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Antioxidants (Basel, Switzerland) Aug 2023Dysregulation of vitamin D receptor (VDR) is implicated in chronic obstructive pulmonary disease. However, whether VDR dysregulation contributes to the development of...
Dysregulation of vitamin D receptor (VDR) is implicated in chronic obstructive pulmonary disease. However, whether VDR dysregulation contributes to the development of pulmonary fibrosis remains largely unknown. Analysis of bulk and single-cell RNA profiling datasets revealed VDR upregulation in lung fibroblasts from patients with pulmonary fibrosis or fibrotic mice, which was validated in lung fibroblasts from bleomycin-exposed mice and bleomycin-treated fibroblasts. Stable VDR knockdown promoted, whereas the VDR agonist paricalcitol suppressed lung fibroblast proliferation and activation. Gene set enrichment analysis (GSEA) showed that the JAK/STAT pathway and unfolded protein response (UPR), a process related to endoplasmic reticulum (ER) stress, were enriched in lung fibroblasts of fibrotic lungs. Stable VDR knockdown stimulated, but paricalcitol suppressed ER stress and JAK1/STAT3 activation in lung fibroblasts. The STAT3 inhibitor blocked bleomycin- or stable VDR knockdown-induced ER stress. Paricalcitol inhibited the bleomycin-induced enrichment of STAT3 to the ATF6 promoter, thereby suppressing ATF6 expression in fibroblasts. Paricalcitol or intrapulmonary VDR overexpression inactivated JAK1/STAT3 and suppressed ER stress in bleomycin-treated mice, thus resulting in the inhibition of fibroblast proliferation and activation. Collectively, this study suggests that fibroblast VDR upregulation may be a self-protective response to limit fibroblast proliferation and activation during pulmonary fibrosis by suppressing the JAK1/STAT3/ER stress pathway.
PubMed: 37627629
DOI: 10.3390/antiox12081634 -
Nutrition, Metabolism, and... Jan 2021Cardiovascular disease is the main cause of death worldwide, but the collective efforts to prevent this pathological condition are directed exclusively to individuals at...
BACKGROUND AND AIMS
Cardiovascular disease is the main cause of death worldwide, but the collective efforts to prevent this pathological condition are directed exclusively to individuals at higher risk due to hypercholesterolemia, hypertension, obesity, diabetes. Recently, vitamin D deficiency was identified as a risk factor for cardiovascular disease in healthy people, as it predisposes to different vascular dysfunctions that can result in plaque development and fragility. In this scenario, the fundamental aim of the study was to reproduce a disease model inducing vitamin D deficiency and atheromatosis in ApoE mice and then to evaluate the impact of this vitamin D status on the onset/progression of atheromatosis, focusing on plaque formation and instability.
METHODS AND RESULTS
In our murine disease model, vitamin D deficiency was achieved by 3 weeks of vitamin D deficient diet along with intraperitoneal paricalcitol injections, while atheromatosis by western-type diet administration. Under these experimental conditions, vitamin D deficient mice developed more unstable atheromatous plaques with reduced or absent fibrotic cap. Since calcium and phosphorus metabolism and also cholesterol and triglycerides systemic concentration were not affected by vitamin D level, our results highlighted the role of vitamin D deficiency in the formation/instability of atheromatous plaque and, although further studies are needed, suggested a possible intervention with vitamin D to prevent or delay the atheromatous disease.
CONCLUSIONS
The data obtained open the question about the potential role of the vitamins in the pharmacological treatments of cardiovascular disorders as coadjutant of the primary drugs used for these pathologies.
Topics: Animals; Aorta; Aortic Diseases; Atherosclerosis; Biomarkers; Diet, High-Fat; Disease Models, Animal; Fibrosis; Lipids; Mice, Knockout, ApoE; Plaque, Atherosclerotic; Rupture, Spontaneous; Vitamin D; Vitamin D Deficiency; Mice
PubMed: 33500110
DOI: 10.1016/j.numecd.2020.08.031 -
International Journal of Molecular... Oct 2021Alport syndrome is a genetic and hereditary disease, caused by mutations in the type IV collagen genes , and , that affects the glomerular basement membrane of the... (Review)
Review
Alport syndrome is a genetic and hereditary disease, caused by mutations in the type IV collagen genes , and , that affects the glomerular basement membrane of the kidney. It is a rare disease with an underestimated prevalence. Genetic analysis of population cohorts has revealed that it is the second most common inherited kidney disease after polycystic kidney disease. Renal involvement is the main manifestation, although it may have associated extrarenal manifestations such as hearing loss or ocular problems. The degree of expression of the disease changes according to the gene affected and other factors, known or yet to be known. The pathophysiology is not yet fully understood, although some receptors, pathways or molecules are known to be linked to the disease. There is also no specific treatment for Alport syndrome; the most commonly used are renin-angiotensin-aldosterone system inhibitors. In recent years, diagnosis has come a long way, thanks to advances in DNA sequencing technologies such as next-generation sequencing (NGS). Further research at the genetic and molecular levels in the future will complete the partial vision of the pathophysiological mechanism that we have, and will allow us to better understand what is happening and how to solve it.
Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Collagen Type IV; Ergocalciferols; High-Throughput Nucleotide Sequencing; Humans; Integrins; Laminin; Nephritis, Hereditary; Polymorphism, Genetic
PubMed: 34681722
DOI: 10.3390/ijms222011063 -
PloS One 2020Paricalcitol, a new vitamin D receptor activator (VDRA), is reported to be more effective than other VDRAs in reducing calcium and phosphorus levels in patients... (Comparative Study)
Comparative Study Meta-Analysis
A comparative analysis of the efficacy and safety of paricalcitol versus other vitamin D receptor activators in patients undergoing hemodialysis: A systematic review and meta-analysis of 15 randomized controlled trials.
Paricalcitol, a new vitamin D receptor activator (VDRA), is reported to be more effective than other VDRAs in reducing calcium and phosphorus levels in patients undergoing hemodialysis. However, the efficacy and safety of paricalcitol remain controversial. This analysis compares paricalcitol with other VDRAs in patients undergoing hemodialysis. We searched the Cochrane Library, PubMed, EMBASE, Web of Science, and CNKI up to April 22, 2019. Standardized mean difference (SMD), risk ratio (RR) and 95% confidence interval (CI) values were estimated to compare the outcomes of the groups. Two reviewers extracted data and assessed trial quality independently. All statistical analyses were performed using the standard statistical procedures of RevMan 5.2 and Stata 12.0. Fifteen studies (N = 110,544) were included in this meta-analysis. Of these studies, 11 were randomized controlled trials (RCTs) and 4 were non-randomized studies of interventions (NRSIs). Patients receiving paricalcitol experienced better overall survival (OS) than patients receiving other VDRAs, with a pooled hazard ratio of 0.86 (95% CI 0.80-0.91; P < 0.00001). Intact parathyroid hormone (iPTH) levels were significantly reduced in the paricalcitol group compared to the group receiving other VDRAs, with a pooled SMD of -0.53 (95% CI -0.89- -0.16; P = 0.004). There was a significant increase in serum calcium levels from baseline in the paricalcitol group compared to the other VDRAs group when limiting the analysis to RCTs, with a pooled SMD of 2.14 (95% CI 0.90-3.38; P = 0.0007). Changes in serum calcium levels were significantly lower in the paricalcitol group when the analysis was limited to NRSIs, with a pooled SMD of -0.85 (95% CI -1.34--0.35; P = 0.0008). The NSRI analysis also showed a significant reduction in serum phosphorus levels in the paricalcitol group, with a pooled SMD of -0.57 (95% CI -1.00--0.13; P = 0.01). No significant differences were observed in the incidence of hypercalcemia, hyperphosphatemia, or adverse events. Generally, paricalcitol seems superior to other VDRAs in reducing mortality and iPTH levels in patients undergoing hemodialysis. However, the comparative effectiveness of paricalcitol in reducing serum calcium and phosphorus levels needs further exploration. No significant difference was found in the rate of adverse events.
Topics: Calcium; Disease-Free Survival; Ergocalciferols; Female; Humans; Male; Parathyroid Hormone; Phosphorus; Randomized Controlled Trials as Topic; Receptors, Calcitriol; Renal Dialysis; Survival Rate
PubMed: 32470067
DOI: 10.1371/journal.pone.0233705 -
International Immunopharmacology Nov 2021Vitamin D receptor (VDR) and NLRP3 inflammasome play critical roles in lupus nephritis (LN) pathogenesis.
BACKGROUND
Vitamin D receptor (VDR) and NLRP3 inflammasome play critical roles in lupus nephritis (LN) pathogenesis.
AIM OF THE STUDY
This study explored the therapeutic effect of VDR agonist on LN and its molecular mechanism to inhibit NLRP3 signalling.
