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PubMed1991

Cultivation of human dermal microvascular endothelial cells in vitro: immunocytochemical and ultrastructural characterization and effect of treatment with three synthetic retinoids.

A new reliable and reproducible technique to culture endothelial cells from the small vessels and capillaries of human skin is introduced, and proliferation and differentiation of the growing cells are characterized. The endothelial origin of the culture cells was confirmed by light- and electron microscopy and by labelling with Ulex europaeus Agglutinin I and an antibody against Factor VIII-related antigen. Further immunocytochemical characterization showed that 92-100% of the cells were positive for beta 2-microglobulin and the entire cell population expressed vimentin, whereas cytokeratins, desmin, HLA-DR antigen, Leu 6 and S 100 protein, could not be detected. As vascular endothelium is a common site of inflammation and retinoids have been shown to be of good clinical efficacy in some chronic inflammatory skin diseases, we investigated the influence of etretinate, etretin and isotretinoin on proliferation and antigen expression of our culture cells. All retinoids applied inhibited proliferation of endothelial cells in a dose- and time-dependent manner whereas they induced neither HLA-DR nor intercellular adhesion molecule-1 (ICAM-1). Furthermore, none of the retinoids applied influenced the gamma-interferon-induced expression of these surface antigens on endothelial cells. Our results suggest that the action of retinoids in skin inflammation is not mediated by modulation of HLA-DR or ICAM-1. The cell culture technique described here is an interesting and reliable model for studying the influence of drugs on endothelial cell growth and differentiation in vitro.

Acitretin↗
PubMed1991

The effect of topical retinoids on the leukotriene-B4-induced migration of polymorphonuclear leukocytes into human skin.

Systemic retinoids are effective in a variety of inflammatory dermatoses. Disorders in which polymorphonuclear leukocytes (PMN) are involved, such as psoriasis and acne, respond particularly well to various retinoids. However, side-effects restrict the use of systemic retinoids to severe manifestations. Topical application might provide the possibility of avoiding the systemic side-effects of these compounds. In this communication we report on the modulation of transepidermal migration of PMN by topical application of all-trans-retinoic acid, 13-cis-retinoic acid, arotinoid methyl sulphone and arotinoid ethyl sulphone. Test areas of healthy volunteers were pretreated with these retinoids in a cream base and with corresponding placebo creams, and intraepidermal accumulation of PMN was quantified 24 h after epicutaneous challenge with leukotriene B4 (LTB4), using elastase as a marker enzyme. Topical treatment with 13-cis-retinoic acid resulted in a marked and statistically significant inhibition of the LTB4-induced migration of PMN. All-trans-retinoic acid, arotinoid methyl sulphone and arotinoid ethyl sulphone reduced the accumulation of PMN slightly, but not statistically significantly. Topical treatment with arotinoid methyl sulphone had no effect.

Administration, Topical↗
PubMed1987

Effect of orally administered aromatic retinoid on murine Langerhans cells.

The effect of orally administered aromatic retinoid (Ro 10-9359) on murine epidermal Langerhans cells (LC) was studied in vivo and in vitro. Daily administration of retinoid caused a transient increase in LC density, as determined by staining for Ia antigens, during the first few days of treatment and thereafter a continuing decrease that reached a maximum at 2 weeks. In addition, the morphology and location in the epidermis had been altered. When the treatment was continued to 4 weeks, the density of LC returned to normal. The Ia-antigen-presenting function of epidermal cells to an allo-Ia-reactive cloned T cell line was elevated at all stages of retinoid treatment examined. This elevation did not correlate with the density of histochemically stainable Ia+ LC. These findings suggest that orally administered retinoid profoundly alters the functional capacity of Ia+ LC.

Administration, Oral↗
PubMed1990

Persistence of added retinoids in organ culture media during induction of mucous metaplasia and glandular morphogenesis in hamster cheek pouches.

The retinoid concentration (determined colorimetrically) did not change significantly in retinyl acetate-supplemented (6 micrograms/ml) Eagle's Minimal Essential Medium containing 10% fetal calf serum when stored at -20 or 4 degrees C over 7 days. After the medium was incubated at 37 degrees C for 48 h, 37-49% of the retinoid remained, whether or not tissue (neonatal Syrian hamster cheek pouch) was present, and irrespective of explant age. The normal retinoid level in the tissue was approximately 0.25 micrograms per gram. Therefore, neonatal hamster cheek pouches, incubated in medium with the addition of 6 micrograms of retinyl acetate per ml of medium and undergoing mucous metaplasia and some mucous gland morphogenesis, were continually being exposed to retinoid levels which, though gradually decreasing, remained well above their normal physiological level.

