retinol-palmitate and Disease-Models--Animal

The 1925 classical observation that vitamin A deficiency leads to squamous metaplasia and epithelial keratinization, coupled with the later finding that excess vitamin A inhibits keratinization of chick embryo skin, set the foundation for the potential therapeutic use of retinoids in cutaneous conditions of keratinization. Significant progress has since been made understanding the molecular biology, biochemistry, pharmacology, and toxicology of vitamin A and its derivatives, collectively named retinoids. Natural and synthetic retinoids are now routinely used to treat acne, psoriasis, skin keratinization disorders, and photodamage. Retinoids also inhibit tumor formation and skin cancer development in experimental systems and in humans. Retinol and retinyl palmitate (RP) are found in cosmetic products and in foods and dietary supplements, which are all considered safe, by inclusion in the Generally Recognized as Safe Substances Database. However, the safety of topical retinoids was questioned in one publication and in a recent National Toxicology Program report of RP-containing topical preparations, suggesting the possible earlier onset of ultraviolet-induced squamous cell carcinomas in the hairless mouse photocarcinogenesis model. This suggestion contradicts a large body of data indicating that topical retinoids are chemoprotective in humans, and it was immediately challenged by new reviews on the safety of RP in general and within sunscreens. This paper will review the preclinical and clinical data supporting the safety and chemopreventive activity of retinoids, with an emphasis on RP, and will examine the experimental systems used to evaluate the safety of topical vitamin A preparations in order to provide perspective relative to human skin.

Topics: Administration, Cutaneous; Animals; Anticarcinogenic Agents; Disease Models, Animal; Diterpenes; Humans; Mice; Mice, Hairless; Neoplasms, Radiation-Induced; Retinoids; Retinyl Esters; Skin Neoplasms; Species Specificity; Ultraviolet Rays; Vitamin A

Overuse of vitamin A as a dietary supplement is a concern in industrialized countries. High-level dietary vitamin A is thought to shift immunity to a T helper 2 (Th2)-dominant one, resulting in the promotion of allergies. We have been studying a fluorescein isothiocyanate (FITC)-induced contact hypersensitivity (CHS) mouse model that involves Th2-type immunity. We fed a diet with a high retinyl palmitate content (250 international units (IU)/g diet) or a control diet (4 IU/g diet) to BALB/c mice for three weeks. No augmentation of FITC-induced CHS was found in mice fed the diet with a high vitamin A content, although accumulation of the vitamin was confirmed in the livers of these animals. The results indicated that relatively short-term feeding of the high-level vitamin A diet did not influence the Th2-driven response at a stage with significant retinol accumulation in the liver. The results were in contrast to the high-dose pyridoxine diets that produced a reduced response in FITC-induced CHS.

Topics: Animals; Dermatitis, Contact; Diet; Dietary Supplements; Disease Models, Animal; Diterpenes; Fluorescein; Fluorescein-5-isothiocyanate; Isothiocyanates; Liver; Mice, Inbred BALB C; Pyridoxine; Retinyl Esters; Severity of Illness Index; Th1-Th2 Balance; Th2 Cells; Vitamin A

Retinol palmitate, an analog of vitamin A, plays multiple roles in the nervous system, including neural differentiation, axon outgrowth, and neural patterning, and is also an antioxidative agent and thereby potential neuroprotectant for brain ischemia. The present study aimed at investigating the protective effects of retinol palmitate against ischemia-induced brain injury in a bilateral common carotid artery occlusion (BCCAO) model in mice. Ischemia induced by 20-min BCCAO resulted in significant neuronal morphological changes and reactive astrocyte proliferation in the hippocampus, particularly in the CA1 region, and these changes were accompanied by increased Notch1 expression. Intraperitoneal retinol palmitate administration before ischemia reduced ischemic neurons with Notch1 expression; the differences were statistically significant in both the 1.2mg/kg group and 12 mg/kg group. These results show that retinol palmitate prevents brain ischemia-induced neuronal injury with Notch1 expression and that Notch1 signaling could be involved in the neuroprotective mechanism. Retinol palmitate could be a treatment option for human brain infarction.

