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Turkish Journal of Medical Sciences Oct 2018Background/aim: The Wnt/ß-catenin pathway has important biological activities, including the differentiation of cells and joint formations. The aim of our study was to...
Background/aim: The Wnt/ß-catenin pathway has important biological activities, including the differentiation of cells and joint formations. The aim of our study was to determine the effect of paricalcitol on experimentally induced arthritis. Materials and methods: Type II collagen combined with Freund's adjuvant was applied to induce arthritis in Wistar albino female rats. Paricalcitol (0.3 μg/kg daily) was subcutaneously injected starting 1 day after collagen applications (prophylactic group) or 1 day after the onset of arthritis (therapeutic group), until day 29. Results: The 29th day arthritis scores were lower compared to the 13th day scores in the paricalcitol groups (P < 0.05), while they were higher in the arthritis group (P < 0.05). Marked cartilage-bone destruction and extensive perisynovial inflammation were detected in the arthritis group. Decreased cartilage-bone destruction and perisynovial inflammation in the paws were observed in the paricalcitol groups. The tissue mRNA levels of DKK1, Wnt5a, and axin-2 were higher in the arthritis group than in the control group. In the paricalcitol groups, mRNA expressions were lower than in the arthritis group. Conclusion: The present study shows that the Wnt/ß-catenin signaling pathway is active in arthritis. Moreover, paricalcitol ameliorates arthritis via inhibiting the Wnt/ß-catenin pathway. Paricalcitol and the Wnt/ß-catenin pathway are candidates for research in human rheumatoid arthritis.
Topics: Animals; Anti-Inflammatory Agents; Arthritis, Experimental; Arthritis, Rheumatoid; Ergocalciferols; Female; Humans; Joints; Rats; Rats, Wistar; Wnt Signaling Pathway
PubMed: 30384579
DOI: 10.3906/sag-1804-62 -
American Journal of Nephrology 2016Chronic kidney disease-mineral and bone disorder (CKD-MBD) is common in kidney transplant recipients (KTRs), where secondary hyperparathyroidism (HPTH) and... (Review)
Review
Chronic kidney disease-mineral and bone disorder (CKD-MBD) is common in kidney transplant recipients (KTRs), where secondary hyperparathyroidism (HPTH) and post-transplantation bone disease (PTBD) are potential effectors of both graft and vascular aging. Reduced 25(OH)D levels are highly prevalent in KTRs. Experimental and clinical evidence support the direct involvement of deranged vitamin D metabolism in CKD-MBD among KTRs. This review analyzes the pathophysiology of vitamin D derangement in KTRs and its fall out on patient and graft outcome, highlighting the roles of both nutritional and active vitamin D compounds to treat PTBD, cardiovascular disease (CVD) and graft dysfunction. Fibroblast growth factor-23-parathyroid hormone (PTH)-vitamin D axis, immunosuppressive therapy and previous bone status have been associated with PTBD. Although several studies reported reduced PTH levels in KTRs receiving nutritional vitamin D, its effects on bone mineral density (BMD) remain controversial. Active vitamin D reduced PTH levels and increased BMD after transplantation, but paricalcitol treatment was not accompanied by benefits on osteopenia. Vitamin D is considered protective against CVD due to the widespread pleiotropic effects, but data among KTRs remain scanty. Although vitamin deficiency is associated with lower glomerular filtration rate (GFR) and faster estimated GFR decline and data on the anti-proteinuric effects of vitamin D receptor activation (VDRA) in KTRs sound encouraging, reports on related improvement on graft survival are still lacking. Clinical data support the efficacy of VDRA against HPTH and show promising evidence of VDRA's effect in counteracting post-transplant proteinuria. New insights are mandatory to establish if the improvement of surrogate outcomes will translate into better patient and graft outcome.
Topics: Chronic Kidney Disease-Mineral and Bone Disorder; Graft Survival; Humans; Kidney Transplantation; Postoperative Complications; Vitamin D
PubMed: 27229347
DOI: 10.1159/000446863 -
British Journal of Pharmacology Jul 2020The synthetic vitamin D3 analogue paricalcitol acts as a selective activator of the vitamin D receptor (VDR). While there is evidence for cardioprotective effects of...
