tretinoin and Body-Weight

Middle East Respiratory Syndrome (MERS) is a novel respiratory illness firstly reported in Saudi Arabia in 2012. It is caused by a new corona virus, called MERS corona virus (MERS-CoV). Most people who have MERS-CoV infection developed severe acute respiratory illness.. This work is done to determine the clinical characteristics and the outcome of intensive care unit (ICU) admitted patients with confirmed MERS-CoV infection.. This study included 32 laboratory confirmed MERS corona virus infected patients who were admitted into ICU. It included 20 (62.50%) males and 12 (37.50%) females. The mean age was 43.99 ± 13.03 years. Diagnosis was done by real-time reverse transcription polymerase chain reaction (rRT-PCR) test for corona virus on throat swab, sputum, tracheal aspirate, or bronchoalveolar lavage specimens. Clinical characteristics, co-morbidities and outcome were reported for all subjects.. Most MERS corona patients present with fever, cough, dyspnea, sore throat, runny nose and sputum. The presence of abdominal symptoms may indicate bad prognosis. Prolonged duration of symptoms before patients' hospitalization, prolonged duration of mechanical ventilation and hospital stay, bilateral radiological pulmonary infiltrates, and hypoxemic respiratory failure were found to be strong predictors of mortality in such patients. Also, old age, current smoking, smoking severity, presence of associated co-morbidities like obesity, diabetes mellitus, chronic heart diseases, COPD, malignancy, renal failure, renal transplantation and liver cirrhosis are associated with a poor outcome of ICU admitted MERS corona virus infected patients.. Plasma HO-1, ferritin, p21, and NQO1 were all elevated at baseline in CKD participants. Plasma HO-1 and urine NQO1 levels each inversely correlated with eGFR (. SnPP can be safely administered and, after its injection, the resulting changes in plasma HO-1, NQO1, ferritin, and p21 concentrations can provide information as to antioxidant gene responsiveness/reserves in subjects with and without kidney disease.. A Study with RBT-1, in Healthy Volunteers and Subjects with Stage 3-4 Chronic Kidney Disease, NCT0363002 and NCT03893799.. HFNC did not significantly modify work of breathing in healthy subjects. However, a significant reduction in the minute volume was achieved, capillary [Formula: see text] remaining constant, which suggests a reduction in dead-space ventilation with flows > 20 L/min. (ClinicalTrials.gov registration NCT02495675).. 3 组患者手术时间、术中显性失血量及术后 1 周血红蛋白下降量比较差异均无统计学意义（. 对于肥胖和超重的膝关节单间室骨关节炎患者，采用 UKA 术后可获满意短中期疗效，远期疗效尚需进一步随访观察。.. Decreased muscle strength was identified at both time points in patients with hEDS/HSD. The evolution of most muscle strength parameters over time did not significantly differ between groups. Future studies should focus on the effectiveness of different types of muscle training strategies in hEDS/HSD patients.. These findings support previous adverse findings of e-cigarette exposure on neurodevelopment in a mouse model and provide substantial evidence of persistent adverse behavioral and neuroimmunological consequences to adult offspring following maternal e-cigarette exposure during pregnancy. https://doi.org/10.1289/EHP6067.. This RCT directly compares a neoadjuvant chemotherapy regimen with a standard CROSS regimen in terms of overall survival for patients with locally advanced ESCC. The results of this RCT will provide an answer for the controversy regarding the survival benefits between the two treatment strategies.. NCT04138212, date of registration: October 24, 2019.. Results of current investigation indicated that milk type and post fermentation cooling patterns had a pronounced effect on antioxidant characteristics, fatty acid profile, lipid oxidation and textural characteristics of yoghurt. Buffalo milk based yoghurt had more fat, protein, higher antioxidant capacity and vitamin content. Antioxidant and sensory characteristics of T. If milk is exposed to excessive amounts of light, Vitamins B. The two concentration of ZnO nanoparticles in the ambient air produced two different outcomes. The lower concentration resulted in significant increases in Zn content of the liver while the higher concentration significantly increased Zn in the lungs (p < 0.05). Additionally, at the lower concentration, Zn content was found to be lower in brain tissue (p < 0.05). Using TEM/EDX we detected ZnO nanoparticles inside the cells in the lungs, kidney and liver. Inhaling ZnO NP at the higher concentration increased the levels of mRNA of the following genes in the lungs: Mt2 (2.56 fold), Slc30a1 (1.52 fold) and Slc30a5 (2.34 fold). At the lower ZnO nanoparticle concentration, only Slc30a7 mRNA levels in the lungs were up (1.74 fold). Thus the two air concentrations of ZnO nanoparticles produced distinct effects on the expression of the Zn-homeostasis related genes.. Until adverse health effects of ZnO nanoparticles deposited in organs such as lungs are further investigated and/or ruled out, the exposure to ZnO nanoparticles in aerosols should be avoided or minimised.

Topics: A549 Cells; Acetylmuramyl-Alanyl-Isoglutamine; Acinetobacter baumannii; Acute Lung Injury; Adaptor Proteins, Signal Transducing; Adenine; Adenocarcinoma; Adipogenesis; Administration, Cutaneous; Administration, Ophthalmic; Adolescent; Adsorption; Adult; Aeromonas hydrophila; Aerosols; Aged; Aged, 80 and over; Aging; Agriculture; Air Pollutants; Air Pollution; Airway Remodeling; Alanine Transaminase; Albuminuria; Aldehyde Dehydrogenase 1 Family; Algorithms; AlkB Homolog 2, Alpha-Ketoglutarate-Dependent Dioxygenase; Alzheimer Disease; Amino Acid Sequence; Ammonia; Ammonium Compounds; Anaerobiosis; Anesthetics, Dissociative; Anesthetics, Inhalation; Animals; Anti-Bacterial Agents; Anti-HIV Agents; Anti-Infective Agents; Anti-Inflammatory Agents; Antibiotics, Antineoplastic; Antibodies, Antineutrophil Cytoplasmic; Antibodies, Monoclonal, Humanized; Antifungal Agents; Antigens, Bacterial; Antigens, CD; Antigens, Differentiation, Myelomonocytic; Antimetabolites, Antineoplastic; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Antioxidants; Antitubercular Agents; Antiviral Agents; Apolipoproteins E; Apoptosis; Arabidopsis; Arabidopsis Proteins; Arsenic; Arthritis, Rheumatoid; Asthma; Atherosclerosis; ATP-Dependent Proteases; Attitude of Health Personnel; Australia; Austria; Autophagy; Axitinib; Bacteria; Bacterial Outer Membrane Proteins; Bacterial Proteins; Bacterial Toxins; Bacterial Typing Techniques; Bariatric Surgery; Base Composition; Bayes Theorem; Benzoxazoles; Benzylamines; beta Catenin; Betacoronavirus; Betula; Binding Sites; Biological Availability; Biological Oxygen Demand Analysis; Biomarkers; Biomarkers, Tumor; Biopsy; Bioreactors; Biosensing Techniques; Birth Weight; Blindness; Blood Chemical Analysis; Blood Gas Analysis; Blood Glucose; Blood Pressure; Blood Pressure Monitoring, Ambulatory; Blood-Brain Barrier; Blotting, Western; Body Mass Index; Body Weight; Bone and Bones; Bone Density; Bone Resorption; Borates; Brain; Brain Infarction; Brain Injuries, Traumatic; Brain Neoplasms; Breakfast; Breast Milk Expression; Breast Neoplasms; Bronchi; Bronchoalveolar Lavage Fluid; Buffaloes; Cadherins; Calcification, Physiologic; Calcium Compounds; Calcium, Dietary; Cannula; Caprolactam; Carbon; Carbon Dioxide; Carboplatin; Carcinogenesis; Carcinoma, Ductal; Carcinoma, Ehrlich Tumor; Carcinoma, Hepatocellular; Carcinoma, Non-Small-Cell Lung; Carcinoma, Pancreatic Ductal; Carcinoma, Renal Cell; Cardiovascular Diseases; Carps; Carrageenan; Case-Control Studies; Catalysis; Catalytic Domain; Cattle; CD8-Positive T-Lymphocytes; Cell Adhesion; Cell Cycle Proteins; Cell Death; Cell Differentiation; Cell Line; Cell Line, Tumor; Cell Movement; Cell Nucleus; Cell Phone Use; Cell Proliferation; Cell Survival; Cell Transformation, Neoplastic; Cell Transformation, Viral; Cells, Cultured; Cellulose; Chemical Phenomena; Chemoradiotherapy; Child; Child Development; Child, Preschool; China; Chitosan; Chlorocebus aethiops; Cholecalciferol; Chromatography, Liquid; Circadian Clocks; Circadian Rhythm; Circular Dichroism; Cisplatin; Citric Acid; Clinical Competence; Clinical Laboratory Techniques; Clinical Trials, Phase I as Topic; Clinical Trials, Phase II as Topic; Clostridioides difficile; Clostridium Infections; Coculture Techniques; Cohort Studies; Cold Temperature; Colitis; Collagen Type I; Collagen Type I, alpha 1 Chain; Collagen Type XI; Color; Connective Tissue Diseases; Copper; Coronary Angiography; Coronavirus 3C Proteases; Coronavirus Infections; Cost of Illness; Counselors; COVID-19; COVID-19 Testing; Creatine Kinase; Creatinine; Cross-Over Studies; Cross-Sectional Studies; Cryoelectron Microscopy; Cryosurgery; Crystallography, X-Ray; Cues; Cultural Competency; Cultural Diversity; Curriculum; Cyclic AMP Response Element-Binding Protein; Cyclin-Dependent Kinase Inhibitor p21; Cycloparaffins; Cysteine Endopeptidases; Cytokines; Cytoplasm; Cytoprotection; Databases, Factual; Denitrification; Deoxycytidine; Diabetes Complications; Diabetes Mellitus; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Diagnosis, Differential; Diatoms; Diet; Diet, High-Fat; Dietary Exposure; Diffusion Magnetic Resonance Imaging; Diketopiperazines; Dipeptidyl Peptidase 4; Dipeptidyl-Peptidase IV Inhibitors; Disease Models, Animal; Disease Progression; Disease-Free Survival; DNA; DNA Damage; DNA Glycosylases; DNA Repair; DNA-Binding Proteins; DNA, Bacterial; DNA, Viral; Docetaxel; Dose Fractionation, Radiation; Dose-Response Relationship, Drug; Down-Regulation; Doxorubicin; Drosophila; Drosophila melanogaster; Drug Carriers; Drug Delivery Systems; Drug Liberation; Drug Repositioning; Drug Resistance, Bacterial; Drug Resistance, Multiple, Bacterial; Drug Resistance, Neoplasm; Drug Screening Assays, Antitumor; Drug Synergism; Drug Therapy, Combination; Edema; Edible Grain; Education, Graduate; Education, Medical, Graduate; Education, Pharmacy; Ehlers-Danlos Syndrome; Electron Transport Complex III; Electron Transport Complex IV; Electronic Nicotine Delivery Systems; Emergency Service, Hospital; Empathy; Emulsions; Endothelial Cells; Endurance Training; Energy Intake; Enterovirus A, Human; Environment; Environmental Monitoring; Enzyme Assays; Enzyme Inhibitors; Epithelial Cells; Epithelial-Mesenchymal Transition; Epoxide Hydrolases; Epoxy Compounds; Erythrocyte Count; Erythrocytes; Escherichia coli; Escherichia coli Infections; Escherichia coli Proteins; Esophageal Neoplasms; Esophageal Squamous Cell Carcinoma; Esophagectomy; Estrogens; Etanercept; Ethiopia; Ethnicity; Ethylenes; Exanthema; Exercise; Exercise Test; Exercise Tolerance; Extracellular Matrix; Extracorporeal Membrane Oxygenation; Eye Infections, Fungal; False Negative Reactions; Fatty Acids; Fecal Microbiota Transplantation; Feces; Female; Femur Neck; Fermentation; Ferritins; Fetal Development; Fibroblast Growth Factor-23; Fibroblast Growth Factors; Fibroblasts; Fibroins; Fish Proteins; Flavanones; Flavonoids; Focus Groups; Follow-Up Studies; Food Handling; Food Supply; Food, Formulated; Forced Expiratory Volume; Forests; Fractures, Bone; Fruit and Vegetable Juices; Fusobacteria; G1 Phase Cell Cycle Checkpoints; G2 Phase Cell Cycle Checkpoints; Gamma Rays; Gastrectomy; Gastrointestinal Microbiome; Gastrointestinal Stromal Tumors; Gefitinib; Gels; Gemcitabine; Gene Amplification; Gene Expression; Gene Expression Regulation; Gene Expression Regulation, Bacterial; Gene Expression Regulation, Neoplastic; Gene Expression Regulation, Plant; Gene Knockdown Techniques; Gene-Environment Interaction; Genotype; Germany; Glioma; Glomerular Filtration Rate; Glucagon; Glucocorticoids; Glycemic Control; Glycerol; Glycogen Synthase Kinase 3 beta; Glycolipids; Glycolysis; Goblet Cells; Gram-Negative Bacterial Infections; Granulocyte Colony-Stimulating Factor; Graphite; Greenhouse Effect; Guanidines; Haemophilus influenzae; HCT116 Cells; Health Knowledge, Attitudes, Practice; Health Personnel; Health Services Accessibility; Health Services Needs and Demand; Health Status Disparities; Healthy Volunteers; Heart Failure; Heart Rate; Heart Transplantation; Heart-Assist Devices; HEK293 Cells; Heme; Heme Oxygenase-1; Hemolysis; Hemorrhage; Hepatitis B; Hepatitis B e Antigens; Hepatitis B Surface Antigens; Hepatitis B virus; Hepatitis B, Chronic; Hepatocytes; Hexoses; High-Throughput Nucleotide Sequencing; Hippo Signaling Pathway; Histamine; Histamine Agonists; Histidine; Histone Deacetylase 2; HIV Infections; HIV Reverse Transcriptase; HIV-1; Homebound Persons; Homeodomain Proteins; Homosexuality, Male; Hospice and Palliative Care Nursing; HSP70 Heat-Shock Proteins; Humans; Hyaluronan Receptors; Hydrogen; Hydrogen Peroxide; Hydrogen-Ion Concentration; Hydrolysis; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypoglycemia; Hypoglycemic Agents; Hypoxia; Idiopathic Interstitial Pneumonias; Imaging, Three-Dimensional; Imatinib Mesylate; Immunotherapy; Implementation Science; Incidence; INDEL Mutation; Induced Pluripotent Stem Cells; Industrial Waste; Infant; Infant, Newborn; Inflammation; Inflammation Mediators; Infliximab; Infusions, Intravenous; Inhibitory Concentration 50; Injections; Insecticides; Insulin-Like Growth Factor Binding Protein 5; Insulin-Secreting Cells; Interleukin-1; Interleukin-17; Interleukin-8; Internship and Residency; Intestines; Intracellular Signaling Peptides and Proteins; Ion Transport; Iridaceae; Iridoid Glucosides; Islets of Langerhans Transplantation; Isodon; Isoflurane; Isotopes; Italy; Joint Instability; Ketamine; Kidney; Kidney Failure, Chronic; Kidney Function Tests; Kidney Neoplasms; Kinetics; Klebsiella pneumoniae; Knee Joint; Kruppel-Like Factor 4; Kruppel-Like Transcription Factors; Lactate Dehydrogenase 5; Laparoscopy; Laser Therapy; Lasers, Semiconductor; Lasers, Solid-State; Laurates; Lead; Leukocyte L1 Antigen Complex; Leukocytes, Mononuclear; Light; Lipid Peroxidation; Lipopolysaccharides; Liposomes; Liver; Liver Cirrhosis; Liver Neoplasms; Liver Transplantation; Locomotion; Longitudinal Studies; Lopinavir; Lower Urinary Tract Symptoms; Lubricants; Lung; Lung Diseases, Interstitial; Lung Neoplasms; Lymphocyte Activation; Lymphocytes, Tumor-Infiltrating; Lymphoma, Mantle-Cell; Lysosomes; Macrophages; Male; Manganese Compounds; MAP Kinase Kinase 4; Mass Screening; Maternal Health; Medicine, Chinese Traditional; Melanoma, Experimental; Memantine; Membrane Glycoproteins; Membrane Proteins; Mesenchymal Stem Cell Transplantation; Metal Nanoparticles; Metalloendopeptidases; Metalloporphyrins; Methadone; Methane; Methicillin-Resistant Staphylococcus aureus; Mexico; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Mice, Inbred ICR; Mice, Knockout; Mice, Nude; Mice, SCID; Mice, Transgenic; Microarray Analysis; Microbial Sensitivity Tests; Microbiota; Micronutrients; MicroRNAs; Microscopy, Confocal; Microsomes, Liver; Middle Aged; Milk; Milk, Human; Minority Groups; Mitochondria; Mitochondrial Membranes; Mitochondrial Proteins; Models, Animal; Models, Molecular; Molecular Conformation; Molecular Docking Simulation; Molecular Dynamics Simulation; Molecular Epidemiology; Molecular Structure; Molecular Weight; Multilocus Sequence Typing; Multimodal Imaging; Muscle Strength; Muscle, Skeletal; Muscular Diseases; Mutation; Mycobacterium tuberculosis; Myocardial Stunning; Myristates; NAD(P)H Dehydrogenase (Quinone); Nanocomposites; Nanogels; Nanoparticles; Nanotechnology; Naphthalenes; Nasal Cavity; National Health Programs; Necrosis; Needs Assessment; Neoadjuvant Therapy; Neonicotinoids; Neoplasm Invasiveness; Neoplasm Metastasis; Neoplasm Proteins; Neoplasm Recurrence, Local; Neoplasm Staging; Neoplasm Transplantation; Neoplasms; Neoplastic Stem Cells; Netherlands; Neuroblastoma; Neuroprotective Agents; Neutrophils; NF-kappa B; NFATC Transcription Factors; Nicotiana; Nicotine; Nitrates; Nitrification; Nitrites; Nitro Compounds; Nitrogen; Nitrogen Dioxide; North Carolina; Nuclear Magnetic Resonance, Biomolecular; Nuclear Proteins; Nucleic Acid Hybridization; Nucleosomes; Nutrients; Obesity; Obesity, Morbid; Oceans and Seas; Oncogene Protein v-akt; Oncogenes; Oocytes; Open Reading Frames; Osteoclasts; Osteogenesis; Osteoporosis; Osteoporosis, Postmenopausal; Outpatients; Ovarian Neoplasms; Ovariectomy; Overweight; Oxazines; Oxidants; Oxidation-Reduction; Oxidative Stress; Oxides; Oxidoreductases; Oxygen; Oxygen Inhalation Therapy; Oxygenators, Membrane; Ozone; Paclitaxel; Paenibacillus; Pain Measurement; Palliative Care; Pancreatic Neoplasms; Pandemics; Parasympathetic Nervous System; Particulate Matter; Pasteurization; Patient Preference; Patient Satisfaction; Pediatric Obesity; Permeability; Peroxiredoxins; Peroxynitrous Acid; Pharmaceutical Services; Pharmacists; Pharmacy; Phaseolus; Phenotype; Phoeniceae; Phosphates; Phosphatidylinositol 3-Kinases; Phospholipid Transfer Proteins; Phospholipids; Phosphorus; Phosphorylation; Photoperiod; Photosynthesis; Phylogeny; Physical Endurance; Physicians; Pilot Projects; Piperidines; Pituitary Adenylate Cyclase-Activating Polypeptide; Plant Extracts; Plant Leaves; Plant Proteins; Plant Roots; Plaque, Atherosclerotic; Pneumonia; Pneumonia, Viral; Point-of-Care Testing; Polyethylene Glycols; Polymers; Polysorbates; Pore Forming Cytotoxic Proteins; Positron Emission Tomography Computed Tomography; Positron-Emission Tomography; Postprandial Period; Poverty; Pre-Exposure Prophylaxis; Prediabetic State; Predictive Value of Tests; Pregnancy; Pregnancy Trimester, First; Pregnancy, High-Risk; Prenatal Exposure Delayed Effects; Pressure; Prevalence; Primary Graft Dysfunction; Primary Health Care; Professional Role; Professionalism; Prognosis; Progression-Free Survival; Prolactin; Promoter Regions, Genetic; Proof of Concept Study; Proportional Hazards Models; Propylene Glycol; Prospective Studies; Prostate; Protein Binding; Protein Biosynthesis; Protein Isoforms; Protein Kinase Inhibitors; Protein Phosphatase 2; Protein Processing, Post-Translational; Protein Serine-Threonine Kinases; Protein Structure, Tertiary; Protein Transport; Proteoglycans; Proteome; Proto-Oncogene Proteins c-akt; Proto-Oncogene Proteins c-myc; Proto-Oncogene Proteins c-ret; Proto-Oncogene Proteins p21(ras); Proton Pumps; Protons; Protoporphyrins; Pseudomonas aeruginosa; Pseudomonas fluorescens; Pulmonary Artery; Pulmonary Disease, Chronic Obstructive; Pulmonary Gas Exchange; Pulmonary Veins; Pyrazoles; Pyridines; Pyrimidines; Qualitative Research; Quinoxalines; Rabbits; Random Allocation; Rats; Rats, Sprague-Dawley; Rats, Wistar; Receptors, Histamine H3; Receptors, Immunologic; Receptors, Transferrin; Recombinant Proteins; Recurrence; Reference Values; Referral and Consultation; Regional Blood Flow; Registries; Regulon; Renal Insufficiency, Chronic; Reperfusion Injury; Repressor Proteins; Reproducibility of Results; Republic of Korea; Research Design; Resistance Training; Respiration, Artificial; Respiratory Distress Syndrome; Respiratory Insufficiency; Resuscitation; Retinal Dehydrogenase; Retreatment; Retrospective Studies; Reverse Transcriptase Inhibitors; Rhinitis, Allergic; Ribosomal Proteins; Ribosomes; Risk Assessment; Risk Factors; Ritonavir; Rivers; RNA Interference; RNA-Seq; RNA, Messenger; RNA, Ribosomal, 16S; RNA, Small Interfering; Rosuvastatin Calcium; Rural Population; Saccharomyces cerevisiae; Saccharomyces cerevisiae Proteins; Salivary Ducts; Salivary Gland Neoplasms; San Francisco; SARS-CoV-2; Satiation; Satiety Response; Schools; Schools, Pharmacy; Seasons; Seawater; Selection, Genetic; Sequence Analysis, DNA; Serine-Threonine Kinase 3; Sewage; Sheep; Sheep, Domestic; Shock, Hemorrhagic; Signal Transduction; Silver; Silymarin; Single Photon Emission Computed Tomography Computed Tomography; Sirolimus; Sirtuin 1; Skin; Skin Neoplasms; Skin Physiological Phenomena; Sleep Initiation and Maintenance Disorders; Social Class; Social Participation; Social Support; Soil; Soil Microbiology; Solutions; Somatomedins; Soot; Specimen Handling; Spectrophotometry, Ultraviolet; Spectroscopy, Fourier Transform Infrared; Spectrum Analysis; Spinal Fractures; Spirometry; Staphylococcus aureus; STAT1 Transcription Factor; STAT3 Transcription Factor; Streptomyces coelicolor; Stress, Psychological; Stroke; Stroke Volume; Structure-Activity Relationship; Students, Medical; Students, Pharmacy; Substance Abuse Treatment Centers; Sulfur Dioxide; Surface Properties; Surface-Active Agents; Surveys and Questionnaires; Survival Analysis; Survival Rate; Survivin; Sweden; Swine; Swine, Miniature; Sympathetic Nervous System; T-Lymphocytes, Regulatory; Talaromyces; Tandem Mass Spectrometry; tau Proteins; Telemedicine; Telomerase; Telomere; Telomere Homeostasis; Temperature; Terminally Ill; Th1 Cells; Thiamethoxam; Thiazoles; Thiophenes; Thioredoxin Reductase 1; Thrombosis; Thulium; Thyroid Cancer, Papillary; Thyroid Carcinoma, Anaplastic; Thyroid Neoplasms; Time Factors; Titanium; Tomography, Emission-Computed, Single-Photon; Tomography, X-Ray Computed; TOR Serine-Threonine Kinases; Transcription Factor AP-1; Transcription Factors; Transcription, Genetic; Transcriptional Activation; Transcriptome; Transforming Growth Factor beta1; Transistors, Electronic; Translational Research, Biomedical; Transplantation Tolerance; Transplantation, Homologous; Transportation; Treatment Outcome; Tretinoin; Tuberculosis, Multidrug-Resistant; Tuberculosis, Pulmonary; Tubulin Modulators; Tumor Microenvironment; Tumor Necrosis Factor Inhibitors; Tumor Necrosis Factor-alpha; Twins; Ultrasonic Therapy; Ultrasonography; Ultraviolet Rays; United States; Up-Regulation; Uranium; Urethra; Urinary Bladder; Urodynamics; Uromodulin; Uveitis; Vasoconstrictor Agents; Ventricular Function, Left; Vero Cells; Vesicular Transport Proteins; Viral Nonstructural Proteins; Visual Acuity; Vital Capacity; Vitamin D; Vitamin D Deficiency; Vitamin K 2; Vitamins; Volatilization; Voriconazole; Waiting Lists; Waste Disposal, Fluid; Wastewater; Water Pollutants, Chemical; Whole Genome Sequencing; Wine; Wnt Signaling Pathway; Wound Healing; Wounds and Injuries; WW Domains; X-linked Nuclear Protein; X-Ray Diffraction; Xanthines; Xenograft Model Antitumor Assays; YAP-Signaling Proteins; Yogurt; Young Adult; Zebrafish; Zebrafish Proteins; Ziziphus

