A miraculous compound for diseases treatment

Resveratrol: 

A miraculous natural compound for diseases treatment

Resveratrol is a nonflavonoid polyphenol that naturally occurs as phytoalexin. It is produced by plant sources such as grapes, apples, blueberries, plums, and peanut. This compound has critical roles in human health and is well known for its diverse biological activities such as antioxidant and anti‐inflammatory properties. Nowadays, due to rising incidence of different diseases such as cancer and diabetes, efforts to find novel and effective disease‐protective agents have led to the identification of plant‐derived compounds such as resveratrol. Furthermore, several in vitro and in vivo studies have revealed the effectiveness of resveratrol in various diseases such as diabetes mellitus, cardiovascular disease, metabolic syndrome, obesity, inflammatory, neurodegenerative, and age‐related diseases. 

Resveratrol is a phenolic micronutrient compound that is formed naturally by 70 different plant species such as grapes, berries, peanuts, and pines. This metabolite was initially recognized as an antibiotic produced in response to various environmental stresses, such as mechanical damage, microbial infection, UV radiation, heat, and pathogenic conditions. Overall, adverse effects of RSV have been minor and it appears to have a good safety. Nowadays, RSV attracts increasing attention due to naturally occurring compound and the wide range of biological activity and preventive effects on different diseases such as cancers, neurodegenerative diseases, cardiovascular disease, anti‐inflammatory, and antioxidant activities. In addition to RSV, different oligomers of this compound were found to exhibit broadly biological activities, such as antiviral, anti‐fungal, antibacterial, and anticancer activities. The overall aim of this study was to reveal the potential beneficial effects of resveratrol and its therapeutic mechanisms in various diseases.

Resveratrol and Diabetes

Diabetes mellitus is a metabolic disease, which affects approximately 5% of people worldwide. Type 1 and type 2 are the most common types of diabetes. Diabetes is associated with metabolic abnormalities and long‐term complications such as antipathies, cardiovascular disorders, retinopathy, renal disorder, and neuropathies. On the other hand, despite many attempts in the management of diabetes, current therapeutic methods are accompanied by side effects. Recent investigation indicates that resveratrol is a natural compound exerting numerous beneficial effects on diabetes, which are extensively studied in animal models and in diabetic humans.

Resveratrol and Heart Disease

Because of increased incidence of cardiovascular diseases (CVDs) including atherosclerosis, hypertension, stroke, ischemic heart disease, and heart failure, which are the major cause of mortality and morbidity in the world, more investigations are underway in this field. Potential cardio‐protective role of RSV against CVDs has also been suggested by studies. Several studies have been shown anti‐atherosclerotic, anti‐hypertensive, anti‐myocardial ischemia, anti‐stroke, and heart failure effects of it. Improvement of bioavailability of nitric oxide (NO) by RSV is one of the cardio‐protective mechanisms of this compound. NO contributes to improved vasodilation and decreased platelet aggregation, leukocyte recruitment, and proliferation of smooth muscle cells, which are inhibitors of atherosclerosis formation and progression. In general, the beneficial effects of RSV via oxygen‐derived radical scavenging or by increasing NO bioavailability in vitro could be promising against CVDs. In the case of anti‐atherosclerotic effects of RSV, atherosclerosis is now may be considered as an inflammatory disease. Since low‐density lipoproteins (LDLs) involved in atherosclerosis, improvement of lipid profile by RSV, could be an anti‐atherosclerotic potential therapeutic agent. Several preclinical studies have shown that RSV could affect lipid profile significantly via decreasing plasma triglyceride content, LDL cholesterol, and also increasing HDL cholesterol levels.

Resveratrol and Alzheimer’s

Alzheimer's disease (AD) is a neurodegenerative disorder and by far the most common cause of dementia. Studies have shown that resveratrol as a natural supplement was involved in various pathophysiologic cycles of AD. Antioxidant, anti‐amyloidogenic properties, and beneficial effects of resveratrol against neuro‐inflammation are promising in AD prevention. Oxidative stress by an excessive production of ROS in the brain has been strongly involved in the pathogenesis of AD. Because of low contents of antioxidants, the greater rate of oxygen consumption, and higher content of peroxidation of fatty acids, brain tissue is more susceptible to oxidative stress.

