Therapeutic application of Resveratrol in human diseases

Resveratrol (3,4,5-trihydroxystilbene) is a member of natural and plantderived chemicals, which is known as polyphenols and it is getting more consideration because of its various health assistances. Largely in the case of neurological problems, cardiovascular disease, antiviral, cancer, antiaging. Although in the past few years, it has been shown that the families of enzymes Sirtuins, particularly situin1 (SIRT1), have an antiaging action. Thus, the natural compound resveratrol shows a very strong activation of SIRT1 and also shows antioxidant properties. The antioxidant effect mainly elicited by the inhibition of important pathways like the NF-κβ pathway. This review highlights the antiviral mechanism of resveratrol in human and animal viral infections. And also, information about cancer-related like colorectum cancer, skin cancer and lung cancer are also mentioned. Resveratrol also gives additional cardioprotective and vasoprotective properties, which include antiatherosclerotic action. Overall observation shows that resveratrol has a high therapeutic potential in the treatment of cardiovascular disease, anti-aging, antiviral and in the treatment of cancer.


INTRODUCTION
Resveratrol is the most categorized stilbene, and this is formed in the grapes through the enzyme known by stilbene synthase in response to injuries like mechanical damage or infection. Resveratrol structure contains mainly two aromatic rings, which are linked by a methylene double bond; these are the part of resorcinol structure from which resveratrol takes its name (Salehi et al., 2018). Excluding in grapes, the resveratrol is naturally originated in several plant species that are berries, peanuts, pines, plums, legumes, and also in many herbs. Some of the large variety of lowers & leaves such as Gnetum, butter ly orchid tree, white hellebore, corn lily, eucalyptus, spruce, etc., also contains RV. Resveratrol also exists in the form of cis form and as well as trans isomeric forms (Figure 1) but in the grape extract cis isomer is not recognized. This is the main molecule & belongs to the polymers known viniferins family. In these plants, glucosides also synthesized.
By the use of natural sources, the removing of resveratrol & their substituted products will be time-consuming & the obtained compound will give less amount of product. When the trans-resveratrol was obtained by the organic synthesis, then the research on biological properties started. By the characteristics of W-spectral & infrared absorption peaks in the rage of 2800 to 3500 cm-(OH band) and at 965cm-(a transform of the double bond) jeandet et al. identi ied the product. Cis form of the RV can be obtained by UV irradiation and now commercially Trans-resveratrol is also available. Transresveratrol remains unchanged for more months (excluding for higher pH buffers) when it is totally protected to the light. This comes to know after conducting various trials in various conditions (Petrovski et al., 2011). It is found as per likely stated that the defensive process correlated to the Resveratrol neurodefense, sirtuins (these are likewise known as SIRT -silent information regulator 2-proteins), belongs toward family histone deacetylase, it is not dependent on the antioxidant attribute (Talero et al., 2012). Similarly, interest in Sirtuins1 has also increased since it has a part as a durability feature in the various animal models. As mentioned, Sirtuins1 is divided into 4 groups which belong to the family of histone deacetylase (HDACs). Yeast Rpd3p and Hda1p proteins are likely to the class 1 and class 2 of HDACs. Yeast transcriptional repressor Sir2p has the same features as class 3 HDACs and these are mentioned as SIRT.
Class 1 and class 2 HDACs are taken for the understanding it by the inhibition done by trichostatin A (TSA), Nicotinamide Adenine dinucleotide (NAD+) dependent is the distinctive feature of class 3 HDACs. Deacetylase HDAC119 L belongs to class 4. Studies done by using the puri ied SIRT1 discovered that for each acetyl-lysine group is removed, the NAD+ molecule is cleaved, nicotinamide and Oacetyl-ADP-ribose are formed. So, SIRT1 will give two enzymatic activities: The deacetylation of a target protein and the metabolism of NAD+. These 2 activities state that SIRT1 can act as an oxidative or metabolic device, adaptable cellular apparatus grounded on this evidence (Tusubira, 2019).
Thus, assumed the pro it of resveratrol is either owed to anti-oxidant possessions or to a particular initiation of SIRT1 included in retorting to the molecular impairment besides metabolic inequities.

