RESUMO
The molecular mechanisms governing orderly shutdown and retraction of CD4+ type 1 helper T (TH1) cell responses remain poorly understood. Here we show that complement triggers contraction of TH1 responses by inducing intrinsic expression of the vitamin D (VitD) receptor and the VitD-activating enzyme CYP27B1, permitting T cells to both activate and respond to VitD. VitD then initiated the transition from pro-inflammatory interferon-γ+ TH1 cells to suppressive interleukin-10+ cells. This process was primed by dynamic changes in the epigenetic landscape of CD4+ T cells, generating super-enhancers and recruiting several transcription factors, notably c-JUN, STAT3 and BACH2, which together with VitD receptor shaped the transcriptional response to VitD. Accordingly, VitD did not induce interleukin-10 expression in cells with dysfunctional BACH2 or STAT3. Bronchoalveolar lavage fluid CD4+ T cells of patients with COVID-19 were TH1-skewed and showed de-repression of genes downregulated by VitD, from either lack of substrate (VitD deficiency) and/or abnormal regulation of this system.
Assuntos
Interferon gama/imunologia , Interleucina-10/imunologia , SARS-CoV-2/imunologia , Células Th1/imunologia , Vitamina D/metabolismo , 25-Hidroxivitamina D3 1-alfa-Hidroxilase/metabolismo , Fatores de Transcrição de Zíper de Leucina Básica/metabolismo , Líquido da Lavagem Broncoalveolar/citologia , COVID-19/imunologia , COVID-19/patologia , Complemento C3a/imunologia , Complemento C3b/imunologia , Humanos , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Ativação Linfocitária/imunologia , Receptores de Calcitriol/metabolismo , Síndrome do Desconforto Respiratório/imunologia , Síndrome do Desconforto Respiratório/patologia , Síndrome do Desconforto Respiratório/virologia , Fator de Transcrição STAT3/metabolismo , Transdução de Sinais/imunologia , Transcrição Gênica/genéticaRESUMO
A primary cause of disease progression in type 2 diabetes (T2D) is ß cell dysfunction due to inflammatory stress and insulin resistance. However, preventing ß cell exhaustion under diabetic conditions is a major therapeutic challenge. Here, we identify the vitamin D receptor (VDR) as a key modulator of inflammation and ß cell survival. Alternative recognition of an acetylated lysine in VDR by bromodomain proteins BRD7 and BRD9 directs association to PBAF and BAF chromatin remodeling complexes, respectively. Mechanistically, ligand promotes VDR association with PBAF to effect genome-wide changes in chromatin accessibility and enhancer landscape, resulting in an anti-inflammatory response. Importantly, pharmacological inhibition of BRD9 promotes PBAF-VDR association to restore ß cell function and ameliorate hyperglycemia in murine T2D models. These studies reveal an unrecognized VDR-dependent transcriptional program underpinning ß cell survival and identifies the VDR:PBAF/BAF association as a potential therapeutic target for T2D.
Assuntos
Proteínas Cromossômicas não Histona/metabolismo , Células Secretoras de Insulina/efeitos dos fármacos , Receptores de Calcitriol/metabolismo , Fatores de Transcrição/metabolismo , Vitamina D/farmacologia , Animais , Calcitriol/análogos & derivados , Calcitriol/farmacologia , Montagem e Desmontagem da Cromatina , Diabetes Mellitus Experimental/induzido quimicamente , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/patologia , Humanos , Insulina/sangue , Insulina/metabolismo , Células Secretoras de Insulina/citologia , Células Secretoras de Insulina/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Obesos , Mutagênese Sítio-Dirigida , Fosforilação Oxidativa/efeitos dos fármacos , Ligação Proteica , Interferência de RNA , RNA Guia de Cinetoplastídeos/genética , RNA Interferente Pequeno/metabolismo , Receptores de Calcitriol/antagonistas & inibidores , Receptores de Calcitriol/genética , Fatores de Transcrição/antagonistas & inibidores , Fatores de Transcrição/genética , Transcrição Gênica/efeitos dos fármacosAssuntos
Receptores de Calcitriol/metabolismo , SARS-CoV-2/imunologia , Células Th1/imunologia , Vitamina D/metabolismo , Fatores de Transcrição de Zíper de Leucina Básica/metabolismo , COVID-19/patologia , Humanos , Interferon gama/imunologia , Interleucina-10/imunologia , Proteína Cofatora de Membrana/imunologia , Proteínas Proto-Oncogênicas c-jun/metabolismo , Receptores de Calcitriol/genética , Fator de Transcrição STAT3/metabolismo , Transdução de Sinais/imunologiaRESUMO
