-
Andrology Sep 2020In rodents and humans, vitamin D deficiency (VDD) is associated with altered sperm structure and function (primarily decreased motility and morphological abnormalities)...
BACKGROUND
In rodents and humans, vitamin D deficiency (VDD) is associated with altered sperm structure and function (primarily decreased motility and morphological abnormalities) that are primarily attributed to VDD-induced hypocalcemia. However, it is suspected that VDD has much more drastic effects on mammalian spermatozoa.
OBJECTIVES
The purpose of this study was to illustrate that VDD, depending on its severity and duration, can alter sperm nuclear integrity and can also lead to the loss of spermatozoa's ability to support embryonic development.
MATERIALS AND METHODS
A mouse model of induced VDD combining the action of a vitamin D-deficient diet, UV exposure limitation, and paricalcitol injections; a vitamin D2 analog that catabolizes endogenous vitamin D by increasing the expression of CYP24A, a member of the cytochrome P450 family, has been used to create different grades of VDD.
RESULTS
We show that the most significant sperm defect recorded concerns the integrity of the paternal nucleus, which is both decondensed and fragmented in moderate-to-severe VDD situations. Consistent with the known consequences of fertilization with DNA-damaged spermatozoa, we show that paternal VDD decreases the ability of spermatozoa to optimally support fertilization and embryonic development.
DISCUSSION AND CONCLUSION
Given the worldwide high prevalence of VDD in humans, and although obtained in an animal model, the data presented here suggest that subfertile/infertile males may benefit from VDD testing and that attempts to correct serum vitamin D levels could be considered prior to conception, either naturally or through ART.
Topics: Animals; Embryonic Development; Female; Fertilization; Male; Mice; Pregnancy; Spermatozoa; Vitamin D Deficiency
PubMed: 32421931
DOI: 10.1111/andr.12820 -
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 -
Clinical Journal of the American... Mar 2020In the United States, intravenous vitamin D analogs are the first-line therapy for management of secondary hyperparathyroidism in hemodialysis patients. Outside the...
BACKGROUND AND OBJECTIVES
In the United States, intravenous vitamin D analogs are the first-line therapy for management of secondary hyperparathyroidism in hemodialysis patients. Outside the United States, oral calcitriol (1,25-dihydroxyvitamin D) is routinely used. We examined standard laboratory parameters of patients on in-center hemodialysis receiving intravenous vitamin D who switched to oral calcitriol.
DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS
We conducted a retrospective cohort study of adult patients treated within Fresenius Kidney Care clinics. During a 6-month period (December 2013 to May 2014), we identified patients on an intravenous vitamin D analog (doxercalciferol or paricalcitol) who switched to oral calcitriol and matched them to patients receiving an intravenous vitamin D analog. Mean serum calcium, phosphate, and intact parathyroid hormone (iPTH) concentrations were examined for up to 12 months of follow-up. We used Poisson and Cox proportional hazards regression models to examine hospitalization and survival rates. The primary analysis was conducted as intention-to-treat; secondary analyses included an as-treated evaluation.
RESULTS
A total of 2280 patients who switched to oral calcitriol were matched to 2280 patients receiving intravenous vitamin D. Compared with patients on intravenous vitamin D, mean calcium and phosphate levels in the oral calcitriol group were lower after the change to oral calcitriol. In contrast, iPTH levels were higher in the oral calcitriol group. At 12 months, the percentage of patients with composite laboratories in target range (calcium <10 mg/dl, phosphate 3.0-5.5 mg/dl, and iPTH 150-600 pg/ml) were comparable between groups (45% versus 45%; =0.96). Hospital admissions, length of hospital stay, and survival were comparable between groups. An as-treated analysis and excluding those receiving cinacalcet did not reveal significant between-group differences.
CONCLUSIONS
Among patients receiving in-center hemodialysis who were switched to oral calcitriol versus those on an intravenous vitamin D analog, the aggregate of all mineral and bone laboratory parameters in range was largely similar between groups.
