100 mg to 2 grams. Free [6]-gingerol,
[8]-gingerol, [10]-gingerol or [6]-shogaol were not detectable in them but
their glucuronides were detected. [38]
Pharmacokinetic analysis of ginger (Zingiber officinale) showed that
half-lives of [6], [8], [10]-gingerols and [6]-shogaols and their metabolites
were 1-3 hours in human-plasma. No accumulation was observed both in colon even
after after multiple daily dosing. [39]
Various studies on rats showed that after oral
administration, 6-gingerol was excreted in bile and underwent metabolic
changes. During 60 hours its metabolic products were slowly excreted in urine.
These findings suggest that the gut flora and the liver enzymes play an
important role in the metabolism of 6-gingerol. [40]
Heatstroke can induce endotoxemia in mice. Gingerol
was used to treat heatstroke-induced enodtoxemia. The study showed that gingerol
enhanced the phagocytic ability, increased the activity of superoxide dismutase
(SOD) and reduced the production of malondialdehyde (MDA) so as to alleviate
the liver damage. [41]
A study showed that on heating the pulp and peal of
Ginger (Zingiber officinale)
[6]-gingerol was converted into [6]-shogaol. The highest yields of [6]-gingerol
and [6]-shogaol were obtained by heating ginger plup at 1300 C and
1900 C for 15 minutes. [6]-shogaol content increased with increasing
temperature and time of extraction. The antioxidant activity of [6]-shogaol
increased on increasing the content of [6]-shogaol. [42]
Another study on extraction showed that moist heat
treatment induced higher quantity of shogaols. The moist heat treatment at 1200
C for 6 hours induced the highest quantity of conversion of [6]-gingerol to
[6]-shogaol, reaching to 2991 mg of [6]-shogaol per kg Ginger (Zingiber officinale). Furthermore
dry-heat treatment on Shunthee (dried
powder of Ginger) induced significantly higher quantity of shogaols than that
on sliced fresh Ginger. [43]
Anti-inflammatory activity of Gingerol
In a study on animal
models; [6], [8], [10]-gingerol and [6]-shogaol exhibited substantial free
radical scavenging and anti-inflammatory activities. Of the three gingerols, [10]-gingerol
was found to be the most potent antioxidant and anti-inflammatory agent. [6]-Shogaol
was found to be most potent antioxidant and anti-inflammatory agent. These
properties of [6]-shogaol were attributed to the presence of α, β-unsaturated
ketone moiety. [44]
Nitric oxide synthase
(iNOS) is a pro-inflammatory enzyme. It has been implicated in the pathogenesis
of various inflammatory diseases. Gingerols exhibit anti-inflammatory
properties in vitro by partially
inhibiting iNOS enzymatic activity and reducing iNOS protein production via
attenuation of NF κB-mediated iNOS gene expression. [45]
By inhibiting
cyclooxigenase-2 (COX-2) expression, [6]-gingerol displays its
anti-inflammatory activity. [46]
On heating Ginger (Zingiber officinale) [6]-gingerol is
converted into [6]-shogaol. In rats [6]-shogaol inhibited carrageenin-induced inflammatory
edema of the paw and prevented prostaglandin I2 (PGI 2) release from aorta. In
rabbits [6]-shogaol inhibited arachidonic acid (AA)-induced platelet
aggregation. These results suggest that [6]-shogaol may have inhibitory action
on the cyclo-oxygenase. [47]
Antioxidant
activity of Gingerol
A study reveals that
the antioxidant activity of [6]-gingerol depends on the structure of side
chain, the reaction of medium and substance with which it reacts. Additionally,
extension of the length of the chain from six to twelve carbons enhances their
anti-hemolysis activity. [48]
The antioxidants found
in Ginger (Zingiber offocinale) are
divided into two groups; gingerol related compounds and diarylheptanoids.
