Renoprotective Effects of the Ginger (Zingiber officinale) in Diabetic Kidney Disease, Current Knowledge and Future Direction: A Systematic Review of Animal Studies

doi:10.21203/rs.3.rs-1321980/v1

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Renoprotective Effects of the Ginger (Zingiber officinale) in Diabetic Kidney Disease, Current Knowledge and Future Direction: A Systematic Review of Animal Studies

https://doi.org/10.21203/rs.3.rs-1321980/v1

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Purpose

approximately 40% of diabetic patients suffer from diabetic kidney disease, and it is the main cause of CKD in the world. Therefore, the prevention of renal complications is of importance in diabetic patients. Ginger (zingiber officinale Rosco) is popular spice and natral medicine. The presence of a systematic review focused on the existing evidence of the renoprotective effect of the ginger extract in Diabetic kidney disease.

Methods

The literature search was performed in online database such as PubMed, Scopus, EMBASE, ProQuest databases, and google scholar inception up to november 2021.

Findings

The review selected 41 articles that met eligibility criteria. Ginger supplementation was found to be associated with a significant decrease in blood glucose 28 studies. nine studies showed a significant reduction in MDA after supplementation. Also, sixteen studies showed a decreasing effect on creatinine. fifteen studies reported a decrease in total cholesterol (TC) and fourteen studies report decrease in triglycerides (TG). In twenty-six studies, ginger reduced renal injuries from diabetes.

Implications

Ginger could improve blood sugar indices, lipid profile, some inflammatory factors, oxidative stress, and pathologic injuries in diabetic kidney disease. However, future high-quality clinical trials and meta-analyses are required for a solid consensus.

ginger

zingiber officinale

diabetes

hyperglycemia

renal

kidney

Diabetic kidney disease (DKD) was formerly known as diabetic nephropathy (DN), is a microvascular complication of diabetes, occurring in about one-third of people with diabetes [1, 2].The International Diabetes Federation estimates that the disease will increase from 463 million in 2019 to 700 million in 2045 [3]. DKD patients have a high prevalence of cardiovascular morbidity and mortality [4]. The cause of pathogenesis DKD is multifactorial. Hyperglycemia is a key factor in the progression of pathologic alterations in the kidneys [5]. Similarly, dyslipidemia is a predictive factor in DKD progression [6]. In diabetes, increased oxidative stress plays a pivotal role in the development of DKD [7]. Also, inflammation has a crucial role in the onset and progression of DKD [8]. Today, the use of nutritional therapies and nutritional supplements along with treatment strategies to control the risk factors for cardiovascular disease in patients, including kidney patients, has received much attention [9].

Ginger is scientifically named zingiber Officinale Roscoe from the Zingiberaceae family [10]. This spice has been used in Chinese medicine and ayurvedic medicine for centuries [11]. The antioxidant properties of medicinal herbs are related to environmental condition, weather, seasonal changes, geographical area, degree of ripe, growth, and many other factors during planting and harvesting [12]. The smell of fresh ginger is due to the presence of a group of phenolic compounds called gingerol, similarly, the smell of dried ginger is due to the presence of shogaols, which are dehydrated compounds of gingerols. Ginger has been declared to be safe by the US food drug administration [13]. Ginger has beneficial features due to bioactive compounds like gingerol, shogaol, paradol, and zingerone [14].

Although several animals studies have been conducted to assess the impact of ginger on metabolic indicators in DKD, a systematic review has not been initiated in association with this matter. The goal of the present systematic review is to investigate the literature on ginger’s influence on glycemic indices, dyslipidemia, inflammatory factors, oxidative stress markers, renal function, and structure. The mechanisms of the impact of ginger are presented in the discussion.

