Table 1.

List of resveratrol (RESV) uses and Nrf2 pathway-based activity in animal models.

Author and Year	Sample (n)	Route of Administration	Intervention Time	Doses	Condition/ Disease	Nrf2 Pathway
Kim et al. [140]	7 mice/ group	Oral	6 months	I: 40 mg/kg	Progressive kidney damage caused by aging	RESV improved proteinuria, histological changes, inflammation and ↑ NRF2Nrf2 expression, improving oxidative stress and mitochondrial dysfunction.
Bhattarai et al. [141]	5 rats/ group	Subcutaneous and palatal gum injection	2 weeks	I: RESV and DMSO groups: 5 mg/kg body weight daily	Alveolar bone loss	RESV almost completely inhibited the alterations promoted by the oxidative stress ↑ HO-1, mediated by NRF2.
Wang et al. [142]	6 rats/ group	Intradermal injection	24 days	I: 10 mg/kg	Rheumatoid arthritis	RESV ↓ AA scores and serum levels of antioxidant enzymes, and inhibited ROS production by activating the SIRT1/Nrf2 signaling pathway.
Kong et al. [143]	10 mice/ group	Gavage	15 days	I: 40 mg/kg or 20 mg/kg)	Alzheimer’s disease	RESV ↑ the antioxidant capacity of animals in the experimental group, such as SOD, CAT, GPx, through the NRF-2/HO-1 signaling pathway.
Cui et al. [144]	10 mice/ group	Gavage	6 weeks	I: 2 mg/kg	Photoaging	A protective effect was seen against photoaging though the ↓ in the expression of matrix metalloproteinases and inflammatory factors, inhibiting the ROS production measured by the MAPK and COX-2 pathways, in addition to promoting the NRF2 signaling pathway.
Zhou et al. [145]	6 rats/ group	Subcutaneous injection	2 weeks	C: rats’ cutaneous wounds were only washed daily with physiological saline I: rats’ cutaneous wounds were washed daily with physiological saline followed by RESV local application.	Wound healing	RESV ↑ Nrf2 and Mn-SOD, and subsequently attenuated oxidative stress, promoting the acceleration and quality of healing of cutaneous wounds.
Xun et al. [146]	6 piglets/ group	Intraperitoneal injection	21 days	I: 10, 30 or 90 mg/kg	Induced intestinal integrity and inflammation	RESV protects intestinal integrity, alleviates intestinal inflammation and oxidative stress by modulating AhR/Nrf2 pathways in piglets challenged with diquat (organic herbicide).
Hosseini et al. [147]	10 mice/ group	Oral	16 weeks	C: Standard chow diet (10 kcal% fat) I1: a high fat diet (HFD, 55.9 kcal% fat) I2: HFD-supplemented with 0.4% HFD + RESV groups	Non-alcoholic fatty liver disease	RESV attenuated HFD induced methylation of the Nrf2 promoter in the liver of mice, and this effect was correlated with ↓ in triglyceride levels and ↓ in expression of genes related to lipogenesis, such as FAS and SREBP-1c.
Zhao et al. [148]	8 rats/ Group	No description	7 days	I: 50 mg/kg for 7 days	Acute respiratory distress induced by seawater inhalation	AC-Res attenuated respiratory distress via Trx-1 and Nrf2, both in animals.
Yang et al. [149]	10 ducks/ group	Oral	15 days	I: the basal diet supplemented with 400 mg/kg RESV	Birds subjected to heat stress	RESV significantly activated the SIRT1-NRF1/NRF2 signaling pathways, and ↑ SOD and CAT. NF-κB/NLRP3 inflammasome signaling pathways were repressed under acute heat stress. Meanwhile, RESV supplement further inhibited the NLRP3 inflammasome pathway.
Rasheed et al. [150]	No description	Intraperitoneal	9 weeks	I: 10 mg/kg	Parkinson’s disease	RESV promotes the catalytic activity of the xenobiotic-metabolizing enzyme, Cyp2d22/CYP2D6, which partially contributes to Nrf2 activation in pesticide-induced parkinsonism.