Researchers feel that the antioxidant activity of these compounds might be due
to not only radical scavenging activity but also their affinity to substrates. [49]
Exposure to ultra
violet B (UVB) radiation increases intracellular production of reactive oxygen
species (ROS) and expression of cyclooxigenase-2 (COX-2) in vitro and in vivo. In vitro, pre-treatment with
[6]-gingerol reduces ultra violet B (UVB)-induced intracellular reactive oxygen
species (ROS) levels and inhibits activation of cyclooxigenase-2 (COX-2). By
this mechanism [6]-gingerol provides protection against ultra violet B
(UVB)-induced skin disorders. [50]
β- Amyloid is involved
in the formation of senile plaques, the typical neuropathological marker for
Alzheimer’s disease. β- Amyloid causes apoptosis in neurons via oxidative
stress. Pretreatment with [6]-gingerol prevents this apoptotic cell death. Thus
[6]-gingerol is useful in prevention of Alzheimer’s disease. This activity is
attributed to antioxidant property of [6]-gingerol. [51]
A study was carried out
to evaluate the effects of [6]-gingerol on free radicals. The study showed that
254 μM/ml of [6]-gingerol significantly inhibited lipid peroxidation of red
blood cell (RBC)-membrane by 85.28% and DNA sugar oxidation by 91.26%. The
chelating ability of [6]-gingerol was 80.2% which was similar to that of EDTA.
In addition 254 μM/ml of [6]-gingerol significantly scavenged the superoxide
hydroxyl free-radicals, DPPH (2, 2-diphenyl-1-picrylhydrazyl, a dark-colored
crystalline powder composed of stable free-radical molecules) which was
supported by Electron Spin Resonance (ESR) studies. Further, 254μM/ml of
[6]-gingerol inhibited the DNA fragmentation and Cytochrome-c oxidation. The
studies reveal that [6]-gingerol could prevent and scavenge free-radicals. [52]
Immunomodulatory
activity of Gingerol
In mice at doses of 50
and 100 mg/kg body weight [8]-gingerol shows immunosuppressive activity on
immune responses to ovalbumin (OVA). [8]-gingerol suppresses humoral and
cellular responses in mice. The mechanism might be related to direct inhibition
of sensitized T and B lymphocytes. [53]
Antibacterial activity of Gingerol
Acinetobacter baumannii is a
Gram-negative bacterium. It is an opportunistic pathogen in humans. It affects
people with compromised immune system. It is becoming serious nosocomial
infection worldwide. Furthermore Acinetobacter
baumannii is resistant to many antibiotics used today. This is worrisome.
The phytochemicals, [6]-gingerol, [10]-gingerol, [6]-dehydrogingerdione and
[6]-shogaol found in Ginger (Zingiber officinale); exhibit antibacterial
activity against Acinetobacter baumannii.
Moreover when combined with tetracycline, they modify the resistance of Acinetobacter baumannii to tetracycline.
This result is attributed to the antioxidant effect of these compounds. The
antioxidant property of these compounds also shows some antibacterial activity Acinetobacter baumannii. [54]
Antiviral activity of Gingerol
A study showed that hot
water extract of fresh Ginger (Zingiber
officinale) containing [6]-gingerol and [6]-shogaol, at a dose of 300 μM/ml
showed antiviral activity against Human orthopneumovirus, formerly known as
Human respiratory syncytial virus (HRSV). The study also revealed that the
dried Ginger i. e. Shunthee (Zingiber
officinale) was not as effective as fresh Ginger. [55]
The lyophilized juice
extract of Ginger (Zingiber officinale)
containing [6]-gingerol and [6]-shogaol, at 100 μg / ml was found to inhibit
hepatocellular carcinoma HepG2 cell line infected with Hepatitis C virus (HCV).
These bioactive compounds inhibited the replication of viral RNA. This study
will help us to formulate an alternative cheap, natural anti-Hepatitis C drug.