2.1 Search strategy

Search engines included were PubMed, Scopus, Embase, ProQuest, and Google Scholar keywords used in the search strategy were selected from MeSH and non-MeSH terms including: (“Ginger” OR “Zingiber” OR “Shogaols” OR “zingerone” OR “Gingerols”) AND (“kidney” OR “renal” OR “dialysis” OR “Hemodialysis” OR “ESRD” OR “CKD” OR “chronic kidney disease” OR “acute renal disease” OR “ARF” OR “nephropathy” OR “diabetic nephropathy” OR “GFR” OR “Albuminuria” OR “Proteinuria” OR “Creatinine”) AND (“diabetes” OR “diabetes mellitus” OR “type 2 diabetes” OR “type 1 diabetes” OR “T2DM” OR “T1DM” OR “GDM” OR “gestational diabetes mellitus” OR “IDDM” OR “NIDDM” OR “fasting blood sugar” OR “fasting blood glucose” OR “glucose intolerance” OR “glucose tolerant” OR “HOMA-IR”. Preferred reporting for systematic reviews (PRISMA) guidelines were followed when conducting this review.

2.2 Eligibility criteria

Studies on the effect of ginger supplementation on DKD were included in this study. The PICO strategy for the research question of the study was patient/ population (p): animals mice or rats); Intervention (I): supplementation with ginger; Comparison (C): placebo group; and outcome (O): changed glycemic indices, lipid profile, inflammatory factors, oxidative stress, and renal function indicator.

(a) animal studies, (b) English published journals, (c) evaluated administration of ginger on DKD were included; Studies were excluded if they: (a) combination of ginger with other spices (b) no access to the full text were excluded, (c) invitro models.

2.3 Data extraction

First and third authors (PV and HR) screened the titles and abstracts of the qualifying studies seperately. the relevant data including first authors name, year of publication, country, study population, sample size, gender of subjects, ginger dosage, duration of intervention, diabetes induction method, and outcome data were extracted). Eligible papers were assessed based on the goal checklist, the question of the study, and inclusion/ exclusion criteria. Articles not meeting the criteria for data collection were eliminated. Any discrepancies among reviewers were resolved in consultation with the authors. The quality of the selected studies was evaluated via a first author. Quality assessment studies were used the syrcle's tool.

2.4 quality assessment

To assess the quality of studies the SYRCLE's RoB tool evaluated studies based on ten criteria: random allocation sequence, animals similar at baseline, allocation concealment, random housing, blinded investigators, random outcome assessment, criteria blinded outcome collection, incomplete data justification, unbiased conclusions and other. Each study could ultimately have a total score of 10 points.

3.1 Selected Articles

Figure 1 depicts a flowchart of the research selection. The initial search resulted in a total of 567 articles, resulting in 543 non-duplicated publications after removing 24 articles. Following a review of titles and abstracts, 494 articles were eliminated. 6 studies were excluded due to the lack of inclusion criteria. Finally, the present review found 41 articles that meet the eligibility criteria. Table 1 summarizes the characteristics of chosen studies.

