tretinoin and 9-13-retinoic-acid

Topics: Animals; Cytochrome P-450 Enzyme System; DNA; Humans; Receptors, Calcitriol; Receptors, Retinoic Acid; Receptors, Thyroid Hormone; Tretinoin

Patients with severe chronic hand eczema (CHE) refractory to topical corticosteroids currently have limited treatment options suited for chronic use, and few controlled clinical studies have investigated new therapies in this setting.. To assess the efficacy and safety of oral alitretinoin (9-cis retinoic acid) taken at 10 mg or 30 mg once daily for up to 24 weeks, compared with placebo control, in the treatment of severe CHE refractory to topical corticosteroids.. A randomized, double-blind, placebo-controlled, prospective, multicentre trial was conducted in 111 dermatology outpatient clinics in Europe and Canada. A total of 1032 patients with severe refractory CHE were randomized in a 1 : 2 : 2 ratio to placebo, or 10 mg or 30 mg of oral alitretinoin once daily for up to 24 weeks. Safety was assessed for all patients during a follow-up period of 4 weeks, and responders were observed for relapse for 24 weeks after the end of therapy. The primary efficacy parameter was Physician Global Assessment of overall CHE severity, with response defined as clear or almost clear hands.. Responses, defined as clear or almost clear hands, were achieved in up to 48% of patients treated with alitretinoin, compared with 17% for placebo (P < 0.001), with up to 75% median reduction in disease signs and symptoms. Treatment was well tolerated, with dose-dependent adverse effects comprising headache, mucocutaneous events, hyperlipidaemia, and decreased free thyroxine and thyroid-stimulating hormone. The median time to relapse, defined as recurrence of 75% of initial signs and symptoms, was 5.5-6.2 months in the absence of anti-eczema medication.. Alitretinoin given at well-tolerated doses induced clearing of CHE in a substantial proportion of patients with severe disease refractory to standard therapy.

Topics: Adolescent; Adult; Aged; Alitretinoin; Chronic Disease; Dermatologic Agents; Dose-Response Relationship, Drug; Drug Administration Routes; Eczema; Epidemiologic Methods; Female; Hand Dermatoses; Humans; Male; Middle Aged; Tretinoin

Although the administration of retinoids represents an important part of treatment for children suffering from high-risk neuroblastomas, approximately 50% of these patients do not respond to this therapy or develop resistance to retinoids during treatment. Our study focused on the comparative analysis of the expression of five genes and corresponding proteins (DDX39A, HMGA1, HMGA2, HOXC9 and PBX1) that have recently been discussed as possible predictive biomarkers of clinical response to retinoid differentiation therapy. Expression of these five candidate biomarkers was evaluated at both the mRNA and protein level in the same subset of 8 neuroblastoma cell lines after treatment with natural or synthetic retinoids. We found that the cell lines that were HMGA2-positive and/or HOXC9-negative have a reduced sensitivity to retinoids. Furthermore, the experiments revealed that the retinoid-sensitive cell lines showed a uniform pattern of change after treatment with both natural and sensitive retinoids: increased DDX39A and decreased PBX1 protein levels. Our results showed that in NBL cells, these putative protein biomarkers are associated with sensitivity or resistance to retinoids, and their endogenous or induced expression can distinguish between these two phenotypes.

Topics: Adolescent; Antineoplastic Agents; Bexarotene; Biomarkers, Pharmacological; Cell Line, Tumor; Cell Proliferation; Child; Child, Preschool; DEAD-box RNA Helicases; Drug Resistance, Neoplasm; Female; Fenretinide; HMGA1a Protein; HMGA2 Protein; Homeodomain Proteins; Humans; Infant; Infant, Newborn; Isotretinoin; Male; Nervous System Neoplasms; Neuroblastoma; Paraffin Embedding; Pre-B-Cell Leukemia Transcription Factor 1; Tissue Fixation; Tretinoin; Young Adult

