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Vitamin D metabolism centers on kidney regulation of Cyp27b1 by mineralotropic hormones, including induction by parathyroid hormone (PTH), suppression by fibroblast growth factor 23 (FGF23) and 1,25-dihydroxyvitamin D3 (1,25(OH)2D3), and reciprocal regulations for Cyp24a1. This coordinated genomic regulation results in production of endocrine 1,25(OH)2D3, which, together with PTH and FGF23, controls mineral homeostasis. However, how these events are coordinated is unclear. Here, using in vivo chromatin immunoprecipitation sequencing in mouse kidney, we demonstrate that PTH activation rapidly induces increased recruitment of phosphorylated (p-133) CREB (pCREB) and its coactivators, CBP (CREB-binding protein) and CRTC2 (CREB-regulated transcription coactivator 2), to previously defined kidney-specific M1 and M21 enhancers near the Cyp27b1 gene. At distal enhancers of the Cyp24a1 gene, PTH suppression dismisses CBP with only minor changes in pCREB and CRTC2 occupancy, all of which correlate with decreased genomic activity and reduced transcripts. Treatment of mice with salt-inducible kinase inhibitors (YKL-05-099 and SK-124) yields rapid genomic recruitment of CRTC2 to Cyp27b1, limited interaction of CBP, and a transcriptional response for both Cyp27b1 and Cyp24a1 that mirrors the actions of PTH. Surprisingly, we find that 1,25(OH)2D3 suppression increases the occupancy of CRTC2 in the M1 enhancer, a novel observation for CRTC2 and 1,25(OH)2D3 action. Suppressive actions of 1,25(OH)2D3 and FGF23 at the Cyp27b1 gene are associated with reduced CBP recruitment at these CREB-module enhancers that disrupts full PTH induction. Our findings show that CRTC2 contributes to transcription of both Cyp27b1 and Cyp24a1, demonstrate salt-inducible kinase inhibition as a key modulator of vitamin D metabolism, and provide molecular insight into the coordinated mechanistic actions of PTH, FGF23, and 1,25(OH)2D3 in the kidney that regulate mineral homeostasis.
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25-Hidroxivitamina D3 1-alfa-Hidroxilasa , Calcitriol , Ratones , Animales , Vitamina D3 24-Hidroxilasa/genética , Calcitriol/metabolismo , Vitamina D/metabolismo , Hormona Paratiroidea/metabolismo , Riñón/metabolismo , Factores de Crecimiento de Fibroblastos/metabolismo , Genómica , Receptores de Calcitriol/metabolismoRESUMEN
Vitamin D3 is terminally bioactivated in the kidney to 1α,25-dihydroxyvitamin D3 (1,25(OH)2D3) via cytochrome P450 family 27 subfamily B member 1 (CYP27B1), whose gene is regulated by parathyroid hormone (PTH), fibroblast growth factor 23 (FGF23), and 1,25(OH)2D3 Our recent genomic studies in the mouse have revealed a complex kidney-specific enhancer module within the introns of adjacent methyltransferase-like 1 (Mettl1) and Mettl21b that mediate basal and PTH-induced expression of Cyp27b1 and FGF23- and 1,25(OH)2D3-mediated repression. Gross deletion of these segments in mice has severe effects on Cyp27b1 regulation and skeletal phenotype but does not affect Cyp27b1 expression in nonrenal target cells (NRTCs). Here, we report a bimodal activity in the Mettl1 intronic enhancer with components responsible for PTH-mediated Cyp27b1 induction and 1,25(OH)2D3-mediated repression and additional activities, including FGF23 repression, within the Mettl21b enhancers. Deletion of both submodules eliminated basal Cyp27b1 expression and regulation in the kidney, leading to systemic and skeletal phenotypes similar to those of Cyp27b1-null mice. However, basal expression and lipopolysaccharide-induced regulation of Cyp27b1 in NRTCs was unperturbed. Importantly, dietary normalization of calcium, phosphate, PTH, and FGF23 rescued the skeletal phenotype of this mutant mouse, creating an ideal in vivo model to study nonrenal 1,25(OH)2D3 production in health and disease. Finally, we confirmed a conserved chromatin landscape in human kidney that is similar to that in mouse. These findings define a finely balanced homeostatic mechanism involving PTH and FGF23 together with protection from 1,25(OH)2D3 toxicity that is responsible for both adaptive vitamin D metabolism and mineral regulation.
