Focus on ginger

By Vince Giuliano

In past blog entries I have focused on research related to a few important plant-derive phyto-substances including resveratrol(ref)(ref),curcumin (ref)(ref), folic acid, valproic acid, caffeic acid, rosmarinic acid, and some of the the phyto-ingredients in olive oil, walnuts, chocolate, hot peppers, and blueberries. But what about good-old-fashioned ginger? It turns out a lot can be said about it.

When I was a child I loved the pungent taste of candied ginger and I would think to myself “This stuff is so strong and exotic that it has to be a powerful good-for-me medicine.” Little did I know! Although long-known as a folk remedy, there was no scientific research evidence for that proposition back then. Now the National Library of Medicine database www.pubmed.org lists 1,369 research citations relating to ginger. Further, the research focus on ginger as well as other phyto substances appears if anything to be intensifying in recent years. Ginger as will see is an antioxidant, a COX-2 inhibitor of inflammation, an inhibitor of inflammatory cytokines, an inhibitor of NF-kappaB, an activator of Nrf2, a modulator of macrophage functions, a cancer chemo preventative, a possible treatment for diarrhea, Alzheimer’s disease pathology and anxiety, can reverse forms of asthma and can help overcome bacterial resistance to an antibiotic.

Ginger “has been traditionally used in Ayurvedic, Chinese and Tibb-Unani herbal medicines for the treatment of various illnesses that involve inflammation and which are caused by oxidative stress(ref).” “Ginger is the rhizome of the plant Zingiber officinale, consumed as a delicacy, medicine, or spice. It lends its name to its genus and family (Zingiberaceae). Other notable members of this plant family are turmeric, cardamom, and galangal(ref).” It is not surprising, therefore, that ginger exerts many of the same biological effects as does curcumin. Curcumin is one of the many ingredients found in ginger although in relatively small amounts. Commercial curcumin is usually derived from turmeric

Some of the most important of these biological effects are covered in the blog entries Neurogenesis, curcumin and longevity and Curcumin, cancer and longevity. The research cited here shows how both ginger and its curcumin component tend to act through the same molecular pathways in organisms.

Image from Kohler’s Medicinal Plants.

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Ginger is a complex substance consisting of more than 60 compounds. “The characteristic odor and flavor of ginger is caused by a mixture of zingerone, shogaols and gingerols, volatile oils that compose one to three percent of the weight of fresh ginger. In laboratory animals, the gingerrols increase the motility of the gastrointestinal tract and have analgesic, sedative, antipyretic and antibacterial properties.^[4] Ginger oil has been shown to prevent skin cancer in mice^[5] and a study at the University of Michigan demonstrated that gingerols can kill ovarian cancer cells.^[6][7][8] [6]-gingerol (1-[4′-hydroxy-3′-methoxyphenyl]-5-hydroxy-3-decanone) is the major pungent principle of ginger. The chemopreventive potentials of [6]-gingerol present a promising future alternative to expensive and toxic therapeutic agents.^[9] — Ginger contains up to three percent of a fragrant essential oil whose main constituents are sesquiterpenoids, with (-)-zingiberene as the main component. Smaller amounts of other sesquiterpenoids (β-sesquiphellandrene, bisabolene and farnesene) and a small monoterpenoid fraction (β-phelladrene, cineol, and citral) have also been identified. — The pungent taste of ginger is due to nonvolatile phenylpropanoid-derived compounds, particularly gingerols and shogaols, which form from gingerols when ginger is dried or cooked. Zingerone is also produced from gingerols during this process; this compound is less pungent and has a spicy-sweet aroma.^[10] ” (ref)

Ginger antioxidant properties

That ginger has antioxidant properties has been known for some time The 2004 publication Antioxidant properties of gingerol related compounds from ginger points out that ginger contains over 50 antioxidant compounds. “Ginger (Zingiber officinale Roscoe) shows an antioxidant activity, and we have been engaging to determine the structures of more than 50 antioxidants isolated from the rhizomes of ginger. The isolated antioxidants are divided into two groups; gingerol related compounds and diarylheptanoids. In this study, structure-activity relationship of gingerol related compounds was evaluated.”