9-cis-Retinoic acid (9cRA), which binds to both retinoic acid receptors and retinoic X receptors, inhibits prostate cancer induction in rats and reduces growth of prostate cancer cells. However, the nature of this growth inhibition and the interactive influence of androgens are not well defined and are the subject of this report. LNCaP and PC-3 cells were cultured and treated with a range of 9cRA concentrations for 3-6 days in the absence or presence of 5α-dehydrotestosterone. 9cRA inhibited cell proliferation in a dose-dependent manner, plateauing at 10 mol/l. Treatment of cells with 10 mol/l 9cRA inhibited 5α-dihydroxytestosterone (DHT)-stimulated proliferation, the effect of which was maximal at 10 mol/l DHT. Treatment of DHT (10 mol/l)-exposed cells with 9cRA caused a dose-dependent increase in prostate-specific antigen in the medium after 6 days, but not 3 days. 9cRA caused a dose-dependent increase in apoptotic cells stained with H33258 after 3 days, but not 6 days; however, on using flow cytometry, apoptosis was apparent at both 3 and 6 days. Flow cytometry also revealed interference of G0/G1 to S phase transition by 9cRA. Inhibition by 9cRA of anchorage-independent growth of PC-3 cells was also found; LNCaP cells did not grow colonies in soft agar. 9cRA inhibited growth and induced differentiation of human LNCaP prostate cancer cells in vitro and inhibited anchorage-independent growth of PC-3 cells. Because 9cRA and 13-cis-retinoic acid, which is retinoic acid receptor-selective, prevent prostate carcinogenesis in rats, and 13-cis-retinoic acid also inhibits growth of human prostate cancer cells, the RAR is a potential molecular target for prostate cancer prevention and therapy.

Topics: Alitretinoin; Cell Differentiation; Cell Line, Tumor; Cell Proliferation; Dose-Response Relationship, Drug; Drug Interactions; Humans; Male; Prostatic Neoplasms; Testosterone; Tretinoin

Removal of cholesterol from macrophage-derived foam cells is a critical step to the prevention of atherosclerotic lesions. We have recently demonstrated the functional importance of retinoids in the regulation of the steroidogenic acute regulatory (StAR) protein that predominantly mediates the intramitochondrial transport of cholesterol in target tissues. In the present study, treatment of mouse macrophages with retinoids, particularly all-trans retinoic acid (atRA) and 9-cis RA, resulted in increases in cholesterol efflux to apolipoprotein AI (Apo-A1). Activation of the PKA pathway by a cAMP analog, (Bu)2cAMP, markedly augmented retinoid mediated cholesterol efflux. Macrophages overexpressing hormone-sensitive lipase increased the hydrolysis of cholesteryl esters and concomitantly enhanced the efficacy of retinoic acid receptor and liver X receptor (LXR) ligands on StAR and ATP-binding cassette transporter A1 (ABCA1) protein levels. RAs elevated StAR promoter activity in macrophages, and an increase in StAR levels augmented cholesterol efflux to Apo-A1, suggesting retinoid-mediated efflux of cholesterol involves enhanced oxysterol production. Further studies revealed that retinoids activate the LXR regulated genes, sterol receptor-element binding protein-1c and ABCA1. These findings provide insights into the regulatory events in which retinoid signaling effectively enhances macrophage cholesterol efflux and indicate that retinoid therapy may have important implications in limiting and/or regressing atherosclerotic cardiovascular disease.

Topics: Animals; Apolipoprotein A-I; ATP Binding Cassette Transporter 1; Biological Transport; Bucladesine; Cell Line; Cholesterol; Cholesterol Esters; Cyclic AMP-Dependent Protein Kinases; Gene Expression Regulation; Hydrolysis; Liver X Receptors; Macrophages; Mice; Mitochondria; Orphan Nuclear Receptors; Phosphoproteins; Receptors, Retinoic Acid; Signal Transduction; Sterol Esterase; Tretinoin

Unusual amounts of retinoic acid (RA) isomers play an important role in abnormal morphological development of mammals; such as rat embryos. Each isomer of RA has a unique function in first steps of embryonic life. In the current study, a new method for preconcentration and simultaneous determination of all-trans retinoic acid, 13-cis retinoic acid, 9-cis retinoic acid and 9,13-di-cis retinoic acid in rat whole rudimentary embryo culture (RWEC) has been developed. RA isomers were extracted from samples by conjugation to appropriate amount of surface modified CdSe quantum dots (QDs) prior to HPLC/UV determination. In order to quickly release of the analytes with unchanged form, separated RA-QD conjugation were irradiated by intensive near infrared wavelength (NIR). Low energy NIR irradiation results in maintaining the primary forms of RA isomers during the release. The conjugation and release mechanisms were described and experimental parameters were investigated in detail. Under optimized conditions, the method was linear in the range of 0.040-34.600 pmol g(-1) for all-trans RA (R(2)=0.9996), 0.070-34.200 pmol g(-1) for 13-cis RA (R(2)=0.9992), 0.050-35.300 pmol g(-1) for 9,13-di-cis RA (R(2)=0.9998) and 0.050-32.900 pmol g(-1) for 9-cis RA (R(2)=0.9990). The present method can be useful for retinoic acid monitoring in clinical studies.