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25-Hidroxivitamina D3 1-alfa-Hidroxilasa/fisiología , Calcio/metabolismo , Elementos de Facilitación Genéticos , Eliminación de Gen , Homeostasis , Riñón/metabolismo , Vitamina D/análogos & derivados , Animales , Sistemas CRISPR-Cas , Femenino , Factor-23 de Crecimiento de Fibroblastos , Humanos , Riñón/efectos de los fármacos , Masculino , Metiltransferasas/antagonistas & inhibidores , Metiltransferasas/genética , Metiltransferasas/metabolismo , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Ratones Transgénicos , Vitamina D/farmacologíaRESUMEN
Cytochrome P450 family 27 subfamily B member 1 (CYP27B1) and CYP24A1 function to maintain physiological levels of 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) in the kidney. Renal Cyp27b1 and Cyp24a1 expression levels are transcriptionally regulated in a highly reciprocal manner by parathyroid hormone (PTH), fibroblast growth factor 23 (FGF23), and 1,25(OH)2D3 In contrast, Cyp24a1 regulation in nonrenal target cells (NRTCs) is limited to induction by 1,25(OH)2D3 Herein, we used ChIP-Seq analyses of mouse tissues to identify regulatory regions within the Cyp24a1 gene locus. We found an extended region downstream of Cyp24a1 containing a cluster of sites, termed C24-DS1, binding PTH-sensitive cAMP-responsive element-binding protein (CREB) and a cluster termed C24-DS2 binding the vitamin D receptor (VDR). VDR-occupied sites were present in both the kidney and NRTCs, but pCREB sites were occupied only in the kidney. We deleted each segment in the mouse and observed that although the overt phenotypes of both cluster deletions were unremarkable, RNA analysis in the C24-DS1-deleted strain revealed a loss of basal renal Cyp24a1 expression, total resistance to FGF23 and PTH regulation, and secondary suppression of renal Cyp27b1; 1,25(OH)2D3 induction remained unaffected in all tissues. In contrast, loss of the VDR cluster in the C24-DS2-deleted strain did not affect 1,25(OH)2D3 induction of renal Cyp24a1 expression yet reduced but did not eliminate Cyp24a1 responses in NRTCs. We conclude that a chromatin-based mechanism differentially regulates Cyp24a1 in the kidney and NRTCs and is essential for the specific functions of Cyp24a1 in these two tissue types.
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Cromatina/metabolismo , Riñón/metabolismo , Elementos de Respuesta , Vitamina D3 24-Hidroxilasa/genética , Animales , Calcitriol/metabolismo , Proteína de Unión a Elemento de Respuesta al AMP Cíclico/metabolismo , Femenino , Factor-23 de Crecimiento de Fibroblastos , Factores de Crecimiento de Fibroblastos/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Hormona Paratiroidea/metabolismo , Receptores de Calcitriol/metabolismo , Vitamina D3 24-Hidroxilasa/metabolismoRESUMEN
Parasitic diseases have serious health, social, and economic impacts, especially in the tropical regions of the world. Diseases caused by protozoan parasites are responsible for considerable mortality and morbidity, affecting more than 500 million people worldwide. Globally, the burden of protozoan diseases is increasing and is been exacerbated because of a lack of effective medication due to the drug resistance and toxicity of current antiprotozoal agents. These limitations have prompted many researchers to search for new drugs against protozoan parasites. In this review, we have compiled the latest information (2012-2017) on the structures and pharmacological activities of newly developed organic compounds against five major protozoan diseases, giardiasis, leishmaniasis, malaria, trichomoniasis, and trypanosomiasis, with the aim of showing recent advances in the discovery of new antiprotozoal drugs.
