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- Vitamin D and experimental invasive aspergillosis. [JOURNAL ARTICLE]
- Med Mycol 2014 Sep 17.
Immune cells express the vitamin D receptor and vitamin D metabolizing enzymes. Favorable vitamin D effects have been indicated in tuberculosis. Vitamin D deficiency increases T helper (Th) 2 responses to Aspergillus, and it suppresses Th2 responses in cystic fibrosis-allergic bronchopulmonary aspergillosis. Can vitamin D modulate the proinflammatory effects of amphotericin B (AmB) therapy in aspergillosis? Groups of mice were infected intravenously (IV) with 3-8 × 10(6) Aspergillus fumigatus conidia. In six experiments, doses of 0.08, 2, or 4 μg/kg calcitriol (active form of vitamin D) were given intraperitoneally +/- AmB-deoxycholate (AmBd) at 0.4, 0.8, 1.2, 1.8, 3.3, or 4.5 mg/kg or 0.8 or 1.2 mg/kg IV. Calcitriol doses were selected to range from doses used in humans to those just below doses shown to decalcify murine bones. In most experiments, doses of calcitriol and AmBd (or control diluents) were given five times, on alternate days, to minimize drug-drug interactions. Calcitriol treatment began on the day of challenge, and survival assessed for 10 days. In no experiments did calcitriol alone significantly worsen or enhance survival or affect residual infection in survivors. Calcitriol also did not affect the efficacy of AmBd. In a representative experiment, AmBd at 0.8 or 1.2 mg/kg IV alone +/- calcitriol at 2 μg/kg enhanced survival (P ≤ 0.01). However, the AmBd regimens with calcitriol were not different than those without, and calcitriol alone was identical to controls. In disseminated invasive aspergillosis, calcitriol did not affect outcome nor influence antifungal efficacy.
- Vitamin D for Prevention and Treatment of Colorectal Cancer: What is the Evidence? [JOURNAL ARTICLE]
- Curr Colorectal Cancer Rep 2014 Sep 1; 10(3):339-345.
Vitamin D insufficiency is highly prevalent in the U.S., particularly among colorectal cancer (CRC) patients. These low levels of vitamin D are concerning in light of increasing evidence that vitamin D may have health benefits beyond skeletal outcomes. Prospective observational studies suggest that higher vitamin D levels are associated with lower risk of incident CRC as well as improved survival in patients with established CRC, and randomized clinical trials are desperately needed to establish causality. Moreover, there remains a great need to improve prognosis for patients with CRC, and investigating vitamin D as a potential therapeutic modality is an attractive option in regards to safety and cost, particularly in this era of expensive and often toxic anti-neoplastic agents. In this review, the available published evidence on vitamin D's activity in CRC will be summarized, spanning preclinical, epidemiological, and clinical studies, and future research directions will be discussed.
- Vitamin D deficiency promotes nonalcoholic steatohepatitis through impaired enterohepatic circulation in Animal Model. [JOURNAL ARTICLE]
- Am J Physiol Gastrointest Liver Physiol 2014 Sep 11.
Vitamin D deficiency (VDD) or insufficiency is recognized for its association with nonalcoholic steatohepatitis (NASH), while the underlying mechanism remains unknown. Using animal models we found that vitamin D deficiency promoted the high fat diet (HFD) initiated simple steatosis into typical NASH, characterized by elevated hepatic inflammation and fat degeneration. The NASH derived from VDD+HFD was related to poor retention of bile acids in the liver and biliary tree, in line with down-regulation of the ileal apical sodium-dependent bile acid cotransporter (iASBT). The impediment of hepatic bile acids by the VDD+HFD mice was related to increased expression of hepatic SREBP1c and fatty acid synthase (FAS), suggesting that VDD may up regulate endogenous fatty acid synthesis into NASH through impaired enterohepatic circulation. Administration of 1,25(OH)2VD3 (calcitriol) corrected the NASH phenotypes in line with restoration of iASBT, promotion of bile filling in the biliary tree, suppression of hepatic lipogenesis and inflammation. Moreover, administration of a bile acid sequestering agent suppressed ileal FGF15 expression, leading increased iASBT expression to restore bile filling in the liver and biliary tree, which ameliorates steatosis and inflammation in the liver. These results suggest a novel mechanism for NASH development, by which VDD down regulates iASBT expression, resulting in poor bile acid pool and elevation of hepatic lipogenesis and inflammation. In conclusion, vitamin D and bile acid sequestration may be explored as new strategies to treat or prevent NASH.