METHODS
C57BL/6 mice, lupus-prone MRL/lpr mice, and VDR agonist paricacitol-treated MRL/lpr mice (300 ng/kg/mouse per dose, 5 times/week for 8 weeks from 8 weeks old) were used to assess kidney histopathology and measure proteinuria, serum anti-ds-DNA antibody and expression of NF-κB/NLRP3/caspase-1/IL-1β/IL-18 axis. We used mouse renal tubular epithelial cells (mRTECs) to identify protein-protein interactions and examine the effects of paricalcitol.
RESULTS AND CONCLUSION
LN pathogenesis decreased after paricalcitol treatment. We observed a marked improvement in renal pathology and a time-dependent decrease urine protein and serum anti-dsDNA antibody levels. In 16-week-old MRL/lpr LN mice, the upregulated expression of NLRP3/caspase-1/IL-1β/IL-18 axis was significantly downregulated after paricalcitol treatment. Paricalcitol can reverse the apoptosis induced by anti-dsDNA antibody via the NF-κB/NLRP3/caspase-1/IL-1β/IL-18 axis in mRTECs. Furthermore, paricalcitol suppressed NF-κB nuclear translocation by competitively binding to importin-4. In summary, the VDR agonist can alleviate LN by modulating the NF-κB/NLRP3/caspase-1/IL-1β/IL-18 axis and suppressing the NF-κB nuclear translocation.
Topics: Animals; Apoptosis; Caspase 1; Caspases; Cell Culture Techniques; Ergocalciferols; Female; Interleukin-18; Interleukin-1beta; Karyopherins; Kidney; Lupus Nephritis; Mice; Mice, Inbred C57BL; NF-kappa B; NLR Family, Pyrin Domain-Containing 3 Protein; Receptors, Calcitriol; Signal Transduction
PubMed: 34536747
DOI: 10.1016/j.intimp.2021.108131 -
Jornal Brasileiro de Nefrologia 2023For the reduction of PTH levels, two classes of drugs are available in the Brazilian market: non-selective and selective vitamin D receptor activators and calcimimetics....
INTRODUCTION
For the reduction of PTH levels, two classes of drugs are available in the Brazilian market: non-selective and selective vitamin D receptor activators and calcimimetics. Among the mentioned drugs, the SUS provides oral calcitriol, paricalcitol and cinacalcet.
OBJECTIVES
Develop cost-effectiveness (CE) and budgetary impact (BI) analysis of cinacalcet versus paricalcitol for patients on dialysis with SHPT, from the perspective of SUS.
METHODOLOGY
A decision tree model was constructed for CE analysis, which considered the outcome of avoided parathyroidectomy and a time horizon of 1 year. As for the BI analysis, two scenarios were considered, one of which was measured demand and other epidemiological, based on data from the Brazilian Society of Nephrology (BSN).
RESULTS
The CE analysis showed that the use of cinacalcet results in one-off savings of R$1,394.64 per year and an incremental effectiveness of 0.08, in relation to avoided parathyroidectomy. The incremental CE ratio (ICER) was - R$ 17,653.67 per avoided parathyroidectomy for cinacalcet, as it was more effective and cheaper compared to paricalcitol. As for the BI analysis, it was estimated that the incremental BI with the expansion of the use of cinacalcet in the SUS will be between - R$ 1,640,864.62 and R$ 166,368.50 in the first year, considering the main and the epidemiological scenarios. At the end of 5 years after the expansion of use, an BI was estimated between - R$ 10,740,743.86 and - R$ 1,191,339.37; considering the same scenarios.
CONCLUSION
Cinacalcet was dominant to avoid parathyroidectomies, being cost-effective.
Topics: Humans; Cinacalcet; Cost-Effectiveness Analysis; Hyperparathyroidism, Secondary; Naphthalenes; Renal Dialysis; Cost-Benefit Analysis; Renal Insufficiency, Chronic; Parathyroid Hormone
PubMed: 37015047
DOI: 10.1590/2175-8239-JBN-2022-0126en -
Journal of Diabetes Research 2020Diabetic nephropathy (DN) is one of the most common microvascular complications of diabetes and is the leading cause of end-stage renal disease (ESRD) and replacement...
BACKGROUND
Diabetic nephropathy (DN) is one of the most common microvascular complications of diabetes and is the leading cause of end-stage renal disease (ESRD) and replacement therapy worldwide. Vitamin D levels in DN patients are very low due to the decrease in the synthesis and activity of 1- hydroxylase in the proximal tubule cells and decrease in the vitamin D receptor abundance. To date, few studies have shown the antioxidant effects of 1,25-dihydroxyvitamin D [1,25(OH)D] on hyperglycemia-induced renal injury. The selective activator of the vitamin D receptor, paricalcitol, reduces proteinuria and slows the progression of kidney injury. The precise mechanism through which vitamin D affects diabetic status and provides kidney protection remains to be determined.