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Antiprotozoarios/uso terapéutico , Parásitos/efectos de los fármacos , Enfermedades Parasitarias/tratamiento farmacológico , Animales , Resistencia a Medicamentos/efectos de los fármacos , Parásitos/patogenicidad , Enfermedades Parasitarias/clasificación , Enfermedades Parasitarias/epidemiología , Enfermedades Parasitarias/parasitologíaRESUMEN
The vitamin D endocrine system regulates mineral homeostasis through its activities in the intestine, kidney, and bone. Terminal activation of vitamin D3 to its hormonal form, 1α,25-dihydroxyvitamin D3 (1,25(OH)2D3), occurs in the kidney via the cytochrome P450 enzyme CYP27B1. Despite its importance in vitamin D metabolism, the molecular mechanisms underlying the regulation of the gene for this enzyme, Cyp27b1, are unknown. Here, we identified a kidney-specific control module governed by a renal cell-specific chromatin structure located distal to Cyp27b1 that mediates unique basal and parathyroid hormone (PTH)-, fibroblast growth factor 23 (FGF23)-, and 1,25(OH)2D3-mediated regulation of Cyp27b1 expression. Selective genomic deletion of key components within this module in mice resulted in loss of either PTH induction or FGF23 and 1,25(OH)2D3 suppression of Cyp27b1 gene expression; the former loss caused a debilitating skeletal phenotype, whereas the latter conferred a quasi-normal bone mineral phenotype through compensatory homeostatic mechanisms involving Cyp24a1 We found that Cyp27b1 is also expressed at low levels in non-renal cells, in which transcription was modulated exclusively by inflammatory factors via a process that was unaffected by deletion of the kidney-specific module. These results reveal that differential regulation of Cyp27b1 expression represents a mechanism whereby 1,25(OH)2D3 can fulfill separate functional roles, first in the kidney to control mineral homeostasis and second in extra-renal cells to regulate target genes linked to specific biological responses. Furthermore, we conclude that these mouse models open new avenues for the study of vitamin D metabolism and its involvement in therapeutic strategies for human health and disease.
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25-Hidroxivitamina D3 1-alfa-Hidroxilasa/biosíntesis , Calcitriol/metabolismo , Colecalciferol/metabolismo , Regulación Enzimológica de la Expresión Génica/fisiología , Homeostasis/fisiología , Riñón/metabolismo , 25-Hidroxivitamina D3 1-alfa-Hidroxilasa/genética , Animales , Calcitriol/genética , Colecalciferol/genética , Factor-23 de Crecimiento de Fibroblastos , Eliminación de Gen , Ratones , Especificidad de Órganos/fisiología , Vitamina D3 24-Hidroxilasa/biosíntesis , Vitamina D3 24-Hidroxilasa/genéticaRESUMEN
We developed a facile method to achieve a homogeneous coating of poly(3,4-ethylenedioxythiophene):polystyrene sulfonate (PEDOT:PSS) on a graphene oxide (GO) layer with outstanding sheet resistance. We fabricated a transparent bilayer GO/PEDOT:PSS film as a flexible transparent conductive electrode (TCF). GO layer was coated on flexible PET and PI substrate by dip coating. The coated GO layers were modulated by their sizes and post heat treatment. The GO layers were thermally reduced and over coated with a PEDOT:PSS layer. Compared to the values of PEDOT:PSS, the sheet resistance of the bilayer film decreased by 5.2% and cyclic bending durability increased by 47.4%. The synergetic conductive network between the reduced graphene oxide (RGO) layer and the PEDOT:PSS layer resulted in low sheet resistance; the initial network retained under cyclic bending. The bilayer TCF film can be applied to multifunctional electrical devices for which flexibility and high conductivity are necessary.
