Therapeutic Value of 6-Gingerol (1-[4′-hydroxy-3′- methoxyphenyl]-5-hydroxy-3-decanone): A Review

Utilization of crude extracts separated from herbal medicine is getting more worthy and ideal, conceivably because of the expense of production, accessibility and availability to bring down harmful effects as much as possible. Various researches have shown that the regular use of particular soil products like fruits and vegetables can minimize the risk of a number of infections. Ginger is among the most commonly and regularly devoured dietary sauces on the planet. One of the major impactful components of ginger, 6-gingerol is suggested for the avoidance of malignancy and different maladies. As a spice and home grown medicine, the rhizome of Zingiber officinale (ginger) is devoured worldwide and it contains sharp phenolic compounds known as gingerols aggregately. The main pharmacologically-dynamic segment of ginger is 6-Gingerol. It is recognized to show a variety of organic actions including anti-cancer, anti-inflammation, and anti-oxidation. 6Gingerol has been found to have anticancer effects by means of its impact on an assortment of natural pathways associated with apoptosis, control of cell cycle, cytotoxic action and restraint of angiogenesis. Consequently, because of its adequacy and control of different targets, just as its Review Article Belachew et al.; JPRI, 33(9): 63-75, 2021; Article no.JPRI.66011 64 security for human use, 6-gingerol has gained impressive enthusiasm as an expected helpful operator for the anticipation and additionally treatment for different maladies. Taken together, this review sums up the different in vitro and in vivo pharmacological aspects of 6-gingerol and their underlying mechanisms.


INTRODUCTION
Utilization of crude extracts separated from herbal medicine is getting more worthy and ideal, conceivably because of the expense of production, accessibility, and availability and to bring down harmful effects as much as possible [1]. The presence of wide assortment of phytochemicals is identified to be able to meddle with various types of sicknesses. Consequently, chemoprevention of illnesses by phytochemicals has become a prospering field of exploration over the previous decade [2]. The rhizome of ginger (Zingiber officinale), family Zingiberaceae is used worldwide as a spice and natural medication and is grown in most tropical areas of the world [3]. Camphene, β-phellandrene, curcumene, cineole, geranyl acetic acid derivation, terpineol, borneol, geraniol, limonene, β-elemene, zingiberol, linalool, α-zingiberene, βsesquiphellandrene, β-bisabolene, zingiberenol and α-Farnesene are volatile chemical constituents incorporated in ginger rhizomes. The non-volatile and impactful phytochemicals comprising in ginger are gingerols, shogaols, paradols and zingerone [4,5]. Many investigations recommended that individuals in South East Asian nations have a much lower incidence of colon, gastrointestinal, prostate, breast and other cancers than their western partners. Thus, it is accepted that the phenolic substances from restorative plants, natural products and vegetables in their eating regimen may assume a significant function in the protection [6]. Ginger contains sharp phenolic substances known as gingerols. One of these, 6gingerol (1-[4'-hydroxy-3'-methoxyphenyl]-5hydroxy-3-decanone), is the major pharmacologically-dynamic segment of ginger [7,8] and the dynamic aspect of the molecule is the aliphatic chain moiety containing a hydroxyl group (Fig. 1) [9]. 6-gingerol is the significant phenolic bioactive part separated from rhizome of ginger (Zingiber officinale) which is answerable for spicy taste of ginger. It has been revealed to show antiproliferative effects against a wide scope of cells by repressing different endurance pathways including NF-КB and β-catenine [10]. Like capsaicin, it has additionally increased intracellular accumulation of daunorubicin and rhodamine 123 by blocking the P-glycoprotein (pgp) inhibition effect in multidrug-resistant human carcinoma KB-C2 cells. It has improved the poisonousness of vinblastine in KB-C2 cells through P-glycoprotein (p-gp) restraint [11]. Nonetheless, the accessible reported data are not adequate to clarify the mechanism of Pglycoprotein (p-gp) restraint by 6-gingerol. 6-Gingerol has been accounted for having an assortment of remedial properties including anticancer, anti-oxidant, ant-inflammation, antiplatelet aggregation and antifungal properties [12][13][14]. The objective of this review is to give an extensive knowledge into the chemo preventive capability of 6-gingerol, including laboratory examines, epidemiological investigations and even potential bearings for future research. On an account of high demise rate related with cancer and high side effects of chemotherapy and radiation treatment, numerous patients look for alternative strategies for therapy. Plant sources have been utilized for treating infections since days of ancient time. More than 50% of current medications in clinical use are of plant source [15]. Ginger is esteemed for its spicy and therapeutic properties and it has been utilized as medication from ancient period and is termed as "maha aushadh", implies the promising medication. Currently, the significance of ginger has been expanded as a result of its low poisonousness and its wide range of organic and pharmacological applications [15-20].