Table 1

characteristics of the included studies
Authors/date	Source	Models	sex	Sample size Int/ctrl	Substance induced diabetes	Daily dose	Ginger form	Duration	Results
Yi, Jun-Koo et al, 2019[51]	South Korea	C57BL/6J mice	M	6/3	STZ	5, 10 mg/kg	6-shogaol	2 weeks	- ↓ histopathological change in kidney - ↓ blood glucose
Rehman, Muneeb U et al., 2019 [24]	India	Albino wister rats	M	6/6	STZ/ HFD	50, 100 mg/kg	Zingerone	16 weeks	- ↓ kidney damage - ↓ HbA1c - ↓ ROS - ↑ GSH, GPx, GR, SOD, and CAT - ↓ TC, LDL, TG and ↑ HDL - ↓TNF-a, IL-6, IL-1β and NF-κB - ↓ BUN, Cr
Xu, Yun, et al., 2018 [49]	China	C57BL/KsJ db/db obese mice	M	10/10	db/db	25, 50 mg/kg	6-shogaol	12 weeks	- ↓ FBS, insulin, C peptide, and HbA1c - ↓ BUN, Cr, urinary albumin - ↓ TG and TC - ↓ pathological injuries of kidneys - ↓ TNFɑ, IL-6 and NFκB - ↓ GSH
Irshad, F et al., 2018[45]	Pakistan	Albino wister rats	M	15/15	Alloxan	200 mg/kg	aqueous extract	5 weeks	- ↓ Cr - ↓ kidney weight
Cui, Yan, et al., 2018 [50]	China	C57BL/KsJ db/db obese mice	M	15/15	db/db	50 mg/kg	Zingerone	10 weeks	- ↓ insulin, C peptide, and HbA1c - ↔FBS - ↓ BUN, Cr, urinary albumin - ↓ TG and TC - ↓ TNF-ɑ and IL-6 - ↓ MDA - ↑ GSH - ↓ ROS - ↓ renal pathological change - ↓ kidney weight
Al Hroob, Amir M., et al., 2018[15]	Egypt	Albino wistar rats	M	6/6	STZ	400, 800 mg/kg	ethanolic extract	6 weeks	- ↓ FBS and HbA1C - ↓ BUN, Cr, urea, and urine albumin - ↓ kidney damage - ↓ MDA - ↑ GSH, SOD, and CAT - ↓ TNF-α, IL-1β, and IL-6 - ↓ TG, TC, and LDL and ↑ HDL
Abdulsalam, K. A., and A. S. Alkalifa., 2016 [32]	Saudi Arabia	Albino wister rats		10/10	NR	(0.5% − 2%) of ginger freeze-dried or extract	zingerone	6 weeks	- ↔ BUN, uric acid and urea - ↑ Cr - ↑ blood glucose
Kazeem, M.I et al., 2015 [47]	Nigeria	Albino Wistar rats	M	8/8	STZ	1.0 mL 500 mg/kg free and bound polyphenol	Acetone extracts	42 days	- ↓ urea - ↔ Cr - ↓ blood glucose - ↑ insulin - ↓ pathological change in kidney
Hanna, Emily T. et al., 2014 [16]	Egypt	Albino wister rats	M	7/7	Alloxan	0.5%, 1%, 5%	powder	6 weeks	- ↓ blood glucose - ↓TC and TG, LDL and ↑ HDL - ↓Cr and urea
Hajhosieni L. et al., 2014 [38]	Iran	Albino wister rats	M	10/10	STZ	100 mg/kg	powder	8 weeks	- ↓MDA - ↑ TAC - ↓ kidney damage
Khaki AA et al., 2010 [39]	Iran	Albino wister rats	M	10/10	STZ	100 mg/kg/day	powder	30 days	- ↓ pathological change in kidney - ↓ MDA - ↑TAC
Afshari et al. 2006 [40]	Iran	Albino wister rats	M	8/8	STZ	5% of daily food intake	powder	8 weeks.	- ↓ MDA - ↑ TAC - ↓ renal nephropathy
Al-Amin et al. 2006 [42]	Kuwait	Sprague Dawley rats	M	8/8	STZ	500 mg/kg	Aqueous extract	7 weeks.	- ↓ blood glucose - ↓ TC, TG - ↓ urine protein
Al-Attar et al. 2007[33]	Saudi Arabia	Albino wister rats	M	10/10	STZ	5% and 2.5% of diet	oil	2 weeks	- ↑blood glucose, TG, TC, LDL, and ↓ HDL - ↑ urine protein, urea, uric acid - ↓ Cr
Elshater et al. 2009[17]	Egypt	Albino wister rats	M	10/10	Alloxan	4ml/kg	Aqueous extract	6 weeks	- ↓ blood glucose - ↓ TC, TG, LDL and ↑ HDL - ↓ Cr, urea, uric acid
Shanmugam et al. 2009[25]	India	Albino wistar rats	M	6/6	STZ	200mg/kg	Ethanolic extract	30 days	- ↓ blood glucose - ↔ kidney weight
El-kott et al. 2010[18]	Egypt	Albino wister rats	M	8/8	Alloxan	400mg/kg	powder	4 weeks	- ↓ blood glucose - ↑ insulin - ↓ BUN - ↔ Cr, uric acid - ↓ pathological change in kidney
Naglaa Hassanen 2019[19]	Egypt	Albino wistar rats	M	8/8	STZ	2.5 g, 0.9%	Powder or oil	8 weeks	- ↓ blood glucose - ↑ insulin - ↓ TC, TG, LDL and ↑ HDL - ↓ urea, Cr - ↑ GPx and GSH - ↓ histopathological change in kidney
Shanmugam et al. 2011[55]	India	Albino wistar rats	M	6/6	STZ	200mg/kg	Ethanolic extract	30 days	- ↓ blood glucose - ↓ renal tissue injuries
Abdulrazaq et al. 2012[54]	Malaysia	Sprague-dawley rats	M	NR	STZ	100, 300, 500 mg/kg	Aqueous extract	30 days	- ↓ blood glucose - ↓ kidney weight
Shanmugam et al. 2011[27]	India	Albino wister rats	M	6/6	STZ	100, 200mg/kg	Ethanolic extract	30 days	- ↓ blood glucose - ↓ MDA - ↓ TC, TG - ↓ pathological changes in kidney tissue
