RESUMEN
INTRODUCTION: Inflammation caused by diabetes can damage multiple organs, including the lungs. Vitamin D (VD) has been shown to potentially reduce inflammation and boost the immune system. VD might play a role in diabetes' inflammatory response. This study aims to elucidate the evidence regarding the lung as the target organ for DM and the possible role of VD in preventing pulmonary damage progression in the diabetes rat model. MATERIAL AND METHODS: Thirty Sprague Dawley rats (3-monthold, 200 to 300 gm) were randomly divided into six groups, namely control (C), 4 weeks diabetes mellitus (DM1), 8 weeks DM (DM2) and three DM1 groups (VD1, VD2, and VD3) who received Vitamin D doses of 0.125, 0.25 and 0.50 µg/kg BW, respectively. After 4 weeks, daily VD was administered intraperitoneally for 30 days. Lung tissues were taken for IL- 6, MCP-1, NFKB and CD68 mRNA expression analysis and paraffin embedding. Immunohistochemical staining against CD68 and MCP-1 was conducted. Data were analysed using one-way ANOVA. p < 0.05 was considered statistically significant. RESULTS: DM2 group represented significantly higher IL6, MCP1, NFKB and CD68 mRNA expression than Control group (p < 0.05). Meanwhile, VD2 and VD3 groups revealed significantly lower mRNA expression of IL-6, MCP1, NFKB and CD68 than DM2 (p < 0.05). Immunostaining revealed the spreading of MCP1 protein expression in lung tissue along with macrophage infiltration in the DM2 group, which was reduced in the VD2 and the VD3 groups. CONCLUSION: VD shows a protective effect on diabetesinduced lung damage by regulating inflammation factors.
Asunto(s)
Calcitriol , Diabetes Mellitus Experimental , Ratas Sprague-Dawley , Animales , Calcitriol/farmacología , Calcitriol/administración & dosificación , Ratas , Diabetes Mellitus Experimental/tratamiento farmacológico , Diabetes Mellitus Experimental/complicaciones , Pulmón/efectos de los fármacos , Pulmón/metabolismo , Pulmón/patología , Masculino , Inflamación/tratamiento farmacológico , Quimiocina CCL2/metabolismo , Modelos Animales de Enfermedad , Interleucina-6/metabolismoRESUMEN
There is a strong association between vitamin D levels and periodontal disease based on numerous epidemiological studies. We have previously shown that experimental deficiency of serum vitamin D in mice leads to gingival inflammation and alveolar bone loss. Treatment of cultured oral epithelial cells with the active form of vitamin D, 1,25(OH)2 vitamin D3 (1,25(OH)2D3), inhibits the extracellular growth and intracellular invasion of bacteria associated with periodontal disease. Maintenance of periodontal health may be due in part to the anti-inflammatory activities of vitamin D. Furthermore, this hormone can induce the expression of an antimicrobial peptide in cultured oral epithelial cells. We have shown that oral epithelial cells are capable of converting inactive vitamin D to the active form, suggesting that topical treatment of the oral epithelium with inactive vitamin D could prevent the development of periodontitis. We subjected mice to ligature-induced periodontitis (LIP), followed by daily treatment with inactive vitamin D or 1,25(OH)2D3. Treatment with both forms led to a reduction in ligature-induced bone loss and inflammation. Gingival tissues obtained from vitamin D-treated LIP showed production of specialized proresolving mediators (SPM) of inflammation. To examine the mechanism, we demonstrated that apical treatment of 3-dimensional cultures of primary gingival epithelial cells with vitamin D prevented lipopolysaccharide-induced secretion of proinflammatory cytokines and led to a similar production of SPM. Analysis of the oral microbiome of the mice treated with vitamin D showed significant changes in resident bacteria, which reflects a shift toward health-associated species. Together, our results show that topical treatment of oral tissues with inactive vitamin D can lead to the maintenance of periodontal health through the regulation of a healthy microbiome and the stimulation of resolution of inflammation. This strongly supports the development of a safe and effective vitamin D-based topical treatment or preventive agent for periodontal inflammation and disease.
