RESUMEN
Colitis-associated colorectal cancer (CAC) frequently develops in patients with inflammatory bowel disease (IBD) who have been exposed to a prolonged state of chronic inflammation. The investigation of pharmacological agents and their mechanisms to prevent precancerous lesions and inhibit their progression remains a significant focus and challenge in CAC research. Previous studies have demonstrated that vitexin effectively mitigates CAC, however, its precise mechanism of action warrants further exploration. This study reveals that the absence of the Vitamin D receptor (VDR) accelerates the progression from chronic colitis to colorectal cancer. Our findings indicate that vitexin can specifically target the VDR protein, facilitating its translocation into the cell nucleus to exert transcriptional activity. Additionally, through a co-culture model of macrophages and cancer cells, we observed that vitexin promotes the polarization of macrophages towards the M1 phenotype, a process that is dependent on VDR. Furthermore, ChIP-seq analysis revealed that vitexin regulates the transcriptional activation of phenazine biosynthesis-like domain protein (PBLD) via VDR. ChIP assays and dual luciferase reporter assays were employed to identify the functional PBLD regulatory region, confirming that the VDR/PBLD pathway is critical for vitexin-mediated regulation of macrophage polarization. Finally, in a mouse model with myeloid VDR gene knockout, we found that the protective effects of vitexin were abolished in mid-stage CAC. In summary, our study establishes that vitexin targets VDR and modulates macrophage polarization through the VDR/PBLD pathway, thereby alleviating the transition from chronic colitis to colorectal cancer.
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Apigenina , Neoplasias Colorrectales , Macrófagos , Receptores de Calcitriol , Apigenina/farmacología , Receptores de Calcitriol/metabolismo , Receptores de Calcitriol/agonistas , Receptores de Calcitriol/genética , Animales , Ratones , Humanos , Neoplasias Colorrectales/patología , Neoplasias Colorrectales/metabolismo , Neoplasias Colorrectales/tratamiento farmacológico , Macrófagos/metabolismo , Macrófagos/efectos de los fármacos , Modelos Animales de Enfermedad , Colitis/tratamiento farmacológico , Colitis/patología , Colitis/metabolismo , Colitis/inducido químicamente , Progresión de la Enfermedad , Células RAW 264.7 , Ratones Endogámicos C57BLRESUMEN
BACKGROUND: Despite evidence indicating the dominance of cell-of-origin signatures in molecular tumor patterns, translating these genome-wide patterns into actionable insights has been challenging. This study introduces breast cancer cell-of-origin signatures that offer significant prognostic value across all breast cancer subtypes and various clinical cohorts, compared to previously developed genomic signatures. METHODS: We previously reported that triple hormone receptor (THR) co-expression patterns of androgen (AR), estrogen (ER), and vitamin D (VDR) receptors are maintained at the protein level in human breast cancers. Here, we developed corresponding mRNA signatures (THR-50 and THR-70) based on these patterns to categorize breast tumors by their THR expression levels. The THR mRNA signatures were evaluated across 56 breast cancer datasets (5040 patients) using Kaplan-Meier survival analysis, Cox proportional hazard regression, and unsupervised clustering. RESULTS: The THR signatures effectively predict both overall and progression-free survival across all evaluated datasets, independent of subtype, grade, or treatment status, suggesting improvement over existing prognostic signatures. Furthermore, they delineate three distinct ER-positive breast cancer subtypes with significant survival in differences-expanding on the conventional two subtypes. Additionally, coupling THR-70 with an immune signature identifies a predominantly ER-negative breast cancer subgroup with a highly favorable prognosis, comparable to ER-positive cases, as well as an ER-negative subgroup with notably poor outcome, characterized by a 15-fold shorter survival. CONCLUSIONS: The THR cell-of-origin signature introduces a novel dimension to breast cancer biology, potentially serving as a robust foundation for integrating additional prognostic biomarkers. These signatures offer utility as a prognostic index for stratifying existing breast cancer subtypes and for de novo classification of breast cancer cases. Moreover, THR signatures may also hold promise in predicting hormone treatment responses targeting AR and/or VDR.
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Biomarcadores de Tumor , Neoplasias de la Mama , Receptores Androgénicos , Receptores de Calcitriol , Receptores de Estrógenos , Humanos , Femenino , Neoplasias de la Mama/genética , Neoplasias de la Mama/patología , Neoplasias de la Mama/mortalidad , Neoplasias de la Mama/metabolismo , Receptores de Calcitriol/genética , Receptores de Calcitriol/metabolismo , Pronóstico , Receptores de Estrógenos/metabolismo , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/metabolismo , Receptores Androgénicos/genética , Receptores Androgénicos/metabolismo , Regulación Neoplásica de la Expresión Génica , Perfilación de la Expresión Génica , Estimación de Kaplan-Meier , TranscriptomaRESUMEN
The extracellular matrix of cartilage primarily constitutes of collagen and aggrecan. Cartilage degradation starts with aggrecan loss in osteoarthritis (OA). Vitamin D (VD) plays an essential role in several inflammation-related diseases and can protect the collagen in cartilage during OA. The present study focused on the role of VD in aggrecan turnover of human articular chondrocytes treated with tumor necrosis factor α (TNF-α) and the possible mechanism. Treatment with different doses of VD and different periods of intervention with TNF-α and TGF-ß1 receptor (TGFßR1) inhibitor SB525334 were investigated. The viability of human chondrocytes and extracellular secretion of TGF-ß1 were measured. The expression of intracellular TGFßR1 and VD receptor was examined. Transcriptional and translational levels of aggrecan and the related metabolic factors were analyzed. The results showed that TNF-α markedly reduced the viability, TGFßR1 expressions and aggrecan levels of human chondrocytes, and increased disintegrin and metalloproteinase with thrombospondin motifs. The alterations were partially inhibited by VD treatment. Furthermore, the effects of VD were blocked by the TGFßR1 inhibitor SB525334 in TNF-α-treated cells. VD may prevent proteoglycan loss due to TNF-α via TGF-ß1 signaling in human chondrocytes.
