Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0851184 (thinning)
 11,252 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Arotinoids, which are analogs of retinoic acid (RA) and retinol (RO) with the carbon skeleton in a rigid conformation, have more favorable therapeutic indices relative to all-trans-RA and all-trans-RO. The purpose of this investigation was to obtain preliminary in vivo toxicity data on SMR-2(analog of RO) and SMR-6 (analog of RA), arotinoids with promising activity (ED50's of 20 X 10(-11) and 5 X 10(-11) M, respectively; ED50 of RA = 1 X 10(-11) M) for reversal of keratinization in tracheal organ culture. A preliminary toxicity study was conducted in male B6D2F1 mice with gavage of retinoids in corn oil (0.01, 0.05, and 0.1 mg/kg/day of SMR-2 or SMR-6; 1, 5, and 10 mg/kg/day of RA as reference control). Due to lack of toxicity, each dose level for SMR-2 and SMR-6 was increased by 4-fold on Day 29 of dosing. The study was terminated on Day 57. Hypervitaminosis A (weight loss, alopecia, skin scaling, and bone thinning) was induced in the mid- and high-dose SMR groups; weight-gain depression was predominant in the high-dose RA group. The SMR compounds were approximately 100-fold more toxic, based on weight loss, than RA. In the SMR dose groups with hypervitaminosis A, white blood cell counts were elevated 2- to 4-fold; and there were microscopic lesions in skin, testes, epididymis, bone, thymus, bone marrow, peripheral lymph nodes, spleen, stomach, adrenal, and pituitary. The leukocytosis was attributed to leukopoiesis in spleen and bone marrow, which may be due to either a direct effect and/or a secondary response to a subacute inflammatory reaction in skin. Only peripheral lymph node hyperplasia was observed in SMR-2 and RA low-dose groups. Enlarged thymus, lymph node hyperplasia, leukopoiesis in spleen and bone marrow, elevated alkaline phosphatase with bone hypertrophy, and testicular degeneration were observed in the mid-dose RA group. The results indicate that immune stimulation may be a primary early response to retinoids and that skin, leukopoietic tissues, reproductive organs, stomach, and bone are primary targets for retinoid toxicity.
 ...
PMID:Preliminary toxicity profile of arotinoids SMR-2 and SMR-6 in male B6D2F1 mice. 360 38

Hypervitaminosis A and D is a potential cause of "hyena disease" in cattle, which results from premature growth-plate closure in long bones of calves. This study showed that vitamin A induced growth-plate closure if calves were given an intramuscular injection of vitamins A and D (2,000,000 IU and 300,000 IU, respectively) on the first day after birth and, in addition, vitamin A (30,000 IU/kg body weight) in a water dispersible form was added to the milk substitute daily. Gross lesions were observed in the proximal tibial growth plates of each of seven calves after 3 weeks of vitamin-A treatment. Microscopical examination showed commencing premature growth-plate closure in the proximal tibia at 2 weeks. After one week, the growth plate showed focal thinning, and there was premature endochondral ossification of columnar cartilage. Longitudinal bone growth was dramatically reduced before growth plate closure at one week (25 microns/day in a treated animal versus 136 microns/day in a control). Liver concentrations of retinol and retinyl palmitate became strikingly elevated at on week, and thereafter increased slowly until the third week. Elevation of plasma retinol and retinyl palmitate was rapid, reaching a maximum on day 10. Plasma all-trans-retinoic acid was undetectable in many samples from treated animals, but plasma concentrations of derivatives of retinoic acid (9-cis-retinoic acid, 13-cis-retinoic acid, 13-cis-4-oxoretinoic acid, and 9, 13 dicis-retinoic acid) were elevated. The vitamin-A intake required to induce growth-plate closure in calves was found to be exceedingly high. Vitamin-A toxicity must be considered as a potential cause of hyena disease, but it would seem likely that other factors also play a role.
 ...
PMID:Vitamin (A and D)-induced premature physeal closure (hyena disease) in calves. 917 48

