Table 2.
Bioactivities and potential mechanisms of resveratrol from experimental studies.
| Study Type | Subject | Dose | Main Findings | Ref. |
|---|---|---|---|---|
| Antioxidative activities | ||||
| In vitro | HepG2 cells | 0–100 μM | Dose-dependently increasing antioxidant effects by enhancing SIRT2’s activity to deacetylate Prx1 | [24] |
| In vitro | HepG2, C2C12, and HEK293 cells |
10, 25 μM | Activating AMPK to maintain the structural stability of FoxO1 | [25] |
| In vitro | MCF-7 cells | 1 nM, 0.02 μM, 0.1 μM, 0.5 μM, 1.5 μM | Upregulating PTEN (except at the highest dose, 1.5 μM), which decreased Akt phosphorylation, leading to an upregulation of antioxidant enzyme mRNA levels such as CAT and SOD | [26] |
| In vivo | Rats | 20 mg kg/b.w./day | Improving the antioxidant defense system by modulating antioxidant enzymes through downregulation of ERK activated by ROS | [27] |
| In vivo | Rats | 10 mg/kg b.w. | Reducing the ischemia-reperfusion injury-induced oxidative stress by inhibiting the activation of p38 MAPK pathway to increase antioxidants like GSH and scavenge free radicals | [28] |
| In vivo | Rats | 5, 10 mg/kg | Activating SIRT1 to scavenge ROS | [29] |
| In vivo | Mice | 15, 30, 60 mg/kg | Activating AMPK, SIRT1, and Nrf2 associated antioxidant defense pathways to improve systemic oxidative and nitrosative stress | [30] |
| In vivo | Sows | 300 mg/kg | Regulating antioxidant gene expression via Keap1/Nrf2 pathway and SIRT1 | [31] |
| In vitro | HUVECs | 10 μM | Inducing autophagy via the activation of TFEB | [32] |
| In vitro | HEK293 cells or HEK293T | 5 μg/mL | Inducing autophagy via the AMPK-mediated inhibition of mTOR signaling | [33] |
| Anti-inflammatory activities | ||||
| In vivo | Mice | 8 mg/kg/day | Inhibiting the activation of NALP3 inflammasome and inducing autophagy via SIRT1 upregulation | [34] |
| In vitro | J774 mouse macrophages, Mouse bone-marrow cells |
0.5–100 μM | Inhibiting the activation of NALP3 inflammasome | [35] |
| In vitro; In vivo |
BEAS-2B cells, Mice |
25 μM, 20 mg/kg |
Inducing NF-κB inhibition, decreasing IL-6 secretion, suppressing STAT3 activation, blocking ERK1/2 activation, and upregulating MyD88 Short | [36] |
| In vitro | RAW264.7 macrophages | 0–20 μM | Inhibiting the production of pro-inflammatory cytokines, such as TNF-α and IL-1β, but also by inducing anti-inflammatory HO-1 | [38] |
| In vitro | RAW264.7 macrophages, MCF-7 cells | 10 μM | Suppressing IL-6 transcription, modulating the inflammatory responses as an ERα ligand mediated by SIRT1. | [39] |
| In vitro | Mouse C2C12 myoblasts | 20, 50, 100 μM | Inhibiting NF-κB signaling independent of SIRT1 | [40] |
| In vitro | RAW264.7 macrophages | 1, 5, 10, 20, 40 μM | Downregulating HMGB1 as well as suppressing NF-κB and JAK/STAT signaling pathways | [41] |
| In vitro | U937 monocytic cells | 15, 30, 50 μM | Inhibiting NF-κB and JAK/STAT signaling pathways | [42] |
| In vitro In vivo |
NRK-52E, Rat |
100 μmol/mL, 0.23 μg/kg |
Inhibiting TLR4/NF-κB signaling cascade | [43] |
| In vivo | Rats | 30, 10 and 3 mg/kg, | Inhibiting TLR4/NF-κBp65/MAPKs signaling cascade | [44] |
| In vitro | Primary chondrocytes and macrophages | 10, 25, 50, 100 μM | Interrupting an inflammatory amplification loop | [45] |
| Immunomodulating effects | ||||
| In vitro | A549 cells | 56.25, 112.5 μg/mL | Triggering an immune response to protect against non-typeable Haemophilus influenzae without developing resistance | [46] |