Asunto(s)
Agrecanos , Cartílago Articular , Condrocitos , Proteoglicanos , Transducción de Señal , Factor de Crecimiento Transformador beta1 , Factor de Necrosis Tumoral alfa , Vitamina D , Humanos , Condrocitos/metabolismo , Condrocitos/efectos de los fármacos , Transducción de Señal/efectos de los fármacos , Factor de Crecimiento Transformador beta1/metabolismo , Agrecanos/metabolismo , Factor de Necrosis Tumoral alfa/metabolismo , Vitamina D/farmacología , Proteoglicanos/metabolismo , Proteoglicanos/farmacología , Cartílago Articular/metabolismo , Cartílago Articular/efectos de los fármacos , Células Cultivadas , Supervivencia Celular/efectos de los fármacos , Osteoartritis/metabolismo , Receptor Tipo I de Factor de Crecimiento Transformador beta/metabolismo , Receptores de Calcitriol/metabolismoRESUMEN
The nuclear hormone family of receptors regulates gene expression. The androgen receptor (AR), upon ligand binding and homodimerization, shuttles from the cytosol into the nucleus to activate gene expression. Thyroid hormone receptors (TRs), retinoic acid receptors (RARs), and the vitamin D receptor (VDR) are present in the nucleus bound to chromatin as a heterodimer with the retinoid X receptors (RXRs) and repress gene expression. Ligand binding leads to transcription activation. The hormonal ligands for these receptors play crucial roles to ensure the proper conduct of very many tissues and exert effects on prostate cancer (PCa) cells. Androgens support PCa proliferation and androgen deprivation alone or with chemotherapy is the standard therapy for PCa. RARγ activation and 3,5,3'-triiodo-L-thyronine (T3) stimulation of TRß support the growth of PCa cells. Ligand stimulation of VDR drives growth arrest, differentiation, and apoptosis of PCa cells. Often these receptors are explored as separate avenues to find treatments for PCa and other cancers. However, there is accumulating evidence to support receptor interactions and crosstalk of regulatory events whereby a better understanding might lead to new combinatorial treatments.
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Neoplasias de la Próstata , Receptores Androgénicos , Receptores de Calcitriol , Receptores de Hormona Tiroidea , Humanos , Neoplasias de la Próstata/metabolismo , Neoplasias de la Próstata/tratamiento farmacológico , Neoplasias de la Próstata/patología , Masculino , Receptores de Calcitriol/metabolismo , Receptores Androgénicos/metabolismo , Receptores de Hormona Tiroidea/metabolismo , Animales , Hormonas Tiroideas/metabolismo , Terapia Molecular DirigidaRESUMEN
INTRODUCTION AND AIM: Vitamin D supplementation in aging subjects manifests a positive effect on various health-related parameters. We performed a functionally-histological analysis of the adrenal cortex regarding the factors of vitamin D activity and corticosterone output after vitamin D3 application in a rat model of the andropause. MATERIAL AND METHODS: Middle-aged Wistar rats were divided into sham operated (SO; n=8), orchidectomized (Orx; n=8) and vitamin D3-treated orchidectomized (Orx+vit. D; n=8) groups. Vitamin D3 (5⯵g/kg b.m.) was administered subcutaneously for three weeks, while the SO and Orx groups received the vehicle alone. Set objectives were achieved using histochemistry/immunohistochemistry, stereology, ultrastructural and biochemical analyses. RESULTS: Orchidectomy (Orx) decreased the adrenal cortex-related volume densities of vascular (p<0,0001), vitamin D receptor (VDR; p<0,0166), cytochrome P450 oxidase 2R1 (CYP 2R1; p<0,0001) and cytochrome P450 oxidase 24 (CYP 24; p<0,0001) depots, but increased the volume density of cytochrome P450 27B1 (CYP 27B1; p<0,0001) depots. In Orx+vit. D rats, increase of the adrenal cortex-related volume densities of collagen (p<0,0001), VDR (p<0,0001) and CYP 2R1 (p<0,0001) depots as well as the lipid-droplet diameter (p<0,0001) in adrenocortical outer zona fasciculata cells was observed, while a decrease of volume densities of the vascular (p<0,0001), CYP 27B1 (p<0,0001) and CYP 24 (p<0,0001) depots was registered, all versus Orx group. Plasma level of ACTH was decreased (p=0,0155) and serum concentrations of 25-hydroxyvitamin D3 and corticosterone were increased (p<0,0001 and p=0,0187, respectively), all after the same treatment. CONCLUSIONS: Increased corticosterone output after vitamin D3 application to andropausal rats appears not to be related to increased availability of 25-hydroxyvitamin D3 and decreased degradation of 1,25-dihydroxyvitamin D3 in adrenal tissue, but rather involves the central regulatory mechanisms.
