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- 1α,25-Dihydroxyvitamin D3 Ameliorates Seawater Aspiration-Induced Acute Lung Injury via NF-κB and RhoA/Rho Kinase Pathways. [Journal Article]
- PLoS One 2014; 9(8):e104507.
Inflammation and pulmonary edema are involved in the pathogenesis of seawater aspiration-induced acute lung injury (ALI). Although several studies have reported that 1α,25-Dihydroxyvitamin D3 (calcitriol) suppresses inflammation, it has not been confirmed to be effective in seawater aspiration-induced ALI. Thus, we investigated the effect of calcitriol on seawater aspiration-induced ALI and explored the probable mechanism.Male SD rats receiving different doses of calcitriol or not, underwent seawater instillation. Then lung samples were collected at 4 h for analysis. In addition, A549 cells and rat pulmonary microvascular endothelial cells (RPMVECs) were cultured with calcitriol or not and then stimulated with 25% seawater for 40 min. After these treatments, cells samples were collected for analysis.Results from real-time PCR showed that seawater stimulation up-regulated the expression of vitamin D receptor in lung tissues, A549 cells and RPMVECs. Seawater stimulation also activates NF-κB and RhoA/Rho kinase pathways. However, we found that pretreatment with calcitriol significantly inhibited the activation of NF-κB and RhoA/Rho kinase pathways. Meanwhile, treatment of calcitriol also improved lung histopathologic changes, reduced inflammation, lung edema and vascular leakage.These results demonstrated that NF-κB and RhoA/Rho kinase pathways are critical in the development of lung inflammation and pulmonary edema and that treatment with calcitriol could ameliorate seawater aspiration-induced ALI, which was probably through the inhibition of NF-κB and RhoA/Rho kinase pathways.
- Breast cancer--new aspects of tumor biology: are calcitriol and cyclooxygenase-2 possible targets for breast cancer? [Journal Article]
- Eur J Gynaecol Oncol 2014; 35(4):341-58.
Up until now there have been many advances in treatment options for breast cancers such as targeted therapies like monoclonal antibodies, tyrosine kinase inhibitors, mTOR antagonists, and vaccines. Despite these advances, there are still many more that warrant further exploration. Two of these targets might be the cyclooxygenase-2 (COX-2), the key enzyme required to convert arachidonic acid to prostaglandins, and calcitriol [1,25(OH)2D3] which is the biologically active form of vitamin D. Both calcitriol and the inhibition of COX-2 have shown antiproliferative and prodifferentiation, as well as pro-apoptotic effects in different malignancies in vitro and in vivo, and the key prostaglandin catabolic enzyme 15-hydroxyprostaglandin dehydrogenase (15-PGDH) is known to have tumor suppressor activity. Furthermore, the combination ofcalcitriol and nonsteroidal anti-inflammatory drugs (NSAIDs), such as non-selective and selective COX-2 inhibitors, acting synergistically to achieve significant cell growth inhibition in prostate cancer. Some epidemiological studies suggest that vitamin D confers a moderate benefit against breast cancer while most epidemiological studies presume that NSAIDs confer the same. Nevertheless there is growing body of evidence that COX-2 expression is a fundamental step in breast cancer carcinogenesis. To date, clinical trials have been conducted in patients with different malignancies using treatment strategies including COX-2 inhibitors and calcitriol and are showing partially encouraging results. The goal of this review is to shed light on the association between the prostaglandin as well as vitamin D metabolism relating to the incidence and therapy of breast cancers. Moreover, this review will also highlight potential treatment options, as well as extract any existing interactions between the two metabolisms.
- A Randomized, Double-Blinded Trial Evaluating the Efficacy and Tolerability of Vectical Ointment (Calcitriol 3 mcg/g Ointment) When Compared to Betamethasone Diproprionate Ointment (64 mg/g) in Patients With Nail Psoriasis. [Journal Article]
- J Drugs Dermatol 2014 Aug 1; 13(8):912-5.