Topics: Analysis of Variance; Animals; Antioxidants; Astrocytes; Brain Ischemia; Disease Models, Animal; Diterpenes; Dose-Response Relationship, Drug; Gene Expression Regulation; Hippocampus; Male; Mice; Mice, Inbred C57BL; Neurons; Receptor, Notch1; Regional Blood Flow; Reperfusion; Retinyl Esters; Signal Transduction; Vitamin A

Calcific aortic valve disease (CAVD) is a major public health problem with no effective treatment available other than surgery. We previously showed that mature heart valves calcify in response to retinoic acid (RA) treatment through downregulation of the SRY transcription factor Sox9. In this study, we investigated the effects of excess vitamin A and its metabolite RA on heart valve structure and function in vivo and examined the molecular mechanisms of RA signaling during the calcification process in vitro.. Using a combination of approaches, we defined calcific aortic valve disease pathogenesis in mice fed 200 IU/g and 20 IU/g of retinyl palmitate for 12 months at molecular, cellular, and functional levels. We show that mice fed excess vitamin A develop aortic valve stenosis and leaflet calcification associated with increased expression of osteogenic genes and decreased expression of cartilaginous markers. Using a pharmacological approach, we show that RA-mediated Sox9 repression and calcification is regulated by classical RA signaling and requires both RA and retinoid X receptors.. Our studies demonstrate that excess vitamin A dietary intake promotes heart valve calcification in vivo. Therefore suggesting that hypervitaminosis A could serve as a new risk factor of calcific aortic valve disease in the human population.

Topics: Animals; Aortic Valve; Calcinosis; Cell Line; Chick Embryo; Collagen Type II; Dietary Supplements; Disease Models, Animal; Diterpenes; Gene Expression Profiling; Gene Expression Regulation; Heart Valve Diseases; Hypervitaminosis A; Mice; Mice, Inbred C57BL; Oligonucleotide Array Sequence Analysis; Osteogenesis; Osteopontin; Receptors, Retinoic Acid; Retinoid X Receptors; Retinyl Esters; RNA Interference; Signal Transduction; SOX9 Transcription Factor; Time Factors; Tissue Culture Techniques; Transfection; Tretinoin; Vitamin A; Vitamins

Topics: Animals; Antioxidants; Disease Models, Animal; Diterpenes; Drug Approval; Humans; Mice; Retinyl Esters; Skin Neoplasms; Sunscreening Agents; United States; Vitamin A

To investigate ability of vitamin A (VA, retinol palmitate) to promote wound healing after injury in rabbit eye.. After keratoconjunctival injury by 20 microL of n-heptanol, VA eye drops at 500, 1000, or 1500 IU/mL were started 6 times a day for 11 days. Fluorescein and rose bengal staining and histological analysis were performed.. Fluorescein staining was significantly reduced by 1000 and 1500 IU/mL of VA and rose bengal staining by all concentrations. Histological examination revealed acceleration of wound healing after 7 days (1500 IU/mL).. VA may be useful in treatment of keratoconjunctival injury.

Topics: Animals; Burns, Chemical; Conjunctival Diseases; Corneal Diseases; Disease Models, Animal; Diterpenes; Epithelial Cells; Eye Burns; Eye Proteins; Fluorescein; Fluorescent Dyes; Heptanol; Male; Mucins; Ophthalmic Solutions; Rabbits; Retinyl Esters; Rose Bengal; Tears; Vitamin A; Wound Healing