Middle East Respiratory Syndrome (MERS) is a novel respiratory illness firstly reported in Saudi Arabia in 2012. It is caused by a new corona virus, called MERS corona virus (MERS-CoV). Most people who have MERS-CoV infection developed severe acute respiratory illness.. This work is done to determine the clinical characteristics and the outcome of intensive care unit (ICU) admitted patients with confirmed MERS-CoV infection.. This study included 32 laboratory confirmed MERS corona virus infected patients who were admitted into ICU. It included 20 (62.50%) males and 12 (37.50%) females. The mean age was 43.99 ± 13.03 years. Diagnosis was done by real-time reverse transcription polymerase chain reaction (rRT-PCR) test for corona virus on throat swab, sputum, tracheal aspirate, or bronchoalveolar lavage specimens. Clinical characteristics, co-morbidities and outcome were reported for all subjects.. Most MERS corona patients present with fever, cough, dyspnea, sore throat, runny nose and sputum. The presence of abdominal symptoms may indicate bad prognosis. Prolonged duration of symptoms before patients' hospitalization, prolonged duration of mechanical ventilation and hospital stay, bilateral radiological pulmonary infiltrates, and hypoxemic respiratory failure were found to be strong predictors of mortality in such patients. Also, old age, current smoking, smoking severity, presence of associated co-morbidities like obesity, diabetes mellitus, chronic heart diseases, COPD, malignancy, renal failure, renal transplantation and liver cirrhosis are associated with a poor outcome of ICU admitted MERS corona virus infected patients.. Plasma HO-1, ferritin, p21, and NQO1 were all elevated at baseline in CKD participants. Plasma HO-1 and urine NQO1 levels each inversely correlated with eGFR (. SnPP can be safely administered and, after its injection, the resulting changes in plasma HO-1, NQO1, ferritin, and p21 concentrations can provide information as to antioxidant gene responsiveness/reserves in subjects with and without kidney disease.. A Study with RBT-1, in Healthy Volunteers and Subjects with Stage 3-4 Chronic Kidney Disease, NCT0363002 and NCT03893799.. HFNC did not significantly modify work of breathing in healthy subjects. However, a significant reduction in the minute volume was achieved, capillary [Formula: see text] remaining constant, which suggests a reduction in dead-space ventilation with flows > 20 L/min. (ClinicalTrials.gov registration NCT02495675).. 3 组患者手术时间、术中显性失血量及术后 1 周血红蛋白下降量比较差异均无统计学意义（. 对于肥胖和超重的膝关节单间室骨关节炎患者，采用 UKA 术后可获满意短中期疗效，远期疗效尚需进一步随访观察。.. Decreased muscle strength was identified at both time points in patients with hEDS/HSD. The evolution of most muscle strength parameters over time did not significantly differ between groups. Future studies should focus on the effectiveness of different types of muscle training strategies in hEDS/HSD patients.. These findings support previous adverse findings of e-cigarette exposure on neurodevelopment in a mouse model and provide substantial evidence of persistent adverse behavioral and neuroimmunological consequences to adult offspring following maternal e-cigarette exposure during pregnancy. https://doi.org/10.1289/EHP6067.. This RCT directly compares a neoadjuvant chemotherapy regimen with a standard CROSS regimen in terms of overall survival for patients with locally advanced ESCC. The results of this RCT will provide an answer for the controversy regarding the survival benefits between the two treatment strategies.. NCT04138212, date of registration: October 24, 2019.. Results of current investigation indicated that milk type and post fermentation cooling patterns had a pronounced effect on antioxidant characteristics, fatty acid profile, lipid oxidation and textural characteristics of yoghurt. Buffalo milk based yoghurt had more fat, protein, higher antioxidant capacity and vitamin content. Antioxidant and sensory characteristics of T. If milk is exposed to excessive amounts of light, Vitamins B. The two concentration of ZnO nanoparticles in the ambient air produced two different outcomes. The lower concentration resulted in significant increases in Zn content of the liver while the higher concentration significantly increased Zn in the lungs (p < 0.05). Additionally, at the lower concentration, Zn content was found to be lower in brain tissue (p < 0.05). Using TEM/EDX we detected ZnO nanoparticles inside the cells in the lungs, kidney and liver. Inhaling ZnO NP at the higher concentration increased the levels of mRNA of the following genes in the lungs: Mt2 (2.56 fold), Slc30a1 (1.52 fold) and Slc30a5 (2.34 fold). At the lower ZnO nanoparticle concentration, only Slc30a7 mRNA levels in the lungs were up (1.74 fold). Thus the two air concentrations of ZnO nanoparticles produced distinct effects on the expression of the Zn-homeostasis related genes.. Until adverse health effects of ZnO nanoparticles deposited in organs such as lungs are further investigated and/or ruled out, the exposure to ZnO nanoparticles in aerosols should be avoided or minimised.

Topics: A549 Cells; Acetylmuramyl-Alanyl-Isoglutamine; Acinetobacter baumannii; Acute Lung Injury; Adaptor Proteins, Signal Transducing; Adenine; Adenocarcinoma; Adipogenesis; Administration, Cutaneous; Administration, Ophthalmic; Adolescent; Adsorption; Adult; Aeromonas hydrophila; Aerosols; Aged; Aged, 80 and over; Aging; Agriculture; Air Pollutants; Air Pollution; Airway Remodeling; Alanine Transaminase; Albuminuria; Aldehyde Dehydrogenase 1 Family; Algorithms; AlkB Homolog 2, Alpha-Ketoglutarate-Dependent Dioxygenase; Alzheimer Disease; Amino Acid Sequence; Ammonia; Ammonium Compounds; Anaerobiosis; Anesthetics, Dissociative; Anesthetics, Inhalation; Animals; Anti-Bacterial Agents; Anti-HIV Agents; Anti-Infective Agents; Anti-Inflammatory Agents; Antibiotics, Antineoplastic; Antibodies, Antineutrophil Cytoplasmic; Antibodies, Monoclonal, Humanized; Antifungal Agents; Antigens, Bacterial; Antigens, CD; Antigens, Differentiation, Myelomonocytic; Antimetabolites, Antineoplastic; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Antioxidants; Antitubercular Agents; Antiviral Agents; Apolipoproteins E; Apoptosis; Arabidopsis; Arabidopsis Proteins; Arsenic; Arthritis, Rheumatoid; Asthma; Atherosclerosis; ATP-Dependent Proteases; Attitude of Health Personnel; Australia; Austria; Autophagy; Axitinib; Bacteria; Bacterial Outer Membrane Proteins; Bacterial Proteins; Bacterial Toxins; Bacterial Typing Techniques; Bariatric Surgery; Base Composition; Bayes Theorem; Benzoxazoles; Benzylamines; beta Catenin; Betacoronavirus; Betula; Binding Sites; Biological Availability; Biological Oxygen Demand Analysis; Biomarkers; Biomarkers, Tumor; Biopsy; Bioreactors; Biosensing Techniques; Birth Weight; Blindness; Blood Chemical Analysis; Blood Gas Analysis; Blood Glucose; Blood Pressure; Blood Pressure Monitoring, Ambulatory; Blood-Brain Barrier; Blotting, Western; Body Mass Index; Body Weight; Bone and Bones; Bone Density; Bone Resorption; Borates; Brain; Brain Infarction; Brain Injuries, Traumatic; Brain Neoplasms; Breakfast; Breast Milk Expression; Breast Neoplasms; Bronchi; Bronchoalveolar Lavage Fluid; Buffaloes; Cadherins; Calcification, Physiologic; Calcium Compounds; Calcium, Dietary; Cannula; Caprolactam; Carbon; Carbon Dioxide; Carboplatin; Carcinogenesis; Carcinoma, Ductal; Carcinoma, Ehrlich Tumor; Carcinoma, Hepatocellular; Carcinoma, Non-Small-Cell Lung; Carcinoma, Pancreatic Ductal; Carcinoma, Renal Cell; Cardiovascular Diseases; Carps; Carrageenan; Case-Control Studies; Catalysis; Catalytic Domain; Cattle; CD8-Positive T-Lymphocytes; Cell Adhesion; Cell Cycle Proteins; Cell Death; Cell Differentiation; Cell Line; Cell Line, Tumor; Cell Movement; Cell Nucleus; Cell Phone Use; Cell Proliferation; Cell Survival; Cell Transformation, Neoplastic; Cell Transformation, Viral; Cells, Cultured; Cellulose; Chemical Phenomena; Chemoradiotherapy; Child; Child Development; Child, Preschool; China; Chitosan; Chlorocebus aethiops; Cholecalciferol; Chromatography, Liquid; Circadian Clocks; Circadian Rhythm; Circular Dichroism; Cisplatin; Citric Acid; Clinical Competence; Clinical Laboratory Techniques; Clinical Trials, Phase I as Topic; Clinical Trials, Phase II as Topic; Clostridioides difficile; Clostridium Infections; Coculture Techniques; Cohort Studies; Cold Temperature; Colitis; Collagen Type I; Collagen Type I, alpha 1 Chain; Collagen Type XI; Color; Connective Tissue Diseases; Copper; Coronary Angiography; Coronavirus 3C Proteases; Coronavirus Infections; Cost of Illness; Counselors; COVID-19; COVID-19 Testing; Creatine Kinase; Creatinine; Cross-Over Studies; Cross-Sectional Studies; Cryoelectron Microscopy; Cryosurgery; Crystallography, X-Ray; Cues; Cultural Competency; Cultural Diversity; Curriculum; Cyclic AMP Response Element-Binding Protein; Cyclin-Dependent Kinase Inhibitor p21; Cycloparaffins; Cysteine Endopeptidases; Cytokines; Cytoplasm; Cytoprotection; Databases, Factual; Denitrification; Deoxycytidine; Diabetes Complications; Diabetes Mellitus; Diabetes Mellitus, Experimental; 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Cushing's disease is almost always caused by an ACTH-secreting pituitary tumor, but effective medical therapy is currently limited. Because retinoic acid has been shown to be potentially useful in decreasing corticotroph secretion and proliferation in rodent models, we have studied its action in dogs with Cushing's disease. A randomized treatment with retinoic acid (n = 22) vs. ketoconazole (n = 20) in dogs with Cushing's disease was assigned for a period of 180 d. Clinical signs, plasma ACTH and alpha-MSH, the cortisol/creatinine urine ratio, and pituitary magnetic resonance imaging were assessed and compared at different time points. We recorded a significant reduction in plasma ACTH and alpha-MSH, and also in the cortisol/creatinine urine ratio, of the dogs treated with retinoic acid. Pituitary adenoma size was also significantly reduced at the end of retinoic acid treatment. Survival time and all the clinical signs evaluated showed an improvement in the retinoic-acid-treated dogs. No adverse events or signs of hepatotoxicity were observed, suggesting that the drug is not only effective but also safe. Retinoic acid treatment controls ACTH and cortisol hyperactivity and tumor size in dogs with ACTH-secreting tumors, leading to resolution of the clinical phenotype. This study highlights the possibility of using retinoic acid as a novel therapy in the treatment of ACTH-secreting tumors in humans with Cushing's disease.

Topics: Adenoma; Adrenocorticotropic Hormone; alpha-MSH; Animals; Body Weight; Creatinine; Dog Diseases; Dogs; Female; Hydrocortisone; Ketoconazole; Magnetic Resonance Imaging; Male; Pituitary ACTH Hypersecretion; Pituitary Gland; Pituitary Neoplasms; Survival Rate; Tretinoin

We investigated changes in serum triglyceride, cholesterol, and high-density lipoprotein cholesterol (HDLC) levels during etretinate administration in 21 patients with psoriasis. Mean serum triglyceride and cholesterol values showed a statistically significant increase during etretinate therapy compared with placebo treatment; mean HDLC levels did not change. During etretinate therapy, elevations out of the normal range occurred in 77% of the patients for serum triglycerides and 25% for serum cholesterol. Eight weeks after discontinuation of the drug regimen, patients' mean serum triglyceride and cholesterol levels were not statistically different from those found prior to therapy. Nevertheless, eight weeks after therapy had been stopped, six (32%) of 19 patients had cholesterol values that were still 20% or more above their baseline levels; the prolonged etretinate excretion time could have been responsible. The mechanisms for the etretinate-induced lipid elevations are unknown.

Topics: Adult; Aged; Body Weight; Cholesterol; Cholesterol, HDL; Double-Blind Method; Etretinate; Female; Humans; Lipids; Lipoproteins, HDL; Male; Middle Aged; Psoriasis; Random Allocation; Tretinoin; Triglycerides

The signaling axis consisting of GH-IGF1-IGFBP3 is the primary signal taht acts prepubertally to influence height development. Growth plate thinning and even premature closure have been reported in children with tumors treated with retinoid chemotherapy, resulting in long bone dysplasia. Growth failure may occur despite received GH treatment, but the reason is unknown. This study investigate the effect of high-dose all-trans retinoic acid (ATRA) on the development of long bones in growing SD rats.. A total of 20 three-week-old male SD rats were randomly divided into a control group and an experimental group (n = 10). Rats were treated by gavage with or without high-dose ATRA for 10 days. The body weights of the rats were recorded daily. At the end of the experiment, we measured the length of nose-tail and tibia, stained the tibia and liver for pathological tissue and RT-PCR reaction, and measured the levels of serum GH, IGF1 and IGFBP3, and so on.. Compared with controls, experimental rats exhibited reduced body weight and shortened nasal-tail and radial tibial length. Cyp26b1 enzyme activity in the liver was elevated, and histopathological staining revealed that the cartilaginous epiphyseal plate was narrowed, the medullary cavity of trabecular bone was sparse, the number of trabecular bones was decreased, trabecular separation was increased, bone marrow mineralization was enhanced, osteoclastic activity was increased, and circulating GH-IGF1-IGFBP3 levels were decreased. However, RT-PCR reaction results of localized proximal tibiae showed upregulation of IGF1 and downregulation of IGFBP3.. High-dose ATRA intake over a short period of time can reduce GH-IGF1-IGFBP3 levels, affect cartilage and bone homeostasis, and inhibit bone growth in developing animals.

Topics: Animals; Body Height; Body Weight; Bone Development; Humans; Insulin-Like Growth Factor Binding Protein 3; Insulin-Like Growth Factor I; Male; Rats; Rats, Sprague-Dawley; Tretinoin

Cardiovascular disorders constitute the principal cause of deaths worldwide and will continue as the major disease-burden by the year 2060. A significant proportion of heart failures occur because of use and misuse of drugs and most of the investigational agents fail to achieve any clinical relevance. Here, we investigated rosuvastatin and retinoic acid for their "pharmacological pleiotropy" against high dose β-adrenergic agonist (isoproterenol)-induced acute myocardial insult. Rats were pretreated with rosuvastatin and/or retinoic acid for seven days and the myocardial injury was induced by administering isoproterenol on the seventh and eighth day. After induction, rats were anaesthetized for electrocardiography, then sacrificed and different samples were collected/stored for various downstream assays. Myocardial injury with isoproterenol resulted in increased cardiac mass, decreased R-wave amplitude, increased QRS and QT durations; elevated levels of cardiac markers like cTnI, CK-MB, ALT and AST; increased lipid peroxidation, protein carbonylation and tissue nitric oxide levels; decreased endogenous antioxidants like SOD, CAT, GR, GST, GPx and total antioxidant activity; increased inflammatory markers like TNF-α and IL-6; decreased the mRNA expression of Nrf2 and Bcl-2; increased the mRNA expression of Bax, eNOS and iNOS genes. Pretreatment with rosuvastatin and/or retinoic acid mitigated many of the above biochemical and pathological alterations. Our results demonstrate that rosuvastatin and retinoic acid exert cardioprotective effects and may act as potential agents in the prevention of β-adrenergic agonist-induced acute myocardial injury in rats. Cardioprotective potential of rosuvastatin and retinoic acid could be attributed to their influence on the redox pathways, immunomodulation, membrane stability, Nrf2 preservation, iNOS and Bax expression levels. Thus, they may act directly or indirectly at various steps, the breakpoints, in the pathophysiological cascade responsible for cardiac injury. Our study gives insights about the pharmacological pleiotropism of rosuvastatin and retinoic acid.

Topics: Adrenergic beta-Agonists; Animals; Anticholesteremic Agents; Antineoplastic Agents; Body Weight; Heart; Isoproterenol; Male; Myocardial Infarction; Organ Size; Random Allocation; Rats; Rats, Wistar; Rosuvastatin Calcium; Signal Transduction; Tretinoin

Previous studies have shown that rambutan peel phenolic (RPP) extract has excellent biological activities due to its abundant phenolic content and profile. In this study, the potential anti-osteoporosis (OP) effects of RPP were evaluated by suppressing receptor activator nuclear factor-kappa B ligand (RANKL)-induced differentiation of RAW264.7 cells into osteoclasts and amelioratingretinoic acid-induced OP in rats. Our results showed that RPP efficiently decreased the formation of tartrate-resistant acid phosphatase (TRAP)-positive cells and reduced total TRAP activity in RAW264.7 cells under RANKL stimulation. RPP treatment significantlyameliorated retinoid acid-induced calcium loss in rats (

Topics: Animals; Biomarkers; Biopsy; Body Weight; Bone Density; Cell Differentiation; Cell Survival; Disease Models, Animal; Immunohistochemistry; Mice; Osteoclasts; Osteogenesis; Osteoporosis; Phenols; Plant Extracts; RANK Ligand; Rats; RAW 264.7 Cells; Sapindaceae; Tretinoin

Pulmonary emphysema is characterized by destruction of alveoli leading to inadequate oxygenation, disability and frequently death. This destruction was understood so far as irreversible. Published data has shown that ATRA (All Trans Retinoic Acid) reverses elastase-induced emphysema in rats. However, the molecular mechanisms governing regeneration process are so far unknown.. To examine the therapeutic potential of ATRA on various molecular pathways and their coordination towards governance of alveolar epithelial regeneration in emphysematous rats.. Emphysema was induced by elastase versus saline in Sprague-Dawley rats. On days 26-37, rats received daily intraperitoneal injections with ATRA (500 μg/kg b.w.) versus olive-oil. Lungs were removed at day 38 for histopathology and investigation of relative mRNA and protein expressions.. Histopathological analysis has shown that losses of alveoli were recovered in therapy (EA) group. Moreover, expressions of markers genes for alveolar cell proliferation, differentiation and EMT events at mRNA and protein levels were significantly increased in EA group than emphysema group (ES). Upon validation at genomics level, expressions of components of Notch, Hedgehog, Wnt, BMP and TGFβ pathways were significantly attenuated in EA group when compared with ES and were well comparable with the healthy group.. Therapeutic supplementation of ATRA rectifies the deregulated Notch, Hedgehog, Wnt, BMP and TGFβ pathways in emphysema condition, resulting in alveolar epithelium regeneration. Hence, ATRA may prove to be a potential drug in the treatment of emphysema. Nevertheless, elaborated studies are to be conducted.

