Recently, diarylheptanoids with a class term of 1,7-diarylheptane skeleton have gathered an increasing interest (Zhang et al., 2021). Literature is replete with a total of 41 diarylheptanoids compounds derived from ginger e.g. Bisgingerdiones B, Dihydrocurcumin, Hexahydrocurcumin, 6-gingeroldiacetate, and 8-isodehydrogingerdion (Figure 1) (Ma et al., 2004; Jiang et al., 2007; Feng et al., 2011; Hong and Oh, 2012; Olennikov and Kashchenko, 2015). These metabolites possess chemopreventive, anti-hepatotoxic, anti-inflammatory, antioxidant, and anti-tumor (Zhang et al., 2021).

Several gingerol analogues such as gingerols, paradols, shogaols, and zingerone possess biting and hot sensations in the mouth and they also exhibit pharmacological effects (Figure 2) (Kubra and Rao, 2012). Gingerols (6-gingerol, 8-gingerol, and 10-gingerol) are the most abundant polyphenol in fresh ginger. Upon dehydration or long-time storage, it can be converted into shogaols which is twice hotter than gingerols. The hydrogenation of shogaols produces paradols (Stoner, 2013). According to Zhang et al. (2021) fresh ginger is not as pungent as dried ginger. In recent years, seventy gingerols analogues compounds have been isolated from ginger such as (5S)-6-gingerol, (5S)-methyl-8-gingerol, (5S)-5-methoxy-6-gingerol, (3R,5S)-6-gingerdiol, dehydro-14-gingerdione, just to mention a few (Jiang et al., 2005; Feng et al., 2011; Lee et al., 2011; Pan et al., 2019).

Six phenylalkanoids compounds (3-hydroxy-1-(4′-hydroxy-3′-methoxy-phenyl)-hexan-5-one, 3-hydroxy-1-(3′,5′-dimethoxy-4′-hydroxyphenyl)-hexan-5-one, 5-hydroxy-1-(4′,5′-dihydroxy-3′-methoxyphenyl)dodecan-3-one, 1-(4′,5′-dihydroxy-3′-methoxyphenyl)dodec-4-en-3-one, (E)-3-hydroxy-1-(4′-dihydroxy-3′,5′-dimethoxy-phenyl)-dodecan-6-en-5-one and (E)-3-hydroxy-1-(4-hydroxy-3,5-dimethoxyphenyl)-tetradecan-6-en-5-one) have been reported to present in ginger rhizome (Chen et al., 2011; Chen and Yeh, 2011; Kuo et al., 2012; Li et al., 2013; Wang et al., 2018).

Additionally, six sulfonates compounds have been isolated from ginger, they are 4-gingesulfonic acid, 6-gingesulfonic acid, and shogasulfonic acids A-D (Figure 3) (Hori et al., 2003).

A total of six steroids compounds including β-sitosterol, daucosterol, stigmast-4-en-3,6-dione, 6β-hydroxystigmast-4-en-3-one, stigmast-4-en-3-one, and stigmasterol have been reported in ginger (Feng et al., 2011). Furthermore, Guo et al. (2018) isolated six monoterpenoid glycosides (Trans-3-hydroxy-1,8-cineole 3,6-dihydroxy 3-O-β-D-glucopyranoside, Trans-3-hydroxy-1,8-cineole3-O-β-D-glucopyranoside,5,9-dihydroxyborneol2-O-β-D-glucopyranoside, Angelicoidenol 2-O-β-D-glucopyranoside, Vicodiol 2-O-β-D-glucopyranoside, and Zingiberoside C) from the fresh rhizome of tongling white ginger (Figure 4).

Several components of terpenes such as monoterpenes and sesquiterpenes are known to be volatile fractions (Butt and Sultan, 2011). The savory component of ginger is attributed to the presence of sesquiterpenes, while monoterpenes are the most abundant terpenes in fresh ginger oil (Dhanik et al., 2017; Balogun et al., 2019). Furthermore, diverse components present in ginger essential oils are responsible for its aromatic scent, these are such as β-bisabolene, α-curcumene, α-farnesene, β-sesquiphellandrene, and zingiberene (Figure 5) (Prasad and Tyagi, 2015).

A double-blind clinical trial study by Javid et al. (2019) evaluated the effects of ginger supplementation on inflammatory, antioxidant, and periodontal parameters in 46 patients with type 2 diabetes mellitus (T2DM) and chronic periodontitis (CP). Treatment with 4 tablets of 500 mg (2 g) of ginger twice per day for 8 weeks with non-surgical periodontal therapy (NSPT) significantly decreased mean levels of tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), pocket depth (PD), hs-C-reactive protein (hs-CRP), clinical attachment loss (CAL) as compared to controls. Also, treatment induced a significant increase in mean serum levels of superoxide dismutase (SOD) and glutathione peroxidase (GPx). It has been suggested that ginger supplementation with NSPT could be recommended for type 2 diabetic patients with CP (Javid et al., 2019).

