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Biochimica Et Biophysica Acta.... Mar 2021Although vitamin D (VD) is chemoprotective and enhances 5-fluorouracil (5-FU) cytotoxicity against colorectal cancer (CRC), little is known about its potential calcium...
Chemopreventive effects of vitamin D and its analogue, paricalcitol, in combination with 5-fluorouracil against colorectal cancer: The role of calcium signalling molecules.
BACKGROUND
Although vitamin D (VD) is chemoprotective and enhances 5-fluorouracil (5-FU) cytotoxicity against colorectal cancer (CRC), little is known about its potential calcium (Ca)-mediated anti-tumorigenic actions. Therefore, this study compared between VD and its non-calcaemic analogue, Paricalcitol (Pcal), ± 5-FU in relation to chemoprevention and Ca-mediated apoptosis in vivo and in vitro.
METHODS
Seventy male mice were distributed to: negative controls, positive controls (PC), VD, Pcal, 5-FU, VD + 5-FU and Pcal+5-FU groups. All groups, except negative, received two consecutive azoxymethane (AOM)-injections (10 mg/Kg/week) for CRC induction. VD (1000 IU/kg; three times/week) and Pcal (1.25 μg/kg; three times/week) injections started week-16 post-AOM and for 10 weeks. Three successive 5-FU cycles began at week-21 (50 mg/Kg/week). Similar protocols with VD, Pcal and/or 5-FU were applied in the HT29 colon cancer cells.
RESULTS
The PC group had abundant malignant tumours, markedly elevated proliferation markers (survivin/CCND1) and declines in cyclin-dependent kinase-inhibitor-1A, pro-apoptotic molecules (p53/BAX/cytochrome_C/caspase-3), tissue Ca concentrations and Ca-dependent proteins (CaSR/CAM/CAMKIIA). All monotherapies equally reduced tumour numbers and proliferation markers whilst promoting the anti-tumorigenic molecules. VD and/or 5-FU, but not Pcal monotherapy, enhanced Ca levels and Ca-related molecules (CaSR/CAM/CAMKIIA/BAX/cytochrome_C) in vivo and in vitro. However, VD + 5-FU co-therapy showed the lowest tumour numbers, the highest cell numbers in sub-G1 phase of cell cycle, alongside the most effective modulations of oncogenes, tumour suppressors and Ca-related molecules at the gene and protein levels in vivo and in vitro.
CONCLUSIONS
VD was superior than Paricalcitol in potentiating 5-FU cytotoxicity, possibly by upregulating several Ca-related molecules involved in tumour suppression.
Topics: Animals; Anticarcinogenic Agents; Calcium; Calcium Signaling; Cell Cycle Checkpoints; Cholecalciferol; Colorectal Neoplasms; Disease Progression; Ergocalciferols; Fluorouracil; HT29 Cells; Humans; Male; Mice; Mice, Inbred BALB C
PubMed: 33338596
DOI: 10.1016/j.bbadis.2020.166040 -
Kidney Medicine 2020Mineral and bone disorder in chronic kidney disease (CKD) is associated with progression of coronary artery calcification (CAC). Mineral and bone disorder often is...
RATIONALE & OBJECTIVE
Mineral and bone disorder in chronic kidney disease (CKD) is associated with progression of coronary artery calcification (CAC). Mineral and bone disorder often is treated with calcitriol and other vitamin D receptor activators, including paricalcitol, agents that may have differential effects on calcium, phosphate, and parathyroid hormone levels. Accordingly, we investigated whether these agents have differential effects on CAC progression in patients with CKD.
STUDY DESIGN
Randomized, double-concealed, 48-week clinical trial.
SETTING & PARTICIPANTS
CKD stage 3 or 4 with secondary hyperparathyroidism with CAC score > 0 and no prior treatment with activated vitamin D.
INTERVENTION
Calcitriol versus paricalcitol.
OUTCOMES
The primary outcome was log-transformed CAC change. Secondary outcomes included percent change in CAC volume, valvular calcifications, and bone mineral metabolism markers.
RESULTS
Among 44 individuals randomly assigned, mean age was 65 years and mean estimated glomerular filtration rate was 27 mL/min/1.73 m. Median CAC score was 140 (IQR, 55-277) Agatston units at baseline. There was no significant difference in CAC progression between treatment arms ( = 0.06). After adjustment for baseline CAC score (log), treatment group remains nonsignificant ( = 0.08). Further adjustment for creatinine level and/or CKD stage did not change the association. In secondary analyses adjusting for dose level of activated vitamin D, treatment group was significant ( = 0.01), and when dose level was also included in the model, the coefficient for individuals in the paricalcitol group was significantly associated with CAC progression ( = 0.02). An interaction term between dosing level and CKD stage was significant at the highest dosing level ( = 0.04).
