Aardraka (Ginger)-(Zingiber officinale) Part 3

Aardraka (Ginger)-(Zingiber officinale) Part 3

Aardraka (Zingiber officinale) contains many bioactive phytochemicals. Here I describe in detail the pharmacology of Shogaol.

Shogaol
Molecular formula: C17H24O3
Structural formula:




Shogaols are pungent constituents of Ginger (Zingiber officinale). The chemical structure of [6]-shogaol is similar to that of [6]-gingerol. On heating or drying Ginger (Zingiber officinale), [6]-gingerol is converted into [6]-shogaol. Applying heat over time or cooking Ginger (Zingiber officinale), shogaols and gingerols are converted into other compounds which is why Ginger (Zingiber officinale) loses its spiciness and pungent taste.

The name shogaol is derived from the Japanese name Shoga for Ginger (Zingiber officinale).

In 1912, Wilbur Scoville created Scoville Scale for the measurement of pungency (spiciness or “heat”) of chilies, peppers and other spicy foods. The Scoville Scale measures the amount capsaicin using Scoville Heat Units (SHU) based on the concentration of capsinoids, among which capsaicin is the predominant component. The pungency or spiciness of shogaol is rated 160, 000 SHU on the Scoville Scale. When compared to other pungent compounds, shogaol is moderately or a shade more pungent than piperine, but less pungent than capsaicin.     

[4]-Shogaol, [6]-shogaol, [8]-shogaol, [10]-shogaol and [12]-shogaol all found in ginger (Zingiber officinale) together constitute the group, ‘shogaols’. A plant variety that has been produced by selective breeding is known as ‘cultivar’. There also exist in Ginger (Zingiber officinale) cultivars methylated shogaols: methylated [6]-shogaol and methyl [8]-shogaol respectively. The ratio of shogaols to gingerols is an indication of the quality of the product.

The process of shogaol synthesis begins with condensation of vanillin and acetone producing dehydrozingerone. With further processing, the synthetic shogaol is obtained.  [133]

Pharmacology of Shogaol

Shogaol is another pleiotropic pharmacological agent found in Ginger (Zingiber officinale). Its pharmacological actions are very much similar to those of gingerol. Here I touch those points that are a shade different from those of gingerol.

Pharmacokinetics

The enzymatic reduction of shogaol changes it from pungent to non-pungent shogaol. The reduction alters the pharmacological properties of shogaol to some extent. [134]
Shogaol is a bioactive chemical isolated from fresh ginger (Zingiber officinale).  produced in the liver. It is involved in many processes in the body, including tissue building and repair, making chemicals and proteins needed in the body and for immune system. Conjugation with glutathione attenuates the biological activities of shogaol. [135] 

On oral administration [6]-shogaol is mostly metabolized in the body and excreted in the urine as metabolites. [136]

The cysteine-conjugated metabolite of [6]-shogaol, M2 exerts its bioactivity by acting as a carrier of [6]-shogaol (6S) in both cancer cells and in mice. [137] 

Anti-inflammatory activity of Shogaol

To evaluate antioxidant and anti-inflammatory properties of [6]-shogaol, N-formyl-methinoyl-leucyl-phenylalanine (f-MLP) was used to induce reactive oxygen species (ROS) in human polymorphonuclear neutrophils (PMN) and increase oxidative stress; to inhibit lipopolysaccharide induced nitrite and prostaglandin E(2) production in RAW 264.7 cells and subsequently induce inflammation. The use of [6]-shogaol in these situations, exhibited the most potent antioxidant and anti-inflammatory properties which can be attributed to the presence of α and β-unsaturated ketone moiety.
[Note: RAW 267.7 cells are the monocyte/macrophage-like cells originating from Abelson leukemia virus transformed cell line derived from BALB/c mice. They are the most commonly used myeloid cell line for research] [138]

A study showed that after 3 hours of heating Ginger (Zingiber officinale) at 75, 100 and 1250 C, the gingerol content was reduced by 6.8, 12.6 and 42.7% respectively, and shogaol content was increased by 2.95, 4.85 and 9.34 fold. This is because of the fact that, on heating, gingerol is converted into shogaol. Thus by heat treatment, tumor necrosis factor- α, prostaglandin E(2) and nitric oxide-inhibitory capacities of Ginger (Zingiber officinale) could be increased. This showed that anti-inflammatory effect of Ginger (Zingiber officinale) is better on heating it. [139]