[56]
Antifungal activity Gingerol
A study on
inhibitory effect of [6]-gingerol, [8]-gingerol and [6]-shogaol on anti-fungal
activity against Candida albicans showed
that [6]-gingerol, and [6]-shogaol inhibited hyphal growth of the fungus. [57]
Antiparasitic activity of Gingerol
At
1g/kg/day dose [6]-gingerol, [6]-shogaol, [10]-gingerol and [10]-shogaol showed
cestocidal activity against Heyminolepis
nana (Dwarf Tapeworm) infestationin 24-72 hours. [58]
Angiostrongylus
cantonensis is a variety of round worm that usually
infests rats. The worm is also known as rat lung-worm. In humans the
infestation of Angiostrongylus
cantonensis can cause severe gastrointestinal or central nervous system
disease. [6]-gingerol and [6]-shogaol show larvicidal activity against this
parasite. [59]
Brugia malayi
thymidylate kinase (BmTMK) plays an important role for the synthesis of DNA in
parasites. [6]-gingerol and [6]-shogaol significantly inhibit this enzyme and
prevent the development of parasites. [60]
Anisakis
is a genus of parasitic nematodes having lifecycles involving fish and marine
mammals. They are infective to humans. People who consume raw or undercooked
seafood containing larvae of the nematode Anisakis
simplex develop infection of the gastrointestinal tract. People who produce
immunoglobulin E in response to this parasite may subsequently have allergic
reaction including anaphylaxis after eating seafood infected with Anisakis species. [61]
A study
showed that [6]-gingerol and [6]-shogaol at doses of 62.5 and 250 μg/ml
could kill Anisakis larvae. Pyrantel
pamoate, an available antinematodal drug, had no lethal effect on Anisakis, even at a concentration of
1mg/ml. [62]
Antiallergic
activity
To evaluate
antiallergic effects of [6]-gingerol and [6]-shogaol, rats were sensitized with
mouse monoclonal IgE. [6]-gingerol and [6]-shogaol were found to show
antiallergic activity. [63]
Actions of Gingerol on the skin
Ultraviolet (UV)
irradiation induces inflammation in the skin. Gingerol and shogaol protect the
skin from UVB-induced hyperplasia, infiltration of leukocytes and dilatation of
blood vessels in dermis of mice. [64]
An in vitro and in vivo study revealed that [6]-gingerol does not promote hair
growth. On the contrary it suppresses human hair growth. Therefore [6]-gingerol
may be useful for hair removal. [65]
With increasing demand
for skin-whitening agents, intensive search is on for chemicals suppressing
melanogenesis. The results of a study revealed that [6]-gingerol at doses of
25-100 μM effectively suppressed murine tyrosinase activity. This activity is
dose-dependent. This shows that [6]-gingerol is a good skin-whitening agent.
[66]
Topical
treatment of mice with [6]-gingerol delayed the onset of tumerogenesis, reduced
cumulative number of tumors and reduced tumor volume. Further, treatment with
[6]-gingerol resulted in release of cytochrome c, caspases activation, increase
in apoptotic protease-activating factor-1 (Apaf-1) as mechanism of apoptosis
induction. [67]
Via generation of
reactive oxygen species (ROS), 6-gingerol induces apoptosis in epidermoid carcinoma
A431 cells. [68]
Actions of gingerol on Mouth
Gingerol
and related components isolated from ethanol and n-hexane extracts of Ginger (Zingiber officinale) exhibited
antibacterial activities against Gram- negative anaerobic bacteria, Porphyromonas gingivalis ATCC 53978, Porphyromonas endodontalis ATCC 35406
and Prevotella intermedia ATCC 25611 causing periodontal diseases. [69]
Actions of Gingerol on Breast
A study revealed that [10]-gingerol inhibited
metastasis of triple negative breast cancers to lungs, bone and brain. The
study suggests that [10]-gingerol may be used as a complimentary agent with
standard chemotherapeutic agents. [70], [71]
MCF-7 is a breast cancer cell line isolated in 1970
from a 69-year-old Caucasian woman. MCF-7 is the acronym of Michigan Cancer
Foundation-7, referring to the institute in Detroit where the cell line was
established in 1973 by Herbert Soule and co-workers. [72]
To evaluate actions of
[6]-gingerol on breast cancer, the MDA-MB-231 human breast cancer cells were cultured
in presence of 0, 2.5, 5 and 10 μ M concentrations of [6]-gingerol. Upto the
concentration of 5 μ M [6]-gingerol had had no effect on the cancer cells but
at the concentration of 10 μ M the growth of cancer cells reduced by 16%. With
increasing concentrations of [6]-gingerol there was decrease in growth,
motility and migration of human breast cancer cells. [73]
For the chemotherapy of human breast cancer the
combination of cyclophosphamide (CPA), doxorubicin (Dox) and 5-fluorouracil
(5-FU) [CDF] is often used. Recent study revealed that 6-gingerol showed
highest anticancer potency that was superior to that of [CDF]. The synthetic
drvatives of [6]-gingerol were also found to be effective in the treatment of
breast cancer. [74]
Actions of Gingerol on Hematopoietic system
Gingerol caused DNA
fragmentation and inhibited Bcl-2 expression to induce cell death in
promyelocytic leukemic HL-60 cells.