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Corteza Suprarrenal , Andropausia , Colecalciferol , Orquiectomía , Ratas Wistar , Animales , Masculino , Corteza Suprarrenal/efectos de los fármacos , Corteza Suprarrenal/metabolismo , Corteza Suprarrenal/ultraestructura , Ratas , Andropausia/efectos de los fármacos , Corticosterona/sangre , Receptores de Calcitriol/metabolismo , InmunohistoquímicaRESUMEN
Sensorineural hearing loss can be caused by lesions to the inner ear during development. Understanding the events and signaling pathways that drive inner ear formation is crucial for determining the possible causes of congenital hearing loss. We have analyzed the innervation and expression of SOX2, JAGGED1, ß-catenin (CTNNB1), and vitamin D receptor (VDR) in the inner ears of human conceptuses aged 5 to 10 weeks after fertilization (W) using immunohistochemistry. The prosensory domains of the human inner ear displayed SOX2 and JAGGED1 expression throughout the analyzed period, with SOX2 expression being more extensive in all the analyzed timepoints. Innervation of vestibular prosensory domains was present at 6 W and extensive at 10 W, while nerve fibers reached the base of the cochlear prosensory domain at 7-8 W. CTNNB1 and VDR expression was mostly membranous and present during all analyzed timepoints in the inner ear, being the strongest in the non-sensory epithelium. Their expression was stronger in the vestibular region compared to the cochlear duct. CTNNB1 and VDR expression displayed opposite expression trends during the analyzed period, but additional studies are needed to elucidate whether they interact during inner ear development.
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Oído Interno , Proteína Jagged-1 , Receptores de Calcitriol , Factores de Transcripción SOXB1 , beta Catenina , Humanos , beta Catenina/metabolismo , Proteína Jagged-1/metabolismo , Proteína Jagged-1/genética , Oído Interno/metabolismo , Oído Interno/inervación , Oído Interno/embriología , Receptores de Calcitriol/metabolismo , Receptores de Calcitriol/genética , Factores de Transcripción SOXB1/metabolismo , Factores de Transcripción SOXB1/genética , Regulación del Desarrollo de la Expresión Génica , FemeninoRESUMEN
Vitamin D deficiency is a common deficiency worldwide, particularly among women of reproductive age. During pregnancy, it increases the risk of immune-related diseases in offspring later in life. However, how the body remembers exposure to an adverse environment during development is poorly understood. Herein, we explore the effects of prenatal vitamin D deficiency on immune cell proportions in offspring using vitamin D deficient mice established by dietary manipulation. We found that prenatal vitamin D deficiency alters immune cell proportions in offspring by changing the transcriptional properties of genes downstream of vitamin D receptor signaling in hematopoietic stem and progenitor cells of both the fetus and adults. Moreover, further investigations of the associations between maternal vitamin D levels and cord blood immune cell profiles from 75 healthy pregnant women and their term offspring also confirm that maternal vitamin D levels in the second trimester significantly affect immune cell proportions in the offspring. These findings imply that the differentiation properties of hematopoiesis act as long-term memories of prenatal vitamin D deficiency exposure in later life.
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Efectos Tardíos de la Exposición Prenatal , Deficiencia de Vitamina D , Vitamina D , Deficiencia de Vitamina D/inmunología , Femenino , Embarazo , Animales , Humanos , Efectos Tardíos de la Exposición Prenatal/inmunología , Ratones , Vitamina D/sangre , Sangre Fetal/citología , Adulto , Receptores de Calcitriol/genética , Receptores de Calcitriol/metabolismo , Células Madre Hematopoyéticas/metabolismo , MasculinoRESUMEN
Despite their significant impact, comprehensive screenings and detailed analyses of per- and polyfluoroalkyl substance (PFAS) binding strengths at the orthosteric and allosteric sites of NRs are currently lacking. This study addresses this gap by focusing on the binding interaction analysis of both common and uncommon PFAS with the nuclear receptors (NRs) vitamin D receptor (VDR), peroxisome proliferator-activated receptor gamma (PPARγ), pregnane X receptor (PXR), and estrogen receptor alpha (ERα). Advanced docking simulations were used to screen 9507 PFAS chemicals at the orthosteric and allosteric sites of PPARγ, PXR, VDR, and ERα. All receptors exhibited strong binding interactions at the orthosteric and allosteric site with a significant number of PFAS. We verified the accuracy of the docking protocol through multiple docking controls and validations. A mixture modeling analysis indicates that PFAS can bind in various combinations with themselves and endogenous ligands simultaneously, to disrupt the endocrine system and cause carcinogenic responses. These findings reveal that PFAS can interfere with nuclear receptor activity by displacing endogenous or native ligands by binding to the orthosteric and allosteric sites. The purpose of this study is to explore the mechanisms through which PFAS exert their endocrine-disrupting effects, potentially leading to more targeted therapeutic strategies. Importantly, this study is the first to explore the binding of PFAS at allosteric sites and to model PFAS mixtures at nuclear receptors. Given the high concentration and persistence of PFAS in humans, this study further emphasizes the urgent need for further research into the carcinogenic mechanisms of PFAS and the development of therapeutic strategies that target nuclear receptors.
