Polydatin: Pharmacological Mechanisms, Therapeutic Targets, Biological Activities, and Health Benefits.

1. Introduction

Polydatin is a stilbenoid polyphenol and a monocrystalline natural compound [ 1 , 2 , 3 ]. The plant families Vitaceae , Liliaceae , and Leguminosae are prominent sources of polydatin extraction [ 4 ]. It is primarily isolated from the rhizome and root of Polygonum cuspidatum [ 5 ], traditionally used against inflammation, infection, jaundice, skin burns, and hyperlipemia [ 6 ]. Reynoutria japonica is an invasive plant from the Far East, and a main source of polydatin in industrial scale [ 7 ]. This plant source of polydatin is so invasive that it has reached even the most remote mountain areas where it unbalances the ecosystem including the agricultural potential of mountain areas, being advantaged by the context of climate change [ 8 ]. This phytochemical is also found in other plant sources such as red wine [ 9 ], nuts, vegetables, fruits [ 5 ], hop cones/pellets, and cocoa- and chocolate-containing products [ 10 ].

Polydatin is a glucoside derivative of resveratrol. Moreover, polydatin has a higher antioxidant [ 3 ] and anti-inflammatory [ 11 ] activity compared to resveratrol [ 1 , 12 , 13 , 14 , 15 , 16 ]. It possesses four leading derivatives in nature, including trans -polydatin, trans -resveratrol, cis -polydatin, and cis -resveratrol [ 10 , 17 ]. trans -polydatin, itself, can be produced from 4-coumaryol-CoA through a stilbene synthase reaction ( Figure 1 ). Several methods have been developed for the isolation of resveratrol from other isomers in P. cuspidatum , including reflux extraction, filtering, hydrolyzing, liquid–liquid extraction, eluting, and high-performance liquid chromatography coupled to an ultraviolet−visible diode array detector [ 18 , 19 ].

The therapeutic and protective effects of polydatin mainly originate from its anti-inflammatory, antioxidant, and anti-apoptotic activities [ 20 ]. Previous studies have shown a wide range of therapeutic effects of polydatin in the treatment of several pathological diseases such as cancer [ 21 ], cardiovascular diseases [ 22 ], diabetes [ 23 ], neurodegenerative diseases [ 24 ], hepatic/respiratory diseases [ 25 , 26 ], gastrointestinal diseases [ 27 ], infectious diseases [ 28 ], rheumatoid diseases [ 29 ], and skeletal/women disorders [ 30 , 31 ].

Previously, the protective effects of polydatin have been disclosed against neurodegenerative diseases [ 20 , 32 , 33 ], atherosclerosis [ 34 , 35 ], and multiple organ ischemia/reperfusion injury [ 36 ]. The protective effects of polydatin on damaged macrophages were also highlighted by Liu et al. [ 37 ]. A more recent study also reviewed the pharmacological effects of polydatin in some diseases [ 38 ]. In the current mechanistic review, the therapeutic targets, pharmacological mechanisms, biological activities, and health benefits of polydatin are highlighted for all related biological/pathological conditions. Moreover, the need to provide different novel delivery systems and clinical trials of polydatin is also considered to reveal new insights to researchers.

2. Pharmacological Mechanisms of Polydatin

Considering the critical role of inflammation, oxidative stress, and apoptosis in the progression of several diseases, polydatin could play therapeutic roles by regulating associated signaling pathways.

2.1. Anti-Inflammatory Effects

As a protective mechanism, the initiation of inflammation is attributed to the involvement of immune system response against diverse factors such as pathogens, injured tissues, and infectious agents, which is generally attributed to favoring tissue repair and organ healing. This defense process is divided into two major categories known as acute and chronic inflammation. At present, chronic inflammation could be considered a vital cause of human diseases (e.g., atherosclerosis, arthritis, diabetes, neurodegenerative diseases, and cancer) [ 39 , 40 ]. In this context, chronic inflammation is induced via uncontrolled acute inflammatory responses through inflammatory mediators such as cytokine production and immune cell recruitment [ 39 , 41 ]. Reportedly, nuclear factor-kappa B (NF-κB) is considered as the key transcription factor in increasing inflammatory mediators/cascades, including tumor necrosis factor-α (TNF-α), interleukin-1 beta (IL-1β), IL-6, and intercellular adhesion molecules (ICAMs) in various diseases. Such inflammatory mediators and interconnected pathways are mainly involved in the underlying mechanisms of the inflammatory state [ 42 ]. Several studies show that phytochemicals are multi-target agents that effectively represent their anti-inflammatory activities through underlying cellular mechanisms against different diseases associated with chronic inflammation [ 43 ]. In the phytochemical context, it has been reported that polydatin is a potent anti-inflammatory plant secondary metabolite [ 44 ], beneficially promoting miR-200a expression to regulate the Kelch-like ECH-associated protein 1 (Keap1)/nuclear factor E2-related factor 2 (Nrf2) antioxidant axis. This pathway, in turn, suppresses nucleotide-binding domain-like receptor protein 3 (NLRP3) inflammasome activation against diverse chronic inflammation-related diseases in vivo [ 25 , 45 ]. Furthermore, under inflammatory conditions, polydatin exhibited anti-inflammatory roles by improving AMP-activated protein kinase (AMPK)/sirtuin1 (Sirt1)/Nrf2 signaling expression, leading to the inhibition of the NF-κB/inhibitor of nuclear factor-kappa B α (IκBα)/NLRP3 pathway, as well as the reduction of pro-inflammatory cytokines such as TNF-α, IL-1β, and IL-6 [ 31 , 46 , 47 ]. Meanwhile, polydatin treatment downregulated the expression of cerebral ischemia or spinal cord injury (SCI)-induced inflammatory mediators such as Toll-like receptor 4 (TLR4), NF-κB, cyclooxygenase-2 (COX-2), inducible nitric oxide synthase (iNOS), nitric oxide (NO), and ICAM-1 [ 48 , 49 , 50 ]. In line with this, polydatin potentially plays a vital role in preventing the inflammatory action by reducing mitogen-activated protein kinases (MAPKs). This response is mainly orchestrated by extracellular-signal-regulated kinases (ERK1/2), c-Jun N-terminal kinase 1/2 (JNK1/2), and p38 protein kinases, and consequently inhibits NF-κB p65 phosphorylation and the release of inflammatory factors such as xanthine oxidase (XOD), prostaglandin E2 (PGE2), TNF-α, IL-1β, and COX-2 [ 51 , 52 ]. Another mechanism of the neuroprotective effect of polydatin is mediated by the CCAAT/enhancer-binding proteinβ (C/EBPβ)/metastasis-associated lung adenocarcinoma transcript 1 (MALAT1)/cAMP response element binding (CREB)/peroxisome proliferator-activated receptor gamma co-activator 1α (PGC-1α)/peroxisome proliferative-activated receptor γ (PPARγ) signaling pathway. This process results in silencing NF-κB-associated downstream inflammatory mediators, which could alleviate cerebral infarct volume and ameliorate the integrity of the blood–brain barrier (BBB) [ 53 ]. Numerous studies have confirmed that polydatin application could suppress phospholipase A2 (PLA2) against lipopolysaccharide (LPS)-induced lung injury [ 54 ], decreasing the serum levels of alanine transaminase (ALT) and aspartate aminotransferase (AST) against fulminant hepatic failure (FHF) [ 55 ]. Additional reports also revealed that polydatin downregulated the retinoic acid receptor-related orphan receptor gamma t (RORγt) and signal transducer and activator of transcription 3 (STAT3) gene expression, attenuated IL-17 production against CD3/DC28-induced peripheral blood mononuclear cells and arthritis [ 11 , 56 ], and ultimately reduced both the NF-κB and vascular endothelial growth factor (VEGF) as well as the circulating levels of the downstream inflammatory cascade including IL-6, TNF-α [ 56 ].

Altogether, polydatin modulates several inflammatory mediators to show potential anti-inflammatory effects in various diseases.

2.2. Antioxidant Effects

Oxidative stress is characterized by aberrant generation of the reactive oxygen species (ROS) and reactive nitrogen species (RNS) as byproducts of this metabolic process which leads to devastating effects on molecular intracellular signaling pathways and to the development of numerous diseases [ 57 , 58 ]. The antioxidant reaction of polydatin is presented via reducing lipid peroxidation while promoting antioxidant enzymatic activity against hepatotoxicity induction in vivo [ 59 ]. Polydatin has also shown modulatory roles on ROS and RNS in peripheral [ 60 ] and central diseases [ 49 ]. Nrf2 could be the most vital antioxidative response-associated transcription factor and alleviates inflammation [ 61 ]. In this regard, polydatin strongly acts as an antioxidant agent on LPS-induced BV2 microglia cells in SCI-induced rat models via promoting the Nrf2/heme oxygenase-1 (HO-1) pathway activity, resulting in improved locomotor performance, suppressing spinal edema, and attenuating neurological deficits [ 24 ]. Additionally, the activation of protein kinase B (Akt) phosphorylation may be accelerated through the Nrf2/HO-1/NAD(P)H quinone dehydrogenase 1 (NQO1) expression-mediated antioxidant pathway after polydatin administration [ 51 ]. It has also been proposed that polydatin could significantly enhance Nrf2/thioredoxin (TRX) antioxidant signaling, and upregulate the Gli1/patched 1 (Ptch1)/superoxide dismutase 1 (SOD1) pathway, indicating its neuro/nephron-protective action against ischemic brain/renal injury-induced ROS generation [ 62 , 63 , 64 ]. Further in vivo studies have also indicated that polydatin supplementation provided an antioxidant ability through the Sirt1/Nrf2/antioxidant-responsive element (ARE) signaling pathway to reduce diabetes-induced renal dysfunction [ 65 ], as well as through the Notch1/Hes1-Pten/Akt axis to improve ischemic/reperfusion-injured diabetic heart disease [ 66 , 67 ]. Further, polydatin consumption is possibility beneficial against atherosclerosis and cardiovascular disease-induced oxidative stress via the scavenging of hydroxyl, oxygen free radicals, myeloperoxidase (MPO), and ROS [ 56 , 68 , 69 ], elevating enzymatic antioxidants such as SOD, glutathione peroxidase (GSH-Px), glutathione transferase (GST), catalase (CAT), and glutathione (GSH) [ 70 ]. Polydatin also induced protein kinase C (PKC) and the mitochondrial adenosine triphosphate (ATP)-sensitive-K + (mito-K ATP ) channel [ 71 ] towards the modulation of mitochondrial function and the Akt signaling pathway [ 35 , 72 ]. The body of this evidence strongly supports that the attenuation of Akt is associated to the antioxidant effect of polydatin [ 50 ]. In addition, polydatin attenuated the activity of hepatic stellate cells (HSCs) through its antioxidant activity on sphingosine kinase 1 (SphK1) signaling to ameliorate mice liver fibrosis induced by carbon tetrachloride (CCl4) [ 73 ].

Overall, polydatin employs several antioxidant mediators while suppressing oxidative pathways towards therapeutic responses in several disorders.

2.3. Anti-Apoptotic Effects

Apoptosis is defined as a programmed model of physiological cell death without the involvement of an inflammatory condition. Nonetheless, the uncontrolled regulation of this mechanism could be engaged in several diseases, including cancer, autoimmune diseases, and neurodegenerative disorders [ 74 ]. In this regard, polydatin significantly exhibited anti-apoptotic effects in a mice model of liver injury through the attenuation of Bcl-2-associated x (Bax) expression and enhancing B-cell lymphoma 2 (Bcl-2) expression [ 59 ]. In another experimental study, polydatin showed its anti-apoptotic activity by increasing Bcl-2 or D-cyclins and reducing caspase-3 or Bax levels in gastrointestinal injury. Such an effect is made by the activation of Gli1 transcription factor followed by the upregulation of the Sonic hedgehog (Shh) signaling pathway as the major component in repairing dextran sulfate sodium-induced colitis-related damaged tissues [ 75 ]. In another study, polydatin exerted its protective effects against acute lung injury-induced mitochondrial apoptosis by increasing Parkin-mediated mitophagy expression via inhibiting Bax, cytochrome c, and caspase-3 activity as well as promoting Bcl-2 and mitochondrial membrane potential proteins [ 76 ]. Furthermore, polydatin administration could attenuate neuronal apoptosis through repressing p53/MAPK/JNK signaling activation in a rat model of ischemic brain injury [ 62 ]. Consequently, polydatin improved autophagy and apoptosis during osteoarthritis through suppressing the MAPK and phosphoinositide 3-kinases (PI3K)/Akt/mammalian target of rapamycin (mTOR) signaling pathway [ 77 ]. Taken together, the described anti-apoptotic activities of polydatin indicate that this compound could be considered as a promising agent for apoptosis-induced tissue damage.

3. Biological Activities of Polydatin

As previously mentioned, polydatin exhibits significant pharmacological effects through its anti-inflammatory, antioxidant, and apoptosis-modifying activities. During different physiological/pathological conditions, the activity and expression of involved signaling pathways would change and polydatin plays a critical modulatory effect. We previously described near interconnections between the aforementioned signaling pathways during diseases which support each other [ 78 , 79 ]. Such effects make polydatin a potential therapeutic compound in the treatment of different pathological conditions.

3.1. Anticancer Effects

According to statistics from the World Health Organization, cancers leave the heaviest strain on the worldwide population based on the disability-adjusted life year (DALY) scale [ 80 ]. Radiotherapy, surgery, and chemotherapy are the main strategies in treating various cancer types [ 81 , 82 ]; however, associated resistance and side effects limit their applications. In addition, considering the multiple signaling pathways involved in cancer pathogenesis, there is an urgent need to provide novel alternatives and safe multi-target phytochemicals [ 83 , 84 , 85 ]. In this regard, the anticancer activity of polydatin has been elucidated against different cancer types [ 86 ].

From the mechanistic point, polydatin modulates oxidative stress to decrease carcinogenesis and mutagenesis [ 87 ]. It is reported that polydatin inhibits tumor growth [ 88 ] and improves radiosensitivity via inducing apoptosis in colorectal cancer models [ 89 ]. Polydatin also plays therapeutic roles in the treatment of leukemia alone or in combination with Janus kinase (JAK) inhibitors [ 86 , 90 ]. Moreover, it is revealed that polydatin is efficacious in the treatment of laryngeal cancer [ 91 ], nasopharyngeal cancer [ 92 ], ovarian cancer [ 93 ], lung cancer [ 94 , 95 , 96 ], glioblastoma multiforme [ 97 ], multiple myeloma [ 98 ], and cervical cancer [ 99 , 100 ]. Consequently, polydatin exerts therapeutic effects against such cancers employing different mechanisms, including the inhibition of proliferation/migration [ 97 ]. Several pre-clinical studies demonstrated that polydatin exerted therapeutic effects against an orthotopic metastatic tongue cancer model via inhibiting glucose 6 phosphate dehydrogenase (G6PD), and reduced tumor size and lymph node size and metastases [ 1 ]. In another study, the inhibition of G6PD by polydatin reduced tyrosine kinase inhibitor (TKI) resistance in breast cancer models [ 21 ]. In addition, polydatin suppressed the growth of MDA-MB-231 and MCF-7 breast cancer cell lines in vitro [ 101 ]. This secondary metabolite also induced apoptosis and inhibited cell proliferation/migration in breast cancer cell lines when used in combination with 2-deoxy-D-glucose [ 102 ].

Osteosarcoma is a malignant bone tumor; however, its etiology and pathogenesis remain unclear [ 103 ]. Prevailing in vitro studies showed that polydatin inhibited cells’ migration [ 103 ] and proliferation [ 103 , 104 , 105 ]. In this regard, inhibition of the β-catenin signaling pathway by polydatin is associated with its anti-proliferative effects [ 105 ]. Polydatin also induced apoptosis [ 103 , 104 ] via different mechanisms such as reducing the expression/phosphorylation of STAT3, increasing autophagy-related gene expression [ 104 ], and caspase-3 activity [ 105 ] in vitro. Polydatin also exerted therapeutic effects against doxorubicin-resistant osteosarcoma by suppressing TUG1/Akt signaling, promoting apoptosis and suppressing cell proliferation. In addition, polydatin reduced tumor size in animal models [ 106 ]. On another point, chronic liver disease and cirrhosis lead to hepatocellular carcinoma (HCC). HCC is a common malignancy of the liver and is classified as the third leading cause of cancer-related deaths in the world [ 107 ]. Similarly, polydatin showed positive effects against HCC through the inhibition of the Akt/STAT3–forkhead box protein O1 (FOXO1) signaling pathway towards apoptosis induction [ 108 ]. It also inhibited proliferation/invasion/migration of cell lines [ 107 ], and reduced tumor growth by increasing caspase-3 expression and terminal deoxynucleotidyl transferase (TdT) dUTP nick-end labeling (TUNEL) activity in animal models of HHC [ 107 ].

On the other hand, it is worth mentioning that polydatin could remarkably induce apoptosis against acute monocytic leukemia cell proliferation via modulating cyclin D1, Bcl-2, cyclin A, and Bax, accompanied by cell cycle arrest at the S phase [ 90 ]. Additionally, polydatin induced apoptosis in human nasopharyngeal carcinoma CNE cells through ROS-mediated mitochondrial dysfunction and endoplasmic reticulum stress. Thus, polydatin might be a promising anti-tumor agent through inducing apoptosis [ 92 ]. Additionally, polydatin inhibited the progression of doxorubicin-resistant osteosarcoma by regulating the taurine-upregulated gene 1 (TUG1)/Akt signaling pathway [ 106 ]. Furthermore, suppressing the phosphorylation of CREB and cyclin D1 gene expression might be associated with the apoptotic effect of polydatin on human breast cancer cells [ 101 ]. Moreover, extensive studies have demonstrated that the suppression of platelet-derived growth factor (PDGF)/Akt signaling [ 91 ], stimulation of cytochrome c release, and activation of poly (ADP-ribose) polymerase (PARP) fragmentation [ 109 ] could induce cell cycle arrest and apoptosis on polydatin-treated laryngeal/cervical cancer and oral squamous cell carcinoma.