METHODS
Diabetes mellitus (DM) was induced in 94 8-week-old DBA/2J mice by intraperitoneal injection of streptozotocin (STZ). DM mice were randomly divided into receiving vehicle or treatment with paricalcitol, the active vitamin D analog, 1 week after DM induction or paricalcitol treatment 3 weeks after DM induction. An additional control group of healthy wild-type mice was not treated. Urine albumin, blood urea nitrogen, and creatinine levels were measured before and at the end of the paricalcitol treatment. Periodic acid-Schiff, immunohistochemistry staining, and western blot of the renal tissues of vitamin D receptor, villin, nephrin, and podocin expressions, were analyzed.
RESULTS
Paricalcitol treatment restored villin, nephrin, and podocin protein levels that were downregulated upon DM induction, and reduced fibronectin protein level. Vitamin D receptor activation by paricalcitol may reduce proteinuria of DN in mice and alleviate high-glucose-induced injury of kidney podocytes by regulating the key molecules such nephrin-podocin.
CONCLUSIONS
Paricalcitol treatment was associated with improved structural changes in type 1 diabetic mice including upregulation of vitamin D receptor expression, and decreased fibrosis markers such as fibronectin. These effects may contribute to the consistent benefit of vitamin D analog to slow the deterioration in glomerular function and reduce the risk of ESRD in patients with type 1 and 2 diabetes mellitus. Our results suggest that additional use of paricalcitol may be beneficial in treating patients with diabetes under standard therapeutic strategies.
Topics: Animals; Diabetes Mellitus, Experimental; Diabetic Nephropathies; Disease Progression; Ergocalciferols; Fibronectins; Fibrosis; Kidney; Mice, Inbred DBA; Proteinuria; Receptors, Calcitriol; Streptozocin
PubMed: 33294462
DOI: 10.1155/2020/7907605 -
International Immunopharmacology Jul 2022Particulate matter (PM) could induce renal injury other than lung and heart damage. The renal injury always displays in the way of renal inflammation. Vitamin D (VitD)...
BACKGROUND
Particulate matter (PM) could induce renal injury other than lung and heart damage. The renal injury always displays in the way of renal inflammation. Vitamin D (VitD) has been identified as renal-protective factor with its anti-inflammatory effect.
AIM OF THE STUDY
This study explored the therapeutic effect of VitD receptor (VDR) agonist (paricalcitol) on PM-induced toxicity and inflammation in mouse renal tubular epithelial cells (mRTECs) and its molecular mechanisms.
METHODS
The variation between PM and paricalcitol solution was investigated in different concentration solutions with transmission electron microscopy (TEM), laser-induced fluorescence (LIF) and liquid chromatography-mass spectrometry (LC-MS). The detoxication and anti-inflammation effects of paricalcitol on PM in vitro were analyzed by LIF, MTT, western blot (WB), ELISA and flow cytometry (FCM).
RESULTS AND CONCLUSION
PM became more compact after paricalcitol treatment on account of stripped polycyclic aromatic hydrocarbons (PAHs). In the cellular experiments, PM (160 μg/ml) evoked mRTECs inflammation and apoptosis through the NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) /IL-1β axis, while paricalcitol (120 μg/ml) reversed these processes. The fluorescence intensity of cell supernatant detected by PAH-LIF was weakened after adding paricalcitol, compared with.PM treatment alone. Interestingly, paricalcitol can significantly reduce the concentration of highly toxic PAHs and increase the proportion of nontoxic small PAHs. Furthermore, VDR expression was negatively correlated with the inflammation and cell apoptosis. In summary, VitD and VDR promote biological detoxication on PM though PAH degradation from a molecular effect, and exert anti-inflammatory effects against NLRP3/IL-1β axis caused by PM.
Topics: Animals; Anti-Inflammatory Agents; Cells, Cultured; Epithelial Cells; Inflammation; Interleukin-1beta; Kidney Tubules; Mice; Mice, Inbred NOD; NLR Family, Pyrin Domain-Containing 3 Protein; Particulate Matter; Vitamin D; Vitamins
PubMed: 35429817
DOI: 10.1016/j.intimp.2022.108747 -
European Review For Medical and... Jan 2022The data on the treatment of secondary hyperparathyroidism (SHPT) provided in scientific publications are divergent and contradictory. Therefore, the aim of our...
OBJECTIVE
The data on the treatment of secondary hyperparathyroidism (SHPT) provided in scientific publications are divergent and contradictory. Therefore, the aim of our systematic review was to evaluate the efficacy of SHPT treatment in (chronic kidney disease) CKD.
