6-Gingerol: Bioactivities & Hepatoprotection

6-gingerol is defined as a major phenolic component of ginger (Zingiber officinale) known for its pungent taste and associated with various biological activities, including anti-inflammatory and anti-apoptotic properties that show potential in cancer treatment and amelioration of cardiotoxic effects. 6-Gingerol has been found to possess anticancer activities via its effect on a variety of biological pathways involved in apoptosis, cell cycle regulation, cytotoxic activity, and inhibition of angiogenesis. Thus, due to its efficacy and regulation of multiple targets, as well as its safety for human use, 6-gingerol has received considerable interest as a potential therapeutic agent for the prevention and/or treatment of various diseases.

Bioactive Compounds and Bioactivities of Ginger

Ginger, which belongs to the Zingiberaceae family and the Zingiber genus, has been commonly consumed as a spice and an herbal medicine for a long time. Ginger root is used to attenuate and treat several common diseases, such as headaches, colds, nausea, and emesis. Many bioactive compounds in ginger have been identified, such as phenolic and terpene compounds. It could prevent an increase in the level of MDA and a decrease in catalase activity as well as the level of glutathione. Moreover, the 6-gingerol-rich fraction from ginger could reduce the levels of H2O2 and MDA, enhance antioxidant enzyme activity, and increase glutathione in rats with oxidative damage induced by chlorpyrifos. Furthermore, treatment with ginger extract elevated the contents of antioxidants and testosterone in serum and protected rat testes from injuries in chemotherapy with cyclophosphamide. Ginger also exhibits cytotoxic activity against other types of cancer, such as breast, cervical, liver, and pancreatic cancer. An in vitro study revealed that 6-gingerol could inhibit the growth of HeLa human cervical adenocarcinoma cells, and it induced cell cycle arrest in the G0/G1-phase by decreasing the protein levels of cyclin A and cyclin D1. Apoptosis in Hela cells was induced by increasing the expression of caspase and inhibiting mammalian target of rapamycin (mTOR) signaling.[1]

An in vitro experiment resulted in both 6-shogaol and 6-gingerol preventing the progression of diabetic complications, and they inhibited the production of AGEs by trapping methylglyoxal (MGO), the precursor of AGEs. Additionally, it reduced the levels of plasma glucose and insulin in mice with high-fat diet-induced obesity. Nε-carboxymethyl-lysine (CML), a marker of AGEs, was decreased by 6-gingerol through Nrf2 activation. In 3T3-L1 adipocytes and C2C12 myotubes, 6-paradol and 6-shogaol promoted glucose utilization by increasing AMPK phosphorylation. In addition, in a mouse model fed a high-fat diet, 6-paradol significantly reduced the level of blood glucose. In another study, 6-gingerol facilitated glucose-stimulated insulin secretion and ameliorated glucose tolerance in type 2 diabetic mice by increasing glucagon-like peptide 1 (GLP-1). Besides, 6-gingerol treatment activated glycogen synthase 1 and increased cell membrane presentation of glucose transporter type 4 (GLUT4), which increased glycogen storage in skeletal muscles. Furthermore, the consumption of ginger could reduce the levels of fasting plasma glucose, glycated hemoglobin A (HbA1C), insulin, TG, and TC in patients with type 2 diabetes mellitus (DM2). Moreover, ginger extract treatment improved insulin sensitivity in rats with metabolic syndrome, which might have been relevant to the energy metabolism improvement induced by 6-gingerol.

Anti-inflammatory therapeutic potential of 6-Gingerol

A small number of ginger compounds addressed their tissue distribution. Extracted or isolated compounds are evaluated in current studies by oral or intravenous administration in rodents and in vitro tests. The low absorption and rapid metabolism of 6-gingerol after oral administration are related to its poor solubility. To eliminate this problem, studies focusing on new drug carrier systems containing gingerol are important. Several studies evaluated the utility of different carrier solutions for efficient delivery of ginger compounds. In vivo studies investigating tissue distribution have shown that 6-gingerol is distributed to the lungs, brain, heart, liver, and kidneys, with the highest concentration in the gastrointestinal tract. After oral administration in rats, it has been determined that 6-gingerol is converted to glucuronide conjugates and its polar metabolites are excreted in small amounts in urine, and the compound is rapidly removed from the plasma after i.v. administration. In the treatment of inflammatory and immune-related diseases resulting from defects or disorders of the immune system, modulation of the immune response is necessary. Immunomodulators are substances used to modulate components of the immune system, and there are many chemical immunomodulators on the market that treat inflammatory diseases.[2]

