The Experts below are selected from a list of 258 Experts worldwide ranked by ideXlab platform
Andrzej Slominski - One of the best experts on this subject based on the ideXlab platform.
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HydroxyLumisterols, Photoproducts of Pre-Vitamin D3, Protect Human Keratinocytes against UVB-Induced Damage.
International journal of molecular sciences, 2020Co-Authors: Anyamanee Chaiprasongsuk, Zorica Janjetovic, Tae Kang Kim, Edith K.y. Tang, Robert C. Tuckey, Uraiwan Panich, Chander Raman, Cynthia J. Schwartz, Andrzej SlominskiAbstract:Lumisterol (L3) is a stereoisomer of 7-dehydrocholesterol and is produced through the photochemical transformation of 7-dehydrocholesteol induced by high doses of UVB. L3 is enzymatically hydroxylated by CYP11A1, producing 20(OH)L3, 22(OH)L3, 20,22(OH)2L3, and 24(OH)L3. HydroxyLumisterols function as reverse agonists of the retinoic acid-related orphan receptors α and γ (RORα/γ) and can interact with the non-genomic binding site of the vitamin D receptor (VDR). These intracellular receptors are mediators of photoprotection and anti-inflammatory activity. In this study, we show that L3-hydroxyderivatives significantly increase the expression of VDR at the mRNA and protein levels in keratinocytes, both non-irradiated and after UVB irradiation. L3-hydroxyderivatives also altered mRNA and protein levels for RORα/γ in non-irradiated cells, while the expression was significantly decreased in UVB-irradiated cells. In UVB-irradiated keratinocytes, L3-hydroxyderivatives inhibited nuclear translocation of NFκB p65 by enhancing levels of IκBα in the cytosol. This anti-inflammatory activity mediated by L3-hydroxyderivatives through suppression of NFκB signaling resulted in the inhibition of the expression of UVB-induced inflammatory cytokines, including IL-17, IFN-γ, and TNF-α. The L3-hydroxyderivatives promoted differentiation of UVB-irradiated keratinocytes as determined from upregulation of the expression at the mRNA of involucrin (IVL), filaggrine (FLG), and keratin 14 (KRT14), downregulation of transglutaminase 1 (TGM1), keratins including KRT1, and KRT10, and stimulation of ILV expression at the protein level. We conclude that CYP11A1-derived hydroxyLumisterols are promising photoprotective agents capable of suppressing UVB-induced inflammatory responses and restoring epidermal function through targeting the VDR and RORs.
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The Role of Classical and Novel Forms of Vitamin D in the Pathogenesis and Progression of Nonmelanoma Skin Cancers.
Advances in experimental medicine and biology, 2020Co-Authors: Andrzej Slominski, Rebecca S Mason, Michal A. Zmijewski, Zorica Janjetovic, Tae Kang Kim, Robert C. Tuckey, Radomir M. Slominski, Anna A. Brożyna, Anton M. Jetten, Purushotham GurojiAbstract:Nonmelanoma skin cancers including basal and squamous cell carcinomas (SCC and BCC) represent a significant clinical problem due to their relatively high incidence, imposing an economic burden to healthcare systems around the world. It is accepted that ultraviolet radiation (UVR: λ = 290–400 nm) plays a crucial role in the initiation and promotion of BCC and SCC with UVB (λ = 290–320 nm) having a central role in this process. On the other hand, UVB is required for vitamin D3 (D3) production in the skin, which supplies >90% of the body’s requirement for this prohormone. Prolonged exposure to UVB can also generate tachysterol and Lumisterol. Vitamin D3 itself and its canonical (1,25(OH)2D3) and noncanonical (CYP11A1-intitated) D3 hydroxyderivatives show photoprotective functions in the skin. These include regulation of keratinocyte proliferation and differentiation, induction of anti-oxidative responses, inhibition of DNA damage and induction of DNA repair mechanisms, and anti-inflammatory activities. Studies in animals have demonstrated that D3 hydroxyderivatives can attenuate UVB or chemically induced epidermal cancerogenesis and inhibit growth of SCC and BCC. Genomic and non-genomic mechanisms of action have been suggested. In addition, vitamin D3 itself inhibits hedgehog signaling pathways which have been implicated in many cancers. Silencing of the vitamin D receptor leads to increased propensity to develop UVB or chemically induced epidermal cancers. Other targets for vitamin D compounds include 1,25D3-MARRS, retinoic orphan receptors α and γ, aryl hydrocarbon receptor, and Wnt signaling. Most recently, photoprotective effects of Lumisterol hydroxyderivatives have been identified. Clinical trials demonstrated a beneficial role of vitamin D compounds in the treatment of actinic keratosis. In summary, recent advances in vitamin D biology and pharmacology open new exciting opportunities in chemoprevention and treatment of skin cancers.
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Neuroendocrine Aspects of Skin Aging
International journal of molecular sciences, 2019Co-Authors: Georgeta Bocheva, Radomir M. Slominski, Andrzej SlominskiAbstract:Skin aging is accompanied by a gradual loss of function, physiological integrity and the ability to cope with internal and external stressors. This is secondary to a combination of complex biological processes influenced by constitutive and environmental factors or by local and systemic pathologies. Skin aging and its phenotypic presentation are dependent on constitutive (genetic) and systemic factors. It can be accelerated by environmental stressors, such as ultraviolet radiation, pollutants and microbial insults. The skin’s functions and its abilities to cope with external stressors are regulated by the cutaneous neuroendocrine systems encompassing the regulated and coordinated production of neuropeptides, neurohormones, neurotransmitters and hormones, including steroids and secosteroids. These will induce/stimulate downstream signaling through activation of corresponding receptors. These pathways and corresponding coordinated responses to the stressors decay with age or undergo pathological malfunctions. This affects the overall skin phenotype and epidermal, dermal, hypodermal and adnexal functions. We propose that skin aging can be attenuated or its phenotypic presentation reversed by the topical use of selected factors with local neurohormonal activities targeting specific receptors or enzymes. Some of our favorite factors include melatonin and its metabolites, noncalcemic secosteroids and Lumisterol derivatives, because of their low toxicity and their desirable local phenotypic effects.