Another study revealed
that [6]-gingerol significantly increased levels of reactive oxygen species in
leukemia cells to induce apoptosis [75], [76]
[10]-gingerol was found
to have beneficial action on hematopoietic system in zebrafish and human
embryos. The compound was useful for the treatment of anemia in zebrafish and
humans. [77]
[10]-gingerol promotes
haematopoietic recovery from acute hemolytic anemia in zebrafish. Future
research into the effect of [10]-gingerol during mammalian hematopoiesis may be
useful to develop novel erythropoiesis promoting agent. [78]
Actions of Gingerol on Musculoskeletal system
A study showed that
crude and dichlormethane extracts of Ginger (Zingiber officinale) containing gingerols were effective in
controlling inflammation, swelling and destruction of rheumatoid arthritis and
streptococcal cell wall-induced arthritis in animal models. Furthermore the
gingerols were useful in preventing joint inflammation and destruction. [79]
Actions of Gingerol on Ear, Nose and Throat
In experimental
studies, ovalbumin (OVA) was used to induce allergic rhinitis. The treatment with
[6]-gingerol suppressed allergic rhinitis. Further the study showed that
[6]-gingerol alleviated the symptoms of allergic rhinitis by suppressing the
production of cytokines and proliferation of T cells but not by causing
activation of B cells and mast cells. [80]
[6]-gingerol
plays an important role in inhibiting the extracellular matrix production (ECM)
in the development nasal polyps through the antioxidant effect. [81]
Actions
of Gingerol on Eye
To evaluate efficacy of
Ginger (Zinziber officinale) in
reducing intraocular pressure (IOP), glaucoma was induced in rabbits by using
carbomer. The hydroalcoholic (water-methanolic) extract of Ginger (Zinziber officinale) containing all
phytochemicals was then administered orally at a dose of 200 mg/kg bodyweight
to these glaucomatous rabbits. The study revealed that the treatment with
Ginger (Zinziber officinale) extract
lowered intra ocular pressure (IOP) which was comparable to 2% pilocarpine
eyedrops. [82]
Actions of Gingerol on Nervous System
Gingerols
and Shogaols found in fresh extract of Ginger (Zingiber officinale) at concentration of 20 μM,
inhibit the production of nitric oxide, interleukin-1β (IL-1 β), interleukin-6 (IL-6) and tumor
necrosis factor-α (TNF- α). These compounds also block the activation of
nuclear factor-κB (NF- κB). Thus they act as potent anti-inflammatory agents
and prevent neuro-inflammations. The anti-neuroiflammatory action was largely
owing to [10]-gingerol. [83]
Different compounds of
dried Ginger-Shunthee- (Zingiber
officinale) showed antispasmodic activity.
Among them [6]-gingerol was found to be the most potent. [6]-gingerol displayed
an unique combination of muscarinic, calcium Ca++ antagonist and
specific butyrylcholinesterase (BuChE) inhibitory activities indicating its
benefit in dementia including Alzheimer’s disease. [84]
Intravenous injection
of [6]-gingerol at 1.75 to 3.5 mg/kg bodyweight and oral administration at 70
to 140 mg/kg bodyweight inhibited motor activity, induced antipyretic and
analgesic activities. [6]-gingerol also displayed intense anti-tussive
activity. [85]
Actions
of Gingerol on Respiratory System
Bronchial epithelial
cells secrete pro-inflammatory chemokines in bronchitis. An oily extract of
Ginger (Zingiber officinale)
containing [6]-gingerol and other pungent compounds exert anti-inflammatory
action to alleviate inflammation. This suggests that the pungent phytochemicals
of Ginger (Zingiber officinale) can
be used to treat infections of lower respiratory tract. [86]
More than 40% of
patients suffering from bronchial asthma opt for herbal therapies to manage
symptoms of bronchial asthma. By modulating intracellular calcium [Ca2+]
in airway smooth muscle (ASM); [6]-gingerol, [8]-gingerol and [6]-shogaol
induce bronchial relaxation. This action of these phytochemicals is similar to β2-agonists.