Recalde et al. [151]	16 rats/ group	Intraperitoneal injection	21 days	I: (RESV ethanol 0.1%) in their drinking water	Hemotherapy-induced peripheral neuropathic pain (cancer)	RESV prevented the upregulation of NFκB, TNF-α, ATF3 and c-fos, while ↑ expression of Nrf2, NQO-1, HO-1 and the redox-sensitive deacetylase SIRT1. RESV treatment was also able to restore TBARS levels and the GSH/GSSG ratio.
Wang et al. [152]	18 mice/ group	Oral	Until 6 months	I: 10 mg/kg/day for 1 month. After another month, a subset of mice was used for experimentation; the remaining mice were maintained for another 2 or 5 months (corresponding to 3 or 6 months after RESV treatment) and then were used for experimentation	Diabetic cardiomyopathy	RESV prevents DM-induced cardiomyopathy, in part, by ↑ Nrf2 expression and transcriptional activity.
Wang et al. [153]	7 mice/ group	Intragastric administration	No description	I: 5, 10, 20 mg/kg	Allergy	RESV exerts an inhibitory effect on MRGPRX2-mediated mast cell activation by targeting the Nrf2 pathway, and may present a promising new therapeutic agent for allergy, avoiding anaphylactoid reactions.
Trusov et al. [154]	No description	Oral	No description	C: standard balanced diet I1: high-fat-high-carbohydrate diet (HFCD) with an excess of total fat (30%) and fructose (20% solution instead of drinking water) I2: the same diets supplemented with RESV in a low (25 mg/kg body weight as RESV and 300 mg/kg as L-carnitine) or high (50 and 600 mg/kg body weight, respectively) doses	Obesity	RESV combined with L-carnitine caused ↓ in the number of positive cells for Nrf2 and ICAM-2 in the liver of rats treated with diets with high concentrations of carbohydrate and fat, but had the opposite effect on the kidneys. RESV + L-carnitine at a low dose by the same group caused alterations in the expression profiles of the studied marker genes, indicating a possible hypolipidemic effect.
Wang et al. [155]	12 rats/ group	Intraperitoneal injection	18 h	I: 30 mg/kg was administered at 6 h after surgery and then again at 12 h	Pediatric acute kidney injury	In the RESV group, the induced kidney injury was alleviated by ↓ the expression of TNF-α, IL-1β and KIM-1. Nrf2 signaling is known to effectively inhibit inflammation. Further, there were ↑ in the expression of HO-1 and NQO1in the RESV group.
Wu et al. [156]	15 mouse/ group	Gavage	Alternate days for 2 weeks	I1: 30 mg/kg I2: 100 mg/kg	Ovarian aging	RESV alleviated the loss of oogonial stem cells and showed a mitigating effect on induced oxidative apoptosis in mouse ovaries, which can be attributed to attenuation of oxidative levels in the ovaries activating Nrf2. Further, ↑ SIRT1 and FOXO1 and ↓ NF-κB.
Sun et al. [157]	6 rats/ group	Gavage	5 weeks	I: 30 mg/kg	Induced myocardial injury	RESV attenuated the oxidative stress through the expression of antioxidant molecules via Nrf2. Furthermore, AMPK may play a role in Nrf2/HO-1 signaling by RESV.
Kabel et al. [158]	10 rats/ group	Gavage	24 weeks	I: 30 mg/kg	Renal carcinoma	Intervention induced improvement in renal functions with a significant ↑ in tissue antioxidant defenses and Nrf2/HO-1 content associated with a significant ↓ in TGF-β1, TNF-α, IL-6 and STAT3 and alleviated histopathological and immunohistochemical changes compared to the untreated renal carcinoma group.
Lian et al. [159]	10 rats/ group	Oral	12 weeks	I: 50 mg kg	Obstructive sleep apnea associated with lung injury	Nrf2 and HO-1 protein levels were ↓ in the chronic intermittent hypoxia group compared to the control group. Rats in the RESV group had ↓ percentages of apoptotic cells, levels of IL-6, TNF-α, Bax, and cleaved caspase-3, and ↑ levels of Nrf2 protein and HO-1.
Yang et al. [160]	60 ducks/ group	Oral	15 days	I: basal diet supplemented with 400 mg/kg RESV	Growth performance and anti-inflammatory ability	Dietary RESV can improve growth performance and ↓ inflammation through Nrf2/HO-1 and TLR4/NF-κB signaling pathways in ducks.