Topics: Administration, Intravenous; Administration, Oral; Aged; Biomarkers; Calcitriol; Calcium; Chronic Kidney Disease-Mineral and Bone Disorder; Drug Substitution; Ergocalciferols; Female; Humans; Hyperparathyroidism, Secondary; Kidney Failure, Chronic; Male; Middle Aged; Parathyroid Hormone; Phosphates; Renal Dialysis; Retrospective Studies; Time Factors; Treatment Outcome; United States; Vitamins
PubMed: 32111702
DOI: 10.2215/CJN.07960719 -
Biomedicine & Pharmacotherapy =... May 2020Multiple sclerosis (MS) is known as an autoimmune disease in the central nervous system (CNS) characterized by motor deficits, pain, fatigue, cognitive impairment, and...
Multiple sclerosis (MS) is known as an autoimmune disease in the central nervous system (CNS) characterized by motor deficits, pain, fatigue, cognitive impairment, and sensory and visual dysfunction. MS is considered to be resulted from significant inflammatory response. Paricalcitol (Pari) is a vitamin D2 analogue, which has been indicated to show anti-inflammatory activities in kidney and heart diseases. In the present study, if Pari could ameliorate the experimental autoimmune encephalomyelitis (EAE) was investigated. Here, the C57BL/6 mice were immunized using myelin oligodendrocyte glycoprotein 35-55 (MOG). Subsequently, Pari was intraperitoneally injected into the mice. As for in vitro analysis, RAW264.7 and Jurkat cells were incubated with Pari together with corresponding stimulus. The results indicated that Pari administration reduced the paralytic severity, neuropathology and apoptosis in MOG-treated mice compared to the MOG single group. Pari also exhibited a significantly inhibitory effect on immune cell infiltration, glial cell activation, expression of pro-inflammatory factors and the activation of nuclear factor κB (NF-κB). The expression of pro-inflammatory regulators and the translocation of NF-κB from cytoplasm into nuclear in RAW264.7 and Jurkat cells under specific stimulation was clearly down-regulated by Pari incubation. Furthermore, we found that suppressing NF-κB with its inhibitor combined with Pari could further reduce the expression of pro-inflammatory factors and associated proteins. These data illustrated that Pari could diminish MOG-triggered EAE, as well as macrophages and T cells activation through blocking NF-κB activation. Collectively, Pari might have therapeutic effects in mouse models with MS.
Topics: Animals; Anti-Inflammatory Agents; Apoptosis; Calcium-Binding Proteins; Caspase 3; Cell Line; Cell Proliferation; Cyclooxygenase 2; Disease Models, Animal; Encephalomyelitis, Autoimmune, Experimental; Ergocalciferols; Glial Fibrillary Acidic Protein; Humans; I-kappa B Proteins; Inflammation; Jurkat Cells; Lipopolysaccharides; Macrophages; Male; Mice; Mice, Inbred C57BL; Microfilament Proteins; Microglia; Multiple Sclerosis; Myelin-Oligodendrocyte Glycoprotein; NF-kappa B; Nitric Oxide Synthase Type II; Peptide Fragments; Poly (ADP-Ribose) Polymerase-1; Primary Cell Culture; RAW 264.7 Cells; Signal Transduction; Spinal Cord
PubMed: 32106388
DOI: 10.1016/j.biopha.2019.109528 -
International Journal of Molecular... Jan 2020Chronic renal insufficiency (CRI) is characterized by increased endothelin 1 (ET-1) synthesis. We studied rat kidney endothelin receptor A (ETA) and receptor B (ETB)...
Chronic renal insufficiency (CRI) is characterized by increased endothelin 1 (ET-1) synthesis. We studied rat kidney endothelin receptor A (ETA) and receptor B (ETB) expressions after 12 and 27 weeks of 5/6 nephrectomy, and after 12 weeks of 0.3% adenine diet, representing proteinuric and interstitial inflammation models of CRI, respectively. Uric acid and calcium-phosphate metabolism were modulated after 5/6 nephrectomy, while ETA blocker and calcimimetic were given with adenine. Endothelin receptor mRNA levels were measured using RT-qPCR and protein levels using autoradiography (5/6 nephrectomy) or ELISA (adenine model). Both 12 and 27 weeks after 5/6 nephrectomy, kidney cortex ETA protein was increased by ~60% without changes in ETB protein, and the ETB:ETA ratio was reduced. However, the ETB:ETA mRNA ratio did not change. In the adenine model, kidney ETA protein was reduced by ~70%, while ETB protein was suppressed by ~95%, and the ETB:ETA ratio was reduced by ~85%, both at the protein and mRNA levels. The additional interventions did not influence the observed reductions in the ETB:ETA ratio. To conclude, unfavorable reduction in the ETB:ETA protein ratio was observed in two different models of CRI. Therefore, ETA blockade may be beneficial in a range of diseases that cause impaired kidney function.