Animals↗
PubMed1988

Inhibition of human non-pancreatic phospholipases A2 by retinoids and flavonoids. Mechanism of action.

The interaction of retinoids and flavonoids with phospholipases A2 (PLA2) was studied to assess the mechanism of inhibition. Retinoids, such as retinal, retinol, retinoic acid and retinol acetate, and flavonoids, such as quercetin, rutin, morin and sciadopitysin, inhibit Ca2+-dependent PLA2 activity of human synovial fluid (HSF) in vitro in a dose-dependent fashion; ID20S ranged from 2-8 microM. Retinal inhibited neutral active Ca2+-dependent PLA2S from human platelets, human plasma, human polymorphonuclear leukocytes and Naja mossambica mossambica venom in a dose-dependent manner while quercetin inhibits extracellular PLA2 activities of human plasma, HSF and N. m. mossambica venom in a dose-dependent manner but not PLA2 activity derived from human platelets and polymorphomonuclear leukocytes. Inhibition of PLA2 activity by both flavonoid and retinoids were independent of Ca2+ or Na+. Increasing substrate concentration (9-144 nmols) relieved the inhibition of HSF-PLA2 activity by quercetin indicating probable interaction with the substrate. The inhibition by retinal is independent of substrate concentration suggesting that inhibition by retinal is probably due to direct interaction with the enzyme. both retinal and quercetin quenched the relative fluorescent intensity of N. m. mossambica PLA2 and in a dose-dependent manner in the same concentration range at which they inhibit in vitro PLA2 activity. Retinal and quercetin shift the thermotropic phase transition of distearoylphosphatidylethanolamine (DSPE) liposomes. Both compounds broadened the transition peak, shifted the Tm to lower temperature, and decreased enthalpy significantly. These findings indicate that inhibition of non-pancreatic human PLA2S by retinoids and flavonoids can be mediated by interaction with enzyme and/or substrate.

Arthritis↗
PubMed1988

Short- and long-term effects of a single dose of bisphosphonates on retinoid-induced bone resorption in thyroparathyroidectomized rats.

The inhibitory effect of a single subcutaneous (s.c.) dose of three different bisphosphonates (Bps)--4-amino-1-hydroxybutylidene-1,1-bisphosphonate (AHBuBP), 2-(2-pyridinyl)-ethylidene-1,1-bisphosphonate (2-PEBP), and dichloromethylene-bisphosphonate (Cl2MBP)--was studied in a model of retinoid-induced bone resorption, which consists of assessing the hypercalcemic effect of the arotinoid Ro 13-6298 given s.c. for three days in thyroparathyroidectomized (TPTX) rats. The retinoid was given on day 0, 1, and 2. Bps were administered together with or at different times prior to the first dose of retinoid. A dose-dependent inhibition was obtained with all three compounds. AHBuBP produced complete inhibition which remained for 3 weeks at 0.1 mg P/kg. The dose-response curves were identical when the compound was given on the first day of retinoid administration (day 0) or 6 days earlier. With 2-PEBP, the dose-response curve was the same as that for AHBuBP when given on day 0. When given 6 days earlier, the curve was shifted to 30 times less potency. Cl2MBP was about 100 times less potent than AHBuBP when given on day 0, with 3 mg P/kg producing complete inhibition. When given 6 days earlier, the curve was also shifted to 10 times less potency, and even 30 mg P/kg failed to produce complete inhibition. With 10 mg P/kg, the inhibitory effect was maintained partially for up to 3 weeks. This study shows that in this model of bone resorption the inhibitory effect of a single dose of certain Bps is effective for at least 3 weeks and that the compounds vary in their activity over time.

Animals↗
PubMed1988

Proliferation and differentiation of human squamous carcinoma cell lines and normal keratinocytes: effects of epidermal growth factor, retinoids, and hydrocortisone.

