P U B L I C A T I O N S CODON Italian Journal of Food Science, 2022; 34 (3): 1–12 ISSN 1120-1770 online, DOI 10.15586/ijfs.v34i3.2212 1 P U B L I C A T I O N S CODON A review of nutritional implications of bioactive compounds of Ginger (Zingiber officinale Roscoe), their biological activities and nano-formulations Muhammad Ishfaq1,2, Wanying Hu2, Zhihua Hu1, Yurong Guan1, and Ruihong Zhang1* 1College of Computer Science, Huanggang Normal University, Huanggang, China; 2College of Medicine, Northeast Agricultural University, Harbin, China *Corresponding Author: Ruihong Zhang, College of Computer Science, Huanggang Normal University, Huanggang 438000, China. Email: jsjrh@hgnu.edu.cn Received: 4 April 2022; Accepted: 22 June 2022; Published: 29 July 2022 © 2022 Codon Publications OPEN ACCESS REVIEW ARTICLE Abstract Ginger is a rhizome of the family Zingiberaceae and is one of the most commonly used spices in food and bev- erages worldwide. The pharmacological activities of ginger, including antioxidant, anti-inflammatory, anticancer, and protective effects against pain and gastrointestinal tract disorders, are primarily attributed to its phenolic compounds. However, knowledge about the mechanisms of toxicity, absorption, molecular targets, and dose– response relationship of ginger in human clinical studies is still elusive. The aim of this review is to give an overview of the current literature in the context of bioactive compounds and biological activities of ginger. Fur- thermore, recent findings regarding the absorption, tissue distribution, and nano-formulations of ginger bioac- tive compounds are discussed. The current in vitro and in vivo studies identified and validated ginger extracts and bioactive compounds, including gingerols, zingiberene, shogaols, and zingerone. Despite the data available regarding the pharmacological uses of ginger together with a deep mechanistic approach about the pharmacoki- netic, pharmacodynamic and dose-response studies in humans is yet to be provided. Studies on the absorption, bioavailability, adverse reactions, and safe doses of the bioactive compounds of ginger will additionally improve its therapeutic applications. Nonetheless, the use of nano-formulations of bioactive compounds of ginger will be a more effective strategy in drug delivery. These novel evidences may bring ginger to the forefront of nutraceuticals for the treatment and/or prevention of various human health disorders. Keywords: absorption; bioactive compounds; biological activities; ginger; nano-formulations Introduction Ginger (scientific name: Zingiber officinale Roscoe) is a perennial and yellow flowering plant, belonging to the Zingiberaceae family. Ginger plant has tuberous roots, named as rhizomes, which have pungent taste and aro- matic odor. Ginger is primarily used for culinary purposes as a flavoring agent mostly in dried, fresh, powdered, and preserved food and/or pickles (Peng et al., 2017). More importantly, ginger has received much attention from researchers because of its therapeutic potential to mod- ulate the activities of several enzymes. Ginger is also used in traditional medicines such as Unani system, Ayurvedic and Chinese medicines since ancient times to treat dif- ferent ailments, including sprains and muscular aches, rheumatoid arthritis, nausea, sore throat, indigestion and constipation, fever, infectious diseases, helminthiasis and cancer (Ali et al., 2008). Nowadays, ginger plant is grown in tropical regions such as Africa, Asia, Europe and America, and has gained an increasing interest because of its medicinal properties (Srinivasan, 2017) and research, including identification and isolation of its bioactive con- stituents (as shown in Figure 1) and its pharmacological, phytochemical and toxicological properties. mailto:jsjrh@hgnu.edu.cn 2 Italian Journal of Food Science, 2022; 34 (3) Ishfaq M et al. following reasons: (1) suppressing of lipid peroxida- tion; (2) Inhibition of enzymes of arachidonate metab- olism: 5-lipoxygenase and 2-cyclooxygenase enzymes; (3) free radical scavenging; (4) stimulating the activities of endogenous antioxidant enzymes; (5) enhancing anti- oxidant molecules in tissues; (6) inhibition of the activ- ity of inducible nitric oxide synthase and (7) inhibition of low-density lipoprotein (LDL) oxidation (Srinivasan 2014). Similarly, ginger has been reported to possess antioxidant activities, and has demonstrated a crucial role in scavenging superoxide anion and hydroxyl radi- cals (Ji et al., 2017; Mao et al., 2019). It has been analyzed that the trend varies with the content of phenolics found in ginger. For example, dried ginger has higher pheno- lic contents and indicates stronger antioxidant activities compared to stir-fried ginger and its other forms (dried ginger > stir-fried ginger > carbonized ginger > fresh gin- ger). On heating, the antioxidant activity decreases due to the conversion of gingerols into shogaols (Li et al., 2016). The type of solvents used for extraction could have an effect on the phenolic contents, and subsequently affect the antioxidant activity of ginger (Yeh et al., 2014). For instance, an aqueous extract and an ethyl acetate extract had higher antioxidant potential than diethyl ether, n- butanol and ethanol extracts (Nile and Park, 2015). The underlying mechanism of ginger’s antioxidant potential were investigated, and it was found that ginger extract reduced the generation of ROS and lipid peroxidation and stimulated the expression of several antioxidant enzymes (Hosseinzadeh et al., 2017). In addition, ginger extract activated the nuclear factor erythroid 2-related factor 2 (Nrf2) signaling pathway and its downstream genes, which, in turn, provide defense against oxidative stress and free radicals (Peng et al., 2015). The bioactive compound of ginger, 6-shogaol, up-regulated Nrf2 target genes and enhanced intracellular glutathione/glutathione Bioactive compounds in ginger Chemical analysis of ginger revealed that if contains more than 400 compounds. The major constituents of ginger are lipids (3–8%), carbohydrates (50–70%), pheno- lic compounds and terpenes (Grzanna et al., 2005). The nutraceutical properties of ginger are attributed to its bioactive constituents, primarily, phenolic compounds and terpenes. Some of these compounds belonging to classes such as shogaols, gingerols, paradols, zingerone and zigiberenes have been reported to possess potential to modulate biological activities. Shogaol (18–25%) and gingerols (23–25%) are found in higher quantities com- pared to other compounds. Besides these, water, raw fiber, protein, ash, phytosterols, minerals and some vita- mins are also present (Ali et al., 2008). Gingerols account for the taste of ginger. However, shogaols are formed at high temperature, for instance, during cooking, and provide spicy–sweet aroma. These active compounds have many biological activities through the modulation of enzyme activities in living systems (Shukla and Singh, 2007; Srinivasan, 2017). Therefore, in this review, the pharmacological activities (as shown in Figure 2) associ- ated with the bioactive compounds, their absorption and distribution, with a special focus on enhancing its bio- availability through nano-formulations are discussed. Biological Activities of Ginger Antioxidant activities Studies have reported that reactive oxygen species (ROS) play a crucial role in the growth of different chronic diseases (Poprac et al., 2017). The antioxidant activity of spices could be due to one or more of the 1-Dehydro-10-gingerdione 1-Dehydro-10-gingerdione 6-paradol 6-gingerol 6-shogaol Gingerenone-A gingerdione Zingerone Ginger Figure 1. Ginger rhizome and chemical structure of some of its bioactive compounds. Italian Journal of Food Science, 2022; 34 (3) 3 Nutritional implications of bioactive compounds of Ginger Anti-inflammatory activities Antioxidant activities Cardiovascular activities Gastroprotective activities Anti-cancer activities Anti-obesity activities Anti-diabetic activities Ginger Figure 2. Schematic diagram showing multiple biological activities exhibited by ginger. disulfide (GSH/GSSG), metallothionein 1 (MT1), heme oxygenase-1 (HO-1), aldo-keto reductase family 1 mem- ber B10 (AKR1B10), γ-glutamyl transferase-like activity 4 (GGTLA4), glutamate-cysteine ligase catalytic sub- unit (GCLC), glutamate-cysteine ligase modifier subunit (GCLM) and ferritin light chain (FTL) (Chen et al., 2014). 