Not only is polydatin efficacious in the treatment of various cancer types, it also reduces adverse effects of some chemotherapeutic agents such as cisplatin [ 110 ] and doxorubicin [ 111 ]. Polydatin plays a protective role against cisplatin-induced toxicity via improving antioxidant mechanisms and tissue regeneration [ 110 ]. It is reported that polydatin attenuated the cardiotoxicity of doxorubicin by increasing heart rate, arterial pressure, and GSH-Px activity while reducing myocardial injury. In addition, polydatin decreased ST, QT, and QRS intervals in an electrocardiogram. Antioxidant effects and the enhancement of metabolism were also associated with the protective effects of polydatin [ 111 ].

Taken together, polydatin could be a potential agent in the treatment of different cancer types. Apoptotic and anti-proliferative effects of polydatin, especially, are associated with its anticancer effects. Considering the protective effects of polydatin against the adverse effects of chemotherapy agents, polydatin might be an excellent choice to be co-administered with other agents. In Table 1 , several in vitro and in vivo studies on the anticancer properties of polydatin are summarized.

3.2. Cardioprotective Effects

It is reported that different cardiovascular diseases are associated with stress oxidative and nitrosative processes, such as atherosclerosis and irreversible injury after ischemic reperfusion [ 112 ]. In addition, the interconnections between inflammatory processes and the symptoms of cardiovascular diseases have been elucidated [ 113 ]. As previously described, polydatin demonstrated potential antioxidant and anti-inflammatory effects. Polydatin has been reported to exert therapeutic effects against cardiovascular diseases such as acute myocardial infarction (AMI) [ 114 ], atherosclerosis [ 115 ], pulmonary hypertension [ 116 ], vascular damages [ 117 ], and sepsis-induced cardiac injury [ 118 ].

Polydatin consistently inhibited ventricular remodeling through neurohormones, especially in the renin–angiotensin system (RAS) and peroxidation [ 119 , 120 , 121 ]. In animal models of cardiac remodeling, including mice and rats, polydatin reduced cardiac weight in both animals, and decreased angiotensin II (Ang II) in mice. Polydatin also decreased cardiomyocyte size, aldosterone levels, TNF-α, endothelin-1, Ang II, blood pressure, and ventricular collagen volume [ 119 ]. Additionally, polydatin also increased NO, improved CAT and GSH-Px activity, and decreased serum hydroxyproline levels [ 120 ].

Insulin deficiency in diabetes causes cardiomyopathy, a disorder of the heart’s ventricles. Polydatin reduced ventricular dysfunction, improved mitochondrial bioenergetics, and increased autophagy flux by upregulating Sirt3 [ 122 ]. In addition, the inhibition of NAPDH oxidase and NF-κB is attributed to the cardioprotective effects of polydatin against diabetic cardiomyopathy [ 35 ]. Diabetes mellitus during myocardial infarction/reperfusion (MI/R) can increase the severity of oxidative/nitrative injury. Polydatin reduced MI/R cardiac damage during diabetes by activating the Notch1/Hes1-dependent Pten/Akt signaling pathway [ 36 , 66 , 123 ]. Assessment of the effects of polydatin on diabetes-associated myocardial hypertrophy showed a decrease in fasting blood glucose, insulin, HbA1C, weight gain, and insulin resistance levels by inhibiting NF-κB, COX-2, and the iNOS signaling pathway and activating PPARβ. It also improved hypertrophy factors in animal models of myocardial hypertrophy [ 124 ].

Studies have shown that polydatin decreased serum levels of total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), triglycerides (TG), hepatic TG concentrations, and LDL-C/high-density lipoprotein cholesterol (HDL-C) and TC/HDL-C ratios. These effects may indicate the protective effect of polydatin on the liver, coronary heart disease, and atherosclerosis [ 125 , 126 , 127 ]. Oxidative stress caused by the proliferation of vascular smooth muscle cells (VSMCs) leads to plaque formation and the progression of atherosclerosis. Polydatin inhibited oxidative stress by activating the NOS/Sirt1 pathway [ 115 ]. Polydatin also exerted potential protective effects against atherosclerosis by regulating pre-B-cell colony-enhancing factor (PBEF) and the inhibition of cholesterol accumulation in PBEF-induced macrophages. During an in vivo study, polydatin reduced blood lipids and atherosclerotic lesions, regulated the expression of cytokines and genes involved in cholesterol metabolism, and decreased PBEF mRNA and PBEF protein [ 128 ]. Moreover, polydatin exerted protective and therapeutic effects against atherosclerosis by inhibiting the PI3K/Akt/mTOR signaling pathway and improving autophagy disorders [ 129 ]. Polydatin’s inhibitory effects on β-hydroxy-β-methyl-glutaryl-CoA reductase (HMG-R) and the expression of proprotein convertase subtilisin/kexin type-9 (PCSK-9) are contributed to its anti-atherosclerotic effects [ 35 ]. Taken together, polydatin is reported to exert beneficial effects against atherosclerosis mainly through the protection of VSMCs, endothelial cells, mitochondria, and regulatory effects on lipid metabolism and antioxidant and anti-inflammatory effects [ 34 ].

In high-fat-diet (HFD)-induced obese mice, polydatin consumption caused weight loss, decreased TC, TG, and LDL, and increased HDL. Polydatin also reduced the size of adipose tissues and the volume of retroperitoneal fat. Polydatin exerted such effects by downregulating PPARγ, upregulating mRNA and leptin expression, and reducing TNF-α/monocyte chemoattractant protein-1 (MCP-1) [ 130 ]. Polydatin also inhibited the formation of foam cells caused by peritoneal macrophages via regulating its intracellular metabolism and antioxidant properties by regulating the PPARγ signaling pathway [ 131 ].

Polydatin exerted protective effects against cardiac ischemia/reperfusion (I/R) injury through various mechanisms, including the activation of the PKC-K ATP -dependent signaling pathway and a direct antioxidative stress effect [ 71 ]. Studies have shown that intravenous administration of polydatin before I/R injury limits the size of the infarcted area, creatine phosphokinase, leakage of lactate dehydrogenase from damaged myocardial cells, changes in SOD activity, and malondialdehyde (MDA) levels [ 132 ]. Other cardioprotective mechanisms of polydatin include increased Bcl-2 protein expression and decreased Bax protein expression, which inhibits I/R-induced apoptosis in rat myocardium. Additionally, polydatin inhibits the rho kinase (ROCK) system, reducing apoptosis and the size of the infarcted area in animal models [ 22 ]. Constitutive nitric oxide synthase (cNOS) and the resulting increase in NO production are other pathways that promote the protective effects of polydatin against I/R injury. The study by Zhang et al. showed that polydatin reduced arrhythmia score and size of myocardial infarction, improved left developed ventricular pressure and coronary flow, increased SOD activity, and decreased MDA compared to the control group [ 133 ]. In addition, polydatin limited myocardial damage induced by I/R through increasing and improving autophagic flux [ 2 , 134 ]. Thus, polydatin cleared damaged mitochondria and reduced ROS in cell lines. The results of an in vivo study on cardiac I/R injury showed that polydatin reduced the size of the infarcted area, increased the ejection fraction, and caused higher left fractional ventricular shortening [ 134 ].

In the final analysis, polydatin could be considered a potential agent in the treatment of various cardiovascular diseases. Decreasing ROS level, NF-κB activity, VSMC proliferation, and RAS system activity and improving Sirt3 activity and lipid metabolisms contribute to polydatin’s therapeutic and protective cardiovascular effects. The details on the cardioprotective activity of polydatin are presented in Table 2 .

3.3. Anti-Diabetic Effects

Pancreatic beta cells are sensitive to oxidative stress and, thus, the development of diabetes. Polydatin has been reported to inhibit inflammation and increase the expression of insulin receptor substrate 2 towards insulin sensitivity, insulin secretion, and the improvement of glucose resistance/fat metabolism. Polydatin exhibits such effects through multiple mechanisms, including ROS scavenging, improving functional cell markers, and modulating anti-apoptotic/antioxidant mediators [ 136 , 137 ].

Diabetic nephropathy is a major cause of end-stage renal disease and one of the most important complications of diabetes progression. Polydatin reduces the expression of fibronectin (FN) protein, an important fibrotic factor, in glomerular mesangial cells (GMCs) by inhibiting the NF-κB signaling pathway. Polydatin also reduced the expression of ICAM-1 and TGF-β in glomerular mesangial cells and, thus, exerted its anti-inflammatory effects [ 138 ]. Activation of the SphK1/sphingosine 1-phosphate (S1P) signaling pathway by high blood sugar is known as another factor that leads to an increase in the expression of FN protein in glomerular mesangial cells. Accordingly, polydatin prevented an increase in FN and the expression of ICAM-1 under the diabetes condition [ 139 ]. In addition, polydatin reduced oxidative stress in glomerular mesangial cells by upregulating the casein kinase 2 interacting protein-1 (CKIP-1)/Nrf2/ARE signaling pathway [ 23 ].

Impaired fat metabolism is another problem observed along with impaired glucose metabolism in diabetic patients. Polydatin improved fat/glucose metabolism by regulating PCSK-9 [ 140 ] and the Akt signaling pathway towards decreasing fasting blood glucose, glycosylated hemoglobin, glycosylated serum proteins, TC, TG, and LDL, while increasing serum insulin levels in diabetic rats [ 141 ].

Cardiovascular problems (e.g., macrovascular and microvascular diseases) are other complications following diabetes [ 142 ]. In this regard, polydatin improved endothelial function [ 72 , 142 , 143 ] in hyperglycemic conditions by activating the PPARβ/NO signaling pathway. Polydatin also improved endothelial damage in the aorta and vasodilation [ 142 ]. Diabetic neuropathy is another problem that affects half of diabetes patients. Mitochondrial dysfunction is closely related to the incidence of diabetic neuropathy. Polydatin improved mitochondrial function through the Sirt3/Nrf2 axis and, thus, reduced thermal and mechanical hyperalgesia in animal models [ 144 ].

In conclusion, polydatin could be an effective natural compound in the treatment of diabetes and complications related to diabetes. Activation of anti-fibrotic mechanisms and Nrf2-related signaling pathways and inhibition of NF-κB could improve glucose and lipid metabolism following polydatin administration.

3.4. Effects on Gastrointestinal Tract

Ulcerative colitis and inflammatory bowel disease are caused/characterized by dysfunction in the intestinal epithelial barrier. In addition to the inflammatory mechanisms involved in this disease, oxidative stress and reactive oxygen and nitrogen species could be involved in tissue damage and intestinal fibrosis [ 47 ]. Studies have shown that polydatin has an inhibitory effect on the NF-κB signaling pathway towards therapeutic effects against colitis [ 47 , 145 , 146 ]. In this regard, polydatin has shown therapeutic effects against ulcerative colitis in animal models by reducing NF-κB expression and increasing Sirt1/Nrf2 expression [ 47 ]. Polygonum cuspidatum root extract and its main constituent polydatin showed therapeutic responses against ulcerative colitis by inhibiting the NF-κB signaling pathway [ 145 ]. Polydatin also suppressed colitis in animal models by regulating the Shh signaling pathway [ 75 ].

Severe hemorrhagic shock causes damage to the small intestine. Increasing free radicals and mitochondrial damage caused by gastrointestinal I/R are among the factors influencing small bowel injury in severe hemorrhagic shock. Polydatin acts on the Sirt1/PGC-1α/SOD2 axis in the small intestine, thereby reducing oxidative stress and small intestinal damage [ 27 , 147 , 148 ].

Taken together, polydatin is an efficacious compound in the treatment of ulcerative colitis and severe hemorrhagic shock through antioxidant and anti-inflammatory effects. Inhibition of NF-κB is a major mechanism of polydatin towards its gastroprotective effects.

3.5. Anti-Microbial Effects

Although polydatin has not shown promising antibacterial effects, it has been shown that polydatin can exert positive antioxidant and anti-inflammatory effects against Staphylococcus aureus -induced mastitis and related lipoteichoic acid (LTA)-induced injury. The inhibitory effect of polydatin is that of TLR2-mediated activation of the p38MAPK/NF-κB signaling pathway and production of ROS [ 28 , 149 ]. Similarly, polydatin inhibited the NF-κB signaling pathway, contributing to the suppression of inflammatory responses and the development of pulmonary fibrosis induced by Mycoplasma pneumoniae infection. Inhibition of NLRP3 inflammasome by polydatin is the other mechanism that is employed by polydatin against Mycoplasma pneumoniae infection [ 45 , 150 ]. It also has been shown that polydatin exerted anti-inflammatory/protective responses against septic lung injury through the upregulation of HO-1 in lung tissue [ 151 ]. Since the coronavirus disease of 2019 (COVID-19) pandemic started, the effects of different natural compounds have been studied. It has been revealed that polydatin has shown inhibitory effects on the entry of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) into cells. This originated from binding directly to main protease (Mpro) of SARS-CoV-2. In addition, activation of sirtuin by polydatin may contribute to potential anti-COVID-19 effects [ 152 ].

To conclude, polydatin might be a good candidate in the treatment of respiratory diseases such as COVID-19 and Mycoplasma pneumonia -induced pulmonary fibrosis. Antioxidant and anti-inflammatory effects are primarily related to therapeutic anti-microbial effects of polydatin.

3.6. Hepatoprotective Effects

Recent studies have demonstrated polydatin’s hepatoprotective effects against alcoholic liver disease [ 153 ], non-alcoholic fatty liver disease (NAFLD) [ 154 ], and liver fibrosis [ 70 ]. Moreover, polydatin showed beneficial effects in drug-induced liver injury, including acetaminophen-induced injury, through antioxidant and anti-inflammatory effects. In one particular study, polydatin decreased the expression and levels of Bax, cytochrome c, cleaved caspase-3, cleaved caspase-9, and apoptotic protease-activating factor 1, while increasing Bcl-2. Polydatin also reduced oxidative stress factors such as ROS, NO, and MDA [ 59 ].

Alcoholic liver disease is one of the problems caused by excessive alcohol consumption, which can occur as a mild steatohepatitis or even severe cirrhosis of the liver [ 153 ]. Evaluation of the effect of polydatin on ethanol-induced liver damage in rats showed that polydatin exerted antioxidant and anti-inflammatory effects against ethanol-induced liver damage through downregulation of cytochrome P450 2E1 (CYP2E1), upregulation of Nrf2/HO-1, and modulation of TLR4/NF-κB p65 [ 48 , 155 ].

The mechanisms involved in the most common liver disease, NAFLD, have not been fully identified. Similar to alcoholic liver disease, it can also occur in the form of steatohepatitis in mild cases or in the form of liver cirrhosis in severe cases [ 156 ]. Polydatin has shown protective and therapeutic effects against NAFLD via various mechanisms [ 154 ]. Further, it reduced animal models’ TG, TC, and free fatty acid (FFA). Polydatin also exerted protective and therapeutic effects against NAFLD by different mechanisms, including lipid peroxidation suppression, reduction of TNF-α, and lipogenesis induced by sterol regulatory element-binding protein (SREBP-1c) [ 156 ]. In addition, polydatin decreased serum levels of AST, ALT, caspase-3, TUNEL-positive cells, TG, and oxidative stress in mice. Polydatin downregulated NADPH oxidase 4 (NOX4), inhibited the TLR4/NF-κB p65 signaling pathway, and exerted antioxidant and anti-inflammatory effects in vivo [ 157 ].

It has been shown that polydatin can exhibit hepatoprotective effects against carbon tetrachloride and sulfur mustard through antioxidant and anti-inflammatory mechanisms [ 158 , 159 ]. Additional studies elucidated that polydatin has protective and therapeutic effects against liver damage caused by carbon tetrachloride [ 70 , 159 , 160 ] through reducing liver fibrosis, suppressing inflammatory factors, and improving liver function/histological parameters. It also suppresses hepatic 4-HNE production andNOX4 expression and increases GSH levels, GST activity, SOD activity, GSH superoxidase, and CAT activity [ 70 , 159 ].

FHF is known as a clinical syndrome with high mortality. Consumption of polydatin prior to FHF induction showed protective effects by reducing TNF-α production and inhibiting NF-κB activity. It was revealed that polydatin reduced ALT, AST, mortality, and improved histopathological lesions [ 55 , 161 ].

Taken together, improvement of antioxidant capacity and anti-inflammatory effects are the major reasons of polydatin’s therapeutic effects against liver diseases. These effects are mainly applied through the activation of Nrf2-related signaling and inhibition of NF-κB. Therefore, polydatin is a potential compound in the treatment of liver diseases such as FHF, NAFLD, and alcoholic liver disease. Details on the hepatoprotective activity of polydatin are presented in Table 3 .

3.7. Neuroprotective Effects

Neurological diseases are known as the second leading cause of death globally. Such disorders are the first cause of severe long-term disability worldwide [ 162 ]. Oxidative stress and inflammatory and apoptotic processes play essential roles in the pathogenesis of neurological diseases [ 112 ]. Regarding the previously described antioxidant, anti-inflammatory, and anti-apoptotic activities of polydatin, it can be a potential agent in the treatment of neurological diseases. Studies revealed therapeutic and protective effects of polydatin against Parkinson’s disease (PD) [ 163 ], intracranial hemorrhage (ICH) [ 164 ], cerebral ischemia [ 5 ], hemorrhagic shock [ 165 , 166 ], SCI [ 24 ], dementia [ 167 ], and traumatic brain injury [ 168 ].