- Preventing Postoperative Hypocalcemia in Patients with Graves Disease: A Prospective Study. [JOURNAL ARTICLE]
- Ann Surg Oncol 2014 Sep 12.
Hypocalcemia occurs after total thyroidectomy (TT) for Graves disease via parathyroid injury and/or from increased bone turnover. Current management is to supplement calcium after surgery. This study evaluates the impact of preoperative calcium supplementation on hypocalcemia after Graves TT.A prospective study of patients with Graves disease undergoing TT was performed. Patients with Graves disease managed over a 9-month period took 1 g of calcium carbonate (CC) three times a day for 2 weeks before TT. Those managed the previous year without supplementation served as historic controls. Age-, gender-, and thyroid weight-matched, non-Graves TT patients were procedure controls. Patient demographics, postoperative laboratory values, complaints, and medications were reviewed. Parathyroid hormone (PTH)-based postoperative protocols dictated postoperative CC and calcitriol use.Forty-five patients with Graves disease were treated with CC before TT, and 38 patients with Graves disease were not. Forty control subjects without Graves disease were identified. Age, gender, and thyroid weight were comparable. Preoperative calcium and PTH levels were equivalent. PTH values immediately after surgery, at postoperative day 1, and at 2-week follow-up were equivalent. Postoperative use of scheduled CC (p = 0.10) and calcitriol (p = 0.60) was similar. Postoperatively, patients with untreated Graves disease had lower serum calcium levels than pretreated patients with Graves disease or control subjects without Graves disease (8.3 mg/dL vs. 8.6 vs. 8.6, p = 0.05). Complaints of numbness and tingling were more common in nontreated Graves disease (26 %) than in pretreated Graves disease (9 %) or in control subjects without Graves disease (10 %, p < 0.05).Calcium supplementation before TT for Graves disease significantly reduced biochemical and symptomatic postoperative hypocalcemia. Preoperative calcium supplementation is a simple treatment that can reduce symptoms of hypocalcemia after Graves TT.
- Interaction of hedgehog and vitamin D signaling pathways in basal cell carcinomas. [Journal Article]
- Adv Exp Med Biol 2014.:329-41.
Basal Cell Carcinomas (BCCs) are the most commonly diagnosed tumors among people in the western world. Most BCCs are caused by mutational inactivation of the tumor suppressor Patched (PTCH), which results in activation of Smoothened (SMO) and of the Hedgehog (HH) signaling pathway. Recent studies indicate that BCC progression involves a crosstalk between Hh signaling, vitamin D derivatives and the vitamin D receptor (Vdr) signaling pathway. This has been demonstrated in BCC-bearing Ptch mutant mice and BCC cell lines, in which both vitamin D3 and its active metabolite calcitriol (1alpha-25(OH)2D3) exert antitumor effects. Interestingly, the antitumor effects are mainly ascribed to an inhibition of Hh signaling. Furthermore, as evident from studies in Vdr deficient mice, calcitriol may also repress the activity of Hh signaling in a Vdr-dependent fashion thereby establishing an additional inhibitory feedback on Hh signaling activity. In this chapter, we discuss the current understanding and controversial findings of the inhibition of Hh signaling by vitamin D derivatives and the implication of these findings for BCC carcinogenesis.
- Outcomes of Total Parathyroidectomy with Autotransplantation versus Subtotal Parathyroidectomy with Routine Addition of Thymectomy to both Groups: Single Center Experience of Secondary Hyperparathyroidism. [Journal Article]
- Balkan Med J 2014 Mar; 31(1):77-82.