LIMITATIONS
Pilot single-center study.
CONCLUSIONS
In patients with CKD with secondary hyperparathyroidism naive to activated vitamin D therapy, there was no difference in CAC or valvular progression in participants receiving calcitriol compared with paricalcitol during a 48-week period.
FUNDING
Abbvie, Inc.
TRIAL REGISTRATION
NCT00752102.
PubMed: 32775985
DOI: 10.1016/j.xkme.2020.05.009 -
International Urology and Nephrology Jul 2023Patients with end-stage renal failure (ESRD) or dialysis frequently suffer from secondary hyperparathyroidism (sHPTH), a severe complication of mineral metabolism... (Observational Study)
Observational Study
Long-term use of etelcalcetide for the treatment of secondary hyperparathyroidism in patients undergoing hemodialysis for end-stage renal failure: a real-life retrospective observational study.
BACKGROUND
Patients with end-stage renal failure (ESRD) or dialysis frequently suffer from secondary hyperparathyroidism (sHPTH), a severe complication of mineral metabolism disorders. The calcimimetic etelcalcetide has been approved and shown efficacy in randomized controlled trials, however, data are limited from real-life studies. This study aimed to evaluate the long-term use etelcalcetide for the treatment of sHPTH (PTH > 600 pg/mL) in patients undergoing extracorporeal hemodialysis for ESRD for at least 2 years.
METHODS
In 45 patients, we administered etelcalcetide for the treatment of sHPTH (PTH > 600 pg/mL); One group of patients (control group, Group A; N = 26) were previously treated with intravenous vitamin D analogues only (paricalcitol 5 µg/ml, three times/week) and then treated with etelcalcetide and a second group of patients already on cinacalcet therapy for at least six months in combination with iv paricalcitol were switched to etelcalcetide (Group B, N = 19).
RESULTS
PTH levels decreased over time in both groups of patients, with higher values for patients previously treated with cinacalcet (Group B) compared to Group A for the entire study duration even if the final value of the two groups was comparable. After 12 months, the percentage of subjects who had PTH concentrations within the targets recommended by KDIGO guidelines was 87% in Group A and 58% in Group B. In seven patients, despite a parathyroid gland volume > 1000 mm, an adequate response in the reduction of PTH was obtained.
CONCLUSION
Findings from this study demonstrate that the efficacy of etelcalcetide is maintained over the long term.
Topics: Humans; Cinacalcet; Calcimimetic Agents; Kidney Failure, Chronic; Hyperparathyroidism, Secondary; Renal Dialysis; Parathyroid Hormone; Calcium
PubMed: 36790677
DOI: 10.1007/s11255-023-03505-4 -
Scientific Reports Aug 2021Idiopathic pulmonary fibrosis (IPF) is a severe disorder leading to progressive and irreversible loss of pulmonary function. In this study we investigated the...
Idiopathic pulmonary fibrosis (IPF) is a severe disorder leading to progressive and irreversible loss of pulmonary function. In this study we investigated the anti-fibrotic effect of vitamin D using a mouse model of IPF. Lung fibrosis was induced with bleomycin in vitamin D-sufficient and vitamin D-deficient C57BL/6 mice. We found that treatment with active vitamin D analog paricalcitol prevented mouse body weight loss and alleviated lung fibrosis, whereas vitamin D deficiency severely aggravated lung injury. At the molecular level, paricalcitol treatment suppressed the induction of fibrotic inducer TGF-β and extracellular matrix proteins α-SMA, collagen type I and fibronectin in the lung, whereas vitamin D deficiency exacerbated the induction of these proteins. Interestingly, bleomycin treatment activated the local renin-angiotensin system (RAS) in the lung, manifested by the induction of renin, angiotensinogen, angiotensin II and angiotensin receptor type 1 (AT1R). Paricalcitol treatment suppressed the induction of these RAS components, whereas vitamin D deficiency enhanced the activation of the lung RAS. We also showed that treatment of bleomycin-induced vitamin D-deficient mice with AT1R antagonist losartan relieved weight loss, substantially ameliorated lung fibrosis and markedly blocked TGF-β induction in the lung. Moreover, we demonstrated that in lung fibroblast cultures, TGF-β and angiotensin II synergistically induced TGF-β, AT1R, α-SMA, collagen type I and fibronectin, whereas 1,25-dihydroxyvitamin D markedly suppressed the induction of these fibrotic markers. Collectively, these observations strongly suggest that vitamin D mitigates lung fibrosis by blocking the activation of the lung RAS in this mouse model of IPF.
