Interestingly, Nrf2 and SIRT1 can positively coregulate each other. For example, treatments of either renal tubular cells or glomerular mesangial cells with resveratrol parallelly increased Nrf2 and SIRT1 expression. Knockdown of Nrf2 with siRNA decreases the expression levels of SIRT1, and vice versa. +erefore, resveratrol can sequentially or separately upregulate SIRT1 and Nrf2, while down regulation of Keap1 expression, resulting in increased expression of phase 2 antioxidant enzymes, which in turn protect the skin from UV irradiation- and oxidative stress-induced damage. Finally, one study showed that inhibition of phosphatidylinositol-3-kinase prevented the activation of Nrf2 induced by pterostilbene, a resveratrol analog, suggesting that resveratrol can also activate Nrf2 via activation of phosphatidylinositol- 3-kinase.For example, pretreatment of keratinocytes with resveratrol almost completely prevents the activation of NFκB induced by UVB irradiation, suggesting that resveratrol-induced inhibition of NFκB activation could contribute to its anti-UV irradiation properties. Resveratrol-induced upregulation of heat-shock protein 27 and down regulation of caspase 3 could also contribute to its anti-UV irradiation property. +us, resveratrol protects skin against UV irradiation and oxidative stress via multiple mechanisms.Both in vitro and in vivo studies have shown that resveratrol also inhibits proliferation, while stimulating apoptosis of cancer cells via several mechanisms. First,blueberry grow pot resveratrol induces apoptosis and phosphorylation of MAPK/ERK and MAPK/p38 in addition to increasing expression levels of caspase 3 and p53, while conversely, inhibition of p38 abolished its apoptotic effects.

It appears that resveratrol-induced phosphorylation of p53 and apoptosis is mediated by c-Jun NH2-terminal kinases because knockdown of c-Jun NH2-terminal kinase genes prevented both phosphorylation of p53 and apoptosis induced by resveratrol. +erefore, resveratrol-induced activation of the MAPK/p38 signaling pathway likely accounts, at least in part, for its anticancer effects. Regarding antiproliferation of cancer cells, resveratrol inhibits expression of MEK1-P and ERK1/2-P, leading to reductions in cyclin D1 and cyclin-dependent kinase 6 expression, resulting in cell cycle at rest. Moreover, resveratrol also decreased c-Jun levels and reduced DNA-binding and transcriptional activity of activator protein-1, which is required for initiation of DNA synthesis. Other studies showed that inhibition of NF-κB, cyclooxygenase 2, phosphatidylinositol-3-kinase, and P450 isoenzyme CYP1A1 and induction of caspases 3 and 9 also could contribute to anticancer effects of resveratrol. +us, resveratrol induced reductions in expression levels of MEK1-P and ERK1/2-P and decreased activator protein-1 activity could contribute to its inhibition of cancer cell proliferation.+e anti-inflammatory effects of resveratrol have been demonstrated in various in vivo and in vitro models, but the mechanisms of the actions of resveratrol are often unclear, depending on the inflammatory models employed in the studies. One possible mechanism is inhibition of NF-κB signaling pathways. Activation of NF-κB can upregulate transcription of cytokines while IκB inhibits NF-κB activity. Hence, degradation of phosphorylated IκB would increase NF-κB activity. Resveratrol-containing mixture inhibited IκB phosphorylation and decreased NF- κB, resulting in reductions in cytokine production in keratinocytes stimulated by TNF-α. Another study suggests that inhibition of cytokine production by resveratrol seems linked to upregulation of miR-17 expression in keratinocytes stimulated with lipopolysaccharide because inhibition of miR-17 overcame the inhibitory effects of resveratrol on inflammation.