Secondary hyperparathyroidism is a common acquired disorder seen in chronic renal failure. It may result in potentially serious complications including metabolic bone diseases, severe atherosclerosis and undesirable cardiovascular events. Parathyroidectomy is required in about 20% of patients after 3-10 years of dialysis and in up to 40% after 20 years.The aim of the current study was to evaluate the short-term and long-term outcomes of patients with secondary hyperparathyroidism who had undergone total parathyroidectomy with autotransplantation and thymectomy or subtotal parathyroidectomy with thymectomy by the same surgical team during the study period.Retrospective comparative study.Clinical data of 50 patients who underwent parathyroid surgery for secondary hyperparathyroidism between 2003 and 2011 were reviewed retrospectively. Patients were divided into two subgroups of total parathyroidectomy with autotransplantation or subtotal parathyroidectomy. Thymectomy was routinely performed for both groups. Short term outcome parameters included intact parathyroid hormone, ionized calcium and alkaline phosphatase levels. Bone pain, bone fractures, persistent or recurrent disease were included in long term outcome parameters.The mean duration of dialysis was eight years. The mean ionized calcium levels dropped significantly in the total parathyroidectomy with autotransplantation group (p=0.016). No serious postoperative complications were observed. Postoperative intravenous calcium supplementation was required in four patients in the total parathyroidectomy with autotransplantation group (total PTX+AT) and in three patients in the subtotal parathyroidectomy group (subtotal PTX). Postoperatively, all patients received oral calcium carbonate and calcitriol. The length of average hospital stay was 5 (3-10) days. Including nine patients who underwent successful renal transplantation pre-operative bone symptoms, hypercalcemia, hyperphosphatemia, and an increased alkaline phosphatase levels were improved or resolved in all patients. After a mean follow-up of 65 months, three patients (6%) had persistent and one (2%) had recurrent disease.Total parathroidectomy with autotransplantation is a beneficial and safe surgical procedure for patients on chronic dialysis with otherwise uncontrollable secondary hyperparathroidism and even in patients who have undergone renal transplantation after parathyroidectomy. Careful cervical exploration and routine thymectomy should be considered as a routine part of the surgical approach regardless of the preferred technique.
- Vitamin D Attenuates Cytokine-Induced Remodeling in Human Fetal Airway Smooth Muscle Cells. [JOURNAL ARTICLE]
- J Cell Physiol 2014 Sep 9.
Asthma in the pediatric population remains a significant contributor to morbidity and increasing healthcare costs. Vitamin D3 insufficiency and deficiency have been associated with development of asthma. Recent studies in models of adult airway diseases suggest that the bioactive Vitamin D3 metabolite, calcitriol (1,25-dihydroxyvitamin D3 ; 1,25(OH)2 D3 ), modulates responses to inflammation; however this concept has not been explored in developing airways in the context of pediatric asthma. We used human fetal airway smooth muscle (ASM) cells as a model of the early postnatal airway to explore how calcitriol modulates remodeling induced by pro-inflammatory cytokines. Cells were pre-treated with calcitriol and then exposed to TNFα or TGFβ for up to 72 h. Matrix metalloproteinase (MMP) activity, production of extracellular matrix (ECM), and cell proliferation were assessed. Calcitriol attenuated TNFα enhancement of MMP-9 expression and activity. Additionally, calcitriol attenuated TNFα and TGFβ-induced collagen III expression and deposition, and separately, inhibited proliferation of fetal ASM cells induced by either inflammatory mediator. Analysis of signaling pathways suggested that calcitriol effects in fetal ASM involve ERK signaling, but not other major inflammatory pathways. Overall, our data demonstrate that calcitriol can blunt multiple effects of TNFα and TGFβ in developing airway, and point to a potentially novel approach to alleviating structural changes in inflammatory airway diseases of childhood. J. Cell. Physiol. © 2014 Wiley Periodicals, Inc.