The low solubility of 6-gingerol is caused by its poor oral absorption and fast metabolism, and this situation limits biological applications such as anti-inflammatory effect. In this study, the alternative formulations for oral administration called the self-microemulsifying drug delivery system (SMEDDS), formed by oil, surfactant, and co-surfactant or water, were prepared with stable physicochemical belongings such as the mean droplet size, ZP, and encapsulation efficiency. The in vitro release of 6-gingerol from the delivery system in the three different media was significantly higher than in the free 6-gingerol. Its administration in humans offers an alternative to synthetic drugs, which often have serious side effects. While a wide range of pharmacological studies focused on ginger show that the spice has functional food value and may offer therapeutic efficacy, further studies could be profitable directed at broadening the understanding of its mechanisms within the context of numerous diseases.

6-Gingerol Induced Liver Injury

The liver is a main homeostatic organ, involved in several biochemical processes such as the metabolism of lipids, carbohydrates, and alcohol and detoxification of various toxins and metabolic waste products. Continuous exposure of the liver to some factors including fatty diet, alcohol, drugs, and certain infections like virus leads to liver damage or injury. Sustained liver damage has been reported to cause chronic liver diseases. Liver diseases are an important and certainly underestimated public health problem worldwide and are known to cause a substantial level of morbidity and mortality. According to information on the global burden of disease project, more than two million people die from liver diseases that include acute hepatitis, cirrhosis, and liver cancer, which represent about 4% of all deaths around the world. 6-Gingerol is the chief pharmacologically active phenolic compound found in the rhizomes of ginger and has been demonstrated to exhibit a variety of biological activities such as antioxidant, anti-inflammatory, anticarcinogenic, and antimutagenic activities. Furthermore, 6-gingerol has been reported to exert a therapeutic effect in osteoarthritis by means of attenuating oxidative stress as well as downregulation of proinflammatory mediators in vitro and in vivo. Recently, 6-gingerol had been shown to induce cell death in the cancer cell line via caspase-3-dependent apoptosis and autophagy.[3]

Diethylnitrosamine (DEN) is a well-known hepatocarcinogen, and its oral administration causes severe liver damage including cancer. DEN induces the pathogenesis of the liver through reactive oxygen species mediated inflammation and modulation of various biological activities. 6-Gingerol, a major component of ginger, is reported to prevent liver diseases by reducing the oxidative stress and proinflammatory mediators. The present study investigated the hepatoprotective effects of 6-gingerol through the measurement of oxidative stress, anti-inflammatory markers, liver function enzyme parameter, and histopathological analysis. The rats were randomly divided into four groups as the control, DEN treated (50 mg/kg b.w.), DEN+6-gingerol (each 50 mg/kg b.w.), and 6-gingerol only. To evaluate the hepatoprotective effects, liver function enzymes (ALT, AST, and ALP), oxidative stress markers (SOD, GSH, GST, and TAC), lipid peroxidation, inflammatory markers (CRP, TNF-α, IL-6, and ICAM1), haematoxylin and eosin staining, Sirius red staining, immunohistochemistry, and electron microscopy were performed.

References

[1]Mao QQ, Xu XY, Cao SY, Gan RY, Corke H, Beta T, Li HB. Bioactive Compounds and Bioactivities of Ginger (Zingiber officinale Roscoe). Foods. 2019 May 30;8(6):185. doi: 10.3390/foods8060185. PMID: 31151279; PMCID: PMC6616534.

[2]Yücel Ç, Karatoprak GŞ, Açıkara ÖB, Akkol EK, Barak TH, Sobarzo-Sánchez E, Aschner M, Shirooie S. Immunomodulatory and anti-inflammatory therapeutic potential of gingerols and their nanoformulations. Front Pharmacol. 2022 Sep 5;13:902551. doi: 10.3389/fphar.2022.902551. PMID: 36133811; PMCID: PMC9483099.

[3]Alsahli MA, Almatroodi SA, Almatroudi A, Khan AA, Anwar S, Almutary AG, Alrumaihi F, Rahmani AH. 6-Gingerol, a Major Ingredient of Ginger Attenuates Diethylnitrosamine-Induced Liver Injury in Rats through the Modulation of Oxidative Stress and Anti-Inflammatory Activity. Mediators Inflamm. 2021 Jan 19;2021:6661937. doi: 10.1155/2021/6661937. PMID: 33531877; PMCID: PMC7837795.