Skin cancer is the most frequently diagnosed cancer in the United States, and solar UVR is an established causative factor for approximately 90% of these cases. Despite efforts aimed at UV protection, including use of sunscreen and clothing, annual cases of skin cancer continue to rise. Here, we report that dietary grape powder mitigates UVB-mediated skin carcinogenesis in an SKH-1 hairless mouse model. Using a UVB initiationpromotion protocol, whereby mice were exposed to 180 mJ/cm 2 UVB two times per week for 28 weeks, we determined the effects of a grape powder-fortified diet (3% or 5%) on skin carcinogenesis. Grape powder consumption at both doses resulted in marked inhibition in tumor incidence, as well as a delay in onset of tumorigenesis. Molecular analyses of skin and tumor tissue showed that grape powder-mediated protective response against UVB-induced skin cancer was accompanied by enhanced DNA damage repair, reduced proliferation, increased apoptosis, and modulations in several oxidative stress markers specifically related to inhibition of oxidative stress and increased reactive oxygen species metabolism. NRF2, an activator of cellular antioxidant response, was decreased by grape powder feeding, suggesting a supportive role in tumor cell survival. Overall, our study suggested that dietary grape, containing several antioxidants in natural amalgamation, may protect against UVB-mediated skin carcinogenesis.

Prostate Cancer (PCa) is a leading cause of cancer-related morbidity and mortality in men. Therefore, novel mechanistically-driven approaches are needed for PCa management. Here, we determined the effects of grape antioxidants quercetin and/or resveratrol (60 and 600 mg/kg, respectively, in diet) against PCa in Transgenic Adenocarcinoma of Mouse Prostate (TRAMP)-model in prevention and intervention settings. We found resveratrol alone and in combination significantly inhibited prostate tumorigenesis in prevention setting, while the same was seen only in combination after intervention. The observed effects were associated with marked inhibition in proliferation, oxidative stress, and tumor survival markers, and induced apoptosis markers. Utilizing PCa PCR array analysis with prevention tumor tissues, we identified that quercetin–resveratrol modulates genes involved in promoter methylation, cell cycle, apoptosis, fatty acid metabolism, transcription factors, androgen response, PI3K/AKT and PTEN signaling. Ingenuity Pathway Analysis (IPA) identified IGF1 and BCL2 as central players in two gene networks. Functional annotation predicted increased apoptosis and inhibited cell viability/proliferation, hyperplasia, vasculogenesis, and angiogenesis with dual treatment. Furthermore, IPA predicted upstream inhibition of major PCa signaling VEGF, Ca2+, PI3K, CSF2, PTH). Based on PCR array, we identified decreased levels of EGFR, EGR3, and IL6, and increased levels of IGFBP7 and NKX3.1, overall supporting anti-PCa effects of quercetin–resveratrol.

Non-melanoma skin cancers (NMSCs) are the most diagnosed cancers in the US and occur more frequently in males. We previously demonstrated chemoprotective effects of dietary grape powder (GP) against UVB-mediated skin tumorigenesis in female SKH-1 mice. To expand on this, here, we determined the effects of GP in a short-term UVB exposure protocol (0 or 5% GP, followed by UVB every other day for 2 weeks) in male and female SKH-1 mice, as well as explored any sex-related differences in UVB carcinogenesis via male SKH-1 mice (0, 3, or 5% GP; UVB twice weekly for 28 weeks). In the short-term study, we found that GP protects against early-stage epithelial hyperplasia and mast cell infiltration in both sexes. In the long term, GP markedly reduced tumor counts and malignant conversion, along with significant decreases in mast cell infiltration, serum IgE and Eotaxin. We also found inhibition of P38 phosphorylation and reduced PCNA, Ki67 and BCL2 levels, suggesting that the anti-inflammatory effects of GP inhibits P38, acting as an upstream regulator to inhibit proliferation and reduce tumor cell survival. Together, GP appears to protect against UVB-mediated skin damage and carcinogenesis in SKH-1 mice and should be explored further as a supplement for NMSC prevention.