To demonstrate the efficacy and safety of calcitriol ointment (3 mcg/g) compared to betamethasone diproprionate ointment in the treatment of nail psoriasis.<br />Single-center, double-blind study.<br />One academic center.<br />10 adult male and female subjects with psoriasis of the fingernails and/or toenails.<br />The primary efficacy evaluation was the absolute reduction of nail thickness (mm) of the target nail. A secondary endpoint was the improvement in the Physician Global Assessment score of disease severity.<br />Patients treated with either betamethasone diproprionate ointment or calcitriol ointment demonstrated a similar reduction of nail thickness of the selected target nail. The difference between the two groups was not statistically significant (<em>P</em>=0.42).<br />This small study illustrates that calcitriol ointment may be as effective as betamethasone diproprionate in the treatment of nail psoriasis, and its promise should be further investigated in a subsequent larger trial. <br /><br /> <em>J Drugs Dermatol</em>. 2014;13(8):912-915.
- Beneficial effects of growth hormone therapy for ossification defects after bone distraction in X linked hypophosphataemic rickets. [Journal Article]
- BMJ Case Rep 2014.
A report on two homozygous twin girls affected by X linked hypophosphataemic rickets. They were examined due to short stature and genu varum of both tibias. They were treated with calcitriol and Joulie's solution, whereon it was observed that serum parathyroid hormone and phosphaturia decreased while phosphataemia increased. They underwent a tibial osteotomy (by means of the insertion of Kirchner needles) at 7.7 years of age for correction of genu varum and a normal consolidation was reached 1 month later. Nonetheless, height was percentile <1 after menarche, so both sisters asked for bone lengthening. Because of this, at 15 years of age femoral distraction was performed, but no bone callus was observed 14 months later. Consequently, they were treated with subcutaneous growth hormone, showing bone callus at 6 months. Finally, the external fixators were removed due to ossification in the lengthened segments.
- Low Levels of 25-Hydroxy Vitamin D and Active 1,25-Dihydroxyvitamin D Independently Associated with Type 2 Diabetes Mellitus in Older Australian Men: The Concord Health and Ageing in Men Project. [JOURNAL ARTICLE]
- J Am Geriatr Soc 2014 Aug 12.
To examine the associations between serum 25-hydroxyvitamin D (25OHD) levels and the active vitamin D metabolite, 1,25-hydroxyvitamin D (1,25OHD), with type 2 diabetes mellitus (DM) in community-living men aged 70 and older.Cross-sectional.A population-based, cross-sectional analysis of the baseline phase of the Concord Health and Ageing in Men Project (CHAMP), a large epidemiological study conducted in Sydney between January 2005 and May 2007.Community dwelling men aged 70 and older taking part in CHAMP (N = 1,659).Serum 25OHD and 1,25OHD levels, presence of DM, age, country of birth, season of blood collection, sun exposure, body mass index, vitamin D supplement use, statin use, income, measures of health, depression, activity of daily living disabilities, parathyroid hormone, estimated glomerular filtration rate, phosphate, and calcium.The prevalence of DM was 20.0%. There was a significant association between low 25OHD and 1,25OHD levels and DM that remained after adjustment for a wide range of confounders and covariates of clinical significance such as comorbidity, renal function, calciotropic hormones, and medications.25OHD and 1,25OHD levels were associated with DM. The independent association between serum 25OHD and 1,25OHD concentrations and DM raises the question of whether each of the two vitamin D metabolites may influence DM through different biological mechanisms and pathways.
- Successful management of repetitive urinary obstruction and anuria caused by double j stent calculi formation after renal transplantation. [Journal Article]
- Case Rep Transplant 2014.:245724.