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CYP27A1 acts on the pre-vitamin D3 photoproduct, Lumisterol, producing biologically active hydroxy-metabolites
The Journal of steroid biochemistry and molecular biology, 2018Co-Authors: Robert C. Tuckey, Tae Kang Kim, Chloe Y.s. Cheng, Katie M. Wang, Saowanee Jeayeng, Andrzej SlominskiAbstract:Abstract Prolonged exposure of the skin to UV radiation causes previtamin D3, the initial photoproduct formed by opening of the B ring of 7-dehydrocholesterol, to undergo a second photochemical reaction where the B-ring is reformed giving Lumisterol3 (L3), a stereoisomer of 7-dehydrocholesterol. L3 was believed to be an inactive photoproduct of excessive UV radiation whose formation prevents excessive vitamin D production. Recently, we reported that L3 is present in serum and that CYP11A1 can act on L3 producing monohydroxy- and dihydroxy-metabolites which inhibit skin cell proliferation similarly to 1α,25-dihydroxyvitamin D3. In this study we tested the ability of human CYP27A1 to hydroxylate L3. L3 was metabolized by purified CYP27A1 to 3 major products identified as 25-hydroxyL3, (25R)-27-hydroxyL3 and (25S)-27-hydroxyL3, by NMR. These three products were also seen when mouse liver mitochondria containing CYP27A1 were incubated with L3. The requirement for CYP27A1 for their formation by mitochondria was confirmed by the inhibition of their synthesis by 5β-cholestane-3α,7α,12α-triol, an intermediate in bile acid synthesis which serves as an efficient competitive substrate for CYP27A1. CYP27A1 displayed a high kcat for the metabolism of L3 (76 mol product/min/mol CYP27A1) and a catalytic efficiency (kcat/Km) that was 260-fold higher than that for vitamin D3. The CYP27A1-derived hydroxy-derivatives inhibited the proliferation of cultured human melanoma cells and colony formation with IC50 values in the nM range. Thus, L3 is metabolized efficiently by CYP27A1 with hydroxylation at C25 or C27 producing metabolites potent in their ability to inhibit melanoma cell proliferation, supporting that L3 is a prohormone which can be activated by CYP-dependent hydroxylations.
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On the role of skin in the regulation of local and systemic steroidogenic activities
Steroids, 2015Co-Authors: Andrzej Slominski, Pulak R. Manna, Robert C. TuckeyAbstract:The mammalian skin is a heterogeneous organ/tissue covering our body, showing regional variations and endowed with neuroendocrine activities. The latter is represented by its ability to produce and respond to neurotransmitters, neuropeptides, hormones and neurohormones, of which expression and phenotypic activities can be modified by ultraviolet radiation, chemical and physical factors, as well as by cytokines. The neuroendocrine contribution to the responses of skin to stress is served, in part, by local synthesis of all elements of the hypothalamo-pituitary-adrenal axis. Skin with subcutis can also be classified as a steroidogenic tissue because it expresses the enzyme, CYP11A1, which initiates steroid synthesis by converting cholesterol to pregnenolone, as in other steroidogenic tissues. Pregnenolone, or steroidal precursors from the circulation, are further transformed in the skin to corticosteroids or sex hormones. Furthermore, in the skin CYP11A1 acts on 7-dehydrocholesterol with production of 7-dehydropregnolone, which can be further metabolized to other Δ7steroids, which after exposure to UVB undergo photochemical transformation to vitamin D like compounds with a short side chain. Vitamin D and Lumisterol, produced in the skin after exposure to UVB, are also metabolized by CYP11A1 to several hydroxyderivatives. Vitamin D hydroxyderivatives generated by action of CYP11A1 are biologically active and are subject to further hydroxylations by CYP27B1, CYP27A1 and CP24A. Establishment of which intermediates are produced in the epidermis in vivo and whether they circulate on the systemic level represent a future research challenge. In summary, skin is a neuroendocrine organ endowed with steroid/secosteroidogenic activities.
Rebecca S Mason - One of the best experts on this subject based on the ideXlab platform.
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The Role of Classical and Novel Forms of Vitamin D in the Pathogenesis and Progression of Nonmelanoma Skin Cancers.
Advances in experimental medicine and biology, 2020Co-Authors: Andrzej Slominski, Rebecca S Mason, Michal A. Zmijewski, Zorica Janjetovic, Tae Kang Kim, Robert C. Tuckey, Radomir M. Slominski, Anna A. Brożyna, Anton M. Jetten, Purushotham GurojiAbstract:Nonmelanoma skin cancers including basal and squamous cell carcinomas (SCC and BCC) represent a significant clinical problem due to their relatively high incidence, imposing an economic burden to healthcare systems around the world. It is accepted that ultraviolet radiation (UVR: λ = 290–400 nm) plays a crucial role in the initiation and promotion of BCC and SCC with UVB (λ = 290–320 nm) having a central role in this process. On the other hand, UVB is required for vitamin D3 (D3) production in the skin, which supplies >90% of the body’s requirement for this prohormone. Prolonged exposure to UVB can also generate tachysterol and Lumisterol. Vitamin D3 itself and its canonical (1,25(OH)2D3) and noncanonical (CYP11A1-intitated) D3 hydroxyderivatives show photoprotective functions in the skin. These include regulation of keratinocyte proliferation and differentiation, induction of anti-oxidative responses, inhibition of DNA damage and induction of DNA repair mechanisms, and anti-inflammatory activities. Studies in animals have demonstrated that D3 hydroxyderivatives can attenuate UVB or chemically induced epidermal cancerogenesis and inhibit growth of SCC and BCC. Genomic and non-genomic mechanisms of action have been suggested. In addition, vitamin D3 itself inhibits hedgehog signaling pathways which have been implicated in many cancers. Silencing of the vitamin D receptor leads to increased propensity to develop UVB or chemically induced epidermal cancers. Other targets for vitamin D compounds include 1,25D3-MARRS, retinoic orphan receptors α and γ, aryl hydrocarbon receptor, and Wnt signaling. Most recently, photoprotective effects of Lumisterol hydroxyderivatives have been identified. Clinical trials demonstrated a beneficial role of vitamin D compounds in the treatment of actinic keratosis. In summary, recent advances in vitamin D biology and pharmacology open new exciting opportunities in chemoprevention and treatment of skin cancers.