The poor clinical outcome in pancreatic ductal adenocarcinoma (PDA) is attributed to intrinsic chemoresistance and a growth-permissive tumor microenvironment. Conversion of quiescent to activated pancreatic stellate cells (PSCs) drives the severe stromal reaction that characterizes PDA. Here, we reveal that the vitamin D receptor (VDR) is expressed in stroma from human pancreatic tumors and that treatment with the VDR ligand calcipotriol markedly reduced markers of inflammation and fibrosis in pancreatitis and human tumor stroma. We show that VDR acts as a master transcriptional regulator of PSCs to reprise the quiescent state, resulting in induced stromal remodeling, increased intratumoral gemcitabine, reduced tumor volume, and a 57% increase in survival compared to chemotherapy alone. This work describes a molecular strategy through which transcriptional reprogramming of tumor stroma enables chemotherapeutic response and suggests vitamin D priming as an adjunct in PDA therapy. PAPERFLICK:
Assuntos
Adenocarcinoma/tratamento farmacológico , Antineoplásicos/farmacologia , Calcitriol/análogos & derivados , Carcinoma Ductal Pancreático/tratamento farmacológico , Neoplasias Pancreáticas/tratamento farmacológico , Receptores de Calcitriol/metabolismo , Adenocarcinoma/patologia , Animais , Calcitriol/farmacologia , Carcinoma Ductal Pancreático/patologia , Linhagem Celular Tumoral , Modelos Animais de Doenças , Perfilação da Expressão Gênica , Humanos , Camundongos Endogâmicos C57BL , Dados de Sequência Molecular , Neoplasias Pancreáticas/patologia , Pancreatite/tratamento farmacológico , Pancreatite/prevenção & controle , Transdução de Sinais , Células Estromais/patologiaRESUMO
Liver fibrosis is a reversible wound-healing response involving TGFß1/SMAD activation of hepatic stellate cells (HSCs). It results from excessive deposition of extracellular matrix components and can lead to impairment of liver function. Here, we show that vitamin D receptor (VDR) ligands inhibit HSC activation by TGFß1 and abrogate liver fibrosis, whereas Vdr knockout mice spontaneously develop hepatic fibrosis. Mechanistically, we show that TGFß1 signaling causes a redistribution of genome-wide VDR-binding sites (VDR cistrome) in HSCs and facilitates VDR binding at SMAD3 profibrotic target genes via TGFß1-dependent chromatin remodeling. In the presence of VDR ligands, VDR binding to the coregulated genes reduces SMAD3 occupancy at these sites, inhibiting fibrosis. These results reveal an intersecting VDR/SMAD genomic circuit that regulates hepatic fibrogenesis and define a role for VDR as an endocrine checkpoint to modulate the wound-healing response in liver. Furthermore, the findings suggest VDR ligands as a potential therapy for liver fibrosis.
Assuntos
Redes Reguladoras de Genes , Fígado/metabolismo , Fígado/patologia , Receptores de Calcitriol/metabolismo , Transdução de Sinais , Animais , Calcitriol/análogos & derivados , Fibrose/prevenção & controle , Estudo de Associação Genômica Ampla , Células Estreladas do Fígado , Fígado/lesões , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Ratos , Receptores de Calcitriol/agonistas , Proteína Smad3/metabolismo , Transcriptoma , Fator de Crescimento Transformador beta1/metabolismoRESUMO
Although evidence exists for a causal association between 25-hydroxyvitamin D (25(OH)D) serum levels, and multiple sclerosis (MS), the role of variation in vitamin D receptor (VDR) binding in MS is unknown. Here, we leveraged previously identified variants associated with allele imbalance in VDR binding (VDR-binding variant; VDR-BV) in ChIP-exo data from calcitriol-stimulated lymphoblastoid cell lines and 25(OH)D serum levels from genome-wide association studies to construct genetic instrumental variables (GIVs). GIVs are composed of one or more genetic variants that serve as proxies for exposures of interest. Here, GIVs for both VDR-BVs and 25(OH)D were used in a two-sample Mendelian Randomization study to investigate the relationship between VDR binding at a locus, 25(OH)D serum levels, and MS risk. Data for 13,598 MS cases and 38,887 controls of European ancestry from Kaiser Permanente Northern California, Swedish MS studies, and the UK Biobank were included. We estimated the association between each VDR-BV GIV and MS. Significant interaction between a VDR-BV GIV and a GIV for serum 25OH(D) was evidence for a causal association between VDR-BVs and MS unbiased by pleiotropy. We observed evidence for associations between two VDR-BVs (rs2881514, rs2531804) and MS after correction for multiple tests. There was evidence of interaction between rs2881514 and a 25(OH)D GIV, providing evidence of a causal association between rs2881514 and MS. This study is the first to demonstrate evidence that variation in VDR binding at a locus contributes to MS risk. Our results are relevant to other autoimmune diseases in which vitamin D plays a role.
