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Combinations of Calcitriol with Anticancer Treatments for Breast Cancer: An Update.
Segovia-Mendoza, M, García-Quiroz, J, Díaz, L, García-Becerra, R
International journal of molecular sciences. 2021;(23)
Abstract
Preclinical, clinical, and epidemiological studies indicate that vitamin D3 (VD) deficiency is a risk factor for the development of breast cancer. Underlying mechanisms include the ability of calcitriol to induce cell differentiation, inhibit oncogenes expression, and modify different signaling pathways involved in the control of cell proliferation. In addition, calcitriol combined with different kinds of antineoplastic drugs has been demonstrated to enhance their beneficial effects in an additive or synergistic fashion. However, a recognized adjuvant regimen based on calcitriol for treating patients with breast cancer has not yet been fully established. Accordingly, in the present work, we review and discuss the preclinical and clinical studies about the combination of calcitriol with different oncological drugs, aiming to emphasize its main therapeutic benefits and opportunities for the treatment of this pathology.
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Influence of Seasonal Vitamin D Changes on Clinical Manifestations of Rheumatoid Arthritis and Systemic Sclerosis.
Cutolo, M, Soldano, S, Sulli, A, Smith, V, Gotelli, E
Frontiers in immunology. 2021;:683665
Abstract
Vitamin D [1,25(OH)2D-calcitriol] is basically a steroid hormone with pleiotropic biologic effects, and its impact on the regulation of immune system may influence several clinical conditions. Calcidiol (25OHD), as precursor of calcitriol, derives, for the most part (80%), from cutaneous cholesterol (7-dehydrocholesterol) under the action of UV-B (sunlight). Consequently, serum concentrations fluctuate during the year following the circannual rhythm of sun exposition. We will update about the available evidence regarding the complex influence of seasonal vitamin D changes on two different chronic connective tissue diseases, namely rheumatoid arthritis (RA) and systemic sclerosis (SSc). Notably, RA is an emblematic model of autoimmune disease with prevalent joint inflammatory features, while SSc is mainly an autoimmune progressive pro-fibrotic disease. However, in both conditions, low serum concentrations of 25OHD are involved in the pathogenesis of the diseases, and emerging data report their impact on clinical manifestations.
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3.
Sarcoidosis and calcium homeostasis disturbances-Do we know where we stand?
Gwadera, Ł, Białas, AJ, Iwański, MA, Górski, P, Piotrowski, WJ
Chronic respiratory disease. 2019;:1479973119878713
Abstract
The majority of cases involving hypercalcemia in the setting of sarcoidosis are explained by the overproduction of calcitriol by activated macrophages. Vitamin D takes part in the regulation of granuloma formation. However, using vitamin D metabolites to assess the activity of the disease is still problematic, and its usefulness is disputable. In some cases, though, a calcium metabolism disorder could be a valuable tool (i.e. as a marker of extrathoracic sarcoidosis). Although sarcoidosis does not cause a decrease in bone mineral density, increased incidence of vertebral deformities is noted. Despite increasing knowledge about calcium homeostasis disorders in patients with sarcoidosis, there is still a need for clear guidelines regarding calcium and vitamin D supplementation in these patients.
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4.
Vitamin D and Calcium for the Prevention of Fracture: A Systematic Review and Meta-analysis.
Yao, P, Bennett, D, Mafham, M, Lin, X, Chen, Z, Armitage, J, Clarke, R
JAMA network open. 2019;(12):e1917789
Abstract
IMPORTANCE Vitamin D and calcium supplements are recommended for the prevention of fracture, but previous randomized clinical trials (RCTs) have reported conflicting results, with uncertainty about optimal doses and regimens for supplementation and their overall effectiveness. OBJECTIVE To assess the risks of fracture associated with differences in concentrations of 25-hydroxyvitamin D (25[OH]D) in observational studies and the risks of fracture associated with supplementation with vitamin D alone or in combination with calcium in RCTs. DATA SOURCES PubMed, EMBASE, Cochrane Library, and other RCT databases were searched from database inception until December 31, 2018. Searches were performed between July 2018 and December 2018. STUDY SELECTION Observational studies involving at least 200 fracture cases and RCTs enrolling at least 500 participants and reporting at least 10 incident fractures were included. Randomized clinical trials compared vitamin D or vitamin D and calcium with control. DATA EXTRACTION AND SYNTHESIS Two researchers independently extracted data according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines and assessed possible bias. Rate