Antioxidant activity of Shogaol

Nuclear factor erythroid 2-related factor (Nrf2) is a multifunctional cytoprotective factor. It has antioxidant and anti-inflammatory properties. It is essential for detoxifying proteins. It is also a powerful modulator of longevity of species. Shogaols express antioxidant activity via nuclear factor erythroid 2-related factor (Nrf2). Due to this shogaols are more potent antioxidants than gingerols. [140]   

Immunomodulatory activity of Shogaol

Administration of shogaol to experimental animals, increased total white blood cell count (WBC). Shogaol restored humoral and cellular response in experimental animals. In a dose dependent manner shogaol restored cellular and humoral responses in cyclophosphamide-induced immunosuppressed animals. Thus shogaol exhibits immunomodulatory activity. [141]

A study showed that [6]-shogaol in chloroform extract inhibited the production of nitric oxide (NO) and prostaglandin E2 (PGE2) by activating macrophages. Pretreatment with shogaol at a concentration of 20μg/ml, also reduced mRNA, iNOS, interleukin-12p40 (IL-20p40) and interleukin-23p19 levels in animals under study. Shogaol also inhibited polymorphonuclear neutrophil (PMN) migration through human vascular endothelial cells. [142]

Anti larval activity of Shogaol

[6]-Shogaol and [6]-gingerol destroy Anisakis larvae in vitro. Anisakis is a parasite in fish. The fish infested with Anisakis cause Anisakiasis or herring worm disease in Chinese people who eat raw fish. Raw fish eaten along with Ginger (Zingiber officinale) protect folks from developing Anisakiasis. [143]

Anti-allergic activity of Shogaol

[6]-Shogaol alleviates allergic dermatitis. It inhibits cytokines and suppresses elevated immunoglobulin-E. [144]

Actions of Shoagol on Skin
Shogalos display free radical scavenging activity, antioxidant activity, promoted epidermal keratinocytes and dermal fibroblast cell growth. [145]
[6]-Shogaol inhibits melanogenesis in B16F10 mouse melanoma cells via activating the extracellular-signal-regulated kinase (ERK) pathway. The ERK pathway contributes to the control of a large number of cellular processes such as: regulation of cell proliferation, synaptic plasticity, proliferation of endothelial cells during angiogenesis etc. [146]
Melanin is formed in the melanocytes, located in the inner layer of the skin. It is synthesized from tyrosine by enzyme tyrosinase. Melanin and carotene blend to produce skin colour as well as the colour in hair and eyes. [6]-shogaol suppresses the tyrosinase activity and amount of melanin synthesis. Further [6]-shogaol inhibits α-melanocyte stimulating hormone (α-MSH)-induced melanogenesis through the acceleration of extracellular responsive kinase (ERK) and phosphatidylinositol-3-kinase (PI3K/Akt-)-mediated microphthalmia-associated transcriptional factor (MITF) degradation. [147] 

Actions of Shogaol on Wound healing

In an experimental study on wound healing, [10]-shogaol showed antioxidant and free radical scavenging activity. It promoted epidermal keratinocytes and dermal fibroblast cell growth. It enhanced the platelet derived growth factor-α β (PDGF- α β), enhanced the growth factor production in transforming growth factor-β (TGF-β) and vascular endothelial growth factor (VRGF). Thus [10]-shogaol promotes wound healing. [148] 

Actions of Shogaol on Head, Neck and Face

[6]-Shogaol has many noteworthy effects on head and neck cancer cell lines. In particular the enhancement of radiosensitivity of squamous cell carcinoma is remarkable. However combination of [6]-shogaol with cisplatin showed no synergistic effect. [149]

Oral administration of [6]-shogaol at 10, 20 and 40 mg/kg body weight considerably reversed tumor incidence of Dimethylbenz[a]nthracene (DMBA)-induced buccal cancer in hamsters. This activity was attributed to antioxidant activity of [6]-shogaol as well as modulating apoptotic signals by the compound. [150]

Actions of Shogaol on Breast

[6]-Shogaol can be used to treat breast and colon cancers. The antitumor effects of [6]-shogaol are mediated through activation of peroxisome proliferator activated receptor γ (PPAR γ). [151]

[4]-Shogaol has been shown to exert anti-metastatic activity against adenocarcinoma of the breast. This activity is attributed to anti-inflammatory and antioxidant properties of shogaols. [152]