BACKGROUND AND PURPOSE
The synthetic vitamin D3 analogue paricalcitol acts as a selective activator of the vitamin D receptor (VDR). While there is evidence for cardioprotective effects of paricalcitol associated with the VDR pathway, less information is available about the structural and functional cardiac effects of paricalcitol on established heart failure (HF) and particularly its effects on associated electrophysiological or Ca handling remodelling.
EXPERIMENTAL APPROACH
We used a murine model of transverse aortic constriction (TAC) to study the effect of paricalcitol on established HF. Treatment was initiated 4 weeks after surgery over five consecutive weeks, and mice were sacrificed 9 weeks after surgery. Cardiac MRI (CMRI) was performed 4 and 9 weeks after surgery. Hearts were used for biochemical and histological studies and to isolate ventricular myocytes for electrophysiological and calcium imaging studies.
KEY RESULTS
CMRI analysis revealed that, compared with vehicle, paricalcitol treatment prevented the progression of ventricular dilation and hypertrophy after TAC and halted the corresponding decline in ejection fraction. These beneficial effects were related to the attenuation of intracellular Ca mishandling remodelling, antifibrotic and antihypertrophic effects and potentially antiarrhythmic effects by preventing the reduction of K current density and the long QT, JT and TpTe intervals observed in HF animals.
CONCLUSION AND IMPLICATIONS
The results suggest that paricalcitol treatment in established HF hampers disease progression and improves adverse electrophysiological and Ca handling remodelling, attenuating the vulnerability to HF-associated ventricular arrhythmias. Paricalcitol may emerge as a potential therapeutic option in the treatment of HF.
Topics: Animals; Cardiomegaly; Disease Models, Animal; Ergocalciferols; Heart Failure; Mice; Myocytes, Cardiac
PubMed: 32154912
DOI: 10.1111/bph.15048 -
Nutrients Apr 2019Epidemiological studies have suggested a survival benefit for hemodialysis patients on paricalcitol or calcitriol, but nutritional vitamin D supplementation of patients...
BACKGROUND
Epidemiological studies have suggested a survival benefit for hemodialysis patients on paricalcitol or calcitriol, but nutritional vitamin D supplementation of patients already on vitamin D receptor (VDR) activators is controversial.
METHODS
This observational retrospective cohort study was conducted with prospectively collected data from all consecutive patients with chronic kidney disease (CKD) who underwent hemodialysis under routine clinical practice conditions for two years.
RESULTS
Of the 129 patients, 89 were treated with calcidiol, paricalcitol, and/or calcitriol. The patients with any vitamin D formulation had higher serum concentrations of 25-hydroxy vitamin D and fibroblast growth factor-23 and tended to have higher mortality rates (42% 25%, = 0.07). On subgroup analysis, any calcidiol treatment or calcidiol combined with paricalcitol associated with significantly higher mortality rates than no treatment (47% and 62.5%, = 0.043 and 0.008, respectively). The association between calcidiol/paricalcitol treatment and elevated mortality remained significant after adjusting for age, sex, diabetes, C-reactive protein, and hemodialysis vintage. Any calcidiol and calcidiol/paricalcitol treatment exhibited a dose-response relationship with mortality ( for trend: 0.002 and 0.005, respectively).
CONCLUSIONS
These data draw attention to the hitherto unexplored safety of calcidiol supplementation in patients on hemodialysis, especially in those already on vitamin D. Until clinical trials demonstrate the safety and efficacy of this approach, caution should be exercised when prescribing these patients ≥0.5 calcidiol mg/month.
