An ochre mutation in the vitamin D receptor gene causes hereditary 1,25-dihydroxyvitamin D sub 3 -resistant rickets in three families

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Ritchie, H.H.; Hughes, M.R.; Thompson, E.T.; Pike, J.W.; O' Malley, B.W. (Baylor College of Medicine, Houston, TX (USA)); Malloy, P.J.; Feldman, D. (Stanford Univ. School of Medicine, CA (USA)); Hochberg, Z. (Rambam Medical Center, Haifa (Israel))

1989-12-01

Hereditary 1,25-dihydroxyvitamin D{sub 3}-resistant rickets is a rare autosomal-recessive disease resulting from target-organ resistance to the action of the active hormonal form of vitamin D. Four affected children from three related families with the classical syndrome of hereditary 1,25-dihydroxyvitamin D{sub 3}-resistant rickets and the absence of detectable binding to the vitamin D receptor (VDR) in cultured fibroblasts or lymphoblasts were examined for genetic abnormalities in the VDR gene. Genomic DNA from Epstein-Barr virus-transformed lymphoblasts of eight family members was isolated and amplified by polymerase chain reaction techniques. Amplified fragments containing the eight structural exons encoding the VDR protein were sequenced. The DNA from all affected children exhibited a single C {yields} A base substitution within exon 7 at nucleotide 970. Although the affected children were all homozygotic for the mutation, the four parents tested all exhibited both wild-type and mutant alleles, indicating a heterozygous state. Recreated mutant receptor exhibited no specific 1,25-({sup 3}H)dihydroxyvitamin D{sub 3} binding and failed to activate a cotransfected VDR promoter-reporter gene construct. Thus these findings identify an ochre mutation in a human steroid hormone receptor in patients with hereditary 1,25-dihydroxyvitamin D{sub 3}-resistant rickets.

1,25-Dihydroxyvitamin D3 regulates genes responsible for detoxification in intestine

International Nuclear Information System (INIS)

Kutuzova, Galina D.; DeLuca, Hector F.

2007-01-01

1α,25-Dihydroxyvitamin D 3 (1,25-(OH) 2 D 3 ), the biologically active form of vitamin D 3 , not only plays a major role in mammalian calcium and phosphorous homeostasis but also exerts pleiotropic effects on cell proliferation, differentiation and the immune system. Further, vitamin D is believed to play a significant role in the prevention of colon, prostate, and breast cancer and in reducing the risk of autoimmune diseases. To gain insight into the mechanism whereby vitamin D can have such diverse actions, we have employed microarray technology. We studied the effect of a single dose of 1,25-(OH) 2 D 3 on gene expression in the intestine of vitamin D-deficient rats. Within 6 h, 1,25-(OH) 2 D 3 stimulates the expression of several phase I and phase II biotransformation genes. There is also an increased expression of antioxidant genes. These results support the idea that vitamin D is a significant factor in detoxification and protection against environmental toxins

Effect of 24,25-dihydroxyvitamin D3 on 1,25-dihydroxyvitamin D3 [1,25-(OH)2D3] metabolism in vitamin D-deficient rats infused with 1,25-(OH)2D3

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Yamato, H.; Matsumoto, T.; Fukumoto, S.; Ikeda, K.; Ishizuka, S.; Ogata, E.

1989-01-01

Previous studies revealed that administration of 24,25-dihydroxyvitamin D3 [24,25-(OH)2D3] to calcium (Ca)-deficient rats causes a dose-dependent reduction in markedly elevated serum 1,25-(OH)2D3 level. Although the results suggested that the metabolism of 1,25-(OH)2D3 was accelerated by 24,25-(OH)2D3, those experiments could not define whether the enhanced metabolism of 1,25-(OH)2D3 played a role in the reduction in the serum 1,25-(OH)2D3 level. In the present study, in order to address this issue more specifically, serum 1,25-(OH)2D3 was maintained solely by exogenous administration through miniosmotic pumps of 1,25-(OH)2D3 into vitamin D-deficient rats. Thus, by measuring the serum 1,25-(OH)2D3 concentration, the effect of 24,25-(OH)2D3 on the MCR of 1,25-(OH)2D3 could be examined. Administration of 24,25-(OH)2D3 caused a dose-dependent enhancement in the MCR of 1,25-(OH)2D3, and 1 microgram/100 g rat.day 24,25-(OH)2D3, which elevated serum 24,25-(OH)2D3 to 8.6 +/- 1.3 ng/ml, significantly increased MCR and suppressed serum levels of 1,25-(OH)2D3. The effect of 24,25-(OH)2D3 on 1,25-(OH)2D3 metabolism developed with a rapid time course, and the recovery of iv injected [1 beta-3H]1,25-(OH)2D3 in blood was significantly reduced within 1 h. In addition, there was an increase in radioactivity in the water-soluble fraction of serum as well as in urine, suggesting that 1,25-(OH)2D3 is rapidly degraded to a water-soluble metabolite(s). Furthermore, the reduction in serum 1,25-(OH)2D3 was associated with a reduction in both serum and urinary Ca levels. Because the conversion of [3H]24,25-(OH)2D3 to [3H]1,24,25-(OH)2D3 or other metabolites was minimal in these rats, 24,25-(OH)2D3 appears to act without being converted into other metabolites. These results demonstrate that 24,25-(OH)2D3 rapidly stimulates the metabolism of 1,25-(OH)2D3 and reduces its serum level

Williams syndrome transcription factor (WSTF) acts as an activator of estrogen receptor signaling in breast cancer cells and the effect can be abrogated by 1α,25-dihydroxyvitamin D3

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Lundqvist, Johan; Kirkegaard, Tove; Laenkholm, Anne Vibeke

2018-01-01

A majority of estrogen receptor positive (ER+) breast cancers are growth stimulated by estrogens. The ability to inhibit the ER signaling pathway is therefore of critical importance in the current treatment of ER+ breast cancers. It has been reported that 1α,25-dihydroxyvitamin D3 down......-regulates the expression of the CYP19A1 gene, encoding the aromatase enzyme that catalyzes the synthesis of estradiol. Furthermore, 1α,25-dihydroxyvitamin D3 has also been reported to down-regulate the expression of estrogen receptor α (ERα), the main mediator of ER signaling.This study reports a novel transcription...... factor critical to 1α,25-dihydroxyvitamin D3-mediated regulation of estrogenic signaling in MCF-7 breast cancer cells. We have investigated the molecular mechanisms for the 1α,25-dihydroxyvitamin D3-mediated down-regulation of CYP19A1 and ERα gene expression in human MCF-7 breast cancer cells and found...

A new point mutation in the deoxyribonuclic acid-binding domain of the vitamine D receptor in a kindred with hereditary 1,25-dihydroxyvitamin d-resistant rickets

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Yagi, Hideki; Miyake, Hiroshi; Nagashima, Kanji; Kuroume, Takayoshi (Gunma Univ. School of Medicine (Japan)); Ozone, K.; Pike, J.W. (Baylor College of Medicine, Houston, TX (United States))

1993-02-01

Hereditary 1,25-dihydroxyvitamin D [1,25-(OH)[sub 2]D]-resistant rickets (HVDRR) is a rare disorder characterized by rickets, alopecia, hypocalcemia, secondary hyperparathyroidism, and normal or elevated serum 1,25-dihydroxyvitamin D levels. The authors describe a patient with typical clinical characteristics of HVDRR, except that elevated levels of serum phosphorus were present coincident with increased levels of serum intact PTH. The patient was treated with high dose calcium infusion after an ineffective treatment with 1[alpha]-hydroxyvitamin D[sub 3]; serum calcium and phosphorus as well as intact PTH and alkaline phosphatase levels were normalized. Evaluation of phytohemagglutinin-activated lymphocytes derived from this patient revealed that 1,25-(OH)[sub 2]D[sub 3] was unable to inhibit thymidine incooperation, a result that contrast with the capacity of 1,25-(OH)[sub 2]D[sub 3] to inhibit uptake into normal activated lymphocytes. 1,25-(OH)[sub 2]D[sub 3] did not induce human osteocalcin promoter activity after transfection of this DNA linked to a reporter gene into patient cells. Cointroduction of a human vitamin D receptor (VDR) cDNA expression vector with the reporter plasmid, however, restored the hormone response. Evaluation of extracts from the patient cells for VDR DNA binding revealed a defect in DNA binding. Analysis of genomic DNA from the patient's cells by PCR confirmed the presence of a point mutation in exon 2 of the VDR. This exon directs synthesis of a portion of the DNA-binding domain of the receptor. We conclude that the genetic basis for 1,25-(OH)[sub 2]D[sub 3] resistance in this kindred with VDR-positive HVDRR is due to a single base mutation in the VDR that leads to production of a receptor unable to interact appropriately with DNA. 20 refs., 3 figs., 1 tab.

Hypercalcemia in hyperthyroidism: patterns of serum calcium, parathyroid hormone, and 1,25-dihydroxyvitamin D3 levels during management of thyrotoxicosis.

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Iqbal, Ayesha A; Burgess, Elizabeth H; Gallina, Daniel L; Nanes, Mark S; Cook, Curtiss B

2003-01-01

To present two cases of hypercalcemia associated with thyrotoxicosis and to describe serial biochemical findings during the course of treatment of hyperthyroidism. We report two cases, illustrate the changes in serum calcium, parathyroid hormone, and 1,25-dihydroxyvitamin D3 levels during management of thyrotoxicosis, and compare our findings with those in previous studies. Hypercalcemia attributable to thyrotoxicosis is well documented, but the mechanism for the hypercalcemia is incompletely understood. Our first patient had a complicated medical history and several potential causes of hypercalcemia, including recurrent hyperparathyroidism, metastatic breast cancer, and relapse of previously treated thyrotoxicosis. A suppressed parathyroid hormone level and negative bone and computed tomographic scans excluded the first two factors. After thyroid ablation with 131I, the serum calcium and thyroxine levels decreased, and the parathyroid hormone and 1,25-dihydroxyvitamin D3 levels normalized. Our second patient, who was referred to our institution with a preliminary diagnosis of hypercalcemia associated with malignant disease and who had no symptoms of hyperthyroidism, was found to have a high free thyroxine level, diffuse enlargement of the thyroid, and high uptake (58%) of 123I on a thyroid scan. After thyroid ablation, the serum calcium, 1,25-dihydroxyvitamin D3, and intact parathyroid hormone levels normalized, and the free thyroxine level declined. The probable pathogenesis of hypercalcemia in thyrotoxicosis is reviewed with respect to thyroid hormone and its effect on bone turnover. Physicians should consider thyrotoxicosis in the differential diagnosis of hypercalcemia.

Stat1-Vitamin D Receptor Interactions Antagonize 1,25-Dihydroxyvitamin D Transcriptional Activity and Enhance Stat1-Mediated Transcription

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Vidal, Marcos; Ramana, Chilakamarti V.; Dusso, Adriana S.

2002-01-01

The cytokine gamma interferon (IFN-γ) and the calcitropic steroid hormone 1,25-dihydroxyvitamin D (1,25D) are activators of macrophage immune function. In sarcoidosis, tuberculosis, and several granulomatoses, IFN-γ induces 1,25D synthesis by macrophages and inhibits 1,25D induction of 24-hydroxylase, a key enzyme in 1,25D inactivation, causing high levels of 1,25D in serum and hypercalcemia. This study delineates IFN-γ-1,25D cross talk in human monocytes-macrophages. Nuclear accumulation of Stat1 and vitamin D receptor (VDR) by IFN-γ and 1,25D promotes protein-protein interactions between Stat1 and the DNA binding domain of the VDR. This prevents VDR-retinoid X receptor (RXR) binding to the vitamin D-responsive element, thus diverting the VDR from its normal genomic target on the 24-hydroxylase promoter and antagonizing 1,25D-VDR transactivation of this gene. In contrast, 1,25D enhances IFN-γ action. Stat1-VDR interactions, by preventing Stat1 deactivation by tyrosine dephosphorylation, cooperate with IFN-γ/Stat1-induced transcription. This novel 1,25D-IFN-γ cross talk explains the pathogenesis of abnormal 1,25D homeostasis in granulomatous processes and provides new insights into 1,25D immunomodulatory properties. PMID:11909970

The Use of 1α,25-Dihydroxyvitamin D3 as an Anticancer Agent

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Ewa Marcinkowska

2016-05-01

Full Text Available The notion that vitamin D can influence the incidence of cancer arose from epidemiological studies. The major source of vitamin D in the organism is skin production upon exposure to ultra violet-B. The very first observation of an inverse correlation between exposure of individuals to the sun and the likelihood of cancer was reported as early as 1941. In 1980, Garland and Garland hypothesised, from findings from epidemiological studies of patients in the US with colon cancer, that vitamin D produced in response to sun exposure is protective against cancer as opposed to sunlight per se. Later studies revealed inverse correlations between sun exposure and the occurrence of prostate and breast cancers. These observations prompted laboratory investigation of whether or not vitamin D had an effect on cancer cells. Vitamin D is not active against cancer cells, but the most active metabolite 1α,25-dihydroxyvitamin D3 (1,25D has profound biological effects. Here, we review the anticancer action of 1,25D, clinical trials of 1,25D to date and the prospects of the future therapeutic use of new and low calcaemic analogues.

1,25-Dihydroxyvitamin D3 protects obese rats from metabolic syndrome via promoting regulatory T cell-mediated resolution of inflammation

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Wen Jin

2018-03-01

Full Text Available Vitamin D3 has been found to produce therapeutic effects on obesity-associated insulin resistance and dyslipidemia through its potent anti-inflammatory activity, but the precise immunomodulatory mechanism remains poorly understood. In the present study we found that 1,25-dihydroxyvitamin D3 [1,25(OH2D3], the biologically active form of vitamin D3, significantly attenuated monosodium glutamate (MSG-induced obesity and insulin resistance as indicated by body weight reduction, oral glucose tolerance improvement, and a glucose infusion rate increase as detected with hyperinsulinemic-euglycemic clamp. Moreover, 1,25(OH2D3 not only restored pancreatic islet functions but also improved lipid metabolism in insulin-targeted tissues. The protective effects of 1,25(OH2D3 on glycolipid metabolism were attributed to its ability to inhibit an obesity-activated inflammatory response in insulin secretory and targeted tissues, as indicated by reduced infiltration of macrophages in pancreas islets and adipose tissue while enhancing the expression of Tgf-β1 in liver tissue, which was accompanied by increased infiltration of Treg cells in immune organs such as spleen and lymph node as well as in insulin-targeted tissues such as liver, adipose, and muscle. Together, our findings suggest that 1,25(OH2D3 serves as a beneficial immunomodulator for the prevention and treatment of obesity or metabolic syndrome through its anti-inflammatory effects. KEY WORDS: Insulin resistance, Dyslipidemia, MSG-obese rat, Treg cell, Vitamin D3, 1,25-Dihydroxyvitamin D3

Effects of 1,25-dihydroxyvitamin D3 and vitamin D3 on the expression of the vitamin D receptor in human skeletal muscle cells

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Vitamin D receptor (VDR) expression and action in non-human skeletal muscle have recently been reported in several studies, yet data on the activity and expression of VDR in human muscle cells are scarce. We conducted a series of studies to examine the (1) effect of 1,25-dihydroxyvitamin D3 (1,25(OH...

25-hydroxyvitamin D3 and 1,25-dihydroxyvitamin D3 exert distinct effects on human skeletal muscle function and gene expression.

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Zaki K Hassan-Smith

Full Text Available Age-associated decline in muscle function represents a significant public health burden. Vitamin D-deficiency is also prevalent in aging subjects, and has been linked to loss of muscle mass and strength (sarcopenia, but the precise role of specific vitamin D metabolites in determining muscle phenotype and function is still unclear. To address this we quantified serum concentrations of multiple vitamin D metabolites, and assessed the impact of these metabolites on body composition/muscle function parameters, and muscle biopsy gene expression in a retrospective study of a cohort of healthy volunteers. Active serum 1,25-dihydroxyvitamin D3 (1α,25(OH2D3, but not inactive 25-hydroxyvitamin D3 (25OHD3, correlated positively with measures of lower limb strength including power (rho = 0.42, p = 0.02, velocity (Vmax, rho = 0.40, p = 0.02 and jump height (rho = 0.36, p = 0.04. Lean mass correlated positively with 1α,25(OH2D3 (rho = 0.47, p = 0.02, in women. Serum 25OHD3 and inactive 24,25-dihydroxyvitamin D3 (24,25(OH2D3 had an inverse relationship with body fat (rho = -0.30, p = 0.02 and rho = -0.33, p = 0.01, respectively. Serum 25OHD3 and 24,25(OH2D3 were also correlated with urinary steroid metabolites, suggesting a link with glucocorticoid metabolism. PCR array analysis of 92 muscle genes identified vitamin D receptor (VDR mRNA in all muscle biopsies, with this expression being negatively correlated with serum 25OHD3, and Vmax, and positively correlated with fat mass. Of the other 91 muscle genes analysed by PCR array, 24 were positively correlated with 25OHD3, but only 4 were correlated with active 1α,25(OH2D3. These data show that although 25OHD3 has potent actions on muscle gene expression, the circulating concentrations of this metabolite are more closely linked to body fat mass, suggesting that 25OHD3 can influence muscle function via indirect effects on adipose tissue. By contrast, serum 1α,25(OH2D3 has limited effects on muscle gene

Dexamethasone, BMP-2, and 1,25-dihydroxyvitamin D enhance a more differentiated osteoblast phenotype

DEFF Research Database (Denmark)

Jørgensen, Niklas Rye; Henriksen, Z; Sørensen, O H

2004-01-01

. Osteoblast phenotypes were induced by either dexamethasone (Dex) or bone morphogenetic protein-2 (BMP-2). Bone marrow was obtained from biopsies at the posterior iliac spine. Cells were isolated by gradient centrifugation and grown to confluence. Cells were treated with 1 nM 1,25-dihydroxyvitamin D (vitamin...... activity was increased by Dex, but not by BMP-2 treatment. P1NP production was decreased after Dex treatment, while BMP-2 had no effect on P1NP levels. Osteocalcin production was low in cultures not stimulated with vitamin D. Dex or BMP-2 treatment alone did not affect the basic osteocalcin levels......, but in combination with vitamin D, BMP-2 increased the osteocalcin production, while Dex treatment completely suppressed osteocalcin production. Further, PTH-induced cAMP production was greatly enhanced by Dex treatment, whereas BMP-2 did not affect cAMP production. Finally, in vitro mineralization was greatly...

1,25-Dihydroxyvitamin D3 inhibits the differentiation and migration of T(H17 cells to protect against experimental autoimmune encephalomyelitis.

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Jae-Hoon Chang

Full Text Available BACKGROUND: Vitamin D(3, the most physiologically relevant form of vitamin D, is an essential organic compound that has been shown to have a crucial effect on the immune responses. Vitamin D(3 ameliorates the onset of the experimental autoimmune encephalomyelitis (EAE; however, the direct effect of vitamin D(3 on T cells is largely unknown. METHODOLOGY/PRINCIPAL FINDINGS: In an in vitro system using cells from mice, the active form of vitamin D(3 (1,25-dihydroxyvitamin D(3 suppresses both interleukin (IL-17-producing T cells (T(H17 and regulatory T cells (Treg differentiation via a vitamin D receptor signal. The ability of 1,25-dihydroxyvitamin D(3 (1,25(OH(2D(3 to reduce the amount of IL-2 regulates the generation of Treg cells, but not T(H17 cells. Under T(H17-polarizing conditions, 1,25(OH(2D(3 helps to increase the numbers of IL-10-producing T cells, but 1,25(OH(2D(3's negative regulation of T(H17 development is still defined in the IL-10(-/- T cells. Although the STAT1 signal reciprocally affects the secretion of IL-10 and IL-17, 1,25(OH(2D(3 inhibits IL-17 production in STAT1(-/- T cells. Most interestingly, 1,25(OH(2D(3 negatively regulates CCR6 expression which might be essential for T(H17 cells to enter the central nervous system and initiate EAE. CONCLUSIONS/SIGNIFICANCE: Our present results in an experimental murine model suggest that 1,25(OH(2D(3 can directly regulate T cell differentiation and could be applied in preventive and therapeutic strategies for T(H17-mediated autoimmune diseases.

The role of monocytes and T cells in 1,25-dihydroxyvitamin D3 mediated inhibition of B cell function in vitro

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Müller, K; Heilmann, C; Poulsen, L K

1991-01-01

1,25-Dihydroxyvitamin D3 (1,25-(OH)2D3) inhibits immunoglobulin production by human mononuclear cells (MNC) in vitro. The present study was undertaken to evaluate the role of T cells and monocytes in 1,25-(OH)2D3 induced suppression of B cell functions. The synthetic vitamin D3 analogue MC 903...... was examined in parallel. 1,25-(OH)2D3 and MC 903 showed a dose-related inhibition of IgM, IgG and IgA plaque-forming cells in poke-weed mitogen (PWM) activated cultures of MNC. This effect was most likely mediated through impairment of T cell and monocyte functions. First, the inhibitory effect was seen after...

FGF23 inhibits extra-renal synthesis of 1,25-dihydroxyvitamin D in human monocytes

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Bacchetta, Justine; Sea, Jessica L; Chun, Rene F; Lisse, Thomas S; Wesseling-Perry, Katherine; Gales, Barbara; Adams, John S.; Salusky, Isidro B; Hewison, Martin

2012-01-01

Vitamin D is a potent stimulator of monocyte innate immunity, with this effect being mediated via intracrine conversion of 25-hydroxyvitamin D (25OHD) to 1,25-dihydroxyvitamin D (1,25(OH)2D). In the kidney synthesis of 1,25(OH)2D is suppressed by fibroblast growth factor 23 (FGF23), via transcriptional suppression of the vitamin D-activating enzyme 1α-hydroxylase (CYP27B1). We hypothesized that FGF23 also suppresses CYP27B1 in monocytes, with concomitant effects on intracrine responses to 1,25(OH)2D. Monocytes from healthy donor peripheral blood mononuclear cells (PBMCm) and from peritoneal dialysate effluent from kidney disease patients (PDm) were assessed at baseline to confirm the presence of mRNA for FGF23 receptors (FGFRs), with Klotho and FGFR1 being more strongly expressed than FGFR2/3/4 in both cell types. Immunohistochemistry showed co-expression of Klotho and FGFR1 in PBMCm and PDm, with this effect being enhanced following treatment with FGF23 in PBMCm but not PDm. Treatment with FGF23 activated MAP kinase (MAPK) and Akt pathways in PBMCm, demonstrating functional FGFR signaling in these cells. FGF23 treatment of PBMCm and PDm decreased expression of mRNA for CYP27B1. In PBMCm this was associated with downregulation of 25OHD to 1,25(OH)2D metabolism, and concomitant suppression of intracrine induced 24-hydroxylase (CYP24A1) and antibacterial cathelicidin (LL37). FGF23 suppression of CYP27B1 was particularly pronounced in PBMCm treated with interleukin-15 to stimulate synthesis of 1,25(OH)2D. These data indicate that FGF23 can inhibit extra-renal expression of CYP27B1 and subsequent intracrine responses to 1,25(OH)2D in two different human monocyte models. Elevated expression of FGF23 may therefore play a crucial role in defining immune responses to vitamin D and this, in turn, may be a key determinant of infection in patients with CKD. PMID:22886720

Discovery of molecular pathways mediating 1,25-dihydroxyvitamin D₃ protection against cytokine-induced inflammation and damage of human and male mouse islets of Langerhans

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Wolden-Kirk, Heidi; Rondas, D; Bugliani, M

2014-01-01

Protection against insulitis and diabetes by active vitamin D, 1,25-dihydroxyvitamin D3 (1,25(OH)2D3), in nonobese diabetic mice has until now mainly been attributed to its immunomodulatory effects, but also protective effects of this hormone on inflammation-induced β-cell death have been reporte...

Diminished internalization and action of 1,25-dihydroxyvitamin D3 in dermal fibroblasts cultured from New World primates

International Nuclear Information System (INIS)

Adams, J.S.; Gacad, M.A.; Baker, A.J.; Kheun, G.; Rude, R.K.

1985-01-01

We investigated the occurrence of 1,25-dihydroxyvitamin D3 [1,25-(OH)2D3]-resistant osteomalacia in the New World primate colony of Saguinus imperator at the Los Angeles Zoo. The mean serum concentration of 1,25-(OH)2D3 was elevated 5-fold in the New World primates compared to that in their Old World counterparts. The specific internalization of 0.6 nM [ 3 H]1,25-(OH)2D3 by cultured dermal fibroblasts from New World primates was reduced 75% compared to that by cells from Old World primates or man. The decrease in hormone uptake resulted from a decrease in the number of high affinity intracellular binding sites for 1,25-(OH)2D3 and apparently caused a 90-95% reduction in 1,25-(OH)2D3-induced 25-hydroxyvitamin-D3-24-hydroxylase activity. There was no alteration in the capacity or avidity of New World primate serum for 1,25-(OH)2D3 compared to that of serum from Old World primates. These data suggest that the occurrence of vitamin D-resistant osteomalacia in New World primates is the result of decreased high affinity, receptor-mediated uptake of 1,25-(OH)2D3 by the target cell

1,25-Dihydroxyvitamin D3 stimulates the production of insulin-like growth factor-binding proteins-2, -3 and -4 in human bone marrow stromal cells

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Kveiborg, Marie; Flyvbjerg, Allan; Eriksen, E F

2001-01-01

1,25-Dihydroxyvitamin D3 (calcitriol) inhibits proliferation and stimulates differentiation of multiple cell types, including osteoblasts. Human (h) bone marrow stromal cells (MSCs) are a homogenous non-hematopoietic population of cells present in the bone marrow and exhibit a less differentiated...

Depigmented-polymerised allergoids favour regulatory over effector T cells: enhancement by 1α, 25-dihydroxyvitamin D3.

Science.gov (United States)

Urry, Zoe L; Richards, David F; Black, Cheryl; Morales, Maria; Carnés, Jerónimo; Hawrylowicz, Catherine M; Robinson, Douglas S

2014-05-29

Allergen immunotherapy (SIT) is the only treatment for allergic disease capable of modifying disease long term. To reduce the risk of anaphylaxis from SIT, allergen-extracts have been modified by polymerisation with glutaraldehyde to reduce IgE binding. It is suggested that these allergoid extracts also have reduced T cell activity, which could compromise clinical efficacy. Effective SIT is thought to act through regulatory T cells (Tregs) rather than activation of effector T cells. There is no published data on the activity of modified extracts on Tregs. We compared the capacity of modified (depigmented-polymerised) versus unmodified (native) allergen extracts of grass pollen and house dust mite to stimulate proliferation/cytokine production and to modulate Treg/effector T cell frequency in cultures of peripheral blood mononuclear cells (PBMC), from volunteers sensitised to both allergens in vitro. Depigmented-polymerised allergen extracts stimulated less proliferation of PBMC, and reduced effector cell numbers after 7 days in culture than did native extracts. However, the frequency of Foxp3+ Tregs in cultures were similar to those seen with native extract so that ratios of regulatory to effector T cells were significantly increased in cultures stimulated with depigmented-polymerised extracts. Addition of 1α, 25-dihydroxyvitamin D3 further favoured Treg, and reduced effector cytokine production, but not interleukin-10. Depigmented-polymerised allergen extracts appear to favour Treg expansion over activation of effector T cells and this may relate to their demonstrated efficacy and safety in SIT. 1α, 25-dihydroxyvitamin D3 further reduces effector T cell activation by allergen extracts and may be a useful adjuvant for SIT.

Etude comparative du contenu en récepteurs de la 1,25-dihydroxyvitamine D3 dans des muqueuses et des adénocarcinomes digestifs

NARCIS (Netherlands)

Meggouh, F.; Lointier, P.; Pezet, D.; Saez, S.

1990-01-01

We have studied and compared the 1,25-dihydroxyvitamin D3 receptor (RD3) content of 154 human digestive carcinoma with the normal mucosa one, removed at distance from the same surgical specimen. The distribution of biopsies is as follows: 5 oesophagus, 10 stomach, 6 small bowel, 35 right colon, 47

The Influence of 1α.25-Dihydroxyvitamin D3 Coating on Implant Osseointegration in the Rabbit Tibia

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Yoshihito

2014-10-01

Full Text Available Objectives: This study aims to evaluate bone response to an implant surface modified by 1α,25-dihydroxyvitamin D3 [1.25-(OH2D3] in vivo and the potential link between 1.25-(OH 2D3 surface concentration and bone response. Material and Methods: Twenty-eight implants were divided into 4 groups (1 uncoated control, 3 groups coated with 1.25-(OH2D3 in concentrations of 10-8, 10-7 and 10-6 M respectively, placed in the rabbit tibia for 6 weeks. Topographical analyses were carried out on coated and uncoated discs using interferometer and atomic-force-microscope (AFM. Twenty-eight implants were histologically observed (bone-to-implant-contact [BIC] and new-bone-area [NBA]. Results: The results showed that the 1.25-(OH2D3 coated implants presented a tendency to osseointegrate better than the non-coated surfaces, the differences were not significant (P > 0.05. Conclusions: The effect of 1.25-(OH2D3 coating to implants suggested possible dose dependent effects, however no statistical differences could be found. It is thought that the base substrate topography (turned could not sustain sufficient amount of 1.25-(OH2D3 enough to present significant biologic responses. Thus, development a base substrate that can sustain 1.25-(OH2D3 for a long period is necessary in future studies.

Vitamin D receptor in the paraventricular nucleus of the hypothalamus is necessary for beneficial effects of 1,25D[3] on peripheral glucose levels

Science.gov (United States)

While a wide range of data correlates low vitamin D levels with type 2 diabetes, few studies examine potential mechanisms by which vitamin D might impact key aspects of metabolism. The active form of 1alpha,25-dihydroxyvitamin D[3] (1,25D[3]; calcitriol) is hydroxylated in the liver and kidney from ...

1,25-dihydroxyvitamin D{sub 3} impairs NF-{kappa}B activation in human naive B cells

Energy Technology Data Exchange (ETDEWEB)

Geldmeyer-Hilt, Kerstin, E-mail: kerstin.hilt@charite.de [Allergie-Centrum-Charite, CCM, Klinik fuer Dermatologie und Allergologie, Charite - Universitaetsmedizin Berlin, Chariteplatz 1, 10117 Berlin (Germany); Heine, Guido, E-mail: guido.heine@charite.de [Allergie-Centrum-Charite, CCM, Klinik fuer Dermatologie und Allergologie, Charite - Universitaetsmedizin Berlin, Chariteplatz 1, 10117 Berlin (Germany); Deutsches Rheuma-Forschungszentrum Berlin, Chariteplatz 1, 10117 Berlin (Germany); Hartmann, Bjoern, E-mail: bjoern.hartmann@charite.de [Allergie-Centrum-Charite, CCM, Klinik fuer Dermatologie und Allergologie, Charite - Universitaetsmedizin Berlin, Chariteplatz 1, 10117 Berlin (Germany); Baumgrass, Ria, E-mail: baumgrass@drfz.de [Deutsches Rheuma-Forschungszentrum Berlin, Chariteplatz 1, 10117 Berlin (Germany); Radbruch, Andreas, E-mail: radbruch@drfz.de [Deutsches Rheuma-Forschungszentrum Berlin, Chariteplatz 1, 10117 Berlin (Germany); Worm, Margitta, E-mail: margitta.worm@charite.de [Allergie-Centrum-Charite, CCM, Klinik fuer Dermatologie und Allergologie, Charite - Universitaetsmedizin Berlin, Chariteplatz 1, 10117 Berlin (Germany)

2011-04-22

Highlights: {yields} In naive B cells, VDR activation by calcitriol results in reduced NF-{kappa}B p105 and p50 protein expression. {yields} Ligating the VDR with calcitriol causes reduced nuclear translocation of NF-{kappa}B p65. {yields} Reduced nuclear amount of p65 after calcitriol incubation results in reduced binding of p65 on the p105 promoter. {yields} Thus, vitamin D receptor signaling may reduce or prevent activation of B cells and unwanted immune responses, e.g. in IgE dependent diseases such as allergic asthma. -- Abstract: 1{alpha},25-dihydroxyvitamin D{sub 3} (calcitriol), the bioactive metabolite of vitamin D, modulates the activation and inhibits IgE production of anti-CD40 and IL-4 stimulated human peripheral B cells. Engagement of CD40 results in NF-{kappa}B p50 activation, which is essential for the class switch to IgE. Herein, we investigated by which mechanism calcitriol modulates NF-{kappa}B mediated activation of human naive B cells. Naive B cells were predominantly targeted by calcitriol in comparison with memory B cells as shown by pronounced induction of the VDR target gene cyp24a1. Vitamin D receptor activation resulted in a strongly reduced p105/p50 protein and mRNA expression in human naive B cells. This effect is mediated by impaired nuclear translocation of p65 and consequently reduced binding of p65 to its binding site in the p105 promoter. Our data indicate that the vitamin D receptor reduces NF-{kappa}B activation by interference with NF-{kappa}B p65 and p105. Thus, the vitamin D receptor inhibits costimulatory signal transduction in naive B cells, namely by reducing CD40 signaling.

Fibroblast growth factor 23 inhibits extrarenal synthesis of 1,25-dihydroxyvitamin D in human monocytes.

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Bacchetta, Justine; Sea, Jessica L; Chun, Rene F; Lisse, Thomas S; Wesseling-Perry, Katherine; Gales, Barbara; Adams, John S; Salusky, Isidro B; Hewison, Martin

2013-01-01

Vitamin D is a potent stimulator of monocyte innate immunity, and this effect is mediated via intracrine conversion of 25-hydroxyvitamin D (25OHD) to 1,25-dihydroxyvitamin D (1,25(OH)(2) D). In the kidney, synthesis of 1,25(OH)(2) D is suppressed by fibroblast growth factor 23 (FGF23), via transcriptional suppression of the vitamin D-activating enzyme 1α-hydroxylase (CYP27B1). We hypothesized that FGF23 also suppresses CYP27B1 in monocytes, with concomitant effects on intracrine responses to 1,25(OH)(2) D. Healthy donor peripheral blood mononuclear cell monocytes (PBMCm) and peritoneal dialysate monocyte (PDm) effluent from kidney disease patients were assessed at baseline to confirm the presence of mRNA for FGF23 receptors (FGFRs), with Klotho and FGFR1 being more strongly expressed than FGFR2/3/4 in both cell types. Immunohistochemistry showed coexpression of Klotho and FGFR1 in PBMCm and PDm, with this effect being enhanced following treatment with FGF23 in PBMCm but not PDm. Treatment with FGF23 activated mitogen-activated protein kinase (MAPK) and protein kinase B (Akt) pathways in PBMCm, demonstrating functional FGFR signaling in these cells. FGF23 treatment of PBMCm and PDm decreased expression of mRNA for CYP27B1. In PBMCm this was associated with downregulation of 25OHD to 1,25(OH)(2) D metabolism, and concomitant suppression of intracrine induced 24-hydroxylase (CYP24A1) and antibacterial cathelicidin (LL37). FGF23 suppression of CYP27B1 was particularly pronounced in PBMCm treated with interleukin-15 to stimulate synthesis of 1,25(OH)(2) D. These data indicate that FGF23 can inhibit extra-renal expression of CYP27B1 and subsequent intracrine responses to 1,25(OH)(2) D in two different human monocyte models. Elevated expression of FGF23 may therefore play a crucial role in defining immune responses to vitamin D and this, in turn, may be a key determinant of infection in patients with chronic kidney disease (CKD). Copyright © 2013 American Society for

1α,25-Dihydroxyvitamin D(3) inhibits vascular cellular adhesion molecule-1 expression and interleukin-8 production in human coronary arterial endothelial cells.

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Kudo, Keiko; Hasegawa, Shunji; Suzuki, Yasuo; Hirano, Reiji; Wakiguchi, Hiroyuki; Kittaka, Setsuaki; Ichiyama, Takashi

2012-11-01

Kawasaki disease is an acute febrile vasculitis of childhood that is associated with elevated production of inflammatory cytokines, causing damage to the coronary arteries. The production of proinflammatory cytokines and expression of adhesion molecules in human coronary arterial endothelial cells (HCAECs) is regulated by nuclear transcription factor-κB (NF-κB) activation. We have previously reported that the active form of vitamin D, 1α,25-dihydroxyvitamin D(3) (1α,25-(OH)(2)D(3)), inhibits tumor necrosis factor-α (TNF-α)-induced NF-κB activation. In this study, we examined the anti-inflammatory effects of 1α,25-(OH)(2)D(3) on TNF-α-induced adhesion molecule expression (vascular cellular adhesion molecule-1 (VCAM-1) and intercellular adhesion molecule-1 (ICAM-1)) and cytokine production (interleukin-6 (IL-6) and IL-8) in HCAECs. Pretreatment with 1α,25-(OH)(2)D(3) significantly inhibited TNF-α-induced VCAM-1 expression and IL-8 production in HCAECs. Our results suggest that adjunctive 1α,25-(OH)(2)D(3) therapy may modulate the inflammatory response during Kawasaki disease vasculitis. Copyright © 2012 Elsevier Ltd. All rights reserved.

Synthesis of 25-hydroxy-[26,27-3H]vitamin D2, 1,25-dihydroxy-[26,27-3H]vitamin D2 and their (24R)-epimers

International Nuclear Information System (INIS)

Sicinski, R.R.; Tanaka, Y.; Phelps, M.; Schnoes, H.K.; DeLuca, H.F.

1987-01-01

Synthesis of a C-24-epimeric mixture of 25-hydroxy-[26,27- 3 H]vitamin D2 and a C-24-epimeric mixture of 1,25-dihydroxy-[26,27- 3 H]vitamin D2 by the Grignard reaction of the corresponding 25-keto-27-nor-vitamin D2 and 1 alpha-acetoxy-25-keto-27-nor-vitamin D3 with tritiated methyl magnesium bromide is described. Separation of epimers by high-performance liquid chromatography afforded pure radiolabeled vitamins of high specific activity (80 Ci/mmol). The identities and radiochemical purities of 25-hydroxy-[26,27- 3 H[vitamin D2 and 1,25-dihydroxy-[26,27- 3 H]vitamin D2 D2 were established by cochromatography with synthetic 25-hydroxyvitamin D2 or 1,25-dihydroxyvitamin D2. Biological activity of 25-hydroxy-[26,27- 3 H]vitamin D2 was demonstrated by its binding to the rat plasma binding protein for vitamin D compounds, and by its in vitro conversion to 1,25-dihydroxy-[26,27- 3 H]vitamin D2 by kidney homogenate prepared from vitamin D-deficient chickens. The biological activity of 1,25-dihydroxy-[26,27- 3 H]vitamin D2 was demonstrated by its binding to the chick intestinal receptor for 1,25-dihydroxyvitamin D3

On the physiological role of 1,24,25-trihydroxyvitamin D/sub 3/

Energy Technology Data Exchange (ETDEWEB)

Castillo, L. (Univ. of Wisconsin, Madison); Tanaka, Y.; DeLuca, H.F.; Ikekawa, N.

1978-01-01

The extent, onset and duration of the biological activity of 1,24(R),25-trihydroxyvitamin D/sub 3/, 1,24(S),25-trihydroxyvitamin D/sub 3/ has been compared with that of 1,25-dihydroxyvitamin D/sub 3/ in the elevation of serum phosphorus, healing of rickets, stimulation of intestinal calcium transport, mobilization of calcium from bone in vitamin D-deficient rats and induction 25-hydroxyvitamin D/sub 3/-24-hydroxylase in chickens. The 1,24,25-trihydroxyvitamin D/sub 3/ S and R isomers are approximately equal in activity but both are less active than 1,25-dihydroxyvitamin D/sub 3/. In some systems their duration of activity is also less than that of 1,25-dihydroxyvitamin D/sub 3/. The time course of response to the 3 forms of vitamin D is approximately equal. These results strongly suggest that 1,24(R),25-trihydroxyvitamin D/sub 3/ is not a further activation product of 1,25-dihydroxyvitamin D/sub 3/, but is likely a product leading to inactivation.

Treatment with 1,25-dihydroxyvitamin D3 reduces impairment of human osteoblast functions during cellular aging in culture

DEFF Research Database (Denmark)

Kveiborg, M.; Rattan, Suresh; Eriksen, E.F.

2001-01-01

is due to impaired responsiveness to calcitriol known to be important for the regulation of biological activities of the osteoblasts. Thus, we examined changes in vitamin D receptor (VDR) system and the osteoblastic responses to calcitriol treatment during in vitro osteoblast aging. We found no change...... in the amount of VDR at either steady state mRNA level or protein level with increasing in vitro osteoblast age and examination of VDR localization, nuclear translocation and DNA binding activity revealed no in vitro age-related changes. Furthermore, calcitriol (10(-8)M) treatment of early-passage osteoblastic......Adequate responses to various hormones, such as 1,25-dihydroxyvitamin D(3) (calcitriol) are a prerequisite for optimal osteoblast functions. We have previously characterized several human diploid osteoblastic cell lines that exhibit typical in vitro aging characteristics during long...

Expression of human kinase suppressor of Ras 2 (hKSR-2) gene in HL60 leukemia cells is directly upregulated by 1,25-dihydroxyvitamin D3 and is required for optimal cell differentiation

International Nuclear Information System (INIS)

Wang Xuening; Wang, T.-T.; White, John H.; Studzinski, George P.

2007-01-01

Induction of terminal differentiation of neoplastic cells offers potential for a novel approach to cancer therapy. One of the agents being investigated for this purpose in preclinical studies is 1,25-dihydroxyvitamin D 3 (1,25D), which can convert myeloid leukemia cells into normal monocyte-like cells, but the molecular mechanisms underlying this process are not fully understood. Here, we report that 1,25D upregulates the expression of hKSR-2, a new member of a small family of proteins that exhibit evolutionarily conserved function of potentiating ras signaling. The upregulation of hKSR-2 is direct, as it occurs in the presence of cycloheximide, and occurs primarily at the transcriptional level, via activation of vitamin D receptor, which acts as a ligand-activated transcription factor. Two VDRE-type motifs identified in the hKSR-2 gene bind VDR-RXR alpha heterodimers present in nuclear extracts of 1,25D-treated HL60 cells, and chromatin immunoprecipitation assays show that these VDRE motifs bind VDR in 1,25D-dependent manner in intact cells, coincident with the recruitment of RNA polymerase II to these motifs. Treatment of the cells with siRNA to hKSR-2 reduced the proportion of the most highly differentiated cells in 1,25D-treated cultures. These results demonstrate that hKSR-2 is a direct target of 1,25D in HL60 cells, and is required for optimal monocytic differentiation

1,25-Dihydroxyvitamin D3 (1,25(OH)2D3) Signaling Capacity and the Epithelial-Mesenchymal Transition in Non-Small Cell Lung Cancer (NSCLC): Implications for Use of 1,25(OH)2D3 in NSCLC Treatment

International Nuclear Information System (INIS)

Upadhyay, Santosh Kumar; Verone, Alissa; Shoemaker, Suzanne; Qin, Maochun; Liu, Song; Campbell, Moray; Hershberger, Pamela A.

2013-01-01

1,25-dihydroxyvitamin D 3 (1,25(OH) 2 D 3 ) exerts anti-proliferative activity by binding to the vitamin D receptor (VDR) and regulating gene expression. We previously reported that non-small cell lung cancer (NSCLC) cells which harbor epidermal growth factor receptor (EGFR) mutations display elevated VDR expression (VDR high ) and are vitamin D-sensitive. Conversely, those with K-ras mutations are VDR low and vitamin D-refractory. Because EGFR mutations are found predominately in NSCLC cells with an epithelial phenotype and K-ras mutations are more common in cells with a mesenchymal phenotype, we investigated the relationship between vitamin D signaling capacity and the epithelial mesenchymal transition (EMT). Using NSCLC cell lines and publically available lung cancer cell line microarray data, we identified a relationship between VDR expression, 1,25(OH) 2 D 3 sensitivity, and EMT phenotype. Further, we discovered that 1,25(OH) 2 D 3 induces E-cadherin and decreases EMT-related molecules SNAIL, ZEB1, and vimentin in NSCLC cells. 1,25(OH) 2 D 3 -mediated changes in gene expression are associated with a significant decrease in cell migration and maintenance of epithelial morphology. These data indicate that 1,25(OH) 2 D 3 opposes EMT in NSCLC cells. Because EMT is associated with increased migration, invasion, and chemoresistance, our data imply that 1,25(OH) 2 D 3 may prevent lung cancer progression in a molecularly defined subset of NSCLC patients

Fractures in the men of a Veterans Administration Nursing Home: relation to 1,25-dihydroxyvitamin D.

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Rudman, D; Rudman, I W; Mattson, D E; Nagraj, H S; Caindec, N; Jackson, D L

1989-08-01

One hundred fifty-three men, age 48-96, 86% white, had resided in this Nursing Home for an average of 6.3 years (range 1.3-36) as of August 1984. At that time, we reviewed their medical charts to record the numbers and sites of fractures which had been diagnosed during the preceding 1 to 5 years of Nursing Home residence, the duration of this period depending on the duration of institutionalization. In addition, a clinical database was compiled comprising 70 attributes, including diagnoses, drugs, plasma (serum) chemistries, and measures of hematologic, nutritional, and functional status. Fractures during the studied period of Nursing Home residence had occurred in 24 of 153 men; six residents had experienced two or more fractures. Fracture rates in hip, spine, and wrist were 2564, 366, and 549 per 100,000 patient years, respectively. The total fracture rate, hip fracture rate, and limb fracture rate were five to 11 times higher than in the age-matched general population of white men in the United States; in Rochester, MN; in Dundee, England; in Oxford, England; or in Finland. Univariate statistical analysis showed that the rates for hip fracture or for fracture at any site were significantly associated with 13 attributes: directly with age, plasma somatomedin C, blood urea N, serum creatinine, serum uric acid, serum 25-hydroxyvitamin D (25-OH-D), degree of functional impairment, and chronic urinary tract infection, and inversely with serum 1,25-dihydroxyvitamin D [1,25-(OH)2-D], serum albumin, hematocrit, and hemoglobin. There was not a significant correlation with the number of falls/month which occurred during the 7 months after August 1984. After the effect of age was partialed out, somatomedin C, 25-OH-D, 1,25-(OH)2-D, and the diagnosis of urinary tract infection were still significantly related to the occurrence of fractures. The fact that Nursing Home fracture cases had significantly higher blood urea nitrogen and 25-OH-D, and significantly lower 1,25-(OH)2

Control of proliferating potential of myeloid leukemia cells during long-term treatment with vitamin D3 analogues and other differentiation inducers in combination with antileukemic drugs: in vitro and in vivo studies.

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Kasukabe, T; Honma, Y; Hozumi, M; Suda, T; Nishii, Y

1987-01-15

Growth inhibition of murine and human myeloid leukemia cells by differentiation inducers during long-term culture was examined to improve the strategy for therapy of myeloid leukemia by differentiation inducers. When the effect of 1 alpha,25-dihydroxyvitamin D3, a typical differentiation inducer, on proliferation of mouse myeloid leukemia M1 cells was examined at a constant product of time and concentration (480 nM in 20 days), the continuous treatment with 24 nM 1 alpha,25-dihydroxyvitamin D3 was the most effective for inhibition of cell proliferation. After 20 days, the cumulative cell number was reduced about 3 X 10(5) times by continuous treatment with 24 nM 1 alpha,25-dihydroxyvitamin D3. Similar results were obtained when M1 cells were treated continuously with dexamethasone. M1 cells resistant to 1 alpha,25-dihydroxyvitamin D3 appeared about 25 days after the start of continuous treatment with 24 nM 1 alpha,25-dihydroxyvitamin D3. On the other hand, when M1 cells were treated continuously with 1 alpha,25-dihydroxyvitamin D3 and noncytotoxic doses of antileukemic drugs such as 1-beta-D-arabinofuranosylcytosine and daunomycin, resistant cells did not appear for at least 35 days. A similar effect of 1 alpha,25-dihydroxyvitamin D3 and antileukemic drugs on cell proliferation was observed with the human monoblast-like cell line U937. The survival of syngeneic SL mice inoculated with M1 cells was prolonged more by treatment with both 1 alpha-hydroxyvitamin D3 and daunomycin than by treatment with either drug alone. These results suggest that continuous treatment with both differentiation inducers and certain antileukemic drugs may be more effective therapeutically than treatment with a differentiation inducer alone.

Biological Evaluation of Double Point Modified Analogues of 1,25-Dihydroxyvitamin D2 as Potential Anti-Leukemic Agents

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Aoife Corcoran

2016-02-01

Full Text Available Structurally similar double-point modified analogues of 1,25-dihydroxyvitamin D2 (1,25D2 were screened in vitro for their pro-differentiating activity against the promyeloid cell line HL60. Their affinities towards human full length vitamin D receptor (VDR and metabolic stability against human vitamin D 24-hydroxylase (CYP24A1 were also tested. The analogues (PRI-1730, PRI-1731, PRI-1732, PRI-1733 and PRI-1734 contained 5,6-trans modification of the A-ring and of the triene system, additional hydroxyl or unsaturation at C-22 in the side chain and reversed absolute configuration (24-epi at C-24 of 1,25D2. As presented in this paper, introduction of selected structural modifications simultaneously in two distinct parts of the vitamin D molecule resulted in a divergent group of analogues. Analogues showed lower VDR affinity in comparison to that of the parent hormones, 1,25D2 and 1,25D3, and they caused effective HL60 cell differentiation only at high concentrations of 100 nM and above. Unexpectedly, introducing of a 5,6-trans modification combined with C-22 hydroxyl and 24-epi configuration switched off entirely the cell differentiation activity of the analogue (PRI-1734. However, this analogue remained a moderate substrate for CYP24A1, as it was metabolized at 22%, compared to 35% for 1,25D2. Other analogues from this series were either less (12% for PRI-1731 and PRI-1733 or more (52% for PRI-1732 resistant to the enzymatic deactivation. Although the inactive analogue PRI-1734 failed to show VDR antagonism, when tested in HL60 cells, its structure might be a good starting point for our design of a vitamin D antagonist.

Simultaneous quantification of vitamin D₃, 25-hydroxyvitamin D-3 and 24,25-dihydroxyvitamin D₃ in human serum by LC-MS/MS

DEFF Research Database (Denmark)

Burild, Anders; Frandsen, Henrik Lauritz; Jakobsen, Jette

2014-01-01

Introduction. Serum 25-hydroxy-vitamin D is the established biomarker of vitamin D status although serum concentrations of vitamin D and 24,25-dihydroxyvitamin D may also be of interest to understand the in vivo kinetics of serum 25-hydroxyvitamin D. Method. An LC-MS/MS method was developed...

1,25-Dihydroxyvitamin D3 Inhibits the RANKL Pathway and Impacts on the Production of Pathway-Associated Cytokines in Early Rheumatoid Arthritis

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Jing Luo

2013-01-01

Full Text Available Objectives. To study effects of 1,25-dihydroxyvitamin D3 (1,25(OH2D3 on RANKL signaling pathway and pathway-associated cytokines in patients with rheumatoid arthritis (RA. Methods. Receptor activator of nuclear factor-kappa B ligand (RANKL, osteoprotegerin (OPG, IFN-γ, IL-6, TNF-α, IL-17, and IL-4 were examined in 54 patients with incipient RA using a cytometric bead array (CBA or an enzyme-linked immunosorbent assay (ELISA. Results. After 72 hours of incubation of peripheral blood mononuclear cells (PBMCs with 1,25(OH2D3 in RA patients, the levels of RANKL, TNF-α, IL-17 and IL-6 significantly decreased compared to those of the control. 1,25(OH2D3 had no significantly impact on the levels of OPG, RANKL/OPG, and IL-4. Conclusions. The present study demonstrated that 1,25(OH2D3 reduced the production of RANKL and the secretion of TNF-α, IL-17, and IL-6 in PBMCs of RA patients, which indicated that 1,25(OH2D3 might be able to decrease damage of cartilage and bone in RA patients by regulating the expression of RANKL signaling pathway and pathway-associated cytokines.

The heterodimeric structure of heterogeneous nuclear ribonucleoprotein C1/C2 dictates 1,25-dihydroxyvitamin D-directed transcriptional events in osteoblasts.

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Lisse, Thomas S; Vadivel, Kanagasabai; Bajaj, S Paul; Chun, Rene F; Hewison, Martin; Adams, John S

2014-01-01

Heterogeneous nuclear ribonucleoprotein (hnRNP) C plays a key role in RNA processing. More recently hnRNP C has also been shown to function as a DNA binding protein exerting a dominant-negative effect on transcriptional responses to the vitamin D hormone,1,25-dihydroxyvitamin D (1,25(OH) 2 D), via interaction in cis with vitamin D response elements (VDREs). The physiologically active form of human hnRNPC is a tetramer of hnRNPC1 (huC1) and C2 (huC2) subunits known to be critical for specific RNA binding activity in vivo , yet the requirement for heterodimerization of huC1 and C2 in DNA binding and downstream action is not well understood. While over-expression of either huC1 or huC2 alone in mouse osteoblastic cells did not suppress 1,25(OH) 2 D-induced transcription, over-expression of huC1 and huC2 in combination using a bone-specific polycistronic vector successfully suppressed 1,25(OH) 2 D-mediated induction of osteoblast target gene expression. Over-expression of either huC1 or huC2 in human osteoblasts was sufficient to confer suppression of 1,25(OH) 2 D-mediated transcription, indicating the ability of transfected huC1 and huC2 to successfully engage as heterodimerization partners with endogenously expressed huC1 and huC2. The failure of the chimeric combination of mouse and human hnRNPCs to impair 1,25(OH) 2 D-driven gene expression in mouse cells was structurally predicted, owing to the absence of the last helix in the leucine zipper (LZ) heterodimerization domain of hnRNPC gene product in lower species, including the mouse. These results confirm that species-specific heterodimerization of hnRNPC1 and hnRNPC2 is a necessary prerequisite for DNA binding and down-regulation of 1,25(OH) 2 D-VDR-VDRE-directed gene transactivation in osteoblasts.

1,25-dihydroxyvitamin D3 is an autonomous regulator of the transcriptional changes leading to a tolerogenic dendritic cell phenotype.

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Széles, Lajos; Keresztes, Gábor; Töröcsik, Dániel; Balajthy, Zoltán; Krenács, László; Póliska, Szilárd; Steinmeyer, Andreas; Zuegel, Ulrich; Pruenster, Monika; Rot, Antal; Nagy, László

2009-02-15

Activation of vitamin D receptor (VDR) by 1,25-dihydroxyvitamin D(3) (1,25-vitD) reprograms dendritic cells (DC) to become tolerogenic. Previous studies suggested that 1,25-vitD could inhibit the changes brought about by differentiation and maturation of DCs. Underpinning the described phenotypic and functional alterations, there must be 1,25-vitD-coordinated transcriptional events. However, this transcriptional program has not been systematically investigated, particularly not in a developmental context. Hence, it has not been explored how 1,25-vitD-regulated genes, particularly the ones bringing about the tolerogenic phenotype, are connected to differentiation. We conducted global gene expression analysis followed by comprehensive quantitative PCR validation to clarify the interrelationship between 1,25-vitD and differentiation-driven gene expression patterns in developing human monocyte-derived and blood myeloid DCs. In this study we show that 1,25-vitD regulates a large set of genes that are not affected by differentiation. Interestingly, several genes, impacted both by the ligand and by differentiation, appear to be regulated by 1,25-vitD independently of the developmental context. We have also characterized the kinetics of generation of 1,25-vitD by using three early and robustly regulated genes, the chemokine CCL22, the inhibitory receptors CD300LF and CYP24A1. We found that monocyte-derived DCs are able to turn on 1,25-vitD sensitive genes in early phases of differentiation if the precursor is present. Our data collectively suggest that exogenous or endogenously generated 1,25-vitD regulates a large set of its targets autonomously and not via inhibition of differentiation and maturation, leading to the previously characterized tolerogenic state.

Importance of apical membrane delivery of 1,25-dihydroxyvitamin D3 to vitamin D-responsive gene expression in the colon.