In another randomized double-blind clinical trial was conducted by (Mohammadzadeh Honarvar and colleagues (2019), 48 diabetic patients were grouped for ginger (2 g) or placebo treatment for 10 weeks. The results demonstrated decreased nuclear factor kappa B (NF-κB) concentration after ginger consumption, but statistically not important. Also, the results showed no significant effect on the anthropometric parameters (hip and waist circumference, and body mass index (BMI) compared to placebo. Owing to insignificant findings, the study suggested that further studies are needed (Mohammadzadeh Honarvar et al., 2019).

In a randomized controlled clinical trial was conducted by Rahimlou et al. (2019), 37 patients with metabolic syndrome (MetS) were randomly allocated to receive ginger powder (2 g) or a placebo for 12 weeks. The application of ginger significantly improved the levels of triglyceride (TG), fasting blood glucose, and insulin resistance as compared to the placebo group. The authors also observed improvements in patients' body weight, waist circumference, total cholesterol level (LDL and HDL), blood pressure, as well as energy intake (Rahimlou et al., 2019).

Recently, a randomized double-blind placebo-controlled clinical trial performed by Hajimoosayi et al. (2020), the determined effect of ginger on the blood glucose level of 70 pregnant women with gestational diabetes mellitus (GDM). They were randomly separated into the ginger group obtained 126 tablets, and the placebo group had 126 tablets for 6 weeks. A significant decrease in fasting blood glucose, fasting insulin, Homeostasis Model Assessment (HOMA) index was observed in the ginger group compared to the placebo group. However, there was no significant reduction in mean blood sugar 2 h post-prandial in both groups (Hajimoosayi et al., 2020).

Another randomized, controlled, and triple-blind clinical trial by Badooei et al. (2021) compared the effects of ginger and aloe vera mouthwashes on xerostomia in type 2 diabetic (TD2) patients. Ginger mouthwash, aloe vera mouthwash, or placebo were used by one-hundred and five (105) patients for 20 ccs three times a day for 14 consecutive days. The study revealed a considerable decreased in all symptoms and severity of xerostomia using ginger and aloe vera mouthwashes. In diabetic patients, a 6.12 ± 2.04 cm decrease of xerostomia was recorded in the ginger group, 4.08 ± 2.09 cm in the aloe vera group when comparing with placebo. The results concluded that ginger mouthwash can effectively ameliorate xerostomia, hence could be prescribed for dry mouth in T2D patients (Badooei et al., 2021).

Research by Fajrin et al. (2018) examined and predicted the binding ability of two ginger constituents to the Transient Receptor potential Vanilloid 1 (TRPV1) using in silico molecular docking method. Shogaol (6-shogaol, 8-shogaol, 10-shogaol) and gingerol (6-gingerol, 8-gingerol, and 10-gingerol) as well as were Capsaicin (reference), were docked against TRPV1. The study revealed that 10-gingerol had many hydrogen bonds (six H-bonds), 8-gingerol (5 H-bonds), 8-shogaol, 10-shogaol, 6-gingerol, and 10-gingerol had (four H-bonds), and 6-shogaol (3 H-bonds) bonded to Phe 49 and Ile 293 residues. However, capsaicin had three H-bonds bonded to Phe 54 and Ile 265 of TRPV1. Among the compounds, 6-shogaol also showed potent binding affinity (-7.10 kcal/mol) for TRPV and capsaicin (-7.36 kcal/mol). Because there was no important difference in kcal/mol between 6-shogaol and the drug; therefore, it was noted that 6-shogaol could be developed as TRPV1 for the treatment of Painful Diabetic Neuropathy (PDN) (Fajrin et al., 2018; Fajrin et al., 2020b).

Another study by (Fajrin et al., 2020b) determined the potential activity of 6-paradol and its derivatives to Transient Receptor potential Vanilloid 1 (TRPV1), a target receptor in Painful Diabetic Neuropathy (PDN). In this study, 2-paradol, 4-paradol, 6-paradol, 8-paradol, and 10-paradol were used as potential inhibitors of TRPV1. Capsaicin used in the treatment of PDN was utilized as a reference. The findings demonstrated that 2-paradol, 4-paradol, 6-paradol, 8-paradol, and 10-paradol had a strong binding affinity to the TRPV1. 2-paradol, 4-paradol, and 8-paradol had hydrogen bond interaction with Leu 32 and Thr 28 as capsaicin. 6-paradol had hydrogen bond interaction with Gln 135 and 143 Glu 140. However, 10-paradol had steric interaction with TRV1. It was concluded that 6-paradol and the derivatives potentially inhibited the TRPV1, hence could be used as a drug for PDN therapy (Fajrin et al., 2020a).