Topics: Angiotensin II; Angiotensin II Type 1 Receptor Blockers; Angiotensinogen; Animals; Bleomycin; Disease Models, Animal; Ergocalciferols; Losartan; Lung; Mice; Mice, Inbred C57BL; Mice, Knockout; Pulmonary Fibrosis; Receptor, Angiotensin, Type 1; Renin; Renin-Angiotensin System; Transforming Growth Factor beta; Vitamin D
PubMed: 34400742
DOI: 10.1038/s41598-021-96152-7 -
Journal of Nippon Medical School =... 2023Oxidative stress is an important mechanism in liver ischemia/reperfusion (I/R) injury. Hepatocyte apoptosis and proliferation occur in parallel with liver I/R injury,...
BACKGROUND
Oxidative stress is an important mechanism in liver ischemia/reperfusion (I/R) injury. Hepatocyte apoptosis and proliferation occur in parallel with liver I/R injury, and the degree of apoptosis and proliferation determines the effects on hepatocytes. Vitamin D receptor (VDR) can lessen liver I/R injury, but previous studies focused mostly on inflammation and immunity.
METHODS
HO was used to induce hepatocyte injury. Before treatment with HO, Hep-3B cells were pretreated with paricalcitol (PC) and siRNA-VDR. Rapamycin and chloroquine were also applied in the study.
RESULTS
The number of apoptotic cells was measured with an annexin V (AV) -fluorescein isothiocyanate apoptosis detection kit. Expression of proteins was measured by western blotting. As compared with the HO+Hep-3B group, levels of AV/PI, cleaved caspase-3, and p62 were lower, and expression levels of Bcl-2, proliferating cell nuclear antigen, and VDR were higher, in the PC+HO+Hep-3B group. When the VDR gene was silenced by siRNA-VDR in the siRNA-VDR+HO+Hep-3B group, expressions of AV/PI, cleaved caspase-3, and p62 were upregulated, and expressions of Bcl-2, proliferating cell nuclear antigen, and VDR were downregulated, as compared with values for the siRNA-NC+HO+Hep-3B group. Treatment with rapamycin or chloroquine partially reversed the effect of PC and siRNA-VDR on apoptosis and proliferation.
CONCLUSIONS
VDR mediates hepatocyte apoptosis and proliferation through autophagy.
Topics: Humans; Apoptosis; Autophagy; Caspase 3; Cell Proliferation; Chloroquine; Hepatocytes; Hydrogen Peroxide; Proliferating Cell Nuclear Antigen; Proto-Oncogene Proteins c-bcl-2; Receptors, Calcitriol; RNA, Small Interfering; Sirolimus
PubMed: 36908130
DOI: 10.1272/jnms.JNMS.2023_90-114 -
Biochemical and Biophysical Research... Nov 2023In the present study, the possible protective effects of paricalcitol (P) were investigated in testicular damage because of 1800 MHz radiofrequency radiation (RFR)...
In the present study, the possible protective effects of paricalcitol (P) were investigated in testicular damage because of 1800 MHz radiofrequency radiation (RFR) exposure. Male Sprague Dawley rats 8-10 weeks old (n = 28) were randomly divided into four groups as control (C) (n = 7), RFR (n = 7, 1800 MHz RFR 1 h/day for 30 days), P (n = 7, 0.2 μg/kg paricalcitol, 3 times a week for 30 days), and RFR + P (n = 7, 1800 MHz RFR 1 h/day for 30 days +0.2 μg/kg paricalcitol, 3 times a week for 30 days). Testicular tissue was evaluated with histological and biochemical methods. No statistically significant differences were detected between the groups in seminiferous tubule diameters and germinal epithelial thicknesses. While ultrastructural changes were observed in the seminiferous tubule and Leydig cells in the RFR group, these changes were decreased in the RFR + P group. It was found that the Johnsen Score, Ki67, and p63 immunoreactivity scores (IRS), superoxide dismutase (SOD), and catalase (CAT) activities in the RFR + P group were statistically increased as compared to the RFR group and the malondialdehyde (MDA) levels were decreased statistically and significantly. These results show that paricalcitol administration may have an ameliorative effect on testicular damage occurring because of 1800 MHz RFR exposure.
