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Nutrition, Metabolism, and... Jan 2024The effect of increased vitamin D levels on vascular function in patients with chronic kidney disease (CKD) is controversial. This meta-analysis aimed to assess the... (Meta-Analysis)
Meta-Analysis
AIM
The effect of increased vitamin D levels on vascular function in patients with chronic kidney disease (CKD) is controversial. This meta-analysis aimed to assess the effect of regulated vitamin D increase on vascular markers in patients with CKD.
DATA SYNTHESIS
We searched PubMed, Web of Science, Embase and ClinicalTrials.gov from database inception up until July 21, 2023. We included randomized controlled trials assessing the effects of using vitamin D and its analogues on vascular function in patients with CKD. Fixed-effects and random-effects model analyses were performed using weighted mean difference effects for each trial by heterogeneity (I2) assessment. Primary outcomes encompassed blood flow-mediated dilation (FMD)、pulse wave velocity (PWV) and augmentation index (AIx).
FINDINGS
From 1964 records we selected 12 trials, 5 (n = 331) on FMD, 8 (n = 626) on PWV and 4 (n = 393) on AIx. Vitamin D and VDRA supplementation failed to significantly improve FMD (WMD 1.68%; 95% CI -0.18 to 3.53; P = 0.08; I = 88%)、PWV (WMD -0.41 m/s; 95%CI -0.95 to 0.13; P = 0.14; I = 57%)and AIx (WMD -0.53%; 95%CI -1.69 to 0.63; P = 0.37; I = 0%). Subgroup analysis revealed that 2 μg paricalcitol significantly improved FMD (WMD 2.09%; 95%CI 1.28 to 2.90; P < 0.00001); I = 0%), as did cholecalciferol (WMD 5.49%; 95% CI 4.35 to 6.63; P < 0.00001).
CONCLUSION
Supplementation vitamin D and VDRA are associated with improved vascular function as measured by FMD, but not arterial stiffness as measured by PWV and AIx, tentatively suggesting that regulating the increase of vitamin D could not potentially reduce the incidence of cardiovascular disease.
Topics: Humans; Vitamin D; Pulse Wave Analysis; Randomized Controlled Trials as Topic; Vitamins; Vascular Stiffness; Renal Insufficiency, Chronic
PubMed: 38000993
DOI: 10.1016/j.numecd.2023.09.015 -
Naunyn-Schmiedeberg's Archives of... Jun 2024Glomerulosclerosis and tubulointerstitial fibrosis (TIF) are closely involved in the development of diabetic nephropathy (DN). Moreover, the development of TIF is...
Glomerulosclerosis and tubulointerstitial fibrosis (TIF) are closely involved in the development of diabetic nephropathy (DN). Moreover, the development of TIF is closely related to epithelial-to-mesenchymal transition (EMT). Tanshinone IIA (Tan) has various pharmacological effects, especially the anti-fibrotic effect. And it is mainly used in the clinical treatment of cardiovascular diseases. Currently, the protective effect of Tan on DN and its possible mechanism have not been clearly elucidated. Our previous studies illustrated that Tan could improve the EMT of HK-2 cells induced by high glucose by regulating the vitamin D receptor (VDR)/Wnt/β-catenin pathway. Here, we collected demographic information and laboratory results from the National Health and Nutrition Examination Survey (NHANES) database in order to investigate the relationship between VD and DN. Then, we established a DN model and treated DN rats with Tan and paricalcitol (Par) for 6 weeks. We subsequently compared the changes in general condition, renal function, pathological changes, and TIF-related protein expression levels of control rats, DN rats induced by STZ, DN rats with Tan at 5.4 mg/kg, DN rats with Tan at 10.8 mg/kg, and DN rats with Par at 0.054 µg/kg, to explore the effect and mechanism of Tan and Par on DN rats. The results showed that VD had a protective effect against DN in diabetic patients. And we found that Tan had a protective effect on renal fibrosis in DN rats, which was superior to Par in improving the symptoms of "three more and one less," reducing fasting blood glucose level, improving renal index, BUN/SCr, and UACR, reducing histopathological damage of kidney, and improving the expression of fibrosis-related proteins in kidney tissue by regulating VDR/Wnt/β-catenin pathway. Tan was superior to Par in ameliorating tubulointerstitial fibrosis by regulating VDR/Wnt/β-catenin pathway in rats with diabetic nephropathy.
Topics: Animals; Diabetic Nephropathies; Receptors, Calcitriol; Abietanes; Wnt Signaling Pathway; Male; Fibrosis; Ergocalciferols; Rats, Sprague-Dawley; Diabetes Mellitus, Experimental; Rats; Kidney; beta Catenin
PubMed: 37991543
DOI: 10.1007/s00210-023-02853-3 -
The Chinese Journal of Physiology 2023Acute cardiomyopathy is a significant global health concern and one of the leading causes of death in developed countries. Prior studies have shown an association...
Paricalcitol improved cardiac hypertrophy and fibrosis through upregulation of fibroblast growth factor-23 and downregulation of transforming growth factor-beta in a rat model of isoproterenol-induced cardiomyopathy.