Of these [8]-gingerol attenuates airway hypersensitiveness. [87]
Actions
of Gingerol on Cardio-vascular System
A Chinese study showed
that [6]-gingerol is angiotensin-II type I receptor antagonist. By reducing
blood pressure, [6]-gingerol prevents the cardiovascular disease. [88]
In an experimental
study hydrogen peroxide was used to induce apoptosis in human umbilical vein
endothelial cells (HUVECs). Pretreatment and treatment with [6]-gingerol
significantly reduced apoptosis by inducing autophagy. [6]-gingerol suppressed
the phosphatidylinositol 3-kinase signaling pathway, increased the expression
of Beclin 1 to promote autophagy and increased Bcl-2 expression to inhibit
apoptosis. In addition [6]-gingerol protected mitochondrial damage and
decreased the level of reactive oxygen species. This data suggests that
[6]-gingerol may be beneficial in the prevention of atherosclerosis. [89]
Diabetes mellitus is
associated with endothelial damage related angiopathy. Pretreatment and
treatment of such angiopathy with [6]-gingerol, was useful to prevent and treat
angiopathy resulting from diabetes mellitus. [90]
A study on [6]-gingerol
showed that the compound is a very potent antiplatelet aggregation agent. [91]
Animal studies reveal
that Ginger (Zingiber officinale) and
its phytochemicals exert anti-inflammatory, antioxidant, anti-platelet
aggregation, hypotensive and hypolipidemic actions on cardiovascular system.
Some human trials were less convincing while some supported the conclusions
drawn by animal studies. [92]
Actions of Gingerol on Gastro-Intestinal System
The most common traditional use of Ginger
(Zingiber officinale) worldwide is
its utilization in alleviating nausea and vomiting. Several clinical studies
have validated its antiemetic activity. The antiemetic effect of Ginger (Zingiber officinale) has been attributed
to carminative and prokinetic actions of [6]-gingerol or [6]-shogaol.
Ginger (Zingiber officinale) is used to prevent seasickness. It is found to
be superior to dimenhydrinate (marketed as Dramamine or Gravol). A study showed
that 1 g of Ginger (Zingiber officinale)
is effective in reducing the severity of seasickness in naval cadates on the
high sea. Further it was found that Ginger (Zingiber
officinale) was not useful in treating motion sickness. The exact mechanism
of antiemetic activity of Ginger (Zingiber
officinale) is not clear. However some evidence suggests that it inhibits
serotonin receptors and exerts its antiemetic effects directly on the
gastrointestinal system and in the central nervous system.
In controlling nausea, vomiting of
pregnancy Ginger (Zingiber officinale)
was as effective as dimenhydrinate (marketed as Dramamine or Gravol) but
without any adverse effects. Vitamin B6 is another drug used to treat nausea,
vomiting of pregnancy. Ginger (Zingiber
officinale) was found to be equally effective as vitamin B6 in controlling
episodes of vomiting during pregnancy.
Gingerol has been recommended to reduce
cisplatin-induced emesis. This action of gingerol is possibly by inhibiting the
central or peripheral increase of 5-hydroxytryptamine, dopamine and substance
P. Cisplatin can cause renal dysfunction. However rats that were administered
cisplatin and [6]-gingerol exhibited lower lipid peroxidation and conservation of
GSH coupled with enhanced superoxide dismutase and catalase, which resulted in
restoration of normal renal function. [93]
Gingerols inhibit the growth of CagA+
strain of Helicobacter pylori in vitro. This activity may be useful to prevent
gastric ulcer and gastric carcinoma. [94]
In conditions like nausea and vomiting, cholinergic M
3, serotonergic 5-HT 3 and 5-HT 4 receptors are involved. In a study on the
whole segment of guinea pig-ileum, at the concentration of 10 μM, [6]-gingerol
and [6]-shogaol, active phytochemicals of Ginger (Zingiber officinale), significantly depressed the maximal carbachol
response. From these findings it is concluded that anti-nausea and
anti-vomiting activity of Ginger (Zingiber
officinale) may be based on the inhibitory effect of [6]-gingerol and
[6]-shogaol on M 3, 5-HT 3 and 5-HT 4 receptors. [95], [96]
Radiotherapy and
chemotherapy for cancer cause severe nausea and vomiting, which hinder the
therapy and interefere with the patient’s compliance to treatment. The pathway
and mechanisms involved in this are poorly understood. Researchers thought the
vomiting centre in the brain stem co-ordinates with the incoming and outgoing
information. Whether the main role in the vomiting reflex arc is accomplished
by the central part (chemoreceptor trigger zone) or the peripheral part
(gastrointestinal tract) needs further confirmation. However the vagus nerve
and the gastrointestinal tract play an important role is generally accepted.
Now the discovery of serotonergic, 5-HT 3 receptors sheds better light on this.