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Koszewski, Nicholas J; Horst, Ronald L; Goff, Jesse P

2012-10-01

Synthetic conjugation of a glucuronide to 1,25-dihydroxyvitamin D3 (1,25D3) to produce β-25-monoglucuronide-1,25D3 (βGluc-1,25D3) renders the hormone biologically inactive and resistant to mammalian digestive enzymes. However, β-glucuronidase produced by bacteria in the lower intestinal tract can cleave off the glucuronide, releasing the active hormone. In mice given a single oral dose of 1,25D3, 24-hydroxylase (Cyp24a1) gene expression was strongly enhanced in the duodenum, but not in the colon, despite circulating concentrations of 1,25D3 that peaked at ∼3.0 nmol/l. In contrast, in mice treated with an equimolar dose of βGluc-1,25D3, Cyp24a1 gene expression increased 700-fold in the colon but was significantly weaker in the duodenum compared with mice treated with 1,25D3. Similar results were observed with another vitamin D-dependent gene. When administered subcutaneously, 1,25D3 weakly stimulated colon Cyp24a1 gene expression while βGluc-1,25D3 again resulted in strong enhancement. Surgical ligation to block passage of ingesta beyond the upper intestinal tract abolished upregulation of colon Cyp24a1 gene expression by orally and subcutaneously administered βGluc-1,25D3. Feeding βGluc-1,25D3 for 5 days revealed a linear, dose-dependent increase in colon Cyp24a1 gene expression but did not significantly increase plasma 1,25D3 or calcium concentrations. This study indicates that the colon is relatively insensitive to circulating concentrations of 1,25D3 and that the strongest gene enhancement occurs when the hormone reaches the colon via the lumen of the intestinal tract. These findings have broad implications for the use of vitamin D compounds in colon disorders and set the stage for future therapeutic studies utilizing βGluc-1,25D3 in their treatment.

Regulation of C/EBPβ isoforms by MAPK pathways in HL60 cells induced to differentiate by 1,25-dihydroxyvitamin D3

International Nuclear Information System (INIS)

Marcinkowska, Ewa; Garay, Edward; Gocek, Elzbieta; Chrobak, Agnieszka; Wang, Xuening; Studzinski, George P.

2006-01-01

C/EBPβ is known to be important for monocytic differentiation and macrophage function. Here, we found that expression of all three C/EBPβ isoforms induced in HL60 cells by 1,25-dihydroxyvitamin D 3 (1,25D) was upregulated in a sustained manner that correlates with the appearance of monocytic phenotype and with the G1 phase cell cycle arrest. In 1,25D-resistant HL60-40AF cells, isoforms β-1 and β-3 were expressed at levels comparable to 1,25D-sensitive HL60-G cells, but isoform β-2 was difficult to detect. Treatment of sensitive HL60 cells with 1,25D resulted in predominantly nuclear localization of C/EBP isoforms β-2 and β-3, while a large proportion of C/EBPβ-1 remained in the cytoplasm. Attenuation of the MEK-ERK MAPK pathway by the inhibitor PD98059 markedly reduced the expression, 1,25D-induced phosphorylation and nuclear localization of C/EBPβ-2 and C/EBPβ-3. Interestingly, only the lower molecular mass isoforms of C/EBPβ phosphorylated on Thr235 were found in the nuclei, while C/EBPβ-1 was constitutively phosphorylated and was detected principally in the cytoplasmic fraction. Although the role of C/EBPβ isoforms in 1,25D-induced differentiation is complex, our results taken together strongly suggest that the phosphorylation of C/EBPβ isoforms on Thr235 takes place mainly via the MEK-ERK pathway and that C/EBPβ-2 is the principal transcription factor in this cell system

NKT cells can help mediate the protective effects of 1,25-dihydroxyvitamin D3 in experimental autoimmune encephalomyelitis in mice.

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Waddell, Amanda; Zhao, Jun; Cantorna, Margherita T

2015-05-01

Active vitamin D [1,25-dihydroxyvitamin D3 (1,25D3)] blocks the development of experimental autoimmune diseases. However, the molecular and immunobiological mechanisms underlying 1,25D3's anti-inflammatory properties are not fully understood. We employed a murine model of experimental autoimmune encephalomyelitis (EAE) in order to determine the role of NKT cells in 1,25D3-mediated protection from EAE. Wild-type (WT) mice or mice lacking all NKT cells (CD1d(-/-)) or invariant NKT cells (Jα18(-/-)) were fed control or 1,25D3-supplemented diets. All mice fed with the control diet developed severe EAE. 1,25D3 treatment of WT mice protected them from developing EAE. CD1d(-/-) and Jα18(-/-) mice treated with 1,25D3 were not protected to the same extent as WT mice. Myelin oligodendrocyte glycoprotein-specific IL-17 and IFN-γ production was significantly reduced in 1,25D3 WT mice compared with WT but was not decreased in 1,25D3 CD1d(-/-) mice compared with CD1d(-/-) mice. IL-4(-/-) mice were utilized to determine how IL-4 deficiency affects susceptibility to EAE. IL-4(-/-) mice were not protected from developing EAE by α-galactosylceramide (α-GalCer) or 1,25D3 treatment. Furthermore, 1,25D3 treatment of splenocytes in vitro decreased α-GalCer-induced IL-17 and increased IL-4, IL-5 and IL-10 production. 1,25D3 alters the cytokine profile of invariant NKT cells in vitro. These studies demonstrate that NKT cells are important mediators of 1,25D3-induced protection from EAE in mice and NKT cell-derived IL-4 may be an important factor in providing this protection. © The Japanese Society for Immunology. 2015. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Suppression of epithelial ovarian cancer invasion into the omentum by 1α,25-dihydroxyvitamin D3 and its receptor.

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Lungchukiet, Panida; Sun, Yuefeng; Kasiappan, Ravi; Quarni, Waise; Nicosia, Santo V; Zhang, Xiaohong; Bai, Wenlong

2015-04-01

Epithelial ovarian cancer (EOC) is the leading cause of gynecological cancer death in women, mainly because it has spread to intraperitoneal tissues such as the omentum in the peritoneal cavity by the time of diagnosis. In the present study, we established in vitro assays, ex vivo omental organ culture system and syngeneic animal tumor models using wild type (WT) and vitamin D receptor (VDR) null mice to investigate the effects of 1α,25-dihydroxyvitamin D3 (1,25D3) and VDR on EOC invasion. Treatment of human EOC cells with 1,25D3 suppressed their migration and invasion in monolayer scratch and transwell assays and ability to colonize the omentum in the ex vivo system, supporting a role for epithelial VDR in interfering with EOC invasion. Furthermore, VDR knockdown in OVCAR3 cells increased their ability to colonize the omentum in the ex vivo system in the absence of 1,25D3, showing a potential ligand-independent suppression of EOC invasion by epithelial VDR. In syngeneic models, ID8 tumors exhibited an increased ability to colonize omenta of VDR null over that of WT mice; pre-treatment of WT, not VDR null, mice with EB1089 reduced ID8 colonization, revealing a role for stromal VDR in suppressing EOC invasion. These studies are the first to demonstrate a role for epithelial and stromal VDR in mediating the activity of 1,25D3 as well as a 1,25D3-independent action of the VDR in suppressing EOC invasion. The data suggest that VDR-based drug discovery may lead to the development of new intervention strategies to improve the survival of patients with EOC at advanced stages. This article is part of a Special Issue entitled "Vitamin D Workshop". Copyright © 2014 Elsevier Ltd. All rights reserved.

Comparison of the biological effects of exogenous and endogenous 1,25-dihydroxyvitamin D3 on the mature osteoblast cell line MLO-A5.

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Yang, Dongqing; Anderson, Paul H; Turner, Andrew G; Morris, Howard A; Atkins, Gerald J

2016-11-01

Clinical and animal data indicate that serum 25-hydroxyvitamin D 3 (25D) exerts an anabolic effect on bone while serum 1α,25-dihydroxyvitamin D 3 (1,25D) stimulates bone mineral loss, although the mechanism responsible for these divergent actions is unknown. Biological effects of 25D on bone cells are dependent on the local conversion to 1,25D by the 25-hydroxyvitamin D-1α-hydroxylase enzyme, CYP27B1. Therefore, identification of possible differential activities of locally produced and exogenously supplied 1,25D in bone is likely to be informative for guiding optimal administration of vitamin D supplements for bone health. The mature osteoblastic cell line MLO-A5 expresses both the vitamin D receptor (Vdr) and Cyp27b1, and therefore is a suitable model for comparing the activities of 1,25D arising from these sources. Biologically, exogenous and endogenous sources of 1,25D have similar effects on proliferation, mineralisation and induction of a range of genes by MLO-A5 osteoblasts under osteogenic conditions although endogenous 1,25D levels are markedly lower than exogenous levels. Significant differences of pharmacokinetics and pharmacodynamics of 1,25D are evident between these two sources particularly in terms of modulating gene expression for Cyp24a1 and other genes largely expressed by embedded osteoblasts/osteocytes suggesting that endogenously synthesised 1,25D is more efficiently utilised by the differentiating osteoblast. Copyright © 2016 Elsevier Ltd. All rights reserved.

Randomized double-blinded placebo-controlled intra-individual trial on topical treatment with a 1,25-dihydroxyvitamin D₃ analogue in polymorphic light eruption.

Science.gov (United States)

Gruber-Wackernagel, A; Bambach, I; Legat, F J; Hofer, A; Byrne, S N; Quehenberger, F; Wolf, P

2011-07-01

Polymorphic light eruption (PLE) is a very frequent photodermatosis whose pathogenesis may involve resistance to ultraviolet (UV)-induced immune suppression. Similar to UV radiation, calcitriol (1,25-dihydroxyvitamin D₃) and its analogues such as calcipotriol have been shown to exhibit immunosuppressive properties. We performed a randomized double-blinded placebo-controlled intraindividual half-body trial (NCT00871052) to investigate the preventive effect of a calcipotriol-containing cream in PLE. Thirteen patients with PLE (10 women, three men; mean age 37 years) pretreated their skin on two symmetrically located test fields with calcipotriol or placebo cream twice daily for 7 days before the start of photoprovocation testing with solar-simulated UV radiation. We established a specific PLE test score [AA + SI + 0·4 P (range 0-12), where AA is affected area score (range 0-4), SI is skin infiltration score (range 0-4) and P is pruritus score on a visual analogue scale (range 0-10)] to quantify PLE severity. Photoprovocation led to PLE lesions in 12/13 (92%) patients. As shown by the PLE test score, compared with placebo calcipotrial pretreatment significantly reduced PLE symptoms in average by 32% (95% confidence interval 21-44%; P = 0·0022, exact Wilcoxon signed-rank test) throughout the observation period starting at 48 h until 144 h after the first photoprovocation exposure. At 48, 72 and 144 h calcipotriol pretreatment resulted in a lower PLE test score in 7 (58%), 9 (75%) and 10 (83%) of the 12 cases, respectively. Considering all time points together, calcipotriol diminished the PLE test score in all 12 photoprovocable patients (P = 0·0005; Wilcoxon signed-rank test). These results suggest a potential therapeutic benefit of topical 1,25-dihydroxyvitamin D₃ analogues as prophylactic treatment in patients with PLE. © 2011 The Authors. BJD © 2011 British Association of Dermatologists 2011.

MART-10, a New Generation of Vitamin D Analog, Is More Potent than 1α,25-Dihydroxyvitamin D3 in Inhibiting Cell Proliferation and Inducing Apoptosis in ER+ MCF-7 Breast Cancer Cells

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Kun-Chun Chiang

2012-01-01

Full Text Available Hormone antagonist therapy for estrogen receptor positive (ER+ breast cancer patients post radical surgery and radiation therapy has a poor prognosis and also causes bone loss. 1α,25-dihydroxyvitamin D3 [1α,25(OH2D3] is a potent antitumor agent in pre-clinical studies, but caused hypercalcemia when its effective antitumor doses were used. Therefore, we investigated the effects of a less-calcemic 1α,25(OH2D3 analog, 19-nor-2α-(3-hydroxypropyl-1α,25-dihydroxyvitamin D3 (MART-10, on ER+MCF-7 cells. We demonstrate that MART-10 is 500- to 1000-fold more potent than 1α,25(OH2D3 in inhibiting cell growth in a dose- and time-dependent manner. MART-10 is also much more potent in arresting MCF-7cell cycle progression at G0/G1 phase as compared to 1α,25(OH2D3, possibly mediated by a greater induction of p21 and p27 expression. Moreover, MART-10 is more active than 1α,25(OH2D3 in causing cell apoptosis, likely through a higher BAX/Bcl expression ratio and the subsequent cytochrome C release from mitochondria to cytosol. Based on our in vitro findings, MART-10 could be a promising vitamin D analog for the potential treatment of breast cancer, for example, ER+ patients, to decrease the tumor relapse rate and the side effect on bone caused by antihormone regimens. Thus, further in vivo animal study is warranted.

1,25-Dihydroxyvitamin D{sub 3} (1,25(OH){sub 2}D{sub 3}) Signaling Capacity and the Epithelial-Mesenchymal Transition in Non-Small Cell Lung Cancer (NSCLC): Implications for Use of 1,25(OH){sub 2}D{sub 3} in NSCLC Treatment

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Upadhyay, Santosh Kumar; Verone, Alissa; Shoemaker, Suzanne [Department of Pharmacology and Therapeutics, Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, NY 14263 (United States); Qin, Maochun; Liu, Song [Department of Biostatistics and Bioinformatics, Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, NY 14263 (United States); Campbell, Moray; Hershberger, Pamela A., E-mail: pamela.hershberger@roswellpark.org [Department of Pharmacology and Therapeutics, Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, NY 14263 (United States)

2013-11-08

1,25-dihydroxyvitamin D{sub 3} (1,25(OH){sub 2}D{sub 3}) exerts anti-proliferative activity by binding to the vitamin D receptor (VDR) and regulating gene expression. We previously reported that non-small cell lung cancer (NSCLC) cells which harbor epidermal growth factor receptor (EGFR) mutations display elevated VDR expression (VDR{sup high}) and are vitamin D-sensitive. Conversely, those with K-ras mutations are VDR{sup low} and vitamin D-refractory. Because EGFR mutations are found predominately in NSCLC cells with an epithelial phenotype and K-ras mutations are more common in cells with a mesenchymal phenotype, we investigated the relationship between vitamin D signaling capacity and the epithelial mesenchymal transition (EMT). Using NSCLC cell lines and publically available lung cancer cell line microarray data, we identified a relationship between VDR expression, 1,25(OH){sub 2}D{sub 3} sensitivity, and EMT phenotype. Further, we discovered that 1,25(OH){sub 2}D{sub 3} induces E-cadherin and decreases EMT-related molecules SNAIL, ZEB1, and vimentin in NSCLC cells. 1,25(OH){sub 2}D{sub 3}-mediated changes in gene expression are associated with a significant decrease in cell migration and maintenance of epithelial morphology. These data indicate that 1,25(OH){sub 2}D{sub 3} opposes EMT in NSCLC cells. Because EMT is associated with increased migration, invasion, and chemoresistance, our data imply that 1,25(OH){sub 2}D{sub 3} may prevent lung cancer progression in a molecularly defined subset of NSCLC patients.

Circulating Endothelial Microparticles and Correlation of Serum 1,25-Dihydroxyvitamin D with Adiponectin, Nonesterified Fatty Acids, and Glycerol from Middle-Aged Men in China

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Zhongxiao Wan

2016-01-01

Full Text Available The aim of the present study is (1 to determine the correlation between circulating 1,25-dihydroxyvitamin D [25(OHD] and adiponectin, nonesterified fatty acids (NEFAs, and glycerol and (2 to determine the alterations in circulating endothelial microparticles (EMPs in Chinese male subjects with increased body mass index (BMI. A total of 45 male adults were enrolled with varied BMI [i.e., lean, overweight (OW, and obese (OB, N=15 per group]. Blood samples were collected under overnight fasting condition, and plasma was isolated for the measurement of endothelial microparticles (EMPs, total and high-molecular weight (HMW adiponectin, 25(OHD, nonesterified fatty acids (NEFAs, and glycerol. Circulating 25(OHD levels were inversely associated with total adiponectin, NEFA, and glycerol levels. There is no difference for CD62E+ or CD31+/CD42b− EMPs among 3 groups. In Chinese male adults with varied BMI, an inverse correlation existed between 25(OHD levels and total adiponectin, NEFA, and glycerol levels; and there is no significant difference for CD62E+ or CD31+/CD42b− EMPs among lean, overweight, and obese subjects.

Effect of 1,24R-dihydroxyvitamin D3 on the growth of human keratinocytes.

LENUS (Irish Health Repository)

Matsumoto, K

1990-02-01

The effect of 1,24R-dihydroxyvitamin D3 (1,24R(OH)2D3), a synthetic analogue of a biologically active form of vitamin D3 (1,25-dihydroxyvitamin D3, 1,25(OH)2D3), on the growth of human keratinocytes cultured in serum-free medium was investigated. The growth of cultured normal human keratinocytes was inhibited by 65% by 10(-8)M 1,24R(OH)2D3 and by 90% by 10(-7)M 1,24(OH)2D3. It inhibited cell growth almost completely at 10(-6)M. The DNA synthesis of keratinocytes was also inhibited with 1,24R(OH)2D3 by 27% at 10(-8)M, 59% at 10(-7)M, and 92% at 10(-6)M. The inhibition of cell growth and DNA synthesis were more remarkable by 1,24R(OH)2D3 than by 1,25(OH)2D3. 1,24R(OH)2D3 also inhibited the growth of keratinocytes derived from patients with psoriasis vulgaris; the growth inhibitory effect was again more remarkable with 1,24R(OH)2D3 than with 1,25(OH)2D3. The viability and protein synthesis of keratinocytes were not affected by 1,24R(OH)2D3, suggesting that the growth inhibitory effect is due to its biological activity, not to cytotoxicity. The binding of [3H]-labeled 1,25(OH)2D3 to its receptor in the cytosolic fraction of cultured keratinocytes was competitively substituted by unlabeled 1,24R(OH)2D3 as well as 1,25(OH)2D3, suggesting that 1,24R(OH)2D3 binds to the 1,25(OH)2D3 receptor. It was found that the affinity of 1,24R(OH)2D3 for the receptor was slightly higher than that of 1,25(OH)2D3. These results demonstrate that 1,24R(OH)2D3 functions as a potent growth inhibitor in vitro in human keratinocytes from both normal and psoriatic epidermis, and it possesses a higher affinity for the 1,25(OH)2D3 receptor in cultured human keratinocytes. The difference in affinity of 1,24R(OH)2D3 for the 1,25(OH)2D3 receptor correlates with its greater inhibition of keratinocyte growth than 1,25(OH)2D3. 1,24R(OH)2D3 may be useful in the treatment of psoriasis.

End product inhibition of hepatic 25-hydroxyvitamin D production in the rat: specificity and kinetics

International Nuclear Information System (INIS)

Milne, M.L.; Baran, D.T.

1985-01-01

The role of vitamin D metabolites in the regulation of hepatic 25-hydroxyvitamin D production was investigated by examining the effects of 25-hydroxyvitamin D, 1,25-dihydroxyvitamin D, and 24,25-dihydroxyvitamin D on the synthesis of [25- 3 H]hydroxyvitamin D by rachitic rat liver homogenates. Production of [25- 3 H]hydroxyvitamin D was inhibited by 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D, but not by 24,25-dihydroxyvitamin D. 25-Hydroxyvitamin D increased the Km of the vitamin D-25-hydroxylase enzyme(s), while 1,25-dihydroxyvitamin D decreased the Vmax with a Ki of 88.7 ng/ml. Inhibition of hepatic 25-hydroxyvitamin D production by 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D may be another control mechanism to regulate circulating vitamin D levels

Resistance to 1,25-dihydroxyvitamin D. Association with heterogeneous defects in cultured skin fibroblasts

International Nuclear Information System (INIS)

Liberman, U.A.; Eil, C.; Marx, S.J.

1983-01-01

The authors evaluated the interaction of [ 3 H]1,25(OH) 2 D3 with skin fibroblasts cultured from normal subjects or from affected members of six kindreds with rickets and resistance to 1-alpha, 25(OH) 2 D [1,25(OH) 2 D]. They analyzed two aspects of the radioligand interaction; nuclear uptake with dispersed, intact cells at 37 degrees C and binding at 0 degrees C with soluble extract (cytosol) prepared from cells disrupted in buffer. With normal fibroblasts the affinity and capacity of nuclear uptake of [ 3 H]1,25(OH) 2 D3 were 0.5 nM and 10,300 sites per cell, respectively; for binding with cytosol these were 0.13 nM and 8,900 sites per cell, respectively. The following four patterns of interaction with [ 3 H]1,25(OH) 2 D3 were observed with cells cultured from affected patients. In all cases where the radioligand bound with high affinity in nucleus or cytosol, the nucleus- or cytosol-associated radioligand exhibited normal sedimentation velocity on sucrose density gradients. When two kindreds exhibited similar patterns (i.e. pattern a or c) with the analyses of cultured fibroblasts, clinical features in affected members suggested that the underlying genetic defects were not identical. In conclusion: (a) Fibroblasts cultured from human skin manifest nuclear uptake and cytosol binding of [ 3 H]1,25(OH) 2 D3 that is an expression of the genes determining these processes in target tissues. (b) Based upon data from clinical evaluations and from analyses of cultured fibroblasts, severe resistance to 1,25(OH) 2 D resulted from five or six distinct genetic mutations in six kindreds

Clinical, biochemical and histological results of a double-blind trial with 1,25-dihydroxyvitamin D3, estradiol and placebo in post-menopausal osteoporosis.

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Caniggia, A; Delling, G; Nuti, R; Lorè, F; Vattimo, A

1984-01-01

Twenty-eight women with postmenopausal osteoporosis were studied in a double-blind trial aimed to compare the effects of a one-year treatment with 1,25-dihydroxyvitamin D3 (1,25(OH)2D3), estradiol valerate (E2) and placebo. Patients were divided into 4 groups: group 1 was given 1,25(OH)2D3 alone, group 2 was given E2 alone, group 3 was given 1,25(OH)2D3 + E2, group 4 received a placebo. The evaluation of the effects of the treatments included clinical examination of patients, the measurement of a number of biochemical parameters, such as plasma and urinary calcium and phosphate, urinary hydroxyproline, serum alkaline phosphatase, the measurement of intestinal calcium absorption and bone mineral content (BMC) and a histomorphometric study of bone biopsies from the iliac crest. The best clinical results were obtained in the patients who were given 1,25(OH)2D3 alone; appreciable results were also noticed in the patients who were given E2 alone or in combination with 1,25(OH)2D3, while patients in the placebo group worsened. BMC decreased in the placebo group and increased, although non significantly, in the patients treated with 1,25(OH)2D3 or E2 or both. The histomorphometric study showed a significant increase in the mean trabecular diameter in patients treated with 1,25(OH)2D3 alone or in combination with E2. Changes in the volume density of trabecular bone paralleled those in BMC. The results of the trial indicate that 1,25(OH)2D3 is an effective therapeutic agent in postmenopausal osteoporosis.

Resistance to 1,25-dihydroxyvitamin D. Association with heterogeneous defects in cultured skin fibroblasts

International Nuclear Information System (INIS)

Liberman, U.A.; Eil, C.; Marx, S.J.

1983-01-01

We evaluated the interaction of [ 3 H]1,25(OH) 2 D 3 with skin fibroblasts cultured from normal subjects or from affected members of six kindreds with rickets and resistance to 1-alpha, 25(OH) 2 D [1,25(OH) 2 D]. We analyzed two aspects of the radioligand interaction; nuclear uptake with dispersed, intact cells at 37 degrees C and binding at 0 degrees C with soluble extract (cytosol) prepared from cells disrupted in buffer containing 300 mM KCl and 10 mM sodium molybdate. With normal fibroblasts the affinity and capacity of nuclear uptake of [ 3 H]1,25(OH) 2 D 3 were 0.5 nM and 10,300 sites per cell, respectively; for binding with cytosol these were 0.13 nM and 8,900 sites per cell, respectively. In all cases where the radioligand bound with high affinity in nucleus or cytosol, the nucleus- or cytosol-associated radioligand exhibited normal sedimentation velocity on sucrose density gradients. When two kindreds exhibited similar patterns (i.e. pattern a or c) with the analyses of cultured fibroblasts, clinical features in affected members suggested that the underlying genetic defects were not identical. In conclusion: (a) Fibroblasts cultured from human skin manifest nuclear uptake and cytosol binding of [ 3 H]1,25(OH) 2 D 3 that is an expression of the genes determining these processes in target tissues. (b) Based upon data from clinical evaluations and from analyses of cultured fibroblasts, severe resistance to 1,25(OH) 2 D resulted from five or six distinct genetic mutations in six kindreds

Evaluation of intraprostatic metabolism of 1,25-dihydroxyvitamin D(3) (calcitriol) using a microdialysis technique.

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Konety, Badrinath R; Somogyi, George; Atan, Ali; Muindi, Josephia; Chancellor, Michael B; Getzenberg, Robert H

2002-06-01

1,25-dihydroxyvitamin D(3) (calcitriol) inhibits prostate cancer growth in vitro and in vivo. We used a prostate microdialysis technique to better understand the intraprostatic pharmacokinetics of calcitriol, which in turn would facilitate planning for systemic calcitriol therapy in patients with prostate cancer. Male Sprague-Dawley rats were treated with 5 microg of calcitriol intravenously. Animals were either intact (group 1, n = 6) or castrated (group 2, n = 3). Prostate microdialysis was performed by perfusing Krebs solution through a 5-mm linear probe. Effluents were collected hourly from 0 to 20 hours or until death. Serum was collected at baseline and at the end of the experiment. Serum was also obtained from untreated rats at 0, 1, 2, 3, 4, 6, 8, 12, and 24 hours after intraperitoneal injection of calcitriol. Calcitriol levels were measured by radioimmunoassay. The average baseline intraprostatic level of calcitriol in prostate dialysate in intact rats was 21.1 pg/mL (+/-7.5); it was 88 pg/mL (+/-98.4) after calcitriol administration. In castrated animals, the values were 16.6 pg/mL (+/-5.3) and 25.3 pg/mL (+/-10.7). Two peaks in intraprostatic calcitriol levels were observed after intravenous administration: at less than 6 hours after injection and at more than 13 hours after injection. The mean total calcitriol exposure (area under the concentration versus time curve) in the prostate was 297.6 (+/-159) pg/hr/mL (intact) and 272.7 (+/-123.6) pg/hr/mL (castrated). The baseline serum levels were 0.1 to 1 ng/mL and reached a peak of more than 100 ng/mL within 1 hour of intraperitoneal injection. This technique permits real-time measurement of intraprostatic pharmacokinetics of calcitriol. The ratio of the intraprostatic area under the concentration versus time curve to the serum area under the concentration versus time curve of calcitriol was less than 1:100. Hence, within 24 hours of calcitriol administration, only a fraction (less than 1%) of the serum

Pakistanis living in Oslo have lower serum 1,25-dihydroxyvitamin D levels but higher serum ionized calcium levels compared with ethnic Norwegians. The Oslo Health Study

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Holvik, Kristin; Meyer, Haakon E; Søgaard, Anne Johanne; Haug, Egil; Falch, Jan A

2007-01-01

Background Persons of Pakistani origin living in Oslo have a much higher prevalence of vitamin D deficiency and secondary hyperparathyroidism but similar bone mineral density compared with ethnic Norwegians. Our objective was to investigate whether Pakistani immigrants living in Oslo have an altered vitamin D metabolism by means of compensatory higher serum levels of 1,25-dihydroxyvitamin D (s-1,25(OH)2D) compared with ethnic Norwegians; and whether serum levels of ionized calcium (s-Ca2+) differ between Pakistanis and Norwegians. Methods In a cross-sectional, population-based study venous serum samples were drawn from 94 Pakistani men and 67 Pakistani women aged 30–60 years, and 290 Norwegian men and 270 Norwegian women aged 45–60 years; in total 721 subjects. Results Pakistanis had lower s-1,25(OH)2D compared with Norwegians (p Oslo with low vitamin D status and secondary hyperparathyroidism have lower s-1,25(OH)2D compared with ethnic Norwegians. However, the Pakistanis have higher s-Ca2+. The cause of the higher s-Ca2+ in Pakistanis in spite of their higher iPTH remains unclear. PMID:17945003

Constitutively active RAS signaling reduces 1,25 dihydroxyvitamin D-mediated gene transcription in intestinal epithelial cells by reducing vitamin D receptor expression.

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DeSmet, Marsha L; Fleet, James C

2017-10-01

High vitamin D status is associated with reduced colon cancer risk but these studies ignore the diversity in the molecular etiology of colon cancer. RAS activating mutations are common in colon cancer and they activate pro-proliferative signaling pathways. We examined the impact of RAS activating mutations on 1,25 dihydroxyvitamin D (1,25(OH) 2 D)-mediated gene expression in cultured colon and intestinal cell lines. Transient transfection of Caco-2 cells with a constitutively active mutant K-RAS (G12 V) significantly reduced 1,25(OH) 2 D-induced activity of both a human 25-hydroxyvitamin D, 24 hydroxyase (CYP24A1) promoter-luciferase and an artificial 3X vitamin D response element (VDRE) promoter-luciferase reporter gene. Young Adult Mouse Colon (YAMC) and Rat Intestinal Epithelial (RIE) cell lines with stable expression of mutant H-RAS had suppressed 1,25(OH) 2 D-mediated induction of CYP24A1 mRNA. The RAS effects were associated with lower Vitamin D receptor (VDR) mRNA and protein levels in YAMC and RIE cells and they could be partially reversed by VDR overexpression. RAS-mediated suppression of VDR levels was not due to either reduced VDR mRNA stability or increased VDR gene methylation. However, chromatin accessibility to the VDR gene at the proximal promoter (-300bp), an enhancer region at -6kb, and an enhancer region located in exon 3 was significantly reduced in RAS transformed YAMC cells (YAMC-RAS). These data show that constitutively active RAS signaling suppresses 1,25(OH) 2 D-mediated gene transcription in colon epithelial cells by reducing VDR gene transcription but the mechanism for this suppression is not yet known. These data suggest that cancers with RAS-activating mutations may be less responsive to vitamin D mediated treatment or chemoprevention. Copyright © 2017 Elsevier Ltd. All rights reserved.

Nongenomic effects of 1α,25-dihydroxyvitamin D3 on cartilage formation deduced from comparisons between Cyp27b1 and Vdr knockout mice

International Nuclear Information System (INIS)

Hirota, Yoshihisa; Nakagawa, Kimie; Mimatsu, Shino; Sawada, Natsumi; Sakaki, Toshiyuki; Kubodera, Noboru; Kamao, Maya; Tsugawa, Naoko; Suhara, Yoshitomo; Okano, Toshio

2017-01-01

The active form of vitamin D, 1α,25-dihydroxyvitamin D 3 (1α,25D 3 ), plays an important role in the maintenance of calcium (Ca) homeostasis, bone formation, and cell proliferation and differentiation via nuclear vitamin D receptor (VDR). It is formed by the hydroxylation of vitamin D at the 1α position by 25-hydroxyvitamin D 1α-hydroxylase (CYP27B1) in the kidney. However, Cyp27b1 −/− mice, deficient in CYP27B1, and VDR-deficient mice (Vdr −/− ) have not been extensively examined, particularly in a comparative framework. To clarify the physiological significance of 1α,25D 3 and VDR, we produced Cyp27b1 −/− mice and compared their phenotypes with those of Vdr −/− mice. Cyp27b1 −/− mice exhibited hypocalcemia, growth defects, and skeletogenesis dysfunction, similar to Vdr −/− mice. However, unlike Cyp27b1 −/− mice, Vdr −/− mice developed alopecia. Cyp27b1 −/− mice exhibited cartilage mass formation and had difficulty walking on hindlimbs. Furthermore, a phenotypic analysis was performed on Cyp27b1 −/− mice provided a high Ca diet to correct for the Ca metabolic abnormality. In addition, the effects of 1α,25D 3 that are not mediated by Ca metabolic regulatory activity were investigated. Even when the blood Ca concentration was corrected, abnormalities in growth and cartilage tissue formation did not improve in Cyp27b1 −/− mice. These results suggested that 1α,25D 3 directly controls chondrocyte proliferation and differentiation. Using Cyp27b1 −/− mice produced in this study, we can analyze the physiological effects of novel vitamin D derivatives in the absence of endogenous 1α,25D 3 . Accordingly, this study provides a useful animal model for the development of novel vitamin D formulations that are effective for the treatment and prevention of osteoporosis. - Highlights: • We produced Cyp27b1 −/− mice and analyzed their phenotypes. • Vdr −/− mice exhibited alopecia and Cyp27b1 −/− mice exhibited

Effects of 1,25-Dihydroxyvitamin D3 on the Prevention of Chronic Obstructive Pulmonary Disease (COPD) in Rats Exposed to Air Pollutant Particles Less than 2.5 Micrometers in Diameter (PM2.5).

Science.gov (United States)

Chen, Lerong; Yuan, Xiaolan; Zou, Luru; Peng, Jianping; Hu, Xinchun

2018-01-18

BACKGROUND This study aimed to investigate the effects of 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) on airway changes in chronic obstructive pulmonary disease (COPD) rats exposed to air pollutant particles less than 2.5 micrometers in diameter (PM2.5), and to evaluate the mechanisms. MATERIAL AND METHODS Three groups were included in this study: a normal group, a COPD model group, and a COPD with 1,25(OH)2D3 treatment group. In each group, the rats were divided into four subgroups: control and different doses of PM2.5 (1.6, 8 and 40 mg/kg body weight). Apoptosis in lung tissue was detected by terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL). The expression of c-Jun N-terminal kinase 1 (JNK1) and mucin 5AC (MUC5AC) were detected by real-time polymerase chain reaction (RT-PCR), Western blotting and immunofluorescence staining. RESULTS Compared with corresponding subgroups in normal group, the apoptotic rates in COPD group were significantly increased. By contrast, 1,25(OH)2D3 treatment group significantly reduced COPD-induced apoptosis in lung tissue. Upon the dose increase of PM2.5, the apoptotic rate was also elevated in each group. Compared with the corresponding control in each group, PM2.5 increased apoptosis in a dose-dependent manner. Importantly, 1,25(OH)2D3 also prevented apoptosis in COPD rats exposed to PM2.5. Mechanically, the expression of MUC5AC and JNK1 in COPD group was significantly upregulated, compared with corresponding subgroups in the normal group. Treatment with 1,25(OH)2D3 reduced expression of MUC5AC and JNK1 in COPD rats. It was found that the expression of MUC5AC and JNK1 was elevated with the dose increase of PM2.5 in each group. Consistently, 1,25(OH)2D3 also reduced the expression of MUC5AC and JNK1 in COPD rats exposed to PM2.5. CONCLUSIONS 1,25(OH)2D3 prevented lung injury in COPD rats with or without PM2.5 exposure. Our results suggest that 1,25(OH)2D3 is useful to mitigate the injury caused by COPD.

1,25-dihydroxyvitamin D3 impairs NF-κB activation in human naive B cells

International Nuclear Information System (INIS)

Geldmeyer-Hilt, Kerstin; Heine, Guido; Hartmann, Bjoern; Baumgrass, Ria; Radbruch, Andreas; Worm, Margitta

2011-01-01

Highlights: → In naive B cells, VDR activation by calcitriol results in reduced NF-κB p105 and p50 protein expression. → Ligating the VDR with calcitriol causes reduced nuclear translocation of NF-κB p65. → Reduced nuclear amount of p65 after calcitriol incubation results in reduced binding of p65 on the p105 promoter. → Thus, vitamin D receptor signaling may reduce or prevent activation of B cells and unwanted immune responses, e.g. in IgE dependent diseases such as allergic asthma. -- Abstract: 1α,25-dihydroxyvitamin D 3 (calcitriol), the bioactive metabolite of vitamin D, modulates the activation and inhibits IgE production of anti-CD40 and IL-4 stimulated human peripheral B cells. Engagement of CD40 results in NF-κB p50 activation, which is essential for the class switch to IgE. Herein, we investigated by which mechanism calcitriol modulates NF-κB mediated activation of human naive B cells. Naive B cells were predominantly targeted by calcitriol in comparison with memory B cells as shown by pronounced induction of the VDR target gene cyp24a1. Vitamin D receptor activation resulted in a strongly reduced p105/p50 protein and mRNA expression in human naive B cells. This effect is mediated by impaired nuclear translocation of p65 and consequently reduced binding of p65 to its binding site in the p105 promoter. Our data indicate that the vitamin D receptor reduces NF-κB activation by interference with NF-κB p65 and p105. Thus, the vitamin D receptor inhibits costimulatory signal transduction in naive B cells, namely by reducing CD40 signaling.

Honey bee venom combined with 1,25-dihydroxyvitamin D3as a highly efficient inducer of differentiation in human acute myeloid leukemia cells.

Science.gov (United States)

Mohseni-Kouchesfahani, Homa; Nabioni, Mohammad; Khosravi, Zahra; Rahimi, Maryam

2017-01-01

Most cancer cells exhibit a defect in their capacity to mature into nonreplicating adult cells and existing in a highly proliferating state. Differentiation therapy by agents such as 1,25-dihydroxyvitamin D3(1,25-(OH)2 VD3) represents a useful approach for the treatment of cancer including acute myeloid leukemia. Human myeloid leukemia cell lines are induced to terminal differentiation into monocyte lineage by 1,25-(OH)2 VD3. However, usage of these findings in the clinical trials is limited by calcemic effects of 1,25-(OH)2 VD3. Attempts to overcome this problem have focused on a combination of low concentrations 1,25-(OH)2 VD3 with other compounds to induce differentiation of HL-60 cells. In this study, the effect of honey bee venom (BV) and 1,25-(OH)2 VD3, individually and in combination, on proliferation and differentiation of human myeloid leukemia HL-60 cells were assayed. In this in vitro study, toxic and nontoxic concentrations of BV and 1,25-(OH)2 VD3 were tested using Trypan blue stained cell counting and (3[4, 5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide) assay. In addition, differentiation of cells was assayed using a Wright-Giemsa staining and nitroblue tetrazolium reduction test. Data were analyzed by a one-way analysis of the variance test using SPSS software. Our findings showed that both the BV and 1,25-(OH)2 VD3, in a dose and time-dependent manner, caused cell death at high concentrations and inhibited cell proliferation at lower concentrations. About 5 nM of 1,25-(OH)2 VD3 induced differentiation of HL-60 cells to monocytes after 72 h. 2.5 μg/ml of BV suppressed proliferation of HL-60 cells but had not any effects on their differentiation, whereas in combination with 5 nM of 1,25-(OH)2 VD3, it enhanced antiproliferative and differentiation potency of 1,25-(OH)2 VD3. These results indicate that BV potentiates the 1,25-(OH)2 VD3-induced HL-60 cell differentiation into monocytes.

The protective effect of 1alpha, 25-dihydroxyvitamin d3 and metformin on liver in type 2 diabetic rats.

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Elattar, Samah; Estaphan, Suzanne; Mohamed, Enas A; Elzainy, Ahmed; Naguib, Mary

2017-10-01

There is an accumulating evidence suggesting an immunomodulatory role of 1α,25(OH) 2 D3. Altered 1α,25(OH) 2 D3 level may play a role in the development of T2DM and contribute to the pathogenesis of liver diseases. Our study was designed to study and compare the effect of metformin and 1α,25(OH) 2 D3 supplementation on liver injury in type 2 diabetic rat. Sixty male Albino rats were divided into 5 groups; group 1: control rats. the remaining rats were fed high fat diet for 2 weeks and injected with streptozotocin (35mg/kg BW, i.p.) to induce T2DM and were divided into: group 2: untreated diabetic rats, group 3: diabetic rats treated by metformin (100mg/kgBW/d, orally), group 4: diabetic rats supplemented by 1α,25(OH) 2 D3 (0.5μg/kg BW, i.p.) 3 times weekly and group 5: supplemented by both 1α,25(OH) 2 D3 and metformin. Eight weeks later, serum glucose and insulin levels were measured, HOMA IR was calculated, lipid profile, Ca2+, ALT and AST were estimated. Liver specimens were taken to investigate PPAR-α (regulator of lipid metabolism), NF-κB p65, caspase 3 and PCNA (proliferating cell nuclear antigen) and for histological examination. The liver enzymes were elevated in the diabetic rats and the histological results revealed an injurious effect of diabetes on the liver. 1α,25(OH) 2 D3, metformin and both drugs treatment significantly improved liver enzymes as compared to the untreated rats. The improvement was associated with a significant improvement in the glycemic control, lipid profile and serum Ca2+ with a significant reduction in NF-κB p65 and caspase 3 and increased PPAR-α, and PCNA expression as compared to the untreated group. 1α,25(OH) 2 D3 induced a slightly better effect as compared to metformin. Both agents together had a synergistic action and almost completely protected the liver. Histological results confirmed the biochemical findings. Our results showed a protective effect of 1α,25(OH) 2 D3 and metformin on liver in diabetic rats as

1,25-dihydroxyvitamin D3 induces LL-37 and HBD-2 production in keratinocytes from diabetic foot ulcers promoting wound healing: an in vitro model.

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Gonzalez-Curiel, Irma; Trujillo, Valentin; Montoya-Rosales, Alejandra; Rincon, Kublai; Rivas-Calderon, Bruno; deHaro-Acosta, Jeny; Marin-Luevano, Paulina; Lozano-Lopez, Daniel; Enciso-Moreno, Jose A; Rivas-Santiago, Bruno

2014-01-01

Diabetic foot ulcers (DFU) are one of the most common diabetes-related cause of hospitalization and often lead to severe infections and poor healing. It has been recently reported that patients with DFU have lower levels of antimicrobial peptides (AMPs) at the lesion area, which contributes with the impairment of wound healing. The aim of this study was to determine whether 1,25-dihydroxyvitamin D3 (1,25 (OH)2 D3) and L-isoleucine induced HBD-2 and LL-37 in primary cultures from DFU. We developed primary cell cultures from skin biopsies from 15 patients with DFU and 15 from healthy donors. Cultures were treated with 1,25 (OH)2D3 or L-isoleucine for 18 h. Keratinocytes phenotype was identified by western blot and flow cytometry. Real time qPCR for DEFB4, CAMP and VDR gene expression was performed as well as an ELISA to measure HBD-2 and LL-37 in supernatant. Antimicrobial activity, in vitro, wound healing and proliferation assays were performed with conditioned supernatant. The results show that primary culture from DFU treated with 1,25(OH)2D3, increased DEFB4 and CAMP gene expression and increased the production of HBD-2 and LL-37 in the culture supernatant. These supernatants had antimicrobial activity over E. coli and induced remarkable keratinocyte migration. In conclusion the 1,25(OH)2D3 restored the production of AMPs in primary cell from DFU which were capable to improve the in vitro wound healing assays, suggesting their potential therapeutic use on the treatment of DFU.

Regulation of 1,25-dihydroxyvitamin D, receptors by [3H]-1,25-dihydroxyvitamin D3 in cultured cells (T-47D): evidence for receptor upregulation

International Nuclear Information System (INIS)

Reinhardt, T.A.; Horst, R.L.

1986-01-01

The authors examined the effect of 1,25-(OH) 2 D 3 on receptor concentration in cultured cells (T-47D). Two days prior to experiment, cells were fed with RPMI 1640 + 10% serum and 24-32 hours prior to experiment the media was replaced with RPMI 1640 + 25 mM Hepes + 1% serum. [ 3 H]-1,25-(OH) 2 D 3 +/- 100-fold molar excess cold hormone was used to treat the cells. Occupied receptors were measured in freshly prepared cytosols. Total receptors were measured following a 16-hour incubation of cytosols in the presence of 0.6 nM [ 3 H]-1,25-(OH) 2 D 3 +/- 100-fold molar excess of cold hormone at 4 0 C. Treatment of cell cultures for 16-18 hours with 0.5-1.0 nM [ 3 H]-1,25-(OH) 2 D 3 resulted in a 30-40% receptor occupancy by the hormone and a 2- to 3-fold increase in total cell receptor as compared to vehicle-treated controls. Time course studies showed a rapid increase in total receptors up to 16 hours post-treatment in the face of declining receptor occupancy. Actinomycin D blocked the [ 3 H]-1,25-(OH) 2 D 3 -dependent rise in cell receptor. The physiological significance of this receptor upregulation is not known nor is it known whether upregulation results from synthesis of new receptors and/or is the result of the activation of preformed receptors by a inducible activator protein

1,25-dihydroxyvitamin D3 induces LL-37 and HBD-2 production in keratinocytes from diabetic foot ulcers promoting wound healing: an in vitro model.

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Irma Gonzalez-Curiel

Full Text Available Diabetic foot ulcers (DFU are one of the most common diabetes-related cause of hospitalization and often lead to severe infections and poor healing. It has been recently reported that patients with DFU have lower levels of antimicrobial peptides (AMPs at the lesion area, which contributes with the impairment of wound healing. The aim of this study was to determine whether 1,25-dihydroxyvitamin D3 (1,25 (OH2 D3 and L-isoleucine induced HBD-2 and LL-37 in primary cultures from DFU. We developed primary cell cultures from skin biopsies from 15 patients with DFU and 15 from healthy donors. Cultures were treated with 1,25 (OH2D3 or L-isoleucine for 18 h. Keratinocytes phenotype was identified by western blot and flow cytometry. Real time qPCR for DEFB4, CAMP and VDR gene expression was performed as well as an ELISA to measure HBD-2 and LL-37 in supernatant. Antimicrobial activity, in vitro, wound healing and proliferation assays were performed with conditioned supernatant. The results show that primary culture from DFU treated with 1,25(OH2D3, increased DEFB4 and CAMP gene expression and increased the production of HBD-2 and LL-37 in the culture supernatant. These supernatants had antimicrobial activity over E. coli and induced remarkable keratinocyte migration. In conclusion the 1,25(OH2D3 restored the production of AMPs in primary cell from DFU which were capable to improve the in vitro wound healing assays, suggesting their potential therapeutic use on the treatment of DFU.

24R,25-Dihydroxyvitamin D3 Protects against Articular Cartilage Damage following Anterior Cruciate Ligament Transection in Male Rats.

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Barbara D Boyan

Full Text Available Osteoarthritis (OA in humans is associated with low circulating 25-hydroxyvitamin D3 [25(OHD3]. In vitamin D replete rats, radiolabeled 24R,25-dihydroxyvitamin D3 [24R,25(OH2D3] accumulates in articular cartilage following injection of [3H]-25(OHD3. Previously, we showed that 24R,25(OH2D3 blocks chondrocyte apoptosis via phospholipase D and p53, suggesting a role for 24R,25(OH2D3 in maintaining cartilage health. We examined the ability of 24R,25(OH2D3 to prevent degenerative changes in articular cartilage in an OA-like environment and the potential mechanisms involved. In vitro, rat articular chondrocytes were treated with IL-1β with and without 24R,25(OH2D3 or 1α,25(OH2D3. 24R,25(OH2D3 but not 1α,25(OH2D3 blocked the effects of IL-1β in a dose-dependent manner, and its effect was partially mediated through the TGF-β1 signaling pathway. In vivo, unilateral anterior cruciate ligament transections were performed in immunocompetent rats followed by intra-articular injections of 24R,25(OH2D3 or vehicle (t = 0, 7, 14, 21 days. Tissues were harvested on day 28. Joints treated with vehicle had changes typical of OA whereas joints treated with 24R,25(OH2D3 had less articular cartilage damage and levels of inflammatory mediators. These results indicate that 24R,25(OH2D3 protects against OA, and suggest that it may be a therapeutic approach for preventing trauma-induced osteoarthritis.

A radioligand immunoassay for 1,25-dihydroxyvitamin D3 receptors using monoclonal antibody: detection of a phenotypic receptor variant in vitamin D-dependency rickets (type II) which does not bind hormone

International Nuclear Information System (INIS)

Pike, J.W.; Dokoh, Shigeharu; Liberman, U.A.; Eil, C.; Haussler, M.R.; Marx, S.J.

1984-01-01

Vitamin D-dependency rickets, type II (VDDRII), is a well recognized heritable disorder characterized by peripheral target organ resistance to 1,25-dihydroxyvitamin D 3 (1,25(OH) 2 D 3 ), the hormonally active form of the vitamin. Recently, cultured skin fibroblasts obtained from a number of patients with VDDRII have been utilized to characterize the underlying molecular defects associated with this malady. Recently monoclonal antibodies to the vitamin D receptor have been generated, and a radioligand immunoassay (RLIA) for the detection of this molecule has been developed which is independent of its hormone-binding capacity. This report describes the application of the immunoassay in the detection of receptor-like molecules in fibroblasts derived from patients with VDDRII. The results indicate that the molecule is generally present in all patients, and provides a mechanism for individual responsiveness to pharmacologic treatment with vitamin D 3 metabolites. 8 refs.; 3 figs.; 1 table

Deletion of the Intestinal Plasma Membrane Calcium Pump, Isoform 1, Atp2b1, in Mice is Associated with Decreased Bone Mineral Density and Impaired Responsiveness to 1, 25-Dihydroxyvitamin D3

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Ryan, Zachary C.; Craig, Theodore A.; Filoteo, Adelaida G.; Westendorf, Jennifer J.; Cartwright, Elizabeth J.; Neyses, Ludwig; Strehler, Emanuel E.; Kumar, Rajiv

2016-01-01

The physiological importance of the intestinal plasma membrane calcium pump, isoform 1, (Pmca1, Atp2b1), in calcium absorption and homeostasis has not been previously demonstrated in vivo. Since global germ-line deletion of the Pmca1 in mice is associated with embryonic lethality, we selectively deleted the Pmca1 in intestinal absorptive cells. Mice with loxP sites flanking exon 2 of the Pmca1 gene (Pmca1fl/fl) were crossed with mice expressing Cre recombinase in the intestine under control of the villin promoter to give mice in which the Pmca1 had been deleted in the intestine (Pmca1EKO mice). Pmca1EKO mice were born at a reduced frequency and were small at the time of birth when compared to wild-type (Wt) litter mates. At two months of age, Pmca1EKO mice fed a 0.81% calcium, 0.34% phosphorus, normal vitamin D diet had reduced whole body bone mineral density (P <0.037), and reduced femoral bone mineral density (P <0.015). There was a trend towards lower serum calcium and higher serum parathyroid hormone (PTH) and 1α,25-dihydroxyvitamin D3 (1α,25(OH)2D3) concentrations in Pmca1EKO mice compared to Wt mice but the changes were not statistically significant. The urinary phosphorus/creatinine ratio was increased in Pmca1EKO mice (P <0.004). Following the administration of 200 ng of 1α,25(OH)2D3 intraperitoneally to Wt mice, active intestinal calcium transport increased ∼2-fold, whereas Pmca1EKO mice administered an equal amount of 1α,25(OH)2D3 failed to show an increase in active calcium transport. Deletion of the Pmca1 in the intestine is associated with reduced growth and bone mineralization, and a failure to up-regulate calcium absorption in response to 1α,25(OH)2D3. PMID:26392310

Hereditary 1,25-dihydroxyvitamin D-resistant rickets with alopecia resulting from a novel missense mutation in the DNA-binding domain of the vitamin D receptor

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Malloy, Peter J.; Wang, Jining; Srivastava, Tarak; Feldman, David

2009-01-01

The rare genetic recessive disease, hereditary vitamin D resistant rickets (HVDRR), is caused by mutations in the vitamin D receptor (VDR) that result in resistance to the active hormone 1,25-dihydroxyvitamin D3 (1,25-(OH)2D3 or calcitriol). In this study, we examined the VDR from a young boy with clinical features of HVDRR including severe rickets, hypocalcemia, hypophosphatemia and partial alopecia. The pattern of alopecia was very unusual with areas of total baldness, adjacent to normal hair and regions of scant hair. The child failed to improve on oral calcium and vitamin D therapy but his abnormal chemistries and his bone x-rays normalized with intravenous calcium therapy. We found that the child was homozygous for a unique missense mutation in the VDR gene that converted valine to methionine at amino acid 26 (V26M) in the VDR DNA-binding domain (DBD). The mutant VDR was studied in the patient’s cultured skin fibroblasts and found to exhibit normal [3H]1,25-(OH)2D3 binding and protein expression. However, the fibroblasts were unresponsive to treatment with high concentrations of 1,25(OH)2D3 as demonstrated by their failure to induce CYP24A1 gene expression, a marker of 1,25(OH)2D3 responsiveness. We recreated the V26M mutation in the WT VDR and showed that in transfected COS-7 cells the mutation abolished 1,25(OH)2D3-mediated transactivation. The mutant VDR exhibited normal ligand-induced binding to RXRα and to the coactivator DRIP205. However, the V26M mutation inhibited VDR binding to a consensus vitamin D response element (VDRE). In summary, we have identified a novel V26M mutation in the VDR DBD as the molecular defect in a patient with HVDRR and an unusual pattern of alopecia. PMID:19815438

ATP and MO25alpha regulate the conformational state of the STRADalpha pseudokinase and activation of the LKB1 tumour suppressor.

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Elton Zeqiraj

2009-06-01

Full Text Available Pseudokinases lack essential residues for kinase activity, yet are emerging as important regulators of signal transduction networks. The pseudokinase STRAD activates the LKB1 tumour suppressor by forming a heterotrimeric complex with LKB1 and the scaffolding protein MO25. Here, we describe the structure of STRADalpha in complex with MO25alpha. The structure reveals an intricate web of interactions between STRADalpha and MO25alpha involving the alphaC-helix of STRADalpha, reminiscent of the mechanism by which CDK2 interacts with cyclin A. Surprisingly, STRADalpha binds ATP and displays a closed conformation and an ordered activation loop, typical of active protein kinases. Inactivity is accounted for by nonconservative substitution of almost all essential catalytic residues. We demonstrate that binding of ATP enhances the affinity of STRADalpha for MO25alpha, and conversely, binding of MO25alpha promotes interaction of STRADalpha with ATP. Mutagenesis studies reveal that association of STRADalpha with either ATP or MO25alpha is essential for LKB1 activation. We conclude that ATP and MO25alpha cooperate to maintain STRADalpha in an "active" closed conformation required for LKB1 activation. It has recently been demonstrated that a mutation in human STRADalpha that truncates a C-terminal region of the pseudokinase domain leads to the polyhydramnios, megalencephaly, symptomatic epilepsy (PMSE syndrome. We demonstrate this mutation destabilizes STRADalpha and prevents association with LKB1. In summary, our findings describe one of the first structures of a genuinely inactive pseudokinase. The ability of STRADalpha to activate LKB1 is dependent on a closed "active" conformation, aided by ATP and MO25alpha binding. Thus, the function of STRADalpha is mediated through an active kinase conformation rather than kinase activity. It is possible that other pseudokinases exert their function through nucleotide binding and active conformations.

1,25 dihydroxyvitamin D3 (1,25) regulation of c-myc mRNA in HL-60 leukemia cells

International Nuclear Information System (INIS)

Simpson, R.U.; Bresnick, E.H.; Begley, D.A.

1986-01-01

Recently, 1,25 was shown to induce differentiation and decrease c-myc levels in HL-60 cells. The authors have confirmed these observations by RNA dot blot analysis. Cells treated with 50 nM 1,25 for 4, 24 and 48 hr showed c-myc mRNA levels of 26, 17 and 15% of control respectively. β-Actin mRNA levels were not altered. To ascertain whether 1, 25 regulated c-myc transcriptionally, an HL-60 nuclear RNA runoff assay was developed. Assay of total nuclei transcriptional activity revealed that 50% of RNA elongation was α-amanitin (0.8 μg/ml) sensitive and was linear with nuclei concentration (0.1-1 x 10 7 nuclei). 1,25 (50 nM) treated (45-96 hr) cells had decreased (approx.40%) total transcription rate relative to control. Decreased total RNA synthesis occurred concomitant with NBT reducing activity. 32 P-RNA runoff transcripts from HL-60 nuclei were hybridized to excess (5 μg DNA was excess) Pst I linearized c-myc and β-actin clones (in pBR322) immobilized on nitrocellulose filter. 32 P-RNA input from 2 x 10 6 to 2 x 10 7 cpm yielded linear hybridization signal. Analysis of blot dot intensity revealed no difference in transcription of c-myc in nuclei from 1,25 dosed or control cells. (myc/actin ratios: 1,25 (50 nM, 72 hr) =1.1 +/- 0.3 and control (72 hr) = 1.0, N=3 or 2 or 3 dots ea). These preliminary data suggest 1,25 does not affect c-myc transcription in HL-60 nuclei and may regulate c-myc mRNA post-transcriptionally

Clinical utility of simultaneous quantitation of 25-hydroxyvitamin D and 24,25-dihydroxyvitamin D by LC-MS/MS involving derivatization with DMEQ-TAD.