Shanmugam et al. 2011[28]	India	Albino wister rats	M	6/6	STZ	1% and 2% of the diet	powder	30 days	- ↓ blood glucose - ↑ SOD, CAT, GPX, GR, and GSH - ↓ MDA - ↓ pathological changes in kidney
Eleazu et al. 2013[48]	Nigeria	Albino wister rats	M	6/6	STZ	10% of food intake	powder	3 weeks	- ↓ blood glucose - ↓ urinary protein - ↔ kidney weight
Sangi et al. 2018[34]	Saudi Arabia	Albino wister rats	M	5/5	STZ	1000 mg/kg	Aqueous extract	3 weeks	- ↓ blood glucose - ↓ urea, creatinine - ↓ TG, TC and HDL
Sangi et al. 2017[35]	Saudi Arabia	Albino wister rats	M	5/5	STZ	6% of diet	powder	8 weeks	- ↓ pathological change of kidney
Irshad, F et al., 2018[46]	Pakistan	Albino wister rats	M	15/15	Alloxan	200 mg/kg	Aqueous extract	5 weeks	- ↓ kidney damage
Azza, H et al. 2015[21]	Egypt	Albino wister rats	M	10/10	Alloxan	300 mg/kg of	Ethanolic extract	4 weeks	- ↓ blood glucose - ↓ urea, Cr and urine albumin - ↓ kidney damage - ↑ GSH - ↓ TNFα
Dalia refaat et al. 2017[20]	Egypt	Albino wister rats	M	7/7	STZ	125, 250, 500 mg / 100 g of diet	powder	4 weeks	- ↓ blood glucose - ↓ MDA - ↑ GSH - ↓ urea, Cr, uric acid
M. K. Jiyil, et al. 2019[29]	India	Albino wister rats	M	5/5	STZ	400 mg/kg	Aqueous extract	21 days	- ↓ blood glucose - ↓ TC, TG and ↑ HDL - ↓ urea, uric acid, Cr
Al-Quadah et al. 2018[52]	Jordan	Albino wister rats	F	5/5	Alloxan	500 mg/kg	Aqueous extract	21 days	- ↓ histopathological change in kidney
Priti kumara et al. 2020[30]	India	mice	NR	NR	Alloxan	80 mg/kg	Aqueous extract	16 weeks	- ↓ urea, uric acid - ↓ Blood glucose - ↓ pathological change in kidney
SA.Almatroodi et al. 2021[36]	Saudi Arabia	Albino wistar rats	M	8/8	STZ	10 mg/kg	6-gingerol	8 weeks	- ↓ FBS - ↓ TC, TG and LDL - ↓ urea, Cr - ↓ MDA - ↑ GSH, CAT, SOD - ↓ TNFα, IL-6, IL-1β - ↓ kidney damage
S A payami et al. 2018[41]	Iran	Albino wister rats	M	4/4	STZ	200, 400 mg/kg	Hydroalcoholic extract	8 weeks	- ↓ Blood glucose - ↓ urinary protein and Cr - ↓ histopathological change in kidney
Taha AM et al. 2020[23]	Egypt	Albino wister rats	M	10/10	STZ	500mg/kg	powder	6 weeks	- ↓ LDL and TC - ↓ urea
Irshad, F et al., 2018[56]	Pakistan	Albino wister rats	M	15/15	Alloxan	200 mg/kg	Aqueous extract	5 weeks	- ↓ Blood glucose - ↓ Histopathological change in kidney
Johti M et al. 2016[31]	India	Albino wister rats	M	6/6	STZ	10 mg/kg	Zingerone	30 days	- ↓ Blood glucose - ↓ TC, TG, LDL and ↑ HDL - ↓ Histopathological change in kidney
Thomson K et al. 2013[43]	Kuwait	Sprague –dawley rats	M	14/10	STZ	500 mg/kg	Aqueous extract	8 weeks	- ↓ Blood glucose - ↓ Urine protein - ↓ Uric acid - ↑ insulin
Al-Qattan K et al. 2007[44]	Kuwait	Sprague¬ dawley rats	M	10/10	STZ	500 mg/kg	extract	7 weeks	- ↓ Blood glucose - ↓ Histopathological change in kidney - ↓ Urine protein
Yasin A et al. 2019[22]	Egypt	Sprague¬ dawley albino rats	M	8/8	STZ	200 mg/kg	Ethanolic extract	42 days	- ↓ Histopathological change - ↓ Uric acid, BUN and Cr - ↓ Blood sugar, HbA1c and ↑ Insulin - ↑ GPx, SOD and CAT - ↓ TC, TG, LDL and ↑ HDL
Ghudhaib K. 2018 [53]	Iraq	Mice	NA	10/10	Alloxan	50, 100 mg/ml	Ethanolic extract	30 days	- ↓ TC, TG and ↑HDL - ↔ Cr, uric acid and ↓ Urea - ↓ Blood sugar and ↑insulin - ↑TAC
Al Malki W et al. 2018[37]	Saudi Arabia	Albino wister rats	M	20/20	STZ/ HFD	NR	6- shogaol	16 weeks	- ↓ Blood glucose - ↓ BUN, Cr and urine protein - ↓ NFκB, TNFα - ↓ Renal damage
Note: Ctrl control; Int Intervention; M Male; F Female; N R not reported; FBS Fasting blood sugar; TC total cholesterol; TG triglycerides; LDL Low-Density lipoprotein; HDL High-density lipoprotein; Cr Creatinine; ROS Reactive oxygen species; SOD Superoxide dismutase, CAT catalase, GPx glutathione peroxidase; GSH Glutathione; BUN Blood urea nitrogen; MDA Malondialdehyde; TAC total antioxidant capacity; IL6 Interleukin6; STZ streptozotocin; HFD High-fat diet; TNFα Tumor necrosis factor α; HbA1c hemoglobin A1c; ↓ decrease; ↑ increase; ↔ not changed