Topics: Aged; Calcifediol; Ergocalciferols; Female; Fibroblast Growth Factor-23; Fibroblast Growth Factors; Humans; Male; Middle Aged; Renal Dialysis; Vitamin D; Vitamin D Deficiency; Vitamins
PubMed: 31035488
DOI: 10.3390/nu11050959 -
Nutrients Mar 2023Lifestyle habits and insufficient sunlight exposure lead to a high prevalence of vitamin D hypovitaminosis, especially in the elderly. Recent studies suggest that in... (Review)
Review
Lifestyle habits and insufficient sunlight exposure lead to a high prevalence of vitamin D hypovitaminosis, especially in the elderly. Recent studies suggest that in central Europe more than 50% of people over 60 years are not sufficiently supplied with vitamin D. Since vitamin D hypovitaminosis is associated with many diseases, such as Alzheimer's disease (AD), vitamin D supplementation seems to be particularly useful for this vulnerable age population. Importantly, in addition to vitamin D, several analogues are known and used for different medical purposes. These vitamin D analogues differ not only in their pharmacokinetics and binding affinity to the vitamin D receptor, but also in their potential side effects. Here, we discuss these aspects, especially those of the commonly used vitamin D analogues alfacalcidol, paricalcitol, doxercalciferol, tacalcitol, calcipotriol, and eldecalcitol. In addition to their pleiotropic effects on mechanisms relevant to AD, potential effects of vitamin D analogues on comorbidities common in the context of geriatric diseases are summarized. AD is defined as a complex neurodegenerative disease of the central nervous system and is commonly represented in the elderly population. It is usually caused by extracellular accumulation of amyloidogenic plaques, consisting of amyloid (Aβ) peptides. Furthermore, the formation of intracellular neurofibrillary tangles involving hyperphosphorylated tau proteins contributes to the pathology of AD. In conclusion, this review emphasizes the importance of an adequate vitamin D supply and discusses the specifics of administering various vitamin D analogues compared with vitamin D in geriatric patients, especially those suffering from AD.
Topics: Humans; Aged; Alzheimer Disease; Neurodegenerative Diseases; Vitamin D; Vitamins; tau Proteins; Amyloid beta-Peptides
PubMed: 37049524
DOI: 10.3390/nu15071684 -
Nephrology, Dialysis, Transplantation :... Sep 2013Chronic kidney disease (CKD) is associated with elevations in serum phosphate, calcium-phosphorus product and bone-specific alkaline phosphatase (BAP), with attendant... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Chronic kidney disease (CKD) is associated with elevations in serum phosphate, calcium-phosphorus product and bone-specific alkaline phosphatase (BAP), with attendant risks of cardiovascular and bone disorders. Active vitamin D can suppress parathyroid hormone (PTH), but may raise serum calcium and phosphate concentrations. Paricalcitol, a selective vitamin D activator, suppressed PTH in CKD patients (stages 3 and 4) with secondary hyperparathyroidism (SHPT) with minimal changes in calcium and phosphate metabolism.
METHODS
The VITAL study enrolled patients with CKD stages 2-4. We examined the effect and relationship of paricalcitol to calcium and phosphate metabolism and bone markers in a post hoc analysis of VITAL. The study comprised patients with diabetic nephropathy enrolled in a double-blind, placebo-controlled, randomized trial of paricalcitol (1 or 2 μg/day). Urinary and serum calcium and phosphate, serum BAP, and intact PTH (iPTH) concentrations were measured throughout the study.
RESULTS
Baseline demographics and calcium, phosphate, PTH (49% with iPTH <70 pg/mL), and BAP concentrations were similar between groups. A transient, modest yet significant increase in phosphate was observed for paricalcitol 2 μg/day (+0.29 mg/dL; P < 0.001). Dose-dependent increases in serum and urinary calcium were observed; however, there were few cases of hypercalcemia: one in the 1-μg/day group (1.1%) and three in the 2-μg/day group (3.2%). Significant reductions in BAP were observed that persisted for 60 days after paricalcitol discontinuation (P < 0.001 for combined paricalcitol groups versus placebo). Paricalcitol dose-dependent reductions in iPTH were observed. Paricalcitol in CKD patients (±SHPT) was associated with modest increases in calcium and phosphate.
CONCLUSION
Paricalcitol reduces BAP levels, which may be beneficial for reducing vascular calcification.
TRIAL REGISTRATION
Trial is registered with ClinicalTrials.gov, number NCT00421733.