The aim of this study was to obtain a prolonged release of Vitamin A palmitate (RAP) and aciclovir from biodegradable microspheres for intraocular administration with an antiviral action and to be capable of preventing the inherent risks of intravitreal administration. The RAP effect on the microsphere characteristics was also studied. Poly(D,L-lactic-co-glycolic) acid microspheres were prepared by the solvent evaporation method. Different quantities of aciclovir (40-80 mg) and RAP (10-80 mg) were added to the internal phase of the emulsion. Microspheres were analysed by scanning electron microscopy, which revealed a spherical surface and a porous structure, and granulometric analysis that showed an adequate particle size for intraocular administration. The aciclovir loading efficiency increased when Vitamin A palmitate was added. Differential scanning calorimetry detected no differences in the polymer glass transition temperature and the aciclovir melting endotherm in all formulations. The release of aciclovir during the first days of the in vitro assay was improved with respect to microspheres without RAP. The microspheres showed a constant release of aciclovir and RAP for 49 days. Best results were obtained for microspheres prepared with 40 mg aciclovir, 80 mg RAP and 400mg polymer. A dose of 4.74 mg of microspheres would be therapeutic for the herpes simplex and Epstein-Barr viruses' treatment in an animal model and would reduce the intravitreal adverse effects. The injectability of a suspension of microspheres in isotonic saline solution resulted appropriate for its injection through a 27 G needle.

Topics: Acyclovir; Administration, Topical; Animals; Antiviral Agents; Biocompatible Materials; Calorimetry, Differential Scanning; Delayed-Action Preparations; Disease Models, Animal; Diterpenes; Drug Administration Routes; Eye; Lactic Acid; Microscopy, Electron, Scanning; Microspheres; Pharmaceutical Preparations; Polyglycolic Acid; Polylactic Acid-Polyglycolic Acid Copolymer; Polymers; Retinyl Esters; Vitamin A

Retinols seem to be of clinical importance in ameliorating the clinical consequences of septic shock. These beneficial effects of retinols are suggested to be due to an antioxidant property. The present study was undertaken in order to confirm or rule out such an effect of retinol palmitate (RP) in experimental septic shock by measuring F2-isoprostanes and a major prostaglandin F2 alpha metabolite as indicators of oxidative injury and inflammatory response, respectively.. Fourteen anaesthetised pigs were randomly given an injection of RP (2.300 IU x kg-1) or the corresponding volume of vehicle. All pigs received a continuous infusion of E. coli endotoxin (10 micrograms x kg-1 x h-1). Blood samples were analysed for lipid peroxidation products (8-iso-PGF2 alpha), indicating free radical induced oxidative injury and 15-keto-dihydro-PGF2 alpha indicating cyclooxygenase-mediated inflammatory response).. Significantly elevated levels of 8-iso-PGF2 alpha were seen at 3, 5 and 6 hours of endotoxaemia in the vehicle + endotoxin group as compared to RP + endotoxin group. Endotoxin induced cyclooxygenase-mediated inflammatory response was not affected by RP.. This study is the first one to show that RP counteracts oxidative injury rather than inflammatory response in experimental septic shock. These results may be of importance for the understanding of some beneficial effects of RP during endotoxaemia (i.e. improved systemic haemodynamics and reduced serum levels of endotoxin). Our results may explain the therapeutic effects of nutrients rich in caroten/retinols used in some clinical studies.

Topics: Analysis of Variance; Animals; Antioxidants; Dinoprost; Disease Models, Animal; Diterpenes; Endotoxins; Escherichia coli Infections; F2-Isoprostanes; Female; Inflammation; Lipid Peroxidation; Male; Oxidative Stress; Radioimmunoassay; Random Allocation; Retinyl Esters; Shock, Septic; Swine; Vitamin A

Retinyl palmitate and its metabolites retinol and retinoic acid control growth and epithelial differentiation. Systemic or local vitamin A deficiency induced by malnutrition, continuous chemical irritation or locally induced by inflammation causes squamous metaplastic changes in the epithelium of mucous membranes. We demonstrate that in an animal model topically applied retinyl palmitate can be taken up by the mucosal cells independently from the systemic supply. Under in vivo conditions metabolic changes in vaginal epithelium of rats were shown to be reversed by treatment with topical retinyl palmitate. - After only two days treatment squamous metaplastic vaginal epithelium in rats shows a reversal of the epithelium into a normal phenotype which continues after cessation of the treatment for 7 to 11 days. Higher concentrations and longer retention times lead to a statistically significant (p = 0.025) increase in the protection time. These data demonstrate that squamous changes induced by vitamin A deficiency can be totally reversed with topically applied retinyl palmitate.