Actions of Shogaol on Hematopoetic System

Verma et al found Ginger (Zingibar officinale) to decrease platelet aggregation. [8]-Gingerol, [8]-shogaol, [8]-paradol and gingerol analogues exhibited anti-platelet activities. In a small study, Shrivastava found that Ginger (Zingibar officinale) decreased thromboxane levels. However Lumb found that Ginger (Zingibar officinale) had no effect on platelet count, bleeding time or platelet aggregation. Similarly, Bordia et al found that Ginger (Zingibar officinale) had no effect on platelet aggregation, fibrinolytic activity and fibrinogen levels. Janssen at al also showed that oral administration of Ginger (Zingibar officinale) had no effect on platelet and thromboxane B2 production. Certainly more study is necessary on these contradictory results. [153]

Myelodysplastic syndromes (MDS) are heterogenous clonal stem cell disorders characterized by dysplastic hematopoesis, peripheral cytopenia and elevated serum ferritin (SF). In MDS, ineffective erythropoiesis enhances iron absorption through downregulation of hepcidin. In a clinical trial, oral administration of 20 mg of Ginger (Zingiber officinale) extract containing [6]-shogaol once a day    decreased ferritin level in the blood. By upregulating hepcidin and its prohormones, [6]-shogaol decreases ferritin levels, possibly through improvement in liver function. [154]

The HL-60 cell line is a human leukemia cell line that has been used for laboratory research on blood cell formation and physiology. A study showed that treatment with [8]-Shogaol caused a rapid loss of mitochondrial transmembrane potential, stimulation of reactive oxygen species (ROS) production, release of mitochondrial cytochrome c into cytosol and subsequently apoptosis of HL-60 leukemia cells. [155]
  
In another study, three leukemia cell lines and primary leukemia cells were used to investigate the effect of [6]-shogaol on apoptosis of these cells. In many cases Eukaryotic Initiation Factor 2 α (eIF2α)-phosphorylation is a biological response that facilitates cells to cope with stressful environments. Deficiency of glucose is an important form of stress that is associated with an induction of apoptosis. [6]-Shogaol induced apoptosis through a process involving dephosphorylation of eukaryotic initiation factor 2 α (eIF2α). Furthermore, [6]-shogaol markedly inhibited tumor growth and induced apoptosis in U937 xenograft mouse model. [156]  

Actions of Shogaol on Musculoskeletal System

The bioavailability of [6]-shogaol is poor. To improve its bioavailability by improving solubility [6]-shogaol was encapsulated in solid lipid nanoparticles via high-pressure homogenization. The resulting [6]-shogaol displayed better pharmacological activity. This nano form of [6]-shogaol lowered the level of uric acid via inhibiting the activity of xanthine oxidase. The nano-[6]-shogaol also reduced the production of interleukin-1 β (IL-1β) and tumor necrosis factor-α   (TNF-α) in rats with hyperuricemia-arthritis (gouty-arthritis). [157]

In an experimental model [6]-shogaol reduced the inflammation in gouty arthritis as was evident by reduction in paw edema, levels and activities of lysosomal enzymes, lipid peroxidation, antioxidant status and inflammatory mediator tumor necrosis factor-α (TNF-α). This indicates that [6]-shogaol can be used for the treatment of gouty arthritis. [158]

Actions of Shogaol on Nervous System

Administration of shogaol was found to prevent pathological changes in traumatic spinal cord injury and to promote the recovery of motor functions in experimental animals. This suggests that shogaol can be used in humans to treat spinal cord injuries. [159]  

While resting, the microglia cells play a key role in defense of the nervous system. When activated, they can be inimical to neurons and can result in neuro-inflammation and neuro-degeneration. [6]-shogaol inhibits the activation of microglia. This activity is better than that of [6]-gingerol. [6]-Shogaol also displayed anti-neuroinflammatory activity. In vivo, [6]-shogaol showed significant neuro-protective effect in transient global ischemia via the inhibition of microglia. [160]

In another study, anti-neuroinflammatory activity of [6]-shogaol was found to be useful for the treatment of Parkinson’s disease, global ischemia, dementia and memory impairment. [161]

A study in animal model showed that administration of [6]-shogaol at a dose of 5mg/kg body weight could ameliorate autoimmune encephalomyelitis. [162]