Zhou et al. [161]	8 rats/ group	Intragastric	18 weeks	I: 50 mg/kg every other day	Breast cancer	RESV treatment could upregulate the expression of Nrf22 and UGT1A8, accelerate metabolic elimination of catechol estrogens, inhibit estrogen-induced DNA damage and suppress the pathological development of breast cancer.
Xu et al. [162]	10 rats/ group	Intraperitoneal injection	7 days	I: 20 mg/kg	Type 2 diabetes	RESV ↑ Nrf2 expression in a diabetic heart by stimulating SIRT1 or inhibiting GSK3β, alleviating myocardial oxidative stress and improving ischemia–reperfusion injury.
Izquierdo et al. [163]	Until 20 mice/ group	Oral	2 months	I: 1 g/kg	Senescence	Maternal RESV supplementation may prevent cognitive impairment in mouse offspring through epigenetic alterations and Nrf2 signaling pathways.
Chen et al. [164]	12 piglets/ group	Intraperitoneal injection	15 days	I: 300 mg/kg	Redox status and intestinal microbiota	RESV and PTS administration ↑ jejunal SOD activity and SOD 2 mRNA and protein expression of IUGR piglets, promoting Nrf2 nuclear translocation. PTS was superior to RESV in ↑ Nrf2 nuclear translocation and inhibiting MDA accumulation in the jejunum of IUGR piglets. Further, RESV modulated the composition of the fecal microbiota of IUGR piglets.
Zeng et al. [165]	10 mice/ group	Intragastric	32 days	I: 10 to 100 mg/kg	Methamphetamine-induced memory deficit	Pretreatment with RESV in methamphetamine-induced memory dysfunction was possibly related to activation of the Keap1-Nrf2 pathway and ↓ of apoptosis, suggesting benefits of using this antioxidant in this condition.
Cong et al. [166]	15 mice/ group	Intraperitoneal injection	10 days	I1: 25 mg/kg I2: 50 mg/kg	Traumatic brain injury	RESV has a protective effect on brain injury induced by chest blast exposure, likely mediated by Nrf2/Keap1 and NF-κB signaling pathways.
Javkhedkar et al. [167]	8–12 rats/ group	Oral	9 weeks	I: 50 mg/kg	Renal interstitial inflammation in the pathogenesis of hypertension	Long-term RESV administration restores Nrf2 expression, improves inflammation and attenuates the development of hypertension.
Rubio-Ruiz et al. [168]	16 rats/ group	Oral	20 weeks	I: RESV and quercetin 50–0.95 mg/kg/day, respectively	Fatty liver in metabolic syndrome	RESV + quercetin has beneficial effects on oxidative stress in fatty liver of rats with metabolic syndrome through the improvement of antioxidant capacity and overexpression of the Nrf2 factor, which increases enzymes antioxidants and GSH recycling.
Chen et al. [169]	5–6 mice/ group	Intragastric	13 days	I: 200 mg/kg	Colitis and colon cancer	The RESV analogue studied has stronger anticolitis effects than RESV, with even greater ability to stimulate the Nrf2 pathway than the parent compound.
Pierre et al. [170]	16–17 mice/ group	Oral	8 weeks	I: 1–10 mg/kg	Erectile Dysfunction	RESV and MitoQ were ineffective in reversing the effects of androgen deprivation on vascular reactivity; however, treatment with high doses of RESV upregulated several important antioxidant genes including CAT, SOD1, GSTm1, Prdx3, and Nrf2.
Kim et al. [140]	8 mice/ group	Oral	2 weeks	I: 2 mg/kg	Photoaging	Nrf2-dependent antioxidant enzymes induced by grape skin extract or RESV, including HO-1 in the liver and skin, as well as inhibited metalloproteinases and attenuated UVB-induced photoaging through activation of the Nrf2/HO-1 signaling pathway.
Wang et al. [171]	9 birds/ group	Oral	21 days	I: 400 mg/kg	Intestinal growth and development	RESV may improve intestinal development and antioxidant function in broiler chickens under heat stress. Further, the RESV group shows ↑activities of GPX, GST and mRNA levels of Nrf2 and SOD1.