Another research examined the potential inhibition activity of ginger compound 6-gingerol on the insulin receptor kinase (3EKK), pancreatic lipase-colipase complex (1N8S), and human alpha-ketoglutarate- dependent dioxygenase FTO (protein 4CXW) for the treatment diabesity. The docking results showed that 6-Gingerol had different binding energy with proteins, 3EKK (−69.79 kcal/mol), IN8S (−53.47 kcal/mol), and 4CXW (−79.33). 6-Gingerol had van der Waal’s interactions with amino residues of 3EKK such as Leu 1002A, Gly 1003A, Gln 1004A, Val 1010A, Ala 1028A, Lys 1030A, Val 1060A, Met 1076A, Met 1139A, Gly 1149A, and Asp 1150A. This compound had also formed hydrophobic interactions with Gly 1003A, Gln 1004A, Gly 1005A, Val 1010A, Ala 1028A, Lys 1030A, Met 1076A, and Met 1139A. On the human pancreatic lipase protein (IN8S), 6-Gingerol formed hydrogen bond interactions with Gln368A andTyr403A amino acid residues. On the human alpha-ketoglutarate-dependent dioxygenase FTO (4CXW) active sites, 6-Gingerol had van der Waal’s interactions with Ile 85A, Pro 93A, Arg 96A, Tyr 108A, Leu 109A, Met 226A, Ala 227A, Val 228A, Ser 229A, His 231A, His 232A, Asp 233A, Glu 234A, and Arg 322A; hydrophobic interactions with Ile 85A, Pro 93A, Leu 109A, Leu 203A, Leu 215A, Val 228A, Ser 229A, and His 231A; aromatic interactions with Tyr 108A and His 231A; hydrogen bonding with Tyr 106A, Glu 234A, and Arg 322A (De et al., 2020). Figure 6 exemplifies the potential anti-diabetic actions of ginger.

Several studies investigated the utilization of ginger for the alleviation of nausea and vomiting induced by surgery. Kamali et al. (2020) conducted a study that determined the effectiveness of ginger to prevent nausea and vomiting after abdominal hysterectomy as compared to dexmedmoidine (Figure 7). The study involved 92 patients who underwent an abdominal hysterectomy, were randomized to receive orally ginger (1 g) and injection dexmedmoidine (25 mg) before and after the anesthesia. The results demonstrated that ginger was most effective than dexmedetomidine. This study also found that ginger treatment significantly reduced vomiting scores, 2 h after the operation as compared to dexmedetomidine; however, 4 h later both treatments completely stopped vomiting. Also, ginger reduced the number or frequency of nausea than dexmedetomidine (Kamali et al., 2020).

In a double-blind study conducted by Naemi et al. (2020) in 88 patients, age ranges from 30–70 years old (both genders) who were randomly allocated to take various treatments such as ginger (4 capsules), Haloperidol, Metoclopramide, and Dexmedetomidine after laparoscopy found no significant effects on vomiting after the operation (Figure 7). Also, there was no significant difference observed in nausea between treatments. Due to the findings, the study suggested that ginger and these drugs can be further used in the management of vomiting and nausea; however, when there are no serious adverse effects (Naemi et al., 2020). Therefore, patients should be advised to cease using therapy when experiencing side effects.

A triple-blind clinical trial study by Sedighmaroufi and co-workers (2020) assessed the effectiveness of ginger in reducing the frequency and severity of both nausea and vomiting in patients who had eye operations (Figure 7). One hundred and forty-eight (148) patients (all genders) were randomized to obtain treatment with ginger, ondansetron (reference), or placebo. It was found that oral administration of ginger capsules (1000 mg) and ondansetron significantly reduced vomiting as compared to placebo, but no significant difference was observed in the number of vomiting and severity of nausea. They also reported that ginger was more effective, safe, and cheaper as compared to ondansetron, hence be used as an alternative therapy for nausea and vomiting (Sedighmaroufi et al., 2020).

A study carried out by Uthaipaisanwong et al. (2020) examined the efficacy of ginger in 47 gynaecological cancer patients who take combined carboplatin-paclitaxel chemotherapy (Figure 7). As compared to the placebos, dried ginger capsules (500 mg) were showed to be effective in reducing the acute nausea score, but no significant difference was noticed in delayed nausea. The study also observed no significant difference in reducing both acute and delayed vomiting. Besides, heartburn, diarrhoea, and constipation were common adverse effects (Uthaipaisanwong et al., 2020).