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STATEMENT OF PROBLEM: Laminate veneers are susceptible to color change during clinical service. Studies that compare the effects of different ceramic and resin cement systems on color stability are lacking. PURPOSE: The purpose of this in vitro study was to evaluate the color stability of laminate veneers after accelerated aging using different ceramic and resin cement systems. MATERIAL AND METHODS: Ceramic specimens (N=168; shade A1; thickness, 0.50 ±0.05 mm; diameter, 10.00 ±0.10 mm) were prepared using nanofluorapatite and lithium disilicate (high translucency [HT] to low translucency [LT]) ceramics. Light-polymerizing (LP) cements were classified by brightness (high or low). Dual-polymerizing cements were classified by composition (base-only [DB] or base-catalyst [DC]) for comparison of color stability on the basis of polymerization type. DB cement was light-polymerizing, whereas DC cement was dual-polymerizing. They were further classified by shade (transparent, white, or yellow [n=7, each]). Color difference (ΔE) values were obtained by spectrophotometric quantification of L* (lightness), a* (green-red), and b* (blue-yellow) values before and after aging. The Kruskal-Wallis, Mann-Whitney U, Wilcoxon signed rank, and Bonferroni post hoc tests were used for statistical analysis. RESULTS: After specimens were subjected to accelerated aging, HT ceramic specimens luted with yellow-shade DC cement exhibited the greatest color change (ΔE=2.11), whereas HT and LT ceramic specimens luted with low-brightness LP cement exhibited the least color change (ΔE=1.37). In HT ceramic specimens, which exhibited the greatest color change of the 3 ceramic types, transparent shade cement exhibited significantly lower ΔE values than the other shades with DB (P<.001) and DC cements (P=.010). High-brightness cement exhibited significantly higher ΔE values than low-brightness cement when used with NF (P=.017), HT (P<.001), and LT (P<.001) ceramics. The ΔE values of DB cement were not always lower than those of DC cement. For all specimens, the aging of laminate veneers decreased the L* values and increased the a* and b* values. CONCLUSIONS: Ceramic and resin-cement systems affected the color stability of laminate veneers. Relative to other ceramics, HT lithium disilicate ceramics exhibited greater color changes upon aging. For HT ceramics, the use of transparent shade resin cement is recommended. The lower the brightness of resin cement, the higher the color stability of veneers. For luting of 0.5-mm-thick laminate veneers with dual-polymerizing cement, light polymerization did not yield better color stability than dual polymerization over time.
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Cerámica/química , Color , Coronas con Frente Estético , Cementos de Resina/química , Apatitas/química , Porcelana Dental/química , Técnicas In Vitro , Ensayo de Materiales , Nanoestructuras/química , Espectrofotometría , Propiedades de SuperficieRESUMEN
The biological actions of 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) are mediated by the vitamin D receptor (VDR), whose expression in bone cells is regulated positively by 1,25(OH)2D3, retinoic acid, and parathyroid hormone through both intergenic and intronic enhancers. In this report, we used ChIP-sequencing analysis to confirm the presence of these Vdr gene enhancers in mesenchyme-derived bone cells and to describe the epigenetic histone landscape that spans the Vdr locus. Using bacterial artificial chromosome-minigene stable cell lines, CRISPR/Cas9 enhancer-deleted daughter cell lines, transient transfection/mutagenesis analyses, and transgenic mice, we confirmed the functionality of these bone cell enhancers in vivo as well as in vitro. We also identified VDR-binding sites across the Vdr gene locus in kidney and intestine using ChIP-sequencing analysis, revealing that only one of the bone cell-type enhancers bound VDR in kidney tissue, and none were occupied by the VDR in the intestine, consistent with weak or absent regulation by the 1,25(OH)2D3 hormone in these tissues, respectively. However, a number of additional sites of VDR binding unique to either kidney or intestine were present further upstream of the Vdr gene, suggesting the potential for alternative regulatory loci. Importantly, virtually all of these regions retained histone signatures consistent with those of enhancers and exhibited unique DNase I hypersensitivity profiles that reflected the potential for chromatin access. These studies define mechanisms associated with hormonal regulation of the Vdr and hint at the differential nature of VDR binding activity at the Vdr gene in different primary target tissues in vivo.