Ma et al. [172]	10 mice/ group	Intraperitoneal injection	5 days	I: 25 mg/kg	Diabetic cardiomyopathy	RESV actives SIRT1, induces ↑ expression of Nrf1 and Nrf2 and ameliorates diabetic cardiomyopathy.
Wang et al. [173]	7–8 mice/ group	Oral	4 months	I: 30 mg/kg	Cognitive impairment caused by type 2 DM	RESV prevented the cognitive impairment induced by DM2 through anti-inflammatory and antioxidant activities. This effect was accompanied by the upregulation of Nrf2 transcriptional activity and ↑ expression of antioxidant genes.
Ikeda et al. [174]	No description	Intraperitoneal injection	on day 15 after periodontitis induction	I: 10 mg/kg	Periodontitis	RESV dimer induced greater periodontal bone healing when compared to the use of RESV monomer. It appears that periodontal bone healing in both groups was likely related to master regulation of Nrf2 and downregulation of IL-1β in the RESV dimer group.
Cirmi et al. [175]	7 mice/ group	Oral or Intraperitoneal injection	14 days	I: 20 mg/kg	Cadmium-induced kidney injury	Cadmium caused damage to glomeruli and tubules and ↑ expression of Nrf2 genes. RESV significantly improved all parameters.
Jia et al. [176]	10 mice/ group	Intraperitoneal injection	6 days	I: Oxyresveratrol 40–80 mg/kg	Acute liver injury	Hepatoprotective efficacy of oxy-resveratrol was seen due to the prevention of TLR4/NF-κB pathway activation, induced activation of the Keap1-Nrf2 signaling pathway, and decreased hepatocyte apoptosis.
Seo et al. [177]	5 mice/ group	Intraperitoneal injection	8 days	I: 20 mg/kg	Atherosclerosis	RESV inhibits ICAM-1 expression via transcriptional regulation of FERM-kinase and Nrf2 interaction, thus blocking monocyte adhesion, suggesting that RESV improves inflammation and delays the onset of atherosclerosis.
Zhang et al. [178]	3 mice/ group	Intragastric	12 weeks	I: 10 mL/kg 10%	Diabetic neuropathy	RESV may attenuate the severity of diabetic neuropathy by protecting peripheral nerves from apoptosis, inhibiting the NF-κB pathway, and ↑ Nrf2 expression.
Krajka-Kuźniak et al. [179]	3 mice/ group	Topical use	3 days	I1: 8 µM/kg I2: 16 µM/kg	Mouse epidermis	RESV and its methylthioderivatives activate Nrf2 in mouse epidermis and promotes upregulation of GST.
Zhou et al. [180]	6 mice/ group	Gavage	Day 14 of pregnancy until parturition	I: 50 mg/kg	Streptococcus uberis infection	RESV can function as an activator of the p62–Keap1/Nrf2 signaling pathway to improve oxidative injury caused by S. uberis in mammary glands as well as in EpH4-Ev cells.
Cheng et al. [181]	10 rats/ group	Intravenous	After ischemia induction, RESV was administered 5 min before reperfusion	I: 100 μmol/L	Myocardial ischemia	RESV exerted significant antioxidant and cardioprotective effects after myocardial ischemia, possibly through activation of the Nrf2/ARE signaling pathway.
El-Fattah et al. [182]	6–8 rats/ group	Oral	30 days before and 45 after the induction of testicular dysfunction	I: 80 mg/kg	Di-(2-ethylhexyl)phthalate-induced testicular dysfunction	Pretreatment with RESV and curcumin were able to recover the lesions induced in this model. The chemoprotective effects of these compounds may be due to their intrinsic antioxidant properties, along with increased gene expression levels of Nrf2, HSP 60, HSP 70 and HSP 90.
Yang et al. [149]	15 ducks/ group	Oral	22 days	I: 300, 400 or 500 mg/kg	Ileitis caused by LPS	RESV alleviated acute ileitis induced by duck LPS through Nrf2 and NF-κB signaling pathways, and dietary RESV 500 mg/kg is more efficient.
Muhammad et al. [183]	7 mice/ group	Oral	8 weeks	I: 200 mg/kg	Alzheimer’s disease	Induced memory deficit was improved by RESV. Both Aβ and Nrf2 ↑ significantly in the group that received RESV, with isolated treatment with this compound being the most effective.