Topics: Administration, Topical; Animals; Anticarcinogenic Agents; Disease Models, Animal; Diterpenes; Dose-Response Relationship, Drug; Epithelium; Female; Metaplasia; Ovariectomy; Rats; Retinyl Esters; Vagina; Vaginal Diseases; Vitamin A

Magnesium (Mg) fortification of drinking water succeeded in inhibition of atherogenesis development in a transgenic model of atherosclerosis-prone mice fed a high-cholesterol content diet. In order to delineate possible mechanisms of action of the anti-atherogenic effect of Mg, the involvement of LDL oxidation was studied. We determined the susceptibility of LDL to Cu+2 oxidation, anti-oxidized LDL antibody levels, and liver content of retinol and retinyl-palmitate. In order to study another possible mechanism we tested platelets interaction with extracellular matrix in both male and female mice with or without Mg fortification of drinking water. No difference was found in susceptibility of LDL to undergo oxidation. Female mice that received Mg had decreased anti-oxidized LDL antibody levels compared with control female mice, while there was no significant difference among male groups. On the other hand, only in the male group with Mg was a higher content of retinol and retinyl-palmitate found in the livers. Platelets coverage area on extracellular matrix was similar between groups. These results suggest that Mg might affect LDL oxidation, and thus atherogenesis.

Topics: Animals; Antibodies; Antioxidants; Arteriosclerosis; Cholesterol, LDL; Copper; Diet, Atherogenic; Disease Models, Animal; Diterpenes; Female; Humans; Lipoproteins, LDL; Liver; Magnesium; Male; Mice; Mice, Transgenic; Receptors, LDL; Retinyl Esters; Vitamin A

Human low-grade gliomas represent a population of brain tumors that remain a therapeutic challenge. Preclinical evaluation of agents, to test their preventive or therapeutic efficacy in these tumors, requires the use of animal models. Spontaneous gliomas develop in models of chemically induced carcinogenesis, such as in the transplacental N-ethyl-N-nitrosourea (ENU) rat model. However, without the ability to detect initial tumor formation, multiplicity or to measure growth rates, it is difficult to test compounds for their interventional or preventional capabilities. In this study Fisher-334 rats, treated transplacentally with ENU, underwent magnetic resonance imaging (MRI) examination in order to evaluate this approach for detection of tumor formation and growth. ENU-induced intracranial cerebral tumors were first observable in T2-weighted images beginning at 4 months of age and grew with a mean doubling time of 0.487 +/- 0.112 months. These tumors were found histologically to be predominately mixed gliomas. Two therapeutic interventions were evaluated using MRI, vitamin A (all-trans retinol palmitate, RP), as a chemopreventative agent and the anti-angiogenic drug SU-5416. RP was found to significantly delay the time to first tumor observation by one month (P = 0.05). No differences in rates of tumor formation or growth rates were observed between control and RP-treated groups. MRI studies of rats treated with SU-5416 resulted in reduction in tumor growth rates compared to matched controls. These results show that MRI can be used to provide novel information relating to the therapeutic efficacy of agents against the ENU-induced tumor model.