Topics: Adenine; Animals; Calcium; Disease Models, Animal; Gene Expression Regulation; Kidney Cortex; Male; Nephrectomy; Phosphates; Rats; Receptor, Endothelin A; Receptor, Endothelin B; Renal Insufficiency, Chronic; Uric Acid
PubMed: 32023824
DOI: 10.3390/ijms21030936 -
Cell Death & Disease Jan 2020Our preliminary work has revealed that vitamin D receptor (VDR) activation is protective against cisplatin induced acute kidney injury (AKI). Ferroptosis was recently...
Our preliminary work has revealed that vitamin D receptor (VDR) activation is protective against cisplatin induced acute kidney injury (AKI). Ferroptosis was recently reported to be involved in AKI. Here in this study, we investigated the internal relation between ferroptosis and the protective effect of VDR in cisplatin induced AKI. By using ferroptosis inhibitor ferrostatin-1 and measurement of ferroptotic cell death phenotype in both in vivo and in vitro cisplatin induced AKI model, we observed the decreased blood urea nitrogen, creatinine, and tissue injury by ferrostatin-1, hence validated the essential involvement of ferroptosis in cisplatin induced AKI. VDR agonist paricalcitol could both functionally and histologically attenuate cisplatin induced AKI by decreasing lipid peroxidation (featured phenotype of ferroptosis), biomarker 4-hydroxynonenal (4HNE), and malondialdehyde (MDA), while reversing glutathione peroxidase 4 (GPX4, key regulator of ferroptosis) downregulation. VDR knockout mouse exhibited much more ferroptotic cell death and worsen kidney injury than wild type mice. And VDR deficiency remarkably decreased the expression of GPX4 under cisplatin stress in both in vivo and in vitro, further luciferase reporter gene assay showed that GPX4 were target gene of transcription factor VDR. In addition, in vitro study showed that GPX4 inhibition by siRNA largely abolished the protective effect of paricalcitol against cisplatin induced tubular cell injury. Besides, pretreatment of paricalcitol could also alleviated Erastin (an inducer of ferroptosis) induced cell death in HK-2 cell. These data suggested that ferroptosis plays an important role in cisplatin induced AKI. VDR activation can protect against cisplatin induced renal injury by inhibiting ferroptosis partly via trans-regulation of GPX4.
Topics: Acute Kidney Injury; Aldehydes; Animals; Antineoplastic Agents; Cell Death; Cell Line; Cisplatin; Creatinine; Cyclohexylamines; Ergocalciferols; Ferroptosis; Glutathione Peroxidase; Humans; Lipid Peroxidation; Male; Malondialdehyde; Mice; Mice, Inbred C57BL; Mice, Knockout; Microscopy, Electron, Scanning Transmission; Mitochondria; Phenylenediamines; Piperazines; RNA, Small Interfering; Receptors, Calcitriol
PubMed: 31996668
DOI: 10.1038/s41419-020-2256-z -
Scientific Reports Jan 2020MicroRNA-27a/b are small non-coding RNAs which are reported to regulate inflammatory response and cell proliferation. Although some studies have demonstrated that...
MicroRNA-27a/b are small non-coding RNAs which are reported to regulate inflammatory response and cell proliferation. Although some studies have demonstrated that miR-27b is down-regulated in the oral specimens of patients suffering with oral lichen planus (OLP), the molecular mechanism of miR-27b decrease remains a large mystery, and the expression of miR-27a in OLP is not well explored. Here, we demonstrated both miR-27a and miR-27b, compared with healthy controls, were reduced in the oral biopsies, serum and saliva samples derived from OLP patients. The reductions of miR-27a/b were also confirmed in the lipopolysaccharide (LPS)- or activated CD4 T cell-treated human oral keratinocytes (HOKs). Furthermore, we found vitamin D receptor (VDR) binding sites in the promoters of miR-27a/b genes and verified this finding. We also tested miR-27a/b levels in the oral epithelium from paricalcitol-treated, vitamin D deficient or VDR knockout mice. In the rescue experiments, we confirmed vitamin D and VDR inhibited LPS- or activated CD4 T cell-induced miR-27a/b reductions in HOKs. In sum, our results show that vitamin D/VDR signaling induces miR-27a/b in oral lichen planus.