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Fluorocarburos , Simulación del Acoplamiento Molecular , Unión Proteica , Receptores Citoplasmáticos y Nucleares , Receptores Citoplasmáticos y Nucleares/metabolismo , Receptores Citoplasmáticos y Nucleares/química , Humanos , Fluorocarburos/química , Fluorocarburos/metabolismo , Sitios de Unión , Ligandos , Sitio Alostérico , Receptor X de Pregnano/metabolismo , Receptor X de Pregnano/química , Disruptores Endocrinos/química , Disruptores Endocrinos/metabolismo , Disruptores Endocrinos/farmacología , Receptores de Calcitriol/metabolismo , Receptores de Calcitriol/químicaRESUMEN
Liver fibrosis is characterized by the excessive accumulation of extracellular matrix proteins, which can lead to cirrhosis and liver cancer. Metabolic dysfunction-associated steatosis liver diseases are common causes of liver fibrosis, sharing a similar pathogenesis with carbon tetrachloride (CCl4) exposure. This process involves the activation of hepatic stellate cells (HSCs) into myofibroblasts. However, the detailed mechanism and effective treatment strategies require further investigation. In this study, we uncovered a negative correlation between VDR expression and YAP within HSCs. Subsequently, we demonstrated that VDR exerted a downregulatory influence on YAP transcriptional activity in HSCs. Intriguingly, activation VDR effectively inhibited the culture induced activation of primary HSCs by suppressing the transcriptional activity of early YAP. Furthermore, in vivo results manifested that hepatic-specific deletion of YAP/TAZ ameliorates CCl4-induced liver fibrosis, and nullified the antifibrotic efficacy of VDR. Importantly, a YAP inhibitor rescued the exacerbation of liver fibrosis induced by hepatic-specific VDR knockout. Moreover, the combined pharmacological of VDR agonist and YAP inhibitor demonstrated a synergistic effect in diminishing CCl4-induced liver fibrosis, primary HSCs activation and hepatic injury in vivo. These effects were underpinned by their collective ability to inhibit HSC activation through AMPK activation, consequently curbing ATP synthesis and HSCs proliferation. In conclusion, our results not only revealed the inhibition of VDR on YAP-activated liver stellate cells but also identified a synergistic effect of VDR agonist and YAP inhibitor in an AMPKα-dependent manner, providing a practical foundation for integration of multi-targeted drugs in the therapy of CCl4-induced hepatic fibrosis.
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Proteínas Adaptadoras Transductoras de Señales , Tetracloruro de Carbono , Células Estrelladas Hepáticas , Cirrosis Hepática , Receptores de Calcitriol , Proteínas Señalizadoras YAP , Animales , Masculino , Ratones , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Proteínas Adaptadoras Transductoras de Señales/genética , Tetracloruro de Carbono/toxicidad , Regulación hacia Abajo/efectos de los fármacos , Células Estrelladas Hepáticas/efectos de los fármacos , Células Estrelladas Hepáticas/metabolismo , Cirrosis Hepática/metabolismo , Cirrosis Hepática/inducido químicamente , Cirrosis Hepática/patología , Ratones Endogámicos C57BL , Ratones Noqueados , Receptores de Calcitriol/metabolismo , Receptores de Calcitriol/genéticaRESUMEN
Several studies have indicated that 1α,25-hydroxyvitamin D [1α,25(OH)2D3] inhibits the proliferation and metastasis of cancer cells through suppressing epithelial-mesenchymal transition. However, its influence on the translocation of ß-catenin remains unclear. In the present study, ovarian cancer stem-like cells (CSCs), including side population (SP) and CD44+/CD117+, were isolated from mouse ovarian surface epithelial (MOSE) cells with malignant transformation. The findings revealed that 1α,25(OH)2D3 obviously reduced the sphere-forming ability, as well as Notch1 and Klf levels. Moreover, the limiting dilution assay demonstrated that 1α,25(OH)2D3 effectively hindered the tumorigenesis of ovarian CSCs in vitro. Notably, treatment with 1α,25(OH)2D3 led to a substantial increase in the cell population of CD44+/CD117+ forming one tumor from ≤ 100 to 445 in orthotopic transplanted model, indicating a pronounced suppression of stemness of ovarian CSCs. Additionally, 1α,25(OH)2D3 robustly promoted the translocation of ß-catenin from the nuclear to the cytoplasm through directly binding to VDR, which resulted in decreased levels of c-Myc and CyclinD1 within late MOSE cells. Taken together, these results strongly supported the role of 1α,25(OH)2D3 in inhibiting stem-like properties in ovarian cancer cells by restraining nuclear translocation of ß-catenin, thereby offering a promising target for cancer therapeutics.
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Núcleo Celular , Células Madre Neoplásicas , Neoplasias Ováricas , Receptores de Calcitriol , Vitamina D , beta Catenina , Femenino , beta Catenina/metabolismo , Neoplasias Ováricas/metabolismo , Neoplasias Ováricas/patología , Neoplasias Ováricas/tratamiento farmacológico , Receptores de Calcitriol/metabolismo , Células Madre Neoplásicas/metabolismo , Células Madre Neoplásicas/efectos de los fármacos , Células Madre Neoplásicas/patología , Animales , Ratones , Vitamina D/análogos & derivados , Vitamina D/farmacología , Vitamina D/metabolismo , Núcleo Celular/metabolismo , Núcleo Celular/efectos de los fármacos , Humanos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacosRESUMEN
Endoplasmic reticulum stress (ERS) and ferroptosis are linked to cerebral ischemia reperfusion injury (CIRI). The neuroprotective properties of 1α, 25-dihydroxyvitamin D3 (VitD3 or 1,25-D3) have been well established; however, the mechanism by which VitD3 treats CIRI through ERS and ferroptosis has not been examined. Hence, we developed middle cerebral artery occlusion/reperfusion (MCAO/R) model in SD rats to ascertain if VitD3 preconditioning mediates ERS and ferroptosis involving of p53 signaling. In this study, we observed that VitD3 can reduce infarction volume and cerebral edema, which leads to the improvement of nerve function. HE, Nissl and Tunel staining showed that VitD3 treatment significantly improved the morphology of neuronal cells and reduced their death. The expression and activation of Vitamin D receptor (VDR), PKR-like ER kinase (PERK), C/EBP-homologous protein (CHOP), p53, nuclear factor erythroid 2-related factor 2 (Nrf2), glutathione peroxidase 4 (GPX4) and reactive oxygen species (ROS) in the ischemic penumbral area were detected by real-time qPCR, Western-blotting and Elisa. The results showed that after VitD3 treatment, VDR increased, ERS-related indices (PERK, CHOP) significantly decreased and ferroptosis-related indices (Nrf2, GPX4) increased. As a VDRs antagonist, pyridoxal-5-phosphate (P5P) can partially block the neuroprotective effects of VitD3. Therefore, CIRI can induce ERS and ferroptosis in the ischemic penumbra area and VitD3 may ameliorate nerve damage in CIRI rats by up-regulating VDR, alleviating p53-associated ERS and ferroptosis.
