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Cell Death Discovery May 2023Activating transcription factor 4 (ATF4) is one of the key effectors of endoplasmic reticulum stress (ERS), ATF4/CHOP pathway-mediated ERS plays an important role in the...
Activating transcription factor 4 (ATF4) is one of the key effectors of endoplasmic reticulum stress (ERS), ATF4/CHOP pathway-mediated ERS plays an important role in the progression of acute kidney disease (AKI). We have previously reported that Vitamin D receptor (VDR) exert renoprotection in rodent AKI models. However, whether ATF4, as well as ERS, is involved in the protective effect of VDR in ischemia-reperfusion (I/R) induced AKI is unknown. Herein, we showed that VDR agonist paricalcitol and VDR overexpression alleviated I/R-induced renal injury and cells apoptosis with decreased ATF4 and attenuated ERS, while VDR deletion significantly resulted in further increased ATF4, more drastic ERS and renal injury in I/R mice models. In addition, paricalcitol remarkably reduced Tunicamycin (TM) induced ATF4 and ERS with attenuated renal injury, while VDR deletion aggravated the above changes in TM mice models. Moreover, overexpression of ATF4 partially abolished the effect of paricalcitol against TM-induced ERS and apoptosis, while inhibition of ATF4 enhanced the protective effect of paricalcitol. Bioinformatics analysis indicated potential VDR binding sites on ATF4 promotor sequence which were further confirmed by ChIP-qPCR and dual-luciferase reporter gene assay. In conclusion, VDR attenuated I/R-induced AKI by suppressing ERS partly via transcriptional regulation of ATF4.
PubMed: 37173347
DOI: 10.1038/s41420-023-01456-4 -
Digestive Diseases and Sciences Jul 2023Pancreatic ductal adenocarcinoma (PDA) has a poor prognosis due to its therapeutic resistance. Inactivation of vitamin D/vitamin D receptor (VDR) signaling may...
BACKGROUND
Pancreatic ductal adenocarcinoma (PDA) has a poor prognosis due to its therapeutic resistance. Inactivation of vitamin D/vitamin D receptor (VDR) signaling may contribute to the malignant phenotype of PDA and altered expression of oncoprotein mucin 1 (MUC1) may be involved in drug resistance of cancer cells.
AIM
To determine whether vitamin D/VDR signaling regulates the expression and function of MUC1 and its effect on acquired gemcitabine resistance of pancreatic cancer cells.
METHODS
Molecular analyses and animal models were used to determine the impact of vitamin D/VDR signaling on MUC1 expression and response to gemcitabine treatment.
RESULTS
RPPA analysis indicated that MUC1 protein expression was significantly reduced in human PDA cells after treatment with vitamin D3 or its analog calcipotriol. VDR regulated MUC1 expression in both gain- and loss-of-function assays. Vitamin D3 or calcipotriol significantly induced VDR and inhibited MUC1 expression in acquired gemcitabine-resistant PDA cells and sensitized the resistant cells to gemcitabine treatment, while siRNA inhibition of MUC1 was associated with paricalcitol-associated sensitization of PDA cells to gemcitabine treatment in vitro. Administration of paricalcitol significantly enhanced the therapeutic efficacy of gemcitabine in xenograft and orthotopic mouse models and increased the intratumoral concentration of dFdCTP, the active metabolite of gemcitabine.
CONCLUSION
These findings demonstrate a previously unidentified vitamin D/VDR-MUC1 signaling axis involved in the regulation of gemcitabine resistance in PDA and suggests that combinational therapies that include targeted activation of vitamin D/VDR signaling may improve the outcomes of patients with PDA.
Topics: Animals; Mice; Humans; Gemcitabine; Mucin-1; Pancreatic Neoplasms; Carcinoma, Pancreatic Ductal; Receptors, Calcitriol; Cell Line, Tumor
PubMed: 37071246
DOI: 10.1007/s10620-023-07931-3 -
Kidney & Blood Pressure Research 2023Restoration of podocyte autophagy is considered as a feasible strategy for the treatment of diabetic kidney disease (DKD). This study aimed at investigating the...
INTRODUCTION
Restoration of podocyte autophagy is considered as a feasible strategy for the treatment of diabetic kidney disease (DKD). This study aimed at investigating the protective effect and potential mechanism of vitamin D on podocyte injury of DKD.
METHODS
Type 2 diabetic db/db mice received intraperitoneal injections of vitamin D analog paricalcitol 400 ng/kg per day for 16 weeks. Immortalized mouse podocytes were cultured in high glucose (HG) medium with active vitamin D3 calcitriol or autophagy inhibitor 3-methyladenine. Renal function and urine albumin creatinine ratio were assessed at week 24. HE, PAS staining, and electron microscopy were used to evaluate renal histopathology and morphological changes. Immunohistochemistry, immunofluorescence, and Western blot were used to evaluate protein expression of nephrin and podocin in kidney tissue and podocytes. The expression of autophagy-related proteins (LC3, Beclin-1, Vps34) and apoptosis-related proteins (cleaved caspase-3, Bax) was determined by Western blotting. Podocyte apoptosis was further evaluated by using flow cytometer.
RESULTS
Albuminuria in a db/db mouse model was markedly attenuated after treatment with paricalcitol. This was accompanied by alleviation of mesangial matrix expansion and podocyte injury. Besides, the impaired autophagy in podocytes under diabetic conditions was also markedly enhanced after paricalcitol or calcitriol treatment, accompanied by restored decreased podocyte slit diaphragm proteins podocin and nephrin. Furthermore, the protective effect of calcitriol against HG-induced podocyte apoptosis could be abated by autophagy inhibitor 3-methyladenine.