Topics: Animals; Aquaporin 4; Body Weight; Bone Morphogenetic Proteins; Epithelium; Male; Pulmonary Alveoli; Pulmonary Emphysema; Rats; Rats, Sprague-Dawley; Regeneration; Signal Transduction; Transforming Growth Factor beta; Tretinoin; Vimentin

The antiresorptive agents still are the mainstay of osteoporosis treatment. This study aimed to investigate the efficacy of recombinant Lingzhi-8 (rLZ-8) on osteoclast in vitro and bone resorption in vivo. The rLZ-8 protein was derived from Ganoderma lucidum transformation and produced by a genetic system. Receptor activator of nuclear factor kappa-Β ligand induced RAW 264.7 cells to differentiate into osteoclastic cells in vitro. Cells were exposed to different doses of rLZ-8 for 7 days to measure differences of osteoclastic differentiation, apoptosis rate and gene expression. rLZ-8 was labeled with Alexa Fluor 568 to observe its intracellular distribution under super-resolution light microscopy. In addition, retinoic acid was administered to female rats for 14 days to develop osteopenia changes. Different doses of rLZ-8 were simultaneously administered to rats treated with retinoic acid to observe changes of bone mineral density, biochemical parameters and organ weight ratio. Results indicated that rLZ-8 regulated receptor activator of nuclear factor kappa-Β (RANK) - tumor necrosis factor receptor-associated factor 6 (TRAF6) - c-Jun N-terminal kinase (JNK) signaling pathway, by which rLZ-8 inhibited osteoclastic differentiation and promoted osteoclastic apoptosis. Through 3D-structured illumination microscopy, it was observed that rLZ-8 entered RAW264.7 cells and accumulated gradually into the cytoplasm but little into nucleus. Administration with rLZ-8 reversed loss of bone mass and improved ALP activity in osteoporotic rats. Low-to high-dose rLZ-8 treatments displayed little toxic effects on rat organs and did not seem to impact their overall health. All data suggested that rLZ-8 has possible action against osteoporosis.

Topics: Animals; Apoptosis; Body Weight; Bone Density; Bone Diseases, Metabolic; Cell Differentiation; Female; Gene Expression Regulation; Mice; Osteoclasts; Osteoporosis; Plant Proteins; Rats; Rats, Sprague-Dawley; RAW 264.7 Cells; Recombinant Proteins; Reishi; Tretinoin

Retinoic acid, an active metabolite of dietary vitamin A, acts as a ligand for nuclear receptor transcription factors with more than 500 known target genes. It is becoming increasingly clear that alcohol has a significant impact on cellular retinoic acid metabolism, with resultant effects on its function. Here, we test the hypothesis that chronic alcohol consumption impairs retinoic acid signaling in brown adipose tissue (BAT), leading to impaired BAT function and thermoregulation. All studies were conducted in age-matched, male mice consuming alcohol-containing liquid diets. Alcohol's effect on BAT was assessed by histology, qPCR, HPLC, LC/MS and measures of core body temperature. Our data show that chronic alcohol consumption decreases BAT mass, with a resultant effect on thermoregulation. Follow-up mechanistic studies reveal a decreased triglyceride content in BAT, as well as impaired retinoic acid homeostasis, associated with decreased BAT levels of retinoic acid in alcohol-consuming mice. Our work highlights a hitherto uncharacterized effect of alcohol on BAT function, with possible implications for thermoregulation and energy metabolism in drinkers. Our data indicate that alcohol's effects on brown adipose tissue may be mediated through altered retinoic acid signaling.

Topics: Acyltransferases; Adipose Tissue, Brown; Alcohol Drinking; Aldehyde Dehydrogenase 1 Family; Animals; Body Temperature Regulation; Body Weight; Diet; Energy Metabolism; Ethanol; Gene Expression Regulation; Isoenzymes; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Protein Isoforms; Retinal Dehydrogenase; Retinoic Acid 4-Hydroxylase; Retinoic Acid Receptor alpha; Signal Transduction; Tretinoin; Triglycerides; Uncoupling Protein 1; Vitamin A

Blood cells are receiving an increasing attention as an easily accessible source of transcript-based biomarkers. We studied the feasibility of using mouse whole blood RNA in this context. Several paradigms were studied: (i) metabolism-related transcripts known to be affected in rat tissues and peripheral blood mononuclear cells (PBMC) by fasting and upon the development of high fat diet (HFD)-induced overweight were assessed in whole blood RNA of fasted rats and mice and of HFD-fed mice; (ii) retinoic acid (RA)-responsive genes in tissues were assessed in whole blood RNA of control and RA-treated mice; (iii) lipid metabolism-related transcripts previously identified in PBMC as potential biomarkers of metabolic health in a rat model were assessed in whole blood in an independent model, namely retinoblastoma haploinsufficient (Rb+/-) mice. Blood was collected and stored in RNAlater® at -80°C until analysis of selected transcripts by real-time RT-PCR. Comparable changes with fasting were detected in the expression of lipid metabolism-related genes when RNA from either PBMC or whole blood of rats or mice was used. HFD-induced excess body weight and fat mass associated with expected changes in the expression of metabolism-related genes in whole blood of mice. Changes in gene expression in whole blood of RA-treated mice reproduced known transcriptional actions of RA in hepatocytes and adipocytes. Reduced expression of Fasn, Lrp1, Rxrb and Sorl1 could be validated as early biomarkers of metabolic health in young Rb+/- mice using whole blood RNA. Altogether, these results support the use of whole blood RNA in studies aimed at identifying blood transcript-based biomarkers of nutritional/metabolic status or metabolic health. Results also support reduced expression of Fasn, Lrp1, Rxrb and Sorl1 in blood cells at young age as potential biomarkers of metabolic robustness.

Topics: Adipocytes; Animals; Body Weight; Diet, High-Fat; DNA-Binding Proteins; Energy Metabolism; Fasting; Fatty Acid Synthase, Type I; Female; Gene Expression Regulation; Haploinsufficiency; Hepatocytes; Leukocytes, Mononuclear; Low Density Lipoprotein Receptor-Related Protein-1; Male; Membrane Transport Proteins; Mice; Mice, Inbred C57BL; Mice, Transgenic; Nutritional Status; Rats; Rats, Wistar; Receptors, LDL; Retinoblastoma Protein; RNA, Messenger; Transcriptome; Tretinoin; Tumor Suppressor Proteins

Vitamin A-derived retinoic acid (RA) signals are critical for the development of several organs, including the pancreas. However, the tissue-specific control of RA synthesis in organ and cell lineage development has only poorly been addressed in vivo. Here, we show that retinol dehydrogenase-10 (Rdh10), a key enzyme in embryonic RA production, has important functions in pancreas organogenesis and endocrine cell differentiation. Rdh10 was expressed in the developing pancreas epithelium and surrounding mesenchyme. Rdh10 null mutant mouse embryos exhibited dorsal pancreas agenesis and a hypoplastic ventral pancreas with retarded tubulogenesis and branching. Conditional disruption of Rdh10 from the endoderm caused increased mortality, reduced body weight, and lowered blood glucose levels after birth. Endodermal Rdh10 deficiency led to a smaller dorsal pancreas with a reduced density of early glucagon

Topics: Alcohol Oxidoreductases; Animals; Blood Glucose; Body Weight; Cell Differentiation; Congenital Abnormalities; Gene Expression Regulation, Developmental; Insulin-Secreting Cells; Mice; Mice, Knockout; Organogenesis; Pancreas; Paracrine Communication; Tretinoin

To explore the effect of combination of Epimedii Folium and Ligustri Lucidi Fructus on osteoporosis rats induced by retinoic acid.. Sixty three-month-old male Wistar rats were randomly divided into the normal control group, the model group, the Epimedii Folium group, the Ligustri Lucidi Fructus group, the combination group of Epimedii Folium and Ligustri Lucidi Fructus and the raloxifene group. The osteoporosis model was established through oral administration with retinoic acid for two weeks. Meanwhile, all of treatment groups were administered with corresponding drugs for three weeks. The contents of serum calcium (Ca), phosphorus (P), alkaline phosphatase (AKP) and tartrate-resistant acid phosphatase (StrACP) were detected, and the pathomorphological changes of femurs were observed.. The model control group showed much lower contents of serum Ca and P than the normal control group, but with significantly higher AKP and StrACP activity than the normal control group. The femoral head area showed reduced, narrow and sparse trabecular bones, with typical osteoporosis-like changes. Compared with the model control group, all of treated groups showed significant increase in Ca and P contents in serum, and down-regulate AKP and StrACP levels, while trabecular bones became more and wider, and densely interweaved as a reticular formation. Among them, the combination group showed the most significant effect.. Epimedii Folium and Ligustri Lucidi Fructus could effectively correct the abnormal bone metabolism and improve pathological conditions of bone tissues, so as to show the anti-osteoporosis effect. The combined application of the two drugs showed a better efficacy.

Topics: Acid Phosphatase; Alkaline Phosphatase; Animals; Body Weight; Calcium; Drug Interactions; Drugs, Chinese Herbal; Epimedium; Femur; Isoenzymes; Ligustrum; Male; Osteoporosis; Phosphorus; Rats; Rats, Wistar; Tartrate-Resistant Acid Phosphatase; Tretinoin

To examine the effects of all-trans retinoic acid (atRA) on renal morphology and function as well as on renal plasminogen activator inhibitor-1 (PAI-1) expression and plasmin activity in rats with 5/6 nephrectomy.. Adult male Sprague Dawley rats were given 5/6 nephrectomy or sham operation. Renal function was measured 2 weeks later. The nephrectomized rats were assigned to groups matched for proteinuria and treated with vehicle or atRA (5 or 10 mg/kg by gastric gavage once daily) for the next 12 weeks. Rats with sham operation were treated with vehicle. At the end of the treatments, kidneys were collected for histological examination, Western blot analysis, and enzymatic activity measurements.. The 5/6 nephrectomy promoted hypertension, renal dysfunction, and glomerulosclerosis. These changes were significantly reduced in the atRA-treated group. The expressions of PAI-1 and α-smooth muscle actin (α-SMA) were significantly increased in the vehicle-treated nephrectomized rats. Treatment with atRA significantly reduced the expressions of PAI-1 and α-SMA. However, plasmin activity remained unchanged following atRA treatment.. Treatment with atRA ameliorates glomerulosclerosis and improves renal function in rats with 5/6 nephrectomy. This is associated with a decrease in PAI-1 and α-SMA, but not with a change in plasmin activity.

Topics: Actins; Animals; Antineoplastic Agents; Blood Pressure; Body Weight; Fibrinolysin; Gene Expression; Glomerulosclerosis, Focal Segmental; Kidney; Kidney Diseases; Male; Matrix Metalloproteinase 2; Nephrectomy; Plasminogen Activator Inhibitor 1; Rats; Rats, Sprague-Dawley; Tretinoin

A mouse model of impaired renal development was developed and the effect of retinoic acid (RA) was investigated in this animal model.. An angiogenesis inhibitor (SU1498) was injected s.c. into day 3 C57BL/6 newborn mice to create a model of arrested renal development. RA (2 mg/kg) was injected i.p. for 10 days. Morphometry and immunohistochemistry were done.. Mice injected with SU1498 demonstrated deranged renal development in tubular structure and glomerular tuft area. Cortical thickness and area of glomerular tuft were significantly decreased after vascular endothelial growth factor (VEGF) inhibitor, and were significantly restored by RA. The length of capillary loops/glomerulus, the number of podocytes/glomerulus, and density of peritubular capillaries on CD31 immunostaining were significantly decreased by VEGF blocking and recovered by RA.. VEGF plays a major role in renal development, and RA reverses the inhibited development caused by an angiogenesis inhibitor.

Topics: Analysis of Variance; Angiogenesis Inhibitors; Animals; Animals, Newborn; Biopsy, Needle; Body Weight; Cinnamates; Female; Immunohistochemistry; Kidney; Kidney Cortex; Kidney Glomerulus; Mice; Mice, Inbred C57BL; Models, Animal; Organ Size; Random Allocation; Statistics, Nonparametric; Tretinoin

Recent investigations have demonstrated that elevated serum retinol-binding protein 4 (RBP4) secreted from adipose tissue plays a role in the development of systemic insulin resistance, and lowering RBP4 improves insulin sensitivity. These observations provide a rationale for the development of new antidiabetic agents aimed at reducing serum RBP4 concentrations. In this study, we sought to determine whether retinoic acid (RA) administration decreases serum RBP4 and suppresses insulin resistance in diabetic ob/ob mice. All-trans RA [100 mug/(moused) in corn oil] was administered by stomach intubation to a group of ob/ob mice, with the control group receiving the vehicle for 16 d. Body weight and food intake were monitored. Glucose and insulin tolerance tests were performed. We quantified serum RBP4 and retinol by Western blotting and HPLC, respectively. RA treatment reduced body weight (P < 0.05), basal serum glucose (P < 0.001), serum retinol (P < 0.01), and RBP4 (P < 0.05). It improved insulin sensitivity and decreased the retinol:RBP4 ratio (P < 0.05). These studies suggest that RA is an effective antidiabetic agent that could be considered in the treatment of type 2 diabetes.

Topics: Animals; Blood Glucose; Blotting, Western; Body Weight; Chromatography, High Pressure Liquid; Diabetes Mellitus, Experimental; Glucose Tolerance Test; Hypoglycemic Agents; Insulin Resistance; Mice; Mice, Obese; Retinol-Binding Proteins, Plasma; Tretinoin; Vitamin A

An earlier study showed that all-trans-retinoic acid (ATRA) prevents the development of monocrotalin-induced pulmonary hypertension (PH). The purpose of the present study was to determine the effect of ATRA on another model of chronic hypoxia-induced PH.. Male Sprague-Dawley rats were given 30 mg/kg ATRA or vehicle only by gavage once daily for 14 days during hypobaric hypoxic exposure. Chronic hypoxic exposure induced PH, right ventricular hypertrophy (RVH), and hypertensive pulmonary vascular changes. Quantitative morphometry of the pulmonary arteries showed that ATRA treatment significantly reduced the percentage of muscularized arteries in peripheral pulmonary arteries only with an external diameter between 15 and 50 microm. ATRA treatment also significantly reduced the medial wall thickness in small muscular arteries only with an external diameter between 50 and 100 microm. Unfortunately, these reductions did not accompany the lowering of pulmonary artery pressure nor decrease in RVH. Chronic hypoxia-induced PH rats with ATRA had a loss in body weight. Chronic hypoxia increased the expression of endothelial nitric oxide synthase in the lung on western blotting and immunohistochemistry, in which ATRA treatment had no effect.. The administration of ATRA might not have a therapeutic role in preventing the development of chronic hypoxia-induced PH, because of body weight loss and the subtle preventable effects of vascular changes.

Topics: Animals; Body Weight; Chronic Disease; Hypertension, Pulmonary; Hypertrophy, Right Ventricular; Hypoxia; Lung; Male; Nitric Oxide Synthase Type III; Pulmonary Artery; Rats; Rats, Sprague-Dawley; Tretinoin; Weight Loss

Conazoles are fungicides used in agriculture and as pharmaceuticals. In a previous toxicogenomic study of triazole-containing conazoles we found gene expression changes consistent with the alteration of the metabolism of all trans-retinoic acid (atRA), a vitamin A metabolite with cancer-preventative properties (Ward et al., Toxicol. Pathol. 2006; 34:863-78). The goals of this study were to examine effects of propiconazole, triadimefon, and myclobutanil, three triazole-containing conazoles, on the microsomal metabolism of atRA, the associated hepatic cytochrome P450 (P450) enzyme(s) involved in atRA metabolism, and their effects on hepatic atRA levels in vivo. The in vitro metabolism of atRA was quantitatively measured in liver microsomes from male CD-1 mice following four daily intraperitoneal injections of propiconazole (210 mg/kg/d), triadimefon (257 mg/kg/d) or myclobutanil (270 mg/kg/d). The formation of both 4-hydroxy-atRA and 4-oxo-atRA were significantly increased by all three conazoles. Propiconazole-induced microsomes possessed slightly greater metabolizing activities compared to myclobutanil-induced microsomes. Both propiconazole and triadimefon treatment induced greater formation of 4-hydroxy-atRA compared to myclobutanil treatment. Chemical and immuno-inhibition metabolism studies suggested that Cyp26a1, Cyp2b, and Cyp3a, but not Cyp1a1 proteins were involved in atRA metabolism. Cyp2b10/20 and Cyp3a11 genes were significantly over-expressed in the livers of both triadimefon- and propiconazole-treated mice while Cyp26a1, Cyp2c65 and Cyp1a2 genes were over-expressed in the livers of either triadimefon- or propiconazole-treated mice, and Cyp2b10/20 and Cyp3a13 genes were over-expressed in the livers of myclobutanil-treated mice. Western blot analyses indicated conazole induced-increases in Cyp2b and Cyp3a proteins. All three conazoles decreased hepatic atRA tissue levels ranging from 45-67%. The possible implications of these changes in hepatic atRA levels on cell proliferation in the mouse tumorigenesis process are discussed.

Topics: Animals; Blotting, Western; Body Weight; Chromatography, High Pressure Liquid; Cytochrome P-450 Enzyme System; Fungicides, Industrial; Gene Expression Profiling; Liver; Male; Mice; Microsomes, Liver; Nitriles; Organ Size; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Spectrometry, Mass, Electrospray Ionization; Tretinoin; Triazoles

Neuroblastoma is the childhood malignancy that mainly occurs in adrenal glands and is found also in the neck, chest, abdomen, and pelvis. New therapeutic strategies are urgently needed for successful treatment of this pediatric cancer. In this investigation, we examined efficacy of the retinoid N-(4-hydroxyphenyl) retinamide (4-HPR) and the isoflavonoid genistein (GST) alone and also in combination for controlling the growth of human malignant neuroblastoma SK-N-BE2 and SH-SY5Y xenografts in nude mice. Combination of 4-HPR and GST significantly reduced tumor volume in vivo due to overwhelming apoptosis in both neuroblastoma xenografts. Time-dependently, combination of 4-HPR and GST caused reduction in body weight, tumor weight, and tumor volume. Combination of 4-HPR and GST increased Bax:Bcl-2 ratio, mitochondrial release of Smac, downregulation of baculovirus inhibitor-of-apoptosis repeat containing (BIRC) proteins including BIRC-2 and BIRC-3, and activation of caspase-3 and apoptosis inducing factor (AIF). Further, downregulation of nuclear factor-kappa B (NF-kappaB), vascular endothelial growth factor (VEGF), and fibroblast growth factor 2 (FGF2) was also detected. In situ immunofluorescent labelings of tumor sections showed overexpression of calpain, caspase-12, and caspase-3, and also AIF in the course of apoptosis. Combination therapy increased apoptosis in the xenografts but did not induce kidney and liver toxicities in the animals. Results demonstrated that combination of 4-HPR and GST induced multiple molecular mechanisms for apoptosis and thus could be highly effective for inhibiting growth of malignant neuroblastoma in preclinical animal models.

Topics: Animals; Anticarcinogenic Agents; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Apoptosis Regulatory Proteins; Body Weight; Cell Line, Tumor; Cell Proliferation; Disease Models, Animal; Genistein; Humans; Intercellular Signaling Peptides and Proteins; Mice; Mice, Nude; Neuroblastoma; NF-kappa B; Transplantation, Heterologous; Treatment Outcome; Tretinoin; Tumor Cells, Cultured; Xenograft Model Antitumor Assays

The present study extends previous investigations examining the behavioral outcomes of all-trans retinoic acid (RA) exposure at embryonic (E) days 14-16. A sublethal dose (2.5 mg/kg b.w.) compatible with high neonatal survival sufficient to supply offspring for later behavioral testing, was used. The results show that E14-16 RA exposure, similar to E8-10 or E11-13 (previous studies), impairs locomotor activity (open field test) as well as motor coordination and motor learning (rotarod/accelerod task) in young-adult rats. The results provide further evidence that RA exposure induces a pattern of motor deficits which are not strictly related to the embryonic stage, compatible with the protracted developmental profile of the cerebellum.

Topics: Analysis of Variance; Animals; Animals, Newborn; Antineoplastic Agents; Body Weight; Escape Reaction; Female; Forelimb; Hand Strength; Motor Activity; Movement Disorders; Pregnancy; Prenatal Exposure Delayed Effects; Rats; Rats, Sprague-Dawley; Reflex; Reproduction; Rotarod Performance Test; Statistics, Nonparametric; Tretinoin

The purpose of the present study was to investigate the behavioral outcomes of all-trans retinoic acid (RA) treatment in the period spanning gestational day (GD) 8-10. A sublethal dose (2.5mg/kg b.w.) compatible with high neonatal survival, sufficient to supply male offspring for later behavioral testing, was used. Indeed, the mortality rate at birth was 7.8%. Reproduction parameters (body weight gain of dams during gestation, number of dams giving birth, pregnancy length, litter size at birth), offspring body weight gain and the development of their somatic characteristics (ear unfolding, auditory conduit opening, eyes opening, hair growth) were not altered by RA. Instead, the onset of righting reflex and negative geotaxis were delayed by 2 days, suggesting vestibular involvement and abnormal functioning of the cerebellum. Then, the performance of RA-treated rats on open field and rotarod/accelerod tasks was assessed from postnatal day (PND) 21 to 90. Similar to the previously investigated GD 11-13 RA treatment, the GD 8-10 RA treatment impaired the open field activity and rotarod/accelerod performance in young adult rats, thus suggesting a task-specific rather than a stage-specific effect of low-dose retinoids during brain development. The delayed appearance of these outcomes underlines the relevance of longitudinal studies to sort out specific RA-targeted neurochemical-behavioral pathways that could be labelled as having no phenotype based on standard examination at birth.