Aging
As per the statement provided, the extra copies of the genes in yeast, worms and lies which encodes sirtuins, are linked with the prolonged lifespan. It has been hypothesized that the chief role of the sirtuin proteins is to provide stress and endurance struggle at the time of adverse actions (Haigis and Sinclair, 2010). An invitro screen for the activators of sirtuin1 recognised the resveratrol as the more potent when it is tested among 18 regulators of deacetylase action. Additional work has proven that the RESV prolongs the lifespan of S. cerevisiae, Caenorhabditis elegans and drosophila melanogaster. This is done solitary that genetic factor that will encrypt sirtuin2 if this is existing in these creatures. Lately, the resveratrol has revealed the prolonged lifecycle, in brief, survived Pisces species up to 59% (Yang et al., 2014).

Properties of Resveratrol on durability
We crosshatched & upstretched Pisces (n = 157) beneath the good circumstances up to 4 weeks, after they are in luenced for a voluptuous prime of life. At three different concentration the 110 ishes are given food with the resveratrol: 24mg/g of food (0.1mM ; n = 20), 120mg/g of food (0.5mM; n= 60), and 600mg/gm of nutrition (2.5mM; n = 20), then the remaining 47 ishes are constantly given the standard food. Ad libitum was not fed to the ishes but they were given an appropriate amount of food twice daily.
Hence it can be ruled out that RESV properties are baf led by food disinclination attributes that account for dietary limitation. Survival of the group of ishes serving as control is similar to the survival of a large population of individuals untreated which accomplish reference data (n= 132). Augmentation of resveratrol accounted for signi icant raise of survival statistically, which was dependent on dose: the minimal dose (24mg/gm of food) was unsuccessful in enhancing longevity when linked to the controller -served and unprocessed Pisces. In 2 individualistic prosecutions 120mg/gm of food resulted in raise of average and extreme longevity of 33% and 27% correspondingly (p < 0.001, log-rank test) & 600mg/gm food persuaded 56% & 59% raise in average & extreme longevity correspondingly (p < 0.001 logrank test). 600mg/gm of food was consequently much ef icacious when compared to 120mg/gm of food in enhancing longevity (p= 0.01, log-rank test) supreme longevity in statistical analysis interpreted as 10 th in longevity (Schultz et al., 1990).

Antiviral
RSV plays an important role in the treatment of infections caused by a virus. Table 1 shows the activity of the RSV against viral infections such as in luenza and herpes caused by the In luenza virus and Epstein-Barr virus.  (Read and Digard, 2010). This activity is not linked with glutathione mediated antioxidant property of the substance.

Epstein-Barr virus
Herpes RSV exhibited raise in inhibition of EBV early antigen initiation by the use of Raji cells. It also decreased papilloma generation in the mouse by 60% after inoculation for about 20 weeks (Mack and Thomson, 2013). In a subsequent study, RSV exhibited dose-dependent blockage of EBV lytic pathway of inhibition of transcription proteins and genes, Rta, Zta & dispersed initial antigen, additionally blocking EBV immediate initial antigen: BRLF1 and BZLF1 protagonists. This activity is seen to minimize virion generation. EBV is a γ-herpes virus that affects human lymphocytes and epithelial cells. The resurrection of Epstein-Barr virus after latent cycle to the lysis cycle is essential for the production of virions from virus and produce manifestations. At the beginning of the lysis cycle, Epstein-Barr virus induces two transcription elements, Rta and Zta, that are transliterated from BRLF1 and BZLF1 correspondingly.

Assertion of EBV lysis proteins by low cytometric studies
The existence of EBV lysis protein in P3HR1 cells was advanced, examined by the low-cytometry. The P3HR1 inhabitants not under treatment with SB that expelled Rta, Zta and EA-D were 4.48%, 2.09% and 4.90% correspondingly. The inhabitants that demonstrated the 3 proteins after treating with SB raised by 51.20%, 61.40% and 46.80% correspondingly. Post-treatment of the cells with 13.8µM of RESV, the inhabitants that demonstrated Rta, Zta and EA-D depleted up to 29.5%, 36.9% and 29.5% respectively, as described in Table 2. The inhabitants that demonstrated Rta, Zta and EA-D depletion in the amount of RESV enhanced the concentration by 27.5µM and 55µM (Gershburg et al., 2007).

Inhibition of Epstein-Barr virus particles generation
P3HR1 cells on treatment with 13.79, 27.49 and 55.0 µM of RESV after induction of lysis. Post culturing for 5 days, Epstein-Barr virus particles uncon ined into the medium were secluded. actual-time qPCR revealed that RSV at a concentration of 27.49µM diminished the production of the virus by 42.0%. RESV at 55µM concentration decreased the generation of EBV particles by 74% (Ruiss et al., 2011).