3.2 Characteristics of the included studies

In total, after screening and deleting duplicate articles, fourty-one studies were selected for this systematic review. All studies assessed diabetic mice or rats. Ginger was used in different shapes in this study, including ginger powder, ginger oil, aqueous ginger extract, ethanolic ginger extract, and bioactive compounds such as zingerone and shogaol. Ginger and ginger extract treatment dosages were ranged from 80 to 1000 mg/kg and bioactive compounds treatment dosages were ranged from 5 to 100 mg/kg. Intervention durations ranged from 2 to 16 weeks. Location of studies performed as follows: 9 in Egypt [15–23], 8 in India [24–31], 6 in Saudi Arabia [32–37], 4 in Iran [38–41], 3 in Kuwait [42–44], 3 in Pakistan [45, 46], 2 in Nigeria [47, 48], 2 in China [49, 50], 1 in South Korea [51], Jordan [52], Iraq [53] and Malaysia [54]. Studies were done from 2006 to2021.

3.3 quality assessment

A summary of The results of quality assessment are demonstrated in Fig. 2. In the majority of studies, performance bias, detection bias, and allocation concealment were found to be an unclear risks of bias.

Figure 2. Results of the SYRCLE’s tool assessing the risk of bias.

3.4.1 Ginger and glycemic control in DKD

Twenty-eight of 31 studies showed that ginger intake lowers blood glucose level [15–22, 25, 27–31, 36, 37, 41–44, 47–49, 51, 53–56]. On the contrary, in 2 studies, blood glucose level increased [32, 33]. One study did not show any meaningful changes [50]. 3 out 4 studies reported that ginger increases serum insulin level [18, 19, 47], whereas in another study the result was reversed [49]. Ginger reduced HbA1C and C peptides in all studies that examining these biomarkers [15, 22, 24, 49, 50].