Diabetes increases susceptibility to chronic ulceration. The cause of chronic wound formation in diabetic individuals is multifactorial but may be accelerated by changes in the structure and function of the skin secondary to impaired fibroblast proliferation, decreased collagen synthesis, and increased matrix metalloproteinase (MMP) expression. This study explored cellular and biochemical changes in organ cultures of skin from streptozotocin-diabetic (STZ-D) rats and the effects of all-trans retinoic acid (RA) on these changes. STZ-D rats were killed after 6 weeks. The skin was cut into 2-mm pieces and incubated in organ culture for 3 or 6 days in the absence or presence of 3 micromol/l RA. After organ culture incubation, control and RA-treated tissue was examined histologically after staining with hematoxylin and eosin. In parallel, organ culture-conditioned medium was assayed for MMPs. Additional organ cultures were examined for collagen synthesis using (3)H-proline incorporation into trichloroacetic acid-precipitable material and for glycosaminoglycan production based on interaction with the cationic dye 1,9-dimethylmethylene blue and by staining of tissue sections with periodic acid Schiff reagents. Skin from 6-week STZ-D rats demonstrated features of dermal atrophy including thinning and disorganization of connective tissue bundles and increased space between bundles. The addition of RA resulted in cellular reactivation and partially reversed the histological features of dermal atrophy. Levels of latent and active MMP-9 and MMP-13 were elevated 4- and 10-fold, respectively, in STZ-D skin and reduced by 50-75% (P < 0.05) by RA. Collagen synthesis was increased by 30% (P < 0.05) by RA, whereas glycosaminoglycan expression was increased by only 9% (NS). RA also increased proliferation of STZ-D skin fibroblasts (approximately threefold over control; P < 0.05). Together, these data suggest that RA has the capacity to improve structure and function of diabetic skin.
 ...
PMID:All-trans retinoic acid improves structure and function of diabetic rat skin in organ culture. 1245 8

Excess of Vitamin A (retinol) and related compounds (retinoids) induces bone fragility and is associated with increased hip fracture incidence in humans. Yet, their impact on the adult skeleton has been studied in relatively little detail. It is assumed that they induce generalized bone loss and decrease long-bone thickness due to reduction of radial bone growth. Here we characterized early skeletal responses of adult rodents to retinoid treatment, revealing novel aspects of retinoid action on the mature skeleton. The retinoid Ro 13-6298, given subcutaneously for 4 days, induced bone loss in the hind limbs of 12- and 56-week-old rats and of 15-week-old mice. In vivo monitoring of bone mass and geometry changes by peripheral quantitative computed tomography demonstrated that bone mass decline was due to subperiosteal cortical bone loss, which induced a shrinkage of bone diameter, whilst cancellous bone mass was preserved. We observed that the native retinoic acid isomer all-trans RA induced an identical pattern of bone loss. Histomorphometric evaluation revealed that increased subperiosteal osteoclastic bone resorption caused the cortical bone destruction. Interestingly, bone resorption was suppressed in cancellous bone, which was in agreement with reduced in vitro formation of osteoclasts from bone marrow cells that were derived from the proximity of cancellous bone. The retinoid-induced increase in subperiosteal bone resorption could be blocked by bisphosphonate as direct potent inhibitor of osteoclast action, but not by estradiol. Retinoid treatment induced a reduction of bone-forming surfaces at the subperiosteal site, but not in cancellous bone. In vitro osteoblast performance was also reduced or unchanged, depending on the cellular system used and assay type/duration. In conclusion, our studies revealed that the impact of retinoids on bone is highly bone-compartment-specific at early treatment phases. Furthermore, we showed that bone diameter shrinks in the adult skeleton after retinoid treatment due to subperiosteal osteoclastic bone resorption. Thus, retinoid-induced bone thinning is not only due to reduced radial bone growth as previously assumed. Our findings might explain why high intake of retinol is associated with increased hip fracture risk in the elderly and suggest a therapy to prevent such potential negative effects.
 ...
PMID:Retinoid-induced bone thinning is caused by subperiosteal osteoclast activity in adult rodents. 1578 Sep 46