Topics: Aged; Alkaline Phosphatase; Biomarkers; Bone Density Conservation Agents; Bone and Bones; Calcium; Diabetic Nephropathies; Double-Blind Method; Ergocalciferols; Female; Humans; Male; Middle Aged; Parathyroid Hormone; Phosphates
PubMed: 23787544
DOI: 10.1093/ndt/gft227 -
Nefrologia : Publicacion Oficial de La... 2013Proteinuria is the main predictor of chronic kidney disease progression. Drugs that block the renin-angiotensin-aldosterone (RAA) system reduce proteinuria and slow down... (Review)
Review
Proteinuria is the main predictor of chronic kidney disease progression. Drugs that block the renin-angiotensin-aldosterone (RAA) system reduce proteinuria and slow down the progression of the disease. However, their effect is suboptimal, and residual proteinuria persists as an important predictor of renal impairment. Vitamin D has pleiotropic effects that could have an impact on these parameters. In this study, we critically review the molecular and experimental bases that suggest an antiproteinuric effect of vitamin D receptor (VDR) activation and the available evidence on its antiproteinuric effect in clinical practice. In animal models, we have observed the antiproteinuric effect of VDR activation, which could be due to direct protective action on the podocyte or other pleiotropic effects that slow down RAA system activation, inflammation and fibrosis. Clinical trials have generally been conducted in patients with a vitamin D deficiency or insufficiency and the main trial (VITAL) did not demonstrate that paricalcitol improved the study's primary endpoint (decrease in the urine albumin to creatinine ratio). In this sense, the information available is insufficient to advise the use of native vitamin D or VDR activators as renoprotective antiproteinuric drugs beyond the experimental level. Two Spanish clinical trials and one Italian trial attempted to determine the effect of paricalcitol and vitamin D on residual proteinuria in various clinical circumstances (PALIFE, NEFROVID and PROCEED).
Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Calcitriol; Clinical Trials as Topic; Cost-Benefit Analysis; Diabetic Nephropathies; Disease Models, Animal; Disease Progression; Drug Evaluation, Preclinical; Ergocalciferols; Gene Expression Regulation; Humans; Kidney Diseases; Mice; Mice, Knockout; Multicenter Studies as Topic; Myocytes, Smooth Muscle; Phosphates; Podocytes; Proteinuria; Rats; Receptors, Calcitriol; Renal Dialysis; Renin-Angiotensin System; Vitamin D
PubMed: 24089164
DOI: 10.3265/Nefrologia.pre2013.Apr.12025 -
Archives of Rheumatology Sep 2018This study aims to determine the prophylactic and therapeutic efficacy of inhibition of Wnt/β-catenin signaling pathway with paricalcitol in an experimental scleroderma...
OBJECTIVES
This study aims to determine the prophylactic and therapeutic efficacy of inhibition of Wnt/β-catenin signaling pathway with paricalcitol in an experimental scleroderma model created with bleomycin (BLM).
MATERIALS AND METHODS
Sixty female BALB/c mice (8-week old and weighing 25 g to 30 g) were divided into six groups as prophylactic-early [group 1 (control I)], sham I (group 2), paricalcitol I (group 3), therapeutic-late [group 4 (control II)], sham II (group 5), and paricalcitol II (group 6) groups. Subcutaneous BLM (100 μg/day) injections were used to induce dermal fibrosis and paricalcitol (0.3 μg/kg/day) was applied subcutaneously to BLM-injected mice during the first three weeks for preventive interventions and in the second three weeks for therapeutic interventions. Tissue samples were harvested for subsequent pathological and real-time polymerase chain reaction analysis. Tissue transforming growth factor-beta 1, axin-1, and Wnt-2 messenger ribonucleic acid expressions were determined by real-time polymerase chain reaction.
RESULTS
Repeated BLM applications increased the dermal inflammatory cell infiltration and dermal thickness, and led to dermal fibrosis, in both early and late stages. Similarly, transforming growth factor-beta 1, axin-1, and Wnt-2 expressions were significantly increased in the sham groups compared to the own control group (p<0.05 for all). Contrarily, prophylactic and therapeutic paricalcitol applications decreased the transforming growth factor-beta 1, axin-1, and Wnt-2 messenger ribonucleic acid expressions compared to the own sham group (p<0.05 for all). In addition, the regressions in dermal necro-inflammation and dermal fibrosis on pathological views were also observed in the paricalcitol applied groups.