Elbaz et al. [184]	8 rats/ group	Oral	7 days	I: 20 mg/kg	Diclofenac-induced hepatorenal toxicity	A potential therapeutic role for RESV in mitigating the hepatorenal insult induced by diclofenac has been demonstrated, possibly via modulation of the Nrf2/GSH axis.
Jia et al. [185]	30 animals/ group	Oral	60 days	I: 0, 0.1, 0.3, and 0.6 g/kg	Induced liver damage	RESV protection against H2O2-induced liver damage, inflammation and immunotoxicity was due to its antioxidant property and its ability to modulate Nrf2 and TLR2-Myd88-NF-κB signaling pathways.
Cheng et al. [186]	6 mice/ group	Oral	12 weeks	I: 10 mg/kg	Hyperglycemia and pancreatic damage	RESV treatment markedly improved the blood glucose level of the oral glucose tolerance test and promoted Nrf2 phosphorylation in the pancreas of mice treated with methylglyoxal.
Liu et al. [187]	90 ducks/ group	Gavage	70 days	I: 500 mg/kg	Acute liver damage induced by aflatoxins	RESV increased phase II enzyme activity, activate Nrf2 signaling pathway, and protect duck liver from toxicity, oxidative stress, and inflammatory reaction.
Wei et al. [188]	10 rats/ group	No description	8 weeks	I: 50 mg/kg	Osteoarthritis	RESV improves inflammatory damage and protects against osteoarthritis in a rat model via NF-κB and HO-1/Nrf-2 signaling.
Zhou et al. [189]	50 animals/ groups	Oral	7 days	I: 500 mg/kg	Diquat-induced intestinal oxidative stress	Dietary supplementation with RESV and apigenin attenuates oxidative stress involving NRF2 signaling pathways in diquat-challenged pullets.
Zhang et al. [190]	5 mice/ group	Intraperitoneal injection	7 days	I: 20 mg/kg	Osteogenic potential	RESV ↓ oxidative stress by alleviating proliferation, mitigating ROS activity, ↑ SOD enzyme activity and improving GSH concentration, been confirmed by gene expression of SOD1 and Sirt1/Nrf2.
Wu et al. [191]	53–54 animals/ group	No description	Until 40 days	I: 0.5 mM/mL	Cerebellar neurotoxicity in spinocerebellar ataxia type 3	RESV and caffeic acid were able to ↑ activation of Nrf2 in this model.
Hussein and Mahfouz [192]	6 rats/ group	Oral	8 weeks	I: 5 mg/kg	Diabetic nephropathy	RESV alone or co-administered with rosuvastatin improved antioxidant status back to control values. RESV with rosuvastatin remarkably normalizes the renal expression of TGF-β1, fibronectin, NF-κB/p65, Nrf2, Sirt1 and FoxO1 in the diabetic rat group.
Li et al. [193]	5 rats/ group	Intragastrical administration	24 h	I: RESV was diluted in sterile saline to 0.23 μg/kg, 1,5 mL	Renal ischemia–reperfusion injury (IRI)	RESV Shows renoprotection exerting significant effects on inflammatory responses, oxidative stress and apoptosis through the Nrf2/TLR4/NF-κB pathway.
Tamaki et al. [194]	6 rats/ group	Oral	3 weeks	I: 10 mg/kg	Periodontitis	RESV exhibited multiple beneficial effects in preventing periodontitis and ↓ oxidative stress through its activation of both Sirt1/AMPK and Nrf2/antioxidant.
Xu et al. [195]	10 rats/ group	Intraperitoneal injection	6 weeks	I: 20 mg/kg	Myocardial ischemia–reperfusion in diabetic rats	RESV can inhibit oxidative stress and alleviate MIR by activating the AMPK/p38/Nrf2 signaling pathway.
Gao et al. [196]	12 rats/ group	Intraperitoneal injection	7 days	I: 40 mg/kg	Hypoxic-ischemic encephalopathy (HIE)	RESV exhibited neurotherapeutic potential through upregulation of expression of Nrf2 and HO-1 signaling pathway proteins and thereby attenuate oxidative stress and inflammatory response.