MATERIALS AND METHODS
The Cochrane, PubMed, and Scopus databases were searched independently by two authors. The search strategy included controlled vocabulary and keywords. The effectiveness and side effects of calcifediol, ergocaliferol, calcitriol, paricalcitol, and cinacalcet were compared and analyzed.
RESULTS
Extended-release (ER) calcifediol raised the total serum 25-hydroxyvitamin D level over the threshold of 30 ng/mL in 80% of the patients analyzed in the study. It is the level required for intact PTH (iPTH) suppression. ER calcifediol reduced the iPTH level by 30% in about 30% of the patients, whereas only 2.1% of them had hypercalcemia. Calcitriol significantly decreased the iPTH values. It was the cause of hypercalcemia in 1.7% of the patients. The reduction of the iPTH level by more than 30% was observed in 85.7% of the patients in the paracalcitol group after 48-week supplementation. Paricalcitol was the cause of hypercalcemia in 1.9% of the patients. The cinacalcet therapy resulted in the highest percentage of patients with the iPTH level within the limits recommended by the KDOQI (70-110 ng/L for stage 4 CKD and 150-300 ng/L for stage 5 CKD). 92% of the patients met the KDOQI guidelines and the mean decrease in the serum iPTH level was 68%.
CONCLUSIONS
Calcifediol ER, paricalcitol, and cinacalcet significantly decreased the iPTH level in the patients under study. Paricalcitol increased the serum calcium concentration the most of all the drugs under analysis. It is noteworthy that only cinacalcet does not carry the risk of hypercalcemia.
Topics: Calcitriol; Calcium; Cinacalcet; Ergocalciferols; Humans; Hyperparathyroidism, Secondary; Parathyroid Hormone; Renal Dialysis; Renal Insufficiency, Chronic
PubMed: 35049000
DOI: 10.26355/eurrev_202201_27773 -
Children (Basel, Switzerland) May 2023Screening for Type 1 Diabetes (T1D, incidence 1:300) with T1D autoantibodies (T1Ab) at ages 2 and 6, while sensitive, lacks a preventive strategy. Cholecalciferol 2000...
Screening for Type 1 Diabetes (T1D, incidence 1:300) with T1D autoantibodies (T1Ab) at ages 2 and 6, while sensitive, lacks a preventive strategy. Cholecalciferol 2000 IU daily since birth reduced T1D by 80% at 1 year. T1D-associated T1Ab negativized within 0.6 years with oral calcitriol in 12 children. To further investigate secondary prevention of T1D with calcitriol and its less calcemic analog, paricalcitol, we initiated a prospective interventional non-randomized clinical trial, the PRECAL study (ISRCTN17354692). In total, 50 high-risk children were included: 44 were positive for T1Ab, and 6 had predisposing for T1D HLA genotypes. Nine T1Ab+ patients had variable impaired glucose tolerance (IGT), four had pre-T1D (3 T1Ab+, 1 HLA+), nine had T1Ab+ new-onset T1D not requiring insulin at diagnosis. T1Ab, thyroid/anti-transglutaminase Abs, glucose/calcium metabolism were determined prior and q3-6 months on calcitriol, 0.05 mcg/Kg/day, or paricalcitol 1-4 mcg × 1-3 times/day p.o. while on cholecalciferol repletion. Available data on 42 (7 dropouts, 1 follow-up < 3 months) patients included: all 26 without pre-T1D/T1D followed for 3.06 (0.5-10) years negativized T1Ab (15 +IAA, 3 IA2, 4 ICA, 2 +GAD, 1 +IAA/+GAD, 1 +ICA/+GAD) within 0.57 (0.32-1.3) years or did not develop to T1D (5 +HLA, follow-up 3 (1-4) years). From four pre-T1D cases, one negativized T1Ab (follow-up 1 year), one +HLA did not progress to T1D (follow-up 3.3 years) and two +T1Ab patients developed T1D in 6 months/3 years. Three out of nine T1D cases progressed immediately to overt disease, six underwent complete remission for 1 year (1 month-2 years). Five +T1Ab patients relapsed and negativized again after resuming therapy. Four (aged <3 years) negativized anti-TPO/TG, and two anti-transglutaminase-IgA. Eight presented mild hypercalciuria/hypercalcemia, resolving with dose titration/discontinuation. Secondary prevention of T1D with calcitriol and paricalcitol seems possible and reasonably safe, if started soon enough after seroconversion.
PubMed: 37238410
DOI: 10.3390/children10050862