INTRODUCTION:

Resveratrol (3, 4′, 5- trihydroxystilbene) may be a nutraceutical that has recently attracted tons of research attention thanks to its exciting pharmacological potential. It is a phytoalexin that may be found in many plants including grapes, peanuts, and berries. Resveratrol was first isolated in Veratrum grandiflorum, or American hellebore plant, within the 1940’s. Stilbene compounds are known for its ability to supply plants with resistance to microbial and mycosis and early research showed that resveratrol was present in large quantities in injured, infected, and ultraviolet-treated leaves¹. Stilbenes provide antioxidant, anticarcinogenic, antitumor and estrogenic/antiestrogenic activity.

Resveratrol is a phytoalexin, a class of compounds produced by many plants when they are infected by pathogens or physically harmed by cutting, crushing, or ultraviolet radiation.

Plants that amalgamateresveratrol include knotweeds, pine trees including Scots pine and Eastern white pine, grape vines, peanut plants, cocoa bushes, and vaccinium shrubs that produce berries, including blueberries, raspberries, mulberries, cranberries, and bilberries².

Chemistry:

Resveratrol is a stilbenoid polyphenol, consisting of two phenolic rings bonded together by a double styrene bond, which forms resvetrol of chemical name 3,5,4′-Trihydroxystilbene and molecular weight 228.25g/mol. It has two geometric isomerscis- (Z) and trans- (E) resulting due to the double bond. The trans isomer when exposed to UV radiation undergoes isomerization to cis isomer. Trans form is very important for its proliferation and various biological functions are called, in reducing cellular responses such as cell cycle arrest, differentiation, apoptosis, and to improve anti-proliferative cancer cells³.

The modification of resveratrol structure has received special attention from researchers and many resveratrol-based compounds have been composed as methoxylated, hydroxylated and halogenated derivatives, all of which show excellent therapeutic potential. Resveratrol is present in food products such as glycosylated forms, known as piceid. Although, plants and pathogens, even the human digestive tract contain enzymes that can produce polyphenols oxidation (as well as inactive function), glycosylation inhibits the enzymatic oxidation of resveratrol, thereby maintaining its biological effects and increasing its stability. All and its availability⁴. In addition, since intestinal cells in the gut can only absorb the form of resveratrol aglycone, theabsorption process requires glycosidases. Therefore, the amount of aglycone and glycosylated resveratrol amounts in food and beverages can measure the absorption rate. The plant species of Polygonumcuspidatum revealed some glycosylated resveratrol congener which were secluded from the invasive plant likeresveratroloside, piceatannol glucoside, piceid which were⁵ identified because the major antibacterial compounds⁶. However, in vitro studies have shown that the glycosylated congener even show more robustbioactivities. For example, resveratrol and piceid have similar antioxidant capacity, but piceid appears to be more efficacious than resveratrol thanks to its reaction with its radical form^7-9. Indeed, resveratrol-glycoside was simpler than resveratrol against hepatitis B virus^10-14. Piceatannol, with a sparehydroxyl, was already reported as having brawny anti-inflammatory, immunomodulatory, anti-proliferative, anti-leishmanial, anti-leukemic, and protein-tyrosine kinase inhibitory effects.

Pterostilbene, a natural methoxylated resveratrol congener, was first secluded from red sandalwood (red sandalwood), a plant employed in traditional medicine for diabetes treatment¹⁵. This kino active constituent is especially found in blueberries, grapes, and a number of other plant woods^16-20. Pterostilbenefacets a similar structure to resveratrol baring of a ring at 3 and 5 position was replaced by a methoxyl group. This compound pro-lipophilicity, exceeding that of resveratrol, increases its bioavailability^21-24 leading to higher bioactivities, including anticancer, anti-lipidemic, antidiabetic, and cardioprotective effects than those of resveratrol.

Mechanism of action:

Resveratrol acts via multiple mechanisms. Bioactivity is dependent on genetic molecule RNA. These molecules usually bind the amino acids and bring them to the protein-synthesizing site to be incorporated into the new protein that is being synthesized. Resveratrol affects a definitetRNA called TyRS, which transports tyrosine to the protein-synthesis site. When resveratrol is produced in higher quantities, as happens in demanding conditions, it binds to TyRS, instead of tyrosine. The resveratrol-TyRS complex proceedsto the nucleus, where it activates a protein called PARP-1. This protein is known to be prominent in the stress response, and for DNA repair. Upon activation PARP-1 turns on a network of genes which protects the cell from stress-induced damage. The genes include the tumor-suppressor gene p53, which suppresses inflammatory chemicals like interleukin-6, and the longevity genes FOXO3A and SIRT6²⁵.