Assuntos
Esclerose Múltipla , Humanos , Esclerose Múltipla/genética , Receptores de Calcitriol/genética , Receptores de Calcitriol/metabolismo , Alelos , Estudo de Associação Genômica Ampla , Vitamina D/metabolismo , Calcitriol , Polimorfismo de Nucleotídeo ÚnicoRESUMO
Macrophage autophagy dysfunction aggravates liver injury by activating inflammasomes, which can cleave pro-IL-1ß to its active, secreted form. We investigated whether the vitamin D/vitamin D receptor (VDR) axis could up-regulate macrophage autophagy function to inhibit the activation of inflammasome-dependent IL-1ß during cholestasis. Paricalcitol (PAL; VDR agonist) was intraperitoneally injected into bile duct-ligated mice for 5 days. Up-regulation of VDR expression by PAL reduced liver injury by reducing the oxidative stress-induced inflammatory reaction in macrophages. Moreover, PAL inhibited inflammasome-dependent IL-1ß generation. Mechanistically, the knockdown of VDR increased IL-1ß generation, whereas VDR overexpression exerted the opposite effect following tert-butyl hydroperoxide treatment. The inflammasome antagonist glyburide, the caspase-1-specific inhibitor YVAD, and the reactive oxygen species (ROS) scavenger N-acetyl-l-cysteine (NAC) blocked the increase in Vdr shRNA-induced IL-1ß production. Interestingly, up-regulation of VDR also enhanced macrophage autophagy. Autophagy reduction impaired the up-regulation of VDR-inhibited macrophage inflammasome-generated IL-1ß, whereas autophagy induction showed a synergistic effect with VDR overexpression through ROS-p38 mitogen-activated protein kinase (MAPK) pathway. This result was confirmed by p38 MAPK inhibitor, MAPK activator, and ROS inhibitor NAC. Collectively, PAL triggered macrophage autophagy by suppressing activation of the ROS-p38 MAPK pathway, which, in turn, suppressed inflammasome-generated cleaved, active forms of IL-1ß, eventually leading to reduced inflammation. Thus, triggering the VDR may be a potential target for the anti-inflammatory treatment of cholestatic liver disease.
Assuntos
Colestase , Inflamassomos , Animais , Camundongos , Acetilcisteína , Autofagia/fisiologia , Colestase/metabolismo , Inflamassomos/metabolismo , Inflamação/metabolismo , Interleucina-1beta/metabolismo , Macrófagos/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Receptores de Calcitriol/metabolismoRESUMO
Vitamin D deficiency is associated with the development of autoimmunity, which arises from defects in T cell tolerance to self-antigens. Interactions of developing T cells with medullary thymic epithelial cells, which express tissue-restricted Ags, are essential for the establishment of central tolerance. However, vitamin D signaling in the thymus is poorly characterized. We find that stromal and hematopoietic cells in the mouse thymus express the vitamin D receptor (Vdr) and Cyp27b1, the enzyme that produces hormonal 1,25-dihydroxyvitamin D (1,25D). Treatment of cultured thymic slices with 1,25D enhances expression of the critical medullary thymic epithelial cell transcription factor autoimmune regulator (Aire), its colocalization with the Vdr, and enhances tissue-restricted Ag gene expression. Moreover, the Vdr interacts with Aire in a 1,25D-dependent manner and recruits Aire to DNA at vitamin D response elements, where it acts as a Vdr coactivator. These data link vitamin D signaling directly to critical transcriptional events necessary for central tolerance.