Acute cardiomyopathy is a significant global health concern and one of the leading causes of death in developed countries. Prior studies have shown an association between acute cardiomyopathy and low vitamin D levels. Although paricalcitol, a vitamin D receptor (VDR) activator, has demonstrated clinical benefits in patients with advanced kidney disease, its effect on cardiac remodeling in cardiomyopathy is unknown. This study aimed to investigate the relative effects of paricalcitol on cardiomyopathy in rats. Wistar-Kyoto rats were administered vehicle (sham control group) or isoproterenol to induce cardiomyopathy. Rats administered isoproterenol were subsequently treated with paricalcitol (experimental group) or vehicle (isoproterenol group). Picrosirius red and immunofluorescence staining were used to analyze cardiac fibrosis and hypertrophy. Immunohistochemistry staining was used to confirm the molecular mechanisms involved in isoproterenol-induced cardiomyopathy in rats. Injection of paricalcitol could reduce collagen and transforming growth factor-beta 1 (TGF-β1) levels while activating fibroblast growth factor receptor 1 (FGFR1) and fibroblast growth factor-23 (FGF23) without the help of Klotho, thereby reducing myocardial hypertrophy and fibrosis. As a VDR activator, paricalcitol reduces isoproterenol-induced cardiac fibrosis and hypertrophy by reducing the expression of TGF-β1 and enhancing the expression of VDR, FGFR1, and FGF23.
Topics: Humans; Rats; Animals; Transforming Growth Factor beta1; Up-Regulation; Isoproterenol; Transforming Growth Factor beta; Down-Regulation; Fibroblast Growth Factor-23; Rats, Inbred WKY; Cardiomyopathies; Cardiomegaly; Fibrosis; Transforming Growth Factors
PubMed: 37929341
DOI: 10.4103/cjop.CJOP-D-23-00048 -
Frontiers in Molecular Biosciences 2023The severe acute respiratory syndrome coronavirus 2 (SARS-COV-2) has posed a significant challenge to individuals' health. Increasing evidence shows that patients with...
The severe acute respiratory syndrome coronavirus 2 (SARS-COV-2) has posed a significant challenge to individuals' health. Increasing evidence shows that patients with metabolic unhealthy obesity (MUO) and COVID-19 have severer complications and higher mortality rate. However, the molecular mechanisms underlying the association between MUO and COVID-19 are poorly understood. We sought to reveal the relationship between MUO and COVID-19 using bioinformatics and systems biology analysis approaches. Here, two datasets (GSE196822 and GSE152991) were employed to extract differentially expressed genes (DEGs) to identify common hub genes, shared pathways, transcriptional regulatory networks, gene-disease relationship and candidate drugs. Based on the identified 65 common DEGs, the complement-related pathways and neutrophil degranulation-related functions are found to be mainly affected. The hub genes, which included SPI1, CD163, C1QB, SIGLEC1, C1QA, ITGAM, CD14, FCGR1A, VSIG4 and C1QC, were identified. From the interaction network analysis, 65 transcription factors (TFs) were found to be the regulatory signals. Some infections, inflammation and liver diseases were found to be most coordinated with the hub genes. Importantly, Paricalcitol, 3,3',4,4',5-Pentachlorobiphenyl, PD 98059, Medroxyprogesterone acetate, Dexamethasone and Tretinoin HL60 UP have shown possibility as therapeutic agents against COVID-19 and MUO. This study provides new clues and references to treat both COVID-19 and MUO.
PubMed: 37877121
DOI: 10.3389/fmolb.2023.1274463 -
Clinical Cancer Research : An Official... Dec 2023Vitamin D analogues remodel the desmoplastic stroma, and improve vascularity and efficacy of chemotherapy in preclinical pancreas cancer models.
PURPOSE
Vitamin D analogues remodel the desmoplastic stroma, and improve vascularity and efficacy of chemotherapy in preclinical pancreas cancer models.
PATIENTS AND METHODS
We conducted a pilot study to evaluate the safety and preliminary efficacy of the vitamin D analogue paricalcitol in combination with nanoliposomal irinotecan (Nal-iri) plus 5-fluorouracil/leucovorin (5-FU/LV) in patients with advanced pancreatic cancer who had progressed on gemcitabine-based therapy. Two dose levels (DL) of paricalcitol were tested: fixed dose weekly (75 mcg, DL1) and weight-based weekly (7 mcg/kg, /DL2). The primary endpoint was safety, and secondary endpoints included overall response rate, progression-free survival (PFS), and overall survival (OS). Correlative objectives aimed to identify molecular predictors of response and alterations in the tumor stroma.
RESULTS
Twenty patients (10 each in DL1 and DL2) enrolled between March 2019 and May 2021. No grade 3/4 adverse events related to paricalcitol were observed. The most common toxicities were nausea, diarrhea and fatigue, which were similar in both cohorts. Three patients discontinued study after one cycle and were not radiographically evaluable. Of the remaining 17 evaluable patients, 2 had partial response and 12 had stable disease. The median PFS for response-evaluable patients in DL1 was 4.14 months, for DL2 was 4.83 months. Intent-to-treat median OS was 6.15 and 6.66 months for DL1 and DL2, respectively. Correlative studies showed increased tumor vascularity in posttreatment samples in patients receiving the higher dose of paricalcitol (DL2).