Topics: Rats; Animals; Male; Rats, Sprague-Dawley; Antioxidants; Testis; Seminiferous Tubules; Superoxide Dismutase; Oxidative Stress
PubMed: 37717340
DOI: 10.1016/j.bbrc.2023.09.024 -
Jornal Brasileiro de Nefrologia 2023Hyperparathyroidism (SHPT) secondary to chronic kidney disease (CKD) is characterized by high levels of parathyroid hormone (PTH), hyperplasia of the parathyroid glands...
INTRODUCTION
Hyperparathyroidism (SHPT) secondary to chronic kidney disease (CKD) is characterized by high levels of parathyroid hormone (PTH), hyperplasia of the parathyroid glands and cardiovascular disease. Selective and non-selective and selective vitamin D-receptor activators, calcimimetics, are available in the Brazilian market to reduce PTH levels.
OBJECTIVES
To develop a cost-effectiveness (C/E) and budgetary impact (BI) analysis of intravenous paricalcitol vs. oral calcitriol for patients on dialysis with SHPT, from the perspective of the Brazilian Public Health Care System (SUS).
METHODOLOGY
We built a decision-tree model to analyze C/E, which considered the outcome of avoided death and a time horizon of 1 year. As for the BI analysis, two scenarios were considered, one of demand and one of epidemiological approach, based on data from the Brazilian Society of Nephrology.
RESULTS
The analysis showed that the C/E ratio was R$ 1,213.68 per year, and an incremental effectiveness of 0.032, referring to avoided death. The incremental C/E ratio was R$37,927.50 per death averted by paricalcitol. It was estimated that the incremental BI with the expansion of paricalcitol use will be between R$1,600,202.28 and R$4,128,565.65 in the first year, considering the main and epidemiological scenarios. At the end of 5 years after the expansion of its use, an incremental BI was estimated between R$ 48,596,855.50 and R$ 62,90,555.73.
CONCLUSION
Intravenous paricalcitol has superior efficacy and similar safety to oral calcitriol, reducing the overall mortality of dialysis patients, although it implies a higher cost.
Topics: Humans; Calcitriol; Cost-Benefit Analysis; Cost-Effectiveness Analysis; Hyperparathyroidism, Secondary; Parathyroid Hormone; Renal Dialysis; Renal Insufficiency, Chronic; Ergocalciferols
PubMed: 35980102
DOI: 10.1590/2175-8239-JBN-2022-0049en -
Biochimica Et Biophysica Acta.... Feb 2023Accumulating evidences suggest that the epigenetic regulation plays a pivotal role in establishing phenotype and function of tumor associated macrophages (TAMs). KDM6B...
Accumulating evidences suggest that the epigenetic regulation plays a pivotal role in establishing phenotype and function of tumor associated macrophages (TAMs). KDM6B is an epigenetic enzyme responsible for the H3K27me3 and reported to influence macrophage polarization. However, the underlying mechanism remains to be determined. Here, we demonstrated that inhibition of KDM6B in TAMs increased M2 polarization induced by coculture of breast cancer cells. Furthermore, we identified that KDM6B downregulation activated β-catenin/c-Myc signaling, and thus promoted the M2-like phenotype. KDM6B accelerated the intranuclear ubiquitination degradation of β-catenin, which depended on its demethylase activity. Therapeutically, our data showed that activated vitamin D analog paricalcitol upregulated the expression of KDM6B and decreased the M2 polarization, consequently protected against tumor progress in the xenograft mouse model of breast cancer. Taken together, our data reveal that epigenetic regulator KDM6B prevents M2 polarization via promoting the intranuclear degradation of β-catenin. Active vitamin D analog induces KDM6B and suppresses tumor progress, suggesting a novel therapeutic potential of epigenetic modulation for the tumor treatment.
Topics: Animals; Humans; Mice; beta Catenin; Cell Line, Tumor; Epigenesis, Genetic; Jumonji Domain-Containing Histone Demethylases; Macrophages; Proto-Oncogene Proteins c-myc; Signal Transduction; Breast Neoplasms
PubMed: 36427698
DOI: 10.1016/j.bbadis.2022.166611 -
Journal of the American Society of... Sep 2020CKD leads to vitamin D deficiency. Treatment with vitamin D receptor agonists (VDRAs) may have nephroprotective and anti-inflammatory actions, but their mechanisms of...