Ginger mechanisms for control of inflammation

The 2011 publication Cyclooxygenase-2 inhibitors in ginger (Zingiber officinale) reports “Ginger roots have been used to treat inflammation and have been reported to inhibit cyclooxygenase (COX). Ultrafiltration liquid chromatography mass spectrometry was used to screen a chloroform partition of a methanol extract of ginger roots for COX-2 ligands, and 10-gingerol, 12-gingerol, 8-shogaol, 10-shogaol, 6-gingerdione, 8-gingerdione, 10-gingerdione, 6-dehydro-10-gingerol, 6-paradol, and 8-paradol bound to the enzyme active site. Purified 10-gingerol, 8-shogaol and 10-shogaol inhibited COX-2 with IC(50) values of 32 μM, 17.5 μM and 7.5 μM, respectively. No inhibition of COX-1 was detected. Therefore, 10-gingerol, 8-shogaol and 10-shogaol inhibit COX-2 but not COX-1, which can explain, in part, the anti-inflammatory properties of ginger.”

Another mechanism used by ginger compounds to inhibit inflammation is attenuation of NF-kappaB-mediated iNOS gene expression. The 2006 publication Gingerol metabolite and a synthetic analogue Capsarol inhibit macrophage NF-kappaB-mediated iNOS gene expression and enzyme activity relates “–Inducible nitric oxide synthase (iNOS), a proinflammatory enzyme responsible for the generation of nitric oxide (NO), has been implicated in the pathogenesis of inflammatory diseases. Gingerols, the main pungent principles of ginger, have anti-inflammatory properties in vitro. In this study we examine the inhibitory effect of a stable [6]-gingerol metabolite, RAC-[6]-dihydroparadol ([6]-DHP) and a closely related gingerol analogue, RAC-2-hydroxy-1-(4-hydroxy-3-methoxyphenyl)dodecan-3-one [a capsaicin/gingerol (Capsarol) analogue referred to as ZTX42] on NO production, inducible nitric oxide synthase (iNOS) activity and protein expression levels in a murine macrophage cell line –. — Although both compounds partially inhibited the catalytic activity of iNOS, their inhibitory effect was predominantly due to attenuation of iNOS protein production. This occurred at the transcriptional level, since the gingerol compounds decreased LPS-induced IkappaB-alpha degradation, prevented nuclear translocation of NF-kappaB p65 and reduced NF-kappaB activity in a concentration-dependent manner. Taken together, these results show that ZTX42 and [6]-DHP suppress NO production in murine macrophages by partially inhibiting iNOS enzymatic activity and reducing iNOS protein production, via attenuation of NF-kappaB-mediated iNOS gene expression, providing a rationale for the anti-inflammatory activity reported for this class of compounds.”

Ginger endrocrine and anti-inflammatory functions

The 2011 publication Physiological and therapeutical roles of ginger and turmeric on endocrine functions relates “The natural product ginger (Zingiber officinale) has active constituents gingerol, Shogaol and Zerumbone, while turmeric (Curcuma longa) contains three active major curcuminoids, namely, curcumin, demethoxycurcumin, and bisdemethoxycurcumin. They have the same scientific classification and are reported to have anti-inflammatory and many therapeutic effects. This article reviews the physiological and therapeutic effects of ginger and turmeric on some endocrine gland functions, and signal pathways involved to mediate their actions. With some systems and adipose tissue, ginger and turmeric exert their actions through some/all of the following signals or molecular mechanisms: (1) through reduction of high levels of some hormones (as: T4, leptin) or interaction with hormone receptors; (2) by inhibition of cytokines/adipokine expression; (3) acting as a potent inhibitor of reactive oxygen species (ROS)-generating enzymes, which play an essential role between inflammation and progression of diseases; (4) mediation of their effects through the inhibition of signaling transcription factors; and/or (5) decrease the proliferative potent by down-regulation of antiapoptotic genes, which may suppress tumor promotion by blocking signal transduction pathways in the target cells. These multiple mechanisms of protection against inflammation and oxidative damage make ginger and curcumin particularly promising natural agents in fighting the ravages of aging and degenerative diseases, and need to be paid more attention by studies.”