CONCLUSIONS
Paricalcitol at 7 mcg/kg/week in combination with Nal-iri/ 5-FU/LV is safely tolerated, may increase tumor vascularity and warrants further investigation.
Topics: Humans; Irinotecan; Gemcitabine; Pilot Projects; Fluorouracil; Liposomes; Pancreatic Neoplasms; Ergocalciferols; Antineoplastic Combined Chemotherapy Protocols; Leucovorin
PubMed: 37801295
DOI: 10.1158/1078-0432.CCR-23-1405 -
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 -
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 -
Scientific Reports Jul 2023To investigate the effects and mechanism of Vitamin D receptor (VDR) signaling on arteriovenous fistula (AVF) endothelial cell injury. Venous tissues of AVF stenosis...
To investigate the effects and mechanism of Vitamin D receptor (VDR) signaling on arteriovenous fistula (AVF) endothelial cell injury. Venous tissues of AVF stenosis patients were collected and analyzed, vascular morphology, reactive oxygen species (ROS), and the expression of VDR, P66Shc, fibronectin (FN), collagen-1 (Col-1) were detected. In addition, human umbilical vein endothelial cells (HUVECs) was used in in vitro studies. HUVECs was incubated with transforming growth factor-beta (TGF-β, 50 ng/ml). Aditionally, paricalcitol, VDR overexpression plasmid and Pin1 inhibitor Juglone were used to investigate the regulatory mechanism of VDR in mitochondrial ROS. The parameters of ROS (e.g. MitoSox) and the expression of FN, Col-1 were tested. Moreover, the mitochondrial translocation of P66Shc was analyzed. The expression of VDR was obviously decreased in the venous tissues of AVF stenosis patients. On the contrary, the expression of P66Shc, P-P66Shc, FN, Col-1 and 8-OHdG were increased significantly in the venous tissues of AVF stenosis patients (P < 0.05). In line with this, the level of mitochondrial ROS and the expression of P66Shc, P-P66Shc, FN, Col-1 increased obviously in HUVECs cells under TGF-β condition. Both VDR over-expression plasmid and Pin1 inhibitor Juglone could alleviate TGF-β induced endothelial injury. Mechanistically, VDR overexpression plasmid and Juglone could inhibit the expression of Pin1, and then restrain P66Shc mitochondrial translocation, eventually reduce the level of mitochondrial ROS. Our research indicated that activation of VDR could alleviate venous endothelial cell dysfunction through inhibiting Pin1-mediated mitochondrial translocation of P66Shc and consequently reducing mitochondrial ROS. It suggested that VDR signaling might be an effective target for AVF stenosis treatment.
Topics: Humans; Reactive Oxygen Species; Src Homology 2 Domain-Containing, Transforming Protein 1; Constriction, Pathologic; Human Umbilical Vein Endothelial Cells; Arteriovenous Fistula; Receptors, Calcitriol
PubMed: 37422508
DOI: 10.1038/s41598-023-37510-5 -
The Journal of Clinical Endocrinology... Oct 2023Secondary hyperparathyroidism (SHPT) is a complication of chronic kidney disease (CKD) affecting mineral and bone metabolism and characterized by excessive parathyroid... (Meta-Analysis)
Meta-Analysis
CONTEXT
Secondary hyperparathyroidism (SHPT) is a complication of chronic kidney disease (CKD) affecting mineral and bone metabolism and characterized by excessive parathyroid hormone (PTH) production and parathyroid hyperplasia.
OBJECTIVE
The objective of this analysis was to compare the efficacy and adverse effects of extended-release calcifediol (ERC) and paricalcitol (PCT) by assessing their effect on the biomarkers PTH, calcium, and phosphate in patients with non-dialysis CKD (ND-CKD).
METHODS
A systematic literature research was performed in PubMed to identify randomized control trials (RCTs). Quality assessment was done with the GRADE method. The effects of ERC vs PCT were compared using random effects in a frequentist setting.
RESULTS
Nine RCTs comprising 1426 patients were included in the analyses. The analyses were performed on 2 overlapping networks, due to nonreporting of outcomes in some of the included studies. No head-to-head trials were identified. No statistically significant differences in PTH reduction were found between PCT and ERC. Treatment with PCT showed statistically significant increases in calcium compared with ERC (0.2 mg/dL increase; 95% CI, -0.37 to -0.05 mg/dL). No differences in effects on phosphate were observed.
CONCLUSION
This network meta-analysis showed that ERC is comparable in lowering PTH levels vs PCT. ERC displayed avoidance of potentially clinically relevant increases in serum calcium, offering an effective and well-tolerated treatment option for the management of SHPT in patients with ND-CKD.
Topics: Humans; Calcifediol; Calcium; Ergocalciferols; Hyperparathyroidism, Secondary; Network Meta-Analysis; Parathyroid Hormone; Phosphates; Renal Insufficiency, Chronic; Randomized Controlled Trials as Topic
PubMed: 37235771
DOI: 10.1210/clinem/dgad289