Age-related neurological disorders (ANDs) are multifactorial disorders. They are characterized by common neuro-pathological conditions such as oxidative stress, neuro-inflammation and disturbed quality control of proteins in the nervous system. Phytochemicals of Ginger (Zingiber officinale) [6]-shogaol, [6]-gingerol, [6]-paradol and dehydrozingerone effectively ameliorate neurological symptoms of these maladies. Researchers suggest that these phytochemicals have therapeutic potential in age-related neurological disorders (ANDs). [163]   

Deposition of amyloid plaques in the nervous system is the hallmark of Alzheimer’s disease. Anti-inflammatory and antioxidant effects of [6]-shogaol protect the nervous system from deposition of amyloid plaques. Furthermore [6]-shogaol can be useful for the treatment of Alzheimer’s disease. [164]

Phytochemicals of Ginger (Zingiber officinale), [6]-shogaol and [6]-gingerol protect humans from neuroblastoma, β-Amyloid insult and protect normal vascular endothelial cells. [165]

Actions of Shogaol on Cardiovascular System

On intravenous injection at lower doses 1.75 to 3 mg/kg body weight, [6]-shogaol and [6]-gingerol lower elevated blood pressure. [166]

Vascular smooth muscle cell (VSMC) proliferation is involved in the pathogenesis of cardiovascular disease. A study showed that the chloromethane extract of Ginger (Zingiber officinale) containing gingerols and shogaols inhibited vascular smooth muscle cell (VSMC) proliferation. The extract did not interfere with endothelial cell proliferation. [6]-Shogaol inhibited DNA synthesis and arrested vascular smooth muscle cell (VSMC) growth at G0/G1 cell-cycle phase. [167]  

Actions of shogaol on Respiratory System

Suekawa M et al showed [6]-Shogaol exerts antitussive activity.
Huang JY et al showed that [6]-Shogaol inhibited cell proliferation by inducing autophagic cell death. They also described anticancer activity of [6]-Shogaol in human non-small cell lung cancer A549 cells. Huang JY et al feel that [6]-Shogaol may be a promising chemo-preventive agent against human non-small cell lung cancer. [168]

Another study on lung cancer cells showed that shogaols initiate toxicity in cancer cells by early modulation of glutathione (GSH) content in cancer cells. The subsequently generated oxidative stress activates p53 pathway that leads to release of mitochondria-associated apoptotic molecules such as cytochrome C. It was shown that a dose of 30 mg/kg body weight of [6]-shogaol was able to decrease tumor burden without causing toxicity to animals tested. [169]   

Actions of Shogaol on Gastro-Intestinal System

A study showed that 150mg of dried ginger rhizome (Shunthee) contains 2mg of   [6]-shogaol. At a dose of 150mg/kg bodyweight of dried ginger rhizome (Shunthee) containing 2mg of [6]-shogaol increased the blood flow in intestine of rats. This suggests that Shunthee/[6]-shogaol can be useful in the treatment of ischemia-related diseases of intestines. [170]

[6]-Shogaol inhibits the growth and induces apoptosis in COLO 205 human colorectal cancer cells through modulation of mitochondrial functions regulated by reactive oxygen species (ROS), caspase activation and DNA fragmentation. [171]

In another study [6]-shogaol was found to induce autophagic and apoptotic cell death in adenocarcinoma (HT-29) of human colon. The study showed that [6]-shogaol induced cell cycle arrest at G2/M phase. [172]

Cysteine-conjugated shogaols (M2, M2’ and M”) are major metabolites of [6], [8], and [10] shogaols in human and in mice. They induce apoptosis through oxidative stress in colon cancer cells. [173]

Actions of Shogaol on Liver

A study showed that [6]-shogaol induced oxidative stress leading to apoptosis in human HepG2 hepatoma cell line. Furthermore [6]-shogaol was found to be useful in hepatic disorders caused by oxidative stress. [174]

Mahlavu cells are poorly differentiated and p53 mutants of human hepatoma subline. They are refractory to a number of chemotherapeutic agents and radiotherapy. A study showed that [6]-shogaol isolated from rhizome of Ginger (Zingiber officinale) induced apoptotic cell death in Mahlavu cells by increasing oxidative stress. [175]  

[6]-Shogaol induces cell cycle arrest apoptosis in human hepetoma cells through pleiotropic mechanisms. [176]

