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Asian Journal of Andrology 2018Signaling through the vitamin D receptor has been shown to be biologically active and important in a number of preclinical studies in prostate and other cancers.... (Review)
Review
Signaling through the vitamin D receptor has been shown to be biologically active and important in a number of preclinical studies in prostate and other cancers. Epidemiologic data also indicate that vitamin D signaling may be important in the cause and prognosis of prostate and other cancers. These data indicate that perturbation of vitamin D signaling may be a target for the prevention and treatment of prostate cancer. Large studies of vitamin D supplementation will be required to determine whether these observations can be translated into prevention strategies. This paper reviews the available data in the use of vitamin D compounds in the treatment of prostate cancer. Clinical data are limited which support the use of vitamin D compounds in the management of men with prostate cancer. However, clinical trials guided by existing preclinical data are limited.
Topics: Antineoplastic Combined Chemotherapy Protocols; Calcifediol; Calcitriol; Clinical Trials as Topic; Ergocalciferols; Humans; Male; Prostatic Neoplasms; Signal Transduction; Vitamin D; Vitamin D Deficiency
PubMed: 29667615
DOI: 10.4103/aja.aja_14_18 -
Nutrients Oct 2023Due to its essential role in calcium and phosphate homeostasis, the secosteroid hormone calcitriol has received growing attention over the last few years. Calcitriol,... (Review)
Review
Due to its essential role in calcium and phosphate homeostasis, the secosteroid hormone calcitriol has received growing attention over the last few years. Calcitriol, like other steroid hormones, may function through both genomic and non-genomic mechanisms. In the traditional function, the interaction between the biologically active form of vitamin D and the vitamin D receptor (VDR) affects the transcription of thousands of genes by binding to repeated sequences present in their promoter region, named vitamin D-responsive elements (VDREs). Non-transcriptional effects, on the other hand, occur quickly and are unaffected by inhibitors of transcription and protein synthesis. Recently, calcifediol, the immediate precursor metabolite of calcitriol, has also been shown to bind to the VDR with weaker affinity than calcitriol, thus exerting gene-regulatory properties. Moreover, calcifediol may also trigger rapid non-genomic responses through its interaction with specific membrane vitamin D receptors. Membrane-associated VDR (mVDR) and protein disulfide isomerase family A member 3 (Pdia3) are the best-studied candidates for mediating these rapid responses to vitamin D metabolites. This paper provides an overview of the calcifediol-related mechanisms of action, which may help to better understand the vitamin D endocrine system and to identify new therapeutic targets that could be important for treating diseases closely associated with vitamin D deficiency.
Topics: Calcitriol; Calcifediol; Receptors, Calcitriol; Vitamin D; Gene Expression Regulation; Homeostasis
PubMed: 37892484
DOI: 10.3390/nu15204409 -
JCI Insight Mar 2019Topical calcipotriol plus 5-fluorouracil (5-FU) combination is an effective immunotherapy against actinic keratosis (AK), which is a precursor to squamous cell carcinoma... (Clinical Trial)
Clinical Trial Randomized Controlled Trial
BACKGROUND
Topical calcipotriol plus 5-fluorouracil (5-FU) combination is an effective immunotherapy against actinic keratosis (AK), which is a precursor to squamous cell carcinoma (SCC). However, the long-term effectiveness of calcipotriol plus 5-FU treatment for SCC prevention is unknown.
METHODS
We performed a blinded prospective cohort study on participants of a randomized double-blind clinical trial in which a 4-day course of topical calcipotriol plus 5-FU combination was compared to Vaseline plus 5-FU (control) for AK treatment. SCC and basal cell carcinoma (BCC) incidences were assessed at 1, 2, and 3 years after trial. Tissues were analyzed for calcipotriol plus 5-FU-induced T cell immunity in the skin.
RESULTS
Calcipotriol plus 5-FU-induced tissue-resident memory T (Trm) cell formation in face and scalp skin associated with significantly higher erythema scores compared with control (P < 0.01). Importantly, more participants in the test cohort remained SCC-free over the more than 1,500-day follow-up period (P = 0.0765), and significantly fewer developed SCC on the treated face and scalp within 3 years (2 of 30 [7%] versus 11 of 40 [28%] in control group, hazard ratio 0.215 [95% CI: 0.048-0.972], P = 0.032). Accordingly, significantly more epidermal Trm cells persisted in the calcipotriol plus 5-FU-treated face and scalp skin compared with control (P = 0.0028). There was no significant difference in BCC incidence between the treatment groups.