Resveratrol and Parkinson disease

Parkinson disease (PD) is a chronic and progressive neurodegenerative disease associated with impairment of motor functions. It is the second most common neurodegenerative disease and about 2% of people over the age of 65 suffer from the disease. Although environmental and genetic factors contribute to PD development, the exact etiology remains unclear yet. Mitochondrial dysfunction plays an important role in the pathogenesis of PD. Production of free radicals occurs in complex I inhibition, and then, oxidative stress could lead to PD. Several lines of evidence showed the improvement of mitochondrial respiratory capacities by RSV treatment. In fact, RSV activates SIRT1‐AMPK pathway and then induces PGC‐1alpha activity. PGC‐1alpha activation leads to mitochondrial biogenesis and amelioration of its function. Studies in PD experimental models have shown that antioxidant property of RSV protects dopaminergic neurons. Moreover, RSV‐mediated activation and expression of SIRT‐1 reduce alpha‐synuclein aggregation in PD. In summary, many environmental factors can activate oxidative pathway, which causes neurodegeneration. On the other hand, RSV has been shown to suppress oxidative pathway. Some studies reported synergic effects of RSV to improve age‐related cognitive decline in AD and PD.

Resveratrol and Cancer

Rates of death by cancer are increasing worldwide with an estimated 12 million deaths in 2030. The number of deaths related to cancer will be expected to be doubled each year in the future. Changes in diet and lifestyle are two main environmental factors causing cancer. RSV as a polyphenolic compound in plants has a broad protective activity against several types of cancer. Broad in vivo and in vitro investigations have performed in different types of cancer in recent years. PubMed (PubMed Central) was searched with resveratrol and cancer keywords resulted in 2,567 article in this regard. Abundant documents demonstrate the inhibitory effects of RSV on cancer cell growth, cell cycle, and apoptosis. In addition, RSV has the ability to induce differentiation in some cell lines. Nowadays, there is a growing attention to applying naturally occurring compounds as preventive and therapeutic agents in cancer management. Due to chemo‐resistance and lack of efficiency of common drugs used in cancer treatment, the development of new nature‐derived compounds with high efficiency and low toxicity seems to be essential for management of this dangerous disease. Results of RSV effects as anticancer agent indicated inhibitory effects of it in three stages of cancer including initiation, progression, and metastasis. In these studies, it was clear that RSV cause cell cycle arrest and finally apoptosis of tumour cells. In addition, many of anticancer properties of RSV were related to its antioxidation effects. Resveratrol as an antioxidant agent can lead to DNA damage prevention that is a major cause of tumour formation. RSV‐based chemoprevention and treatment of cancer consist of cellular and molecular mechanisms. One of the anticancer mechanisms of RSV is through induction of apoptosis. RSV causes apoptotic effects in various cell lines including JB6, HL‐60 cells, and various human cancer cell lines.

Resveratrol and Cancer Prevention

Cancer prevention property of RSV revealed in multiple studies; nevertheless, accurate anticancer mechanisms of RSV remained unknown. Induction of apoptosis is the main approach to cancer prevention as well as therapy. Induction of apoptosis by RSV reported in several in vitro cell culture and in vivo studies. P53 is a tumour‐suppressor gene and plays a critical role in resveratrol‐induced apoptosis.

Resveratrol and Kidney disease

Kidney disorders usually occur due to oxidative stress and inflammation. Polycystic kidney disease (PKD) is an autosomal dominant kidney disorder with mutations in polycystin‐1 (PC1) and polycystin‐2 (PC2) encoding genes (i.e., PKD1 and PKD2). These mutations are initiator cysts formation and progression of disease.  Anti‐inflammatory and antioxidant properties of RSV by inducing antioxidant enzymes production and modulating nuclear factors involved in the inflammation‐oxidative stress cycle and established in numerous studies; therefore, it can act as a novel therapeutic agent in kidney disease treatments demonstrated that RSV acts as an anti‐inflammatory substance, which delayed PKD progression through attenuation of NF‐κB‐induced inflammation. CKD, also known as chronic renal disease, is a progressive loss of kidney function. Of CKD^’s risk factors, inflammation and oxidative stress are most important. Given that inflammation and oxidative stress are related to CKD pathogenesis, RSV attracted specific interest in its treatment. In 2013, Liang et al. suggested that resveratrol inhibits oxidative stress and renal interstitial fibrosis in mice. In addition, polyphenol supplementation showed that antioxidant activity and lipid profile improvements in haemodialysis patients.