MOA of RESV on various viruses resulting in viral inhibition
The RESV acts by blocking nuclear-cytoplasmic translocation of viral ribonucleoproteins, inhibiting early antigen induction, ROS production, phosphorylation and viral protein production. The detailed mechanism of action of resveratrol, along with their properties, are been discussed in Table 3.

Anti-bacteria
P. acnes (in vitro) -Acne is a bacterial infection caused by P. acnes, which is a dwelling microbial population in follicular cells of the skin of a human. Reduction in the expression of late viral proteins which is related to inhibition of protein kinase C related pathways (Kirby et al., 2011).

Vero cell
Inhibits early and late viral protein production and virion development Reduction of viral DNA replication leading to 97.9-99.9% decrease in viral titers P. acnes grows by utilizing sebum as the nutrient medium and releases a lipase enzyme. The degradation of Lipase in sebum results in the formation of triglyceride frees fatty acid, and persuades a sequence of in lammatory reactions; white blood cells go awry and intrusion to the dermis and release of an in lammatory mediator.
The in lammatory mediator aggravates the skin and hastens the corni ication of the epidermis in accumulation to in lammation.
Test -Resveratrol was added to an agar medium The concentration of resveratrol -300 µg/ml or higher Effect -Resveratrol has an intense antiin lammatory action, controls acne and its propagation by its antibacterial activity as well (Kong, 2011).

Cancer
Cancers or tumor is a huge family of disorder that induces excessive growth of abnormal cells which has the latent to conquer and invade normal cells of organs or tissues of the body (Schneider, 2011).
Genes expressing tumor growth and multiplication must be transformed. Causes (90-95%): Genetic mutations caused by environmental factors, whilst the rest 4.9-10% are due to the expression of genetic genes.

Role of RESV in the prevention of cancer
Cancer is a disease characterized by the abnormal growth of cells and tissues. In order for a tumor to develop completely, it undergoes 3 processes such as initiation, promotion and progression, as shown in Figure 2.
In this, the therapeutic and chemo deterrent characters of RESV in colorectal and skin malignances are a precise emphasis. The deprived BA of RESV and its stout accretion in the colon may make the colon the furthermost expedient mark for submission; correspondingly, the skin is an expedient goal over application on the skin.

Cancer of colorectum
The pathogenesis and progress of Cancer of colorectum are multiple-stage developments composed of composite molecular signaling processes, counting transmutations in numerous genes, like protooncogenes and tumor suppressor genes Approximately 96% of Cancer of colorectum outcomes is erratic, which are produced by nutritional and ecological characteristics. Earlier stage and routine (intake of fat-enriched diet and red meat, less-iber diet, overweightness, de iciency of physical commotion, the convention of tobacco (smoking), more intake of alcoholic beverages and diabetes mellitus are the prominent attributes accounting emergence of CRC (Yamauchi et al., 2012).