It is now accepted that serotonergic 5-HT 3 receptors play a key role in
radiotherapy and chemotherapy-induced vomiting. Further, it is found that
inhibiting 5-HT 3 receptors relieve radiotherapy and chemotherapy-induced
vomiting. By inhibiting 5-HT 3 receptors [6]-gingerol and [6]-shogaol relieve
radiotherapy and chemotherapy-induced vomiting. [97]
Administration of the ethanolic extract of ginger
containing [6]-gingerol, at doses of 10, 100 and 300 mg/mL reduced the motility
of small intestine. This activity is due to anti-acetyl choline (ACh) activity
of [6]-gingerol. The result supports the clinical application of ginger for
disorders of gastrointestinal motility. [98]
[6]-gingerol increases the levels of reactive oxygen
species (ROS) in tumor cells, decreases the mitochondrial membrane potential
(MMP) and subsequently induces the apoptosis in human gastric cancer cells.
[99]
By inducing mitotic arrest, [6]-gingerol inhibits the
viability gastric cancer cells. [100]
Recently researchers have developed a specific
population of nano-particles derived from Ginger (Zingiber officinale) known as ginger derived nanoparticles 2 (GDNPs
2). The average particle size was 230nm. The nanoparticles contained high
levels of lipids, a few proteins, 125 micro RNAs (miRNAs) and large amounts of
bioactive phytochemicals of Ginger (Zingiber
officinale), [6]-gingerol and [6]-shogaol. Gginger derived nanoparticles 2
(GDNPs 2) were mainly taken up by intestinal epithelial cells (IES) and
macrophages, and were nontoxic. Furthermore studies on mouse colitis models,
ginger derived nanoparticles 2 (GDNPs 2) reduced acute colitis, enhanced
intestinal repair, prevented the development of chronic colitis and colitis
associated cancer. [101]
In experimental studies, Phorbol
Myristate Acetate (PMA) is used to induce colonic carcinoma. In a study
[6]-gingerol inhibited cell proliferation and induced apoptosis in Phorbol
Myristate Acetate (PMA) colonic cancer. [102]
The anti-GI cancer
activity of [6]-gingerol and [6]-shogaol is attributed to their ability to
modulate molecules like NF- κB, STAT3, MAPK, PI3K, ERK1 and 2, Akt, TNF- α
COX-2, cyclin D1, cdk, MMP-9, surviving, cIAP, XIAP, Bcl-2, caspases and other
cell growth regulatory proteins. [103]
In vitro studies show
that [6]-gingerol suppresses adenocarcinoma of the colon. [6]-gingerol has two
types of antitumor effects: (1) direct suppression of growth of colon cancer
cells and (2) inhibition of the blood supply of the tumor. This suggests that
[6]-gingerol is a potential plant derived anticancer agent that can be used as
an adjuvant with the convential cancer chemotherapy. [104]
Anticancer chemotherapy
agents target leukotriene A(4) hydrolase [LTA(4)H] protein to suppress cancers.
[6]-gingerol suppresses cancer cell growth by inhibiting leukotriene A(4)
hydrolase [LTA(4)H] protein activity in human colon cancer cell line (HCT116).
By inhibiting leukotriene A(4) hydrolase [LTA(4)H] protein activity
[6]-gingerol can also prevent the development of colorectal cancer. [105]
Recently researchers
created nanoparticles from Ginger (Zingiber
officinale) and reassembled their lipids in ginger-derived nanovectors
(GDNVs). Ginger-derived nanovectors (GDNVs) were taken up efficiently by
colon-cancer cells. Ginger-derived nanolipids loaded with doxorubicin can be a
novel drug-delivery approach for colon cancer therapy. [106]
Actions of Gingerol on Liver
The acetone extract of Ginger (Zingiber officinale)
containing [6]-gingerol and [10]-gingerol increased bile secretion in rats.