6-Shogaol, 6-dehydroshogaol and 1-dehydro-6-gingerdi- one inhibited the synthesis of nitric oxide (NO) in mac- rophages (Li et al., 2011). A previous study demonstrated that gingerol reduced the peroxidation of phospholipid liposomes in the presence of ascorbate and ferric ions (Fe3+) (Aeschbach et al., 1994). Another study reported the antioxidant effects of ginger in cerebellum, cerebral cortex, hypothalamus and hippocampus in diabetic mice (Shanmugam et al., 2011). It is worthy to mention here that there are several factors, such as individual differ- ences, health conditions, other dietary factors, the life- styles of people, solubility, route, dosage, and solubility, that could affect the bioavailability and bioaccessibility of antioxidants, which are probably associated with the effi- cacy of antioxidants in the real world. Digestive stimulant and gastroprotective activities Ginger exerts potential protective effects on the gastro- intestinal membrane and lowers the chances of muco- sal injury (Prakash and Srinivasan, 2010a). It has been reported that dietary ginger altered the permeability and fluidity of the intestinal membrane, resulting in increased absorptive surface of the small intestine with an increase in microvilli length (Prakash and Srinivasan, 2010b). It was demonstrated that dietary ginger (0.05%) fed for 8 weeks significantly altered the ultrastructural morphol- ogy in Wistar mice. Besides, ginger enhanced the activity of enzymes such as leucine aminopeptidase, g-glutamyl transpeptidase and glycyl-glycine dipeptidase, accompa- nied by a decrease in the ratio of cholesterol and phos- pholipid in the small intestinal mucosa. Ginger also increased the absorption of zinc, iron, β-carotene and calcium in the intestines (Prakash and Srinivasan, 2013). In another study, higher intestinal absorption of micro- nutrients has been noted in ginger-fed animals. This may be presumably associated with alteration in per- meation characteristics, including increased absorptive surface and antioxidant status in the intestines (Veda and Srinivasan, 2011). Despite providing increased sur- face area for absorption, ginger acts as a sialagogue, stim- ulates the production of saliva and thus enhances the swallowing process (Platel and Srinivasan, 2004). Ginger stimulated bile acid secretion from the liver (Bhat et al., 1985), leading to the absorption and digestion of dietary fat. Dietary ginger significantly increased the activity of several digestive enzymes, for example, amylase, prote- ases (chymotrypsin, trypsin and carboxy peptidase) and pancreas’ lipase (Platel and Srinivasan, 2000). Enzymes such as disaccharides are also stimulated by ginger, and food transit time is reduced due to facilitated digestion and increased intestinal motility (Platel and Srinivasan, 1996). Among spices, ginger ranks at the top level based on its pharmacological evidence (Platel and Srinivasan, 2004), and is used for alleviating the gastrointestinal tract (GIT) disorders in traditional medicines (Afzal et al., 2001). Moreover, ginger’s free phenolic and hydrolyzed phenolic fractions inhibited growth of Helicobacter pylori and gastric cell proton potassium ATPase activity. It has been suggested that these two steps are associated with the inhibition of ulcers (Siddaraju and Dharmesh, 2007). Anti-inflammatory activities Currently, gastric ulcer and adverse effects have been observed due to extensive use of nonsteroidal anti- inflammatory drugs. In general, the anti-inflammatory mechanism of ginger and its active compounds has been probably associated with the suppression of pro- tein kinase B (Akt) and nuclear factor kappa B (NF-κB) 4 Italian Journal of Food Science, 2022; 34 (3) Ishfaq M et al. 6-gingerol and 6-shogaol enhanced the catabolism of cellular fatty acid through activation of peroxisome pro- liferator-activated receptor δ (PPARδ)-dependent gene expression (Misawa et al., 2015). In high-fat diet mice, both orlistat and ginger decreased lipid profile and body weight. However, ginger proved effective than orlistat by reducing the level of high-density lipoprotein cholesterol (HDL-C) (Mahmoud and Elnour, 2013). In addition, in a double blind, randomized and placebo-controlled study, daily intake of 2 g of ginger powder decreased body mass index (BMI) in obese women (Ebrahimzadeh Attari et al., 2016). A study reported that ginger oleoresin interfered with cholesterol absorption (Gujral et al., 1978). It was demonstrated that fecal cholesterol increased and liver and serum cholesterol levels decreased compared to con- trol group in mice fed with 1% cholesterol diet along with 0.5% ginger oleoresin for 20 days (Gujral et al., 1978). In hypercholesterolemic mice, aqueous ginger infusion sig- nificantly reduced serum total cholesterol, triglycerides and LDL-cholesterol (ElRokh el et al., 2010). However, dietary ginger (0.04% dry powder) did not reduce cho- lesterol in hypercholesterolemic mice (Sambaiah and Srinivasan, 1991). It is important to observe that dietary ginger stimulated the absorption and digestion of dietary fat by enhancing the activity of pancreatic lipase and secretion of bile salts (Prakash and Srinivasan, 2012). It has been observed that gingerol significantly reduced glucose and insulin resistance, body weight gain, expres- sion of inflammatory markers and activity of enzymes of cholesterol biosynthesis, which results in the prevention of high-fat diet (HFD)-induced hyperlipidemia through modulating the expression of enzymes associated with cholesterol homeostasis (Brahma Naidu et al., 2016). Thus, ginger helps in management of weight through suppression of body cholesterol and reducing accumula- tion of lipids. Anti-diabetic activity Diabetes mellitus caused by insulin deficiency is a severe metabolic disorder that results in hyperglycemia. Numerous studies have evaluated the antidiabetic poten- tial of ginger and its bioactive compounds. In an in vitro study, 6-gingerol and 6-shogaol prevented diabetic com- plications by inhibiting advanced glycation end prod- ucts (AGEs) by trapping methylglyoxal (MGO) (Zhu et al., 2015). In addition, 6-gingerol decreased the level of plasma glucose and insulin in mice through Nrf2 activa- tion (Sampath et al., 2017). In C2C12 myotubes and 3T3-L1 adipocytes, 6-shogaol and 6-paradol promoted glucose utilization via AMPK phosphorylation. Besides, 6-paradol decreased the level of glucose in the blood of mice fed with high-fat diet (Wei et al., 2017). Another study reported that 6-gingerol pathway, up-regulation of anti-inflammatory cytokines and inhibition of pro-inflammatory cytokines. A pre- vious study demonstrated that ginger suppressed pro- inflammatory cytokines such as tumor necrosis factor-α (TNF-α), Interlukin (IL)-1 and IL-8 (Pan et al., 2008). Another study established that ginger oil (33 mg/kg, orally) for 26 days significantly alleviated joint swell- ing in mice during chronic adjuvant arthritis (Sharma et al., 1994). Ginger extract administered at a dose of 100 mg/kg body weight suppressed the elevated expres- sion TNF-α in mice (Habib et al., 2008). Besides, ginger inhibited both cyclooxygenase and 5-lipoygenase in vitro and in vivo (Kiuchi et al., 1992; Mustafa et al., 1993), and reduced the expression of inflammatory genes (Ho et al., 2013; Tripathi et al., 2008) through the suppression of NF-κB gene expression (Kim et al., 2004; Oyagbemi et al., 2010; Takada et al., 2005). In addition, 6-shogaol sup- pressed Claudin-1 and Claudin-2 through PI3K/Akt and NF-κB pathway and inhibited TNF-α-induced intestinal barrier dysfunction in human cell models (Luettig et al., 2016). It has been noted that 6-dehydroshogaol proved to be more effective than 6-gingerol and 6-shogaol in reducing prostaglandin E2 (PGE2) and nitric oxide (NO) in mouse macrophage RAW 264.7 cell line (Zhang et al., 2013). Moreover, 6-gingerol decreased the expres- sion of inflammatory markers such as NO, TNF-α and myeloperoxidase in the ovaries, uterus and brain of mice treated with chlorpyrifos (Abolaji et al., 2017). Capsules containing ginger powder (500 mg) alleviated the increased levels of plasma IL-1β, IL-6 and TNF-α after running exercise in 28 male endurance runners (Zehsaz et al., 2014). The anti-inflammatory effects of ginger and its bioactive constituents, such as zingerone, 6-, 8-, 10- gingerol and 6-shogaol proved effective against lipopolysaccharide (LPS)-induced inflammation in vivo and in vitro (Hsiang et al., 2015). These studies revealed that ginger and its bioactive compounds act as a broad spectrum anti-inflammatory agents through suppression of inflammatory cells infiltrates, NF-κB, IL-1β and other pro- inflammatory cytokines. Anti-obesity activity Previous research has reported