Oxidative stress and mitochondrial dysfunction are two critical factors involved in PD pathogenesis [ 163 ]. It is shown that polydatin has neuroprotective effects against PD through various mechanisms [ 9 , 163 , 169 , 170 ]. Polydatin attenuated motor dysfunction in animal models of PD via lowering pro-inflammatory cytokine and microglial suppression. Inhibition of microglial activation leads to the decrement of dopaminergic neurodegeneration. Consequently, polydatin regulated the Akt/glycogen synthase kinase-3β (GSK-3β)/Nrf2/NF-κB signaling axis towards such effects [ 169 ]. In addition, polydatin improved cell viability and Sirt1 expression. It also decreased mitochondrial dysfunction and ROS level [ 170 ]. Moreover, it was revealed that polydatin exerted therapeutic and protective effects in animal models of PD, including decreasing dopaminergic neuronal degeneration, neural apoptosis, and improving motor function via enhancement of glucose metabolism in neurons [ 171 ]. Polydatin also has the ability to pass through the blood–brain barrier [ 163 ]. Taken together, polydatin can be a potential therapeutic agent for treatment of PD.

Neurological I/R conditions due to oxygen and glucose deprivation lead to the occurrence of neurotoxicity and apoptosis [ 53 , 172 ]. Production of ROS and the inflammatory process are some of the main factors that contribute to neurological damages of I/R conditions. It has been demonstrated that polydatin, through its antioxidant, anti-inflammatory, and anti-apoptotic activities, exerts neuroprotective effects [ 53 , 62 , 63 , 167 , 172 , 173 , 174 ]. It is reported that polydatin improved neurological dysfunction and reduced infarcted area in animal models through inhibition of various CAMs, ameliorating mitochondrial dysfunction and decreasing ROS and pro-inflammatory factors [ 173 , 174 , 175 ]. Moreover, polydatin causes an enhancement in behavioral scores, reducing brain edema and hemiplegia in animal models [ 176 ].

Polydatin can improve cognitive function in conditions such as dementia [ 167 ], ethanol toxicity [ 177 ], and doxorubicin-induced cognitive impairment [ 81 ] via antioxidant [ 81 , 167 ], anti-inflammatory, and anti-apoptotic effects in the hippocampus [ 167 ]. Upregulation of the Nrf2/ARE signaling pathway plays an essential role in this polydatin effect [ 81 ]. In addition, polydatin ameliorated memory impairment in animal models via upregulation of brain-derived neurotrophic factor (BDNF) [ 178 ].

It is reported that polydatin has protective and therapeutic effects on SCI, such as improving motor function, reducing apoptosis, and enhancing neuron and bone marrow stromal cell (BMSC) viability [ 24 , 49 , 179 ]. Mitochondrial injury plays an essential role in SCI. Polydatin also attenuates mitochondrial dysfunction via activation of the Nrf2/ARE signaling pathway [ 24 , 180 ]. In addition, it is revealed that activation of the Nrf2/ARE signaling pathway by polydatin administration and BMSC transplantation led to the improvement of neuronal regeneration in animal models of SCI, facilitating BMSC differentiation and reducing glial scar formation in glial cells [ 181 ]. The reduction in inflammatory factors is another mechanism associated with polydatin’s protective and therapeutic effects against SCI [ 49 ].

It is demonstrated that polydatin has therapeutic effects against intracranial hemorrhage (ICH) and its complication [ 164 , 182 ]. Polydatin improved neuronal function [ 164 ] and inhibited brain edema in animal models [ 182 ]. Regulation of the Nrf2/ARE signaling pathway and downstream genes are mechanisms that are associated with the antioxidant activity of polydatin against ICH [ 164 ]. In addition, increasing levels of excitatory amino acids by polydatin may be associated with the protective and therapeutic effects of polydatin against ICH [ 182 ].

As mentioned in Table 4 , activation of Nrf2-related signaling is one of the primary mechanisms involved in polydatin’s therapeutic effects against neurological diseases such as ICH, PD, and cognitive impairment. Moreover, the anti-apoptotic effects play essential roles in this field. Polydatin can be a suitable choice in the treatment of neurological diseases ( Table 4 ).

Therapeutic targets of polydatin against cancer, cardiovascular diseases, diabetes, gastric/hepatic failure, and infection are presented in Figure 2 .

3.8. Effects on Renal System

It has been shown that polydatin exerts therapeutic and protective effects against renal I/R injury, acute kidney injury (AKI), renal fibrosis, sepsis shock, hyperuricemia, and diabetic nephropathy through antioxidant, anti-apoptotic, and anti-inflammatory pathways [ 65 , 183 , 184 , 185 , 186 , 187 ].

Studies demonstrated that polydatin can decrease uric acid levels and creatinine in serum and urine [ 46 , 188 , 189 ] via the inhibition of XOD [ 52 ] in animal models of hyperuricemia. In addition, polydatin attenuated oxidative stress induced by inflammation and urates [ 52 ]. Polydatin can also ameliorate renal inflammation by activating the AMPK/Sirt1 pathway [ 46 , 189 ]. Consequently, polydatin showed positive effects against AKI in animal models through different mechanisms such as enhancing mitochondrial function (176) and inhibiting inflammatory and oxidative pathways [ 186 , 190 ]. Polydatin also decreased blood urea nitrogen (BUN) and serum creatinine in AKI animal models [ 186 , 191 ]. Improvement of mitophagy, inhibition of mitochondrial dysfunction [ 187 , 191 ], and NLRP3 inflammasome activation are related to protective effects of polydatin against AKI [ 187 ].

Oxidative stress and autophagy imbalance are two important factors associated with high-fructose-induced nephropathy. It has been depicted that polydatin activating the Nrf2 pathway leads to the attenuation of autophagy imbalance in a mTORC1-dependent manner [ 192 ]. In addition, activation of the Sirt1/Nrf2/ARE signaling pathway exerts protective effects against diabetic nephropathy. By activating this pathway, polydatin inhibited upregulation of fibronectin and TGF-β1 induced by advanced glycation end-products [ 65 ].

In conclusion, polydatin exerts therapeutic/protective effects in the treatment of renal diseases, primarily via the activation of the Nrf2 signaling pathway and inhibition of NF-κB/NLRP3 inflammasome activity ( Table 5 ).

3.9. Effects on Respiratory System

Inflammatory and oxidative processes are associated with respiratory diseases such as asthma and radiation-induced lung injury. Polydatin shows protective and therapeutic effects against such diseases through antioxidant, anti-inflammatory, and anti-fibrotic mechanisms [ 193 , 194 , 195 ]. Moreover, it is shown that polydatin exerts protective and therapeutic effects against fetal conditions such as pulmonary fibrosis [ 196 ], acute respiratory distress syndrome (ARSD) [ 26 ], and lung I/R injury [ 197 , 198 ].

In various animal models of lung injury, polydatin showed protective and therapeutic effects such as reducing mortality, pathological alternation [ 151 , 199 ], lung water content [ 199 ], and formation of fibrotic tissue [ 193 ]. It also improved the ratio of arterial oxygen partial pressure (PaO2 in mmHg) to fractional inspired oxygen (PaO2/FIO2) [ 199 ]. In burning-induced lung injury models, polydatin reduced the thickness of alveolar walls, neutrophil accumulation, microvascular hyper-permeability, and polymorphonuclear leukocytes (PMNs) in bronchoalveolar lavage fluid (BAFL). In addition, polydatin reduced wet-to-dry lung weight (W/D) ratio and improved histopathological lung damage [ 200 ]. Results of radiation-induced and LPS-induced lung injury models demonstrated that polydatin exerts such effects through upregulation of HO-1 [ 151 ], club cell secretory protein (CCSP) [ 54 , 169 , 201 ], Sirt3 expression, and inhibition of epithelial–mesenchymal transition (EMT) [ 193 ]. In addition, polydatin caused anti-inflammatory effects that lead to decreases in W/D, MPO, and the number of neutrophils via regulation of the TLR4/MyD88/NF-κB signaling pathway in animal models [ 202 ]. Studies showed that polydatin exerts therapeutic effects against asthma through antioxidant and anti-inflammatory pathways [ 194 , 195 ]. Polydatin reduced inflammatory factors, oxidative and nitrosative stresses, fibroblasts levels, and histopathological factors via the activation of Nrf2, and reduced ROS and TGF-β levels [ 195 ]. In addition, it is revealed that the attenuation of surfactant-d (SP-D) and urocortin (UCN) is another mechanism that is associated with the anti-asthma effects of polydatin [ 194 ].

Taken together, polydatin can be a potential agent in the treatment of asthma, lung injuries, and other conditions that can lead to lung fibrosis. Anti-inflammatory, anti-apoptotic, and antioxidant activities of polydatin are obtained through decreasing PLA2 and NF-κB activity, increasing Nrf2-related signaling activity, and improving antioxidant capacities ( Table 6 ).

3.10. Effects on Rheumatoid Diseases

Systematic lupus erythematosus and rheumatoid arthritis are two autoimmune diseases that can be present in various organs and systems such as the cardiovascular system, kidneys, joints, and eyes. Inflammatory and oxidative processes have essential roles in the pathogenesis of such autoimmune disorders [ 56 , 206 , 207 ]. It is revealed that polydatin has therapeutic effects against rheumatoid arthritis and its progression [ 56 , 206 , 208 ]. In vitro and in vivo studies showed that polydatin ameliorated arthritis severity and neutrophil extracellular trap (NET) accumulation in the ankles of mice [ 208 ]. In addition, it reduced matrix metalloproteinase-9 (MMP-9) [ 206 ] and ankle/hind paw diameter [ 56 ]. Regulation of the IL-6/STAT3/IL-17/NF-κB pathway is attributed to polydatin’s effects against rheumatoid arthritis [ 56 ].

The NET formation is also associated with systematic lupus erythematous pathogenesis. It is shown that polydatin inhibits ROS-mediated NET formation and NET release in vitro and in vivo. Polydatin reduced lupus markers as much as chemical drugs such as mycophenolate mofetil and cyclophosphamide. Polydatin also reduced proteinuria, circulating autoantibody levels, and the immune complex in the kidney [ 207 ].

To conclude, polydatin can be a potential compound in treating rheumatoid diseases. Lowering NET formation and decreasing inflammatory cytokines are two main mechanisms involved in such effects ( Table 7 ).

3.11. Effects on the Skeletal System

Osteoporosis is one of the most common diseases among the elderly population of societies. Because of its complications such as hip fracture, it can impose much cost on the healthcare system [ 209 ]. Studies showed that polydatin exerts therapeutic and protective effects through various mechanisms in the field of osteoporosis [ 209 , 210 , 211 ], such as activation of tafazzin (TAZ) [ 210 ] and regulation of osteoprotegerin, the receptor activator of NF-κB ligand (RANKL), and B-catenin [ 209 ]. Moreover, polydatin improved osteogenic differentiation, migration of hBMSCs, and protection of the bone matrix [ 210 , 211 , 212 ]. In animal models of osteoporosis, polydatin increased ALP serum levels, calcium, ferrous, W/D, and osteoprotegerin [ 209 ]. In addition to osteoporosis, polydatin showed therapeutic effects on other skeletal diseases, including intervertebral disc degeneration and ankylosing spondylitis [ 30 , 213 ]. Endplate chondrocyte apoptosis is associated with the degeneration of the cartilaginous endplate (CEP) that leads to intervertebral disc degeneration [ 30 ]. Polydatin ameliorated mitochondrial injury and oxidative stress, leading to protective effects on CEP and discs against degeneration via upregulation of Nrf2 [ 30 , 214 ]. In addition, activation of Nrf2 caused protective effects on nucleus pulposus cells. Nucleus pulposus cells play an essential role in the inhibition/degradation of the extracellular matrix [ 214 ].

Increasing the proliferation of fibroblasts is a crucial factor in manifesting ankylosing spondylitis. In vitro studies revealed that polydatin can increase fibroblast apoptosis via upregulation of active caspase-3 expression and Bax and decreasing Bcl2. It also increased autophagy mechanisms and therapeutic effects on ankylosing spondylitis [ 213 ].

Taken together, we can consider polydatin as an efficacious agent in the treatment of osteoporosis, ankylosing spondylitis, and intervertebral disc degeneration; therefore, it could be an interesting subject for further studies in this field ( Table 8 ).

3.12. Effects on Women’s Health

Endometriosis targets the female population with a prevalence of 10% [ 215 ]. There is a connection between endometriosis and inflammatory processes [ 31 ]. Mast cells that are close to nerve fibers in endometrial lesions play an essential role in regulating inflammatory processes [ 215 ]. Mast cell activation leads to the aggravation of pain and hyperalgesia in endometriosis [ 216 ]. In different studies, the effectiveness of palmitoylethanolamide (PEA)/polydatin combination was evaluated on endometriosis. PEA showed anti-inflammatory and inhibitory effects on mast cells. On the other hand, polydatin is known for its antioxidant and anti-inflammatory effects in different diseases [ 216 ]. Results in animal models of endometriosis showed that PEA/polydatin combination reduced cyst diameter, mast cell number, uterus impairment, inflammatory factors, and inflammatory cell infiltration [ 31 , 217 ]. In addition, clinical studies showed that PEA/polydatin combination improved chronic pelvic pain, dysmenorrhea, deep dyspareunia, and dyschezia [ 215 , 216 , 218 ]. It also improved life quality and psychological condition [ 218 ]. In addition to endometriosis, polydatin showed therapeutic and protective effects against hemorrhagic shock during pregnancy in vivo. It also improved survival time and microcirculation in animal models [ 219 ]. Table 9 shows the main benefits of polydatin on women’s health.

Therapeutic targets of polydatin against kidney injury, neurodegeneration, respiratory dysfunction, skeletal problems, and women’s disorders are presented in Figure 3 .

3.13. Miscellaneous Effects

Polydatin is reported to have protective and therapeutic effects on other diseases and pathological conditions, including allergies [ 221 , 222 , 223 ], benign prostatic hyperplasia (BPH) [ 224 ], anxiety [ 225 ], Graves’ orbitopathy [ 226 ], pain [ 227 ], and age-related diseases [ 228 ]. Moreover, it is revealed that polydatin exerts protective effects in skin-related problems [ 229 , 230 ], such as facilitating epidermal growth factor receptor (EGFR) and inhibiting cutaneous side effects [ 230 ]. Studies showed that polydatin reduced pigmentation and histamine serum levels in passive cutaneous anaphylaxis and passive systemic anaphylaxis, respectively [ 221 ]. Mast cell stabilization [ 221 , 222 ] and decreasing inflammatory cytokines [ 221 ] are associated with such effects. In addition, polydatin attenuated food allergies via mast cell stabilization, reducing immunoglobulin E (IgE) production and improving integrity of the mucosal barrier [ 223 ]. Using polydatin in combination with PEA reduced dihydrotestosterone production and prostate weight through anti-apoptotic and anti-inflammatory mechanisms in animal models of BPH [ 224 ].

As previously mentioned, polydatin exhibited analgesic effects on endometriosis, chronic pelvic pain, and dysmenorrhea [ 215 , 216 , 218 ]. In addition, polydatin ameliorated osteoarthritis [ 227 ], cystitis/bladder pain syndrome [ 231 ], and diabetic neuropathy [ 232 ]. Polydatin reduced inflammatory factors and matrix-degrading protease in osteoarthritis through anti-inflammatory and chondroprotective effects [ 227 ]. Activation of the Nrf2 pathway is related to therapeutic and protective effects of polydatin on osteoarthritis [ 227 ] and diabetic neuropathy [ 232 ]. Polydatin also demonstrated protective effects on sciatic neurons and Schwann cells in animal models of diabetic neuropathy via inhibition of Keap 1, and activation of Nrf2/glyoxalase 1 [ 232 ].

4. Clinical Trials on Polydatin

Therapeutic and protective effects of polydatin have been evaluated in different clinical trials involving disorders such as chronic pelvic pain, inflammatory bowel syndrome (IBS), liver disease, and EGFR TKI-related rashes. As previously described, the effectiveness of polydatin on chronic pelvic pain related to endometriosis has been elucidated. Loi et al. assessed the effects of polydatin against chronic pelvic pain related to endometriosis in thirty symptomatic women desiring pregnancy. Patients administered 600 mg ultramicronized PEA (um-PEA) twice a day for 10 days followed by 400/40 mg co-micronized PEA/polydatin twice a day for 80 days demonstrated protective responses. The um-PEA and PEA/polydatin regimen improved pain symptoms, psychological condition, and the quality of life effectively. In addition, no adverse events were reported by this regimen, so it can be considered a potential regimen in the therapy of endometriosis symptoms [ 218 ]. Soave et al. showed that taking PEA/polydatin 400/40 mg twice a day for 90 days decreased pelvic pain and dysmenorrhea/dyspareunia. It also improved the quality of life in the 24 patients with suspected endometriosis suffering from severe pelvic pain who were involved in this study [ 233 ]. In addition, results of a review study showed that administration of PEA/polydatin 400 mg/40 mg twice a day exerted positive effects against endometriotic chronic pelvic pain, including improving chronic pelvic pain, dysmenorrhea, and deep dyspareunia [ 215 ].

Moreover, the assessment of PEA/polydatin effects against IBS on 54 patients with IBS and 12 healthy people showed potential approaches toward pain management in the IBS patients. Consequently, PEA/polydatin 200 mg/20 mg twice a day for 12 weeks reduced the fatty acid amide oleoylethanolamide. It also increased the expression of cannabinoid receptor 2, thereby significantly decreasing abdominal pain severity [ 234 ].

The protective and therapeutic effects of polydatin were investigated in 20 alcoholic patients hospitalized for rehabilitative therapy. They were given one of two oral nutritional supplements containing vitamin C or vitamin C/polydatin. It was shown that the later regiment reduced levels of AST, ALT, and lipid peroxidation in patients. Moreover, the polydatin-receiving group improved cognitive performance. Taken together, polydatin administration can be considered as a protective and therapeutic strategy in liver disease and cognitive impairment in alcoholic patients [ 235 ]. In another study, dietary supplements including polydatin and precursors for the endogenous synthesis of glutathione in healthy people are reported to be more effective on the redox status than dietary supplements containing precursors for the endogenous synthesis of glutathione alone. In the first supplement group, levels of vitamins C, E, and A are increased more than in the second group. Neopterin levels also decreased more effectively in the first group [ 236 ].