Topics: Angiogenesis Inhibitors; Animals; Brain Neoplasms; Carcinogens; Diet; Disease Models, Animal; Diterpenes; Ethylnitrosourea; Glioma; Indoles; Magnetic Resonance Imaging; Neoplasms, Multiple Primary; Neoplasms, Second Primary; Pyrroles; Rats; Rats, Inbred F344; Receptor Protein-Tyrosine Kinases; Receptors, Growth Factor; Receptors, Vascular Endothelial Growth Factor; Retinyl Esters; Survival Analysis; Time Factors; Vitamin A

Postprandial hyperlipidemia is frequently accompanied with intra-abdominal visceral accumulation in human subjects. We have found that the decreased lipoprotein lipase (LPL) mass and activity is negatively associated with the amount of visceral fat accumulation. Here, we studied the postprandial hyperlipidemia using the OLETF rat, a model with visceral obesity, in order to clarify the molecular mechanism causing postprandial hyperlipidemia accompanied with visceral obesity. At the same age of 32 weeks, the OLETF rats showed obviously higher plasma leptin, total cholesterol, triglyceride, and HDL-cholesterol levels than the control LETO rats, although the plasma glucose level was not significantly different. Fat-loading test revealed the delayed metabolism of exogenous fat in the OLETF rats compared to the LETO rats, similar to human subjects with visceral obesity. In the obese rats, plasma levels of LPL mass and activities were 60 and 49% of control rats. The expression of LPL gene was decreased in subcutaneous adipose tissues and skeletal muscle of OLETF rats to 40 and 52% compared to those of LETO rats. In OLETF rats, plasma tumor necrosis factor-alpha (TNF-alpha) and insulin levels were increased to 2.0- and 2.3-folds compared to those in control rats. Furthermore, plasma insulin and TNF-alpha levels in OLETF rats were negatively correlated with the expression levels of LPL gene in subcutaneous fat and muscle. These results indicate that decreased LPL mass and activity in the animal model with visceral obesity is possibly caused by decreased expression of LPL gene in tissues mediated by the increased levels of insulin and TNF-alpha. The different expression of LPL gene in tissues associated with the increased levels of insulin and TNF-alpha possibly elucidate the underlying mechanisms involving the postprandial hyperlipidemia observed in visceral obesity.

Topics: Adipose Tissue; Animals; Blood Glucose; Blotting, Northern; Body Weight; Cholesterol; Cholesterol, HDL; Cloning, Molecular; Disease Models, Animal; Diterpenes; Humans; Hyperlipidemias; Insulin; Leptin; Lipoprotein Lipase; Male; Muscle, Skeletal; Obesity; Rats; Rats, Long-Evans; Retinyl Esters; RNA, Messenger; Time Factors; Tissue Distribution; Triglycerides; Tumor Necrosis Factor-alpha; Vitamin A

Vitamin A reduces the pathophysiological effects of endotoxin in animals, but the mechanism and the lowest effective dose are not clear.. An intravenous bolus of endotoxin 20 microg. kg(-1) was given to 30 rabbits. In 10 of them, 1000 IE. kg(-1) retinyl palmitate was injected intravenously 1 h before the endotoxin and in another 10 rabbits 1 h after the endotoxin. A one-compartment open model was fitted to the time-concentration profile of endotoxin in plasma.. The half-life of endotoxin was half as long when vitamin A was given for prophylaxis (median 35 min) and for treatment (33 min) than in the controls (67 min; p < 0.004). The plasma concentrations of immunoglobulin G and M endotoxin-core antibodies, the leucocyte count and the acid-base balance did not differ between the groups during the experiment, but the pyrogenic reaction was more pronounced in the controls.. A fairly low dose of vitamin A reduced the half-life of endotoxin.

Topics: Analysis of Variance; Animals; Antibodies, Bacterial; Bacteremia; Disease Models, Animal; Diterpenes; Drug Evaluation, Preclinical; Endotoxins; Escherichia coli; Escherichia coli Infections; Immunoglobulin G; Immunoglobulin M; Injections, Intravenous; Leukocyte Count; Metabolic Clearance Rate; Nonlinear Dynamics; Rabbits; Random Allocation; Regression Analysis; Retinyl Esters; Time Factors; Vitamin A