[107]
[6]-Gingerol and [6]-shogaol effectively
inhibit invasion and metastasis of hepatocellular carcinoma through diverse
molecular mechanisms. [108]
Patulin (PAT) is a mycotoxin produced by several Penicillium, Aspergillus and Byssochlamys
species. Patulin (PAT) causes increase in intracellular reactive oxygen species
(ROS) and reduction of the level of glutathione (GSH). Patulin (PAT) also
causes oxidative DNA damage. [6]-gingerol has a strong protective ability
against genotoxicity caused by Patulin (PAT) in HepG2 cells. [6]-gingerol
effectively suppresses Patulin (PAT)-induced intracellular reactive oxygen
species (ROS) formation, reduces DNA strand breaks and micronuclei formation
caused by Patulin (PAT). These activities of [6]-gingerol are due to its
antioxidant property. [109]
Actions of Gingerol on Pancreas
Researchers found that [6]-gingerol inhibited human
pancreatic cancer cell line (HPAC) wild type and mutant p-53 pancreatic cancer
cells through cell cycle arrest at G1 phase. [110]
In another study, the ethanol extract of Ginger (Zingiber officinale) containing
[6]-gingerol induced death of human pancreatic cancercell lines including
Panc-1 cells. It is said that the ethanol-extracted materials of Ginger (Zingiber officinale) suppressed the cell
cycle progression to induce the death of human pancreatic cancer cells. [111]
Actions of Gingerol on Metabolism
After a single intraperitoneal injection of 25mg/kg
bodyweight of [6]-gingerol induced a rapid and marked drop in resting body
temperature in rats. The results of this study suggest that in rats, the
decrease in metabolic rate is responsible for the [6]-gingerol-induced hypothermia,
and (b) [6]-gingerol modulates the mechanisms underlying body temperature
regulation, while other bioactive constituents of Ginger (Zingiber officinale) may counteract the hypothermic effect of
[6]-gingerol. [112]
Actions of Gingerol against Diabetes
Gingerol isolated from Shunthee, freeze
dried ginger powder (Zingiber officinale);
enhances glucose uptake by increasing cell surface GLUT4 in cultured L6
myotubes. [113]
To evaluate
antidiabetic activity of [6]-gingerol, diabetes was induced in rats by
administering 60 mg of streptozotocin (STZ). The diabetic rats were treated by
oral administration of 25 and 50 mg/kg body weight of [6]-gingerol once a day
for 42 days. Blood glucose levels were measured on 1st, 21st
and 42nd day. The results showed that [6]-gingerol had significant
hypoglycemic activity which was comparable to 0.05/kg body weight of
glibenclamide. [114]
Glucose
transporter type 4 (GLUT-4) is a protein encoded in humans by the solute
carrier family 2, member 4 (SLC2A4) gene. Glucose transporter type 4 (GLUT-4)
is the insulin-regulated glucose transporter found primarily in adipose
tissues, skeletal and cardiac muscles. Diseases associated with solute carrier
family 2, member 4 (SLC2A4) include diabetes mellitus. Ethyl acetate extract
(EAG) of Ginger (Zingiber officinale)
containing gingerol and shogaol enhance glucose uptake in cell lines in L6
mouse myoblasts and myotubes. Ethyl acetate extract was effective at a
concentration of 5μg/mL. Furthermore antibody based
studies in treated cells revealed that ethyl
acetate extract (EAG) of Ginger (Zingiber
officinale) was effective in expressing glucose transporter type 4 (GLUT-4)
protein in the surface of cell membrane. [115]
By preventing the protein glycation
in diabetics, [6]-Gingerol and [6]-shogaol prevent many complications
associated with protein glycation. This activity was attributed to trapping of
methylglyoxal that alleviate protein glycation. [116], [117]
Actions of Gingerol on Urinary System
Acute kidney injury (AKI) and metabolic
dysfunction are critical complications in sepsis. A study showed that
[6]-gingerol and [10]-gingerol modulated acute kidney injury (AKI) in a rat
model of sepsis. Intraperitoneal injection of 25 mg/kg bodyweight of
[6]-gingerol improved the creatinine clearance and renal antioxidant activity.
Researchers feel gingerols attenuated acute kidney injury (AKI) by decreasing
renal disturbances, oxidative stress, and inflammatory response through a
mechanism possibly correlated with increased production of dimethylamine and
methylsulfonylmethane. [118]
Actions of Gingerol on Male Reproductive System
Phytochemicals
[6]-gingerol, [10]-gingerol, [6]-shogaol and [10]-shogaol found in ginger
(Zingiber officinale) inhibit cell growth and modulate docetaxel resistant
prostate cancer cells. [119]
LNCaP
cells are androgen-sensitive human prostate-adenocarcinoma cells derived from
the left supraclavicular lymph node metastasis from a 50-year-old Caucasian
male in 1977. LNCaP sublines have been generated to provide the most clinically
relevant tissue culture tools to date. Treatment with [6]-gingerol resulted in
apoptosis in testosterone-induced LNCaP cells. [6]-gingerol is also effective
in preventing prostate cancer in Swiss albino mice. [120], [121]
Actions of Gingerol on Female Reproductive
System
Cumulus cells are a group of closely associated
granulose cells that surround and nourish oocytes. Cumulus cells contribute to
oocyte maturation and fertilization. Gingerols induce apoptosis in cumulus
cells. This suggests that gingerols may be used as female contraceptive agents.