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Kaufmann, Martin; Gallagher, J Christopher; Peacock, Munro; Schlingmann, Karl-Peter; Konrad, Martin; DeLuca, Hector F; Sigueiro, Rita; Lopez, Borja; Mourino, Antonio; Maestro, Miguel; St-Arnaud, René; Finkelstein, Joel S; Cooper, Donald P; Jones, Glenville

2014-07-01

The discovery of hypercalcemic diseases due to loss-of-function mutations in 25-hydroxyvitamin D-24-hydroxylase has placed a new demand for sensitive and precise assays for 24,25-dihydroxyvitamin D [24,25-(OH)2D]. We describe a novel liquid chromatography and tandem mass spectrometry-based method involving derivatization with DMEQ-TAD {4-[2-(6,7-dimethoxy-4-methyl-3,4-dihydroquinoxalinyl)ethyl]-1,2,4-triazoline-3,5-dione} to simultaneously assay multiple vitamin D metabolites including 25-hydroxyvitamin D (25-OH-D) and 24,25-(OH)2D using 100 μL of serum with a 5-minute run time. The assay uses a newly synthesized internal standard d6-24,25-(OH)2D3 enabling the quantitation of 24,25-(OH)2D3 as well as the determination of the ratio of 25-OH-D3 to 24,25-(OH)2D3, a physiologically useful parameter. We report data on more than 1000 normal and disease samples involving vitamin D deficiency or hypercalcemia in addition to studies involving knockout mouse models. The assay showed good correlation with samples from quality assurance schemes for 25-OH-D (25-OH-D2 and 25-OH-D3) determination (-2% to -5% bias) and exhibited low inter- and intraassay coefficients of variation (4%-7%) and lower limits of quantitation of 0.25-0.45 nmol/L. In clinical studies, we found a strong correlation between serum levels of 25-OH-D3 and 24,25-(OH)2D3 (r(2) = 0.80) in subjects over a broad range of 25-OH-D3 values and a marked lack of production of 24,25-(OH)2D3 below 25 nmol/L of 25-OH-D. The ratio of 25-OH-D3 to 24,25-(OH)2D3, which remained less than 25 in vitamin D-sufficient subjects (serum 25-OH-D < 50 nmol/L) but was greatly elevated (80-100) in patients with idiopathic infantile hypercalcemia. The new method showed good utility in clinical settings involving vitamin D deficiency; supplementation with vitamin D and idiopathic infantile hypercalcemia, as well as in animal models with ablation of selected cytochrome P450-containing enzymes involved in vitamin D metabolism.

Partial deficiency of HIF-1 alpha stimulates pathological cardiac changes in streptozotocin-induced diabetic mice

Czech Academy of Sciences Publication Activity Database

Bohuslavová, Romana; Kolář, František; Sedmera, David; Škvorová, Lada; Papoušek, František; Neckář, Jan; Pavlínková, Gabriela

2014-01-01

Roč. 14, Feb 6 (2014) ISSN 1472-6823 R&D Projects: GA ČR GA301/09/0117; GA MŠk(CZ) ED1.1.00/02.0109 Institutional research plan: CEZ:AV0Z50520701 Institutional support: RVO:68378271 Keywords : Echocardiographic parameters * Hypoxia inducible factor 1 alpha * Diabetic cardiomyopathy Subject RIV: FB - Endocrinology, Diabetology, Metabolism, Nutrition Impact factor: 1.710, year: 2014

Pediatric Endocrinology Nurses Society

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... Join Now International Welcome to PENS The Pediatric Endocrinology Nursing Society (PENS) is committed to the development ... nurses in the art and science of pediatric endocrinology nursing. Learn More Text1 2018 PENS Call for ...

1,25-Dihydroxyvitamin-D3 Induces Avian β-Defensin Gene Expression in Chickens.

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Long Zhang

Full Text Available Host defense peptides (HDPs play a critical role in innate immunity. Specific modulation of endogenous HDP synthesis by dietary compounds has been regarded as a novel approach to boost immunity and disease resistance in animal production. 1,25-dihydroxy vitamin D3 (1,25D3 is well known as a powerful HDP inducer in humans, but limited information about the effect of 1,25D3 on HDPs in poultry is available. Here, we sought to examine whether 1,25D3 could stimulate avian β-defensin (AvBD expression in chickens. We used chicken embryo intestinal epithelial cells (CEIEPCs and peripheral blood mononuclear cells (PBMCs to study the effect of 1,25D3 on the expression of AvBDs. We observed that 1,25D3 is able to up-regulate the expression of several AvBDs in CEIEPCs and PBMCs, whereas it increased the amounts of AvBD4 mRNA in CEIEPCs only in the presence of lipopolysaccharide (LPS. On the other hand, LPS treatment not only inhibited the expression of CYP24A1 but also altered the expression pattern of VDR in CEIEPCs. Furthermore, AvBDs were not directly regulated by 1,25D3, as cycloheximide completely blocked 1,25D3-induced expression of AvBDs. Our observations suggest that 1,25D3 is capable of inducing AvBD gene expression and is a potential antibiotic alternative through augmentation of host innate immunity as well as disease control in chickens.

The effects of 1α, 25-dihydroxyvitamin D3 and transforming growth factor-β3 on bone development in an ex vivo organotypic culture system of embryonic chick femora.

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Emma L Smith

Full Text Available Transforming growth factor-beta3 (TGF-β3 and 1α,25-dihydroxyvitamin D3 (1α,25 (OH 2D3 are essential factors in chondrogenesis and osteogenesis respectively. These factors also play a fundamental role in the developmental processes and the maintenance of skeletal integrity, but their respective direct effects on these processes are not fully understood. Using an organotypic bone rudiment culture system the current study has examined the direct roles the osteotropic factors 1α,25 (OH2D3 and TGF-β3 exert on the development and modulation of the three dimensional structure of the embryonic femur. Isolated embryonic chick femurs (E11 were organotypically cultured for 10 days in basal media, or basal media supplemented with either 1α,25 (OH 2D3 (25 nM or TGF-β3 (5 ng/mL & 15 ng/mL. Analyses of the femurs were undertaken using micro-computed tomography (μCT, histology and immunohistochemistry. 1α,25 (OH2D3 supplemented cultures enhanced osteogenesis directly in the developing femurs with elevated levels of osteogenic markers such as type 1 collagen. In marked contrast organotypic femur cultures supplemented with TGF-β3 (5 ng/mL & 15 ng/mL demonstrated enhanced chondrogenesis with a reduction in osteogenesis. These studies demonstrate the efficacy of the ex vivo organotypic embryonic femur culture employed to elucidate the direct roles of these molecules, 1α,25 (OH 2D3 and TGF-β3 on the structural development of embryonic bone within a three dimensional framework. We conclude that 1α,25(OH2D and TGF-β3 modify directly the various cell populations in bone rudiment organotypic cultures effecting tissue metabolism resulting in significant changes in embryonic bone growth and modulation. Understanding the roles of osteotropic agents in the process of skeletal development is integral to developing new strategies for the recapitulation of bone tissue in later life.

1α,25-Dihydroxyvitamin D3 Ameliorates Seawater Aspiration-Induced Lung Injury By Inhibiting The Translocation Of NF-κB and RhoA.

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Zhang, Minlong; Jin, Faguang

2017-06-01

Our previous study have reported that 1α,25-Dihydroxyvitamin D3 (calcitriol) suppresses seawater aspiration-induced ALI in vitro and in vivo. We also have confirmed that treatment with calcitriol ameliorates seawater aspiration-induced inflammation and pulmonary edema via the inhibition of NF-κB and RhoA/Rho kinase pathway activation. In our further work, we investigated the effect of calcitriol on nuclear translocation of NF-κB and membrane translocation of RhoA in vitro. A549 cells and rat pulmonary microvascular endothelial cells (RPMVECs) were cultured with calcitriol or not for 48 h and then stimulated with 25% seawater for 40 min. After these treatments, cells were collected and performed with immunofluorescent staining to observe the translocation of NF-κB and RhoA and the cytoskeleton remodeling. In vitro, seawater stimulation activates nuclear translocation of NF-κB and membrane translocation of RhoA in A549 cells. In addition, seawater administration also induced cytoskeleton remodeling in A549 cells and RPMVECs. However, pretreatment with calcitriol significantly inhibited the activation of NF-κB and RhoA/Rho kinase pathways, as demonstrated by the reduced nuclear translocation of NF-κB and membrane translocation of RhoA in A549 cells. Meanwhile, treatment of calcitriol also regulated the cytoskeleton remodeling in both A549 cells and RPMVECs. These results demonstrated that treatment with calcitriol ameliorates seawater aspiration-induced ALI via inhibition of nuclear translocation of NF-κB and membrane translocation of RhoA and protection of alveolar epithelial and pulmonary microvascular endothelial barrier.

1α,25-Dihydroxyvitamin D3 Ameliorates Seawater Aspiration-Induced Acute Lung Injury via NF-κB and RhoA/Rho Kinase Pathways

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Liu, Wei; Wang, Li; Luo, Ying; Li, Zhichao; Jin, Faguang

2014-01-01

Introduction 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. Methods 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 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. Conclusions 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. PMID:25118599

Hereditary 1,25-dihydroxyvitamin D-resistant rickets (HVDRR) caused by a VDR mutation: A novel mechanism of dominant inheritance.

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Isojima, Tsuyoshi; Ishizawa, Michiyasu; Yoshimura, Kazuko; Tamura, Mayuko; Hirose, Shinichi; Makishima, Makoto; Kitanaka, Sachiko

2015-06-01

Hereditary 1,25-dihydroxyvitamin D-resistant rickets (HVDRR) is caused by mutations in the VDR gene, and its inheritance is autosomal recessive. In this report, we aimed to confirm whether HVDRR is occasionally inherited as a dominant trait. An 18-month-old Japanese boy was evaluated for short stature and bowlegs. His father had been treated for rickets during childhood, and his paternal grandfather had bowlegs. We diagnosed him with HVDRR based on laboratory data and radiographic evidence of rickets. Sequence analyses of VDR were performed, and the functional consequences of the detected mutations were analyzed for transcriptional activity, ligand binding, and interaction with the retinoid X receptor, cofactors, and the vitamin D response element (VDRE). A novel mutation (Q400LfsX7) and a reported variant (R370H) were identified in the patient. Heterozygous Q400LfsX7 was detected in his father, and heterozygous R370H was detected in his healthy mother. Functional studies revealed that the transcriptional activity of Q400LfsX7-VDR was markedly disturbed. The mutant had a dominant-negative effect on wild-type-VDR, and the ligand binding affinity of Q400LfsX7-VDR was completely impaired. Interestingly, Q400LfsX7-VDR had a strong interaction with corepressor NCoR and could interact with VDRE without the ligand. R370H-VDR was functionally similar to wild-type-VDR. In conclusion, we found a dominant-negative mutant of VDR causing dominantly inherited HVDRR through a constitutive corepressor interaction, a mechanism similar to that in dominantly inherited thyroid hormone receptor mutations. Our report together with a reported pedigree suggested a distinct inheritance of HVDRR and enriched our understanding of VDR abnormalities.

Hereditary 1,25-dihydroxyvitamin D-resistant rickets (HVDRR caused by a VDR mutation: A novel mechanism of dominant inheritance

Directory of Open Access Journals (Sweden)

Tsuyoshi Isojima

2015-06-01

Full Text Available Hereditary 1,25-dihydroxyvitamin D-resistant rickets (HVDRR is caused by mutations in the VDR gene, and its inheritance is autosomal recessive. In this report, we aimed to confirm whether HVDRR is occasionally inherited as a dominant trait. An 18-month-old Japanese boy was evaluated for short stature and bowlegs. His father had been treated for rickets during childhood, and his paternal grandfather had bowlegs. We diagnosed him with HVDRR based on laboratory data and radiographic evidence of rickets. Sequence analyses of VDR were performed, and the functional consequences of the detected mutations were analyzed for transcriptional activity, ligand binding, and interaction with the retinoid X receptor, cofactors, and the vitamin D response element (VDRE. A novel mutation (Q400LfsX7 and a reported variant (R370H were identified in the patient. Heterozygous Q400LfsX7 was detected in his father, and heterozygous R370H was detected in his healthy mother. Functional studies revealed that the transcriptional activity of Q400LfsX7-VDR was markedly disturbed. The mutant had a dominant-negative effect on wild-type-VDR, and the ligand binding affinity of Q400LfsX7-VDR was completely impaired. Interestingly, Q400LfsX7-VDR had a strong interaction with corepressor NCoR and could interact with VDRE without the ligand. R370H-VDR was functionally similar to wild-type-VDR. In conclusion, we found a dominant-negative mutant of VDR causing dominantly inherited HVDRR through a constitutive corepressor interaction, a mechanism similar to that in dominantly inherited thyroid hormone receptor mutations. Our report together with a reported pedigree suggested a distinct inheritance of HVDRR and enriched our understanding of VDR abnormalities.

Potencies of vitamin D analogs, 1α-hydroxyvitamin D3 , 1α-hydroxyvitamin D2 and 25-hydroxyvitamin D3 , in lowering cholesterol in hypercholesterolemic mice in vivo.

Science.gov (United States)

Quach, Holly P; Dzekic, Tamara; Bukuroshi, Paola; Pang, K Sandy

2018-04-01

Vitamin D 3 and the synthetic vitamin D analogs, 1α-hydroxyvitamin D 3 [1α(OH)D 3 ], 1α-hydroxyvitamin D 2 [1α(OH)D 2 ] and 25-hydroxyvitamin D 3 [25(OH)D 3 ] were appraised for their vitamin D receptor (VDR) associated-potencies as cholesterol lowering agents in mice in vivo. These precursors are activated in vivo: 1α(OH)D 3 and 1α(OH)D 2 are transformed by liver CYP2R1 and CYP27A1 to active VDR ligands, 1α,25-dihydroxyvitamin D 3 [1,25(OH) 2 D 3 ] and 1α,25-dihydroxyvitamin D 2 [1,25(OH) 2 D 2 ] , respectively. 1α(OH)D 2 may also be activated by CYP24A1 to 1α,24-dihydroxyvitamin D 2 [1,24(OH) 2 D 2 ], another active VDR ligand. 25(OH)D 3 , the metabolite formed via CYP2R1 and or CYP27A1 in liver from vitamin D 3 , is activated by CYP27B1 in the kidney to 1,25(OH) 2 D 3 . In C57BL/6 mice fed the high fat/high cholesterol Western diet for 3 weeks, vitamin D analogs were administered every other day intraperitoneally during the last week of the diet. The rank order for cholesterol lowering, achieved via mouse liver small heterodimer partner (Shp) inhibition and increased cholesterol 7α-hydroxylase (Cyp7a1) expression, was: 1.75 nmol/kg 1α(OH)D 3  > 1248 nmol/kg 25(OH)D 3 (dose ratio of 0.0014) > > 1625 nmol/kg vitamin D 3 . Except for 1.21 nmol/kg 1α(OH)D 2 that failed to lower liver and plasma cholesterol contents, a significant negative correlation was observed between the liver concentration of 1,25(OH) 2 D 3 formed from the precursors and liver cholesterol levels. The composite results show that vitamin D analogs 1α(OH)D 3 and 25(OH)D 3 exhibit cholesterol lowering properties upon activation to 1,25(OH) 2 D 3 : 1α(OH)D 3 is rapidly activated by liver enzymes and 25(OH)D 3 is slowly activated by renal Cyp27b1 in mouse. Copyright © 2018 John Wiley & Sons, Ltd.

Dexamethasone/1alpha-25-dihydroxyvitamin D3-treated dendritic cells suppress colitis in the SCID T-cell transfer model

DEFF Research Database (Denmark)

Pedersen, Anders Elm; Schmidt, Esben Gjerløff Wedebye; Gad, Monika

2008-01-01

severe combined immunodeficient (SCID) mice adoptively transferred with CD4(+) CD25(-) T cells from the development of wasting disease and colitis. We therefore established an in vitro test that could predict the in vivo function of DCs and improve strategies for the preparation of immunomodulatory DCs...... in this model. Based on these in vitro findings, we here evaluate three methods for DC generation including short-term and long-term IL-10 exposure or DC exposure to dexamethasone in combination with vitamin D3 (Dex/D3). All DCs resulted in lower CD4(+) CD25(-) T-cell enteroantigen-specific responses in vitro...

25-Hydroxyvitamin D3 1-Alpha-Hydroxylase-Dependent Stimulation of Renal Klotho Expression by Spironolactone

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Ioana Alesutan

2013-11-01

Full Text Available Background: Klotho, a transmembrane protein, protease and hormone mainly expressed in kidney, is required for the suppression of 1,25(OH2D3-generating 25-hydroxyvitamin D3 1-alpha-hydroxylase (Cyp27b1 by FGF23. Conversely, 1,25(OH2D3 stimulates, by activating the vitamin D3 receptor (Vdr, the expression of klotho, thus establishing a negative feedback loop. Klotho protects against renal and vascular injury. Klotho deficiency accelerates aging and early death, effects at least partially due to excessive formation of 1,25(OH2D3 and subsequent hyperphosphatemia. Klotho expression is inhibited by aldosterone. The present study explored the interaction of aldosterone and DOCA as well as the moderately selective mineralocorticoid receptor antagonist spironolactone on klotho expression. Methods: mRNA levels were determined utilizing quantitative RT-PCR in human embryonic kidney cells (HEK293 or in renal tissues from mice without or with prior mineralocorticoid (aldosterone or DOCA and/or spironolactone treatment. In HEK293 cells, protein levels were determined by western blotting. The experiments in HEK293 cells were performed without or with silencing of CYP27B1, of vitamin D3 receptor (VDR or of mineralocorticoid receptor (NR3C2. Results: In HEK293 cells aldosterone and in mice DOCA significantly decreased KLOTHO gene expression, effects opposed by spironolactone treatment. Spironolactone treatment alone significantly increased KLOTHO and CYP27B1 transcript levels in HEK293 cells (24 hours and mice (8 hours or 5 days. Moreover, spironolactone significantly increased klotho and CYP27B1 protein levels in HEK293 cells (48 hours. Reduced NR3C2 expression following silencing did not significantly affect KLOTHO and CYP27B1 transcript levels in presence or absence of spironolactone. Silencing of CYP27B1 and VDR significantly blunted the stimulating effect of spironolactone on KLOTHO mRNA levels in HEK293 cells. Conclusion: Besides blocking the effects of

Characterization of vitamin D-deficient klotho(-/-) mice: do increased levels of serum 1,25(OH)2D3 cause disturbed calcium and phosphate homeostasis in klotho(-/-) mice?

NARCIS (Netherlands)

Woudenberg-Vrenken, T.E.; van der Eerden, B.C.; van der Kemp, A.W.; Leeuwen, J.P. van; Bindels, R.J.M.; Hoenderop, J.G.J.

2012-01-01

BACKGROUND: Klotho(-/-) mice display disturbed Ca(2+) and vitamin D homeostasis. Renal cytochrome p450 27b1 (Cyp27b1), the enzyme that catalyzes the hydrolysis to 1,25-dihydroxyvitamin D(3) (1,25(OH)(2)D(3)), is increased in klotho(-/-) mice, and a 1,25(OH)(2)D(3)-deficient diet partially normalized

Vitamin D enhances IL-1β secretion and restricts growth of Mycobacterium tuberculosis in macrophages from TB patients

Directory of Open Access Journals (Sweden)

Daniel Eklund

2013-01-01

Full Text Available The emergence of multidrug-resistant strains of Mycobacterium tuberculosis (MTB, the bacterium responsible for tuberculosis (TB, has rekindled the interest in the role of nutritional supplementation of micronutrients, such as vitamin D, as adjuvant treatment. Here, the growth of virulent MTB in macrophages obtained from the peripheral blood of patients with and without TB was studied. The H37Rv strain genetically modified to express Vibrio harveyi luciferase was used to determine the growth of MTB by luminometry in the human monocyte-derived macrophages (hMDMs from study subjects. Determination of cytokine levels in culture supernatants was performed using a flow cytometry-based bead array technique. No differences in intracellular growth of MTB were observed between the different study groups. However, stimulation with 100nM 1,25-dihydroxyvitamin D significantly enhanced the capacity of hMDMs isolated from TB patients to control the infection. This effect was not observed in hMDMs from the other groups. The interleukin (IL-1β and IL-10 release by hMDMs was clearly increased upon stimulation with 1,25-dihydroxyvitamin D. Furthermore, the 1,25-dihydroxyvitamin D stimulation also led to elevated levels of TNF-α (tumor necrosis factor-alpha and IL-12p40. It was concluded that vitamin D triggers an inflammatory response in human macrophages with enhanced secretion of cytokines, as well as enhancing the capacity of hMDMs from patients with active TB to restrict mycobacterial growth.

Evaluation on a radioimmunoassay of. alpha. /sub 1/ microglobulin (. alpha. /sub 1/-m) with simplified procedures

Energy Technology Data Exchange (ETDEWEB)

Matsui, Kazuyo; Moriuma, Hatsuko; Mishima, Chiho; Honda, Minoru; Tomonobu, Masahiro; Kanao, Keisuke; Fushimi, Hisako (Sumitomo Hospital, Osaka (Japan))

1989-06-01

A newly established double antibody radioimmunoassay (RIA) was fundamentally and clinically evaluated. Original procedures were partially modified as follows: Sample volume for serum and urine was changed to 25{mu}l, and thus 200 mg/l of {alpha}/sub 1/-m standard was prepared using 50 {mu}l of original standard solution (100 mg/l). The results were satisfactory in sensitivity (0.3 mg/l obtained from -2SD method), intraassay precision with its coefficient variation (CV) ranging from 3.0 to 7.4%, interassay precision with its CV ranging from 3.0 to 10.7%, and recovery with the mean value of 102.4% in serum and 108.2% in urine respectively. There were no changes about {alpha}/sub 1/-m value between diluted (2 times) and undiluted with high concentration samples. Normal levels of {alpha}/sub 1/-m were less than 25 mg/l is serum and less than 10 mg/l in urine. The present results indicate that the determination of {alpha}/sub 1/-m could be very simple and useful for the most sensitive screening test for the evaluation of renal function. (author).

Characterization of Makrofol ® DE 1-1 for alpha particle radiography

Science.gov (United States)

El Ghazaly, M.; Aydarous, Abdulkadir; Al-Thomali, Talal A.

2017-09-01

Makrofol ® DE 1-1 (bisphenol-A polycarbonate) was investigated for alpha particle radiography. The edge spread function (ESF) was measured by razor-blade's edge. Makrofol ® DE 1-1 detectors were irradiated with perpendicular incident alpha particles of energy 2.5, 4 and 5.4 MeV, thereafter they were etched in 75% 6N KOH+25% C2H5OH at a temperature of 50 °C for different durations. The etched Makrofol®DE 1-1 detectors were imaged with an optical microscope equipped with a CCD camera. The results revealed that the green channel of the original RGB image provides the highest contrast comparing with red and blue channel by a factor of 27.6% of the original RGB image. The image contrast of alpha particle-irradiated Makrofol®DE 1-1 detector was found to be inversely related to the etching time since the alpha particle tracks proceed from a conical phase to spherical phase. The spatial resolution of alpha particle-irradiated Makrofol®DE 1-1 detector, in terms of line spread function, was found to deteriorate as the etching time increases for all examined alpha particle energies. The results revealed the potential capability of Makrofol®DE 1-1 detector as an efficient detector for alpha particle radiography such as autoradiography.

Phenotypic and functional markers for 1alpha,25-dihydroxyvitamin D(3)-modified regulatory dendritic cells

DEFF Research Database (Denmark)

Pedersen, A W; Holmstrøm, K; Jensen, S S

2009-01-01

The clinical use of dendritic cells (DCs) to induce antigen-specific immune tolerance has been hampered by the lack of a widely acknowledged method for generating human regulatory DCs but even more so by the non-existence of reliable markers. Thus, we set out to find reliable markers that can...... CD14 and reduced CD1a on the cell surface. These VD3-treated DCs exert a long-lasting inefficient T cell stimulation and induce T cell hyporesponsiveness with regulatory potential. Importantly, such VD3-treated DCs were readily distinguishable from untreated DCs by low levels of interleukin-23...

Create new research directions in comparative endocrinology from Asia and Oceania.

Science.gov (United States)

Tsutsui, Kazuyoshi

2013-01-15

The Asia and Oceania Society for Comparative Endocrinology (AOSCE) was founded in 1987, when the first congress was held in Nagoya, Japan. The purpose of the AOSCE is to progress scientific activities in the field of comparative endocrinology in Asia and Oceania and to establish a deep relationship among the members. For this purpose, the AOSCE holds a congress or an intercongress symposium every 2 years, which organizes an attractive scientific program covering the latest progress in the broad aspect of comparative endocrinology. 2012 was the 25th anniversary of AOSCE. Our scientific activities have increased dramatically during the past 25 years. The 7th AOSCE congress was held in Kuala Lumpur, Malaysia in 2012. The theme of this congress was "Overcoming challenges in the 21st century". To overcome challenges in the 21st century, we further need to create new research directions in comparative endocrinology from Asia and Oceania. This paper describes a brief history of the AOSCE and also highlights the discovery of gonadotropin-inhibitory hormone (GnIH) and the progress of GnIH research as one of new research directions in comparative endocrinology. In 2000, GnIH was discovered in Japan and now more than 50 laboratories are working on GnIH in the world. The discovery of GnIH has changed our understanding about regulation of the reproductive axis drastically in the past decade. Copyright © 2012 Elsevier Inc. All rights reserved.

Vitamin D enhances IL-1β secretion and restricts growth of Mycobacterium tuberculosis in macrophages from TB patients.

Science.gov (United States)

Eklund, Daniel; Persson, Hans Lennart; Larsson, Marie; Welin, Amanda; Idh, Jonna; Paues, Jakob; Fransson, Sven-Göran; Stendahl, Olle; Schön, Thomas; Lerm, Maria

2013-03-01

The emergence of multidrug-resistant strains of Mycobacterium tuberculosis (MTB), the bacterium responsible for tuberculosis (TB), has rekindled the interest in the role of nutritional supplementation of micronutrients, such as vitamin D, as adjuvant treatment. Here, the growth of virulent MTB in macrophages obtained from the peripheral blood of patients with and without TB was studied. The H37Rv strain genetically modified to express Vibrio harveyi luciferase was used to determine the growth of MTB by luminometry in the human monocyte-derived macrophages (hMDMs) from study subjects. Determination of cytokine levels in culture supernatants was performed using a flow cytometry-based bead array technique. No differences in intracellular growth of MTB were observed between the different study groups. However, stimulation with 100nM 1,25-dihydroxyvitamin D significantly enhanced the capacity of hMDMs isolated from TB patients to control the infection. This effect was not observed in hMDMs from the other groups. The interleukin (IL)-1β and IL-10 release by hMDMs was clearly increased upon stimulation with 1,25-dihydroxyvitamin D. Furthermore, the 1,25-dihydroxyvitamin D stimulation also led to elevated levels of TNF-α (tumor necrosis factor-alpha) and IL-12p40. It was concluded that vitamin D triggers an inflammatory response in human macrophages with enhanced secretion of cytokines, as well as enhancing the capacity of hMDMs from patients with active TB to restrict mycobacterial growth. Copyright © 2013 Asian-African Society for Mycobacteriology. Published by Elsevier Ltd. All rights reserved.

42 CFR 493.933 - Endocrinology.

Science.gov (United States)

2010-10-01

... 42 Public Health 5 2010-10-01 2010-10-01 false Endocrinology. 493.933 Section 493.933 Public... Proficiency Testing Programs by Specialty and Subspecialty § 493.933 Endocrinology. (a) Program content and frequency of challenge. To be approved for proficiency testing for endocrinology, a program must provide a...

Hydroxylation of 25-hydroxyvitamin D3 by renal mitochondria from rats of different ages.

Science.gov (United States)

Ishida, M; Bulos, B; Takamoto, S; Sacktor, B

1987-08-01

The hydroxylation of 25-hydroxyvitamin D3 (25OHD3) in kidney mitochondria from female rats of different ages was studied. The specific activity of 1 alpha-hydroxylase was highest in mitochondria isolated from the 2-month-old rat (0.47 pmol/10 min X mg protein), falling gradually with age to 0.17, 0.10, 0.07, and 0.06 pmol/10 min X mg protein in 6-, 12-, 18-, and 24-month-old rats, respectively. The alteration in 1 alpha-hydroxylase activity with age was due to a change in the V'm of the system; the K'm for 25OHD3 was unchanged (3.9-4.0 microM). The specific activity of 24-hydroxylase was lowest in mitochondria isolated from the 2-month-old rat (8.2 pmol/10 min X mg protein), increasing to 37.8, 37.4, 38.2, and 55.7 pmol/10 min X mg protein in 6-, 12-, 18-, and 24-month-old rats, respectively. The alteration in 24-hydroxylase activity with age was due to a change in the V'm of the system; the K'm value for 25OHD3 was unchanged (1.1-1.2 microM). The age-dependent decrease in 1 alpha-hydroxylase and concomitant increase in 24-hydroxylase activities observed in mitochondria isolated from kidneys of 2-, 6-, 12-, 18-, and 24-month-old rats could not be attributed to changes in the bioenergetic properties, i.e. the respiratory chain, of the mitochondria. The relative mitochondrial content of the kidney, however, probably decreased with age. These findings support the view that the kidneys of aged rats produce less 1,25-dihydroxyvitamin D3 because of lower mitochondrial 1 alpha-hydroxylase specific activity and reduced number of mitochondria. This would be consistent with the lower levels of vitamin D hormone reported in the serum of senescent rats.

Establishment of sandwich ELISA for soluble alpha-Klotho measurement: Age-dependent change of soluble alpha-Klotho levels in healthy subjects.

Science.gov (United States)

Yamazaki, Yuji; Imura, Akihiro; Urakawa, Itaru; Shimada, Takashi; Murakami, Junko; Aono, Yukiko; Hasegawa, Hisashi; Yamashita, Takeyoshi; Nakatani, Kimihiko; Saito, Yoshihiko; Okamoto, Nozomi; Kurumatani, Norio; Namba, Noriyuki; Kitaoka, Taichi; Ozono, Keiichi; Sakai, Tomoyuki; Hataya, Hiroshi; Ichikawa, Shoji; Imel, Erik A; Econs, Michael J; Nabeshima, Yo-Ichi

2010-07-30

Alpha-Klotho (alphaKl) regulates mineral metabolism such as calcium ion (Ca(2+)) and inorganic phosphate (Pi) in circulation. Defects in mice result in clinical features resembling disorders found in human aging. Although the importance of transmembrane-type alphaKl has been demonstrated, less is known regarding the physiological importance of soluble-type alphaKl (salphaKl) in circulation. The aims of this study were: (1) to establish a sandwich ELISA system enabling detection of circulating serum salphaKl, and (2) to determine reference values for salphaKl serum levels and relationship to indices of renal function, mineral metabolism, age and sex in healthy subjects. We successively developed an ELISA to measure serum salphaKl in healthy volunteers (n=142, males 66) of ages (61.1+/-18.5year). The levels (mean+/-SD) in these healthy control adults were as follows: total calcium (Ca; 9.46+/-0.41mg/dL), Pi (3.63+/-0.51mg/dL), blood urea nitrogen (BUN; 15.7+/-4.3mg/dL), creatinine (Cre; 0.69+/-0.14mg/dL), 1,25 dihydroxyvitamin D (1,25(OH)(2)D; 54.8+/-17.7pg/mL), intact parathyroid hormone (iPTH; 49.2+/-20.6pg/mL), calcitonin (26.0+/-12.3pg/mL) and intact fibroblast growth factor (FGF23; 43.8+/-17.6pg/mL). Serum levels of salphaKl ranged from 239 to 1266pg/mL (mean+/-SD; 562+/-146pg/mL) in normal adults. Although salphaKl levels were not modified by gender or indices of mineral metabolism, salphaKl levels were inversely related to Cre and age. However, salphaKl levels in normal children (n=39, males 23, mean+/-SD; 7.1+/-4.8years) were significantly higher (mean+/-SD; 952+/-282pg/mL) than those in adults (mean+/-SD; 562+/-146, Plevel was notably lower than those of age-matched controls. We established a detection system to measure human serum salphaKl for the first time. Age, Ca and Pi seem to influence serum salphaKl levels in a normal population. This detection system should be an excellent tool for investigating salphaKl functions in mineral metabolism. Copyright

42 CFR 493.1212 - Condition: Endocrinology.

Science.gov (United States)

2010-10-01

... 42 Public Health 5 2010-10-01 2010-10-01 false Condition: Endocrinology. 493.1212 Section 493.1212 Public Health CENTERS FOR MEDICARE & MEDICAID SERVICES, DEPARTMENT OF HEALTH AND HUMAN SERVICES....1212 Condition: Endocrinology. If the laboratory provides services in the subspecialty of Endocrinology...

Computerized tomography in endocrinology

Energy Technology Data Exchange (ETDEWEB)

Kurtz, B.; Schmiedl, U.; Huebener, K.H.

1987-01-05

The role of CT in the evaluation of endocrinologic disorders is discussed and typical CT-findings in disease of the hypophysis, the thyroid, the parathyroid, the thymus and the pancreas are shown. Special interest is laid on adrenal disorders. This survey informs the clinician about the diagnostic value of CT in endocrinology.

Induction of regulatory dendritic cells by dexamethasone and 1alpha,25-Dihydroxyvitamin D(3)

DEFF Research Database (Denmark)

Pedersen, Anders Elm; Gad, Monika; Walter, Mark R

2004-01-01

D(3) the active form of Vitamin D(3) (D(3)) in combination with dexamethasone (Dex) has a synergistic effect on LPS-induced maturation of DC. Monocyte-derived DCs cultured with D(3) and Dex during LPS-induced maturation have a low stimulatory effect on allogeneic T cells comparable...

Computerized tomography in endocrinology

International Nuclear Information System (INIS)

Kurtz, B.; Schmiedl, U.; Huebener, K.H.

1987-01-01

The role of CT in the evaluation of endocrinologic disorders is discussed and typical CT-findings in disease of the hypophysis, the thyroid, the parathyroid, the thymus and the pancreas are shown. Special interest is laid on adrenal disorders. This survey informs the clinician about the diagnostic value of CT in endocrinology. (orig.) [de

Find an Endocrinology - Thyroid Specialist

Science.gov (United States)

... History Resource Center Patients Thyroid Information Find an Endocrinology – Thyroid Specialist Patient Support Links Clinical Thyroidology for ... Access Thyroid Online Access Clinical Thyroidology Online Video Endocrinology Donate Give Online Research Accomplishments Ridgway Legacy Fund ...

Selected maternal, fetal and placental trace element and heavy metal and maternal vitamin levels in preterm deliveries with or without preterm premature rupture of membranes.

Science.gov (United States)

Kucukaydin, Zehra; Kurdoglu, Mertihan; Kurdoglu, Zehra; Demir, Halit; Yoruk, Ibrahim H

2018-01-25

To compare maternal, fetal and placental trace element (magnesium, zinc and copper) and heavy metal (cadmium and lead) and maternal vitamin (retinol, α [alpha]-tocopherol, vitamin D 3 , 25-hydroxyvitamin D 3 and 1,25-dihydroxyvitamin D 3 ) levels in preterm deliveries with and without preterm premature rupture of membranes (PPROM). Sixty-eight patients giving birth preterm were grouped into preterm deliveries with PPROM (n = 35) and without PPROM (n = 33). Following delivery, maternal and umbilical cord blood sera and placental tissue samples were obtained. While magnesium, zinc, copper, cadmium and lead levels were measured in all samples, the levels of retinol, α-tocopherol, vitamin D 3 , 25-hydroxyvitamin D 3 and 1,25-dihydroxyvitamin D 3 were measured only in maternal serum. While magnesium level in maternal serum and zinc levels in both maternal and umbilical cord sera were lower, placental magnesium level was higher in preterm deliveries with PPROM (P 0.05). In preterm deliveries with PPROM, 25-hydroxyvitamin D 3 and retinol levels were higher, while vitamin D 3 and 1,25-dihydroxyvitamin D 3 levels were lower in maternal serum (P < 0.05). Maternal serum α-tocopherol levels were similar between the groups. Compared to spontaneous preterm births, PPROM is associated with low maternal serum together with high placental tissue magnesium and low maternal and umbilical cord sera zinc levels. Higher retinol and 25-hydroxyvitamin D 3 and lower vitamin D 3 and 1,25-dihydroxyvitamin D 3 maternal serum levels are also evident in these patients. © 2018 Japan Society of Obstetrics and Gynecology.

24,25,28-Trihydroxyvitamin D2 and 24,25,26-trihydroxyvitamin D2: Novel metabolites of vitamin D2

International Nuclear Information System (INIS)

Reddy, G.S.; Tserng, K.

1990-01-01

Understanding of the inactivation pathways of 25-hydroxyvitamin D 2 and 24-hydroxyvitamin D 2 , the two physiologically significant monohydroxylated metabolites of vitamin D 2 , is of importance, especially during hypervitaminosis D 2 . At present, little information is available regarding the inactivation pathway of 25-hydroxyvitamin D 2 except its further metabolism into 24,25-dihydroxyvitamin D 2 . In our present study, the authors investigated the metabolic fate of 25-hydroxyvitamin D 2 in the isolated perfused rat kidney and demonstrated its conversion not only into 24,25-dihydroxyvitamin D 2 but also into two other new metabolites, namely, 24,25,28-trihydroxyvitamin D 2 and 24,25,26-trihydroxyvitamin D 2 . The structure identification of the new metabolites was established by the techniques of ultraviolet absorption spectrophotometry and mass spectrometry and by the characteristic nature of each new metabolite's susceptibility to sodium metaperiodate oxidation. In order to demonstrate the physiological significance of the two new trihydroxy metabolites of vitamin D 2 , induced hypervitaminosis D 2 in a rat using [3α- 3 H]vitamin D 2 and analyzed its plasma for the various [3α- 3 H]vitamin D 2 metabolites on two different high-pressure liquid chromatography systems. The results indicate that both 24,25,26-trihydroxyvitamin D 2 and 24,25,26-trihydroxyvitamin D 2 circulate in the vitamin D 2 intoxicated rat in significant amounts along with other previously identified monohydroxy and dihydroxy metabolites of vitamin D 2 , namely, 24-hydroxyvitamin D 2 , 25-hydroxyvitamin D 2 , and 24,25-dihydroxyvitamin D 2

Differential Protein Pathways in 1,25-Dihydroxyvitamin D-3 and Dexamethasone Modulated Tolerogenic Human Dendritic Cells

DEFF Research Database (Denmark)

Ferreira, Gabriela Bomfim; Kleijwegt, Fleur S.; Waelkens, Etienne

2012-01-01

spots (p MALDI-TOF/TOF analysis. In parallel, morphological and phenotypical analyses were performed, revealing that 1,25(OH)(2)D-3- and combi-mDCs are closer related to each other than DEX-mDCs. This was translated in their protein profile, indicating that 1,25(OH)(2)D-3...

Enthalpies of combustion and formation of {alpha}-D-glucoheptono-1,4-lactone and {alpha},{beta}-glucooctanoic-1,4-lactone

Energy Technology Data Exchange (ETDEWEB)

Amador, Patricia [Facultad de Ciencias Qui' micas, Benemerita Universidad Autonoma de Puebla, 14 Sur y Av. San Claudio, Col. Manuel, C.P. 72570 Puebla Pue (Mexico)], E-mail: cs000721@siu.buap.mx; Mata, Marian Y.; Flores, Henoc [Facultad de Ciencias Qui' micas, Benemerita Universidad Autonoma de Puebla, 14 Sur y Av. San Claudio, Col. Manuel, C.P. 72570 Puebla Pue (Mexico)

2008-05-15

The standard molar energies of combustion, {delta}{sub c}U{sub m}{sup 0}(cr,298.15K), of {alpha}-D-glucoheptono-1,4-lactone (GH) and {alpha},{beta}-glucooctanoic-1,4-lactone (GO) were obtained by micro-combustion calorimetry. The obtained values are -(2924.6 {+-} 2.3) kJ . mol{sup -1} and -(3459.5 {+-} 2.5) kJ . mol{sup -1}, respectively. From combustion energies, the standard molar enthalpies of formation in crystalline phase, {delta}{sub f}H{sub m}{sup 0}(cr,298.15K), for GH and GO were determined as -(1546.2 {+-} 2.5) kJ . mol{sup -1} and -(1690.6 {+-} 2.7) kJ . mol{sup -1}, respectively. Also it was found that when the hydroxyl group number increases in the aldonolactones their standard molar enthalpies of formation increase too.

1α,25(OH2D3 Induces Actin Depolymerization in Endometrial Carcinoma Cells by Targeting RAC1 and PAK1

Directory of Open Access Journals (Sweden)

Ni Zeng

2016-12-01

Full Text Available Background: Cell proliferation and motility require actin reorganization, which is under control of various signalling pathways including ras-related C3 botulinum toxin substrate 1 (RAC1, p21 protein-activated kinase 1 (PAK1 and actin related protein 2 (ARP2. Tumour cell proliferation is modified by 1α,25-Dihydroxy-Vitamin D3 (1α,25(OH2D3, a steroid hormone predominantly known for its role in calcium and phosphorus metabolism. The present study explored whether 1α,25(OH2D3 modifies actin cytoskeleton in Ishikawa cells, a well differentiated endometrial carcinoma cell line. Methods: To this end, actin cytoskeleton was visualized by confocal microscopy. Globular over filamentous actin ratio was determined utilizing Western blotting and flow cytometry, transcript levels by qRT-PCR and protein abundance by immunoblotting. Results: A 24 hour treatment with 1α,25(OH2D3 (100 nM significantly decreased RAC1 and PAK1 transcript levels and activity, decreased ARP2 protein levels and depolymerized actin. The effect of 1α,25(OH2D3 on actin polymerization was mimicked by pharmacological inhibition of RAC1 and PAK1. Conclusions: 1α,25(OH2D3 leads to disruption of RAC1 and PAK1 activity with subsequent actin depolymerization of endometrial carcinoma cells.

Microbial Endocrinology: An Ongoing Personal Journey.

Science.gov (United States)

Lyte, Mark

2016-01-01

The development of microbial endocrinology is covered from a decidedly personal perspective. Specific focus is given to the role of microbial endocrinology in the evolutionary symbiosis between man and microbe as it relates to both health and disease. Since the first edition of this book series 5 years ago, the role of microbial endocrinology in the microbiota-gut-brain axis is additionally discussed. Future avenues of research are suggested.

Transcriptional effects of 1,25 dihydroxyvitamin D3 physiological and supra-physiological concentrations in breast cancer organotypic culture

International Nuclear Information System (INIS)

Milani, Cintia; Góes, João Carlos Guedes Sampaio; Nonogaki, Suely; Tamura, Rodrigo Esaki; Folgueira, Maria Aparecida Azevedo Koike; Katayama, Maria Lucia Hirata; Lyra, Eduardo Carneiro de; Welsh, JoEllen; Campos, Laura Tojeiro; Brentani, M Mitzi; Maciel, Maria do Socorro; Roela, Rosimeire Aparecida; Valle, Paulo Roberto del

2013-01-01

Vitamin D transcriptional effects were linked to tumor growth control, however, the hormone targets were determined in cell cultures exposed to supra physiological concentrations of 1,25(OH) 2 D 3 (50-100nM). Our aim was to evaluate the transcriptional effects of 1,25(OH) 2 D 3 in a more physiological model of breast cancer, consisting of fresh tumor slices exposed to 1,25(OH) 2 D 3 at concentrations that can be attained in vivo. Tumor samples from post-menopausal breast cancer patients were sliced and cultured for 24 hours with or without 1,25(OH) 2 D 3 0.5nM or 100nM. Gene expression was analyzed by microarray (SAM paired analysis, FDR≤0.1) or RT-qPCR (p≤0.05, Friedman/Wilcoxon test). Expression of candidate genes was then evaluated in mammary epithelial/breast cancer lineages and cancer associated fibroblasts (CAFs), exposed or not to 1,25(OH) 2 D 3 0.5nM, using RT-qPCR, western blot or immunocytochemistry. 1,25(OH) 2 D 3 0.5nM or 100nM effects were evaluated in five tumor samples by microarray and seven and 136 genes, respectively, were up-regulated. There was an enrichment of genes containing transcription factor binding sites for the vitamin D receptor (VDR) in samples exposed to 1,25(OH) 2 D 3 near physiological concentration. Genes up-modulated by both 1,25(OH) 2 D 3 concentrations were CYP24A1, DPP4, CA2, EFTUD1, TKTL1, KCNK3. Expression of candidate genes was subsequently evaluated in another 16 samples by RT-qPCR and up-regulation of CYP24A1, DPP4 and CA2 by 1,25(OH) 2 D 3 was confirmed. To evaluate whether the transcripitonal targets of 1,25(OH) 2 D 3 0.5nM were restricted to the epithelial or stromal compartments, gene expression was examined in HB4A, C5.4, SKBR3, MDA-MB231, MCF-7 lineages and CAFs, using RT-qPCR. In epithelial cells, there was a clear induction of CYP24A1, CA2, CD14 and IL1RL1. In fibroblasts, in addition to CYP24A1 induction, there was a trend towards up-regulation of CA2, IL1RL1, and DPP4. A higher protein expression of CD14 in

Autoradiographic localization of target cells for 1α, 25-dihydroxyvitamin D3 in bones from fetal rats

International Nuclear Information System (INIS)

Narbaitz, R.; Stumpf, W.E.; Sar, M.; Huang, S.; DeLuca, H.F.

1983-01-01

Thaw-mount autoradiographic studies after injection of 3 H-1,25-D 3 were conducted on 18- and 20-day-old rat fetuses. In maxillary bones, ribs, and tibia, nuclear concentration of radioactivity was found in osteoprogenitor cells and osteoblasts. Osteocytes and chondrocytes in epiphyseal plates were either unlabeled or weakly labeled. In competition experiments, nuclear concentration of radioactivity was blocked by the injection of a high dose of nonradioactive 1,25-D 3 prior to the administration of the labeled hormone, but not by a similar dose of nonradioactive 25-D 3 . The results are interpreted as indicating that osteoprogenitor cells and osteoblasts are target cells for the direct action of 1,25-D 3 on fetal bone. (orig.)

Role of nongenomic activation of phosphatidylinositol 3-kinase/Akt and mitogen-activated protein kinase/extracellular signal-regulated kinase kinase/extracellular signal-regulated kinase 1/2 pathways in 1,25D3-mediated apoptosis in squamous cell carcinoma cells.

Science.gov (United States)

Ma, Yingyu; Yu, Wei-Dong; Kong, Rui-Xian; Trump, Donald L; Johnson, Candace S

2006-08-15

Vitamin D is a steroid hormone that regulates calcium homeostasis and bone metabolism. The active form of vitamin D [1 alpha,25-dihydroxyvitamin D(3) (1,25D3)] acts through both genomic and nongenomic pathways. 1,25D3 has antitumor effects in a variety of cancers, including colorectal, prostate, breast, ovarian, and skin cancers. 1,25D3 exerts growth-inhibitory effects in cancer cells through the induction of apoptosis, cell cycle arrest, and differentiation. The mechanisms regulating 1,25D3-induced apoptosis remain unclear. We investigated the role of nongenomic signaling in 1,25D3-mediated apoptosis in squamous cell carcinoma (SCC) cells. 1,25D3 induced rapid and sustained activation of phosphatidylinositol 3-kinase/Akt and mitogen-activated protein kinase/extracellular signal-regulated kinase (ERK) 1/2 pathways in SCC cells. These effects were nongenomic: they occurred rapidly and were not inhibited by cycloheximide or actinomycin D. To examine whether the nongenomic activation of Akt and ERK1/2 plays a role in 1,25D3-mediated apoptosis, the expression of Akt or ERK1/2 was reduced by small interfering RNA (siRNA). siRNA-Akt significantly enhanced 1,25D3-induced apoptosis as indicated by increased levels of Annexin V-positive cells and increased sub-G(1) population and DNA fragmentation. In contrast, siRNA-ERK1/2 had no effects on 1,25D3-induced apoptosis. In addition, siRNA-Akt transfection followed by 1,25D3 treatment induced apoptosis much sooner than 1,25D3 alone. siRNA-Akt and 1,25D3 induced caspase-10 activation, suppressed the expression of c-IAP1 and XIAP, and promoted 1,25D3-induced caspase-3 activation. These results support a link between 1,25D3-induced nongenomic signaling and apoptosis. 1,25D3 induces the activation of phosphatidylinositol 3-kinase/Akt, which suppresses 1,25D3-mediated apoptosis and prolongs the survival of SCC cells.

Synthesis of tritiated 1-alpha-methadol and 1-alpha-acetylmethadol

Energy Technology Data Exchange (ETDEWEB)

Thang, D.C.; Nam, N.H.; Pontikis, R. (Institut National de la Sante et de la Recherche Medicale (INSERM), Hopital Fernand Widal, 75 - Paris (France)); Pichat, L. (CEA Centre d' Etudes Nucleaires de Saclay, 91 - Gif-sur-Yvette (France). Service des Molecules Marquees)

1982-04-01

dl-Methadone was resolved by crystallization of its ammonium d- ..cap alpha.. -bromocamphor-..pi..-sulfonate salt to give d-methadone. The latter in ethyl acetate solution was reduced with tritium gas to 1-..cap alpha..-methadol /sup 3/H in presence of Adams platinum oxide at normal temperature and pressure. Acetylation of 1-..cap alpha..-carbinol hydrochloride by means of acetyl chloride afforded 1-..cap alpha..-acetylmethadol /sup 3/H, specific activity: 20 Ci/mMole. The positions and extent of tritium labelling were determined by /sup 3/H NMR spectroscopy.

GSK-3 Inhibition Sensitizes Acute Myeloid Leukemia Cells to 1,25D-Mediated Differentiation

Science.gov (United States)

Gupta, Kalpana; Stefan, Tammy; Ignatz-Hoover, James; Moreton, Stephen; Parizher, Gary; Saunthararajah, Yogen; Wald, David N.

2017-01-01

1,25-dihydroxyvitamin D3 (1,25D), the biologically active form of vitamin D, is widely considered a promising therapy for acute myeloid leukemia (AML) based on its ability to drive differentiation of leukemic cells. However, clinical trials have been disappointing in part to dose-limiting hypercalcemia. Here we show how inhibiting glycogen synthase kinase 3 (GSK3) can improve the differentiation response of AML cells to 1,25D-mediated differentiation. GSK3 inhibition in AML cells enhanced the differentiating effects of low concentrations of 1,25D. In addition, GSK3 inhibition augmented the ability of 1,25D to induce irreversible growth inhibition and slow the progression of AML in mouse models. Mechanistic studies revealed that GSK3 inhibition led to the hyperphosphorylation of the vitamin D receptor (VDR), enabling an interaction between VDR and the coactivator, SRC-3 (NCOA3), thereby increasing transcriptional activity. We also found that activation of JNK-mediated pathways in response to GSK3 inhibition contributed to the potentiation of 1,25D-induced differentiation. Taken together, our findings offer a preclinical rationale to explore the repositioning of GSK3 inhibitors to enhance differentiation-based therapy for AML treatment. PMID:26964622

Female Physicians and the Future of Endocrinology.

Science.gov (United States)

Pelley, Elaine; Danoff, Ann; Cooper, David S; Becker, Carolyn

2016-01-01

Given that approximately 70% of current endocrinology fellows are women, female physicians will compose the majority of the future endocrinology workforce. This gender shift partly reflects an apparent waning of interest in endocrinology among male trainees. It also coincides with a projected shortage of endocrinologists overall. Female physicians face unique challenges in the workplace. To continue to attract trainees to the specialty and support their success, it is imperative that these challenges be recognized, understood, and addressed. A PubMed search using the terms "female physician" and "physician gender" covering the years 2000-2015 was performed. Additional references were identified through review of the citations of the retrieved articles. The following topics were identified as key to understanding the impact of this gender shift: professional satisfaction, work-life balance, income, parenthood, academic success, and patient satisfaction. Several changes can be predicted to occur as endocrinology becomes a female-predominant specialty. Although professional satisfaction should remain stable, increased burnout rates are likely. Work-life balance challenges will likely be magnified. The combined effects of occupational gender segregation and a gender pay gap are predicted to negatively impact salaries of endocrinologists of both genders. The underrepresentation of women in academic leadership may mean a lesser voice for endocrinology in this arena. Finally, gender biases evident in patient satisfaction measures--commonly used as proxies for quality of care--may disproportionately impact endocrinology. Endocrinology is predicted to become the most female-predominant subspecialty of internal medicine. The specialty of endocrinology should take a lead role in advocating for changes that support the success of female physicians. Strengthening and supporting the physician workforce can only serve to attract talented physicians of both genders to the

Alpha spectroscopy by the Φ25 mm×0.1 mm YAlO{sub 3}:Ce scintillation detector under atmospheric conditions

Energy Technology Data Exchange (ETDEWEB)

Kvasnicka, Jiri [Radiation Detection Systems, Unit 10, 186 Pulteney Street, Adelaide SA 5000 (Australia); Urban, Tomas, E-mail: tomas.urban@fjfi.cvut.cz [Czech Technical University in Prague, Faculty of Nuclear Sciences and Physical Engineering, Brehova 78/7, 115 19 Prague, Czech Republic (Czech Republic); Tous, Jan; Smejkal, Jan; Blazek, Karel [Crytur Ltd, Palackeho 175, 511 01 Turnov (Czech Republic); Nikl, Martin [Institute of Physics AS CR, Cukrovarnicka 10, 162 53 Prague (Czech Republic)

2017-06-01

The YAlO{sub 3}:Ce scintillation crystal has excellent mechanical properties and is not affected if used in chemically aggressive environments. The detector with the diameter of Φ25.4 mm and thickness of 0.1 mm was coupled with the PMT, associated electronics and the MCA in order to study its alpha spectroscopy properties. The measured alpha spectra of the surface calibration sources of {sup 241}Am and {sup 230}Th were compared with results of a Monte Carlo simulation. The experiment and the simulation were carried out for three distances between the detector and the surface alpha source in order to assess the effect of the distance on the detected energy of alpha radiation. Finally, the detector was used for the monitoring of radon ({sup 222}Rn) decay products (radon daughters) in the air. It was concluded that the detector is suitable for the in-situ alpha spectroscopy monitoring under ambient atmospheric conditions. Nevertheless, in order to identify radionuclides and their activity from the measured alpha spectra a computer code would need to be developed. - Highlights: • Thin YAP: Ce scintillator crystal is proposed to be used for alpha spectrometry. • Experimental alpha spectra were compared with Monte Carlo simulated spectra. • The proposed detector assembly is suitable for the monitoring of radon decay products in air. • The results give a good potential for a quantitative analysis of the spectrum.

African Journal of Endocrinology and Metabolism

African Journals Online (AJOL)

The African Journal of Endocrinology and Metabolism (AJEM) is a biomedical peer-reviewed journal with international circulation. It publishes Reports of Original Work, preferably briefly described, in the fields of endocrinology, metabolism and related subjects. Reviews are authoritative, evidence-based articles on topical ...

The Mahabharata and reproductive endocrinology

OpenAIRE

Kalra, Bharti; Baruah, Manash P.; Kalra, Sanjay

2016-01-01

This communication approaches the Mahabharata through the prism of reproductive endocrinology. Descriptions of episodes related to reproduction are listed here, to provide fodder for the endocrinologically minded brain. The cases described here are perhaps, the first documented observations of fetal orgasm, pseudocyesis and assisted reproductive technology, including assisted insemination by donor, induction of ovulation, and in vitro fertilization as well as precocious growth and intersex. W...

No evidence for induction of key components of the Notch signaling pathway (Notch-1, Jagged-1) by treatment with UV-B, 1,25(OH)(2)D(3), and/or epigenetic drugs (TSA, 5-Aza) in human keratinocytes in vitro.