Resveratrol also activates the sirtui enzymes, most predominantly the SIRT1 enzyme activated by resveratrol and other sirtuin-activating compounds (STACs, for short), only if a specific amino acid is present at a specific location on the protein. Replacement of amino acid with another, STACs fail to activate the enzyme, when the substrate, or the chemical on which the enzyme acts, lacks a particular amino acid at a specific location, STACs cannot activate the reaction. The outcomeof activating this enzyme is to increase mitochondrial activity, improve mitochondrial aerobic capacity, and promote oxidative dephosphorylation. The SIRT1 effect results the genes as a key to producing homeostasis and energy regulation²⁶.

The TyRS-resveratrol complex, contrarily, exerts its protective effects at far lower concentrations. This explains a plausible explanation as to how a glass or two of red wine could protect the body from aging, inflammation and cancer, as well as give out to heart health. This mechanism is called hormesis, theoperation of activating a natural stress response in a linent, health-promoting manner²⁷.

Bioavailability and Pharmacokinetics of Resveratrol:

Resveratrol is not absorbed by active dissusion but it occurs by passive diffusion or by forming complexes with membrane transporters accompanied by release into the bloodstream, where it can be found mainly as a glucuronide, sulfate, or free²⁸ after oral administration. Phase II metabolism of Resveratrol or metabolites occurs in the liver, after anenterohepatic transport in the bile that may expeditesome drug to put back to the small intestine. The clinical trials in human divulged thatresveratrolhas a rapid first pass hepaticmetabolism, and promotes the production of conjugated glucuronides and sulfate metabolites, which have biological activity²⁹. The metabolites were pin-poined and were measured by HPLC and followed by mass spectrometry. RV-3-O-sulfate, RV-4′-O-glucuronide, and RV-3-O-glucuronide are various metabolites resulted from profouse clinical trials. RV-3-O-sulfate propogating levels showed the elevated highest peak aggragation compared to the other conjugated RV metabolites^30-34, except in one study where RV-3-O-glucuronide presented the highest peak concentration when the dose of RV was 2500mg³⁰. Pharmacokinetic studies concluded that RV concentration in plasma confide on the doses ingested.

Biological Activities of Resveratrol:

Antioxidant Effects:

Resveratrol may be a powerful antioxidant that beneficial effect is hampered by its low bioavailability. Many attempts are made to urge resveratrol derivatives by process of esterification to increase or enhance their lipophilicity and application in lipid-based foods and biological environments. About 12 different esterified acyl chlorides are known including caproyl chloride, butyryl chloride, myristoyl chloride, capryloyl chloride, docosahexaenoyl chloride, capryl chloride, eicosapentaenoylchloride, oleoyl chloride, palmitoyl chloride, lauroyl chloride, propionyl chloride, and stearoyl chloride. These derivatives were able to effectively inhibit copper ion-induced low-density lipoprotein (LDL) oxidation and inhibited hydroxyl radical-induced DNA scission³⁵. These results clearly demonstrated that resveratrol derivatives might function potential antioxidants in foods and biological systems.

Anticancer Effects:

Resveratrol has received great attention as an upcoming preventive and therapeutic agent against breast cancer³⁶. Enhanced chemotherapy of using resveratrol is obtained by inactivating the protein named as NF-κB which is also a transcription factor formed by cancer cells and which controls certain genes expression. The acts of occludingthe factor of transcription by resveratrol is controlled due towhichit enables chemotherapeutics to act at their targeted sites^37-40. Resveratrol has also shown promise as a part of combination therapy, particularly in carcinoma. This compound has been shown to reverse drug resistance in a wide variety of in vitro cell systems by sensitizing tumor cells to drug-mediated effects in combination with other chemotherapeutic agents [50]. Resveratrol demonstrates ability to strengthen the sensitivity of carcinoma cells to gemcitabine therapy⁴¹. Cisplatin, a cancer chemotherapy agent against ovarian, bladder, testicular, and much of other cancers, high risk of nephrotoxicity is reduce by Resveratrol⁴². Silver-nanoparticles loaded with resveratrol have also demonstrated antioxidant potential in cancer cells⁴³. In addition, resveratrol beneficial effects also are present when adopted as a standard treatment support to cancer, using chemotherapy and radiotherapy^44-46.

