4 research outputs found
The Putative Role of Resveratrol in SIRT-1 Mediated Modulation of the Vitamin D Pathway
The nuclear vitamin D receptor (VDR) modulates gene transcription in 1,25-dihydroxyvitamin D (1,25D) target tissues such as kidney, colon, and bone. The 1,25D hormone is derived from vitamin D in the skin or from the diet, and binds to and activates the VDR. We have previously shown that resveratrol, an antioxidant found in the skin of red grapes, has the ability to activate the VDR signaling pathway. Moreover, cells treated with both resveratrol and 1,25D resulted in an additive or even synergistic stimulation of VDR-mediated transcription compared to cells treated with 1,25D alone. Based on these initial results, experiments were designed to test the significance of mutations in the hormone-binding domain of VDR. Identical hormone treatments were applied to âwild-typeâ (non-mutated) and single point VDR mutations. 1,25D displayed a significant drop in activity caused by these mutations, while the ability of resveratrol to activate VDR was only modestly attenuated. One possible interpretation of these results is that resveratrol may affect VDR activity indirectly, perhaps via the ability of resveratrol to activate SIRT1, an enzyme which has been shown to deacetylate (and thereby activate) other nuclear receptors such as the liver X receptor (LXR). In support of this hypothesis, radiolabeled 1,25D displacement assays revealed an increase in bound radiolabeled 1,25D only in the presence of resveratrol, suggesting that direct binding of resveratrol to VDR is unlikely. Additionally, we observed increased transcriptional activity in response to resveratrol in a subset of other nuclear receptors, including the liver X receptor (LXR), which is closely related to VDR and is known to be deacetylated by SIRT1. Finally, we tested receptor-mediated transcriptional activity in a system containing VDR in the absence and presence of overexpressed SIRT1. Transcriptional activity was higher in cells expressing SIRT1, and synergistic activity of 1,25D combined with resveratrol was observed. We are currently conducting additional experiments employing the VDR/SIRT1 assay in multiple cellular contexts. In conclusion, this study elucidates, for the first time, a potential novel pathway for crosstalk between two nutritionally derived lipids, vitamin D and resveratrol
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Vitamin D, Resveratrol, and Control of LCE3 Genes with Implications for Psoriasis
A Thesis submitted to The University of Arizona College of Medicine - Phoenix in partial fulfillment of the requirements for the Degree of Doctor of Medicine.Psoriasis (Psx) is a chronic inflammatory skin disease with abnormal keratinocyte proliferation and differentiation. One genetic risk factor for psoriasis (denoted PSORS4) is a deletion of LCE3B and LCE3C genes encoding structural proteins in terminally differentiated keratinocytes. Analogs of the hormonal form of vitamin D, 1,25âdihydroxyvitamin D3 (1,25D) are routinely used to treat Psx, a skin disease that affects over 7 million patients in the US. However, this therapy, even when combined with an antiâinflammatory (e.g., betamethasone), is ineffective in some patients, particularly those with a severe disease phenotype, underscoring the need for better agents. Further, the mechanism of action of vitamin D analogs is not understood, although their ability to reduce proliferation and promote differentiation of psoriatic keratinocytes is both valued in therapy and is complementary to antiâinflammatory agents. Given that 1,25D acts via the vitamin D receptor (VDR) to regulate gene expression, this project is focused on elucidating expression alterations in psoriasisrelevant genes mediated by the 1,25Dâliganded VDR in human keratinocytes. Whereas VDR activity is increased when bound to 1,25D, less is known about the ability of other nutritionallyderived lipids to act on VDR. The current study is designed to: 1) evaluate resveratrol, an antioxidant found in the skin of red grapes, as an effector of VDR signaling and potent activator of LCE gene transcription in human keratinocytes, and 2) determine whether resveratrol acts synergistically with 1,25D to regulate the expression of LCE3 genes, with the potential to boost skin repair and ameliorate the symptoms of psoriasis.This item is part of the College of Medicine - Phoenix Scholarly Projects 2016 collection. For more information, contact the Phoenix Biomedical Campus Library at [email protected]
Granular cell tumor in the scrotum of a pediatric patient: A case report of a rare clinical entity
Granular cell tumors are rare tumors of Schwann cell origin that present in any anatomic location, age or sex. We present a case of a granular cell tumor in the scrotum of a prepubescent male. The tumor was excised, with histology revealing abundant eosinophilic cytoplasm and positive S-100 staining. No stigmata of malignancy were identified and no recurrence has been reported during follow-up
Testicular relapse of acute lymphoblastic leukemia
Contemporary chemotherapy regimens have led to improved survival and decreased incidence of testicular relapse for pediatric patients with acute lymphoblastic leukemia (ALL). Local therapies to the testes, such as radiotherapy and orchiectomy, are often not necessary given that high-dose chemotherapy agents can overcome the relative blood-testis barrier. However, urologists should be aware of clinical scenarios involving ALL which still warrant testicular biopsy to guide management. Here, we present a case of a 12-year-old boy with high-risk pre-B cell ALL presenting with a testicular relapse and a clinical presentation overlapping with non-infectious epididymo-orchitis