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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 -
Annals of Palliative Medicine Oct 2021This study aimed to assimilate relevant domestic Chinese and international literature to describe and review the progress of research on the pharmacological actions of... (Review)
Review
OBJECTIVE
This study aimed to assimilate relevant domestic Chinese and international literature to describe and review the progress of research on the pharmacological actions of the multiple clinical effects and selectivity of the vitamin D (VD) analogue paricalcitol in multiple organs of the body.
BACKGROUND
Paricalcitol was the first VD analogue proven to be effective in the treatment of SHPT. With the discovery of vitamin D receptor (VDR) expression in different tissues and the disclosure of the corresponding physiological role, a large number of studies have shown that paricalcitol has a certain effect not only on SHPT, but also on other diseases such as kidney disease, cardiovascular disease, immune inflammatory response, and tumors.
METHODS
By referring to the relevant literature on vitamin D and its analogues at home and abroad from 1999 to 2020, the pharmacological characteristics of the pleiotropic and selective effects of paricalcitol were reviewed. PS software was used to map the molecular mechanism of paricalcitol in kidney, cardiovascular, bone metabolism, immune inflammation, and anti-tumor.
CONCLUSIONS
The novel VD analogue, paricalcitol, with its high selectivity for binding to VDR in vivo, maintains the efficacy of traditional VD drugs (targeting PTH and calcium and phosphorus metabolism) while providing additional benefits (reduction of urinary protein, reduction of inflammation, reduction of vascular calcification and renal fibrosis, and so on), thus expanding the application scope of future clinical practice.
Topics: Ergocalciferols; Humans; Vitamin D
PubMed: 34763476
DOI: 10.21037/apm-21-2249 -
Experimental Biology and Medicine... Jan 2023The vascular endothelium is one of the main targets of oxidative stress which plays an important role in the pathophysiology of vascular damage. Recent studies show that...
The vascular endothelium is one of the main targets of oxidative stress which plays an important role in the pathophysiology of vascular damage. Recent studies show that vitamin D can positively regulate endothelial functions in various chronic diseases and in cases of increased oxidative stress. In our study, we investigated the restorative and protective potentials of paricalcitol which is frequently used in patients with chronic renal failure, a vitamin D analogue, in human umbilical vein endothelial cells (HUVEC) before and after HO-induced oxidative stress. Paricalcitol treatment after the oxidative stress induced by HO increased cell viability in endothelial cells depending on the dose that was used. While paricalcitol (500 nM) decreased caspase-3 activity and mitochondrial membrane potential loss, it increased nitric oxide (NO) production and reduced glutathione (GSH) levels. Paricalcitol treatment before oxidative stress increased cell viability. It increased NO production and mitochondrial membrane potential while significantly reducing caspase-3 activity. While paricalcitol caused a significant inhibition of protein disulfide isomerase (PDI) reductase activity in healthy endothelial cells, it did not cause a significant change on the PDI reductase activity under oxidative stress conditions. Present study showed that paricalcitol has restorative and protective effects on endothelial cells against oxidative injury, but these effects occur at high concentrations of paricalcitol.
Topics: Humans; Hydrogen Peroxide; Caspase 3; Apoptosis; Human Umbilical Vein Endothelial Cells; Oxidative Stress; Ergocalciferols; Nitric Oxide; Oxidoreductases; Reactive Oxygen Species
PubMed: 36373746
DOI: 10.1177/15353702221101615 -
Journal of Cellular and Molecular... Oct 2017Renal podocytes form the main filtration barrier possessing unique phenotype maintained by proteins including podocalyxin and nephrin, which are modulated in...
Renal podocytes form the main filtration barrier possessing unique phenotype maintained by proteins including podocalyxin and nephrin, which are modulated in pathological conditions. In diabetic nephropathy (DN), podocytes become structurally and functionally compromised. Nephrin, a structural backbone protein of the slit diaphragm, acts as regulator of podocyte intracellular signalling with renoprotective role. Vitamin D through its receptor, VDR, provides renal protection in DN but limited data exist about its effect on podocytes. In this study, we used isolated rat glomeruli to assess podocalyxin and nephrin expression after treatment with the 1,25-dihydroxyvitamin D analogue paricalcitol in the presence of normal and diabetic glucose levels. The role of 1,25-dihydroxyvitamin D (calcitriol) and its analogue, paricalcitol, on podocyte morphology and survival was also investigated in the streptozotocin (STZ)-diabetic animal model. In our ex vivo model, glomeruli exhibited high glucose-mediated down-regulation of podocalyxin, and nephrin, while paricalcitol reversed the high glucose-induced decrease of nephrin and podocalyxin expression. Paricalcitol treatment enhanced VDR expression and promoted VDR and RXR co-localization in the nucleus. Our data also indicated that hyperglycaemia impaired survival of cultured glomeruli and suggested that the implemented nephrin down-regulation was reversed by paricalcitol treatment, initiating Akt signal transduction which may be involved in glomerular survival. Our findings were further verified in vivo, as in the STZ-diabetic animal model, calcitriol and paricalcitol treatment resulted in significant amelioration of hyperglycaemia and restoration of nephrin signalling, suggesting that calcitriol and paricalcitol may provide molecular bases for protection against loss of the permselective renal barrier in DN.