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54. 1a,25-Dihydroxyvitamin D3 reduces several types of UV induced DNA damage in human ex vivo skin
Pathology, 2015Co-Authors: Eric J. Song, Clare Gordon-thomson, Vanessa B. Sequeira, Mark S Rybchyn, Gary M Halliday, Rebecca S MasonAbstract:1α,25dihydroxyvitamin D 3 (1,25(OH) 2 D 3 ) is produced in skin following exposure to ultraviolet radiation (UVR). On the other hand, UVR can also cause DNA damage. Cyclobutane pyrimidine dimers (CPD) are produced as a direct consequence of UVB exposure. Other photolesions, such as 8-oxo-7,8-dihydroguanosine (8-oxodG) and 8-nitroguanine (8-NG) are produced by UV-induced oxidative and nitrosative stress. All these DNA lesions are potentially mutagenic and may lead to photocarcinogenesis unless repaired promptly through DNA repair processes. Nitric oxide products and reactive nitrogen species (RNS) are known to hinder DNA repair and promote carcinogenesis. Previous studies have shown that 1,25(OH) 2 D 3 and the analog 1α,25(OH) 2 -Lumisterol (JN) protect skin cells from UV-induced DNA damage (CPD), immunosuppression and photocarcinogenesis in mice. 1 The aim of this study was to test whether topical application of 1,25(OH) 2 D 3 is also photoprotective in UV-irradiated human skin explants. UV-induced DNA damage was quantified by immunohistochemistry and image analysis using antibodies to 3 different types of DNA damage: CPD, 8-oxodG, and 8-NG. Quantification by image analysis showed 1,25(OH) 2 D 3 post-UVR, significantly reduced all 3 types of DNA damage. CPD was reduced by 57% (±SEM=2.6; p p p 2 D 3 (37% reduction; p p 2 D 3 reduces UV induced nitrosative stress in skin. This data suggests that 1,25(OH) 2 D 3 provides photoprotection in human ex vivo skin through reduction in UV induced CPD, oxidative and nitrosative stress.
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Novel vitamin D compounds and skin cancer prevention
Dermato-endocrinology, 2014Co-Authors: Wannit Tongkao-on, Clare Gordon-thomson, Vanessa B. Sequeira, Vivienne E. Reeve, Katie M Dixon, Eric J. Song, Sally E. Carter, Rebecca S MasonAbstract:As skin cancer is one of the most costly health issues in many countries, particularly in Australia, the possibility that vitamin D compounds might contribute to prevention of this disease is becoming increasingly more attractive to researchers and health communities. In this article, important epidemiologic, mechanistic and experimental data supporting the chemopreventive potential of several vitamin D-related compounds are explored. Evidence of photoprotection by the active hormone, 1α,25dihydroxyvitamin D3, as well as a derivative of an over-irradiation product, Lumisterol, a fluorinated analog and bufalin, a potential vitamin D-like compound, are provided. The aim of this article is to understand how vitamin D compounds contribute to UV adaptation and potentially, skin cancer prevention.
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1α 25 oh vitamin d and a nongenomic vitamin d analogue inhibit ultraviolet radiation induced skin carcinogenesis
Cancer Prevention Research, 2011Co-Authors: Katie M Dixon, Vanessa B. Sequeira, Vivienne E. Reeve, Anthony W. Norman, Ritu Mohan, Mark S Rybchyn, Gary M Halliday, Rebecca S MasonAbstract:Exposure to ultraviolet radiation (UVR) can lead to a range of deleterious responses in the skin. An important form of damage is the DNA photolesion cyclobutane pyrimidine dimer (CPD). CPDs can be highly mutagenic if not repaired prior to cell division and can lead to UV-induced immunosuppression, making them potentially carcinogenic. UVR exposure also produces vitamin D, a prehormone. Different shapes of the steroid hormone 1α,25-dihydroxyvitamin D₃ [1,25(OH)₂D₃] can produce biological responses through binding either to its cognate nuclear receptor (VDR) to regulate gene transcription or to the VDR associated with plasma membrane caveolae to produce, via signal transduction, nongenomic physiologic responses. Here, we show that both 1,25(OH)₂D₃ and 1α,25(OH)₂-Lumisterol (JN), a conformationally restricted analogue that can generate only nongenomic responses, are effective inhibitors of UV damage in an immunocompetent mouse (Skh:hr1) model susceptible to UV-induced tumors. Both 1,25(OH)₂D₃ and JN significantly reduced UVR-induced CPD, apoptotic sunburn cells, and immunosuppression. Furthermore, these compounds inhibited skin tumor development, both papillomas and squamous cell carcinomas, in these mice. The observed reduction of these UV-induced effects by 1,25(OH)₂D₃ and JN suggests a role for these compounds in prevention against skin carcinogenesis. To the best of our knowledge, this is the first comprehensive report of an in vivo long-term biological response generated by chronic dosing with a nongenomic-selective vitamin D steroid.
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1α,25(OH)₂-vitamin D and a nongenomic vitamin D analogue inhibit ultraviolet radiation-induced skin carcinogenesis.