CONCLUSION
A short course of calcipotriol plus 5-FU treatment on the face and scalp is associated with induction of robust T cell immunity and Trm formation against AKs and significantly lowers the risk of SCC development within 3 years of treatment.
FUNDING
This research was supported by internal academic funds and by grants from the Burroughs Wellcome Fund, Sidney Kimmel Foundation, Cancer Research Institute, and NIH.
Topics: Adaptive Immunity; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Calcitriol; Carcinoma, Basal Cell; Carcinoma, Squamous Cell; Double-Blind Method; Female; Fluorouracil; Humans; Immunotherapy; Male; Middle Aged; Prospective Studies; Skin; Skin Neoplasms
PubMed: 30895944
DOI: 10.1172/jci.insight.125476 -
Nutrients Mar 2022Classically, a secosteroid hormone, vitamin D, has been implicated in calcium and phosphate homeostasis and has been associated with the pathogenesis of rickets and... (Review)
Review
Classically, a secosteroid hormone, vitamin D, has been implicated in calcium and phosphate homeostasis and has been associated with the pathogenesis of rickets and osteomalacia in patients with severe nutritional vitamin D deficiency. The spectrum of known vitamin D-mediated effects has been expanded in recent years. However, the mechanisms of how exactly this hormone elicits its biological function are still not fully understood. The interaction of this metabolite with the vitamin D receptor (VDR) and, subsequently, with the vitamin D-responsive element in the region of specific target genes leading to the transcription of genes whose protein products are involved in the traditional function of calcitriol (known as genomic actions). Moreover, in addition to these transcription-dependent mechanisms, it has been recognized that the biologically active form of vitamin D, as well as its immediate precursor metabolite, calcifediol, initiate rapid, non-genomic actions through the membrane receptors that are bound as described for other steroid hormones. So far, among the best candidates responsible for mediating rapid membrane response to vitamin D metabolites are membrane-associated VDR (VDRm) and protein disulfide isomerase family A member 3 (Pdia3). The purpose of this paper is to provide an overview of the rapid, non-genomic effects of calcifediol and calcitriol, whose elucidation could improve the understanding of the vitamin D endocrine system. This will contribute to a better recognition of the physiological acute functions of vitamin D, and it could lead to the identification of novel therapeutic targets able to modulate these actions.
Topics: Calcifediol; Calcitriol; Genome; Humans; Rickets; Vitamin D
PubMed: 35334948
DOI: 10.3390/nu14061291 -
Physiological Research Nov 2018Resistance to vitamin D has been known for decades as vitamin D resistant rickets, caused by mutations of the gene encoding for vitamin D receptor (VDR). Findings of... (Review)
Review
Resistance to vitamin D has been known for decades as vitamin D resistant rickets, caused by mutations of the gene encoding for vitamin D receptor (VDR). Findings of extra-skeletal effects of vitamin D and learning of the molecular mechanisms used by its biologically active metabolite calcitriol revealed other ways leading to its impaired sensitivity. Calcitriol takes advantage of both genomic and non-genomic mechanisms through its binding to vitamin D receptor, located not only in the cell nuclei but also in a perinuclear space. On the genomic level the complex of calcitriol bound to VDR binds to the DNA responsive elements of the controlled gene in concert with another nuclear receptor, retinoid X receptor, and expression of the VDR itself is controlled by its own ligand. These elements were found not only in the promotor region, but are scattered over the gene DNA. The gene expression includes a number of nuclear transcription factors which interact with the responsive elements and with each other and learning how they operate would further contribute to revealing causes of the impaired vitamin D sensitivity. Finally, the examples of major disorders are provided, associated with impairment of the vitamin D function and its receptor.
Topics: Calcitriol; Humans; Mutation; Receptors, Calcitriol; Vitamin D; Vitamin D Deficiency
PubMed: 30484666
DOI: 10.33549/physiolres.934006 -
Medical Science Monitor Basic Research May 2022BACKGROUND Melanoma is one of the most aggressive types of cancer and it has shown a remarkable surge in incidence during the last 50 years. Melanoma has been projected...