A systematic review involved three studies, a pilot, randomized, open-label clinical trial; a randomized controlled trial; and a randomized, double-blind clinical trial was performed to examine the efficacy of ginger on nausea and vomiting associated with chemotherapy (Figure 7). The study found that oral administration of ginger (1–1.5 g) was effective in reducing nausea in patients who had breast cancer chemotherapy, and did not reduce the number of vomiting (Fitriyanti and Sulung, 2020).

Furthermore, the health benefits of ginger in controlling nausea and vomiting during pregnancy have been reported. A study conducted by Anita et al. (2020) evaluated the efficacy of ginger candy in 51 first-trimester pregnant women who experience vomiting three to five times per day (Figure 7). They were grouped (17 each) and recommended to take ginger candy (1/day), vitamin B6 (3 times/day), or a placebo for 7 days. Treatment with ginger candy was effective in reducing the frequency of vomiting (76.5%) as compared to vitamin B6 (5.9%) and placebo (no changes). The study concluded that ginger candy can be used to ameliorate emesis gravidarum or morning sickness (Anita et al., 2020).

A meta-analysis by Hu et al. (2020) conducted on 30 studies or 1174 patients reported that the application of ginger appears to be effective in reducing nausea and vomiting symptoms in pregnant women and nausea as compared to control, but no important effect was detected on vomiting (Figure 7). Besides, intake of ginger showed to be effective than vitamin B6 in the alleviation of nausea and vomiting during gestation (Hu et al., 2020).

Recently, the study by (Bauer Faria et al., 2021), examined the anti-inflammatory and antimicrobial activity of mouthwash containing 0.5% of ginger essential oil in 31 adult males and females with orthodontic appliances compared with chlorhexidine (0.12%) mouthwash and placebo. The patients were randomized to receive mouthwashes with CLX, ginger, and flavored sterile water (placebo) for 7 days with 15-days intervals between each treatment. Saliva and bleeding were used to assess the efficacy of the mouthwashes. Both ginger and CLX mouthwashes exhibited antimicrobial activity against Streptococcus mutans, but different substantivity. Also, ginger mouthwash showed an anti-inflammatory effect, markedly reduced the bleeding as compared to placebo; however, the taste was unpleasant. The study suggested that ginger taste should be improved (Bauer Faria et al., 2021).

A randomized, double-blind, controlled clinical trial conducted by Heidari-Beni et al. (2020) evaluated the efficacy of turmeric extract, black pepper, and ginger formulation on the prostaglandin E₂ (PGE₂) in 60 patients with Grade 2 and chronic knee osteoarthritis. The patients were grouped to receive herbal formulation or Naproxen capsule twice a day for 4 weeks. Both oral administration of herbal formulation and Naproxen significantly reduced PGE₂ levels. The anti-inflammatory effect is associated with gingerol and piperine, some of the known active constituents from ginger and black pepper. It has been concluded that oral intakes of turmeric extract, black pepper, and ginger formulation can ameliorate the PGE₂ levels in patients with chronic knee osteoarthritis. Therefore, future research examining the anti-inflammatory effect on biomarkers such as ILs and TNF-α is of paramount importance (Heidari-Beni et al., 2020).

Another interesting study by Mutthuraj and co-workers (2020) found that topical application of ginger essential oil on patients suffering from arthritis for 30 days inhibited the pro-inflammatory molecules by reducing the serum levels of rheumatoid arthritis (RA) factor, C reactive protein (CPR), and erythrocyte sedimentation rate (ESR). These results suggest that ginger has pungent anti-inflammatory potential, which can be used in the treatment of joint pain and swelling (Mutthuraj et al., 2020).

A systematic review and meta-analysis by Jalali et al. (2020) assessed the efficacy of ginger on the biomarkers of inflammatory and oxidative stress. The study included clinical studies that determined the effects of ginger on serum CRP (C- reactive protein), TNF-α (tumour necrosis factor-alpha), IL-6 (interleukin-6), PGE2 (prostaglandin E2), TAC (total antioxidant capacity), and MDA (malondialdehyde) until 2019. The effects of ginger on serum CRP, TNF-α, IL-6, TAC, MDA, PGE2 levels were statistically significant. It was concluded that ginger may be used in the treatment or mitigation of inflammation and oxidative stress. Therefore, large-scale randomized clinical trials should be conducted to confirm its safety (Jalali et al., 2020).