Topics: Animals; Binding Sites; Case-Control Studies; Disease Models, Animal; Down-Regulation; Epithelial Cells; Ergocalciferols; Humans; Keratinocytes; Lichen Planus, Oral; Lipopolysaccharides; Mice; Mice, Inbred C57BL; Mice, Knockout; MicroRNAs; Promoter Regions, Genetic; Receptors, Calcitriol; Signal Transduction; Vitamin D
PubMed: 31942011
DOI: 10.1038/s41598-019-57288-9 -
International Journal of Nephrology and... 2019In a high percentage of patients with chronic kidney disease (CKD) low levels of vitamin D are detected. The purpose of this study was to evaluate if the native vitamin...
UNLABELLED
In a high percentage of patients with chronic kidney disease (CKD) low levels of vitamin D are detected. The purpose of this study was to evaluate if the native vitamin D therapy (cholecalciferol) in the patients with stage 3 and hypovitaminosis D allows to modify markers of bone and mineral metabolism once normal serum levels have been achieved.
MATERIALS AND METHODS
From an initial base of 297 patients with CKD and hypovitaminosis D, those with normal or high levels of PTH were chosen for therapy with native vitamin D. The initial administered dose was 1000 IU/day, with adjustments every 4 months of 1000 IU (maximum 4000 IU/day, according to RDA and IOM), until achieving serum levels of 25 hydroxyvitamin D greater than 30 ng/mL and lower than 80 ng/mL. The variables calcium, phosphorus, intact parathormone (iPTH), creatinine and glomerular filtration rate (GFR) were also evaluated every 4 months.
RESULTS
The total number of patients included in this study was 170. Seventy-three patients were excluded along the follow-up: 17 non-responders (never achieved the projected serum levels of vitamin D), and 56 for not completing one year of follow-up. A total of 97 patients were finally included. In 82 patients, follow-up was achieved for 12 months (G1) and in 38 patients for 24 months (G2). In 15 patients despite achieving satisfactory levels of vitamin D at 12 months, it was not possible to obtain adequate levels of iPTH for their GFR according to K/DOQI 2003 guidelines and they were called refractory to therapy (G3). In both groups 1 and 2, a non-significant tendency to increase calcium and serum phosphorus was observed. iPTH decreased significantly at 12 and 24 months follow-up. In group 3, we opted at 12 months for conversion to calcitriol, with a significant reduction in iPTH values. In this group, the initial value of GFR was close to 30 mL/min, and its fall in time more significant than the other two groups to CKD stage 4.
CONCLUSION
Cholecalciferol with adjustment in its dose, and obtaining normal serum levels is an excellent therapeutic alternative for the treatment of patients with CKD stage 3, and hypovitaminosis D. In the group of patients with GFR close to 30 mL/min, or lower values (stage 4), and with the presence of secondary hyperparathyroidism, the use of active form of vitamin D (calcitriol, paricalcitol) is recommended as the first therapeutic alternative.
PubMed: 31827333
DOI: 10.2147/IJNRD.S214194 -
Nefrologia 2020Cardiovascular events are the major cause of morbidity and mortality in patients with chronic kidney disease (CKD). Inflammation and mineral-bone disorder are...
BACKWARD
Cardiovascular events are the major cause of morbidity and mortality in patients with chronic kidney disease (CKD). Inflammation and mineral-bone disorder are pathological conditions that have been associated with an increased cardiovascular risk.
OBJECTIVE
Show paricalcitol regulation overinflammatory, fibrotic and mineral disorder parameters in CKD.
MATERIAL AND METHODS
Prospective Study in 46 CKD stages III-V patients without dialysis patients whith elevated parathormone in which we introduced paricalcitol. We evaluated classic and newest mineral and bone metabolism serum parameters (calcium, phosphorus, parathormone, fibroblast growth factor-23 [FGF-23], Klotho, calcidiol), inflammatory-fibrosis and anticalcifying parameters (interleukin-6 and 10, tumor necrosis factor-a [TNF- α], transforming growth factor-b [TGF-β],bone morphogenic protein-7 [BMP-7] and fetuin-A) for four months.