that obesity is a risk fac- tor for cardiovascular diseases, hypertension and dia- betes (Misawa et al., 2015). Recently, ginger has gained an increasing interest in the prevention and manage- ment of obesity (Ebrahimzadeh Attari et al., 2018). In 3T3-L1 preadipocyte cells, gingerenone A attenuated diet-induced obesity through modulation of fatty acid metabolism via up-regulation of 5’ AMP-activated pro- tein kinase (AMPK) in vivo, and exhibited an effective inhibitory effect on lipid accumulation and adipogene- sis compared to 6-shogaol and gingerols (Ebrahimzadeh Attari et al., 2018). In cultured skeletal muscle myotubes, Italian Journal of Food Science, 2022; 34 (3) 5 Nutritional implications of bioactive compounds of Ginger HDL (Oh et al., 2017). The hypercholesterolemic prop- erties of ginger attribute to its cardioprotective function. In Wistar mice, ginger extract prevented isoproterenol- induced myocardial infarction (Amran et al., 2015). Pretreatment with ginger extract at a dose of 400 mg/ kg for 4 weeks significantly reduced cardiac markers, including enzyme activities of creatine kinase-MB isoen- zyme, infarction–troponin, alanine transaminase, aspar- tate transaminase and lactate dehydrogenase. In addition, significant increase was found in cardiac antioxidant enzymes and improvement in cell membrane integrity in ginger-pretreated mice (Srinivasan, 2017). Aqueous ginger extract at a low dose (50 mg/kg) admin- istered orally or intraperitoneally did not cause signifi- cant reduction in platelet thromboxane-B2 (TBX2) level. However, significant changes were observed in serum prostaglandin-E2 (PGE2) levels when ginger extract was given orally. These results provided an insight regard- ing the anti-thrombotic potential of ginger (Thomson et al., 2002). In anesthetized mice, crude extract of gin- ger (0.3–3 mg/kg) induced a dose-dependent decrease in arterial blood pressure. Crude extract depicted a car- diodepressant activity on the force and rate of sponta- neous contractions in guinea pig paired atria. In addition, crude extract of ginger at a dose 10 times higher than required against K-induced contraction resulted in the relaxation of phenylephrine-induced vascular contrac- tion in rabbits. These results demonstrated that ginger lowered blood pressure through the blockage of voltage- dependent calcium channels (Ghayur and Gilani, 2005). Another study reported that aqueous ginger extract mediated blood pressure lowering effect by inhibition of both Ca2+ channels and muscarinic receptors (Ghayur et  al., 2005). It has been observed that cardiovascular protective effects of ginger are attributed to its potential to alleviate hypertension and dyslipidemia. Anti-cancer activity Recently, increasing number of studies have focused on the anticancer effects of ginger and its bioactive com- pounds in different cancer cell lines, including cervical, breast, leukemia, colorectal, lung, liver, nasopharyngeal, prostate, retinoblastoma and ovarian cell lines. In the breast cancer cell line MDA-MB-231, 86.7-μg/mL and 57.5-μg/mL methanolic solution of ginger given for 24 h and 48 h, respectively, exhibited cytotoxic effect in a time-dependent manner (Ansari et al., 2016). In MCF-7 cell line, Z-6-oxo-6-shogaol and Z-6-oxo-8-shogaol treatment with half-maximum inhibition concentration (IC50) values of 6.27-μM and 47.22-μM for 48 h demon- strated significant cytotoxic action (Li et al., 2018). In addition, 6-shogaol inhibited growth of both breast and alleviated glucose tolerance through activation of gluca- gon-like peptide-1 (GLP-1) in type 2 diabetic mice and facilitated glucose-mediated secretion of insulin. It has been found that 6-gingerol enhanced cell membrane presentation of glucose transporter type 4 (GLUT4) and activated glycogen synthase 1, resulting in enhanc- ing storage of glycogen in skeletal muscles (Samad et al., 2017). Moreover, consumption of ginger could decrease the levels of glycated hemoglobin A (HbA1C), plasma glucose, insulin, total cholesterol (TC) and triglyceride (TG) in patients with type 2 diabetes mellitus (Arablou et al., 2014). In mice, ginger extract promoted insulin sensitivity during metabolic syndrome, which might be associated with improvement in energy metabolism by the active component, 6-gingerol (Li et al., 2014). Apart from direct protective effects on diabetes mellitus, ginger demon- strated protective effects against diabetes mellitus- induced secondary complications of the kidney, eye, liver and neural system (Li et al., 2012). Studies have estab- lished that ginger and its bioactive compounds possess potential therapeutic properties that could protect from diabetes mellitus. The main mechanism of action could be one of the following: (1) ginger maintains blood glu- cose homeostasis by promoting glucose uptake in insulin responsive peripheral tissues, (2) ginger enhances insulin sensitivity and release and/or (3) it improves lipid metab- olism and inhibits enzymes in carbohydrate metabolism. These mechanisms provide evidence for the future stud- ies to evaluate these steps in the clinical investigations of ginger and its bioactive compounds for treating diabetes mellitus. Cardiovascular and blood protective activities Ginger has the potential to treat cardiovascular diseases and has preventive effects on the blood. It is well docu- mented that high blood cholesterol is primarily associ- ated with cardiovascular diseases. Studies reported that cardiovascular diseases cause 17.9 million premature deaths annually (Du et al., 2016). Hypertension and dys- lipidemia are well known risk factors for stroke, coronary heart disease and cardiovascular diseases (Khosravani et al., 2016). Several studies have investigated the cardiovascular pro- tective properties of ginger and indicated that ginger treatment primarily decreased blood pressure and level of blood lipids (Natalia et al., 2017). In high-fat diet-fed mice, ginger extract increased the level of serum HDL-C and reduced body weight, thus protecting against coro- nary heart disease. Besides, the levels of lecithin-choles- terol acyltransferase and apolipoprotein A-1 mRNA were increased in the liver, associated with the formation of 6 Italian Journal of Food Science, 2022; 34 (3) Ishfaq M et al. hippocampi in mice by the activation of cyclic adenosine monophosphate (cAMP) response element-binding pro- tein (CREB) and nerve growth factor (NGF) (Lim et  al., 2014). Moreover, ginger alleviated narcotics-induced neurotoxicity and memory deficits in the hippocampus through modulation of cholinergic activity and memory retrieval ability (Gomar et al., 2014). A previous study demonstrated that ginger extract effectively alleviated epilepsy-like symptoms. For example, pentylenetetrazole (PTZ)-induced incidence of seizures and its duration was reduced by ginger therapy (Hosseini and Mirazi, 2014). Overall, ginger and its compounds alleviated epileptic symptoms, including involuntary movement and recur- rent seizures; these findings provided evidence for the application of ginger against epileptic patients. Ginger also demonstrated antiallergic, nephroprotec- tive and hepatoprotective effects. A study conducted by Rodrigues et al. (2014) demonstrated that gingerol alle- viated gentamicin-induced kidney damage by reducing stress and lipid peroxidation and increased superoxide dismutase (SOD) activity and levels of glutathione (GSH) in a dose-dependent manner. Similarly, ginger extract attenuated biochemical and histological alterations through anti-inflammatory and antioxidant activities in a radiation-induced kidney model of mice (Saberi et al., 2017). The above-mentioned discussion established that ginger and its bioactive compounds played a crucial role in treating various diseases and, therefore, must be evalu- ated additionally for their nutraceutical properties. Absorption and Tissue Distribution of Ginger Compounds Information about the pharmacokinetics and bioavail- ability profile of an active substance is very important for understanding its nutraceutical properties. A previous study investigated the distribution profile of 6-gingerol in the blood and other tissues of mice. It was observed that this component was absorbed quickly if given orally at a dose of 240 mg/kg (ginger extract having 53% 6-gingerol). The maximum concentration found in the plasma was 4.24 mg/mL after 10 min that declined in a biexponential pattern with time. 6-gingerol is distributed to the heart, brain, spleen, lung, kidney, liver, small intes- tine and stomach. The highest concentration was found in the GIT, and