CONCLUSION
Vitamin D ameliorates podocyte injury of DKD by enhancing podocyte autophagy activity, which may become a potential candidate autophagy activator for the therapeutic interventions for DKD.
Topics: Mice; Animals; Diabetic Nephropathies; Podocytes; Vitamin D; Calcitriol; Diabetes Mellitus, Experimental; Vitamins; Autophagy
PubMed: 37054686
DOI: 10.1159/000530403 -
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 -
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 -
Frontiers in Physiology 2023Our previous study showed that vitamin D (VD)-vitamin D receptor () plays a nephroprotective role in lipopolysaccharide (LPS)-induced acute kidney injury (AKI)....
Our previous study showed that vitamin D (VD)-vitamin D receptor () plays a nephroprotective role in lipopolysaccharide (LPS)-induced acute kidney injury (AKI). Recently, glucose metabolism reprogramming was reported to be involved in the pathogenesis of AKI. To investigate the role of VD- in glucose metabolism reprogramming in LPS-induced AKI. We established a model of LPS-induced AKI in knockout (-KO) mice, renal proximal tubular-specific -overexpressing (-OE) mice and wild-type C57BL/6 mice. , human proximal tubular epithelial cells (HK-2 cells), knockout and overexpression HK-2 cell lines were used. Paricalcitol (an active vitamin D analog) or -OE reduced lactate concentration, hexokinase activity and PDHA1 phosphorylation (a key step in inhibiting aerobic oxidation) and simultaneously ameliorated renal inflammation, apoptosis and kidney injury in LPS-induced AKI mice, which were more severe in -KO mice. In experiments, glucose metabolism reprogramming, inflammation and apoptosis induced by LPS were alleviated by treatment with paricalcitol or dichloroacetate (DCA, an inhibitor of p-). Moreover, paricalcitol activated the phosphorylation of -activated protein kinase (), and an inhibitor partially abolished the protective effect of paricalcitol in LPS-treated HK-2 cells. VD- alleviated LPS-induced metabolic reprogramming in the kidneys of AKI mice, which may be attributed to the inactivation of phosphorylation the pathway.
PubMed: 36909229
DOI: 10.3389/fphys.2023.1083643 -
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 -
Giornale Italiano Di Nefrologia :... Feb 2023Secondary hyperparathyroidism (SHPT) is a common and major complication of chronic kidney disease (CKD) among patients on dialysis and in patients with CKD stage G3 to... (Meta-Analysis)
Meta-Analysis
Secondary hyperparathyroidism (SHPT) is a common and major complication of chronic kidney disease (CKD) among patients on dialysis and in patients with CKD stage G3 to G5. SHPT in CKD is caused by disturbances in metabolic parameters. Paricalcitol (PCT), other active vitamin D analogous (doxercalciferol and alfacalcidol), and active vitamin D (calcitriol) have been commonly used to treat SHPT in non-dialysis CKD (ND-CKD) for several years. However, recent studies indicate that these therapies adversely increase serum calcium, phosphate, and fibroblast growth factor 23 (FGF-23) levels. Extended release calcifediol (ERC) has been developed as an alternative treatment for SHPT in ND-CKD. The present meta-analysis compares the effect of ERC against PCT in the control of PTH and calcium levels. A systematic literature review was conducted, according to Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guidelines to identify studies for inclusion in the Network Meta-Analysis (NMA). 18 publications were eligible for inclusion in the network meta-analysis and 9 articles were included in the final NMA. The estimated PTH reduction from PCT (-59.5 pg/ml) was larger than the PTH reduction from ERC (-45.3 pg/ml), but the difference in treatment effects did not show statistical significance. Treatment with PCT caused statistically significant increases in calcium vs. placebo (increase: 0.31 mg/dl), while the marginal increase in calcium from treatment with ERC (increase: 0.10 mg/dl) did not reach statistical significance. The evidence suggests that both PCT and ERC are effective in reducing levels of PTH, whereas calcium levels tended to increase from treatment with PCT. Therefore, ERC may be an equally effective, but more tolerable treatment alternative to PCT.
Topics: Humans; Calcifediol; Calcium; Network Meta-Analysis; Vitamin D; Hyperparathyroidism, Secondary; Renal Insufficiency, Chronic; Parathyroid Hormone
PubMed: 36883925
DOI: No ID Found -
Cancers Feb 2023Numerous clinical studies have been conducted to improve the outcomes of patients suffering from pancreatic cancer. Different approaches using targeted therapeutic... (Review)
Review
Numerous clinical studies have been conducted to improve the outcomes of patients suffering from pancreatic cancer. Different approaches using targeted therapeutic strategies and precision medicine methods have been investigated, and synergies and further therapeutic advances may be achieved through combinations with integrative methods. For pancreatic tumors, a particular challenge is the presence of a microenvironment and a dense stroma, which is both a physical barrier to drug penetration and a complex entity being controlled by the immune system. Therefore, the state of immunological tolerance in the tumor microenvironment must be overcome, which is a considerable challenge. Integrative approaches, such as hyperthermia, percutaneous irreversible electroporation, intra-tumoral injections, phytotherapeutics, or vitamins, in combination with standard-oncological therapies, may potentially contribute to the control of pancreatic cancer. The combined application of standard-oncological and integrative methods is currently being studied in ongoing clinical trials. An actual overview is given here.
PubMed: 36831465
DOI: 10.3390/cancers15041116 -
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