| In vitro | H1HeLa cells, Human nasal epithelia | 0–300 μM | Inhibiting human rhinoviruses-16 replication and normalized virus-induced IL-6, IL-8, and RANTES as well as the expression of ICAM-1 | [47] |
| In vitro | Rhabdosarcoma cells | 2.5–100 μg/mL | Preventing EV71 replication, reducing the virus-induced elevated IL-6 and TNF-α secretion via suppressing IKK/NF-κB signaling pathway | [48] |
| In vivo | Chickens | 200, 400, 800 mg/kg | Reducing immunocyte apoptosis in chickens receiving conventional vaccinations, and improving the growth of young chickens | [49] |
| In vivo | Piglets | 3, 10, 30 mg/kg/d | Maintaining the immune function and attenuating diarrhea and inflammation | [51] |
| In vitro | Atlantic salmon macrophages | 10, 30, 50 μM | Reducing bacterial and inflammatory biomarkers in LPS-challenged primary Atlantic salmon macrophages | [52] |
| In vivo | Mice | 30 mg/kg | Upregulating SIRT1 and reducing cytokines such as TNF-α, IFN-γ, IL-6, and MCP-1 | [53] |
| In vivo | Mice | 30 mg/kg | Enhancing immune activity in immunosuppressive mice, showing a bidirectional regulatory effect on immunity | [54] |
| In vitro | Human CD4+ T cells | 10, 30, or 50 μM | Suppressing the AhR pathway, resulting in the reversal of imbalanced Th17/Treg | [56] |
| Cardiovascular diseases | ||||
| In vivo | Rhesus monkeys | 80 mg/day (1st year), 480 mg/day (2nd year) | Improving central arterial wall stiffening based on its antioxidative and anti-inflammation | [7] |
| In vivo | Rabbits | 2.5 mg/kg | Mitigating atrial fibrillation by upregulating PI3K/AKT/eNOS | [8] |
| In vitro | Peripheral blood mononuclear cells |
3–80 μM | Blocking atherosclerotic plaque progression by acting against pro-atherogenic oxysterol signaling in M1 and M2 macrophages | [57] |
| In vitro In vivo |
THP-1 monocytes, Mice |
0, 25, 50, 100 μM (dose-dependent), 10 mg/kg/day |
Ameliorating atherosclerosis partially through restoring intracellular GSH via AMPK-α activation, inhibiting monocyte differentiation, and reducing pro-inflammatory cytokine production | [59] |
| In vivo | Rats | 50 mg/L | Preventing the pathological progression of hypertension through Nrf2 activation | [60] |
| In vitro; In vivo |
Rat aortic smooth muscle cells; Mice |
100 μmol/L, ~320 mg/kg |
Lowering blood pressure by inducing oxidative activation of cGMP-dependent PKG1α | [61] |
| In vivo | Rats | 50 mg/kg/day | Preventing the activation of inflammasome via downregulating NF-κB p65 and p38 MAPK expression, and upregulating SIRT1 expression | [62] |
| In vivo | Mice | 20 mg/kg | Regulated the FERM-kinase and Nrf2 interaction, decreasing the expression of ICAM-1, and inhibiting monocyte adhesion | [63] |
| In vivo | Rats | 1.24 μg/d | Improving the cardiac and vascular autonomic function | [65] |
| In vitro | Human RBCs | 100 μM | Protecting the erythrocytes via interacting with hemoglobin and reducing heme-iron oxidation | [66] |
| Cancers | ||||
| In vitro | LNCaP cells | 5, 10, 20, 50 μM | Inducing the expression of COX-2, promoting ERK1/2 activation, and facilitating p53-dependent anti-proliferation gene expression | [14] |
| In vitro; In vivo |
tBregs; Mice |
12.5 μM; 20, 50, 500 μg/mouse |
Preventing breast cancer metastasis by promoting antitumor immune responses via blunting STAT3, leading to inhibited generation and function of tBregs as well as decreased production of TGF-β | [67] |
| In vivo | Mice | 150, 300 ppm | Inhibiting the formation and growth of colorectal cancer by downregulating oncogenic KRAS expression | [68] |
| In vitro; In vivo |
NSCLC cells Mice |
25, 50, 100 μM, 30 mg/kg every 3 days |