The 2010 publication Comparative antioxidant and anti-inflammatory effects of [6]-gingerol, [8]-gingerol, [10]-gingerol and [6]-shogaol relates “Although gingerols and shogaols are the major bioactive compounds present in Zingiber officinale, their molecular mechanisms of actions and the relationship between their structural features and the activity have not been well studied. — The aim of the present study was to examine and compare the antioxidant and anti-inflammatory activities of gingerols and their natural analogues to determine their structure-activity relationship and molecular mechanisms.” The in-vitro antioxidant assay produced the conclusions “Shogaol has exhibited the most potent antioxidant and anti-inflammatory properties which can be attributed to the presence of alpha,beta-unsaturated ketone moiety. The carbon chain length has also played a significant role in making 10-gingerol as the most potent among all the gingerols. This study justifies the use of dry ginger in traditional systems of medicine.”

Ginger and phagocytosis

Ginger can enhance the functional capability of phagocytes “to protect the body by ingesting (phagocytosing) harmful foreign particles, bacteria, and dead or dying cells.” (ref). The 2009 publication Modulation of macrophage functions by compounds isolated from Zingiber officinale reports on the most bioactive ginger compounds in this regard: “Bioactivity-guided fractionation of Zingiber Officinale (zingiberaceae) led us to isolate 14 compounds, -gingerol ( 1), -gingerol ( 2), -gingerol ( 3), -gingerol ( 4), -paradol ( 5), -shogaol ( 6), -shogaol ( 7), 1-dehydro- -gingerdione ( 8), -gingerdione ( 9), hexahydrocurcumin ( 10), tetrahydrocurcumin ( 11), gingerenone A ( 12), 1,7-bis-(4′ hydroxyl-3′ methoxyphenyl)-5-methoxyhepthan-3-one ( 13), and methoxy- -gingerol ( 14). Using the RAW 264.7 cell line, the inhibitory effects on nitric oxide production induced by lipopolysaccharide and the stimulatory effects on phagocytosis of these compounds were evaluated. Compounds 7, 8, and 9 significantly decreased lipopolysaccharide-induced nitric oxide production, and compounds 7 and 8 significantly reduced inducible nitric oxide synthase expression. Among them, compound 8 also showed significant stimulatory effects on phagocytosis.”

Cancer chemoprevention

In my blog post Cancer, epigenetics and dietary substances I introduced the post by stating “We have long known from large population studies that regular consumption of certain dietary substances and supplements like green tea, olive oil, blueberries, oregano, ginger and hot chili peppers can negatively impact on incidences of cancer. We also know from multiple studies that certain plant-based polyphenol substances like rosmarinic acid, curcumin, lycopene, caffeic acid, resveratrol and gingerol inhibit the development of certain cancers. Indeed this research has been the basis for my suggested lifestyle and dietary supplement anti-aging regimens.” The same seems to be true for ginger as related in the 2007 publication Cancer preventive properties of ginger: a brief review.

Ginger induces apoptosis in various lines of cancer cells. For example, the 2010 document Induction of apoptosis by [8]-shogaol via reactive oxygen species generation, glutathione depletion, and caspase activation in human leukemia cells reports “This study examined the growth inhibitory effects of [8]-shogaol, one of the pungent phenolic compounds in ginger, on human leukemia HL-60 cells. It demonstrated that [8]-shogaol was able to induce apoptosis in a time- and concentration-dependent manner. 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 subsequent induction of procaspase-9 and procaspase-3 processing. Taken together, these results suggest for the first time that ROS production and depletion of glutathione that contributed to [8]-shogaol-induced apoptosis in HL-60 cells.”

