Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011570 (depression)
 172,036 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The effects of all-trans-retinoic acid were investigated on the immune responses in C57Bl/6 mice after daily oral administration for one week. In selected experiments the immunosuppressive chemicals, cyclophosphamide and cyclosporin A were used in conjunction with retinoic acid. Retinoic acid stimulated the production of antibodies against sheep red blood cells and DNP-Ficoll; however, retinoic acid did not reverse the depression caused by immunosuppressive chemicals. In non-immunized animals retinoic acid stimulated the production of IL-1 but not of IL-2. The mitogenic responses of splenocytes against concanavalin A, phytohemagglutinin and pokeweed mitogen were depressed after the retinoic acid treatment; those against lipopolysaccharide were not influenced. Treatment with retinoic acid did not alter the mixed leukocyte responses but increased the activity of NK cells. Results indicate that retinoic acid may act as an adjuvant via activating macrophages, however, retinoic acid cannot reverse the immunosuppression induced by potent chemicals.
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PMID:Adjuvant activity of all-trans-retinoic acid in C57Bl/6 mice. 162 15

It is known that nerve growth factor (NGF) induces neurite outgrowth and elevation of the activity of adrenergic marker enzyme, tyrosine hydroxylase (TH) in clonal rat pheochromocytoma cells (PC12), whereas glioma-conditioned medium (GCM) induces neurite outgrowth and elevation of the activity of cholinergic marker enzyme, choline acetyltransferase (ChAT) in PC12 cells. In the previous study we have shown that retinoic acid (RA) induces specific elevation of ChAT activity and depression of TH activity without morphological differentiation (Matsuoka, I. et al., Brain Res., 502 (1989]. In the present study, we compared the effects of NGF, GCM and RA on the intracellular signalings in PC12 cells in relation to the mechanism of cholinergic differentiation. Addition of NGF, GCM or RA to the culture medium of PC12 cells caused a rapid rise in intracellular Ca2+ concentration [( Ca2+]i) reaching the level of almost 2.5-fold the resting condition within 3-18 h. Thereafter, [Ca2+]i of NGF-treated cells were decreased to the resting level within 12 h. On the other hand, [Ca2+]i of GCM-and RA-treated cells decreased to a level which was 1.8- to 2-fold the resting condition within 24-48 h and stayed at this level for up to 4-7 days. When homogenates of GCM- and RA-treated PC12 cells were incubated with [gamma-32P]ATP, phosphorylation of a protein with molecular mass of 27 kDa (27 K-protein) was specifically enhanced. The phosphorylation of the 27 K-protein was not seen in the homogenate of the NGF-treated cells. The phosphorylation of the 27 K-protein was dependent on Ca2+ and inhibited by inhibitors of Ca2+-dependent protein kinase, H-7 and W-7. Addition of H-7 and W-7 to the culture medium of PC12 cells abolished the elevation of ChAT activity specifically induced by GCM and RA. These observations suggested that the sustained increase of [Ca2+]i and Ca2+-dependent protein phosphorylation are involved in the intracellular signaling mechanism required for the cholinergic differentiation of PC12 cells induced by GCM and RA.
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PMID:Possible involvements of intracellular Ca2+ and Ca2+ -dependent protein phosphorylation in cholinergic differentiation of clonal rat pheochromocytoma cells (PC12) induced by glioma-conditioned medium and retinoic acid. 258

Retinoic acid, an endogenous metabolite of vitamin A (retinol), possesses striking biological activity akin to a morphogen in developing and regenerating vertebrate limbs. Systemic administration of retinoic acid (RA) to pregnant mammals during the period of limb organogenesis invariably results in dose-dependent dysmorphogenesis. In an attempt to uncover the mode of action of RA in the developing limb bud we analyzed, by HPLC methods, the levels of RA and its metabolic precursor, retinol, in embryonic mouse tissues prior to and following maternal exposure to a teratogenic dose of RA. Detectable levels of both RA and its isomer 13-cis-retinoic acid were found in the limb buds of Day 11 mouse embryos (40 +/- 2 somites). Although retinol was the major retinoid found in ethanolic extracts of either whole embryo or the limb buds, the latter is enriched in RA compared to the whole embryo. This indicated either a higher degree of retinol metabolism or a sequestration of RA in the limb bud compared to the rest of the embryo at this stage of development. A study of the time course of retinoid levels in treated embryos showed that changes occur rapidly, are stable for several hours, and then begin to return to pretreatment levels. After a maternal dose of 10 mg/kg RA, which resulted in a mild degree of limb anomalies, peak RA levels in the limb bud increased 50-fold over the endogenous level; a full 300-fold increase was found after a 100 mg/kg dose which results in 100% incidence of phocomelia. Interestingly, a dose-dependent depression in retinol levels was observed after RA treatment both in maternal plasma as well as the embryo. Studies are in progress to trace the intracellular disposition of both retinol and RA as well as any further active metabolite of RA in the limb buds and other embryonic tissues.
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PMID:Elevations in the endogenous levels of the putative morphogen retinoic acid in embryonic mouse limb-buds associated with limb dysmorphogenesis. 273 39