Asunto(s)
Administración Tópica , Pérdida de Hueso Alveolar , Modelos Animales de Enfermedad , Periodontitis , Vitamina D , Animales , Ratones , Pérdida de Hueso Alveolar/prevención & control , Vitamina D/farmacología , Vitamina D/administración & dosificación , Vitamina D/uso terapéutico , Periodontitis/prevención & control , Encía/efectos de los fármacos , Calcitriol/farmacología , Calcitriol/administración & dosificación , Calcitriol/uso terapéutico , Ratones Endogámicos C57BL , Gingivitis/prevención & controlRESUMEN
OBJECTIVE: Vitamin D deficiency (VDD) is emerging as a predictor of poor prognosis in various neurological conditions, where clinical outcomes are often worse in stroke patients with VDD. This study aimed to provide experimental evidence on whether and how pre-existing VDD would affect survival and neurofunctional outcomes in intracerebral haemorrhage (ICH), and to evaluate whether acute vitamin D (VD) supplementation would improve post-stroke outcomes. METHODS: Experimental ICH models were induced in mice with and without VDD. Haematoma size was measured using T2*-weighted MRI and haemoglobin concentration. Post-ICH mortality, neurofunctional outcomes and the extent of blood-brain barrier (BBB) leakage were assessed to identify their correlations with VD status. Therapeutic benefits of acute VD administration were also evaluated. RESULTS: Mice with VDD exhibited significantly higher acute mortality rates and more severe motor deficits than mice without VDD post-ICH. Marked haematoma expansion and increased Evans blue extravasation were observed in VDD mice, suggesting that VDD was associated outcomes with increased BBB disruption. Acute treatment with a loading dose of VD (calcitriol) significantly improved outcomes in VDD mice. CONCLUSION: This study provides novel insights into the pathophysiological mechanisms at play in ICH concomitant with VDD and a scientific rationale for acute treatment with VD.
Asunto(s)
Barrera Hematoencefálica , Calcitriol , Hemorragia Cerebral , Deficiencia de Vitamina D , Animales , Hemorragia Cerebral/tratamiento farmacológico , Deficiencia de Vitamina D/tratamiento farmacológico , Deficiencia de Vitamina D/complicaciones , Calcitriol/farmacología , Calcitriol/uso terapéutico , Calcitriol/administración & dosificación , Masculino , Barrera Hematoencefálica/efectos de los fármacos , Barrera Hematoencefálica/metabolismo , Ratones , Ratones Endogámicos C57BLRESUMEN
BACKGROUND: The combined use of topical calcipotriol/betamethasone dipropionate (Cal/BDP) is commonly used and demonstrated to be effective for the management of psoriasis and is shown to confer local anti-inflammatory and immunoregulatory effects. The use of the two agents in combination is synergistic. Despite the demonstrated efficacy of topically applied combination Cal/BDP, successful management of a chronic, relapsing inflammatory skin disease such as psoriasis in the real-world setting may be hindered if patients do not adhere to the dosing or frequency of application recommendations from their prescriber. Patient preference for and satisfaction with the topical treatment vehicle have been shown to influence adherence. A recent analysis has determined that patients perceived Cal/BDP cream vehicle with PAD technology as having favorable characteristics. This randomized, split-body study was undertaken to further assess patient satisfaction with Cal/BDP cream and Cal/BDP foam formulations. TRIAL DESIGN: This was a split-body, subject-blind study. Study cream was administered in a single application to one side of the scalp and/or body; study foam was applied to the contralateral side. Patient self-administered questionnaires were completed before and after product application after a single site visit. RESULTS: Mean overall Vehicle Preference Measure (VPM) scores were higher for Cal/BDP cream than Cal/BDP foam (P=0.0043). Cal/BDP cream also achieved higher individual scores for ease of application, feeling to the touch, smell, and feeling on the skin (P<0.03). With regards to scalp application, subject assessments show that the cream was significantly more preferred in terms of limiting daily disruption (P=0.0008) Conclusion: Results of this study suggest that patients may prefer Cal/BDP cream over Cal/BDP foam for the management of psoriasis on the body and the scalp. Cal/BDP cream outperformed Cal/BDP foam on several specific measures of satisfaction and overall satisfaction measures. J Drugs Dermatol. 2024;23(8):607-611. doi:10.36849/JDD.7993.