Topics: Age Factors; Analysis of Variance; Animals; Animals, Newborn; Antineoplastic Agents; Body Weight; Female; Hand Strength; Male; Motor Activity; Motor Skills; Pregnancy; Prenatal Exposure Delayed Effects; Rats; Rats, Sprague-Dawley; Reflex; Reproduction; Rotarod Performance Test; Statistics, Nonparametric; Tretinoin

The relation between vitamin A (VA) nutritional status and the metabolism of all-trans-retinoic acid (RA) is not well understood. In this study, we determined the tissue distribution and metabolism of a test dose of [(3)H]-RA in rats with graded, diet-dependent, differences in VA status. The design included 3 groups, designated VA-deficient, VA-marginal, and VA-adequate, with liver total retinol concentrations of 9.7, 35.7 and 359 nmol/g, respectively, (P < 0.05), and an additional group of VA-deficient rats treated with a single oral dose of retinyl palmitate (RP) 20 h before the injection of [(3)H]-RA. Plasma, liver, lung, and small intestines, collected 30 min after [(3)H]-RA, were analyzed for total (3)H, unmetabolized [(3)H]-RA, polar organic-phase metabolites of [(3)H]-RA, and aqueous phase [(3)H]-labeled metabolites. In all groups, [(3)H]-RA was rapidly removed from plasma and concentrated in the liver. VA deficiency did not prevent the oxidative metabolism of RA. Nevertheless, the quantity of [(3)H]-RA metabolites in plasma and the ratio of total [(3)H]-polar metabolites to unmetabolized [(3)H]-RA in liver varied directly with VA status (VA-adequate > VA-marginal > VA-deficient, P < 0.05). Moreover, supplementation of VA-deficient rats with RP reduced the metabolism of [(3)H]-RA, similar to that in VA-adequate or VA-marginal rats. Liver retinol concentration, considered a proxy for VA status, was correlated (P < 0.05) with [(3)H]-RA metabolites in liver (R(2) = 0.54), plasma (R(2) = 0.44), lung (R(2) = 0.40), intestine (R(2) = 0.62), and all combined (R(2) = 0.655). Overall, the results demonstrate close linkage between dietary VA intake, hepatic storage of VA, and the degradation of RA and suggest that measuring plasma retinoid metabolites after a dose of RA may provide insight into the metabolism of this bioactive retinoid by visceral organs.

Topics: Animals; Body Weight; Cytochrome P-450 Enzyme System; Diterpenes; Female; Organ Size; Rats; Rats, Sprague-Dawley; Retinoic Acid 4-Hydroxylase; Retinyl Esters; RNA, Messenger; Tretinoin; Vitamin A

Novel potent C-4 azolyl retinoic acid metabolism blocking agents (RAMBAs)-VN/14-1, VN/50-1, VN/66-1, VN/67-1, and VN/69-1, have been synthesized and investigated for their in vitro and in vivo effects against breast and prostate cancers. These RAMBAs, in addition to being potent inhibitors of all-trans-retinoic acid (ATRA) metabolism have potent anti-cancer properties and in vivo anti-tumor efficacies as characterized in breast and prostate cancer models. Here we determined the toxicity and pharmacokinetics (PK) of these various RAMBAs.. Preliminary acute toxicity studies of these RAMBAs were carried out using Swiss NIH mice. The toxicity profile of the RAMBAs was evaluated relative to ATRA. Three different doses (8.3, 33, and 100 micromol/kg/day) of ATRA and RAMBAs were administered on a daily basis subcutaneously for 14 days to the mice. Clinical signs of toxicity alopecia, scaly skin, and loss of body weight in the mice were observed during the study and the maximum tolerated dose was determined. PK of selected agents (VN/14-1, VN/50-1, and VN/66-1) was studied in Balb/C mice after a single dose subcutaneous administration. Plasma concentrations of the agents were quantitatively determined using a high-performance liquid chromatographic method with ultraviolet detection. Plasma concentration versus time profiles were fit to various PK structural models and relevant PK parameters were estimated.. VN/66-1 and VN/69-1 were found to be the least toxic even at the highest doses when compared to the other RAMBAs and ATRA. VN/66-1 had the longest half-life, the slowest clearance, and the greatest exposure.. Based on PK characteristics and toxicity studies, VN/66-1 appeared to be the most favorable agent. However, both VN/14-1 and VN/66-1 are our leads based on the fact that VN/14-1 has been found to be highly effective in endocrine-sensitive and -resistant breast cancer cells and tumors with little toxicity. Our findings provide valuable information that will be used to select RAMBAs and establish therapeutic regimens that provide optimal efficacy with minimal toxicity.

Topics: Alopecia; Animals; Antineoplastic Agents; Area Under Curve; Body Weight; Chromatography, High Pressure Liquid; Dose-Response Relationship, Drug; Female; Half-Life; Imidazoles; Injections, Subcutaneous; Mice; Mice, Inbred BALB C; Skin Diseases; Tissue Distribution; Tretinoin

A reduced nephron complement at birth renders the kidney susceptible to renal disease in adulthood. Retinoic acid (RA; the active metabolite of vitamin A) is linked to nephrogenesis in vitro and in vivo. The aim of this study was to determine the effect of administration of retinoic acid in midgestation in rats on nephron endowment in offspring exposed to maternal protein restriction. Rats were fed either a normal-protein diet (NPD) or a low-protein diet (LPD) during pregnancy and lactation. Half of the dams in the LPD group were injected intraperitoneally with retinoic acid (20 mg/kg) during gestation at embryonic day 11.5. At 4 weeks of age, the offspring were anesthetized and perfusion-fixed, and nephron number estimated using unbiased stereological techniques. Body weight and kidney volume was significantly reduced in all LPD offspring. There was a significant 29% reduction in nephron number in the LPD group compared with the NPD offspring, whereas the number of nephrons in kidneys from the LPD + RA offspring was not significantly different compared with controls. In conclusion, administration of a single bolus dose of retinoic acid during midgestation restored nephron endowment to normal in offspring exposed to maternal protein restriction.

Topics: Animals; Antineoplastic Agents; Body Weight; Diet, Protein-Restricted; Dietary Proteins; Female; Fetal Nutrition Disorders; Gestational Age; Injections, Intraperitoneal; Kidney Glomerulus; Male; Nephrons; Organ Size; Pregnancy; Prenatal Exposure Delayed Effects; Rats; Rats, Inbred WKY; Tretinoin

All-trans retinoic acid (ATRA) stimulates platelet-derived growth factor (PDGF)-A expression and enhances alveolarization in rat lungs. On d 16 of gestation, pregnant Sprague-Dawley rats were randomly assigned to either a retinoic acid group (intragastric ATRA at 10 mg/kg body weight) or a vehicle group. We punctured each amniotic sac, and fetuses in the opposite uterine horn served as controls. On d 21 of gestation, the fetuses were delivered by cesarean section. Rats subjected to oligohydramnios exhibited significantly lower lung weights and lung/body weight ratios, and ATRA had no effects on the body or lung weights of oligohydramnios-exposed rats. Lung PDGF-A and -B mRNA expression was significantly lower in oligohydramnios-exposed rats compared with control littermates of maternal vehicle-treated dams. Maternal retinoic acid treatment significantly increased PDGF-A and -B mRNA expression in control and oligohydramnios-exposed rats compared with all rats and oligohydramnios-exposed rats of maternal vehicle-treated dams, respectively. Rats exposed to oligohydramnios exhibited a significantly lower generation of alveolar saccules than did control rats in the maternal retinoic acid- and vehicle-treated groups. In this model, maternal retinoic acid treatment showed no positive effects on oligohydramnios-induced pulmonary hypoplasia in the pseudoglandular stage.

Topics: Amnion; Animals; Body Weight; Disease Models, Animal; Female; Fetal Organ Maturity; Gestational Age; Immunohistochemistry; Lung; Lung Diseases; Oligohydramnios; Organ Size; Platelet-Derived Growth Factor; Pregnancy; Proto-Oncogene Proteins c-sis; Pulmonary Alveoli; Rats; Rats, Sprague-Dawley; RNA, Messenger; Tretinoin; Up-Regulation

Histone deacetylase (HDAC) inhibitors have been shown to reverse repression of some genes, including retinoic acid (RA) receptor beta2. In this work, we studied the effects of RA alone or combined with the HDAC inhibitor sodium butyrate (NaB) in a poorly differentiated thyroid carcinoma cell line (FTC-133) cultured in vitro or transplanted into nude mice. In vitro, the action of the xenobiotics on cell differentiation was evaluated by the measurement of alkaline phosphatase (ALP) activity. In vivo, FTC cells were injected in nude mice divided into four groups: controls, RA (1 mg/kg), NaB (50 mg/kg) in two daily injections or both RA plus NaB. Body weight, tumoral volume (TV), doubling time of the tumor, specific growth delay and inhibition of tumoral growth at day 35 were determined in each group. In vitro, RA increased the NaB-induced increase in ALP activity. In vivo, body weight and TV decreased with RA or NaB. Specific growth delay significantly increased with RA (72.5%; P < 0.001) and with NaB (31.3%; 0.02

Topics: Alkaline Phosphatase; Animals; Body Weight; Butyrates; Cell Differentiation; Cell Proliferation; Drug Synergism; Female; Humans; Mice; Mice, Nude; Neoplasm Transplantation; Thyroid Neoplasms; Tretinoin

Corticosteroids are highly effective anti-inflammatory or immunosuppressive drugs used commonly to treat human systemic lupus erythematosus (SLE). All-trans-retinoic acid (ATRA), which belongs to a class of retinoids that exert immunomodulatory and anti-inflammatory functions, can also suppress the development of lupus nephritis in an animal model. However, both agents can inflict serious adverse effects. Here, we have asked whether ATRA can serve as a steroid-sparing drug in the treatment of lupus nephritis. To examine the efficacy of combining predonisolone (PSL) with ATRA, we treated intraperitoneally New Zealand black/white F1 (NZB/W F1) mice with PSL, ATRA or both agents. Survival rate and proteinuria were determined once a month. Cytokine and anti-DNA antibody production were determined by enzyme-linked immunosorbent assay (ELISA) and reverse transcription-polymerase chain reaction (RT-PCR). Renal histopathology was observed by haematoxylin and periodic acid Schiff (PAS), immunoperoxidase and immunohistochemical assay. Survival rate and proteinuria were improved in all experimental groups, and were much improved in the mice receiving the combination of ATRA and PSL (P <0.05). A single administration of ATRA reduced the Th1 [interleukin (IL)-2, interferon (IFN)-gamma and IL-12], and a Th2 (IL-4) cytokine level, as effectively as administration of PSL. ATRA also suppressed the expression of inducible nitric oxide synthetase (iNOS) and monocyte chemoattractant protein-1 (MCP-1) in the kidney. The combination of PSL and ATRA significantly reduced IgG2 (especially IgG2b)-specific anti-DNA antibody levels in comparison with administration of either agent alone. These data suggest that ATRA might have the potential to act as a new therapeutic and steroid-sparing drug against lupus nephritis.

Topics: Animals; Anti-Inflammatory Agents; Antibodies, Antinuclear; Body Weight; Chemokine CCL2; Cytokines; DNA; Drug Therapy, Combination; Female; Glucocorticoids; Immunoglobulin G; Immunohistochemistry; Keratolytic Agents; Kidney; Lupus Nephritis; Mice; Mice, Inbred NZB; Nitric Oxide Synthase; Nitric Oxide Synthase Type II; Prednisolone; Proteinuria; RNA, Messenger; Spleen; Tretinoin

All-trans retinoic acid is the bioactive form of vitamin A (retinol). Retinoids have been used clinically as therapeutic agents against a number of cancers. Retinoids have been reported to induce the phase I drug metabolizing enzymes, cytochrome P-450s. In contrast, effects of retinoids on sulfotransferases have not been as well studied. The present investigation evaluates the role of retinoic acid on the expression of aryl sulfotransferase IV and hydroxysteroid sulfotransferase a in male and female Sprague-Dawley rat liver and intestine. Cultured human hepatic carcinoma cells (Hep G2) and intestinal carcinoma cells (Caco-2) were also used to study retinoic acid's effect on simple phenol sulfating sulfotransferase, dehydroepiandrosterone sulfotransferase and oestrogen sulfotransferase. Enzyme assay and Western blot were used to determine sulfotransferase protein expression. Retinoic acid induced aryl sulfotransferase IV in liver of female rats and sulfotransferase a in liver of male rats. Intestinal rat aryl sulfotransferase IV and sulfotransferase a in male rats and intestinal aryl sulfotransferase IV in female rats were also induced after retinoic acid treatment. In Hep G2 and Caco-2 cells, retinoic acid differentially induced the three human sulfotransferase isoforms. In general, intestinal sulfotransferases were found to be more responsive than hepatic sulfotransferases to retinoic acid treatment. mRNA expressions were investigated using reverse transcription polymerase chain reaction with gene specific primers. Reverse transcription polymerase chain reaction results are in good agreement with enzyme activity and Western blot results. This suggests that retinoic acid induction of sulfotransferases is at the transcriptional level.

Topics: Animals; Blotting, Western; Body Weight; Caco-2 Cells; Cell Line, Tumor; Cytosol; Dehydroepiandrosterone Sulfate; Dose-Response Relationship, Drug; Enzyme Induction; Female; Gene Expression Regulation, Enzymologic; Humans; Male; Rats; Rats, Sprague-Dawley; Retinoid X Receptors; Reverse Transcriptase Polymerase Chain Reaction; RNA; Sulfotransferases; Tretinoin

Chemopreventive activities of all-trans retinoic acid (AtRA), 9-cis retinoic acid (9cRA), retinol (ROL) and beta-carotene (betaC) were evaluated during hepatocarcinogenesis. Rats received 1 mg/100 g body wt AtRA (AtRA group), 9cRA (9cRA group), ROL (ROL group), 7 mg/100 g body wt betaC (betaC group) or corn oil (CO group, controls). Hepatocyte nodule incidence was reduced (P < 0.05) in betaC group (46%), but not (P > 0.05) in AtRA (92%), 9cRA (92%) and ROL (82%) groups, compared with the CO group (100%). Multiplicity of these preneoplastic lesions (PNL) was different (P < 0.05) between CO group (44 +/- 9) and 9cRA (11 +/- 4), ROL (7 +/- 3) and betaC (4 +/- 2) groups, except for AtRA group (27 +/- 9; P > 0.05). Number/cm(2) liver section, mean area (mm(2)) and percent liver section area occupied by total (persistent + remodeling) placental glutathione S-transferase (GST-P) positive PNL was reduced (P < 0.05) in AtRA (107 +/- 13; 0.12 +/- 0.06; 13.9 +/- 3.9), 9cRA (71 +/- 12; 0.12 +/- 0.06; 6.8 +/- 2.2), ROL (96 +/- 13; 0.11 +/- 0.22; 6.8 +/- 2.0) and betaC (106 +/- 13; 0.08 +/- 0.03; 10.8 +/- 2.5) groups compared with CO group (166 +/- 14; 0.18 +/- 0.09; 28.6 +/- 5.2). Percent of remodeling GST-P positive PNL was increased (P < 0.05) in 9cRA (92 +/- 1), ROL (96 +/- 1) and betaC (93 +/- 1) groups, but not (P > 0.05) in AtRA group (90 +/- 2), compared with the CO group (86 +/- 1). Compared with the CO group, all groups present in PNL reduced (P < 0.05) cell proliferation and no differences (P > 0.05) in apoptosis. DNA damage [comet length (mum)] was reduced (P < 0.05) in ROL (87.9 +/- 2.6) and betaC (89.2 +/- 4.0) groups, but not in AtRA (94.8 +/- 4.1) and 9cRA (94.2 +/- 1.5) groups, compared with the CO group (100.4 +/- 3.9). AtRA, 9cRA, ROL and betaC presented chemopreventive activities against hepatocarcinogenesis. These involve inhibition of cell proliferation, but not induction of apoptosis. Increased remodeling of GST-P positive PNL relates to 9cRA, ROL and betaC actions, while inhibition of DNA damage relates to ROL and betaC actions.

Topics: Alitretinoin; Animals; Antineoplastic Agents; Antioxidants; Apoptosis; beta Carotene; Body Weight; Cell Proliferation; Chemoprevention; Comet Assay; DNA Damage; Glutathione Transferase; Hepatocytes; Incidence; Liver Neoplasms, Experimental; Male; Organ Size; Precancerous Conditions; Rats; Rats, Wistar; Tretinoin; Vitamin A

Treatment of cultured PANC-1, MIA PaCa-2, and BxPC-3 human pancreatic adenocarcinoma cells with 0.1 to 1.6 nM 12-O-tetradecanoylphorbol-13-acetate (TPA) for 96 h inhibited the proliferation of these cells in a dose-dependent manner, and PANC-1 and MIA PaCa-2 cells were more sensitive to TPA than BxPC-3 cells. Inhibition of proliferation by TPA in PANC-1 cells was associated with an increase in the level of p21, but this was not observed in MIA PaCa-2 or BxPC-3 cells. The TPA-induced increase of p21 in PANC-1 cells was blocked by bisindolylmaleimide or rottlerin (inhibitors of protein kinase C). Studies in NCr-immunodeficient mice with well established PANC-1 tumor xenografts indicated that daily i.p. injections of TPA strongly inhibited tumor growth, increased the percentage of caspase-3-positive cells, and decreased the ratio of mitotic cells to caspase-3-positive cells in the tumors. Studies with BxPC-3 tumors in NCr mice receiving daily i.p. injections of vehicle, TPA, all-trans retinoic acid (ATRA), or a TPA/ATRA combination showed that TPA had an inhibitory effect on tumor growth, but treatment of the animals with the TPA/ATRA combination had a greater inhibitory effect on tumor growth than TPA alone. Treatment with the TPA/ATRA combination resulted in a substantially decreased ratio of the percentage of mitotic cells to the percentage of caspase-3-positive cells in the tumors compared with tumors from the vehicle-treated control animals. The inhibitory effects of TPA on tumor growth occurred at clinically achievable blood levels.

Topics: Animals; Apoptosis; Body Weight; Cell Cycle; Cell Proliferation; Humans; Immunohistochemistry; Male; Mice; Neoplasm Transplantation; Paclitaxel; Pancreatic Neoplasms; Phosphorylation; Prostatic Neoplasms; Protein Kinase C; Retinoblastoma Protein; Sulindac; Tetradecanoylphorbol Acetate; Transplantation, Heterologous; Tretinoin; Tumor Cells, Cultured

Oral treatment with the anti-acne drug Accutane (isotretinoin, 13-cis-retinoic acid) has been associated with suicide ideation and depression. Here, depression-like behaviors (i.e., behavioral despair and anhedonia) were quantified in adult Sprague-Dawley rats gavaged daily beginning at postnatal day (PND) 82 with 13-cis-RA (7.5 or 22.5 mg/kg) or all-trans-retinoic acid (10 or 15 mg/kg ). Tested at PND 130-131 in the Forced Swim Test, 7.5 mg/kg 13-cis-RA marginally decreased immobility and slightly increased climb/struggle durations whereas neither all-trans-retinoic acid group differed from controls. Voluntary saccharin solution (0.03%) intake at PND 102-104 and PND 151-153 was not different from controls in any treated group, although all RA-treated groups had lower intakes. Swim speed in a water maze at PND 180 was similar across groups, indicating no RA-induced differences in physical ability. Open field activity was mildly decreased at PND 91 in 7.5 mg/kg-treated males only, but it was within the control range at PND 119, 147, and 175. Thus, at serum levels similar to those in humans receiving the drug, chronic 13-cis-RA treatment did not severely affect depression-like behaviors in rats. These data do not substantiate the hypothesis of 13-cis-RA-induced depression.

Topics: Aging; Animals; Behavior, Animal; Body Weight; Depression; Dose-Response Relationship, Drug; Drinking; Eating; Female; Isotretinoin; Keratolytic Agents; Male; Motor Activity; Rats; Saccharin; Sex Characteristics; Sweetening Agents; Swimming; Tretinoin

We have investigated the role of Vitamin A (retinoid) proteins in hepatic retinoid processing under normal conditions and during chemical stress induced by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), a chemical known to interfere with retinoid turnover and metabolism. Three separate studies were performed in wildtype control mice and transgenic mice that lack one or more isoforms of retinoic acid receptors (RAR), retinoid X receptors (RXR), or intracellular retinoid-binding proteins (CRABP I, CRABP II, CRBP I). Body and organ weight development was monitored from 2 weeks of age to adult, and hepatic levels of retinyl esters, retinol, and retinoic acid were investigated. In addition, hepatic concentrations of 9-cis-4-oxo-13,14-dihydro-retinoic acid, a recently discovered retinoid metabolite that has proven sensitive to both TCDD exposure and Vitamin A status, were also determined. Mice absent in the three proteins CRBP I, CRABP I, and CRABP II (CI/CAI/CAII-/-) displayed significantly lower hepatic retinyl ester, retinol, and all-trans-retinoic acid levels compared to wildtype mice, whereas the liver concentrations of 9-cis-4-oxo-13,14-dihydro-retinoic acid was considerably higher. After treatment with TCDD, hepatic total retinoids were almost entirely depleted in the CI/CAI/CAII-/- mice, whereas wildtype mice and mice lacking CRABP I, and CRABP II (CAI/CAII-/-) retained approximately 60-70% of their Vitamin A content compared to controls at 28 days. RAR and RXR knockout mice responded similarly to wildtype mice with respect to TCDD-induced retinoid disruption, with the exception of RXRbeta-/- mice which showed no decrease in hepatic Vitamin A concentration, suggesting that the role of RXRbeta in TCDD-induced retinoid disruption should be further investigated. Overall, the abnormal retinoid profile in the triple knockout mice (CI/CAI/CAII-/-), but not double knockout (CAI/CAII-/-) mice, suggests that a loss of CRBP I may account for the difference in retinoid profile in CI/CAI/CAII-/- mice, and is likely to result in an increased susceptibility to hepatic retinoid depletion following dioxin exposure.