Resveratrol and Liver disorders

Liver disorders include several maladies such as inborn metabolic disease, alcoholic cirrhosis, viral hepatitis, and drug‐induced hepatotoxicity. The liver disease remains a major cause of morbidity and mortality with significant economic and social costs. Several novel approaches are currently being studied which may provide a better therapeutic outcome for sufferers. RSV, a grape polyphenol, has shown a considerable promise as a therapeutic agent in the treatment of the aforementioned liver ailments. The use of RSV supplements with therapeutic and protective potential has investigated in hepatic disease models. Several preclinical and clinical studies have demonstrated the therapeutic usefulness of RSV in several chronic illnesses such as arthritis, diabetes, neoplastic, and neurodegenerative diseases. Recently, the studies have shown that RSV has much therapeutic potential on liver disorders. RSV significantly decreased lipid accumulation and apoptosis and provided liver protection against chemical and alcohol‐induced injury. It is able to improve glucose metabolism and lipid profile and decrease liver steatosis. RSV improved hepatic lipid accumulation and progression of non-alcoholic steatohepatitis through down‐regulation of inflammatory signalling pathways. In a recent study, it was found that mice fed with a methionine–choline‐deficient diet and receive daily intra‐gastric administration of RSV (100 or 250 mg/kg body weight) resulted in reduction of hepatic steatosis and inflammation, while the curative effects of RSV were not seen in the improvement of steatohepatitis. In another study, the findings have shown that daily consumption of RSV with a dose of 500 mg for 12 weeks improved non-alcoholic fatty liver disease in a clinical trial. The bases for the beneficial effects of RSV are unclear yet. RSV has direct antioxidant effects but also stimulates the expression of antioxidant enzymes and the activity of SIRT‐1 and adenosine monophosphate AMPK both of which have major effects on glucose and fat metabolism and may play a role in aging.

Resveratrol and our Eyes

Glaucoma is a multifactorial neurodegenerative ocular disease which characterized by progressive apoptosis of retinal ganglion cells and mitochondrial dysfunction are damaging factors in glaucoma, and underlying mechanisms are under investigation still. Laser trabeculoplasty and surgery may be used to slow the disease progression. Luna et al. studied RSV effects on glaucoma markers in trabecular meshwork cells. In this study, the authors reported decreased production of iROS and inflammatory factors. The results of the recent studies have shown the antioxidant potency of RSV in trabecular meshwork cells. It is believed that neuroprotective drug from RGCs against apoptosis could be an effective way in the management of glaucoma. One of the factors that contribute to glaucoma pathogenesis is the role of mitochondrial dysfunction. In this regard, Chen and colleagues evaluated RSV‐induced mitochondrial biogenesis in retinal ganglion cell line RGC‐5. Diabetic retinopathy, the most common diabetic eye disease, occurs when the blood vessels of retina change. Sometimes, these vessels swell and leak fluid or even close off completely. In other cases, abnormal new blood vessels grow on the surface of the retina. Evaluation of the RSV effects on vascular damage and induction of VEGF in the retinas of mice with induced diabetes have shown that increasing of vessel leakage and VEGF protein levels are prevented by RSV treatment.  Li, Wang, Huang, and Zheng have shown that RSV has inhibition effects on endoplasmic reticulum stress (ERS), which is related to retinal vascular degeneration.

 Resveratrol antiviral effects

Antiviral effects of RSV have been investigated in several human and animal viruses. Results from most of these studies indicate that RSV can prevent inhibiting protein synthesis and thus inhibit virus proliferation. Chan evaluated the antimicrobial activity of RSV against bacteria and dermatophytes as skin infection agents and indicated the anti‐fungal effects of RSV. However, the author suggested that resveratrol may have also potential novel applications in diabetic wounds treatment.

In conclusion

Natural compounds for prevention and treatment of different diseases especially cancer and chronic diseases attracted more interest in recent years. Resveratrol is a natural polyphenol that is present in different human dietary sources. Investigations have shown that resveratrol supplementation has many beneficial effects for prevention and treatment of a variety of diseases with different pathophysiological mechanisms.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6261232/