Melanoma incidences are increasing rapidly, and ultraviolet (UV) radiation from the sun is believed to be its major contributing factor. UV exposure causes DNA damage in skin which may initiate cutaneous skin cancers including melanoma. Melanoma arises from melanocytes, the melanin-producing skin cells, following genetic dysregulations resulting into hyperproliferative phenotype and neoplastic transformation. Both UVA and UVB exposures to the skin are believed to trigger melanocytic hyperplasia and melanomagenesis. Melanocytes by themselves are deficient in repair of oxidative DNA damage and UV-induced photoproducts. Nicotinamide, an active form of vitamin B3 and a critical component of the human body's defense system has been shown to prevent certain cancers including nonmelanoma skin cancers. However, the mechanism of nicotinamide's protective effects is not well understood. Here, we investigated potential protective effects and mechanism of nicotinamide against UVA- and/or UVB- induced damage in normal human epidermal melanocytes. Our data demonstrated an appreciable protective effect of nicotinamide against UVA- and/or UVB- induced DNA damage in melanocytes by decreasing both cyclobutane pyrimidine dimers and 8-hydroxy-2'-deoxyguanosine levels. We found that the photoprotective response of nicotinamide was associated with the activation of nucleotide excision repair genes and NRF2 signaling. Further studies are needed to validate our findings in in vivo models.

We recently showed that dietary grape powder (GP) imparts considerable protection against ultraviolet B (UVB)-mediated skin carcinogenesis in SKH-1 mice. To determine molecular mechanisms of this response, we employed tandem mass tag (TMT) quantitative global proteomics approach on skin tumors from mice exposed to 180 mJ/cm2 UVB twice per week and fed control or 5% GP diet. We found 2629 proteins modulated by GP feeding, with 34 identified using stringent cutoffs (false discovery rate (FDR) q-value ≤ 0.1, fold change ≥ 1.2, p-value ≤ 0.05, ≥ 3 unique peptides). Ingenuity Pathway Analysis helped identify seven proteins involved in protein ubiquitination, including the deubiquitinase UCHL5 and 6 subunits of the 20S proteasome (PSMA1,3,4,6 and PSMB4,7). A second data set without the FDR q-value identified 239 modulated proteins, seven of which are involved in protein ubiquitination. Further, 14 proteins involved in acute phase response signaling were modulated >1.5-fold, including acute phase proteins APCS, FGA, FGB, HP, HPX, and RBP1. Evaluation of upstream regulators found inhibition of ERK1/2 phosphorylation and NF-κB p65, and an increase in IκBα in GP-treated tumors. Overall, our data suggested that GP consumption may mitigate tumorigenesis by enhancing protein ubiquitination and degradation caused by oxidative stress, and manipulates an otherwise tumor-promoting anti-inflammatory environment.

Skin is arguably the largest organ of the body and is continuously subjected to intrinsic, extrinsic, and environmental stresses. Therefore, skin developed elaborate mechanisms to maintain homeostasis, including antioxidant, antiinflammatory, and DNA damage repair capabilities. However, repeated and excessive stresses can overwhelm these systems, causing serious cutaneous damages, including skin carcinogenesis. Phytonutrients present in the diet possess a myriad of health-promoting effects by protecting skin from damaging free radicals as well as by other mechanisms. Although many chemoprotective phytonutrients have been shown to be efficacious individually, a combination of multiple agents could have synergistic response in curtailing or preventing cutaneous damages. Here, we discuss the benefits of natural amalgamation of phytonutrients in select fruits against skin damage including carcinogenesis. However, a majority of these studies have been done in preclinical models. Therefore, clinical studies are needed to determine the human relevance of the available preclinical data, especially in the human population who are at higher risk for skin cancers (e.g., organ transplant patients). In addition, detailed well-structured preclinical animal studies in the models of high-risk skin carcinogenesis could also be useful toward informing the design for human trials.

No abstract

Atopic dermatitis (AD) is a chronic inflammatory skin disease with significant health/economic burdens. Existing therapies are not fully effective, necessitating development of new approaches for AD management. Here, we report that dietary grape powder (GP) mitigates AD-like symptoms in 2,4-dinitrofluorobenzene (DNFB)-induced AD in NC/NgaTndCrlj mice. Using prevention and intervention protocols, we tested the efficacy of 3% and 5% GP-fortified diet in a 13-weeks study. We found that GP feeding markedly inhibited development and progression of AD-like skin lesions, and caused reduction in i) epidermal thickness, mast cell infiltration, ulceration, excoriation and acanthosis in dorsal skin, ii) spleen weight, extramedullary hematopoiesis and lymph nodes sizes, and iii) ear weight and IgE levels. We also found significant modulations in 15 AD-associated serum cytokines/chemokines. Next, using quantitative global proteomics, we identified 714 proteins. Of these, 68 (normal control) and 21 (5% GP-prevention) were significantly modulated (≥2-fold) vs AD control (DNFB-treated) group, with many GP-modulated proteins reverting to normal levels. Ingenuity pathway analysis of GP-modulated proteins followed by validation using ProteinSimple identified changes in acute phase response signaling (FGA, FGB, FGG, HP, HPX, LRG1). Overall, GP supplementation inhibited DNFB-induced AD in NC/NgaTndCrlj mice in both prevention and intervention trials, and should be explored further.