Topics: Animals; Body Weight; Dose-Response Relationship, Drug; Liver; Mice; Organ Size; Polychlorinated Dibenzodioxins; Receptors, Retinoic Acid; Retinoids; Retinol-Binding Proteins; Retinol-Binding Proteins, Cellular; Species Specificity; Time Factors; Tretinoin

Chemopreventive activity by retinoic acid (RA) has been demonstrated previously in rat colon. The spontaneous tumourigenesis in the Min/+ mouse, which harbours a germline mutation in the tumour suppressor gene adenomatous polyposis coli (Apc), is characterized by inactivation of Apc, nuclear accumulation of beta-catenin and the enhanced expression of specific genes activated by T cell factor (TCF)/beta-catenin signalling. Recently it was reported that beta-catenin interacts with retinoic acid receptor in a retinoid-dependent manner, reducing beta-catenin/TCF regulated transcription. Our hypothesis was therefore that dietary supplementation with all-trans RA may inhibit the Apc-driven tumourigenesis in Min/+ mice. Surprisingly, in two different experiments the results showed that dietary RA significantly stimulated both the formation and growth of small intestinal tumours. In the first experiment Min/+ mice were exposed to 50 mg 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine/kg bodyweight at day 3-6 after birth and then treated with 50 mg/kg dietary RA in 1-3 weeks from the age of 2 weeks. In the second experiment the mice were not treated with carcinogen, and the diet was supplemented with 5 or 10 mg/kg RA from the age of 4 weeks until termination of the experiment at 11 weeks. Immunohistochemical studies revealed no differences in beta-catenin, cyclin D1 or proliferating cell nuclear antigen staining following RA treatment. There was no intestinal toxicity in mice fed 10 mg/kg RA, indicating that the increased tumourigenesis in Min/+ mice is a specific effect of all-trans RA.

Topics: Animals; beta Catenin; Body Weight; Cyclin D1; Cytoskeletal Proteins; Dietary Supplements; Female; Genes, APC; Germ-Line Mutation; Imidazoles; Intestinal Neoplasms; Male; Mice; Mice, Inbred C57BL; Proliferating Cell Nuclear Antigen; Trans-Activators; Tretinoin

We have previously shown that in diabetes nitrergic neurones innervating the urogenital and gastrointestinal organs undergo a selective degenerative process. This comprises an initial insulin-reversible decrease in neuronal nitric oxide synthase (nNOS) in the axons, followed by apoptosis of the nitrergic neurones, a process that is not reversible by insulin. Since apoptosis was independent of serum glucose concentrations, and advanced glycation endproducts (AGEs) have been implicated in the pathogenesis of diabetic complications, we have now measured AGEs in the serum and penis, pyloric sphincter and pelvic ganglia of diabetic animals at different times after streptozotocin treatment. Furthermore, we have studied their effect in vitro on human neuroblastoma (SH-SY5Y) cells in the presence or absence of nNOS expression.. Serum AGEs were measured using fluorometry and ELISA. Accumulation of AGEs in the tissues was evaluated with immunohistochemistry. The viability, apoptosis and oxidative stress in SH-SY5Y cells were measured upon exposure to AGEs or high concentrations of glucose.. AGEs increased gradually in the serum and tissues of streptozotocin-induced diabetic rats; this process was not affected by delayed insulin treatment. In SH-SY5Y cells, AGEs, but not high glucose concentrations, increased the reactive oxygen species and caspase-3-dependent apoptosis in a synergistic fashion with endogenous nitric oxide (NO). Apoptosis was prevented by treatment with a NOS inhibitor, a pan-caspase inhibitor, a soluble receptor of AGEs or an anti-oxidant, but not an inhibitor of soluble guanylate cyclase.. The synergistic actions of NO and AGEs account for the irreversible nitrergic degeneration in diabetes.

Topics: Animals; Apoptosis; Blood Glucose; Body Weight; Caspase 3; Caspase Inhibitors; Caspases; Cell Line, Tumor; Choline O-Acetyltransferase; Diabetes Mellitus, Experimental; Diabetic Neuropathies; Drug Synergism; Enzyme Inhibitors; Esophagogastric Junction; Ganglia; Gene Expression; Glucose; Glycation End Products, Advanced; Immunohistochemistry; Insulin; Male; Nitrergic Neurons; Nitric Oxide; Nitric Oxide Synthase; Nitric Oxide Synthase Type I; Penis; Rats; Rats, Wistar; Reactive Oxygen Species; Receptor for Advanced Glycation End Products; Receptors, Immunologic; Serum Albumin; Tretinoin

The mechanisms of teratogenic action of ethanol (EtOH) were investigated by testing the hypothesis that all-trans-retinoic acid and/or alpha-tocopherol ameliorates ethanol-induced embryonic growth retardation. Chicken embryos were explanted in shell-less cultures and a single dose of EtOH (15, 30, or 50%) or 50% EtOH with either all-trans-retinoic acid (10(-8)M) or alpha-tocopherol (0.05 M) or a mix of all-trans-retinoic acid (10(-8)M) and alpha-tocopherol (0.05 M) was applied to the center of the blastodisc. EtOH significantly increased the mortality rate and induced growth retardation in a dose-dependent manner. In addition, EtOH increased malondialdehyde (MDA) levels, an indicator of oxidative stress and cell damage, in a dose dependent manner. All-trans-retinoic acid, the active form of Vitamin A, and/or alpha-tocopherol, an antioxidant, co-treatment with EtOH significantly diminished both the EtOH-induced mortality and growth retardation. However, only alpha-tocopherol co-treatment reduced the MDA levels. Thus, the mechanisms of teratogenic action of EtOH appear to involve initiation of oxidative stress as well as perturbation of retinoic acid (RA) signaling. It also appears likely that these mechanisms work independently of each other.

Topics: Animals; Antioxidants; Body Weight; Chick Embryo; Dose-Response Relationship, Drug; Embryo Culture Techniques; Ethanol; Fetal Growth Retardation; Malondialdehyde; Teratogens; Tretinoin; Vitamin E

Retinoic acid (tRA) is an active metabolite of vitamin A with potent anti-inflammatory properties. We analyzed the effects of tRA on the development of lupus nephritis in MRL/lpr mice.. MRL/lpr mice received chow supplemented with vehicle or tRA (daily 10 mg/kg) from 8 to 14 weeks until their sacrifice. MRL/wt mice served as an additional control.. tRA-treated MRL/lpr mice showed reduced lymphoadenopathy and splenomegaly as compared to vehicle-treated controls. Treatment reduced proteinuria to almost basal levels. Plasma IgG and anti-DNA antibodies increased comparably in both vehicle and tRA-treated mice. Vehicle-treated mice showed characteristic renal lesions. In contrast tRA-treated mice showed almost normal glomerular histology with a pronounced reduction in endocapillary cell proliferation. T-cell and macrophage infiltrates were reduced after tRA treatment within glomeruli and interstitium as compared to vehicle-treated animals. In spite of this, immune complex and complement deposition were comparable in both groups. Adoptively transferred T cells from vehicle-treated to tRA-treated MRL/lpr mice did not induce renal lesions or proteinuria. These beneficial effects of tRA treatment were associated with reduced renal expression of chemokines and inflammatory cytokines. Surprisingly, renal transforming growth factor-beta (TGF-beta) mRNA levels of tRA-treated mice were elevated, possibly indicating that TGF-beta acts as an anti-inflammatory signal in this lupus model.. tRA treatment reduces lymphoproliferation and glomerulonephritis in MRL/lpr mice. This occurs in spite of unaltered anti-DNA titers and glomerular immune complex deposition, and cannot be overcome by T-cell transfer from nephritic MRL/lpr mice.

Topics: Adoptive Transfer; Animals; Antineoplastic Agents; Body Weight; Chemokines; Cytokines; Immunoglobulin G; Kidney Glomerulus; Lupus Nephritis; Macrophages; Mice; Mice, Inbred MRL lpr; Organ Size; RNA, Messenger; T-Lymphocytes; Tretinoin

Chronic and excessive ethanol intake in rats results in low levels of hepatic retinoic acid (RA) either by inhibiting the biosynthesis of RA or by enhancing its catabolism of RA. Chronic ethanol intake also decreases both hepatic expression of insulin-like growth factor-I (IGF-I) and plasma IGF-I concentration in rats. It is not known whether RA supplementation in alcohol-fed rats can restore plasma IGF-I concentrations and hepatic IGF-I expression. In the present study, we examined both plasma IGF-I level and hepatic IGF-I mRNA expression in alcohol-fed rats with or without RA (100 microg/kg body weight) supplementation for 6 mo. Hepatic IGF-I mRNA levels and plasma IGF-I concentration were decreased (84 and 29%, respectively) significantly in alcohol-fed rats compared with the control. In contrast, RA supplementation in ethanol-fed rats partially restored both hepatic IGF-I mRNA levels and plasma IGF-I concentration compared with rats fed ethanol alone. These data suggest that alcohol-impaired hepatic RA status contributes to the decreased plasma IGF-I level and hepatic IGF-I expression in alcoholics.

Topics: Animals; Body Weight; Dietary Supplements; Ethanol; Gene Expression; Insulin-Like Growth Factor I; Liver; Rats; Rats, Sprague-Dawley; RNA, Messenger; Tretinoin; Vitamin A

Recently, high frequencies of malformations have been reported in amphibians across the United States. It has been suggested that the malformations may be the result of xenobiotic disruption of retinoid signaling pathways during embryogenesis and tadpole development. Therefore, a series of experiments were undertaken to examine life-stage specific effects of continuous retinoid exposure on Xenopus laevis. Continuous all-trans retinoic acid (RA) concentrations were delivered using a column saturator and a flow-through diluter system. Stage 8 embryos were exposed to RA concentrations ranging from 0.013 to 2 microgram/l. At the onset of hindlimb bud emergence (NF stage 48), a subset of tadpoles was moved to clean water, and remaining organisms were exposed continuously through metamorphosis. In addition, early limb-bud-stage tadpoles were exposed for 1 week, 2 weeks, or until tail resorption was complete, to eight concentrations of RA in the range of 0.031-3 microgram/l. RA exposure resulted in a concentration-dependent increase in mortality and dysmorphogenesis in embryos at concentrations of 0.24 microgram/l and above. However, this early embryonic exposure did not result in hindlimb abnormalities in surviving tadpoles allowed to mature in clean water. RA did not induce limb malformations in any surviving tadpole exposed during larval stages. We are confident that the concentrations used were high enough, given that the highest concentration used resulted in 100% mortality within 2 weeks of initiating the exposure. This result suggests that other aspects of growth and development, which are not externally obvious, are more sensitive to retinoids than skeletal development. From these experiments and our previous work, we conclude that it is unlikely that retinoid mimics would produce the spectrum of limb malformations which recently have been observed in amphibians collected from the field.

Topics: Abnormalities, Drug-Induced; Animals; Body Weight; Embryonic and Fetal Development; Extremities; Larva; Metamorphosis, Biological; Receptors, Retinoic Acid; Tretinoin; Water; Xenopus laevis

There are in vitro data linking all-trans retinoic acid (atRA) with inhibition of hypertrophy and hyperplasia in cardiomyocytes, vascular smooth muscle cells, and fibroblasts. In the present study, we tested the hypothesis that chronic treatment with atRA may blunt the process of myocardial remodeling in spontaneously hypertensive rats (SHR). Four-week-old male SHR were treated with atRA (5 or 10 mg.kg-1.day-1) given daily for 3 mo by gavage; age- and sex-matched Wistar-Kyoto rats (WKY) and placebo-treated SHR served as controls. At the end of the treatment period, cardiac geometry and function were assessed by Doppler echocardiography. Histological examination and RIA were performed to evaluate medial thickening of intramyocardial and renal arteries, perivascular and interstitial collagen content, and atrial natriuretic peptide (ANP) and IGF-I in the heart, respectively. The novel finding of the present study is that atRA prevented hypertrophy of intramyocardial and intrarenal arteries and ventricular fibrosis. However, atRA treatment did not lower blood pressure or left ventricular weight and left ventricular weight-to-body weight ratio in SHR. atRA did not change cardiac geometry and function as assessed by Doppler echocardiography. atRA showed no influence on either ANP or IGF-I levels. In conclusion, the present study suggests that chronic atRA treatment prevents medial thickening of intramyocardial and intrarenal arteries and ventricular fibrosis during the development of hypertension. Left ventricular hypertrophy and cardiac geometry and function are not changed by atRA treatment.

Topics: Animals; Body Weight; Coronary Vessels; Drug Administration Schedule; Fibrosis; Heart; Heart Ventricles; Hemodynamics; Hypertension; Hypertrophy; Male; Myocardium; Organ Size; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Renal Artery; Tretinoin; Tunica Media

All-trans retinoic acid (ATRA) has antiproliferative and anti-inflammatory effects and is currently used in the treatment of leukemia and dermatologic diseases. We tested the therapeutic potential of ATRA on anti-glomerular basement membrane (GBM) glomerulonephritis rats.. Glomerulonephritis was induced in male Wistar-Kyoto rats on day 0 by an intravenous injection of antirat GBM antibody. On day 14 after the induction of anti-GBM glomerulonephritis, some rats were sacrificed (N = 5). Another 10 rats were divided into two groups: the vehicle group (N = 5) and the ATRA treated group (N = 5). ATRA was orally administrated from day 14 to day 27 after disease induction. Blood pressure, body weight, urinary protein excretion, and blood chemistry was determined on days 1, 14, 21, and 27. Kidney samples were obtained on day 28. The kidneys were examined with periodic acid-Schiff staining (PAS) and immunohistochemistry using antibodies against the proliferative cell nuclear antigen (PCNA), rat monocyte and macrophage (ED-1), and alpha-smooth muscle actin (alpha-SMA). Glomerular RNA was extracted from isolated glomeruli, and reverse transcription (RT) followed by polymerase chain reaction (PCR) was performed.. ATRA administration produced a 55% reduction of proteinuria in glomerulonephritis rats. Light microscopic analysis revealed severe necrosis/crescent formation (>50% of the glomerulus) affecting 34% of glomeruli in vehicle rats, whereas ATRA treatment reduced the glomeruli showing severe change to 14%. ATRA also significantly reduced PCNA-positive cells, ED-1-positive cells and alpha-SMA-positive area in the glomeruli. RT-PCR analyses revealed that a wide variety of genes including inflammation related [tumor necrosis factor-alpha (TNF-alpha), interleukin-1beta (IL-1beta), and CCAAT enhancer-binding protein delta (C/EBPdelta)], cell proliferation-related [platelet-derived growth factor (PDGF)] and fibrosis-related [transforming growth factor-beta1 (TGF-beta1), type I collagen, and alpha-SMA) genes were suppressed in the glomeruli of ATRA-treated rats.. ATRA administration significantly reduced severe necrosis/crescent formation and urinary protein excretion in glomerulonephritis rats. Suppression of a wide variety of gene expression may partly explain the mechanism of ATRA's antiproliferative and anti-inflammatory effects. These data suggest a novel therapeutic application of ATRA toward glomerulonephritis.

Topics: Animals; Anti-Glomerular Basement Membrane Disease; Anti-Inflammatory Agents; Blood Pressure; Body Weight; Cell Division; Gene Expression; Kidney; Kidney Glomerulus; Male; Necrosis; Proteinuria; Rats; Rats, Inbred WKY; Tretinoin

The retinamide, N-(4-hydroxyphenyl)retinamide (4-HPR), has shown promising anti-tumor activity, but it is unclear whether this compound is hydrolyzed to all-trans retinoic acid (atRA) and if so, whether this plays any role in its chemotherapeutic activity. To address this issue, the ability of 4-hydroxybenzylretinone (4-HBR), a carbon-linked analog of 4-HPR, to support growth in vitamin A-deficient (VAD) animals and to activate an atRA-responsive gene in vivo was compared to 4-HPR and atRA. Further, the non-hydrolyzable 4-HBR analog was used to determine whether the presence of the labile amide linkage in 4-HPR is essential for the induction of apoptosis in cultured MCF-7 breast cancer cells. Studies in VAD rats showed that 4-HPR, like atRA, supports animal growth and induces CYP26B1 mRNA expression in lung whereas 4-HBR does not. Analysis of plasma from 4-HPR- and atRA-treated VAD animals revealed the presence of atRA whereas it was not detected in plasma from animals given 4-HBR. To determine whether hydrolysis to atRA is necessary for apoptosis induced by 4-HPR in MCF-7 breast cancer cells, morphological and biochemical assays for apoptosis were performed. 4-HBR, like 4-HPR, induced apoptosis in MCF-7 cells. Apoptosis was not induced even at high concentrations of atRA, showing that 4-HPR and 4-HBR act in cells via a distinct signaling pathway. These results show that although limited hydrolysis of 4-HPR occurs in vivo, the ability to liberate atRA is not required for these 4-hydroxyphenyl retinoids to induce apoptosis in MCF-7 breast cancer cells. Thus the non-hydrolyzable analog, 4-HBR, may have significant therapeutic advantage over 4-HPR because it does not liberate atRA that can contribute to the adverse side effects of drug administration in vivo.

Topics: Administration, Oral; Animals; Apoptosis; Body Weight; Breast Neoplasms; Cell Line, Tumor; Cell Survival; Dose-Response Relationship, Drug; Fenretinide; Humans; Hydrolysis; Male; Rats; Rats, Sprague-Dawley; Tretinoin; Vitamin A; Vitamin A Deficiency

In most previous studies, the incidence and multiplicity of chemically induced prostate tumors have been used as end points for assessing the efficacy of various chemopreventive agents. In this study, we used prostate intraepithelial neoplasia (PIN) in Noble rats as an intermediate end point to examine the chemopreventive efficacy of two retinoids, 9-cis-retinoic acid (9cRA) and 4-(hydroxyphenyl)retinamide, which in previous studies have shown promising inhibitory effects on various carcinogenesis models. We found that 80-100% of Noble rats treated for 36 weeks with testosterone + 17beta-estradiol developed multiple PIN lesions predominantly in the dorso-lateral prostate, which appears relevant to the place of origin of PIN and carcinoma in the human prostate. 9cRA at 50 or 100 mg/kg diet significantly decreased the multiplicity of PIN, whereas 4-(hydroxyphenyl) retinamide at 392 or 784 mg/kg diet, did not have an inhibitory effect on PIN. Thus, we provide for the first time evidence that the testosterone + 17beta-estradiol-induced PIN in Noble rats could be used as a potential intermediate end point in assessing the efficacy of retinoids and possibly of other agents on prostate carcinogenesis, and that 9cRA alone or in combination with other agents may have clinical promise in preventing the development of prostate cancer in men.

Topics: Alitretinoin; Animals; Anticarcinogenic Agents; Body Weight; Estradiol; Fenretinide; Male; Prostatic Intraepithelial Neoplasia; Prostatic Neoplasms; Rats; Testosterone; Tretinoin

Beta-MHC-hRARalpha transgenic mice express a constitutively active (truncated) form of the human retinoic acid receptor which triggers development of dilated cardiomyopathy. In those hearts, we studied expression of gap junction proteins in relation to electrical impulse propagation.. As compared to wildtype mice, hearts of 4-6 month old mice with 7-12 inserted hRARalpha copies are marked by an increased heart weight/body weight- and heart weight/tibia length ratio. 3-extremity lead ECGs revealed prolongation of the Q-j interval suggesting delayed ventricular activation. Mapping of electrical activity of epi- and endocardial left ventricular free wall revealed activation delay, increased heterogeneity in conduction and regional conduction block. Ventricular tachycardias did not occur spontaneously nor could be induced by ventricular pacing. Immunohistochemical analysis showed profound and heterogeneous redistribution and down-regulation of the gap junction protein connexin43 (Cx43) in the left ventricular free wall. Here, hRARalpha expression induced re-expression of the hypertrophic markers alpha-skeletal actin and beta-MHC, and in 3 out of 10 severely affected mice, re-expression of Cx40. Concomitant with changes in expression/distribution of Cx43, changes in expression and distribution of beta-catenin and N-cadherin (two other intercalated disk associated proteins) were observed.. Beta-MHC-hRARalpha transgenic hearts show heterogeneous re-expression of (early) sarcomeric genes while expression of connexin43, N-cadherin and beta-catenin is down-regulated. We postulate that the resulting aberrant ventricular activation does not trigger development of lethal arrhythmias due to the small size of remaining healthy ventricular tissue where the transgene is not expressed.

Topics: Actins; Animals; beta Catenin; Biomarkers; Blotting, Western; Body Weight; Cadherins; Cardiomegaly; Connexin 43; Cytoskeletal Proteins; Down-Regulation; Electric Stimulation; Electrocardiography; Gap Junctions; Mice; Mice, Transgenic; Myocardium; Organ Size; Receptors, Retinoic Acid; Signal Transduction; Trans-Activators; Tretinoin

This study was designed to test the hypothesis that cigarette smoke-induced inflammation and emphysema are amplified by the presence of latent adenoviral (Ad) infection, and to determine whether this emphysematous process can be reversed by all-trans-retinoic acid (RA) treatment. The results confirm that in guinea pigs, chronic cigarette-smoke exposure caused lesions similar to human centrilobular emphysema. They also show that latent Ad infection combined with cigarette-smoke exposure caused an excess increase in lung volume (P < 0.001), air-space volume (P < 0.001), and lung weight (P < 0.01), and further decrease in surface-to-volume ratio (P < 0.001) compared with smoke exposure alone. RA treatment failed to reverse these emphysematous changes. Analysis of inflammatory response in parenchymal and airway tissue showed that smoking caused an increase of polymorphonuclear leukocytes (PMNs) (P < 0.0002), macrophages (P < 0.001), and CD4 cells (P < 0.0009), and that latent Ad infection independently increased PMNs (P < 0.001), macrophages (P = 0.003), and CD8 cells (P < 0.001). We conclude that latent Ad infection amplifies the emphysematous lung destruction and increases the inflammatory response produced by cigarette-smoke exposure. In this study, the increase in CD4 was associated with cigarette smoke and the increase in CD8 cells with latent Ad infection.