Patients with nonexudative ("dry") age-related macular degeneration (AMD) frequently also develop neovascular ("wet") AMD, suggesting a common pathomechanism. Increased vascular endothelial growth factor A (VEGF-A) has been implicated in the pathogenesis of choroidal neovascularization (CNV) in neovascular AMD, while its role in nonexudative AMD that manifests with progressive retinal pigment epithelium (RPE) and photoreceptor degeneration is not well defined. Mice with overall increased VEGF-A levels develop progressive morphological features of both forms of AMD, suggesting that an increase in VEGF-A has a direct age-dependent adverse effect on RPE and photoreceptor function independently of its CNV-promoting proangiogenic effect. Here we provide evidence for this hypothesis and show that morphological RPE abnormalities and retinal thinning in mice with increased VEGF-A levels correlate with progressive age-dependent attenuation of visual function with abnormal electroretinograms and reduced retinal rhodopsin levels. Retinoid profiling revealed a progressive reduction of 11-cis and all-trans retinal in the retinas of these mice, consistent with an impaired retinoid transport between the RPE and photoreceptors. These findings suggest that increased VEGF-A leads to an age-dependent RPE and retinal dysfunction that occurs also at sites where no CNV lesions form. The data support a central role of increased VEGF-A not only in the pathogenesis of neovascular but also of nonexudative AMD.
 ...
PMID:Progressive dysfunction of the retinal pigment epithelium and retina due to increased VEGF-A levels. 2455 95

Adducts of retinaldehyde (bisretinoids) form nonenzymatically in photoreceptor cells and accumulate in retinal pigment epithelial (RPE) cells as lipofuscin; these fluorophores are implicated in the pathogenesis of inherited and age-related macular degeneration (AMD). Here we demonstrate that bisretinoid photodegradation is ongoing in the eye. High-performance liquid chromatography (HPLC) analysis of eyes of dark-reared and cyclic light-reared wild-type mice, together with comparisons of pigmented versus albino mice, revealed a relationship between intraocular light and reduced levels of the bisretinoids A2E and A2-glycero-phosphoethanolamine (A2-GPE). Analysis of the bisretinoids A2E, A2-GPE, A2-dihydropyridine-phosphatidylethanolamine (A2-DHP-PE), and all-trans-retinal dimer-phosphatidylethanolamine (all-trans-retinal dimer-PE) also decreases in albino Abca4(-/-) mice reared in cyclic light compared with darkness. In albino Abca4(-/-) mice receiving a diet supplemented with the antioxidant vitamin E, higher levels of RPE bisretinoid were evidenced by HPLC analysis and quantitation of fundus autofluorescence; this effect is consistent with photooxidative processes known to precede bisretinoid degradation. Amelioration of outer nuclear layer thinning indicated that vitamin E treatment protected photoreceptor cells. Conversely, in-cage exposure to short-wavelength light resulted in reduced fundus autofluorescence, decreased HPLC-quantified A2E, outer nuclear layer thinning, and increased methylglyoxal (MG)-adducted protein. MG was also released upon bisretinoid photodegradation in cells. We suggest that the lower levels of these diretinal adducts in cyclic light-reared and albino mice reflect photodegradative loss of bisretinoid. These mechanisms may underlie associations among AMD risk, oxidative mechanisms, and lifetime light exposure.
 ...
PMID:Photodegradation of retinal bisretinoids in mouse models and implications for macular degeneration. 2727 68

Sphingosine 1-phosphate (S1P) is a potent lipid mediator that modulates inflammation and angiogenesis. In this study, we investigated the possible involvement of S1P in the pathology of light-induced retinal degeneration in vivo and in vitro. The intracellular S1P and sphingosine kinase (SphK) activity in a photoreceptor cell line (661W cells) was significantly increased by exposure to light. The enhancement of SphK1 expression was dependent on illumination, and all-trans-retinal significantly promoted SphK1 expression. S1P treatment reduced protein kinase B (Akt) phosphorylation and increased the protein expression of cleaved caspase-3, and induced photoreceptor cell apoptosis. In vivo, light exposure enhanced the expression of SphK1 in the outer segments of photoreceptors. Intravitreal injection of a SphK inhibitor significantly suppressed the thinning of the outer nuclear layer and ameliorated the attenuation of the amplitudes of a-waves and b-waves of electroretinograms during light-induced retinal degeneration. These findings imply that light exposure induces the synthesis of S1P in photoreceptors by upregulating SphK1, which is facilitated by all-trans-retinal, causing retinal degeneration. Inhibition of this enhancement may be a therapeutic target of outer retinal degeneration, including age-related macular degeneration.
 ...
PMID:Light Stress-Induced Increase of Sphingosine 1-Phosphate in Photoreceptors and Its Relevance to Retinal Degeneration. 3135 84