Role of resveratrol in treatment, prevention of CRC
Numerous appearances of indication have marked the action of resveratrol in the treatment and prevention of CRC. It reportedly prevents the occurrence of colon tumor in F344 rat as it suggestively decreases a sum of anomalous crypt foci with a mechanism concerning induction of pro-apoptotic protein Bax in ACF cells and decrease of P21 expression in adjacent mucous membrane it's demonstrated that the resveratrol inhibits the generation of colon tumors and diminishes SI tumors in ApcMin/+ mice by downregulation of genetic factor unswervingly in progression and proliferation of cancerous cells (ex: cyclins D1 and D2) and upregulating numerous genes intricated in the initiation of immune cells Besides, resveratrol constrains tumor generation in a genetically concocted mouse specimen of sporadic CRC (APCCKO/Krasmut). In this instance, resveratrol has been revealed to epigenetically downregulate Kras by cumulative raise in the appearance of miR-96 (Li et al., 2015). 1. Regulates the generation of Nitric oxide, this is a potent vasodilator, by counterbalancing the effect of the vasoconstrictor ET-1, thus providing thromboresistance and preventing atherogenesis. 2. RESV inhibits the atherosclerosis-related to in lammation through regulating the COX-2 activity at a transcriptional level 3. Inhibits uptake of oxidized LDLs in the vascular wall. 4. Evidence exhibited that 1-100 µmol/Lit resveratrol signi icantly inhibits intracellular and extracellular reductive oxidative stress production 2 Hypertension 1.
Higher systemic BP (blood pressure) (SBP) associated with increasing the heart weight, serum ET-1, angiotensin II (AngII) concentrations, and decreased serum Nitric oxide.
1. RESV decreases SBP, heart weight, ET-1, and AngII concentrations while increases the vasodilator Nitric oxide concentration, which will protect against increased SBP 2. After the treatment with RESV, the Mean arterial pressure decreased signi icantly in spontaneously hypertensive rats 3 Ischemia/ reperfusion injury and preconditioning 1. brief episodes of ischemia and reperfusion render the heart resistant to ischemic injury from a subsequent ischemic insult 2. the protective and adaptive mechanism 1. RESV gives cardioprotection as evidenced by superior postischemic ventricular recovery, decreased number of apoptotic cardiomyocytes, and reduced myocardial infarct size. 2. RESV activates together adenosine A1 and A3 receptors that phosphorylate phosphatidylinositol-3 kinase (PI3K), and then phosphorylates protein kinase B (Akt) and thus preconditions the heart by generating Nitric oxide, and by the activation of antioxidant Bcl-2 4 Angiogenesis 1. Angiogenesis is the development of new blood vessels. This process involves the growth, migration, and differentiation of endothelial cells, which line the inside wall of blood vessels. 2. By the chemical signals in the body, the angiogenesis process is controlled.
1. RESV is a polyphenol, which defends the heart by showing its anti-oxidative properties by various redox signaling mechanisms. 2. By Angiosuppressive effect-decreases the size of rat gliomas after treating with RESV. 3. Prevents the migration and proliferation of vascular endothelial cells and by activating eukaryotic elongation factor-2 kinase 4. prevents the development of new blood vessels in animals by directly inhibiting capillary endothelial cell growth-it blocked the VEGF and ibroblast growth factor (FGF) receptor-mediated angiogenic responses and signi icantly delayed angiogenesis-dependent wound healing.

Skin cancer
Skin cancer is one of the rapidly occurring malignancies (Kraemer et al., 1992).
Two prominent non-melanoma skin cancers of keratinocyte basis are, 1. Basal cell

Squamous cell carcinoma
In the entire UNITED STATES OF AMERICA, more than three million cases of skin cancer have been projected to arise per year, frequently occurring carcinoma of the skin is of non-melanomatous type. Malignant nonmelanoma skin carcinoma instigates from the keratinized epithelium. Malignant carcinoma comprises basal cell cancer (BCC) and squamous cell cancer (SCC). Skin cancer itself contributes to about 2% of malignant melanoma but results in the most death case. BCC is the rapidly occurring, quiet progressing and locally hostile carcinoma. SCC is the further most occurring nonmelanomatous type of melanoma, contributing to roughly 20% to 30% of the outcomes.

Role of resveratrol in skin carcinoma
The chemo defensive accomplishment of resveratrol in melanoma is demonstrated in numerous present studies. It's been observed the reduction in the emergence of melanoma originated by 7,12dimethylbenz[a]anthracene (DMBA) and endorsed by 12-O-tetradecanoylphorbol-13-acetate (TPA) in CD-1 mice. Furthermore, it has been described that resveratrol defends in contradiction of UVB interceded carcinoma of the skin in the bald SKH-1 mouse. Reagan-Shaw and his contemporaries exposed that resveratrol suggestively hinders the initiation of epidermal hyperplasia, arbitrated by numerous UVB via a diminution in multiplying cell nuclear antigen and the downregulation of CDK-2, −4, and −6, as well as cyclin-D1 and -D2. Additionally, resveratrol averts photo-impairment of the skin concluded by the initiation of p66Shc phosphorylation in HaCaT cells (Ko et al., 2017).

Cancer of lungs
Tumors of lungs are malignantly categorized by unrestrained cell progress in tissues of the lungs. It is found to be prominently occurring cancer midst men in equal frequency and mortality. Whereas in women, the occurrence of lung cancer is found to be third uppermost in frequency and second in mortality afterward breast carcinoma. About 1.83 million novel cases and 1.57 million demises worldwide was found to occur due to lung cancer in lieu of roughly 19.4% of entire bereavements from all categories of malignancies (Oskarsson et al., 2011).