But one study showed that resveratrol increases IL-8 production in keratinocytes stimulated with a combination of TNF-α and IFNc via upregulation of aryl hydrocarbon receptor expression. Inhibition of allergic contact dermatitis by resveratrol could be attributable to the down regulation of interferon regulatory factor 1/ STAT1 signaling pathway and inhibition of phosphorylation of MAPK/p38 and/or phospholipase Cc. Moreover, resveratrol inhibited proliferation and differentiation of CD+ T cells and proliferation of +17 T cells via upregulation of phosphorylated MAPK and downregulation of phosphorylated mammalian target of rapamycin in Jurkat cells. Furthermore, resveratrol-induced inhibition of TNF- α-induced cytokine production in fibroblasts is via activation of SIRT1 because knockdown of SIRT1 abolishes the inhibitory effect resveratrol on inflammation.Cutaneous wound healing is a complex process that can be accelerated by resveratrol via stimulation of neovascularization, keratinocyte differentiation, permeability barrier maturation, and antimicrobial activity. One study showed that resveratrol accelerates cutaneous wound healing and vascularization in aged rats through upregulation of SIRT1 and adenosine monophosphate-activated protein kinase pathway. +e role of SIRT1 signaling in vascularization has also been demonstrated in cutaneous wounds of diabetic mice. Topical applications of resveratrol to the wounded area of diabetic mice stimulated proliferation and inhibited apoptosis of endothelial cells, leading to accelerated wound healing, while either SIRT1 inhibitor or knockout of SIRT1 abolished the benefits of resveratrol in wound healing. SIRT1-mediated benefits of resveratrol in diabetic wound healing can also be attributable to protection of endothelial cells from oxidative stress. In addition, studies in mice indicate that resveratrol accelerates cutaneous wound healing by upregulation of vascular endothelial growth factor mediated by activation of at least two antioxidant enzymes. Because wound infections are the major cause of delayed wound healing, the antimicrobial properties of resveratrol could be another mechanism whereby wound healing is accelerated.

Lastly, the ultimate goal of cutaneous wound healing is the formation of intact permeability barrier, which requires both lipid production and keratinocyte differentiation. +us, resveratrol could also accelerate cutaneous wound healing through its well-known ability to stimulate keratinocyte differentiation and lipid production. Collectively, the resveratrol-induced acceleration of cutaneous wound healing can be attributable to activation of SIRT1 and AMPK signaling, antioxidative stress, and enhanced formation of epidermal permeability barrier.+e mechanisms whereby resveratrol induces apoptosis and inhibition of fibroblasts include inhibition of hypoxia-inducible factor 1, in which activation stimulates fibroblast proliferation while inhibiting apoptosis, downregulation of transforming growth factor β1, miR-17, as well as expression levels of mRNA for collagen 1 and procollagen 3, whereas resveratrolinduced upregulation of antimicrobial peptides is via enhancing expression of sphingosine-1-phosphate, leading to activation of N-FκB-C/EBPα signaling pathway. Resveratrol inhibits melanogenesis by at least four different mechanisms: in human melanocyte cultures, resveratrol inhibited tyrosinase synthesis and activity along with accelerated transport of newly synthesized tyrosinase to proteasomal complex, without dramatic alterations in mRNA levels of either melanocytic microphthalmia-associated transcription factor or tyrosinase; in melan-A cells, inhibition of melanogenesis by resveratrol is via induction of autophagy, leading to reduction in α melanocyte-stimulating hormone levels. +e latter stimulates melanin production and release via activation of melanocortin-1 receptor. Deletion of autophagy-related genes could prevent resveratrol-induced reduction in melanogenesis; in human melanocyte cultures, resveratrol activated c-Jun N-terminal kinase,hydroponic bucket resulting downregulation of MITF expression; and anti-inflammatory effects of resveratrol can be an additional mechanism contributing to decreasing pigmentation. +e antioxidant properties of resveratrol largely account for its antiaging effects.Nutritional overload induced by high dietary intake of fats and sugars is one of the main causes of obesity. Increased consumption of fructose has been associated with the prevalence of metabolic syndrome and obesity. MetS is a group of conditions that elevate risk of cardiovascular disease, stroke, and diabetes type 2, and include glucose intolerance, hypertension, and hyperlipidemia, and only recently neurological dysfunction have become part of the scenario. Fructose is a functional/constitutional isomer of glucose naturally found in fruits and honey, and high fructose consumption is getting recognition as a major cause of MetS . Fructose is a natural sugar that when consumed as part of fruits, vegetables and honey has healthy benefits. For example, blueberry powder dietary supplementation, which contains a high concentration of fructose, counteracts several of the deleterious effects of brain trauma. Since fructose has a chemical structure similar to glucose, and does not