A randomized double-blind placebo-controlled clinical trial conducted by Aryaeian et al. (2019) evaluated the effects of ginger on the expression of some immune factors and inflammatory genes in 70 patients with rheumatoid arthritis (RA). The patients were randomized to receive 1500 mg of ginger powder or placebo daily for 12 weeks. The treatment with ginger improved RA through increasing genes expression such as forkhead box P3 (FoxP3), peroxisome proliferator-activated receptor-gamma (PPAR-γ), and GATA binding protein 3(GATA- 3) genes expressions. And downregulation of T-box transcription factor TBX (T-bet), and RAR-related orphan receptor γt (RORγt) genes expression (Aryaeian et al., 2019).

The current study by Zammel et al. (2021) investigated the potential ability of ginger bioactive constituents to bind to the crystal structure of Toll-like receptor 6 (TRL6 4OM7) protein using in silico molecular docking. The results showed several ginger phytocompounds were bonded to the TRL6 with different binding affinities ranging between −5.4 and −10.8 kcal/mol. 6-Gingerol had four hydrogen bonds bonded to His651 residue. 8-gingerol showed three hydrogen bonds bonded to Glu 710. 10-Gingerol showed three hydrogen bonds interacting with Tyr 648. 6-Shogaol had five hydrogen bonds linked to Ser 728. Caffeic acid exhibited three hydrogen bonds interacting with Lys 769. Rosmarinic acid and syringic acid formed seven and five hydrogen bonds bonded to His 674 and Ser 728, respectively. Also, amentoflavone and ferulic acid showed five and three hydrogen bonds connected to His 674 and Gln 757 residues. The compounds were further evaluated into human TLR6 and indomethacin, the anti-inflammatory drug was used as a reference. The study found that 6-shogaol was bonded to Ile 684, Asn 687, Glu 675, His 674, Asn 705, Glu 710, and Tyr 648 residues in the pocket region of TLR6. And Rosmarinic acid was interacting with residues Ala 780, Ile 732, Leu 733, Leu 731, Thr 759, His 725, Ser 728, and Gly 727; as compared to indomethacin was bonded to Glu 675, His 651, Glu 650, Glu 710, and Ile 684 (Zammel et al., 2021).

Saptarini et al. (2013), investigated the potential inhibitory effect of gingerol, 6-shogaol, and 6-paradol for anti-inflammation. Molecular docking was studied on COX-1 and COX-2 enzymes. The interaction energy of the compounds toward COX-1 and 2 was ranging from −2.40 to −7.40 kcal/mol, and −7.80 to −11.13 kcal/mol, respectively. The selective index value was further calculated, revealed that all these compounds could induce anti-inflammation vis COX-2. The results of the research suggested that gingerol, 6-shogaol, and 6-paradol should be developed as COX-2 inhibitors for the treatment of inflammation (Saptarini et al., 2013).

Murugesan et al. (2020) examined the potential molecular interactions of nine bioactive constituents of ginger selected from gas chromatography-mass spectrometry (GC-MS) analysis with novel rheumatoid arthritis (RA) target proteins (COX-2, IL-1b, MCSF, MMP-9, and TNF-alpha) for the treatment of rheumatoid arthritis. Ginger methanol extract active compounds included 2,5 dibutylfuran, 6-gingerol, 8-gingingerol, benzoic acid, dihydrocapsaicin, dihydropseudoionone, ferulic acid ethyl ester, geranylacetone, and zingerone. The results indicated different binding affinities toward the proteins, COX-2 (−4.4 to −7.8 kcal/mol), TNF-a (−3.3 to 5.6 kcal/mol, MCSF (−3.6 to 5.7 kcal/mol), IL-1b (−3.2 to 5.7 kcal/mol), and MMP-9 (−4.9 to −7.4 kcal/mol). Amongst nine phytoconstituents, 6-gingerol displayed the best binding affinity with COX-2 and IL-1b (−7.8 and −5.7 kcal/mol, respectively). 8-Gingerol showed a good binding affinity with MCSF (−5.7 kcal/mol) and TNF alpha (−5.6 kcal/mol). Zingerone had a higher binding affinity with MMP-9 protein (−7.4 kcal/mol). 8-Gingerol, 6-gingerol, and zingerone formed the strongest interactions with RA target proteins residues. Moreover, the pharmacokinetic and bioactivity analysis results showed that 6- and 8-Gingerol can act as enzyme inhibitors of Rheumatoid arthritis (RA) proteins (Murugesan et al., 2020).

A few clinical studies have been published that evaluate the use of ginger or phytochemicals for the prevention, alleviation, and or treatment of male infertility.