Cancer prevention research (Philadelphia Pa.), 2011Co-Authors: Katie M Dixon, Vanessa B. Sequeira, Vivienne E. Reeve, Anthony W. Norman, Ritu Mohan, Mark S Rybchyn, Gary M Halliday, Rebecca S MasonAbstract:Exposure to ultraviolet radiation (UVR) can lead to a range of deleterious responses in the skin. An important form of damage is the DNA photolesion cyclobutane pyrimidine dimer (CPD). CPDs can be highly mutagenic if not repaired prior to cell division and can lead to UV-induced immunosuppression, making them potentially carcinogenic. UVR exposure also produces vitamin D, a prehormone. Different shapes of the steroid hormone 1α,25-dihydroxyvitamin D₃ [1,25(OH)₂D₃] can produce biological responses through binding either to its cognate nuclear receptor (VDR) to regulate gene transcription or to the VDR associated with plasma membrane caveolae to produce, via signal transduction, nongenomic physiologic responses. Here, we show that both 1,25(OH)₂D₃ and 1α,25(OH)₂-Lumisterol (JN), a conformationally restricted analogue that can generate only nongenomic responses, are effective inhibitors of UV damage in an immunocompetent mouse (Skh:hr1) model susceptible to UV-induced tumors. Both 1,25(OH)₂D₃ and JN significantly reduced UVR-induced CPD, apoptotic sunburn cells, and immunosuppression. Furthermore, these compounds inhibited skin tumor development, both papillomas and squamous cell carcinomas, in these mice. The observed reduction of these UV-induced effects by 1,25(OH)₂D₃ and JN suggests a role for these compounds in prevention against skin carcinogenesis. To the best of our knowledge, this is the first comprehensive report of an in vivo long-term biological response generated by chronic dosing with a nongenomic-selective vitamin D steroid.
Robert C. Tuckey - One of the best experts on this subject based on the ideXlab platform.
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HydroxyLumisterols, Photoproducts of Pre-Vitamin D3, Protect Human Keratinocytes against UVB-Induced Damage.
International journal of molecular sciences, 2020Co-Authors: Anyamanee Chaiprasongsuk, Zorica Janjetovic, Tae Kang Kim, Edith K.y. Tang, Robert C. Tuckey, Uraiwan Panich, Chander Raman, Cynthia J. Schwartz, Andrzej SlominskiAbstract:Lumisterol (L3) is a stereoisomer of 7-dehydrocholesterol and is produced through the photochemical transformation of 7-dehydrocholesteol induced by high doses of UVB. L3 is enzymatically hydroxylated by CYP11A1, producing 20(OH)L3, 22(OH)L3, 20,22(OH)2L3, and 24(OH)L3. HydroxyLumisterols function as reverse agonists of the retinoic acid-related orphan receptors α and γ (RORα/γ) and can interact with the non-genomic binding site of the vitamin D receptor (VDR). These intracellular receptors are mediators of photoprotection and anti-inflammatory activity. In this study, we show that L3-hydroxyderivatives significantly increase the expression of VDR at the mRNA and protein levels in keratinocytes, both non-irradiated and after UVB irradiation. L3-hydroxyderivatives also altered mRNA and protein levels for RORα/γ in non-irradiated cells, while the expression was significantly decreased in UVB-irradiated cells. In UVB-irradiated keratinocytes, L3-hydroxyderivatives inhibited nuclear translocation of NFκB p65 by enhancing levels of IκBα in the cytosol. This anti-inflammatory activity mediated by L3-hydroxyderivatives through suppression of NFκB signaling resulted in the inhibition of the expression of UVB-induced inflammatory cytokines, including IL-17, IFN-γ, and TNF-α. The L3-hydroxyderivatives promoted differentiation of UVB-irradiated keratinocytes as determined from upregulation of the expression at the mRNA of involucrin (IVL), filaggrine (FLG), and keratin 14 (KRT14), downregulation of transglutaminase 1 (TGM1), keratins including KRT1, and KRT10, and stimulation of ILV expression at the protein level. We conclude that CYP11A1-derived hydroxyLumisterols are promising photoprotective agents capable of suppressing UVB-induced inflammatory responses and restoring epidermal function through targeting the VDR and RORs.
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The Role of Classical and Novel Forms of Vitamin D in the Pathogenesis and Progression of Nonmelanoma Skin Cancers.
Advances in experimental medicine and biology, 2020Co-Authors: Andrzej Slominski, Rebecca S Mason, Michal A. Zmijewski, Zorica Janjetovic, Tae Kang Kim, Robert C. Tuckey, Radomir M. Slominski, Anna A. Brożyna, Anton M. Jetten, Purushotham GurojiAbstract:Nonmelanoma skin cancers including basal and squamous cell carcinomas (SCC and BCC) represent a significant clinical problem due to their relatively high incidence, imposing an economic burden to healthcare systems around the world. It is accepted that ultraviolet radiation (UVR: λ = 290–400 nm) plays a crucial role in the initiation and promotion of BCC and SCC with UVB (λ = 290–320 nm) having a central role in this process. On the other hand, UVB is required for vitamin D3 (D3) production in the skin, which supplies >90% of the body’s requirement for this prohormone. Prolonged exposure to UVB can also generate tachysterol and Lumisterol. Vitamin D3 itself and its canonical (1,25(OH)2D3) and noncanonical (CYP11A1-intitated) D3 hydroxyderivatives show photoprotective functions in the skin. These include regulation of keratinocyte proliferation and differentiation, induction of anti-oxidative responses, inhibition of DNA damage and induction of DNA repair mechanisms, and anti-inflammatory activities. Studies in animals have demonstrated that D3 hydroxyderivatives can attenuate UVB or chemically induced epidermal cancerogenesis and inhibit growth of SCC and BCC. Genomic and non-genomic mechanisms of action have been suggested. In addition, vitamin D3 itself inhibits hedgehog signaling pathways which have been implicated in many cancers. Silencing of the vitamin D receptor leads to increased propensity to develop UVB or chemically induced epidermal cancers. Other targets for vitamin D compounds include 1,25D3-MARRS, retinoic orphan receptors α and γ, aryl hydrocarbon receptor, and Wnt signaling. Most recently, photoprotective effects of Lumisterol hydroxyderivatives have been identified. Clinical trials demonstrated a beneficial role of vitamin D compounds in the treatment of actinic keratosis. In summary, recent advances in vitamin D biology and pharmacology open new exciting opportunities in chemoprevention and treatment of skin cancers.