Topics: Alitretinoin; Animals; Cadmium Compounds; Chromatography, High Pressure Liquid; Embryo, Mammalian; Female; Isomerism; Isotretinoin; Quantum Dots; Rats; Selenium Compounds; Tretinoin

Apolipoprotein E (apoE) is the major cholesterol transport protein in the brain. Among the three human APOE alleles (APOE2, APOE3, and APOE4), APOE4 is the strongest genetic risk factor for late-onset Alzheimer disease (AD). The accumulation of amyloid-β (Aβ) is a central event in AD pathogenesis. Increasing evidence demonstrates that apoE isoforms differentially regulate AD-related pathways through both Aβ-dependent and -independent mechanisms; therefore, modulating apoE secretion, lipidation, and function might be an attractive approach for AD therapy. We performed a drug screen for compounds that modulate apoE production in immortalized astrocytes derived from apoE3-targeted replacement mice. Here, we report that retinoic acid (RA) isomers, including all-trans-RA, 9-cis-RA, and 13-cis-RA, significantly increase apoE secretion to ~4-fold of control through retinoid X receptor (RXR) and RA receptor. These effects on modulating apoE are comparable with the effects recently reported for the RXR agonist bexarotene. Furthermore, all of these compounds increased the expression of the cholesterol transporter ABCA1 and ABCG1 levels and decreased cellular uptake of Aβ in an apoE-dependent manner. Both bexarotene and 9-cis-RA promote the lipidation status of apoE, in which 9-cis-RA promotes a stronger effect and exhibits less cytotoxicity compared with bexarotene. Importantly, we showed that oral administration of bexarotene and 9-cis-RA significantly increases apoE, ABCA1, and ABCG1 levels in mouse brains. Taken together, our results demonstrate that RXR/RA receptor agonists, including several RA isomers, are effective modulators of apoE secretion and lipidation and may be explored as potential drugs for AD therapy.

Topics: Alleles; Alzheimer Disease; Animals; Anticarcinogenic Agents; Apolipoproteins E; Astrocytes; ATP Binding Cassette Transporter 1; ATP Binding Cassette Transporter, Subfamily G, Member 1; ATP-Binding Cassette Transporters; Bexarotene; Brain; Cell Line, Transformed; Humans; Lipoproteins; Lipoylation; Mice; Mice, Transgenic; Nerve Tissue Proteins; Receptors, Retinoic Acid; Retinoid X Receptors; Tetrahydronaphthalenes; Tretinoin

This paper reports the development of a method based on high-performance liquid chromatography (HPLC) coupled to second-order data modeling with multivariate curve resolution-alternating least-squares (MCR-ALS) for quantification of retinoic acid and its main isomers in plasma in only 5.5 min. The compounds retinoic acid (RA), 13-cis-retinoic acid, 9-cis-retinoic acid, and 9,13-di-cis-retinoic acid were partially separated by use of a Poroshell 120 EC-C18 (3.0 mm × 30 mm, 2.7 μm particle size) column. Overlapping not only among the target analytes but also with the plasma interferents was resolved by exploiting the second-order advantage of the multi-way calibration. A validation study led to the following results: trueness with recoveries of 98.5-105.9 % for RA, 95.7-110.1 % for 13-cis-RA, 97.1-110.8 % for 9-cis-RA, and 99.5-110.9 % for 9,13-di-cis-RA; repeatability with RSD of 3.5-3.1 % for RA, 3.5-1.5 % for 13-cis-RA, 4.6-2.7 % for 9-cis-RA, and 5.2-2.7 % for 9,13-di-cis-RA (low and high levels); and intermediate precision (inter-day precision) with RSD of 3.8-3.0 % for RA, 2.9-2.4 % for 13-cis-RA, 3.6-3.2 % for 9,13-di-cis-RA, and 3.2-2.9 % for 9-cis-RA (low and high levels). In addition, a robustness study revealed the method was suitable for monitoring patients with dermatological diseases treated with pharmaceutical products containing RA and 13-cis-RA.