Science.gov (United States)

Reichrath, Sandra; Reichrath, Jörg

2012-01-01

Notch signaling is of high importance for growth and survival of various cell types. We now analyzed the protein expression of two key components of the Notch signaling pathway (Notch-1, Jagged-1) in spontaneously immortalized (HaCaT) and in malignant (SCL-1) human keratinocytes, using western analysis. We found that Notch-1 and its corresponding ligand Jagged-1 are expressed in both cell lines, with no marked change following UV-B treatment. Moreover, treatment of both cell lines before or after UV-B irradiation with 1,25-dihydroxyvitamin D(3), the biologically active form of vitamin D, and/or epigenetic modulating drugs (TSA; 5-Aza) did not result in a marked modulation of the protein expression of Notch-1 or Jagged-1. Under the experimental conditions of this study, treatment with 1,25(OH)(2)D(3) protected human keratinocytes in part against the antiproliferative effects of UV-B-radiation. In conclusion, our findings do not point at a differential expression of these two key components of Notch signaling in non-malignant as compared to malignant human keratinocytes, indicating that alterations in their expression are not of importance for the photocarcinogenesis of human squamous cell carcinomas. Moreover, our findings do not support the hypothesis that modulation of Notch signaling may be involved in the photoprotective effect of 1,25-dihydroxyvitamin D(3), that we and others reported previously. Additionally, we demonstrate that epigenetic modulating drugs (TSA, 5-Aza) do not markedly modulate the expression Notch-1 or Jagged-1 in UV-B-treated human keratinocytes in vitro.

Conservation endocrinology

Science.gov (United States)

McCormick, Stephen; Romero, L. Michael

2017-01-01

Endocrinologists can make significant contributions to conservation biology by helping to understand the mechanisms by which organisms cope with changing environments. Field endocrine techniques have advanced rapidly in recent years and can provide substantial information on the growth, stress, and reproductive status of individual animals, thereby providing insight into current and future responses of populations to changes in the environment. Environmental stressors and reproductive status can be detected nonlethally by measuring a number of endocrine-related endpoints, including steroids in plasma, living and nonliving tissue, urine, and feces. Information on the environmental or endocrine requirements of individual species for normal growth, development, and reproduction will provide critical information for species and ecosystem conservation. For many taxa, basic information on endocrinology is lacking, and advances in conservation endocrinology will require approaches that are both “basic” and “applied” and include integration of laboratory and field approaches.

Vitamin D and 1,25(OH2D Regulation of T cells

Directory of Open Access Journals (Sweden)

Margherita T. Cantorna

2015-04-01

Full Text Available Vitamin D is a direct and indirect regulator of T cells. The mechanisms by which vitamin D directly regulates T cells are reviewed and new primary data on the effects of 1,25 dihydroxyvitamin D (1,25(OH2D on human invariant natural killer (iNKT cells is presented. The in vivo effects of vitamin D on murine T cells include inhibition of T cell proliferation, inhibition of IFN-γ, IL-17 and induction of IL-4. Experiments in mice demonstrate that the effectiveness of 1,25(OH2D requires NKT cells, IL-10, the IL-10R and IL-4. Comparisons of mouse and human T cells show that 1,25(OH2D inhibits IL-17 and IFN-γ, and induces T regulatory cells and IL-4. IL-4 was induced by 1,25(OH2D in mouse and human iNKT cells. Activation for 72h was required for optimal expression of the vitamin D receptor (VDR in human and mouse T and iNKT cells. In addition, T cells are potential autocrine sources of 1,25(OH2D but again only 48–72h after activation. Together the data support the late effects of vitamin D on diseases like inflammatory bowel disease and multiple sclerosis where reducing IL-17 and IFN-γ, while inducing IL-4 and IL-10, would be beneficial.

Perceptions about Training during Endocrinology Residency Programs in India over the Years: A Cross-sectional Study (PEER India Study)

Science.gov (United States)

Khandelwal, Deepak; Dutta, Deep; Singla, Rajiv; Surana, Vineet; Aggarwal, Sameer; Gupta, Yashdeep; Kalra, Sanjay; Khadgawat, Rajesh; Tandon, Nikhil

2017-01-01

Background: Residents' perception on quality of endocrinology training in India is not known. This study aimed to evaluate the perceptions about endocrinology residency programs in India among current trainees as compared to practicing endocrinologists. Methods: Trainees attending a preconference workshop at the annual conference of Endocrine Society of India (ESI) were given a questionnaire designed to evaluate their perceptions on their training. These evaluated the reasons for choosing endocrinology, their experiences during residency, and career plans. Practicing endocrinologists attending ESICON with at least 5-year experience were evaluated as controls. Results: Questionnaires from 63 endocrine trainees and 78 practicing endocrinologists were analyzed. Endocrinology is perceived to be the super-specialty with the best quality of life (QOL) but fair with regard to financial remuneration. Among current trainees, 61.89%, 31.74%, and 34.91% are satisfied with training in clinical endocrinology, laboratory endocrinology, and clinical/translational research, respectively. The corresponding figures for practicing endocrinologists are 71.78%, 25.63%, and 30.75%, respectively. Exposure to national endocrinology conferences during their endocrinology residency was adequate. However, exposure to international endocrinology conferences, research publications, project writing, and grant application are limited. Laboratory endocrinology is rated as the most neglected aspect during endocrine residency. Most of the trainees want to establish their own clinical practice in the long run. Very few trainees (17.46%) wish to join the medical education services. Conclusion: There is a good perception of QOL in endocrinology in spite of average financial remuneration. There is dissatisfaction with the quality of training in laboratory endocrinology and clinical research. Very few endocrine trainees consider academics as a long-term career option in India. PMID:28459024

Reproductive endocrinology of vitamin D

DEFF Research Database (Denmark)

Lorenzen, Mette; Boisen, Ida Marie; Mortensen, Li Juel

2017-01-01

Vitamin D is a versatile hormone with several functions beyond its well-established role in maintenance of skeletal health and calcium homeostasis. The effects of vitamin D are mediated by the vitamin D receptor, which is expressed together with the vitamin D metabolizing enzymes in the reproduct...... suffering from reproductive problems and abnormal endocrinology research addressing the role of vitamin D in reproductive endocrinology may be of clinical importance....

TRANSFER FROM PEDIATRIC TO ADULT ENDOCRINOLOGY.

Science.gov (United States)

Jones, Marybeth R; Robbins, Brett W; Augustine, Marilyn; Doyle, Jackie; Mack-Fogg, Jean; Jones, Heather; White, Patience H

2017-07-01

Adult and pediatric endocrinologists share responsibility for the transition of youth with type 1 diabetes from pediatric to adult healthcare. This study aimed to increase successful transfers to adult care in subspecialty practices by establishing a systematic health care transition (HCT) process. Providers from the adult and pediatric endocrinology divisions at the University of Rochester Medical Center met monthly to customize and integrate the Six Core Elements (6CEs) of HCT into clinical workflows. Young adult patients with type 1 diabetes having an outpatient visit during a 34-month pre-post intervention period were eligible (N = 371). Retrospective chart review was performed on patients receiving referrals to adult endocrinology (n = 75) to obtain (1) the proportion of patients explicitly tracked during transfer from the pediatric to adult endocrinology practice, (2) the providers' documentation of the use of the 6CEs, and (3) the patients' diabetes control and healthcare utilization during the transition period. The percent of eligible patients with type 1 diabetes who were explicitly tracked in their transfer more than doubled compared to baseline (11% vs. 27% of eligible patients; P<.01). Pediatric providers started to use transition readiness assessments and create medical summaries, and adult providers increased closed-loop communication with pediatric providers after a patient's first adult visit. Glycemic control and healthcare utilization remained stable. Successful implementation of the 6CEs into pediatric and adult subspecialty practices can result in improvements of planned transfers of pediatric patients with type 1 diabetes to adult subspecialty providers. 6CEs = six core elements; AYA = adolescent and young adult; DKA = diabetic ketoacidosis; ED = emergency department; HbA1c = hemoglobin A1c; HCT = health care transition.

42 CFR 493.843 - Standard; Endocrinology.

Science.gov (United States)

2010-10-01

... 42 Public Health 5 2010-10-01 2010-10-01 false Standard; Endocrinology. 493.843 Section 493.843 Public Health CENTERS FOR MEDICARE & MEDICAID SERVICES, DEPARTMENT OF HEALTH AND HUMAN SERVICES... These Tests § 493.843 Standard; Endocrinology. (a) Failure to attain a score of at least 80 percent of...

Transcriptional effects of 1,25 dihydroxyvitamin D{sub 3} physiological and supra-physiological concentrations in breast cancer organotypic culture

Energy Technology Data Exchange (ETDEWEB)

Milani, Cintia [Disciplina de Oncologia, LIM24, Departamento de Radiologia e Oncologia, Faculdade de Medicina da Universidade de São Paulo, Av. Dr. Arnaldo 455,Sala 4124, São Paulo, SP, 01246-903 (Brazil); Góes, João Carlos Guedes Sampaio [Instituto Brasileiro de Controle do Câncer, IBCC, São Paulo (Brazil); Nonogaki, Suely [Instituto Adolfo Lutz, Centro de Patologia, Núcleo de Patologia Quantitativa, São Paulo (Brazil); Tamura, Rodrigo Esaki [Post-doctoral fellow, Viral Vectors Laboratory, Instituto do Câncer do Estado de São Paulo, ICESP, São Paulo (Brazil); Folgueira, Maria Aparecida Azevedo Koike; Katayama, Maria Lucia Hirata [Disciplina de Oncologia, LIM24, Departamento de Radiologia e Oncologia, Faculdade de Medicina da Universidade de São Paulo, Av. Dr. Arnaldo 455,Sala 4124, São Paulo, SP, 01246-903 (Brazil); Lyra, Eduardo Carneiro de [Disciplina de Oncologia, LIM24, Departamento de Radiologia e Oncologia, Faculdade de Medicina da Universidade de São Paulo, Av. Dr. Arnaldo 455,Sala 4124, São Paulo, SP, 01246-903 (Brazil); Instituto Brasileiro de Controle do Câncer, IBCC, São Paulo (Brazil); Welsh, JoEllen [Department of Environmental Health Sciences, School of Public Health, University at Albany, Rensselaer, NY, 12144 (United States); Campos, Laura Tojeiro; Brentani, M Mitzi [Disciplina de Oncologia, LIM24, Departamento de Radiologia e Oncologia, Faculdade de Medicina da Universidade de São Paulo, Av. Dr. Arnaldo 455,Sala 4124, São Paulo, SP, 01246-903 (Brazil); Maciel, Maria do Socorro [Hospital do Câncer A. C. Camargo, São Paulo (Brazil); Roela, Rosimeire Aparecida; Valle, Paulo Roberto del [Disciplina de Oncologia, LIM24, Departamento de Radiologia e Oncologia, Faculdade de Medicina da Universidade de São Paulo, Av. Dr. Arnaldo 455,Sala 4124, São Paulo, SP, 01246-903 (Brazil)

2013-03-15

Vitamin D transcriptional effects were linked to tumor growth control, however, the hormone targets were determined in cell cultures exposed to supra physiological concentrations of 1,25(OH){sub 2}D{sub 3} (50-100nM). Our aim was to evaluate the transcriptional effects of 1,25(OH){sub 2}D{sub 3} in a more physiological model of breast cancer, consisting of fresh tumor slices exposed to 1,25(OH){sub 2}D{sub 3} at concentrations that can be attained in vivo. Tumor samples from post-menopausal breast cancer patients were sliced and cultured for 24 hours with or without 1,25(OH){sub 2}D{sub 3} 0.5nM or 100nM. Gene expression was analyzed by microarray (SAM paired analysis, FDR≤0.1) or RT-qPCR (p≤0.05, Friedman/Wilcoxon test). Expression of candidate genes was then evaluated in mammary epithelial/breast cancer lineages and cancer associated fibroblasts (CAFs), exposed or not to 1,25(OH){sub 2}D{sub 3} 0.5nM, using RT-qPCR, western blot or immunocytochemistry. 1,25(OH){sub 2}D{sub 3} 0.5nM or 100nM effects were evaluated in five tumor samples by microarray and seven and 136 genes, respectively, were up-regulated. There was an enrichment of genes containing transcription factor binding sites for the vitamin D receptor (VDR) in samples exposed to 1,25(OH){sub 2}D{sub 3} near physiological concentration. Genes up-modulated by both 1,25(OH){sub 2}D{sub 3} concentrations were CYP24A1, DPP4, CA2, EFTUD1, TKTL1, KCNK3. Expression of candidate genes was subsequently evaluated in another 16 samples by RT-qPCR and up-regulation of CYP24A1, DPP4 and CA2 by 1,25(OH){sub 2}D{sub 3} was confirmed. To evaluate whether the transcripitonal targets of 1,25(OH){sub 2}D{sub 3} 0.5nM were restricted to the epithelial or stromal compartments, gene expression was examined in HB4A, C5.4, SKBR3, MDA-MB231, MCF-7 lineages and CAFs, using RT-qPCR. In epithelial cells, there was a clear induction of CYP24A1, CA2, CD14 and IL1RL1. In fibroblasts, in addition to CYP24A1 induction, there was a

Effect of hypoxia-inducible factor 1-alpha (HIF-1α) on proliferation ...

African Journals Online (AJOL)

Jane

2011-07-25

Jul 25, 2011 ... Full Length Research Paper. Effect of hypoxia-inducible factor 1-alpha ... 1Department of Neurosurgery, Ruijin Hospital, Shanghai JiaoTong University School of Medicine, Shanghai 200025,. China. 2Department of Neurosurgery, Chaoyang Hospital, Huainan, Anhui, China. 3Department of Neurosurgery ...

[The current state and prospectives of military endocrinology].

Science.gov (United States)

Nagibovich, O A; Golota, A S; Krassiĭ, A B

2014-10-01

The article is dedicated to the current state and prospectives of military endocrinology demonstrated on the examples of the endocrinology services of armed forces of Serbia, Poland, France, and USA. It is shown that this branch of military healthcare receives much attention abroad. The prospectives of military endocrinology are demonstrated in the context of two nosological forms which dominate in this section of military medicine, namely, primary hypothyroidism an diabetes mellitus.

1α-hydroxylase and innate immune responses to 25-hydroxyvitamin D in colonic cell lines

Science.gov (United States)

Lagishetty, Venu; Chun, Rene F.; Liu, Nancy Q.; Lisse, Thomas S.; Adams, John S.; Hewison, Martin

2010-01-01

Vitamin D-insufficiency is a prevalent condition in populations throughout the world, with low serum levels of 25-hydroxyvitamin D (25OHD) linked to a variety of human health concerns including cancer, autoimmune disease and infection. Current data suggest that 25OHD action involves localized extra-renal conversion to 1,25-dihydroxyvitamin D (1,25(OH)2D) via tissue-specific expression of the enzyme 25-hydroxyvitamin D-1α-hydroxylase (1α-hydroxylase). In cells such as macrophages, expression of 1α-hydroxylase is intimately associated with toll-like receptor (TLR) recognition of pathogens. However, this mechanism may not be exclusive to extra-renal generation of 1,25(OH)2D. To investigate the relationship between TLR-mediated pathogen recognition and vitamin D-induced antibacterial activity, intracrine responses to 25OHD metabolism were explored in vitro using the established colonic cell lines Caco-2 and Caco-2 clone BBe. Analysis of antibacterial factors such as cathelicidin (LL37) and β-defensin-4 (DEFB4) was carried out following co-treatment with TLR ligands. Data indicate that, unlike macrophages, Caco-2 and BBe colonic cell lines are unresponsive to TLR-induced 1α-hydroxylase. Alternative activators of 1α-hydroxylase such as transforming growth factor β were also ineffective at priming intracrine responses to 25OHD. Thus, in common with other barrier sites such as the skin or placenta, colonic epithelial cells may require specific factors to initiate intracrine responses to vitamin D. PMID:20152900

Community health orientation of Indian Journal of Endocrinology and Metabolism: A bibliometric analysis of Indian Journal of Endocrinology and Metabolism

Science.gov (United States)

Kaushal, Kanica; Kalra, Sanjay

2015-01-01

Background: Endocrine and metabolic diseases especially diabetes have become focus areas for public health professionals. Indian Journal of Endocrinology and Metabolism (IJEM), a publication of Endocrine Society of India, is a peer-reviewed online journal, which covers technical and clinical studies related to health, ethical and social issues in field of diabetes, endocrinology and metabolism. This bibliometric analysis assesses the journal from a community health perspective. Materials and Methods: Every article published in IJEM over a period of 4 years (2011–2014) was accessed to review coverage of community health in the field of endocrinology. Results: Seven editorials, 30 review articles, 41 original articles, 12 brief communications, 20 letter to editors, 4 articles on guidelines and 2 in the section “endocrinology and gender” directly or indirectly dealt with community health aspects of endocrinology. Together these amounted to 17% of all articles published through these 4 years. There were 14 articles on general, 60 pertaining to pancreas and diabetes, 10 on thyroid, 7 on pituitary/adrenal/gonads, 21 on obesity and metabolism and 4 on parathyroid and bone; all community medicine related. Conclusion: Community health is an integral part of the modern endocrinology diabetology and metabolism practice and it received adequate journal space during the last 4 years. The coverage is broad based involving all the major endocrine disorders. PMID:25932398

Community health orientation of Indian Journal of Endocrinology and Metabolism: A bibliometric analysis of Indian Journal of Endocrinology and Metabolism

Directory of Open Access Journals (Sweden)

Kanica Kaushal

2015-01-01

Full Text Available Background: Endocrine and metabolic diseases especially diabetes have become focus areas for public health professionals. Indian Journal of Endocrinology and Metabolism (IJEM, a publication of Endocrine Society of India, is a peer-reviewed online journal, which covers technical and clinical studies related to health, ethical and social issues in field of diabetes, endocrinology and metabolism. This bibliometric analysis assesses the journal from a community health perspective. Materials and Methods: Every article published in IJEM over a period of 4 years (2011-2014 was accessed to review coverage of community health in the field of endocrinology. Results: Seven editorials, 30 review articles, 41 original articles, 12 brief communications, 20 letter to editors, 4 articles on guidelines and 2 in the section "endocrinology and gender" directly or indirectly dealt with community health aspects of endocrinology. Together these amounted to 17% of all articles published through these 4 years. There were 14 articles on general, 60 pertaining to pancreas and diabetes, 10 on thyroid, 7 on pituitary/adrenal/gonads, 21 on obesity and metabolism and 4 on parathyroid and bone; all community medicine related. Conclusion: Community health is an integral part of the modern endocrinology diabetology and metabolism practice and it received adequate journal space during the last 4 years. The coverage is broad based involving all the major endocrine disorders.

Fifty-Five Years of Pediatric Endocrinology and 50 Years of the Department of Pediatric Endocrinology, Diabetes and Metabolic Diseases in Slovenia

Science.gov (United States)

BATTELINO, Tadej

2015-01-01

Paediatric endocrinology started its independent development early in the general development of this specialty, with a strong focus on research and clinical excellence. Slovenian paediatric endocrinology was an integral part of the European paediatric endocrinology from its beginnings and a founding member of the first ‘International Study Group for Diabetes in Children and Adolescents’. After the pioneering work of Prof. Lev Matajc, Prof. Ciril Kržišnik firmly integrated the Department of Pediatric Endocrinology, Diabetes and Metabolic Diseases at the University Children’s Hospital in Ljubljana in the international scientific community. In the last decade, the department participates in cutting-edge research and provides clinical services at highest international standards. PMID:27646909

Transgender Health in Endocrinology: Current Status of Endocrinology Fellowship Programs and Practicing Clinicians.

Science.gov (United States)

Davidge-Pitts, Caroline; Nippoldt, Todd B; Danoff, Ann; Radziejewski, Lauren; Natt, Neena

2017-04-01

The transgender population continues to face challenges in accessing appropriate health care. Adequate training of endocrinologists in this area is a priority. Assess the status of transgender health care education in US endocrinology fellowship training programs and assess knowledge and practice of transgender health among practicing US endocrinologists. Mayo Clinic and the Endocrine Society developed and administered a Web-based anonymous survey to 104 endocrinology fellowship program directors (PDs; members of the Association of Program Directors in Endocrinology, Diabetes and Metabolism) and 6992 US medical doctor members of Endocrine Society. There were 54 total responses from 104 PDs (51.9%). Thirty-five of these 54 programs (72.2%) provide teaching on transgender health topics; however, 93.8% respondents indicated that fellowship training in this area is important. Barriers to provision of education included lack of faculty interest or experience. The most desired strategies to increase transgender-specific content included online training modules for trainees and faculty. Of 411 practicing clinician responders, almost 80% have treated a transgender patient, but 80.6% have never received training on care of transgender patients. Clinicians were very or somewhat confident in terms of definitions (77.1%), taking a history (63.3%), and prescribing hormones (64.8%); however, low confidence was reported outside of the hormonal realm. The most requested methods of education included online training modules and presentation of transgender topics at meetings. Confidence and competence in transgender health needs to increase among endocrinologists. Strategies include the development of online training modules, expansion of formal transgender curricula in fellowship programs, and presentations at national and international meetings. Copyright © 2017 by the Endocrine Society

The alpha-spectrin gene is on chromosome 1 in mouse and man.

Science.gov (United States)

Huebner, K; Palumbo, A P; Isobe, M; Kozak, C A; Monaco, S; Rovera, G; Croce, C M; Curtis, P J

1985-06-01

By using alpha-spectrin cDNA clones of murine and human origin and somatic cell hybrids segregating either mouse or human chromosomes, the gene for alpha-spectrin has been mapped to chromosome 1 in both species. This assignment of the mouse alpha-spectrin gene to mouse chromosome 1 by DNA hybridization strengthens the previous identification of the alpha-spectrin locus in mouse with the sph locus, which previously was mapped by linkage analysis to mouse chromosome 1, distal to the Pep-3 locus. By in situ hybridization to human metaphase chromosomes, the human alpha-spectrin gene has been localized to 1q22-1q25; interestingly, the locus for a non-Rh-linked form of elliptocytosis has been provisionally mapped to band 1q2 by family linkage studies.

1,25-Dihydroxyvitamin D3 induces biphasic NF-κB responses during HL-60 leukemia cells differentiation through protein induction and PI3K/Akt-dependent phosphorylation/degradation of IκB

International Nuclear Information System (INIS)

Tse, A.K.-W.; Wan, C.-K.; Shen, X.-L.; Zhu, G.-Y.; Cheung, H.-Y.; Yang, M.; Fong, W.-F.

2007-01-01

1,25-Dihydroxyvitamin D 3 (VD 3 ) induces differentiation in a number of leukemia cell lines and under various conditions is able to either stimulate or inhibit nuclear factor kappa B (NF-κB) activity. Here we report a time-dependent biphasic regulation of NF-κB in VD 3 -treated HL-60 leukemia cells. After VD 3 treatment there was an early ∼ 4 h suppression and a late 8-72 h prolonged reactivation of NF-κB. The reactivation of NF-κB was concomitant with increased IKK activities, IKK-mediated IκBα phosphorylation, p65 phosphorylation at residues S276 and S536, p65 nuclear translocation and p65 recruitment to the NF-κB/vitamin D responsive element promoters. In parallel with NF-κB stimulation, there was an up-regulation of NF-κB controlled inflammatory and anti-apoptotic genes such as TNFα, IL-1β and Bcl-xL. VD 3 -triggered reactivation of NF-κB was associated with PI3K/Akt phosphorylation. PI3K/Akt antagonists suppressed VD 3 -stimulated IκBα phosphorylation as well as NF-κB-controlled gene expression. The early ∼ 4 h VD 3 -mediated NF-κB suppression coincided with a prolonged increase of IκBα protein which require de novo protein synthesis, lasted for as least 72 h and was insensitive to MAPK, IKK or PI3K/Akt inhibitors. Our data suggest a novel biphasic regulation of NF-κB in VD 3 -treated leukemia cells and our results may have provided the first molecular explanation for the contradictory observations reported on VD 3 -mediated immune-regulation

1,25(OH)2D3 attenuates TGF-β1/β2-induced increased migration and invasion via inhibiting epithelial-mesenchymal transition in colon cancer cells.

Science.gov (United States)

Chen, Shanwen; Zhu, Jing; Zuo, Shuai; Ma, Ju; Zhang, Junling; Chen, Guowei; Wang, Xin; Pan, Yisheng; Liu, Yucun; Wang, Pengyuan

1,25-Dihydroxyvitamin D3 (1,25(OH)2D3) has been reported to inhibit proliferation and migration of multiple types of cancer cells. However, the mechanism underlying its anti-metastasis effect is not fully illustrated. In this study, the effect of 1,25(OH)2D3 on TGF-β1/β2-induced epithelial-mesenchymal transition (EMT) is tested in colon cancer cells. The results suggest that 1,25(OH)2D3 inhibited TGF-β1/β2-induced increased invasion and migration of in SW-480 and HT-29 cells. 1,25(OH)2D3 also inhibited the cadherin switch in SW-480 and HT-29 cells. TGF-β1/β2-induced increased expression of EMT-related transcription factors was also inhibited by 1,25(OH)2D3. 1,25(OH)2D3 also inhibited the secretion of MMP-2 and MMP-9 and increased expression of F-actin induced by TGF-β1/β2 in SW-480 cells. Taken together, this study suggests that the suppression of EMT might be one of the mechanisms underlying the anti-metastasis effect of 1,25(OH)2D3 in colon cancer cells. Copyright © 2015 Elsevier Inc. All rights reserved.

AMERICAN ASSOCIATION OF CLINICAL ENDOCRINOLOGISTS, AMERICAN COLLEGE OF ENDOCRINOLOGY, AND ASSOCIAZIONE MEDICI ENDOCRINOLOGI MEDICAL GUIDELINES FOR CLINICAL PRACTICE FOR THE DIAGNOSIS AND MANAGEMENT OF THYROID NODULES - 2016 UPDATE

DEFF Research Database (Denmark)

Gharib, Hossein; Papini, Enrico; Garber, Jeffrey R

2016-01-01

by the American Association of Clinical Endocrinologists (AACE), American College of Endocrinology (ACE) and Associazione Medici Endocrinologi (AME). ABBREVIATIONS: AACE = American Association of Clinical Endocrinologists ACE = American College of Endocrinology AME = Associazione Medici Endocrinologi BEL = best...

Historical view of development of comparative endocrinology in Japan.

Science.gov (United States)

Kikuyama, Sakae; Tsutsui, Kazuyoshi

2011-04-01

This article describing a brief history of development of comparative endocrinology in Japan is contributed to the journal General and Comparative Endocrinology, in commemoration of the 50th anniversary of its publication. It covers significant works in the field of comparative endocrinology that have been done by Japanese endocrinologists, focusing those achieved during the past 70 years. The contents were arranged according to the taxonomical order of the experimental animals with which individual researchers or research groups have contributed to the acquisition of important knowledge in comparative endocrinology. Copyright © 2011 Elsevier Inc. All rights reserved.

Regulation of the human SLC25A20 expression by peroxisome proliferator-activated receptor alpha in human hepatoblastoma cells

Energy Technology Data Exchange (ETDEWEB)

Tachibana, Keisuke, E-mail: nya@phs.osaka-u.ac.jp [Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamadaoka, Suita, Osaka 565-0871 (Japan); Takeuchi, Kentaro; Inada, Hirohiko [Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamadaoka, Suita, Osaka 565-0871 (Japan); Yamasaki, Daisuke [Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamadaoka, Suita, Osaka 565-0871 (Japan); The Center for Advanced Medical Engineering and Informatics, Osaka University, 2-2 Yamadaoka, Suita, Osaka 565-0871 (Japan); Ishimoto, Kenji [Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamadaoka, Suita, Osaka 565-0871 (Japan); Graduate School of Medicine, Osaka University, 2-2 Yamadaoka, Suita, Osaka 565-0871 (Japan); Tanaka, Toshiya; Hamakubo, Takao; Sakai, Juro; Kodama, Tatsuhiko [Laboratory for System Biology and Medicine, Research Center for Advanced Science and Technology, University of Tokyo, 4-6-1 Komaba, Meguro, Tokyo 153-8904 (Japan); Doi, Takefumi [Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamadaoka, Suita, Osaka 565-0871 (Japan); The Center for Advanced Medical Engineering and Informatics, Osaka University, 2-2 Yamadaoka, Suita, Osaka 565-0871 (Japan); Graduate School of Medicine, Osaka University, 2-2 Yamadaoka, Suita, Osaka 565-0871 (Japan)

2009-11-20

Solute carrier family 25, member 20 (SLC25A20) is a key molecule that transfers acylcarnitine esters in exchange for free carnitine across the mitochondrial membrane in the mitochondrial {beta}-oxidation. The peroxisome proliferator-activated receptor alpha (PPAR{alpha}) is a ligand-activated transcription factor that plays an important role in the regulation of {beta}-oxidation. We previously established tetracycline-regulated human cell line that can be induced to express PPAR{alpha} and found that PPAR{alpha} induces the SLC25A20 expression. In this study, we analyzed the promoter region of the human slc25a20 gene and showed that PPAR{alpha} regulates the expression of human SLC25A20 via the peroxisome proliferator responsive element.

Cytokine vaccination: neutralising IL-1alpha autoantibodies induced by immunisation with homologous IL-1alpha

DEFF Research Database (Denmark)

Svenson, M; Hansen, M B; Thomsen, Allan Randrup

2000-01-01

with IL-1alpha coupled to purified protein derivative of tuberculin (PPD). Both unprimed and primed animals developed IgG aAb to IL-1alpha. These aAb persisted at high levels more than 100 days after vaccination and did not cross-react with murine IL-1beta. The induced anti-IL-1alpha aAb inhibited binding...... in mice by vaccination with recombinant murine IL-1alpha conjugated to PPD. Studies of the effects of IL-1alpha aAb in such animals may help clarify the importance of naturally occurring IL-1alpha aAb in humans and permit the evaluation of future therapies with cytokine aAb in patients...

Analysis of Prescriptions of Alpha-Blockers and Phosphodiesterase 5 Inhibitors from the Urology Department and Other Departments

Directory of Open Access Journals (Sweden)

Dong Hyuk Kang

2011-12-01

Full Text Available PurposeWe analyzed the prescriptions of alpha-blockers and phosphodiesterase 5 inhibitors (PDE5Is in the urology department as well as in other departments of the general hospital.MethodsWe investigated the frequency of prescription of alpha-blockers and PDE5Is from 3 general hospitals from January 1, 2007 to December 31, 2009. For alpha-blockers, data were collected from patients to whom alpha-blockers were prescribed from among patients recorded as having benign prostatic hyperplasia according to the 5th Korean Standard Classification of Diseases. For PDE5Is, data were collected from patients to whom PDE5Is were prescribed by the urology department and by other departments. Alpha-blockers were classified into tamsulosin, alfuzosin, doxazosin, and terazosin, whereas PDE5Is were classified into sildenafil, tadalafil, vardenafil, udenafil, and mirodenafil.ResultsAlpha-blockers were prescribed to 11,436 patients in total over 3 years, and the total frequency of prescriptions was 68,565. Among other departments, the nephrology department had the highest frequency of prescription of 3,225 (4.7%, followed by the cardiology (3,101, 4.5%, neurology (2,576, 3.8%, endocrinology (2,400, 3.5%, pulmonology (1,102, 1.6%, and family medicine (915, 1.3% departments in order. PDE5Is were prescribed to 2,854 patients in total over 3 years, and the total frequency of prescriptions was 10,558. The prescription frequency from the urology department was 4,900 (46.4%. Among other departments, the endocrinology department showed the highest prescription frequency of 3,488 (33.0%, followed by the neurology (542, 5.1%, cardiology (467, 4.4%, and family medicine (407, 3.9% departments in order.ConclusionsA high percentage of prescriptions of alpha-blockers and PDE5Is were from other departments. For more specialized medical care by urologists is required in the treatment of lower urinary tract symptoms and erectile dysfunction.

Experimental investigation of the reactions {sup 25}Mg({alpha},n){sup 28}Si, {sup 26}Mg({alpha},n){sup 29}Si, {sup 18}O({alpha},n){sup 21}Ne and their impact on stellar nucleosynthesis

Energy Technology Data Exchange (ETDEWEB)

Falahat, Sascha

2010-06-10

In the present dissertation, the nuclear reactions {sup 25}Mg({alpha},n){sup 28}Si, {sup 26}Mg({alpha},n){sup 29}Si, {sup 18}O({alpha},n){sup 21}Ne are investigated in the astrophysically interesting energy region from E{sub {alpha}}=1000 keV to E{sub {alpha}}=2450 keV. The experiments were performed at the Nuclear Structure Laboratory of the University of Notre Dame (USA) with the Van-de-Graaff accelerator KN. Solid state targets with evaporated magnesium or anodized oxygen were bombarded with {alpha}-particles and the released neutrons detected. For the detection of the released neutrons, computational simulations were used to construct a neutron detector based on {sup 3}He counters. Because of the strong occurrence of background reactions, different methods of data analysis were employed. Finally, the impact of the reactions {sup 25}Mg({alpha},n){sup 28}Si, {sup 26}Mg({alpha},n){sup 29}Si, {sup 18}O({alpha},n){sup 21}Ne on stellar nucleosynthesis is investigated by means of network calculations. (orig.)

The Mahabharata and reproductive endocrinology

Directory of Open Access Journals (Sweden)

Bharti Kalra

2016-01-01

Full Text Available This communication approaches the Mahabharata through the prism of reproductive endocrinology. Descriptions of episodes related to reproduction are listed here, to provide fodder for the endocrinologically minded brain. The cases described here are perhaps, the first documented observations of fetal orgasm, pseudocyesis and assisted reproductive technology, including assisted insemination by donor, induction of ovulation, and in vitro fertilization as well as precocious growth and intersex. We do not presume to offer a definite explanation for these interesting episodes from the Mahabharata. We do, however, hope to stimulate interest in ancient Indian literature, and encourage a literary “forensic endocrine” analysis of events relevant to our specialty.

Radiocompetitive estimation of 25-hydroxyvitamin D human serum

International Nuclear Information System (INIS)

Guillemant, S.; Kremer, R.

1978-01-01

A radiocompetitive estimation of 25-hydroxyvitamin D in human serum is described. After extraction, a stage of purification by chromatography on a Sephadex LH 20 column permits separation of 25-hydroxyvitamin D from Vitamin D and other metabolites. The reaction of radiocompetition uses as tracer tritialed 25-hydroxycholecalciferol and as source of binding protein, rat renal cytosol. The characteristics of the binding protein and the presence in human plasma of significant quantities of 24,25-dihydroxyvitamin D render necesssary the chromatographic stage. This technic permits one to measure simply and specifically 25-hydroxyvitamin D in the human serum, of which normal levels (average + - standard deviation) are 12.88 + - 5.42 μg/l (3.2.10 -8 + - 1.35.10 -8 mol/l) [fr

Classification of alpha 1-adrenoceptor subtypes

NARCIS (Netherlands)

Michel, M. C.; Kenny, B.; Schwinn, D. A.

1995-01-01

Two alpha 1-adrenoceptor subtypes (alpha 1A and alpha 1B) have been detected in various tissues by pharmacological techniques, and three distinct cDNAs encoding alpha 1-adrenoceptor subtypes have been cloned. The profile of an increasing number of subtype-selective compounds at cloned and endogenous

Adverse effects of cyclosporine A on HSP25, alpha B-crystallin and myofibrillar cytoskeleton in rat heart

International Nuclear Information System (INIS)

Stacchiotti, Alessandra; Bonomini, Francesca; Lavazza, Antonio; Rodella, Luigi Fabrizio; Rezzani, Rita

2009-01-01

Cyclosporine (CsA) is a universally used immunosuppressive drug which induces adverse side effects in several organs, but its impact on the heart is still controversial. Small heat shock proteins (sHSPs), such as HSP25 and alpha B-crystallin, are cytoprotective stress proteins exceptionally represented in the heart. They act as myofibrillar chaperones that help actin and desmin to maintain their optimum configuration and stability, thereby antagonizing oxidative damage. The present study examined: (1) the cardiac distribution and abundance of HSP25 and alpha B-crystallin in rats receiving CsA at a therapeutic dosage (15 mg/kg/day) for 42 days and 63 days; (2) the presence of myofibrillar proteins, such as actin, alpha-actinin and desmin following the CsA treatments; (3) the subcellular effects of prolonged CsA exposure on the cardiomyocytes by histopathology and transmission electron microscopy. After 63 days CsA intake, sHSPs translocated from a regular sarcomeric pattern to peripheral sarcolemma and intercalated discs, together with actin and desmin. In contrast, the sarcomeric alpha-actinin pattern did not change in all experimental groups. The abundance of actin and HSP25 was unchanged in every time point of treatment while after 63 days CsA, alpha B-crystallin and desmin levels significantly decreased. Furthermore CsA induced fibrosis, irregular sarcomeric alignment and damaged desmosomes. These findings indicate that following prolonged CsA exposure, the cardiac muscle network was affected. In particular, the translocation of sHSPs to intercalated discs merits special consideration as a direct compensatory mechanism to limit CsA cardiotoxicity.

Syntheses of 24R,25-dihydroxy-[6,19,19-3H]vitamin D3 and 24R,25-dihydroxy-[6,19,19-2H]vitamin D3

International Nuclear Information System (INIS)

Yamada, S.; Shimizu, M.; Fukushima, K.; Niimura, K.; Maeda, Y.

1989-01-01

24R,25-Dihydroxy-[6,19,19-3H]vitamin D3 with a specific activity of 54 Ci/mmol and 24R,25-dihydroxy-[6,19,19-2H]vitamin D3 with 2.6 deuterium atoms/mol were synthesized in four steps starting from 24R,25-Dihydroxyvitamin D3 via its sulfur dioxide adduct

Clinical differences between patients with MODY-3, MODY-2 and type 2 diabetes mellitus with I27L polymorphism in the HNF1alpha gene.

Science.gov (United States)

Pinés Corrales, Pedro José; López Garrido, María P; Aznar Rodríguez, Silvia; Louhibi Rubio, Lynda; López Jiménez, Luz M; Lamas Oliveira, Cristina; Alfaro Martínez, Jose J; Lozano García, Jose J; Hernández López, Antonio; Requejo Castillo, Ramón; Escribano Martínez, Julio; Botella Romero, Francisco

2010-01-01

The aim of our study was to describe and evaluate the clinical and metabolic characteristics of patients with MODY-3, MODY-2 or type 2 diabetes who presented I27L polymorphism in the HNF1alpha gene. The study included 31 previously diagnosed subjects under follow-up for MODY-3 (10 subjects from 5 families), MODY-2 (15 subjects from 9 families), or type 2 diabetes (6 subjects) with I27L polymorphism in the HNF1alpha gene. The demographic, clinical, metabolic, and genetic characteristics of all patients were analyzed. No differences were observed in distribution according to sex, age of onset, or form of diagnosis. All patients with MODY-2 or MODY-3 had a family history of diabetes. In contrast, 33.3% of patients with type 2 diabetes mellitus and I27L polymorphism in the HNF1alpha gene had no family history of diabetes (p MODY-3 patients, but not required by 100% of MODY-2 patients or 16.7% of patients with type 2 diabetes mellitus and I27L polymorphism in the HNF1alpha gene (p MODY-2, MODY-3 or type 2 diabetes of atypical characteristics, in this case patients who present I27L polymorphism in the HNF1alpha gene. Copyright 2010 Sociedad Española de Endocrinología y Nutrición. Published by Elsevier Espana. All rights reserved.

Age-dependent changes in expression of alpha1-adrenergic receptors in rat myocardium

International Nuclear Information System (INIS)

Schaffer, W.; Williams, R.S.

1986-01-01

The expression of alpha 1 -adrenergic receptors within ventricular myocardium of rats ranging in age from 21 days of fetal life to 24 months after birth was measured from [ 125 I] 2-(β hydroxy phenyl) ethylaminomethyl tetralone binding isotherms. No difference was observed in binding affinity between any of the age groups studied. The number of alpha 1 -adrenergic receptors was found to be 60-120% higher in membranes from fetal or immature rats up to 25 days of age when compared with adult animals. The increased expression of alpha 1 -adrenergic receptors in the developing heart relative to that observed in adult heart is consistent with the hypothesis that alpha 1 -adrenergic receptor stimulation may modulate protein synthesis and growth in mammalian myocardium

1,25D3 enhances antitumor activity of gemcitabine and cisplatin in human bladder cancer models

Science.gov (United States)

Ma, Yingyu; Yu, Wei-Dong; Trump, Donald L.; Johnson, Candace S.

2010-01-01

Background 1,25 dihydroxyvitamin D3 (1,25D3) potentiates the cytotoxic effects of several common chemotherapeutic agents. The combination of gemcitabine and cisplatin (GC) is a current standard chemotherapy regimen for bladder cancer. We investigated whether 1,25D3 could enhance the antitumor activity of GC in bladder cancer model systems. Methods Human bladder cancer T24 and UMUC3 cells were pretreated with 1,25D3 followed by GC. Apoptosis were assessed by annexin V staining. Caspase activation was examined by immunoblot analysis and substrate-based caspase activity assay. The cytotoxic effects were examined using MTT and in vitro clonogenic assay. p73 protein levels were assessed by immunoblot analysis. Knockdown of p73 was achieved by siRNA. The in vivo antitumor activity was assessed by in vivo excision clonogenic assay and tumor regrowth delay in the T24 xenograft model. Results 1,25D3 pretreatment enhanced GC-induced apoptosis and the activities of caspases- 8, 9 and 3 in T24 and UMUC3 cells. 1,25D3 synergistically reduced GC-suppressed surviving fraction in T24 cells. 1,25D3, gemcitabine, or cisplatin induced p73 accumulation, which was enhanced by GC or 1,25D3 and GC. p73 expression was lower in human primary bladder tumor tissue compared with adjacent normal tissue. Knockdown of p73 increased clonogenic capacity of T24 cells treated with 1,25D3, GC or 1,25D3 and GC. 1,25D3 and GC combination enhanced tumor regression compared with 1,25D3 or GC alone. Conclusions 1,25D3 potentiates GC-mediated growth inhibition in human bladder cancer models in vitro and in vivo, which involves p73 induction and apoptosis. PMID:20564622

TRPV6 determines the effect of vitamin D3 on prostate cancer cell growth.

Directory of Open Access Journals (Sweden)

V'yacheslav Lehen'kyi

Full Text Available Despite remarkable advances in the therapy and prevention of prostate cancer it is still the second cause of death from cancer in industrialized countries. Many therapies initially shown to be beneficial for the patients were abandoned due to the high drug resistance and the evolution rate of the tumors. One of the prospective therapeutical agents even used in the first stage clinical trials, 1,25-dihydroxyvitamin D3, was shown to be either unpredictable or inefficient in many cases. We have already shown that TRPV6 calcium channel, which is the direct target of 1,25-dihydroxyvitamin D3 receptor, positively controls prostate cancer proliferation and apoptosis resistance (Lehen'kyi et al., Oncogene, 2007. However, how the known 1,25-dihydroxyvitamin D3 antiproliferative effects may be compatible with the upregulation of pro-oncogenic TRPV6 channel remains a mystery. Here we demonstrate that in low steroid conditions 1,25-dihydroxyvitamin D3 upregulates the expression of TRPV6, enhances the proliferation by increasing the number of cells entering into S-phase. We show that these pro-proliferative effects of 1,25-dihydroxyvitamin D3 are directly mediated via the overexpression of TRPV6 channel which increases calcium uptake into LNCaP cells. The apoptosis resistance of androgen-dependent LNCaP cells conferred by TRPV6 channel is drastically inversed when 1,25-dihydroxyvitamin D3 effects were combined with the successful TRPV6 knockdown. In addition, the use of androgen-deficient DU-145 and androgen-insensitive LNCaP C4-2 cell lines allowed to suggest that the ability of 1,25-dihydroxyvitamin D3 to induce the expression of TRPV6 channel is a crucial determinant of the success or failure of 1,25-dihydroxyvitamin D3-based therapies.

[Acne vulgaris: morphologic, endocrinologic and psychosomatic aspects].

Science.gov (United States)

Welp, K; Gieler, U

1990-12-01

25 male patients suffering from acne vulgaris were examined by means of endocrinological, morphological, and 5 psychometric procedures in order to check the correlations and interactions between the psychological and dermatological aspects of the disease. In comparison with a control group, the acne patients did not show any striking endocrinological abnormalities; we found no correlation between the extensiveness of the lesions and the level of DHEA sulphate. All the psychological tests yielded results deviating from those achieved by the representative controls, but they were comparable with those of other patients suffering from psychosomatic diseases. The individual feeling of being "disfigured" found its expression in self-consciousness, lack of trust in his/her own body, as well as the clinically relevant difference between his/her conception of self and the ideal of self. During times of enhanced psychosocial strains subjectively assumed by the patients, the lesions increased and the patients were disturbed in social interaction and communication. Surprisingly, we did not find any correlation between the clinical status and significant psychometric findings. Our results show that in acne vulgaris, the individual experience of wanting physical attractiveness, associated with a predominantly neurotic depressive personal structure, may play a central part in a disturbed process of interaction with the environment and suggest the influence of psychic factors in the pathogenesis of acne vulgaris.

Expression and functional importance of collagen-binding integrins, alpha 1 beta 1 and alpha 2 beta 1, on virus-activated T cells

DEFF Research Database (Denmark)

Andreasen, Susanne Ø; Thomsen, Allan R; Koteliansky, Victor E

2003-01-01

decreased responses were seen upon transfer of alpha(1)-deficient activated/memory T cells. Thus, expression of alpha(1)beta(1) and alpha(2)beta(1) integrins on activated T cells is directly functionally important for generation of inflammatory responses within tissues. Finally, the inhibitory effect......Adhesive interactions are crucial to cell migration into inflammatory sites. Using murine lymphocytic choriomeningitis virus as an Ag model system, we have investigated expression and function of collagen-binding integrins, alpha(1)beta(1) and alpha(2)beta(1), on activated and memory T cells. Using...... this system and MHC tetramers to define Ag-specific T cells, we demonstrate that contrary to being VLAs, expression of alpha(1)beta(1) and alpha(2)beta(1) can be rapidly induced on acutely activated T cells, that expression of alpha(1)beta(1) remains elevated on memory T cells, and that expression of alpha(1...

p25alpha relocalizes in oligodendroglia from myelin to cytoplasmic inclusions in multiple system atrophy

DEFF Research Database (Denmark)

Song, Yun Ju C; Lundvig, Ditte M S; Huang, Yue

2007-01-01

cytoplasmic inclusions. Overall, the data indicate that changes in the cellular interactions between MBP and p25alpha occur early in MSA and contribute to abnormalities in myelin and subsequent alpha-synuclein aggregation and the ensuing neuronal degeneration that characterizes this disease....

Alpha1 and Alpha2 Integrins Mediate Invasive Activity of Mouse Mammary Carcinoma Cells through Regulation of Stromelysin-1 Expression

Energy Technology Data Exchange (ETDEWEB)

Lochter, Andre; Navre, Marc; Werb, Zena; Bissell, Mina J

1998-06-29

Tumor cell invasion relies on cell migration and extracellular matrix proteolysis. We investigated the contribution of different integrins to the invasive activity of mouse mammary carcinoma cells. Antibodies against integrin subunits {alpha}6 and {beta}1, but not against {alpha}1 and {alpha}2, inhibited cell locomotion on a reconstituted basement membrane in two-dimensional cell migration assays, whereas antibodies against {beta}1, but not against a6 or {alpha}2, interfered with cell adhesion to basement membrane constituents. Blocking antibodies against {alpha}1 integrins impaired only cell adhesion to type IV collagen. Antibodies against {alpha}1, {alpha}2, {alpha}6, and {beta}1, but not {alpha}5, integrin subunits reduced invasion of a reconstituted basement membrane. Integrins {alpha}1 and {alpha}2, which contributed only marginally to motility and adhesion, regulated proteinase production. Antibodies against {alpha}1 and {alpha}2, but not {alpha}6 and {beta}1, integrin subunits inhibited both transcription and protein expression of the matrix metalloproteinase stromelysin-1. Inhibition of tumor cell invasion by antibodies against {alpha}1 and {alpha}2 was reversed by addition of recombinant stromelysin-1. In contrast, stromelysin-1 could not rescue invasion inhibited by anti-{alpha}6 antibodies. Our data indicate that {alpha}1 and {alpha}2 integrins confer invasive behavior by regulating stromelysin-1 expression, whereas {alpha}6 integrins regulate cell motility. These results provide new insights into the specific functions of integrins during tumor cell invasion.

Alpha 1A and alpha 1B-adrenoceptors enhance inositol phosphate generation in rat renal cortex

NARCIS (Netherlands)

Michel, M. C.; Büscher, R.; Philipp, T.; Brodde, O. E.

1993-01-01

We have studied the role of alpha 1A- and alpha 1B-adrenoceptors in noradrenaline- and methoxamine-stimulated inositol phosphate accumulation in rat renal cortical slices. [3H]Prazosin binding studies with and without inactivation of alpha 1B-adrenoceptors by chloroethylclonidine treatment suggested

Reproductive endocrinology and infertility fellowships: is the 'reproductive endocrinology' portion obsolete?

Science.gov (United States)

Omurtag, Kenan; Lebovic, Dan I

2015-08-01

To take inventory of the past and present and project the future direction of our field to help train the next generation of providers. Review the history of the subspecialty and factors contributing to its evolution. Reproductive endocrinology and infertility's in-vitro fertilization future is shaping the intellectual priorities and surgical skill requirements of the next generation.

Alpha 1 B- but not alpha 1 A-adrenoceptors mediate inositol phosphate generation

NARCIS (Netherlands)

Michel, M. C.; Hanft, G.; Gross, G.

1990-01-01

We used novel highly subtype-selective antagonists to study whether alpha 1A- and/or alpha 1B-adrenoceptors mediate the stimulation of inositol phosphate generation by noradrenaline in rat cerebral cortex. Phentolamine (10 microM) and prazosin (100 nM) completely abolished the stimulated inositol

Historia de la Endocrinología en Colombia

Directory of Open Access Journals (Sweden)

Alfredo Jácome Roca

2001-08-01

Full Text Available

La especialidad clínica de la endocrinología lleva ya más de medio siglo en nuestro país, y si nos ponemos a ver la actividad de algunos precursores, esta historia bien puede remontarse al siglo XIX.

El académico Antonio Ucrós Cuellar se puso en la tarea de recopilar las actuaciones de los especialistas en problemas hormonales y en las actividades de las asociaciones científicas de este ramo de la medicina y para ello contó con la ayuda editorial de los endocrinólogos y discípulos suyos, Eric Hernández y Stella Acosta.

Ucrós ha participado personalmente en el devenir histórico de la endocrinología en Colombia, como investigador de la problemática del bocio, como fundador de la Asociación Colombiana de Endocrinología y de la sección de endocrinología del Hospital de San José, que recientemente cumplió sus Bodas de Oro, y en la cual se han formado numerosos y distinguidos especialistas que ejercen en el país su profesión.

Comentar esta obra viene como anillo al dedo en este número especial sobre endocrinología que publica la revista “Medicina” de la Academia. Este libro de 230 páginas recoge en su parte inicial los antecedentes históricos y los estudios sobre el bocio en el país que el autor tan elegantemente lideró, finaliza esta parte inicial con su propia versión de la endocrinología en Colombia, que comienza con él y otros eminentes especialistas como Hernán Mendoza Hoyos, Tomás Quintero, Alonso Gutiérrez, Jaime Cortázar, Efraím tero, Mario Sánchez Medina (en el campo de la diabetes, Iván Molina en Medellín, Alberto Jamis en Barranquilla, y el importante grupo de Cali donde figuraron entre otros Eduardo Gaitán, Heins Wahner (actualmente en la Clínica Mayo, William Jubiz y Matilde de Bernal, todos de talla internacional.

Mi interés por la endocrinología se inició con las magistrales clases de Mendoza Hoyos en la Javeriana, sobre el tema de la Fisiología Endocrina

[Cardiovascular risk factor control in a population with longstanding diabetes attending endocrinology departments].

Science.gov (United States)

Comi-Diaz, Cristina; Miralles-García, José M; Cabrerizo, Lucio; Pérez, María; Masramon, Xavier; De Pablos-Velasco, Pedro

2010-12-01

To determine the degree of control of cardiovascular risk factors (CVRF) in a sample of patients with diabetes mellitus (DM) attending Endocrinology and Nutrition Departments in Spain. An epidemiological, cross-sectional, multicenter and observational study involving 41 Departments of Endocrinology and Nutrition in Spain. Each department selected patients with DM with over 10 years of evolution, which were treated in outpatient settings. Demographic, anthropometric, clinical and biochemical data, including medication, were collected for each participant. 1159 patients who met the inclusion criteria were recruited. 52% of the participants were patients with type 2 DM. The mean duration of DM was 19.6 years. A proportion of 37%, 44%, 27.6% and 25.5% had good control of their blood pressure (BP), low density cholesterol (LDLc), lipids and glucose, respectively, and only 4.3% did well in all factors evaluated. The percentage of poorly controlled BP was four times higher in type 2 than in type 1 DM. Obesity, low cultural level and aggregation of cardiovascular risk factors were associated with poorer control. The degree of control of CVRF in diabetic patients with long disease duration is insufficient. Copyright © 2010 SEEN. Published by Elsevier Espana. All rights reserved.

Radioreceptor assay for 1,25-dihydroxyvitamin D3 in serum and its application in the study of rachitis

International Nuclear Information System (INIS)

Shi Yuyuan; Zhang Peiyin; Li Yajuan

1988-01-01

A modifed radioreceptor assay for 1,25-(OH) 2 -D 3 (1,25-Dihydroxy vitamin D 3 , Dihydroxycholecalciferol, DHCC) in serum was established, which was proved to have high sensitivity, stability and accuracy, and was applied in patients with rachitis. The results showed that DHCC level in serum in rachictic patients was lower than that of the control. The detection rate of DHCC was obviously higher than that through symptoms, laboratory tests and X-ray examination in patients with rachitis. Therefore, this assay technique can be used as a sensitive indicator for diagnosis of rachitis. It was also found that DHCC level in mothers was cor-relative with their infants, so that assay for DHCC level in pregnant mothers has significance in prevention and treatment of rachitis in their infants

Cadmium-induced bone effect is not mediated via low serum 1,25-dihydroxy vitamin D

International Nuclear Information System (INIS)

Engstroem, Annette; Skerving, Staffan; Lidfeldt, Jonas; Burgaz, Ann; Lundh, Thomas; Samsioe, Goeran; Vahter, Marie; Akesson, Agneta

2009-01-01

Cadmium is a widespread environmental pollutant, which is associated with increased risk of osteoporosis. It has been proposed that cadmium's toxic effect on bone is exerted via impaired activation of vitamin D, secondary to the kidney effects. To test this, we assessed the association of cadmium-induced bone and kidney effects with serum 1,25-dihydroxyvitamin D (1,25(OH) 2 D); measured by enzyme immunoassay. For the assessment, we selected 85 postmenopausal women, based on low (0.14-0.39 μg/L) or high (0.66-2.1 μg/L) urinary cadmium, within a cross-sectional population-based women's health survey in Southern Sweden. We also measured 25-hydroxy vitamin D, cadmium in blood, bone mineral density and several markers of bone remodeling and kidney effects. Although there were clear differences in both kidney and bone effect markers between women with low and high cadmium exposure, the 1,25(OH) 2 D concentrations were not significantly different (median, 111 pmol/L (5-95th percentile, 67-170 pmol/L) in low- and 125 pmol/L (66-200 pmol/L) in high-cadmium groups; p=0.08). Also, there was no association between 1,25(OH) 2 D and markers of bone or kidney effects. It is concluded that the low levels of cadmium exposure present in the studied women, although high enough to be associated with lower bone mineral density and increased bone resorption, were not associated with lower serum concentrations of 1,25(OH) 2 D. Hence, decreased circulating levels of 1,25(OH) 2 D are unlikely to be the proposed link between cadmium-induced effects on kidney and bone

Acute effect of oral, intraperitoneal, and intravenous 1 alpha-hydroxycholecalciferol on markers of bone metabolism

DEFF Research Database (Denmark)

Joffe, P; Ladefoged, S D; Cintin, C

1994-01-01

,25-(OH)2D3 was measured. DESIGN: Single doses of 1 alpha-OHD3 (80 ng/kg body wt) were given in randomized cross-over fashion, orally, intraperitoneally (i.p.) and intravenously (i.v.) on three occasions. Blood was sampled at 0, 1, 6, 12, and 24 h after administration of 1 alpha-OHD3. MAIN RESULTS...