Assuntos
Receptores de Calcitriol , Fatores de Transcrição , Animais , Camundongos , Células Epiteliais , Regulação da Expressão Gênica , Receptores de Calcitriol/metabolismo , Timo , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Vitamina D/metabolismo , Proteína AIRERESUMO
BACKGROUND: Ectopic lymphoid tissues (eLTs) and associated follicular helper T (TFH) cells contribute to local immunoglobulin hyperproduction in nasal polyps (NPs). Follicular regulatory T (TFR) cells in secondary lymphoid organs counteract TFH cells and suppress immunoglobulin production; however, the presence and function of TFR cells in eLTs in peripheral diseased tissues remain poorly understood. OBJECTIVE: We sought to investigate the presence, phenotype, and function of TFR cells in NPs. METHODS: The presence, abundance, and phenotype of TFR cells in NPs were examined using single-cell RNA sequencing, immunofluorescence staining, and flow cytometry. Sorted polyp and circulating T-cell subsets were cocultured with autologous circulating naïve B cells, and cytokine and immunoglobulin production were measured by ELISA. RESULTS: TFR cells were primarily localized within eLTs in NPs. TFR cell frequency and TFR cell/TFH cell ratio were decreased in NPs with eLTs compared with NPs without eLTs and control inferior turbinate tissues. TFR cells displayed an overlapping phenotype with TFH cells and FOXP3+ regulatory T cells in NPs. Polyp TFR cells had reduced CTLA-4 expression and decreased capacity to inhibit TFH cell-induced immunoglobulin production compared with their counterpart in blood and tonsils. Blocking CTLA-4 abolished the suppressive effect of TFR cells. Lower vitamin D receptor expression was observed on polyp TFR cells compared with TFR cells in blood and tonsils. Vitamin D treatment upregulated CTLA-4 expression on polyp TFR cells and restored their suppressive function in vitro. CONCLUSIONS: Polyp TFR cells in eLTs have decreased CLTA-4 and vitamin D receptor expression and impaired capacity to suppress TFH cell-induced immunoglobulin production, which can be reversed by vitamin D treatment in vitro.
Assuntos
Pólipos Nasais , Estruturas Linfoides Terciárias , Humanos , Linfócitos T Reguladores/patologia , Linfócitos T Auxiliares-Indutores/patologia , Antígeno CTLA-4/metabolismo , Receptores de Calcitriol/metabolismo , Pólipos Nasais/patologia , Estruturas Linfoides Terciárias/patologia , Imunoglobulinas/metabolismo , Vitamina D/metabolismoRESUMO
Concerns regarding toxicity and resistance of current drugs in visceral leishmaniasis have been reported. Antimicrobial peptides are considered to be promising candidates and among them human cathelicidin hCAP18/LL-37 showed significant parasite killing on drug-sensitive and resistant Leishmania promastigotes, in addition to its apoptosis-inducing role. Administration of hCAP18/LL-37 to infected macrophages also decreased parasite survival and increased the host favorable cytokine interleukin 12. However, 1,25-dihydroxyvitamin D3 (vitamin D3)-induced endogenous hCAP18/LL-37 production was hampered in infected THP-1 cells. Infection also suppressed the vitamin D3 receptor (VDR), transcription factor of hCAP18/LL-37. cAMP response element modulator (CREM), the repressor of VDR, was induced in infection, resulting in suppression of both VDR and cathelicidin expression. PGE2/cAMP/PKA axis was found to regulate CREM induction during infection and silencing CREM in infected cells and BALB/c mice led to decreased parasite survival. This study documents the antileishmanial potential of cathelicidin and further identifies CREM as a repressor of cathelicidin in Leishmania infection.
Assuntos
Peptídeos Catiônicos Antimicrobianos , Catelicidinas , Modulador de Elemento de Resposta do AMP Cíclico , Leishmania donovani , Leishmaniose Visceral , Macrófagos , Camundongos Endogâmicos BALB C , Leishmania donovani/efeitos dos fármacos , Animais , Peptídeos Catiônicos Antimicrobianos/metabolismo , Peptídeos Catiônicos Antimicrobianos/farmacologia , Humanos , Leishmaniose Visceral/parasitologia , Leishmaniose Visceral/tratamento farmacológico , Camundongos , Macrófagos/parasitologia , Macrófagos/metabolismo , Células THP-1 , Modulador de Elemento de Resposta do AMP Cíclico/metabolismo , Modulador de Elemento de Resposta do AMP Cíclico/genética , Receptores de Calcitriol/metabolismo , Receptores de Calcitriol/genética , Antiprotozoários/farmacologia , FemininoRESUMO
We found previously that nuclear receptors (NRs) compete for heterodimerization with their common partner, retinoid X receptor (RXR), in a ligand-dependent manner. To investigate potential competition in their DNA binding, we monitored the mobility of retinoic acid receptor (RAR) and vitamin D receptor (VDR) in live cells by fluorescence correlation spectroscopy. First, specific agonist treatment and RXR coexpression additively increased RAR DNA binding, while both agonist and RXR were required for increased VDR DNA binding, indicating weaker DNA binding of the VDR/RXR dimer. Second, coexpression of RAR, VDR, and RXR resulted in competition for DNA binding. Without ligand, VDR reduced the DNA-bound fraction of RAR and vice versa, i.e., a fraction of RXR molecules was occupied by the competing partner. The DNA-bound fraction of either RAR or VDR was enhanced by its own and diminished by the competing NR's agonist. When treated with both ligands, the DNA-bound fraction of RAR increased as much as due to its own agonist, whereas that of VDR increased less. RXR agonist also increased DNA binding of RAR at the expense of VDR. In summary, competition between RAR and VDR for RXR is also manifested in their DNA binding in an agonist-dependent manner: RAR dominates over VDR in the absence of agonist or with both agonists present. Thus, side effects of NR-ligand-based (retinoids, thiazolidinediones) therapies may be ameliorated by other NR ligands and be at least partly explained by reduced DNA binding due to competition. Our results also complement the model of NR action by involving competition both for RXR and for DNA sites.