RESULTS
At the end of study soluble Klotho increased (p=.001), FGF-23 remained stable, calcium and phosphorus levels were not increased, calcidiol increased (p=.010) and PTH decreased (p=.002). Inflammation-fibrosis and calcification parameters showed positive regulation after paricalcitol treatment: interleukin-6 decreased significantly (p=.001) and also TNF-α did (p=.005), on the contrary, interleukin-10 and fetuin-A increased (p=.001 for both). Anti-fibrosis marker BMP-7 increased (p=.001) and TGF-b decreased (p=.001). We did not find significant changes in renal function.
CONCLUSIONS
Paricalcitol treatment might be profitable in regulating inflammatory and anticalcificant parameters, unmodified calcium or phosphorus seric levels and preserving kidney function in renal patients with no dialysis. Our selected parameters could indicate paricalcitol effects in mineral and endothelial disorder related to renal disease.
Topics: Aged; Bone Density Conservation Agents; Bone Morphogenetic Protein 7; Calcifediol; Calcium; Ergocalciferols; Female; Fibroblast Growth Factor-23; Fibroblast Growth Factors; Glomerular Filtration Rate; Glucuronidase; Humans; Interleukin-10; Interleukin-6; Klotho Proteins; Male; Parathyroid Hormone; Phosphorus; Prospective Studies; Proteinuria; Renal Insufficiency, Chronic; Transforming Growth Factor beta; Tumor Necrosis Factor-alpha; Vascular Calcification; alpha-2-HS-Glycoprotein
PubMed: 31740151
DOI: 10.1016/j.nefro.2019.08.001 -
Journal of Medical Economics Mar 2020Patients with chronic kidney disease (CKD) not on dialysis frequently have vitamin D insufficiency (VDI) and secondary hyperparathyroidism (SHPT), which are associated... (Randomized Controlled Trial)
Randomized Controlled Trial
Patients with chronic kidney disease (CKD) not on dialysis frequently have vitamin D insufficiency (VDI) and secondary hyperparathyroidism (SHPT), which are associated with an increased risk of cardiovascular (CV) disease, fracture, CKD progression, and death. This study estimated the cost-effectiveness of extended-release calcifediol (ERC) vs paricalcitol for the treatment of patients with CKD stages 3-4 that have SHPT and VDI. An economic analysis of SHPT treatments among a hypothetical cohort of 1,000 patients with CKD Stage 3 and 4 with SHPT and VDI was developed to estimate differences in the rates and costs of CV events, fractures, CKD stage progression, and mortality in patients treated with ERC and paricalcitol. A Markov model was developed with 1-year cycles and a 5-year time horizon from a US Medicare payer perspective with costs valued in 2017 US dollars. The outcomes of the model were rates of clinical events, total costs, quality-adjusted life-years (QALYs), and incremental cost-effectiveness ratio (ICER). Across a 1,000-person cohort, ERC was the dominant (less costly, more effective) treatment strategy when compared with paricalcitol. Treatment with ERC resulted in cost savings of $14.8 M (95% CI = -$10.0 M-$45.2 M) and an incremental gain of 340 QALYs (95% CI = 200-496) compared to treatment with paricalcitol. Bridging biochemical levels to clinical outcomes may not represent real-world risk of the clinical events modeled. Future real-world outcomes of patients treated with ERC and paricalcitol may be used to evaluate the model results. This model demonstrated favorable short- and long-term clinical benefits associated with the use of ERC in patients with CKD Stage 3 and 4 with SHPT and VDI, suggesting ERC may be cost-effective from the Medicare perspective compared to paricalcitol.
Topics: Aged; Aged, 80 and over; Calcifediol; Cardiovascular Diseases; Cost-Benefit Analysis; Delayed-Action Preparations; Ergocalciferols; Female; Fractures, Bone; Health Expenditures; Humans; Hyperparathyroidism, Secondary; Male; Markov Chains; Medicare; Quality-Adjusted Life Years; Renal Insufficiency, Chronic; Risk Factors; United States
PubMed: 31726882
DOI: 10.1080/13696998.2019.1693385