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.
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PMID:Preliminary toxicity profile of arotinoids SMR-2 and SMR-6 in male B6D2F1 mice. 360 38

Results from this study demonstrate that L1210 lymphocytic leukemia cells generate tumor cell colonies in plasma clot culture, and that the cells can be maintained in suspension cultures for 3 days without a loss in viability or clonogeneticy. Additions of 10(-5)-10(-8) M retinoic acid (RA) or 1,25-dihydroxyvitamin D3 (1,25VD3) to suspension cultures had no effect on cell viability. However, there was an increase in cellular adherence, nuclear chromatin condensation and a depression of clonogenic potential by 99-25%. Flow cytometry analysis of 3-day suspension cultures revealed that both RA or 1,25VD3 promoted an accumulation of cells in G1-phase, with 1,25VD3 being the most effective. For example, treatment with 10(-5) M 1,25VD3 yielded a 76.7% G1-phase accumulation as contrasted with 36.3% for controls, and associated with this G1-shift was a 97% loss in clonogeneticy. Treatment with RA gave a slightly less G1-phase accumulation (64%), which was associated with a 74% loss in clonogeneticy. It is suggested that RA and 1,25VD3 exert their cell cycle and anti-tumor effects by modulating cellular events or metabolism, or by promoting the accumulation of a quiescent cell population.
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PMID:Abolition of L1210 clonogeneticy and G1 arrest by retinoic acid and 1,25-dihydroxyvitamin D3. 383 65

E-Rosette formation in vitro, lymphocyte mitogenesis and natural killer (NK) activity of human blood lymphocytes were strongly inhibited by high concentration (10(-4) M) of retinol or retinal. Other retinoids at 10(-4) M (retinoic acid and 13-cis-retinoic acid) and lower concentrations (10(-7) or 10(-9) M) of retinol, retinal and carotenes also inhibited E-rosette formation. Lymphocyte transformation responses induced by concanavalin A (Con A) or pokeweed mitogen (PWM) were also inhibited while NK activity was not affected. There was a remarkable depression of the total number of viable lymphocytes after incubation with retinol or retinal 10(-4) M. However, other retinoids, 10(-7) and 10(-9) M of retinol and retinal and carotenes did not show marked decrease of lymphocyte number or viability even after prolonged incubation (48 h). The mechanism of inhibition by retinol or retinal (10(-4) M) is due in part to the decrease of viable lymphocytes. It is unclear how other retinoids, carotenes and lower concentrations (10(-7) or 10(-9) M) of retinol or retinal inhibit E-rosette formation or lymphocyte transformation.
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PMID:Effects of retinoids on human lymphocyte functions in vitro. 401 16

In order to better understand the mechanism by which changes in the fatty acid composition of cellular lipids occur in leukemia cell lines induced to differentiate, the activity of the first enzyme of fatty acid biosynthesis, acetyl-CoA carboxylase (EC 6.4.1.2) was measured in HL-60 promyelocytic leukemia cells before, during and after treatment with compounds that induce these cells to mature to neutrophillike cells. After 24 h of exposure to dimethylsulfoxide, retinoic acid, or butyric acid, no morphological or biochemical (nitroblue tetrazolium reduction) evidence of differentiation occurred, but acetyl-CoA carboxylase activity decreased 44, 44.5, and 49% respectively, compared to untreated cells. After 7 days of culture in the presence of these agents, 79, 83, and 72% of cells acquired the ability to reduce nitroblue tetrazolium (versus 15% of control cells) and enzyme activity decreased 92.7, 99.7, and 98%, compared to control cultures, with the three compounds respectively. Thus, some of the reported changes in fatty acid composition of leukemia cells with differentiation may arise, in part, from the depression of the de novo fatty acid biosynthetic pathway and the loss of acetyl-CoA carboxylase activity may be a useful marker for neutrophilic differentiation in HL-60 cells.
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PMID:Decreased activity of acetyl-CoA carboxylase during chemically induced neutrophilic differentiation of human promyelocytic leukemia cells. 615 50