Asunto(s)
Betametasona , Calcitriol , Fármacos Dermatológicos , Combinación de Medicamentos , Prioridad del Paciente , Psoriasis , Crema para la Piel , Humanos , Psoriasis/tratamiento farmacológico , Psoriasis/psicología , Calcitriol/análogos & derivados , Calcitriol/administración & dosificación , Betametasona/administración & dosificación , Betametasona/análogos & derivados , Femenino , Masculino , Persona de Mediana Edad , Adulto , Fármacos Dermatológicos/administración & dosificación , Crema para la Piel/administración & dosificación , Administración Cutánea , Método Simple Ciego , Índice de Severidad de la Enfermedad , Anciano , Resultado del Tratamiento , Satisfacción del Paciente , Encuestas y CuestionariosRESUMEN
Under inflammatory conditions, macrophage dominance affects the degree of inflammation. We assessed the effects of the active vitamin D (calcitriol) administration on inflammatory processes and macrophage dominance and aimed to determine the potential positive macroscopic and histological effects in supermicrosurgical arterial anastomosis model of rats. Forty rats were divided into five groups: control surgery (Group 1), surgery with preoperative (Group 2), post-operative (Group 3), perioperative (Group 4) systemic calcitriol and surgery with local calcitriol (Group 5). Eighty femoral artery anastomoses were planned in both legs of rats. Systemic calcitriol was administered intraperitoneally daily to the animals in the relevant groups. Preoperative vessel diameter measurements were taken before anastomosis. Three weeks post-surgery, post-operative vessel diameter measurements were taken, anastomosis patency was assessed and vascular segments were collected for histological examination, which included assessment of M1 and M2 macrophage depolarisation, leucocyte infiltration, intima-media ratio and luminal gap scoring. Systemic calcitriol administration (pre-, post- or perioperative) significantly improved the vessel diameter (p < 0.001); there was no significant difference among Groups 2-4. Histological findings revealed that Groups 3 and 4 had lower intima-media ratios (p < 0.05 and p < 0.01), higher M2-M1 macrophage ratios (p < 0.01 and p < 0.001) and lower leucocyte infiltration (p < 0.05, p < 0.01 and p < 0.001). Local calcitriol administration had no vasodilatory effects or resulted in positive histological outcomes. Although the administration of calcitriol pre- and post-operatively increased the vessel diameter, the latter appeared to have a more favourable impact on the histological analyses.
Asunto(s)
Anastomosis Quirúrgica , Calcitriol , Arteria Femoral , Animales , Arteria Femoral/cirugía , Arteria Femoral/efectos de los fármacos , Ratas , Calcitriol/farmacología , Masculino , Grado de Desobstrucción Vascular/efectos de los fármacos , Ratas Wistar , Macrófagos/efectos de los fármacos , Modelos Animales de Enfermedad , Ratas Sprague-DawleyRESUMEN
RUNX1 with CBFß functions as an activator or repressor of critical mediators regulating cellular function. The aims of this study were to clarify the role of RUNX1 on regulating TGF-ß1-induced COL1 synthesis and the mechanism of calcipotriol (Cal) on antagonizing COL1 synthesis in PSCs. RT-qPCR and Western Blot for determining the mRNAs and proteins of RUNX1 and COL1A1/1A2 in rat PSC line (RP-2 cell). Luciferase activities driven by RUNX1 or COL1A1 or COL1A2 promoter, co-immunoprecipitation and immunoblotting for pSmad3/RUNX1 or CBFß/RUNX1, and knockdown or upregulation of Smad3 and RUNX1 were used. RUNX1 production was regulated by TGF-ß1/pSmad3 signaling pathway in RP-2 cells. RUNX1 formed a coactivator with CBFß in TGF-ß1-treated RP-2 cells to regulate the transcriptions of COL1A1/1A2 mRNAs under a fashion of pSmad3/RUNX1/CBFß complex. However, Cal effectively abrogated the levels of COL1A1/1A2 transcripts in TGF-ß1-treated RP-2 cells by downregulating RUNX1 production and hindering the formation of pSmad3/RUNX1/CBFß complexes. This study suggests that RUNX1 may be a promising antifibrotic target for the treatment of chronic pancreatitis.
Asunto(s)
Calcitriol , Colágeno Tipo I , Subunidad alfa 2 del Factor de Unión al Sitio Principal , Regulación hacia Abajo , Células Estrelladas Pancreáticas , Proteína smad3 , Factor de Crecimiento Transformador beta1 , Animales , Calcitriol/farmacología , Calcitriol/análogos & derivados , Factor de Crecimiento Transformador beta1/metabolismo , Proteína smad3/metabolismo , Ratas , Regulación hacia Abajo/efectos de los fármacos , Colágeno Tipo I/metabolismo , Colágeno Tipo I/biosíntesis , Colágeno Tipo I/genética , Subunidad alfa 2 del Factor de Unión al Sitio Principal/genética , Subunidad alfa 2 del Factor de Unión al Sitio Principal/metabolismo , Células Estrelladas Pancreáticas/efectos de los fármacos , Células Estrelladas Pancreáticas/metabolismo , Línea Celular , Transducción de Señal/efectos de los fármacosRESUMEN
Intestinal absorption of phosphate is bimodal, consisting of a transcellular pathway and a poorly characterized paracellular mode, even though the latter one contributes to the bulk of absorption under normal dietary conditions. Claudin-3 (Cldn3), a tight junction protein present along the whole intestine in mice, has been proposed to tighten the paracellular pathway for phosphate. The aim of this work was to characterize the phosphate-related phenotype of Cldn3-deficient mice. Cldn3-deficient mice and wildtype littermates were fed standard diet or challenged for 3 days with high dietary phosphate. Feces, urine, blood, intestinal segments and kidneys were collected. Measurements included fecal, urinary, and plasma concentrations of phosphate and calcium, plasma levels of phosphate-regulating hormones, evaluation of trans- and paracellular phosphate transport across jejunum and ileum, and analysis of intestinal phosphate and calcium permeabilities. Fecal and urinary excretion of phosphate as well as its plasma concentration was similar in both genotypes, under standard and high-phosphate diet. However, Cldn3-deficient mice challenged with high dietary phosphate had a reduced urinary calcium excretion and increased plasma levels of calcitriol. Intact FGF23 concentration was also similar in both groups, regardless of the dietary conditions. We found no differences either in intestinal phosphate transport (trans- or paracellular) and phosphate and calcium permeabilities between genotypes. The intestinal expression of claudin-7 remained unaltered in Cldn3-deficient mice. Our data do not provide evidence for a decisive role of Cldn3 for intestinal phosphate absorption and phosphate homeostasis. In addition, our data suggest a novel role of Cldn3 in regulating calcitriol levels.