In 2012, Mares and Najam evaluated the efficacy of taking ginger supplements in 75 infertile men patients aged between 19 and 40 years. In these patients, administration of ginger supplements resulted in a significant increase in spermatozoa parameters (count, motility, viability, and normal morphology), and semen volume compared to before therapy. Also, the use of ginger induced a significant increase in serum glutathione, FSH, LH, and decreased MDA (Mares and Najam, 2012; Gholamnezhad et al., 2018).

A double-blind randomized clinical study by Hosseini et al. (2016) examined the efficacy of ginger on spermatozoa DNA fragmentation in 100 infertile men patients. Patients were randomized to receive 250 mg of ginger powder per capsule and placebo, two times a day for 3 months. Semen samples, before and after treatment were used to assess the spermatozoa count, motility, and DNA fragmentation. Treatment with ginger significantly reduced spermatozoa DNA fragmentation compared to placebo. However, there were no statistically important differences for spermatozoa parameters (count and motility) between the study groups. Besides, no side effects were reported by patients (Hosseini et al., 2016; Gholamnezhad et al., 2018; Banihani, 2019).

In a randomized, double-blind, placebo-controlled clinical trial, 80 healthy obese participants were assigned randomly to steam ginger ethanolic extract (SGE) capsules (100 mg plus 5.89–8.83 mg/g of 6-Shogaol) and placebo for 12 weeks. A significant decreased in mean body, body mass index, and body fat level was observed in SGE subjects as compared to placebo. Common cold and dyspepsia were observed in participants after SGE consumption. Nevertheless, the study suggested that SGE and lifestyle modifications together may be useful for maintaining body weight and fat mass (Park et al., 2020).

In another study, Farhadi et al. (2020) assessed the health benefits of aerobic exercise and consumption of ginger extract on lipid profiles, body composition, and liver enzymes in obese menopause women (53–58 years old). Fourth-eighth (48) women were recruited and assigned randomly to the ginger extract (500 mg capsules, 3 times/day) for 24 weeks, aerobic training (3 times/week), and aerobic training -ginger extract, and control. The study found that 12- and 24-weeks of training ginger supplementation, and a combination of ginger and training significantly reduced aspartate aminotransferase (AST) and alanine aminotransferase (ALT) liver enzymes. Also, the combination of ginger and training (12- and 24-weeks) improved lipid profiles and body composition in obese women, and changes were most after 6 months. The results of this study suggested that the combination of aerobic training and ginger extract consumption might be an effective way to improved obesity (Farhadi et al., 2020).

El Gayar et al. (2019) conducted a study on the effect of ginger powder supplementation on glycemic status, lipid profile, and beta-cell function in 80 obese patients with newly diagnosed type 2 diabetes mellitus. The patients were randomized to receive a daily dose of 1.8 g (∼600 mg powered/capsule, 3 times/day) of ginger plus one metformin tablet (850 mg, 2 times/day) with meals for 8 weeks or placebo. The results showed that supplementation with ginger powder resulted in a significant reduction of body mass index, fasting plasma glucose, 2-h postprandial blood glucose, glycated hemoglobin, total cholesterol levels, low-density lipoprotein cholesterol, triglycerides, fasting insulin levels, and homeostasis model assessment-insulin resistance index (HOMA2-IR). The study also found a significant increase in beta-cell function index (HOMA2-%β), insulin sensitivity index (HOMA2-%S), as well as high-density lipoprotein cholesterol levels in the ginger group compared to placebo. The authors concluded that ginger supplements could be used as an adjuvant therapy to improve the efficacy of type 2 diabetes mellitus treatment (El Gayar et al., 2019).

In the study by (Ebrahimzadeh Attari et al., 2016), eighty (80) obese women (18–45 years old) were randomized to receive ginger powered (2 g/day) and placebo for 12 weeks. As compared to the placebo group, oral administration of ginger significantly reduced body mass index, serum insulin, and HOMA-IR index and correlated with increasing quantitative insulin sensitivity check index (QUICKI). Ginger supplementation also significantly reduced serum leptin, resistin, and glucose with both groups, but there was no significant difference. Moreover, there were no significant changes were observed in the body composition and serum levels of adiponectin in both groups. It was concluded that consumption of 2 g of ginger for 12 weeks was not effective enough for weight loss and reducing some of the metabolic features associated with obesity (Ebrahimzadeh Attari et al., 2016; Anh et al., 2020).

A systematic review with meta-analysis was conducted on 14 randomized controlled trials/473 participants to evaluate the effects of ginger on bodyweight loss, glycemic control, and lipid profiles in overweight and obese individuals. The study revealed that ginger supplementation significantly reduced body weight, waist-to-hip ratio, hip ratio, fasting blood glucose, and insulin resistance index (HOMA-IR), and significantly improved HDL-cholesterol levels. But had no significant effect was found on body mass index (BMI), insulin, triglycerides, and low-density lipoprotein (LDL) (Maharlouei et al., 2019; Venkatakrishnan et al., 2019). The molecular mechanisms for the anti-obesity effects of ginger phytochemicals are illustrated in Figure 8.