CONCLUSION
In this model, increased axin-1 and Wnt-2 messenger ribonucleic acid expressions suggest that Wnt/β-catenin pathway is active in dermal fibrosis.
PubMed: 30632522
DOI: 10.5606/ArchRheumatol.2018.6648 -
Frontiers in Endocrinology 2021Vitamin D is a potent steroid hormone that induces widespread changes in gene expression and controls key biological pathways. Here we review pathophysiology of vitamin... (Review)
Review
Vitamin D is a potent steroid hormone that induces widespread changes in gene expression and controls key biological pathways. Here we review pathophysiology of vitamin D with particular reference to COVID-19 and pancreatic cancer. Utility as a therapeutic agent is limited by hypercalcemic effects and attempts to circumvent this problem have used vitamin D superagonists, with increased efficacy and reduced calcemic effect. A further caveat is that vitamin D mediates multiple diverse effects. Some of these (anti-fibrosis) are likely beneficial in patients with COVID-19 and pancreatic cancer, whereas others (reduced immunity), may be beneficial through attenuation of the cytokine storm in patients with advanced COVID-19, but detrimental in pancreatic cancer. Vitamin D superagonists represent an untapped resource for development of effective therapeutic agents. However, to be successful this approach will require agonists with high cell-tissue specificity.
Topics: Carcinoma, Pancreatic Ductal; Cytokine Release Syndrome; Humans; Pancreatic Neoplasms; Vitamin D; Vitamins; COVID-19 Drug Treatment
PubMed: 33868174
DOI: 10.3389/fendo.2021.644298 -
Journal of the American Society of... May 2015Secondary hyperparathyroidism contributes to post-transplant CKD mineral and bone disorder. Paricalcitol, a selective vitamin D receptor activator, decreased serum... (Randomized Controlled Trial)
Randomized Controlled Trial
Secondary hyperparathyroidism contributes to post-transplant CKD mineral and bone disorder. Paricalcitol, a selective vitamin D receptor activator, decreased serum parathyroid hormone levels and proteinuria in patients with secondary hyperparathyroidism. This single-center, prospective, randomized, crossover, open-label study compared the effect of 6-month treatment with paricalcitol (1 μg/d for 3 months and then uptitrated to 2 µg/d if tolerated) or nonparicalcitol therapy on serum parathyroid hormone levels (primary outcome), mineral metabolism, and proteinuria in 43 consenting recipients of renal transplants with secondary hyperparathyroidism. Participants were randomized 1:1 according to a computer-generated sequence. Compared with baseline, median (interquartile range) serum parathyroid hormone levels significantly declined on paricalcitol from 115.6 (94.8-152.0) to 63.3 (52.0-79.7) pg/ml (P<0.001) but not on nonparicalcitol therapy. At 6 months, levels significantly differed between treatments (P<0.001 by analysis of covariance). Serum bone-specific alkaline phosphatase and osteocalcin decreased on paricalcitol therapy only and significantly differed between treatments at 6 months (P<0.001 for all comparisons). At 6 months, urinary deoxypyridinoline-to-creatinine ratio and 24-hour proteinuria level decreased only on paricalcitol (P<0.05). L3 and L4 vertebral mineral bone density, assessed by dual-energy x-ray absorption, significantly improved with paricalcitol at 6 months (P<0.05 for both densities). Paricalcitol was well tolerated. Overall, 6-month paricalcitol supplementation reduced parathyroid hormone levels and proteinuria, attenuated bone remodeling and mineral loss, and reduced eGFR in renal transplant recipients with secondary hyperparathyroidism. Long-term studies are needed to monitor directly measured GFR, ensure that the bone remodeling and mineral effects are sustained, and determine if the reduction in proteinuria improves renal and cardiovascular outcomes.
Topics: Adult; Bone Density; Bone Density Conservation Agents; Bone Remodeling; Calcium; Creatinine; Cross-Over Studies; Ergocalciferols; Female; Humans; Hyperparathyroidism, Secondary; Kidney Transplantation; Male; Middle Aged; Parathyroid Hormone; Phosphates; Postoperative Complications; Prospective Studies; Proteinuria; Vitamin D
PubMed: 25194004
DOI: 10.1681/ASN.2013111185