Asunto(s)
Claudina-3 , Factor-23 de Crecimiento de Fibroblastos , Absorción Intestinal , Fosfatos , Animales , Fosfatos/metabolismo , Fosfatos/orina , Ratones , Claudina-3/metabolismo , Claudina-3/genética , Factor-23 de Crecimiento de Fibroblastos/metabolismo , Calcitriol/metabolismo , Calcitriol/sangre , Calcio/metabolismo , Ratones Endogámicos C57BL , Masculino , Ratones Noqueados , Factores de Crecimiento de Fibroblastos/metabolismo , Factores de Crecimiento de Fibroblastos/genética , Mucosa Intestinal/metabolismoRESUMEN
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.
Asunto(s)
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/metabolismoAsunto(s)
Aerosoles , Betametasona , Calcitriol , Fármacos Dermatológicos , Combinación de Medicamentos , Enfermedades de la Uña , Psoriasis , Humanos , Psoriasis/tratamiento farmacológico , Calcitriol/análogos & derivados , Calcitriol/administración & dosificación , Calcitriol/uso terapéutico , Betametasona/administración & dosificación , Betametasona/análogos & derivados , Betametasona/uso terapéutico , Fármacos Dermatológicos/administración & dosificación , Fármacos Dermatológicos/uso terapéutico , Enfermedades de la Uña/tratamiento farmacológico , Masculino , Femenino , Urea/administración & dosificación , Urea/uso terapéutico , Urea/análogos & derivados , Adulto , Resultado del Tratamiento , Persona de Mediana EdadRESUMEN
The human monocytic THP-1 cell line is the most routinely employed in vitro model for studying monocyte-to-macrophage differentiation. Despite the wide use of this model, differentiation protocols using phorbol 12-myristate-13-acetate (PMA) or 1,25-dihydroxyvitamin D3 (1,25D3) vary drastically between studies. Given that differences in differentiation protocols have the potential to impact the characteristics of the macrophages produced, we aimed to assess the efficacy of three different THP-1 differentiation protocols by assessing changes in morphology and gene- and cell surface macrophage marker expression. THP-1 cells were differentiated with either 5 nM PMA, 10 nM 1,25D3, or a combination thereof, followed by a rest period. The results indicated that all three protocols significantly increased the expression of the macrophage markers, CD11b (p < 0.001) and CD14 (p < 0.010). Despite this, THP-1 cells exposed to 1,25D3 alone did not adopt the morphological and expression characteristics associated with macrophages. PMA was required to produce these characteristics, which were found to be more pronounced in the presence of 1,25D3. Both PMA- and PMA with 1,25D3-differentiated THP-1 cells were capable of M1 and M2 macrophage polarization, though the gene expression of polarization-associated markers was most pronounced in PMA with 1,25D3-differentiated THP-1 cells. Moreover, the combination of PMA with 1,25D3 appeared to support the process of commitment to a particular polarization state.