Topics: Adenoviridae; Analysis of Variance; Animals; Body Weight; CD4-Positive T-Lymphocytes; CD8-Positive T-Lymphocytes; Chromatography, High Pressure Liquid; Emphysema; Female; Guinea Pigs; Inflammation; Lung; Macrophages; Neutrophils; Organ Size; Smoking; Tretinoin

In experimental trials using the N-nitroso-N-methylurea (NMU)-induced rat mammary tumor model, a significant decrease in tumor incidence (to 5%) was observed in rats treated with melatonin and 9-cis-retinoic acid (9 cRA) compared to controls (55%). Although 9cRA alone decreased tumor incidence to 26%, this response did not reach statistical significance. Tumor incidence was significantly inhibited to 20% in the animals that received melatonin and 9cRA on alternating days. Latency to tumor onset was prolonged in animals receiving either of the combination treatments compared with controls, and tumor multiplicity was also significantly decreased.

Topics: Adenocarcinoma; Alitretinoin; Animals; Anticarcinogenic Agents; Antioxidants; Body Weight; Carcinogens; Drug Synergism; Drug Therapy, Combination; Estradiol; Estrogen Receptor alpha; Female; Free Radical Scavengers; Mammary Neoplasms, Experimental; Melatonin; Methylnitrosourea; Organ Size; Rats; Rats, Sprague-Dawley; Receptors, Estrogen; Receptors, Retinoic Acid; Retinoic Acid Receptor alpha; Tretinoin; Uterus

Neuroblastoma, a childhood tumour of the sympathetic nervous system, may undergo spontaneous differentiation or regression due to apoptosis after no or minimal therapy. However, the majority of neuroblastomas are diagnosed as metastatic tumours with a poor prognosis in spite of intensive multimodal therapy. Vitamin A and its analogues (retinoic acid, RA) play an important role in normal cel lular differentiation and programmed cell death. RA regulates neuroblastoma growth and differentiation in vitro, and has shown activity against human neuroblastoma in vivo.. Recently, 9-cis RA was shown to induce apoptosis in vitro in neuroblastoma using a 5 days short-term treatment and subsequent washout. In the present study, nude rats with human neuroblastoma SH-SY5Y xenografts were treated with 13-cis RA (4 mg po daily), 9-cis RA (5 mg po daily) or the novel analogue Ro 13-6307 (0.3 mg po daily) using either a continuous or short-term schedule.. ALL three different retinoids decreased neuroblastoma growth significantly in terms of tumour weight after 8-12 days when compared to untreated controls (P < 0.05). Minor signs of toxicity in 13-cis RA treated rats were observed. However, severe toxicity with significant weight loss was seen in all rats treated with 9-cis RA and Ro 13-6307. Toxicity was more pronounced with the continuous regimen.. We conclude that different retinoids reduce neuroblastoma tumour growth in vivo. Drug scheduling and dosage may affect both therapeutic efficacy and toxic side effects. Further in vivo studies are warranted, including pharmacokinetic and molecular analyses, before clinical trials with promising retinoids like 9-cis RA and Ro 13-6307 can be started in children with neuroblastoma.

Topics: Alitretinoin; Animals; Antineoplastic Agents; Body Weight; Cell Differentiation; Cell Division; Diarrhea; Drug Administration Schedule; Fatty Acids, Unsaturated; Female; Humans; Isotretinoin; Male; Mice; Neoplasm Transplantation; Neuroblastoma; Rats; Rats, Nude; Tretinoin; Tumor Cells, Cultured; Xenograft Model Antitumor Assays

To gain insight into the in vivo modulation of the expression of the adipogenic transcription factors PPAR gamma 2, C/EBP alpha, and ADD1/SREBP1c by retinoids and its relationship with whole-body adiposity.. Three-week-old mice were fed with standard chow or a vitamin A-deficient diet for 10 weeks. During the 4 days immediately before they were killed, the animals were treated either with all-trans retinoic acid (tRA; 100 mg/kg per day, subcutaneously) or vehicle. The specific levels of the mRNAs for the three transcription factors were analyzed in epididymal white adipose tissue (eWAT) and inguinal white adipose tissue and in brown adipose tissue (BAT). Other parameters determined were leptin and UCP2 levels in white adipose tissue depots, total cholesterol and triglyceride serum levels, energy intake, body weight, and adiposity.. Vitamin A-deficient diet feeding led to a marked increase of adiposity and to a small increase of body weight. Hypertrophy of white adipose tissue depots correlated with enhanced PPAR gamma 2 expression. Hypertrophy of BAT, in contrast, correlated with a decrease of PPAR gamma 2 expression that may contribute to the known reduced thermogenic potential of BAT under conditions of vitamin A restriction. Treatment with tRA triggered a reduction of adiposity and body weight that correlated with a down-regulation of PPAR gamma 2 expression in all adipose tissues. The effects of tRA were more pronounced in eWAT, where C/EBP alpha and ADD1/SREBP1c levels were also reduced. The response to tRA was impaired in the eWAT and BAT of animals fed the vitamin A-deficient diet.. The results emphasize the importance of retinoids as physiological regulators of adipose tissue development and function in intact animals.

Topics: Adipose Tissue; Adipose Tissue, Brown; Animals; Body Weight; Cholesterol; Energy Intake; Gene Expression; Gene Expression Regulation; Ion Channels; Male; Membrane Transport Proteins; Mice; Mitochondrial Proteins; Nutritional Status; Proteins; Receptors, Cytoplasmic and Nuclear; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Transcription Factors; Tretinoin; Triglycerides; Uncoupling Agents; Uncoupling Protein 2; Vitamin A; Vitamin A Deficiency

The relationship between interscapular brown adipose tissue (IBAT) thermogenic potential and vitamin A status was investigated by studying the effects of feeding a vitamin A-deficient diet and all-trans retinoic acid (tRA) treatment on body weight and IBAT parameters in mice. Feeding a vitamin A-deficient diet tended to trigger opposite effects to those of tRA treatment, namely increased body weight, IBAT weight, adiposity and leptin mRNA expression, and reduced IBAT thermogenic potential in terms of uncoupling protein 1 (UCP1) mRNA and UCP2 mRNA expression. The results emphasize the importance of retinoids as physiological regulators of brown adipose tissue.

Topics: Adipose Tissue, Brown; Animals; Blotting, Northern; Body Temperature Regulation; Body Weight; Carrier Proteins; Hypertrophy; Ion Channels; Leptin; Male; Membrane Proteins; Membrane Transport Proteins; Mice; Mice, Inbred Strains; Mitochondrial Proteins; Proteins; RNA, Messenger; Tretinoin; Uncoupling Protein 1; Uncoupling Protein 2; Vitamin A Deficiency

Halogenatedorganic environmental contaminants such as dioxins are well-known to affect tissue levels of retinoids. To further investigate the effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) on retinoid homeostasis, adult male Sprague-Dawley rats were killed 1-112 days after a single oral dose of 10 microg TCDD/kg body wt. Additional groups of rats were killed three days after a single oral dose of 0.1, 1, 10, or 100 microg TCDD/kg body wt. Serum and renal retinoic acid levels were measured, as were levels of serum retinol-binding protein (RBP) in liver, kidneys, and serum. Hepatic and renal formation as well as hepatic hydrolysis of retinyl esters were determined, together with hepatic and renal retinoid levels. In addition, one of the retinyl ester hydrolase (REH) activities was investigated in isolated hepatocytes and hepatic stellate cells from rats killed 7 days after a single oral dose of 10 microg TCDD/kg body wt. No increased hepatic REH activity that could explain the decreased hepatic retinyl ester levels following TCDD treatment was found. In the liver, TCDD increased protein levels, but not mRNA levels, of RBP. A causal relationship is suggested for the increased renal lecithin:retinol acyltransferase (LRAT) activity and increased renal retinyl ester levels in TCDD-treated rats. Importantly, TCDD was shown to substantially increase serum and renal levels of retinoic acid. The ability of TCDD to cause increased tissue retinoic acid levels suggests that TCDD may alter the transcription of retinoic acid-responsive genes.

Topics: Animals; Body Weight; Cytochrome P-450 CYP1A1; Dose-Response Relationship, Drug; Esters; In Vitro Techniques; Kidney; Liver; Male; Organ Size; Polychlorinated Dibenzodioxins; Rats; Rats, Sprague-Dawley; Retinol-Binding Proteins; Time Factors; Tretinoin; Vitamin A

We have previously reported that the retinoids, 4-(hydroxyphenyl)retinamide (4-HPR) and 9-cis-retinoic acid (RA) prevented azoxymethane (AOM)-induced colon tumors and along with 2-(carboxyphenyl)retinamide (2-CPR) prevented aberrant crypt foci (ACF). In this study, we evaluated the effect of 2-CPR on AOM-induced colon tumors and the effect of the three retinoids on apoptosis and cell proliferation. Male F344 rats were administrated 15 mg/kg AOM at weeks 7 and 8 of age. 2-CPR (315 mg/kg) was administered in the diet starting either 1 week before or at week 12 after the first dose of AOM. The rats continued to receive the 2-CPR until killed at week 46. Unlike the demonstrated prevention of colon cancer by the other two retinoids, both dosing schedules of 2-CPR resulted in an approximate doubling of the yield of colon tumors. In adenomas, 2-CPR, 4-HPR and 9-cis-RA were equally effective in reducing mitotic activity, while only 4-HPR and 9-cis-RA but not 2-CPR enhanced apoptosis. When administered for only the 6 days prior to killing 4-HPR but not 2-CPR decreased the Mitotic Index and increased the Apoptotic Index in adenomas. In non-involved crypts, chronic exposure to 4-HPR and 9-cis-RA in contrast to 2-CPR reduced the Mitotic Index and enhanced the Apoptotic Index. In concurrence with our previous study, both 2-CPR and 4-HPR were very potent in preventing ACF when administered in the diet starting 1 week before the first dose of AOM and continuing for the 5 weeks of the study. Hence, unlike the other two retinoids, 2-CPR, although very potent in preventing ACF, enhanced rather than prevented AOM-induced colon cancer. Furthermore, our results suggest that the effect of 2-CPR on tumor yield is different from 4-HPR and 9-cis-RA because, unlike them, it does not enhance apoptosis.

Topics: Adenocarcinoma; Adenoma; Animals; Anticarcinogenic Agents; Apoptosis; Azoxymethane; Body Weight; Carcinogens; Colon; Colonic Neoplasms; Drug Screening Assays, Antitumor; Fenretinide; Male; Precancerous Conditions; Rats; Rats, Inbred F344; Tretinoin

Peripheral nervous system alterations were induced in adult rats by administration of cisplatin (CDDP) 2 mg/kg twice weekly for 4.5 weeks. Dorsal root ganglion neurons showed pathological changes. Morphometric determinations demonstrated a reduction in size of the somatic, nuclear and nucleolar area. The nucleoli were the most involved subcellular structures. Nerve conduction velocity and the tail-flick test for pain were both significantly altered in CDDP treated rats, whereas the rota-rod test for coordination revealed no changes in either treated or control rats. Analytical determinations demonstrated platinum accumulation in the DRG of CDDP treated rats. Spontaneous recovery, demonstrated by morphometric, electrophysiological, functional and analytical determinations, occurred after treatment discontinuation within about 7 weeks. A pilot study of the possible neuroprotective action of retinoic acid (RA) was also performed with this model of cisplatin neuronopathy. The rationale for using RA was based on its assumed antioxidant and neurotrophic effect. However, RA failed to prevent morphometric, electrophysiological, functional and analytical alterations induced by CDDP on DRG neurons. RA induced only a mild generalized protective effect.

Topics: Animals; Body Weight; Cisplatin; Female; Ganglia, Spinal; Injections, Intraperitoneal; Neural Conduction; Peripheral Nervous System Diseases; Random Allocation; Rats; Rats, Wistar; Tail; Tretinoin

Chronic ethanol intake may interfere with retinoid signal transduction by inhibiting retinoic acid synthesis and by enhancing activator protein-1 (AP-1) (c-Jun and c-Fos) expression, thereby contributing to malignant transformation. To determine the effect of ethanol on hepatic retinoid levels, retinoic acid receptors (RARs) and AP-1 (c-Jun and c-Fos) gene expression, chronic ethanol (36% of total calorie intake) pair-feeding was conducted on rats for a 1-month period. Retinoic acid, retinol, and retinyl ester concentrations in both liver and plasma were examined by using high-performance liquid chromatography (HPLC). Both retinoic acid receptor (alpha, beta, gamma) and AP-1 (c-Jun and c-Fos) expression in the rat liver were examined by using Western blot analysis. Treatment with high-dose ethanol led to a significant reduction of retinoic acid concentration in both the liver and the plasma (11- and 8.5-fold reduction, respectively), as compared with animals pair-fed an isocaloric control diet containing the same amount of vitamin A. Similar to the retinoic acid reductions, both retinol and retinyl palmitate levels in the livers of the alcohol-fed group decreased significantly, but in smaller fold reduction (6.5- and 2.6-fold reduction, respectively). Ethanol did not modulate the expression of RARalpha, -beta, and -gamma genes in the liver. However, chronic alcohol feeding enhanced AP-1 (c-Jun and c-Fos) expression by 7- to 8-fold, as compared with the control group. These data suggest that functional downregulation of RARs by inhibiting biosynthesis of retinoic acid and up-regulation of AP-1 gene expression may be important mechanisms for causing malignant transformation by ethanol.

Topics: Animals; Body Weight; Ethanol; Liver; Male; Proto-Oncogene Proteins c-fos; Proto-Oncogene Proteins c-jun; Rats; Rats, Sprague-Dawley; Receptors, Retinoic Acid; Transcription Factor AP-1; Tretinoin

The tissue concentration of retinol and its metabolites was determined in a group of vitamin A deficient rats after a single dose of 53 micrograms of [11,12-3H]retinol. The sensitive technique of high performance liquid chromatography was used to analyse the metabolites of retinol. The analysis of the metabolites in tissues at different days after the administration of radioactive retinol showed a rapid decrease in the amount of retinol and retinyl esters in the liver tissue, accompanied by an increase in the retinol and retinyl ester values in the kidney. In addition, the content of retinoic acid was higher in liver and kidney compared with intestine, testis, and blood. It reached maximum at 4 and 11 days, respectively. After 17 days the retinoid(s) concentrations decreased markedly in all tissues studied; yet the kidney showed higher concentrations of retinoic acid and retinyl esters. These studies indicate that the kidney retains more vitamin A as vitamin A becomes depleted in the body, probably as a reserve for the production of the active metabolite retinoic acid, needed for the growth and differentiation.

Topics: Animals; Body Weight; Esters; Male; Rats; Rats, Sprague-Dawley; Tissue Distribution; Tretinoin; Tritium; Vitamin A; Vitamin A Deficiency

Dexamethasone, a glucocorticosteroid hormone, inhibits the formation of alveoli; retinoids and glucocorticosteroid hormones can be mutually antagonistic. These observations led us to test the hypothesis that the administration of retinoic acid to postnatal rats would prevent the low alveolar number and the low body mass-specific gas-exchange surface area (Sa) produced by treatment with dexamethasone. We used serial lung sections to distinguish alveoli from alveolar ducts and stereological procedures that allow quantitation of alveoli uninfluenced by their size, shape, or distribution. Treatment with retinoic acid prevented the low number of alveoli and the low body mass-specific Sa caused by treatment with dexamethasone. In otherwise untreated rats, retinoic acid caused a 50% increase in the number of alveoli, but without an increase in Sa, suggesting the action of a regulatory mechanism to prevent unneeded Sa. These findings provide the first experimental support for the possibility that, in individuals with too few alveoli for adequate gas exchange, treatment with a pharmacological agent may provide preventative or remedial therapy.

Topics: Animals; Animals, Newborn; Body Weight; Dexamethasone; Drug Combinations; Lung; Lung Volume Measurements; Male; Pulmonary Alveoli; Pulmonary Gas Exchange; Rats; Rats, Sprague-Dawley; Tretinoin

(2E, 4E, 6E)-8-[3'-Ethyl-2'-(1-methylethyl)-2'-cyclohexen-1'-ylidene] -3, 7-dimethyl-2,4,6-octatrienoic acid (UAB-8) has potent activity in preventing papillomas on the skin of mice similar to that determined in a previous study for the homolog containing one less carbon atom. To evaluate the toxicological profile for UAB-8, relative to all-trans-retinoic acid (RA), female mice were dosed by oral gavage for 29 days with amounts of 0.05, 0.1, or 0.2 mmol/kg/day. For the two compounds, the effects on body weights were similar. Mice dosed with UAB-8, however, had a lower incidence of clinical signs of toxicity (alopecia, scaly skin, and limping). At necropsy, bone fractures, skin abnormalities, and splenomegaly were observed in some mice dosed with RA but not in any dosed with UAB-8. Lymph node hyperplasia was noted in some mice dosed with either dose of RA but only in those dosed with the highest dose of UAB-8. All dose levels of RA produced microscopic lesions in the bones of mice; only the highest dose of UAB-8 had this effect. RA and UAB-8 had similar effects on chondrogenesis in cultures of cells from mouse limb buds, an indication of comparable teratogenic effects. For mice dosed i.v. (10 mg/kg), there was a saturated phase of elimination of RA from plasma (Km = 0.61 microgram/ml and Vmax = 2572 micrograms/hr); no such phase was noted when UAB-8 was administered. UAB-8 had values for t1/2 alpha and t1/2 beta of 0.47 and 17.1 hr, respectively. Relative to RA, UAB-8 has a favorable toxicological profile and different pharmacokinetics.

Topics: Animals; Body Weight; Calcification, Physiologic; Erythrocyte Count; Female; Hematocrit; Hemoglobins; Keratolytic Agents; Limb Buds; Lymph Nodes; Mice; Papilloma; Skin; Skin Neoplasms; Tretinoin

To obtain insight into the hemodynamics of abnormal cardiac development, a chick embryo model was recently developed in which a spectrum of double outlet right ventricle was induced with all-trans-retinoic acid. In Hamburger and Hamilton (HH) stage 34 white Leghorn chick embryos, we simultaneously measured dorsal aortic flow velocities with a 20 MHz pulsed Doppler velocity meter and vitelline artery blood pressures with a servonull system. These measurements were performed in embryos treated at HH stage 15 with 1 microgram of all-trans-retinoic acid (n = 47), or with the solvent DMSO (n = 15), and in control embryos (n = 21). After the wave form recordings were collected, all embryos were examined histologically. Embryos treated with all-trans-retinoic acid showed in 15 cases hearts with a rightward positioned aorta with an additional subaortic ventricular septal defect and 32 cases without septation abnormalities of the heart. The hemodynamic data were correlated with the morphology. Statistical comparison was performed between control and experimental values. There was no significant discrepancy in hemodynamics of sham-operated and control embryos. Heart rate, peak systolic and mean velocities, peak systolic and mean blood flows, and peak acceleration and stroke volume were reduced in embryos treated with all-trans-retinoic acid (p < 0.01). Furthermore, in the presence of a subaortic ventricular septal defect the diameter of the dorsal aorta was reduced. Pressure readings were not statistically significant. Our findings suggest that the hemodynamic changes are the result of a decrease in cardiac contraction force.

Topics: Animals; Aorta; Blood Flow Velocity; Body Weight; Chick Embryo; Disease Models, Animal; Heart; Heart Defects, Congenital; Heart Septal Defects, Ventricular; Hemodynamics; Humans; Organ Size; Tretinoin; Vascular Resistance

Previously we reported that vitamin A-deficient rats have a low number of natural killer (NK) cells in their blood and spleen. The current studies were designed to address whether other cells of the immune system are also affected and whether dietary retinoic acid is able to reverse the changes caused by a deficiency of retinol and its metabolites. Total white blood cells, differential counts and spleen cell numbers were compared in vitamin A-sufficient rats (controls) and rats deficient in vitamin A, and lymphocyte and NK cell populations were identified and enumerated by flow cytometry. In comparison with control rats, the blood of deficient rats had three times the number of granulocytes, and fewer B lymphocytes (73% of control) and NK cells (38% of control). The numbers of splenic B cells (OX12+), CD5+ (OX19+) and CD4+ (W3/25+) T lymphocytes and NK cells (NKR-P1+) were also significantly reduced. When vitamin A-deficient rats were fed a retinoic acid supplement (4.2 mg all-trans retinoic acid/kg diet) for 28 d, the numbers of blood granulocytes and NK cells equaled those of control rats and NK cell cytotoxicity was significantly elevated. Blood lymphocyte number was increased 40% due to increases of B cells and T cells of the CD5+, CD4+ and CD8+ subsets. These data indicate that vitamin A deficiency affects a number of cells of the immune system and that repletion with retinoic acid effectively reestablishes the number of circulating lymphocytes. In addition, retinoic acid may stimulate NK cell function.

Topics: Animals; Body Weight; Diet; Flow Cytometry; Killer Cells, Natural; Leukocyte Count; Leukocytes; Phenotype; Rats; Rats, Inbred Lew; Spleen; Tretinoin; Vitamin A Deficiency

The main objectives were to determine the modulating effects of all-trans retinoic acid on the number, size and multiplicity of aberrant crypt foci as well as the in vivo expression of the genes c-myc and c-fos. These foci, which are hypothesized to be the pre-malignant lesions of colon cancer, were induced in Sprague-Dawley rats with a single injection of azoxymethane. Rats were fed either a control diet (AIN-76) or the control diet to which had been added 75 mg/kg or 150 mg/kg all-trans retinoic acid. Within 4 weeks, we observed that the diets containing all-trans retinoic acid reduced the total number and multiplicity of aberrant crypt foci in the colon. However, all-trans retinoic acid increased the size of the lesions that persisted, possibly due to a greater proportion of lesions with dilated crypts. In situ hybridization and immunohistochemistry were performed on the colons for the in vivo analysis of gene expression in these lesions. The expression of myc-specific mRNA and protein in aberrant crypt foci significantly decreased with both levels of all-trans retinoic acid. In contrast, fos-specific mRNA and protein in aberrant crypt foci significantly increased when 150 mg/kg all-trans retinoic acid was added to the diet. The most important findings of this investigation are that intervention with all-trans retinoic acid in the pre-malignant stage of colon carcinogenesis is effective in decreasing the number and growth of aberrant crypt foci and altering the expression of the c-myc and c-fos genes.