Ginger compounds can promote P53 apoptosis of cancer cells. The 2010 publication Induction of apoptosis by [6]-gingerol associated with the modulation of p53 and involvement of mitochondrial signaling pathway in B[a]P-induced mouse skin tumorigenesis reports “Topical treatment of [6]-gingerol (2.5 muM/animal) was given to the animals 30 min prior and post to B[a]P (5 mug/animal) for 32 weeks. At the end of the study period, the skin tumors/tissues were dissected out and examined histopathologically. Flow cytometry was employed for cell cycle analysis. Further immunohistochemical localization of p53 and regulation of related apoptogenic proteins were determined by Western blotting. — Chemopreventive properties of [6]-gingerol were reflected by delay in onset of tumorigenesis, reduced cumulative number of tumors, and reduction in tumor volume. Cell cycle analysis revealed that the appearance of sub-G1 peak was significantly elevated in [6]-gingerol treated animals with post treatment showing higher efficacy in preventing tumorigenesis induced by B[a]P. Moreover, elevated apoptotic propensity was observed in tumor tissues than the corresponding non-tumor tissues. Western blot analysis also showed the same pattern of chemoprevention with [6]-gingerol treatment increasing the B[a]P suppressed p53 levels, also evident by immunohistochemistry, and Bax while decreasing the expression of Bcl-2 and Survivin. Further, [6]-gingerol treatment resulted in release of Cytochrome c, Caspases activation, increase in apoptotic protease-activating factor-1 (Apaf-1) as mechanism of apoptosis induction. — On the basis of the results we conclude that [6]-gingerol possesses apoptotic potential in mouse skin tumors as mechanism of chemoprevention hence deserves further investigation.”

Ginger compounds limit cancer-related angiogenesis. The 2005 publication [6]-Gingerol, a pungent ingredient of ginger, inhibits angiogenesis in vitro and in vivo relates “[6]-Gingerol, a pungent ingredient of ginger (Zingiber officinale Roscoe, Zingiberaceae), has anti-bacterial, anti-inflammatory, and anti-tumor-promoting activities. Here, we describe its novel anti-angiogenic activity in vitro and in vivo. In vitro, [6]-gingerol inhibited both the VEGF- and bFGF-induced proliferation of human endothelial cells and caused cell cycle arrest in the G1 phase. It also blocked capillary-like tube formation by endothelial cells in response to VEGF, and strongly inhibited sprouting of endothelial cells in the rat aorta and formation of new blood vessel in the mouse cornea in response to VEGF. Moreover, i.p. administration, without reaching tumor cytotoxic blood levels, to mice receiving i.v. injection of B16F10 melanoma cells, reduced the number of lung metastasis, with preservation of apparently healthy behavior. Taken together, these results demonstrate that [6]-gingerol inhibits angiogenesis and may be useful in the treatment of tumors and other angiogenesis-dependent diseases.”

Another of the impacts of ginger on certain cancer cells appears to be inhibition of proliferation-related genes through inhibiting expression of NF-kappaB and COX-2 induction.  The 2004 publication Inhibitory effects of [6]-gingerol on PMA-induced COX-2 expression and activation of NF-kappaB and p38 MAPK in mouse skin relates “. Previous studies have demonstrated that [6]-gingerol inhibits mouse skin tumor promotion and anchorage-independent growth of cultured mouse epidermal cells stimulated with epidermal growth factor. Cyclooxygenase-2 (COX-2), a key enzyme in the prostaglandin biosynthesis, has been recognized as a molecular target for many anti-inflammatory as well as chemopreventive agents. Topical application of [6]-gingerol inhibited phorbol 12-myristate 13-acetate -induced COX-2 expression. One of the essential transcription factors responsible for COX-2 induction is NF-kappaB. [6]-Gingerol suppressed NF-kappaB DNA binding activity in mouse skin. In addition, [6]-gingerol inhibited the phoshorylation of p38 mitogen-activated protein kinase which may account for its inactivation of NF-kappaB and suppression of COX-2 expression.”

These same factors are also discussed in the 2007 publication Ginger inhibits cell growth and modulates angiogenic factors in ovarian cancer cells. “Ginger (Zingiber officinale Rosc) is a natural dietary component with antioxidant and anticarcinogenic properties. The ginger component [6]-gingerol has been shown to exert anti-inflammatory effects through mediation of NF-kappaB. NF-kappaB can be constitutively activated in epithelial ovarian cancer cells and may contribute towards increased transcription and translation of angiogenic factors. In the present study, we investigated the effect of ginger on tumor cell growth and modulation of angiogenic factors in ovarian cancer cells in vitro. The effect of ginger and the major ginger components on cell growth was determined in a panel of epithelial ovarian cancer cell lines. Activation of NF-kappaB and and production of VEGF and IL-8 was determined in the presence or absence of ginger. — Ginger treatment of cultured ovarian cancer cells induced profound growth inhibition in all cell lines tested. We found that in vitro, 6-shogaol is the most active of the individual ginger components tested. Ginger treatment resulted in inhibition of NF-kB activation as well as diminished secretion of VEGF and IL-8. — Ginger inhibits growth and modulates secretion of angiogenic factors in ovarian cancer cells. The use of dietary agents such as ginger may have potential in the treatment and prevention of ovarian cancer.”