Asunto(s)
Calcitriol , Diferenciación Celular , Macrófagos , Monocitos , Acetato de Tetradecanoilforbol , Humanos , Diferenciación Celular/efectos de los fármacos , Acetato de Tetradecanoilforbol/farmacología , Macrófagos/efectos de los fármacos , Macrófagos/metabolismo , Células THP-1 , Monocitos/efectos de los fármacos , Monocitos/metabolismo , Monocitos/citología , Calcitriol/farmacología , Receptores de Lipopolisacáridos/metabolismo , Antígeno CD11b/metabolismoRESUMEN
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
Dendritic cells (DCs) undergo glycolytic reprogramming, a metabolic conversion process essential for their activation. Vitamin D has been reported to affect the function of DCs, but studies in metabolic diseases are insufficient. This study investigates the effects of in vitro 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) treatment on glycolytic reprogramming of bone marrow-derived dendritic cells (BMDCs) from control, obese, and atherosclerosis mice. Six-week-old male C57BL/6J mice were fed a control diet (CON) or a Western diet (WD), and B6.129S7-Ldlrtm1Her/J mice were fed a Western diet (LDLR-/-) for 16 weeks. BMDCs were cultured in a medium containing 1,25(OH)2D3 (10 nM) for 7 days and stimulated with lipopolysaccharide (LPS, 50 ng/mL) for 24 h. In mature BMDCs, 1,25(OH)2D3 treatment decreased basal and compensatory glycolytic proton efflux rates (glycoPER), the expression of surface markers related to immune function of DCs (MHC class II, CD80, and CD86), and IL-12p70 production. In addition, mTORC1 activation and nitric oxide (NO) production were suppressed by 1,25(OH)2D3 treatment in mature BMDCs. The effect of 1,25(OH)2D3 treatment on IL-12p70 production and mTORC1 activity in the LDLR-/- group was greater than in the CON group. These findings suggest that vitamin D can affect the metabolic environment of BMDCs by regulating glycolytic reprogramming as well as by inducing tolerogenic phenotypes of DCs.
Asunto(s)
Células Dendríticas , Glucólisis , Ratones Endogámicos C57BL , Ratones Noqueados , Receptores de LDL , Vitamina D , Animales , Células Dendríticas/metabolismo , Células Dendríticas/efectos de los fármacos , Glucólisis/efectos de los fármacos , Ratones , Masculino , Receptores de LDL/metabolismo , Receptores de LDL/genética , Vitamina D/farmacología , Células de la Médula Ósea/metabolismo , Células de la Médula Ósea/efectos de los fármacos , Células de la Médula Ósea/citología , Aterosclerosis/metabolismo , Aterosclerosis/tratamiento farmacológico , Aterosclerosis/patología , Células Cultivadas , Calcitriol/farmacología , Obesidad/metabolismo , Obesidad/tratamiento farmacológico , Obesidad/patología , Reprogramación Celular/efectos de los fármacosRESUMEN
Host-directed therapy (HDT) with vitamin D in tuberculosis (TB) is beneficial only if the subject is deficient in vitamin D. We investigated pulmonary delivery of 1,25-dihydroxy vitamin D3 (calcitriol) in mice infected with Mycobacterium tuberculosis (Mtb). We made two kinds of dry powder inhalations (DPI)- soluble particles or poly(lactide) (PLA) particles. We compared treatment outcomes when infected mice were dosed with a DPI alone or as an adjunct to standard oral anti-TB therapy (ATT). Mice infected on Day 0 were treated between Days 28-56 and followed up on Days 57, 71, and 85. Neither DPI significantly reduced Mtb colony forming units (CFU) in the lungs. Combining DPI with ATT did not significantly augment bactericidal activity in the lungs, but CFU were 2-log lower in the spleen. CFU showed a rising trend on stopping treatment, sharper in groups that did not receive calcitriol. Lung morphology and histology improved markedly in animals that received PLA DPI; with or without concomitant ATT. Groups receiving soluble DPI had high mortality. DPI elicited cathelicidin, interleukin (IL)-1 and induced autophagy on days 57, 71, and 85. Macrophage-targeted calcitriol is therefore bacteriostatic, evokes innate microbicidal mechanisms, and mitigates pathology arising from the host response to Mtb.
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Antituberculosos , Calcitriol , Modelos Animales de Enfermedad , Pulmón , Macrófagos , Mycobacterium tuberculosis , Animales , Calcitriol/farmacología , Mycobacterium tuberculosis/efectos de los fármacos , Pulmón/microbiología , Pulmón/efectos de los fármacos , Pulmón/patología , Pulmón/inmunología , Pulmón/metabolismo , Macrófagos/efectos de los fármacos , Macrófagos/microbiología , Macrófagos/inmunología , Antituberculosos/farmacología , Antituberculosos/uso terapéutico , Femenino , Administración por Inhalación , Catelicidinas , Tuberculosis Pulmonar/tratamiento farmacológico , Tuberculosis Pulmonar/microbiología , Tuberculosis Pulmonar/patología , Tuberculosis Pulmonar/inmunología , Poliésteres , Interacciones Huésped-Patógeno , Factores de Tiempo , Ratones Endogámicos C57BL , Bazo/efectos de los fármacos , Bazo/microbiología , Bazo/patología , Bazo/inmunología , Quimioterapia Combinada , Péptidos Catiónicos Antimicrobianos/farmacología , RatonesRESUMEN
Calcitriol as a biologically active form of vitamin D3 has beneficial effects on all body systems. This vitamin has a potent neuroprotective effect via several independent mechanisms against brain insults induced by anticancer drugs. The present study was designed to examine the neuroprotective effects of calcitriol against neurotoxicity induced by cisplatin. Induction of neurotoxicity was done with cisplatin administration (5 mg/kg/week) for 5 successive weeks in male Wistar rats. The neuroprotective influence of calcitriol supplementation (100ng/kg/day for 5 weeks) was assessed through behavioral, electrophysiological, and molecular experiments. Cisplatin administration impaired spatial learning and memory and decreased prefrontal brain-derived neurotrophic factor (BDNF). Peripheral sensory neuropathy was induced through cisplatin administration. Cisplatin also reduced the amplitudes of the compound action potential of sensory nerves in electrophysiological studies. Cisplatin treatment elevated MDA levels and reduced anti-oxidant (SOD and GPx) enzymes. Pro-inflammatory cytokines (IL-1ß and TNF-α) and metalloproteinase-2 and 9 (MMP-2/9) were augmented through treatment with cisplatin. Learning and memory impairments along with BDNF changes caused by cisplatin were amended with calcitriol supplementation. Reduced sensory nerve conduction velocity in the cisplatin-treated group was improved by calcitriol. Calcitriol partially improved redox imbalance and diminished the pro-inflammatory cytokines and MMP-2/9 levels. Our findings showed that calcitriol supplementation can relieve cisplatin-induced peripheral neurotoxicity. Calcitriol can be regarded as a promising new neuroprotective agent.