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Estrés del Retículo Endoplásmico , Ferroptosis , Receptores de Calcitriol , Transducción de Señal , Proteína p53 Supresora de Tumor , Animales , Masculino , Ratas , Isquemia Encefálica/metabolismo , Isquemia Encefálica/patología , Isquemia Encefálica/tratamiento farmacológico , Calcitriol/farmacología , Estrés del Retículo Endoplásmico/efectos de los fármacos , Ferroptosis/efectos de los fármacos , Infarto de la Arteria Cerebral Media/complicaciones , Infarto de la Arteria Cerebral Media/metabolismo , Fármacos Neuroprotectores/farmacología , Fármacos Neuroprotectores/uso terapéutico , Factor 2 Relacionado con NF-E2/metabolismo , Fosfolípido Hidroperóxido Glutatión Peroxidasa/metabolismo , Ratas Sprague-Dawley , Especies Reactivas de Oxígeno/metabolismo , Receptores de Calcitriol/metabolismo , Daño por Reperfusión/metabolismo , Daño por Reperfusión/patología , Transducción de Señal/efectos de los fármacos , Factor de Transcripción CHOP/metabolismo , Proteína p53 Supresora de Tumor/metabolismoRESUMEN
The vitamin D receptor (VDR) plays a critical role in the regulation of mineral and bone homeostasis. Upon binding of 1α,25-dihydroxyvitamin D3 to the VDR, the activation function 2 (AF2) domain repositions and recruits coactivators for the assembly of the transcriptional machinery required for gene transcription. In contrast to coactivator-induced transcriptional activation, the functional effects of coactivator-independent VDR signaling remain unclear. In humans, mutations in the AF2 domain are associated with hereditary vitamin D-resistant rickets, a genetic disorder characterized by impaired bone mineralization and growth. In the present study, we used mice with a systemic or conditional deletion of the VDR-AF2 domain (VdrΔAF2) to study coactivator-independent VDR signaling. We confirm that ligand-induced transcriptional activation was disabled because the mutant VDRΔAF2 protein was unable to interact with coactivators. Systemic VdrΔAF2 mice developed short, undermineralized bones with dysmorphic growth plates, a bone phenotype that was more pronounced than that of systemic Vdr knockout (Vdr-/-) mice. Interestingly, a rescue diet that is high in calcium, phosphate, and lactose, normalized this phenotype in Vdr-/-, but not in VdrΔAF2 mice. However, osteoblast- and osteoclast-specific VdrΔAF2 mice did not recapitulate this bone phenotype indicating coactivator-independent VDR effects are more important in other organs. In addition, RNA-sequencing analysis of duodenum and kidney revealed a decreased expression of VDR target genes in systemic VdrΔAF2 mice, which was not observed in Vdr-/- mice. These genes could provide new insights in the compensatory (re)absorption of minerals that are crucial for bone homeostasis. In summary, coactivator-independent VDR effects contribute to mineral and bone homeostasis.
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Calcio , Lactosa , Fosfatos , Receptores de Calcitriol , Raquitismo , Transducción de Señal , Animales , Receptores de Calcitriol/metabolismo , Receptores de Calcitriol/genética , Ratones , Raquitismo/metabolismo , Raquitismo/genética , Raquitismo/patología , Raquitismo/prevención & control , Fosfatos/metabolismo , Calcio/metabolismo , Lactosa/metabolismo , Ratones Noqueados , Dieta , Ratones Endogámicos C57BLRESUMEN
Several auto-immune diseases have been linked to vitamin D deficiency as a contributing environmental factor. Its pleiotropic effects on the immune system, especially its essential role in maintaining immune tolerance, make the vitamin D pathway of great interest. In this study, we focused on Pemphigus foliaceous (PF) in Tunisian population. we aimed to quantify the Serum 25[OH]D levels using chemiluminescence assay and to analyze the differential expression of the VDR, CYP27B1 and CYP24A1 genes in the circulating blood cells and lesional skin tissue of PF patients using Q-PCR. A genetic explanation was then sought to explore any direct relationship between tag polymorphisms and the inherited features of PF. Results confirmed a vitamin D hypovitaminosis in Tunisian PF patients. Interestingly, a differential gene expression correlated to the disease stratification was noted. Indeed, at the systemic level, an upregulation of VDR and CYP27B1 genes was observed in healthy controls compared to PF patients. Notably, in lesional skin tissue, the clinical and serological remission phase was correlated with high transcriptional levels of the VDR gene and conversely a drop in expression of the CYP24A1 gene. Genetic analysis indicated the involvement of the most appealing polymorphisms, rs2228570 and poly (A) microsatellite, in PF etiopathogenesis. Indeed, CAC13 haplotype was associated with a higher risk of PF development. Our findings suggest that alterations in the vitamin D-VDR pathway may influence PF physiopathology, making this pathway a potential target for pharmacological modulation, especially for cortico-resistant PF patients.
