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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