Assuntos
Receptores de Calcitriol , Receptores do Ácido Retinoico , Receptores X de Retinoides , DNA/metabolismo , Ligantes , Receptores de Calcitriol/química , Receptores de Calcitriol/metabolismo , Receptores Citoplasmáticos e Nucleares , Receptores X de Retinoides/química , Receptores X de Retinoides/metabolismo , Tretinoína/farmacologia , Receptores do Ácido Retinoico/química , Receptores do Ácido Retinoico/metabolismoRESUMO
Mycophenolate mofetil (MMF) is one of the most used immunosuppressive drugs in organ transplantation, but frequent gastrointestinal (GI) side effects through unknown mechanisms limit its clinical use. Gut microbiota and its metabolites were recently reported to play a vital role in MMF-induced GI toxicity, but the specific mechanism of how they interact with the human body is still unclear. Here, we found that secondary bile acids (BAs), as bacterial metabolites, were significantly reduced by MMF administration in the gut of mice. Microbiome data and fecal microbiota transfer model supported a microbiota-dependent effect on the reduction of secondary BAs. Supplementation of the secondary BA lithocholic acid alleviated MMF-induced weight loss, colonic inflammation, and oxidative phosphorylation damage. Genetic deletion of the vitamin D3 receptor (VDR), which serves as a primary colonic BA receptor, in colonic epithelial cells (VDRΔIEC) abolished the therapeutic effect of lithocholic acid on MMF-induced GI toxicity. Impressively, we discovered that paricalcitol, a Food and Drug Administration-approved VDR agonist that has been used in clinics for years, could effectively alleviate MMF-induced GI toxicity. Our study reveals a previously unrecognized mechanism of gut microbiota, BAs, and VDR signaling in MMF-induced GI side effects, offering potential therapeutic strategies for clinics.
Assuntos
Ácidos e Sais Biliares , Microbioma Gastrointestinal , Ácido Micofenólico , Receptores de Calcitriol , Animais , Ácido Micofenólico/farmacologia , Camundongos , Microbioma Gastrointestinal/efeitos dos fármacos , Receptores de Calcitriol/metabolismo , Ácidos e Sais Biliares/metabolismo , Imunossupressores , Camundongos Endogâmicos C57BL , Masculino , Gastroenteropatias/induzido quimicamente , Ácido Litocólico , HumanosRESUMO
The occurrence and severity of osteonecrosis in sickle cell anaemia (SCA) vary due to risk factors, including genetic modifiers. Bone morphogenetic proteins (BMPs), particularly BMP6, and the vitamin D receptor (VDR) play key roles in cartilage and bone metabolism, making them potential contributors to orthopaedic outcomes in SCA. Here, we evaluated the association of polymorphisms in BMP6 (rs3812163, rs270393 and rs449853) and VDR (FokI rs2228570 and Cdx2 rs11568820) genes with osteonecrosis risk in a Brazilian SCA cohort. A total of 177 unrelated SCA patients were selected. The AA genotype of BMP6 rs3812163 was independently associated with a lower osteonecrosis risk (p = 0.015; odds ratio (OR): 0.38; 95% confidence interval (CI): 0.18-0.83) and with the long-term cumulative incidence of osteonecrosis (p = 0.029; hazard ratio: 0.56, 95% CI: 0.34-0.94). The VDR rs2228570 TT genotype was independently associated with a lower osteonecrosis risk (p = 0.039; OR: 0.14; 95% CI: 0.02-0.90). In summary, our results provide evidence that BMP6 rs3812163 and the VDR rs2228570 might be implicated in osteonecrosis pathophysiology in SCA and might help identify individuals at high risk.