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25-Hidroxivitamina D3 1-alfa-Hidroxilasa , Pénfigo , Receptores de Calcitriol , Deficiencia de Vitamina D , Vitamina D3 24-Hidroxilasa , Vitamina D , Humanos , Pénfigo/inmunología , Pénfigo/genética , Pénfigo/diagnóstico , Receptores de Calcitriol/genética , Receptores de Calcitriol/metabolismo , Vitamina D3 24-Hidroxilasa/genética , Vitamina D3 24-Hidroxilasa/metabolismo , 25-Hidroxivitamina D3 1-alfa-Hidroxilasa/genética , 25-Hidroxivitamina D3 1-alfa-Hidroxilasa/metabolismo , Vitamina D/metabolismo , Vitamina D/sangre , Vitamina D/análogos & derivados , Femenino , Masculino , Persona de Mediana Edad , Adulto , Deficiencia de Vitamina D/complicaciones , Deficiencia de Vitamina D/inmunología , Deficiencia de Vitamina D/sangre , Túnez , Anciano , Polimorfismo de Nucleótido Simple , Piel/patología , Piel/inmunología , Piel/metabolismo , Predisposición Genética a la Enfermedad , Estudios de Casos y ControlesRESUMEN
Vitamin D signals through the vitamin D receptor (VDR) to induce its end-organ effects. Hepatic stellate cells control development of liver fibrosis in response to stressors and vitamin D signaling decreases fibrogenesis. VDR expression in hepatocytes is low in healthy liver, and the role of VDR in hepatocyte proliferation is unclear. Hepatocyte-VDR null mice (hVDR) were used to assess the role of VDR and vitamin D signaling in hepatic regeneration. hVDR mice have impaired liver regeneration and impaired hepatocyte proliferation associated with significant differential changes in bile salts. Notably, mice lacking hepatocyte VDR had significant increases in expression of conjugated bile acids after partial hepatectomy, consistent with failure to normalize hepatic function by the 14-day time point tested. Real-time PCR of hVDR and control livers showed significant changes in expression of cell-cycle genes including cyclins D1 and E1 and cyclin-dependent kinase 2. Gene expression profiling of hepatocytes treated with vitamin D or control showed regulation of groups of genes involved in liver proliferation, hepatitis, liver hyperplasia/hyperproliferation, and liver necrosis/cell death. Together, these studies demonstrate an important functional role for VDR in hepatocytes during liver regeneration. Combined with the known profibrotic effects of impaired VDR signaling in stellate cells, the studies provide a mechanism whereby vitamin D deficiency would both reduce hepatocyte proliferation and permit fibrosis, leading to significant liver compromise.
Asunto(s)
Ácidos y Sales Biliares , Proliferación Celular , Hepatectomía , Hepatocitos , Regeneración Hepática , Ratones Noqueados , Receptores de Calcitriol , Animales , Regeneración Hepática/efectos de los fármacos , Regeneración Hepática/fisiología , Receptores de Calcitriol/metabolismo , Receptores de Calcitriol/genética , Masculino , Ratones , Hepatocitos/metabolismo , Hepatocitos/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Ácidos y Sales Biliares/metabolismo , Hígado/metabolismo , Ciclina D1/metabolismo , Ciclina D1/genética , Ciclina E/metabolismo , Ciclina E/genética , Quinasa 2 Dependiente de la Ciclina/metabolismo , Quinasa 2 Dependiente de la Ciclina/genética , Ratones Endogámicos C57BL , Vitamina D/farmacología , Transducción de Señal/efectos de los fármacos , Proteínas OncogénicasRESUMEN
The activation of the vitamin D receptor (VDR) in the ileum has been shown to regulate Paneth cell-specific defensins, a large family of antimicrobial peptides; hence, this may serve as a potential mechanism to maintain intestinal homeostasis. Previously, we have demonstrated that a combination of vitamin D3 (VD) and fructooligosaccharides (FOSs) upregulates colonic Vdr in mice. Here, we aim to examine the effect of VD, alone or in combination with FOSs, on intestinal barrier integrity and the secretion of antimicrobial peptides, as well as the gut microbial community. Male and female C57BL/6J mice at 6 weeks old were randomized into three groups to receive the following dietary regimens (n = 10/sex/group) for 8 weeks: (1) standard AIN-93G control diet (CTR), (2) CTR + 5000 IU vitamin D3 (VD), and (3) VD + 5% fructooligosaccharides (VF). VD and VF differentially regulated the mRNA expressions of tight junction proteins in the colon and ileum. VF suppressed the upregulation of colonic ZO-1 and occludin, which was induced by VD supplementation alone. In the ileum, occludin but not ZO-1 was upregulated 20-fold in the VF-treated mice. While VD did not alter the mRNA expressions of Vdr and defensins in the ileum, these targets were downregulated by VF. Microbial analysis further reveals a shift of microbial beta diversity and a reduction in Romboutsia ilealis, a pathobiont, in VF-treated mice. Though the implications of these phenotypical and microbial changes remain to be determined, the administration of FOSs in the presence of VD may serve as an effective dietary intervention for maintaining intestinal homeostasis.
