ISSN:0730-2312    

DOI:10.1002/jcb.240490102

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1992

数据来源: WILEY

摘要:

AbstractThere are three mixed function oxidases which catalyze hydroxylations of vitamin D and its derivatives. These include the hepatic mitochondrial or microsomal vitamin D3‐25‐hydroxylase and the two renal mitochondrial enzymes which further hydroxylate 25‐hydroxyvitamin‐D3(25‐OH‐D3) to form 24R,25‐dihydroxyvitamin D3(24,25(OH)2D3) and 1,25‐dihydroxyvitamin D3[1,25(OH)2D3], the primary steroid hormonal derivative of vitamin D3. All three enzymes are cytochrome P450 dependent. The two renal mitochondrial enzymes are regulated, usually in a reciprocal fashion. The intracellular signalling systems involved in this regulation include 1,25(OH)2D3itself and both protein kinases A and C. Recent progress has been made in the purification and cloning of the vitamin D3‐25‐hydroxylase and the 25‐OH‐D3‐24‐hydroxylase. When the 25‐OH‐D3‐1‐hydroxylase is purified and cloned, efforts which have thus far been frustrated by its low abundance, fertile new ground for the study of the regulation of vitamin D metabolism at th

ISSN:0730-2312    

DOI:10.1002/jcb.240490103

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1992

数据来源: WILEY

摘要:

AbstractThere is continuing and emerging new interest in the development of vitamin D analogs resulting from the recognition that analogs of 1α,25‐dihydroxyvitamin D3[1α,25‐(OH)2D3] may be therapeutically useful. Side chain analogs of this steroid hormone are of particular interest because a family of lead structures have recently emerged for possible use in the treatment of certain types of cancers and skin diseases. Because of the chaotic array of side chain structures which exhibit useful therapeutic indices for these purposes, a more systematic approach towards developing intelligible structure‐function information needs development. Accordingly, a method has been devised to analyze analogs as to their side chain topology based on identifying specific occupancy volumes through conformational analysis. Dot maps have been constructed as an indication of the volume in space which the side chain of 1α,25‐(OH)2‐D3or analogs is permitted to occupy. Volume exclusion analyses based on comparison of structural and biological data for 1α,257‐(OH)2‐D3and analogs are anticipated to lead to a more cogent model for drug design. A cautionary note on the limitations of this appr

ISSN:0730-2312    

DOI:10.1002/jcb.240490104

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1992

数据来源: WILEY

摘要:

AbstractBone “density” (bone mass/bone volume) declines with age from the menopause in women and from about age 55 in men. This fall in bone density (osteoporosis) weakens the bones and leads to a progressive rise in fracture rates, particularly in women. Many risk factors contribute to the bone‐losing process, but one which attracts increasing attention is calcium absorption.The main physiological regulator of calcium absorption is vitamin D. This is manufactured in the skin under the influence of UV‐light and then converted to more potent metabolites in the liver and kidney. Although the serum levels of the most potent metabolite 1,25(OH)2D3(calcitriol) are generally normal in osteoporotic women, treatment with small doses of calcitriol (about 0.25 μg daily) has a remarkable effect on absorptive performance and slows down the rate of bone loss. Improved synthetic metabolites are under development.There is likely also to be greatly increased scope for the use of vitamin D itself in osteoporosis. With advancing age, there is a tendency for men and women to be exposed to less and less sunlight, which is the main natural source of vitamin D. Vitamin D levels, therefore, decline with age, particulaly in those who are housebound, and are found to be low in most reported series of hip fractures. It is likely that this form of vitamin D “insufficiency” has an adverse effect on calcium absorption in the elderly which accelerates bone loss and increases the risk of hip fracture and can be treated with small doses of vitamin D or its 25‐hydroxy derivative. This offers a second important role for vitamin D in the prevention and management o

ISSN:0730-2312    

DOI:10.1002/jcb.240490105

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1992

数据来源: WILEY

摘要:

AbstractThe active vitamin D metabolite 1,25‐dihydroxyvitamin D3[1,25‐D3] is thought to promote many of its actions through interaction with a specific intracellular receptor. The discovery of such receptors in monocytes and activated lymphocytes has led investigators to evaluate the role of the hormone on the immune system. The sterol inhibits lymphocyte proliferation and immunoglobulin production in a dose‐dependent fashion. At a molecular level, 1,25‐D3inhibits the accumulation of mRNA for IL‐2, IFN‐γ, and GM‐CSF. At a cellular level, the hormone interferes with T helper cell (Th) function, reducing Th‐induction of immunoglobulin production by B cells and inhibiting the passive transfer of cellular immunity by Th‐clones in vivo. The sterol promotes suppressor cell activity and inhibits the generation of cytotoxic and NK cells. Class II antigen expression on lymphocytes and monocytes is also affected by the hormone.When given in vivo, 1,25‐D3has been particularly effective in the prevention of autoimmune diseases such as experimental autoimmune encephalomyelitis and murine lupus but its efficacy has been limited by its hypercalcemic effect. Synthetic vitamin D3analogues showing excellent 1,25‐D3‐receptor binding but less pronounced hypercalcemic effects in vivo have recently enhanced the immunosuppressive properties of the hormone in autoimmu

ISSN:0730-2312    

DOI:10.1002/jcb.240490106

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1992

数据来源: WILEY

摘要:

AbstractThe rapid actions of vitamin D compounds are surveyed in a variety of target tissues, including intestine, muscle, bone, hepatocytes, fibroblasts, HL‐60 cells, kidney, mammary gland, and parathyroid. Evidence for non‐nuclear receptors vs. membranophilic effects is discussed, followed by a consideration of signal transduction mechanisms including steroid hormone activated Ca2+channels, phospholipid metabolism, protein kinases, and the role of G‐pro

ISSN:0730-2312    

DOI:10.1002/jcb.240490107

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1992

数据来源: WILEY

摘要:

AbstractVitamin D is a physiological regulator of gene transcription associated with control of a broad spectrum of biological processes that include but is not restricted to growth, differentiation and calcium‐mediated homeostatic control. Transcriptional regulation is mediated by sequence‐specific interactions of a 1,25(OH)2D3‐vitamin D receptor‐accessory factor complex with vitamin D responsive elements (VDRE) residing in the promoters of hormone responsive genes. Functioning primarily as a transcription enhancer, activity at the VDRE is controlled by diverse and integrated cellular signalling pathways acting synergistically and/or antagonistically with a series of basal regulatory elements and other hormone regulated sequences that are components of modularly organized vitamin D‐responsive gene promoters. Molecular mechanisms that integrate the activities at promoter elements contributing to vitamin D‐related transcriptional control include overlapping transcription factor binding domains within regulatory elements and cooperative activities at independent regulatory sequences that determine the level of vitamin D res

ISSN:0730-2312    

DOI:10.1002/jcb.240490108

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1992

数据来源: WILEY

摘要:

AbstractPsoriasis is a chronic hyperproliferative skin disease in which inflammatory and immunologic processes may play important pathophysiologic roles. Recently the skin has been identified as a target tissue for vitamin D. Because 1,25‐dihydroxy vitamin D3inhibits epidermal proliferation and promotes epidermal differentiation, it has been introduced for the treatment of psoriasis vulgaris. In addition to 1,25‐(OH)2‐D3, synthetic vitamin D3analogues have undergone clinical evaluation. Calcipotriol (INN) (calcipotriene [USAN]) has been studied most extensively. Compared with 1,25‐(OH)2‐D3, calcipotriol is about 200 times less potent in its effects on calcium metabolism, although similar in receptor affinity. Topical calcipotriol 50 μg/g applied twice daily is efficacious and safe for the treatment of psoriasis. Because topical calcipotriol is slightly more efficacious than betamethasone 17‐valerate and dithranol, calcipotriol should be considered a first line drug in the management of psoriasis. These results illustrate that it is possible to separate the vitamin D effects on the cellular level from those on calcium metabolism not only in vitro, but also in a clin

ISSN:0730-2312    

DOI:10.1002/jcb.240490109

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1992

数据来源: WILEY

摘要:

AbstractThe idea that vitamin D must function at the bone site to promote bone mineralization has long existed since its discovery as an anti‐rachitic agent. However, the definite evidence for this is still lacking. In contrast, much evidence has accumulated that 1α,25(OH)2D3is involved in bone resorption. 1α,25(OH)2D3tightly regulates differentiation of osteoclast progenitors into osteoclasts. Osteoclast progenitors have been thought to belong to the monocyte‐macrophage lineage. 1α,25(OH)2D3greatly stimulates differentiation and activation of mononuclear phagocytes. Recent reports have indicated that differentiation of mononuclear phagocytes into osteoclasts is strictly regulated by osteoblastic cells, the process of which is also stimulated by 1α,25(OH)2D3. In the differentiation of mononuclear phagocytes into osteoclasts, the target cells for 1α,25(OH)2D3appear to be osteoblastic stromal cells. Osteoblastic cells produce several proteins such as BGP, MGP, osteopontin and the third component of complement (C3) in response to the vitamin. They appear to be somehow involved in osteoclast differentiation and functions. Thus, 1α,25(OH)2D3seems to be involved in the differentiation of osteoclast progenitors into osteoclasts directly and also by an indirect mechanism involving osteoblastic cells. The precise role of osteoblastic cells in osteoclast development has to be elucidated in t

ISSN:0730-2312    

DOI:10.1002/jcb.240490110

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1992

数据来源: WILEY

摘要:

AbstractThe immunological crossreactivity between the two granule‐specific membrane glycoproteins, synaptophysin and granulophysin, was studied using a series of site‐specific monoclonal and polyclonal antibodies. The epitope relatedness of six monoclonal antibodies against granulophysin was examined by competitive ELISA. The antibodies are shown to recognize distinct, but overlapping epitopes within a compact region that is constructed by the three‐dimensional configuration of the molecule. All these antibody clones also recognize rat neuronal synaptophysin. Two monoclonal antibodies against synaptophysin, of which one is the well‐characterized SY38 antibody, directed against the carboxy terminal of the molecule, are also shown to react with granulophysin. Characterized polyclonal antibodies against different peptide antigens of synaptophysin failed to recognize granulophysin. Synaptophysin and granulophysin are distinctly recognized in brain cell (white matter) and the pituitary both qualitatively and quantitatively. Based on these and other observations, it is suggested that the repeat motif in the cytoplasmic tail of synaptophysin represents an immunodominant construct that is the target for the observed crossreactive antibodies and that a similar tertiary construct has been preserved in granulophysin and in other transmembrane p

ISSN:0730-2312    

DOI:10.1002/jcb.240490111

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1992

数据来源: WILEY