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Calcitriol/metabolismo , Elementos de Facilitación Genéticos/fisiología , Regulación de la Expresión Génica/fisiología , Hormonas/metabolismo , Receptores de Calcitriol/metabolismo , Animales , Calcitriol/genética , Línea Celular , Hormonas/genética , Ratones , Ratones Transgénicos , Receptores de Calcitriol/genéticaRESUMEN
1,25-Dihydroxyvitamin D3 (1,25(OH)2D3) plays an integral role in calcium homeostasis in higher organisms through its actions in the intestine, kidney, and skeleton. Interestingly, although several intestinal genes are known to play a contributory role in calcium homeostasis, the entire caste of key components remains to be identified. To examine this issue, Cyp27b1 null mice on either a normal or a high calcium/phosphate-containing rescue diet were treated with vehicle or 1,25(OH)2D3 and evaluated 6 h later. RNA samples from the duodena were then subjected to RNA sequence analysis, and the data were analyzed bioinformatically. 1,25(OH)2D3 altered expression of large collections of genes in animals under either dietary condition. 45 genes were found common to both 1,25(OH)2D3-treated groups and were composed of genes previously linked to intestinal calcium uptake, including S100g, Trpv6, Atp2b1, and Cldn2 as well as others. An additional distinct network of 56 genes was regulated exclusively by diet. We then conducted a ChIP sequence analysis of binding sites for the vitamin D receptor (VDR) across the proximal intestine in vitamin D-sufficient normal mice treated with vehicle or 1,25(OH)2D3. The residual VDR cistrome was composed of 4617 sites, which was increased almost 4-fold following hormone treatment. Interestingly, the majority of the genes regulated by 1,25(OH)2D3 in each diet group as well as those found in common in both groups contained frequent VDR sites that likely regulated their expression. This study revealed a global network of genes in the intestine that both represent direct targets of vitamin D action in mice and are involved in calcium absorption.
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Calcio/metabolismo , Regulación de la Expresión Génica/efectos de los fármacos , Intestinos/efectos de los fármacos , Receptores de Calcitriol/metabolismo , Vitamina D/análogos & derivados , Vitaminas/farmacología , 25-Hidroxivitamina D3 1-alfa-Hidroxilasa/genética , Animales , Femenino , Eliminación de Gen , Redes Reguladoras de Genes/efectos de los fármacos , Mucosa Intestinal/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Vitamina D/farmacologíaRESUMEN
Benign prostatic hyperplasia (BPH) is the non-malignant enlargement of the prostate, associated with lower urinary tract symptoms (LUTSs). Taraxaci Herba (TH), commonly known as dandelion, has traditionally been utilized in East Asia to treat symptoms related to LUTSs. Based on this traditional use, our study aimed to explore the inhibitory effects of TH on BPH progression using a testosterone propionate-induced rat model. To induce BPH, male Sprague Dawley rats were castrated and injected subcutaneously with testosterone propionate (3 mg/kg/day) for 28 days. Concurrently, TH extract was administered orally at doses of 100 and 300 mg/kg/day throughout the four-week period of testosterone propionate injections. The TH extract significantly reduced both the absolute and relative weights of the prostate, along with histopathological changes in the gland. Moreover, it lowered serum levels of testosterone and dihydrotestosterone and reduced the expression of the androgen receptor in the prostate. Additionally, the TH extract modulated the protein expressions of Bax and Bcl-2, which are key regulators of apoptosis in prostate cells. Collectively, our findings suggest that TH inhibits BPH development partially by modulating androgen signaling and inducing apoptosis within the prostate.
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Extractos Vegetales , Próstata , Hiperplasia Prostática , Ratas Sprague-Dawley , Propionato de Testosterona , Masculino , Animales , Hiperplasia Prostática/inducido químicamente , Hiperplasia Prostática/tratamiento farmacológico , Hiperplasia Prostática/patología , Próstata/efectos de los fármacos , Próstata/patología , Extractos Vegetales/farmacología , Ratas , Apoptosis/efectos de los fármacos , Modelos Animales de Enfermedad , Testosterona/sangre , Receptores Androgénicos/metabolismo , Dihidrotestosterona/sangre , Proteína X Asociada a bcl-2/metabolismo , Proteínas Proto-Oncogénicas c-bcl-2/metabolismoRESUMEN
The immune benefits of vitamin D3 supplementation beyond calcium and phosphate maintenance are highly clinically debated. Kidney expression of CYP27B1 is the source of endocrine, circulating 1,25(OH)2D3 (active form of vitamin D) that maintains serum calcium and phosphate. 1,25(OH)2D3 may also be made by the CYP27B1 enzyme in nonrenal cells, like immune cells, in a process driven by cellular availability of 25(OH)D3 and inflammation. Due to the endocrine nature of 1,25(OH)2D3 in circulation, it is difficult to discern between these 2 sources. We recently created a regulatory deletion model of Cyp27b1 (M1/M21-DIKO) where mice have normal inflammatory-regulated Cyp27b1 expression in nonrenal tissues (unlike global Cyp27b1-KO) but no expression within the kidney. Here, utilizing on-tissue chemical derivatization and matrix assisted laser desorption ionization-mass spectrometry imaging (MALDI-MSI), we investigated the distribution of 1,25(OH)2D3 and 25(OH)D3 in the kidney, liver, spleen, and thymus. MALDI-MSI demonstrated increased 1,25(OH)2D3 in nonrenal tissues such as the spleen after vitamin D3 supplementation in M1/M21-DIKO mice. Additionally, from this, we found increased Il4 and decreased Tnfa in the spleen after vitamin D3 supplementation. Taken together, these data demonstrate nonrenal production of 1,25(OH)2D3 in vivo and provide a consequence of vitamin D3 supplementation and nonrenal 1,25(OH)2D3 production in cytokine changes.