ratios (RRs) were estimated using fixed-effects meta-analysis. Data extraction and synthesis took place between July 2018 and June 2019. MAIN OUTCOMES AND MEASURES Any fracture and hip fracture. RESULTS In a meta-analysis of 11 observational studies (39 141 participants, 6278 fractures, 2367 hip fractures), each increase of 10.0 ng/mL (ie, 25 nmol/L) in 25 (OH)D concentration was associated with an adjusted RR for any fracture of 0.93 (95% CI, 0.89-0.96) and an adjusted RR for hip fracture of 0.80 (95% CI, 0.75-0.86). A meta-analysis of 11 RCTs (34 243 participants, 2843 fractures, 740 hip fractures) of vitamin D supplementation alone (daily or intermittent dose of 400-30 000 IU, yielding a median difference in 25[OH]D concentration of 8.4 ng/mL) did not find a reduced risk of any fracture (RR, 1.06; 95% CI, 0.98-1.14) or hip fracture (RR, 1.14; 95% CI, 0.98-1.32), but these trials were constrained by infrequent intermittent dosing, low daily doses of vitamin D, or an inadequate number of participants. In contrast, a meta-analysis of 6 RCTs (49 282 participants, 5449 fractures, 730 hip fractures) of combined supplementation with vitamin D (daily doses of 400-800 IU, yielding a median difference in 25[OH]D concentration of 9.2 ng/mL) and calcium (daily doses of 1000-1200 mg) found a 6% reduced risk of any fracture (RR, 0.94; 95% CI, 0.89-0.99) and a 16% reduced risk of hip fracture (RR, 0.84; 95% CI, 0.72-0.97). CONCLUSIONS AND RELEVANCE In this systematic review and meta-analysis, neither intermittent nor daily dosing with standard doses of vitamin D alone was associated with reduced risk of fracture, but daily supplementation with both vitamin D and calcium was a more promising strategy.
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5.
Mechanisms of action of vitamin D in colon cancer.
Ferrer-Mayorga, G, Larriba, MJ, Crespo, P, Muñoz, A
The Journal of steroid biochemistry and molecular biology. 2019;:1-6
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Abstract
Colorectal cancer (CRC) is the neoplasia that is most frequently associated with vitamin D deficiency in epidemiological and observational studies in terms of incidence and mortality. Many mechanistic studies show that the active vitamin D metabolite (1α,25-dihydroxyvitamin D3 or calcitriol) inhibits proliferation and promotes epithelial differentiation of human colon carcinoma cell lines that express vitamin D receptor (VDR) via the regulation of a high number of genes. A key action underlining this effect is the multilevel inhibition of the Wnt/β-catenin signaling pathway, whose abnormal activation in colon epithelial cells initiates and promotes CRC. Recently, our group has shown that calcitriol modulates gene expression and inhibits protumoral properties of patient-derived colon cancer-associated fibroblasts (CAFs). Accordingly, high VDR expression in tumor stromal fibroblasts is associated with longer survival of CRC patients. Moreover, many types of immune cells express VDR and are regulated by calcitriol, which probably contributes to its action against CRC. Given the role attributed to the intestinal microbiota in CRC and the finding that it is altered by vitamin D deficiency, an indirect antitumoral effect of calcitriol is also plausible at this level. In summary, calcitriol has an array of potential protective effects against CRC by acting on carcinoma cells, CAFs, immune cells and probably also the gut microbiota.
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Acute hypercalcemia and hypervitaminosis D associated with pulmonary tuberculosis in an elderly patient : A case report and review of the literature.
Wada, T, Hanibuchi, M, Saijo, A
The journal of medical investigation : JMI. 2019;(3.4):351-354
Abstract
An 80-year-old man was referred to our hospital for further examination of fever, cough and left pleural effusion. The laboratory findings showed acute inflammation, and the elevation of albumin-corrected serum calcium and 1,25-dihydroxyvitamin D3. A chest CT revealed centrilobular particulate opacity in the bilateral lung fields and left pleural effusion, indicating acute hypercalcemia and hypervitaminosis D associated with pulmonary tuberculosis. By the confirmation of Mycobacterium tuberculosis on polymerase chain reaction and cultures of the sputum and pleural effusion, a diagnosis of pulmonary tuberculosis was made. The patient successfully completed a 9-month course of the anti-tuberculosis treatment, and bilateral infiltrative shadows and left pleural effusion in chest X-ray disappeared. Symptoms progressively improved and serum level of albumin-corrected calcium and 1,25-dihydroxyvitamin D3 eventually normalized. While pulmonary tuberculosis is an infrequent cause of hypercalcemia, it should be considered in patients with hypercalcemia and elevated serum level of 1,25-dihydroxyvitamin D3. J. Med. Invest. 66 : 351-354, August, 2019.
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7.
Vitamin D: Classic and Novel Actions.