Also see the 2009 publication Ginger’s (Zingiber officinale Roscoe) inhibition of rat colonic adenocarcinoma cells proliferation and angiogenesis in vitro and the 2008 publication 6-Shogaol suppressed lipopolysaccharide-induced up-expression of iNOS and COX-2 in murine macrophages.

.Another mechanism of action of ginger on cancer cells onvolves TRAIL. TRAIL stand for tumor necrosis factor–related apoptosis-inducing ligand. TRAIL is also called APO-2L and consists of 281 amino acids. Regarding TRAIL as an approach to cancer therapy see the blog entry On the TRAIL of a selective cancer treatment. The 2007 publication Ginger ingredients reduce viability of gastric cancer cells via distinct mechanisms reports “We found that 6-gingerol, a phenolic alkanone isolated from ginger, enhanced the TRAIL-induced viability reduction of gastric cancer cells while 6-gingerol alone affected viability only slightly. 6-Gingerol facilitated TRAIL-induced apoptosis by increasing TRAIL-induced caspase-3/7 activation. 6-Gingerol was shown to down-regulate the expression of cIAP1, which suppresses caspase-3/7 activity, by inhibiting TRAIL-induced NF-kappaB activation. As 6-shogaol has a chemical structure similar to 6-gingerol, we also assessed the effect of 6-shogaol on the viability of gastric cancer cells. Unlike 6-gingerol, 6-shogaol alone reduced the viability of gastric cancer cells. 6-Shogaol was shown to damage microtubules and induce mitotic arrest. These findings indicate for the first time that in gastric cancer cells, 6-gingerol enhances TRAIL-induced viability reduction by inhibiting TRAIL-induced NF-kappaB activation while 6-shogaol alone reduces viability by damaging microtubules.”

The anti-cancer effects of ginger involving TRAIL seem to be similar to those of many other plant phytochemicals. In an my blog entry on TRAIL I wrote “Certain of the supplements in the Susceptibility to Cancer firewall, particularly curcumin(ref), resveratrol(ref) and green tea, owe at least some of their anti-cancer effects to the operation of TRAIL. In the case of prostate and other cancers, curcumin inhibits the activation of NF-kappaB which makes them more sensitive to apoptosis by TRAIL(ref,ref,ref). Resveratrol appears to have the same effect in certain tumors(ref)(ref). The same appears to be true for EGCG, the major active constituent of green tea(ref). I speculate that other plant-derived polyphenols in the anti-cancer firewall might have similar effects, enhancing TRAIL-mediated death receptor activation in cancer cells. Possibly, most of the 39 inhibitors of NF-kappaB in the firewall might work to empower TRAIL and fight cancers in the same way.”

Ginger has also been shown to inhibit the expression of telomerase in certain cancer cells. The December 2010 publication Ginger extract inhibits human telomerase reverse transcriptase and c-Myc expression in A549 lung cancer cells reports “. Here we show that the ethyl acetate fraction of ginger extract can inhibit the expression of the two prominent molecular targets of cancer, the human telomerase reverse transcriptase (hTERT) and c-Myc, in A549 lung cancer cells in a time- and concentration-dependent manner. The treated cells exhibited diminished telomerase activity because of reduced protein production rather than direct inhibition of telomerase. The reduction of hTERT expression coincided with the reduction of c-Myc expression, which is one of the hTERT transcription factors; thus, the reduction in hTERT expression might be due in part to the decrease of c-Myc. As both telomerase inhibition and Myc inhibition are cancer-specific targets for cancer therapy, ginger extract might prove to be beneficial as a complementary agent in cancer prevention and maintenance therapy.”