[122]
Gingerols and shogaols inhibit growth and modulate
secretion of angiogenic factors in ovarian cancers. These compounds may have
potential in the treatment and prevention of ovarian cancers. [123]
HeLa (also Hela or hela) is an immortal cell line used
in scientific research on cancer. The cell line was derived from cervical
cancer cells taken taken on February 8, 1951 from Henrietta Lacs, the patient
who died of cervical cancer on October 4, 1951. Gingerol altered the cell
morphology, increased cytotoxicity, induced changes in mitochondria-dependent
pathway and arrested cell growth of HeLa cancer cells. [124]
Although [6]-gingerol
and [6]-shogaol were found to inhibit endometrial carcinoma they had very weak
activity in this regard. However terpenoids present in steam distilled ginger
extract (SDGE) were found to be potent inhibitors of proliferation of
endometrial carcinoma cells. Steam distilled ginger extract (SDGE) at a dose of
1.25 μg/mL inhibited proliferation of the cancer cell lines Ishikawa and
endometrial cancer cells-1 (ECC-1). Decreased proliferation of Ishikawa and
endometrial cancer cells-1 (ECC-1) was a direct result of steam distilled
ginger extract (SDGE)-induced apoptosis. Steam distilled ginger extract (SDGE)
also enhanced the anti-proliferative effect of radiation and cicplatin. The
terpenoids from steam distilled ginger extract (SDGE) mediate apoptosis by
activating p53. [125]
Anti-tumor activity of
Gingerol
Several studies by now reveal that
[6]-gingerol plays an important role in prevention of various cancers,
treatment of some cancers and in arrest of the process of cancer metastasis.
[126]
Anti-inflammatory, antioxidant, antiproliferative,
antitumor and anti-invasive properties of [6]-gingerol are instrumental in
cancer prevention, in protection from cancer and in cancer therapeutics. [127]
The
content of [6]-gingerol is very low in fresh ginger (Zingiber officinale), but significantly higher after steaming and
in dried rhizome, shunthee. Shunthee, the dried ginger (Zingiber officinale) is better suited for prevention of cancers. [128]
[6]-Gingerol
is one of the pleiotropic phytochemical
of Ginger (Zingiber officinale) but
it is not freely soluble in water. Hence [6]-Gingerol falls short of many
desired and important pharmacological activities. However on heating Ginger (Zingiber officinale) for water extract
(quaath or kaadhaa) [6]-Gingerol is converted into [6]-shogaol. Therefore
Ginger (Zingiber officinale) quaath
has a better pharmacological activity. To overcome these limitations,
researchers prepared [6] gingerol proliposomes through modified thin-film
dispersion method. This modification increases bioavailability of [6] gingerol
5-fold. Its antitumor effect was enhanced by this new formulation. [129]
A study
on metabolism of [6]-gingerol showed that [6]-gingerol is mstabolized in H-1299
human lung cancer cells, CL-13 mouse lung cancer cells, HCT-116 in human colon
cancer cells and HT-29 mice colon cancer cells. The two major metabolites in
H-1299 cells were purified and identified as (3-R, 5S)-6-gingerdiol (M1) and
(3S, 5S)-6-gingerdiol (M2). Both metabolites induced cytotoxicity in cancer
cells after 24 hours, with M1 having comparable effect to [6]-gingerol in H1299
cells. [130]
In
vitro and in vivo, [6]-gingerol inhibited vascular endothelial growth factor
(VEGF) and basic fibroblast growth factor (bFGF)-induced proliferation of human
endothelial cells and caused cell cycle arrest in G1 phase. [6]-gingerol
strongly inhibited neo-angio-genesis in the muuse retina. Intraperitoneal
injection of [6]-gingerol reduced the number of lung metastasis. This suggests
that [6]-gingerol may be useful in arresing tumor growth dependent on
angiogenesis and other angio-genesis dependent diseases. [131]
Pharmacologically
active chemicals of ginger (Zingiber
officinale) are effective in ameliorating side effects of γ-radiation and
of cisplatin and doxorubicin. They are effective in chemosensitizing certain
neoplastic cells in vitro and in vivo. [132]
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