This report firstly describes an extremely rare case of repetitive double J stent calculi formation after renal transplantation caused by the antihyperparathyroidism (HPT) drug calcitriol. In 2012, a woman initially presented to our hospital for anuria with lower abdominal pain. She was diagnosed with allograft hydronephrosis and double J stents obstruction by calculi formation after transplantation and treated with triplicate stents replacements in another hospital without clinical manifestations improvements. Through detailed exploration of medical history, we conclude that the abnormal calculi formation is due to the calcitriol (1,25-dihydroxyvitamin D3) administration, a drug which can increase renal tubular reabsorption of calcium for treating posttransplant HPT bone disease. After discontinuing calcitriol, the patient was stone-free and had a good recovery without severe complications during the 9-month follow-up. Our novel findings may provide an important clue and approach to managing formidable repetitive double J stent calculi formation in the clinical trial.
- Parathyroid hormone levels predict posttotal thyroidectomy hypoparathyroidism. [Journal Article]
- Am Surg 2014 Aug; 80(8):817-20.
We hypothesized that parathyroid hormone (PTH) determination would be the most effective strategy to identify posttotal thyroidectomy hypoparathyroidism (PTTHP) compared with other clinical and laboratory parameters. We retrospectively reviewed our recent experience with total thyroidectomy. We recorded demographics, malignancy, thyroid weight, parathyroid autotransplantation, hospital stay, use of postoperative calcium and hormonally active vitamin D3 (calcitriol), and postoperative serum calcium and PTH levels. Patients were divided into two groups depending on whether supplemental calcitriol was required to maintain eucalcemia and therefore reflecting the diagnosis of PTTHP. From October 2010 to June 2013, a total of 202 total thyroidectomies were performed. Twenty-four patients (12%) developed PTTHP and required calcitriol replacement. Logistic regression analysis revealed that only postoperative calcium levels (P = 0.02) and PTH levels (P < 0.0001) statistically significantly predicted PTTHP. Twenty-two of 29 patients with PTH 13 pg/mL or less had PTTHP. Only two of 173 patients with a PTH level greater than 13 pg/mL were diagnosed with PTTHP. We recommend using PTH levels after total thyroidectomy to determine which patients will have hypoparathyroidism requiring calcitriol therapy. An early determination of PTTHP allows for prompt management that can shorten hospital stay and improve outcomes.
- Active Vitamin D (1,25 Dihydroxyvitamin D) Is Associated With Chronic Pain in Older Australian Men: The Concord Health and Ageing in Men Project. [JOURNAL ARTICLE]
- J Gerontol A Biol Sci Med Sci 2014 Aug 7.
Although there is a conflicting evidence for an association between low serum 25-hydroxyvitamin D (25D) levels and pain, the relationship between pain and the active vitamin D metabolite, 1,25-hydroxyvitamin D (1,25D), has not been investigated. The aim of this study was to examine the associations between serum vitamin D metabolites: 25D and 1,25D with intrusive or chronic pain in community-living men aged ≥70 years.Population-based, cross-sectional analysis of the baseline phase of the Concord Health and Ageing in Men Project, a large epidemiological study conducted in Sydney between January 2005 and May 2007. Participants included 1,659 community dwelling men aged ≥70 years, taking part in Concord Health and Ageing in Men Project. Main outcome measurements were symptoms of chronic or intrusive pain. Covariates included 25D and 1,25D, parathyroid hormone, estimated glomerular filtration rate as well as age, country of birth, season of blood collection, body mass index, health conditions, and medication, including nonsteroidal anti-inflammatory drugs and statins.The prevalence of intrusive pain was 22.9% and of chronic pain was 29.7%. Low serum 25D concentrations were associated with intrusive and chronic pain in unadjusted analysis, but after adjustment, the associations were no longer significant. Low 1,25D levels (<62.0 pmol/L) remained independently associated with chronic pain (odds ratio: 1.53 [1.05, 2.21, p = .02]), even after adjustment for a wide range of potential confounders and covariates of clinical significance.Low serum 1,25D concentrations are associated with chronic pain in older men. This raises the question whether vitamin D metabolites may influence pain states, mediated through different biological mechanisms and pathways.