Li et al. [197]	6 rats/ group	Oral	6 weeks	I: RESV supplement of 0.03%	Oxidative stress in obese asthmatic rats	RESV significantly ↑ CAT, GSH, GPx, and total SOD levels compared to obese, asthmatic, and untreated obese asthmatic rats. Furthermore, it significantly ↓ levels of Keap-1 and↑ Nrf2 in the heart, lung and kidney tissues of rats compared to untreated controls.
Li et al. [198]	6 mice/ group	Intraperitoneal injection	72 h	I: 30 mg/kg	Lung injury	RESV is a SIRT1 activator and strongly ↑ SIRT1 expression and attenuated lung injury. Furthermore, RESV treatment ↑ the expression of NRF2 and GSH, ↑ the activity of HO-1, SOD and CAT, but ↓ the MDA expression.
Singh et al. [199]	No description	Subcutaneous pellet	Every other month, until 8 months	I: 50 mg/kg	Breast cancer	RESV alone or in combination with 17β-estradiol significantly ↑ the expression of Nrf2 in breast tissues. Expression of antioxidant genes regulated by NRF2, NQO1, SOD3 and OGG1 that are involved in protection against oxidative DNA damage were ↑ in breast tissues treated with RESV and RESV + 17β-estradiol.
Xu et al. [200]	6 mice/ group	Intraperitoneal injection	7 days	I: 10 mg/kg	Acute liver toxicity	RESV/FGF1↓ oxidative stress and thereby alleviated liver injury by promoting nuclear translocation of Nrf2 and subsequently ↑ expression of antioxidant proteins in an AMPK-dependent.
Lu et al. [201]	6 mice/ group	Intraperitoneal injection	7 days	I: 10 mg/kg	Doxorubicin-induced cardiotoxicity	RESV could reduce the growth-promoting activity of FGF1. The co-treatment of RESV and FGF1 exhibits a more powerful cardio-antioxidative capacity in a treated model. The inhibition of SIRT1/NRF2 abolished RESV in combination with FGF1 on cardioprotective action.
Meng et al. [202]	20 animals/ group	Oral	20 days	I: 30 mg/kg	Pregnancy and lactation	In the placenta, Nrf2 protein expression was ↑ and Keap1 protein expression was ↓ by dietary RESV. mRNA expression of antioxidant genes including CAT, GPX1, GPX4, SOD1 and HO1.
Wang et al. [203]	10 animals/ group	Oral or intraperitoneal injection	28 days	I: 600 mg/kg	Ovarian oxidative stress	RESV reversed the tryptophan-kynurenine pathway, ↑ levels of Nrf2 and SIRT1, and ↓ FoxO1 and P53.

↑: increase; ↓: decrease; AC-Res: acetylresveratrol; AMPK: adenine monophosphate-activated protein kinase; ATF3: activating transcription factor 3; C33: imazosulfuron, pesticide/herbicide; CAT: catalase; C-fos: The cellular oncogene c-Fos; COX-2: cyclooxygenase 2; DM: diabetes mellitus; DMBA: 7,12-dimethylbenz(a)anthracene; FERM: kinase-ezrin, radixin, moesin homology domain; FGF1: Fibroblast growth factor 1; GSH/GSSG: oxidized glutathione/reduced glutathione ratio; GSK3β: glycogen synthase kinase 3β; GSTm1: glutathione s-transferase; HFD: high fat diet; HO-1: heme oxigenase-1; ICAM: intercellular adhesion molecule 1; IRA-2-methoxyl-3,6-dihydroxyl; LPS: lipopolysaccharide; MIR: myocardial ischemia–reperfusion; NF-κB: nuclear factor kappa b; NQO-1: NAD(P)H quinone-oxidoreductase-1; Nrf2: nuclear erythroid 2-related factor; OXA: oxaliplatin; Prdx3: peroxiredoxin 3; RESV: resveratrol; ROS: oxygen reactive species; SIRT1: sirtuin 1; SOD: superoxide dismutase; SREBP-1c: sterol regulatory element binding proteins; STAT-3: signal transducer and activator of transcription 3; Trx-1: thioredoxin; TBARS: thiobarbituric acid reactive species.