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25-Hidroxivitamina D3 1-alfa-Hidroxilasa , Calcitriol , Riñón , Ratones Noqueados , Animales , Calcitriol/metabolismo , 25-Hidroxivitamina D3 1-alfa-Hidroxilasa/metabolismo , 25-Hidroxivitamina D3 1-alfa-Hidroxilasa/genética , Ratones , Riñón/metabolismo , Espectrometría de Masa por Láser de Matriz Asistida de Ionización Desorción/métodos , Masculino , Colecalciferol/metabolismo , Inflamación/metabolismo , FemeninoRESUMEN
We elucidated the distance-dependent plasmonic effects on radiative transitions from an Eu(3+) ion-doped phosphor by varying the thickness of the dielectric spacer. Magnesium oxide prepared by electron-beam evaporation was chosen for the dielectric spacer. Spectral overlap between emission from Eu(3+) ions and the plasmon band of Ag nanoparticles led to improved luminescence intensity. This luminous enhancement was effective within the area of influence by localized surface plasmon resonance. At a long distance, the plasmon-enhanced luminescence was not effective. In addition, the numerical analysis results were in good agreement with the distance-dependent decay characteristics of plasmon resonance.
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The regulation of mineral homeostasis involves the three mineralotropic hormones PTH, FGF23 and 1,25-dihydroxyvitamin D3 (1,25(OH)2D3). Early research efforts focused on PTH and 1,25(OH)2D3 and more recently on FGF23 have revealed that each of these hormones regulates the expression of the other two. Despite early suggestions of transcriptional processes, it has been only recently that research effort have begun to delineate the genomic mechanisms underpinning this regulation for 1,25(OH)2D3 and FGF23; the regulation of PTH by 1,25(OH)2D3, however, remains obscure. We review here our molecular understanding of how PTH induces Cyp27b1 expression, the gene encoding the enzyme responsible for the synthesis of 1,25(OH)2D3. FGF23 and 1,25(OH)2D3, on the other hand, function by suppressing production of 1,25(OH)2D3. PTH stimulates the PKA-induced recruitment of CREB and its coactivator CBP at CREB occupied sites within the kidney-specific regulatory regions of Cyp27b1. PKA activation also promotes the nuclear translocation of SIK bound coactivators such as CRTC2, where it similarly interacts with CREB occupied Cyp27b1 sites. The negative actions of both FGF23 and 1,25(OH)2D3 appear to suppress Cyp27b1 expression by opposing the recruitment of CREB coactivators at this gene. Reciprocal gene actions are seen at Cyp24a1, the gene encoding the enzyme that degrades 1,25(OH)2D3, thereby contributing to the overall regulation of blood levels of 1,25(OH)2D3. Relative to PTH regulation, we summarize what is known of how 1,25(OH)2D3 regulates PTH suppression. These studies suggest that it is not 1,25(OH)2D3 that controls PTH levels in healthy subjects, but rather calcium itself. Finally, we describe current progress using an in vivo approach that furthers our understanding of the regulation of Fgf23 expression by PTH and 1,25(OH)2D3 and provide the first evidence that P may act to induce Fgf23 expression via a complex transcriptional mechanism in bone. It is clear, however, that additional advances will need to be made to further our understanding of the inter-regulation of each of these hormonal genes.