The β3-AR has become a promising therapeutic target for the treatment of obesity and other metabolic disorders. This is owing to its presence in the adipose tissue and its ability to activate brown adipocytes which promote energy expenditure, weight loss, improved glucose, and lipid metabolism (Arch and Ainsworth, 1983; Hao et al., 2019). A study conducted by Sampath and co-worker (2021) determined the interactions of 6-gingerol and 6-shogaol as potential ligands for β3-adrenergic receptor membrane protein (β3-AR). They also compared their binding affinity with β3-AR protein by in silico molecular docking studies. The study revealed that both 6-gingerol and 6-shogaol had the best binding affinities to the receptor, but 6-gingerol indicated a better −82.364 kcal/mol docking score as compared to 6-shogaol (−79.987 kcal/mol). The study also found that 6-gingerol has powerful hydrogen bond interaction with β3-AR than 6-shogaol. 6-gingerol showed hydrogen bond interaction with serine amino acid residue, and 6-shogaol was bonded to the serine and tryptophan residues. Moreover, the results showed that 6-gingerol enhances the browning effects in white adipocytes via activation of the β3-AR signaling pathway. Therefore, 6-gingerol is a potential treatment for obesity (Sampath et al., 2021).

A systemic review and meta-analysis of Negi et al. (2021) compared the efficacy of ginger, non-steroidal anti-inflammatory (NSAID), and placebo for primary dysmenorrhea. The application of ginger was found to be effective in the alleviation of menstrual pain as compared to placebo, but no significant difference was observed in the duration of pain. Nevertheless, the use of ginger and non-steroidal anti-inflammatory (NSAID) was useful to treat pain severity (Negi et al., 2021).

A randomized clinical trial by Munir et al. (2021) determined the effectiveness and safety of ginger capsules and naproxen tablets for the treatment of knee osteoarthritis. The study involved 60 male and female patients (>50 years of age), were randomized to receive twice-daily doses of 550 mg of ginger capsules (550 mg) plus 550 mg of naproxen tablets and placebo for 6 weeks. The concomitant administration of ginger with naproxen was more effective than naproxen alone, alleviated pain and stiffness in knee osteoarthritis. Minimal adverse effects were reported. Mild diarrhea was common in patients. In addition, the authors suggested long-term multicenter studies (Munir et al., 2021).

Coronaviruses disease 2019 (COVID-19) is a pandemic virus caused by severe acute respiratory syndrome coronavirus 2 (SARS-Cov-2). The virus was first discovered or diagnosed in Wuhan, China by the Chinese Center for Disease Control and Prevention (Guan et al., 2020; Zhu et al., 2020). SARS-Cov-2 is a single-stranded genome (positive sense) made of ribonucleic acid (RNA). The structure of SARS-Cov-2 consists of four main proteins including the membrane (M) glycoprotein, the envelope (E) protein, nucleoprotein (N), and the spike (S) protein (Boheemen et al., 2012; Lu et al., 2020; Tai et al., 2020). The main target of the virus is the angiotensin-converting enzyme 2 (ACE2), an enzyme expressed in several body tissues such as the heart, lungs, testis, and kidneys (Santos et al., 2018; Ni et al., 2020; Fan et al., 2021). The attachment of virus spike protein to the ACE2 receptor on the host cells is the critical step for SARS-Cov-2 entry into cells. After binding to the receptor, the protease enzyme (TMPRSS2) activates the spike protein, and the virus enters the human cells. Once in the cells, the viral replication process takes place (Baughn et al., 2020; Hoffmann et al., 2020; Ren et al., 2020). Fever, dry cough, and feeling tiredness have been reported to be the most common symptoms of COVID-19. Besides, some patients suffer from diarrhea, headache, nasal congestion or runny nose, sore throat, body aches and pains, lymphopenia, and dyspnea (Guan et al., 2020; Orisakwe et al., 2020; Silveira et al., 2020; Wang et al., 2020). The inhibition of SARS-Cov-2 spike protein binding ACE2 using natural herbs or phytochemicals is the promising approach in the prevention and treatment of Covid-19 infection (Abinaya et al., 2020; Mehrotra, 2020; Orisakwe et al., 2020; Silveira et al., 2020; Haridas et al., 2021).