Cardioprotective Effects:

Resveratrol protective effect has been shown to improve cardiovascular function in diabetic mice by maintaining the functional capacity of stem / progenitor cell cells and mature heart cells, improving the cardiovascular environment by reducing inflammation and reducing remodeling. ventricular abnormal heart disease, leading to significant restoration of ventricular function⁴⁷. Resveratrol has shown a beneficial effect on heart failure by improving left ventricular function, reducing cardiac hypertrophy, contraceptive dysfunction and remodeling, interstitial fibrosis, and plasma BNP levels⁴⁸. Alternative molecular mechanisms of resveratrol action include inhibition of prohypertrophic signaling molecules, myocardial Ca2 + handling, phosphorylation of prosurvival (Akt-1, GSK-3β) and stress signaling pathways (MKP-1) and reduction of stress. -oxidative and inflammatory (NOS, COX-2 activity, and ROS formation).

Neuroprotective Effects:

Resveratrol has many roles to prevent dysfunction in various neurodegenerative disorders, such as Alzheimer's disease, Huntington's and Parkinson's, amyotrophic lateral sclerosis and neurodegenerative disorders⁴⁹. It has been shown that the protective effects of resveratrol not only have anti-inflammatory and antioxidant effects but also enhance mitochondrial activity and biogenesis via SIRT1 (sirtuin 1)/ AMPK/ PGC1cy pathway and vitagenes, preventing the dramatic effects of stress. Oxidative. Resveratrol limits the neurotrophic factor expression, cholinergic neurotransmission and oxidative stress, promotes the approval of β-amyloid peptides and anti-amyloidogenic cleavage of APP, and reduces neuronal apoptosis. Meta-analyzes have shown that resveratrol has significantly reduced the Status Scale (POMS) including energy and fatigue but has not had a significant effect on memory and cognitive functioning. Among resveratrol its content like, heyneanol A, vitisin A and have been reported to have better dose-dependent effects compared to a standard inhibitor (galantamine) in both acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) activity. Resveratrol is also able to improve the strength of the rat car and activate the neuroinfigueatory response following intracerebral bleeding. It can be used as a novel therapeutic agent to treat bleeding within the intracerebral⁵⁰.

Anti-Inflammatory Function:

Stilbenoids containing resveratrol are nitrogenous non-nitrogenous polyphenols with acid and amphiphilic compounds that have anti-inflammatory activity. Most of their targets occur in cyclooxygenase (COX), 5-lipoxygenase (5-LOX) and protein kinase B, which are associated with its COX-1 and COX-2 inhibitory activity and transcription factors, which are directly involved in the regulation of activity of COX. Studies have reported the ability of resveratrol to reduce fluid and the manifestation of inflammatory factors. The anti-inflammatory activity of resveratrol prevents acute inflammation of pharyngitis by inhibiting NF-κB, tumor necrosis factor-α and interleukin-6 serum levels, macrophage-2 inflammatory proteins and cyclooxygenase- 2, the production of oxygen species and caspase 3/9 in rabbit models⁵¹.

Antimicrobial Activity:

Resveratrol, in addition to the activities described above in organic matter, has been studied for its ability to inhibit the growth of certain bacteria, such as Gram-positive and Gram-negative bacteria and fungi. Indeed, resveratrol has been shown to effectively inhibit the growth of Candida albicans. Dimethoxy resveratrol findings showed lethal activity against albicans in small amounts of inhibitory concentration (MIC) of 29-37μg/ mL, including 11 other types of Candida. However, the putative candidacidal activity of resveratrol is controversial. In fact, research shows that resveratrol does not work in albicans and non-C. Types of albicans. Campylobacter june and Campylobacter coli are major causes of bacterial gastroenteritis, while Arcobacter species are also known as human and animal diseases. The properties of the Resveratrol-hydroxypropyl-γ-cyclodextrin formulation improved the solubility of resveratrol and showed anti-Campylobacter and anti-Arcobacter effects. In addition, it inhibited the formation of biofilm and promoted the distribution of biofilm even in sub-regions of MIC and could therefore be developed as a new anti-biofilm agent to improve shelf-health and safety⁵². Resveratrol has shown antibacterial activity against Gram-positive bacteria and time-tested experiments suggesting that its effects are due to its bacteriostatic action. However, the mechanism of action of its antimicrobial activity is poorly understood. Resveratrol has also been able to affect cells with mutations in cell morphology and DNA content.