Fuggetta et al. showed that topical administration of 1.5% polydatin-based cream twice a day lowered the incidence of grade ≥2 skin toxicities in patients with mutated non-small-cell lung cancer (NSCLC) taking afatinib (40 mg/day) [ 230 ]. In addition, administration of 1.5% polydatin cream in patients with papulopustular adverse effects improved cutaneous adverse effects. Plydatin 0.8% also prevented the development of cutaneous adverse effects in patients without papulopustular adverse effects, and was used twice a day for 6 months [ 237 ].

Therefore, polydatin’s efficacy has been proven in clinical trials. Polydatin can be a good choice in the management of chronic pelvic pain, IBS, liver disease, and EGFR TKI-related rashes. Moreover, the therapeutic effects of polydatin can be considered as rational subjects for clinical trials ( Table 10 ).

5. Novel Delivery Systems of Polydatin

Various novel drug delivery systems, including nanoparticles [ 238 ], liposomes [ 239 ], micelles [ 240 ], quantum dots [ 241 ], and polymeric nanocapsules [ 242 ], are designed to enhance polydatin pharmacodynamics and pharmacokinetics [ 243 ].

ZnO#ZnS quantum dot (QD) heterojunctions (QDHJs) have been reported to lower free concentration of stilbenes such as polydatin and their pharmacological effects through increasing the affinity of polydatin for common bovine plasma proteins [ 241 ]. Polydatin-loaded chitosan nanoparticles (polydatin-CSNPs) showed better efficacy than free polydatin against type 2 diabetes [ 244 ], diabetic nephropathy [ 245 ], and diabetic cardiomyopathy [ 238 ]. Polydatin-CSNPs also showed a prolonged profile release [ 238 , 244 ]. In animal models, polydatin-CSNPs exerted better attenuating effects against diabetic cardiomyopathy than metformin [ 238 ]. Moreover, it has been demonstrated that polydatin-loaded chitosan nanoparticles (polydatin-CSNPs) attenuated diabetic liver damage through different mechanisms, including anti-inflammatory and antioxidant effects, regulating glucose transporter 2 expression, and influencing carbohydrate metabolism enzymes. Polydatin-CSNPs had higher bioavailability than naïve polydatin, which also showed a prolonged release pattern. Therefore, polydatin-CSNPs showed more efficacy than naïve polydatin [ 243 ]. In addition to polydatin-CSNPs, the effects of a polydatin-loaded micelle (polydatin-MC) were assessed against liver fibrosis. Polydatin-MC is designed based on the ROS and pH dual-sensitive block polymer PEG-P (PBEM- co -DPA). The micelle enhanced the biocompatibility of polydatin, and it also improved drug release in the liver in response to the fibrotic microenvironment. Interestingly, blank micelles exerted anti-inflammatory effects by improving hepatic ROS consumption and enhancing polydatin’s therapeutic effects [ 240 ]. Polydatin-loaded liposome is another drug delivery system designed to improve polydatin’s release profile. This drug delivery system improved the oral bioavailability of polydatin and prolonged drug circulation time remarkably [ 239 ].

Polydatin-loaded polymeric nanocapsules are reported to have the same therapeutic effects as naïve polydatin against anti-inflammatory and antioxidant activities on LPS-induced changes in hippocampal organotypic cultures. On the other hand, the encapsulation procedure enhanced polydatin bioavailability and stability [ 242 ]. Polydatin-encapsulated poly [lactic-co-glycolic acid] (polydatin-PLGA-NPs) showed preventive effects against oral squamous cell carcinoma (OSCC) in animal models. It also inhibited lipid peroxidation, oxidative stress, and modulated phase I and phase II of the detoxification system [ 246 ].

Polydatin gold nanoparticles (polydatin-AuNP) significantly reduced dense tumor cells in Ehrlich ascites carcinoma animal models. Polydatin-AuNPs also exerted protective effects against doxorubicin’s cardiovascular side effects [ 247 ]. Moreover, polydatin-modified Au@AgNPs exerted positive effects in topical wound healing. Administration of topical polydatin-modified Au@AgNPs led to higher migration of keratinocytes [ 248 ].

To sum up, novel drug delivery systems have improved the pharmacokinetics and pharmacodynamics properties of polydatin. Improvements in bioavailability, biocompatibility, and efficacy are the main beneficial effects of polydatin’s novel drug delivery systems.

6. Conclusions

The complex pathophysiological mechanisms behind chronic diseases urge the need for providing novel multi-targeting agents with higher efficacy/bioavailability and lower side effects. The plant kingdom is now a great source of natural secondary metabolites with the potential of targeting multiple dysregulated pathways in diseases. Polydatin is a glucoside derivative of resveratrol possessing better bioavailability and higher health-promoting/disease-modifying activities. The anti-inflammatory, antioxidant, and apoptotic-modifying properties of polydatin provide protective effects against inflammatory, oxidative stress, and apoptotic responses. Prevailing evidence reveals the biological activities and health-promoting effects of polydatin in various conditions, including cancer, cardiovascular diseases, diabetes, gastrointestinal/hepatic diseases, neurodegeneration, and infectious conditions, as well as protective roles in the respiratory system, the renal system, rheumatoid diseases, the skeletal system, and women’s health. Polydatin applies such effects through multiple mediators ( Figure 4 ). As such, the broad therapeutic potential of polydatin urges the need for finding potential sources to promote the application of polydatin in industrial, commercial, and research sectors. Of polydatin sources, Reynoutria japonica is a useful highly invasive plant and a rich source in the pharmaceutical industry [ 7 ]. However, to better improve the bioavailability and efficacy of polydatin in clinical trials, investigating appropriate delivery systems in order to solve the pharmacokinetic limitation is of great importance.

Today, pan-assay interference compounds (PAINS) have been proposed as a threat to identifying the bioactivity of natural compounds, including compounds such as resveratrol [ 249 ]. PAINS cause disruption in the membrane by reducing the membrane dipole potential and, as a result, can affect intracellular signaling pathways. PAINS-type behavior can affect intracellular signaling pathways in a non-specific way. The cell-based data of some phytochemicals might be a product of such effects and not caused by specific binding to therapeutic targets. Recent studies have shown that C-glucosylation of polyphenol compounds causes the PAINS effect, while O -glucosylation has no effect on this behavior [ 250 ]. As per previous data [ 250 ], polydatin, an O -glucosylated derivative of resveratrol, is expected to present the same concerns as the aglycone with regards to inducing non-specific reductions in the membrane dipole potential. Therefore, in order to assess if C -glucosylation of resveratrol is able to preserve the promising bioactivities of polydatin described in this review while addressing the mentioned PAINS-related issue, the biological evaluation of this C -glucosyl analog of polydatin is of utmost importance. All biological activities, health benefits, and pharmacological mechanisms of action of polydatin have been highlighted in the current study. A further area of research should include extensive pre-clinical studies to reveal the precise pharmacological mechanisms of polydatin followed by well-controlled clinical trials towards therapeutic potentials. Such reports will help to provide more biological applications of polydatin and other stilbenoids in the prevention, management, and treatment of several diseases.

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Author Contributions

Conceptualization: S.F. and H.K.; drafting of the manuscript: A.K., L.K. and S.F.; software: S.F.; reviewing and editing: S.F. and H.K. All authors have read and agreed to the published version of the manuscript.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

Data sharing is not applicable to this article as no new data were created or analyzed in this study.

Conflicts of Interest

The authors declare that no conflict of interest could be perceived as prejudicing the impartiality of the research reported.

References

1. Mele L. Paino F. Papaccio F. Regad T. Boocock D. Stiuso P. Lombardi A. Liccardo D. Aquino G. Barbieri A. A new inhibitor of glucose-6-phosphate dehydrogenase blocks pentose phosphate pathway and suppresses malignant proliferation and metastasis in vivo Cell Death Dis. 2018 9 572 10.1038/s41419-018-0635-5 29760380 PMC5951921

2. Zhang M. Zhao Z. Shen M. Zhang Y. Duan J. Guo Y. Zhang D. Hu J. Lin J. Man W. Polydatin protects cardiomyocytes against myocardial infarction injury by activating Sirt3 Biochim. Biophys. Acta (BBA)-Mol. Basis Dis. 2017 1863 1962 1972 10.1016/j.bbadis.2016.09.003 27613967

3. Şöhretoğlu D. Baran M.Y. Arroo R. Kuruüzüm-Uz A. Recent advances in chemistry, therapeutic properties and sources of polydatin Phytochem. Rev. 2018 17 973 1005 10.1007/s11101-018-9574-0

4. Mei X. Wang Y. Li J. Liu Z. Lang S. Ouyang W. Zhang J. Comprehensive metabolism study of polydatin in rat plasma and urine using ultra-high performance liquid chromatography coupled with high-resolution mass spectrometry J. Chromatogr. B 2019 1117 22 35 10.1016/j.jchromb.2019.04.005 30991203

5. San Tang K. Tan J.S. The protective mechanisms of polydatin in cerebral ischemia Eur. J. Pharmacol. 2019 842 133 138 10.1016/j.ejphar.2018.10.039 30385347

6. Peng W. Qin R. Li X. Zhou H. Botany, phytochemistry, pharmacology, and potential application of Polygonum cuspidatum Sieb. et Zucc.: A review J. Ethnopharmacol. 2013 148 729 745 10.1016/j.jep.2013.05.007 23707210

7. Negrea B.-M. Stoilov-Linu V. Pop C.-E. Deák G. Crăciun N. Făgăraș M.M. Expansion of the Invasive Plant Species Reynoutria japonica Houtt in the Upper Bistrița Mountain River Basin with a Calculus on the Productive Potential of a Mountain Meadow Sustainability 2022 14 5737 10.3390/su14095737

8. Neag M.A. Mocan A. Echeverría J. Pop R.M. Bocsan C.I. Crişan G. Buzoianu A.D. Berberine: Botanical occurrence, traditional uses, extraction methods, and relevance in cardiovascular, metabolic, hepatic, and renal disorders Front. Pharmacol. 2018 9 557 10.3389/fphar.2018.00557 30186157 PMC6111450

9. Potdar S. Parmar M.S. Ray S.D. Cavanaugh J.E. Protective effects of the resveratrol analog piceid in dopaminergic SH-SY5Y cells Arch. Toxicol. 2018 92 669 677 10.1007/s00204-017-2073-z 28980048

10. Du Q.-H. Peng C. Zhang H. Polydatin: A review of pharmacology and pharmacokinetics Pharm. Biol. 2013 51 1347 1354 10.3109/13880209.2013.792849 23862567

11. Lanzilli G. Cottarelli A. Nicotera G. Guida S. Ravagnan G. Fuggetta M.P. Anti-inflammatory effect of resveratrol and polydatin by in vitro IL-17 modulation Inflammation 2012 35 240 248 10.1007/s10753-011-9310-z 21369944

12. Muzio L.L. Bizzoca M.E. Ravagnan G. New intriguing possibility for prevention of coronavirus pneumonitis: Natural purified polyphenols Oral Dis. 2020 28 899 903 10.1111/odi.13518 32597513 PMC7361353

13. Zhao G. Yang L. Zhong W. Hu Y. Tan Y. Ren Z. Ban Q. Yang C.S. Wang Y. Wang Z. Polydatin, A Glycoside of Resveratrol, Is Better Than Resveratrol in Alleviating Non-alcoholic Fatty Liver Disease in Mice Fed a High-Fructose Diet Front. Nutr. 2022 9 857879 10.3389/fnut.2022.857879 35651514 PMC9149290

14. Bokkenheuser V.D. Shackleton C. Winter J. Hydrolysis of dietary flavonoid glycosides by strains of intestinal Bacteroides from humans Biochem. J. 1987 248 953 956 10.1042/bj2480953 3435494 PMC1148642

15. Marín L. Miguélez E.M. Villar C.J. Lombó F. Bioavailability of dietary polyphenols and gut microbiota metabolism: Antimicrobial properties BioMed Res. Int. 2015 2015 905215 10.1155/2015/905215 25802870 PMC4352739

16. Kim M. Lee J. Han J. Deglycosylation of isoflavone C-glycosides by newly isolated human intestinal bacteria J. Sci. Food Agric. 2015 95 1925 1931 10.1002/jsfa.6900 25199800

17. de Lima M.T.R. Waffo-Téguo P. Teissedre P.L. Pujolas A. Vercauteren J. Cabanis J.C. Mérillon J.M. Determination of stilbenes (trans-astringin, cis-and trans-piceid, and cis-and trans-resveratrol) in Portuguese wines J. Agric. Food Chem. 1999 47 2666 2670 10.1021/jf9900884 10552542

18. Wang D.-G. Liu W.-Y. Chen G.-T. A simple method for the isolation and purification of resveratrol from Polygonum cuspidatum J. Pharm. Anal. 2013 3 241 247 10.1016/j.jpha.2012.12.001 29403824 PMC5760951

19. Romero-Pérez A.I. Lamuela-Raventós R.M. Andrés-Lacueva C. de la Torre-Boronat M.C. Method for the quantitative extraction of resveratrol and piceid isomers in grape berry skins. Effect of powdery mildew on the stilbene content J. Agric. Food Chem. 2001 49 210 215 10.1021/jf000745o 11170579

20. Fakhri S. Gravandi M.M. Abdian S.A.-O. Akkol E.A.-O. Farzaei M.A.-O. Sobarzo-Sánchez E.A.-O. The Neuroprotective Role of Polydatin: Neuropharmacological Mechanisms, Molecular Targets, Therapeutic Potentials, and Clinical Perspective Molecules 2021 26 5985 10.3390/molecules26195985 34641529 PMC8513080

21. Mele L. la Noce M. Paino F. Regad T. Wagner S. Liccardo D. Papaccio G. Lombardi A. Caraglia M. Tirino V. Glucose-6-phosphate dehydrogenase blockade potentiates tyrosine kinase inhibitor effect on breast cancer cells through autophagy perturbation J. Exp. Clin. Cancer Res. 2019 38 1 13 10.1186/s13046-019-1164-5 30987650 PMC6466760

22. Ming D. Songyan L. Yawen C. Na Z. Jing M. Zhaowen X. Ye L. Wa D. Jie L. trans-Polydatin protects the mouse heart against ischemia/reperfusion injury via inhibition of the renin–angiotensin system (RAS) and Rho kinase (ROCK) activity Food Funct. 2017 8 2309 2321 10.1039/C6FO01842D 28589995

23. Gong W. Li J. Chen Z. Huang J. Chen Q. Cai W. Liu P. Huang H. Polydatin promotes Nrf2-ARE anti-oxidative pathway through activating CKIP-1 to resist HG-induced up-regulation of FN and ICAM-1 in GMCs and diabetic mice kidneys Free Radic. Biol. Med. 2017 106 393 405 10.1016/j.freeradbiomed.2017.03.003 28286065

24. Lv R. Du L. Zhang L. Zhang Z. Polydatin attenuates spinal cord injury in rats by inhibiting oxidative stress and microglia apoptosis via Nrf2/HO-1 pathway Life Sci. 2019 217 119 127 10.1016/j.lfs.2018.11.053 30481506

25. Zhao X.-J. Yu H.-W. Yang Y.-Z. Wu W.-Y. Chen T.-Y. Jia K.-K. Kang L.-L. Jiao R.-Q. Kong L.-D. Polydatin prevents fructose-induced liver inflammation and lipid deposition through increasing miR-200a to regulate Keap1/Nrf2 pathway Redox Biol. 2018 18 124 137 10.1016/j.redox.2018.07.002 30014902 PMC6068203

26. Li T. Liu Y. Xu W. Dai X. Liu R. Gao Y. Chen Z. Li Y. Polydatin mediates Parkin-dependent mitophagy and protects against mitochondria-dependent apoptosis in acute respiratory distress syndrome Lab. Investig. 2019 99 819 829 10.1038/s41374-019-0191-3 30808930

27. Zeng Z. Chen Z. Xu S. Song R. Yang H. Zhao K.-S. Polydatin alleviates small intestine injury during hemorrhagic shock as a SIRT1 activator Oxidative Med. Cell. Longev. 2015 2015 965961 10.1155/2015/965961 PMC4537745 26301045

28. Jiang K.-F. Zhao G. Deng G.-Z. Wu H.-C. Yin N.-N. Chen X.-Y. Qiu C.-W. Peng X.-L. Polydatin ameliorates Staphylococcus aureus-induced mastitis in mice via inhibiting TLR2-mediated activation of the p38 MAPK/NF-κB pathway Acta Pharmacol. Sin. 2017 38 211 222 10.1038/aps.2016.123 27890916 PMC5309755

29. Masodsai K. Lin Y.Y. Chaunchaiyakul R. Su C.T. Lee S.D. Yang A.L. Twelve-Week Protocatechuic Acid Administration Improves Insulin-Induced and Insulin-Like Growth Factor-1-Induced Vasorelaxation and Antioxidant Activities in Aging Spontaneously Hypertensive Rats Nutrients 2019 11 699 10.3390/nu11030699 PMC6471824 30934575

30. Kang L. Liu S. Li J. Tian Y. Xue Y. Liu X. Parkin and Nrf2 prevent oxidative stress-induced apoptosis in intervertebral endplate chondrocytes via inducing mitophagy and anti-oxidant defenses Life Sci. 2020 243 117244 10.1016/j.lfs.2019.117244 31891721

31. Li R. Maimai T. Yao H. Liu X. He Z. Xiao C. Wang Y. Xie G. Protective effects of polydatin on LPS-induced endometritis in mice Microb. Pathog. 2019 137 103720 10.1016/j.micpath.2019.103720 31494302

32. Tang K.S. Protective Effects of Polydatin Against Dementia-Related Disorders Curr. Neuropharmacol. 2020 19 127 135 10.2174/1570159X18666200611144825 32525774 PMC8033983