Topics: Animals; Azoxymethane; Body Weight; Colon; Colonic Neoplasms; Genes, fos; Genes, myc; Male; Precancerous Conditions; Proto-Oncogene Proteins c-fos; Proto-Oncogene Proteins c-myc; Rats; Rats, Sprague-Dawley; RNA, Messenger; Tretinoin

The comparative toxicity studies of amsacrine and retinic acid administrated in solution and in liposome form were performed. The maximum survival time was longer for prepared liposome form than in the case of solution. The toxic effect was also lower for liposome preparations.

Topics: Amsacrine; Animals; Body Weight; Drug Carriers; Liposomes; Male; Mice; Survival Rate; Tretinoin

All-trans retinoyl beta-glucose was chemically synthesized in good yield by reaction of retinoyl fluoride with glucose. Retinoyl glucose, which is soluble in water, shows growth-promoting activity similar to retinyl acetate in vitamin A-deficient rats. In metabolic studies, retinoyl glucose was found to be hydrolyzed to retinoic acid, but at a slower rate. The possible therapeutic uses of retinoyl glucose are discussed.

Topics: Animals; Body Weight; Chromatography, High Pressure Liquid; Glucose; Male; Rats; Rats, Inbred Strains; Retinoids; Tretinoin; Vitamin A Deficiency

Ellagic acid (EA) and 13-cis-retinoic acid (CRA), both alone and in combination, were tested for their ability to inhibit N-nitrosobenzylmethylamine-induced tumors in the rat esophagus. Groups of male rats were fed AIN-76A diet containing EA (4 g/kg), CRA (240 mg/kg), or a combination of EA and CRA (4 g/kg and 240 mg/kg), respectively, for 25 weeks. Two weeks after initiation of the diets, NBMA (0.5 mg/kg per injection) was administered s.c. once weekly for 15 weeks. After 25 weeks on the diets, the animals were necropsied. The incidence of esophageal tumors was 97-100% in all NBMA-treated groups. The multiplicity of tumors in NBMA-treated groups was reduced significantly by EA (60%), but not by CRA, or by EA + CRA. These results demonstrate that EA and CRA do not act synergistically to inhibit NBMA-induced esophageal tumorigenesis.

Topics: Animals; Antineoplastic Agents; Body Weight; Carcinogens; Diet; Dimethylnitrosamine; Drug Synergism; Ellagic Acid; Esophageal Neoplasms; Male; Rats; Rats, Inbred F344; Tretinoin

Time-mated Sprague-Dawley rats were administered all-trans-retinoic acid (RA) dermally on gestational days 11 through 14 at three dosage levels (25, 100, and 250 mg/kg body weight). Dams administered ethylenethiourea (ETU) dermally on gestational days 11 to 12 or RA orally on day 12 were used to indicate the strain's sensitivity to teratogenesis. The chemicals were dissolved in dimethylsulfoxide (DMSO) for dermal application or suspended in corn oil for treatment by gavage. The maternal weight gain, pup weight, number of resorptions and number of fetuses with gross malformations, and skeletal/organ-level anomalies were determined. Beginning with day 15, dams dermally treated with RA exhibited dermal lesions at the site of application, most dams showed vaginal bleeding by day 16, and approximately 20% did not survive to day 19. Relative to the DMSO control group, maternal weight gain in the dermal RA groups was decreased by approximately 50% at the lowest dose, with essentially no weight gain at the intermediate- and high-dose levels. The decrease in average fetal weight at the two higher doses was significant, whereas the resorption and malformation frequencies were not significantly increased by dermal treatment with RA. Without significantly affecting fetal weight or resorption frequency, dermal application of ETU significantly increased the frequency of skeletal anomalies, primarily tail defects. Oral administration of RA did not increase the malformation frequency nor produce significant maternal or fetotoxic effects. In summary, treatment of pregnant Sprague-Dawley rats by dermal application of RA dissolved in DMSO resulted in significant toxicity to the dam.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Abnormalities, Drug-Induced; Administration, Topical; Animals; Behavior, Animal; Body Weight; Female; Fetal Resorption; Fetus; Pregnancy; Rats; Rats, Inbred Strains; Tretinoin

MtT/F84 grew well in Fischer rats (F344), but tumor growth was promoted in hyperestrogenized rats. Effects of dietary retinoic acid (RA) on tumor growth, estrogen receptor (ER) and serum growth hormone (GH) level were examined. Tumor latency became shortened, and tumor take and weight were promoted by all-trans RA at dosages of 50 and 200 mg/kg basal diet, but not dose-dependently. ER level was elevated in tumor of RA-treated rats, whereas the retinoic acid-binding protein level remained unchanged. RA also elevated incorporation of 5-bromo-2'-deoxyuridine, a thymidine analogue, into DNA of tumor cells. Average serum GH level was increased in tumor-bearing rats treated with RA and was well correlated with tumor weight. RA may directly affect ER level and enhance estrogenic action, resulting in promotion of tumor growth, or it may act independently for tumor growth and elevation of serum GH level.

Topics: Animals; Body Weight; Bromodeoxyuridine; Carrier Proteins; DNA, Neoplasm; Estradiol; Growth Hormone; Neoplasm Transplantation; Pituitary Neoplasms; Rats; Rats, Inbred F344; Receptors, Estrogen; Receptors, Retinoic Acid; Tamoxifen; Tretinoin

TCDD is one of the most toxic man-made compounds and an extremely potent teratogen in mice. Many of its toxic symptoms resemble those seen during vitamin A deficiency. Vitamin A and its derivatives, such as alltrans-retinoic acid (RA), are also teratogenic in mice, as well as many other species. Both TCDD and RA produce cleft palate in susceptible strains of mice. However, while TCDD produces hydronephrosis, RA does not, and TCDD does not produce limb bud defects while RA does. To determine whether TCDD and RA would enhance or antagonize the teratogenic effects of the other compound, C57BL/6N dams were treated po on Gestation Day (gd) 10 or 12 with 10 ml corn oil/kg containing TCDD (0-18 micrograms/kg), RA (0-200 mg/kg), or combinations of the two chemicals. Dams were killed on gd 18 and toxicity and teratogenicity assessed. Coadministration of TCDD and RA had no effect on maternal or fetal toxicity beyond what would be expected by either compound alone. Cleft palate was induced by RA at lower doses on gd 10 than on gd 12, but by TCDD at lower doses on gd 12 than on gd 10. Sensitivity to TCDD-induced hydronephrosis was similar on both gd 10 and 12. The limb bud defects were only observed when RA was administered on gd 10, not when given on gd 12. No other soft tissue or skeletal malformations were related to administration of TCDD or RA. No effect of TCDD was observed on the incidence or severity of limb bud defects induced by RA, nor did RA influence the incidence or severity of hydronephrosis induced by TCDD. However, the incidence of cleft palate was dramatically enhanced by coadministration of the xenobiotic and vitamin. On both gd 10 and 12, the dose-response curves for cleft palate induction were parallel, suggesting some similarities in mechanism between the two compounds. However, combination treatment resulted in a synergistic response that varied with the stage of development and was tissue specific.

Topics: Abnormalities, Drug-Induced; Animals; Body Weight; Bone and Bones; Cleft Palate; Dioxins; Dose-Response Relationship, Drug; Drug Synergism; Female; Hydronephrosis; Mice; Mice, Inbred C57BL; Polychlorinated Dibenzodioxins; Pregnancy; Tretinoin

Prophylactic treatment (p.o.) of rats with adjuvant-induced arthritis (AA) with two retinoid-like 2,4,6,8-nonatetraenoic acids (NTA), Ro 23-6457 and Ro 23-2895, significantly reduced hind paw swelling between days 10-23 and the level of plasma fibrinogen (MED approximately 25 mumoles/kg). When given therapeutically (75 mumoles/kg between day 21 and 28) either NTA arrested the progression of the disease (MED, 25-75 mumoles/kg). Unseparated and adherent cell (AC) depleted spleen cells from rats with AA (day 12-15) responded poorly to the T cell mitogen, Con A (2.5 micrograms/ml) and the B cell mitogen, LPS (10 micrograms/ml). The responses were partially restored (approximately 30% of normal responses) in AC-depleted (but not unseparated) spleen cells from Ro 23-6457 treated rats (75 and 250 mumoles/kg/day). These data demonstrate an immunomodulatory effect of Ro 23-6457 in the adjuvant rat which may contribute to its anti-inflammatory activity in AA.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Arthritis; Arthritis, Experimental; Body Weight; Cell Division; Fibrinogen; Immunosuppressive Agents; Male; Mitogens; Rats; Tretinoin

Calcium glucarate and N-(4-hydroxyphenyl)retinamide were evaluated individually and in combination in the diet as preventative chemical agents, by using the induction of rat mammary tumors by 7,12-dimethylbenz[a]anthracene as the test system. When tested separately over 18 weeks, optimal doses of calcium glucarate (128 mmol/kg of diet) or N-(4-hydroxyphenyl)retinamide (1.5 mmol/kg of diet) administered daily inhibited tumor incidence by 50% or 57% and tumor multiplicity by 50% or 65%, respectively. Suboptimal doses of calcium glucarate (32 mmol/kg) and of N-(4-hydroxyphenyl)retinamide (0.75 mmol/kg) inhibited tumor incidence by 15% and 5% but had no inhibitory effect on tumor multiplicity. In contrast, the combination of calcium glucarate (32 mmol/kg) and N-(4-hydroxyphenyl)retinamide (0.75 mmol/kg) inhibited tumor incidence and tumor multiplicity by 50%. Similar synergism was observed with the combination of calcium glucarate (64 mmol/kg) and N-(4-hydroxyphenyl)retinamide (0.75 mmol/kg), the inhibition being 55-60%. HPLC analysis of the bile of female rats injected intraperitoneally with a single dose of the retinamide [60 mg/kg (body weight)] showed that the excretion of the retinamide and its glucuronide were markedly suppressed by pretreatment with an oral dose of calcium glucarate [4.5 mmol/kg (body weight)].

Topics: 9,10-Dimethyl-1,2-benzanthracene; Animals; Body Weight; Diet; Drug Synergism; Fenretinide; Glucaric Acid; Mammary Neoplasms, Experimental; Rats; Rats, Inbred Strains; Sugar Acids; Tretinoin

The present study was designed to investigate the embryo-fetotoxicity of vitamin A in protein-energy malnourished animals. Retinyl palmitate (66, 99 and 132 mg/kg) suspended in corn oil was given by gavage to well-nourished and malnourished rats from gestational days 8 to 10 and cesarean sections were performed on day 20. All fetuses were weighed and examined for malformations before being prepared for skeletal evaluation. The proportion of malformed fetuses was higher in the malnourished group at each one of the three dose levels. The data indicate that malnourished animals are more susceptible to the toxic effects of retinyl esters.

Topics: Animals; Body Weight; Congenital Abnormalities; Diterpenes; Female; Hypervitaminosis A; Pregnancy; Protein-Energy Malnutrition; Rats; Rats, Inbred Strains; Retinyl Esters; Tretinoin; Vitamin A

Sprague-Dawley rats were dosed by gavage daily for 28 days with 5, 15, or 50 mg/kg of N-(all-trans-retinoyl)-DL-leucine (RL), N-(all-trans-retinoyl)glycine (RG), or all-trans-retinoic acid (RA). On the basis of mortality incidence, fracture incidence, body weight, and histopathologic effects, RG was slightly to moderately less toxic than RA, and RL was significantly less toxic than RA or RG. Doses that had no effect on weight loss and produced no bone fractures were approximately 5 and 15 mg/kg/day for RA administered to males or females, respectively; greater than 15 mg/kg/day for RG administered to males or females; and greater than 50 mg/kg/day for RL administered to males or females. At these doses, RA and RG produced effects, detectable at the microscopic level, of lymphoid hyperplasia and hematopoietic cell proliferation in the spleen, lymphoid hyperplasia in lymph nodes, necrosis of the cortex of the thymus, hypertrophy of the zona fasciculata of the adrenal, a periportal pattern of cytoplasmic vacuolization in hepatocytes, hematopoietic cell proliferation in the liver, epithelial hyperplasia and subacute inflammation in the forestomach, and osteodystrophy. Serological alterations consisted of reduced serum albumin levels and elevated levels of triglycerides and alkaline phosphatase. For RL, similar microscopic effects, dependent on dose level and sex, were observed in spleen, thymus, adrenal, and liver. In vitro, RL was as active as RA in potentiating pokeweed mitogen-induced lymphocyte proliferation; RG was inactive. This study indicates that, relative to RA and RG, RL has less toxicity but similar immunological effects. Since RL and RG expressed little or no binding affinity for cellular RA-binding protein, the immunological effects of these retinoids may be expressed by mechanisms not linked to this protein.

Topics: Alkaline Phosphatase; Amino Acids; Animals; Body Weight; Bone and Bones; Female; Glycine; Isomerism; Leucine; Male; Rats; Rats, Inbred Strains; Serum Albumin; Tretinoin; Triglycerides

A 9-year-old boy, treated with high-dose isotretinoin therapy for fibrodysplasia ossificans progressiva, developed dense metaphyseal bands and growth arrest. Discontinuance of isotretinoin therapy was followed by gradual decrease of metaphyseal bands and resumption of clinical growth. The dense metaphyseal bands may be related to the known action of retinoids as modulators of chondrocyte phenotype and gene expression.

Topics: Adolescent; Body Weight; Bone and Bones; Bone Development; Child; Growth; Humans; Isotretinoin; Male; Myositis Ossificans; Radiography; Torticollis; Tretinoin

The influence of an arotinoid without a polar end group (Ro 15-0778) on rat mammary carcinogenesis was investigated. Mammary tumors were induced by oral administration of 15 mg, 7,12-dimethylbenz-(a) anthracene (DMBA) to 50-day-old female Sprague-Dawley rats. Ro 15-0778 inhibited the development of mammary adenocarcinomas. The percentage of tumor-bearing rats, the mean number of tumors per rat as well as the mean total volume of tumors per rat were dose-dependently reduced by Ro 15-0778. The results are of particular interest, since this compound--probably because of the lack of a polar end group--does not induce the signs and symptoms of hypervitaminosis A. The inhibition of mammary cancer development by Ro 15-0778 compares favorably with that of N-(4-hydroxyphenyl) retinamide the hitherto most effective retinoid for prevention of chemically-induced mammary cancers in rats.

Topics: 9,10-Dimethyl-1,2-benzanthracene; Animals; Antineoplastic Agents; Body Weight; Dose-Response Relationship, Drug; Female; Fenretinide; Mammary Neoplasms, Experimental; Rats; Rats, Inbred Strains; Retinoids; Time Factors; Tretinoin

We studied the effects of vitamin A deficiency and repletion on rat insulin release and islet cellular retinol binding protein (CRBP) and cellular retinoic acid binding protein (CRABP). Biphasic insulin release from vitamin A-deficient perifused islets was markedly impaired. Release remained impaired with retinoic acid (RA) repletion, 2 micrograms/g diet compared to release from islets of rats repleted with retinol in the form of retinyl palmitate, 4 micrograms/g diet. Release normalized with RA, 8 micrograms/g diet. Vitamin A deficiency did not affect islet insulin content, cell size, number or structure. In vivo, vitamin A-deficient rats had impaired glucose-induced acute insulin release and glucose intolerance, which improved with repletion. Normal islets had greater concentrations of CRBP than CRABP; vitamin A deficiency reduced CRBP but not CRABP levels. We conclude retinol is required for normal insulin secretion. Retinoic acid may substitute for retinol in this function.

Topics: Animals; Blood Glucose; Body Weight; Carrier Proteins; Energy Intake; In Vitro Techniques; Insulin; Insulin Secretion; Islets of Langerhans; Proteins; Rats; Receptors, Retinoic Acid; Retinol-Binding Proteins; Retinol-Binding Proteins, Cellular; Tretinoin; Vitamin A; Vitamin A Deficiency

All-trans-retinol reacts with methyl (2,3,4-tri-O-acetyl-1-bromo-1-deoxy-beta-D-glucopyran)uronate in the presence of Ag2CO3 to give the triacetate methyl ester of retinyl beta-glucuronide. Hydrolysis of this ester with sodium methylate in methanol gives retinyl beta-D-glucuronide in about 15% yield. The water-soluble retinyl beta-D-glucuronide was characterized by u.v.-visible, n.m.r. and mass spectra, by elemental analysis and by its susceptibility to hydrolysis by bacterial beta-glucuronidase. Retinyl beta-glucuronide, when administered intraperitoneally in saline (0.9% NaCl), supports well the growth of vitamin A-deficient rats.

Topics: Animals; Body Weight; Chromatography, High Pressure Liquid; Glucuronidase; Male; Rats; Rats, Inbred Strains; Spectrophotometry; Tretinoin

The synthetic retinoid, N-(4-hydroxyphenyl)retinamide (4-HPR), and bilateral ovariectomy act synergistically to inhibit mammary cancer induction in female rats. Two parallel studies were conducted to determine if a similar interaction would be obtained with 4-HPR and the anti-estrogen, tamoxifen. Fifty-day-old, virgin, female Sprague-Dawley rats were given a single i.v. injection of 50 mg N-methyl-N-nitrosourea/kg body weight. Beginning 7 days post-carcinogen, groups of 30 rats were administered 4-HPR (391 or 782 mg/kg diet) and/or tamoxifen (2.5, 5, 10 or 100 micrograms s.c. three times per week); controls received a placebo diet and injections of vehicle only. Exposure to 4-HPR alone or tamoxifen alone reduced mammary cancer multiplicity and increased tumor latent period compared with the control. Combined administration of 4-HPR plus tamoxifen resulted in an enhanced inhibition of mammary carcinogenesis and caused a significant reduction in tumor-related mortality. These data suggest that retinoid administration may provide a means to increase the efficacy of hormonal manipulation in cancer prevention and therapy.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Body Weight; Dose-Response Relationship, Drug; Drug Synergism; Female; Fenretinide; Mammary Neoplasms, Experimental; Methylnitrosourea; Mice; Ovariectomy; Rats; Rats, Inbred Strains; Tamoxifen; Tretinoin

The effects of the newly synthesized polyprenoic acid, 3,7,11,15-tetramethyl-2,4,6,10,14-hexadecapentaenoic acid (E-5166) on N-2-fluorenylacetamide (FAA)-initiated hepatocarcinogenesis were examined in 6 groups of male ACI rats. The numbers of altered hepatocellular foci in rats of group 1 given a basal diet containing 0.02% FAA for 13 weeks and in rats of group 2 which received E-5166 by gavage (40 mg/kg, 3 times/week) at the same time as receiving the FAA diet were almost the same, indicating that E-5166 had no effect at the stage of carcinogen exposure. However, the number of foci in group 4, in which rats were given the basal diet and E-5166 after the termination of the carcinogen exposure, and were sacrificed 16 weeks later, was significantly smaller than that in group 3 maintained on the basal diet alone (P less than 0.05). The results suggests some anticarcinogenic activity of E-5166, possibly involving the phenotypic expression of the preneoplastic foci. Furthermore, the number of altered foci in rats of group 6 (given the liver-tumor promoter phenobarbital with E-5166 for 16 weeks after the administration of carcinogen) was also significantly smaller than that in rats of group 5, which received the promoter (P less than 0.05). The incidence of neoplastic nodules of the liver in group 6 at the end of the experiment was also lower than in group 5 (P less than 0.0014). These results suggest an antipromoting effect of the polyprenoic acid E-5166 on rat chemical hepatocarcinogenesis.

Topics: 2-Acetylaminofluorene; Animals; Body Weight; Drug Antagonism; Liver; Liver Neoplasms, Experimental; Male; Necrosis; Organ Size; Rats; Rats, Inbred ACI; Tretinoin

Topics: Animals; Benzofurans; Body Weight; Female; Food Contamination; Isotretinoin; Liver; Macaca fascicularis; Polymers; Squalene; Tretinoin

The long-term effects of N-ethylretinamide (NER) on the haematology of the rat, and the dose-related effects of retinoids on lymphoid organs of the mouse and rat were investigated. Retinoid-induced long-bone changes were used to develop a method for quantifying skeletal effects. This technique was used to investigate the activity of five retinamides in inducing long-bone changes in the rat. The ability of non-steroidal anti-inflammatory compounds (NSAICs) to prevent retinoid-induced skeletal effects was examined, and preliminary investigations made into the mechanisms of retinoid-induced long-bone remodelling. NER-fed rats had reduced red blood cell counts and fibrinogen values. Retinoids caused dose-related proliferation of the spleen and lymph nodes in the mouse and to a lesser extent in the rat. They induced dose-related reductions in femoral diaphysis and medullary cavity diameters in both rats and mice. Aspirin prevented NER-induced changes of rat long bones, but subsequent studies indicated this effect may be closely dependent on the dose level of both the retinoid and NSAIC administered. Retinoids induce rapid long-bone remodelling in the rat which tends to revert on feeding a control diet, but remodelling processes are different in the young growing rat and the mature animal.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Blood; Body Weight; Bone and Bones; Dose-Response Relationship, Drug; Female; Femur; Lymphoid Tissue; Mice; Mice, Inbred Strains; Organ Size; Rats; Rats, Inbred F344; Retinoids; Species Specificity; Tretinoin

The effect of 1 alpha, 25-dihydroxyvitamin D3 (1 alpha, 25-(OH)2D3) and its 24,24-difluoro analog on the formation of skin tumors in mice was evaluated in a complete carcinogenesis model using 7,12-dimethylbenz[a]anthracene (DMBA) as the carcinogen. Twice weekly topical application of 0.25-0.50 nmol of 1 alpha, 25-(OH)2D3 or 0.05-0.10 nmol of the difluoro analog of 1 alpha, 25-(OH)2D3 1 hour prior to treatment with 50 nmol DMBA stimulated tumor formation several fold compared to animals receiving DMBA alone. Topical application of 0.50 nmol of 1 alpha, 25-(OH)2D3 24 hours after treatment with DMBA, or half of this dose of the vitamin D3 metabolite, applied 1 hour before and 24 hours after treatment with DMBA, also stimulated tumor formation several fold. These results are in marked contrast to the potent inhibitory effect of 1 alpha, 25-(OH)2D3 and its difluoro analog on the formation of skin tumors in mice promoted by 12-O-tetradecanoylphorbol-13-acetate.