A 2008 publication relates to cytotoxicity of ginger compounds to cancer cells: Cytotoxic components from the dried rhizomes of Zingiber officinale Roscoe. “Five compounds were isolated from the chloroform-soluble fraction of the methanolic extract of the dried rhizomes of Zingiber officinale (Zingiberaceae) through repeated column chromatography. Their chemical structures were elucidated as 4-, 6-, 8-, and 10-gingerols, and 6-shogaol using spectroscopic analysis. Among the five isolated compounds, 6-shogaol exhibited the most potent cytotoxicity against human A549, SK-OV-3, SK-MEL-2, and HCT15 tumor cells. 6-shogaol inhibited proliferation of the transgenic mouse ovarian cancer cell lines, C1 (genotype: p53(-/-), c-myc, K-ras) and C2 (genotype: p53(-/-), c-myc, Akt), with ED(50) values of 0.58 microM (C1) and 10.7 microM (C2).”

The relative anti-carcinogenic effectiveness of gingerol and shogaol compounds in ginger is dealt with in the 2009 publication Increased growth inhibitory effects on human cancer cells and anti-inflammatory potency of shogaols from Zingiber officinale relative to gingerols. “Ginger, the rhizome of the plant Zingiber officinale , has received extensive attention because of its antioxidant, anti-inflammatory, and antitumor activities. Most researchers have considered gingerols as the active principles and have paid little attention to shogaols, the dehydration products of corresponding gingerols during storage or thermal processing. In this study, we have purified and identified eight major components, including three major gingerols and corresponding shogaols, from ginger extract and compared their anticarcinogenic and anti-inflammatory activities. Our results showed that shogaols ([6], [8], and [10]) had much stronger growth inhibitory effects than gingerols ([6], [8], and [10]) on H-1299 human lung cancer cells and HCT-116 human colon cancer cells, especially when comparing [6]-shogaol with [6]-gingerol (IC50 of approximately 8 versus approximately 150 microM). In addition, we found that [6]-shogaol had much stronger inhibitory effects on arachidonic acid release and nitric oxide (NO) synthesis than [6]-gingerol.”

You can also see Comparative antioxidant and anti-inflammatory effects of [6]-gingerol, [8]-gingerol, [10]-gingerol and [6]-shogaol and Mode of action of gingerols and shogaols on 5-HT3 receptors: binding studies, cation uptake by the receptor channel and contraction of isolated guinea-pig ileum.

In my blog entry Nrf2 and cancer chemoprevention by phytochemicals I indicated “A cluster of research reports has appeared during the last few years looking at mechanisms through which substances rich in phytochemicals (e.g. coffee, chocolate, turmeric, olive oil, broccoli, red hot peppers, green tea, garlic, blueberries, rosemary, oregano, sage) are cancer-preventative. While these foods have been studied for many years a new focal point has been moving to center stage – study of what these substances are doing in terms of gene expression as a key to understanding their therapeutic value. — Recent studies have provided strong evidence that many daily-consumed dietary compounds possess cancer-protective properties that might interrupt the carcinogenesis process. These properties include the induction of cellular defense detoxifying and antioxidant enzymes, which can protect against cellular damage caused by environmental carcinogens or endogenously generated reactive oxygen species. These compounds can also affect cell-death signaling pathways, which could prevent the proliferation of tumor cells.” — One master activator of antioxidant and anticancer genes appears to be Nuclear factor-erythroid-2-related factor 2 (Nrf2). The sequence of events involved in phytochemical chemoprevention mediated by Nrf2 is complex and is summarized in the 2008 publication Nrf2 as a master redox switch in turning on the cellular signaling involved in the induction of cytoprotective genes by some chemopreventive phytochemicals. “A wide array of dietary phytochemicals have been reported to induce the expression of enzymes involved in both cellular antioxidant defenses and elimination/inactivation of electrophilic carcinogens. Induction of such cytoprotective enzymes by edible phytochemicals largely accounts for their cancer chemopreventive and chemoprotective activities.” For those of you who have a taste for molecular biology, that document goes on to explain “Nuclear factor-erythroid-2-related factor 2 (Nrf2) plays a crucial role in the coordinated induction of those genes encoding many stress-responsive and cytoptotective enzymes and related proteins. These include NAD(P)H:quinone oxidoreductase-1, heme oxygenase-1, glutamate cysteine ligase, glutathione S-transferase, glutathione peroxidase, thioredoxin, etc. In resting cells, Nrf2 is sequestered in the cytoplasm as an inactive complex with the repressor Kelch-like ECH-associated protein 1 (Keap1). The release of Nrf2 from its repressor is most likely to be achieved by alterations in the structure of Keap1. Keap1 contains several reactive cysteine residues that function as sensors of cellular redox changes. Oxidation or covalent modification of some of these critical cysteine thiols would stabilize Nrf2, thereby facilitating nuclear accumulation of Nrf2. After translocation into nucleus, Nrf2 forms a heterodimer with other transcription factors, such as small Maf, which in turn binds to the 5′-upstream CIS-acting regulatory sequence, termed antioxidant response elements (ARE) or electrophile response elements (EpRE), located in the promoter region of genes encoding various antioxidant and phase 2 detoxifying enzymes. Certain dietary chemopreventive agents target Keap1 by oxidizing or chemically modifying one or more of its specific cysteine thiols, thereby stabilizing Nrf2. In addition, phosphorylation of specific serine or threonine residues present in Nrf2 by upstream kinases may also facilitate the nuclear localization of Nrf2. Multiple mechanisms of Nrf2 activation by signals mediated by one or more of the upstream kinases, such as mitogen-activated protein kinases, phosphatidylionositol-3-kinase/Akt, protein kinase C, and casein kinase-2 have recently been proposed.”