Topics: Alitretinoin; Chromatography, High Pressure Liquid; Humans; Isomerism; Isotretinoin; Limit of Detection; Time Factors; Tretinoin

Zebrafish (Danio rerio) embryos were comparably exposed to seven known agonists of retinoid X receptors (RXRs) including two endogenous compounds (9-cis-retinoic acid and docosahexaenoic acid), four man-made selective ligands (LGD1069, SR11237, fluorobexarotene and CD3254), and a biocide (triphenyltin). The dominant phenotypes of malformation were sharp mouths and small caudal fins in 1 mg/L SR11237-treated group after 5 days exposure. 9-cis-retinoic acid and LGD1069 induced multiple malformations including small eyes, bent notochords, reduced brain, enlarged proctodaems, absence of fins, short tails and edema after 5 days exposure. Fluorobexarotene and CD3254 induced similar phenotypes of malformations after 5 days exposure at low concentration (20 μg/L) to those after the 1st d exposure at high concentrations (50 and 100 μg/L). Triphenlytin induced multiple malformations including deformed eyes, bent notochords, bent tails, and edema in hearts after 5 days exposure at concentrations of 1-10 μg Sn/L. In contrast, no discernible malformations were observed in triphenlytin-treated groups after each separate day exposure. These agonists not only showed different ability of teratogenicity but also induced different phenotypes of malformation in zebrafish embryos. In addition, the sensitive stages of zebrafish embryos were different in response to these agonists. Therefore, our results suggest that the agonists of RXRs had divergent teratogenicity in zebrafish embryos.

Topics: Animals; Embryo, Nonmammalian; Environmental Exposure; Female; Male; Organotin Compounds; Phenotype; Retinoid X Receptors; Teratogens; Tretinoin; Water Pollutants, Chemical; Zebrafish

The MtT/E and MtT/S cells have been established from a mammotrophic pituitary tumor, and postulated to be progenitor and premature growth hormone (GH) cells, respectively. The difference in the regulation of GH and GH-releasing hormone (GHRH) receptor gene transcription in relation to the developmental stage of GH cells were examined in these two cell lines. In MtT/S cells, triiodothyronine (T3), all-trans retinoic acid (RA) and 9-cis retinoic acid (9cRA) stimulated GH promoter activity but dexamethasone (DEX) did not. On the other hand, DEX stimulated GHRH-receptor promoter alone. T3, RA and 9cRA showed little effect alone but each of them augmented the effect of DEX when used together with DEX. In MtT/E cells, DEX, RA and 9cRA showed similar effect as observed in MtT/S cells on both GH and GHRH-receptor promoter activity. However, T3 neither stimulated GH promoter activity nor augmented the DEX-induced GHRH-receptor gene transcription in MtT/E cells. RT-PCR analyses revealed that both cell types expressed TRalpha1, TRbeta1 and TRalpha2, but expression of TRbeta2, a pituitary specific isoform of TR, was only detected in MtT/S cells. However, the deficiency of TRbeta2 for its own sake does not appear to be a reason why T3 action was not observed in MtT/E cells, because co-transfection of expression plasmids for TRbeta2 and RXRalpha failed in conferring on the cells an ability to respond to T3 by increased GH or GHRH-receptor promoter activity. These results suggest that the acquisition of mechanisms responsible for the regulation of GH or GHRH-receptor transcription by T3 may be involved in the process of functional development of GH cells.

Topics: Animals; Cell Line, Tumor; Chlorocebus aethiops; COS Cells; Gene Expression Regulation; Gene Expression Regulation, Neoplastic; Growth Hormone; Pituitary Neoplasms; Promoter Regions, Genetic; Rats; Receptors, Neuropeptide; Receptors, Pituitary Hormone-Regulating Hormone; Receptors, Somatotropin; Tretinoin; Triiodothyronine