Preventing tumorigenesis and progression by interrupting glycolysis via inhibition of hexokinase II expression, which was mediated by downregulation of EGFR/Akt/ERK1/2 signaling pathway | [69] |
| In vitro | MCF-7 cells MVLN cells |
Low: 0.1 and 1 μM; High: 10 and 25 μM; | Low concentrations: Increasing the growth of ERα+ cells High concentrations: Inhibiting the proliferation of eERα+ breast cancer |
[75] |
| In vitro | KPL-1, MCF-7, MKL-F cells | Low (KPL-1, ≤22 μM; MCF-7, ≤4 μM); High: ≥44 μM | Low concentrations: Causing cell proliferation ER+ cells High concentrations: Suppressing cell growth |
[76] |
| In vitro In vivo |
Apc10.1 cells; Mice; Humans |
0.001–1 μM; 0.7, 14.3 mg/kg diet; 5 mg, 1 g |
Lower doses of resveratrol: Showing superior efficacy than high doses due to the pro-oxidant activity and AMPK signaling upregulation | [79] |
| In vitro | A2780, OVCAR-3, SKOV-3 cells | 10, 50, 100 μM | Decreasing the efficiency of ovarian cancer cells adhering to peritoneal mesothelium by downregulating the production of α5β1 integrins and upregulating the release of soluble hyaluronic acid | [70] |
| In vitro | Hela cells | 0.1, 1, 10 μM, 10, 20, 50, 100 μM |
Inhibiting the expression of PLSCR1, leading to the growth inhibition of HeLa cells | [71] |
| In vitro | HepG2 cells | 25, 50, 100, 200 μM | Inhibiting proliferation and inducing apoptosis by activating caspase-3 and caspase-9, upregulating the Bax/Bcl-2 ratio, and inducing p53 expression | [72] |
| In vitro | SGC7901 and BGC823 cells | 5, 10, 25, 50, 100, 200, and 400 μM | Inhibiting the invasion and migration of human gastric cancer cells by blocking the MALAT1-mediated epithelial-to-mesenchymal transition | [73] |
| Liver diseases | ||||
| In vivo | Mice | 0.2% of diet | Improving HFD-induced fatty liver by downregulating adipose differentiation-related proteins and increasing the numbers of CD68+ Kupffer cells | [9] |
| In vivo | Rats | 10 mg/kg | Attenuating hepatic fibrosis by restoring the architecture and normalizing collagen deposition, mainly due to its antioxidative activities and downregulation of α-SMA | [80] |
| In vivo | Rats | 50, 100 mg/kg | Alleviating NAFLD by upregulating LDLR and SRB1 gene expressions | [83] |
| In vivo | Rats | 250 mg/kg/day | Downregulating HIF-1α expression and mitochondrial ROS production | [85] |
| In vitro; In vivo |
HepG2 cells; Mice |
45 μmol 10, 30, 100 mg/kg |
Restoring the morphology and function of alcohol-injured liver through inducing autophagy | [86] |
| In vivo | Rats | 10 mg/kg | Mitigating liver cirrhosis by improving the homing of bone marrow-derived mesenchymal stem cells | [87] |
| Diabetes | ||||
| In vivo | Rats | 20 mg/kg | Increasing insulin action and glucose utilization due to visfatin expression restoration, SIRT1 activation, and glucose transporter modulation | [89] |
| In vivo | Mice | 50 mg/kg | Increasing glucose uptake to improve insulin resistance in the muscle by decreasing DAG accumulation and PKC-θ translocation, and preventing lipolysis under the condition of adipose hypoxia | [90] |
| In vivo | Rats | 147.6 mg/kg/day | Preventing the offspring’s glucose intolerance and islet dysfunction | [91] |
| In vivo | Mice | 0.3% diet | Reducing blood glucose levels, plasma lipids, and free fatty acids, inhibiting the expression of inflammatory mediators both in the aorta and in the blood, by inhibiting the NF-κB pathway | [92] |
| In vivo | Mice | 50 mg/kg | Preventing ROS-mediated mitochondrial fission via AMPK-dependent upregulation of Drp1 phosphorylation, and blocking the activation of NALP3 inflammasome via inhibition of ERS | [93] |