Exposure of squamous carcinoma cell (SCC) lines, exhibiting high levels of epidermal growth factor (EGF) receptors, to EGF for 6 d caused a dose-dependent inhibition of cell proliferation. This EGF-induced inhibition of cell proliferation occurred under both low (0.06 mM) and normal (1.6 mM) Ca2+ concentrations. Furthermore, the extent of EGF-induced inhibition of cell proliferation seemed to be independent of the number of EGF-receptors. This conclusion is based on the notion that the various SCC lines exhibited an increasing number of EGF receptors accompanied by a decreasing ability to differentiate, whereas no relationship was observed with the EGF-induced inhibition of cell proliferation in these cell lines. Retinoids caused also a dose-dependent inhibition of cell proliferation. The effects of EGF and retinoids were additive, indicating that different regulatory mechanisms are involved. On the other hand, hydrocortisone caused a stimulation of SCC-proliferation, also independent of EGF. In contrast to SCC cells, EGF did not affect significantly the rate of proliferation of normal keratinocytes. However, the simultaneous addition of EGF and hydrocortisone resulted in a significant increase in the rate of keratinocyte proliferation only in cells grown under normal calcium conditions. Differentiation capacity of normal keratinocytes and SCC lines was not affected by EGF. Furthermore, the retinoid-induced decrease and hydrocortisone-induced increase of competence of cells to form cornified envelopes was not affected by EGF. These observations suggest that the action of retinoids and hydrocortisone on both cell proliferation and cell differentiation occurs independently of EGF receptors.

Calcium↗
PubMed1998

Properties of retinoids. Structure, handling, and preparation.

Retinoids are unstable compounds being readily oxidized and/or isomerized to altered compounds, especially in the presence of oxidants including air, light, and excessive heat. They are labile toward strong acids and solvents that have dissolved oxygen or peroxides. In this review, procedures for handling and storage of retinoids and biological samples containing them have been described. The physical and chemical properties of retinoids have been reported. Simplified procedures for derivatizations and purification, and methods for quantitation of retinoids have been presented.

Chromatography↗
PubMed1985

Retinoids and tumorigenesis: mechanistic considerations.

Retinoids enhanced adhesion of spontaneously-transformed mouse fibroblasts to the substrate of culture in a reversible way. They also caused an increase in the incorporation of radioactively-labeled mannose into 'complex type' oligosaccharides of glycopeptides isolated from the cell surface. Consistent with this response was a similar increase in 'complex type' oligosaccharide chains from the collagen binding domain of fibronectin from retinoid-treated, more adhesive rat sternal chondrocytes. Tumor promoting phorbol esters caused a decrease in adhesion and the shedding of fibronectin from the cell surface. Opposing actions of tumor promoting agents and retinoids exist at the level of expression of squamoid metaplasia of the respiratory tract. Both hepatomas with minimal and a maximal growth rate contained less retinyl palmitate than host liver. Similarly, the level of the cellular retinol binding protein (CRBP) was greatly reduced in the hepatoma tissue. Considerations on the antagonistic actions of tumor promoters and retinoids, the phenotype of squamous cell carcinomas of the bronchus and the vitamin A deficient status of hepatoma tissue suggested the following concepts: compounds which perform essential functions (e.g. vitamin A) may prevent initiated cells from expressing the tumorigenic phenotype; tumor promoters may act by interfering either directly or indirectly with the essential function of these compounds; normal cells respond to deficiency of essential function by differentiation and/or cell death; and initiated cells express the new phenotype, have a growth advantage and become self-sufficient.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMedDate not supplied

Pharmacokinetics, tissue distribution and placental permeability of tetrahydro-tetramethyl-naphthalenyl-propenyl benzoic acid (a retinoidal benzoic acid derivative) in hamsters.

Tritiated tetrahydro-tetramethyl-naphthalenyl-propenyl benzoic acid (TTNPB; Ro 13-7410) was administered as a single oral bolus to pregnant hamsters (day 8) to determine the maternal plasma pharmacokinetic profile and peripheral tissue distribution patterns. Blood and tissue, including embryo or fetus, were collected at specific time intervals to 96 h and assayed for total radioactive compounds and/or parent retinoid. No lag time was required to describe retinoid absorption (t 1/2 pi = 1.2 h) with peak plasma levels at 2.4 h; the concentrations then declined with exponential elimination from the central compartment (t 1/2 e = 3 h). The maximum concentrations of circulating radioactive compound or metabolites after 100 micrograms/kg [3H]2-TTNPB occurred in liver greater than fetus greater than adrenal greater than lung approximately equal to kidney greater than plasma; after 1000 micrograms/kg, maternal liver accumulated the highest concentration followed by plasma greater than fetus = placenta = uterus. An unidentified, polar metabolite was detected in plasma at 0.5 h and by 12 h constituted greater than 90% of the total circulating radioactivity. TTNPB was absorbed and cleared more slowly, concentrated in the conceptus to a higher degree and possessed greater intrinsic activity than the naturally-occurring tetraene retinoids. These properties contribute to the marked teratogenic activity of TTNPB as compared to the tetraene retinoids.