Topics: Animals; Bone Density Conservation Agents; Cell Survival; Cholecalciferol; Diabetes Mellitus, Experimental; Diabetic Nephropathies; Ergocalciferols; Glucose; Kidney Glomerulus; Membrane Proteins; Podocytes; Rats, Wistar; Sialoglycoproteins; Signal Transduction; Tissue Culture Techniques
PubMed: 28664547
DOI: 10.1111/jcmm.13180 -
Experimental and Therapeutic Medicine Oct 2020Paricalcitol and cinacalcet have been recommended to reduce parathyroid hormone (PTH) levels for patients with secondary hyperparathyroidism (SHPT) and chronic kidney...
Paricalcitol and cinacalcet have been recommended to reduce parathyroid hormone (PTH) levels for patients with secondary hyperparathyroidism (SHPT) and chronic kidney disease (CKD), and they are able to reduce the risk of hypercalcemia and hyperphosphatemia. However, to date, it has remained uncertain which is the better drug. The aim of the present meta-analysis was to evaluate the effects on PTH, calcium and phosphorus metabolism between the two drugs. The PubMed, the Cochrane Library and Embase databases were searched from inception to June 1, 2019 and eligible studies comparing paricalcitol and cinacalcet for SHPT were included. Data were analysed using Review Manager version 5.3. A total of 7 trials from six articles, comprising 456 patients in the paricalcitol group and 412 patients in the cinacalcet group, were included in the meta-analysis. There were no differences in PTH levels [mean difference (MD): 71.82, 95% CI: -185.20-328.85, P=0.58] and phosphorus levels (standard MD: 0.59, 95% CI: -0.82-2.00, P=0.41). The calcium levels in the paricalcitol group were significantly higher than those in the cinacalcet group (MD: 1.10, 95% CI: 0.92-1.28, P<0.05). In conclusion, paricalcitol and cinacalcet exhibited no difference in their efficacy to control of PTH levels, as they were similarly effective in decreasing the PTH levels. They also had comparable efficacy in the management of phosphorus levels. However, cinacalcet produced a significantly greater reduction in serum calcium levels. More large multicentre randomized controlled trials are necessary to confirm the conclusions of the present analysis.
PubMed: 32855693
DOI: 10.3892/etm.2020.9044 -
Journal of Cancer Research and... 2007Vitamin D, a fat-soluble prohormone is synthesized in response to sunlight. Experimental evidence suggests that vitamin D may reduce the risk of cancer through... (Review)
Review
Vitamin D, a fat-soluble prohormone is synthesized in response to sunlight. Experimental evidence suggests that vitamin D may reduce the risk of cancer through regulation of cellular proliferation and differentiation as well as inhibition of angiogenesis. These anticancer properties have been attributed primarily to 1,25-dihydroxyvitamin D [1,25(OH) 2 D] (calcitriol), the hormonal form of vitamin D. Extensive research has shown that cells, including cancer cells, express specific receptors (VDR) for 1,25-dihydroxyvitamin D. When bound to the VDR, 1,25-dihydroxyvitamin D regulates> 60 genes that exert prodifferentiating, antiproliferative and antimetastatic effects on cells, including effects on cell cycle. The amount of exposure to the sun has been found to correlate inversely with cancer mortality and survival in numerous epidemiological studies. An inverse relationship between solar ultraviolet-B (UV-B) exposure and non-skin cancer mortality has long been reported. Several ecological studies suggest that sunlight may protect against prostate, colon, rectal, female breast and ovarian cancer, all diseases that contribute to a substantially higher proportion of cancer mortality in the western industrialized world. Some analytical studies also suggest a protective association between circulating vitamin D in blood, which is largely derived from sunlight, or dietary vitamin D. Paricalcitol (calcitriol analogue) is as effective as 1,25-dihydroxyvitamin D in transactivating the prostatic VDR and in inhibiting the growth of prostate cancer cell lines and primary cultures of prostate cancer cells in vitro. Promising preclinical evaluations of calcitriol and analogues have appeared in prostate cancer animal models.