| Obesity | ||||
| In vivo | Zebrafish | 40 mg/kg/day | Inhibiting transcriptional regulators such as EP300 | [95] |
| In vivo | Mice | 0.06% diet | Decreasing the body weight and fat mass, reducing leptin and lipids in plasma, modulating metabolism of glucose and insulin, and restoring immune dysfunction by activating PI3K/SIRT1 and Nrf2 signaling pathway | [96] |
| In vitro; In vivo |
3T3-L1 cells; Mice |
0.03 to 100 μM; 1, 10, 30 mg/kg |
In vitro: low concentrations of resveratrol (1-10 μM) suppressed adipogenic differentiation in pre-adipocytes, downregulated the expression of PPAR-γ and perilipin protein in differentiated adipocytes, and inhibiting TNF-α-induced lipolysis in mature adipocytes In vivo: Dose-dependently decreasing weight gain and lipid deposition in the liver and adipose tissue |
[97] |
| In vitro | RAW 264.7 macrophage cells | 25 μM | Enhancing the catecholamine production, accompanying by suppressing the pro-inflammatory M1 macrophages, and activating anti-inflammatory M2 macrophages in white adipose tissue | [98] |
| In vivo | Mice | 0.2% diet | Promoting white adipose browning and thermogenesis in the male descendants, and these health benefits persisted and prevented obesity in their future life | [99] |
| In vitro; In vivo |
L6 myogenic cell line; Rats |
1, 5, 10, 25 or 50 μM; 0.4% diet |
In vitro: Improving mitochondrial function and reducing oxidative stress through the PKA/LKB1/AMPK pathway; In vivo: Preventing muscle loss and myofiber size decrease, improving grip strength, and abolishing excessive fat accumulation |
[100] |
| In vivo | Mice | 0.06% diet | Improving obesity-related complications by restoring plasma thyroid hormone levels, and attenuating oxidative stress in the heart | [101] |
| In vitro | Human sperm | 2.6, 6, 15, 30, 50, 100 μmol/L | Improving obesity-related complications by restoring reproductive dysfunction like infertility | [102] |
| Alzheimer’s disease and Parkinson’s disease | ||||
| In vivo | Rats | 20 mg/kg/day | Ameliorating ERS by downregulating the gene expression of CHOP and GRP78, inhibiting caspase-3 activity, and ameliorating oxidative damage via suppressing xanthine oxidase activity and protein carbonyl formation as well as activating glutathione peroxidase and Nrf2 signaling pathway | [10] |
| In vitro | CL2006 cells | 100 μM | Inhibiting the aggregation of Aβ by modulating specific proteins such as UBL/XBP-1 involved in proteostasis | [103] |
| In vivo | Mice | 16 mg/kg/day | Preventing memory loss by decreasing elevated levels of mitochondrial complex IV protein in the mouse brain via the activation of SIRT1 and AMPK pathways | [104] |
| In vivo | Mice | 100 mg/kg/day | Preventing memory loss via the activation of SIRT1 and AMPK pathways | [105] |
| In vitro; In vivo |
SH-SY5Y cells; Mice |
50 μM; 50 mg/kg |
Elevating miR-214 expression, leading to decreased mRNA expression of α-synuclein | [106] |
| Sex-dependent effects of resveratrol | ||||
| In vivo | Rats | 2.5 mg/kg/day | Superior improvements of MI in females in terms of IVSDs, ESV, EF, FS, and IVRT, among which IVRT is purely sex-dependent | [109] |
| In vivo | Rats | 50 mg/L in drinking water | Increasing the relaxations to estrogen in aortae, more potent in males, probably due to resveratrol’s promoting nitric oxide and/or suppressing superoxide effects | [110] |
| In vitro; In vivo |
MESC2.10 and SN4741 cells; Mice | 20 mg/kg; 10 μM |