To determine the effects of peroxisome proliferator-activated receptor alpha (PPARalpha) and retinoid X receptor (RXR) agonists on insulin action, we investigated the effects of Wy-14643 and 9- cis-retinoic acid (9- cis-RA) on insulin signalling and glucose uptake in human myotubes.. Primary cultures of differentiated human skeletal muscle cells, established from healthy subjects and Type 2 diabetic patients, were used to study the effects of Wy-14643 and 9- cis-RA on the expression and activity of proteins involved in the insulin signalling cascade. Glucose transport was assessed by measuring the rate of [(3)H]2-deoxyglucose uptake.. Wy-14643 and 9- cis-RA increased IRS-2 and p85alpha phosphatidylinositol 3-kinase (PI 3-kinase) mRNA and protein expression in myotubes from non-diabetic and Type 2 diabetic subjects. This resulted in increased insulin stimulation of protein kinase B phosphorylation and increased glucose uptake in cells from control subjects. Myotubes from diabetic patients displayed marked alterations in the stimulation by insulin of the IRS-1/PI 3-kinase pathway. These alterations were associated with blunted stimulation of glucose transport. Treatment with Wy-14643 and 9- cis-RA did not restore these defects but increased the basal rate of glucose uptake.. These results demonstrate that PPARalpha and RXR agonists can directly affect insulin signalling in human muscle cells. They also indicate that an increase in the IRS-2/PI 3-kinase pathway does not overcome the impaired stimulation of the IRS-1-dependent pathway and does not restore insulin-stimulated glucose uptake in myotubes from Type 2 diabetic patients.

Topics: Adult; Diabetes Mellitus, Type 2; Glucose; Humans; Insulin; Insulin Receptor Substrate Proteins; Intracellular Signaling Peptides and Proteins; Muscle Fibers, Skeletal; Muscle, Skeletal; Phosphatidylinositol 3-Kinases; Phosphoproteins; Pyrimidines; Reference Values; Signal Transduction; Tretinoin

9-cis-Retinoic acid (9CRA) and all-trans-retinoic acid (ATRA) are known to be involved in the regulation of glucose homeostasis in vertebrates by inducing insulin release and expression of glucose transporter proteins. In view of the fact that both 9CRA and ATRA are endogenous to the fiddler crab, Uca pugilator, that a retinoid X receptor exists in this fiddler crab and that activities of insulin-like and insulin-like growth factor-like peptides have been reported for crustaceans, we investigated whether 9CRA and ATRA also play a role in glucose homeostasis in U. pugilator. Neither 9CRA nor ATRA was found to produce hypoglycemic effects at a dose of 10 microg/g live mass. However, 9CRA, but not ATRA, induced hyperglycemia. Such 9CRA-induced hyperglycemia was apparently mediated by the eyestalk hormone CHH since injection of 9CRA into eyestalk-ablated crabs did not result in hyperglycemia. ATRA was found to have an inhibitory effect on the recovery of blood glucose concentration following ATRA administration. Discussion on the possible mechanisms for the actions of 9CRA and ATRA was presented.

Topics: Animals; Arthropod Proteins; Blood Glucose; Brachyura; Eye; Homeostasis; Hyperglycemia; Invertebrate Hormones; Nerve Tissue Proteins; Ophthalmologic Surgical Procedures; Tretinoin

Topics: Antineoplastic Agents; Antioxidants; Benzamides; Breast Neoplasms; Drug Resistance, Neoplasm; Enzyme Inhibitors; Female; Genes, BRCA1; Genes, BRCA2; Humans; Imatinib Mesylate; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Lung Neoplasms; Male; Mastectomy; Ovarian Neoplasms; Ovariectomy; Piperazines; Protein-Tyrosine Kinases; Pyrimidines; Receptors, Retinoic Acid; Smoking; Tobacco Smoke Pollution; Tretinoin; Vitamins

Peroxisome proliferator-activated receptor (PPAR) gamma is expressed in human colon cancer, prostate cancer and breast cancer cells, and PPARgamma activation induces growth inhibition in these cells. PPARgamma expression in human gastric cancer cells, however, has not been fully investigated. We report the PPARgamma expression in human gastric cancer, and the effect of PPARgamma ligands on proliferation of gastric carcinoma cell lines. Immunohistochemistry was used to demonstrate the presence of PPARgamma protein in surgically resected specimens from well differentiated, moderately differentiated and poorly differentiated adenocarcinoma. We used reverse transcription-polymerase chain reaction and Northern and Western blot analyses to demonstrate PPARgamma expression in four human gastric cancer cell lines. PPARgamma agonists (troglitazone and 15-deoxy-Delta(12,14)-prostaglandin J2) showed dose-dependent inhibitory effects on the proliferation of the gastric cancer cells, and their effect was augmented by the simultaneous addition of 9- cis retinoic acid, a ligand of RXRalpha. Flow cytometry demonstrated G1 cell cycle arrest and a significant increase of annexin V-positive cells after treatment with troglitazone. These results suggest that induction of apoptosis together with G1 cell cycle arrest may be one of the mechanisms of the antiproliferative effect of PPARgamma activation in human gastric cancer cells.

