Biomedical subjects

L A Plum

Publications and source records attributed to L A Plum.

7 recordsLinked to original sources

PubMed2006

2MD, a new anabolic agent for osteoporosis treatment.

INTRODUCTION: 2-Methylene-19-nor-(20S)-1alpha,25-dihydroxyvitamin D3 (2MD) is a new analog of 1alpha,25-dihydroxyvitamin D3 (1,25-(OH)2D3) that has unique properties (distinct from 1alpha,25-dihydroxyvitamin D3) in stimulating osteoblasts to form bone in culture. This analog has now been extensively tested in aged ovariectomized female rats maintained on a diet adequate in calcium and phosphorus. METHODS: Retired female rats obtained from Sprague-Dawley were ovariectomized, and were either dosed with vehicle or 2MD at 5-7 ng/kg body weight each day. RESULTS: A marked increase in total bone mass resulted during the 28-week study. This increase in bone mass resulted from an increase in both cortical and trabecular bone, with increases to the order of 25% in the cancellous bone. Histomorphometry revealed that 2MD increased bone mass primarily by increasing bone formation. It also revealed little or no effect on bone resorption. The resulting bone is of high quality revealed by histology and biomechanical testing. CONCLUSION: Throughout the study, serum calcium remained within the normal range and thus 2MD shows great promise for the treatment of bone diseases characterized by bone loss, including osteoporosis.

Anabolic Agents↗

PubMed2002

A mammalian homolog of unc-53 is regulated by all-trans retinoic acid in neuroblastoma cells and embryos.

The vitamin A metabolite, all-trans retinoic acid (atRA), plays an important role in neuronal development, including neurite outgrowth. However, the genes that lie downstream of atRA and its receptors in neuronal cells are largely unknown. By using the human neuroblastoma cell line, SH-SY5Y, we have identified an atRA-responsive gene (RAINB1: retinoic acid inducible in neuroblastoma cells) that is induced within 4 h after exposure of SH-SY5Y cells to atRA. RAINB1 mRNA is highly expressed in the nervous system (10.5- to 11-kb transcript) in both developing embryos and adults. Its expression is perturbed in developing rat embryos exposed to excess or insufficient atRA. RAINB1 is present on chromosome 11 and is spread over 38 exons, resulting in a putative ORF of 2,429 amino acids. The RAINB1 protein shows high similarity to a gene in Caenorhabditis elegans, unc-53, that is required for axonal elongation of mechanosensory neurons, suggesting that these proteins are orthologs. Thus, RAINB1 may represent a critical downstream gene in atRA-mediated neurite outgrowth.

Aging↗

PubMed2001

Retinoic acid combined with neurotrophin-3 enhances the survival and neurite outgrowth of embryonic sympathetic neurons.

Both nerve growth factor (NGF) and neurotrophin-3 (NT-3) are necessary for the survival of embryonic sympathetic neurons in vivo. All-trans retinoic acid (atRA) has been shown to promote neurite outgrowth and long-term survival of chick embryonic sympathetic neurons cultured in the presence of NGF. The present study shows that atRA can also potentiate the survival and neurite outgrowth-promoting activities of NT-3. This was accomplished by enhancing the survival of existing neurons, as cell proliferation was unaffected by exposure to atRA. atRA also enhanced neurite outgrowth of the NT-3-treated cells; however, the neurites appeared thicker and less branched than cells treated with atRA in combination with NGF. Using a quantitative PCR assay, trkA and p75(NTR) mRNAs, but not trkC mRNA, were increased ( approximately 1.5- to 2-fold) after 72 and 48 hr of exposure of the cultures to atRA, respectively. The atRA-induced increase in trkA mRNA may play a role in the enhanced survival of neurons cultured in the presence of either NGF or NT-3, as both neurotrophins have been shown to signal through this receptor. The time course of these mRNA changes would indicate that atRA does not regulate the neurotrophin receptor mRNA directly, rather, intervening gene transcription is required. Thus, during development, atRA may play a role in fine-tuning embryonic responsiveness to both NT-3 and NGF.

Animals↗

PubMed1997

Retinoid-regulated gene expression in neural development.

The discovery and development of information surrounding the retinoic acid receptors (RAR and RXR) has ushered in a new era in understanding the molecular mechanism of action of vitamin A in embryonic development and cellular differentiation. The mechanisms involved in the regulation of gene expression by the retinoids is at least partially known and involves binding of the RAR and RXR to retinoic acid response elements. Additional factors, including coregulatory proteins, associated regulatory elements, and cell-specific factors, may also be involved in determining the specificity of retinoid-regulation of gene expression during development. During embryogenesis, retinoids are required for the development of the posterior hindbrain and its associated structures, as well as for the survival and differentiation of certain classes of neurons and neural crest cell derivatives. At least some of the effects of retinoid on hindbrain development are related to the regulation of Hox gene expression. Additional retinoid-regulated genes have been implicated in nervous system development, and the manner in which they lead to phenotypic changes during embryogenesis remains to be determined.