Assuntos
Anemia Falciforme , Osteonecrose , Humanos , Predisposição Genética para Doença , Polimorfismo de Nucleotídeo Único , Fatores de Risco , Osteonecrose/genética , Anemia Falciforme/complicações , Anemia Falciforme/genética , Genótipo , Estudos de Casos e Controles , Proteína Morfogenética Óssea 6/genética , Receptores de Calcitriol/genéticaRESUMO
PURPOSE: Vitamin D has some anticancer properties that may decrease breast cancer risk and improve prognosis. The aim was to investigate associations between four previously studied VDR SNPs (Taq1, Tru91, Bsm1, and Fok1) and prognosis in different groups of breast cancer patients. METHODS: VDR genotyping of 1,017 breast cancer patients included 2002-2012 in Lund, Sweden, was performed using Oncoarray. Follow-up was until June 30, 2019. Clinical data and patient information were collected from medical records and questionnaires. Cox regression was used for survival analyses. RESULTS: Genotype frequencies were as follows: Fok1 (AA 15.7%, AG 49.1%, GG 35.1%), Bsm1 (CC 37.2%, CT 46.1%, TT 16.7%), Tru91 (CC 77.8%, CT 20.7%, TT 1.5%), and Taq1 (AA 37.2%, AG 46.2%, GG 16.6%). During follow-up there were 195 breast cancer events. The homozygous variants of Taq1 and Bsm1 were associated with reduced risk of breast cancer events (adjusted HR = 0.59, 95% CI 0.38-0.92 for Taq1 and adjusted HR = 0.61, 95% CI 0.40-0.94 for Bsm1). The G allele of the Fok1 was associated with increased risk of breast cancer events in small tumors (pT1, adjusted HR = 1.83, 95% CI 1.04-3.23) but not in large tumors (pT2/3/4, adjusted HR = 0.80, 95% CI 0.41-1.59) with a borderline interaction (Pinteraction = 0.058). No interactions between VDR genotypes and adjuvant treatments regarding breast cancer prognosis were detected. CONCLUSION: VDR genotypes were associated with breast cancer prognosis and the association might be modified by tumor size. Further research is needed to confirm the findings and elucidate their potential clinical implications.
Assuntos
Neoplasias da Mama , Polimorfismo de Nucleotídeo Único , Receptores de Calcitriol , Humanos , Receptores de Calcitriol/genética , Feminino , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Prognóstico , Pessoa de Meia-Idade , Estudos Prospectivos , Suécia/epidemiologia , Genótipo , Idoso , Adulto , Predisposição Genética para DoençaRESUMO
Nuclear receptors (NRs) are ligand-activated transcription factors, which constitute one of the most important targets for drug discovery. Current computational strategies mainly focus on a single target, and the transfer of learned knowledge among NRs was not considered yet. Herein we proposed a novel computational framework named NR-Profiler for prediction of potential NR modulators with high affinity and specificity. First, we built a comprehensive NR data set including 42 684 interactions to connect 42 NRs and 31 033 compounds. Then, we used multi-task deep neural network and multi-task graph convolutional neural network architectures to construct multi-task multi-classification models. To improve the predictive capability and robustness, we built a consensus model with an area under the receiver operating characteristic curve (AUC) = 0.883. Compared with conventional machine learning and structure-based approaches, the consensus model showed better performance in external validation. Using this consensus model, we demonstrated the practical value of NR-Profiler in virtual screening for NRs. In addition, we designed a selectivity score to quantitatively measure the specificity of NR modulators. Finally, we developed a freely available standalone software for users to make profiling predictions for their compounds of interest. In summary, our NR-Profiler provides a useful tool for NR-profiling prediction and is expected to facilitate NR-based drug discovery.