[6]-Shogaol induces apoptosis in humal hepatocellular carcinoma cells by causing prolonged stress in endoplasmic reticulum. The anticancer effect was much better when [6]-Shogaol was combined with salubrinal. [177]

An extensive study on mouse, rat, dog, monkey and human showed that [6]-shogaol is metabolized in liver cancer cells but the mechanism of anticancer activity is different. This should be considered when planning preclinical trials toward chemoprevention by [6]-shogaol. [178]

Actions of Shogaol on Pancreas

[6]-Shogaol induces Ca2+ signals in β cells of the pancreas and sensitizes them to stimulation by glucose. [179]

Actions of Shogaol on Metabolism

Adiponectin is a protein hormone that modulates a number of metabolic processes including that of glucose and oxidation of fatty acids. Adiponectin is secreted from adipose tissue and placenta in pregnancy. Its blood level is inversely correlated with body mass index. Circulating concentration of adiponectin increases during starvation and caloric restriction. This is because the adipose tissue within the bone marrow which increases during caloric restriction, contributes to elevated circulating adiponectin.

Mice with increased adiponectin show reduced adipocyte differentiation and increased energy expenditure. The hormone plays a role in the suppression of the metabolic derangements that may result in type 2 diabetes, obesity, atherosclerosis, non alcoholic fatty liver disease (NAFLD) and other risk factors for metabolic syndrome.  Adiponectin exerts its weight reduction effect via the brain. This is similar to the action of leptin. The two hormones perform complementary actions and can have synergistic effects. In mice, adiponectin in combination with leptin has been shown to completely reverse insulin resistance. [180]

Via inhibition of tumor necrosis factor-α (TNF-α), [6]-shogaol and [6]-gingerol mediated downregulation of the adiponectin regulation in 3T3-L1 adipocytes. [181]

Anti-adipogenesis activityof [6]-shagaol and [6]-gingerol can stimulate lipolysis and prevent adipogenesis. They can be effective anti-obesity drugs. [182]

Hyperlipidemia is said to be due to oxidative stress and inflammation. In recent years, [6]-shogaol has been found to correct hyperlipidemia and restore lipid profile to normal level. [183]

Phytochemicals of Ginger (Zingiber officinale) such as [6]-shogaol and [6]-gingerol ameliorate obesity and inflammation via regulating micro RNA-21/132 expression and activated protein kinase (AMPK) activation in white adipose tissue. [184]

Phytochemicals of Ginger (Zingiber officinale) such as [6]-shogaol and [6]-gingerol can decrease plasma total cholesterol (TC), total triglycerides (TG) and inhibit liver steatosis by regulating the expression of hepatic genes. [185]

The term metabolic syndrome includes obesity, dyslipidemia, hyperglycemia and insulin resistance. The ethanolic extract of Ginger (Zingiber officinale) at doses of 100, 200 and 400 mg/kg body weight was found to be effective in preventing metabolic syndrome in high-fat diet-fed rats. This effect was attributed to [6]-shogaol and [6]-gingerol. [186]

In studies on rats, gingerols and shogaols of Ginger (Zingiber officinale) increased intracellular calcium concentration. In this regard, the shogaols are more potent than gingerols. Gingerols and shogaols increased adrenaline secretion which influenced energy consumption. [187]

Ginger (Zingiber officinale) is known to warm body. In healthy women with cold-sensitive extremities the warming effect of Ginger (Zingiber officinale) was studied. Six women drank 280mL of 0.07% ginger extract containing bioactive chemicals in a temperature-controlled room with room temperature 210 C. Before intake of Ginger (Zingiber officinale) extract their palm temperatures were recorded. After intake of extract temperatures were recorded every 10 minutes for 60 minutes. The palm temperature increased 20 minutes after intake of Ginger (Zingiber officinale) beverage. Thus beverages containing Ginger (Zingiber officinale) may improve cold sensitivity. [188]  

Actions of Shogaol against Diabetes

In a study, streptozotocin was used to induce diabetes in mice. Intraperitoneal injection of [6]-shogaol at 5 and 10 mg/kg body weight lowered blood sugar. Furthermore [6]-shogaol was found to prevent diabetes related complications in these mice. The researchers feel [6]-shogaol can be used in humans to prevent complications in diabetic patients. [189]    