Topics: Calcitriol; Cell Differentiation; Cell Proliferation; Humans; Neoplasms; Vitamin D
PubMed: 18270398
DOI: 10.4103/0973-1482.38998 -
Journal of Diabetes and Its... Apr 2015Patients with type 2 diabetes (T2DM) and chronic kidney disease (CKD) have impaired endothelial function. Vitamin D and its analogs may play a role in regulation of... (Randomized Controlled Trial)
Randomized Controlled Trial
AIMS
Patients with type 2 diabetes (T2DM) and chronic kidney disease (CKD) have impaired endothelial function. Vitamin D and its analogs may play a role in regulation of endothelial function and inflammation. We studied effects of paricalcitol compared to placebo on endothelial function and markers of inflammation and oxidative stress in patients with T2DM and CKD.
METHODS
A double blind, randomized, placebo-controlled trial was conducted in 60 patients with T2DM and stage 3 or 4 CKD. Paricalcitol 1 mcg or placebo was administered orally once daily for three months. Brachial artery flow mediated dilatation (FMD), nitroglycerine mediated dilation (NMD), and plasma concentrations of inflammatory cytokines, tumor necrosis factor -α and interleukin-6, highly-sensitive C-reactive protein; endothelial surface proteins, intercellular adhesion molecule -1 and monocyte chemo attractant protein-1, and plasma glucose, insulin, free fatty acids, and urinary isoprostane were measured at baseline and end of three months.
RESULTS
27 patients in the paricalcitol group and 28 patients in the control group completed the study, though analysis of FMD at both time points was possible in 23 patients in each group. There was no significant difference in the change in FMD, NMD or the biomarkers examined after paricalcitol or placebo treatment.
CONCLUSIONS
Treatment with paricalcitol at this dose and duration did not affect brachial artery FMD or biomarkers of inflammation and oxidative stress. The lack of significance may be due to the fact that the study patients had advanced CKD and that effects of paricalcitol are not additive to the effects of glycemic, lipid and anti-hypertensive therapies.
Topics: Adolescent; Adult; Aged; Blood Glucose; C-Reactive Protein; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Double-Blind Method; Endothelium, Vascular; Ergocalciferols; Female; Humans; Inflammation; Insulin; Male; Middle Aged; Placebos; Renal Insufficiency, Chronic; Young Adult
PubMed: 25633573
DOI: 10.1016/j.jdiacomp.2015.01.004 -
Nutrients Nov 2023Vitamin D (VitD) and Vitamin D receptor () are suggested to play protective roles in the intestinal barrier in ulcerative colitis (UC). However, the underlying...
Vitamin D (VitD) and Vitamin D receptor () are suggested to play protective roles in the intestinal barrier in ulcerative colitis (UC). However, the underlying mechanisms remain elusive. Evidence demonstrates that Na/H exchanger isoform 8 (NHE8, SLC9A8) is essential in maintaining intestinal homeostasis, regarded as a promising target for UC therapy. Thus, this study aims to investigate the effects of VitD/VDR on NHE8 in intestinal protection. VitD-deficient mice, mice and mice were employed in this study. Colitis mice were established by supplementing DSS-containing water. Caco-2 cells and 3D-enteroids were used for in vitro studies. VDR siRNA (siVDR), VDR over-expression plasmid (pVDR), TNF-α and NF-κb p65 inhibitor QNZ were used for mechanical studies. The expression of interested proteins was detected by multiple techniques. In colitis mice, paricalcitol upregulated NHE8 expression was accompanied by restoring colonic mucosal injury. In VitD-deficient and colitis mice, NHE8 expression was compromised with more serious mucosal damage. Noteworthily, paricalcitol could not prevent intestinal barrier dysfunction and histological destruction in mice. In Caco-2 cells and enteroids, siVDR downregulated NHE8 expression, further promoted TNF-α-induced NHE8 downregulation and stimulated TNF-α-induced NF-κb p65 phosphorylation. Conversely, QNZ blocked TNF-α-induced NHE8 downregulation in the absence or presence of siVDR. Our study indicates depressed NHE8 expression is responsible for VitD-deficient-induced colitis aggravation. These findings provide novel insights into the molecular mechanisms of VitD/VDR in intestine protection in UC.