Animals↗

PubMed1996

All-trans retinoic acid stimulates and maintains neurite outgrowth in nerve growth factor-supported developing chick embryonic sympathetic neurons.

In explanted embryonic chick sympathetic neurons, all-trans retinoic acid (RA) as well as nerve growth factor (NGF) were found to be required for neuronal survival and neurite outgrowth at early stages of development (day 6.5-7) in agreement with previous work (Rodriguez-Tébar and Rohrer [1991] Development 112:813-820). The dependence of neurons on all-trans RA for survival diminished at later stages of development. However, all-trans RA was found to be needed at all stages of development in order to maximize neurite outgrowth. Further, removal of all-trans RA from the cultures led to a rapid degeneration of the formed neurites, demonstrating the essentiality of all-trans RA for both the development of neurites, and for the maintenance of existing neurites in cultured embryonic sympathetic neurons. The mechanism whereby all-trans RA exerts its effects on embryonic sympathetic neurons may involve activation of the nuclear retinoic acid and retinoid-X receptor (RAR and RXR) families. The results of Northern blot analyses and/or reverse transcriptase-polymerase chain reaction (RT-PCR) studies show that embryonic sympathetic ganglia express RAR beta, RAR gamma and RXR gamma mRNAs. RXR gamma mRNA is expressed at highest levels in immature neurons that are not yet responsive to NGF (day 6.5-7) and message levels decline with increasing developmental age. In contrast, RAR beta transcript levels are barely detectable at day 6.5-7, and increase approximately 4-fold in ganglia from embryos at day 8.5-9 and decline thereafter. RT-PCR studies show that RAR gamma mRNA is expressed both early (day 6.5-7) and late (day 15) in ganglionic development. Transcripts for the NGF receptors, p75NGFR and p140trk were also examined. The appearance of a single 2.7 kb p140trk transcript coincides with the time when RAR beta mRNA is maximally expressed, raising the possibility that NGF receptors may be targets of retinoid action. Evidence is also presented that all-trans RA may enhance neurite outgrowth by mechanisms other than simply inducing NGF-responsiveness of neurons.

Animals↗

PubMed1996

All-trans 3,4-didehydroretinoic acid equals all-trans retinoic acid in support of chick neuronal development.

All-trans 3,4-didehydroretinoic acid (at-ddRA) has been identified as a biologically important retinoid in avian, but not mammalian, embryonic development. In this report, we show that at-ddRA, like all-trans retinoic acid (atRA), supports the survival and differentiation of sympathetic neurons of the embryonic chick. Furthermore, the expression of the retinoid-responsive gene RARbeta2 is increased in neurons exposed to either at-ddRA or atRA. The mechanism whereby at-ddRA exerts its effects in chick neurons may involve binding to and activation of nuclear retinoid receptors. For this reason, the binding of recombinant chick RARbeta2 to at-ddRA and to receptor-specific DNA response elements was examined and compared with the binding characteristics of recombinant murine RARbeta2. The chick RARbeta2, like the mammalian RAR, binds to [3H]atRA with high affinity (Kd=0.7-2 nM). Furthermore, both chick and murine RARbeta2 bind equally well to at-ddRA, atRA, and 9-cis RA, but neither receptor shows appreciable binding to 13-cis RA. The chick RARbeta2 recognizes previously described retinoic acid response elements of mammalian gene promoters and, like mammalian RARbeta2, shows enhanced binding in the presence of RXR. This study provides evidence that at-ddRA, like atRA, supports neuronal development in the chick by its interaction with nuclear retinoid receptors.

Animals↗

PubMed1995

9-cis-retinoic acid selectively activates the cellular retinoic acid binding protein-II gene in human neuroblastoma cells.

Two families of nuclear retinoid receptors, retinoic acid receptor and retinoid X receptor (RAR and RXR respectively), and a family of cellular retinoic acid-binding proteins (CRABPI and II) participate in the retinoic acid (RA) signaling pathway. The presence and function of many of these receptors and cellular binding proteins have not been fully explored in RA-responsive human neuroblastoma cells. We have previously shown that RAR transcripts and protein are present in human neuroblastoma cells, and that all-trans RA induces the expression of the RAR beta mRNA. In this paper, we demonstrate that human neuroblastoma cells express mRNA for RXR alpha and beta. The mRNA for CRABPI is present in untreated human neuroblastoma cells, whereas the mRNA for CRABPII is induced in cells treated with either all-trans RA or 9-cis RA. Furthermore, 9-cis RA, a ligand that binds to both the RAR and the RXR families, selectively activates the CRABPII gene. In contrast, all-trans RA and 9-cis RA are equally effective in the induction of RAR beta transcript and inhibition of cell proliferation. Since both retinoids inhibit human neuroblastoma cell proliferation, it appears that induction of RAR beta rather than of CRABPII is more likely linked to the regulation of human neuroblastoma cell growth.

Base Sequence↗