Topics: Apoptosis; Cell Cycle; Cell Division; Flow Cytometry; Gene Expression Regulation, Neoplastic; Humans; Ligands; Receptors, Cytoplasmic and Nuclear; Stomach Neoplasms; Transcription Factors; Tretinoin; Tumor Cells, Cultured

9-cis-Retinoic acid (9cRA), a geometric isomer of all-trans-retinoic acid (atRA), is an endogenous high-affinity ligand for retinoid X receptors and retinoic acid receptors activating them with high potency. 9,13-di-cis-Retinoic acid (9,13dcRA) has been described as a major plasma metabolite of 9cRA. In this study, the biological activity and the metabolism of 9cRA and 9,13dcRA were investigated and compared with those of atRA in a retinol-free culture system of HaCaT keratinocytes. 9cRA exhibited a slightly weaker activity overall than atRA in inhibiting cell proliferation, inducing cellular retinoic acid binding protein II (CRABP II) mRNA levels and upregulating cytokeratin 19 expression. 9,13dcRA regulated HaCaT keratinocyte activity only at the highest concentration tested (10(-6) M). In cultures of HaCaT keratinocytes with atRA and 9cRA, rapid intracellular accumulation of atRA was observed within 2 h, and atRA levels were higher with atRA treatment than with 9cRA treatment. 9,13dcRA remained relatively stable in the medium with intracellular 9,13dcRA levels below the level of detection. Taken together, 9cRA seems to be slightly less potent than atRA in regulating the biological activity of HaCaT keratinocytes, while its metabolite 9,13dcRA is effectively inactive at biologically relevant concentrations. Our data suggest a prodrug/drug relationship between 9cRA and atRA in human keratinocytes. 9,13dcRA seems to be a weaker prodrug of atRA or an inactive metabolic derivative.

Topics: Alitretinoin; Antineoplastic Agents; Cell Division; Cell Line; Dose-Response Relationship, Drug; Humans; Keratinocytes; Keratins; Receptors, Retinoic Acid; RNA, Messenger; Tretinoin

During hepatic fibrosis, hepatic stellate cells (HSCs) transform into myofibroblastic cells and lose their intracellular droplets of retinyl esters, the storage form of vitamin A. Recently, we have demonstrated that 9,13-di-cis-retinoic acid (RA), a geometric isomer identified as a stable and major metabolite of vitamin A in circulation, stimulates the synthesis of plasminogen activator (PA) and induces PA/plasmin-dependent latent transforming growth factor (TGF)-beta activation in HSC cultures, probably via induction and activation of RA receptor (RAR) alpha. The aim of the present study was to address a potential link between the loss of retinyl esters to increased formation of RA(s), which might play a role in facilitating TGF-beta-mediated liver fibrogenesis in vivo.. We examined the effect of 9,13-di-cis-RA on transactivating activity of RARalpha in HeLa cells as well as its effect on PA- and TGF-beta-dependent collagen synthesis in rat and human HSC cultures. We measured the changes in 9,13-di-cis-RA levels both during activation of rat HSCs in vitro and during porcine serum-induced rat hepatic fibrosis in vivo and correlated this with RAR alpha/beta, PA, TGF-beta and type I procollagen mRNA expression in the fibrotic liver.. 9,13-di-cis-RA transactivated RARalpha, and provoked PA/plasmin and TGF-beta-dependent procollagen synthesis in HSCs. 9,13-di-cis-RA levels were increased both in activated HSCs in vitro and in fibrotic liver accompanying the enhanced expression of RAR alpha/beta, PA, TGF-beta and procollagen in vivo.. These findings suggest a potential link between 9,13-di-cis RA formation and hepatic fibrosis via formation of TGF-beta in vivo, and thus provide further insight into the biologic role of retinoids during hepatic fibrogenesis.