Other Biological Activities:

Besides the cardioprotective, antioxidant, anticancer, neuroprotective, anti-inflammatory, anti-dyslipidemia, and antidiabetic effects of resveratrol, it also exhibits antiproliferative and androgen-lowering effects on theca-interstitial cells of ovary. Moreover, it exerts a cytostatic but not cytotoxic effect in granulosa cells, while inhibiting aromatization and vascular endothelial growth factor (VEGF) expression. These actions may be of clinical relevance in conditions associated with theca-interstitial cell hyperplasia, androgen excess, and abnormal angiogenesis, such as polycystic ovary syndrome. In addition, resveratrol may increase ovarian follicular reserve and prolong ovarian life span, serving as a potential anti-aging agent⁵³.

Side-Effects of Resveratrol:

Resveratrol has been reported to both reduce cell growth and induce apoptosis in normal cells, when administered at high doses, which confirm its biphasic effects over low to high concentrations spectrum ⁵⁴. Resveratrol rapidly activate mitogen-activated protein kinase (MAPK) in a MEK-1, Src, matrix metalloproteinase, and epidermal growth factor receptor in a dependent manner. It activates MAPK and endothelial nitric-oxide synthase (eNOS) at nanomolar concentrations (i.e., magnitude less than that required for ER genomic activity) and at concentrations possibly/transiently achieved in serum following oral red wine consumption⁵⁵.

Resveratrol Interactions:

Interaction with Cytochrome P450:

Consumption of natural products is prevalent in patients taking generic drugs, leading to a higher risk of exposure to natural products and drugs. Resveratrol can interact with several drugs. It can lead to interactions with various cytochromes P450 (CYP), especially when taken in high doses. As this polyphenol has been reported to have significant interactions with phase I and II enzymes in both in vitro and in vivo, it can be beneficial or harmful as well. In addition to digestive enzymes, it is now widely accepted that transformation of the transport function. Resveratrol has been reported to strongly inhibit P-glycoprotein (P-gp), multidrug-resistant protein (MRP2), and organic anion transporter 1/3 (OAT1/ OAT3). However, the interaction of resveratrol with carriers is still quite clear. In addition, several clinical studies were conducted to detect the interaction of the resveratrol-drug interorter. On the other hand, it is also hypothesized that high doses of resveratrol compete with other polyphenol of transporters, reducing both their detection and potential confounding effects. In addition, the absorption, distribution, kidney excretion, and / or hepatic elimination of active resveratrol compounds in humans have not been adequately evaluated than is required in the prediction of resveratrol-drug interactions^56-58. Therefore, the effects of resveratrol reuptake on transporter-drug interactions confirm further investigation.

Interaction with Anticoagulant and Antiplatelet Drugs:

Resveratrol has been reported to inhibit human platelet aggregation in vitro⁵⁹. Considering that high resveratrol supplementation in the form of supplements can increase the risk of injury and bleeding when taken with anticoagulant drugs, antiplatelet drugs and even non-inflammatory drugs (NSAIDs) like diclofenac, aceclofenac⁶⁰.

CONCLUSION:

Resveratrol is majorly synthesized from the skin of red grapes and also from some berries and peanuts. It is considered as a table top food including various types of health benefits including anti-ageing properties, sun protective property, also helpful in improvising digestion and skin toning. This nutraceutical belongs to the stilbenoid group which consists of two aromatic rings linked by an ethylene or ethene bridge with a variety of substituent’s. Resveratrol occurs in two isomeric forms such as cis- as well as trans-form. The trans-form is usually more stable than the cis and is also having high bioactive effects. Resveratrol is a tradional medicine which has been used for the treatment ofstomachache, hepatitis, arthritis, urinary tract infections, fungal diseases or skin inflammation treatment.But the biological activity of resveratrol not only is limited to these uses but majorly it has been used as a cardioprotective agent. Apart from these use resveratrol has also been used as a anti-inflammatory agent and also as a anti-carcinogenic agent. Future perspective for the study of resveratrol includes various researchfields like in-vivo study with in-vitro and in-vivo correlation studies. Various formulations including resveratrol along with other drug s can be formulated for different uses.

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Received on 07.09.2021 Modified on 26.12.2021

Asian J. Res. Pharm. Sci. 2022; 12(2):157-162.

DOI: 10.52711/2231-5659.2022.00027