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Protective effects of novel derivatives of vitamin D3 and Lumisterol against UVB-induced damage in human keratinocytes involve activation of Nrf2 and P53 defense mechanisms
Redox biology, 2019Co-Authors: Anyamanee Chaiprasongsuk, Michael F Holick, Zorica Janjetovic, Tae Kang Kim, Stuart G. Jarrett, John A. D'orazio, Edith K.y. Tang, Robert C. Tuckey, Uraiwan PanichAbstract:Abstract We tested whether novel CYP11A1-derived vitamin D3- and Lumisterol-hydroxyderivatives, including 1,25(OH)2D3, 20(OH)D3, 1,20(OH)2D3, 20,23(OH)2D3, 1,20,23(OH)3D3, Lumisterol, 20(OH)L3, 22(OH)L3, 20,22(OH)2L3, and 24(OH)L3, can protect against UVB-induced damage in human epidermal keratinocytes. Cells were treated with above compounds for 24 h, then subjected to UVB irradiation at UVB doses of 25, 50, 75, or 200 mJ/cm2, and then examined for oxidant formation, proliferation, DNA damage, and the expression of genes at the mRNA and protein levels. Oxidant formation and proliferation were determined by the DCFA-DA and MTS assays, respectively. DNA damage was assessed using the comet assay. Expression of antioxidative genes was evaluated by real-time RT-PCR analysis. Nuclear expression of CPD, phospho-p53, and Nrf2 as well as its target proteins including HO-1, CAT, and MnSOD, were assayed by immunofluorescence and western blotting. Treatment of cells with the above compounds at concentrations of 1 or 100 nM showed a dose-dependent reduction in oxidant formation. At 100 nM they inhibited the proliferation of cultured keratinocytes. When keratinocytes were irradiated with 50–200 mJ/cm2 of UVB they also protected against DNA damage, and/or induced DNA repair by enhancing the repair of 6-4PP and attenuating CPD levels and the tail moment of comets. Treatment with test compounds increased expression of Nrf2-target genes involved in the antioxidant response including GR, HO-1, CAT, SOD1, and SOD2, with increased protein expression for HO-1, CAT, and MnSOD. The treatment also stimulated the phosphorylation of p53 at Ser-15, increased its concentration in the nucleus and enhanced Nrf2 translocation into the nucleus. In conclusion, pretreatment of keratinocytes with 1,25(OH)2D3 or CYP11A1-derived vitamin D3- or Lumisterol hydroxy-derivatives, protected them against UVB-induced damage via activation of the Nrf2-dependent antioxidant response and p53-phosphorylation, as well as by the induction of the DNA repair system. Thus, the new vitamin D3 and Lumisterol hydroxy-derivatives represent promising anti-photodamaging agents.
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CYP27A1 acts on the pre-vitamin D3 photoproduct, Lumisterol, producing biologically active hydroxy-metabolites
The Journal of steroid biochemistry and molecular biology, 2018Co-Authors: Robert C. Tuckey, Tae Kang Kim, Chloe Y.s. Cheng, Katie M. Wang, Saowanee Jeayeng, Andrzej SlominskiAbstract:Abstract Prolonged exposure of the skin to UV radiation causes previtamin D3, the initial photoproduct formed by opening of the B ring of 7-dehydrocholesterol, to undergo a second photochemical reaction where the B-ring is reformed giving Lumisterol3 (L3), a stereoisomer of 7-dehydrocholesterol. L3 was believed to be an inactive photoproduct of excessive UV radiation whose formation prevents excessive vitamin D production. Recently, we reported that L3 is present in serum and that CYP11A1 can act on L3 producing monohydroxy- and dihydroxy-metabolites which inhibit skin cell proliferation similarly to 1α,25-dihydroxyvitamin D3. In this study we tested the ability of human CYP27A1 to hydroxylate L3. L3 was metabolized by purified CYP27A1 to 3 major products identified as 25-hydroxyL3, (25R)-27-hydroxyL3 and (25S)-27-hydroxyL3, by NMR. These three products were also seen when mouse liver mitochondria containing CYP27A1 were incubated with L3. The requirement for CYP27A1 for their formation by mitochondria was confirmed by the inhibition of their synthesis by 5β-cholestane-3α,7α,12α-triol, an intermediate in bile acid synthesis which serves as an efficient competitive substrate for CYP27A1. CYP27A1 displayed a high kcat for the metabolism of L3 (76 mol product/min/mol CYP27A1) and a catalytic efficiency (kcat/Km) that was 260-fold higher than that for vitamin D3. The CYP27A1-derived hydroxy-derivatives inhibited the proliferation of cultured human melanoma cells and colony formation with IC50 values in the nM range. Thus, L3 is metabolized efficiently by CYP27A1 with hydroxylation at C25 or C27 producing metabolites potent in their ability to inhibit melanoma cell proliferation, supporting that L3 is a prohormone which can be activated by CYP-dependent hydroxylations.
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Article Antitumor Effects of Vitamin D Analogs on Hamster and Mouse Melanoma Cell Lines in Relation to Melanin Pigmentation
2015Co-Authors: Tomasz Wasiewicz, Zorica Janjetovic, Robert C. Tuckey, Andrzej T. Slominski, Paulina Szyszka, Miroslawa Cichorek, Michal A. ZmijewskiAbstract:Abstract: Deregulated melanogenesis is involved in melanomagenesis and melanoma progression and resistance to therapy. Vitamin D analogs have anti-melanoma activity. While the hypercalcaemic effect of the active form of Vitamin D (1,25(OH)2D3) limits its therapeutic use, novel Vitamin D analogs with a modified side chain demonstrate low calcaemic activity. We therefore examined the effect of secosteroidal analogs, both classic (1,25(OH)2D3 and 25(OH)D3), and novel relatively non-calcemic ones (20(OH)D3, calcipotriol, 21(OH)pD, pD and 20(OH)pL), on proliferation, colony formation in monolayer and soft-agar, and mRNA and protein expression by melanoma cells. Murine B16-F10 and hamster Bomirski Ab cell lines were shown to be effective models to study how melanogenesis affects anti-melanoma treatment. Novel Vitamin D analogs with a short side-chain and Lumisterol-like 20(OH)pL efficiently inhibited rodent melanoma growth. Moderate pigmentation sensitized rodent melanoma cells towards Vitamin
Michael F Holick - One of the best experts on this subject based on the ideXlab platform.