Neurological actions of ginger

Ginger fractions bind to a serotonin receptor and reduces levels of anxiety in animals. The 2010 publication Identification of serotonin 5-HT1A receptor partial agonists in ginger reports: “Animal studies suggest that ginger (Zingiber officinale Roscoe) reduces anxiety. In this study, bioactivity-guided fractionation of a ginger extract identified nine compounds that interact with the human serotonin 5-HT(1A) receptor with significant to moderate binding affinities (K(i)=3-20 microM). [(35)S]-GTP gamma S assays indicated that 10-shogaol, 1-dehydro-6-gingerdione, and particularly the whole lipophilic ginger extract (K(i)=11.6 microg/ml) partially activate the 5-HT(1A) receptor (20-60% of maximal activation). In addition, the intestinal absorption of gingerols and shogaols was simulated and their interactions with P-glycoprotein were measured, suggesting a favourable pharmacokinetic profile for the 5-HT(1A) active compounds.”

Relevant to Alzheimer’s disease pathology is the 2011 publication [6]-Gingerol attenuates β-amyloid-induced oxidative cell death via fortifying cellular antioxidant defense system. “β-Amyloid (Aβ) is involved in the formation of senile plaques, the typical neuropathological marker for Alzheimer’s disease (AD) and has been reported to cause apoptosis in neurons via oxidative and/or nitrosative stress. In this study, we have investigated the neuroprotective effect and molecular mechanism of [6]-gingerol, a pungent ingredient of ginger against Αβ(25-35)-induced oxidative and/or nitrosative cell death in SH-SY5Y cells. [6]-Gingerol pretreatment protected against Aβ(25-35)-induced cytotoxicity and apoptotic cell death such as DNA fragmentation, disruption of mitochondrial membrane potential, elevated Bax/Bcl-2 ratio, and activation of caspase-3. To elucidate the neuroprotective mechanism of [6]-gingerol, we have examined Aβ(25-35)-induced oxidative and/or nitrosative stress and cellular antioxidant defense system against them. [6]-Gingerol effectively suppressed Aβ(25-35)-induced intracellular accumulation of reactive oxygen and/or nitrogen species and restored Aβ(25-35)-depleted endogenous antioxidant glutathione levels. Furthermore, [6]-gingerol treatment up-regulated the mRNA and protein expression of antioxidant enzymes such as γ-glutamylcysteine ligase (GCL) and heme oxygenase-1 (HO-1), the rate limiting enzymes in the glutathione biosynthesis and the degradation of heme, respectively. The expression of aforementioned antioxidant enzymes seemed to be mediated by activation of NF-E2-related factor 2 (Nrf2). These results suggest that [6]-gingerol exhibits preventive and/or therapeutic potential for the management of AD via augmentation of antioxidant capacity.” I discussed the roles of Nrf2 above.

