A J Brown

..In previous studies, 1alpha(OH)D3, a vitamin D prodrug, inhibited PTH secretion in cultured bovine parathyroid cells, but it was unclear whether 1alpha(OH)D3 itself or an active metabolite produced this inhibition...

..A clear understanding of the molecular basis for the selectivity of vitamin D analogues on parathyroid function may allow the design of even more effective analogues...

..The selectivity of the other analogs is achieved by distinct mechanisms. Understanding how these compounds exert their selective actions on the parathyroid glands will aid in the design of safer, more effective analogs...

..Understanding how analogues exert their selective actions may allow for the design of more effective and safer vitamin D compounds for the treatment of a wide range of clinical disorders...

..In conclusion, the low calcemic activity of 19-norD(2) seems to be due to an acquired, postreceptor resistance of the intestine and bone to chronic treatment with the analog...

..A thorough understanding of the influence of these analog/protein interactions on the biological profile of vitamin D analogs will be invaluable for the design of future analogs with enhanced target specificity...

..Knowledge of how these compounds exert their selective actions on the parathyroid glands may allow the design of more effective analogs in the future...

..However, 1,25(OH)(2)D(3) can control the expression of many genes involved in a plethora of biological actions. Many of these nonclassic responses have suggested a number of therapeutic applications for 1,25(OH)(2)D(3) and its analogs...

..The cause of this down-regulation is unknown. Here we examined the roles of uremia and parathyroid hyperplasia on parathyroid gland (PTG) CaR expression in the rat model of renal failure...

..Understanding of the molecular basis for the selectivity of the vitamin D analogues will allow the design of more effective and safer vitamin D compounds for the treatment of a wide range of clinical disorders...

..In summary, the reduced calcemic and phosphatemic activities of 19-norD(2) can be attributed to lower potency in stimulating intestinal calcium and phosphate absorption...

..CONCLUSION: These data indicate that parathyroid cell hyperplasia precedes down-regulation of CaR expression in the uremic rat model...

..Clotrimazole enhanced 24-hydroxylase mRNA induction, presumably by inhibiting catabolism of 25(OH)D(3). In conclusion, 25(OH)D(3) suppresses PTH synthesis by parathyroid cells, possibly by direct activation of the VDR...

..In addition to reducing p21, high P-induced PT growth could result from increased PT expression of the growth promoter transforming growth factor-alpha (TGF-alpha), known to be elevated in hyperplastic and adenomatous human PT glands...

..Unfortunately, the absence of a parathyroid cell line is slowing the progress in understanding the molecular mechanism(s) involved in phosphorus regulation of PTH...

..This section discusses the molecular mechanisms involved in the transcriptional control of gene expression by 1,25(OH)2D3...

..This suggests that the catalytic activity of the CYP1alpha protein may be reduced by free radical damage in these cells. Future studies will focus on detecting oxidative damage in this model system and in vivo...

..We tested a new analog of vitamin D, 2MbisP, and found that it suppresses PTH at doses that do not affect serum Ca or P...

..Combining these agents with higher doses of vitamin D compounds may achieve greater suppression of PTH and possibly enhance survival in patients with chronic kidney disease...

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..Although many new analogs show tremendous promise in cell-based models, this article will limit it focus on the development of analogs currently in use and those that have demonstrated efficacy in animal models or in clinical trials...

..The lower Ca x P product in 19-nor-1,25(OH)(2)D(2)-treated rats may be an important consideration in patient therapy. Further studies in patients are necessary to define these differences...

..However, increasing cytosolic Ca with thapsigargin or the Ca ionophore A23187 decreased PTH mRNA levels. In summary, Ca-mediated destabilization of PTH mRNA requires gene transcription and involves increases in cytosolic Ca...

..These findings suggest that the apical calcium channels, along with calbindin and the calcium pump, may play a role in intestinal calcium transport and its modulation by age, dietary calcium, and 1,25(OH)2D3...

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..05) by Gcm2 silencing. Exon 1A-containing transcripts from promoter 1 were expressed at very low levels in the cultures. These results indicate that one function of Gcm2 is to maintain high levels of CaR expression in parathyroid cells...

..This local production of 1,25(OH)(2)D(3) is dependent on circulating precursor levels, providing a potential explanation for the association of vitamin D deficiency with various cancers and autoimmune diseases...

..5 mg/dl) was nearly 80 times higher. These findings indicate that 1alphaOH-3-epi-D3 is a highly selective vitamin D analog with tremendous potential for treatment of secondary hyperparathyroidism in chronic renal failure patients...

..These findings indicate that oral P(i) increases PTH release in vivo more rapidly than previously reported; this response may be from both plasma phosphate and an additional signal arising from the gastrointestinal tract...

..This effect is not mediated by changes in ionized calcium, phosphorus, pH, glucose, or insulin. These data suggest there may be an as yet unknown enteral signal that rapidly suppresses PTH...

..Residual FGF-23 may contribute to the hypophosphatemia in post-transplant patients...

..We conclude that although phosphate restriction restores CaR expression and function in parathyroid glands of uremic rats, it is a late event and not involved in the arrest of secondary HPT...

..Further studies will be necessary to confirm these findings and to confirm the clinical utility of 1,24(OH)(2)D(2)...

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..05). ABD produced in mice with CKD in the absence of hyperparathyroidism was successfully reversed with a bone anabolic, BMP-7, associated with a reduction in plasma phosphorus...

..Dimethylated analogue strongly suppresses parathyroid hormone (PTH) secretion...