BACKGROUND Melanoma is one of the most aggressive types of cancer and it has shown a remarkable surge in incidence during the last 50 years. Melanoma has been projected to be continuously rising in the future. Therapy for advanced-type melanoma is still a challenge due to the low response rate and poor 10-year survival. Interestingly, several epidemiological and preclinical studies had reported that vitamin D deficiency was associated with disease progression in several cancer types. In vivo and in vitro studies revealed anti-proliferative, anti-angiogenic, apoptosis, and differentiation induction effects of calcitriol in various cancers. However, information on the effects of calcitriol (1,25(OH)₂D₃) on melanoma is still limited, and its mechanism remains unclear. MATERIAL AND METHODS In the present study, by utilizing B16-F10 cells, which is a melanoma cell line, we explored the anti-proliferative effect of calcitriol using cell viability assay, near-infrared imaging, expression of apoptosis-related genes using real-time polymerase chain reactions (PCR), and the expression of apoptosis proteins levels using western blot. In addition, we also assessed calcitriol uptake by B16-F10 cells using high-performance liquid chromatography (HPLC). RESULTS We found that calcitriol inhibits melanoma cell proliferation with an IC₅₀ of 93.88 ppm (0.24 μM), as shown by cell viability assay. Additionally, we showed that B16-F10 cells are capable of calcitriol uptake, with a peak uptake time at 60 min after administration. Calcitriol was also able to induce apoptosis-related proteins such as caspase-3, caspase 8, and caspase-9. These effects of calcitriol reflect its potential utility as a potent adjuvant therapy for melanoma. CONCLUSIONS Calcitriol inhibits cell proliferation and induces apoptosis in B16-F10 cells.
Topics: Animals; Apoptosis; Calcitriol; Cell Line, Tumor; Cell Proliferation; Melanoma, Experimental
PubMed: 35642437
DOI: 10.12659/MSMBR.935139 -
Acta Cirurgica Brasileira 2020To evaluate protective effects of dexmedetomidine, calcitriol and their combination.
PURPOSE
To evaluate protective effects of dexmedetomidine, calcitriol and their combination.
METHODS
Forty Wistar-albino rats were divided into 4 groups; group of Sham (Group Sham); group of dexmedetomidine (Group DEX); group of calcitriol (Group CAL) and group of dexmedetomidineandcalcitriol (Group DEX-CAL). Photographic analysis was used for macroscopic analysis and perfusion analyses were evaluated by scintigraphy. Additionally, tissue malondialdehyde (MDA) and total oxidant status (TOS) and total antioxidant activity (TAS) were recorded and oxidative stress index (OSI) was calculated. Each flap was assessed by histopathology.
RESULTS
Compared to Group Sham, the viable flap areas were higher in all treatment groups both by photographic image analyses and perfusion analyses (p<0.05). Group DEX-CAL had the highest viable flap percentage both in scintigraphic and photographic analyses; whereas Group Sham had the lowest viable flap percentage. Similarly, TAS and MDA levels were elevated and TOS levels were declined in all treatment groups compared to Group Sham (p<0.005). Histopathological analysis at flap demarcation zone confirmed neovascularization was significantly higher and edema, necrosis and inflammation were significantly lower in all treatment groups compared to Group Sham.
CONCLUSION
The outcomes show that additional premedication with either dexmedetomidine or calcitriol or their combination reduces ischemia-reperfusion injury of flap area and show significant increase in the percentage of viable flap tissue.
Topics: Animals; Calcitriol; Dexmedetomidine; Rats; Rats, Wistar; Reperfusion Injury; Surgical Flaps
PubMed: 33027360
DOI: 10.1590/s0102-865020200090000003 -
JCI Insight Sep 2023Intact fibroblast growth factor 23 (iFGF23) is a phosphaturic hormone that is cleaved by furin into N-terminal and C-terminal fragments. Several studies have implicated...
Intact fibroblast growth factor 23 (iFGF23) is a phosphaturic hormone that is cleaved by furin into N-terminal and C-terminal fragments. Several studies have implicated vitamin D in regulating furin in infections. Thus, we investigated the effect of 1,25-dihydroxyvitamin D3 [1,25(OH)2D] and the vitamin D receptor (VDR) on furin-mediated iFGF23 cleavage. Mice lacking VDR (Vdr-/-) had a 25-fold increase in iFGF23 cleavage, with increased furin levels and activity compared with wild-type (WT) littermates. Inhibition of furin activity blocked the increase in iFGF23 cleavage in Vdr-/- animals and in a Vdr-knockdown osteocyte OCY454 cell line. Chromatin immunoprecipitation revealed VDR binding to DNA upstream of the Furin gene, with more transcription in the absence of VDR. In WT mice, furin inhibition reduced iFGF23 cleavage, increased iFGF23, and reduced serum phosphate levels. Similarly, 1,25(OH)2D reduced furin activity, decreased iFGF23 cleavage, and increased total FGF23. In a post hoc analysis of a randomized clinical trial, we found that ergocalciferol treatment, which increased serum 1,25(OH)2D, significantly decreased serum furin activity and iFGF23 cleavage, compared with placebo. Thus, 1,25(OH)2D inhibits iFGF23 cleavage via VDR-mediated suppression of Furin expression, thereby providing a mechanism by which vitamin D can augment phosphaturic iFGF23 levels.