3.4.2 Ginger and dyslipidmia in DKD

sixteen out 41 articles examined the effect of ginger on the lipid profile. The reduction of TC and TG were also reported by 15 [15–17, 19, 22–24, 27, 29, 31, 34, 36, 42, 50, 53] and 14 [15–17, 19, 22, 24, 27, 29, 31, 34, 36, 42, 50, 53] studies respectively. Ginger has been shown to improve LDL [15–17, 19, 22–24, 31, 36] and HDL [15–17, 19, 22, 24, 29, 31, 53] levels in nine studies. In one study contarary results were reported for TC, TG, LDL as well as two studies for HDL [33, 34].

3.4.3 Ginger and oxidative stress indices in DKD

Ginger reduced MDA level in all 9 studies that examined it [15, 20, 27, 28, 36, 38, 40, 50, 57]. In all studies the impact of ginger on the antioxidant defense system was evaluated, positive results were found. In all studies, ginger elevated the level of GSH [15, 19, 20, 24, 28, 29, 36, 49, 50], CAT, SOD [15, 22, 24, 36], GR [24, 28], GPx [19, 22, 24, 28] and TAC [38, 40, 53, 57] factors. Similarly 2 studies reported that administration of ginger decreased ROS levels [24, 50].

3.4.4 Ginger and inflammation biomarkers in DKD

Eight out 41 studies investigated the influence of ginger on inflammatory factors. Ginger diminished TNFα, IL6, IL1β, and NFκB serum levels in 7 [15, 21, 24, 36, 37, 49, 50], 5 [15, 24, 36, 49, 50], 3 [15, 24, 36], and 3 [24, 37, 49] studies, respectively. The studies did not show any adverse effects.

3.4.5 Ginger and renal function in DKD

Twenty-eight studies evaluated the potential effect of ginger on kidney function indicators. In 16 of 20 studies ginger supplementation reduced serum creatinine levels [15–17, 19–22, 24, 29, 33, 34, 36, 41, 45, 49, 50]. On the contrary, creatinine levels were increased in one study [32] and not changed in 3 studies [18, 47, 53]. Ginger decreased serum levels of urea, BUN, and uric acid in 13 [15–17, 19–21, 23, 29, 30, 34, 36, 47, 53], 6 [15, 18, 22, 24, 49, 50], and 6 [17, 20, 22, 29, 30, 43] studies, respectively. On the contrary, urea and uric acid levels were increased in one study [33]. Uric acid levels was not significantly changed in three studies [18, 32, 53]. One study showed no meaningful changes in urea and BUN levels [32]. Urinary protein was decreased in 10 studies [15, 21, 37, 41–44, 48–50] and increased in one study [33].

3.4.6 Ginger and changes in histomorphology and structural renal in DKD

Among the studies, twenty-six evaluated the influence of ginger on histopathological changes in kidneys [15, 18, 19, 21, 22, 24, 27, 28, 30, 31, 35–38, 40, 41, 44, 46, 47, 49–52, 55–57]. All studies examining histomorphological changes showed beneficial effects. The beneficial impacts of ginger on bowman’s capsule atrophy, the surface area of bowman’s capsule, and bowman’s space were demonstrated in seven studies [35, 40, 46, 47, 49–51]. In 8 articles, necrosis of tubular and glomerular cells were reduced [15, 22, 27, 28, 44, 49, 50, 55], also hajhosseini et al. found that the quantity of apoptotic cells was reduced [38]. In 12 studies ginger reduced dilation and degeneration of tubules [15, 21, 22, 27, 28, 37, 40, 49–51, 55, 57]. Additionally, in four studies, the weight of the kidneys were decreased at the end [45, 49, 50, 54]. although in two studies, the weight of kidneys did not change significantly [25, 48].

The present systematic review was conducted to discover the impact of different forms of ginger on metabolic indicators in DKD. The findings, to the best of our knowledge, show some positive effects of ginger in DKD. The result of the current systematic review exhibited that ginger has a beneficial effect on blood levels of glucose, insulin, C-peptide and HbA1C. Although, results from blood glucose in Abdulsalam et al. and Al-Attar et al. studies were contradictory [32, 33]. These results seem to be contradictory due to ginger supplementation was a percentage of the diet, does not have a specific dose and may be low or high, while other studies showed favorable results as they prescribed ginger as mg/kg body weight. Also, Xu Yun et al. showed that 25 or 50 mg/kg of 6-shogaol reduced insulin serum levels [49]. The difference between this study and other studies appears to be owing to the assumption that this study was based on 6-shogaol supplementation while other studies were based on ginger supplementation. There is not enough evidence to conclude about HOMA-IR.