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25-Hidroxivitamina D3 1-alfa-Hidroxilasa , Calcitriol , Humanos , Calcitriol/metabolismo , 25-Hidroxivitamina D3 1-alfa-Hidroxilasa/genética , Hormona Paratiroidea/metabolismo , Riñón/metabolismo , Calcio/metabolismoRESUMEN
Phosphate (P) is an essential element involved in various biological actions, such as bone integrity, energy production, cell signaling and molecular component. P homeostasis is modulated by 4 main tissues; intestine, kidney, bone, and parathyroid gland, where 1,25-dihydroxyvitamin D3 (1,25(OH)2D3), parathyroid hormone and fibroblast growth factor 23 (FGF23) are produced and/or have an influence. In bone, serum P level modulates the production of FGF23 which then controls not only P excretion but also vitamin D metabolism in kidney in an endocrine manner. The hormonally active form of vitamin D, 1,25(OH)2D3, also has a significant effect on skeletal cells via its receptor, the vitamin D receptor, to control gene expression which mediates bone metabolism as well as mineral homeostasis. In this study, we adopted RNA-seq analysis to understand genome-wide skeletal gene expression regulation in response to P and 1,25(OH)2D3. We examined lumbar 5 vertebrae from the mice that were fed P deficient diet for a week followed by an acute high P diet for 3, 6, and 24 h as well as mice treated with 1,25(OH)2D3 intraperitoneally for 6 h. Further identification and exploration of the genes regulated by P and 1,25(OH)2D3 showed that P dynamically modulates the expression of skeletal genes involved in various biological processes while 1,25(OH)2D3 regulates genes highly related to bone metabolism. Our in vivo data were then compared with in vitro data that we previously obtained, which suggests that the gene expression profiles presented in this report mainly represent those of osteocytes. Interestingly, it was found that even though the skeletal response to P is distinguished from that to 1,25(OH)2D3, both factors have an effect on Wnt signaling pathway to modulate bone homeostasis. Taken together, this report presents genome-wide data that provide a foundation to understand molecular mechanisms by which skeletal cells respond to P and 1,25(OH)2D3.
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Calcitriol , Fosfatos , Ratones , Animales , Calcitriol/farmacología , Calcitriol/metabolismo , Transcriptoma , Estudio de Asociación del Genoma Completo , Vitamina D/farmacología , Vitamina D/metabolismo , 24,25-Dihidroxivitamina D 3 , Calcio/metabolismoRESUMEN
The 24th Workshop on Vitamin D was held September 7-9, 2022 in Austin, Texas and covered a wide diversity of research in the vitamin D field from across the globe. Here, we summarize the meeting, individual sessions, awards and presentations given.
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Deficiencia de Vitamina D , Vitamina D , Humanos , VitaminasRESUMEN
The renal actions of parathyroid hormone (PTH) promote 1,25-vitamin D generation; however, the signaling mechanisms that control PTH-dependent vitamin D activation remain unknown. Here, we demonstrated that salt-inducible kinases (SIKs) orchestrated renal 1,25-vitamin D production downstream of PTH signaling. PTH inhibited SIK cellular activity by cAMP-dependent PKA phosphorylation. Whole-tissue and single-cell transcriptomics demonstrated that both PTH and pharmacologic SIK inhibitors regulated a vitamin D gene module in the proximal tubule. SIK inhibitors increased 1,25-vitamin D production and renal Cyp27b1 mRNA expression in mice and in human embryonic stem cell-derived kidney organoids. Global- and kidney-specific Sik2/Sik3 mutant mice showed Cyp27b1 upregulation, elevated serum 1,25-vitamin D, and PTH-independent hypercalcemia. The SIK substrate CRTC2 showed PTH and SIK inhibitor-inducible binding to key Cyp27b1 regulatory enhancers in the kidney, which were also required for SIK inhibitors to increase Cyp27b1 in vivo. Finally, in a podocyte injury model of chronic kidney disease-mineral bone disorder (CKD-MBD), SIK inhibitor treatment stimulated renal Cyp27b1 expression and 1,25-vitamin D production. Together, these results demonstrated a PTH/SIK/CRTC signaling axis in the kidney that controls Cyp27b1 expression and 1,25-vitamin D synthesis. These findings indicate that SIK inhibitors might be helpful for stimulation of 1,25-vitamin D production in CKD-MBD.