Assuntos
Aprendizado Profundo , Receptores Artificiais , Receptores dos Hormônios Gastrointestinais , Receptores de Imunoglobulina Polimérica , Receptor do Fator Ativador de Células B , Proteína Semelhante a Receptor de Calcitonina , Receptor gp130 de Citocina , Antagonistas dos Receptores H2 da Histamina , Ligantes , Antagonistas dos Receptores de Neurocinina-1 , Proteínas Proto-Oncogênicas c-met , Receptor de Glutamato Metabotrópico 5 , Proteínas Tirosina Fosfatases Classe 2 Semelhantes a Receptores , Receptores de Hidrocarboneto Arílico , Receptores de Calcitriol , Receptores Citoplasmáticos e Nucleares , Receptores MuscarínicosRESUMO
Dentin is a permeable and complex tubular composite formed by the mineralization of predentin that mineralization and repair are of considerable clinical interest during dentin homeostasis. The role of Vdr, a receptor of vitamin D, in dentin homeostasis remains unexplored. The aim of the present study was to assess the impact of Vdr on predentin mineralization and dental repair. Vdr-knockout (Vdr-/-) mice models were constructed; histology and immunohistochemistry analyses were conducted for both WT and Vdr-/- mice. The finding revealed a thicker predentin in Vdr-/- mice, characterized by higher expression of biglycan and decorin. A dental injury model was employed to observe tertiary dentin formation in Vdr-/- mice with dental injuries. Results showed that tertiary dentin was harder to form in Vdr-/- mice with dental injury. Over time, heightened pulp invasion was observed at the injury site in Vdr-/- mice. Expression of biglycan and decorin was reduced in the predentin at the injury site in the Vdr-/- mice by immunohistochemistry. Taken together, our results imply that Vdr plays a regulatory role in predentin mineralization and tertiary dentin formation during dentin homeostasis.
Assuntos
Dentina , Camundongos Knockout , Receptores de Calcitriol , Animais , Receptores de Calcitriol/metabolismo , Dentina/metabolismo , Camundongos , Biglicano/metabolismo , Cicatrização , Camundongos Endogâmicos C57BL , Decorina/metabolismo , Calcificação FisiológicaRESUMO
BACKGROUND: A fine-tuned pro-inflammatory and anti-inflammatory balance in the follicular unit is essential for cumulus expansion and successful ovulation. While the long pentraxin 3 (PTX3) gene is required for the expansion of cumulus cells (CCs), ovulation, resumption of meiosis and fertilization, the vitamin D receptor gene (VDR-X2) is required for intra-follicle redox balance. This study was planned to determine the expression pattern of VDR-X2 and PTX3 mRNA in CCs isolated from germinal vesicle (GV), metaphase I (MI), and metaphase II (MII) oocytes of PCOS patients with ovulatory dysfunction. METHODS: The relative expression of CC-PTX3 and CC-VDR-X2 mRNA were evaluated using qRT-PCR in a total of 79 CC samples collected from individual cumulus-oocyte complex of 40 infertile patients (20 PCOS and 20 non-PCOS normal responders) who underwent ovarian stimulation with the GnRH antagonist protocol. RESULTS: Relative PTX3 mRNA expressions of CCMI-control and CCMII-control showed 3- and 9-fold significant upregulation compared to CCGV-control, respectively. The relative PTX3 mRNA expression of CCMII-control increased approximately three fold compared to CCMI-control. Compared to CCGV-pcos, a 3-fold increase was noted in the relative PTX3 mRNA expression of CCMI-pcos and an approximately 4-fold increase in the PTX3 mRNA expression of CCMII-pcos. Relative PTX3 mRNA expression values of CCMII-pcos and CCMI-pcos were similar. A 6-fold upregulation of relative PTX3 mRNA and a 4-fold upregulation of VDR-X2 mRNA were detected in CCMII-control compared to CCMII-pcos. CC-VDR-X2 expression patterns of the PCOS and control groups overlapped with the CC-PTX3 pattern. Fertilization rates of the PCOS group exhibiting failed transcript expression were similar to normal responders. CONCLUSION: The fact that relative CC-PTX3 and CC-VDR mRNA expression does not increase during the transition from MI to MII stage in PCOS as in normal responders suggests that PTX3 and VDR expression may be defective in cumulus cells of PCOS patients with ovulatory dysfunction.