Asunto(s)
Calcitriol , Cisplatino , Metaloproteinasa 2 de la Matriz , Metaloproteinasa 9 de la Matriz , Fármacos Neuroprotectores , Estrés Oxidativo , Ratas Wistar , Animales , Cisplatino/toxicidad , Masculino , Estrés Oxidativo/efectos de los fármacos , Ratas , Metaloproteinasa 2 de la Matriz/metabolismo , Fármacos Neuroprotectores/farmacología , Fármacos Neuroprotectores/uso terapéutico , Metaloproteinasa 9 de la Matriz/metabolismo , Calcitriol/farmacología , Calcitriol/uso terapéutico , Antineoplásicos/toxicidad , Factor Neurotrófico Derivado del Encéfalo/metabolismo , Síndromes de Neurotoxicidad/tratamiento farmacológico , Síndromes de Neurotoxicidad/metabolismoRESUMEN
Severe burn patients frequently suffer from 1,25-Dihydroxyvitamin D3 (1,25-[OH]2-D3) deficiency. In this study, we investigated the effect of 1,25-[OH]2-D3 on early mortality post severe burn and potential underlying mechanisms. Our results indicate that 1,25-[OH]2-D3 significantly reduced early mortality in mice post severe burn injury. A decrease in serum lipopolysaccharide levels and an increase in serum superoxide dismutase activity were found after administration of 1,25-[OH]2-D3. Furthermore, 1,25-[OH]2-D3 demonstrated protective effects on both intestinal and lung histology and ameliorated lung inflammation. Its anti-inflammatory effect was further confirmed in airway epithelial cells. In conclusion, our study provides evidence that 1,25-[OH]2-D3 has a significant impact on the reduction of early mortality post severe burn injury, possibly through its ability to alleviate endotoxemia, oxidative stress, and inflammation. Our findings highlight the potential of 1,25-[OH]2-D3 to protect the intestinal mucosal barrier in the early stage following major burn injury and opens up new avenues for clinical application of 1,25-[OH]2-D3 in burn patients.
Asunto(s)
Quemaduras , Endotoxemia , Inflamación , Mucosa Intestinal , Estrés Oxidativo , Animales , Quemaduras/metabolismo , Quemaduras/complicaciones , Quemaduras/mortalidad , Estrés Oxidativo/efectos de los fármacos , Ratones , Endotoxemia/mortalidad , Endotoxemia/tratamiento farmacológico , Mucosa Intestinal/metabolismo , Mucosa Intestinal/patología , Mucosa Intestinal/efectos de los fármacos , Calcitriol/farmacología , Calcitriol/uso terapéutico , Masculino , Pulmón/patología , Pulmón/efectos de los fármacos , Pulmón/metabolismo , Superóxido Dismutasa/metabolismo , Lipopolisacáridos/farmacología , Neumonía/prevención & control , Ratones Endogámicos C57BL , Vitaminas/uso terapéutico , Vitaminas/farmacología , Modelos Animales de EnfermedadRESUMEN
Objective: To quantitatively assess all dosage forms of three active vitamin D and its analogs, namely, calcitriol, alfacalcidol, and eldecalcitol, to provide a basis for the selection of active vitamin D and its analogs in hospitals. Methods: In this study, three active vitamin D and its analogs were evaluated by quantitative scoring in five dimensions, including pharmaceutical properties (28 points), efficacy (27 points), safety (25 points), economy (10 points), and other attributes (10 points). Results: The final scores of quantitative assessment for the selection of alfacalcidol soft capsules, calcitriol soft capsules I, calcitriol soft capsules II, alfacalcidol tablets, alfacalcidol capsules, alfacalcidol oral drops, calcitriol injection, and eldecalcitol soft capsules were 73.17, 72.06, 71.52, 71.29, 69.62, 68.86, 65.60, 64.05 points. Conclusion: Based on the scoring results, alfacalcidol soft capsules, calcitriol soft capsules I, calcitriol soft capsules II, alfacalcidol tablets can be entered into the medication list of medical institutions as strongly recommended drugs. This study offers guidance on selecting and using active vitamin D and its analogs in hospitals, with consideration for the patient's needs.