Owing to the urgent need for effective treatment of COVID-19 and fewer treatment options (Ibrahim et al., 2020), ginger extract is prepared by patients as a medication for the management, and melioration of SARS-Cov-2 (Abinaya et al., 2020; Orisakwe et al., 2020). A homemade ginger remedy has been reported. Ginger is prepared alone or in combination with other natural herbs. Ginger, garlic cloves (20), and lime are blended. One tablespoon of paste, Lipton tea and crushed paracetamol tablets (1000 mg) is added to boiling water. One cup of concoction is drunk once after 4 h. The remission of signs and symptoms of COVID-19 has been observed to occur within 3 days. Ginger is cooked with turmeric powder, garlic, and lemon for steam inhalation. The patient covers their head with a towel and deep breath through the nose. The patient recovers from the illness within 3 days. Also, ginger is cooked with garlic, paw leaf, Neem (Dogoyaro) leaf, artemisia, lime, and oranges. Steam is inhaled for 30 min. This is most effective therapy to clear lungs or chest congestion. It takes one to 2 weeks to recuperate (Orisakwe et al., 2020). At the moment, there are no scientific studies and or clinical trials support the efficacy and safety of these medications. Therefore, further studies are needed to prevent their chronic health effects.

In silico and molecular docking studies have been conducted to screen the potential inhibition activity of ginger phytochemicals against SARS-Cov-2 and to assess its binding affinities to block SARS-Cov-2. Research by Rajagopal et al. (2020) explored the potential anti-COVID-19 (PD: id-5R82) effectiveness of ginger phytocompounds. The docking results revealed that 8-Gingerol and 10-Gingerol had significant inhibition towards Covid-19. The compounds exhibited higher Glidescore (−5.88 and −5.72 kcal/mol, respectively), high binding affinity to the receptor when compared to that of Hydroxychloroquine drug (−5.47 kcal/mol), and other ginger constituents. Multiple active site residues such Ser 46, Met 49, Hie 41, Gln 189, Arg 189, Asp 187, Met 165, Hie 164, Thr 24, Thr 25, Leu 27, Asn 142, and Gly 143 were involved in the antiviral (5R82) potential of ginger phytochemicals (Rajagopal et al., 2020).

In another study, Haridas et al. (2021) examined 16 compounds isolated from ginger as inhibitors of SARS-Cov-2 spike protein and ACE-2. This study was targeted against COVID-19 protein called SARS-CoV-2 main protease receptor cocrystallized with 6-(ethylamino) pyridine-3-carbonitrile (PDB ID:5R82) using in silico molecular docking model. Molecular docking results at the active sites of spike protein two possible inhibitors, adenine and 6-Gingerol showed higher binding affinity (−24.18 and −36.60 kcal/mol, respectively). Adenine formed two hydrogen bonds by interacting with residues Tyr 495, and Gly 496. 6-Gingerol formed four hydrogen bonds with residues Tyr 453, Ser 494, Gly 496, and Tyr 505. Results of the ACE-2 revealed that 6 compounds (10-paradol, 8-paradol, scopoletin, 10-shogaol, 8-gingerol, and 10-gingerol) could be powerful inhibitors of ACE-2 against Covid-19. Docking scores was ranging from −33.72 to −51.27 kcal/mol. 10-Paradol formed two bonds with Arg 273 and Lys 363 residues. 8-paradol formed three bonds with Asn 149 and Lys 363. Scopoletin formed three hydrogen bonds, interacting with residues Asn 149, Asn 368, and Lys 363. 10-shogaol formed three hydrogen bonds, interacting with Asn 277, Lys 363, and Asp 367 residues. 8-gingerol formed three bonds with residues Asp 367 and Lys 363. Also, 10-gingerol formed two hydrogen bonds, interacting with residues Glu 406 and Arg 518 (Haridas et al., 2021).

Moreover, comparative research by Al-Sanea et al. (2021) evaluated the potential inhibition activity of methanolic extract of ginger, ginger silver nanoparticles (AgNPs), strawberry methanolic extract, and strawberry AgNPs to treat SARS-Cov-2. The MTT assay was used to assess the anti-SARS-CoV-2 activity. Ginger AgNPs and strawberry methanolic extract displayed antivirus potentials against Covid-19 with IC₅₀ values of 0.034 µg/ml and 0.0062 µg/ml, respectively. Strawberry AgNPs with IC₅₀ value of 0.0989 µg/ml and ginger methanolic extract with IC₅₀ value of 206.4 mg/ml. To further evaluate the antiviral activity, in silico molecular docking study was conducted to examine the potential phytochemicals that might bind to and inhibit SARS-CoV-2 proteins. Among 30 compounds, neohesperidin showed better binding affinity to SARS-CoV-2 NSP16 protein (Al-Sanea et al., 2021).