Asunto(s)
Colecalciferol , Defensinas , Suplementos Dietéticos , Microbioma Gastrointestinal , Oligosacáridos , Animales , Femenino , Masculino , Ratones , Colecalciferol/farmacología , Colon/metabolismo , Colon/efectos de los fármacos , Defensinas/metabolismo , Defensinas/genética , Regulación hacia Abajo/efectos de los fármacos , Microbioma Gastrointestinal/efectos de los fármacos , Íleon/metabolismo , Íleon/efectos de los fármacos , Mucosa Intestinal/metabolismo , Mucosa Intestinal/efectos de los fármacos , Ratones Endogámicos C57BL , Ocludina/metabolismo , Ocludina/genética , Oligosacáridos/farmacología , Oligosacáridos/administración & dosificación , Células de Paneth/metabolismo , Células de Paneth/efectos de los fármacos , Receptores de Calcitriol/metabolismo , Receptores de Calcitriol/genética , Proteína de la Zonula Occludens-1/metabolismo , Proteína de la Zonula Occludens-1/genéticaRESUMEN
The major role of bioactive vitamin 1,25-dihydroxyvitamin D3 (1,25(OH)2D or calcitriol) is to maintain the levels of calcium and phosphorus to achieve bone and mineral homeostasis. Dietary intake and adequate natural light exposure are the main contributors to normal vitamin D status. In addition to regulating metabolism, vitamin D exerts various immunomodulatory effects that regulate innate and adaptive immunity through immune effector cells such as monocytes, macrophages, T and B lymphocytes, and natural killer cells and nonimmune cells that express vitamin D receptors. Systemic lupus erythematosus (SLE) is an autoimmune disease with an unknown etiology, and the association between vitamin D and SLE remains incompletely understood. Given that the current treatment for SLE relies heavily on corticosteroids and that SLE patients tend to have low vitamin D status, vitamin D supplementation may help to reduce the dosage of corticosteroids and/or attenuate disease severity. In this review, we address the associations between vitamin D and several clinical aspects of SLE. In addition, the underlying immunomodulatory mechanisms accounting for the potential vitamin D-mediated therapeutic effects are discussed. Finally, several confounding factors in data interpretation and the execution of clinical trials and perspectives targeting vitamin D supplementation in patients with SLE are also addressed.
Asunto(s)
Lupus Eritematoso Sistémico , Vitamina D , Humanos , Lupus Eritematoso Sistémico/tratamiento farmacológico , Lupus Eritematoso Sistémico/inmunología , Lupus Eritematoso Sistémico/metabolismo , Vitamina D/uso terapéutico , Vitamina D/administración & dosificación , Animales , Suplementos Dietéticos , Deficiencia de Vitamina D/tratamiento farmacológico , Deficiencia de Vitamina D/inmunología , Deficiencia de Vitamina D/complicaciones , Receptores de Calcitriol/metabolismoRESUMEN
Emerging evidence has reported that acute lung injury (ALI), characterized by inflammation and oxidative stress in airway epithelium, is regulated by programmed cell death. Ferroptosis, a regulated form of cell death spurred by uncontrolled lipid peroxidation, has been proven to implicate various diseases. Inhibiting ferroptosis represents a feasible strategy for ALI through the suppression of lipid peroxidation, while the mechanism remains to be further elucidated. Here, we identified Sequestosome 1 (SQSTM1) as a negative regulator of airway epithelium ferroptosis during ALI. SQSTM1 knockdown cells manifested higher sensitivity to ferroptosis. Mechanistically, SQSTM1 was found to directly interact with vitamin D receptor (VDR) through its nuclear receptor (NR) box motif, facilitating its nuclear translocation and initiating autophagy at the transcriptional level. To further validate these findings, an in vivo preventive model utilizing spermidine, a proven inducer of SQSTM1 was established. The results consistently demonstrated that spermidine supplementation significantly induced SQSTM1 and ameliorated ALI by mitigating airway epithelial ferroptosis. Notably, these effects were abrogated in the absence of SQSTM1. Taken together, this study identified SQSTM1 as a negative regulator of airway epithelium ferroptosis in a VDR-mediated autophagy manner, making it a potential therapeutic target for the treatment of ALI.
Asunto(s)
Lesión Pulmonar Aguda , Autofagia , Ferroptosis , Receptores de Calcitriol , Proteína Sequestosoma-1 , Proteína Sequestosoma-1/metabolismo , Proteína Sequestosoma-1/genética , Lesión Pulmonar Aguda/metabolismo , Lesión Pulmonar Aguda/patología , Lesión Pulmonar Aguda/genética , Ferroptosis/genética , Ferroptosis/efectos de los fármacos , Receptores de Calcitriol/metabolismo , Receptores de Calcitriol/genética , Animales , Humanos , Ratones , Masculino , Ratones Endogámicos C57BL , Mucosa Respiratoria/metabolismo , Mucosa Respiratoria/patología , Estrés Oxidativo , Peroxidación de Lípido/efectos de los fármacosRESUMEN
Calcitriol, the bioactive form of vitamin D, exerts its biological functions by binding to its cognate receptor, the vitamin D receptor (VDR). The indicators of the severity of allergies and asthma have been linked to low vitamin D levels. However, the role of calcitriol in regulating IL-4 and IL-13, two cytokines pivotal to allergic inflammation, remained unclear. Our study observed diminished IL-4 and IL-13 secretion in murine and human Th2 cells treated with calcitriol. In murine Th2 cells, Gata3 expression was attenuated by calcitriol. However, the expression of the transcriptional repressor Gfi1, too, was attenuated in the presence of calcitriol. Ectopic expression of either Gfi1 or VDR impaired the secretion of IL-13 in Th2 cells. In murine Th2 cells, VDR interacted with Gata3 but not Gfi1. Gfi1 significantly impaired Il13 promoter activation, which calcitriol failed to restore. Conversely, calcitriol augmented Gfi1 recruitment to the Il13 promoter. Ecr, a conserved region between these two genes, which enhanced the transactivation of Il4 and Il13 promoters, is essential for calcitriol-mediated suppression of both the genes. Calcitriol augmented the recruitment of VDR to the Il13 promoter and Ecr regions. Gata3 recruitment was significantly impaired at the Il13 and Ecr loci in the presence of calcitriol but increased at the Il4 promoter. Furthermore, the recruitment of the histone deacetylase HDAC1 was universally increased at the promoters of Il4, Il13, and Ecr when calcitriol was present. Together, our data clearly elucidate that calcitriol modulates VDR, Gata3, and Gfi1 to suppress IL-4 and IL-13 production in Th2 cells.