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Sun-induced production of vitamin D_3 throughout 1 year in tropical and subtropical regions: relationship with latitude, cloudiness, UV-B exposure and solar zenith angle
Photochemical & Photobiological Sciences, 2021Co-Authors: Angela C. G. B. Leal, Michael F Holick, Marcelo P. Corrêa, Enaldo V. Melo, Marise Lazaretti-castroAbstract:This study evaluated the differences in vitamin D_3 synthesis in two different latitudes throughout 1 year using an in vitro model, which simulates cutaneous vitamin D photoproduction. Borosilicate ampoules containing 7-dehydrocholesterol (7-DHC) were exposed to sunlight hourly throughout the daylight hours, 1 day per month for a year, in Fortaleza (latitude 03° 43′ 01" S—LAT3° S) and Sao Paulo (latitude 23° 32′ 53" S—LAT23° S). Later, vitamin D_3 and photoisomers of 7-DHC (tachysterol and Lumisterol) were measured by a high-performance liquid chromatography system (HPLC). Vitamin D synthesis weighted UV radiation (UVBVitD) and solar zenith angle (SZA) were calculated during the same periods for both latitudes. Vitamin D_3 synthesis occurred throughout the year in both locations, as expected in latitudes lower than 35°. Median of photoconversion to vitamin D_3 through the year was higher in LAT3°S [median (IQR): LAT 3°S 4.1% (6.0); LAT 23°S 2.9% (4.5); p value = 0.020]. Vitamin D_3 production strongly correlated with UV-B (LAT3° S, r = 0.917; p
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sun induced production of vitamin d3 throughout 1 year in tropical and subtropical regions relationship with latitude cloudiness uv b exposure and solar zenith angle
Photochemical and Photobiological Sciences, 2021Co-Authors: Michael F Holick, Angela C. G. B. Leal, Enaldo V. Melo, Marcelo De Paula Correa, Marise LazaretticastroAbstract:This study evaluated the differences in vitamin D3 synthesis in two different latitudes throughout 1 year using an in vitro model, which simulates cutaneous vitamin D photoproduction. Borosilicate ampoules containing 7-dehydrocholesterol (7-DHC) were exposed to sunlight hourly throughout the daylight hours, 1 day per month for a year, in Fortaleza (latitude 03° 43' 01" S-LAT3° S) and Sao Paulo (latitude 23° 32' 53" S-LAT23° S). Later, vitamin D3 and photoisomers of 7-DHC (tachysterol and Lumisterol) were measured by a high-performance liquid chromatography system (HPLC). Vitamin D synthesis weighted UV radiation (UVBVitD) and solar zenith angle (SZA) were calculated during the same periods for both latitudes. Vitamin D3 synthesis occurred throughout the year in both locations, as expected in latitudes lower than 35°. Median of photoconversion to vitamin D3 through the year was higher in LAT3°S [median (IQR): LAT 3°S 4.1% (6.0); LAT 23°S 2.9% (4.5); p value = 0.020]. Vitamin D3 production strongly correlated with UV-B (LAT3° S, r = 0.917; p < 0.0001 and at LAT23° S, r = 0.879; p < 0.0001) and SZA (LAT3° S, r = - 0.924; p < 0.0001 and in LAT23°S, r = - 0.808; p < 0.0001). Vitamin D3 production starts later in LAT23° S, especially in winter. Lowest percentages were observed in June in both cities, although, compared to LAT3° S, in LAT 23° S the conversion was over 50% lower in the winter period. Cloudiness impaired photoproduction of Vitamin D3 even in summer months in both latitudes. Our results provide data to help guide medical recommendations for sensible sun exposure to promote the cutaneous production of vitamin D3 at different latitudes, seasonality, time of day and cloudiness status in Brazil.
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Protective effects of novel derivatives of vitamin D3 and Lumisterol against UVB-induced damage in human keratinocytes involve activation of Nrf2 and P53 defense mechanisms
Redox biology, 2019Co-Authors: Anyamanee Chaiprasongsuk, Michael F Holick, Zorica Janjetovic, Tae Kang Kim, Stuart G. Jarrett, John A. D'orazio, Edith K.y. Tang, Robert C. Tuckey, Uraiwan PanichAbstract:Abstract We tested whether novel CYP11A1-derived vitamin D3- and Lumisterol-hydroxyderivatives, including 1,25(OH)2D3, 20(OH)D3, 1,20(OH)2D3, 20,23(OH)2D3, 1,20,23(OH)3D3, Lumisterol, 20(OH)L3, 22(OH)L3, 20,22(OH)2L3, and 24(OH)L3, can protect against UVB-induced damage in human epidermal keratinocytes. Cells were treated with above compounds for 24 h, then subjected to UVB irradiation at UVB doses of 25, 50, 75, or 200 mJ/cm2, and then examined for oxidant formation, proliferation, DNA damage, and the expression of genes at the mRNA and protein levels. Oxidant formation and proliferation were determined by the DCFA-DA and MTS assays, respectively. DNA damage was assessed using the comet assay. Expression of antioxidative genes was evaluated by real-time RT-PCR analysis. Nuclear expression of CPD, phospho-p53, and Nrf2 as well as its target proteins including HO-1, CAT, and MnSOD, were assayed by immunofluorescence and western blotting. Treatment of cells with the above compounds at concentrations of 1 or 100 nM showed a dose-dependent reduction in oxidant formation. At 100 nM they inhibited the proliferation of cultured keratinocytes. When keratinocytes were irradiated with 50–200 mJ/cm2 of UVB they also protected against DNA damage, and/or induced DNA repair by enhancing the repair of 6-4PP and attenuating CPD levels and the tail moment of comets. Treatment with test compounds increased expression of Nrf2-target genes involved in the antioxidant response including GR, HO-1, CAT, SOD1, and SOD2, with increased protein expression for HO-1, CAT, and MnSOD. The treatment also stimulated the phosphorylation of p53 at Ser-15, increased its concentration in the nucleus and enhanced Nrf2 translocation into the nucleus. In conclusion, pretreatment of keratinocytes with 1,25(OH)2D3 or CYP11A1-derived vitamin D3- or Lumisterol hydroxy-derivatives, protected them against UVB-induced damage via activation of the Nrf2-dependent antioxidant response and p53-phosphorylation, as well as by the induction of the DNA repair system. Thus, the new vitamin D3 and Lumisterol hydroxy-derivatives represent promising anti-photodamaging agents.