Ginger and respiratory diseases

Interesting new findings related to asthma are reported in the April 2011 publication Ginger suppresses phthalate ester-induced airway remodeling. “This study has two novel findings: it is not only the first to demonstrate inflammatory cytokines, which are produced by the bronchial epithelium after exposure to phthalate esters and contribute to airway remodeling by increasing human bronchial smooth muscle cells (BSMC) migration and proliferation, but it is also the first to reveal that ginger reverses phthalate ester-mediated airway remodeling. –. Moreover, [6]-shogaol, [6]-gingerol, [8]-gingerol, and [10]-gingerol, which are major bioactive compounds present in Zingiber officinale , suppress phthalate ester-mediated airway remodeling. This study suggests that ginger is capable of preventing phthalate ester-associated asthma.”

Ginger and gastrointestinal diseases

Ginger compounds may be useful for controlling some intestinal diseases. The 2011 publication Effects of Ginger Constituents on the Gastrointestinal Tract: Role of Cholinergic M3 and Serotonergic 5-HT3 and 5-HT4 Receptors reports “The herbal drug ginger ( ZINGIBER OFFICINALE Roscoe) may be effective for treating nausea, vomiting, and gastric hypomotility.”

The 2011 publication Intraluminal administration of zingerol, a non-pungent analogue of zingerone, inhibits colonic motility in rats reports “Zingerone, a pungent component of ginger, may exert beneficial therapeutic effects on hypermotilityinduced diarrhea because it has the ability to inhibit contractions of colonic smooth muscles. However, the pungency is undesirable for possible therapeutic use. The purpose of this study was to examine effects of zingerol, a non-pungent analogue of zingerone, in rats. — These findings suggest that zingerol can inhibit colonic motility without adverse effects on small intestinal motility and the cardiovascular system. The non-pungent property of zingerol will be useful as an oral or suppository medicine for treating diarrhea and other gastrointestinal disorders.”

Ginger and the immune system

At least one component of ginger is immunosuppressive as pointed out in the 2011 publication Immunosuppressive activity of 8-gingerol on immune responses in mice. “8-gingerol is one of the principal components of ginger, which is widely used in China and elsewhere as a food, spice and herb. It shows immunosuppressive activity on the immune responses to ovalbumin (OVA) in mice. In the present study, we found that 8-gingerol suppressed lipopolysaccharide (LPS) and concanavalin A (ConA)-stimulated splenocyte proliferation in vitro. In vivo, 8-gingerol not only significantly suppressed Con A-, LPS- and OVA-induced splenocyte proliferation (P < 0.05) but also decreased the percentage of CD19+ B cells and CD3+ T cell (P < 0.05) at high doses (50, 100 mg/kg). Moreover, OVA-specific IgG, IgG1 and IgG2b levels in OVA-immunized mice were reduced by 8-gingerol at doses of 50, 100 mg/kg. These results suggest that 8-gingerol could suppress humoral and cellular immune responses in mice. The mechanism might be related to direct inhibition of sensitized T and B lymphocytes.”

Ginger and bacterial resistance to tetracycline

The 2010 publication Zingiber officinale (ginger) compounds have tetracycline-resistance modifying effects against clinical extensively drug-resistant Acinetobacter baumannii reports “Extensively drug-resistant Acinetobacter baumannii (XDRAB) is a growing and serious nosocomial infection worldwide, such that developing new agents against it is critical. The antimicrobial activities of the rhizomes from Zingiber officinale, known as ginger, have not been proven in clinical bacterial isolates with extensive drug-resistance. This study aimed to investigate the effects of four known components of ginger, [6]-dehydrogingerdione, [10]-gingerol, [6]-shogaol and [6]-gingerol, against clinical XDRAB. All these compounds showed antibacterial effects against XDRAB. Combined with tetracycline, they showed good resistance modifying effects to modulate tetracycline resistance.”

Final observations

Ginger is an impressive and far from boring substance when looked at through the lenses of current medical-related research. I expect we will be hearing more and more about curative and life-extending properties of ginger-derived compounds as time proceeds.

However, I have seen little-to-no research so far regarding the effects of ginger as an epigenetic modifier, whether or how ginger affects gene promotion, or regarding possible impacts of ginger compounds on stem cell quiescence or activation. The same is true for most of the other important dietary phyto-substances, resveratrol and curcumin being partial exemptions. I am looking forward to seeing and reporting on such research as it eventually appears.