the elimination half-life was 1.77 h (Jiang et al., 2008). A clinical trial studied the pharmacokinetics of the following ginger constituents: 6-shogaol, 6-gingerol, 8-gingerol and 10-gingerol. In human volunteers, gin- ger was given orally at a dose of 100–2.0 g. The ginger constituents were absorbed and detected as sulfate and glucuronide conjugates in blood samples after 15 min to colon cancer cells through up-regulation of peroxisome proliferator-activated receptor gamma (PPARγ) (Tan et al., 2013), and 10-gingerol inhibited orthotopic tumor growth by inducing apoptosis through caspase-3 in breast cancer and suppressed metastasis to lung, brain and bone cancers (Martin et al., 2017). Researchers demonstrated that ginger and its bioactive compounds were found effective against prostate cancer cell lines such as LNCaP, DU145, C4-2, PC-3 and C4-2B. 10-gin- gerol with IC50 value of 59.7-μM was more effective than 6-shogaol with IC50 value of 100.0 μM against PC-3 cells (Peng et al., 2012). In LNCaP human prostate cancer cell lines, 6-gingerol induced apoptosis via caspase-3 in time- and dose- dependent manner and degraded poly(ADP-ribose) poly- merase (PARP) (Kim et al., 2011). In H-1299 lung cancer cells, 6-gingerol demonstrated cytotoxic effect with IC50 value of 136.73-μM for 24 h (Lv et al., 2012), and initi- ated autophagy by inhibiting the AKT/mTOR pathway (Hung et al., 2009). In liver cancer, ginger extract sup- pressed NF-κB and TNF-α in mice (Habib et al., 2008). Additionally, Z-6-oxo-8-shogaol, Z-6-oxo-6-shogaol and E-4-isoshogaol revealed cytotoxic effect against HepG2 cell lines (van Breemen et al., 2011). In HL-60 and K562 leukemic cell lines, 6-shogaol (with IC50 values of 24.2 μM and 7.9 μM) proved more effective than 10-gin- gerol (Mahomoodally et al., 2021). In another study, 6-shogaol induced apoptosis and transformed cellular leukemia through eIF2α dephosphorylation (Liu et al., 2013). It has been noted that 6-gingerol induced apop- tosis in colorectal cancer cells by up-regulating G1 and NAG-1 cell cycle arrest through down-regulation of cyclin D1 (Lee et al., 2008). Another study confirmed that p53/p21 contributed to cell cycle arrest by G2/M check point induced by 6-shogaol (Radhakrishnan et al., 2014). Besides, 6-shogaol induced apoptosis primarily through mitochondrial pathway and Bcl-2 family proteins (Qi et al., 2015). However, additional studies are required to elucidate the complete molecular mechanisms associated with the anticancer effects of ginger. Other beneficial effects In addition to the above-mentioned bioactivities, ginger and its bioactive compounds have several other multiple health benefits. Recently, a study has reported that gin- ger demonstrated several positive effects on neuroin- flammatory disorders and memory function (Huh et al., 2018). 10-gingerol inhibited neuroinflammation through the suppression of NF-κB, NO, IL-1β, TNF-α and IL-6 in LPS-stimulated BV2 microglia culture model (Ho et al., 2013). Ginger extract alleviated scopolamine-induced memory deficits in mice. In addition, ginger extract pro- moted the formation of synapses in C6 glioma cells and Italian Journal of Food Science, 2022; 34 (3) 7 Nutritional implications of bioactive compounds of Ginger (Behroozeh et al., 2018). Similarly, 6-shogaol-made lipo- somes in a 1,2-dimyristoyl-sn-glycero-3-phosphoglyc- erol-sodium (DMPG-Na) carrier exhibited anticancer action both in vitro and in vivo. It was observed that 6-shogaol was released slower from liposomes compared to ginger oleoresin (Ahmad et al., 2015). In a recent in vitro study, drug delivery system was designed with gin- ger nanoparticles and chitosan for controlled release of 5-amino salicylic acid (5-ASA) to treat inflammatory bowel disease. It was concluded that design system for the controlled release of 5-ASA was appropriate and favorable at gastrointestinal pH and beneficial in treating inflamma- tory bowel disease (Markam and Bajpai, 2020). However, additional studies are required to investigate and develop ginger as an effective candidate of nanomedicines for treating different cancers and neurodegenerative diseases. Conclusion and future trends This review demonstrated the biological activities of ginger and its bioactive constituents in a number of dis- eases, with particular interest for having digestive stimu- lation and antioxidant potential, and anti-inflammatory, antiobesity, antidiabetic, cardiovascular and blood pro- tective, and anticancer activities. The underlying mech- anisms of ginger and its bioactive compounds were discussed from the context of modulating various cellular enzymes, including cytochrome p450, cyclooxygenases, lipoxygenases, Nrf2, NF-κB and several other pathways considering apoptotic and cell cycle check points. In addition, available information about the absorption and tissue distribution of ginger and its bioactive compounds was highlighted. The use of ginger and its bioactive com- pounds in nanomedicine, especially nano-formulations, was viewed in the light of available literature. The future studies should provide a complete under- standing of the interactions of ginger and its bioactive compounds. However, lack of knowledge makes it diffi- cult to use ginger in human clinical cases. Although nan- otechnology provides effective delivery system for ginger and its constituents, more pharmacokinetic and pharma- codynamics trials could provide in-depth information regarding the bioavailability and molecular pathways associated with these nano-formulations. Omic studies such as proteomics, transcriptomics and metabolomics are recommended to dig out the possible adverse reactions and molecular targets of ginger and its compounds. There is still a challenge for researchers to evaluate ginger and its constituents as nutraceuticals because of the complex systems that involve multiple signaling pathways, choice of route administration, dose optimization, intensity, and treatment duration. Notably, the efficacy of ginger and its active constituents against 72 h. Importantly, no free 6-shogaol, 6-, 8-, or 10- gingerol was detected and the calculated half-lives of these com- pounds was less than 2 h (Zick et al., 2008). Another clinical trial reported the pharmacokinetics of 6-shogaol, 6-, 8-, and 10-gingerols in colon tissues and plasma. Free forms of 6-shogaol and 10-gingerol were observed in plasma after oral intake, with a maximum level reach- ing in 1 h. However, no free forms of 6-gingerol and 8-gingerol were detected in plasma. The half-lives of these ginger constituents in plasma ranged from 1 to 3  h. Traces of 10-gingerol sulfate and glucuronide con- jugate were detected in colon tissue, while traces of free forms of 6-shogaol and 10-gingerol, as well as glucuron- ide metabolites of 6-shogaol and 6-, 8-, and 10-gingerol, were detected with a more sensitive technique 1 h after oral intake (Yu et al., 2011). In experimental mice, free 6-shogaol, 8-, and 10-gingerols were discovered in the plasma after single oral dose of ginger oleoresin (300 mg/ kg) whereas 6-gingerol administered orally at a rate of 50  mg/kg was excreted in bile as glucuronide conjugate over 60 h (Wang et al., 2009). In addition, 6-shogaol (78.5%) was excreted in bile over 48 h after oral intake (Asami et al., 2010). Nano-formulations Recently, owing to certain beneficial effects in treat- ing diseases, nano-formulations in nanomedicine have received increasing interest from researchers (Kumar et al., 2017). Nanomedicine has certain benefits in drug delivery system, for the drug is delivered at correct sites, thereby making drug absorption more successful (Aneja et al., 2014). Significant research is in progress in the area to study its pharmacokinetics, mechanisms and delivery along with exploring of new nanocomposites, such as hybrid polymer-metal composites or grapheme, for drug delivery (Rahman et al., 2015). Rahman et al. (2017) reviewed the therapeutic applica- tions and benefits of nano-formulations in the context of liposomal-based drug delivery. The study demonstrated that PEGylated nanoliposomal formulation of gingerol allowed a slower release of drug and enhanced its cyto- toxic effect in breast cancer MCF-7 cells compared to standard gingerol and liposomal gingerol. PEGylation has the advantage of controlled drug release and ensures longer blood circulation to reach the target site by pro- tecting liposomes against lipase enzymes and immune system (Khalili et al., 2013). Another research established that PEGylated nanolipo- somal gingerol proved more effective than the standard drug. The release of gingerol from nanoparticles enclosed in PEGylated nanoliposomal formulation (76% gingerol) was fast and instant at the start and then became slower 8 Italian Journal of Food Science, 2022; 34 (3) Ishfaq M et al. Drug Metabol Drug Interact. 