- Elimination of Vitamin D Receptor in Vascular Endothelial Cells Alters Vascular Function. [JOURNAL ARTICLE]
- Hypertension 2014 Sep 8.
Vitamin D deficiency has been associated with cardiovascular dysfunction. We evaluated the role of the vitamin D receptor (VDR) in vascular endothelial function, a marker of cardiovascular health, at baseline and in the presence of angiotensin II, using an endothelial-specific knockout of the murine VDR gene. In the absence of endothelial VDR, acetylcholine-induced aortic relaxation was significantly impaired (maximal relaxation, endothelial-specific VDR knockout=58% versus control=73%; P<0.05). This was accompanied by a reduction in endothelial NO synthase expression and phospho-vasodilator-stimulated phosphoprotein levels in aortae from the endothelial-specific VDR knockout versus control mice. Although blood pressure levels at baseline were comparable at 12 and 24 weeks of age, the endothelial VDR knockout mice demonstrated increased sensitivity to the hypertensive effects of angiotensin II compared with control mice (after 1-week infusion: knockout=155±15 mm Hg versus control=133±7 mm Hg; P<0.01; after 2-week infusion: knockout=164±9 mm Hg versus control=152±13 mm Hg; P<0.05). By the end of 2 weeks, angiotensin II infusion-induced, hypertrophy-sensitive myocardial gene expression was higher in endothelial-specific VDR knockout mice (fold change compared with saline-infused control mice, type-A natriuretic peptide: knockout mice=3.12 versus control=1.7; P<0.05; type-B natriuretic peptide: knockout mice=4.72 versus control=2.68; P<0.05). These results suggest that endothelial VDR plays an important role in endothelial cell function and blood pressure control and imply a potential role for VDR agonists in the management of cardiovascular disease associated with endothelial dysfunction.
- In vitro 25-hydroxycholecalciferol treatment of lipopolysaccharide-stimulated chicken macrophages increases nitric oxide production and mRNA of interleukin- 1beta and 10. [JOURNAL ARTICLE]
- Vet Immunol Immunopathol 2014 Aug 21.
25-hydroxycholecalciferol (25(OH)D) is an intermediate metabolite during the biosynthesis of active vitamin D. In vitro studies were conducted in chicken monocytes and a chicken macrophage cell line (HD11) to study the effects of supplementing with 25(OH)D on nitrite production and mRNA amounts of interleukin (IL)-1β, IL-10, 1α-hydroxylase and 24-hydroxylase post- lipopolysaccharide (LPS) challenge. Supplementing HD11 cells and monocytes with 25(OH)D in the presence of LPS increased nitrite production by approximately 3-fold and 5-fold, respectively, compared to the LPS group. There was a linear increase in nitrite production by HD11 cells when treated with increasing doses of 25(OH)D. At 48h post-LPS treatment, HD11 cells treated with either 25(OH)D or 1,25-dihydroxycholecalciferol(1,25(OH)2D) in the presence of LPS had higher amounts of IL-1β mRNA compared to the LPS group or the group treated with LPS and cholecalciferol (Chol). At 48h, HD11 cells treated with 25(OH)D and stimulated with LPS had higher amounts of IL-10 mRNA compared to the LPS group or the groups treated with LPS and Chol or 1,25(OH)2D. At 48h post-LPS treatment, HD11 cells treated with either 25(OH)D or 1,25(OH)2D and stimulated with LPS had higher amounts of 1α-hydroxylase and 24-hydroxylase mRNA compared to the group treated with LPS and Chol. In summary, a 25(OH)D treatment increased nitrite production and mRNA amounts of IL-1β, IL-10, 1α-hydroxylase and 24-hydroxylase in HD11 cells following LPS stimulation.
- Changes of fibroblast growth factor 23 (FGF23) levels following calcitriol treatment in a vitamin D deficient patient. [Journal Article]
- J Musculoskelet Neuronal Interact 2014 Sep; 14(3):398-400.