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Photobiology of vitamin D in mushrooms and its bioavailability in humans
Dermato-endocrinology, 2013Co-Authors: Raphael-john H. Keegan, Jaimee Bogusz, Jennifer E. Williams, Michael F HolickAbstract:Mushrooms exposed to sunlight or UV radiation are an excellent source of dietary vitamin D2 because they contain high concentrations of the vitamin D precursor, provitamin D2. When mushrooms are exposed to UV radiation, provitamin D2 is converted to previtamin D2. Once formed, previtamin D2 rapidly isomerizes to vitamin D2 in a similar manner that previtamin D3 isomerizes to vitamin D3 in human skin. Continued exposure of mushrooms to UV radiation results in the production of Lumisterol2 and tachysterol2. It was observed that the concentration of Lumisterol2 remained constant in white button mushrooms for up to 24 h after being produced. However, in the same mushroom tachysterol2 concentrations rapidly declined and were undetectable after 24 h. Shiitake mushrooms not only produce vitamin D2 but also produce vitamin D3 and vitamin D4. A study of the bioavailability of vitamin D2 in mushrooms compared with the bioavailability of vitamin D2 or vitamin D3 in a supplement revealed that ingestion of 2000 IUs of...
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Generation of potentially bioactive ergosterol-derived products following pulsed ultraviolet light exposure of mushrooms (Agaricus bisporus)
Food chemistry, 2012Co-Authors: Michael D. Kalaras, Michael F Holick, Robert B. Beelman, Ryan J. EliasAbstract:The production of vitamin D(2) from ergosterol in mushrooms upon exposure to ultraviolet (UV) irradiation has been well established in recent years. However, the effect of this treatment on the generation of non-vitamin D(2) products of ergosterol in mushrooms has not been reported. In this study, the ergosterol-derived photoproducts previtamin D(2), Lumisterol(2) and tachysterol(2) were, for the first time, identified and quantified in white button mushrooms (Agaricus bisporus) following treatment with pulsed UV (PUV) light. Mushrooms were treated with up to 60pulses of PUV irradiation and the formation of major photoproducts was observed to increase as a function of dose. Vitamin D(2) was the most abundant product, followed by previtamin D(2), Lumisterol(2) and tachysterol(2) in order of decreasing abundance. Untreated mushroom samples were not observed to contain detectable levels of any photoproduct. This study shows for the first time the production of these photoproducts in UV irradiated mushrooms. A complete understanding of the potential biological significance of these products remains to be seen.
Anthony W. Norman - One of the best experts on this subject based on the ideXlab platform.
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1α 25 oh vitamin d and a nongenomic vitamin d analogue inhibit ultraviolet radiation induced skin carcinogenesis
Cancer Prevention Research, 2011Co-Authors: Katie M Dixon, Vanessa B. Sequeira, Vivienne E. Reeve, Anthony W. Norman, Ritu Mohan, Mark S Rybchyn, Gary M Halliday, Rebecca S MasonAbstract:Exposure to ultraviolet radiation (UVR) can lead to a range of deleterious responses in the skin. An important form of damage is the DNA photolesion cyclobutane pyrimidine dimer (CPD). CPDs can be highly mutagenic if not repaired prior to cell division and can lead to UV-induced immunosuppression, making them potentially carcinogenic. UVR exposure also produces vitamin D, a prehormone. Different shapes of the steroid hormone 1α,25-dihydroxyvitamin D₃ [1,25(OH)₂D₃] can produce biological responses through binding either to its cognate nuclear receptor (VDR) to regulate gene transcription or to the VDR associated with plasma membrane caveolae to produce, via signal transduction, nongenomic physiologic responses. Here, we show that both 1,25(OH)₂D₃ and 1α,25(OH)₂-Lumisterol (JN), a conformationally restricted analogue that can generate only nongenomic responses, are effective inhibitors of UV damage in an immunocompetent mouse (Skh:hr1) model susceptible to UV-induced tumors. Both 1,25(OH)₂D₃ and JN significantly reduced UVR-induced CPD, apoptotic sunburn cells, and immunosuppression. Furthermore, these compounds inhibited skin tumor development, both papillomas and squamous cell carcinomas, in these mice. The observed reduction of these UV-induced effects by 1,25(OH)₂D₃ and JN suggests a role for these compounds in prevention against skin carcinogenesis. To the best of our knowledge, this is the first comprehensive report of an in vivo long-term biological response generated by chronic dosing with a nongenomic-selective vitamin D steroid.
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1α,25(OH)₂-vitamin D and a nongenomic vitamin D analogue inhibit ultraviolet radiation-induced skin carcinogenesis.
Cancer prevention research (Philadelphia Pa.), 2011Co-Authors: Katie M Dixon, Vanessa B. Sequeira, Vivienne E. Reeve, Anthony W. Norman, Ritu Mohan, Mark S Rybchyn, Gary M Halliday, Rebecca S MasonAbstract:Exposure to ultraviolet radiation (UVR) can lead to a range of deleterious responses in the skin. An important form of damage is the DNA photolesion cyclobutane pyrimidine dimer (CPD). CPDs can be highly mutagenic if not repaired prior to cell division and can lead to UV-induced immunosuppression, making them potentially carcinogenic. UVR exposure also produces vitamin D, a prehormone. Different shapes of the steroid hormone 1α,25-dihydroxyvitamin D₃ [1,25(OH)₂D₃] can produce biological responses through binding either to its cognate nuclear receptor (VDR) to regulate gene transcription or to the VDR associated with plasma membrane caveolae to produce, via signal transduction, nongenomic physiologic responses. Here, we show that both 1,25(OH)₂D₃ and 1α,25(OH)₂-Lumisterol (JN), a conformationally restricted analogue that can generate only nongenomic responses, are effective inhibitors of UV damage in an immunocompetent mouse (Skh:hr1) model susceptible to UV-induced tumors. Both 1,25(OH)₂D₃ and JN significantly reduced UVR-induced CPD, apoptotic sunburn cells, and immunosuppression. Furthermore, these compounds inhibited skin tumor development, both papillomas and squamous cell carcinomas, in these mice. The observed reduction of these UV-induced effects by 1,25(OH)₂D₃ and JN suggests a role for these compounds in prevention against skin carcinogenesis. To the best of our knowledge, this is the first comprehensive report of an in vivo long-term biological response generated by chronic dosing with a nongenomic-selective vitamin D steroid.