Vitamin A-deficient humans and animals are more susceptible to infections than are healthy humans and animals. This study compares the early corneal response (within 24 hours) to an experimental Pseudomonas aeruginosa infection between vitamin A deficient and control rats.. Male WAG/Rij/MCW rats were fed either a vitamin A- deficient diet (A-) or the same diet with retinyl palmitate added back in a nonrestricted manner (N) or under pair-fed conditions (A+) to yield weight-matched rats. Some A-rats were repleted wih retinyl palmitate 16 days before being killed and then given free access to the retinyl palmitate-supplemented diet (R). Twenty-four hours before being killed, the corneas of anesthetized rats were scratched and P. aeruginosa organisms were applied to the corneal surface. The rats were killed using an overdose of sodium pentobarbital. Corneas were either processed for light and electron microscopic examination or extracted for proteinase and myeloperoxidase determination. Corneal myeloperoxidase concentrations relative to neutrophil myeloperoxidase concentrations were used to determine the number of neutrophils in the cornea. Zymography was used to study caseinases, gelatinases, and plasminogen activators. Reverse zymography was used to detect proteinase inhibitors. Similar results were noted at early, mid, and late weight plateau stages of vitamin A deficiency.. Ulceration occurred within 24 hours when low numbers of P. aeruginosa (10(4) cpu) were applied topically onto scratched A- corneas, whereas no ulceration was observed in the A+, R, and N corneas. When higher numbers of P. aeruginosa (10(7)-10(8)) were applied to the scratched corneas, all corneas became ulcerated within 24 hours. The extent of ulceration in the control corneas was greater than that in A- corneas by a factor of two. Only the A- corneas contained inflammatory cells with unusual striated deposits in phagolysosomes. The total number of neutrophils in the cornea and the concentrations of caseinases, plasminogen activators, and gelatinases in the infected corneal extracts were similar; however, the concentrations of cysteine proteinase inhibitors were elevated under A- conditions.. Vitamin A deficiency alters the response of the cornea to a P. aeruginosa infection during the first 24 hours. The alterations observed are probably due to multiple factors: an insufficient tear film for bacterial clearance and migration of neutrophils, epithelial keratinization, alterations in corneal wound healing, and changes in polymorphonuclear function.

Topics: Animals; Anticarcinogenic Agents; Blotting, Western; Cornea; Corneal Ulcer; Disease Models, Animal; Disease Susceptibility; Diterpenes; Electrophoresis, Polyacrylamide Gel; Endopeptidases; Eye Infections, Bacterial; Female; Liver; Male; Neutrophils; Peroxidase; Pseudomonas Infections; Rats; Retinyl Esters; Vitamin A; Vitamin A Deficiency

Infection by LP-BM5 murine leukemia virus (MuLV) produces an AIDS-like condition in mice. The viral infection suppressed the percentage of peripheral blood cells showing surface markers for macrophages, activated macrophages, T lymphocytes and activated lymphoid cells. High dietary vitamin A (retinyl palmitate) caused increased numbers of activated macrophages. It also increased the percentage of cells with markers for Ia+ cells and macrophages in the retrovirally infected mice compared to infected controls. In uninfected mice retinyl palmitate stimulated the percentage of cells with activated lymphocytes bearing IL-2R, and T cytotoxic cells. These were associated with a retarded death rate during infection with LP-BM5 murine leukemia in C57BL/6 mice. By 25 weeks of infection and 20 weeks of retinyl palmitate supplementation 71.3% survived, while 45.0% virally infected controls survived. The mice also had elevated numbers of B cells measured in the blood after 4 and 8 weeks of dietary treatment. Vitamin A stimulation may play a role in the slower death rate for retrovirally infected mice.

Topics: Acquired Immunodeficiency Syndrome; Animals; B-Lymphocytes; Disease Models, Animal; Diterpenes; Female; Leukemia Virus, Murine; Leukemia, Experimental; Leukocyte Count; Macrophage Activation; Macrophages; Mice; Mice, Inbred C57BL; Retinyl Esters; T-Lymphocytes; T-Lymphocytes, Cytotoxic; T-Lymphocytes, Helper-Inducer; T-Lymphocytes, Regulatory; Vitamin A