ANTICANCER EFFECTS
The different phytochemical composition present in ginger 6-gingerol is the most strong and pharmacologically active biomolecules and have anti-tumor and ant-proliferative properties. Due to this reason, 6-gingerol is a preffered target for anti-cancer drug development studies. The result of Pharmacological studies reported that the ginger and its major pungent phytochemical compositions like 6-gingerol have chemo preventive and chemotherapeutic activities on many cancer cell lines and on animal models [21]. 6-Gingerol has been researched in numerous human carcinomas, including leukemia, breast, colon, pancreatic, prostate, gastric and liver malignant growths [22][23][24][25]. Nevertheless, the mechanisms by which 6-gingerol protects from cancer are not yet known.

Apoptosis (Program Cell Death)
6-Gingerol is known to facilitate its anticancer properties by encouraging apoptosis [26]. Apoptosis is interceded by two pathways, namely the death receptor (extrinsic) and mitochondrial (intrinsic) pathways [27]. Various mechanisms are associated with 6-gingerol incited apoptosis. Cyclin D1 is a proto-oncogene, overexpressed in colorectal cancer and may contribute to a vital role in β-catenin signaling. Nonetheless, nonsteroidal anti-inflammatory drug (NSAID) -gene-1 (NAG-1) is a cytokine with anti-tumorigenic properties [28,29]. In gastric cells, 6-gingerol encouraged TRAIL-incited apoptosis by expanding TRAIL-induced caspase-3/7 initiation [30]. In the previous researches, the result revealed that 6-gingerol can initiate apoptosis via the lysosomal-mitochondrial axis in human hepatoma G2 cells. Cathepsin D might be a positive facilitator of 6-gingerol induced apoptosis in HepG2 cells, acting upstream of cytochrome c discharge and the apoptosis might be related with oxidative stress [31]. In the investigation of Nigam and team, the mouse skin carcinogenesis model was utilized. Topical treatment with 6gingerol (2.5 μM/animal) was injected to the mouse 30 min earlier and post to benzo[a]pyrene (B[a]P) (5 μg/animal) for 8 months. It was seen that 6-gingerol had apoptotic potential in mouse skin tumors. The mechanism might be related with the modulation of p53 and inclusion of the mitochondrial signaling pathway [32]. Fig.  2.describes the projected pathway of 6-gingerol-induced autophagy in HUVECs with the reported evidences on its action against apoptosis.

Cytotoxic Activity and Inhibition of Angiogenesis
The cytotoxic effect of 6-gingerol is additionally identified with its anticancer capacities. and in mice. The significant metabolites were known as 6-gingerdiols, which could encourage cytotoxicity in these cancer cells [35]. 6-Gingerol is persuasive in forestalling carcinogenesis in numerous organs. A potential clarification for this outcome is that the compound may hinder angiogenesis. Angiogenesis is the development of new blood vessels from the previous endothelium, which is the major one in the physiological and pathological processes of tumor progression and metastasis [36]. In a past report by Eok-Cheon Kim and coworkers revealed that the 6-gingerol had an inhibitory effect on angiogenesis in vitro and in vivo. It is evidenced by hinderance of the multiplication and tube formation of human endothelial cells in retort of vascular endothelial growth factor in vitro [37]. Fig. 3depicts about the action of 6-gingerol hindering the cancer progression, angiogenesis and metastasis with the supporting reports.