directly stimulate insulin secretion , the presence of this compound in the diet produces a lower increase in blood glucose when compared to the amount of other carbohydrates. Furthermore, the presence of water, fiber and antioxidants in the fruit causes fructose to be absorbed more slowly and thus tolerable to the body. On the other hand, fructose when ingested in high concentration for a prolonged time as an additive to meals has a myriad of unhealthy consequences within the spectrum of MetS, such as obesity, systemic inflammation, and behavioral dysfunction. In addition, the long term consumption of high fructose can result in development of nonalcoholic fatty liver disease, a manifestation of MetS which is common in Western industrialized countries. An increasing line of clinical and experimental evidence indicates that high fructose consumption correlates with rising rates of neurologic disorders, such that the study of the mechanisms involved on the impact of fructose on the brain is becoming an area of intense research. Research so far indicates that fructose can affect the brain directly and/ or indirectly by involving peripheral metabolism. This review will mainly discuss how fructose affects the brain via systemic physiology, as the direct effects of fructose on brain cells have been thoroughly reviewed somewhere else. Most fructose is metabolized in the liver after being absorbed by the intestine to the bloodstream. Given the action of liver on detoxification, synthesis of lipids and proteins essential for brain homeostasis, liver dysfunction can have devastating consequences for the brain.

We are starting to understand that liver disorders such as hepatic encephalopathy have serious neurological consequences that have been out of sight of mainstream studies. It is becoming to be understood that byproducts of fructose metabolism in the liver such as triglycerides and other lipid forms may influence brain function. Before agriculture was developed around 10,000 years ago, hunting, gathering, and fishing were the main strategies to procure food. Food was scarce and unpredictable to obtain such that accumulation of calories in the form of adipose tissue was an important strategy to survive times of scarcity. In this context, consumption of foods high in caloric content provided to our ancestors a secure way to cope with times of rainy days. Although it is difficult to establish how much sugar our prehistoric ancestors consumed, it is plausibly that wild fruits and honey were accessible to our ancestors, particularly to those who lived in regions of warm climate and forest such as in the African continent. Nowadays, regions in Tanzania are considered living remnant of full time hunter-gatherers, in which contemporary inhabitants live on what they find: game, plants, honey and fruits rich in fructose. It is important to consider that food procurement demanded high levels of physical activity for our ancestors, and this activity seems to have provided the caloric balance necessary to maintain overall health. The advent of agriculture approximately 10,000 years ago provided a more secure supply of foods, including fruits rich in fructose. The industrial revolution of the nineteen century represents a dramatic game changer for dietary practices as it enabled massive production of processed foods containing high levels of sugary components. In particular, high-fructose corn syrup , main form of currently consumed fructose in the U.S., was launched to market in 1970 based on enhanced sweetness and low price. Depending on the type of HFCS, fructose occupies between 42% and 55% of its composition. Today, fructose is widely consumed in many types of processed foods and fructose appears as an important factor in metabolic and neurological disorders. It has been shown that fructose exerts an impact on metabolic genes related to several metabolic disorders. It is noteworthy that the genomic makeup of living individuals is the product of dietary habits occurring thousands of years ago, as mutations occur in the range of many thousands of years. Therefore, increases in fructose consumption pose a big challenge to our conservative genes, and current habits can tip homeostatic balance towards disease stages. These limitations are even more alarming when considering that sudden increases in sugar consumption post-industrialization have been accompanied by a dramatic decrease in exercise. Although isolated fructose is poorly absorbed by the intestine, over-consumption of fructose results in unhealthy metabolic phenotypes including increased intrahepatic fat content, decreased insulin sensitivity, dyslipidemia and adiposity. In spite of the slow absorption rate of fructose by part of the intestine, excessive dietary fructose can remain in the gut for extensive time as fructose can reach up to a concentration of 2–3 mM before being utilized. The fructose in the gut is transported into the enterocyte through the specific fructose transporter GLUT5, independently from ATP hydrolysis and sodium absorption. Once inside the enterocyte, fructose is transported into the bloodstream via the GLUT2 transporter. It is noteworthy that excessive dietary fructose can overwhelm the absorptive capacity of the small intestine leading to incomplete absorption of fructose.