18(3–4):159–190. https://doi. org/10.1515/DMDI.2001.18.3-4.159 Ahmad J., Akhter S., Rizwanullah M., Amin S., Rahman M., Ahmad M.Z., Rizvi M.A., Kamal M.A. and Ahmad F.J. 2015. Nanotechnology-based inhalation treatments for lung cancer: state of the art. Nanotechnol Sci Appl. 8:55–66. https://doi. org/10.2147/NSA.S49052 Ali B.H., Blunden G., Tanira M.O. and Nemmar A. 2008. Some phytochemical, pharmacological and toxicological properties of ginger (Zingiber officinale Roscoe): a review of recent research. Food Chem Toxicol. 46(2):409–420. https://doi.org/10.1016/j. fct.2007.09.085 Amran A.Z., Jantan I., Dianita R. and Buang F. 2015. Protective effects of the standardized extract of Zingiber officinale on myo- cardium against isoproterenol-induced biochemical and histo- pathological alterations in rats. Pharm Biol. 53(12):1795–1802. https://doi.org/10.3109/13880209.2015.1008147 Aneja P., Rahman M., Beg S., Aneja S., Dhingra V. and Chugh R. 2014. Cancer targeted magic bullets for effective treatment of cancer. Recent Pat Antiinfect Drug Discov 9(2):121–135. https:// doi.org/10.2174/1574891X10666150415120506 Ansari J.A., Ahmad M.K., Khan A.R., Fatima N., Khan H.J., Rastogi N., Mishra D.P. and Mahdi A.A. 2016. Anticancer and antioxidant activity of Zingiber officinale Roscoe rhizome. Indian J Exp Biol. 54(11):767–773. https://doi.org/10.9734/BJPR/2016/26198 Arablou T., Aryaeian N., Valizadeh M., Sharifi F., Hosseini A.F. and Djalali M. 2014. The effect of ginger consumption on glycemic status, lipid profile and some inflammatory markers in patients with type 2 diabetes mellitus. Int J Food Sci Nutr. 65(4):515–520. https://doi.org/10.3109/09637486.2014.880671 Asami A., Shimada T., Mizuhara Y., Asano T., Takeda S., Aburada T., Miyamoto K. and Aburada M. 2010. Pharmacokinetics of [6]-shogaol, a pungent ingredient of Zingiber officinale Roscoe (part I). J Nat Med. 64(3):281–287. https://doi.org/10.1007/ s11418-010-0404-y Behroozeh A., Mazloumi Tabrizi M., Kazemi S.M., Choupani E., Kabiri N., Ilbeigi D., Heidari Nasab A., Akbarzadeh Khiyavi  A. and Seif Kurdi A. 2018. Evaluation the anti-cancer effect of PEGylated nano-niosomal gingerol, on breast cancer cell lines (T47D), in vitro. Asian Pac J Cancer Prev. 19(3):645–648. Bhat B.G., Sambaiah K. and Chandrasekhara N. 1985. The effect of feeding fenugreek and ginger on bile composition in the albino rat. Nutr Rep Int. 32(5):1145–1151. Brahma Naidu P., Uddandrao V.V., Ravindar Naik R., Suresh P., Meriga B., Begum M.S., Pandiyan R. and Saravanan G. 2016. Ameliorative potential of gingerol: promising modulation of inflammatory factors and lipid marker enzymes expressions in HFD induced obesity in rats. Mol Cell Endocrinol 419:139–147. https://doi.org/10.1016/j.mce.2015.10.007 Chen H., Fu J., Chen H., Hu Y., Soroka D.N., Prigge J.R., Schmidt E.E., Yan F., Major M.B., Chen X. and Sang S. 2014. Ginger compound [6]-shogaol and its cysteine-conjugated metabolite (M2) acti- vate Nrf2 in colon epithelial cells in vitro and in vivo. Chem Res Toxicol. 27(9):1575–1585. https://doi.org/10.1021/tx500211x Du H., Li L., Bennett D., Guo Y., Key T.J., Bian Z., Sherliker P., Gao  H., Chen Y., Yang L., Chen J., Wang S., Du R., Su H., diseases requires more well-designed human clinical tri- als. Gas chromatography and high-performance liquid chromatography fingerprinting could provide valuable insights into the nutraceutical uses, and more bioactive compounds of ginger could be identified and isolated. Nevertheless, we established in this review the potential uses of ginger as a safe herbal medicine and food ingredi- ent for managing various diseases; still this spice deserves to be considered for additional investigations to enhance its bioavailability and controlled release via advance tech- nologies, including nano-formulations. Declaration of competing interest None. Acknowledgments The work was supported in 2021 by the Natural Science Foundation of Hubei Province of China (project name: Research on Brain Tumor Diagnosis Based on Capsule Neural Network), and the New Generation Information Technology Innovation Project, Ministry of Education (project No.: 20202020ITA05022), and Hundreds of Schools Unite with Hundreds of Counties-University Serving Rural Revitalization Science and Technology Support Action Plan (grant No.: BXLBX0847). Author contributions Muhammad Ishfaq was involved in the conceptualization of project, writing of original draft, review, and editing. Wanying Hu was involved in writing-review and editing. Ruihong Zhang did the visualization of project. Yurong Guan was involved in project administration and soft- ware. Zhihua Hu was involved in project administration and data curation. References Abolaji A.O., Ojo M., Afolabi T.T., Arowoogun M.D., Nwawolor D. and Farombi E.O. 2017. Protective properties of 6-gingerol-rich fraction from Zingiber officinale (Ginger) on chlorpyrifos- induced oxidative damage and inflammation in the brain, ovary and uterus of rats. Chem Biol Interact. 270:15–23. https://doi. org/10.1016/j.cbi.2017.03.017 Aeschbach R., Loliger J., Scott B.C., Murcia A., Butler J., Halliwell B. and Aruoma O.I. 1994. Antioxidant actions of thymol, carvacrol, 6-gingerol, zingerone and hydroxytyrosol. Food Chem Toxicol. 32(1):31–36. https://doi.org/10.1016/0278-6915(84)90033-4 Afzal M., Al-Hadidi D., Menon M., Pesek J. and Dhami M.S. 2001. Ginger: an ethnomedical, chemical and pharmacological review. https://doi.org/10.1515/DMDI.2001.18.3-4.159� https://doi.org/10.1515/DMDI.2001.18.3-4.159� https://doi.org/10.2147/NSA.S49052� https://doi.org/10.2147/NSA.S49052� https://doi.org/10.1016/j.fct.2007.09.085� https://doi.org/10.1016/j.fct.2007.09.085� https://doi.org/10.3109/13880209.2015.1008147� https://doi.org/10.2174/1574891X10666150415120506� https://doi.org/10.2174/1574891X10666150415120506� https://doi.org/10.9734/BJPR/2016/26198� https://doi.org/10.3109/09637486.2014.880671� https://doi.org/10.1007/s11418-010-0404-y� https://doi.org/10.1007/s11418-010-0404-y� https://doi.org/10.1016/j.mce.2015.10.007� https://doi.org/10.1021/tx500211x� https://doi.org/10.1016/j.cbi.2017.03.017� https://doi.org/10.1016/j.cbi.2017.03.017� https://doi.org/10.1016/0278-6915(84)90033-4� Italian Journal of Food Science, 2022; 34 (3) 9 Nutritional implications of bioactive compounds of Ginger oxidative stress and mitochondrial apoptosis induced by Interleukin-1beta in cultured chondrocytes. Cells Tissues Organs 204(5–6):241–250. https://doi.org/10.1159/000479789 Hsiang C.Y., Cheng H.M., Lo H.Y., Li C.C., Chou P.C., Lee Y.C. and Ho T.Y. 2015. Ginger and zingerone ameliorate lipopolysaccha- ride-induced acute systemic inflammation in mice, assessed by nuclear factor-kappab bioluminescent imaging. J Agric Food Chem. 63(26):6051–6058. https://doi.org/10.1021/acs. jafc.5b01801 Huh E., Lim S., Kim H.G., Ha S.K., Park H.Y., Huh Y. and Oh M.S. 2018. Ginger fermented with Schizosaccharomyces pombe alle- viates memory impairment via protecting hippocampal neuro- nal cells in amyloid beta1–42 plaque injected mice. Food Funct 9(1):171–178. https://doi.org/10.1039/C7FO01149K Hung J.Y., Hsu Y.L., Li C.T., Ko Y.C., Ni W.C., Huang M.S. and Kuo P.L. 2009. 6-Shogaol, an active constituent of dietary gin- ger, induces autophagy by inhibiting the AKT/mTOR pathway in human non-small cell lung cancer A549 cells. J Agric Food Chem. 57(20):9809–9816. https://doi.org/10.1021/jf902315e Ji K., Fang L., Zhao H., Li Q., Shi Y., Xu C., Wang Y., Du L., Wang J. and Liu Q. 2017. Ginger Oleoresin alleviated gamma-ray irradiation-induced reactive oxygen species via the Nrf2 protec- tive response in human mesenchymal stem cells. Oxid Med Cell Longev. 2017:1480294. https://doi.org/10.1155/2017/1480294 Jiang S.Z., Wang N.S. and Mi S.Q. 2008. Plasma pharmacokinetics and tissue distribution of [6]-gingerol in rats. Biopharm Drug Dispos. 29(9):529–537. https://doi.org/10.1002/bdd.638 Khalili M., Akbarzadeh A., Chiani M. and Torabi S. 2013. The effect of nanoliposomal and PE gylated nanoliposomal forms of 6-gin- gerol on breast cancer cells. 2:29–33. Khosravani M., Azarbayjani M.A., Abolmaesoomi M., Yusof A., Zainal Abidin N., Rahimi E., Feizolahi F., Akbari M., Seyedjalali  S. and Dehghan F. 2016. Ginger extract and aerobic training reduces lipid profile in high-fat fed diet rats. Eur Rev Med Pharmacol Sci. 20(8):1617–1622. Kim S.O., Chun K.S., Kundu J.K. and Surh Y.J. 2004. Inhibitory effects of [6]-gingerol on PMA-induced COX-2 expres- sion and activation of NF-kappaB and p38 MAPK in mouse skin. Biofactors. 