Topics: Humans; Animals; Mice; Caco-2 Cells; Tumor Necrosis Factor-alpha; NF-kappa B; Colitis; Intestinal Mucosa; Vitamin D; Vitamin D Deficiency; Mice, Inbred C57BL; Dextran Sulfate; Colitis, Ulcerative
PubMed: 38004229
DOI: 10.3390/nu15224834 -
Fertility and Sterility Sep 2015To provide a detailed summary of current scientific knowledge on uterine fibroids (leiomyomas) in vitro and in in vivo animal models, as well as to postulate the... (Review)
Review
OBJECTIVE
To provide a detailed summary of current scientific knowledge on uterine fibroids (leiomyomas) in vitro and in in vivo animal models, as well as to postulate the potential role of vitamin D3 as an effective, inexpensive, safe, long-term treatment option for uterine fibroids.
DESIGN
PubMed search articles were used to identify the most relevant studies on uterine fibroids, as well as effects of vitamin D3 on uterine fibroid cells and fibroid tumor growth in in vivo animal models.
SETTING
University research laboratory.
PATIENT(S)
Not applicable.
INTERVENTION(S)
None.
MAIN OUTCOME MEASURE(S)
Not applicable.
RESULT(S)
Despite numerous publications available on uterine fibroids, information about the role that vitamin D3 plays in the regulation of uterine fibroids is limited. Most of the recent vitamin D3-related studies on uterine fibroids were published from our group. Recent studies have demonstrated that vitamin D deficiency plays a significant role in the development of uterine fibroids. Our recent studies have demonstrated that vitamin D3 reduces leiomyoma cell proliferation in vitro and leiomyoma tumor growth in in vivo animal models. These results postulate the potential role of vitamin D3 for an effective, safe, nonsurgical medical treatment option for uterine fibroids.
CONCLUSION(S)
This article reviews human and animal studies and uncovers new possibilities for understanding the vitamin D-based therapeutic option for an effective, safe, long-term treatment of uterine fibroids. On the basis of these results, a clinical trial with vitamin D3 or a hypocalcemic analog, paricalcitol, may be warranted for nonsurgical medical treatment of uterine fibroids.
Topics: Black or African American; Animals; Antineoplastic Agents; Cholecalciferol; Dietary Supplements; Ergocalciferols; Female; Humans; Leiomyoma; Risk Factors; Signal Transduction; Treatment Outcome; Uterine Neoplasms; Vitamin D; Vitamin D Deficiency
PubMed: 26079694
DOI: 10.1016/j.fertnstert.2015.05.031 -
International Journal of Molecular... Jan 2023Effective and targeted prevention and treatment methods for acute kidney injury (AKI), a common clinical complication, still needs to be explored. Paricalcitol is a...
Effective and targeted prevention and treatment methods for acute kidney injury (AKI), a common clinical complication, still needs to be explored. Paricalcitol is a biologically active chemical that binds to vitamin D receptors in the body to exert anti-oxidant and anti-inflammatory effects. However, the molecular mechanism of the effect of paricalcitol on AKI remains unclear. The current study uses a paricalcitol pretreatment with a mouse AKI model induced by cisplatin to detect changes in renal function, pathology and ultrastructure. Results showed that paricalcitol significantly improved renal function in mice and reduced inflammatory cell infiltration and mitochondrial damage in renal tissue. Furthermore, paricalcitol markedly suppressed reactive oxygen species and malondialdehyde levels in the kidneys of AKI mice and increased the levels of glutathione, superoxide dismutase, Catalase and total anti-oxidant capacity. In addition, we detected renal necrosis and inflammation-related proteins in AKI mice by immunofluorescence and Western blot, and found that their levels were markedly decreased after paricalcitol pretreatment. Moreover, paricalcitol promotes nuclear factor erythroid 2-related factor 2 () in the nucleus and activates the /heme oxygenase-1 () signaling pathway; while HO-1 is inhibited, the protective effect of paricalcitol on the kidney is attenuated. In conclusion, paricalcitol exerts a renoprotective effect by decreasing renal oxidative injury and inflammation through / signaling, providing a new insight into AKI prevention.
Topics: Mice; Animals; Antioxidants; NF-E2-Related Factor 2; Heme Oxygenase-1; Oxidative Stress; Signal Transduction; Acute Kidney Injury; Kidney; Inflammation
PubMed: 36674485
DOI: 10.3390/ijms24020969