ANTIOXIDANT EFFECT
The natural antioxidant property of 6-gingerol suggeststhat it avoids numerous illnesses. The anti-oxidant effect properties of the phenolic compound might be identified with its capacity to give electrons and to go about as a free radical scavenger by the development of a stable phenoxyl radical [49]. Figure 4 summarizes the mechanism of protection by 6-gingerol for putative action against injury to the cells. The pretreatment of 6-Gingerol is important for the protection of Aβ-induced cytotoxicity and apoptotic cell demise. For this mechanism, 6gingerol has successfully diminished the level of reactive oxygen and additionally nitrogen species and returned the anti-oxidant glutathione levels. The mRNA and protein expression of antioxidant enzymes such as γ-glutamylcysteine ligase (GCL) and heme oxygenase-1 (HO-1) were upregulated by 6-gingerol [50]. This recommended that 6-gingerol lessened Aβ-induced oxidative cell demise fortifying the cellular antioxidant protective mechanism. Kuhad and his team portrayed that 6-gingerol could act against cisplatin-induced oxidative stress and renal dysfunctions in rats. As a powerful antioxidant, it meaningfully returned renal capacities, decreased lipid peroxidation and expanded the levels of glutathione and role of superoxide dismutase and catalase [51]. Also, 6-gingerol could diminish peroxidation of phospholipid liposomes within the sight of iron (III) and ascorbate [52]. Park and his coworkers discovered that ROS are delivered during the phenotypic change of fibroblasts to myofibroblasts, a cycle that is engaged with the development of nasal polyps by prompting extracellular network (ECM) accumulation. In another investigation, sodium arsenite (iAs) was utilized to incite stress mediated impaired insulin signaling in mice. 6-Gingerol impacted by decreasing the raised blood glucose level and oxidative stress by expanding the degree of super oxide dismutase (SOD), catalase, glutathione peroxidase (GPx) and GSH [53]. Consequently, 6-gingerol may become a significant natural antioxidant food additive. The description of the research results reported by various research studies on the effect of 6gingerol both in vitro and in vivoare tabulated in Table 1 [54-84].

CONCLUSION
Utilization of regular treatments, for example, phytochemical constituents, isolated from herbal medicine, to combat different kinds of diseases has pulled in the consideration of the scientific and medical communities because of their minimal side effects and lower cost. In this specific situation, 6-gingerol, a flavonoid antioxidant and the promising constituent of ginger, has been perceived and utilized as an elective medication in treating various diseases, alone or in blending with other chemotherapeutic medications. Besides showing significant antioxidant activity, it has anti-inflammatory activities also which could be utilized in forestalling and treating diseases. Ginger is among the most commonly and regularly devoured dietary sauces on the planet. One of the major impactful components of ginger, 6-gingerol, is suggested for the avoidance of malignancy and different maladies. In summation of the past studies, enormous effects of 6-gingerol has been exhibited in curing various maladies. Nonetheless, a large portion of the investigations with this compound have been made in vitro and with laboratory animals. In this way, additional investigations on determining the effect of 6gingerol ought to embrace human intervention trails. Nevertheless, further mechanistic work is needed to explain the molecular mechanism dissection studies underlying the impacts of 6gingerol on gene expression, the signaling pathway, and involvement of efficacious protein.
With all these authentic information available on 6-gingerol, it can be a significant complementary medication for health protection and significant therapy for various types of diseases, attributable to its natural origin, safety and its cost effectiveness relative to synthetic drugs. 6gingerol could also be a valuable part of dietary or pharmacological treatment for additional drug formulation to create novel and powerful clinical competitors.

DISCLAIMER
The products used for this research are commonly and predominantly use products in our area of research and country. There is absolutely no conflict of interest between the authors and producers because we do not intend to use these products as an avenue for any litigation but for the advancement of knowledge. Also the research was not funded by the producing company rather it was funded by personal efforts of the authors.

CONSENT
It is not applicable.

ETHICAL APPROVAL
It is not applicable.