Several possible mechanisms have been suggested for ginger's function on glycemic indices. The authors hypothesized a mechanism shown in Fig. 3 that ginger can improve blood glucose levels in liver cells. Ginger activates the Ampk pathway. Activation of this pathway leads to inhibition of FOXO1, which is an important transcription factor in regulating the expression of genes involved in hepatic glucose production (gluconeogenesis) such as PEPCK and G6pase, thereby reducing hepatic glucose production [58]. Also, ginger inhibits the hepatic phosphorylase enzyme and inhibits glycogenolysis in liver cells, and increases the activity of glycogenesis enzymes [59]. According to a study, ginger can also increase the activity of hepatic glycolytic enzymes such as glucokinase, phosphofructokinase, and pyruvate kinase [15]. Another mechanism can inhibit the hepatic glucose 6 phosphatase enzyme, thereby reducing the conversion of glucose 6 phosphates to glucose and finally decreasing blood glucose level [60].

Figure 3. the possible effect of zingiber officinale on reduced gluconeogenesis and lipogenesis in the hepatocyte cell. Through the AMPK pathway, ginger reduces hepatic cholesterol production and lowers blood sugar levels.

In one study, glucose uptake in rat muscle cells were increased due to translocation in GLUT4 transporter to the plasma membrane, and rise in GLUT 4 gene expression facilitated insulin-independent glucose uptake [61]. Also, ginger can reduce Insulin resistance in skeletal muscle [62]. In addition, Ginger activates the Ampk pathway [63]. Activation of AMPK by increasing the phosphorylation of IRS, PI3K, and Akt tyrosine roots improves insulin signaling and increases the translocation GLUT4 transporter to the plasma membrane surface, and increases the entry of glucose into the cell [64]. Figure 4 shows how ginger may affect insulin sensitivity.

Figure 4. The possible effect of ginger on insulin sensitivity in the skeletal muscle cells. Ginger increases the expression of the GLUT4 gene and the translocation of GLUT4 to the plasma membrane of muscle cells via the AMPK pathway, which leads to enhanced glucose uptake.

Dyslipidemia is one of the predictors of DKD progression [6, 65, 66]. In general, the lipid profile was improved in the present study. Despite this, the Al-attar study 2.5% or 5% of the diet was supplementedwith ginger oil for two weeks and reported that TC, TG, and LDL levels increased, but HDL decreased [33]. Also, sangi et al showed that the application of 1000 mg/kg ginger aqueous extract for 3 weeks reduced serum HDL [34]. These results appear to be inconsistent due to the short duration of supplementation.

As shown in Fig. 3, ginger increases the expression of the PPAR-α gene by activating the AMPK-SIRT-PGC-1α pathway in the liver, which leads to inhibiting the expression of regulatory genes such as SREBP-1c and ACC in lipogenesis. Eventually, the synthesis of cholesterol and fatty acids is decreased [62]. Several possible mechanisms are proposed for lowering lipid levels with ginger intake in 2 systematic reviews [67, 68]: 1) reduce cholesterol biosynthesis by reducing farnesyl diphosphate liver production. 2) induction of the conversion of cholesterol into bile acids and increased cholesterol excretion. 3) liver uptake LDL from circulation and reduces cholesterol synthesis. 4) increased pancreatic lipase. 5) inhibition of lipid hydrolysis in the intestine. 6) PPARδ pathway activation. 7) decreased RBP expression, which is an indicator of hyperlipidemia. 8) ginger contains niacin, which reduces TG and VLDL and liver uptake LDL. 9) reduce the conversion of excess carbohydrate to TG by reducing the expression ChREBP gene.