Increasing DAT in the striatum in females but not in males; Upregulating DAT in the dopaminergic cells by inducing its gene transcription |
[111] |
| In vivo | Mice | 100 mg/kg | Adverse effects in females but not in males, regarding weight loss, stool consistency, and discomfort | [112] |
Abbreviations used in the table: AC, acetyl; AhR, aryl hydrocarbon receptor; Akt, protein Kinase B; AMPK, AMP-activated protein kinase; Aβ, amyloid β; cAMP, cyclic adenosine monophosphate; CAT, catalase; cGMP, cyclic guanosine monophosphate; CHOP, C/EBP homologous protein; COX-2, cyclooxygenase-2; DAG, diacylglycerol; DAT, dopamine transporter; EF, ejection fraction; EGFR, epidermal growth factor receptor; eNOS, endothelial nitric oxide synthase; ERK, extracellular signal-regulated kinases; ERRα, estrogen related receptor α; ERS, endoplasmic reticulum stress; Erα, estrogen receptor α; ERα+, estrogen receptor alpha positive; ESV, end systolic volume; EV71, enterovirus 71; FERM, band 4.1, ezrin, radixin, and moesin; FoxO1, forkhead box protein O1; FS, fractional shortening; GPx, glutathione peroxidase; GRP78, glucose-regulated protein 78; GβL, G protein beta subunit-like; HFD, high-fat diet; HIF-1α, hypoxia-inducible factor 1α; HMGB1, high mobility group box 1; HMGB1, high mobility group box 1; HO-1, heme oxygenase (decycling) 1; HSL, hormone-sensitive lipase; ICAM-1, intercellular adhesion molecule-1; IFN-γ, interferon γ; IKK, IκB kinase; IL-1β, interleukin-1β; IVRT, isovolumic relaxation time; IVSDs, interventricular septal wall dimension at systole; IκBα, nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor α; JAK, Janus kinase; Keap1, Kelch-like ECH-associated protein 1; LDLR, low-density lipoprotein receptor; LKB1, liver kinase B1; LPS, lipopolysaccharides; MALAT1, metastasis-associated lung adenocarcinoma transcript 1; MAP2K, mitogen-activated protein kinase kinase; MAPK, mitogen-activated protein kinase; MCP-1, monocyte chemoattractant protein-1; MI, myocardial infarction; mSIN1, mammalian stress-activated protein kinase interacting protein 1; mTOR, mammalian target of rapamycin; mTORC2, mTOR Complex 2; NAD, nicotinamide adenine dinucleotide; NAFLD, non-alcoholic fatty liver disease; NALP3, NACHT, LRR, and PYD domains-containing protein 3; NF-κB, nuclear factor kappa-light-chain-enhancer of activated B cells; Nrf2, nuclear factor (erythroid-derived 2)-like 2; p53, phosphoprotein p53; PDE 3B, phosphodiesterase 3B expression; PDK1, phosphoinositide dependent kinase 1; PGC, peroxisome proliferator-activated receptor gamma coactivator 1α; PI3K, phosphatidylinositol 3-kinase; PIP2, phosphatidylinositol 4,5-bisphosphate; PIP3, phosphatidylinositol-3,4,5--trisphosphate; PKA, protein kinase A; PKC-θ, protein kinase C θ; PKG1α, cGMP-dependent protein kinase 1α; PLSCR1, phospholipid scramblase 1; PPAR-γ, peroxisome proliferator-activated receptor γ; PTEN, phosphatase and tensin homolog; RANTES, regulated on activation normal T cell expressed and secreted; RICTOR, the rapamycin-insensitive companion of mTOR; SARM, sterile α and armadillo motif protein; SIRT, sirtuin 1; α-SMA, smooth muscle actin; SOD, superoxide dismutase; SRB1, scavenger receptor class B type I; STAT, signal transducer and activator of transcription; tBregs, tumor-evoked regulatory B cells; TF, transcription factor; TGF-β, transforming growth factor β; TLR4, toll-like receptor 4; TNF-α, tumor necrosis factor α; TRIF, toll/IL-1 receptor domain-containing adaptor inducing β interferon; UBL, ubiquitin-like protein; XBP-1, X-box binding protein 1.