The effects of 12-O-tetradecanoylphorbol-13-acetate (TPA), all trans-retinoic acid (RA), 5-azacytidine (5-AC), and phenobarbital (PB) on the activities of seven enzymes and/or isozymes of a diploid rat liver epithelial cell line have been studied. At 0.1 microgram/ml, TPA depressed the specific activities of lactate dehydrogenase and gamma-glutamyl transpeptidase, whereas 2 mM PB depressed gamma-glutamyl transpeptidase and alkaline phosphatase. At 0.01 microgram/ml, RA markedly depressed the activity of NADH-diaphorase and lactate dehydrogenase but enhanced the activity of alkaline phosphatase. Only 2 microM 5-AC caused the most significant shift of lactate dehydrogenase isozyme toward the "muscle"-type isozyme. Histochemical studies revealed that PB and 5-AC induced focal areas of cells with glycogen deposits, but no significant changes in either ultrastructure or alpha-fetoprotein and albumin immunohistochemical staining pattern were observed to suggest hepatocytic differentiation. Although none of the enzymatic changes could be consistently correlated with the effects of these biological modifiers on the cellular growth rate, the effect of RA on NADH-diaphorase, lactate dehydrogenase, and alkaline phosphatase activities was the opposite of the changes observed during carcinogenesis of these rat liver epithelial cells by multiple treatments with N-methyl-N'-nitro-N-nitrosoguanidine. The depression of gamma-glutamyl transpeptidase activity by PB is contradictory to that observed histochemically in hepatocytes in vivo, but such discrepancy may be related to the differences in cell type, growth conditions, or duration of exposure.
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PMID:Biochemical effects of 12-O-tetradecanoylphorbol-13-acetate, retinoic acid, phenobarbital, and 5-azacytidine on a normal rat liver epithelial cell line. 620 84

Sprague-Dawley rats received daily oral gavage doses of either 2-retinylidene-5,5-dimethyl-1,3-cyclohexanedione (retinylidene dimedone; 14, 50, 150, or 330 mg/kg) or all-trans-retinoic acid (1, 4, 14, or 50 mg/kg) for 13 weeks. Rats given 50 mg/kg of all-trans-retinoic acid developed numerous long-bone fractures and became moribund during the third week of the study. Those receiving lower dosages survived until scheduled termination, but the 14 mg/kg group showed clear signs of retinoid intoxication including growth depression, anemia, serum alkaline phosphatase elevation, bone fracture, and testicular degeneration. Exposure to retinylidene dimedone did not result in any treatment-related deaths, growth depression, or histopathologic lesions, even at the highest dose, 300 mg/kg. Animals given this dosage exhibited mild anemia, equivocal evidence of bone fracture, but no increase in alkaline phosphatase activity. Retinylidene dimedone appears to be considerably less toxic than all-trans-retinoic acid.
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PMID:Subchronic toxicity of all-trans-retinoic acid and retinylidene dimedone in Sprague-Dawley rats. 671 May 36

Numerous studies have indicated that the activities of the polyamine biosynthetic enzymes, ornithine decarboxylase (ODC) and S-adenosyl methionine decarboxylase (SAM.D) are increased in hyperplastic and neoplastic growth. The levels of the polyamines themselves, putrescine, spermidine, and spermine are also often altered in these situations. Epidermal ODC activity is greatly elevated in response to tumor promoting chemicals and also in response to irradiation with short-wave length and mid-wave length ultraviolet. In addition, the levels of the epidermal polyamines change after mid-wavelength ultraviolet irradiation, leading to elevation of putrescine and spermidine, but depression of the spermine level. The spermidine to spermine ratio was significantly elevated after chronic ultraviolet irradiation. Preliminary studies on human skin also shows that mid-wavelength ultraviolet light is capable of inducing ODC. Different pharmacological agents have been found to significantly inhibit the ultraviolet induction of epidermal ODC. Topical corticosteroids and indomethacin significantly inhibit ultraviolet induced opidermal ODC. In addition, retinoic acid inhibited the ultraviolet induction of this enzyme in some experimental situations. Long-wave length ultraviolet alone produced no significant induction of ODC, however, certain phototoxic drugs (8-methoxypsoralen and anthracene) in combination with long-wave length ultraviolet did induce epidermal ODC. It is possible that further studies of changing epidermal polyamine metabolism in response to ultraviolet and tumor promoting agents, may lead to a greater understanding of cutaneous carcinogenesis.
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PMID:Ultraviolet light and epidermal polyamines. 725 49


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