Regulation of PGE2 signaling pathways and TNF-alpha signaling pathways on the function of bone marrow-derived dendritic cells and the effects of CP-25.

Science.gov (United States)

Li, Ying; Sheng, Kangliang; Chen, Jingyu; Wu, Yujing; Zhang, Feng; Chang, Yan; Wu, Huaxun; Fu, Jingjing; Zhang, Lingling; Wei, Wei

2015-12-15

This study was to investigate PGE2 and TNF-alpha signaling pathway involving in the maturation and activation of bone marrow dendritic cells (DCs) and the effect of CP-25. Bone marrow DCs were isolated and stimulated by PGE2 and TNF-alpha respectively. The markers of maturation and activation expressed on DCs, such as CD40, CD80, CD83, CD86, MHC-II, and the ability of antigen uptake of DCs were analyzed by flow cytometry. The proliferation of T cells co-cultured with DCs, the signaling pathways of PGE2-EP4-cAMP and TNF-alpha-TRADD-TRAF2-NF-κB in DCs were analyzed. The results showed that both PGE2 and TNF-alpha up-regulated the expressions of CD40, CD80, CD83, CD86, and MHC-II, decreased the antigen uptake of DCs, and DCs stimulated by PGE2 or TNF-alpha could increase T cell proliferation. CP-25 (10(-5), 10(-6), and 10(-7)mol/l) decreased significantly the expressions of CD40, CD80, CD83, CD86 and MHC-II, increased the antigen uptake of DCs, and suppressed T cell proliferation induced by DCs. PGE2 increased the expressions of EP4, NF-κB and down-regulated cAMP level of DCs. TNF-alpha could also up-regulate TNFR1, TRADD, TRAF2, and NF-κB expression of DCs. CP-25 (10(-5), 10(-6), and 10(-7)mol/l) decreased the expressions of EP4 and NF-κB, increased cAMP level in DCs stimulated by PGE2. CP-25 (10(-5), 10(-6), and 10(-7)mol/l) also could down-regulate significantly TNFR1, TRADD, TRAF2, and NF-κB expression in DCs stimulated by TNF-alpha. These results demonstrate that PGE2 and TNF-alpha could enhance DCs functions by mediating PGE2-EP4-cAMP pathway, TNF-alpha-TNFR1-TRADD-TRAF2-NF-κB pathway respectively. CP-25 might inhibit the function of DCs through regulating PGE2-EP4-cAMP and TNF-alpha-TNFR1-TRADD-TRAF2-NF-κB pathways. Copyright © 2015 Elsevier B.V. All rights reserved.

Catabolism of 6-ketoprostaglandin F1alpha by the rat kidney cortex.

Science.gov (United States)

Pace-Asciak, C R; Domazet, Z; Carrara, M

1977-05-25

Homogenates of the rat kidney cortex converted 5,8,9,11,12,14,15-hepta-tritiated 6-ketoprostaglandin F 1alpha into one major product identified by gas chromatography-mass spectrometry of the methoxime-methyl ester trimethylsilyl ether derivative as 6,15-diketo-9,11-dihydroxyprost-13-enoic acid. The sequence of derivatisation i.e. methoximation prior to methylation, was crucial as methylation of 15-keto catabolites of the E, F and 6-keto-F series affords degradation products. The corresponding 15-keto-13,14-dihydro catabolite was formed in much smaller quantities. Time course studies indicated that 6-keto-prostaglandin F1alpha was catabolised at a slower rate (about 2-5 fold) than prostaglandin F1alpha. The catabolic activity was blocked by NADH.

Cdc25A promotes cell survival by stimulating NF-{kappa}B activity through I{kappa}B-{alpha} phosphorylation and destabilization

Energy Technology Data Exchange (ETDEWEB)

Hong, Hey-Young; Choi, Jiyeon [Department of Biochemistry, College of Natural Sciences, Kangwon National University, 192-1 Hyoja-2-dong, Chuncheon 200-701 (Korea, Republic of); Cho, Young-Wook [Korea Basic Science Institute, Chuncheon Center, Gangwondaehak-gil 1, Chuncheon 200-701 (Korea, Republic of); Kim, Byung-Chul, E-mail: bckim@kangwon.ac.kr [Department of Biochemistry, College of Natural Sciences, Kangwon National University, 192-1 Hyoja-2-dong, Chuncheon 200-701 (Korea, Republic of)

2012-04-06

Highlights: Black-Right-Pointing-Pointer We examine the antiapoptotic mechanisms of Cdc25A. Black-Right-Pointing-Pointer Smad7 decreases the phosphorylation of I{kappa}B-alpha at Ser-32. Black-Right-Pointing-Pointer Smad7 positively regulates NF-{kappa}B activity through I{kappa}B-alpha ubiquitination. -- Abstract: Cell division cycle 25A (Cdc25A), a dual specificity protein phosphatase, exhibits anti-apoptotic activity, but the underlying molecular mechanisms are poorly characterized. Here we report that Cdc25A inhibits cisplatin-induced apoptotic cell death by stimulating nuclear factor-kappa B (NF-{kappa}B) activity. In HEK-293 cells, Cdc25A decreased protein level of inhibitor subunit kappa B alpha (I{kappa}-B{alpha}) in association with increased serine 32-phosphorylation, followed by stimulation of transcriptional activity of NF-{kappa}B. Inhibition of NF-{kappa}B activity by chemical inhibitor or overexpression of I{kappa}-B{alpha} in Cdc25A-elevated cancer cells resistant to cisplatin improved their sensitivity to cisplatin-induced apoptosis. Our data show for the first time that Cdc25A has an important physiological role in NF-{kappa}B activity regulation and it may be an important survival mechanism of cancer cells.

Microbial endocrinology and the microbiota-gut-brain axis.

Science.gov (United States)

Lyte, Mark

2014-01-01

Microbial endocrinology is defined as the study of the ability of microorganisms to both produce and recognize neurochemicals that originate either within the microorganisms themselves or within the host they inhabit. As such, microbial endocrinology represents the intersection of the fields of microbiology and neurobiology. The acquisition of neurochemical-based cell-to-cell signaling mechanisms in eukaryotic organisms is believed to have been acquired due to late horizontal gene transfer from prokaryotic microorganisms. When considered in the context of the microbiota's ability to influence host behavior, microbial endocrinology with its theoretical basis rooted in shared neuroendocrine signaling mechanisms provides for testable experiments with which to understand the role of the microbiota in host behavior and as importantly the ability of the host to influence the microbiota through neuroendocrine-based mechanisms.

Effect of dietary calcium and phosphorus on intestinal calcium absorption and vitamin D metabolism

International Nuclear Information System (INIS)

Ribovich, M.L.; DeLuca, H.F.

1978-01-01

To understand better dietary regulation of intestinal calcium absorption, a quantitative assessment of the metabolites in plasma and duodenum of rats given daily doses of radioactive vitamin D 3 and diets differing in calcium and phosphorus content was made. All known vitamin D metabolites were ultimately identified by high-pressure liquid chromatography. In addition to the known metabolites (25-hydroxyvitamin D 3 , 24,25-dihydroxyvitamin D 3 , 1,25-dihydroxyvitamin D 3 , 25,26-dihydroxyvitamin D 3 , and 1,24,25-trihydroxyvitamin D 3 ), several new and unidentified metabolites were found. In addition to 1,25-dihydroxyvitamin D 3 and 1,24,25-trihydroxyvitamin D 3 , the levels of some of the unknown metabolites could be correlated with intestinal calcium transport. However, whether or not any of these metabolites plays a role in the stimulation of intestinal calcium absorption by low dietary calcium or low dietary phosphorus remains unknown

Alpha1-antitrypsin deficiency

DEFF Research Database (Denmark)

Stolk, Jan; Seersholm, Niels; Kalsheker, Noor

2006-01-01

The Alpha One International Registry (AIR), a multinational research program focused on alpha1-antitrypsin (AAT) deficiency, was formed in response to a World Health Organization recommendation. Each of the nearly 20 participating countries maintains a national registry of patients with AAT defic...

[Endocrinology in Portugal - Census 2016. Board of the Portuguese College of Endocrinology and Nutrition of the Portuguese Medical Association].

Science.gov (United States)

Guimarães, Joana; Afonso, António; Carvalho, Davide; Marques, Ana Paula; Martins, Teresa; Mascarenhas, Mário Rui; Pereira, Conceição; Rodrigues, Dírcea; Saraiva, Catarina; Cardoso, Helena

2017-09-29

On September 2016, the Board of the College of Endocrinology and Nutrition of the Portuguese Medical Association carried out a national survey, about all Endocrinology, Diabetes and Metabolism Departments of the public hospitals included in the Portuguese National Health Service and a simplified version of this survey was sent to all endocrinologists working in Portugal and registered with the Portuguese Medical Association. Data related to organizational and human resources were collected, reporting the situation by the end of year 2015. The census registered 107 individuals and 27 Departments. The ratio of endocrinologists-population was 1.4, much lower than in the other European countries (varies between 2 to 4), resulting in alarming shortages of services in some areas of Portugal and in worse quality indicators. These data suggest that actions should be taken to increase the number of endocrinologists and departments in the country. In recent years, the number of residents has significantly increased, which will make it possible to correct this situation.

An interactive E-Learning portal in pediatric endocrinology : Practical experience

NARCIS (Netherlands)

Kranenburg-van Koppen, L.J.C.; Grijpink-van den Biggelaar, K.; Drop, S.L.S.

2013-01-01

Based on educational considerations, the European Society for Paediatric Endocrinology (ESPE) e-learning portal has been developed, providing an interactive learning environment for up-to-date information in pediatric endocrinology. From March 2011 to January 2012, five small-scale pilot studies

Endocrinology Telehealth Consultation Improved Glycemic Control Similar to Face-to-Face Visits in Veterans.

Science.gov (United States)

Liu, Winnie; Saxon, David R; McNair, Bryan; Sanagorski, Rebecca; Rasouli, Neda

2016-09-01

Rates of diabetes for veterans who receive health care through the Veterans Health Administration are higher than rates in the general population. Furthermore, many veterans live in rural locations, far from Veterans Affairs (VA) hospitals, thus limiting their ability to readily seek face-to-face endocrinology care for diabetes. Telehealth (TH) technologies present an opportunity to improve access to specialty diabetes care for such patients; however, there is a lack of evidence regarding the ability of TH to improve glycemic control in comparison to traditional face-to-face consultations. This was a retrospective cohort study of all new endocrinology diabetes consultations at the Denver VA Medical Center over a 1-year period. A total of 189 patients were included in the analysis. In all, 85 patients had received face-to-face (FTF) endocrinology consultation for diabetes and 104 patients had received TH consultation. Subjects were mostly males (94.7%) and the mean age was 62.8 ± 10.1 years old. HbA1c improved from 9.76% (9.40% to 10.11%) to 8.55% (8.20% to 8.91%) (P Endocrinology TH consultations improved short-term glycemic control as effectively as traditional FTF visits in a veteran population with diabetes. © 2016 Diabetes Technology Society.

Effect of ovariectomy and 17 beta-estradiol implantation on bone metabolism in female rats fed 1,25 dihydroxyvitamin D3

International Nuclear Information System (INIS)

Osborne, M.; Sherman, S.; Soares, J.H. Jr.

1986-01-01

Eight-week old Sprague-Dawley female rats were used in two experiments to test the effects of 17-B estradiol (E 2 ) via silastic tubing implants on 3 H-labelled tetracycline (TC) incorporation into bone. 1,25(OH) 2 D 3 was the dietary source of vitamin D in a low calcium (.2%) semipurified eggwhite diet. In experiment I, the Ovx + E 2 animals showed a significantly (p 3 H TC uptake in scapula during a 2-week labelling experiment. An increase in 3 H TC content resulted (p 2 was implanted in 1,25(OH) 2 D 3 fed Ovx rats. However, the calcium content was not significantly different. The effect of dietary 1,25(OH) 2 D 3 and E 2 implantation appears to be additive. Optimal action of the Vitamin D endocrine system may be dependent on presence of E 2

Development of the Clinic of Endocrinology, diabetes and metabolic disorders.

Science.gov (United States)

Shubeska Stratrova, S

2013-01-01

The Clinic of Endocrinology, diabetes and metabolic disorders was founded in 1975 by Prof d-r Alexandar Plashevski. Healthcare, educational and scientific activities in the Clinic of Endocrinology are performed in its departments. The Department for hospitalized diabetic and endocrine patients consists of the metabolic and endocrine intensive care unit, the department for diagnosis and treatment of diabetics and endocrine patients, day hospital, the department for education of diabetic patients, and the national center for insulin pump therapy. The Center for Diabetes was established in 1972 by Prof d-r Dimitar Arsov. In 1975, Prof d-r Alexandar Plasheski broadened the activities of the Center for Diabetes. It was dislocated in 1980, with new accommodation outside the clinic. Since then the Center has consisted of several organized units: two specialist outpatient clinics for diabetic patients, biochemical and endocrine laboratory, sub-departments for: diabetic foot, cardiovascular diagnosis, ophthalmology, and urgent interventions. The Department of Endocrinology and Metabolic Disorders for outclinic endocrine patients was established in 1980, and it integrates the following sub-departments: thyrology, andrology, reproductive endocrinology, obesity and lipid disorders and sub-department for osteoporosis. The educational staff of the Clinic of Endocrinology organizes theoretical and practical education about Clinical Investigation and Internal Medicine with credit transfer system course of study of the Medical Faculty, Faculty of Stomatology, postgraduate studies, specializations and sub-specializations. Symposiums, 3 congresses, schools for diabetes and osteoporosis and continuous medical education were also organized. The Clinic of Endocrinology was initiator, organizer, founder and the seat of several medical associations.

Metabolism of 25-hydroxyvitamin D in copper-laden rat: A model of Wilson's disease

International Nuclear Information System (INIS)

Carpenter, T.O.; Pendrak, M.L.; Anast, C.S.

1988-01-01

Wilson's disease results in excess tissue accumulation of copper and is often complicated by skeletal and mineral abnormalities. The authors investigated vitamin D metabolism in rats fed a copper-laden diet rendering hepatic copper content comparable with that found in Wilson's disease. Injection of 25-hydroxyvitamin D 3 [25(OH)D 3 ] resulted in reduced 1,25--dihydroxyvitamin D [1,25(OH) 2 D] levels in copper-intoxicated rats. In vitro 25(OH)D-1α-hydroxylase activity was impaired in renal mitochondria from copper-intoxicated animals. Activity was also inhibited in mitochondrial from controls when copper was added to incubation media. Impaired conversion of 25(OH)D to 1,25(OH) 2 D occurs in copper intoxication and suggests that altered vitamin D metabolism is a potential factor in the development of bone and mineral abnormalities in Wilson's disease

Outcome of Doctors Attending the European Society for Paediatric Endocrinology Winter Schools 2008-2014.

Science.gov (United States)

Donaldson, Malcolm D C

2017-01-01

Since 1995, the European Society for Paediatric Endocrinology (ESPE) has hosted Winter School (WS), a 5-day interactive meeting of 25 trainees and 7 teachers designed to cover all main endocrine topics. The aim of the present study was to determine subsequent outcome in ex-WS "students." A questionnaire was sent in August 2016 to all ESPE WS participants between 2008 and 2014. Information was requested on job/training status at WS attendance and in 2016, and subsequent involvement with ESPE. Of 174 participants (144 women, 30 men) including 5 attending two WS, 129 (74.5%) responded. At the time of WS/2016 survey 58/3 participants were junior trainees, 38/21 senior trainees, and 33/101 consultants. One hundred and seventeen (90.6%) responders were still involved with endocrinology, 107 (82%) rating WS as having a strong/very strong influence on their careers. Following WS, 80/174 (46%) participants had attended at least one ESPE main meeting, 28 (16%) had been awarded ESPE fellowships, and 34 (19%) had become ESPE members. The great majority of WS participants responding to the questionnaire are still involved with endocrinology and rated WS as influential. This favourable outcome supports the continuing funding of WS and similar educational programmes. © 2017 S. Karger AG, Basel.

1,25(OH)2D3 attenuates TGF-β1/β2-induced increased migration and invasion via inhibiting epithelial–mesenchymal transition in colon cancer cells

Energy Technology Data Exchange (ETDEWEB)

Chen, Shanwen; Zhu, Jing; Zuo, Shuai; Ma, Ju; Zhang, Junling; Chen, Guowei; Wang, Xin; Pan, Yisheng; Liu, Yucun; Wang, Pengyuan, E-mail: wangpengyuan2014@126.com

2015-12-04

1,25-Dihydroxyvitamin D3 (1,25(OH)2D3) has been reported to inhibit proliferation and migration of multiple types of cancer cells. However, the mechanism underlying its anti-metastasis effect is not fully illustrated. In this study, the effect of 1,25(OH)2D3 on TGF-β1/β2-induced epithelial–mesenchymal transition (EMT) is tested in colon cancer cells. The results suggest that 1,25(OH)2D3 inhibited TGF-β1/β2-induced increased invasion and migration of in SW-480 and HT-29 cells. 1,25(OH)2D3 also inhibited the cadherin switch in SW-480 and HT-29 cells. TGF-β1/β2-induced increased expression of EMT-related transcription factors was also inhibited by 1,25(OH)2D3. 1,25(OH)2D3 also inhibited the secretion of MMP-2 and MMP-9 and increased expression of F-actin induced by TGF-β1/β2 in SW-480 cells. Taken together, this study suggests that the suppression of EMT might be one of the mechanisms underlying the anti-metastasis effect of 1,25(OH)2D3 in colon cancer cells. - Highlights: • TGF-β1/β2-induced model of EMT was used in this study to test the effect of 1,25(OH)2D3 on EMT in colon cancer cells. • 1,25(OH)2D3 inhibited TGF-β1/β2-induced increased migration and invasion. • 1,25(OH)2D3 inhibited TGF-β1/β2-induced increased level of EMT-related transcription factors. • 1,25(OH)2D3 inhibited TGF-β1/β2-induced increased expression of F-actin in SW-480 cells.

Hypercalcemia in Upper Urinary Tract Urothelial Carcinoma: A Case Report and Literature Review

Directory of Open Access Journals (Sweden)

Keiko Asao

2013-01-01

Full Text Available Objective. We here report a patient with upper urinary tract urothelial carcinoma with hypercalcemia likely due to elevated 1,25-dihydroxyvitamin D. Methods. We present a clinical case and a summary of literature search. Results. A 57-year-old man, recently diagnosed with a left renal mass, for which a core biopsy showed renal cell carcinoma, was admitted for hypercalcemia of 11.0 mg/mL He also had five small right lung nodules with a negative bone scan. Both intact parathyroid hormone and parathyroid hormone-related peptide were appropriately low, and 1,25-dihydroxyvitamin D was elevated at 118 pg/dL. The patient’s calcium was normalized after hydration, and he underwent radical nephrectomy. On the postoperative day 6, a repeat 1,25-dihydroxyvitamin D was 24 pg/mL with a calcium of 8.1 mg/dL. Pathology showed a 6 cm high-grade urothelial carcinoma with divergent differentiation. We identified a total of 27 previously reported cases with hypercalcemia and upper tract urothelial carcinoma in English. No cases have a documented elevated 1,25-dihydroxyvitamin D level. Conclusion. This clinical course suggests that hypercalcemia in this case is from the patient’s tumor, which was likely producing 1,25-dihydroxyvitamin D. Considering the therapeutic implications, hypercalcemia in patients with upper urinary tract urothelial carcinoma should be evaluated with 1,25-dihydroxyvitamin D.

Bariatric Endocrinology: Principles of Medical Practice

Science.gov (United States)

Gonzalez-Campoy, J. Michael; Richardson, Bruce; Gonzalez-Cameron, David; Ebrahim, Ayesha; Strobel, Pamela; Martinez, Tiphani; Blaha, Beth; Ransom, Maria; Quinonez-Weislow, Jessica; Pierson, Andrea; Gonzalez Ahumada, Miguel

2014-01-01

Obesity, is a chronic, biological, preventable, and treatable disease. The accumulation of fat mass causes physical changes (adiposity), metabolic and hormonal changes due to adipose tissue dysfunction (adiposopathy), and psychological changes. Bariatric endocrinology was conceived from the need to address the neuro-endocrinological derangements that are associated with adiposopathy, and from the need to broaden the scope of the management of its complications. In addition to the well-established metabolic complications of overweight and obesity, adiposopathy leads to hyperinsulinemia, hyperleptinemia, hypoadiponectinemia, dysregulation of gut peptides including GLP-1 and ghrelin, the development of an inflammatory milieu, and the strong risk of vascular disease. Therapy for adiposopathy hinges on effectively lowering the ratio of orexigenic to anorexigenic signals reaching the the hypothalamus and other relevant brain regions, favoring a lower caloric intake. Adiposopathy, overweight and obesity should be treated indefinitely with the specific aims to reduce fat mass for the adiposity complications, and to normalize adipose tissue function for the adiposopathic complications. This paper defines the principles of medical practice in bariatric endocrinology—the treatment of overweight and obesity as means to treat adiposopathy and its accompanying metabolic and hormonal derangements. PMID:24899894

Differentiation of the mRNA transcripts originating from the alpha 1- and alpha 2-globin loci in normals and alpha-thalassemics.

OpenAIRE

Liebhaber, S A; Kan, Y W

1981-01-01

The alpha-globin polypeptide is encoded by two adjacent genes, alpha 1 and alpha 2. In the normal diploid state (alpha alpha/alpha alpha) all four alpha-globin genes are expressed. Loss or dysfunction of one or more of these genes leads to deficient alpha-globin production and results in alpha-thalassemia. We present a technique to differentially assess the steady-state levels of the alpha 1- and alpha-2-globin messenger RNA (mRNA) transcripts and thus delineate the relative level of expressi...

Quercetin suppresses hypoxia-induced accumulation of hypoxia-inducible factor-1alpha (HIF-1alpha) through inhibiting protein synthesis.

Science.gov (United States)

Lee, Dae-Hee; Lee, Yong J

2008-10-01

Quercetin, a ubiquitous bioactive plant flavonoid, has been shown to inhibit the proliferation of cancer cells and induce the accumulation of hypoxia-inducible factor-1alpha (HIF-1alpha) in normoxia. In this study, under hypoxic conditions (1% O(2)), we examined the effect of quercetin on the intracellular level of HIF-1alpha and extracellular level of vascular endothelial growth factor (VEGF) in a variety of human cancer cell lines. Surprisingly, we observed that quercetin suppressed the HIF-1alpha accumulation during hypoxia in human prostate cancer LNCaP, colon cancer CX-1, and breast cancer SkBr3 cells. Quercetin treatment also significantly reduced hypoxia-induced secretion of VEGF. Suppression of HIF-1alpha accumulation during treatment with quercetin in hypoxia was not prevented by treatment with 26S proteasome inhibitor MG132 or PI3K inhibitor LY294002. Interestingly, hypoxia (1% O(2)) in the presence of 100 microM quercetin inhibited protein synthesis by 94% during incubation for 8 h. Significant quercetin concentration-dependent inhibition of protein synthesis and suppression of HIF-1alpha accumulation were observed under hypoxic conditions. Treatment with 100 microM cycloheximide, a protein synthesis inhibitor, replicated the effect of quercetin by inhibiting HIF-1alpha accumulation during hypoxia. These results suggest that suppression of HIF-1alpha accumulation during treatment with quercetin under hypoxic conditions is due to inhibition of protein synthesis. (c) 2008 Wiley-Liss, Inc.

Field endocrinology of nonhuman primates: past, present, and future.

Science.gov (United States)

Higham, James P

2016-08-01

In the past few decades, research on nonhuman primate endocrinology has moved from the lab to the field, leading to a huge increase in both the breadth and depth of primate field studies. Here, I discuss the past, present, and future of primate field endocrinology. I review the history of the field, and go on to discuss methodological developments and the issues that they sometimes entail. Next, I consider ways in which we might conceptualize the role of hormones, and focus on the need to distinguish proximate from ultimate levels of explanation. Current potentially problematic issues in the field include: 1) an inability to obtain noninvasive measurements of Central Nervous System (CNS) rather than peripheral hormone concentrations; 2) research questions that become stuck (e.g., questions regarding sexual swelling expression mechanisms); 3) data dredging and post-hoc linking of hormones to any plausible variable, leading to a lack of clarity on their role in animal ecology and behavior. I finish by discussing several unanswered questions that might benefit from further research. These are how we might: 1) best obtain measurements for CNS hormone concentrations non-invasively; 2) measure hormone receptor expression alongside hormone concentrations; 3) consider the human endocrinology literature more thoroughly and perhaps take more multimarker approaches; 4) better consider the social environment, including audience and dyadic familiarity effects; and 5) apply our findings to conservation issues. Copyright © 2016 Elsevier Inc. All rights reserved.

The variation of estrus in endocrinological levels and behaviour in endocrinological ewes throughout the year

International Nuclear Information System (INIS)

Basaran, A.; Saban, E. D.

2002-01-01

An investigation was carried out to determine reproductive activity of endocrinological and behavior in Akkaraman sheep (n=20.25 years, 74±7.7 body weight) throughout the year in the Middle Anatolian (39 57 deg. N 32.53 deg. W). The onset of estrous was detected by using apron ram for 30-minute period twice a day. Blood samples collected twice a week were analyzed by Enzyme immunoassay for progesterone (p 4 ), by Radio immunoassay for estradiol. Estrus cycle lengths and estrous lengths were (mean±SD) 18.33±1.03 day, 35.16±5.95 hours, respectively. The breeding season lengths were 283±63.36 day and 229.64±63.74 day according to hormonal and behavior data, respectively (P≤0.0032). Frequency of occurrence estrus was high between August and March however the highest peak was in October. The lowest peaks were both in June and July. Plasma progesterone levels were changed between 0.01-9 ng/ml throughout the year and 0.2-0.16 ng/ml in anoestrus. P 4 level of 11-th day of luteal phase of estrus was 3.73±1.50 ng/ml (n=11). Plasma estradiol level was 8.42±2.51 pg/ml between of 1-st and 2-nd day and 3.50±1.50 pg/ml on day 15. Second peak of estradiol determined on day 11 of estrus cycle was 6.09±2.87 pg/ml (n=11)

Microbial Endocrinology in the Pathogenesis of Infectious Disease.

Science.gov (United States)

Lyte, Mark

2016-04-01

Microbial endocrinology represents the intersection of two seemingly disparate fields, microbiology and neurobiology, and is based on the shared presence of neurochemicals that are exactly the same in host as well as in the microorganism. The ability of microorganisms to not only respond to, but also produce, many of the same neurochemicals that are produced by the host, such as during periods of stress, has led to the introduction of this evolutionary-based mechanism which has a role in the pathogenesis of infectious disease. The consideration of microbial endocrinology-based mechanisms has demonstrated, for example, that the prevalent use of catecholamine-based synthetic drugs in the clinical setting contributes to the formation of biofilms in indwelling medical devices. Production of neurochemicals by microorganisms most often employs the same biosynthetic pathways as those utilized by the host, indicating that acquisition of host neurochemical-based signaling system in the host may have been acquired due to lateral gene transfer from microorganisms. That both host and microorganism produce and respond to the very same neurochemicals means that there is bidirectionality contained with the theoretical underpinnings of microbial endocrinology. This can be seen in the role of microbial endocrinology in the microbiota-gut-brain axis and its relevance to infectious disease. Such shared pathways argue for a role of microorganism-neurochemical interactions in infectious disease.

The future endocrine patient. Reflections on the future of clinical endocrinology

NARCIS (Netherlands)

S.W.J. Lamberts (Steven); J.A. Romijn (Johannes); W.M. Wiersinga (Wilmar)

2003-01-01

textabstractIn recent years the future position of clinical endocrinology has been extensively discussed by Western European endocrine societies. Clinical endocrinology seems to suffer from being too intellectual, generating too little income, and lacking too few spectacular

Inhibition of protein kinase CK2 reduces CYP24A1 expression and enhances 1,25-dihydroxyvitamin D3 anti-tumor activity in human prostate cancer cells

Science.gov (United States)

Luo, Wei; Yu, Wei-Dong; Ma, Yingyu; Chernov, Mikhail; Trump, Donald L.; Johnson, Candace S.

2013-01-01

Vitamin D has broad range of physiological functions and anti-tumor effects. 24-hydroxylase, encoded by the CYP24A1 gene, is the key enzyme for degrading many forms of vitamin D including the most active form, 1,25D3. Inhibition of CYP24A1 enhances 1,25D3 anti-tumor activity. In order to isolate regulators of CYP24A1 expression in prostate cancer cells, we established a stable prostate cancer cell line PC3 with CYP24A1 promoter driving luciferase expression to screen a small molecular library for compounds that inhibit CYP24A1 promoter activity. From this screening, we identified, 4,5,6,7-tetrabromobenzimidazole (TBBz), a protein kinase CK2 selective inhibitor as a disruptor of CYP24A1 promoter activity. We show that TBBz inhibits CYP24A1 promoter activity induced by 1,25D3 in prostate cancer cells. In addition, TBBz downregulates endogenous CYP24A1 mRNA level in TBBz treated PC3 cells. Furthermore, siRNA-mediated CK2 knockdown reduces 1,25D3 induced CYP24A1 mRNA expression in PC3 cells. These results suggest that CK2 contributes to 1,25D3 mediated target gene expression. Lastly, inhibition of CK2 by TBBz or CK2 siRNA significantly enhanced 1,25D3 mediated anti-proliferative effect in vitro and in vivo in a xenograft model. In summary, our findings reveal that protein kinase CK2 is involved in the regulation of CYP24A1 expression by 1,25D3 and CK2 inhibitor enhances 1,25D3 mediated anti-tumor effect. PMID:23358686

Transplantation of bone marrow-derived mesenchymal stem cells rescues partially rachitic phenotypes induced by 1,25-Dihydroxyvitamin D deficiency in mice

OpenAIRE

Zhang, Zengli; Yin, Shaomeng; Xue, Xian; Ji, Ji; Tong, Jian; Goltzman, David; Miao, Dengshun

2016-01-01

To determine whether the transplantation of bone marrow-derived mesenchymal stem cells (BM-MSCs) can improve the 1,25(OH)2D deficiency-induced rachitic phenotype, 2×106 BM-MSCs from wild-type mice or vehicle were transplanted by tail vein injection into mice deficient in 1,25(OH)2D due to targeted deletion of 1α(OH)ase (1α(OH)ase-/-). Our results show that 1α(OH)ase mRNA was expressed in the BM-MSCs derived from wild-type mice, and was detected in long bone, kidney and intestine from BM-MSC-t...

Alternative splicing of T cell receptor (TCR) alpha chain transcripts containing V alpha 1 or V alpha 14 elements.

Science.gov (United States)

Mahotka, C; Hansen-Hagge, T E; Bartram, C R

1995-10-01

Human acute lymphoblastic leukemia cell lines represent valuable tools to investigate distinct steps of the complex regulatory pathways underlying T cell receptor recombination and expression. A case in point are V delta 2D delta 3 and subsequent V delta 2D delta 3J alpha rearrangements observed in human leukemic pre-B cells as well as in normal lymphopoiesis. The functional expression of these unusual (VD) delta (JC) alpha hybrids is almost exclusively prevented by alternative splicing events. In this report we show that alternative splicing at cryptic splice donor sites within V elements is not a unique feature of hybrid TCR delta/alpha transcripts. Among seven V alpha families analyzed by RT-PCR, alternatively spliced products were observed in TCR alpha recombinations containing V alpha 1 or V alpha 14 elements. In contrast to normal peripheral blood cells and thymocytes, the leukemia cell line JM expressing functional V alpha 1J alpha 3C alpha transcripts lacked evidence of aberrant TCR alpha RNA species.

Murine elongation factor 1 alpha (EF-1 alpha) is posttranslationally modified by novel amide-linked ethanolamine-phosphoglycerol moieties. Addition of ethanolamine-phosphoglycerol to specific glutamic acid residues on EF-1 alpha

International Nuclear Information System (INIS)

Whiteheart, S.W.; Shenbagamurthi, P.; Chen, L.; Cotter, R.J.; Hart, G.W.

1989-01-01

Elongation Factor 1 alpha (EF-1 alpha), an important eukaryotic translation factor, transports charged aminoacyl-tRNA from the cytosol to the ribosomes during poly-peptide synthesis. Metabolic radiolabeling with [ 3 H] ethanolamine shows that, in all cells examined, EF-1 alpha is the major radiolabeled protein. Radiolabeled EF-1 alpha has an apparent Mr = 53,000 and a basic isoelectric point. It is cytosolic and does not contain N-linked oligosaccharides. Trypsin digestion of murine EF-1 alpha generated two major [ 3 H]ethanolamine-labeled peptides. Three peptides were sequenced and were identical to two distinct regions of the human EF-1 alpha protein. Blank sequencing cycles coinciding with glutamic acid in the human cDNA-derived sequence were also found to release [ 3 H]ethanolamine, and compositional analysis of these peptides confirmed the presence of glutamic acid. Dansylation analysis demonstrates that the amine group of the ethanolamine is blocked. These results indicate that EF-1 alpha is posttranslationally modified by the covalent attachment of ethanolamine via an amide bond to at least two specific glutamic acid residues (Glu-301 and Glu-374). The hydroxyl group of the attached ethanolamine was shown by mass spectrometry and compositional analysis, to be further modified by the addition of a phosphoglycerol unit. This novel posttranslational modification may represent an important alteration of EF-1 alpha, comparable to the regulatory effects of posttranslational methylation of EF-1 alpha lysine residues

The future endocrine patient. Reflections on the future of clinical endocrinology

NARCIS (Netherlands)

Lamberts, S. W. J.; Romijn, J. A.; Wiersinga, W. M.

2003-01-01

In recent years the future position of clinical endocrinology has been extensively discussed by Western European endocrine societies. Clinical endocrinology seems to suffer from being too intellectual, generating too little income, and lacking too few spectacular interventions. In this manuscript we

CP-25, a Novel Anti-inflammatory and Immunomodulatory Drug, Inhibits the Functions of Activated Human B Cells through Regulating BAFF and TNF-alpha Signaling and Comparative Efficacy with Biological Agents

Directory of Open Access Journals (Sweden)

Feng Zhang

2017-12-01

Full Text Available Paeoniflorin-6′-O-benzene sulfonate (code: CP-25 was the chemistry structural modifications of Paeoniflorin (Pae. CP-25 inhibited B cells proliferation stimulated by B cell activating factor belonging to the TNF family (BAFF or Tumor necrosis factor alpha (TNF-alpha. CP-25, Rituximab and Etanercept reduced the percentage and numbers of CD19+ B cells, CD19+CD20+ B cells, CD19+CD27+ B cells and CD19+CD20+CD27+ B cells induced by BAFF or TNF-alpha. There was significant difference between CP-25 and Rituximab or CP-25 and Etanercept. CP-25 down-regulated the high expression of BAFFR, BCMA, and TACI stimulated by BAFF or TNF-alpha. The effects of Rituximab and Etanercept on BAFFR or BCMA were stronger than that of CP-25. CP-25, Rituximab and Etanercept down-regulated significantly the expression of TNFR1 and TNFR2 on B cell stimulated by BAFF or TNF-alpha. CP-25, Rituximab and Etanercept down-regulated the expression of MKK3, P-p38, P-p65, TRAF2, and p52 in B cells stimulated by BAFF and the expression of TRAF2 and P-p65 in B cells stimulated by TNF-alpha. These results suggest that CP-25 regulated moderately activated B cells function by regulating the classical and alternative NF-κB signaling pathway mediated by BAFF and TNF-alpha-TRAF2-NF-κB signaling pathway. This study suggests that CP-25 may be a promising anti-inflammatory immune and soft regulation drug.

CP-25, a Novel Anti-inflammatory and Immunomodulatory Drug, Inhibits the Functions of Activated Human B Cells through Regulating BAFF and TNF-alpha Signaling and Comparative Efficacy with Biological Agents.

Science.gov (United States)

Zhang, Feng; Shu, Jin-Ling; Li, Ying; Wu, Yu-Jing; Zhang, Xian-Zheng; Han, Le; Tang, Xiao-Yu; Wang, Chen; Wang, Qing-Tong; Chen, Jing-Yu; Chang, Yan; Wu, Hua-Xun; Zhang, Ling-Ling; Wei, Wei

2017-01-01

Paeoniflorin-6'- O -benzene sulfonate (code: CP-25) was the chemistry structural modifications of Paeoniflorin (Pae). CP-25 inhibited B cells proliferation stimulated by B cell activating factor belonging to the TNF family (BAFF) or Tumor necrosis factor alpha (TNF-alpha). CP-25, Rituximab and Etanercept reduced the percentage and numbers of CD19 + B cells, CD19 + CD20 + B cells, CD19 + CD27 + B cells and CD19 + CD20 + CD27 + B cells induced by BAFF or TNF-alpha. There was significant difference between CP-25 and Rituximab or CP-25 and Etanercept. CP-25 down-regulated the high expression of BAFFR, BCMA, and TACI stimulated by BAFF or TNF-alpha. The effects of Rituximab and Etanercept on BAFFR or BCMA were stronger than that of CP-25. CP-25, Rituximab and Etanercept down-regulated significantly the expression of TNFR1 and TNFR2 on B cell stimulated by BAFF or TNF-alpha. CP-25, Rituximab and Etanercept down-regulated the expression of MKK3, P-p38, P-p65, TRAF2, and p52 in B cells stimulated by BAFF and the expression of TRAF2 and P-p65 in B cells stimulated by TNF-alpha. These results suggest that CP-25 regulated moderately activated B cells function by regulating the classical and alternative NF-κB signaling pathway mediated by BAFF and TNF-alpha-TRAF2-NF-κB signaling pathway. This study suggests that CP-25 may be a promising anti-inflammatory immune and soft regulation drug.

A low plasma 1,25(OH)2 vitamin D/PTH (1-84) ratio predicts worsening of renal function in patients with chronic heart failure.

Science.gov (United States)

Masson, Serge; Barlera, Simona; Colotta, Francesco; Magnoli, Michela; Bonelli, Fabrizio; Moro, Milena; Marchioli, Roberto; Tavazzi, Luigi; Tognoni, Gianni; Latini, Roberto

2016-12-01

Dysregulation of the vitamin D system promotes renal dysfunction and has direct detrimental effects on the heart. Progressive deterioration of renal function is common in patients with chronic heart failure (HF) and is invariably associated with unfavorable outcomes which can be improved by early identification and timely interventions. We examined the relation between two plasma markers of vitamin D metabolism and worsening of renal function (WRF) in a large cohort of patients with chronic HF. Plasma levels of 1,25-dihydroxyvitamin D (1,25(OH) 2 D) and parathyroid hormone PTH (1-84) were measured in 1237 patients with clinical evidence of chronic and stable HF enrolled in the multicentre GISSI-HF trial and followed for 3.9years. We examined the relation of 1,25(OH) 2 D, PTH(1-84), and their ratio with WRF, defined as first increase in serum creatinine concentration ≥0.3mg/dL and ≥25% at two consecutive measurements at any time during the study. Lower 1,25(OH) 2 D/PTH(1-84) ratio was associated with a higher baseline serum concentration of creatinine, winter season, female sex and older age; 335 patients (29.6%) experienced an episode of WRF. After adjustment, a lower 1,25(OH) 2 D/PTH(1-84) ratio remained significantly associated with a higher risk of WRF (HR=0.75 [0.62-0.90], p=0.002) and correctly reclassified events. This ratio also independently predicted mortality and admission to hospital for cardiovascular reasons. The plasma 1,25(OH) 2 D/PTH(1-84) ratio is a promising indicator of future risk of deterioration of renal function in patients with chronic HF and mild renal impairment, that may serve to optimize therapies and improve outcomes. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Current situation of hospital-based endocrinology and clinical nutrition in Spain.

Science.gov (United States)

Angeles Gálvez Moreno, M

2008-01-01

In 2006, the Healthcare Commission of Spanish Society of Endocrinology and Nutrition did a survey in order to know the actual situation of endocrinology and clinical nutrition healthcare in Public Sanitary Systems in Spain. The survey has been more extensive than the last and it has taken up number and geographical distribution of specialists in Spain in addition to data about clinical assistance. The mean of public hospitals with endocrinologist participation has been 50%. Copyright © 2008 Sociedad Española de Endocrinología y Nutrición. Published by Elsevier Espana. All rights reserved.

Bovine serum albumin-catalyzed deprotonation of [1-(13)C]glycolaldehyde: protein reactivity toward deprotonation of the alpha-hydroxy alpha-carbonyl carbon.

Science.gov (United States)

Go, Maybelle K; Malabanan, M Merced; Amyes, Tina L; Richard, John P

2010-09-07

Bovine serum albumin (BSA) in D(2)O at 25 degrees C and pD 7.0 was found to catalyze the deuterium exchange reactions of [1-(13)C]glycolaldehyde ([1-(13)C]GA) to form [1-(13)C,2-(2)H]GA and [1-(13)C,2,2-di-(2)H]GA. The formation of [1-(13)C,2-(2)H]GA and [1-(13)C,2,2-di-(2)H]GA in a total yield of 51 +/- 3% was observed at early reaction times, and at later times, [1-(13)C,2-(2)H]GA was found to undergo BSA-catalyzed conversion to [1-(13)C,2,2-di-(2)H]GA. The overall second-order rate constant for these deuterium exchange reactions [(k(E))(P)] equals 0.25 M(-1) s(-1). By comparison, (k(E))(P) values of 0.04 M(-1) s(-1) [Go, M. K., Amyes, T. L., and Richard, J. P. (2009) Biochemistry 48, 5769-5778] and 0.06 M(-1) s(-1) [Go, M. K., Koudelka, A., Amyes, T. L., and Richard, J. P. (2010) Biochemistry 49, 5377-5389] have been determined for the wild-type- and K12G mutant TIM-catalyzed deuterium exchange reactions of [1-(13)C]GA, respectively, to form [1-(13)C,2,2-di-(2)H]GA. These data show that TIM and BSA exhibit a modest catalytic activity toward deprotonation of the alpha-hydroxy alpha-carbonyl carbon. We suggest that this activity is intrinsic to many globular proteins, and that it must be enhanced to demonstrate meaningful de novo design of protein catalysts of proton transfer at alpha-carbonyl carbon.

Cloning, expression, and mapping of allergenic determinants of alphaS1-casein, a major cow's milk allergen.

Science.gov (United States)

Schulmeister, Ulrike; Hochwallner, Heidrun; Swoboda, Ines; Focke-Tejkl, Margarete; Geller, Beate; Nystrand, Mats; Härlin, Annika; Thalhamer, Josef; Scheiblhofer, Sandra; Keller, Walter; Niggemann, Bodo; Quirce, Santiago; Ebner, Christoph; Mari, Adriano; Pauli, Gabrielle; Herz, Udo; Valenta, Rudolf; Spitzauer, Susanne

2009-06-01

Milk is one of the first components introduced into human diet. It also represents one of the first allergen sources, which induces IgE-mediated allergies in childhood ranging from gastrointestinal, skin, and respiratory manifestations to severe life-threatening manifestations, such as anaphylaxis. Here we isolated a cDNA coding for a major cow's milk allergen, alphaS1-casein, from a bovine mammary gland cDNA library with allergic patients' IgE Abs. Recombinant alphaS1-casein was expressed in Escherichia coli, purified, and characterized by circular dichroism as a folded protein. IgE epitopes of alphaS1-casein were determined with recombinant fragments and synthetic peptides spanning the alphaS1-casein sequence using microarrayed components and sera from 66 cow's milk-sensitized patients. The allergenic activity of ralphaS1-casein and the alphaS1-casein-derived peptides was determined using rat basophil leukemia cells transfected with human FcepsilonRI, which had been loaded with the patients' serum IgE. Our results demonstrate that ralphaS1-casein as well as alphaS1-casein-derived peptides exhibit IgE reactivity, but mainly the intact ralphaS1-casein induced strong basophil degranulation. These results suggest that primarily intact alphaS1-casein or larger IgE-reactive portions thereof are responsible for IgE-mediated symptoms of food allergy. Recombinant alphaS1-casein as well as alphaS1-casein-derived peptides may be used in clinical studies to further explore pathomechanisms of food allergy as well as for the development of new diagnostic and therapeutic strategies for milk allergy.

The effect of the Z mutation on the ability of alpha 1-antitrypsin to prevent neutrophil mediated tissue damage.

Science.gov (United States)

Llewellyn-Jones, C G; Lomas, D A; Carrell, R W; Stockley, R A

1994-11-29

Recent studies have shown that alpha 1-antitrypsin (alpha 1-AT) from Z antitrypsin deficiency subjects has a slightly lower association rate constant with neutrophil elastase (NE) than alpha 1-AT from normal subjects, although it is unknown whether this is of clinical importance. We have purified alpha 1-AT from a normal (M alpha 1-AT) and from a deficient (Z alpha 1-AT) subject and have confirmed that the association rate constants for NE are different (5.28; S.E. 0.06.10(7) M-1 s-1 and 1.2; S.E. 0.2.10(7) M-1 s-1, respectively). We have assessed the ability of both of these proteins to inhibit neutrophil mediated fibronectin (FN) degradation in vitro. Both proteins inhibited FN degradation in a dose dependant manner although Z alpha 1-AT was less effective than M alpha 1-AT at equivalent concentrations of active inhibitor (P < 0.05). Inhibition by M alpha 1-AT was 28.5% S.E. 3.9 at 0.01 microM; 35.5% S.E. 7.3 at 0.1 microM and 37% S.E. 8.4 at 0.5 microM, whereas inhibition by Z alpha 1-AT was 9.25% S.E. 3.9; 19.25% S.E. 7.7 and 21.2% S.E. 9.7, respectively. When the time course of inhibition of FN degradation was studied the difference (although less at 1.0 microM) became greater over the 3 h period of the assay. These results suggest that Z alpha 1-AT is less able than the M phenotype to inhibit connective tissue degradation by neutrophils at equivalent concentrations. This is probably due to the lower association rate constant although the reduced stability of the Z molecule may play a role. The differences, together with the reduced plasma concentration, may accentuate the susceptibility of deficient subjects to the development of emphysema.

Radiation endocrinology as science and its tasks in Republic Kazakhstan

International Nuclear Information System (INIS)

Abylaev, Zh.A.

1997-01-01

It is known, that radiation endocrinology as science was formed comparatively not long ago and it is developing at the turn of endocrinology, medical radiology, radiobiology and immunology. Tasks of clinic radiation endocrinology for scientists of Kazakhstan are related with following problems: - radiation effects in condition of Semipalatinsk test site (Semipalatinsk, Karaganda, Pavlodar, East-Kazakhstan regions); - with definition of radiation factors (related with nuclear explosions) in ecologic systems for solution of national problems; - with contamination of Kazakhstan territory, associated with industrial radioactive materials handling ; - with goiter enemy in districts with unfavorable radiation situation; - with mass character of injuries of both the radiation exposure and the iodine deficit on territory of Republic. It was emphasised, that there is principle problem of population rehabilitation through systems of mass measures including prevention of endocrine complication in late time

Reproductive endocrinology of vitamin D.

Science.gov (United States)

Lorenzen, Mette; Boisen, Ida Marie; Mortensen, Li Juel; Lanske, Beate; Juul, Anders; Blomberg Jensen, Martin

2017-09-15

Vitamin D is a versatile hormone with several functions beyond its well-established role in maintenance of skeletal health and calcium homeostasis. The effects of vitamin D are mediated by the vitamin D receptor, which is expressed together with the vitamin D metabolizing enzymes in the reproductive tissues. The reproductive organs are therefore responsive to and able to metabolize vitamin D locally. The exact role remains to be clarified but several studies have suggested a link between vitamin D and production/release of reproductive hormones into circulation, which will be the main focus of this review. Current evidence is primarily based on small human association studies and rodent models. This highlights the need for randomized clinical trials, but also functional animal and human in vitro studies, and larger, prospective cohort studies are warranted. Given the high number of men and women suffering from reproductive problems and abnormal endocrinology research addressing the role of vitamin D in reproductive endocrinology may be of clinical importance. Copyright © 2017 Elsevier B.V. All rights reserved.

Positive correlation between circulating cathelicidin antimicrobial peptide (hCAP18/LL-37) and 25-hydroxyvitamin D levels in healthy adults

DEFF Research Database (Denmark)

Dixon, Brian M; Barker, Tyler; McKinnon, Toni

2012-01-01

ABSTRACT: BACKGROUND: Transcription of the cathelicidin antimicrobial peptide (CAMP) gene is induced by binding of the bioactive form of vitamin D, 1,25-dihydroxyvitamin D, to the vitamin D receptor. Significant levels of the protein hCAP18/LL-37 are found in the blood and may protect against...... = 0.63). CONCLUSIONS: We conclude that plasma hCAP18 levels correlate with serum 25(OH)D levels in subjects with concentrations of 25(OH)D 32 ng/ml and that vitamin D status may regulate systemic levels of hCAP18/LL-37....

Regulation of the human cathelicidin antimicrobial peptide gene by 1α,25-dihydroxyvitamin D3 in primary immune cells

DEFF Research Database (Denmark)

Lowry, Malcolm B; Guo, Chunxiao; Borregaard, Niels

2014-01-01

and osteoclasts. We also tested whether treatment with parathyroid hormone in combination with 1,25D3 would enhance hCAP18 induction as has been reported in skin cells, but we did not find enhancement in any immune cells tested. Our results indicate that hCAP18 is expressed at different levels according to cell...

Radioprotection of the intestinal crypts of mice by recombinant human interleukin-1 alpha

International Nuclear Information System (INIS)

Wu, S.G.; Miyamoto, T.

1990-01-01

Recombinant human interleukin-1 alpha (rHIL-1 alpha or IL-1) protected the intestinal crypt cells of mice against X-ray-induced damage. The survival of crypt cells measured in terms of their ability to form colonies of regenerating duodenal epithelium in situ was increased when IL-1 was given either before or after irradiation. The maximum degree of radioprotection was seen when the drug was given between 13 and 25 h before irradiation. The IL-1 dose producing maximum protection was about 6.3 micrograms/kg. This is the first report indicating that the cytokine IL-1 has a radioprotective effect in the intestine. The finding suggests that IL-1 may be of potential value in preventing radiation injury to the gut in the clinic

1,25(OH)2D3 and Ca-binding protein in fetal rats: Relationship to the maternal vitamin D status

International Nuclear Information System (INIS)

Verhaeghe, J.; Thomasset, M.; Brehier, A.; Van Assche, F.A.; Bouillon, R.

1988-01-01

The autonomy and functional role of fetal 1,25-dihydroxyvitamin D 3 [1,25(OH) 2 D 3 ] were investigated in nondiabetic and diabetic BB rats fed diets containing 0.85% calcium-0.7% phosphorus or 0.2% calcium and phosphorus and in semistarved rats on the low calcium-phosphorus diet. The changes in maternal and fetal plasma 1,25(OH) 2 D 3 were similar: the levels were increased by calcium-phosphorus restriction and decreased by diabetes and semistarvation. Maternal and fetal 1,25(OH) 2 D 3 levels were correlated. The vitamin D-dependent calcium-binding proteins (CaBP 9K and CaBP 28K ) were measured in multiple maternal and fetal tissues and in the placenta of nondiabetic, diabetic, and calcium-phosphorus-restricted rats. The distributions of CaBP 9K and CaBP 28K in the pregnant rat were similar to that of the growing rat. The increased maternal plasma 1,25(OH) 2 D 3 levels in calcium-phosphorus-restricted rats were associated with higher duodenal CaBP 9K and renal CaBPs, but placental CaBP 9K was not different. In diabetic pregnant rats, duodenal CaBP 9K was not different. In diabetic pregnant rats, duodenal CaBP 9K tended to be lower, while renal CaBPs were normal; placental CaBP 9K was decreased. The results indicate that in the rat fetal 1,25(OH) 2 D 3 depends on maternal 1,25(OH) 2 D 3 or on factors regulating maternal 1,25(OH) 2 D 3 . The lack of changes in fetal CaBP in the presence of altered fetal plasma 1,25(OH) 2 D 3 levels confirms earlier data showing that 1,25(H) 2 D 3 has a limited hormonal function during perinatal development in the rat

Safety and efficacy outcome of mentor alpha-1 inflatable penile prosthesis implantation for impotence treatment.

Science.gov (United States)

Goldstein, I; Newman, L; Baum, N; Brooks, M; Chaikin, L; Goldberg, K; McBride, A; Krane, R J

1997-03-01

We investigated safety and efficacy outcome pertaining to the Mentor Alpha-1, 3-piece inflatable penile prosthesis for impotence treatment. A 2-phase, multi-institutional, large scale retrospective study, with independently analyzed medical record (phase I) and questionnaire (phase II) data from consecutive eligible patients of 7 physician investigators was performed from March to October 1993. In phase I there were no morbidities of any type in 394 of the 434 patients (90.8%) (mean age 61 years, range 24 to 88) who underwent Alpha-1 implantation (mean followup 22.2 months, range 0.67 to 44.5). The risk of prosthesis malfunction (fluid leak and auto-inflation) was 2.5%. No cylinder aneurysms were reported. A total of 93.1% of Alpha-1 devices was free from explantation (4.4%) or revision surgery (2.5%) for approximately 2 years from the original implant date. Kaplan-Meier actuarial analyses revealed that cumulative survival of the Alpha-1 prostheses at 12, 24 and 36 months was 98 +/- 1%, 93 +/- 2% and 85 +/- 7% until device malfunction, and 91 +/- 2% 83 +/- 4% and 75 +/- 7% until surgical intervention (revision or explantation). In phase II 89% of the men claimed fulfilled expectations with the Alpha-1 prosthesis as impotence treatment. Satisfaction responses 80% or greater were noted with regard to intercourse ability and confidence, and device rigidity and function. Implantation did not result in greater than 80% satisfaction in partner relationships or feelings (as judged by the patient), social or work confidence, or intercourse frequency. Factors adversely affecting satisfaction included partner feelings of dissatisfaction (as judged by the patient), specific physician investigators and need for explantation/revision surgery. In 1 of the largest multi-institutional implant outcome studies thus far performed, safety and efficacy data concerning the Alpha-1 contemporary inflatable device were found markedly improved over earlier inflatable prostheses and now

[The and beginnings of Chilean endocrinology in the 1920s].

Science.gov (United States)

Sánchez Delgado, Marcelo

2016-01-01

Rejuvenation was a chapter of critical importance for the worldwide development of endocrinology in the 1920s. This work explores the acceptance of these techniques in Chile. Starting in the late 19th century, the Chilean Medical Journal (Revista Médica de Chile) incorporated references to experiments with endocrine gland preparations that were being conducted in Europe at the time. An appropriation of the experiments by the Austrian Eugen Steinach began in 1920, with prominent figures such as the Italian professor Juan Noe Crevani and the young Chilean student Ottmar Wilhelm. Between 1922 and 1924, Wilhelm developed a series of experiments on dogs, bulls, pigs, rats and Welfare Board patients through the so-called Steinach operation, which consisted of the sectioning of the efferent channel in one of the testicles. Professor Noe's scientific patronage policy and Wilhelm's strategy of succession in the field led the latter to hold a chair in the new School of Medicine of Universidad de Concepci6n at the age of 25. From this position, the. figure of Wilhelm was fundamental for the development of a line of endocrinological research that was able to position Universidad de Concepci6n as a scientific development centre, which was strengthened by the arrival of another disciple of Steinach in Chile, the Latvian professor Alejandro Lipschütz.

Anti-IL-1alpha autoantibodies in early rheumatoid arthritis

DEFF Research Database (Denmark)

Forslind, K; Svensson, Birte; Svenson, M

2001-01-01

To investigate the potential predictive value of autoantibodies against IL1-alpha (anti-IL-1alpha) in patients with early rheumatoid arthritis (RA).......To investigate the potential predictive value of autoantibodies against IL1-alpha (anti-IL-1alpha) in patients with early rheumatoid arthritis (RA)....

Alpha-1 Antitrypsin Deficiency (Inherited Emphysema)

Science.gov (United States)

... antitrypsin inactivates elastase once it has finished its job. Without alpha 1 antitrypsin, elastase can destroy the air sacs of the lung. How is the diagnosis made? Because Alpha-1 related disease is COPD, the diagnosis is made by the same methods. Your doctor may have you do a number ...

[Services portfolio of a department of endocrinology and clinical nutrition].

