Structural Evaluation of the Agonistic Action of a Vitamin D Analog with Two Side Chains Binding to the Nuclear Vitamin D Receptor

2003 ◽  
Vol 63 (6) ◽  
pp. 1230-1237 ◽  
Author(s):  
Sami Väisänen ◽  
Mikael Peräkylä ◽  
Jouni I. Kärkkäinen ◽  
Milan R. Uskokovic ◽  
Carsten Carlberg
Keyword(s):  
Vitamin D ◽  
Vitamin D Receptor ◽  
Side Chains ◽  
Structural Evaluation ◽  
Vitamin D Analog

scholarly journals The Vitamin D Analog ED-71 Is a Potent Regulator of Intestinal Phosphate Absorption and NaPi-IIb

Endocrinology ◽  
2012 ◽  
Vol 153 (11) ◽  
pp. 5150-5156 ◽  
Author(s):  
Alex J. Brown ◽  
Fanjie Zhang ◽  
Cynthia S. Ritter
Keyword(s):  
Vitamin D ◽  
Vitamin D Receptor ◽  
Mineral Metabolism ◽  
Oral Treatment ◽  
Fold Increase ◽  
Alveolar Type ◽  
Mrna Levels ◽  
Potent Inducer ◽  
Vitamin D Analog ◽  
Fold Induction

Abstract The vitamin D analog ED-71 [1α,25-dihydroxy-2β-(3-hydroxypropyloxy)vitamin D3] has been approved for treatment of osteoporosis in Japan, but its effects on mineral metabolism have not been fully explored. We investigated the actions of ED-71 on phosphate (Pi) absorption and induction of the intestinal sodium/phosphate cotransporters. Oral treatment of vitamin D-deficient rats with ED-71 (20 pmol every other day for 8 d) produced a maximal 8-fold increase in duodenal Pi absorption, measured by the in situ loop method, whereas 1,25-dihyroxyvitamin D3 [1,25(OH)2D3], at doses up to 150 pmol, had no effect. This action of ED-71 was attributable to a dramatic 24-fold induction of sodium-dependent Pi transporter type IIb (NaPi-IIb) mRNA in the duodenum; Pit-1 and Pit-2 mRNA levels were not increased. In vitamin D-replete rats, ED-71 treatment (50 pmol) at 72 and 24 h before death increased NaPi-IIb mRNA in the duodenum and jejunum, but not the ileum, whereas 1,25(OH)2D3 at 1000 pmol was ineffective in all segments. Single oral doses of ED-71 increased mouse intestinal NaPi-IIb mRNA and protein between 6 and 24 h. Surprisingly, rat lung NaPi-IIb was not increased by ED-71, despite its coexpression with the vitamin D receptor in alveolar type II cells. However, ED-71 did not induce intestinal NaPi-IIb in vitamin D receptor-ablated mice. The greater potency of ED-71 than 1,25(OH)2D3 on NaPi-IIb appears to be due to much higher and more prolonged levels of ED-71 in the circulation. In summary, ED-71, due to its disparate pharmacokinetics, is a much more potent inducer of intestinal Pi absorption and NaPi-IIb than 1,25(OH)2D3, suggesting a role for this analog in the treatment of Pi-wasting disorders.

scholarly journals The Therapeutic Effect of Active Vitamin D Supplementation in Preventing the Progression of Diabetic Nephropathy in a Diabetic Mouse Model

2020 ◽  
Vol 2020 ◽  
pp. 1-10
Author(s):  
Nakhoul Nakhoul ◽  
Tina Thawko ◽  
Evgeny Farber ◽  
Inbal Dahan ◽  
Hagar Tadmor ◽  
...  
Keyword(s):  
Diabetes Mellitus ◽  
Vitamin D ◽  
Diabetic Nephropathy ◽  
Vitamin D Receptor ◽  
Receptor Activation ◽  
Receptor Expression ◽  
Active Vitamin ◽  
Active Vitamin D ◽  
Vitamin D Analog