- 1,25-dyhydroxyvitamin D3 Attenuates L-DOPA-Induced Neurotoxicity in Neural Stem Cells. [JOURNAL ARTICLE]
- Mol Neurobiol 2014 Aug 8.
The neurotoxicity of levodopa (L-DOPA) on neural stem cells (NSCs) and treatment strategies to protect NSCs from this neurotoxicity remain to be elucidated. Recently, an active form of vitamin D3 has been reported to display neuroprotective properties. Therefore, we investigated the protective effect of 1,25-dyhydroxyvitamin D3 (calcitriol) on L-DOPA-induced NSC injury. We measured cell viability via the cell counting kit-8 (CCK-8) and lactate dehydrogenase (LDH) assays and Annexin V/PI staining followed by flow cytometry, cell proliferation using the BrdU and colony-forming unit (CFU) assays, cell differentiation via immunocytochemistry, the levels of free radicals via 2',7'-dichlorodihydrofluorescein diacetate (DCFH-DA) staining, apoptosis via DAPI and TUNEL staining, and intracellular signaling protein expression via Western blot. Antibody microarrays were also employed to detect changes in the expression of prosurvival- and death-related proteins. Treatment of NSCs with L-DOPA reduced their viability and proliferation. This treatment also increased the levels of free radicals and decreased the expression levels of intracellular signaling proteins that are associated with cell survival. However, simultaneous exposure to calcitriol significantly reduced these effects. The calcitriol-mediated protection against L-DOPA toxicity was blocked by the phosphoinositide 3-kinase (PI3K) inhibitor LY294004. L-DOPA also inhibited the expression of Nestin and Ki-67, and co-treatment with calcitriol alleviated these effects. The expression levels of GFAP, DCX, and Tuj1 were not significantly affected by treatment with L-DOPA or calcitriol. Calcitriol protects against L-DOPA-induced NSC injury by promoting prosurvival signaling, including activation of the PI3K pathway, and reducing oxidative stress.
- IL-10 inhibits while calcitriol reestablishes placental antimicrobial peptides gene expression. [JOURNAL ARTICLE]
- J Steroid Biochem Mol Biol 2014 Jul 31.
IL-10 and calcitriol help to achieve a successful pregnancy by suppressing active maternal immunity; however, these factors exert opposite effects upon microbial infections. In the skin and immune cells, IL-10 downregulates β-defensins while calcitriol induces cathelicidin gene expression in various tissues including placenta. Though, the regulation of human placental β-defensins by IL-10 and calcitriol has not been studied. Therefore, we explored the regulation of these antimicrobial peptides expression in cultured placental cells by calcitriol and IL-10 alone and combined. Real time PCR showed that calcitriol stimulated, while IL-10 inhibited, β-defensins and cathelicidin gene expression (P<0.05). In coincubations studies, calcitriol was able to maintain antimicrobial peptides gene expression above control values, overriding IL-10 inhibitory effects. Calcitriol downregulated endogenous IL-10 secretion. Interestingly, calcitriol and TNF-α cooperatively enhanced β-defensins, while TNF-α reduced basal and calcitriol-stimulated cathelicidin gene expression. In summary, calcitriol and IL-10 exerted opposite effects on antimicrobial peptides expression in the human placenta, suggesting that unbalanced production of IL-10, and calcitriol could be deleterious to innate immune responses during gestation. Our results suggest that calcitriol enhancement of placental defenses involves two mechanisms: (1) downregulation of IL-10 secretion and (2) direct upregulation of β-defensins and cathelicidin gene expression. Considering that IL-10 and calcitriol differentially regulate the innate immune response in the placenta, in the case of an infection, calcitriol might restrict IL-10 permissive actions towards microbial invasion while restrains inflammation, allowing for pregnancy to continue in quiescence. These results strongly advice maternal vitamin D sufficiency during pregnancy.