BACKGROUND
CKD leads to vitamin D deficiency. Treatment with vitamin D receptor agonists (VDRAs) may have nephroprotective and anti-inflammatory actions, but their mechanisms of action are poorly understood.
METHODS
Modulation of the noncanonical NF-B2 pathway and its component TNF receptor-associated factor 3 (TRAF3) by the VDRA paricalcitol was studied in PBMCs from patients with ESKD, cytokine-stimulated cells, and preclinical kidney injury models.
RESULTS
In PBMCs isolated from patients with ESKD, TRAF3 protein levels were lower than in healthy controls. This finding was associated with evidence of noncanonical NF-B2 activation and a proinflammatory state. However, PBMCs from patients with ESKD treated with paricalcitol did not exhibit these features. Experiments in cultured cells confirmed the link between TRAF3 and NF-B2/inflammation. Decreased TRAF3 ubiquitination in K48-linked chains and cIAP1-TRAF3 interaction mediated the mechanisms of paricalcitol action.TRAF3 overexpression by CRISPR/Cas9 technology mimicked VDRA's effects. In a preclinical model of kidney injury, paricalcitol inhibited renal NF-B2 activation and decreased renal inflammation. In VDR knockout mice with renal injury, paricalcitol prevented TRAF3 downregulation and NF-B2-dependent gene upregulation, suggesting a VDR-independent anti-inflammatory effect of paricalcitol.
CONCLUSIONS
These data suggest the anti-inflammatory actions of paricalcitol depend on TRAF3 modulation and subsequent inhibition of the noncanonical NF-B2 pathway, identifying a novel mechanism for VDRA's effects. Circulating TRAF3 levels could be a biomarker of renal damage associated with the inflammatory state.
Topics: Animals; Anti-Inflammatory Agents; Cells, Cultured; Cytokine TWEAK; Ergocalciferols; Female; Humans; Kidney Failure, Chronic; Male; Mice; Mice, Inbred C57BL; NF-kappa B; Receptors, Calcitriol; Signal Transduction; TNF Receptor-Associated Factor 3
PubMed: 32631974
DOI: 10.1681/ASN.2019111206 -
World Journal of Diabetes Sep 2023Diabetic nephropathy (DN) is frequently seen in the development of diabetes mellitus, and its pathogenic factors are complicated. Its current treatment is controversial,...
BACKGROUND
Diabetic nephropathy (DN) is frequently seen in the development of diabetes mellitus, and its pathogenic factors are complicated. Its current treatment is controversial, and there is a lack of a relevant efficacy prediction model.
AIM
To determine the effects of paricalcitol combined with hemodiafiltration on bone-metabolism-related indexes in patients with DN and chronic renal failure (CRF), and to construct an efficacy prediction model.
METHODS
We retrospectively analyzed 422 patients with DN and CRF treated in Cangzhou Central Hospital between May 2020 and May 2022. We selected 94 patients who met the inclusion and exclusion criteria. Patients were assigned to a dialysis group ( = 45) and a joint group ( = 49) in relation to therapeutic regimen. The clinical efficacy of the two groups was compared after treatment. The changes in laboratory indexes after treatment were evaluated, and the two groups were compared for the incidence of adverse reactions. The predictive value of laboratory indexes on the clinical efficacy on patients was analyzed.
RESULTS
The dialysis group showed a notably worse improvement in clinical efficacy than the joint group ( = 0.017). After treatment, the joint group showed notably lower serum levels of serum creatinine, uric acid (UA) and blood urea nitrogen (BUN) than the dialysis group ( < 0.05). After treatment, the joint group had lower serum levels of phosphorus, procollagen type I amino-terminal propeptide (PINP) and intact parathyroid hormone than the dialysis group, but a higher calcium level ( < 0.001). Both groups had a similar incidence of adverse reactions ( > 0.05). According to least absolute shrinkage and selection operator regression analysis, UA, BUN, phosphorus and PINP were related to treatment efficacy. According to further comparison, the non-improvement group had higher risk scores than the improvement group ( < 0.0001), and the area under the curve of the risk score in efficacy prediction was 0.945.
CONCLUSION
For treatment of CRF and DN, combined paricalcitol and hemodiafiltration can deliver higher clinical efficacy and improve the bone metabolism of patients, with good safety.
PubMed: 37771325
DOI: 10.4239/wjd.v14.i9.1385