33. Zhang H. Li Y. Xun Y. Liu H. Wei C. Wang H. Yang X. Yuan S. Liu N. Xiang S. Polydatin protects neuronal cells from hydrogen peroxide damage by activating CREB/Ngb signaling Mol. Med. Rep. 2022 25 1 10 10.3892/mmr.2021.12525 34751416 PMC8600421

34. Wu M. Li X. Wang S. Yang S. Zhao R. Xing Y. Liu L. Polydatin for treating atherosclerotic diseases: A functional and mechanistic overview Biomed. Pharmacother. 2020 128 110308 10.1016/j.biopha.2020.110308 32480216

35. Ahmad P. Alvi S.S. Iqbal D. Khan M.S. Insights into pharmacological mechanisms of polydatin in targeting risk factors-mediated atherosclerosis Life Sci. 2020 254 117756 10.1016/j.lfs.2020.117756 32389832

36. Sun Z. Wang X. Protective effects of polydatin on multiple organ ischemia-reperfusion injury Bioorganic Chem. 2019 94 103485 10.1016/j.bioorg.2019.103485 31836186

37. Liu C. Wang W. Zhang K. Liu Q. Ma T. Tan L. Ma L. Protective Effects of Polydatin from Grapes and Reynoutria japonica Houtt. on Damaged Macrophages Treated with Acetaminophen Nutrients 2022 14 2077 10.3390/nu14102077 35631218 PMC9147135

38. Salem M.A. Serag A. El-Seedi H.R. Hamdan D.I. Ezzat S.M. Zayed A. Identification and analysis of toxic phytochemicals Phytochemistry, the Military and Health Elsevier Amsterdam, The Netherlands 2021 443 479

39. Rajendran P. Chen Y.F. Chen Y.F. Chung L.C. Tamilselvi S. Shen C.Y. Day C.H. Chen R.J. Viswanadha V.P. Kuo W.W. The multifaceted link between inflammation and human diseases J. Cell. Physiol. 2018 233 6458 6471 10.1002/jcp.26479 29323719 PMC13482531

40. Furman D. Campisi J. Verdin E. Carrera-Bastos P. Targ S. Franceschi C. Ferrucci L. Gilroy D.W. Fasano A. Miller G.W. Chronic inflammation in the etiology of disease across the life span Nat. Med. 2019 25 1822 1832 10.1038/s41591-019-0675-0 31806905 PMC7147972

41. Chen L. Deng H. Cui H. Fang J. Zuo Z. Deng J. Li Y. Wang X. Zhao L. Inflammatory responses and inflammation-associated diseases in organs Oncotarget 2017 9 7204 7218 10.18632/oncotarget.23208 29467962 PMC5805548

42. Mitchell S. Vargas J. Hoffmann A. Signaling via the NFκB system Wiley Interdiscip. Rev. Syst. Biol. Med. 2016 8 227 241 10.1002/wsbm.1331 26990581 PMC8363188

43. Wang R.X. Zhou M. Ma H.L. Qiao Y.B. Li Q.S. The Role of Chronic Inflammation in Various Diseases and Anti-inflammatory Therapies Containing Natural Products ChemMedChem 2021 16 1576 1592 10.1002/cmdc.202000996 33528076

44. Mikulski D. Molski M. Quantitative structure–antioxidant activity relationship of trans-resveratrol oligomers, trans-4,4′-dihydroxystilbene dimer, trans-resveratrol-3-O-glucuronide, glucosides: Trans-piceid, cis-piceid, trans-astringin and trans-resveratrol-4′-O-β-D-glucopyranoside Eur. J. Med. Chem. 2010 45 2366 2380 20199826 10.1016/j.ejmech.2010.02.016

45. Tang J. Li Y. Wang J. Wu Q. Yan H. Polydatin suppresses the development of lung inflammation and fibrosis by inhibiting activation of the NACHT domain-, leucine-rich repeat-, and pyd-containing protein 3 inflammasome and the nuclear factor-κB pathway after Mycoplasma pneumoniae infection J. Cell. Biochem. 2019 120 10137 10144 10.1002/jcb.28297 30548648

46. Chen L. Lan Z. Polydatin attenuates potassium oxonate-induced hyperuricemia and kidney inflammation by inhibiting NF-κB/NLRP3 inflammasome activation via the AMPK/SIRT1 pathway Food Funct. 2017 8 1785 1792 10.1039/C6FO01561A 28428988

47. Peritore A.F. D’Amico R. Cordaro M. Siracusa R. Fusco R. Gugliandolo E. Genovese T. Crupi R. Di Paola R. Cuzzocrea S. PEA/Polydatin: Anti-Inflammatory and Antioxidant Approach to Counteract DNBS-Induced Colitis Antioxidants 2021 10 464 10.3390/antiox10030464 33809584 PMC8000209

48. Huang Q.-H. Xu L.-Q. Liu Y.-H. Wu J.-Z. Wu X. Lai X.-P. Li Y.-C. Su Z.-R. Chen J.-N. Xie Y.-L. Polydatin Protects Rat Liver against Ethanol-Induced Injury: Involvement of CYP2E1/ROS/Nrf2 and TLR4/NF-κB p65 Pathway Evid. Based Complement. Altern. Med. 2017 2017 7953850 10.1155/2017/7953850 PMC5698823 29250126

49. Lv R. Du L. Liu X. Zhou F. Zhang Z. Zhang L. Polydatin alleviates traumatic spinal cord injury by reducing microglial inflammation via regulation of iNOS and NLRP3 inflammasome pathway Int. Immunopharmacol. 2019 70 28 36 10.1016/j.intimp.2019.02.006 30785088

50. Liu H.-B. Meng Q.-H. Huang C. Wang J.-B. Liu X.-W. Nephroprotective Effects of Polydatin against Ischemia/Reperfusion Injury: A Role for the PI3K/Akt Signal Pathway Oxidative Med. Cell. Longev. 2015 2015 362158 10.1155/2015/362158 PMC4630419 26576221

51. Chen G. Yang Z. Wen D. Guo J. Xiong Q. Li P. Zhao L. Wang J. Wu C. Dong L. Polydatin has anti-inflammatory and antioxidant effects in LPS-induced macrophages and improves DSS-induced mice colitis Immun. Inflamm. Dis. 2021 9 959 970 10.1002/iid3.455 34010516 PMC8342204

52. Chen L. Lan Z. Lin Q. Mi X. He Y. Wei L. Lin Y. Zhang Y. Deng X. Polydatin ameliorates renal injury by attenuating oxidative stress-related inflammatory responses in fructose-induced urate nephropathic mice Food Chem. Toxicol. 2013 52 28 35 10.1016/j.fct.2012.10.037 23137955

53. Ruan W. Li J. Xu Y. Wang Y. Zhao F. Yang X. Jiang H. Zhang L. Saavedra J.M. Shi L. MALAT1 Up-Regulator Polydatin Protects Brain Microvascular Integrity and Ameliorates Stroke Through C/EBPβ/MALAT1/CREB/PGC-1α/PPARγ Pathway Cell. Mol. Neurobiol. 2019 39 265 286 10.1007/s10571-018-00646-4 30607811 PMC11469806

54. Shiyu S. Zhiyu L. Mao Y. Lin B. Lijia W. Tianbao Z. Jie C. Tingyu L. Polydatin up-regulates Clara cell secretory protein to suppress phospholipase A2 of lung induced by LPS in vivo and in vitro BMC Cell Biol. 2011 12 31 10.1186/1471-2121-12-31 21787397 PMC3199855

55. Wu M.J. Gong X. Jiang R. Zhang L. Li X.H. Wan J.Y. Polydatin Protects against Lipopolysaccharide-Induced Fulminant Hepatic Failure in D-Galactosamine-Sensitized Mice Int. J. Immunopathol. Pharmacol. 2012 25 923 934 10.1177/039463201202500410 23298483

56. Kamel K.M. Gad A.M. Mansour S.M. Safar M.M. Fawzy H.M. Novel anti-arthritic mechanisms of Polydatin in complete Freund’s adjuvant-induced arthritis in rats: Involvement of IL-6, STAT-3, IL-17, and NF-κB Inflammation 2018 41 1974 1986 10.1007/s10753-018-0841-4 29982962

57. Pizzino G. Irrera N. Cucinotta M. Pallio G. Mannino F. Arcoraci V. Squadrito F. Altavilla D. Bitto A. Oxidative Stress: Harms and Benefits for Human Health Oxidative Med. Cell. Longev. 2017 2017 8416763 10.1155/2017/8416763 PMC5551541 28819546

58. Storz G. Imlayt J.A. Oxidative stress Curr. Opin. Microbiol. 1999 2 188 194 10.1016/S1369-5274(99)80033-2 10322176

59. Liu Y.-H. Huang Q.-H. Wu X. Wu J.-Z. Liang J.-L. Lin G.-S. Xu L.-Q. Lai X.-P. Su Z.-R. Chen J.-N. Polydatin protects against acetaminophen-induced hepatotoxicity in mice via anti-oxidative and anti-apoptotic activities Food Funct. 2018 9 5891 5902 10.1039/C8FO01078A 30375606

60. Liu M. Huang Q. Zhu Y. Chen L. Li Y. Gong Z. Ai K. Harnessing reactive oxygen/nitrogen species and inflammation: Nanodrugs for liver injury Mater. Today Bio 2022 13 100215 10.1016/j.mtbio.2022.100215 PMC8850330 35198963

61. Kobayashi E. Suzuki T. Yamamoto M. Roles Nrf2 Plays in Myeloid Cells and Related Disorders Oxidative Med. Cell. Longev. 2013 2013 529219 10.1155/2013/529219 PMC3684031 23819012

62. Shah F.A. Kury L.A. Li T. Zeb A. Koh P.O. Liu F. Zhou Q. Hussain I. Khan A.U. Jiang Y. Polydatin Attenuates Neuronal Loss via Reducing Neuroinflammation and Oxidative Stress in Rat MCAO Models Front. Pharmacol. 2019 10 663 10.3389/fphar.2019.00663 31293416 PMC6606791

63. Ji H. Zhang X. Du Y. Liu H. Li S. Li L. Polydatin modulates inflammation by decreasing NF-κB activation and oxidative stress by increasing Gli1, Ptch1, SOD1 expression and ameliorates blood–brain barrier permeability for its neuroprotective effect in pMCAO rat brain Brain Res. Bull. 2012 87 50 59 10.1016/j.brainresbull.2011.09.021 22001340

64. Meng Q.-h. Liu H.-b. Wang J.-b. Polydatin ameliorates renal ischemia/reperfusion injury by decreasing apoptosis and oxidative stress through activating sonic hedgehog signaling pathway Food Chem. Toxicol. 2016 96 215 225 10.1016/j.fct.2016.07.032 27481074

65. Huang K. Chen C. Hao J. Huang J. Wang S. Liu P. Huang H. Polydatin promotes Nrf2-ARE anti-oxidative pathway through activating Sirt1 to resist AGEs-induced upregulation of fibronetin and transforming growth factor-β1 in rat glomerular messangial cells Mol. Cell. Endocrinol. 2015 399 178 189 10.1016/j.mce.2014.08.014 25192797

66. Yu L. Li Z. Dong X. Xue X. Liu Y. Xu S. Zhang J. Han J. Yang Y. Wang H. Polydatin Protects Diabetic Heart against Ischemia-Reperfusion Injury via Notch1/Hes1-Mediated Activation of Pten/Akt Signaling Oxidative Med. Cell. Longev. 2018 2018 2750695 10.1155/2018/2750695 PMC5831600 29636838

67. Tan Y.-Y. Chen L.-X. Fang L. Zhang Q. Cardioprotective effects of polydatin against myocardial injury in diabetic rats via inhibition of NADPH oxidase and NF-κB activities BMC Complement. Med. Ther. 2020 20 12 10.1186/s12906-020-03177-y 33308195 PMC7733248

68. Dan S. Bangle Z. Menglei H. Qiuju H. Chunlai Z. Siyuan Z. Comparison of Resveratrol and Polydatin on Anti-oxidative Activities China Pharm. 2010 4 471 473

69. Chai Y.-y. Wang F. Li Y.-l. Liu K. Xu H. Antioxidant Activities of Stilbenoids from Rheum emodi Wall Evid. Based Complement. Altern. Med. 2012 2012 603678 10.1155/2012/603678 PMC3488939 23193425

70. Zhang H. Yu C.-H. Jiang Y.-P. Peng C. He K. Tang J.-Y. Xin H.-L. Protective effects of polydatin from Polygonum cuspidatum against carbon tetrachloride-induced liver injury in mice PLoS ONE 2012 7 e46574 10.1371/journal.pone.0046574 23029551 PMC3461010

71. Miao Q. Wang S. Miao S. Wang J. Xie Y. Yang Q. Cardioprotective effect of polydatin against ischemia/reperfusion injury: Roles of protein kinase C and mito KATP activation Phytomedicine 2011 19 8 12 10.1016/j.phymed.2011.06.023 21795031

72. Pang N. Chen T. Deng X. Chen N. Li R. Ren M. Li Y. Luo M. Hao H. Wu J. Polydatin Prevents Methylglyoxal-Induced Apoptosis through Reducing Oxidative Stress and Improving Mitochondrial Function in Human Umbilical Vein Endothelial Cells Oxidative Med. Cell. Longev. 2017 2017 7180943 10.1155/2017/7180943 29057033 PMC5615983

73. Lan T. Zhuang L. Li S. Yang G. Xuan Y. Guo J. Polydatin attenuates hepatic stellate cell proliferation and liver fibrosis by suppressing sphingosine kinase 1 Biomed. Pharmacother. 2020 130 110586 10.1016/j.biopha.2020.110586 34321171

74. Carson D.A. Ribeiro J.M. Apoptosis and disease Lancet 1993 341 1251 1254 10.1016/0140-6736(93)91154-E 8098400

75. Lv T. Shen L. Yang L. Diao W. Yang Z. Zhang Y. Yu S. Li Y. Polydatin ameliorates dextran sulfate sodium-induced colitis by decreasing oxidative stress and apoptosis partially via Sonic hedgehog signaling pathway Int. Immunopharmacol. 2018 64 256 263 10.1016/j.intimp.2018.09.009 30218952

76. Yu H.I. Shen H.C. Chen S.H. Lim Y.P. Chuang H.H. Tai T.S. Kung F.P. Lu C.H. Hou C.Y. Lee Y.R. Autophagy Modulation in Human Thyroid Cancer Cells following Aloperine Treatment Int. J. Mol. Sci. 2019 20 5315 10.3390/ijms20215315 PMC6862658 31731481

77. Wu Z. Luan Z. Zhang X. Zou K. Ma S. Yang Z. Feng W. He M. Jiang L. Li J. Retraction Note: Chondro-protective effects of polydatin in osteoarthritis through its effect on restoring dysregulated autophagy via modulating MAPK, and PI3K/Akt signaling pathways Sci. Rep. 2020 10 11511 10.1038/s41598-020-68880-9 32661311 PMC7359308

78. Fakhri S. Abbaszadeh F. Moradi S.Z. Cao H. Khan H. Xiao J. Effects of Polyphenols on Oxidative Stress, Inflammation, and Interconnected Pathways during Spinal Cord Injury Oxidative Med. Cell. Longev. 2022 2022 8100195 10.1155/2022/8100195 PMC8759836 35035667

79. Fakhri S. Piri S. Moradi S.Z. Khan H. Phytochemicals Targeting Oxidative Stress, Interconnected Neuroinflammatory, and Neuroapoptotic Pathways Following Radiation Curr. Neuropharmacol. 2022 20 836 856 10.2174/1570159X19666210809103346 34370636 PMC9881105

80. Mattiuzzi C. Lippi G. Current cancer epidemiology J. Epidemiol. Glob. Health 2019 9 217 10.2991/jegh.k.191008.001 31854162 PMC7310786

81. Tong Y. Wang K. Sheng S. Cui J. Polydatin ameliorates chemotherapy-induced cognitive impairment (chemobrain) by inhibiting oxidative stress, inflammatory response, and apoptosis in rats Biosci. Biotechnol. Biochem. 2020 84 1201 1210 10.1080/09168451.2020.1722057 31992173

82. Schirrmacher V. From chemotherapy to biological therapy: A review of novel concepts to reduce the side effects of systemic cancer treatment Int. J. Oncol. 2019 54 407 419 30570109 10.3892/ijo.2018.4661 PMC6317661

83. Fakhri S. Abbaszadeh F. Jorjani M. Pourgholami M.H. The effects of anticancer medicinal herbs on vascular endothelial growth factor based on pharmacological aspects: A review study Nutr. Cancer 2021 73 1 15 10.1080/01635581.2019.1673451 31648565

84. Fakhri S. Khodamorady M. Naseri M. Farzaei M.H. Khan H. The ameliorating effects of anthocyanins on the cross-linked signaling pathways of cancer dysregulated metabolism Pharmacol. Res. 2020 159 104895 10.1016/j.phrs.2020.104895 32422342

85. Nouri Z. Fakhri S. Nouri K. Wallace C.E. Farzaei M.H. Bishayee A. Targeting multiple signaling pathways in cancer: The rutin therapeutic approach Cancers 2020 12 2276 10.3390/cancers12082276 32823876 PMC7463935

86. Cao W.J. Wu K. Wang C. Wan D.M. Polydatin-induced cell apoptosis and cell cycle arrest are potentiated by Janus kinase 2 inhibition in leukemia cells Mol. Med. Rep. 2016 13 3297 3302 10.3892/mmr.2016.4909 26934953

87. Quagliariello V. Berretta M. Buccolo S. Iovine M. Paccone A. Cavalcanti E. Taibi R. Montopoli M. Botti G. Maurea N. Polydatin reduces cardiotoxicity and enhances the anticancer effects of sunitinib by decreasing pro-oxidative stress, pro-inflammatory cytokines, and NLRP3 inflammasome expression Front. Oncol. 2021 11 2188 10.3389/fonc.2021.680758 34178667 PMC8226180