21(1–4):27–31. https://doi.org/10.1002/ biof.552210107 Kim H.W., Oh D.H., Jung C., Kwon D.D. and Lim Y.C. 2011. Apoptotic effects of 6-gingerol in LNCaP human prostate can- cer cells. Soonchunhyang Med Sci. 17(2):75–79. https://doi. org/10.15746/sms.11.017 Kiuchi F., Iwakami S., Shibuya M., Hanaoka F. and Sankawa U. 1992. Inhibition of prostaglandin and leukotriene biosynthesis by gingerols and diarylheptanoids. Chem Pharm Bull (Tokyo). 40(2):387–391. https://doi.org/10.1248/cpb.40.387 Kumar V., Bhatt P.C., Rahman M., Kaithwas G., Choudhry H., Al-Abbasi F.A., Anwar F. and Verma A. 2017. Fabrication, optimization, and characterization of umbelliferone beta-D- galactopyranoside-loaded PLGA nanoparticles in treatment of hepatocellular carcinoma: in vitro and in vivo studies. Int J Nanomed. 12:6747–6758. https://doi.org/10.2147/IJN.S136629 Lee S.H., Cekanova M. and Baek S.J. 2008. Multiple mechanisms are involved in 6-gingerol-induced cell growth arrest and apoptosis Collins  R., Peto R., Chen Z. and S. China Kadoorie Biobank. 2016. Fresh fruit consumption and major cardiovascular dis- ease in China. N Engl J Med. 374(14):1332–1343. https://doi. org/10.1056/NEJMoa1501451 Ebrahimzadeh Attari V., Malek Mahdavi A., Javadivala Z., Mahluji S., Zununi Vahed S. and Ostadrahimi A. 2018. A systematic review of the anti-obesity and weight lowering effect of ginger (Zingiber officinale Roscoe) and its mechanisms of action. Phytother Res. 32(4):577–585. https://doi.org/10.1002/ptr.5986 Ebrahimzadeh Attari V., Ostadrahimi A., Asghari Jafarabadi M., Mehralizadeh S. and Mahluji S. 2016. Changes of serum adipo- cytokines and body weight following Zingiber officinale supple- mentation in obese women: a RCT. Eur J Nutr. 55(6):2129–2136. https://doi.org/10.1007/s00394-015-1027-6 ElRokh el S.M., Yassin N.A., El-Shenawy S.M. and Ibrahim B.M. 2010. Antihypercholesterolaemic effect of ginger rhizome (Zingiber officinale) in rats. Inflammopharmacol. 18(6):309– 315. https://doi.org/10.1007/s10787-010-0053-5 Ghayur M.N. and Gilani A.H. 2005. Ginger lowers blood pres- sure through blockade of voltage-dependent calcium chan- nels. J Cardiovasc Pharmacol. 45(1):74–80. https://doi.org/ 10.1097/00005344-200501000-00013 Ghayur M.N., Gilani A.H., Afridi M.B. and Houghton P.J. 2005. Cardiovascular effects of ginger aqueous extract and its phe- nolic constituents are mediated through multiple pathways. Vas Pharmacol. 43(4):234–241. https://doi.org/10.1016/j.vph. 2005.07.003 Gomar A., Hosseini A. and Mirazi N. 2014. Memory enhancement by administration of ginger (Zingiber officinale) extract on mor- phine-induced memory impairment in male rats. J Acute Dis. 3(3). https://doi.org/10.1016/S2221-6189(14)60047-0 Grzanna R., Lindmark L. and Frondoza C.G. 2005. Ginger— an herbal medicinal product with broad anti-inflammatory actions. J Med Food. 8(2):125–132. https://doi.org/10.1089/jmf. 2005.8.125 Gujral S., Bhumra H. and Swaroop M. 1978. Effect of gin- ger (Zingebar officinate Roscoe) oleoresin on serum and hepatic cholesterol levels in cholesterol fed rats. Nutr Rep Int. 17(2):183–189. Habib S.H.M., Makpol S., Hamid N.A.A., Das S., Ngah W.Z.W. and Yusof Y.A.M. 2008. Ginger extract (Zingiber officinale) has anti-cancer and anti-inflammatory effects on ethionine-induced hepatoma rats. Clinics. 63(6):807–813. https://doi.org/10.1590/ S1807-59322008000600017 Ho S.C., Chang K.S. and Lin C.C. 2013. Anti-neuroinflammatory capacity of fresh ginger is attributed mainly to 10-gingerol. Food Chem. 141(3):3183–3191. https://doi.org/10.1016/j. foodchem.2013.06.010 Hosseini A. and Mirazi N. 2014. Acute administration of ginger (Zingiber officinale rhizomes) extract on timed intravenous pentylenetetrazol infusion seizure model in mice. Epilepsy Res. 108(3):411–419. https://doi.org/10.1016/j.eplepsyres.2014. 01.008 Hosseinzadeh A., Bahrampour Juybari K., Fatemi M.J., Kamarul T., Bagheri A., Tekiyehmaroof N. and Sharifi A.M. 2017. Protective effect of ginger (Zingiber officinale Roscoe) extract against https://doi.org/10.1159/000479789� https://doi.org/10.1021/acs.jafc.5b01801� https://doi.org/10.1021/acs.jafc.5b01801� https://doi.org/10.1039/C7FO01149K� https://doi.org/10.1021/jf902315e� https://doi.org/10.1155/2017/1480294� https://doi.org/10.1002/bdd.638� https://doi.org/10.1002/biof.552210107� https://doi.org/10.1002/biof.552210107� https://doi.org/10.15746/sms.11.017� https://doi.org/10.15746/sms.11.017� https://doi.org/10.1248/cpb.40.387� https://doi.org/10.2147/IJN.S136629� https://doi.org/10.1056/NEJMoa1501451� https://doi.org/10.1056/NEJMoa1501451� https://doi.org/10.1002/ptr.5986� https://doi.org/10.1007/s00394-015-1027-6� https://doi.org/10.1007/s10787-010-0053-5� https://doi.org/10.1097/00005344-200501000-00013� https://doi.org/10.1097/00005344-200501000-00013� https://doi.org/10.1016/j.vph.2005.07.003� https://doi.org/10.1016/j.vph.2005.07.003� https://doi.org/10.1016/S2221-6189(14)60047-0� https://doi.org/10.1089/jmf.2005.8.125� https://doi.org/10.1089/jmf.2005.8.125� https://doi.org/10.1590/S1807-59322008000600017� https://doi.org/10.1590/S1807-59322008000600017� https://doi.org/10.1016/j.foodchem.2013.06.010� https://doi.org/10.1016/j.foodchem.2013.06.010� https://doi.org/10.1016/j.eplepsyres.2014.01.008� https://doi.org/10.1016/j.eplepsyres.2014.01.008� 10 Italian Journal of Food Science, 2022; 34 (3) Ishfaq M et al. officinale Roscoe). Foods. 8(6): 185. https://doi.org/10.3390/ foods8060185 Markam R. and Bajpai A.K. 2020. Functionalization of ginger derived nanoparticles with chitosan to design drug delivery system for con- trolled release of 5-amino salicylic acid (5-ASA) in treatment of inflammatory bowel diseases: an in vitro study. React Funct Polym. 149:104520. https://doi.org/10.1016/j.reactfunctpolym.2020.104520 Martin A., Fuzer A.M., Becceneri A.B., da Silva J.A., Tomasin  R., Denoyer D., Kim S.H., McIntyre K.A., Pearson H.B., Yeo  B., Nagpal A., Ling X., Selistre-de-Araujo H.S., Vieira P.C., Cominetti M.R. and Pouliot N. 2017. [10]-Gingerol induces apoptosis and inhibits metastatic dissemination of triple neg- ative breast cancer in vivo. Oncotarget. 8(42):72260–72271. https://doi.org/10.18632/oncotarget.20139 Misawa K., Hashizume K., Yamamoto M., Minegishi Y., Hase T. and Shimotoyodome A. 2015. Ginger extract prevents high-fat diet-induced obesity in mice via activation of the peroxisome proliferator-activated receptor delta pathway. J Nutr Biochem. 26(10):1058–1067. https://doi.org/10.1016/j.jnutbio.2015.04.014 Mustafa, T., Srivastava K.C. and Jensen K.B. 1993. Drug develop- ment report 9. Pharmacology of ginger. Natalia D., Valero-Muñoz M., Martín-Fernández B., Ballesteros S., López-Farré A., Ruiz-Roso B. and Lahera V. 2017. Molecular factors involved in the hypolipidemic- and insulin-sensitizing effects of a ginger (Zingiber officinale Roscoe) extract in rats fed a high-fat diet. Appl Physiol Nutr Metab. 42(2):209–215. https:// doi.org/10.1139/apnm-2016-0374 Nile S.H. and Park S.W. 2015. Chromatographic analysis, antioxi- dant, anti-inflammatory, and xanthine oxidase inhibitory activi- ties of ginger extracts and its reference compounds. Indust Crops Prod. 70:238–244. https://doi.org/10.1016/j.indcrop.2015.03.033 Oh S., Lee M.S., Jung S., Kim S., Park H., Park S., Kim S.Y., Kim C.T., Jo Y.H. and Kim I.H. 2017. Ginger extract increases muscle mitochondrial biogenesis and serum HDL-cholesterol level in high-fat diet-fed rats. J Funct Foods. 29:193–200. https://doi. org/10.1016/j.jff.2016.12.023 Oyagbemi A.A., Saba A.B. and Azeez O.I. 2010. Molecular targets of [6]-gingerol: Its potential roles in cancer chemoprevention. Biofactors. 36(3):169–178. https://doi.org/10.1002/biof.78 Pan M.H., Hsieh M.C., Kuo J.M., Lai C.S., Wu H., Sang S. and Ho  C.T. 2008. 6-Shogaol induces apoptosis in human colorec- tal carcinoma cells via ROS production, caspase activation, and GADD 153 expression. Mol Nutr Food Res. 52(5):527–537. https://doi.org/10.1002/mnfr.200700157 Peng L.Q., Cao J., Du L.J., Zhang Q.D., Xu J.J., Chen Y.B., Shi Y.T. and Li R.R. 2017. Rapid ultrasonic and microwave-assisted micellar extraction of zingiberone, shogaol and gingerols from gingers using biosurfactants. J Chromatogr A. 1515:37–44. https://doi. org/10.1016/j.fitote.2011.12.028 Peng F., Tao Q., Wu X., Dou H., Spencer S., Mang C., Xu L., Sun L., Zhao Y., Li H., Zeng S., Liu G. and Hao X. 2012. Cytotoxic, cytoprotective and antioxidant effects of isolated phenolic com- pounds from fresh ginger. Fitoterapia. 