Science.gov (United States)

Vicente Delgado, Almudena; Gómez Enterría, Pilar; Tinahones Madueño, Francisco

2011-03-01

Endocrinology and Clinical Nutrition are branches of Medicine that deal with the study of physiology of body glands and hormones and their disorders, intermediate metabolism of nutrients, enteral and parenteral nutrition, promotion of health by prevention of diet-related diseases, and appropriate use of the diagnostic, therapeutic, and preventive tools related to these disciplines. Development of Endocrinology and Clinical Nutrition support services requires accurate definition and management of a number of complex resources, both human and material, as well as adequate planning of the care provided. It is therefore essential to know the services portfolio of an ideal Department of Endocrinology and Clinical Nutrition because this is a useful, valid and necessary tool to optimize the available resources, to increase efficiency, and to improve the quality of care. Copyright © 2010 SEEN. Published by Elsevier Espana. All rights reserved.

Actions of alpha2 adrenoceptor ligands at alpha2A and 5-HT1A receptors: the antagonist, atipamezole, and the agonist, dexmedetomidine, are highly selective for alpha2A adrenoceptors.

Science.gov (United States)

Newman-Tancredi, A; Nicolas, J P; Audinot, V; Gavaudan, S; Verrièle, L; Touzard, M; Chaput, C; Richard, N; Millan, M J

1998-08-01

This study examined the activity of chemically diverse alpha2 adrenoceptor ligands at recombinant human (h) and native rat (r) alpha2A adrenoceptors compared with 5-HT1A receptors. First, in competition binding experiments at h alpha2A and h5-HT1A receptors expressed in CHO cells, several compounds, including the antagonists 1-(2-pyrimidinyl)piperazine (1-PP), (+/-)-idazoxan, benalfocin (SKF 86466), yohimbine and RX 821,002, displayed preference for h alpha2A versus h5-HT1A receptors of only 1.4-, 3.6-, 4-, 10- and 11-fold, respectively (based on differences in pKi values). Clonidine, brimonidine (UK 14304), the benzopyrrolidine fluparoxan and the guanidines guanfacine and guanabenz exhibited intermediate selectivity (22- to 31-fold) for h alpha2A receptors. Only the antagonist atipamezole and the agonist dexmedetomidine (DMT) displayed high preference for alpha2 adrenoceptors (1290- and 91-fold, respectively). Second, the compounds were tested for their ability to induce h5-HT1A receptor-mediated G-protein activation, as indicated by the stimulation of [35S]GTPgammaS binding. All except atipamezole and RX 821,002 exhibited agonist activity, with potencies which correlated with their affinity for h5-HT1A receptors. Relative efficacies (Emax values) were 25-35% for guanabenz, guanfacine, WB 4101 and benalfocin, 50-65% for 1-PP, (+/-)-idazoxan and clonidine, and over 70% for fluparoxan, oxymetazoline and yohimbine (relative to 5-HT = 100%). Yohimbine-induced [35S]GTPgammaS binding was inhibited by the selective 5-HT1A receptor antagonist WAY 100,635. In contrast, RX 821,002 was the only ligand which exhibited antagonist activity at h5-HT1A receptors, inhibiting 5-HT-stimulated [35S]GTPgammaS binding. Atipamezole, which exhibited negligeable affinity for 5-HT1A receptors, was inactive. Third, the affinities for r alpha2A differed considerably from the affinities for h alpha2A receptors whereas the affinities for r5-HT1A differed much less from the affinities for h5-HT

Serum concentrations of interleukin (IL-)1alpha, 1beta, 6 and tumor necrosis factor (TNF-) alpha in patients with thyroid eye disease (TED).

Science.gov (United States)

Laban-Guceva, Nevenka; Bogoev, Milko; Antova, Magdalena

2007-01-01

Serum proinflamatory cytokines were found to be altered in Graves disease (GD) and in TED. Serum values of IL1alpha, IL-1beta, IL-6, TNF-alpha were assessed in 22 patients with TED before and after treatment (aged 46.82 +/- 12.47, M:F=16:6). Free thyroxin was high, TSH low, thyroid ultrasound showed diffuse thyroid enlargement, treatment with antithyroid drugs propylthyouracil (PTU) or methymasol (MMI) resulted in clinical and hormonal remission. Several months after the initiation of the signs of hyperthyroidism, a progression in the ophthalmopathy was observed (Hertel up to 25 mm: normal 15-17 mm) while patients were clinically and hormonally euthyroid. Blood was collected in euthyroid state (with TED signs present, before corticosteroid therapy (CS) treatment) and after 3 months of treatment (patients without TED and without TED treatment). CS resulted in response of 8/22 patients. Ophthalmic irradiation (01) given with CS therapy, resulted in a response in twelve patients (12/12). Lack of response to CS treatment, with rapid increase in proptosis, and loss of visual acuity prompted ophthalmic decompression (OD) in two patients. Both recovered visual acuity, while proptosis fell under 25 mm Hertel. The control group had 29 persons (aged 51.86 +/-10.52, M:F = 16:13). A significant difference was found in the serum levels of IL-1alpha between the groups of controls (0.74+/-0.55 pg/ml) and patients before treatment (1.85 +/- 1.85 pg/ml; p TED treatment its concentration raised to 2.07 +/- 1.82 pg/ml (higher than the pretreatment; NS). For patients with low Clinical Activity Score (CAS) scores (1-5) there was no change in IL-6 concentrations before (1.03+/-o.64 pg/ml) and after treatment (1.07 +/- 0.63 pg/ml). Patients with higher CAS scores (6-10) had a change in IL-6 levels (from 1.32+/-1.00 to 2.67 +/- 4.84; p > 0.05). In addition, patients with pathological VEP had no changes in IL-6 (from 0.93 +/- 0.53 to 0.97 +/- 0.32 pg/ml), while patients with normal VEP had

Genetic variations of VDR/NR1I1 encoding vitamin D receptor in a Japanese population.

Science.gov (United States)

Ukaji, Maho; Saito, Yoshiro; Fukushima-Uesaka, Hiromi; Maekawa, Keiko; Katori, Noriko; Kaniwa, Nahoko; Yoshida, Teruhiko; Nokihara, Hiroshi; Sekine, Ikuo; Kunitoh, Hideo; Ohe, Yuichiro; Yamamoto, Noboru; Tamura, Tomohide; Saijo, Nagahiro; Sawada, Jun-ichi

2007-12-01

The vitamin D receptor (VDR) is a transcriptional factor responsive to 1alpha,25-dihydroxyvitamin D(3) and lithocholic acid, and induces expression of drug metabolizing enzymes CYP3A4, CYP2B6 and CYP2C9. In this study, the promoter regions, 14 exons (including 6 exon 1's) and their flanking introns of VDR were comprehensively screened for genetic variations in 107 Japanese subjects. Sixty-one genetic variations including 25 novel ones were found: 9 in the 5'-flanking region, 2 in the 5'-untranslated region (UTR), 7 in the coding exons (5 synonymous and 2 nonsynonymous variations), 12 in the 3'-UTR, 19 in the introns between the exon 1's, and 12 in introns 2 to 8. Of these, one novel nonsynonymous variation, 154A>G (Met52Val), was detected with an allele frequency of 0.005. The single nucleotide polymorphisms (SNPs) that increase VDR expression or activity, -29649G>A, 2T>C and 1592((*)308)C>A tagging linked variations in the 3'-UTR, were detected at 0.430, 0.636, and 0.318 allele frequencies, respectively. Another SNP, -26930A>G, with reduced VDR transcription was found at a 0.028 frequency. These findings would be useful for association studies on VDR variations in Japanese.

Taraxacum officinale induces cytotoxicity through TNF-alpha and IL-1alpha secretion in Hep G2 cells.

Science.gov (United States)

Koo, Hyun-Na; Hong, Seung-Heon; Song, Bong-Keun; Kim, Cheorl-Ho; Yoo, Young-Hyun; Kim, Hyung-Min

2004-01-16

Taraxacum officinale (TO) has been frequently used as a remedy for women's disease (e.g. breast and uterus cancer) and disorders of the liver and gallbladder. Several earlier studies have indicated that TO exhibits anti-tumor properties, but its mechanism remains to be elucidated. In this study, we investigated the effect of TO on the cytotoxicity and production of cytokines in human hepatoma cell line, Hep G2. Our results show that TO decreased the cell viability by 26%, and significantly increased the tumor necrosis factor (TNF)-alpha and interleukin (IL)-1alpha production compared with media control (about 1.6-fold for TNF-alpha, and 2.4-fold for IL-1alpha, P < 0.05). Also, TO strongly induced apoptosis of Hep G2 cells as determined by flow cytometry. Increased amounts of TNF-alpha and IL-1alpha contributed to TO-induced apoptosis. Anti-TNF-alpha and IL-1alpha antibodies almost abolished it. These results suggest that TO induces cytotoxicity through TNF-alpha and IL-1alpha secretion in Hep G2 cells.

Endocrinology in the Ramayana

Directory of Open Access Journals (Sweden)

Sanjay Kalra

2016-01-01

Full Text Available This article is one of a series of publications which highlight the possible endocrine conditions and interventions listed in the ancient texts. This compendium lists episodes from the Indian epic Ramayana and from the associated genealogy of Lord Rama′s dynasty, the Suryavanshis. These episodes are chosen for their relevance to endocrinology and are listed in a gland-based order. It is hoped that this communication will encourage further work on endocrine literary forensics.

The delta-opioid receptor agonist SNC80 [(+)-4-[alpha(R)-alpha-[(2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl]-(3-methoxybenzyl)-N,N-diethylbenzamide] synergistically enhances the locomotor-activating effects of some psychomotor stimulants, but not direct dopamine agonists, in rats.

Science.gov (United States)

Jutkiewicz, Emily M; Baladi, Michelle G; Folk, John E; Rice, Kenner C; Woods, James H

2008-02-01

The nonpeptidic delta-opioid agonist SNC80 [(+)-4-[alpha(R)-alpha-[(2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl]-(3-methoxybenzyl)-N,N-diethylbenzamide] produces many stimulant-like behavioral effects in rodents and monkeys, such as locomotor stimulation, generalization to cocaine in discrimination procedures, and antiparkinsonian effects. Tolerance to the locomotor-stimulating effects of SNC80 develops after a single administration of SNC80 in rats; it is not known whether cross-tolerance develops to the effects of other stimulant compounds. In the initial studies to determine whether SNC80 produced cross-tolerance to other stimulant compounds, it was discovered that amphetamine-stimulated locomotor activity was greatly enhanced in SNC80-pretreated rats. This study evaluated acute cross-tolerance between delta-opioid agonists and other locomotor-stimulating drugs. Locomotor activity was measured in male Sprague-Dawley rats implanted with radiotransmitters, and activity levels were recorded in the home cage environment. Three-hour SNC80 pretreatment produced tolerance to further delta-opioid receptor stimulation but also augmented greatly amphetamine-stimulated locomotor activity in a dose-dependent manner. Pretreatments with other delta-opioid agonists, (+)BW373U86 [(+)-4-[alpha(R)-alpha-[(2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl]-3-hydroxybenzyl]-N,N-diethylbenzamide] and oxymorphindole (17-methyl-6,7-dehydro-4,5-epoxy-3,14-dihydroxy-6,7,2',3'-indolomorphinan), also modified amphetamine-induced activity levels. SNC80 pretreatment enhanced the stimulatory effects of the dopamine/norepinephrine transporter ligands cocaine and nomifensine (1,2,3,4-tetrahydro-2-methyl-4-phenyl-8-isoquinolinanmine maleate salt), but not the direct dopamine receptor agonists SKF81297 [R-(+)-6-chloro-7,8-dihydroxy-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrobromide] and quinpirole [trans-(-)-(4alphaR)-4,4a, 5,6,7,8,8a,9-octahydro-5-propyl-1H-pyrazolo[3,4-g] quinoline

Biosynthesis, purification and receptor binding properties of high specific radioactivity 1α,24(R), 25-trihydroxy-[26,27-methyl-3H]-vitamin D3

International Nuclear Information System (INIS)

Chandler, J.S.; Pike, J.W.; Haussler, M.R.

1982-01-01

A procedure for the biosynthesis and purification of 1α,24(R),25-trihydroxy[26,27-methyl- 3 H]-vitamin D 3 (1,24,25-(OH) 3 [ 3 H]D 3 ) is reported. A kidney homogenate from chicks receiving a high calcium diet (3%) and oral supplements of 1α,25-dihydroxyvitamin D 3 (1,25-(OH) 2 D 3 ) was used for C-24-hydroxylation of 1α,25-dihydroxy[26,27-methyl- 3 H]-vitamin D 3 (1,25-(OH) 2 [ 3 H]D 3 ), in vitro. Extraction and purification of the homogenate lipid fraction by Sephadex LH-20 and high performance liquid chromatography yielded radiochemically pure 1,24,25-(OH) 3 [ 3 H]D 3 with a specific radioactivity equivalent to the initial substrate (166 Ci/mmol). The authenticity of the generated metabolite was assessed by co-migration with synthetic 1,24,25-(OH) 3 D 3 on high performance liquid chromatography and by equimolar competition with authentic radioinert 1,24,25-(OH) 3 D 3 for binding to a purified receptor protein from rat kidney. Binding studies indicate the trihydroxylated metabolite competes 40-50% as effectively as 1,25-(OH) 2 D 3 for hormone binding sites. Further analysis of 1,24,25-(OH) 3 D 3 -receptor interaction reveals a high-affinity, saturable binding with an apparent Ksub(d) of 2.2 x 10 -9 M. These studies demonstrate that although slightly less active than 1,25-(OH) 2 D 3 , 1,24,25-(OH) 3 D 3 is capable of hormone-like interactions, in vitro. The availability of this high specific radioactivity sterol should allow for clarification of its potential physiologic significance. (author)

Immunodetection of Thyroid Hormone Receptor (Alpha1/Alpha2) in the Rat Uterus and Oviduct

International Nuclear Information System (INIS)

Öner, Jale; Öner, Hakan

2007-01-01

The aim of this study was to investigate the immunolocalization and the existence of thyroid hormone receptors (THR) (alpha1/alpha2) in rat uterus and oviduct. For this purpose 6 female Wistar albino rats found in estrous period were used. Tissue samples fixed in 10% neutral formalin were examined immunohistochemically. Sections were incubated with primary mouse-monoclonal THR (alpha1/alpha2) antibody. In uterus, THR (alpha1/alpha2) immunoreacted strongly with uterine luminal epithelium, endometrial gland epithelium and endometrial stromal cells and, moderately with myometrial smooth muscle. In oviduct, they were observed moderately in the epithelium of the tube and the smooth muscle cells of the muscular layer. In conclusion, the presence of THR in uterus and oviduct suggests that these organs are an active site of thyroid hormones

High frequency of HIF-1 alpha overexpression in BRCA1 related breast cancer

NARCIS (Netherlands)

van der Groep, Petra; Bouter, Alwin; Menko, Fred H.; van der Wall, Elsken; van Diest, Paul J.

2008-01-01

Hypoxia is a hallmark of cancer. Hypoxia inducible factor-1 alpha (HIF-1 alpha) is the key regulator of the hypoxia response. HIF-1 alpha is overexpressed during sporadic breast carcinogenesis and correlated with poor prognosis. Little is known on the role of HIF-1 alpha in hereditary breast

Lack of co-ordinate expression of the alpha1(I) and alpha1(III) procollagen genes in fibroblast clonal cultures.

Science.gov (United States)

Yamaguchi, Y; Crane, S; Zhou, L; Ochoa, S M; Falanga, V

2000-12-01

Several extracellular matrix genes, most notably alpha1(I) and alpha1(III) procollagen, are reported to be co-ordinately expressed in cultures of dermal fibroblasts. However, it remains unclear whether the expression of these genes is truly co-ordinate or whether it may be the result of averaging the phenotypic expression of different fibroblast subpopulations present within each culture. Objectives To determine by Northern analysis the correlation between alpha1(I) and alpha1(III) procollagen mRNA levels in clonal populations of human dermal fibroblasts. As previously described, clonal cultures were derived from parent strains of human dermal fibroblasts by a microscopically controlled dilution technique and by stimulation of single cells with low oxygen tension in the early phases of clonal growth. In agreement with previous reports, we found that baseline steady-state levels of alpha1(I) procollagen mRNA were co-ordinately regulated with the alpha1(III) procollagen mRNA in 26 parent strains (r = 0. 9003; P ordinate regulation observed in non-clonal cultures, suggesting that these two genes operate under different sets of regulatory controls. This clonal heterogeneity may provide additional flexibility to the process of tissue repair and fibroblast clonal expansion.

Flavonoids-induced accumulation of hypoxia-inducible factor (HIF)-1alpha/2alpha is mediated through chelation of iron.

Science.gov (United States)

Park, Sung-Soo; Bae, Insoo; Lee, Yong J

2008-04-15

Hypoxia-inducible factor-1 alpha (HIF-1alpha) is the regulatory subunit of the heterodimeric transcription factor HIF-1 that is the key regulator of cellular response to low oxygen tension. Under normoxic conditions, HIF-1alpha is continuously degraded by the ubiquitin-proteasome pathway through pVHL (von Hippel-Lindau tumor suppressor protein). Under hypoxic conditions, HIF-1alpha is stabilized and induces the transcription of HIF-1 target genes. Quercetin, a flavonoid with anti-oxidant, anti-inflammatory, and kinase modulating properties, has been found to induce HIF-1alpha accumulation and VEGF secretion in normoxia. In this study, the molecular mechanisms of quercetin-mediated HIF-1alpha accumulation were investigated. Previous studies have shown that, in addition to being induced by hypoxia, HIF-1alpha can be induced through the phosphatidylinositol 3-kinase (PI3K)/Akt and p53 signaling pathways. But our study revealed, through p53 mutant-type as well as p53 null cell lines, that neither the PI3K/Akt nor the p53 signaling pathway is required for quercetin-induced HIF-1alpha accumulation. And we observed that HIF-1alpha accumulated by quercetin is not ubiquitinated and the interaction of HIF-1alpha with pVHL is reduced, compared with HIF-1alpha accumulated by the proteasome inhibitor MG132. The use of quercetin's analogues showed that only quercetin and galangin induce HIF-1/2alpha accumulation and this effect is completely reversed by additional iron ions. This is because quercetin and galangin are able to chelate cellular iron ions that are cofactors of HIF-1/2alpha proline hydroxylase (PHD). These data suggest that quercetin inhibits the ubiquitination of HIF-1/2alpha in normoxia by hindering PHD through chelating iron ions.

Alpha-1 antitrypsin phenotypes in patients with lung, prostate and breast cancer

International Nuclear Information System (INIS)

El-Akawi, Zeyad J.; Al-Hindawi, Fatin K.

2004-01-01

Determination of Alpha1-antitryspin (AT) phenotypes in Jordanian patients with lung, prostate and breast cancerto find a prevalent phenotype that could be recommended for the diagnosis of cancer. This study was conducted at Jordan University of Science and Technology, School of Medicine Jordan during the period May 2001 to May 2002. Alpha1-antitryspin (AT) phenotypes for 83 Jordanian cancer patients distributed as follows, 25 lung cancer, 25 prostate cancer and 33 with breast cancer were tested using isoelectric focusing gel electrophoresis and immunofluxation techniques. Isoelectric focusing results demonstrated that 96% of lung cancer patients were of PiMM phenotype and 4% of PiFM phenotype. All prostate cancer patients (100%) were found to be of PiMM and 3% PiMS. These findings demonstrated that there was no significant differences in the distribution of AT phenotypes among Jordanian patients with lung, prostae and breast cancerand they matched those reported for healthy individuals. Thus, we can nor recommand a given AT phentype for early diagnosis of the above mentioned types of cancer. (author)

Downregulation of MIP-1alpha/CCL3 with praziquantel treatment in Schistosoma haematobium and HIV-1 co-infected individuals in a rural community in Zimbabwe

DEFF Research Database (Denmark)

Zinyama-Gutsire, Rbl; Gomo, E.; Kallestrup, P

2009-01-01

influence. METHODS: To determine levels of MIP-1alpha/CCL3 chemokine in plasma of S. haematobium and HIV-1 co-infected and uninfected individuals in a rural black Zimbabwean community.A cohort was established of HIV-1 and schistosomiasis infection and co-infection comprising 379 participants. Outcome...... measures consisted of HIV-1 and schistosomiasis status and levels of MIP-1alpha/CCL3 in plasma at baseline and three months post treatment. An association was established between MIP-1alpha/CCL3 plasma levels with HIV-1 and S. haematobium infections. RESULTS: A total of 379 adults formed the established...... cohort comprising 76 (20%) men and 303 (80%) women. Mean age was 33.25, range 17 - 62 years. The median MIP-1alpha/CCL3 plasma concentration was significantly higher in S. haematobium infected compared with uninfected individuals (p = 0.029). In contrast, there was no difference in the median MIP-1alpha...

Structural complex of sterol 14[alpha]-demethylase (CYP51) with 14[alpha]-methylenecyclopropyl-[delta]7-24, 25-dihydrolanosterol[S

Energy Technology Data Exchange (ETDEWEB)

Hargrove, Tatiana Y.; Wawrzak, Zdzislaw; Liu, Jialin; Waterman, Michael R.; Nes, W. David; Lepesheva, Galina I. (Vanderbilt); (TTU); (NWU)

2012-06-28

Sterol 14{alpha}-demethylase (CYP51) that catalyzes the removal of the 14{alpha}-methyl group from the sterol nucleus is an essential enzyme in sterol biosynthesis, a primary target for clinical and agricultural antifungal azoles and an emerging target for antitrypanosomal chemotherapy. Here, we present the crystal structure of Trypanosoma (T) brucei CYP51 in complex with the substrate analog 14{alpha}-methylenecyclopropyl-{Delta}7-24,25-dihydrolanosterol (MCP). This sterol binds tightly to all protozoan CYP51s and acts as a competitive inhibitor of F105-containing (plant-like) T. brucei and Leishmania (L) infantum orthologs, but it has a much stronger, mechanism-based inhibitory effect on I105-containing (animal/fungi-like) T. cruzi CYP51. Depicting substrate orientation in the conserved CYP51 binding cavity, the complex specifies the roles of the contact amino acid residues and sheds new light on CYP51 substrate specificity. It also provides an explanation for the effect of MCP on T. cruzi CYP51. Comparison with the ligand-free and azole-bound structures supports the notion of structural rigidity as the characteristic feature of the CYP51 substrate binding cavity, confirming the enzyme as an excellent candidate for structure-directed design of new drugs, including mechanism-based substrate analog inhibitors.

Motor function is associated with 1,25(OH)(2)D and indices of insulin-glucose dynamics in non-diabetic older adults.

Science.gov (United States)

Justice, Jamie N; Pierpoint, Lauren A; Mani, Diba; Schwartz, Robert S; Enoka, Roger M

2014-06-01

Advancing age is accompanied by changes in metabolic characteristics, such as reduced insulin sensitivity and low levels of vitamin D, which may exacerbate age-related declines in physical function. The aim of the present study was to determine the associations between insulin-glucose dynamics, vitamin D metabolites, and performance on a battery of motor tasks in healthy, non-diabetic older adults. Sixty-nine community-dwelling men and women (65-90 years) were recruited. Insulin-glucose dynamics were determined by an intravenous glucose tolerance test, and vitamin D metabolites were measured. Motor function was characterized by the time to walk 500 m, chair-rise time, lower body strength, dorsiflexor steadiness and endurance time, and muscle coactivation. Significant unadjusted correlations were found between insulin-glucose dynamics and 1,25-dihydroxyvitamin D [1,25(OH)2D] with walk time, strength, steadiness, endurance time, and muscle activation (p glucose (R (2) = 0.55, p glucose dynamics and the bio-active vitamin D metabolite 1,25(OH)2D. Walking endurance and strength were explained by 1,25(OH)2D and fasting blood glucose and insulin, even after adjusting for age, sex, and body fat. Motor function in a relatively small sample of non-diabetic older men and women was associated with metabolic factors that increase in prevalence with aging.

Hypothalamic PGC-1 alpha Protects Against High-Fat Diet Exposure by Regulating ER alpha

NARCIS (Netherlands)

Morselli, Eugenia; Fuente-Martin, Esther; Finan, Brian; Kim, Min; Frank, Aaron; Garcia-Caceres, Cristina; Navas, Carlos Rodriguez; Gordillo, Ruth; Neinast, Michael; Kalainayakan, Sarada P.; Li, Dan L.; Gao, Yuanqing; Yi, Chun-Xia; Hahner, Lisa; Palmer, Biff F.; Tschöp, Matthias H.; Clegg, Deborah J.

2014-01-01

High-fat diets (HFDs) lead to obesity and inflammation in the central nervous system (CNS). Estrogens and estrogen receptor alpha (ER alpha) protect premenopausal females from the metabolic complications of inflammation and obesity-related disease. Here, we demonstrate that hypothalamic PGC-1 alpha

Reproductive endocrinology of llamas and alpacas.

Science.gov (United States)

Bravo, P W

1994-07-01

The physiology of reproduction with emphasis in endocrinology of llamas and alpacas is addressed. Basic concepts of ovarian follicular dynamics, endocrine events associated with induction of ovulation, corpus luteum formation, pregnancy, parturition, postpartum interval, puberty, and sexual behavior on the female are reviewed. Pathologic conditions of the reproductive process are also reviewed.

1α,25(OH2 Vitamin D3 Modulates Avian T Lymphocyte Functions without Inducing CTL Unresponsiveness.

Directory of Open Access Journals (Sweden)

Nitish Boodhoo

Full Text Available 1,25-Dihydroxyvitamin D3 (Vitamin D is a naturally synthesized fat soluble vitamin shown to have immunomodulatory, anti-inflammatory and cancer prevention properties in human and murine models. Here, we studied the effects of Vitamin D on the functional abilities of avian T lymphocytes using chicken Interferon (IFN-γ ELISPOT assay, BrdU proliferation assay, Annexin V apoptosis assay and PhosFlow for detecting phosphorylated signalling molecules. The results demonstrate that Vitamin D significantly inhibited the abilities of T lymphocytes to produce IFN-γ and proliferate in vitro (P≤0.05, but retained their ability to undergo degranulation, which is a maker for cytotoxicity of these cells. Similarly, Vitamin D did not inhibit Extracellular signal-Regulated Kinase (ERK 1/2 phosphorylation, a key mediator in T cell signalling, in the stimulated T lymphocytes population, while reduced ERK1/2 phosphorylation levels in the unstimulated cells. Our data provide evidence that Vitamin D has immuno-modulatory properties on chicken T lymphocytes without inducing unresponsiveness and by limiting immuno-pathology can promote protective immunity against infectious diseases of poultry.

Pharmacokinetics of 1,25(OH)(2)D(3) and 1alpha(OH)D(3) in normal and uraemic men

DEFF Research Database (Denmark)

Brandi, Lisbet; Egfjord, Martin; Olgaard, Klaus

2002-01-01

,25(OH)(2)D(3) (n=6) protocol. RESULTS: After oral administration of 1,25(OH)(2)D(3) the bioavailability of 1,25(OH)(2)D(3) was 70.6+/-5.8/72.2+/-4.8% in healthy volunteers/uraemic patients (n.s.). After i.v. administration the volume of distribution of 1,25(OH)(2)D(3) was similar, 0.49+/-0.14 vs 0...

Alpha-1-antitrypsin augmentation therapy in deficient individuals enrolled in the Alpha-1 Foundation DNA and Tissue Bank

Directory of Open Access Journals (Sweden)

Adriano R Tonelli

2009-12-01

Full Text Available Adriano R Tonelli1, Farshid Rouhani1, Ning Li2, Pam Schreck1, Mark L Brantly11Alpha-1 Research Program, Division of Pulmonary, Critical Care and Sleep Medicine, Department of Internal Medicine, 2Department of Epidemiology and Biostatistics, University of Florida, Gainesville, Florida, USAIntroduction: Intravenous augmentation therapy with purified intravenous alpha-1 antitrypsin replaces the deficient protein and is the only currently approved treatment for alpha-1 antitrypsin deficiency (AATD related lung disease. While augmentation therapy has been available for more than 20 years, there are a limited number of studies evaluating the effect of augmentation on lung function.Material and methods: We examined the decline in forced expiratory volume in one second (FEV1 in patients enrolled in the Alpha-1 Foundation DNA and Tissue Bank in relation to the use or not of alpha-1 antitrypsin augmentation therapy. For the purpose of our analysis we included 164 patients with AATD and PI ZZ genotype.Results: Mean age of the patients was 60 years, 52% were females, 94% were white and 78% ex-smokers. The mean FEV1 at baseline was 1.7 L and the mean FEV1 % of predicted was 51.3%. The mean follow-up time was 41.7 months. A total of 124 (76% patients received augmentation therapy (augmented group while 40 patients (24% did not received it (non-augmented group. When adjusted by age at baseline, sex, smoking status, baseline FEV1 % of predicted, the mean overall change in FEV1 was 47.6 mL/year, favoring the augmented group (?FEV1 10.6 ± 21.4 mL/year in comparison with the non-augmented group (?FEV1 −36.96 ± 12.1 mL/year (P = 0.05. Beneficial ?FEV1 were observed in ex-smokers and the group with initial FEV1 % of predicted of <50%. No differences were observed in mortality.Conclusions: In conclusion, augmentation therapy improves lung function in subjects with AATD when adjusted by age, gender, smoking status and baseline FEV1 % of predicted. The beneficial

Oligosaccharide binding to barley alpha-amylase 1

DEFF Research Database (Denmark)

Robert, X.; Haser, R.; Mori, H.

2005-01-01

Enzymatic subsite mapping earlier predicted 10 binding subsites in the active site substrate binding cleft of barley alpha-amylase isozymes. The three-dimensional structures of the oligosaccharide complexes with barley alpha-amylase isozyme 1 (AMY1) described here give for the first time a thorough...... in barley alpha-amylase isozyme 2 (AMY2), and the sugar binding modes are compared between the two isozymes. The "sugar tongs" surface binding site discovered in the AMY1-thio-DP4 complex is confirmed in the present work. A site that putatively serves as an entrance for the substrate to the active site...

Serum concentrations of interleukin-1 alpha, interleukin-6 and tumor necrosis factor-alpha in neonatal sepsis and meningitis

International Nuclear Information System (INIS)

Fida, Nadia M.; Fadelallah, Mohamed F.; Al-Mughales, Jamil A.

2006-01-01

To investigate whether serum levels of interleukin-1alpha (IL-1alpha), IL-6, tumor necrosis factor alpha (TNF-alpha), C-reactive protein (CRP) are useful in the diagnosis of neonatal sepsis and meningitis and differentiate them. Blood samples were collected from 35 full term neonates with suspected infection who admitted to the Neonatology Unit, Pediatric Department, King Abdul-Aziz University Hospital, Jeddah, Saudi Arabia during January 2002 - June 2003. On the basis of laboratory and bacteriological results, newborns were classified into: sepsis (n=28), meningitis (n=7), and healthy controls (n=16). Sepsis groups were further subdivided according to culture results into: group 1 = proven sepsis (n=6), group 2 = clinical sepsis (n=14), and group 3 = possible-infected (n=8). Serum levels of IL-1alpha, IL-6, TNF-alpha were measured using Enzyme-Linked Immunosorbent Assay while CRP by nephelometer: In sepsis and meningitis patients, serum levels of CRP (p<0.01, p<0.05,) and IL-1alpha (p<0.001, p<0.05) were elevated than controls. C-reactive protein levels elevated in proven sepsis (p<0.001) and IL-1alpha elevated in all subgroups of sepsis (groups 1, 2, 3) compared with (p<0.05, p<0.001, p<0.01) controls. Interleukin-6, TNF-alpha showed no significant differences between studied groups. In sepsis and meningitis, IL-1alpha had a highest sensitivity (89%, 86%), and negative predictive values (89% and 93%). Interleukin-1alpha and CRP increased in neonatal sepsis and meningitis, but cannot differentiate between them. Interleukin-1alpha had a highest sensitivity in prediction of neonatal infection and its assessment may improve accuracy of diagnosis. (author)

Kinetic analysis of human CYP24A1 metabolism of vitamin D via the C24-oxidation pathway.

Science.gov (United States)

Tieu, Elaine W; Tang, Edith K Y; Tuckey, Robert C

2014-07-01

CYP24A1 is the multicatalytic cytochrome P450 responsible for the catabolism of vitamin D via the C23- and C24-oxidation pathways. We successfully expressed the labile human enzyme in Escherichia coli and partially purified it in an active state that permitted detailed characterization of its metabolism of 1,25-dihydroxyvitamin D3 [1,25(OH)2 D3] and the intermediates of the C24-oxidation pathway in a phospholipid-vesicle reconstituted system. The C24-oxidation pathway intermediates, 1,24,25-trihydroxyvitamin D3, 24-oxo-1,25-dihydroxyvitamin D3, 24-oxo-1,23,25-trihydroxyvitamin D3 and tetranor-1,23-dihydroxyvitamin D3, were enzymatically produced from 1,25(OH)2 D3 using rat CYP24A1. Both 1,25(OH)2 D3 and 1,23-dihydroxy-24,25,26,27-tetranorvitamin D3 were found to partition strongly into the phospholipid bilayer when in aqueous medium. Changes to the phospholipid concentration did not affect the kinetic parameters for the metabolism of 1,25(OH)2 D3 by CYP24A1, indicating that it is the concentration of substrates in the membrane phase (mol substrate·mol phospholipid(-1) ) that determines their rate of metabolism. CYP24A1 exhibited Km values for the different C24-intermediates ranging from 0.34 to 15 mmol·mol phospholipid(-1) , with 24-oxo-1,23,25-trihydroxyvitamin D3 [24-oxo-1,23,25(OH)3 D3] displaying the lowest and 1,24,25-trihydroxyvitamin D3 [1,24,25(OH)3 D3] displaying the highest. The kcat values varied by up to 3.8-fold, with 1,24,25(OH)3 D3 displaying the highest kcat (34 min(-1) ) and 24-oxo-1,23,25(OH)3 D3 the lowest. The data show that the cleavage of the side chain of 24-oxo-1,23,25(OH)3 D3 occurs with the highest catalytic efficiency (kcat /Km ) and produces 1-hydroxy-23-oxo-24,25,26,27-tetranorvitamin D3 and not 1,23-dihydroxy-24,25,26,27-tetranorvitamin D3, as the primary product. These kinetic analyses also show that intermediates of the C24-oxidation pathway effectively compete with precursor substrates for binding to the active site of the

The future of vitamin D analogs

Directory of Open Access Journals (Sweden)

Carlien eLeyssens

2014-04-01

Full Text Available The active form of vitamin D3, 1,25-dihydroxyvitamin D3, is a major regulator of bone and calcium homeostasis. In addition, this hormone also inhibits the proliferation and stimulates the differentiation of normal as well as malignant cells. Supraphysiological doses of 1,25-dihydroxyvitamin D3 are required to reduce cancer cell proliferation. However, these doses will lead in vivo to calcemic side effects such as hypercalcemia and hypercalciuria. During the last 25 years, many structural analogs of 1,25-dihydroxyvitamin D3 have been synthesized by the introduction of chemical modifications in the A-ring, central CD-ring region or side chain of 1,25-dihydroxyvitamin D3 in the hope to find molecules with a clear dissociation between the beneficial antiproliferative effects and adverse calcemic side effects. One example of such an analog with a good dissociation ratio is calcipotriol (DaivonexR, which is clinically used to treat the hyperproliferative skin disease psoriasis. Other vitamin D analogs were clinically approved for the treatment of osteoporosis or secondary hyperparathyroidism. No vitamin D analog is currently used in the clinic for the treatment of cancer although several analogs have been shown to be potent drugs in animal models of cancer. Omics studies as well as in vitro cell biological experiments unraveled basic mechanisms involved in the antineoplastic effects of vitamin D and its analogs. 1,25-dihydroxyvitamin D3 and analogs act in a cell type- and tissue-specific manner. Moreover, a blockade in the transition of the G0/1 towards S phase of the cell cycle, induction of apoptosis, inhibition of migration and invasion of tumor cells together with effects on angiogenesis and inflammation have been implicated in the pleiotropic effects of 1,25-dihydroxyvitamin D3 and its analogs. In this review we will give an overview of the action of vitamin D analogs in tumor cells and look forward how these compounds could be introduced in the

Studies on the analysis of 25-hydroxyvitamin D3 by isotope-dilution liquid chromatography–tandem mass spectrometry using enzyme-assisted derivatisation

International Nuclear Information System (INIS)

Abdel-Khalik, Jonas; Crick, Peter J.; Carter, Graham D.; Makin, Hugh L.; Wang, Yuqin; Griffiths, William J.

2014-01-01

Highlights: • New method for the analysis of 25-hydroxyvitamin D 3 exploiting Girard P derivatisation. • Method also applicable to vitamin D 3 , 1α,25- and 24,25-dihydroxyvitamin D 3 . • By modification of the method 3-epi-25-hydroxyvitamin D 3 can also be analysed. - Abstract: The total serum concentration of 25-hydroxyvitamins D (25-hydroxyvitamin D 3 and 25-hydroxyvitamin D 2 ) is currently used as an indicator of vitamins D status. Vitamins D insufficiency is claimed to be associated with multiple diseases, thus accurate and precise reference methods for the quantification of 25-hydroxyvitamins D are needed. Here we present a novel enzyme-assisted derivatisation method for the analysis of vitamins D metabolites in adult serum utilising 25-[26,26,26,27,27,27- 2 H 6 ]hydroxyvitamin D 3 as the internal standard. Extraction of 25-hydroxyvitamins D from serum is performed with acetonitrile, which is shown to be more efficient than ethanol. Cholesterol oxidase is used to oxidize the 3β-hydroxy group in the vitamins D metabolites followed by derivatisation of the newly formed 3-oxo group with Girard P reagent. 17β-Hydroxysteroid dehydrogenase type 10 is shown to oxidize selectively the 3α-hydroxy group in the 3α-hydroxy epimer of 25-hydroxyvitamin D 3 . Quantification is achieved by isotope-dilution liquid chromatography–tandem mass spectrometry. Recovery experiments for 25-hydroxyvitamin D 3 performed on adult human serum give recovery of 102–106%. Furthermore in addition to 25-hydroxyvitamin D 3 , 24,25-dihydroxyvitamin D 3 and other uncharacterised dihydroxy metabolites, were detected in adult human serum

The clinical endocrinology workforce: current status and future projections of supply and demand.

Science.gov (United States)

Vigersky, Robert A; Fish, Lisa; Hogan, Paul; Stewart, Andrew; Kutler, Stephanie; Ladenson, Paul W; McDermott, Michael; Hupart, Kenneth H

2014-09-01

Many changes in health care delivery, health legislation, and the physician workforce that affect the supply and demand for endocrinology services have occurred since the first published workforce study of adult endocrinologists in 2003. The objective of the study was to assess the current adult endocrinology workforce data and provide the first analysis of the pediatric endocrinology workforce and to project the supply of and demand for endocrinologists through 2025. A workforce model was developed from an analysis of proprietary and publicly available databases, consultation with a technical expert panel, and the results of an online survey of board-certified endocrinologists. The Endocrine Society commissioned The Lewin Group to estimate current supply and to project gaps between supply and demand for endocrinologists. A technical expert panel of senior endocrinologists provided context, clinical information, and direction. The following were measured: 1) the current adult and pediatric endocrinology workforce and the supply of and demand for endocrinologists through 2025 and 2) the number of additional entrants into the endocrinology work pool that would be required to close the gap between supply and demand. Currently there is a shortage of approximately 1500 adult and 100 pediatric full-time equivalent endocrinologists. The gap for adult endocrinologists will expand to 2700 without an increase in the number of fellows trained. An increase in the prevalence of diabetes mellitus further expands the demand for adult endocrinologists. The gap can be closed in 5 and 10 years by increasing the number of fellowship positions by 14.4% and 5.5% per year, respectively. The gap between supply and demand for pediatric endocrinologists will close by 2016, and thereafter an excess supply over demand will develop at the current rate of new entrants into the work force. There are insufficient adult endocrinologists to satisfy current and future demand. A number of proactive

Longevity of daily oral vitamin D3 supplementation: differences in 25OHD and 24,25(OH)2D observed 2 years after cessation of a 1-year randomised controlled trial (VICtORy RECALL).

Science.gov (United States)

Macdonald, H M; Gryka, A; Tang, J C Y; Aucott, L S; Fraser, W D; Wood, A D

2017-12-01

To determine how long vitamin D lasts after supplementation ceases, the marker of status was measured 2 and 3 years after a 1-year trial. Compared to placebo, the proportion of vitamin D-deficient women was still lower, if they had taken daily vitamin D3, after 2 years, indicating its longevity. The purpose of this study was to determine longevity of vitamin D status following cessation of vitamin D3 supplementation, 2 and 3 years after a 1-year randomised, double-blind placebo controlled trial and to investigate possible predictive factors. Caucasian non-smoking postmenopausal women randomised to ViCtORY (2009-2010), who had not taken vitamin D supplements since the trial ended, were invited to attend follow-up visits. Total 25-hydroxyvitamin D (25OHD) and 24,25-dihydroxyvitamin D (24,25OH2D) were measured by dual tandem mass spectrometry of serum samples following removal of protein and de-lipidation; the original randomised controlled trial (RCT) samples were re-analysed simultaneously. Vitamin D-binding protein (VDBP) was measured by monoclonal immunoassay. In March 2012 and March 2013, 159 women (mean (SD) age 67.6 (2.1) years) re-attended, equally distributed between the original treatment groups: daily vitamin D3 (400 IU, 1000 IU) and placebo. One month after the RCT ended (March 2010), the proportion of women in placebo, 400 IU and 1000 IU vitamin D3 groups, respectively, with 25OHD  25 nmol/L.

Reactivation of the chloroplast CF1-ATPase beta subunit by trace amounts of the CF1 alpha subunit suggests a chaperonin-like activity for CF1 alpha.

Science.gov (United States)

Avni, A; Avital, S; Gromet-Elhanan, Z

1991-04-25

Incubation of tobacco and lettuce thylakoids with 2 M LiCl in the presence of MgATP removes the beta subunit from their CF1-ATPase (CF1 beta) together with varying amounts of the CF1 alpha subunit (CF1 alpha). These 2 M LiCl extracts, as with the one obtained from spinach thylakoids (Avital, S., and Gromet-Elhanan, Z. (1991) J. Biol. Chem. 266, 7067-7072), could form active hybrid ATPases when reconstituted into inactive beta-less Rhodospirillum rubrum chromatophores. Pure CF1 beta fractions that have been isolated from these extracts could not form such active hybrids by themselves, but could do so when supplemented with trace amounts (less than 5%) of CF1 alpha. A mitochondrial F1-ATPase alpha subunit was recently reported to be a heat-shock protein, having two amino acid sequences that show a highly conserved identity with sequences found in molecular chaperones (Luis, A. M., Alconada, A., and Cuezva, J. M. (1990) J. Biol. Chem. 265, 7713-7716). These sequences are also conserved in CF1 alpha isolated from various plants, but not in F1 beta subunits. The above described reactivation of CF1 beta by trace amounts of CF1 alpha could thus be due to a chaperonin-like function of CF1 alpha, which involves the correct, active folding of isolated pure CF1 beta.

Worldwide research productivity in the field of endocrinology and metabolism--a bibliometric analysis.

Science.gov (United States)

Zhao, Xiyan; Ye, Ru; Zhao, Linhua; Lin, Yiqun; Huang, Wenjing; He, Xinhui; Lian, Fengmei; Tong, Xiaolin

2015-01-01

Recently, significant contributions to the study of endocrinology and metabolism have been made. The national contribution, however, has not been reported. The aim of this study was to assess national efforts in the field of endocrinology and metabolism. A Web of Science search was performed using subject categories "endocrinology & metabolism" to identify articles published from 2010 to 2014. The total and per capita numbers of articles and citations were analysed for different countries. A total of 79,394 articles were published on endocrinology and metabolism from 2010 to 2014. Most were published in North America, East Asia, and Europe. The majority (82.28%) were reported by authors in high-income countries, 17.64% were published in middle-income countries, and only 0.08% were published in low-income countries. Authors in the United States published the most articles (27.38%), followed by China (7.22%), Italy (5.70%), the United Kingdom (5.6%), and Japan (5.54%). Articles published by authors in the United States had the most citations (260,934). A positive correlation was found between the number of publications and population/gross domestic product (GDP; p endocrinology and metabolism articles were published by authors from high-income countries with few from low-income countries. The United States was the most productive country. However, when population size and GDP were considered, some European countries were ranked higher.

Trends in endocrinology related research articles in a medical journal from India

Science.gov (United States)

Kumar, K. V. S. H; Aravinda, Konidena

2012-01-01

Background: The details about the research productivity in the specialty of endocrinology from India is lacking. We plan to assess the publishing trends and the research productivity of Endocrinology related research articles published in the Journal of the Association of Physicians of India (JAPI). Materials and Methods: We carried the bibliometric analysis of endocrinology related articles from JAPI. The data were obtained from the JAPI website for the publications between 2000 and 2011. The articles were analyzed for the type (original article, case reports, correspondence, and pictorial image), subspecialty (diabetes, thyroid, etc.), and place of the research. Data were presented with descriptive statistics in numbers and percentages. Results: Out of a total 2977 articles published by JAPI, 312 articles belong to endocrine subspecialty. Endocrinology related articles constitute about 11.2%–23.2% of the published articles per year in JAPI and the percentage is increasing every year. Original articles (52%) and case reports (27%) constituite the majority, while the rest were letters to editor (9%) and pictorial images (12%). Diabetes (57%) and metabolic bone disorders (16%) lead the subspecialty articles, followed by thyroid (9%), adrenal and gonad (8%), and pituitary (8%). Chennai (20%), Mumbai (14%), and Delhi (9%) are the top 3 places contributing to the articles followed by Chandigarh and Varanasi. Conclusion: Majority of endocrinology related research productivity is seen in form of original articles and case reports. Diabetes is the leading disease with maximum research articles from Chennai and other glands are equally represented in the research productivity. PMID:23226637

Trends in endocrinology related research articles in a medical journal from India

Directory of Open Access Journals (Sweden)

K. V. S. Hari Kumar

2012-01-01

Full Text Available Background: The details about the research productivity in the specialty of endocrinology from India is lacking. We plan to assess the publishing trends and the research productivity of Endocrinology related research articles published in the Journal of the Association of Physicians of India (JAPI. Materials and Methods: We carried the bibliometric analysis of endocrinology related articles from JAPI. The data were obtained from the JAPI website for the publications between 2000 and 2011. The articles were analyzed for the type (original article, case reports, correspondence, and pictorial image, subspecialty (diabetes, thyroid, etc., and place of the research. Data were presented with descriptive statistics in numbers and percentages. Results: Out of a total 2977 articles published by JAPI, 312 articles belong to endocrine subspecialty. Endocrinology related articles constitute about 11.2%-23.2% of the published articles per year in JAPI and the percentage is increasing every year. Original articles (52% and case reports (27% constituite the majority, while the rest were letters to editor (9% and pictorial images (12%. Diabetes (57% and metabolic bone disorders (16% lead the subspecialty articles, followed by thyroid (9%, adrenal and gonad (8%, and pituitary (8%. Chennai (20%, Mumbai (14%, and Delhi (9% are the top 3 places contributing to the articles followed by Chandigarh and Varanasi. Conclusion: Majority of endocrinology related research productivity is seen in form of original articles and case reports. Diabetes is the leading disease with maximum research articles from Chennai and other glands are equally represented in the research productivity.

Role of macrophage inflammatory protein-1 alpha (MIP-1 alpha) in acute lung injury in rats

DEFF Research Database (Denmark)

Shanley, T P; Schmal, H; Friedl, H P

1995-01-01

in bronchoalveolar lavage (BAL) fluids by Western blot analysis. Anti-MIP-1 alpha administered at commencement of IgG immune complex- or LPS-induced injury resulted in significant reductions in BAL neutrophils as well as in injury as measured by pulmonary vascular permeability. Under such conditions, in both models...... to production of TNF-alpha, which in turn up-regulates vascular adhesion molecules required for neutrophil influx....

Polycystic ovary syndrome | Maharaj | Journal of Endocrinology ...

African Journals Online (AJOL)

Polycystic ovary syndrome. ... Journal of Endocrinology, Metabolism and Diabetes of South Africa ... the disorder, that we now know as the polycystic ovary (or ovarian) syndrome (PCOS), in seven women with amenorrhoea, enlarged ovaries with multiple cysts and hirsutism.2 These patients were treated with ovarian wedge ...

The use of noninvasive and minimally invasive methods in endocrinology for threatened mammalian species conservation.

Science.gov (United States)

Kersey, David C; Dehnhard, Martin

2014-07-01

Endocrinology is an indispensable tool in threatened species research. The study of endocrinology in threatened species not only advances knowledge of endocrine mechanism but also contributes to conservation efforts of studied species. To this end, endocrinology has been traditionally used to understand reproductive and adrenocortical endocrine axes by quantifying excreted steroid metabolites. From these studies a large body of knowledge was created that contributed to the field of endocrinology, aided conservation efforts, and created a template by which to validate and conduct this research for other species. In this regard noninvasive hormone monitoring has become a favored approach to study the basic endocrinology of wildlife species. Due to the increased understanding of endocrine physiology of threatened species, breeding rates of captive population have improved to levels allowing for reintroduction of species to restored natural ecosystems. Although these approaches are still employed, advances in biochemical, molecular, and genomic technologies are providing inroads to describe lesser known endocrine activity in threatened species. These new avenues of research will allow for growth of the field with greater depth and breadth. However, for all approaches to endocrinology, limitations on resources and access to animals will require innovation of current methodologies to permit broad application for use in threatened species research. Crown Copyright © 2014. Published by Elsevier Inc. All rights reserved.

HIF-1alpha and HIF-2alpha are differentially activated in distinct cell populations in retinal ischaemia.

Directory of Open Access Journals (Sweden)

Freya M Mowat

2010-06-01

Full Text Available Hypoxia plays a key role in ischaemic and neovascular disorders of the retina. Cellular responses to oxygen are mediated by hypoxia-inducible transcription factors (HIFs that are stabilised in hypoxia and induce the expression of a diverse range of genes. The purpose of this study was to define the cellular specificities of HIF-1alpha and HIF-2alpha in retinal ischaemia, and to determine their correlation with the pattern of retinal hypoxia and the expression profiles of induced molecular mediators.We investigated the tissue distribution of retinal hypoxia during oxygen-induced retinopathy (OIR in mice using the bio-reductive drug pimonidazole. We measured the levels of HIF-1alpha and HIF-2alpha proteins by Western blotting and determined their cellular distribution by immunohistochemistry during the development of OIR. We measured the temporal expression profiles of two downstream mediators, vascular endothelial growth factor (VEGF and erythropoietin (Epo by ELISA. Pimonidazole labelling was evident specifically in the inner retina. Labelling peaked at 2 hours after the onset of hypoxia and gradually declined thereafter. Marked binding to Müller glia was evident during the early hypoxic stages of OIR. Both HIF-1alpha and HIF-2alpha protein levels were significantly increased during retinal hypoxia but were evident in distinct cellular distributions; HIF-1alpha stabilisation was evident in neuronal cells throughout the inner retinal layers whereas HIF-2alpha was restricted to Müller glia and astrocytes. Hypoxia and HIF-alpha stabilisation in the retina were closely followed by upregulated expression of the downstream mediators VEGF and EPO.Both HIF-1alpha and HIF-2alpha are activated in close correlation with retinal hypoxia but have contrasting cell specificities, consistent with differential roles in retinal ischaemia. Our findings suggest that HIF-2alpha activation plays a key role in regulating the response of Müller glia to hypoxia.

Intravenous alpha-1 antitrypsin augmentation therapy: systematic review

DEFF Research Database (Denmark)

Gøtzsche, Peter C; Johansen, Helle Krogh

2010-01-01

We reviewed the benefits and harms of augmentation therapy with alpha-1 antitrypsin in patients with alpha-1 antitrypsin deficiency and lung disease. We searched for randomised trials comparing augmentation therapy with placebo or no treatment in PubMed and ClinicalTrials (7 January 2010). Two...... (difference 1.14 g/l; 95% confidence interval 0.14 to 2.14; p = 0.03) over the total course of the trials. Augmentation therapy with alpha-1 antitrypsin cannot be recommended in view of the lack of evidence of clinical benefit and the cost of treatment....

MspI and PvuII polymorphisms in the Na,K-ATPase. alpha. subunit related gene ATP1AL1

Energy Technology Data Exchange (ETDEWEB)

Shull, M.M.; Pugh, D.G.; Lingrel, J.B. (Univ. of Cincinnati, OH (USA))

1990-01-11

ATP1AL1 78-1-3 is a 0.56 kb genomic EcoRI-XbaI fragment from within the Na,K-ATPase {alpha} subunit related gene, previously referred to as {alpha}D on chromosome 13. The fragment was subcloned into pIBI31. MspI identifies a two-allele polymorphism (M1: 2.8 kb, M2: 2.5 kb). PvuII, which cuts within the probe sequence, detects two two-allele polymorphism (A1: 6.0 kb, A2: 5.7 kb, B1: 1.3 kb, B2: 1.1 kb). A1 and A2 appear to result from an insertion/deletion polymorphism that is also identified by MspI. ATP1AL1 78-1-3 has been assigned to chromosome 13q by somatic cell hybrid analysis. Codominant segregation of the RELPs was observed in 2 two-generation families.

Reggeon field theory for alpha (0)>1

CERN Document Server

Amati, Daniele; Le Bellac, M; Marchesini, G

1976-01-01

The asymptotic behaviour of the scattering amplitude is obtained when the pomeron has intercept alpha (0) larger than one. The reggeon field theory is studied by introducing a lattice in impact parameter space. Use is made of a previous result showing that asymptotically the dynamics is controlled at each lattice site ( alpha '=0 case) by a two-level structure. This leads to a non-Hermitean Hamiltonian expressed in terms of spin operators in which the intersite interaction term is proportional to the pomeron slope alpha '. The spectrum of such a system shows a degenerate ground state for alpha (0)> alpha /sub c/>or approximately=1 and a continuum with vanishing excitation gap at alpha (0)= alpha /sub c/. The vacuum does not change structure at the critical value. The criticality is shown by an order parameter which is given by the matrix element of a field operator between the vacuum and its degenerate companion. The nature of this critical phenomenon is better understood by continuously transforming the Hami...

Compensatory increase in alpha 1-globin gene expression in individuals heterozygous for the alpha-thalassemia-2 deletion.

OpenAIRE

Liebhaber, S A; Cash, F E; Main, D M

1985-01-01

alpha-Globin is encoded by the two adjacent genes, alpha 1 and alpha 2. Although it is clearly established that both alpha-globin genes are expressed, their relative contributions to alpha-globin messenger RNA (mRNA) and protein synthesis are not fully defined. Furthermore, changes that may occur in alpha-globin gene activity secondarily to the loss of function of one or more of these genes (alpha-thalassemia [Thal]) have not been directly investigated. This study further defines the expressi...

Hyperfine interaction of {sup 25}Al in {alpha}-Al{sub 2}O{sub 3} and its quadrupole moment

Energy Technology Data Exchange (ETDEWEB)

Matsuta, K., E-mail: matsuta@vg.phys.sci.osaka-u.ac.jp; Mihara, M. [Osaka University, Department of Physics (Japan); Nagatomo, T. [RIKEN (Japan); Matsumiya, R. [Osaka University, Department of Physics (Japan); Momota, S. [Kochi University of Technology (Japan); Ohtsubo, T. [Niigata University, Department of Physics (Japan); Izumikawa, T. [Niigata University, Radioisotope Center (Japan); Hirano, H.; Takahashi, S. [Niigata University, Department of Physics (Japan); Nishimura, D.; Komurasaki, J. [Osaka University, Department of Physics (Japan); Kitagawa, A.; Kanazawa, M.; Torikoshi, M.; Sato, S. [National Institute of Radiological Sciences (Japan); Fukuda, M. [Osaka University, Department of Physics (Japan); Minamisono, T. [Fukui University of Technology (Japan); Sumikama, T. [Tokyo University of Science (Japan); Tanaka, K.; Takechi, M. [RIKEN (Japan)

2007-11-15

The electric quadrupole (Q) moment of short-lived nucleus {sup 25}Al (I{sup {pi}} = 5/2{sup +}, T{sub 1/2} = 7.18 s) has been measured for the first time, by means of the {beta}-NQR technique. The spin polarization of {sup 25}Al was produced in heavy ion collisions and was kept in a {alpha}-Al{sub 2}O{sub 3} single crystal for as long as 2 s and the quadrupole coupling frequency was obtained as vertical bar eqQ / h({sup 25}Al in Al{sub 2}O{sub 3}) vertical bar = (4.05 {+-}0.30) MHz. From the result, the Q moment was determined as |Q({sup 25}Al)| = (240 {+-}20) mb. The present Q moment is larger by 30% than the shell model value of 184 mb, calculated by OXBASH code, which may show additional deformation of the nucleus.