Topics: Animals; Cells, Cultured; Collagen; HeLa Cells; Humans; Liver; Liver Cirrhosis, Experimental; Male; Plasminogen Activators; Procollagen; Rats; Rats, Wistar; Receptors, Retinoic Acid; Retinoids; RNA; Transforming Growth Factor beta; Tretinoin

Certain thiol-containing compounds catalyze, in a chemical reaction, the isomerization of 9-cis-retinoic acid to a mixture of all-trans-retinoic acid, 9-cis-retinoic acid, 13-cis-retinoic acid, and 9,13-dicis-retinoic acid. In the presence of such catalysts, all-trans-retinoic acid gives rise to the same mixture. Reactions approaching equilibrium contain more all-trans-retinoic acid than either of the other isomers. Small molecules effective as catalysts are mercaptoethanol, L-cysteine methyl ester, glutathione, and N-acetyl-L-cysteine. Apoferritin (a thiol-containing protein), native microsomes, and, to a lesser extent, boiled microsomes catalyze the reaction. In intact cells, these interconversions also occur in a process inhibited by a sulfhydryl-specific reagent. The thiol-catalyzed isomerization of 9-cis-retinoic acid may be relevant in the biological activity of this compound.

Topics: Alitretinoin; Animals; Cell Line; Humans; In Vitro Techniques; Isotretinoin; Mice; Microsomes, Liver; Sulfhydryl Compounds; Tretinoin

We studied the mechanism by which 9,13-di-cis-retinoic acid (9,13dcRA), a novel and endogenous stereoisomer of all-trans-RA, induces TGF-beta formation in a human liver stellate cell line, LI90. 9,13dcRA induced the expression of RAR alpha and RARbeta, enhanced the production of tissue-type plasminogen activator (tPA), thereby, surface plasmin levels, and induced the activation of latent TGF-beta. Similar effects were obtained with RAR alpha-selective retinoid, but not with RARbeta- or RARgamma-selective retinoid, and the induction was inhibited by RAR alpha-selective antagonist. These results suggest that 9,13dcRA up-regulates tPA expression, resulting in the formation of TGF-beta by LI90 cells, at least in part, via induction and activation of RAR alpha.

Topics: Animals; Cell Line; Cells, Cultured; Humans; Liver; Rats; Receptors, Retinoic Acid; Retinoic Acid Receptor alpha; RNA, Messenger; Tissue Plasminogen Activator; Transforming Growth Factor beta; Tretinoin

Topics: Alitretinoin; Animals; Humans; Isomerism; Tretinoin

The predominant isomer of retinoic acid in the plasma of dairy cows during the periparturient period is 9,13-di-cis-retinoic acid. Because retinoic acids influence the activity of cells in a variety of tissues, including the immune system, the potential for this isomer to modulate the bovine immune system during the periparturient period must be considered. The present study examined the in vitro effects of 9,13-di-cis-retinoic acid on the reactivity and phenotype of blood mononuclear leukocytes from nongravid Holstein heifers that were sensitized to antigens and that had naturally low plasma concentrations of 9,13-di-cis-retinoic acid. In this system, 9,13-di-cis-retinoic acid, approximating the highest plasma concentrations occurring in vivo during the periparturient period, had no effect on DNA synthesis, secretion of interleukin-2 or interferon-gamma, or secretion of immunoglobulin by unstimulated cultures or cultures stimulated by mitogen (pokeweed mitogen) or antigen (ovalbumin). The composition of unstimulated and stimulated mononuclear leukocyte populations, based on percentages of specific cell types, was unaffected by 9,13-di-cis-retinoic acid at the physiologic concentration of 10(-8) M. 9,13-di-cis-Retinoic acid did not affect the actual number of cells in unstimulated cultures and cultures stimulated by antigen but did cause a moderate reduction in the number of cells, primarily CD4+ lymphocytes, in cultures stimulated by mitogen. Overall, these results suggest that the elevated concentration of 9,13-di-cis-retinoic acid in maternal plasma may have a negligible effect on the reactivity and phenotype of cells constituting the circulating mononuclear leukocyte population.

Topics: Animals; Cattle; Cell Division; Cytokines; DNA; Female; Immunoglobulins; Interferon-gamma; Interleukin-2; Leukocytes, Mononuclear; Phenotype; Tretinoin