88. Jin Y. Zhan X. Zhang B. Chen Y. Liu C. Yu L. Polydatin exerts an antitumor effect through regulating the miR-382/PD-L1 axis in colorectal cancer Cancer Biother. Radiopharm. 2020 35 83 91 10.1089/cbr.2019.2999 31755739

89. Chen Q. Zeng Y.-N. Zhang K. Zhao Y. Wu Y.-Y. Li G. Cheng H.-Y. Zhang M. Lai F. Wang J.-B. Polydatin increases radiosensitivity by inducing apoptosis of stem cells in colorectal cancer Int. J. Biol. Sci. 2019 15 430 10.7150/ijbs.27050 30745832 PMC6367551

90. Wang C. Luo Y. Lu J. Wang Y. Sheng G. Polydatin induces apoptosis and inhibits growth of acute monocytic leukemia cells J. Biochem. Mol. Toxicol. 2016 30 200 205 10.1002/jbt.21779 26616494

91. Li H. Shi B. Li Y. Yin F. Polydatin inhibits cell proliferation and induces apoptosis in laryngeal cancer and HeLa cells via suppression of the PDGF/AKT signaling pathway J. Biochem. Mol. Toxicol. 2017 31 e21900 10.1002/jbt.21900 28266802

92. Liu H. Zhao S. Zhang Y. Wu J. Peng H. Fan J. Liao J. Reactive oxygen species-mediated endoplasmic reticulum stress and mitochondrial dysfunction contribute to polydatin-induced apoptosis in human nasopharyngeal carcinoma CNE cells J. Cell. Biochem. 2011 112 3695 3703 10.1002/jcb.23303 21815196

93. Hogg S.J. Chitcholtan K. Hassan W. Sykes P.H. Garrill A. Resveratrol, acetyl-resveratrol, and polydatin exhibit antigrowth activity against 3D cell aggregates of the SKOV-3 and OVCAR-8 ovarian cancer cell lines Obstet. Gynecol. Int. 2015 2015 279591 10.1155/2015/279591 26617640 PMC4651797

94. Zou J. Yang Y. Yang Y. Liu X. Polydatin suppresses proliferation and metastasis of non-small cell lung cancer cells by inhibiting NLRP3 inflammasome activation via NF-κB pathway Biomed. Pharmacother. 2018 108 130 136 10.1016/j.biopha.2018.09.051 30218857

95. Verma N. Tiku A.B. Polydatin-Induced Direct and Bystander Effects in A549 Lung Cancer Cell Line Nutr. Cancer 2021 74 237 249 10.1080/01635581.2020.1870705 33445975

96. Zhang Y. Zhuang Z. Meng Q. Jiao Y. Xu J. Fan S. Polydatin inhibits growth of lung cancer cells by inducing apoptosis and causing cell cycle arrest Oncol. Lett. 2014 7 295 301 10.3892/ol.2013.1696 24348867 PMC3861602

97. Chen Y. Niu J. Li L. Li Z. Jiang J. Zhu M. Dong T. Zhang J. Shi C. Xu P. Polydatin executes anticancer effects against glioblastoma multiforme by inhibiting the EGFR-AKT/ERK1/2/STAT3-SOX2/Snail signaling pathway Life Sci. 2020 258 118158 10.1016/j.lfs.2020.118158 32750435

98. Yang B. Zhao S. Polydatin regulates proliferation, apoptosis and autophagy in multiple myeloma cells through mTOR/p70s6k pathway OncoTargets Ther. 2017 10 935 10.2147/OTT.S123398 PMC5317338 28243129

99. Pan J.-H. Wang H.-B. Du X.-F. Liu J.-Y. Zhang D.-J. Polydatin induces human cervical cancer cell apoptosis via PI3K/AKT/mTOR signaling pathway Zhongguo Zhong Yao Za Zhi China J. Chin. Mater. Med. 2017 42 2345 2349 10.19540/j.cnki.cjcmm.2017.0111 28822191

100. Bai L. Ma Y. Wang X. Feng Q. Zhang Z. Wang S. Zhang H. Lu X. Xu Y. Zhao E. Polydatin Inhibits Cell Viability, Migration, and Invasion Through Suppressing the c-Myc Expression in Human Cervical Cancer Front. Cell Dev. Biol. 2021 9 587218 10.3389/fcell.2021.587218 33912552 PMC8072354

101. Chen S. Tao J. Zhong F. Jiao Y. Xu J. Shen Q. Wang H. Fan S. Zhang Y. Polydatin down-regulates the phosphorylation level of Creb and induces apoptosis in human breast cancer cell PLoS ONE 2017 12 e0176501 10.1371/journal.pone.0176501 28467448 PMC5415055

102. Zhang T. Zhu X. Wu H. Jiang K. Zhao G. Shaukat A. Deng G. Qiu C. Targeting the ROS/PI3K/AKT/HIF-1α/HK2 axis of breast cancer cells: Combined administration of Polydatin and 2-Deoxy-d-glucose J. Cell. Mol. Med. 2019 23 3711 3723 10.1111/jcmm.14276 30920152 PMC6484306

103. Zhao W. Chen Z. Guan M. Polydatin enhances the chemosensitivity of osteosarcoma cells to paclitaxel J. Cell. Biochem. 2019 120 17481 17490 10.1002/jcb.29012 31106479

104. Jiang C.-q. Ma L.-l. Lv Z.-d. Feng F. Chen Z. Liu Z.-D. Polydatin induces apoptosis and autophagy via STAT3 signaling in human osteosarcoma MG-63 cells J. Nat. Med. 2020 74 533 544 10.1007/s11418-020-01399-5 32222939

105. Xu G. Kuang G. Jiang W. Jiang R. Jiang D. Polydatin promotes apoptosis through upregulation the ratio of Bax/Bcl-2 and inhibits proliferation by attenuating the β-catenin signaling in human osteosarcoma cells Am. J. Transl. Res. 2016 8 922 27158379 PMC4846936

106. Hu T. Fei Z. Su H. Xie R. Chen L. Polydatin inhibits proliferation and promotes apoptosis of doxorubicin-resistant osteosarcoma through LncRNA TUG1 mediated suppression of Akt signaling Toxicol. Appl. Pharmacol. 2019 371 55 62 10.1016/j.taap.2019.04.005 30974157

107. Jiao Y. Wu Y. Du D. Polydatin inhibits cell proliferation, invasion and migration, and induces cell apoptosis in hepatocellular carcinoma Braz. J. Med. Biol. Res. 2018 51 e6867 10.1590/1414-431x20176867 29513792 PMC5856444

108. Jiang J. Chen Y. Dong T. Yue M. Zhang Y. An T. Zhang J. Liu P. Yang X. Polydatin inhibits hepatocellular carcinoma via the AKT/STAT3-FOXO1 signaling pathway Corrigendum in /10.3892/ol.2019.10856 Oncol. Lett. 2019 17 4505 4513 30944640 10.3892/ol.2019.10123 PMC6444395

109. Bang T.-H. Park B.-S. Kang H.-M. Kim J.-H. Kim I.-R. Polydatin, a Glycoside of Resveratrol, Induces Apoptosis and Inhibits Metastasis Oral Squamous Cell Carcinoma Cells In Vitro Pharmaceuticals 2021 14 902 10.3390/ph14090902 34577602 PMC8468100

110. Ince S. Acaroz D.A. Neuwirth O. Demirel H.H. Denk B. Kucukkurt I. Turkmen R. Protective effect of polydatin, a natural precursor of resveratrol, against cisplatin-induced toxicity in rats Food Chem. Toxicol. 2014 72 147 153 10.1016/j.fct.2014.07.022 25051394

111. Xu Z. Feng W. Shen Q. Yu N. Yu K. Wang S. Chen Z. Shioda S. Guo Y. Rhizoma Coptidis and Berberine as a Natural Drug to Combat Aging and Aging-Related Diseases via Anti-Oxidation and AMPK Activation Aging Dis. 2017 8 760 777 10.14336/AD.2016.0620 29344415 PMC5758350

112. Fakhri S. Abbaszadeh F. Dargahi L. Jorjani M. Astaxanthin: A mechanistic review on its biological activities and health benefits Pharmacol. Res. 2018 136 1 20 10.1016/j.phrs.2018.08.012 30121358

113. Goldstein L. Brown S. The low-density lipoprotein pathway and its relation to atherosclerosis Annu. Rev. Biochem. 1977 46 897 930 10.1146/annurev.bi.46.070177.004341 197883

114. Chen G. Liu G. Cao D. Jin M. Guo D. Yuan X. Polydatin protects against acute myocardial infarction-induced cardiac damage by activation of Nrf2/HO-1 signaling J. Nat. Med. 2019 73 85 92 10.1007/s11418-018-1241-7 30191382

115. Ma Y. Gong X. Mo Y. Wu S. Polydatin inhibits the oxidative stress-induced proliferation of vascular smooth muscle cells by activating the eNOS/SIRT1 pathway Int. J. Mol. Med. 2016 37 1652 1660 10.3892/ijmm.2016.2554 27081912

116. Miao Q. Shi X.-P. Ye M.-X. Zhang J. Miao S. Wang S.-W. Li B. Jiang X.-X. Zhang S. Hu N. Polydatin attenuates hypoxic pulmonary hypertension and reverses remodeling through protein kinase C mechanisms Int. J. Mol. Sci. 2012 13 7776 7787 10.3390/ijms13067776 22837726 PMC3397558

117. Gugliandolo E. Fusco R. Biundo F. D’Amico R. Benedetto F. Di Paola R. Cuzzocrea S. Palmitoylethanolamide and Polydatin combination reduces inflammation and oxidative stress in vascular injury Pharmacol. Res. 2017 123 83 92 10.1016/j.phrs.2017.06.014 28676456

118. Yuan X. Chen G. Guo D. Xu L. Gu Y. Polydatin alleviates septic myocardial injury by promoting SIRT6-mediated autophagy Inflammation 2020 43 785 795 10.1007/s10753-019-01153-4 32394287

119. Gao J.P. Chen C.X. Gu W.L. Wu Q. Wang Y. Lü J. Effects of polydatin on attenuating ventricular remodeling in isoproterenol-induced mouse and pressure-overload rat models Fitoterapia 2010 81 953 960 10.1016/j.fitote.2010.06.023 20603198

120. Gao Y. Gao J. Chen C. Wang H. Guo J. Wu R. Cardioprotective effect of polydatin on ventricular remodeling after myocardial infarction in coronary artery ligation rats Planta Med. 2015 81 568 577 10.1055/s-0035-1545907 25905591

121. Zhang Q. Tan Y. Zhang N. Yao F. Polydatin prevents angiotensin II-induced cardiac hypertrophy and myocardial superoxide generation Exp. Biol. Med. 2015 240 1352 1361 10.1177/1535370214561958 PMC4935258 25488910

122. Zhang M. Wang S. Cheng Z. Xiong Z. Lv J. Yang Z. Li T. Jiang S. Gu J. Sun D. Polydatin ameliorates diabetic cardiomyopathy via Sirt3 activation Biochem. Biophys. Res. Commun. 2017 493 1280 1287 10.1016/j.bbrc.2017.09.151 28965951

123. Pessina A. Di Vincenzo M. Maradonna F. Marchegiani F. Olivieri F. Randazzo B. Gioacchini G. Carnevali O. Polydatin Beneficial Effects in Zebrafish Larvae Undergoing Multiple Stress Types Int. J. Environ. Res. Public Health 2021 18 1116 10.3390/ijerph18031116 33513921 PMC7908490

124. Huang B. Xue L. Wu Y. Jiang Q. Effect and mechanism of polydatin on diabetic myocardial hypertrophy in mice Zhongguo Zhong Yao Za Zhi China J. Chin. Mater. Med. 2015 40 4256 4261 27071267

125. Du J. Sun L.-N. Xing W.-W. Huang B.-K. Jia M. Wu J.-Z. Zhang H. Qin L.-P. Lipid-lowering effects of polydatin from Polygonum cuspidatum in hyperlipidemic hamsters Phytomedicine 2009 16 652 658 10.1016/j.phymed.2008.10.001 19106037

126. Xing W.-W. Wu J.-Z. Jia M. Du J. Zhang H. Qin L.-P. Effects of polydatin from Polygonum cuspidatum on lipid profile in hyperlipidemic rabbits Biomed. Pharmacother. 2009 63 457 462 10.1016/j.biopha.2008.06.035 18657948

127. Peng Y. Xu J. Zeng Y. Chen L. Le Xu X. Polydatin attenuates atherosclerosis in apolipoprotein E-deficient mice: Role of reverse cholesterol transport Phytomedicine 2019 62 152935 10.1016/j.phymed.2019.152935 31085374

128. Huang Z. Tian G. Cheng S. Zhao D. Zhang Y. Jia Y. Zhou F. Polydatin attenuates atherosclerosis in ApoE−/− mice through PBEF mediated reduction of cholesterol deposition Am. J. Chin. Med. 2018 46 1841 1859 10.1142/S0192415X18500921 30537866

129. Xiong Q. Yan Z. Liang J. Yuan J. Chen X. Zhou L. Hu Y. Wu J. Jing Y. Zhang Q. Polydatin alleviates high-fat diet induced atherosclerosis in apolipoprotein E-deficient mice by autophagic restoration Phytomedicine 2021 81 153301 10.1016/j.phymed.2020.153301 33243482

130. Zheng L. Wu J. Mo J. Guo L. Wu X. Bao Y. Polydatin inhibits adipose tissue inflammation and ameliorates lipid metabolism in high-fat-fed mice BioMed Res. Int. 2019 2019 7196535 10.1155/2019/7196535 31828124 PMC6885157

131. Wu M. Liu M. Guo G. Zhang W. Liu L. Polydatin inhibits formation of macrophage-derived foam cells Evid. Based Complement. Altern. Med. 2015 2015 729017 10.1155/2015/729017 PMC4629028 26557864

132. Zhang L.-P. Ma H.-J. Bu H.-M. Wang M.-L. Li Q. Qi Z. Zhang Y. Polydatin attenuates ischemia/reperfusion-induced apoptosis in myocardium of the rat Sheng Li Xue Bao 2009 61 367 372 19701589

133. Zhang L.-P. Yang C.-Y. Wang Y.-P. Cui F. Zhang Y. Protective effect of polydatin against ischemia/reperfusion injury in rat heart Sheng Li Xue Bao [Acta Physiol. Sin.] 2008 60 161 168 18425301

134. Ling Y. Chen G. Deng Y. Tang H. Ling L. Zhou X. Song X. Yang P. Liu Y. Li Z. Polydatin post-treatment alleviates myocardial ischaemia/reperfusion injury by promoting autophagic flux Clin. Sci. 2016 130 1641 1653 10.1042/CS20160082 27340138

135. Jiang X. Liu W. Deng J. Lan L. Xue X. Zhang C. Cai G. Luo X. Liu J. Polydatin protects cardiac function against burn injury by inhibiting sarcoplasmic reticulum Ca2+ leak by reducing oxidative modification of ryanodine receptors Free Radic. Biol. Med. 2013 60 292 299 10.1016/j.freeradbiomed.2013.02.030 23499836

136. Yousef A.I. Shawki H.H. El-Shahawy A.A. Abd El-Twab S.M. Abdel-Moneim A. Oishi H. Polydatin mitigates pancreatic β-cell damage through its antioxidant activity Biomed. Pharmacother. 2021 133 111027 10.1016/j.biopha.2020.111027 33249283

137. Zhang Q. Tan Y. Zhang N. Yao F. Polydatin supplementation ameliorates diet-induced development of insulin resistance and hepatic steatosis in rats Mol. Med. Rep. 2015 11 603 610 10.3892/mmr.2014.2708 25333896

138. Xie X. Peng J. Huang K. Huang J. Shen X. Liu P. Huang H. Polydatin ameliorates experimental diabetes-induced fibronectin through inhibiting the activation of NF-κB signaling pathway in rat glomerular mesangial cells Mol. Cell. Endocrinol. 2012 362 183 193 10.1016/j.mce.2012.06.008 22732364

139. Chen C. Huang K. Hao J. Huang J. Yang Z. Xiong F. Liu P. Huang H. Polydatin attenuates AGEs-induced upregulation of fibronectin and ICAM-1 in rat glomerular mesangial cells and db/db diabetic mice kidneys by inhibiting the activation of the SphK1-S1P signaling pathway Mol. Cell. Endocrinol. 2016 427 45 56 10.1016/j.mce.2016.03.003 26948947

140. Wang Y. Ye J. Li J. Chen C. Huang J. Liu P. Huang H. Polydatin ameliorates lipid and glucose metabolism in type 2 diabetes mellitus by downregulating proprotein convertase subtilisin/kexin type 9 (PCSK9) Cardiovasc. Diabetol. 2016 15 1 13 10.1186/s12933-015-0325-x 26833058 PMC4736185

141. Hao J. Chen C. Huang K. Huang J. Li J. Liu P. Huang H. Polydatin improves glucose and lipid metabolism in experimental diabetes through activating the Akt signaling pathway Eur. J. Pharmacol. 2014 745 152 165 10.1016/j.ejphar.2014.09.047 25310908

142. Wu Y. Xue L. Du W. Huang B. Tang C. Liu C. Qiu H. Jiang Q. Polydatin restores endothelium-dependent relaxation in rat aorta rings impaired by high glucose: A Novel insight into the PPARβ-NO signaling pathway PLoS ONE 2015 10 e0126249 10.1371/journal.pone.0126249 25941823 PMC4420467

143. Wang D. Zhou Z. Yuan L. Polydatin reverses oxidation low lipoprotein (oxLDL)-induced apoptosis of human umbilical vein endothelial cells via regulating the miR-26a-5p/BID axis Eur. J. Histochem. 2022 66 10.4081/ejh.2022.3505 36128773 PMC9528534