Inflammation and Oxidative stress performs an important role in the pathogenesis and progression of DKD [69, 70]. The results of the current systematic review support the beneficial effect of ginger on inflammation and oxidative stress. Possible mechanisms for reducing inflammation by ginger: 1) NF-κB signaling pathway suppression [62]. 2) inhibition of COX-2 and lipoxygenase, thus suppressing AA metabolism. 3) inhibition of prostaglandin synthesis. 4) some ginger compounds are serotonin blockers that reduce inflammation and prostaglandins [71]. Hyperglycemia increases the production of ROS. Ginger reduces ROS directly or indirectly by lowering blood glucose [15]. Also ginger reduces oxidative stress and lipid peroxidation by scavenging free radicals [72]. Figure 5 shows the possible mechanisms for reducing oxidative stress, which are as follows: 1) preventing the formation of AGEs via Nrf2 dependent pathway [73]. 2) inhibition of protein kinase C [74]. 3) inhibition of polyol pathway [75].

Figure 5. Schematic representation of possible mechanisms of the effect of ginger on oxidative stress.

Overall, renal function indicators were improved in the present study. On the contrary, urea, uric acid, and urinary protein levels in Al-Attar et al. study and creatinine level in Abdulsalam et al. study were increased [32, 33]. These results seem to be contradictory as ginger supplementation was a percentage of the diet, does not have a specific dose and may be low or high, while other studies that showed favorable results were ginger in mg/kg body weight. Ginger improves renal function through scavenging free radicals [72]. A study showed that the reduction of urea by ginger may be due to a mechanism of re-absorption inhibition of urea in the nephrons. Polyphenols and flavonoids present in ginger may paly a role in renoprotective activities and lowering serum urea, creatinine and uric acid levels [76]. Also, It is suggested that ginger can have a protective effect on renal function by improving antioxidants status, reversing fatty acid changes, and regulating glycoprotein components

All studies that examined histomorphological changes showed beneficial effects. Several studies have shown that ginger improves pathological changes such as cytotoxicity caused by hyperglycemia, cell apoptosis, bleeding in the cortical area of the kidney. A number of studies have shown that ginger improves and repairs kidney damage. For example, ginger restored membrane integrity in renal tissue and structural derangement.

Knowledge gaps and future direction

Due to the lack of human studies, more studies are needed to evaluate the effects of ginger on DKD, as there is a gap in current knowledge in this field. The consistency in the result could be related to ginger dosage, supplementation duration, and diverse forms of ginger.

As a whole, the results of the present systematic review indicated that ginger may beneficially affect the glycaemic indices, oxidative stress,inflammatoryfactors, lipid profile, and renal function indicators. Although, the results seem promising, Further human trials are required to achieve precise results.

Ethical Standards Disclosure: this is a review article and this part is not applied to this paper.

Acknowledgement: we thank Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran.

Conflict of interest: The authors confirm that there is no conflict of interest.

Financial Support: this is a review article and this part is not applied to this paper.

Author contribution: subject of article: ZGh. literature review: ZGh, PV. screen the title and abstract of the qualifying studies: PV, HR. quality assessment: PV, MZ. Drafting of the manuscript: PV, MZ, HR. reviewing the manuscript: ZGh, PV, MZ, HR. drawing figures: PV.

Consent for publication:All authors gave final approval of the version to be published and agree to be accountable for all aspects of the work. Z.Gh also accept all responsibility for the manuscript on behalf of all the authors.

Availability of data and materials:Data will be available at the request. Please contanct the corresponding or the first author.

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Renoprotective Effects of the Ginger (Zingiber officinale) in Diabetic Kidney Disease, Current Knowledge and Future Direction: A Systematic Review of Animal Studies

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Abstract

Figures

1. Introduction

2. Methods

2.1 Search strategy

2.2 Eligibility criteria

2.3 Data extraction

2.4 quality assessment

3. Results

3.1 Selected Articles

3.2 Characteristics of the included studies

3.3 quality assessment

3.4.1 Ginger and glycemic control in DKD

3.4.2 Ginger and dyslipidmia in DKD

3.4.3 Ginger and oxidative stress indices in DKD

3.4.4 Ginger and inflammation biomarkers in DKD

3.4.5 Ginger and renal function in DKD

3.4.6 Ginger and changes in histomorphology and structural renal in DKD

4. Discussion

Conclusion

Declarations

References

Additional Declarations

Status:

Version 1