Animals↗
PubMed2001

Acidic fibroblast growth factor overexpression partially protects 3T3 fibroblasts from apoptosis induced by synthetic retinoid CD437.

Retinoids are proapoptotic compounds with therapeutic potential for treating cancer. We evaluated the apoptotic effect of the novel retinoid CD437, and particularly its relationship to Akt and acidic fibroblast growth factor (aFGF). We hypothesized that the novel synthetic retinoid CD437 would exert its apoptotic effect by reducing the activity of Akt. We further hypothesized that aFGF would protect against CD437 apoptosis by preserving the activity of Akt. Initially we demonstrated that CD437 produces apoptotic cell death in NIH 3T3 fibroblasts, and that this effect is attenuated in fibroblasts transfected to express aFGF. Next we assessed Akt activity and showed that phospho-Akt is significantly reduced in 3T3 cells exposed to CD437. We showed that this effect is less pronounced in aFGF transfected 3T3 cells. Furthermore, we observed that the addition of exogenous aFGF to 3T3 cells significantly increases Akt phosphorylation. These findings tend to confirm our hypothesis that reduction in Akt activation is a mechanism involved in the apoptotic effect of the retinoid CD437, and that preservation of Akt phosphorylation occurs in response to aFGF and appears to explain the partially protective effect of aFGF for 3T3 cells vis a vis CD437.

3T3 Cells↗
PubMed2003

Structural development of synthetic retinoids and thalidomide-related molecules.

The full-scale commercial appearance of antibiotics in the 1950s caused a shift in the nature of lethal diseases from infectious and acute to noninfectious and chronic. In this situation, biological response modifiers (BRMs), which are not based on selective toxicity, could be expected to be useful. Several types of BRM exist, including retinoids, which act directly on cells at the level of gene expression, and thalidomide and related molecules, which modulate the production of various cytokines. We have been engaged in medicinal, chemical, and structural development studies based on these bioactive compounds. Retinoids include all- trans-retinoic acid (ATRA), a major active form of vitamin A (retinol), and its bioisosters, which elicit their biological effects by binding to their nuclear receptors, retinoic acid receptors (RARs). ATRA has been used in differentiation therapy, typically for the treatment of acute promyelocytic leukemia, and the treatment of dermatological diseases. Our structural development studies of retinoids, including computer-assisted molecular design, have yielded class/subtype-selective agonists, synergists, and antagonists of RARs and their partner nuclear receptors, retinoid X receptors. Among them, the benzanilide-type compounds, Am80 and TAC101, are under phase II and I/II clinical studies in Japan and the USA, respectively. Thalidomide is a hypnotic/sedative drug that was withdrawn from the market because of teratogenicity. However, thalidomide has been established to be useful in the treatment of various diseases including cancer. Thalidomide elicits a wide range of pharmacological effects, including anticachexia, anti-tumor-promoting, antiangiogenic, immunosuppressing, antiviral, hypoglycemic, and antimetastatic activities. We have found that thalidomide is a multitarget drug. Hypothetical target events/molecules of thalidomide include tumor necrosis factor-alpha production, nuclear androgen receptor, cyclooxygenases, aminopeptidases, and alpha-glucosidase. Specific and potent compounds for each of these target phenomena/molecules have been prepared by appropriate modification of the thalidomide structure, and are expected to be superior lead compounds for novel immunomodulators, antiangiogenic agents, and anti-tumor-promoting agents.

Computer Simulation↗
PubMed2006

Mild whole-body heat stress alters retinoid metabolism in the rat small intestine.

Mild heat treatment can modulate metabolism and prevent stress-induced alterations in cells and tissues. Retinoids are known to influence cellular metabolism and are essential for growth and differentiation, particularly of epithelial tissue. This study examines the effect of mild heat treatment on retinoid alterations in enterocytes in the rat small intestine. Heat treatment changed the differentiation pattern of enterocytes along the villus-crypt axis, accompanied by increases in retinol, retinaldehyde, and retinoic acid in proliferating crypt cells. Activities of retinoid metabolizing enzymes such as retinaldehyde oxidase and retinaldehyde reductase were also increased. These results suggest that mild heat treatment can alter retinoid metabolism in the small intestine, which might influence epithelial cell proliferation and differentiation.