144. Bheereddy P. Yerra V.G. Kalvala A.K. Sherkhane B. Kumar A. SIRT1 activation by polydatin alleviates oxidative damage and elevates mitochondrial biogenesis in experimental diabetic neuropathy Cell. Mol. Neurobiol. 2020 41 1563 1577 10.1007/s10571-020-00923-1 32683581 PMC11448605

145. Liu B. Li S. Sui X. Guo L. Liu X. Li H. Gao L. Cai S. Li Y. Wang T. Root extract of Polygonum cuspidatum Siebold & Zucc. ameliorates DSS-induced ulcerative colitis by affecting NF-kappaB signaling pathway in a mouse model via synergistic effects of polydatin, resveratrol, and emodin Front. Pharmacol. 2018 9 347 29695964 10.3389/fphar.2018.00347 PMC5904535

146. Yao J. Wang J.-Y. Liu L. Zeng W.-S. Li Y.-X. Xun A.-Y. Zhao L. Jia C.-H. Feng J.-L. Wei X.-X. Polydatin ameliorates DSS-induced colitis in mice through inhibition of nuclear factor-kappaB activation Planta Med. 2011 77 421 427 10.1055/s-0030-1250462 20979017

147. Zeng Z. Yang Y. Dai X. Xu S. Li T. Zhang Q. Zhao K.-s. Chen Z. Polydatin ameliorates injury to the small intestine induced by hemorrhagic shock via SIRT3 activation-mediated mitochondrial protection Expert Opin. Ther. Targets 2016 20 645 652 10.1080/14728222.2016.1177023 27067422

148. Li P. Wang X. Zhao M. Song R. Zhao K.-s. Polydatin protects hepatocytes against mitochondrial injury in acute severe hemorrhagic shock via SIRT1-SOD2 pathway Expert Opin. Ther. Targets 2015 19 997 1010 10.1517/14728222.2015.1054806 26073907

149. Zhao G. Jiang K. Wu H. Qiu C. Deng G. Peng X. Polydatin reduces Staphylococcus aureus lipoteichoic acid-induced injury by attenuating reactive oxygen species generation and TLR 2-NF κB signalling J. Cell. Mol. Med. 2017 21 2796 2808 10.1111/jcmm.13194 28524642 PMC5661256

150. Qiu Y. Pan X. Hu Y. Polydatin ameliorates pulmonary fibrosis by suppressing inflammation and the epithelial mesenchymal transition via inhibiting the TGF-β/Smad signaling pathway RSC Adv. 2019 9 8104 8112 10.1039/C8RA08659A 35521205 PMC9061874

151. Li X.-h. Gong X. Zhang L. Jiang R. Li H.-z. Wu M.-j. Wan J.-y. Protective effects of polydatin on septic lung injury in mice via upregulation of HO-1 Mediat. Inflamm. 2013 2013 354087 10.1155/2013/354087 PMC3570923 23431240

152. Ricordi C. Pacifici F. Lanzoni G. Palamara A.T. Garaci E. Della-Morte D. Dietary and protective factors to halt or mitigate progression of autoimmunity, COVID-19 and its associated metabolic diseases Int. J. Mol. Sci. 2021 22 3134 10.3390/ijms22063134 33808574 PMC8003583

153. Lai Y. Zhou C. Huang P. Dong Z. Mo C. Xie L. Lin H. Zhou Z. Deng G. Liu Y. Polydatin alleviated alcoholic liver injury in zebrafish larvae through ameliorating lipid metabolism and oxidative stress J. Pharmacol. Sci. 2018 138 46 53 10.1016/j.jphs.2018.08.007 30245287

154. Chen X. Chan H. Zhang L. Liu X. Ho I.H. Zhang X. Ho J. Hu W. Tian Y. Kou S. The phytochemical polydatin ameliorates non-alcoholic steatohepatitis by restoring lysosomal function and autophagic flux J. Cell. Mol. Med. 2019 23 4290 4300 10.1111/jcmm.14320 30973211 PMC6533566

155. Luo J.-L. Chen S. Wang L. Zhao X.-H. Piao C.-L. Pharmacological effects of polydatin in the treatment of metabolic diseases: A review Phytomedicine 2022 154161 10.1016/j.phymed.2022.154161 35636169

156. Zhang J. Tan Y. Yao F. Zhang Q. Polydatin alleviates non-alcoholic fatty liver disease in rats by inhibiting the expression of TNF-α and SREBP-1c Mol. Med. Rep. 2012 6 815 820 10.3892/mmr.2012.1015 22858825

157. Li R. Li J. Huang Y. Li H. Yan S. Lin J. Chen Y. Wu L. Liu B. Wang G. Polydatin attenuates diet-induced nonalcoholic steatohepatitis and fibrosis in mice Int. J. Biol. Sci. 2018 14 1411 10.7150/ijbs.26086 30262993 PMC6158724

158. Zhang H. Chen Y. Pei Z. Gao H. Shi W. Sun M. Xu Q. Zhao J. Meng W. Xiao K. Protective effects of polydatin against sulfur mustard-induced hepatic injury Toxicol. Appl. Pharmacol. 2019 367 1 11 10.1016/j.taap.2019.01.013 30677423

159. Zhao X. Li R. Liu Y. Zhang X. Zhang M. Zeng Z. Wu L. Gao X. Lan T. Wang Y. Polydatin protects against carbon tetrachloride-induced liver fibrosis in mice Arch. Biochem. Biophys. 2017 629 1 7 10.1016/j.abb.2017.06.017 28666738

160. Huang Z.-S. Wang Z.-W. Liu M.-P. Zhong S.-Q. Li Q.-M. Rong X.-L. Protective effects of polydatin against CCl4-induced injury to primarily cultured rat hepatocytes World J. Gastroenterol. 1999 5 41 10.3748/wjg.v5.i1.41 11819383 PMC4688498

161. Zeng Z. Chen Z. Li T. Zhang J. Gao Y. Xu S. Cai S. Zhao K.S. Polydatin: A new therapeutic agent against multiorgan dysfunction J. Surg. Res. 2015 198 192 199 10.1016/j.jss.2015.05.041 26095424

162. Dumurgier J. Tzourio C. Epidemiology of neurological diseases in older adults Rev. Neurol. 2020 176 642 648 10.1016/j.neurol.2020.01.356 32145981

163. Chen Y. Zhang D.-q. Liao Z. Wang B. Gong S. Wang C. Zhang M.-z. Wang G.-h. Cai H. Liao F.-F. Anti-oxidant polydatin (piceid) protects against substantia nigral motor degeneration in multiple rodent models of Parkinson’s disease Mol. Neurodegener. 2015 10 1 14 10.1186/1750-1326-10-4 26013581 PMC4506434

164. Zhao X. Qin J. Li H. Feng X. Lv Y. Yang J. Effect of Polydatin on Neurological Function and the Nrf2 Pathway during Intracerebral Hemorrhage J. Mol. Neurosci. 2020 70 1332 1337 10.1007/s12031-020-01546-3 32406041

165. Wang X. Song R. Chen Y. Zhao M. Zhao K.-s. Polydatin–a new mitochondria protector for acute severe hemorrhagic shock treatment Expert Opin. Investig. Drugs 2013 22 169 179 10.1517/13543784.2013.748033 23241098

166. Wang X. Song R. Bian H.N. Brunk U.T. Zhao M. Zhao K.-s. Polydatin, a natural polyphenol, protects arterial smooth muscle cells against mitochondrial dysfunction and lysosomal destabilization following hemorrhagic shock Am. J. Physiol. Regul. Integr. Comp. Physiol. 2012 302 R805 R814 10.1152/ajpregu.00350.2011 22277937

167. Li R.-P. Wang Z.-Z. Sun M.-X. Hou X.-L. Sun Y. Deng Z.-F. Xiao K. Polydatin protects learning and memory impairments in a rat model of vascular dementia Phytomedicine 2012 19 677 681 10.1016/j.phymed.2012.03.002 22483554

168. Huang L. He S. Cai Q. Li F. Wang S. Tao K. Xi Y. Qin H. Gao G. Feng D. Polydatin alleviates traumatic brain injury: Role of inhibiting ferroptosis Biochem. Biophys. Res. Commun. 2021 556 149 155 10.1016/j.bbrc.2021.03.108 33839410

169. Huang B. Liu J. Meng T. Li Y. He D. Ran X. Chen G. Guo W. Kan X. Fu S. Polydatin prevents lipopolysaccharide (LPS)-induced Parkinson’s disease via regulation of the AKT/GSK3β-Nrf2/NF-κB signaling axis Front. Immunol. 2018 9 2527 10.3389/fimmu.2018.02527 30455692 PMC6230593

170. Bai H. Ding Y. Li X. Kong D. Xin C. Yang X. Zhang C. Rong Z. Yao C. Lu S. Polydatin protects SH-SY5Y in models of Parkinson’s disease by promoting Atg5-mediated but parkin-independent autophagy Neurochem. Int. 2020 134 104671 10.1016/j.neuint.2020.104671 31926197

171. Zhang S. Wang S. Shi X. Feng X. Polydatin alleviates parkinsonism in MPTP-model mice by enhancing glycolysis in dopaminergic neurons Neurochem. Int. 2020 139 104815 10.1016/j.neuint.2020.104815 32758587

172. Schimith L.E. Dos Santos M.G. Arbo B.D. André-Miral C. Muccillo-Baisch A.L. Hort M.A. Polydatin as a therapeutic alternative for central nervous system disorders: A systematic review of animal studies Phytother. Res. PTR 2022 36 2852 2877 10.1002/ptr.7497 35614539

173. Gao Y. Chen T. Lei X. Li Y. Dai X. Cao Y. Ding Q. Lei X. Li T. Lin X. Neuroprotective effects of polydatin against mitochondrial-dependent apoptosis in the rat cerebral cortex following ischemia/reperfusion injury Mol. Med. Rep. 2016 14 5481 5488 10.3892/mmr.2016.5936 27840959 PMC5355690

174. Bonucci M. Raggi R. Vacca R.A. Polydatin and its potential protective effect on COVID-19 Clin. Nutr. 2020 39 3850 3851 10.1016/j.clnu.2020.09.052 33097304 PMC7543899

175. Cheng Y. Zhang H.-T. Sun L. Guo S. Ouyang S. Zhang Y. Xu J. Involvement of cell adhesion molecules in polydatin protection of brain tissues from ischemia–reperfusion injury Brain Res. 2006 1110 193 200 10.1016/j.brainres.2006.06.065 16870162

176. Chen F. Fang X. Zhang H. Effect of polydatin on expression of p53 and Notch1 in brain tissue of ischemic cerebrovascular disease J. Biol. Regul. Homeost. Agents 2018 32 133 138 29504377

177. Xu C.-Y. Li S. Hao W. Zhang R.-L. Effect of polydatin on expression of CDK5 in the prefrontal cortex of rats with chronic alcoholism Zhongguo Ying Yong Sheng Li Xue Za Zhi Chin. J. Appl. Physiol. 2012 28 158 188 22737920

178. Sun J. Qu Y. He H. Fan X. Qin Y. Mao W. Xu L. Protective effect of polydatin on learning and memory impairments in neonatal rats with hypoxic-ischemic brain injury by up-regulating brain-derived neurotrophic factor Mol. Med. Rep. 2014 10 3047 3051 10.3892/mmr.2014.2577 25241777

179. Chen M. Hou Y. Lin D. Polydatin protects bone marrow stem cells against oxidative injury: Involvement of Nrf 2/ARE pathways Stem Cells Int. 2016 2016 9394150 10.1155/2016/9394150 27022401 PMC4684894

180. Zhan J. Li X. Luo D. Yan W. Hou Y. Hou Y. Chen S. Luan J. Zhang Q. Lin D. Polydatin Attenuates OGD/R-Induced Neuronal Injury and Spinal Cord Ischemia/Reperfusion Injury by Protecting Mitochondrial Function via Nrf2/ARE Signaling Pathway Oxidative Med. Cell. Longev. 2021 2021 6687212 10.1155/2021/6687212 PMC8081604 33995825

181. Zhan J. Li X. Luo D. Hou Y. Hou Y. Chen S. Xiao Z. Luan J. Lin D. Polydatin promotes the neuronal differentiation of bone marrow mesenchymal stem cells in vitro and in vivo: Involvement of Nrf2 signalling pathway J. Cell. Mol. Med. 2020 24 5317 5329 10.1111/jcmm.15187 32299154 PMC7205798

182. Liu H. Zhang G. Bie X. Liu M. Yang J. Wan H. Zhang Y. Effect of polydatin on dynamic changes of excitatory amino acids in cerebrospinal fluid of cerebral hemorrhage rats Zhongguo Zhong Yao Za Zhi China J. Chin. Mater. Med. 2010 35 3038 3042 21355278

183. Maoka T. Yasui H. Ohmori A. Tokuda H. Suzuki N. Osawa A. Shindo K. Ishibashi T. Anti-oxidative, anti-tumor-promoting, and anti-carcinogenic activities of adonirubin and adonixanthin J. Oleo Sci. 2012 62 181 186 10.5650/jos.62.181 23470446

184. Wiwanitkit V. Polydatin and COVID-19 Clin. Nutr. 2021 10.1016/j.clnu.2021.03.027 33933296 PMC8006510

185. Chen Z.-q. Sun X.-h. Li X.-j. Xu Z.-c. Yang Y. Lin Z.-y. Xiao H.-m. Zhang M. Quan S.-j. Huang H.-q. Polydatin attenuates renal fibrosis in diabetic mice through regulating the Cx32-Nox4 signaling pathway Acta Pharmacol. Sin. 2020 41 1587 1596 10.1038/s41401-020-0475-6 32724174 PMC7921128

186. Gu L. Liu J. Xu D. Lu Y. Polydatin prevents LPS-induced acute kidney injury through inhibiting inflammatory and oxidative responses Microb. Pathog. 2019 137 103688 10.1016/j.micpath.2019.103688 31445125

187. Gao Y. Dai X. Li Y. Li G. Lin X. Ai C. Cao Y. Li T. Lin B. Role of Parkin-mediated mitophagy in the protective effect of polydatin in sepsis-induced acute kidney injury J. Transl. Med. 2020 18 114 10.1186/s12967-020-02283-2 32131850 PMC7055075

188. Han B. Gong M. Li Z. Qiu Y. Zou Z. NMR-based metabonomic study reveals intervention effects of polydatin on potassium oxonate-induced hyperuricemia in rats Oxidative Med. Cell. Longev. 2020 2020 6943860 10.1155/2020/6943860 PMC7362289 32695259

189. Sun Z. Wang X. Xu Z. SIRT1 provides new pharmacological targets for polydatin through its role as a metabolic sensor Biomed. Pharmacother. 2021 139 111549 10.1016/j.biopha.2021.111549 33901876

190. Gao Y. Zeng Z. Li T. Xu S. Wang X. Chen Z. Lin C. Polydatin inhibits mitochondrial dysfunction in the renal tubular epithelial cells of a rat model of sepsis-induced acute kidney injury Anesth. Analg. 2015 121 1251 1260 10.1213/ANE.0000000000000977 26484460

191. Zeng Z. Chen Z. Xu S. Zhang Q. Wang X. Gao Y. Zhao K.-s. Polydatin protecting kidneys against hemorrhagic shock-induced mitochondrial dysfunction via SIRT1 activation and p53 deacetylation Oxidative Med. Cell. Longev. 2016 2016 1737185 10.1155/2016/1737185 PMC4783550 27057271

192. Gu T.-T. Zhang D.-M. Wan Z.-Y. Li T.-S. Jiao R.-Q. Chen T.-Y. Zhao X.-J. Kong L.-D. Polydatin enhances glomerular podocyte autophagy homeostasis by improving Nrf2-dependent antioxidant capacity in fructose-fed rats Mol. Cell. Endocrinol. 2021 520 111079 10.1016/j.mce.2020.111079 33189863

193. Cao K. Lei X. Liu H. Zhao H. Guo J. Chen Y. Xu Y. Cheng Y. Liu C. Cui J. Polydatin alleviated radiation-induced lung injury through activation of Sirt3 and inhibition of epithelial–mesenchymal transition J. Cell. Mol. Med. 2017 21 3264 3276 10.1111/jcmm.13230 28609013 PMC5706589

194. Hanna D.A. Khalaf M.M. Abo-Saif A.A. Polydatin protects against ovalbumin-induced bronchial asthma in rats; involvement of urocortin and surfactant-D expression Immunopharmacol. Immunotoxicol. 2019 41 403 412 10.1080/08923973.2018.1536985 30422021

195. Zeng H. Wang Y. Gu Y. Wang J. Zhang H. Gao H. Jin Q. Zhao L. Polydatin attenuates reactive oxygen species-induced airway remodeling by promoting Nrf2-mediated antioxidant signaling in asthma mouse model Life Sci. 2019 218 25 30 10.1016/j.lfs.2018.08.013 30092299

196. Liu Y.-L. Chen B.-Y. Nie J. Zhao G.-H. Zhuo J.-Y. Yuan J. Li Y.-C. Wang L.-L. Chen Z.-W. Polydatin prevents bleomycin-induced pulmonary fibrosis by inhibiting the TGF-β/Smad/ERK signaling pathway Exp. Ther. Med. 2020 20 1 10.3892/etm.2020.9190 32952652 PMC7485305

197. Jin X.-F. Xu Z.-J. Wang W.-T. Xu Y.-X. Zhang X.-L. The regulative effects of polydatin on toll-like receptor 4 signal transduction pathway in lung ischemia/reperfusion injury in rabbits Zhongguo Ying Yong Sheng Li Xue Za Zhi Chin. J. Appl. Physiol. 2009 25 41 44 21186612

198. Wang F.-Y. Xu Z.-J. Zhang X.-L. Wang W.-T. Ha M.-L. Wang Y. Protective effects of polydatin against lung ischemia/reperfusion injury and the initial exploration for its mechanism Zhongguo Ying Yong Sheng Li Xue Za Zhi Chin. J. Appl. Physiol. 2008 24 62 65 21141560