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Hidroxicolecalciferoles , Osteoporosis , Vitamina D , Humanos , Osteoporosis/tratamiento farmacológico , Vitamina D/administración & dosificación , Vitamina D/análogos & derivados , Hidroxicolecalciferoles/administración & dosificación , Hidroxicolecalciferoles/uso terapéutico , Evaluación de la Tecnología Biomédica , Conservadores de la Densidad Ósea/administración & dosificación , China , Calcitriol/análogos & derivados , Calcitriol/administración & dosificación , CápsulasRESUMEN
INTRODUCTION: Postoperative hypocalcaemia is common after thyroidectomy. This study aimed to evaluate whether a standardised post-thyroidectomy protocol using prophylactic calcium and calcitriol reduces hypocalcaemia incidence after total thyroidectomy in children and adolescents. METHODS: A cohort children and adolescents ≤18 years of age undergoing total thyroidectomy between January 2016 and October 2022 in one institution were retrospectively identified and divided into pre-protocol and post-protocol groups. The primary outcome measure was hypocalcaemia (total serum calcium of <2.0 mmol/L; ionised serum calcium of 0.9 mmol/L). Secondary outcome measures were the occurrence of hypercalcaemia (serum Calcium >2.7 mmol/L; ionised calcium >1.31 mmol/L), length of hospitalisation and number of postoperative blood tests. RESULTS: There were 22 patients in each group (mean age 11.8; SD 4.3 years, female 36 %). The rate of hypocalcaemia was significantly higher in the pre-protocol group than the post-protocol group (54 % vs 13.6 %, p = 0.010). Patients in the pre-protocol group had more inpatient blood tests (mean 5.4; SD 3.2) than the post-protocol group (mean 3.3; SD 1.8, p = 0.011), although the total postoperative blood test count was similar between the groups. Six (13.6 %) patients developed hypercalcaemia. The rate of hypercalcaemia was similar between groups (pre-protocol 2, 9.1 %; post-protocol 4, 18.1 %; p = 0.664). Length of hospitalisation was similar between groups. CONCLUSION: Our standardized protocol decreased hypocalcemia and inpatient blood tests after total thyroidectomy in children. Future research should explore if incorporating preoperative calcium and calcitriol treatment, along with intraoperative PTH levels for risk management, can further reduce hypocalcemia rates in paediatric patients.
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Calcitriol , Calcio , Protocolos Clínicos , Hipocalcemia , Complicaciones Posoperatorias , Tiroidectomía , Humanos , Hipocalcemia/prevención & control , Hipocalcemia/etiología , Hipocalcemia/epidemiología , Hipocalcemia/sangre , Tiroidectomía/efectos adversos , Tiroidectomía/métodos , Femenino , Niño , Masculino , Adolescente , Estudios Retrospectivos , Calcio/sangre , Calcitriol/uso terapéutico , Complicaciones Posoperatorias/prevención & control , Complicaciones Posoperatorias/epidemiología , Complicaciones Posoperatorias/sangre , Complicaciones Posoperatorias/diagnóstico , Hormonas y Agentes Reguladores de Calcio/uso terapéuticoRESUMEN
Vitamin D plays an important pleiotropic role in maintaining global homeostasis of the human body. Its functions go far beyond skeletal health, playing a crucial role in a plethora of cellular functions, as well as in extraskeletal health, ensuring the proper functioning of multiple human organs, including the skin. Genes from the Grainyhead-like (GRHL) family code for transcription factors necessary for the development and maintenance of various epithelia. Even though they are involved in many processes regulated by vitamin D, a direct link between vitamin D-mediated cellular pathways and GRHL genes has never been described. We employed various bioinformatic methods, quantitative real-time PCR, chromatin immunoprecipitation, reporter gene assays, and calcitriol treatments to investigate this issue. We report that the vitamin D receptor (VDR) binds to a regulatory region of the Grainyhead-like 1 (GRHL1) gene and regulates its expression. Ectopic expression of VDR and treatment with calcitriol alters the expression of the GRHL1 gene. The evidence presented here indicates a role of VDR in the regulation of expression of GRHL1 and correspondingly a role of GRHL1 in mediating the actions of vitamin D.