Background. Diabetic nephropathy (DN) is one of the most common microvascular complications of diabetes and is the leading cause of end-stage renal disease (ESRD) and replacement therapy worldwide. Vitamin D levels in DN patients are very low due to the decrease in the synthesis and activity of 1-α hydroxylase in the proximal tubule cells and decrease in the vitamin D receptor abundance. To date, few studies have shown the antioxidant effects of 1α,25-dihydroxyvitamin D3 [1,25(OH)2D3] on hyperglycemia-induced renal injury. The selective activator of the vitamin D receptor, paricalcitol, reduces proteinuria and slows the progression of kidney injury. The precise mechanism through which vitamin D affects diabetic status and provides kidney protection remains to be determined. Methods. Diabetes mellitus (DM) was induced in 94 8-week-old DBA/2J mice by intraperitoneal injection of streptozotocin (STZ). DM mice were randomly divided into receiving vehicle or treatment with paricalcitol, the active vitamin D analog, 1 week after DM induction or paricalcitol treatment 3 weeks after DM induction. An additional control group of healthy wild-type mice was not treated. Urine albumin, blood urea nitrogen, and creatinine levels were measured before and at the end of the paricalcitol treatment. Periodic acid-Schiff, immunohistochemistry staining, and western blot of the renal tissues of vitamin D receptor, villin, nephrin, and podocin expressions, were analyzed. Results. Paricalcitol treatment restored villin, nephrin, and podocin protein levels that were downregulated upon DM induction, and reduced fibronectin protein level. Vitamin D receptor activation by paricalcitol may reduce proteinuria of DN in mice and alleviate high-glucose-induced injury of kidney podocytes by regulating the key molecules such nephrin-podocin. Conclusions. Paricalcitol treatment was associated with improved structural changes in type 1 diabetic mice including upregulation of vitamin D receptor expression, and decreased fibrosis markers such as fibronectin. These effects may contribute to the consistent benefit of vitamin D analog to slow the deterioration in glomerular function and reduce the risk of ESRD in patients with type 1 and 2 diabetes mellitus. Our results suggest that additional use of paricalcitol may be beneficial in treating patients with diabetes under standard therapeutic strategies.

The vitamin D receptor as a target for the treatment of breast cancer: Studies with the low calcemic vitamin D analog, inecalcitol.

2016 ◽  
Vol 34 (15_suppl) ◽  
pp. e12011-e12011
Author(s):  
Alyson M. Murray ◽  
Stephen F. Madden ◽  
Naoise C Synnott ◽  
John Crown ◽  
Norma O'Donovan ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Vitamin D ◽  
Vitamin D Receptor ◽  
Vitamin D Analog ◽  
Cancer Studies

scholarly journals Carborane-based design of a potent vitamin D receptor agonist

2016 ◽  
Vol 7 (2) ◽  
pp. 1033-1037 ◽  
Author(s):  
Rocio Otero ◽  
Samuel Seoane ◽  
Rita Sigüeiro ◽  
Anna Y. Belorusova ◽  
Miguel A. Maestro ◽  
...  
Keyword(s):  
Vitamin D ◽  
Vitamin D Receptor ◽  
Receptor Agonist ◽  
Side Chain ◽  
Vitamin D Analog ◽  
Dihydrogen Bonding

The development of a promising clinical antitumor vitamin D analog possessing a side-chain o-carborane cluster that efficiently binds to VDR by unconventional dihydrogen bonding (BH⋯HN) is described.

scholarly journals Analysis of Vitamin D Analog-Induced Heterodimerization of Vitamin D Receptor with Retinoid X Receptor Using the Yeast Two-Hybrid System

1997 ◽  
Vol 11 (3) ◽  
pp. 366-378 ◽  
Author(s):  
Xiao-Yan Zhao ◽  
T. Ross Eccleshall ◽  
Aruna V. Krishnan ◽  
Coleman Gross ◽  
David Feldman
Keyword(s):  
Vitamin D ◽  
Vitamin D Receptor ◽  
Hybrid System ◽  
Retinoid X Receptor ◽  
Yeast Two Hybrid ◽  
Yeast Two Hybrid System ◽  
Vitamin D Analog ◽  
Two Hybrid

Effects of alkyl side chains and terminal hydrophilicity on vitamin D receptor (VDR) agonistic activity based on the diphenylpentane skeleton