Gil, Á, Plaza-Diaz, J, Mesa, MD
Annals of nutrition & metabolism. 2018;(2):87-95
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Abstract
BACKGROUND Classically, vitamin D has been implicated in bone health by promoting calcium absorption in the gut and maintenance of serum calcium and phosphate concentrations, as well as by its action on bone growth and reorganization through the action of osteoblasts and osteoclasts cells. However, in the last 2 decades, novel actions of vitamin D have been discovered. The present report summarizes both classic and novel actions of vitamin D. SUMMARY 1,25(OH)2 vitamin D, the active metabolite of vitamin D, also known as calcitriol, regulates not only calcium and phosphate homeostasis but also cell proliferation and differentiation, and has a key a role to play in the responses of the immune and nervous systems. Current effects of vitamin D include xenobiotic detoxification, oxidative stress reduction, neuroprotective functions, antimicrobial defense, immunoregulation, anti-inflammatory/anticancer actions, and cardiovascular benefits. The mechanism of action of calcitriol is mediated by the vitamin D receptor, a subfamily of nuclear receptors that act as transcription factors into the target cells after forming a heterodimer with the retinoid X receptor. This kind of receptors has been found in virtually all cell types, which may explain its multiple actions on different tissues. Key Messages: In addition to classic actions related to mineral homeostasis, vitamin D has novel actions in cell proliferation and differentiation, regulation of the innate and adaptative immune systems, preventive effects on cardiovascular and neurodegenerative diseases, and even antiaging effects.
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The Use of Vitamin D Metabolites and Analogues in the Treatment of Chronic Kidney Disease.
Zand, L, Kumar, R
Endocrinology and metabolism clinics of North America. 2017;(4):983-1007
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Abstract
Chronic kidney disease (CKD) and end-stage renal disease (ESRD) are associated with abnormalities in bone and mineral metabolism, known as CKD-bone mineral disorder. CKD and ESRD cause skeletal abnormalities characterized by hyperparathyroidism, mixed uremic osteodystrophy, osteomalacia, adynamic bone disease, and frequently enhanced vascular and ectopic calcification. Hyperparathyroidism and mixed uremic osteodystrophy are the most common manifestations due to phosphate retention, reduced concentrations of 1,25-dihydroxyvitamin D, intestinal calcium absorption, and negative calcium balance. Treatment with 1-hydroxylated vitamin D analogues is useful.
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Effects of 1,25(OH)₂D₃ on Cancer Cells and Potential Applications in Combination with Established and Putative Anti-Cancer Agents.
Abu El Maaty, MA, Wölfl, S
Nutrients. 2017;(1)
Abstract
The diverse effects of 1,25-dihydroxyvitamin D₃ (1,25(OH)₂D₃), the bio-active form of vitamin D, on cancer cell metabolism and proliferation has made it an interesting candidate as a supporting therapeutic option in cancer treatment. An important strategy in cancer therapy is the use of combination chemotherapy to overcome drug resistance associated with numerous anti-cancer agents and to provide better means of avoiding undesirable side effects. This complex strategy is widely adopted by oncologists and several established "cocktails" of chemotherapeutics are routinely administered to cancer patients. Among the principles followed in designing such treatment regimens is the use of drugs with different mechanisms of action to overcome the issue of tumor heterogeneity and to evade resistance. In light of the profound and diverse effects of 1,25(OH)₂D₃ reported by in vitro and in vivo studies, we discuss how these effects could support the use of this molecule in combination with "classical" cytotoxic drugs, such as platins and anti-metabolites, for the treatment of solid and hematological tumors. We also examine recent evidence supporting synergistic activities with other promising anti-cancer drug candidates, and postulate mechanisms through which 1,25(OH)₂D₃ may help evade chemoresistance.
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Regulation of calcitriol biosynthesis and activity: focus on gestational vitamin D deficiency and adverse pregnancy outcomes.
Olmos-Ortiz, A, Avila, E, Durand-Carbajal, M, Díaz, L
Nutrients. 2015;(1):443-80
Abstract
Vitamin D has garnered a great deal of attention in recent years due to a global prevalence of vitamin D deficiency associated with an increased risk of a variety of human diseases. Specifically, hypovitaminosis D in pregnant women is highly common and has important implications for the mother and lifelong health of the child, since it has been linked to maternal and child infections, small-for-gestational age, preterm delivery, preeclampsia, gestational diabetes, as well as imprinting on the infant for life chronic diseases. Therefore, factors that regulate vitamin D metabolism are of main importance, especially during pregnancy. The hormonal form and most active metabolite of vitamin D is calcitriol. This hormone mediates its biological effects through a specific nuclear receptor, which is found in many tissues including the placenta. Calcitriol synthesis and degradation depend on the expression and activity of CYP27B1 and CYP24A1 cytochromes, respectively, for which regulation is tissue specific. Among the factors that modify these cytochromes expression and/or activity are calcitriol itself, parathyroid hormone, fibroblast growth factor 23, cytokines, calcium and phosphate. This review provides a current overview on the regulation of vitamin D metabolism, focusing on vitamin D deficiency during gestation and its impact on pregnancy outcomes.