Alpha 1-blockers vs 5 alpha-reductase inhibitors in benign prostatic hyperplasia. A comparative review

DEFF Research Database (Denmark)

Andersen, J T

1995-01-01

During recent years, pharmacological treatment of symptomatic benign prostatic hyperplasia (BPH) has become the primary treatment choice for an increasing number of patients. The 2 principal drug classes employed are alpha 1-blockers and 5 alpha-reductase inhibitors. Current information from...... of patients who will respond well to alpha 1-blockers have yet to be identified, and data concerning the long term effects of these drugs are not yet available. 5 alpha-Reductase inhibitors have a slow onset of effect, but treatment leads to improvement in symptoms, reduction of the size of the prostate gland...... and improvement in objective parameters for bladder outflow obstruction. Approximately 30 to 50% of patients will respond to treatment with 5 alpha-reductase inhibitors. The definitive role of pharmacological treatment in symptomatic BPH remains to be established, although it seems that patients unfit...

Inhibition of HIF-2.alpha. heterodimerization with HIF1.beta. (ARNT)

Science.gov (United States)

Bruick, Richard K.; Caldwell, Charles G.; Frantz, Doug E.; Gardner, Kevin H.; MacMillan, John B.; Scheuermann, Thomas H.; Tambar, Uttam K.

2017-09-12

Provided is a method of inhibiting heterodimerization of HIF-2.alpha. to HIF1.beta. (ARNT) comprising binding certain small molecules to the HIF-2.alpha. PAS-B domain cavity but not to HIF1.alpha. and inhibiting HIF-2.alpha. heterodimerization to HIF1.beta. (ARNT) but not inhibiting HIF1.alpha. heterodimerization to HIF1.beta. (ARNT). Those certain small molecules are also referenced synonymously as HIF2-HDI and HIF2.alpha. heterodimerization inhibitors and also simply as certain small molecules.

Tissue-specific expression and regulation by 1,25(OH)2D3 of chick protein kinase inhibitor (PKI) mRNA.

Science.gov (United States)

Marchetto, G S; Henry, H L

1997-02-01

The heat-stable protein kinase inhibitor (PKI) protein is a specific and potent competitive inhibitor of the catalytic subunit of cAMP-dependent protein kinase (PKA). Previously, it has been shown that vitamin D status affects chick kidney PKI activity: a 5- to 10-fold increase in PKI activity was observed in kidneys of chronically vitamin D-deficient chicks and treatment with 1,25-dihydroxyvitamin D3 (1,25[OH]2D3) in cultured kidney cells resulted in a 95% decrease in PKI activity. The authors have recently cloned the cDNA for chick kidney PKI and have used the coding sequence to study the regulation of PKI mRNA. Northern analysis showed the expression of two PKI messages, which are 2.7 and 3.3 kb in size. These mRNAs are expressed in brain, muscle, testis, and kidney, but not in pancreas, liver, or intestine. PKI mRNA steady-state levels are downregulated by 47% in kidneys from vitamin D-replete chicks as compared to vitamin D-deficient chicks. PKI mRNA levels in brain, muscle, and testis are not affected by vitamin D status. Treatment of primary chick kidney cultures treated with 10(-7) M 1,25(OH)2D3 for 24h resulted in a 20-30% decrease in PKI mRNA. 1,25(OH)2D3 treatment does not affect the stability of PKI mRNA as determined by treatment of cell cultures with actinomycin D. This study shows that 1,25(OH)2D3 directly and tissue-specifically downregulates PKI mRNA in the chick kidney.

Journal of Endocrinology, Metabolism and Diabetes of South Africa

African Journals Online (AJOL)

JEMDSA) is published by the South African Medical Association and publishes papers related to endocrinology, metabolism and diabetes. Other websites related to this journal: http://www.jemdsa.co.za ...

Fasting induces basolateral uptake transporters of the SLC family in the liver via HNF4alpha and PGC1alpha.

Science.gov (United States)

Dietrich, Christoph G; Martin, Ina V; Porn, Anne C; Voigt, Sebastian; Gartung, Carsten; Trautwein, Christian; Geier, Andreas

2007-09-01

Fasting induces numerous adaptive changes in metabolism by several central signaling pathways, the most important represented by the HNF4alpha/PGC-1alpha-pathway. Because HNF4alpha has been identified as central regulator of basolateral bile acid transporters and a previous study reports increased basolateral bile acid uptake into the liver during fasting, we hypothesized that HNF4alpha is involved in fasting-induced bile acid uptake via upregulation of basolateral bile acid transporters. In rats, mRNA of Ntcp, Oatp1, and Oatp2 were significantly increased after 48 h of fasting. Protein expression as determined by Western blot showed significant increases for all three transporters 72 h after the onset of fasting. Whereas binding activity of HNF1alpha in electrophoretic mobility shift assays remained unchanged, HNF4alpha binding activity to the Ntcp promoter was increased significantly. In line with this result, we found significantly increased mRNA expression of HNF4alpha and PGC-1alpha. Functional studies in HepG2 cells revealed an increased endogenous NTCP mRNA expression upon cotransfection with either HNF4alpha, PGC-1alpha, or a combination of both. We conclude that upregulation of the basolateral bile acid transporters Ntcp, Oatp1, and Oatp2 in fasted rats is mediated via the HNF4alpha/PGC-1alpha pathway.

Generation of Affibody ligands binding interleukin-2 receptor alpha/CD25.

Science.gov (United States)

Grönwall, Caroline; Snelders, Eveline; Palm, Anna Jarelöv; Eriksson, Fredrik; Herne, Nina; Ståhl, Stefan

2008-06-01

Affibody molecules specific for human IL-2Ralpha, the IL-2 (interleukin-2) receptor alpha subunit, also known as CD25, were selected by phage-display technology from a combinatorial protein library based on the 58-residue Protein A-derived Z domain. The IL-2R system plays a major role in T-cell activation and the regulation of cellular immune responses. Moreover, CD25 has been found to be overexpressed in organ rejections, a number of autoimmune diseases and T-cell malignancies. The phage-display selection using Fc-fused target protein generated 16 unique Affibody molecules targeting CD25. The two most promising binders were characterized in more detail using biosensor analysis and demonstrated strong and selective binding to CD25. Kinetic biosensor analysis revealed that the two monomeric Affibody molecules bound to CD25 with apparent affinities of 130 and 240 nM respectively. The Affibody molecules were, on biosensor analysis, found to compete for the same binding site as the natural ligand IL-2 and the IL-2 blocking monoclonal antibody 2A3. Hence the Affibody molecules were assumed to have an overlapping binding site with IL-2 and antibodies targeting the IL-2 blocking Tac epitope (for example, the monoclonal antibodies Daclizumab and Basiliximab, both of which have been approved for therapeutic use). Furthermore, immunofluorescence microscopy and flow-cytometric analysis of CD25-expressing cells demonstrated that the selected Affibody molecules bound to CD4+ CD25+ PMBCs (peripheral-blood mononuclear cells), the IL-2-dependent cell line NK92 and phytohaemagglutinin-activated PMBCs. The potential use of the CD25-binding Affibody molecules as targeting agents for medical imaging and for therapeutic applications is discussed.

Morbilidad en la consulta de endocrinología del Centro de Investigaciones Medicoquirúrgicas de Angola Morbidity at the Endocrinology outpatient department of the Center for Medicosurgical Research in Angola

Directory of Open Access Journals (Sweden)

Rubén S. Padrón Durán

2006-04-01

Full Text Available Los datos de la morbilidad en consulta externa pueden ser útiles para conocer las causas por las que los pacientes acuden al centro de salud, así como para planificar el ofrecimiento de consultas especiales y de exámenes complementarios. El objetivo de este estudio es presentar y analizar la morbilidad en la consulta externa de endocrinología del Centro de Investigaciones Medicoquirúrgicas de Angola (CIMECA. Se compilaron todos los diagnósticos de cada caso durante 28 meses consecutivos. Los diagnósticos específicos se clasificaron en 7 grandes grupos: 1 alteraciones de la glucemia, 2 obesidad y otros trastornos metabólicos, 3 medicina reproductiva, 4 trastornos del tiroides, 5 endocrinología pediátrica, 6 otras endocrinopatías y 7 sin endocrinopatías. Se atendieron 2 294 pacientes. Los grupos diagnósticos más frecuentes fueron: alteración de la glucemia (60,07 y obesidad y otros trastornos metabólicos (42,07; relativamente frecuentes fueron medicina reproductiva (19,4 y trastornos del tiroides (11,07. Sin embargo, los pacientes de endocrinología pediátrica (1,53 y otras endocrinopatías (0,22 fueron muy poco numerosos. Los diagnósticos específicos más comunes fueron la diabetes mellitus tipo 2 (DM2 y la obesidad exógena (53,01 y 24,72 respectivamente, seguidos por las hiperlipoproteinemias (11,73. En un rango entre 4,5 y 10 % observamos bocio difuso eutiroideo, glucemia en ayunas alterada, infertilidad femenina e hiperuricemia; el resto se halló en menos del 3 % del total de casos. Lo resultados y conclusiones más importantes del estudio son: a Los grupos diagnósticos más comunes fueron las alteraciones de la glucemia y la obesidad y otros trastornos metabólicos, entre ellos la DM2 y la obesidad exógena, b Los diagnósticos de medicina reproductiva y trastornos del tiroides fueron relativamente comunes, c Los trastornos endocrinos en edades pediátricas y otras endocrinopatías fueron muy poco frecuentes, d

A basic research of gadolinium hydrogen [alpha], [alpha]', [alpha]'', [alpha]'''-tetramethly- 1,4,7,10-tetraazacyclododecane- 1,4,7,10-tetraacetate with high complex stability as a contrast agent for MRI

Energy Technology Data Exchange (ETDEWEB)

Seri, Shigemi; Hashiguchi, Yuji; Kubomura, Kan; Abe, Yukiko; Iguchi, Toshio; Iwai, Kumiko [Nihon Medi-Physics Co., Ltd., Sodegaura, Chiba (Japan); Watanabe, Tokuko

1993-05-01

Gadolinium hydrogen [alpha], [alpha]', [alpha]'', [alpha]'''-tetramethyl- 1,4,7,10-tetraazacyclododecane- 1,4,7,10-tetraacetate (abbreviated Gd-DOTMA) was developed as a new contrast agent for magnetic resonance imaging. Our study focused on the evaluation of the pharmaceutical properties as in vivo agent. The new modified process by which Gd-DOTMA was synthesized resulted in high yields of this agent. A high stability constant of 10[sup 26] fro Gd-DOTMA was determined at physiological pH. It is more stable than Gd complex with tetraazacyclododecanetetraacetic acid (which is regarded as the most stable Gd complex). The strong T[sub 1] relaxivities of 4.0 and 3.7 (mM [center dot] s)[sup -1] at 0.5 tesla and 1.5 tesla were measured in the aqueous solution. The osmolarity of 0.5 M solution, dissolved with equal amounts of meglumine as a solubilizer is 1020 mOsmol/kg. This contrasting agent was studied in vivo by using rats as the experimental group. The agent showed strong enhancement of transplanted tumors within the rat population studied. This compound is rapidly excreted by the kidneys, and has a half-life of 26 min in blood. The median lethal dose (LD[sub 50] value) of the stable Gd-DOTMA has a favorable tolerance of over 12.3 mmol/kg. (author).

Does alpha 1-acid glycoprotein act as a non-functional receptor for alpha 1-adrenergic antagonists?

Science.gov (United States)

Qin, M; Oie, S

1994-11-01

The ability of a variety of alpha 1-acid glycoproteins (AAG) to affect the intrinsic activity of the alpha 1-adrenergic antagonist prazosin was studied in rabbit aortic strip preparations. From these studies, the activity of AAG appears to be linked to their ability to bind the antagonist. However, a capability to bind prazosin was not the only requirement for this effect. The removal of sialic acid and partial removal of the galactose and mannose residues by periodate oxidation of human AAG all but eliminated the ability of AAG to affect the intrinsic pharmacologic activity of prazosin, although the binding of prazosin was not significantly affected. The presence of bovine AAG, a protein that has a low ability to bind prazosin, reduced the effect of human AAG on prazosin activity. Based upon these results, we propose that AAG is able to bind in the vicinity of the alpha 1-adrenoceptors, therefore extending the binding region for antagonists in such a way as to decrease the ability of the antagonist to interact with the receptor. The carbohydrate side-chains are important for the binding of AAG in the region of the adrenoceptor.

Peptides and the new endocrinology

Science.gov (United States)

Schwyzer, Robert

1982-01-01

The discovery of regulatory peptides common to the nervous and the endocrine systems (brain, gut, and skin) has brought about a revolution in our concepts of endocrinology and neurology. We are beginning to understand some of the complex interrelationships between soma and psyche that might, someday, be important for an integrated treatment of diseases. Examples of the actions of certain peptides in the periphery and in the central nervous system are given, and their biosynthesis and molecular anatomy as carriers for information are discussed.

Gastrointestinal Hormones Induced the Birth of Endocrinology.

Science.gov (United States)

Wabitsch, Martin

2017-01-01

The physiological studies by British physiologists William Maddock Bayliss and Ernest Henry Starling, at the beginning of the last century, demonstrated the existence of specific messenger molecules (hormones) circulating in the blood that regulate the organ function and physiological mechanisms. These findings led to the concept of endocrinology. The first 2 hormones were secretin, discovered in 1902, and gastrin, discovered in 1905. Both hormones that have been described are produced in the gut. This chapter summarizes the history around the discovery of these 2 hormones, which is perceived as the birth of endocrinology. It is noteworthy that after the discovery of these 2 gastrointestinal hormones, many other hormones were detected outside the gut, and thereafter gut hormones faded from both the clinical and scientific spotlight. Only recently, the clinical importance of the gut as the body's largest endocrine organ producing a large variety of hormones has been realized. Gastrointestinal hormones are essential regulators of metabolism, growth, development and behavior and are therefore the focus of a modern pediatric endocrinologist. © 2017 S. Karger AG, Basel.

Studies on the analysis of 25-hydroxyvitamin D{sub 3} by isotope-dilution liquid chromatography–tandem mass spectrometry using enzyme-assisted derivatisation

Energy Technology Data Exchange (ETDEWEB)

Abdel-Khalik, Jonas, E-mail: J.A.F.A.ABDEL-KHALIK.744116@swansea.ac.uk [Institute of Mass Spectrometry, College of Medicine, Swansea University, Singleton Park, Swansea SA2 8PP (United Kingdom); Crick, Peter J. [Institute of Mass Spectrometry, College of Medicine, Swansea University, Singleton Park, Swansea SA2 8PP (United Kingdom); Carter, Graham D. [DEQAS, Imperial College Healthcare NHS Trust, Clinical Biochemistry Department, Charing Cross Hospital, Fulham Palace Rd, London W6 8RF (United Kingdom); Makin, Hugh L. [Barts and the Royal London School of Medicine and Dentistry, Queen Mary University of London, London E1 2AD (United Kingdom); Wang, Yuqin [Institute of Mass Spectrometry, College of Medicine, Swansea University, Singleton Park, Swansea SA2 8PP (United Kingdom); Griffiths, William J., E-mail: w.j.griffiths@swansea.ac.uk [Institute of Mass Spectrometry, College of Medicine, Swansea University, Singleton Park, Swansea SA2 8PP (United Kingdom)

2014-04-11

Highlights: • New method for the analysis of 25-hydroxyvitamin D{sub 3} exploiting Girard P derivatisation. • Method also applicable to vitamin D{sub 3}, 1α,25- and 24,25-dihydroxyvitamin D{sub 3}. • By modification of the method 3-epi-25-hydroxyvitamin D{sub 3} can also be analysed. - Abstract: The total serum concentration of 25-hydroxyvitamins D (25-hydroxyvitamin D{sub 3} and 25-hydroxyvitamin D{sub 2}) is currently used as an indicator of vitamins D status. Vitamins D insufficiency is claimed to be associated with multiple diseases, thus accurate and precise reference methods for the quantification of 25-hydroxyvitamins D are needed. Here we present a novel enzyme-assisted derivatisation method for the analysis of vitamins D metabolites in adult serum utilising 25-[26,26,26,27,27,27-{sup 2}H{sub 6}]hydroxyvitamin D{sub 3} as the internal standard. Extraction of 25-hydroxyvitamins D from serum is performed with acetonitrile, which is shown to be more efficient than ethanol. Cholesterol oxidase is used to oxidize the 3β-hydroxy group in the vitamins D metabolites followed by derivatisation of the newly formed 3-oxo group with Girard P reagent. 17β-Hydroxysteroid dehydrogenase type 10 is shown to oxidize selectively the 3α-hydroxy group in the 3α-hydroxy epimer of 25-hydroxyvitamin D{sub 3}. Quantification is achieved by isotope-dilution liquid chromatography–tandem mass spectrometry. Recovery experiments for 25-hydroxyvitamin D{sub 3} performed on adult human serum give recovery of 102–106%. Furthermore in addition to 25-hydroxyvitamin D{sub 3}, 24,25-dihydroxyvitamin D{sub 3} and other uncharacterised dihydroxy metabolites, were detected in adult human serum.

Immunoassay of serum alpha-1 antitrypsin level in uveitis.

OpenAIRE

Gupta, A K; Sarin, G S

1984-01-01

The serum alpha-1 antitrypsin level was measured in 60 patients with endogenous uveitis, 27 patients with phacoallergic endophthalmitis, 12 patients with phacolytic glaucoma, and 58 healthy subjects. Thirty-four patients with endogenous uveitis were also followed up for 6 months after treatment, and the serum alpha-1 antitrypsin level was measured again. There was a significant rise in the serum alpha-1 antitrypsin level in cases of endogenous uveitis and phacoallergic endophthalmitis but no ...

Genetic evidence that HNF-1alpha-dependent transcriptional control of HNF-4alpha is essential for human pancreatic beta cell function

DEFF Research Database (Denmark)

Hansen, Sara K; Párrizas, Marcelina; Jensen, Maria L

2002-01-01

Mutations in the genes encoding hepatocyte nuclear factor 4alpha (HNF-4alpha) and HNF-1alpha impair insulin secretion and cause maturity onset diabetes of the young (MODY). HNF-4alpha is known to be an essential positive regulator of HNF-1alpha. More recent data demonstrates that HNF-4alpha...... in human islets and exocrine cells is primarily mediated by the P2 promoter. Furthermore, we describe a G --> A mutation in a conserved nucleotide position of the HNF-1alpha binding site of the P2 promoter, which cosegregates with MODY. The mutation results in decreased affinity for HNF-1alpha...

Motivational interviewing in health care: results of a brief training in endocrinology.

Science.gov (United States)

Bean, Melanie K; Biskobing, Diane; Francis, Gary L; Wickham, Edmond

2012-09-01

Despite the importance of lifestyle change in disease management and the growing evidence supporting motivational interviewing (MI) as an effective counseling method to promote behavioral change, to date there are few published reports about MI training in graduate medical education. The study aimed to pilot the feasibility and effectiveness of a brief MI training intervention for endocrinology fellows and other providers. We used a pretest/posttest design to evaluate a brief MI training for 5 endocrinology fellows and 9 other providers. All participants completed subjective assessments of perceived confidence and beliefs about behavioral counseling at pretest and posttest. Objective assessment of MI was conducted using fellows' audiotaped patient encounters, which were coded using a validated tool for adherence to MI before and after the training. Paired t tests examined changes in objective and subjective assessments. The training intervention was well received and feasible in the endocrinology setting. At posttest, participants reported increased endorsement of the MI spirit and improved confidence in MI skills. Objective assessment revealed relative improvements in MI skills across several domains. However, most domains, as assessed by a validated tool, did not reach competency level after the training intervention. Although more intensive training may be needed to develop MI competence, the results of our pilot study suggest that brief, targeted MI training has short-term efficacy and is well received by endocrinology fellows and other providers.

Some applications of Photon/Electron-Rejecting Alpha Liquid Scintillation (PERALS) spectrometry to the assay of alpha emitters

International Nuclear Information System (INIS)

McDowell, W.J.; Case, G.N.

1988-01-01

The combination of certain solvent extraction separations and a special kind of liquid scintillation detector and electronics designed for alpha spectrometry allows some highly accurate, yet simple determinations of alpha-emitting nuclides. Counting efficiency is 99.68% with backgrounds of 99.95%. The Photon/Electron Rejecting Alpha Liquid Scintillation (PERALS) equipment is described and procedures for the separation and determination of uranium, thorium, plutonium, polonium, radium, and trivalent actinides are outlined. 25 refs., 10 figs., 1 tab

Inecalcitol, an analog of 1,25D₃, displays enhanced antitumor activity through the induction of apoptosis in a squamous cell carcinoma model system

Science.gov (United States)

Ma, Yingyu; Yu, Wei-Dong; Hidalgo, Alejandro A.; Luo, Wei; Delansorne, Remi; Johnson, Candace S.; Trump, Donald L.

2013-01-01

Epidemiological data suggest an important role of vitamin D signaling in cancer development and progression, and experimental studies demonstrate that the active vitamin D metabolite 1α, 25-dihydroxyvitamin D₃ (1,25D₃) has broad spectrum antitumor activity. Hypercalcemia has often been suggested to limit the clinical application of these data. The 14-epi-analog of 1,25D₃, inecalcitol [19-nor-14-epi-23-yne-1,25-(OH)₂D₃; TX522], was developed to have superagonistic antitumor activities but low hypercalcemia potential. We examined the antitumor activity of inecalcitol and the underlying mechanisms in a murine squamous cell carcinoma (SCC) model system. In vitro, compared with 1,25D₃, inecalcitol showed enhanced vitamin D receptor (VDR)-mediated transcriptional activity. Inecalcitol suppressed SCC cell proliferation in a dose-dependent manner with an IC₅₀ value 30 times lower than that of 1,25D₃. Both inecalcitol and 1,25D₃ induced a comparable level of G₀/G₁ cell cycle arrest in SCC cells. The level of apoptosis induced by inecalcitol was markedly higher than that of 1,25D₃. Apoptosis was mediated through the activation of the caspase 8/10- caspase 3 pathway. Further, inecalcitol markedly inhibited the mRNA and protein expression of c-IAP1 and XIAP compared with 1,25D₃. In vivo, inecalcitol inhibits SCC tumor growth in a dose-dependent fashion. Notably, inecalcitol induced a significantly higher level of apoptosis in the SCC xenograft model. While in vitro inecalcitol demonstrates apparent enhanced VDR binding and antiproliferative effects compared to 1,25D₃, in vivo these advantages disappear; at doses of inecalcitol that have equivalent antitumor effects, similar hypercalcemia is seen. This may be explained by the pharmacokinetics of 1,25D₃ vs. inecalcitol and attributed to the much shorter serum half-life of inecalcitol.We show that inecalcitol has potent antitumor activity in the SCC model system, and this is associated with a

46 CFR 25.25-1 - Application.

Science.gov (United States)

2010-10-01

... 46 Shipping 1 2010-10-01 2010-10-01 false Application. 25.25-1 Section 25.25-1 Shipping COAST GUARD, DEPARTMENT OF HOMELAND SECURITY UNINSPECTED VESSELS REQUIREMENTS Life Preservers and Other Lifesaving Equipment § 25.25-1 Application. This subpart applies to each vessel to which this part applies...

Molecular determinants of desensitization and assembly of the chimeric GABA(A) receptor subunits (alpha1/gamma2) and (gamma2/alpha1) in combinations with beta2 and gamma2

DEFF Research Database (Denmark)

Elster, L; Kristiansen, U; Pickering, D S

2001-01-01

Two gamma-aminobutyric acid(A) (GABA(A)) receptor chimeras were designed in order to elucidate the structural requirements for GABA(A) receptor desensitization and assembly. The (alpha1/gamma2) and (gamma2/alpha1) chimeric subunits representing the extracellular N-terminal domain of alpha1 or gamma......, as opposed to the staining of the (gamma2/alpha1)-containing receptors, which was only slightly higher than background. To explain this, the (alpha1/gamma2) and (gamma2/alpha1) chimeras may act like alpha1 and gamma2 subunits, respectively, indicating that the extracellular N-terminal segment is important...... for assembly. However, the (alpha1/gamma2) chimeric subunit had characteristics different from the alpha1 subunit, since the (alpha1/gamma2) chimera gave rise to no desensitization after GABA stimulation in whole-cell patch-clamp recordings, which was independent of whether the chimera was expressed...

Reconstruction of spin-tensor of 4. 43 MeV state density matrix of the /sup 12/C nucleus in the /sup 12/C(. cap alpha. ,. cap alpha. sub(1). gamma. sub(4,43))/sup 12/C reaction at Esub(. cap alpha. )=25 MeV

Energy Technology Data Exchange (ETDEWEB)

Gurevich, G.S.; Lebedev, V.M.; Orlova, N.V.; Spasskij, A.V.; Teplov, I.B.; Shakhvorostova, G.V.; Belkina, M.R. (Moskovskij Gosudarstvennyj Univ. (USSR). Nauchno-Issledovatel' skij Inst. Yadernoj Fiziki)

1984-01-01

The results of measuring double differential cross sections of the reaction of inelastic scattering 24.8 MeV ..cap alpha..-particles sup(12)C(..cap alpha.., ..cap alpha..sub(1)..gamma..sub(4.43))sup(12)C in different planes of ..gamma..-quantum escape relatively to the plane of the reaction phisub(..gamma..)=30, 60 and 90 deg are presented. Non-monochromaticity of the beam made up 1%. Functions of angular correlation of the reaction are measured for four angles THETAsub(..cap alpha..)=21, 39, 59 and 135 deg corresponding to maxima of differential cross section in angular distribution of inelastically scattered ..cap alpha..-particles and for THETAsub(..cap alpha..)=89 deg corresponding to the minimum of angular distribution. The results of measurements permit to reconstruct all the components of irreducible spin-tensors of the matrix of state density 4.43 MeV (2/sup +/) formed in this reaction. The values of populations of substates by the projection of the spin of this state are obtained. The analysis of the obtained results testify to the fact that mechanism of inelastic scattering is not reduced to impulse approximation and mechanisms associated with delay in interaction do not make noticeable contribution for the given angles of ..cap alpha..-particle escape.

Raman spectrum, quantum mechanical calculations and vibrational assignments of (95% alpha-TeO2/5% Sm2O3) glass.

Science.gov (United States)

Shaltout, I; Mohamed, Tarek A

2007-06-01

Chozen system of tellurite glasses doped with rare earth oxides (95% alpha-TeO(2)+5% Sm2O3) was prepared by melt quenching. Consequently, the Raman spectrum (150-1250 cm(-1)) of the modified tellurite have been recorded. As a continuation to our normal coordinate analysis, force constants and quantum mechanical (QM) calculations for tbp TeO4(4-) (triagonal bipyramid, C(2v)) and TeO(3+1); Te2O7(6-) (bridged tetrahedral), we have carried out ab initio frequency calculations for tpy TeO3(2-) (triagonal pyramidal, C(3v) and C(s)) and tp TeO3(2-) (triagonal planar, D(3h)) ions. The quantum mechanical calculations at the levels of RHF, B3LYP and MP2 allow confident vibrational assignments and structural identification in the binary oxide glass (95% alpha-TeO2 +5% Sm2O3). The dominant three-dimensional network structures in the modified glass are triagonal pyramidal TeO3 with minor features of short range distorted tbp TeO4 and bridged tetrahedral unit of TeO(3+1), leading to a structure of infinite chain. Therefore, alpha-TeO2/Sm2O3 (95/5%) glass experience structural changes from TeO4 (tbp); Te2O7 (TeO(3+1))-->TeO3 (tpy).

Journal of Endocrinology, Metabolism and Diabetes of South Africa ...

African Journals Online (AJOL)

Journal of Endocrinology, Metabolism and Diabetes of South Africa. ... Management of diabetic ketoacidosis · EMAIL FREE FULL TEXT EMAIL FREE FULL TEXT ... Prediabetes: a focus on the role of diabetes education in prevention of type 2 ...

Contribution to the study of alpha-alpha interaction; Contribution a l'etude de l'interaction alpha - alpha

Energy Technology Data Exchange (ETDEWEB)

Darriulai, P [Commissariat a l' Energie Atomique, Saclay (France). Centre d' Etudes Nucleaires

1965-03-01

Two sets of measurements of the {alpha}-{alpha} elastic scattering differential cross section are presented. The first set - angular distributions from 50 up to 120 MeV - shows two new resonances, 6{sup +} and 8{sup +}, at 25 and 57 MeV. Complex phase shifts are extracted from the data and a phenomenological potential is given. A description of the 3 {alpha}-particle 0{sup +} states in C{sup 12} is made with this interaction potential. The second set - excitation curves between 20 and 50 MeV - allows investigation of the Be{sup 8} level structure within this energy range - It identifies the 16.6 and 16.9 MeV states as 2{sup +}, but the rise of inelastic processes at higher energies makes further identification of spins and parities more and more difficult. (author) [French] Deux series de mesures de la section efficace differentielle de diffusion {alpha}-{alpha} sont presentees. La premiere - distributions angulaires entre 50 et 120 MeV - fait apparaitre deux nouvelles resonances, 6{sup +} et 8{sup +}, a 25 et 57 MeV d'excitation. Des dephasages complexes en sont extraits et un potentiel phenomenologique est presente. Une etude des etats 0{sup +} a parentage (3{alpha}) de {sup 12}C est faite a partir de ce potentiel. La seconde - courbes d'excitation s'etendant de 20 a 50 MeV - met en evidence la structure de {sup 8}Be dans cette region. Elle montre que les niveaux a 16,6 et 16,9 MeV sont des 2{sup +} mais l'importance des processus inelastiques rend difficile l'identification des niveaux d'excitation plus elevee. (auteur)

Therapeutics: Gene Therapy for Alpha-1 Antitrypsin Deficiency.

Science.gov (United States)

Gruntman, Alisha M; Flotte, Terence R

2017-01-01

This review seeks to give an overview of alpha-1 antitrypsin deficiency, including the different disease phenotypes that it encompasses. We then describe the different therapeutic endeavors that have been undertaken to address these different phenotypes. Lastly we discuss future potential therapeutics, such as genome editing, and how they may play a role in treating alpha-1 antitrypsin deficiency.

Fibrinogen and alpha(1)-antitrypsin in COPD exacerbations

DEFF Research Database (Denmark)

Sylvan Ingebrigtsen, Truls; Marott, J. L.; Rode, L.

2015-01-01

Background We tested the hypotheses that fibrinogen and alpha(1)-antitrypsin are observationally and genetically associated with exacerbations in COPD. Methods We studied 13 591 individuals with COPD from the Copenhagen General Population Study (2003-2013), of whom 6857 were genotyped for FGB -455...... and exacerbations in instrumental variable analyses. Results Elevated fibrinogen and alpha(1)-antitrypsin levels were associated with increased risk of exacerbations in COPD, HR=1.14 (1.07 to 1.22, p...

25-Hydroxycholesterol Inhibition of Lassa Virus Infection through Aberrant GP1 Glycosylation

Directory of Open Access Journals (Sweden)

Punya Shrivastava-Ranjan

2016-12-01

Full Text Available Lassa virus (LASV infection is a major public health concern due to high fatality rates and limited effective treatment. The interferon-stimulated gene cholesterol 25-hydroxylase (CH25H encodes an enzyme that catalyzes the production of 25-hydroxycholesterol (25HC. 25HC is involved in regulating cholesterol biosynthesis and has recently been identified as a potent antiviral targeting enveloped virus entry. Here, we show a previously unrecognized role of CH25H in inhibiting LASV glycoprotein glycosylation and the production of infectious virus. Overexpression of CH25H or treatment with 25HC decreased LASV G1 glycoprotein N-glycan maturation and reduced the production of infectious LASV. Depletion of endogenous CH25H using small interfering RNA (siRNA enhanced the levels of fully glycosylated G1 and increased infectious LASV production. Finally, LASV particles produced from 25HC-treated cells were found to be less infectious, to incorporate aberrantly glycosylated GP1 species, and to be defective in binding alpha-dystroglycan, an attachment and entry receptor. Our findings identify a novel role for CH25H in controlling LASV propagation and indicate that manipulation of the expression of CH25H or the administration of 25HC may be a useful anti-LASV therapy.

Aspects of ecological radiation endocrinology and occupational pathology

International Nuclear Information System (INIS)

Ajtbembetov, B.M.

1997-01-01

The collection consists of works on radiation endocrinology and occupational pathology in different branches of industry - petroleum, mining, cotton, non-ferrous metallurgy as well as agriculture. Collection is intended for endocrinologists and occupational pathologists, for specialists of labour protection and occupational safety, for doctors examining of industrial and agricultural workers (author)

Management of prediabetes: a comparison of the treatment approaches utilized by a family practice clinic and an internal medicine/endocrinology practice.

Science.gov (United States)

Anderson, Zachary L; Scopelliti, Emily M; Trompeter, Jessica M; Havrda, Dawn E

2015-02-01

To compare the management of prediabetes between a family practice clinic and internal medicine/endocrinology practice. A randomized, retrospective evaluation of the medical history in 168 eligible patients with a diagnosis of prediabetes or abnormal blood glucose (BG) at a family practice clinic (n = 78) and an internal medicine/endocrinology practice (n = 90). The internal medicine/endocrinology practice provided more counseling regarding lifestyle modifications (91.1% vs 76.9%, P = .039), specific physical activity recommendations (26.7% vs 7.7%, P = .003), and recommended more patients receive 150 minutes/week of moderate exercise (8.9% vs 1.3%, P = .038). The family practice clinic provided more written dietary information (16.9% vs 13.3%, P = .044) and specific weight loss goals (20.5% vs 6.7%, P = .015). The internal medicine/endocrinology practice initiated pharmacological therapy in more patients (51.1% vs 3.8%, P< .001) and had a significant decrease in fasting BG from baseline compared to the family practice clinic (-9.0 vs -5.6 mg/dL, P< .001). Providers are likely to initiate nonpharmacological therapy but may not provide specific education recommended by the American Diabetes Association. The integration of a multidisciplinary team to provide guideline-based nonpharmacologic counseling may be beneficial in improving outcomes in the management of prediabetes. © The Author(s) 2013.

The experience with setting-up radioimmunoassay for alpha-1 fetoprotein

International Nuclear Information System (INIS)

Fingerova, H.

1981-01-01

The decisive factor in the preparation of radioimmunological alpha-1-fetoprotein determination, provided sufficient commercial or own antisera and standards are available for calibration, is the quality of the preparation for labelling. Alpha-1-fetoprotein was separated by affinity chromatography using Sepharose with alpha-1-fetoprotein-bound antibodies. The isolates thus obtained were labelled with 125 I using enzyme and chloramine T and Iodogen techniques. The labelled alpha-1-fetoprotein can be used for RIA. In view of reduced immunoreactivity of the preparation, however, the performance of the radioimmunological determination has so far not matched the quality of imported kits. The technique is currently being optimized. (author)

Effect of alpha1-blockers on stentless ureteroscopic lithotripsy

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Jianguo Zhu

2016-02-01

Full Text Available ABSTRACT Objective To evaluate the clinical efficiency of alpha1-adrenergic antagonists on stentless ureteroscopic lithotripsy treating uncomplicated lower ureteral stones. Materials and Methods From January 2007 to January 2013, 84 patients who have uncomplicated lower ureteral stones treated by ureteroscopic intracorporeal lithotripsy with the holmium laser were analyzed. The patients were divided into two groups, group A (44 patients received indwelled double-J stents and group B (40 patients were treated by alpha1-adrenergic antagonists without stents. All cases of group B were treated with alpha1 blocker for 1 week. Results The mean operative time of group A was significantly longer than group B. The incidences of hematuria, flank/abdominal pain, frequency/urgency after surgery were statistically different between both groups. The stone-free rate of each group was 100%. Conclusions The effect of alpha1-adrenergic antagonists is more significant than indwelling stent after ureteroscopic lithotripsy in treating uncomplicated lower ureteral stones.

Inhibitory activity and conformational transition of alpha 1-proteinase inhibitor variants

NARCIS (Netherlands)

Schulze, A.J.; Huber, R.; Degryse, E.; Speck, D.; Bischoff, Rainer

1991-01-01

Several variants of alpha 1-proteinase inhibitor (alpha 1-PI) were investigated by spectroscopic methods and characterized according to their inhibitory activity. Replacement of Thr345 (P14) with Arg in alpha 1-PI containing an Arg residue in position 358 (yielding [Thr345----Arg,

Complete primary structure of rainbow trout type I collagen consisting of alpha1(I)alpha2(I)alpha3(I) heterotrimers.

Science.gov (United States)

Saito, M; Takenouchi, Y; Kunisaki, N; Kimura, S

2001-05-01

The subunit compositions of skin and muscle type I collagens from rainbow trout were found to be alpha1(I)alpha2(I)alpha3(I) and [alpha1(I)](2)alpha2(I), respectively. The occurrence of alpha3(I) has been observed only for bonyfish. The skin collagen exhibited more susceptibility to both heat denaturation and MMP-13 digestion than the muscle counterpart; the former had a lower denaturation temperature by about 0.5 degrees C than the latter. The lower stability of skin collagen, however, is not due to the low levels of imino acids because the contents of Pro and Hyp were almost constant in both collagens. On the other hand, some cDNAs coding for the N-terminal and/or a part of triple-helical domains of proalpha(I) chains were cloned from the cDNA library of rainbow trout fibroblasts. These cDNAs together with the previously cloned collagen cDNAs gave information about the complete primary structure of type I procollagen. The main triple-helical domain of each proalpha(I) chain had 338 uninterrupted Gly-X-Y triplets consisting of 1014 amino acids and was unique in its high content of Gly-Gly doublets. In particular, the bonyfish-specific alpha(I) chain, proalpha3(I) was characterized by the small number of Gly-Pro-Pro triplets, 19, and the large number of Gly-Gly doublets, 38, in the triple-helical domain, compared to 23 and 22, respectively, for proalpha1(I). The small number of Gly-Pro-Pro and the large number of Gly-Gly in proalpha3(I) was assumed to partially loosen the triple-helical structure of skin collagen, leading to the lower stability of skin collagen mentioned above. Finally, phylogenetic analyses revealed that proalpha3(I) had diverged from proalpha1(I). This study is the first report of the complete primary structure of fish type I procollagen.

Linguistic aspects of eponymic professional endocrinologic terminology

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N.I. Bytsko

2017-03-01

Full Text Available Background. Special linguistic researches of terminological units of different branches of medicine allow analyzing in details the ways of creating the systems of clinical terminology from different aspects: historical, scientific, cultural, linguistic and semantic. There is a wide area of terminology related to the clinical and experimental endocrino­logy within general medical terminological system. The purpose of the study: to demonstrate the structure of endocrine medical terms — eponyms through the prism of systematization of methodological researches on eponymic vocabulary. Materials and methods. The actual material received as a result of a total choice of eponyms (there were 296 terms from the “Reference dictionary for endocrinologist”, which was composed by the scientists of V. Danilevsky Institute of Endocrine Pathology Problems and Kharkiv Medical Academy of Postgraduate education — A.V. Kozakov, N.A. Kravchun, I.M. Ilyina, M.I. Zubko, O.A. Goncharova, I.V. Cherniavska has 10,000 endocrine terms, the authors successfully streamlined medical terms of the clinical and experimental endocrinology into the vocabulary. The method of total choice of terms from professional literature, the descriptive method and distributive method were used in the study that allowed distinguishing lexical and semantic features of eponymic terms in the branch of endocrinology. Results. The obtained results point out to the modernity of studies in the field of clinical and experimental endocrinology, which is due to the fact that this is the oldest terminology, by the example of which it is possible to trace the ways of formation, development and improvement of terms, the realization of semantic processes, certain trends, ways and means of word formation. Conclusions. The results of the research on the above mentioned sublanguage of clinical medicine at the level of linguistic observations of the functio­ning in dictionaries and scientific works will

Long-term effects of intermittent oral alphacalcidol, calcium carbonate and low-calcium dialysis (1.25 mmol L-1) on secondary hyperparathyroidism in patients on continuous ambulatory peritoneal dialysis

DEFF Research Database (Denmark)

Brandi, L; Nielsen, P K; Bro, S

1998-01-01

of the secondary hyperparathyroidism was seen. CONCLUSIONS: A calcium concentration of 1.25 mmol L-1 in the CAPD dialysate made it possible to reduce the amount of aluminium-containing phosphate binder, to increase the doses of CaCO3 and to use pulse oral 1 alpha(OH)D3 without causing severe hyper...... L-1 to 1.25 mmol L-1. Increasing doses of oral 1 alpha(OH)D3 were then administered under careful control of p-ionized calcium (p-Ca2+) and p-inorganic phosphate (p-P1). Blood samples were obtained every 2-4 weeks for 52 weeks. PET was performed using standard dialysis fluid and 1 week later using...... low-calcium dialysis fluid after a preceding overnight dwell. Two litres of glucose 22.7 mg mL-1 were used. MAIN OUTCOME MEASURES: Intact parathyroid hormone (PTH), p-Ca2+, p-P1, doses of CaCO3, doses of 1 alpha(OH)D3, peritoneal mass transfer for calcium, inorganic phosphate, magnesium, lactate...

Evaluation and Referral of Diabetic Eye Disease in the Endocrinology and Primary Care Office Settings.

Science.gov (United States)

Silva, Fabiana Q; Adhi, Mehreen; Wai, Karen M; Olansky, Leann; Lansang, M Cecilia; Singh, Rishi P

2016-10-01

The purpose of this study was to identify whether endocrinologists and primary care physicians (PCP) adequately screen for ophthalmic symptoms/signs within office visits and provide timely ophthalmology referrals in patients with diabetes. Patients between the ages of 18 years and 80 years with diabetes who underwent an office visit with an endocrinologist or a PCP between January 1, 2014, and December 31, 2014, were identified. Demographics, ophthalmic assessments, and referral information were collected. A total of 1,250 patient records were reviewed. Providers asked about ophthalmic symptoms/signs in 95.5% and 71% of endocrinology and primary care office encounters, respectively (P endocrinology and PCP visits, respectively (P < .0001). Ophthalmic complications from diabetes are not adequately screened, especially within the primary care setting, and further quality improvement measures may improve adherence to recommended screening protocols. [Ophthalmic Surg Lasers Imaging Retina. 2016;47:930-934.]. Copyright 2016, SLACK Incorporated.

Radial-velocity variations in Alpha Ori, Alpha Sco, and Alpha Her

International Nuclear Information System (INIS)

Smith, M.A.; Patten, B.M.; Goldberg, L.

1989-01-01

Radial-velocity observations of Alpha Ori, Alpha Sco A, and Alpha Her A are used to study radial-velocity periodicities in M supergiants. The data refer to several metallic lines in the H-alpha region and to H-alpha itself. It is shown that Alpha Ori and Alpha Sco A have cycle lengths of about 1 yr and semiamplitudes of 2 km/s. It is suggested that many semiregular red supergiant varibles such as Alpha Ori may be heading toward chaos. All three stars show short-term stochastic flucutations with an amplitude of 1-2 km/s. It is found that the long-term variability of H-alpha velocities may be a consequence of intermittent failed ejections. 58 refs

Resting alpha activity predicts learning ability in alpha neurofeedback

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Wenya eNan

2014-07-01

Full Text Available Individuals differ in their ability to learn how to regulate the alpha activity by neurofeedback. This study aimed to investigate whether the resting alpha activity is related to the learning ability of alpha enhancement in neurofeedback and could be used as a predictor. A total of 25 subjects performed 20 sessions of individualized alpha neurofeedback in order to learn how to enhance activity in the alpha frequency band. The learning ability was assessed by three indices respectively: the training parameter changes between two periods, within a short period and across the whole training time. It was found that the resting alpha amplitude measured before training had significant positive correlations with all learning indices and could be used as a predictor for the learning ability prediction. This finding would help the researchers in not only predicting the training efficacy in individuals but also gaining further insight into the mechanisms of alpha neurofeedback.

Expression of GDNF and GFR alpha 1 in mouse taste bud cells.

Science.gov (United States)

Takeda, Masako; Suzuki, Yuko; Obara, Nobuko; Uchida, Nobuhiko; Kawakoshi, Kentaro

2004-11-01

GDNF (glial cell line-derived neurotrophic factor) affects the survival and maintenance of central and peripheral neurons. Using an immunocytochemical method, we examined whether the taste bud cells in the circumvallate papillae of normal mice expressed GDNF and its GFR alpha 1 receptor. Using double immunostaining for either of them and NCAM, PGP 9.5, or alpha-gustducin, we additionally sought to determine what type of taste bud cells expressed GDNF or GFR alpha 1, because NCAM is reported to be expressed in type-III cells, PGP 9.5, in type-III and some type-II cells, and alpha-gustducin, in some type-II cells. Normal taste bud cells expressed both GDNF and GFR alpha 1. The percentage of GDNF-immunoreactive cells among all taste bud cells was 31.63%, and that of GFR alpha 1-immunoreactive cells, 83.21%. Confocal laser scanning microscopic observations after double immunostaining showed that almost none of the GDNF-immunoreactive cells in the taste buds were reactive with anti-NCAM or anti-PGP 9.5 antibody, but could be stained with anti-alpha-gustducin antibody. On the other hand, almost all anti-PGP 9.5- or anti-alpha-gustducin-immunoreactive cells were positive for GFR alpha 1. Thus, GDNF-immunoreactive cells did not include type-III cells, but type-II cells, which are alpha-gustducin-immunoreactive; on the other hand, GFR alpha 1-immunoreactive cells included type-II and -III cells, and perhaps type-I cells. We conclude that GDNF in the type-II cells may exert trophic actions on type-I, -II, and -III taste bud cells by binding to their GFR alpha 1 receptors.

Transformation of mouse embryo (C3H 10T1/2) cells by alpha particles

International Nuclear Information System (INIS)

Lloyd, E.L.; Gemmell, A.; Henning, C.B.; Gemmell, D.S.; Zabransky, B.J.

1977-01-01

Mammalian cells in culture (C3H mouse 10T1/2 cells) have been shown here for the first time to be transformed by alpha irradiation when cells were irradiated with 5.6 MeV alpha particles from a Tandem Van de Graaff machine. Malignant tumors were induced following inoculation of the transformed cells into syngeneic hosts. Unirradiated control cells injected at the same concentration have, so far, failed to produce tumors. The morphology of the transformed foci was remarkably similar to that obtained by x rays and chemicals but different from virally transformed cells. When the cells were seeded at low density in the exponential growth phase, the transformation frequency per surviving cell increased approximately as the cube of the dose and peaked at an alpha particle fluence between 1.5 and 2.5 x 10 7 alpha particles per cm 2 (205 to 342 rads). The frequency of the transformation was found to be greatly dependent on the number of cells per dish irradiated. Irradiation of larger numbers resulted in much lower frequencies of transformation. The maximum transformation frequency observed in nine separate experiments was 4 percent of the surviving cells. At doses greater than 200 rads the transformation frequency per surviving cell remained constant. The present results permit us to conclude that alpha irradiation may, indeed, be able to exert a direct effect on the genome of the cell to produce malignancy without any external immunological or hormonal influences

Endocrinología en la Javeriana. Recuerdos de una época.

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Alfredo Jácome Roca

2001-08-01

Full Text Available

La Facultad de Medicina de la Universidad Javeriana enseñó clínicas durante sus primeros 25 años de existencia en hospitales tradicionales de Bogotá tales como el San José, la Samaritana y el Instituto de Cancerología. La medicina en adultos era manejada por internistas generales como De Zubiría o Carrizosa o por cardiólogos como Consuegra.

Poca cabida había para especialistas, los que con el tiempo empezaron a llegar del exterior. Cuando el Hospital San José se encargaba de la docencia en Medicina Interna, allí se rotaba por el servicio de endocrinología donde se formó como endocrinólogo el doctor Julio Gómez Afanador, quien ha sido casi que el secretario perpetuo de la Sociedad Colombiana de Endocrinología y quien es coautor de muchos de los estudios de bocio endémico y crecimiento producidos por este servicio; en 1965 él organizó una consulta de endocrinología en el Hospital San Ignacio, que a partir de 1968 empecé a dirigir.

La endocrinología se enseñaba poco, que recuerde; hubo clases de fisiología endocrina por Hernán Mendoza y algunas pocas charlas que sobre el tema nos dio Bernardo Reyes en la Samaritana. Con mi amigo y colega Alvaro Mesa resolvimos indagar en un tema que se había puesto de moda merced a las investigaciones de los inmunólogos ingleses Deborah Doniach y su asociado el doctor Roitt: la autoinmunidad tiroidea.

El Instituto de Cancerología nos pareció el sitio adecuado para trabajar en este proyecto que serviría para nuestra tesis de grado pues convocamos el grupo liderado por Jaime Cortázar, quien contaba con Efraím Otero como su asociado y a Jaime Ahumada como residente. Ellos habían sido pioneros en el manejo de los isótopos radioactivos en Colombia y el hecho de que aplicaran una novedosa e impactante tecnología, la gamagrafía en el diagnóstico tiroideo, les daba una aureola de científicos que sin duda nos atrajo.

Tomando sueros de pacientes de su nutrida

A GH57 4-alpha-glucanotransferase of hyperthermophilic origin with potential for alkyl glycoside production

NARCIS (Netherlands)

Paul, Catherine J.; Leemhuis, Hans; Dobruchowska, Justyna M.; Grey, Carl; Onnby, Linda; van Leeuwen, Sander S.; Dijkhuizen, Lubbert; Karlsson, Eva Nordberg

4-alpha-Glucanotransferase (GTase) enzymes (EC 2.4.1.25) modulate the size of alpha-glucans by cleaving and reforming alpha-1,4 glycosidic bonds in alpha-glucans, an essential process in starch and glycogen metabolism in plants and microorganisms. The glycoside hydrolase family 57 enzyme (GTase57)

A randomized clinical trial of alpha(1)-antitrypsin augmentation therapy.

Science.gov (United States)

Dirksen, A; Dijkman, J H; Madsen, F; Stoel, B; Hutchison, D C; Ulrik, C S; Skovgaard, L T; Kok-Jensen, A; Rudolphus, A; Seersholm, N; Vrooman, H A; Reiber, J H; Hansen, N C; Heckscher, T; Viskum, K; Stolk, J

1999-11-01

We have investigated whether restoration of the balance between neutrophil elastase and its inhibitor, alpha(1)-antitrypsin, can prevent the progression of pulmonary emphysema in patients with alpha(1)-antitrypsin deficiency. Twenty-six Danish and 30 Dutch ex-smokers with alpha(1)-antitrypsin deficiency of PI*ZZ phenotype and moderate emphysema (FEV(1) between 30% and 80% of predicted) participated in a double-blind trial of alpha(1)-antitrypsin augmentation therapy. The patients were randomized to either alpha(1)-antitrypsin (250 mg/kg) or albumin (625 mg/kg) infusions at 4-wk intervals for at least 3 yr. Self-administered spirometry performed every morning and evening at home showed no significant difference in decline of FEV(1) between treatment and placebo. Each year, the degree of emphysema was quantified by the 15th percentile point of the lung density histogram derived from computed tomography (CT). The loss of lung tissue measured by CT (mean +/- SEM) was 2.6 +/- 0.41 g/L/yr for placebo as compared with 1.5 +/- 0.41 g/L/yr for alpha(1)-antitrypsin infusion (p = 0.07). Power analysis showed that this protective effect would be significant in a similar trial with 130 patients. This is in contrast to calculations based on annual decline of FEV(1) showing that 550 patients would be needed to show a 50% reduction of annual decline. We conclude that lung density measurements by CT may facilitate future randomized clinical trials of investigational drugs for a disease in which little progress in therapy has been made in the past 30 yr.

Proceedings of the 16. Brazilian Congress of Endocrinology and Metabology

International Nuclear Information System (INIS)

1984-01-01

Studies in endocrinology and metabolism are presented. The primordial role of the use of radioisotopes in diagnosis, treatment and research is emphasized. Subjects like adrenal, gonads, diabetes, hypothalamus, parathyroid and thyroid are discussed. (M.A.C.) [pt

[Endocrinology, what's new in 2016].

Science.gov (United States)

Mavromati, Maria; Philippe, Jacques

2017-01-11

The European Society of Endocrinology has published this year a series of guidelines for hypoparathyroidism, the management of adrenal incidentalomas as well as for the long-term follow-up of patients operated on for a phaeochromocytoma/paraganglioma (PPGL). For hypoparathyroidism, guidelines insist on screening for chronic complications and monitoring treatment with calcium and vitamin D; the use of recombinant PTH may provide new opportunities for the future. Concerning adrenal incidentalomas, the panel of the guidelines primarily recommends non contrast CT for the evaluation of the risk of malignancy. Patients operated on for a PPGL, should be offered an individualized follow-up plan based on assessment of their risk of tumor recurrence.

Endocrinological analysis of 122 Japanese childhood cancer survivors in a single hospital

International Nuclear Information System (INIS)

Miyoshi, Yoko; Ohta, Hideaki; Hashii, Yoshiko; Tokimasa, Sadao; Namba, Noriyuki; Mushiake, Sotaro; Ozono, Keiichi; Hara, Junichi

2008-01-01

With recent improvements in the diagnosis and treatment of cancer, the number of childhood cancer survivors (CCSs) has been increasing in Japan. The importance of quality of life during the lifetime of CCSs has now been recognized, and the late effects of cancer treatments are essential and important issues. In this study we analyzed the endocrinological abnormalities of CCSs by retrospectively evaluating 122 outpatients (62 males and 60 females) who had been referred from pediatric oncologists to our follow-up clinic among 151 CCSs attending our hospital more than two years after their cancer treatment. Follow-up duration varied from 2 to 30 (median 8.0) years. Their average age was 17.3 (range 4-36, median 17.0) years, and 38 patients (31.1%) reached adulthood. Endocrinological abnormalities were found in 82 (67%) of 122 survivors. Gonadal dysfunction was observed in 60 patients (49%). Thirty-nine patients (32%) were short or grew at a slower rate. Twenty-six patients (21%) showed thyroid dysfunction. Other abnormalities were as follows: obesity in 20 patients (16%), leanness in 10 (8%), central diabetes insipidus in 11 (9%) and adrenocortical dysfunction in 9 (7%). Low bone mineral density was observed in 41 (42%) of 98 patients evaluated. These endocrinological abnormalities were caused by the combined effects of cancer itself and various treatments (chemotherapy, radiation therapy, surgery, and hematopoietic stem cell transplantation). Lifetime medical surveillance and continuous follow-up are necessary for CCSs, because treatment-related complications may occur during childhood and many years after the therapy as well. Endocrinologists should participate in long-term follow-up of these survivors in collaboration with pediatric oncologists. (author)

Endocrinological analysis of 122 Japanese childhood cancer survivors in a single hospital.

Science.gov (United States)

Miyoshi, Yoko; Ohta, Hideaki; Hashii, Yoshiko; Tokimasa, Sadao; Namba, Noriyuki; Mushiake, Sotaro; Hara, Junichi; Ozono, Keiichi

2008-12-01

With recent improvements in the diagnosis and treatment of cancer, the number of childhood cancer survivors (CCSs) has been increasing in Japan. The importance of quality of life during the lifetime of CCSs has now been recognized, and the late effects of cancer treatments are essential and important issues. In this study we analyzed the endocrinological abnormalities of CCSs by retrospectively evaluating 122 outpatients (62 males and 60 females) who had been referred from pediatric oncologists to our follow-up clinic among 151 CCSs attending our hospital more than two years after their cancer treatment. Follow-up duration varied from 2 to 30 (median 8.0) years. Their average age was 17.3 (range 4-36, median 17.0) years, and 38 patients (31.1%) reached adulthood. Endocrinological abnormalities were found in 82 (67%) of 122 survivors. Gonadal dysfunction was observed in 60 patients (49%). Thirty-nine patients (32%) were short or grew at a slower rate. Twenty-six patients (21%) showed thyroid dysfunction. Other abnormalities were as follows: obesity in 20 patients (16%), leanness in 10 (8%), central diabetes insipidus in 11 (9%) and adrenocortical dysfunction in 9 (7%). Low bone mineral density was observed in 41 (42%) of 98 patients evaluated. These endocrinological abnormalities were caused by the combined effects of cancer itself and various treatments (chemotherapy, radiation therapy, surgery, and hematopoietic stem cell transplantation). Lifetime medical surveillance and continuous follow-up are necessary for CCSs, because treatment-related complications may occur during childhood and many years after the therapy as well. Endocrinologists should participate in long-term follow-up of these survivors in collaboration with pediatric oncologists.