As a Sole Mediator contrary to Lung Malignancy: In Vitro Studies
RSV repressed the growth of lung cancer in A549 and H460 cell lines, up-delimited microtubulelinked protein 1 light chain 3 (LC3) and ampli ied Proline-, glutamic acid-, and leucine-enriched protein-1(PELP1) accretion in autophagosomes with GFP-LC3.
RSV persuaded apoptosis in A549 cell lines in addition to the G1 cell cycle seizure. Furthermore, it was observed for an augmented initiation of caspases, an up-regulation of p53 and p21, transformed the appearance of cyclin A, chk1, CDC27 and Eg5 and an interruption of the mitochondrial membrane complex. These properties were instituted to be facilitated over the TGF-_/Smad pathway. RSV even exhibited down-regulation of Smad activators 2 and 4 and up-regulation of repressor Smad 7 (Gülçin, 2010).

In a Combined Treatment against Lung Cancer: In Vitro Studies
In vitro studies demonstrated the following aspects: 1. Pre-treatment of A549 and H460 cells with RSV accompanied by Gy IR treatment lead to a synergistic augmentation of the IR-persuaded cell death in NSCLC over an apoptosis-autonomous process. This process enhanced the percentile of SA-_-gal positive senescent cells with a raise in double-stranded DNA discontinuities.

Combinational treatment of H-2452 cells using
RSV and Clofarabine demonstrated a synergistic diminution in Msl-1 protein expression with a slight consequence of Bcl-xL expression. The intensi ication in apoptosis observed via combination treatment using RSV and Clofarabine was instituted through G2/M phase cell cycle detention and augmented caspase-3 and -7 commotion along with an intensi ication in caspase-3 cleavage (Nakagawa et al., 2012).   (Gülçin, 2010).

Cardiovascular disease
After intake of red wine, Resveratrol elevates the activity of endothelial NO synthase. This enzyme is used for the production of potent vasodilator NO. This drug also reduces the activity of vasoconstrictor ET. It also results in the protection of the cardiac system by suppressing the aggregation of platelets (Das et al., 2007).
RESV exhibits its mode of action in treating various diseases and ailments. The action of RESV in treating atherosclerosis, hypertension, ischemia and angiogenesis is described in Table 4.

Pharmacokinetics of resveratrol
Absorption: well absorbed Metabolism RSV extensively undergoes irst-pass metabolism in the small intestine and liver. De Santi et al. carried out studies and it was observed that RSV undergoes extensive sulfation and glucuronidation in the liver and duodenum.

Dose
A repeatedly -dosing study of RSV in four discrete groups of 10 volunteers, using six doses daily of trans-resveratrol at 25, 50, 100, or 150 mg for 13 doses, discovered a mean peak plasma concentration at 48-90 minutes after subsequent dosing. Substantial discrete studies in volunteers exhibited inconsistency in absorption. Though a mean half-life of 1-3 hours was inveterate after an individual dose, and 2-5 hours after succeeding dosing. An individual-dose study in which 40 volunteers were provided with one out of four doses (0.5, 1.0, 2.5, or 5.0 g) exhibited peak plasma transresveratrol stages at 1.5 hours. The mean peak plasma levels of resveratrol scaled from 73-539 ng/mL (0.3-2.4µmol) transversely the dosing schedule (Rotches-Ribalta et al., 2012).
Additionally, resveratrol has a short initial half-life 8-14 min for the chief substance and is metabolized expansively in the human body.

Researchers
Walle177 et al.

Observation
Large IV dose of RSV is transformed to sulphate substitutes within~30 min in peoples. Metabolites derived from urine were resveratrol monosulphate, two isomeric methods of resveratrol monoglucuronide, dihydro resveratrol monosulphate and dihydro resveratrol monoglucuronide (Radko et al., 2013).
The experimental data obtained by collecting plasma metabolites from experimental animals and the daily dose of RESV are discussed in Table 5.
The extreme abided dose of RSV has not been systematically resolute, but 300 mg per kilogram body mass exhibited no detrimental properties in rats. The plasma silhouette was igured out from the peak serum concentrations of~2.4 nM untouched RSV;~30-fold augmentation of RSV over serum concentrations has been pragmatically observed in the intestinal mucosa. The RSV was found in an accumulated amount in the sample of liver, bile, stomach, and kidneys latent interactions of resveratrol with the dietary constituents (Calder et al., 2009)

CONCLUSION
Resveratrol shows a high antiviral potential, which can be seen in both animals and human infections and also resveratrol shows its major mechanism of action towards various human-related diseases like antiaging, antiviral, cancer and as well as in cardiovascular diseases. Furthermore, research study and more clinical studies are required in order to ensure the safety of resveratrol and also for ascertaining the optimum doses for the prevention and treatment.