83(3):568–585. https:// doi.org/10.1016/j.fitote.2011.12.028 Peng S., Yao J., Liu Y., Duan D., Zhang X. and Fang J. 2015. Activation of Nrf2 target enzymes conferring protection against in human colorectal cancer cells. Mol Carcinog. 47(3):197–208. https://doi.org/10.1002/mc.20374 Li Y., Hong Y., Han Y., Wang Y. and Xia L. 2016. Chemical char- acterization and antioxidant activities comparison in fresh, dried, stir-frying and carbonized ginger. J Chromatogr B Analyt Technol Biomed Life Sci. 1011:223–232. https://doi. org/10.1016/j.jchromb.2016.01.009 Li Y., Tran V.H., Duke C.C. and Roufogalis B.D. 2012. Preventive and protective properties of Zingiber officinale (ginger) in diabetes mellitus, diabetic complications, and associated lipid and other metabolic disorders: a brief review. Evid Based Compl Alternat Med. 2012:516870. https://doi.org/10.1155/2012/516870 Li Y., Tran V.H., Kota B.P., Nammi S., Duke C.C. and Roufogalis B.D. 2014. Preventative effect of Zingiber officinale on insulin resis- tance in a high-fat high-carbohydrate diet-fed rat model and its mechanism of action. Basic Clin Pharmacol Toxicol. 115(2):209– 215. https://doi.org/10.1111/bcpt.12196 Li Z., Wang Y., Gao M.L., Cui W., Zeng M., Cheng Y. and Li J. 2018. Nine new gingerols from the rhizoma of Zingiber officinale and their cytotoxic activities. Molecules. 23(2):315. https://doi. org/10.3390/molecules23020315 Li, F, Wang Y., Parkin K.L., Nitteranon V., Liang J., Yang W., Li Y., Zhang G. and Hu Q. 2011. Isolation of quinone reductase (QR) inducing agents from ginger rhizome and their in vitro anti- inflammatory activity. Food Res Int. 44(6):1597–1603. https:// doi.org/10.1016/j.foodres.2011.04.010 Lim S., Moon M., Oh H., Kim H.G., Kim S.Y. and Oh M.S. 2014. Ginger improves cognitive function via NGF-induced ERK/ CREB activation in the hippocampus of the mouse. J Nutr Biochem. 25(10):1058–1065. https://doi.org/10.1016/j.jnutbio. 2014.05.009 Liu Q., Peng Y.B., Zhou P., Qi L.W. and Li P. 2013. 6-Shogaol induces apoptosis in human leukemia cells through a process involving caspase-mediated cleavage of eIF2α. Mol Cancer. 12(1):1–12. https://doi.org/10.1186/1476-4598-12-135 Luettig J., Rosenthal R., Lee I.M., Krug S.M. and Schulzke J.D. 2016. The ginger component 6-shogaol prevents TNF-alpha-induced barrier loss via inhibition of PI3K/Akt and NF-kappaB signaling. Mol Nutr Food Res. 60(12):2576–2586. https://doi.org/10.1002/ mnfr.201600274 Lv L., Chen H., Soroka D., Chen X., Leung T.C. and Sang S. 2012. 6-Gingerdiols as the major metabolites of 6-gingerol in cancer cells and in mice and their cytotoxic effects on human cancer cells. J Agric Food Chem. 60(45):11372–11377. https://doi. org/10.1021/jf303879b Mahmoud R.H. and Elnour W.A. 2013. Comparative evaluation of the efficacy of ginger and orlistat on obesity management, pan- creatic lipase and liver peroxisomal catalase enzyme in male albino rats. Eur Rev Med Pharmacol Sci. 17(1):75–83. Mahomoodally M.F., Aumeeruddy M.Z., Rengasamy K.R.R., Roshan S., Hammad S., Pandohee J., Hu X. and Zengin G. 2021. Ginger and its active compounds in cancer therapy: from folk uses to nano-therapeutic applications. Semin Cancer Biol. 69:140–149. https://doi.org/10.1016/j.semcancer.2019.08.009 Mao Q.Q., Xu X.Y., Cao S.Y., Gan R.Y., Corke H., Beta T. and Li H.B. 2019. Bioactive compounds and bioactivities of ginger (Zingiber https://doi.org/10.3390/foods8060185� https://doi.org/10.3390/foods8060185� https://doi.org/10.1016/j.reactfunctpolym.2020.104520� https://doi.org/10.18632/oncotarget.20139� https://doi.org/10.1016/j.jnutbio.2015.04.014� https://doi.org/10.1139/apnm-2016-0374 https://doi.org/10.1139/apnm-2016-0374 https://doi.org/10.1016/j.indcrop.2015.03.033� https://doi.org/10.1016/j.jff.2016.12.023� https://doi.org/10.1016/j.jff.2016.12.023� https://doi.org/10.1002/biof.78� https://doi.org/10.1002/mnfr.200700157� https://doi.org/10.1016/j.fitote.2011.12.028� https://doi.org/10.1016/j.fitote.2011.12.028� https://doi.org/10.1016/j.fitote.2011.12.028� https://doi.org/10.1016/j.fitote.2011.12.028� https://doi.org/10.1002/mc.20374� https://doi.org/10.1016/j.jchromb.2016.01.009� https://doi.org/10.1016/j.jchromb.2016.01.009� https://doi.org/10.1155/2012/516870� https://doi.org/10.1111/bcpt.12196� https://doi.org/10.3390/molecules23020315� https://doi.org/10.3390/molecules23020315� https://doi.org/10.1016/j.foodres.2011.04.010� https://doi.org/10.1016/j.foodres.2011.04.010� https://doi.org/10.1016/j.jnutbio.2014.05.009� https://doi.org/10.1016/j.jnutbio.2014.05.009� https://doi.org/10.1186/1476-4598-12-135� https://doi.org/10.1002/mnfr.201600274� https://doi.org/10.1002/mnfr.201600274� https://doi.org/10.1021/jf303879b� https://doi.org/10.1021/jf303879b� https://doi.org/10.1016/j.semcancer.2019.08.009� Italian Journal of Food Science, 2022; 34 (3) 11 Nutritional implications of bioactive compounds of Ginger and Havt A. 2014. Gingerol fraction from Zingiber offici- nale protects against gentamicin-induced nephrotoxicity. Antimicrob Agents Chemother. 58(4):1872–1878. https://doi. org/10.1128/AAC.02431-13 Saberi H., Keshavarzi B., Shirpoor A., Gharalari F.H. and Rasmi Y. 2017. Rescue effects of ginger extract on dose dependent radiation- induced histological and biochemical changes in the kidneys of male Wistar rats. Biomed Pharmacother. 94:569–576. https://doi.org/10.1016/j.biopha.2017.07.128 Samad M.B., Mohsin M., Razu B.A., Hossain M.T., Mahzabeen S., Unnoor N., Muna I.A., Akhter F., Kabir A.U. and Hannan J.M.A. 2017. [6]-Gingerol, from Zingiber officinale, potentiates GLP-1 mediated glucose-stimulated insulin secretion pathway in pan- creatic beta-cells and increases RAB8/RAB10-regulated mem- brane presentation of GLUT4 transporters in skeletal muscle to improve hyperglycemia in Lepr(db/db) type 2 diabetic mice. BMC Compl Altern Med. 17(1):395. https://doi.org/10.1186/ s12906-017-1903-0 Sambaiah K. and Srinivasan K. 1991. Effect of cumin, cinnamon, ginger, mustard and tamarind in induced hypercholesterol- emic rats. Nahrung. 35 (1):47–51. https://doi.org/10.1002/ food.19910350112 Sampath C., Rashid M.R., Sang S. and Ahmedna M. 2017. Specific bioactive compounds in ginger and apple alleviate hyperglyce- mia in mice with high fat diet-induced obesity via Nrf2 medi- ated pathway. Food Chem. 226:79–88. https://doi.org/10.1016/j. foodchem.2017.01.056 Shanmugam K.R., Mallikarjuna K., Kesireddy N. and Sathyavelu Reddy K. 2011. Neuroprotective effect of ginger on anti- oxidant enzymes in streptozotocin-induced diabetic rats. Food Chem Toxicol. 49(4):893–897. https://doi.org/10.1016/j. fct.2010.12.013 Sharma J.N., Srivastava K.C. and Gan E.K. 1994. Suppressive effects of eugenol and ginger oil on arthritic rats. Pharmacology. 49(5):314–318. https://doi.org/10.1159/000139248 Shukla Y. and Singh M. 2007. Cancer preventive properties of gin- ger: a brief review. Food Chem Toxicol. 45(5):683–690. https:// doi.org/10.1016/j.fct.2006.11.002 Siddaraju M.N. and Dharmesh S.M. 2007. Inhibition of gastric H+, K+-ATPase and helicobacter pylori growth by phenolic antioxi- dants of Zingiber officinale. Mol Nutr Food Res. 51(3):324–332. https://doi.org/10.1002/mnfr.200600202 Srinivasan K. 2014. Antioxidant potential of spices and their active constituents. Crit Rev Food Sci Nutr. 54(3):352–372. https://doi. org/10.1080/10408398.2011.585525 Srinivasan K. 2017. Ginger rhizomes (Zingiber officinale): a spice with multiple health beneficial potentials. Pharma Nutr. 5 (1):18–28. https://doi.org/10.1016/j.phanu.2017.01.001 Takada Y., Murakami A. and Aggarwal B.B. 2005. Zerumbone abolishes NF-kappaB and IkappaB alpha kinase activation leading to suppression of antiapoptotic and metastatic gene expression, upregulation of apoptosis, and downregulation of invasion. Oncogene. 24(46):6957–6969. https://doi.org/10.1038/ sj.onc.1208845 Tan B.S., Kang O., Mai C.W., Tiong K.H., Khoo S.B., Pichika M.R., Bradshaw T.D. and Leong C.O. 2013. 6-Shogaol inhibits breast oxidative stress in PC12 cells by ginger principal constituent 6-shogaol. Food Funct. 6(8):2813–2823. https://doi.org/10.1039/ C5FO00214A Platel K. and Srinivasan K. 1996. Influence of dietary spices or their active principles on digestive enzymes of small intestinal mucosa in rats. Int J Food Sci Nutr. 47(1):55–59. https://doi. org/10.3109/09637489609028561 Platel K. and Srinivasan K. 2000. Influence of dietary spices and their active principles on pancreatic digestive enzymes in albino rats. Food Nahrung. 