Assuntos
Síndrome do Ovário Policístico , Feminino , Humanos , Síndrome do Ovário Policístico/genética , Síndrome do Ovário Policístico/metabolismo , Células do Cúmulo/metabolismo , Receptores de Calcitriol/genética , Oócitos/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismoRESUMO
BACKGROUND: Evidence on the association between single nucleotide polymorphisms (SNPs) in the vitamin D receptor (VDR) and depressive symptoms is inconclusive. OBJECTIVES: The primary aim of the study was to investigate the association between SNPs in the VDR gene and depressive symptoms. METHODS: In a sample of older adults from the Longitudinal Ageing Study Amsterdam (n = 922), depressive symptoms were assessed using the Centre for Epidemiological Studies Depression scale (CES-D scale) at baseline and after 3, 6, and 10 y of follow-up. Blood samples for SNP and serum 25-hydroxyvitamin D3 (25(OH)D3) determination were obtained at baseline. The association between 13 SNPs in the VDR gene and the course of depressive symptoms were evaluated using linear mixed models. The interaction between SNPs and serum 25(OH)D3 in relation to depressive symptoms was evaluated using multiple linear regression. RESULTS: No SNPs were associated with the course of depressive symptoms. Significant interactions between serum 25(OH)D3 and SNPs in the VDR gene were found. Stratified analysis revealed that within the GG genotype strata, 10 nmol/L higher serum 25(OH)D3 was associated with 0.27 (95% CI: -0.50, -0.04) and 0.23 (95% CI: -0.48, 0.02) lower scores on the CES-D scale for Cdx-2 and 1b-G-886A, respectively. This association was not found in persons having the GA or AA genotype. CONCLUSIONS: No SNPs are associated with the course of depressive symptoms. Stratified analysis shows that the effect of serum 25(OH)D3 concentrations on depressive symptoms is different among genotypes of Cdx-2 and 1b-G-886A. Future research should elucidate on the function of Cdx-2 and 1b-G-886A to describe their effect.
Assuntos
Depressão , Polimorfismo de Nucleotídeo Único , Receptores de Calcitriol , Humanos , Receptores de Calcitriol/genética , Depressão/genética , Masculino , Feminino , Idoso , Estudos Longitudinais , Países Baixos , Calcifediol/sangue , Genótipo , Pessoa de Meia-IdadeRESUMO
Cross talk between immune cells and the intestinal crypt is critical in maintaining intestinal homeostasis. Recent studies highlight the direct impact of vitamin D receptor (VDR) signaling on intestinal and microbial homeostasis. However, the tissue-specific role of immune VDR signaling is not fully understood. Here, we generated a myeloid-specific VDR knockout (VDRΔLyz ) mouse model and used a macrophage/enteroids coculture system to examine tissue-specific VDR signaling in intestinal homeostasis. VDRΔLyz mice exhibited small intestine elongation and impaired Paneth cell in maturation and localization. Coculture of enteroids with VDR-/- macrophages increased the delocalization of Paneth cells. VDRΔLyz mice exhibited significant changes in the microbiota taxonomic and functional files, and susceptibility to Salmonella infection. Interestingly, loss of myeloid VDR impaired Wnt secretion in macrophages, thus inhibiting crypt ß-catenin signaling and disrupting Paneth cell differentiation in the epithelium. Taken together, our data have demonstrated that myeloid cells regulate crypt differentiation and the microbiota in a VDR-dependent mechanism. Dysregulation of myeloid VDR led to high risks of colitis-associated diseases. Our study provided insight into the mechanism of immune/Paneth cell cross talk in regulating intestinal homeostasis.
Assuntos
Celulas de Paneth , Receptores de Calcitriol , Animais , Camundongos , Epitélio , Transdução de Sinais , HomeostaseRESUMO
Vitamin D receptor was previously reported to be protective in acute kidney injury (AKI) with the mechanism unclear, while the role of renal localized glutathione peroxidase 3 (GPX3) was not illustrated. The present study aims to investigate the role of GPX3 as well as its correlation with vitamin D-vitamin D receptor (VD-VDR) in ischemia-reperfusion (I/R)-induced renal oxidative stress injury. We showed that the expression of GPX3 and VDR were consistently decreased in renal tissues of I/R-related AKI patients and mice models. VDR agonist paricalcitol could reverse GPX3 expression and inhibit oxidative stress in I/R mice or hypoxia-reoxygenation (H/R) insulted HK-2 cells. VDR deficiency resulted in aggregated oxidative stress and severer renal injury accompanied by further decreased renal GPX3, while tubular-specific VDR overexpression remarkably reduced I/R-induced renal injury with recovered GPX3 in mice. Neither serum selenium nor selenoprotein P was affected by paricalcitol administration nor Vdr modification in vivo. In addition, inhibiting GPX3 abrogated the protective effects of VD-VDR in HK-2 cells, while GPX3 overexpression remarkably attenuated H/R-induced oxidative stress and apoptosis. Mechanistic probing revealed the GPX3 as a VDR transcriptional target. Our present work revealed that loss of renal GPX3 may be a hallmark that promotes renal oxidative stress injury and VD-VDR could protect against I/R-induced renal injury via inhibition of oxidative stress partly by trans-regulating GPX3. In addition, maintenance of renal GPX3 could be a therapeutic strategy for ischemic AKI.