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Vitamin D Sterol/VDR Conformational Dynamics and Nongenomic Actions
Vitamin D, 2011Co-Authors: Mathew T Mizwicki, Anthony W. NormanAbstract:The process of involvement of the classical nuclear receptor with hormone-dependent nongenomic, extranuclear cell signaling contributes to cell biology at multiple levels. The classical view/assumption that the binding of 1,25(OH) 2 D 3 to the VDR simply activates its translocation to the nucleus of the cell where it cis- regulates the genome has been proven to be an oversimplification for the VDR and many other NRs. We have described and highlighted the vitamin D/VDR structure–function studies that differentiate nuclear and extranuclear signaling. Specifically, the presence of two overlapping ligand-binding sites within the VDR provides a physicochemical explanation for the analog-specific functions known for 1α,25(OH) 2 -Lumisterol D 3 (JN) and 1β,25(OH) 2 -vitamin D 3 (HL) and the ability of 1,25(OH) 2 D 3 to send signals dynamically by functioning as both a nongenomic and genomic agonist ligand. 1,25(OH) 2 D 3 extranuclear, nongenomic, rapid responses include the regulation of phospholipases, phosphatases, kinases, ion channels, and second messengers. These signaling factors can themselves regulate the genome and transcribed/translated products via mechanisms that integrate with 1,25(OH) 2 D 3 -VDR cis regulation of genes. In this way, extranuclear signaling can alter cell physiology in a manner independent of nuclear VDR transregulation. Thus by expanding our understanding of nongenomic structure–function and combining this knowledge with what is known regarding genomic structure–function, we hope to elucidate the mechanistic nuances that underpin the adverse responses of hypercalcemia and soft tissue calcification.
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1alpha,25(OH)2-Vitamin D3 stimulation of secretion via chloride channel activation in Sertoli cells.
The Journal of steroid biochemistry and molecular biology, 2010Co-Authors: Danusa Menegaz, Anthony W. Norman, Mathew T Mizwicki, Antonio Barrientos-duran, Andrew Kline, Fatima R M B Silva, Laura P ZanelloAbstract:Sertoli cell secretory activities are highly dependent on ion channel functions and critical to spermatogenesis. The steroid hormone 1alpha,25(OH)2-vitamin D3 (1,25(OH)2-D3) stimulates exocytosis in different cell systems by activating a nongenotropic vitamin D receptor (VDR). Here, we described 1,25(OH)2-D3 stimulation of secretion via Cl(-) channel activation in the mouse immature Sertoli cell line TM4. 1,25(OH)2-D3 potentiation of chloride currents was dependent on hormone concentration, and correlated with a significant increase in whole-cell capacitance within 20-40 min. In addition, Cl(-) currents were potentiated by the nongenomic VDR agonist 1alpha,25(OH)2 Lumisterol D3 (JN), while 1,25(OH)2-D3 potentiation of channels was suppressed by nongenomic VDR antagonist 1beta,25(OH)2-vitamin D3 (HL). Treatment of TM4 cells with PKC and PKA activators PMA and forskolin respectively, increased Cl(-) currents significantly, while PKC and PKA inhibitors Go6983 and H-89, respectively, abolished 1,25(OH)2-D3 stimulation of Cl(-) currents, suggesting phosphorylation pathways in 1,25(OH))2-D3 mediated channel responses. RT-PCR demonstrated the expression of outwardly rectifying ClC-3 channels in TM4 cells. Taken together, our results demonstrate a PKA/PKC-dependent 1,25(OH)2-D3/VDR nongenotropic pathway leading to Cl(-) channel and exocytosis activation in Sertoli cells. We conclude that 1,25(OH)2-D3 appears to be a modulator of male reproductive functions at least in part by stimulating Sertoli cell secretory functions.
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1α,25(OH)2-Vitamin D3 stimulation of secretion via chloride channel activation in Sertoli cells
The Journal of Steroid Biochemistry and Molecular Biology, 2010Co-Authors: Danusa Menegaz, Anthony W. Norman, Mathew T Mizwicki, Antonio Barrientos-duran, Andrew Kline, Fatima R M B Silva, Laura P ZanelloAbstract:Sertoli cell secretory activities are highly dependent on ion channel functions and critical to spermatogenesis. The steroid hormone 1alpha,25(OH)2-vitamin D3 (1,25(OH)2-D3) stimulates exocytosis in different cell systems by activating a nongenotropic vitamin D receptor (VDR). Here, we described 1,25(OH)2-D3 stimulation of secretion via Cl(-) channel activation in the mouse immature Sertoli cell line TM4. 1,25(OH)2-D3 potentiation of chloride currents was dependent on hormone concentration, and correlated with a significant increase in whole-cell capacitance within 20-40 min. In addition, Cl(-) currents were potentiated by the nongenomic VDR agonist 1alpha,25(OH)2 Lumisterol D3 (JN), while 1,25(OH)2-D3 potentiation of channels was suppressed by nongenomic VDR antagonist 1beta,25(OH)2-vitamin D3 (HL). Treatment of TM4 cells with PKC and PKA activators PMA and forskolin respectively, increased Cl(-) currents significantly, while PKC and PKA inhibitors Go6983 and H-89, respectively, abolished 1,25(OH)2-D3 stimulation of Cl(-) currents, suggesting phosphorylation pathways in 1,25(OH))2-D3 mediated channel responses. RT-PCR demonstrated the expression of outwardly rectifying ClC-3 channels in TM4 cells. Taken together, our results demonstrate a PKA/PKC-dependent 1,25(OH)2-D3/VDR nongenotropic pathway leading to Cl(-) channel and exocytosis activation in Sertoli cells. We conclude that 1,25(OH)2-D3 appears to be a modulator of male reproductive functions at least in part by stimulating Sertoli cell secretory functions.