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Regulación de la Expresión Génica , Receptores de Calcitriol , Factores de Transcripción , Receptores de Calcitriol/genética , Receptores de Calcitriol/metabolismo , Humanos , Factores de Transcripción/metabolismo , Factores de Transcripción/genética , Regulación de la Expresión Génica/efectos de los fármacos , Calcitriol/farmacología , Proteínas de Unión al ADN/genética , Proteínas de Unión al ADN/metabolismo , Unión Proteica , Regiones Promotoras Genéticas , Proteínas RepresorasRESUMEN
The study aims to evaluate the performance of Vitamin D/calcitriol-induced miR-589-3p in predicting the prognosis of cervical cancer patients and its role in cancer cell function. To identify differentially expressed miRNAs (DEMs) related to calcitriol treatment, the GSE61829 dataset was analyzed. MiR-589-3p expression levels were verified in cervical cancer patients. The association of miR-589-3p with overall survival was investigated using Kaplan-Meier survival analyses and the multi-variate Cox proportional hazards model analysis. The effects of miR-589-3p on cervical cancer cells and calcitriol-treated cells were examined using the MTT assay and Transwell migration/invasion assay. From GSE61829 dataset, a total of eleven DEMs were identified, including miR-589-3p. MiR-589-3p was found to be decreased in cervical cancer but increased after one-year intake of Vitamin D. Low miR-589-3p after one-year intake of Vitamin D was identified as a predictive factor for low survival probability (p = 0.0059) with a significant impact on the death risk (HR: 3.04; 95%CI: 1.47-6.29; p = 0.003). MiR-589-3p overexpression inhibited the proliferation and migration/invasion of cervical cancer cells and calcitriol-treated cervical cancer cells. In conclusion, miR-589-3p can be induced by Vitamin D/calcitriol treatment and inhibit cervical cancer progression. MiR-589-3p has the potential to predict overall survival in patients with cervical cancer.
Asunto(s)
Movimiento Celular , MicroARNs , Neoplasias del Cuello Uterino , Vitamina D , Humanos , Neoplasias del Cuello Uterino/genética , Neoplasias del Cuello Uterino/patología , Neoplasias del Cuello Uterino/tratamiento farmacológico , Neoplasias del Cuello Uterino/mortalidad , Femenino , MicroARNs/genética , MicroARNs/metabolismo , Pronóstico , Vitamina D/farmacología , Progresión de la Enfermedad , Calcitriol/farmacología , Persona de Mediana Edad , Línea Celular Tumoral , Regulación Neoplásica de la Expresión Génica , Proliferación Celular/efectos de los fármacosRESUMEN
BACKGROUND: Vitamin D was shown to directly exert a protective effect on diabetic kidney disease (DKD) in our previous study. However, whether it has an effect on perirenal adipose tissue (PRAT) or the intestinal flora and its metabolites (trimethylamine N-oxide, TMAO) is unclear. METHODS: DKD mice were received different concentrations of 1,25-(OH)2D3 for 2 weeks. Serum TNF-α levels and TMAO levels were detected. 16S rRNA sequencing was used to analyze gut microbiota. qPCR was used to detect the expression of TLR4, NF-Κb, PGC1α, and UCP-1 in kidney and adipose tissue. Histological changes in kidney and perirenal adipose tissue were observed using HE, PAS, Masson and oil red staining. Immunofluorescence and immunohistochemistry were used to detect the expression of VDR, PGC1α, podocin, and UCP-1 in kidney and adipose tissue. Electron microscopy was used to observe the pathological changes in the kidney. VDR knockout mice were constructed to observe the changes in the gut and adipose tissue, and immunofluorescence and immunohistochemistry were used to detect the expression of UCP-1 and collagen IV in the kidney. RESULTS: 1,25-(OH)2D3 could improve the dysbiosis of the intestinal flora of mice with DKD, increase the abundance of beneficial bacteria, decrease the abundance of harmful bacteria, reduce the pathological changes in the kidney, reduce fat infiltration, and downregulate the expression of TLR4 and NF-κB in kidneys. The serum TMAO concentration in mice with DKD was significantly higher than that of the control group, and was significantly positively correlated with the urine ACR. In addition, vitamin D stimulated the expression of the surface markers PGC1α, UCP-1 and VDR in the PRAT in DKD mice, and TMAO downregulated the expression of PRAT and renal VDR. CONCLUSIONS: The protective effect of 1,25-(OH)2D3 in DKD mice may affect the intestinal flora and its related metabolite TMAO on perirenal fat and kidneys.