199. Li T. Liu Y. Li G. Wang X. Zeng Z. Cai S. Li F. Chen Z. Polydatin attenuates ipopolysaccharide-induced acute lung injury in rats Int. J. Clin. Exp. Pathol. 2014 7 8401 25674204 PMC4314025

200. Li T. Cai S. Zeng Z. Zhang J. Gao Y. Wang X. Chen Z. Protective effect of polydatin against burn-induced lung injury in rats Respir. Care 2014 59 1412 1421 10.4187/respcare.02831 24825914

201. Matacchione G. Gurău F. Silvestrini A. Tiboni M. Mancini L. Valli D. Rippo M.R. Recchioni R. Marcheselli F. Carnevali O. Anti-SASP and anti-inflammatory activity of resveratrol, curcumin and β-caryophyllene association on human endothelial and monocytic cells Biogerontology 2021 22 297 313 10.1007/s10522-021-09915-0 33704623 PMC8084815

202. Jiang Q. Yi M. Guo Q. Wang C. Wang H. Meng S. Liu C. Fu Y. Ji H. Chen T. Protective effects of polydatin on lipopolysaccharide-induced acute lung injury through TLR4-MyD88-NF-κB pathway Int. Immunopharmacol. 2015 29 370 376 10.1016/j.intimp.2015.10.027 26507165

203. Shu S. Wang X. Ling Z. Lu Z. Effect of polydatin on phospholipase A2 in lung tissues in rats with endotoxic shock Chin. J. Traumatol. 2004 7 239 243 15294104

204. Zhang Y. Chen L. Liang B. Effects of polydatin on bleomycin-induced pulmonary fibrosis in rats Zhongguo Zhong Yao Za Zhi China J. Chin. Mater. Med. 2011 36 3528 3534 22368872

205. Fu Y. Yan M. Xie C. Hu J. Zeng X. Hu Q. Polydatin relieves paraquat-induced human MRC-5 fibroblast injury through inhibiting the activation of the NLRP3 inflammasome Ann. Transl. Med. 2020 8 765 10.21037/atm-20-4570 32647690 PMC7333108

206. Li B. Wang X.L. Effective treatment of polydatin weakens the symptoms of collagen-induced arthritis in mice through its anti-oxidative and anti-inflammatory effects and the activation of MMP-9 Mol. Med. Rep. 2016 14 5357 5362 10.3892/mmr.2016.5903 27840936

207. Liao P. He Y. Yang F. Luo G. Zhuang J. Zhai Z. Zhuang L. Lin Z. Zheng J. Sun E. Polydatin effectively attenuates disease activity in lupus-prone mouse models by blocking ROS-mediated NET formation Arthritis Res. Ther. 2018 20 1 11 10.1186/s13075-018-1749-y 30419963 PMC6235205

208. Yang F. Luo X. Luo G. Zhai Z. Zhuang J. He J. Han J. Zhang Y. Zhuang L. Sun E. Inhibition of NET formation by polydatin protects against collagen-induced arthritis Int. Immunopharmacol. 2019 77 105919 10.1016/j.intimp.2019.105919 31655341

209. Zhou Q.L. Qin R.Z. Yang Y.X. Huang K.B. Yang X.W. Polydatin possesses notable anti-osteoporotic activity via regulation of OPG, RANKL and β-catenin Mol. Med. Rep. 2016 14 1865 1869 10.3892/mmr.2016.5432 27357904

210. Shen Y.-S. Chen X.-J. Wuri S.-N. Yang F. Pang F.-X. Xu L.-L. He W. Wei Q.-S. Polydatin improves osteogenic differentiation of human bone mesenchymal stem cells by stimulating TAZ expression via BMP2-Wnt/β-catenin signaling pathway Stem Cell Res. Ther. 2020 11 204 10.1186/s13287-020-01705-8 32460844 PMC7251742

211. Di Benedetto A. Posa F. De Maria S. Ravagnan G. Ballini A. Porro C. Trotta T. Grano M. Muzio L.L. Mori G. Polydatin, natural precursor of resveratrol, promotes osteogenic differentiation of mesenchymal stem cells Int. J. Med. Sci. 2018 15 944 10.7150/ijms.24111 30008608 PMC6036093

212. Chen Z. Wei Q. Hong G. Chen D. Liang J. He W. Chen M.H. Polydatin induces bone marrow stromal cells migration by activation of ERK1/2 Biomed. Pharmacother. 2016 82 49 53 10.1016/j.biopha.2016.04.059 27470338

213. Ma C. Wen B. Zhang Q. Shao P. Gu W. Qu K. Shi Y. Wang B. Polydatin regulates the apoptosis and autophagy of fibroblasts obtained from patients with ankylosing spondylitis Biol. Pharm. Bull. 2018 42 50 56 10.1248/bpb.b18-00522 30333377

214. Wang J. Huang C. Lin Z. Pan X. Chen J. Zheng G. Tian N. Yan Y. Zhang Z. Hu J. Polydatin suppresses nucleus pulposus cell senescence, promotes matrix homeostasis and attenuates intervertebral disc degeneration in rats J. Cell. Mol. Med. 2018 22 5720 5731 10.1111/jcmm.13848 30358118 PMC6201341

215. Indraccolo U. Indraccolo S.R. Mignini F. Micronized palmitoylethanolamide/trans-polydatin treatment of endometriosis-related pain: A meta-analysis Ann. Dell’istituto Super. Sanita 2017 53 125 134 10.4415/ANN_17_02_08 28617258

216. Indraccolo U. Barbieri F. Effect of palmitoylethanolamide–polydatin combination on chronic pelvic pain associated with endometriosis: Preliminary observations Eur. J. Obstet. Gynecol. Reprod. Biol. 2010 150 76 79 10.1016/j.ejogrb.2010.01.008 20176435

217. Di Paola R. Fusco R. Gugliandolo E. Crupi R. Evangelista M. Granese R. Cuzzocrea S. Co-micronized palmitoylethanolamide/polydatin treatment causes endometriotic lesion regression in a rodent model of surgically induced endometriosis Front. Pharmacol. 2016 7 382 10.3389/fphar.2016.00382 27790149 PMC5063853

218. Loi E.S. Pontis A. Cofelice V. Pirarba S. Fais M.F. Daniilidis A. Melis I. Paoletti A.M. Angioni S. Effect of ultramicronized-palmitoylethanolamide and co-micronized palmitoylethanolamide/polydatin on chronic pelvic pain and quality of life in endometriosis patients: An open-label pilot study Int. J. Women’s Health 2019 11 443 31496832 10.2147/IJWH.S204275 PMC6697671

219. Sheng C. Yu Y.-h. Zhao K.-s. Qin W. Wang C.-h. Hypotensive resuscitation combined with polydatin improve microcirculation and survival in a rabbit model of uncontrolled hemorrhagic shock in pregnancy J. Surg. Res. 2011 168 103 110 10.1016/j.jss.2009.09.007 20056244

220. Ou C. Song H. Zhou Y. Peng J. Peng Q. Exploring the Molecular Mechanism of Qing Guang An Granule in Treating Glaucoma Using Network Pharmacology and Molecular Docking Evid. Based Complement. Altern. Med. Ecam 2020 2020 8824150 10.1155/2020/8824150 PMC7704137 33299458

221. Ye J. Piao H. Jiang J. Jin G. Zheng M. Yang J. Jin X. Sun T. Choi Y.H. Li L. Polydatin inhibits mast cell-mediated allergic inflammation by targeting PI3K/Akt, MAPK, NF-κB and Nrf2/HO-1 pathways Sci. Rep. 2017 7 11895 10.1038/s41598-017-12252-3 28928455 PMC5605538

222. Yuan M. Li J. Lv J. Mo X. Yang C. Chen X. Liu Z. Liu J. Polydatin (PD) inhibits IgE-mediated passive cutaneous anaphylaxis in mice by stabilizing mast cells through modulating Ca2+ mobilization Toxicol. Appl. Pharmacol. 2012 264 462 469 10.1016/j.taap.2012.08.024 22959927

223. Yang B. Li J.-J. Cao J.-J. Yang C.-B. Liu J. Ji Q.-M. Liu Z.-G. Polydatin attenuated food allergy via store-operated calcium channels in mast cell World J. Gastroenterol. WJG 2013 19 3980 10.3748/wjg.v19.i25.3980 23840142 PMC3703184

224. Cordaro M. Impellizzeri D. Siracusa R. Gugliandolo E. Fusco R. Inferrera A. Esposito E. Di Paola R. Cuzzocrea S. Effects of a co-micronized composite containing palmitoylethanolamide and polydatin in an experimental model of benign prostatic hyperplasia Toxicol. Appl. Pharmacol. 2017 329 231 240 10.1016/j.taap.2017.06.005 28610993

225. Guan S.-Y. Zhang K. Wang X.-S. Yang L. Feng B. Tian D.-D. Gao M.-R. Liu S.-B. Liu A. Zhao M.-G. Anxiolytic effects of polydatin through the blockade of neuroinflammation in a chronic pain mouse model Mol. Pain 2020 16 1744806919900717 10.1177/1744806919900717 31964240 PMC6977205

226. Li H. Min J. Chen Y. Li H. Zhang Y. Polydatin attenuates orbital oxidative stress in Graves’ orbitopathy through the NRF2 pathway Chem. Biol. Interact. 2020 315 108894 10.1016/j.cbi.2019.108894 31705858

227. Tang S. Tang Q. Jin J. Zheng G. Xu J. Huang W. Li X. Shang P. Liu H. Polydatin inhibits the IL-1β-induced inflammatory response in human osteoarthritic chondrocytes by activating the Nrf2 signaling pathway and ameliorates murine osteoarthritis Food Funct. 2018 9 1701 1712 10.1039/C7FO01555K 29484338

228. Xu L.-Q. Xie Y.-L. Gui S.-H. Zhang X. Mo Z.-Z. Sun C.-Y. Li C.-L. Luo D.-D. Zhang Z.-B. Su Z.-R. Polydatin attenuates d-galactose-induced liver and brain damage through its anti-oxidative, anti-inflammatory and anti-apoptotic effects in mice Food Funct. 2016 7 4545 4555 10.1039/C6FO01057A 27714005

229. Ravagnan G. De Filippis A. Cartenì M. De Maria S. Cozza V. Petrazzuolo M. Tufano M.A. Donnarumma G. Polydatin, a natural precursor of resveratrol, induces β-defensin production and reduces inflammatory response Inflammation 2013 36 26 34 10.1007/s10753-012-9516-8 22956122

230. Fuggetta M.P. Migliorino M.R. Ricciardi S. Osman G. Iacono D. Leone A. Lombardi A. Ravagnan G. Greco S. Remotti D. Prophylactic dermatologic treatment of afatinib-induced skin toxicities in patients with metastatic lung cancer: A pilot study Scientifica 2019 2019 9136249 10.1155/2019/9136249 30838155 PMC6374781

231. Cervigni M. Nasta L. Schievano C. Lampropoulou N. Ostardo E. Micronized palmitoylethanolamide-polydatin reduces the painful symptomatology in patients with interstitial cystitis/bladder pain syndrome BioMed Res. Int. 2019 2019 9828397 10.1155/2019/9828397 31828153 PMC6885282

232. Chen L. Chen Z. Xu Z. Feng W. Yang X. Qi Z. Polydatin protects Schwann cells from methylglyoxal induced cytotoxicity and promotes crushed sciatic nerves regeneration of diabetic rats Phytother. Res. 2021 35 4592 4604 10.1002/ptr.7177 34089208

233. Soave I. Marci R. Administration of micronized palmitoylethanolamide (PEA)-transpolydatin in the treatment of chronic pelvic pain in women affected by endometriosis: Preliminary results Minerva Ginecol. 2013 65 453 463 23486373

234. Cremon C. Stanghellini V. Barbaro M. Cogliandro R. Bellacosa L. Santos J. Vicario M. Pigrau M. Alonso Cotoner C. Lobo B. Randomised clinical trial: The analgesic properties of dietary supplementation with palmitoylethanolamide and polydatin in irritable bowel syndrome Aliment. Pharmacol. Ther. 2017 45 909 922 10.1111/apt.13958 28164346

235. Pace M.C. Passavanti M.B. Aurilio C. Sansone P. Aurilio R. De Maria S. Lama S. Federico A. Ravagnan G. Caraglia M. Polydatin administration improves serum biochemical parameters and oxidative stress markers during chronic alcoholism: A pilot study Vivo 2015 29 405 408 25977389

236. Biswas P. Dellanoce C. Vezzoli A. Mrakic-Sposta S. Malnati M. Beretta A. Accinni R. Antioxidant Activity with Increased Endogenous Levels of Vitamin C, E and A Following Dietary Supplementation with a Combination of Glutathione and Resveratrol Precursors Nutrients 2020 12 3224 10.3390/nu12113224 33105552 PMC7690269

237. Bavetta M. Silvaggio D. Campione E. Sollena P. Formica V. Coletta D. Graziani G. Romano MC P. Roselli M. Peris K. The Effects of Association of Topical Polydatin Improves the Preemptive Systemic Treatment on EGFR Inhibitors Cutaneous Adverse Reactions J. Clin. Med. 2021 10 466 10.3390/jcm10030466 33530427 PMC7866016

238. Mostafa F. Abdel-Moneim A. Abdul-Hamid M. Galaly S.R. Mohamed H.M. Polydatin and polydatin-loaded chitosan nanoparticles attenuate diabetic cardiomyopathy in rats J. Mol. Histol. 2021 52 135 152 10.1007/s10735-020-09930-4 33389430

239. Wang X. Guan Q. Chen W. Hu X. Li L. Novel nanoliposomal delivery system for polydatin: Preparation, characterization, and in vivo evaluation Drug Des. Dev. Ther. 2015 9 1805 10.2147/DDDT.S77615 PMC4386770 25848217

240. Lin L. Gong H. Li R. Huang J. Cai M. Lan T. Huang W. Guo Y. Zhou Z. An Y. Nanodrug with ROS and pH Dual-Sensitivity Ameliorates Liver Fibrosis via Multicellular Regulation Adv. Sci. 2020 7 1903138 10.1002/advs.201903138 PMC7140994 32274310

241. Xiao J. Wang F. Liu J. Wang L. Kai G. Yu X. Effect of ZnO# ZnS QDs heterojunctures on the stilbenes–plasma proteins interactions Mol. BioSystems 2011 7 2452 2458 10.1039/c1mb05087g 21611669

242. Basta-Kaim A. Ślusarczyk J. Szczepanowicz K. Warszyński P. Leśkiewicz M. Regulska M. Trojan E. Lasoń W. Protective effects of polydatin in free and nanocapsulated form on changes caused by lipopolysaccharide in hippocampal organotypic cultures Pharmacol. Rep. 2019 71 603 613 10.1016/j.pharep.2019.02.017 31176102

243. Abd El-Hameed A.M. Yousef A.I. Abd El-Twab S.M. El-Shahawy A.A. Abdel-Moneim A. Hepatoprotective Effects of Polydatin-Loaded Chitosan Nanoparticles in Diabetic Rats: Modulation of Glucose Metabolism, Oxidative Stress, and Inflammation Biomarkers Biochemistry 2021 86 179 189 10.1134/S0006297921020061 33832416

244. Abdel-Moneim A. El-Shahawy A. Yousef A.I. Abd El-Twab S.M. Elden Z.E. Taha M. Novel polydatin-loaded chitosan nanoparticles for safe and efficient type 2 diabetes therapy: In silico, in vitro and in vivo approaches Int. J. Biol. Macromol. 2020 154 1496 1504 10.1016/j.ijbiomac.2019.11.031 31758992

245. Abd El-Hameed A.M. Polydatin-loaded chitosan nanoparticles ameliorates early diabetic nephropathy by attenuating oxidative stress and inflammatory responses in streptozotocin-induced diabetic rat J. Diabetes Metab. Disord. 2020 19 1599 10.1007/s40200-020-00699-7 33520856 PMC7843669

246. Vijayalakshmi S. Mariadoss AV A. Ramachandran V. Shalini V. Agilan B. Sangeetha C.C. Balu P. Kotakadi V.S. Karthikkumar V. Ernest D. Polydatin encapsulated poly [lactic-co-glycolic acid] nanoformulation counteract the 7, 12-dimethylbenz [a] anthracene mediated experimental carcinogenesis through the inhibition of cell proliferation Antioxidants 2019 8 375 10.3390/antiox8090375 PMC6770361 31491872

247. Samra Y.A. Abdelghany A.M. Zaghloul R.A. Polydatin gold nanoparticles potentiate antitumor effect of doxorubicin in Ehrlich ascites carcinoma-bearing mice J. Biochem. Mol. Toxicol. 2021 35 e22869 10.1002/jbt.22869 34339076

248. Orlowski P. Zmigrodzka M. Tomaszewska E. Ranoszek-Soliwoda K. Pajak B. Slonska A. Cymerys J. Celichowski G. Grobelny J. Krzyzowska M. Polyphenol-conjugated bimetallic Au@ AgNPs for improved wound healing Int. J. Nanomed. 2020 15 4969 10.2147/IJN.S252027 PMC7369312 32764930

249. Magalhães P.R. Reis P.B. Vila-Viçosa D. Machuqueiro M. Victor B.L. Identification of Pan-Assay INterference compoundS (PAINS) Using an MD-Based Protocol Computational Design of Membrane Proteins Springer Berlin/Heidelberg, Germany 2021 263 271 10.1007/978-1-0716-1468-6_15 34302681

250. de Matos A.M. Blázquez-Sánchez M.T. Sousa C. Oliveira M.C. de Almeida R.F. Rauter A.P. C-Glucosylation as a tool for the prevention of PAINS-induced membrane dipole potential alterations Sci. Rep. 2021 11 4443 10.1038/s41598-021-83032-3 33627687 PMC7904931