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Trastorno Mineral y Óseo Asociado a la Enfermedad Renal Crónica , Insuficiencia Renal Crónica , Ratones , Humanos , Animales , Vitamina D/metabolismo , Hormona Paratiroidea/genética , Hormona Paratiroidea/metabolismo , Calcio/metabolismo , 25-Hidroxivitamina D3 1-alfa-Hidroxilasa/metabolismo , Trastorno Mineral y Óseo Asociado a la Enfermedad Renal Crónica/metabolismo , Riñón/metabolismo , Insuficiencia Renal Crónica/metabolismo , Homeostasis , Proteínas Serina-Treonina Quinasas/genética , Proteínas Serina-Treonina Quinasas/metabolismoRESUMEN
Plasmon-enhanced transparent plasma display devices are demonstrated via the resonant interface between Ag nanoparticles and a Eu(3+)-doped phosphor. Enhanced emission from the phosphor by metallic nanoparticles leads to an increase of the luminous efficacy in the transparent plasma display device. This is a prototype of the plasmon-enhanced transparent plasma display device.
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We demonstrate the optical characteristics of YVO4:Eu3+ phosphor in close proximity to Ag nanofilm to create a highly efficient emitting layer in mirror-type self-emissive displays. The propagating surface plasmon mode induced between the dielectric layer (MgO) and the Ag nanofilm activates the electric dipole transition of Eu3+ ions. The transmittance of a 100 nm-thick Ag nanofilm is zero in the visible wavelength range, making this nanofilm a good reflector in the visible wavelength range and capable of fulfilling a mirror function. The emission of an YVO4:Eu3+ phosphor layer with a 100 nm-thick Ag nanofilm was enhanced to the point that it was eight times higher than that of a reference sample without Ag nanofilm. Therefore, the present work shows potential for application to mirror-type displays with high luminous efficacy.
Asunto(s)
Lentes , Iluminación/instrumentación , Membranas Artificiales , Nanoestructuras/química , Refractometría/instrumentación , Plata/química , Resonancia por Plasmón de Superficie/instrumentación , Diseño de Equipo , Análisis de Falla de Equipo , Nanoestructuras/ultraestructura , Itrio/químicaRESUMEN
The wild boar (Sus scrofa), a polygynous species, rapidly expanded its geographical range and increased its population size in South Korea following the extinction of large carnivores and changes to rural environments. Understanding wild boar reproductive traits and strategies is essential for their effective management; however, studies in this area are lacking. Using samples collected from hunting bags, the relationships between 1) litter size and female weight and 2) fetal sex ratio and female body condition were examined to understand wild boar life-history strategies. Wild boars showed a seasonal breeding pattern that maximized reproduction. Litter size (mean = 5.7 ± 1.7) was correlated with female weight, whereas fetal sex ratio was not explained by female body condition. However, the heaviest ranked fetuses within the litters were male-biased. Wild boars aged three years or less accounted for 90% of the total population, and sexual dimorphism developed from two years of age. Considering that their reproductive strategy is more effective (i.e., early gestation and large litter size) than that of other polygynous species, the Trivers-Willard model was not supported for the wild boars in this study. Instead, females adjusted the sex of the heaviest fetus in the litter to maximize lifetime reproductive success.
Asunto(s)
Reproducción , Razón de Masculinidad , Embarazo , Masculino , Femenino , Animales , Porcinos , Tamaño de la Camada , Densidad de Población , Sus scrofaRESUMEN
We elucidate that the luminescence from Eu3+-doped phosphor excited by the electron collision can be modified on location near the metallic nanoparticles. The Eu3+-doped phosphor was fabricated on the nanoscaled Ag particles ranging of 5 nm to 30 nm diameter. As a result of the cathodoluminescence measurements, the phosphor films on the Ag particles showed up to twofold more than that of an isolated phosphor film. Enhanced cathodoluminescence originated from the resonant coupling between the localized surface plasmon of Ag nanoparticles and radiating energy of the phosphor. Cathodoluminescent phosphor for high luminous display devices can be addressed by locating phosphor near the surface of metallic nanoparticles.