Through anti-inflammatory, antioxidative, hypoglycemic and antihyperlipidemic activities [6]-shogaol ameliorates diabetic nephropathy. [190]

Actions of Shogaol on Urinary System

[6]-Shogaol has anti-inflammatory and anticancer activity. [6]-Shogaol enhances tumor necrosis factor-related apoptosis to kill cancer cells. [6]-Shogaol induces apoptosis in renal carcinoma Caki cells via reactive oxygen species (ROS)-mediated cytochrome c release. [191]      

Actions of Shogaol on Male Reproductive System

Daily oral feeding of 100mg/kg body weight of Ginger (Zingiber officinale) extract containing [6)-Shogaol and [6]-gingerol inhibited the progression of PC-3 xenografts of prostate cancer by 56%. The effect was attributed to anti-inflammatory, antioxidant and antiproliferative activity of these phytochemicals. [192]

[6]-Shogaol (6-SHO) found in Ginger (Zingiber officinale) is a potent anti-inflammatory, antioxidant and anticancer agent. To investigate anticancer effect of [6]-shogaol; LNCaP, DU 145, and PC3 human and HMVP2 mouse prostate cancer cells were cultured. [6]-Shogaol (6-SHO) effectively induced apoptosis in these cells. Further analysis showed that [6]-Shogaol (6-SHO) reduced interleukin-6 (IL-6)-induced signal transducer and activator of transcription 3 (STAT 3) and inhibited tumor necrosis factor-α (TNF- α)-induced NF- κB activity in these cells. [193]

Docetaxel is an important anticancer chemotherapeutic agent. PC 3 Human prostate cancer cell lines are sensitive to docetaxel but PC3R cell lines are resistant to it. A study showed that [6]-gingerol, [6]-shogaol and [10]-shogaol inhibited the proliferation of PC3R i. e. docetaxel resistant prostate cancer cells through the downregulation of multidrug resistance-associated protein 1 (MRP1) and Glutathione S-transferase Pi (GST π) protein expression.  [194] 

 Actions of Shogaol on Female Reproductive System

Pathogenesis of endometriosis is poorly understood. Inflammatory process is reported to be involved in the pathogenesis of endometriosis. In the animal study model, oral administration of [6]-shogaol at 100 to 150 mg/kg body weight for five weeks arrested/prevented progression of the pathology. Histological analysis reported atrophy of the lesions. [6]-Shogaol also inhibited the lesions in vivo. This effect was due to inhibition of COX-2 and PEG-2 mediated inflammatory process and via regulation of VEGF. [195]

[6]-Shogaol and [6]-gingerol modulate the growth of ovarian cancer cells via angiogenic factor. [196]

A study showed that [6]-shogaol induced apoptosis and arrest of human cervical cancer cells at G2/M phase. [197]

Antitumor Activities of Shogaol

By various mechanisms, carbonyl compounds, [6]-Shogaol and [6]-gingerol of Ginger (Zingiber officinale), induce cell death in cancer cells e.g. extensive cytoplasmic vacuolation, autophagy-apoptosis, DNA fragmentation and proteasomal inhibition etc. [198]

Studies thus far found that [6]-shogaol is extensively metabolized in cancer cells. Recently twelve metabolites of [6]-shogaol have been synthesized. Growth inhibition assay showed that [6]-shogaol and synthetic metabolites of [6]-shogaol were equally effective in arresting the growth of various tumors. [199]   

Anti-inflammatory, antioxidant and antiproliferative properties of [6], [8] and [10]-shogaols are used by research workers to treat various cancers. Shogaols are more potent in this regard than gingerols. [200]

Thiol-conjugated metabolites of shogaol play an important role in cancer prevention. [201]

The researchers have identified more than a dozen metabolites of [6]-shogaol. They remain bioactive in the cells. All the metabolites show anticancer activity and induce apoptosis in various cancer cells. They are selectively lethal to cancer cells. They have very low toxicity in normal cells. [202]

The content of [6]-shogaol is very low in fresh Ginger (Zingiber officinale), but significantly higher after steaming. [6]-Shogaol is a lead compound for the synthesis of new anticancer compounds originating from Ginger (Zingiber officinale) [203]  

Enterohepatic recirculation of bioactive phytochemicals from Ginger (Zingiber officinale) is associated with enhanced tumor growth-inhibitory activity of Ginger (Zingiber officinale)-extract. [204]


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