Topics: Animals; Mice; Calcitriol; Cell Line; Chromatin Immunoprecipitation; Furin; Vitamin D
PubMed: 37681408
DOI: 10.1172/jci.insight.168957 -
Journal of Medicinal Chemistry Aug 2019For many individuals, in particular during winter, supplementation with the secosteroid vitamin D is essential for the prevention of bone disorders, muscle weakness,... (Review)
Review
For many individuals, in particular during winter, supplementation with the secosteroid vitamin D is essential for the prevention of bone disorders, muscle weakness, autoimmune diseases, and possibly also different types of cancer. Vitamin D acts via its metabolite 1α,25-dihydroxyvitamin D [] as potent agonist of the transcription factor vitamin D receptor (VDR). Thus, vitamin D directly affects chromatin structure and gene regulation at thousands of genomic loci, i.e., the epigenome and transcriptome of its target tissues. Modifications of at its side-chain, A-ring, triene system, or C-ring, alone and in combination, as well as nonsteroidal mimics provided numerous potent VDR agonists and some antagonists. The nearly 150 crystal structures of VDR's ligand-binding domain with various vitamin D compounds allow a detailed molecular understanding of their action. This review discusses the most important vitamin D analogs presented during the past 10 years and molecular insight derived from new structural information on the VDR protein.
Topics: Animals; Calcifediol; Calcitriol; Humans; Protein Structure, Secondary; Protein Structure, Tertiary; Receptors, Calcitriol; Vitamin D
PubMed: 30916559
DOI: 10.1021/acs.jmedchem.9b00208 -
Annales de Dermatologie Et de... Mar 2001Calcipotriol is a vitamin D derivative synthesized in 1985 by the Léo Laboratories. Its mode of action is identical to that of 1-25 vitamin D3 (calcitriol), essentially... (Review)
Review
Calcipotriol is a vitamin D derivative synthesized in 1985 by the Léo Laboratories. Its mode of action is identical to that of 1-25 vitamin D3 (calcitriol), essentially by regulating the activity of genes capable of responding to vitamin D. Calcipotriol leads to reduction in keratinocyte proliferation and induces their differentiation as well as having important immunomodulator functions. Toxicology studies have demonstrated that phosphorus calcium metabolism anomalies are only observed for doses above those recommended for clinical use (100 g per week). The half-life of Calcipotriol is much shorter than that of calcitriol and its metabolites are inactive. The effects of Calcipotriol on phosphorus calcium metabolism are much less pronounced than those of calcitriol. Therapeutic trials in psoriasis have demonstrated the superiority of Calcipotriol over its excipient, class 2 dermatocorticoids, and reducers. Given in combination with phototherapy, cyclosporin or retinoids, Calcipotriol provides more complete improvement in lesions and allows a reduction in the cumulative doses of these treatments. Calcipotriol is effective in certain keratinization disorders (ichtyoses) as well as in localized sclerodermia and vitiligo, although the effect is less certain for the latter conditions. At recommended doses, adverse effects are limited to skin reactions with lesional and perilesional irritation in about 20 p. 100 of the cases. Contact dermatitis is rare. Photosensitivization can be observed when Calcipotriol is applied in patients undergoing UVB phototherapy. The marketing approval in France includes indications for psoriasis not involving more than 40 p. 100 of the skin surface. Several studies have demonstrated the efficacy and safety of Calcipotriol in children using the dose of 50 g per week per m2 body surface area. Contraindications include hypercalcemia, pregnancy and nursing. Three formulations are available (salve, cream, and lotion, all at 0.005 p. 100 concentration) for different administration schemes: two applications per day, alternative applications with dermocorticoid or in combination with systemic treatment for psoriasis. Long-term treatment protocols have not been determined.
Topics: Calcitriol; Dermatologic Agents; Humans
PubMed: 11319386
DOI: No ID Found