Animals↗
PubMed1989

An overview of the retinoids.

The retinoids, a group of compounds consisting of vitamin A and its derivatives, have been the subject of intense investigation over the past 30 years. These molecules have shown beneficial effects in the areas of acne, psoriasis, neoplastic processes and, most recently, reversal of extrinsically aged skin. Additional retinoids are currently under development. Adverse reactions to these drugs include mucocutaneous irritation, hyperlipidemia, and profound teratogenicity. Appropriate patient selection is imperative before beginning therapy with these medications. An overview of retinoid metabolism and the currently available compounds is presented. The newest class of retinoids, the arotinoids, is also discussed.

Abnormalities, Drug-Induced↗
PubMed1983

Infrared spectroscopy of retinoids.

The Fourier transform infrared spectra of 15 purified retinoids were compared. Retinoids with conjugated C = O groups revealed the presence of a band between 1730 and 1630 cm-1 X A characteristic of retinoids is the presence of a band between 1650 and 1620 cm-1 due to C = C stretching where three to four conjugated C = O and C = C bonds were present or between 1610 and 1555 cm-1 where more conjugated unsaturations were present. The presence of cis double bonds was confirmed by a band at 1380 cm-1 while unsubstituted trans double bonds gave absorbances at 990 to 955 cm-1. Epoxy rings, which are present in some retinoids, resulted in bands at 1250, 880, and 790 cm-1 while a furan structure was confirmed by bands at 1175, 1083, and 1065 cm-1.

Chemical Phenomena↗
PubMed1990

Retinoids affect collagen synthesis through inhibition of ascorbate-induced lipid peroxidation in cultured human dermal fibroblasts.

Ascorbate has been shown to stimulate collagen synthesis in cultured human dermal fibroblasts by increasing transcription of the collagen genes. In the present studies, ascorbate stimulates lipid peroxidation at concentrations similar to those necessary to affect collagen synthesis. Molecules which inhibit lipid peroxidation, such as propyl gallate, cobalt chloride, and alpha-naphthol, also inhibit collagen synthesis, suggesting a correlation between the two phenomena. Retinoic acid and some synthetic retinoids have previously been shown to inhibit collagen synthesis in cultured human dermal fibroblasts. In our studies two different retinoids, at similar concentrations, inhibit both ascorbate-stimulated lipid peroxidation and collagen synthesis. Since high concentrations of retinoids were required, the ability of retinoids to inhibit the oxidant effect of ascorbate, and not their receptor-mediated activity, may be responsible for their effect on collagen synthesis.

Antioxidants↗
PubMed1994

Temporal distribution of endogenous retinoids in the embryonic mouse mandible.

Retinoids play an important part in embryonic pattern formation. They are necessary for normal differentiation of odontogenic tissues and, in excess, disrupt the pattern of tooth formation. Excess retinoids produce supernumerary buds of the dental lamina in the diastema region of the mouse embryonic mandible where teeth do not normally form. This effect is coincident with an increase in epithelial proliferation and an alteration in epidermal growth factor mRNA expression (a gene product necessary for tooth formation). It was found by high-performance liquid chromatography that endogenous retinoids are present in the developing murine mandible and that concentrations of some retinoids reach a peak at the time of the initiation of odontogenesis (dental lamina formation).

Animals↗
PubMed1994

Effects of the intermediate retinoid metabolite retinal on the pattern of the dental lamina in vitro.

Retinoids have important roles in pattern formation during embryonic development and might act as endogenous morphogens. They are necessary for normal odontogenesis and excess retinol alters the pattern of odontogenesis producing supernumerary buds of the dental lamina in the diastema region of the mouse mandible. Because the metabolism of retinoids in the developing mandible is unknown, the effects of retinal (an intermediate metabolite in the local conversion of retinol to retinoic acid) on the patterning of odontogenesis were examined. Retinal produces supernumerary buds and enhanced epithelial proliferation in day-9 mandibles in vitro. The endogenous levels of retinal in the mandible at the time of initiation of odontogenesis were also measured by high-performance liquid chromatography. Retinal was detected only at day 10 and not at later stages of development. Local metabolism of this intermediate retinoid may be a rate-determining step in the production of active retinoid metabolites that may control the pattern of the dentition, which is established at the time of the appearance of the dental lamina at embryonic day 12.

Animals↗