Microbial endocrinology: Host-microbiota neuroendocrine interactions influencing brain and behavior.

Science.gov (United States)

Lyte, Mark

2014-01-01

The ability of microorganisms, whether present as commensals within the microbiota or introduced as part of a therapeutic regimen, to influence behavior has been demonstrated by numerous laboratories over the last few years. Our understanding of the mechanisms that are responsible for microbiota-gut-brain interactions is, however, lacking. The complexity of the microbiota is, of course, a contributing factor. Nonetheless, while microbiologists approaching the issue of microbiota-gut-brain interactions in the behavior well recognize such complexity, what is often overlooked is the equal complexity of the host neurophysiological system, especially within the gut which is differentially innervated by the enteric nervous system. As such, in the search for common mechanisms by which the microbiota may influence behavior one may look for mechanisms which are shared by both host and microbiota. Such interkingdom signaling can be found in the shared production of neurochemical mediators that are found in both eukaryotes and prokaryotes. The study of the production and recognition of neurochemicals that are exactly the same in structure to those produced in the vertebrate organisms is known as microbial endocrinology. The examination of the microbiota from the vantage point of host-microbiota neuroendocrine interactions cannot only identify new microbial endocrinology-based mechanisms by which the microbiota can influence host behavior, but also lead to the design of interventions in which the composition of the microbiota may be modulated in order to achieve a specific microbial endocrinology-based profile beneficial to overall host behavior.

Tumour suppression in skin and other tissues via cross-talk between vitamin D- and p53-signalling

Directory of Open Access Journals (Sweden)

Joerg eReichrath

2014-06-01

Full Text Available P53 and its family members have been implicated in the direct regulation of the vitamin D receptor (VDR. Vitamin D- and p53-signaling pathways have a significant impact on spontaneous or carcinogen-induced malignant transformation of cells, with VDR and p53 representing important tumour suppressors. VDR and the p53/p63/p73 proteins all function typically as receptors or sensors that turn into transcriptional regulators upon stimulus, with the main difference being that the nuclear VDR is activated as a transcription factor after binding its naturally occurring ligand 1,25-dihydroxyvitamin D with high affinity while the p53 family of transcription factors, mostly in the nucleoplasm, responds to a large number of alterations in cell homeostasis commonly referred to as stress. An increasing body of evidence now convincingly demonstrates a cross-talk between vitamin D- and p53-signaling that occurs at different levels, has genome-wide implications and that should be of high importance for many malignancies, including non-melanoma skin cancer. One interaction involves the ability of p53 to increase skin pigmentation via POMC derivatives including alpha-MSH and ACTH. Pigmentation protects the skin against UV-induced DNA damage and skin carcinogenesis, yet on the other hand reduces cutaneous synthesis of vitamin D. A second level of interaction may be through the ability of 1,25-dihydroxyvitamin D to increase the survival of skin cells after UV irradiation. UV irradiation-surviving cells show significant reductions in thymine dimers in the presence of 1,25-dihydroxyvitamin D that are associated with increased nuclear p53 protein expression, and significantly reduced NO products. A third level of interaction is documented by the ability of vitamin D compounds to regulate the expression of the murine double minute 2 (MDM2 gene in dependence of the presence of wild-type p53. MDM2 has a well established role as a key negative regulator of p53 activity

Involvement of reversible binding to alpha 2u-globulin in 1,4-dichlorobenzene-induced nephrotoxicity.

Science.gov (United States)

Charbonneau, M; Strasser, J; Lock, E A; Turner, M J; Swenberg, J A

1989-06-01

Similarly to unleaded gasoline, 1,4-dichlorobenzene (1,4-DCB) administered for 2 years caused a dose-related increase in the incidence of renal tumors in male but not in female rats or in either sex of mice. Unleaded gasoline and 2,2,4-trimethylpentane (TMP), a component of unleaded gasoline, increased protein droplet formation and cell proliferation in male but not in female rat kidneys. These protein droplets contained, alpha 2u-globulin, a male rat-specific low-molecular-weight protein and 2,4,4-trimethyl-2-pentanol, a metabolite of TMP that was reversibly bound to this protein. Studies were undertaken to determine if 1,4-DCB produced similar effects; 1,2-DCB was used for comparison since it did not produce renal carcinogenesis in male rats. Gel filtration chromatography of a 116,000g supernatant prepared from kidneys of 1,4-[14C]DCB-treated rats showed that radiolabel coeluted with alpha 2u-globulin as one sharp peak as opposed to a multipeak pattern observed for 1,2-[14C]DCB; the maximal quantity of radiolabel for 1,4-DCB was twice that for 1,2-DCB. Equilibrium dialysis of kidney cytosol in the presence or absence of sodium dodecyl sulfate demonstrated that the radiolabel was reversibly bound to alpha 2u-globulin; the amount for 1,4-[14C]DCB-treated rats was almost twice as much as that for 1,2-[14C]DCB-treated rats. 1,2-DCB was also shown to be covalently bound to renal alpha 2u-globulin, and covalently bound to liver and plasma high-molecular-weight proteins. 1,4-DCB and, to a minor extent, 2,5-dichlorophenol, the major metabolite of 1,4-DCB, were reversibly bound to renal alpha 2u-globulin from 1,4-DCB-treated rats. 1,4-DCB increased protein droplet formation in male but not in female rat kidneys, whereas equimolar doses of 1,2-DCB showed no effect in either sex. Renal cell proliferation, measured by [3H]thymidine incorporation into renal DNA, was increased after 1,4-DCB but not after 1,2-DCB treatment. Nephrotoxicity and biochemical alterations induced by

Effects of vitamin D and its metabolites on cell viability and Staphylococcus aureus invasion in bovine mammary epithelial cells

DEFF Research Database (Denmark)

Yue, Yuan; Hymøller, Lone; Jensen, Søren Krogh

2017-01-01

Vitamin D has been found have various biological effects that may be potent in preventing bovine mastitis. Two forms of vitamin D, vitamin D2 (D2) and vitamin D3 (D3), can be hydroxylated to functional metabolites in cattle. The objectives of the present study were to investigate the effects of D2...... and D3 compounds on bovine mammary epithelial cell proliferation and Staphylococcus aureus (S. aureus) invasion.. Results showed that 1,25-dihydroxyvitamin D2 have an anti-proliferation activity comparable to 1,25-dihydroxyvitamin D3, while D2 and 25-hydroxyvitamin D2 (25(OH)D2) was slightly more potent...

Mandibular atrophy and metabolic bone loss. Endocrinology, radiology and histomorphometry

NARCIS (Netherlands)

Habets, L. L.; Bras, J.; Borgmeyer-Hoelen, A. M.

1988-01-01

In 11 edentulous patients with a severe atrophy of the mandible and submitted for ridge augmentation, endocrinological, radiological and histomorphometrical studies were carried out. The results showed that metabolic bone loss, histologically in nearly all patients characterized as a disturbance in

Vitamin D and cancer

Directory of Open Access Journals (Sweden)

Ali Minu

2007-01-01

Full Text Available 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.

Regulation of the human SLC25A20 expression by peroxisome proliferator-activated receptor alpha in human hepatoblastoma cells

International Nuclear Information System (INIS)

Tachibana, Keisuke; Takeuchi, Kentaro; Inada, Hirohiko; Yamasaki, Daisuke; Ishimoto, Kenji; Tanaka, Toshiya; Hamakubo, Takao; Sakai, Juro; Kodama, Tatsuhiko; Doi, Takefumi

2009-01-01

Solute carrier family 25, member 20 (SLC25A20) is a key molecule that transfers acylcarnitine esters in exchange for free carnitine across the mitochondrial membrane in the mitochondrial β-oxidation. The peroxisome proliferator-activated receptor alpha (PPARα) is a ligand-activated transcription factor that plays an important role in the regulation of β-oxidation. We previously established tetracycline-regulated human cell line that can be induced to express PPARα and found that PPARα induces the SLC25A20 expression. In this study, we analyzed the promoter region of the human slc25a20 gene and showed that PPARα regulates the expression of human SLC25A20 via the peroxisome proliferator responsive element.

Stromal cell-derived factor-1 alpha (SDF-1 alpha) improves neural recovery after spinal cord contusion in rats

NARCIS (Netherlands)

Zendedel, A.; Nobakht, M.; Bakhtiyari, M.; Beyer, C.; Kipp, M.; Baazm, M.; Joghataie, M.T.

2012-01-01

Stromal cell-derived factor-1 alpha (SDF-1α) is an important cytokine, implicated in the control of stem cell trafficking and bone marrow-derived stem cell mobilization. Generally, SDF-1α regulates multiple physiological processes such as embryonic development and organ homeostasis. There is also

Differential vascular alpha1-adrenoceptor antagonism by tamsulosin and terazosin

NARCIS (Netherlands)

Schäfers, R. F.; Fokuhl, B.; Wasmuth, A.; Schumacher, H.; Taguchi, K.; de Mey, C.; Philipp, T.; Michel, M. C.

1999-01-01

AIMS: In patients with lower urinary tract symptoms suggestive of benign prostatic obstruction the alpha1-adrenoceptor antagonist terazosin lowers blood pressure whereas only very small if any alterations were reported with the alpha1-adrenoceptor antagonist tamsulosin. Therefore, we have compared

Important Literature in Endocrinology: Citation Analysis and Historial Methodology.

Science.gov (United States)

Hurt, C. D.

1982-01-01

Results of a study comparing two approaches to the identification of important literature in endocrinology reveals that association between ranking of cited items using the two methods is not statistically significant and use of citation or historical analysis alone will not result in same set of literature. Forty-two sources are appended. (EJS)

1,25(OH)2D3 disrupts glucose metabolism in prostate cancer cells leading to a truncation of the TCA cycle and inhibition of TXNIP expression.

Science.gov (United States)

Abu El Maaty, Mohamed A; Alborzinia, Hamed; Khan, Shehryar J; Büttner, Michael; Wölfl, Stefan

2017-10-01

Prostate cell metabolism exhibits distinct profiles pre- and post-malignancy. The malignant metabolic shift converts prostate cells from "citrate-producing" to "citrate-oxidizing" cells, thereby enhancing glucose metabolism, a phenotype that contrasts classical tumoral Warburg metabolism. An on-line biosensor chip system (BIONAS 2500) was used to monitor metabolic changes (glycolysis and respiration) in response to the putative anti-cancer nutraceutical 1,25-dihydroxyvitamin D 3 [1,25(OH) 2 D 3 ], in different prostate cancer (PCa) cell lines (LNCaP, VCaP, DU145 and PC3). LNCaP cells exhibited profound metabolic responsiveness to the treatment and thus extensive analysis of metabolism-modulating effects of 1,25(OH) 2 D 3 were performed, including mRNA expression analysis of key metabolic genes (e.g. GLUT1 and PDHK1), analysis of TCA cycle metabolites, glucose uptake/consumption measurements, ATP production, and mitochondrial biogenesis/activity. Altogether, data demonstrate a vivid disruption of glucose metabolism by 1,25(OH) 2 D 3 , illustrated by a decreased glucose uptake and an accumulation of citrate/isocitrate due to TCA cycle truncation. Depletion of glycolytic intermediates led to a consistent decrease in TXNIP expression in response to 1,25(OH) 2 D 3 , an effect that coincided with the activation of AMPK signaling and a reduction in c-MYC expression. Reduction in TXNIP levels in response to 1,25(OH) 2 D 3 was rescued by an AMPK signaling inhibitor and mimicked by a MYC inhibitor highlighting the possible involvement of both pathways in mediating 1,25(OH) 2 D 3 's metabolic effects in PCa cells. Furthermore, pharmacological and genetic modulation of the androgen receptor showed similar and disparate effects on metabolic parameters compared to 1,25(OH) 2 D 3 treatment, highlighting the AR-independent nature of 1,25(OH) 2 D 3 's metabolism-modulating effects. Copyright © 2017 Elsevier B.V. All rights reserved.

Differential Recognition of CD1d-[alpha]-Galactosyl Ceramide by the V[beta]8.2 and V[beta]7 Semi-invariant NKT T Cell Receptors

Energy Technology Data Exchange (ETDEWEB)

Pellicci, Daniel G.; Patel, Onisha; Kjer-Nielsen, Lars; Pang, Siew Siew; Sullivan, Lucy C.; Kyparissoudis, Konstantinos; Brooks, Andrew G.; Reid, Hugh H.; Gras, Stephanie; Lucet, Isabelle S.; Koh, Ruide; Smyth, Mark J.; Mallevaey, Thierry; Matsuda, Jennifer L.; Gapin, Laurent; McCluskey, James; Godfrey, Dale I.; Rossjohn, Jamie; PMCI-A; Monash; UCHSC; Melbourne

2009-09-02

The semi-invariant natural killer T cell receptor (NKT TCR) recognizes CD1d-lipid antigens. Although the TCR{alpha} chain is typically invariant, the {beta} chain expression is more diverse, where three V{beta} chains are commonly expressed in mice. We report the structures of V{alpha}14-V{beta}8.2 and V{alpha}14-V{beta}7 NKT TCRs in complex with CD1d-{alpha}-galactosylceramide ({alpha}-GalCer) and the 2.5 {angstrom} structure of the human NKT TCR-CD1d-{alpha}-GalCer complex. Both V{beta}8.2 and V{beta}7 NKT TCRs and the human NKT TCR ligated CD1d-{alpha}-GalCer in a similar manner, highlighting the evolutionarily conserved interaction. However, differences within the V{beta} domains of the V{beta}8.2 and V{beta}7 NKT TCR-CD1d complexes resulted in altered TCR{beta}-CD1d-mediated contacts and modulated recognition mediated by the invariant {alpha} chain. Mutagenesis studies revealed the differing contributions of V{beta}8.2 and V{beta}7 residues within the CDR2{beta} loop in mediating contacts with CD1d. Collectively we provide a structural basis for the differential NKT TCR V{beta} usage in NKT cells.

Endocrinological and Cardiological Late Effects Among Survivors of Childhood Acute Lymphoblastic Leukemia

Directory of Open Access Journals (Sweden)

Hale Ören

2013-09-01

Full Text Available Objective: Survival rates for childhood acute lymphoblastic leukemia (ALL have significantly improved and late effects of therapy have been important in the follow-up of survivors. The objective of this study is to identify the endocrinological and cardiological late effects of ALL patients treated in our pediatric hematology unit. Materials and Methods: Patients treated for ALL with BFM protocols after at least 5 years of diagnosis and not relapsed were included in the study. Endocrinological late effects (growth failure, obesity, insulin resistance, dyslipidemia, thyroid gland disorders, osteopenia/osteoporosis, and pubertal disorders and cardiological late effects were evaluated. The study group was evaluated with anthropometric measurements, body mass index, and laboratory testing of fasting glucose, insulin, serum lipids, thyroid functions, and bone mineral densities. Echocardiography and pulsed wave Doppler imaging were performed for analysis of cardiac functions. Results: Of the 38 ALL survivors, at least 1 adverse event occurred in 23 (60%, with 8 of them (21% having multiple problems. Six (16% of the survivors were obese and 8 (21% of them were overweight. Subjects who were overweight or obese at the time of diagnosis were more likely to be overweight or obese at last follow-up. Obesity was more frequently determined in patients who were younger than 6 years of age at the time of diagnosis. Insulin resistance was observed in 8 (21% subjects. Insulin resistance was more frequently seen in subjects who had family history of type 2 diabetes mellitus. Hyperlipidemia was detected in 8 (21% patients. Hypothyroidism or premature thelarche were detected in 2 children. Two survivors had osteopenia. Cardiovascular abnormalities occurred in one of the subjects with hypertension and cardiac diastolic dysfunction. Conclusion: We point out the necessity of follow-up of these patients for endocrinological and cardiological late effects, since at least

Evaluation of pGL1-TNF-alpha therapy in combination with radiation

Science.gov (United States)

Li, J.; Andres, M. L.; Fodor, I.; Nelson, G. A.; Gridley, D. S.

1998-01-01

Long-term control of high-grade brain tumors is rarely achieved with current therapeutic regimens. In this study a new plasmid-based human tumor necrosis factor-alpha (TNF-alpha) expression vector was synthesized (pGL1-TNF-alpha) and evaluated together with radiation in the aggressive, rapidly growing C6 rat glioma model. pGL1-TNF-alpha was successfully transfected into C6 cells in vitro using a cationic polyamine method. Expression was detected up to 7 days and averaged 0.4 ng of TNF-alpha in the culture medium from 1x10(5) cells. The expressed protein was biologically functional, as evidenced by growth inhibition of L929, a TNF-alpha-susceptible cell line. Using fluorescence-labeled monoclonal antibodies and laser scanning cytometry, we confirmed that both the P55 and P75 receptors for TNF-alpha were present on the C6 cell membrane. However, the receptors were present at low density and P55 was expressed more than the P75 receptor. These findings were in contrast to results obtained with TNF-alpha-susceptible L929 cells. Tests in athymic mice showed that pGL1-TNF-alpha administered intratumorally 16-18 h before radiation (each modality given three times) significantly inhibited C6 tumor progression (Palpha alone did not slow tumor growth and radiation alone had little effect on tumor growth. These results indicate that pGL1-TNF-alpha has potential to augment the antitumor effects of radiation against a tumor type that is virtually incurable.

AlphaScreen-based homogeneous assay using a pair of 25-residue artificial proteins for high-throughput analysis of non-native IgG.

Science.gov (United States)

Senga, Yukako; Imamura, Hiroshi; Miyafusa, Takamitsu; Watanabe, Hideki; Honda, Shinya

2017-09-29

Therapeutic IgG becomes unstable under various stresses in the manufacturing process. The resulting non-native IgG molecules tend to associate with each other and form aggregates. Because such aggregates not only decrease the pharmacological effect but also become a potential risk factor for immunogenicity, rapid analysis of aggregation is required for quality control of therapeutic IgG. In this study, we developed a homogeneous assay using AlphaScreen and AF.2A1. AF.2A1 is a 25-residue artificial protein that binds specifically to non-native IgG generated under chemical and physical stresses. This assay is performed in a short period of time. Our results show that AF.2A1-AlphaScreen may be used to evaluate the various types of IgG, as AF.2A1 recognizes the non-native structure in the constant region (Fc region) of IgG. The assay was effective for detection of non-native IgG, with particle size up to ca. 500 nm, generated under acid, heat, and stirring conditions. In addition, this technique is suitable for analyzing non-native IgG in CHO cell culture supernatant and mixed with large amounts of native IgG. These results indicate the potential of AF.2A1-AlphaScreen to be used as a high-throughput evaluation method for process monitoring as well as quality testing in the manufacturing of therapeutic IgG.

An Evaluation of Mobile Applications for Reproductive Endocrinology and Infertility Providers.

Science.gov (United States)

Shaia, Kathryn L; Farag, Sara; Chyjek, Kathy; Knopman, Jaime; Chen, Katherine T

2017-03-01

To identify and rate reproductive endocrinology and infertility (REI) mobile applications (apps) targeted toward REI providers. A list of REI apps was found in both the Apple iTunes and Google Play stores using the following seven MeSH terms: reproductive endocrinology, REI, infertility, fertility, In Vitro Fertilization, IVF, and embryology. Patient-centered apps were excluded. The remaining apps were then evaluated for accuracy using reliable references. Mobile technology. None. Accurate apps were evaluated for comprehensiveness (the extent of the ability to aid in clinical decision-making) and rated with objective and subjective components using the APPLICATIONS scoring system. Using the seven REI-related MeSH terms, 985 apps and 1,194 apps were identified in the Apple iTunes and Google Play stores, respectively. Of these unique apps, only 20 remained after excluding patient-centered apps. Upon further review for applicability to REI specifically and content accuracy, only seven apps remained. These seven apps were then rated using the APPLICATIONS scoring system. Only 0.32% of 2,179 apps reviewed for this study were useful to REI providers. There is potential for further mobile resource development in the area of REI, given the limited number and varying comprehensiveness and quality of available apps.

Inhibition of HIF-1{alpha} activity by BP-1 ameliorates adjuvant induced arthritis in rats

Energy Technology Data Exchange (ETDEWEB)

Shankar, J. [Department of Microbiology and Immunology, University of Illinois at Chicago, Chicago (United States); Thippegowda, P.B., E-mail: btprabha@uic.edu [Department of Pharmacology, (M/C 868), College of Medicine, University of Illinois at Chicago, 835 S. Wolcott Ave., Chicago, IL 60612 (United States); Kanum, S.A. [Department of Chemistry, Yuvaraj' s College, University of Mysore, Mysore (India)

2009-09-18

Rheumatoid arthritis (RA) is a chronic inflammatory, angiogenic disease. Inflamed synovitis is a hallmark of RA which is hypoxic in nature. Vascular endothelial growth factor (VEGF), one of the key regulators of angiogenesis, is overexpressed in the pathogenesis of RA. VEGF expression is regulated by hypoxia-inducible factor-1{alpha} (HIF-1{alpha}), a master regulator of homeostasis which plays a pivotal role in hypoxia-induced angiogenesis. In this study we show that synthetic benzophenone analogue, 2-benzoyl-phenoxy acetamide (BP-1) can act as a novel anti-arthritic agent in an experimental adjuvant induced arthritis (AIA) rat model by targeting VEGF and HIF-1{alpha}. BP-1 administered hypoxic endothelial cells and arthritic animals clearly showed down regulation of VEGF expression. Further, BP-1 inhibits nuclear translocation of HIF-1{alpha}, which in turn suppresses transcription of the VEGF gene. These results suggest a further possible clinical application of the BP-1 derivative as an anti-arthritic agent in association with conventional chemotherapeutic agents.

Saw palmetto extracts potently and noncompetitively inhibit human alpha1-adrenoceptors in vitro.

Science.gov (United States)

Goepel, M; Hecker, U; Krege, S; Rübben, H; Michel, M C

1999-02-15

We wanted to test whether phytotherapeutic agents used in the treatment of lower urinary tract symptoms have alpha1-adrenoceptor antagonistic properties in vitro. Preparations of beta-sitosterol and extracts of stinging nettle, medicinal pumpkin, and saw palmetto were obtained from several pharmaceutical companies. They were tested for their ability to inhibit [3H]tamsulosin binding to human prostatic alpha1-adrenoceptors and [3H]prazosin binding to cloned human alpha1A- and alpha1B-adrenoceptors. Inhibition of phenylephrine-stimulated [3H]inositol phosphate formation by cloned receptors was also investigated. Up to the highest concentration which could be tested, preparations of beta-sitosterol, stinging nettle, and medicinal pumpkin were without consistent inhibitory effect in all assays. In contrast, all tested saw palmetto extracts inhibited radioligand binding to human alpha1-adrenoceptors and agonist-induced [3H]inositol phosphate formation. Saturation binding experiments in the presence of a single saw palmetto extract concentration indicated a noncompetitive antagonism. The relationship between active concentrations in vitro and recommended therapeutic doses for the saw palmetto extracts was slightly lower than that for several chemically defined alpha1-adrenoceptor antagonists. Saw palmetto extracts have alpha1-adrenoceptor-inhibitory properties. If bioavailability and other pharmacokinetic properties of these ingredients are similar to those of the chemically defined alpha1-adrenoceptor antagonists, alpha1-adrenoceptor antagonism might be involved in the therapeutic effects of these extracts in patients with lower urinary tract symptoms suggestive of benign prostatic obstruction.

Involvement of 1,25D{sub 3}-MARRS (membrane associated, rapid response steroid-binding), a novel vitamin D receptor, in growth inhibition of breast cancer cells

Energy Technology Data Exchange (ETDEWEB)

Richard, Cynthia L. [Department of Human Health and Nutritional Sciences, University of Guelph, Guelph, Ontario, Canada N1G2W1 (Canada); Farach-Carson, Mary C.; Rohe, Ben [Department of Biological Sciences, University of Delaware, Newark, DE 19716 (United States); Nemere, Ilka [Department of Nutrition and Food Sciences, Center for Integrated BioSystems, Utah State University, Logan, UT 84322 8700 (United States); Meckling, Kelly A., E-mail: kmecklin@uoguelph.ca [Department of Human Health and Nutritional Sciences, University of Guelph, Guelph, Ontario, Canada N1G2W1 (Canada)

2010-03-10

In addition to classical roles in calcium homeostasis and bone development, 1,25 dihydroxyvitamin D{sub 3} [1,25(OH){sub 2}D{sub 3}] inhibits the growth of several cancer types, including breast cancer. Although cellular effects of 1,25(OH){sub 2}D{sub 3} traditionally have been attributed to activation of a nuclear vitamin D receptor (VDR), a novel receptor for 1,25(OH){sub 2}D{sub 3} called 1,25D{sub 3}-MARRS (membrane-associated, rapid response steroid-binding) protein was identified recently. The purpose of this study was to determine if the level of 1,25D{sub 3}-MARRS expression modulates 1,25(OH){sub 2}D{sub 3} activity in breast cancer cells. Relative levels of 1,25D{sub 3}-MARRS protein in MCF-7, MDA MB 231, and MCF-10A cells were estimated by real-time RT-PCR and Western blotting. To determine if 1,25D{sub 3}-MARRS receptor was involved in the growth inhibitory effects of 1,25(OH){sub 2}D{sub 3} in MCF-7 cells, a ribozyme construct designed to knock down 1,25D{sub 3}-MARRS mRNA was stably transfected into MCF-7 cells. MCF-7 clones in which 1,25D{sub 3}-MARRS receptor expression was reduced showed increased sensitivity to 1,25(OH){sub 2}D{sub 3} ( IC{sub 50} 56 {+-} 24 nM) compared to controls (319 {+-} 181 nM; P < 0.05). Reduction in 1,25D{sub 3}-MARRS receptor lengthened the doubling time in transfectants treated with 1,25(OH){sub 2}D{sub 3}. Knockdown of 1,25D{sub 3}-MARRS receptor also increased the sensitivity of MCF-7 cells to the vitamin D analogs KH1060 and MC903, but not to unrelated agents (all-trans retinoic acid, paclitaxel, serum/glucose starvation, or the isoflavone, pomiferin). These results suggest that 1,25D{sub 3}-MARRS receptor expression interferes with the growth inhibitory activity of 1,25(OH){sub 2}D{sub 3} in breast cancer cells, possibly through the nuclear VDR. Further research should examine the potential for pharmacological or natural agents that modify 1,25D{sub 3}-MARRS expression or activity as anticancer agents.

Brown-Sèquard, otro Precursor de la Endocrinología.

Directory of Open Access Journals (Sweden)

Alfredo Jácome Roca Rodriguez

2008-03-01

Admitimos que cada tejido y –más generalmente- cada célula del organismo, segregue por su propia cuenta productos o fermentos especiales que –derramados en la sangre- influyen por mediación de este líquido en todas las otras células, las cuales llegan a ser de este modo solidarias entre sí por un mecanismo diferente al del sistema nervioso… Como era frecuente que a aquellas glándulas sin conducto se les considerara un papel neutralizador de toxinas, propone su utilidad para el organismo, bien por este efecto antitóxico o por una influencia directa favorable. De cualquier manera, este sorpresivo pregón anunció el nacimiento de la endocrinología. Que -a juzgar por los avisos que hemos encontrado en el primer número de los Anales Franceses de Endocrinología en 1939- se interesaba mucho en las hormonas sexuales, las que en aquella época campeaban en la opoterapia.

Isolation of a new anti-inflammatory 20, 21, 22, 23, 24, 25, 26, 27-octanorcucurbitacin-type triterpene from Ibervillea sonorae.

Science.gov (United States)

Jardón-Delgado, Angel; Magos-Guerrero, Gil Alfonso; Martínez-Vázquez, Mariano

2014-01-01

A new cucurbitane-type triterpene, 20, 21, 22, 23, 24, 25, 26, 27-octanorcucurbita-5-ene-3, 11, 16-trione (1), named kinoin D, was isolated from the roots of the medicinal plant Ibervillea sonorae, (wereque). The structure of 1 was established on the basis of extensive NMR and MS studies. In addition, the known kinoins B (3) and C (5) were isolated, as were 16alpha-20,25-trihydroxy-3alpha-(2-O-alpha-L-rhamnopyranosiyl-D-glucopyranosyloxy)-(10alpha)-cucurbit-5-en-11,22-dione (6), (22S)-16alpha,22-diacetoxy-20,25-dihydroxy-3alpha-[3,4,6-tri-O-acetyl-2-O-(2,3,4-tri-O-acetyl-alpha-L-rhamnopyranosyl)-beta-glucopyranosyl]-(10alpha)-cucurbita-5,23t-dien-11-one (7) and 16alpha-acetoxy-20,25-dihydroxy-3alpha-[3,4,6-tri-O-acetyl-2-O-(2,3,4,-tri-O-acetyl-alpha-L-rhamnopyranosyl)-beta-D-glucopyranosyl]-(10alpha)-cucurbita-5-ene-11,22-dione (8). Compound 1 exhibited anti-inflammatory activity in TPA-induced edema in mice.

Production of interleukin-1alpha by human endometrial stromal cells is triggered during menses and dysfunctional bleeding and is induced in culture by epithelial interleukin-1alpha released upon ovarian steroids withdrawal.

Science.gov (United States)

Pretto, Chrystel M; Gaide Chevronnay, Héloïse P; Cornet, Patricia B; Galant, Christine; Delvaux, Denis; Courtoy, Pierre J; Marbaix, Etienne; Henriet, Patrick

2008-10-01

Endometrial breakdown during menstruation and dysfunctional bleeding is triggered by the abrupt expression of matrix metalloproteinases (MMPs), including interstitial collagenase (MMP-1). The paracrine induction of MMP-1 in stromal cells via epithelium-derived IL-1alpha is repressed by ovarian steroids. However, the control by estradiol (E) and progesterone (P) of endometrial IL-1alpha expression and bioactivity remains unknown. Variations of endometrial IL-1alpha mRNA and protein along the menstrual cycle and during dysfunctional bleeding were determined using RT-PCR, in situ hybridization, and immunolabeling. The mechanism of EP control was analyzed using culture of explants, laser capture microdissection, and purified cells. Data were compared with expression changes of IL-1beta and IL-1 receptor antagonist. IL-1alpha is synthesized by epithelial cells throughout the cycle but E and/or P prevents its release. In contrast, endometrial stromal cells produce IL-1alpha only at menses and during irregular bleeding in areas of tissue breakdown. Stromal expression of IL-1alpha, like that of MMP-1, is repressed by P (alone or with E) but triggered by epithelium-derived IL-1alpha released upon EP withdrawal. Our experiments in cultured endometrium suggest that IL-1alpha released by epithelial cells triggers the production of IL-1alpha by stromal cells in a paracrine amplification loop to induce MMP-1 expression during menstruation and dysfunctional bleeding. All three steps of this amplification cascade are repressed by EP.

Early studies reported extreme findings with large variability: a meta-epidemiologic study in the field of endocrinology.

Science.gov (United States)

Wang, Zhen; Alahdab, Fares; Almasri, Jehad; Haydour, Qusay; Mohammed, Khaled; Abu Dabrh, Abd Moain; Prokop, Larry J; Alfarkh, Wedad; Lakis, Sumaya; Montori, Victor M; Murad, Mohammad Hassan

2016-04-01

To evaluate the presence of extreme findings and fluctuation in effect size in endocrinology. We systematically identified all meta-analyses published in 2014 in the field of endocrinology. Within each meta-analysis, the effect size of the primary binary outcome was compared across studies according to their order of publication. We pooled studies using the DerSimonian and Laird random-effects method. Heterogeneity was evaluated using the I(2) and tau(2). Twelve percent of the included 100 meta-analyses reported the largest effect size in the very first published study. The largest effect size occurred in the first 2 earliest studies in 31% of meta-analyses. When the effect size was the largest in the first published study, it was three times larger than the final pooled effect (ratio of rates, 3.26; 95% confidence interval: 1.80, 5.90). The largest heterogeneity measured by I(2) was observed in 18% of the included meta-analyses when combining the first 2 studies or 17% when combing the first 3 studies. In endocrinology, early studies reported extreme findings with large variability. This behavior of the evidence needs to be taken into account when used to formulate clinical policies. Copyright © 2016 Elsevier Inc. All rights reserved.

In-vitro investigations of the speed of pyrrole formation of 2,5-hexanedione and 2,5-heptanedione with N{alpha}-acetyl-L-lysine as a precondition for a comparative assessment of the neurotoxic potentials of the two {gamma}-diketones; In-vitro-Untersuchungen zur Pyrrolbildungsgeschwindigkeit von 2,5-Hexandion und 2,5-Heptandion mit N{alpha}-Acetyl-L-lysin als Voraussetzung fuer eine vergleichende Abschaetzung der neurotoxischen Potentiale beider {gamma}-Diketone

Energy Technology Data Exchange (ETDEWEB)

Richter, M.F.

1997-09-01

N-hexane and n-heptane are important solvents. Chronic exposure to n-hexane causes polyneuropathies, which are attributed to the metabolite 2,5-hexanedione, a {gamma} diketone. As a basis for a comparative assessment of the neurotoxic potentials of 2,5-hexanedione and 2,5-heptanedione, an in-vitro test was developed and used to investigate the speed of pyrrole formation of the two {gamma} diketones in reacting with the {epsilon} amino group of N{alpha}-acetyl L-lysine. The speed of the formation of pyrrole was always directly proportional to the respective reactant concentration. It consequently is subject to a second-order kinetics. As a further result, the pyrrole formation speed of 2,5-heptanedione was found to be only half that of 2,5-hexanedione. The results lead to the conclusion that 2,5-heptanedione poses a smaller risk of developing peripheral neuropathy than 2,5-hexanedione. (orig./MG) [Deutsch] n-Hexan und n-Heptan sind wichtige Loesungsmittel. Chronische Exposition gegenueber n-Hexan ruft Polyneuropathien hervor, die auf den Metaboliten 2,5-Hexandion, ein {gamma}-Diketon, zurueckgefuehrt werden. Als Grundlage fuer eine vergleichende Abschaetzung der neurotoxischen Potentiale von 2,5-Hexandion und 2,5-Heptandion wurde in der vorliegenden Arbeit ein In-vitro-Test entwickelt, mit dem die Pyrrolbildungsgeschwindigkeiten der beiden {gamma}-Diketone mit der {epsilon}-Aminogruppe von N{alpha}-Acetyl-L-Iysin untersucht wurden. Die Pyrrolbildungsgeschwindigkeit war stets direkt proportional zur jeweiligen Reaktantenkonzentration. Somit unterliegt sie einer Kinetik 2. Ordnung. Weiterhin wurde gezeigt, dass die Pyrrolbildungsgeschwindigkeit fuer 2,5-Heptandion nur etwa halb so gross ist wie fuer 2,5-Hexandion. Aus den Ergebnissen wird gefolgert, dass das von 2,5-Heptandion ausgehende Risiko an peripheren Neuropathien zu erkranken geringer ist, als das von 2,5-Hexandion ausgehende. (orig./MG)

Physiology and Endocrinology Symposium. Factors controlling puberty in beef heifers

Science.gov (United States)

The Physiology and Endocrinology Symposium on “Factors controlling puberty in beef heifers” was held at the joint annual meeting of the American Dairy Science Association and the American Society of Animal Science in New Orleans, Louisiana, USA, July 10 to 14, 2011. The objective of the symposium w...

Deficiency Mutations of Alpha-1 Antitrypsin. Effects on Folding, Function, and Polymerization.

Science.gov (United States)

Haq, Imran; Irving, James A; Saleh, Aarash D; Dron, Louis; Regan-Mochrie, Gemma L; Motamedi-Shad, Neda; Hurst, John R; Gooptu, Bibek; Lomas, David A

2016-01-01

Misfolding, polymerization, and defective secretion of functional alpha-1 antitrypsin underlies the predisposition to severe liver and lung disease in alpha-1 antitrypsin deficiency. We have identified a novel (Ala336Pro, Baghdad) deficiency variant and characterized it relative to the wild-type (M) and Glu342Lys (Z) alleles. The index case is a homozygous individual of consanguineous parentage, with levels of circulating alpha-1 antitrypsin in the moderate deficiency range, but is a biochemical phenotype that could not be classified by standard methods. The majority of the protein was present as functionally inactive polymer, and the remaining monomer was 37% active relative to the wild-type protein. These factors combined indicate an 85 to 95% functional deficiency, similar to that seen with ZZ homozygotes. Biochemical, biophysical, and computational studies further defined the molecular basis of this deficiency. These studies demonstrated that native Ala336Pro alpha-1 antitrypsin could populate the polymerogenic intermediate-and therefore polymerize-more readily than either wild-type alpha-1 antitrypsin or the Z variant. In contrast, folding was far less impaired in Ala336Pro alpha-1 antitrypsin than in the Z variant. The data are consistent with a disparate contribution by the "breach" region and "shutter" region of strand 5A to folding and polymerization mechanisms. Moreover, the findings demonstrate that, in these variants, folding efficiency does not correlate directly with the tendency to polymerize in vitro or in vivo. They therefore differentiate generalized misfolding from polymerization tendencies in missense variants of alpha-1 antitrypsin. Clinically, they further support the need to quantify loss-of-function in alpha-1 antitrypsin deficiency to individualize patient care.

Alpha-amylase inhibitor-1 gene from Phaseolus vulgaris expressed in Coffea arabica plants inhibits alpha-amylases from the coffee berry borer pest.

Science.gov (United States)

Barbosa, Aulus E A D; Albuquerque, Erika V S; Silva, Maria C M; Souza, Djair S L; Oliveira-Neto, Osmundo B; Valencia, Arnubio; Rocha, Thales L; Grossi-de-Sa, Maria F

2010-06-17

Coffee is an important crop and is crucial to the economy of many developing countries, generating around US$70 billion per year. There are 115 species in the Coffea genus, but only two, C. arabica and C. canephora, are commercially cultivated. Coffee plants are attacked by many pathogens and insect-pests, which affect not only the production of coffee but also its grain quality, reducing the commercial value of the product. The main insect-pest, the coffee berry borer (Hypotheneumus hampei), is responsible for worldwide annual losses of around US$500 million. The coffee berry borer exclusively damages the coffee berries, and it is mainly controlled by organochlorine insecticides that are both toxic and carcinogenic. Unfortunately, natural resistance in the genus Coffea to H. hampei has not been documented. To overcome these problems, biotechnological strategies can be used to introduce an alpha-amylase inhibitor gene (alpha-AI1), which confers resistance against the coffee berry borer insect-pest, into C. arabica plants. We transformed C. arabica with the alpha-amylase inhibitor-1 gene (alpha-AI1) from the common bean, Phaseolus vulgaris, under control of the seed-specific phytohemagglutinin promoter (PHA-L). The presence of the alpha-AI1 gene in six regenerated transgenic T1 coffee plants was identified by PCR and Southern blotting. Immunoblotting and ELISA experiments using antibodies against alpha-AI1 inhibitor showed a maximum alpha-AI1 concentration of 0.29% in crude seed extracts. Inhibitory in vitro assays of the alpha-AI1 protein against H. hampei alpha-amylases in transgenic seed extracts showed up to 88% inhibition of enzyme activity. This is the first report showing the production of transgenic coffee plants with the biotechnological potential to control the coffee berry borer, the most important insect-pest of crop coffee.

PGC-1alpha mediates exercise-induced skeletal muscle VEGF expression in mice

DEFF Research Database (Denmark)

Leick, Lotte; Hellsten, Ylva; Fentz, Joachim

2009-01-01

The aim of the present study was to test the hypothesis that PGC-1alpha is required for exercise-induced VEGF expression in both young and old mice and that AMPK activation leads to increased VEGF expression through a PGC-1alpha-dependent mechanism. Whole body PGC-1alpha knockout (KO......) and littermate wild-type (WT) mice were submitted to either 1) 5 wk of exercise training, 2) lifelong (from 2 to 13 mo of age) exercise training in activity wheel, 3) a single exercise bout, or 4) 4 wk of daily subcutaneous AICAR or saline injections. In skeletal muscle of PGC-1alpha KO mice, VEGF protein...... expression was approximately 60-80% lower and the capillary-to-fiber ratio approximately 20% lower than in WT. Basal VEGF mRNA expression was similar in WT and PGC-1alpha KO mice, but acute exercise and AICAR treatment increased the VEGF mRNA content in WT mice only. Exercise training of young mice increased...

Development of an e-learning portal for pediatric endocrinology : Educational considerations

NARCIS (Netherlands)

K. Grijpink-Van den Biggelaar; S.L.S. Drop (Stenvert); L. Schuwirth

2010-01-01

textabstractBackground: Global accessibility and dissemination of developments in pediatric endocrinology prompted to examine how to develop an educational interactive e-SPE web portal. Methods: A systematic approach was used to identify the relevant aspects of accessibility and dissemination. An

Association of alpha-1 antitrypsin level and lung function in patients with chronic obstructive pulmonary disease

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Serapinas Danielius

2017-01-01

Full Text Available Introduction/Objective. Alpha-1 antitrypsin deficiency is a well established inherited risk factor for chronic obstructive pulmonary disease (COPD; however, alpha-1 antitrypsin level may result in different lung function reduction. The aim of our study was to evaluate possible associations of alpha-1 antitrypsin level and lung function in COPD patients with different alpha-1 antitrypsin phenotypes. Methods. Serum alpha-1 antitrypsin concentration from patients (n = 1,167 with COPD, defined according to the GOLD criteria, were analyzed by nephelometry, and alpha-1 antitrypsin phenotype was determined by means of isoelectric-focusing. Results. In COPD patients without alpha-1 antitrypsin deficiency (MM, a significant negative association of lung function (FEV1 with serum alpha-1 antitrypsin (r = -0.511; p < 0.05 and C-reactive protein (CRP concentrations (r = -0.583; p < 0.05 was detected; moreover, the level of alpha-1 antitrypsin positively correlated with CRP concentration (r = 0.667; p < 0.05. Conclusions. In patients without alpha-1 antitrypsin deficiency, detected negative association of alpha-1 antitrypsin level with FEV1 and positive association with the CRP level defined the importance of alpha-1 antitrypsin for lung function in COPD patients.

Rational design, synthesis, biologic evaluation, and structure-activity relationship studies of novel 1-indanone alpha(1)-adrenoceptor antagonists.

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Li, Minyong; Xia, Lin

2007-11-01

In the present report, a novel series of 1-indanone alpha(1)-adrenoceptor antagonists were designed and synthesized based on 3D-pharmacophore model. Their in vitro alpha(1)-adrenoceptor antagonistic assay showed that three compounds (2a, 2m, and 2o) had similar or improved alpha(1)-adrenoceptor antagonistic activities relative to the positive control prazosin. Based on these results, a three-dimensional quantitative structure-activity relationship study was performed using a Self-Organizing Molecular Field Analysis method to provide insight for the future development of alpha(1)-adrenoceptor antagonists.

Hypoxia-inducible factor-1 alpha has a key role in hypoxic preconditioning.

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Taie, Satoshi; Ono, Junichiro; Iwanaga, Yasuyuki; Tomita, Shuhei; Asaga, Takehiko; Chujo, Kosuke; Ueki, Masaaki

2009-08-01

Sublethal hypoxia induces tolerance to subsequent hypoxic insults in a process known as hypoxic preconditioning (HP). Hypoxia-inducible factor-1 alpha (HIF-1 alpha) is a key transcription protein involved in the mechanism of HP. In this study, we investigated the effects of HP on tissue oxygenation and expression of HIF-1 alpha gene targets in the brain using neural cell-specific HIF-1 alpha-deficient mice. The animals were exposed to 8% oxygen for 3 hours. Twenty-four hours later, the oxygen partial pressure (pO(2)) of brain tissue and gene expression were measured during hypoxia. HP improved the pO(2) of brain tissue during subsequent hypoxia with upregulated inducible nitric oxide synthase in wild-type mice, whereas HP had no detectable effect in the mutant mice. Our results indicate that the protective effects of HP may be partially mediated by improving tissue oxygenation via HIF-1 alpha and inducible nitric oxide synthase.

Alpha-defensins 1-3 release by dendritic cells is reduced by estrogen

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Sperling Rhoda

2011-08-01

Full Text Available Abstract Background During pregnancy the immune system of the mother must protect any activation that may negatively affect the fetus. Changes in susceptibility to infection as well as resolution of some autoimmune disorders represent empirical evidence for pregnancy related alterations in immunity. Sex hormones reach extremely high levels during pregnancy and have been shown to have direct effects on many immune functions including the antiviral response of dendritic cells. Among the immunologically active proteins secreted by monocyte derived DCs (MDDC are the alpha-defensins 1-3. This family of cationic antimicrobial peptides has a broad spectrum of microbicidal activity and has also been shown to link innate to adaptive immunity by attracting T cells and immature DCs, which are essential for initiating and polarizing the immune response. Methods We compare culture-generated monocyte derived DCs (MDDCs with directly isolated myeloid dendritic cells (mDCs and plasmacytoid dendritic cells (pDCs and measure their alpha-defensins 1-3 secretion by ELISA both, in basal situations and after hormone (E2 or PG treatments. Moreover, using a cohort of pregnant women we isolated mDCs from blood and also measure the levels of these anti-microbial peptides along pregnancy. Results We show that mDCs and pDCs constitutively produce alpha-defensins 1-3 and at much higher levels than MDDCs. Alpha-defensins 1-3 production from mDCs and MDDCs but not pDCs is inhibited by E2. PG does not affect alpha-defensins 1-3 in any of the populations. Moreover, alpha-defensins 1-3 production by mDCs was reduced in the later stages of pregnancy in 40% of the patients. Conclusions Here, we demonstrate that mDCs and pDCs secrete alpha-defensins 1-3 and present a novel effect of E2 on the secretion of alpha-defensins 1-3 by dendritic cells.

Endocrinology in the 21st century: unmasking the mysteries of biology

NARCIS (Netherlands)

Romijn, J. A.

1999-01-01

The traditional concept of endocrinology has provided a model, that enabled to understand and treat endocrine diseases. Molecular and (patho)physiological differentiations of this concept will further improve the treatment of complex endocrine and metabolic diseases. Nature has lifted a tip of her

Identification and characterization of an alternative promoter of the human PGC-1{alpha} gene

Energy Technology Data Exchange (ETDEWEB)

Yoshioka, Toyo; Inagaki, Kenjiro [Division of Diabetes, Metabolism, and Endocrinology, Department of Internal Medicine, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe 650-0017 (Japan); Noguchi, Tetsuya, E-mail: noguchi@med.kobe-u.ac.jp [Division of Diabetes, Metabolism, and Endocrinology, Department of Internal Medicine, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe 650-0017 (Japan); Sakai, Mashito; Ogawa, Wataru; Hosooka, Tetsuya [Division of Diabetes, Metabolism, and Endocrinology, Department of Internal Medicine, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe 650-0017 (Japan); Iguchi, Haruhisa; Watanabe, Eijiro; Matsuki, Yasushi; Hiramatsu, Ryuji [Genomic Science Laboratories, DainipponSumitomo Pharma Co. Ltd., 4-2-1 Takatsukasa, Takarazuka 665-8555 (Japan); Kasuga, Masato [Division of Diabetes, Metabolism, and Endocrinology, Department of Internal Medicine, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe 650-0017 (Japan); Research Institute, International Medical Center of Japan, 1-21-1 Toyama, Shinjuku-ku, Tokyo 162-8655 (Japan)

2009-04-17

The transcriptional regulator peroxisome proliferator-activated receptor-{gamma} coactivator-1{alpha} (PGC-1{alpha}) controls mitochondrial biogenesis and energy homeostasis. Although physical exercise induces PGC-1{alpha} expression in muscle, the underlying mechanism of this effect has remained incompletely understood. We recently identified a novel muscle-enriched isoform of PGC-1{alpha} transcript (designated PGC-1{alpha}-b) that is derived from a previously unidentified first exon. We have now cloned and characterized the human PGC-1{alpha}-b promoter. The muscle-specific transcription factors MyoD and MRF4 transactivated this promoter through interaction with a proximal E-box motif. Furthermore, either forced expression of Ca{sup 2+}- and calmodulin-dependent protein kinase IV (CaMKIV), calcineurin A, or the p38 mitogen-activated protein kinase (p38 MAPK) kinase MKK6 or the intracellular accumulation of cAMP activated the PGC-1{alpha}-b promoter in cultured myoblasts through recruitment of cAMP response element (CRE)-binding protein (CREB) to a putative CRE located downstream of the E-box. Our results thus reveal a potential molecular basis for isoform-specific regulation of PGC-1{alpha} expression in contracting muscle.

Treatment of lung disease in alpha-1 antitrypsin deficiency: a systematic review

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Edgar RG

2017-05-01

Full Text Available Ross G Edgar,1,2 Mitesh Patel,3 Susan Bayliss,4 Diana Crossley,2,5 Elizabeth Sapey,2,5 Alice M Turner4,6 1Therapy Services, University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK; 2Institute of Inflammation and Ageing, University of Birmingham, Birmingham, UK; 3Division of Primary Care, University of Nottingham, Nottingham, UK; 4Institute of Applied Health Research, University of Birmingham, Birmingham, UK; 5Department of Respiratory Medicine, University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK; 6Department of Respiratory Medicine, Heart of England NHS Foundation Trust, Birmingham, UK Background: Alpha-1 antitrypsin deficiency (AATD is a rare genetic condition predisposing individuals to chronic obstructive pulmonary disease (COPD. The treatment is generally extrapolated from COPD unrelated to AATD; however, most COPD trials exclude AATD patients; thus, this study sought to systematically review AATD-specific literature to assist evidence-based patient management.Methods: Standard review methodology was used with meta-analysis and narrative synthesis (PROSPERO-CRD42015019354. Eligible studies were those of any treatment used in severe AATD. Randomized controlled trials (RCTs were the primary focus; however, case series and uncontrolled studies were eligible. All studies had ≥10 participants receiving treatment or usual care, with baseline and follow-up data (>3 months. Risk of bias was assessed appropriately according to study methodology.Results: In all, 7,296 studies were retrieved from searches; 52 trials with 5,632 participants met the inclusion criteria, of which 26 studies involved alpha-1 antitrypsin augmentation and 17 concerned surgical treatments (largely transplantation. Studies were grouped into four management themes: COPD medical, COPD surgical, AATD specific, and other treatments. Computed tomography (CT density, forced expiratory volume in 1 s, diffusing capacity of the lungs for carbon monoxide

Calcineurin signaling and PGC-1alpha expression are suppressed during muscle atrophy due to diabetes.

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Roberts-Wilson, Tiffany K; Reddy, Ramesh N; Bailey, James L; Zheng, Bin; Ordas, Ronald; Gooch, Jennifer L; Price, S Russ

2010-08-01

PGC-1alpha is a transcriptional coactivator that controls energy homeostasis through regulation of glucose and oxidative metabolism. Both PGC-1alpha expression and oxidative capacity are decreased in skeletal muscle of patients and animals undergoing atrophy, suggesting that PGC-1alpha participates in the regulation of muscle mass. PGC-1alpha gene expression is controlled by calcium- and cAMP-sensitive pathways. However, the mechanism regulating PGC-1alpha in skeletal muscle during atrophy remains unclear. Therefore, we examined the mechanism responsible for decreased PGC-1alpha expression using a rodent streptozotocin (STZ) model of chronic diabetes and atrophy. After 21days, the levels of PGC-1alpha protein and mRNA were decreased. We examined the activation state of CREB, a potent activator of PGC-1alpha transcription, and found that phospho-CREB was paradoxically high in muscle of STZ-rats, suggesting that the cAMP pathway was not involved in PGC-1alpha regulation. In contrast, expression of calcineurin (Cn), a calcium-dependent phosphatase, was suppressed in the same muscles. PGC-1alpha expression is regulated by two Cn substrates, MEF2 and NFATc. Therefore, we examined MEF2 and NFATc activity in muscles from STZ-rats. Target genes MRF4 and MCIP1.4 mRNAs were both significantly reduced, consistent with reduced Cn signaling. Moreover, levels of MRF4, MCIP1.4, and PGC-1alpha were also decreased in muscles of CnAalpha-/- and CnAbeta-/- mice without diabetes indicating that decreased Cn signaling, rather than changes in other calcium- or cAMP-sensitive pathways, were responsible for decreased PGC-1alpha expression. These findings demonstrate that Cn activity is a major determinant of PGC-1alpha expression in skeletal muscle during diabetes and possibly other conditions associated with loss of muscle mass.

Sunlight and Vitamin D

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Wacker, Matthias; Holick, Michael F.

2013-01-01

Vitamin D is the sunshine vitamin that has been produced on this earth for more than 500 million years. During exposure to sunlight 7-dehydrocholesterol in the skin absorbs UV B radiation and is converted to previtamin D3 which in turn isomerizes into vitamin D3. Previtamin D3 and vitamin D3 also absorb UV B radiation and are converted into a variety of photoproducts some of which have unique biologic properties. Sun induced vitamin D synthesis is greatly influenced by season, time of day, latitude, altitude, air pollution, skin pigmentation, sunscreen use, passing through glass and plastic, and aging. Vitamin D is metabolized sequentially in the liver and kidneys into 25-hydroxyvitamin D which is a major circulating form and 1,25-dihydroxyvitamin D which is the biologically active form respectively. 1,25-dihydroxyvitamin D plays an important role in regulating calcium and phosphate metabolism for maintenance of metabolic functions and for skeletal health. Most cells and organs in the body have a vitamin D receptor and many cells and organs are able to produce 1,25-dihydroxyvitamin D. As a result 1,25-dihydroxyvitamin D influences a large number of biologic pathways which may help explain association studies relating vitamin D deficiency and living at higher latitudes with increased risk for many chronic diseases including autoimmune diseases, some cancers, cardiovascular disease, infectious disease, schizophrenia and type 2 diabetes. A three-part strategy of increasing food fortification programs with vitamin D, sensible sun exposure recommendations and encouraging ingestion of a vitamin D supplement when needed should be implemented to prevent global vitamin D deficiency and its negative health consequences. PMID:24494042

Sunlight and Vitamin D: A global perspective for health.

Science.gov (United States)

Wacker, Matthias; Holick, Michael F

2013-01-01

Vitamin D is the sunshine vitamin that has been produced on this earth for more than 500 million years. During exposure to sunlight 7-dehydrocholesterol in the skin absorbs UV B radiation and is converted to previtamin D3 which in turn isomerizes into vitamin D3. Previtamin D3 and vitamin D3 also absorb UV B radiation and are converted into a variety of photoproducts some of which have unique biologic properties. Sun induced vitamin D synthesis is greatly influenced by season, time of day, latitude, altitude, air pollution, skin pigmentation, sunscreen use, passing through glass and plastic, and aging. Vitamin D is metabolized sequentially in the liver and kidneys into 25-hydroxyvitamin D which is a major circulating form and 1,25-dihydroxyvitamin D which is the biologically active form respectively. 1,25-dihydroxyvitamin D plays an important role in regulating calcium and phosphate metabolism for maintenance of metabolic functions and for skeletal health. Most cells and organs in the body have a vitamin D receptor and many cells and organs are able to produce 1,25-dihydroxyvitamin D. As a result 1,25-dihydroxyvitamin D influences a large number of biologic pathways which may help explain association studies relating vitamin D deficiency and living at higher latitudes with increased risk for many chronic diseases including autoimmune diseases, some cancers, cardiovascular disease, infectious disease, schizophrenia and type 2 diabetes. A three-part strategy of increasing food fortification programs with vitamin D, sensible sun exposure recommendations and encouraging ingestion of a vitamin D supplement when needed should be implemented to prevent global vitamin D deficiency and its negative health consequences.