44(1):42–46. https://doi.org/10.1002/ (SICI)1521-3803(20000101)44:1<42::AID-FOOD42>3.0.CO;2-D Platel K. and Srinivasan K. 2004. Digestive stimulant action of spices: a myth or reality? Indian J Med Res. 119(5):167–179. Poprac P., Jomova K., Simunkova M., Kollar V., Rhodes C.J. and Valko M. 2017. Targeting free radicals in oxidative stress-related human diseases. Trends Pharmacol Sci. 38(7):592–607. https:// doi.org/10.1016/j.tips.2017.04.005 Prakash U.N. and Srinivasan K. 2010a. Beneficial influence of dietary spices on the ultrastructure and fluidity of the intes- tinal brush border in rats. Br J Nutr. 104(1):31–39. https://doi. org/10.1017/S0007114510000334 Prakash U.N. and Srinivasan K. 2010b. Gastrointestinal protective effect of dietary spices during ethanol-induced oxidant stress in experimental rats. Appl Physiol Nutr Metab. 35(2):134–141. https://doi.org/10.1139/H09-133 Prakash U.N. and Srinivasan K. 2012. Fat digestion and absorption in spice-pretreated rats. J Sci Food Agric. 92(3):503–510. https:// doi.org/10.1002/jsfa.4597 Prakash U.N.S. and Srinivasan K. 2013. Enhanced intestinal uptake of iron, zinc and calcium in rats fed pungent spice principles— piperine, capsaicin and ginger (Zingiber officinale). J Trace Elements Med Biol. 27(3):184–190. https://doi.org/10.1016/j. jtemb.2012.11.003 Qi, L.W., Zhang Z., Zhang C.F., Anderson S., Liu Q., Yuan C.S. and Wang C.Z. 2015. Anti-colon cancer effects of 6-Shogaol through G2/M cell cycle arrest by p53/p21-cdc2/cdc25A cross- talk. Am J Chin Med. 43(04):743–756. https://doi.org/10.1142/ S0192415X15500469 Radhakrishnan E.K., Bava S.V., Narayanan S.S., Nath L.R., Thulasidasan A.K., Soniya E.V. and Anto R.J. 2014. [6]-Gingerol induces caspase-dependent apoptosis and prevents PMA-induced prolifera- tion in colon cancer cells by inhibiting MAPK/AP-1 signaling. PLoS One. 9(8):e104401. https://doi.org/10.1371/journal.pone.0104401 Rahman M., Akhter S., Ahmad M.Z., Ahmad J., Addo R.T., Ahmad  F.J. and Pichon C. 2015. Emerging advances in cancer nanotheranostics with graphene nanocomposites: opportuni- ties and challenges. Nanomedicine (Lond). 10 (15):2405–2422. https://doi.org/10.2217/nnm.15.68 Rahman M., Beg S., Verma A., Kazmi I., Patel D.K., Anwar F., Al Abbasi F.A. and Kumar V. 2017. Therapeutic applications of liposomal based drug delivery and drug targeting for immune linked inflammatory maladies: a contemporary view point. Curr Drug Targets. 18(13):1558–1571. https://doi.org/10.2174/13894 50118666170414113926 Rodrigues F.A., Prata M.M., Oliveira I.C., Alves N.T., Freitas R.E., Monteiro H.S., Silva J.A., Vieira P.C., Viana D.A., Liborio  A.B. https://doi.org/10.1128/AAC.02431-13� https://doi.org/10.1128/AAC.02431-13� https://doi.org/10.1016/j.biopha.2017.07.128� https://doi.org/10.1186/s12906-017-1903-0� https://doi.org/10.1186/s12906-017-1903-0� https://doi.org/10.1002/food.19910350112� https://doi.org/10.1002/food.19910350112� https://doi.org/10.1016/j.foodchem.2017.01.056� https://doi.org/10.1016/j.foodchem.2017.01.056� https://doi.org/10.1016/j.fct.2010.12.013� https://doi.org/10.1016/j.fct.2010.12.013� https://doi.org/10.1159/000139248� https://doi.org/10.1016/j.fct.2006.11.002� https://doi.org/10.1016/j.fct.2006.11.002� https://doi.org/10.1002/mnfr.200600202� https://doi.org/10.1080/10408398.2011.585525� https://doi.org/10.1080/10408398.2011.585525� https://doi.org/10.1016/j.phanu.2017.01.001� https://doi.org/10.1038/sj.onc.1208845� https://doi.org/10.1038/sj.onc.1208845� https://doi.org/10.1039/C5FO00214A� https://doi.org/10.1039/C5FO00214A� https://doi.org/10.3109/09637489609028561� https://doi.org/10.3109/09637489609028561� https://doi.org/10.1002/(SICI)1521-3803(20000101)44:1<42::AID-FOOD42>3.0.CO;2-D� https://doi.org/10.1002/(SICI)1521-3803(20000101)44:1<42::AID-FOOD42>3.0.CO;2-D� https://doi.org/10.1016/j.tips.2017.04.005� https://doi.org/10.1016/j.tips.2017.04.005� https://doi.org/10.1017/S0007114510000334� https://doi.org/10.1017/S0007114510000334� https://doi.org/10.1139/H09-133� https://doi.org/10.1002/jsfa.4597� https://doi.org/10.1002/jsfa.4597� https://doi.org/10.1016/j.jtemb.2012.11.003� https://doi.org/10.1016/j.jtemb.2012.11.003� https://doi.org/10.1142/S0192415X15500469� https://doi.org/10.1142/S0192415X15500469� https://doi.org/10.1371/journal.pone.0104401� https://doi.org/10.2217/nnm.15.68� https://doi.org/10.2174/1389450118666170414113926� https://doi.org/10.2174/1389450118666170414113926� 12 Italian Journal of Food Science, 2022; 34 (3) Ishfaq M et al. Yeh H.-y., Chuang C.-h., Chen H.-c., Wan C.-j., Chen T.-l. and Lin  L.-y. 2014. Bioactive components analysis of two various gingers (Zingiber officinale Roscoe) and antioxidant effect of ginger extracts. LWT Food Sci Technol. 55(1):329–334. https:// doi.org/10.1016/j.lwt.2013.08.003 Yu Y., Zick S., Li X., Zou P., Wright B. and Sun D. 2011. Examination of the pharmacokinetics of active ingredients of ginger in humans. AAPS J. 13(3):417–426. https://doi.org/10.1208/ s12248-011-9286-5 Zehsaz F., Farhangi N. and Mirheidari L. 2014. The effect of Zingiber officinale R. rhizomes (ginger) on plasma pro-inflam- matory cytokine levels in well-trained male endurance runners. Cent Eur J Immunol. 39(2):174–180. https://doi.org/10.5114/ ceji.2014.43719 Zhang G., Nitteranon V., Chan L.Y. and Parkin K.L. 2013. Glutathione conjugation attenuates biological activities of 6-dehydroshogaol from ginger. Food Chem. 140(1–2):1–8. https://doi.org/10.1016/j.foodchem.2013.02.073 Zhu Y., Zhao Y., Wang P., Ahmedna M. and Sang S. 2015. Bioactive ginger constituents alleviate protein glycation by trapping meth- ylglyoxal. Chem Res Toxicol. 28(9):1842–1849. https://doi. org/10.1021/acs.chemrestox.5b00293 Zick S.M., Djuric Z., Ruffin M.T., Litzinger A.J., Normolle D.P., Alrawi S., Feng M.R. and Brenner D.E. 2008. Pharmacokinetics of 6-gingerol, 8-gingerol, 10-gingerol, and 6-shogaol and conjugate metabolites in healthy human subjects. Cancer Epidemiol Biomarkers Prev. 17(8):1930–1936. https://doi. org/10.1158/1055-9965.EPI-07-2934 and colon cancer cell proliferation through activation of peroxi- somal proliferator activated receptor γ (PPARγ). Cancer Lett. 336(1):127–139. https://doi.org/10.1016/j.canlet.2013.04.014 Thomson M., Al-Qattan K.K., Al-Sawan A.M., Alnaqeeb M.A., Khan I. and Ali M. 2002. The use of ginger (Zingiber officinale Rosc.) as a potential anti-inflammatory and antithrombotic agent. Prostaglandins Leukot Essential Fatty Acids. 67(6):475– 478. https://doi.org/10.1054/plef.2002.0441 Tripathi S., Bruch D. and Kittur D.S. 2008. Ginger extract inhibits LPS induced macrophage activation and function. BMC Compl Altern Med. 8:1. https://doi.org/10.1186/1472-6882-8-1 van Breemen R.B., Tao Y. and Li W. 2011. Cyclooxygenase-2 inhib- itors in ginger (Zingiber officinale). Fitoterapia. 82(1):38–43. https://doi.org/10.1016/j.fitote.2010.09.004 Veda S. and Srinivasan K. 2011. Influence of dietary spices on the in vivo absorption of ingested beta-carotene in experimental rats. Br J Nutr. 105(10):1429–1438. https://doi.org/10.1017/ S0007114510005179 Wang W., Li C.Y., Wen X.D., Li P. and Qi L.W. 2009. Simultaneous determination of 6-gingerol, 8-gingerol, 10-gingerol and 6-shogaol in rat plasma by liquid chromatography-mass spec- trometry: application to pharmacokinetics. J Chromatogr B Anal Technol Biomed Life Sci. 877(8–9):671–679. https://doi. org/10.1016/j.jchromb.2009.01.021 Wei C.K., Tsai Y.H., Korinek M., Hung P.H., El-Shazly M., Cheng Y.B., Wu Y.C., Hsieh T.J. and Chang F.R. 2017. 6-Paradol and 6-shogaol, the pungent compounds of ginger, promote glucose utilization in adipocytes and myotubes, and 6-paradol reduces blood glucose in high-fat diet-fed mice. Int J Mol Sci. 18(1):168. https://doi.org/10.3390/ijms18010168 https://doi.org/10.1016/j.lwt.2013.08.003� https://doi.org/10.1016/j.lwt.2013.08.003� https://doi.org/10.1208/s12248-011-9286-5� https://doi.org/10.1208/s12248-011-9286-5� https://doi.org/10.5114/ceji.2014.43719� https://doi.org/10.5114/ceji.2014.43719� https://doi.org/10.1016/j.foodchem.2013.02.073� https://doi.org/10.1021/acs.chemrestox.5b00293� https://doi.org/10.1021/acs.chemrestox.5b00293� https://doi.org/10.1158/1055-9965.EPI-07-2934� https://doi.org/10.1158/1055-9965.EPI-07-2934� https://doi.org/10.1016/j.canlet.2013.04.014� https://doi.org/10.1054/plef.2002.0441� https://doi.org/10.1186/1472-6882-8-1� https://doi.org/10.1016/j.fitote.2010.09.004� https://doi.org/10.1017/S0007114510005179� https://doi.org/10.1017/S0007114510005179� https://doi.org/10.1016/j.jchromb.2009.01.021� https://doi.org/10.1016/j.jchromb.2009.01.021� https://doi.org/10.3390/ijms18010168� _Hlk37838113 _Hlk99541523 OLE_LINK14 OLE_LINK16 OLE_LINK15 OLE_LINK17 _Hlk38970032 _Hlk95556063