2015 ◽  
Vol 25 (22) ◽  
pp. 5362-5366 ◽  
Author(s):  
Takashi Misawa ◽  
Momoko Yorioka ◽  
Yosuke Demizu ◽  
Tomomi Noguchi-Yachide ◽  
Nobumichi Ohoka ◽  
...  
Keyword(s):  
Vitamin D ◽  
Vitamin D Receptor ◽  
Side Chains ◽  
Alkyl Side Chains ◽  
Agonistic Activity

scholarly journals Corepressor Excess Shifts the Two-Side Chain Vitamin D Analog Gemini from an Agonist to an Inverse Agonist of the Vitamin D Receptor

2003 ◽  
Vol 17 (10) ◽  
pp. 2028-2038 ◽  
Author(s):  
Manuel Macias Gonzalez ◽  
Petra Samenfeld ◽  
Mikael Peräkylä ◽  
Carsten Carlberg
Keyword(s):  
Vitamin D ◽  
Vitamin D Receptor ◽  
Inverse Agonist ◽  
Side Chain ◽  
Vitamin D Analog

Vitamin D3 Derivatives with Adamantane or Lactone Ring Side Chains are Cell Type-Selective Vitamin D Receptor Modulators

2007 ◽  
Vol 71 (5) ◽  
pp. 1298-1311 ◽  
Author(s):  
Yuka Inaba ◽  
Keiko Yamamoto ◽  
Nobuko Yoshimoto ◽  
Manabu Matsunawa ◽  
Shigeyuki Uno ◽  
...  
Keyword(s):  
Vitamin D ◽  
Vitamin D Receptor ◽  
Vitamin D3 ◽  
Lactone Ring ◽  
Side Chains ◽  
Cell Type ◽  
Receptor Modulators

scholarly journals The Enhanced Hypercalcemic Response to 20-Epi-1,25-Dihydroxyvitamin D3 Results from a Selective and Prolonged Induction of Intestinal Calcium-Regulating Genes

Endocrinology ◽  
2009 ◽  
Vol 150 (8) ◽  
pp. 3448-3456 ◽  
Author(s):  
Lee A. Zella ◽  
Mark B. Meyer ◽  
Robert D. Nerenz ◽  
J. Wesley Pike
Keyword(s):  
Vitamin D ◽  
Rna Polymerase Ii ◽  
Vitamin D Receptor ◽  
Duration Of Action ◽  
Dihydroxyvitamin D3 ◽  
1,25 Dihydroxyvitamin D3 ◽  
Vitamin D Analog ◽  
Sustained Action ◽  
Specific Degradation

20-Epi-1,25-dihydroxyvitamin D3 (20-epi-1,25(OH)2D3) is a vitamin D analog that exhibits unique biologic properties. The mechanism(s) responsible for these activities remains unclear. Here we explore the ability of 20-epi-1,25(OH)2D3 to induce calcemic responses in mice in vivo and identify a potential mechanism. Surprisingly, the levels of calcemia induced at 24 h after single injections of equivalent doses of 1,25(OH)2D3 or 20-epi-1,25(OH)2D3 were similar, suggesting that both compounds were equal in both potency and efficacy. This similarity was also observed at genes involved in calcium homeostasis including, S100g (calbindin D9K), Trpv6, Cldn2 (claudin 2), Trpv5, and Tnfsf11 (Rankl) as well as Cyp24a1. Despite this, the activities of the two compounds at 48 h were strikingly different. Thus, whereas the activity of 1,25-dihydroxyvitamin D3 declined at this time point, the response to 20-epi-1,25(OH)2D3 was increased. This unique profile was not due to an exaggerated induction of calcium regulating genes in the intestine, kidney, or bone but to a sustained action on these genes in the intestine. This conclusion was supported by studies using in vivo chromatin immunoprecipitation analysis, which revealed a prolonged presence of vitamin D receptor and RNA polymerase II at the Trpv6 and Cyp24a1 promoters and a sustained increase in histone 4 acetylation in these gene regions as well. We conclude that 20-epi-1,25(OH)2D3 displays superagonist properties largely as a result of its duration of action in the intestine. This action is likely due to a decrease in the rate of intestinal-specific degradation of the ligand rather than to an increase in the functional stability of the vitamin D receptor.

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