Asunto(s)
Calcitriol , Factor de Transcripción GATA3 , Interleucina-13 , Interleucina-4 , Receptores de Calcitriol , Células Th2 , Factor de Transcripción GATA3/metabolismo , Factor de Transcripción GATA3/genética , Receptores de Calcitriol/metabolismo , Receptores de Calcitriol/genética , Calcitriol/farmacología , Animales , Interleucina-4/metabolismo , Interleucina-4/inmunología , Interleucina-13/metabolismo , Interleucina-13/inmunología , Ratones , Células Th2/inmunología , Humanos , Factores de Transcripción/metabolismo , Factores de Transcripción/genética , Proteínas de Unión al ADN/metabolismo , Proteínas de Unión al ADN/genéticaRESUMEN
Pharmacokinetic changes induced by radiation following radiotherapy ("RT-PK" phenomenon) are of great significance to the effectiveness and safety of chemotherapeutic agents in clinical settings. The aims of this study were to clarify the organic anion transporters (Oats) involved in the "RT-PK" phenomenon of bestatin in rats following X-ray irradiation and to elucidate its potential mechanism via vitamin D signalling. Pharmacokinetic studies, uptake assays using rat kidney slices and primary proximal tubule cells, and molecular biological studies were performed. Significantly increased plasma concentrations and systemic exposure to bestatin were observed at 24 and 48 h following abdominal X-ray irradiation, regardless of oral or intravenous administration of the drugs in rats. Reduced renal clearance and cumulative urinary excretion of bestatin were observed at 24 and 48 h post-irradiation in rats following intravenous administration. The uptake of the probe substrates p-aminohippuric acid and oestrone 3-sulfate sodium in vitro and the expression of Oat1 and Oat3 in vivo were reduced in the corresponding models following irradiation. Moreover, the upregulation of the vitamin D receptor (Vdr) in mRNA and protein levels negatively correlated with the expressions and functions of Oat1 and Oat3 following irradiation. Additionally, elevated plasma urea nitrogen levels and histopathological changes were observed in rats after exposure to irradiation. The "RT-PK" phenomenon of bestatin occurs in rats after exposure to irradiation, possibly resulting in the regulation of the expressions and activities of renal Oats via activation of the Vdr signalling pathway.
Asunto(s)
Regulación hacia Abajo , Riñón , Receptores de Calcitriol , Animales , Ratas , Receptores de Calcitriol/metabolismo , Masculino , Riñón/metabolismo , Riñón/efectos de la radiación , Regulación hacia Abajo/efectos de los fármacos , Regulación hacia Abajo/efectos de la radiación , Ratas Sprague-Dawley , Rayos X , Proteína 1 de Transporte de Anión Orgánico/metabolismo , Proteína 1 de Transporte de Anión Orgánico/genética , Transportadores de Anión Orgánico/metabolismo , Túbulos Renales Proximales/metabolismo , Túbulos Renales Proximales/efectos de la radiación , Túbulos Renales Proximales/efectos de los fármacos , Leucina/análogos & derivadosRESUMEN
Carbon tetrachloride (CCl4) has a wide range of toxic effects, especially causing acute liver injury (ALI), in which rapid compensation for hepatocyte loss ensures liver survival, but proliferation of surviving hepatocytes (known as endoreplication) may imply impaired residual function. Yes-associated protein (YAP) drives hepatocytes to undergo endoreplication and ploidy, the underlying mechanisms of which remain a mystery. In the present study, we uncover during CCl4-mediated ALI accompanied by increased hepatocytes proliferation and YAP activation. Notably, bioinformatics analyses elucidate that hepatic-specific deletion of YAP substantially ameliorated CCl4-induced hepatic proliferation, effectively decreased the vitamin D receptor (VDR) expression. Additionally, a mouse model of acute liver injury substantiated that inhibition of YAP could suppress hepatocytes proliferation via VDR. Furthermore, we also disclosed that the VDR agonist nullifies CCl4-induced ALI alleviated by the YAP inhibitor in vivo. Importantly, hepatocytes were isolated from mice, and it was spotlighted that the anti-proliferative impact of the YAP inhibitor was abolished by the activation of VDR within these hepatocytes. Similarly, primary hepatic stellate cells (HSCs) were isolated and it was manifested that YAP inhibitor suppressed HSC activation via VDR during acute liver injury. Our findings further elucidate the YAP's role in ALI and may provide new avenues for protection against CCl4-drived acute liver injury.