Topics: 9,10-Dimethyl-1,2-benzanthracene; Acetone; Animals; Body Weight; Calcitriol; Cocarcinogenesis; Female; Mice; Skin Neoplasms; Tetradecanoylphorbol Acetate; Time Factors; Tretinoin

Two synthetic retinoids were examined for their ability to support growth in male vitamin A-deficient rats. One of the compounds, (E)-4-[2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)-1 -propenyl]-benzoic acid (TTNPB), was found to be highly effective; it was 35-fold more active than all-trans-retinoic acid. Thus, the in vivo results were in agreement with the in vitro activity of this compound published by previous investigators, and support the view that this compound may be useful in determining the molecular mechanism of action of the retinoids. Another analog, 4,4-difluororetinoic acid, was only 12% as effective as retinoic acid. However, the possible instability of this compound and the electronegativity of the fluoro groups prohibited conclusions concerning the biological function of metabolic modification on the 4 position of retinoic acid.

Topics: Animals; Benzoates; Body Weight; Growth; Male; Rats; Retinoids; Tretinoin; Vitamin A Deficiency

Rats of the Sprague-Dawley strain were administered 2-acetylaminofluorene (2-AAF) in different diet regimens to ascertain the effect of retinoic acid(RA), butylated hydroxytoluene (BHT), propylgallate (PG), and selenium on induced hepatotoxicity. In the first study, groups of young male albino rats of the Sprague-Dawley strain were fed a diet containing 0.05% 2-AAF. Carcinogen was added to the diet for 3 weeks, omitted 1 week, added 2 weeks, omitted 2 weeks, added 3 weeks, and omitted for the final 4 weeks. Animals were terminated at the end of 15 weeks. Supplementation of the diet by 0.5% BHT, PG or 4 ppm selenium as sodium selenite in the drinking water either throughout the entire feeding period or only during the administration of the carcinogen-free diet greatly inhibited the hepatotoxicity of 2-AAF. In contrast, addition of 0.02% RA to the diet in the above feeding regimens enhanced the hepatotoxicity of 2-AAF. In the second study, male and female Sprague-Dawley rats were administered a diet containing 0.03% 2-AAF for 16 weeks or a diet containing 0.03% 2-AAF supplemented with 0.02% RA for the first 4 weeks and the last 6 weeks of the 16-week feeding period. Addition of the 0.02% RA to the diet enhanced the hepatotoxicity of 2-AAF, especially in the female rats.

Topics: 2-Acetylaminofluorene; Animals; Body Weight; Butylated Hydroxytoluene; Drug Interactions; Female; Gallic Acid; Liver; Male; Propyl Gallate; Rats; Rats, Inbred Strains; Selenium; Sex Factors; Time Factors; Tretinoin

Repeated ingestion of high doses of retinoids cause the so-called hypervitaminosis A syndrome. In rats the main symptoms are weight loss, alopecia, erythema, desquamation of the skin, and alterations of the skeletal system, including bone fractures. In the present study, three retinoids (Ro 15-1570, arotinoid ethylsulfone, 6 mg/kg; retinoic acid, 100 mg/kg and etretinate, 50 mg/kg) were administered orally to rats for 1 and 2 weeks, respectively, to six male and six female rats/group. All the above changes were induced by all three retinoids, with the exception that the arotinoid ethylsulfone Ro 15-1570 did not cause bone alterations. The absence of toxic effects on the bones by Ro 15-1570 was confirmed by X-ray-film examinations, densitometry of the X-rayed femora and tibiae, examination of the thickness of the femoral and tibial compacta in histological slides plus the determination of the femoral ash weight and its main inorganic constituents (calcium, magnesium, sodium, and potassium). The present demonstration that the arotinoid ethylsulfone Ro 15-1570 was devoid of bone toxicity constitutes major progress in the pharmacologic development of retinoids with a better balance between therapeutic and adverse effects.

Topics: Animals; Body Weight; Bone and Bones; Etretinate; Female; Femoral Fractures; Femur; Male; Rats; Retinoids; Skin; Tibia; Tibial Fractures; Tretinoin

All-trans [11-3H]4,4- difluororetinyl acetate was synthesized by treating methyl all-trans [11-3H]4- oxoretinoate with diethylaminosulfurtrifluoride , followed by reduction and acetylation of the product. After oral administration of the radioactive difluoro analog in oil to rats, difluororetinol , difluororetinyl palmitate and related esters, 4- oxoretinol , 4- oxoretinoic acid and polar conjugated derivatives were identified in the intestine, liver, kidney and/or blood. The major metabolic products were difluororetinyl palmitate and related esters, which were stored in the liver. The presence of the difluoro analog in liver oil from treated rats was confirmed by 19F-NMR spectroscopy. Neither retinol nor retinyl esters were detected as products of the metabolism of the difluoro analog. Nonetheless, all-trans difluororetinyl acetate showed 26 +/- 12% of the biological activity of all-trans retinyl acetate in the rat growth assay. Presumably, the difluoro analog is active per se in growth rather than by conversion to retinol or to one of its known growth-promoting metabolites. In general, however, the difluoro analog was metabolized in a manner very similar to vitamin A. The vitamin A moiety of administered difluororetinyl acetate and retinyl acetate was poorly stored (1.8-3.3%) in the liver of vitamin A-depleted rats, confirming and extending past reports that the liver storage mechanism is severely impaired when initial liver stores are very low.

Topics: Animals; Biological Assay; Body Weight; Diterpenes; Feces; Kinetics; Liver; Magnetic Resonance Spectroscopy; Male; Rats; Rats, Inbred Strains; Retinyl Esters; Tissue Distribution; Tretinoin; Vitamin A

Using etretinate as a model compound, the bone changes characteristic of hypervitaminosis A were evaluated in the rat in terms of tibial bone-breaking strain. Dose-related effects were observed in the dose range of 5-30 mg/kg p.o. for 15 days. The model proved a simple and precise means of assessing hypervitaminosis A in this species. Isotretinoin also showed a small but significant reduction in tibial breaking strain, but with a shallow dose-response curve in the range of 50-150 mg/kg.

Topics: Animals; Body Weight; Bone and Bones; Dose-Response Relationship, Drug; Etretinate; Female; Isotretinoin; Rats; Tensile Strength; Tibial Fractures; Tretinoin; Vitamin A

The daily food intake of a large dose of retinol (as palmitate) or retinoic acid (as all-trans retinoic acid) modifies numerous parameters of the thyroidal status in the rat. There were decreases of the serum total thyroxine (TT4) and triiodothyronine (TT3), and of the biological half-life of T4, while there were increases of the dialyzable fractions of T4 and T3 and of the apparent distribution space of T3. The possible causes of these changes are discussed.

Topics: Animals; Body Weight; Dialysis; Diet; Male; Rats; Rats, Inbred Strains; Thyroid Hormones; Tretinoin; Vitamin A

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.

Topics: Animals; Blood; Body Weight; Bone Diseases; Dose-Response Relationship, Drug; Female; Fractures, Bone; Male; Organ Size; Rats; Rats, Inbred Strains; Retinoids; Tretinoin

Weanling rats were fed for 4 weeks semipurified diets containing 0, 100 or 300 mg 13-cis retinoic acid per kg diet. The activities of (Na+ + K+)-ATPase, Mg2+-ATPase and gamma-glutamyltranspeptide were measured in submandibular salivary gland (SMSG) homogenates. The activity of (Na+ + K+)-ATPase in the SMSG was reduced in rats fed 13-cis retinoic acid. There was no effect on the activities of the other two enzymes. Fatty acid composition of total lipids in SMSG suggest that decrease in (Na+ + K+)-ATPase activity may be associated with changes in fatty acid composition of total lipids.

Topics: Adenosine Triphosphatases; Animals; Body Weight; Ca(2+) Mg(2+)-ATPase; Cell Membrane; Fatty Acids; gamma-Glutamyltransferase; Isotretinoin; Male; Organ Size; Rats; Rats, Inbred Strains; Sodium-Potassium-Exchanging ATPase; Submandibular Gland; Tretinoin

Feeding of N-(hydroxyphenyl)retinamide (4-HPR) (1.0 mM/kg diet) for 39 weeks to 2 month old nulliparous C3H/Crgl mice significantly (p less than 0.01) reduced the incidence of mammary tumors; 98 control mice developed a total of 235 mammary tumors, 100 4-HPR treated mice developed 171 mammary tumors. Feeding the same dietary level of 4-HPR to 4-6 month old multiparous C3H mice for 14 weeks did not significantly influence the development of mammary tumors; 78 control mice developed a total of 115 mammary tumors; 78 4-HPR treated mice developed 130 mammary tumors. Body weight gains were comparable among 4-HPR treated mice and control mice. Significant suppression of mouse mammary gland tumorigenesis in vivo by dietary retinoids (nulliparous C3H mice) has heretofore not been reported.

Topics: Animals; Body Weight; Female; Fenretinide; Mammary Neoplasms, Experimental; Mice; Mice, Inbred C3H; Pregnancy; Tretinoin

Food intake and growth were depressed during the first week of feeding the anticarcinogenic retinoid N-(4-hydroxyphenyl) retinamide (HPR) at a concentration of 782 mg/kg diet to female rats. Food intake was normalized thereafter, but body weight did not reach that of control animals until 40 days later. The use of a pair-fed group demonstrated that weight depression in HPR fed animals was entirely due to reduced food intake. Mammary glands from HPR-fed animals showed decreased ductal branching and decreased end bud proliferation relative to control glands. Total hepatic retinol and retinol concentration were lower (P less than 0.05) for HPR fed animals than for controls. The effects of HPR on mammary development and retinol storage were attributable to dietary HPR per se. HPR was detected in mammary gland and body fat at concentrations of 27 and 53.7 nmol/g, respectively.

Topics: Adipose Tissue; Aging; Animals; Body Weight; Diet; Eating; Female; Fenretinide; Liver; Mammary Glands, Animal; Rats; Rats, Inbred Strains; Tretinoin; Vitamin A

Carcinogenesis induced by 7,12-dimethylbenz[a]anthracene (DMBA) and 12-O-tetradecanoylphorbol 13-acetate (TPA) in the forestomach epithelium of mice was delayed by ethyl all-trans-9-(4-methoxy-2,3,6-trimethylphenyl)-3,7-dimethyl-2,4,6,8-nonatetraenoate (etretinate). Beside the clear inhibitory effect during the promotion phase, however, considerable side effects occurred when administering effective doses.

Topics: 9,10-Dimethyl-1,2-benzanthracene; Animals; Body Weight; Carcinogens; Epithelium; Etretinate; Female; Mice; Mice, Inbred C57BL; Neoplasms, Experimental; Stomach Neoplasms; Tetradecanoylphorbol Acetate; Tretinoin

Syrian hamsters were treated with either a low (10 mg/kg body weight) or high (40 mg/kg body weight) single dose of bis(2-oxopropyl)nitrosamine (BOP) and beginning 1 week later fed either low (0.2 mmol/kg diet) or high (0.4-1.0 mmol/kg diet) levels of one of four retinoids [13 cis retinoic acid (13-cis-RA), N-ethylretinamide (ERA), N-(2-hydroxyethyl)retinamide (OHERA) or N-(phenyl)retinamide (PRA)] for periods of 40 or 50 weeks. The high retinoid levels (0.4-1.0 mmol/kg diet) fed following the highest BOP treatment enhanced pancreatic carcinoma yields (average number/effective animal) in males fed all four retinoids, and in females fed ERA and 13-cis-RA. Enhanced adenoma yields were also seen in all groups when high retinoid levels were fed following 40 mg BOP/kg body weight. However, these retinoid levels caused an increased adenoma yield in male hamsters only and did not modify carcinoma yields when fed following 10 mg BOP/kg body weight. Similarly, tumor yields at extra-pancreatic sites were elevated in retinoid-fed hamsters of both sexes after 40 mg BOP/kg body weight and in males fed ERA and 13-cis-RA after 10 mg BOP/kg body weight when retinoids were given at the high levels (0.4-1.0 mmol/kg diet). Increased incidences of bile duct and liver tumors in particular were found in hamsters given 40 mg BOP/kg body weight. Consumption of retinoid levels of 0.4 mmol/kg diet and above was also associated with a high incidence of liver cell necrosis, ovarian cysts and ovarian hemorrhage. Retinoids (ERA, OHERA, and PRA) fed at the low level (0.2 mmol/kg diet) following the low BOP dose did not enhance carcinogenesis in the pancreas or at other sites and did not cause alterations in morphologic observations.

Topics: Animals; Body Weight; Cricetinae; Dose-Response Relationship, Drug; Female; Isomerism; Isotretinoin; Male; Mesocricetus; Neoplasms; Nitrosamines; Pancreatic Neoplasms; Sex Factors; Tretinoin

Swiss Webster female mice weighing 25-30 gm were injected subcutaneously on days 6-15 of gestation with the synthetic sex steroid Delalutin (17 alpha-hydroxyprogesterone caproate). Treatment was given daily in doses ranging from 42 to 833 mg/kg body weight, or 10, 100, and 200 times the human therapeutic dose. On day 18 fetuses were removed from the uterus and examined for malformations and other fetotoxic effects. Prenatal treatment with the two higher doses resulted in 8 and 13% maternal deaths, and all doses resulted in a slight increase (4-12% above control) in resorption frequency. Treatment with Delalutin did not significantly affect intrauterine growth, sex ratio, or malformation rate of the offspring. The results of the present study confirm other reports that Delalutin is not androgenic, and that it, like progesterone and certain other sex steroids, does not alter the development of nonreproductive organs.

Topics: 17 alpha-Hydroxyprogesterone Caproate; Abnormalities, Drug-Induced; Animals; Body Weight; Dose-Response Relationship, Drug; Female; Fetal Resorption; Hydroxyprogesterones; Muridae; Pregnancy; Progestins; Sex Factors; Tretinoin

The effects of a vitamin A-deficient diet and the subsequent supplementation with retinoic acid (10 micrograms/g dry diet) on serum thyroid hormones in rats were studied. In vitamin A-deficient animals there are increased levels of thyroxine and triiodothyronine and changes in serum transport of these hormones. Retinoic acid was able to restitute both levels and serum transport of hormones as in control rats.

Topics: Animals; Blood Proteins; Body Weight; Male; Protein Binding; Rats; Rats, Inbred Strains; Serum Albumin; Thyroxine; Tretinoin; Triiodothyronine; Vitamin A Deficiency

Groups of Charles River Sprague-Dawley male rats were given intragastric intubations of methylbenzylnitrosamine after receiving one of the following diets for 4 weeks: control, zinc-deficient, or zinc-deficient diet plus 4% ethanol in the drinking water. One zinc-deficient group was zinc repleted after the dosing period; the other group, zinc-deficient plus 4% ethanol, received 13-cis-retinoic acid (13-cis-RA) after the dosing period. Zinc deficiency significantly enhanced esophageal tumor incidence; the addition of ethanol further enhanced tumor incidence. Zinc repletion reduced tumor incidence, whereas the addition of 13-cis-RA enhanced tumor incidence.

Topics: Animals; Body Weight; Cocarcinogenesis; Copper; Diet; Dimethylnitrosamine; Esophageal Neoplasms; Ethanol; Isotretinoin; Male; Neoplasms, Experimental; Rats; Rats, Inbred Strains; Tretinoin; Zinc

Outbred male Sprague-Dawley CD rats were fed a complete semisynthetic diet and were given supplemental low doses (2 ppm) of selenium as H2SeO3 in their drinking water or 50 mg 13-cis-retinoic acid (13-cis-RA) and 2 g beta-sitosterol/kg diet either singly, in combinations of two, or in combinations of all three. Intestinal tumors were induced with eight weekly sc injections of 8 mg azoxymethane (AOM)/kg body weight, and inhibition of tumor formation was determined by tumor counts after 26 weeks. Noncarcinogen controls for each dietary group received eight injections of sterile water. Tumor inhibition was statistically significant in 2 groups of animals: Dietary control animals had a tumor frequency of 5.07 tumors/rat, rats receiving selenium- plus 13-cis-RA supplementation had a tumor frequency of 3.77, and those being given the combination of all three inhibitors had 2.75 tumors/rat. Analysis of fecal steroids from 3 AOM groups (dietary controls, the beta-sitosterol plus 13-cis-RA-supplemented group, and the group receiving all three additives) after 4 months of supplementation showed that the addition of beta-sitosterol to the diet had no effect on acidic or neutral steroids, regardless of the observed difference in tumor frequency. These results suggest that subpharmacologic doses of inhibitors, particularly those that inhibit the process by different mechanisms, while ineffective alone, may provide significant inhibition of tumorigenesis when used in combination.

Topics: Animals; Azo Compounds; Azoxymethane; Body Weight; Drinking; Eating; Intestinal Neoplasms; Male; Rats; Rats, Inbred Strains; Selenium; Sitosterols; Tretinoin

Timed-pregnant rats were injected with a total of 90 microgram of retinoic acid from day 13 until delivery. Other pregnant groups were given either a total of 390 microgram of retinol from day 5 or a total of 270 microgram of retinol from day 13 until delivery. Although the weight gains and food intake of the dams during gestation showed no difference between groups, the long bones were slightly heavier in pups born from retinoic acid-injected dams. Total collagen content in both mandibles and long bones did not show differences between retinoic acid- and retinol-injected groups, but collagen synthesis in both bones was greatly increased in the retinoic acid-injected groups. Calcium content of the mandible in the retinol-injected group from day 13 of gestation was increased, whereas 45Ca uptake of long bone of this group was increased. Retinoic acid, when injected in physiological doses during gestation, may have some effects on the organic phase of bone, long bones being slightly more sensitive to retinoic acid than the mandibles.

Topics: Animals; Body Weight; Bone and Bones; Calcium; Collagen; Mandible; Organ Size; Rats; Rats, Inbred Strains; Tretinoin

Topics: Body Weight; Edema; Etretinate; Humans; Male; Middle Aged; Tretinoin

The failure of N-ethylretinamide and N-(2-hydroxyethyl)retinamide to inhibit the incidence or severity of bladder carcinoma in female Fischer rats initiated with N-[4-(5-nitro-2-furyl)-2-thiazolyl]formamide supports the concept that the inhibition of bladder carcinogenesis by natural and synthetic retinoids is carcinogen-class specific.

Topics: Animals; Body Weight; FANFT; Female; Neoplasms, Experimental; Rats; Rats, Inbred F344; Thiazoles; Tretinoin; Urinary Bladder Neoplasms

Many reports have appeared in the literature suggesting that vitamin A may exert some of its effects via changes in adrenocortical activity. A series of experiments were performed in order to assess the possible role of the adrenal gland in vitamin A-induced lipid alterations in rats. Adrenalectomized, sham-operated, and intact rats were fed retinoic acid or retinyl acetate at several levels. Either 25 or 100 retinol equivalents (RE)/g dry diet were fed to male Sprague-Dawley rats for periods of 7 or 28 days. Neither compound had an effect on the concentration of liver glycerides, phospholipids, cholesterol, or total lipids. Vitamin A, especially in the form of retinoic acid, was found to induce an elevation of plasma triglycerides. The presence of the adrenal gland was not necessary for the induction of hypertriglyceridemia nor was there any indication of increased adrenocortical output (as measured by plasma corticosterone level) as a result of vitamin A feeding. There was a reduction in circulating retinol as a result of retinoic acid feeding at either 25 or 100 RE in sham-operated and adrenalectomized rats but not in unoperated rats. These experiments demonstrate that vitamin A, especially in the form of retinoic acid, fed at as low as 25 RE/g diet to the rat can induce hypertriglyceridemia, and that the adrenal gland does not mediate this effect.

Topics: Adrenal Glands; Adrenalectomy; Animals; Body Weight; Cholesterol; Corticosterone; Hyperlipidemias; Lipid Metabolism; Liver; Male; Phospholipids; Rats; Tretinoin; Triglycerides; Vitamin A

Rats were fed diets deficient [-A] or sufficient [+A] (3 mg retinol equivalents/kg) in vitamin A, and without [-RA] or with [+RA] (12 mg/kg) retinoic acid supplementation for up to 33 days. Rats with plasma vitamin A levels ranging from 7 to 62 micrograms/dl were studied at intervals during progressive depletion of liver stores of vitamin A (expt. 2) and when liver stores were nearly exhausted (less than 10 micrograms/g) or replete (up to 100 micrograms/g) with vitamin A (expt. 1). A dose of retinyl acetate in corn oil (20 micrograms retinol equivalents) was administered by intubation directly into the stomach. The relative dose response (RDR), expressed as a percentage and defined as the absolute magnitude of the rise in plasma vitamin A levels 5 hours after the dose of retinyl acetate, divided by the plasma level of vitamin A attained after 5 hours, was determined for each rat and correlated over a wide range of vitamin A plasma and liver levels. An RDR above 50% invariably was associated with low plasma levels (10 to 30 micrograms/dl) and low liver stores (less than 10 micrograms/g) of vitamin A, whereas an RDR of less than 40% was associated with plasma levels above 30 micrograms/dl and liver stores ranging from 3 to 100 micrograms/g.

Topics: Animals; Body Weight; Dose-Response Relationship, Drug; Liver; Male; Rats; Tretinoin; Vitamin A; Vitamin A Deficiency

Rats were fed vitamin A-deficient diets either alone, supplemented with retinoic acid (RA), or of limited protein quality or quantity (7%rice or 7% casein protein); one group was fed 7% rice protein supplemented with vitamin A. Plasma and liver levels of vitamin A were determined serially. Plasma levels in rats fed otherwise adequate vitamin A-deficient diets remained above 30 micrograms/dl until liver reserves were below 10 micrograms/g tissue, at which point plasma levels decreased in some but not all rats while liver levels continued to decline (at a slower rate) to levels as low as 3 micrograms/g. Supplementation with RA caused an immediate and sustained reduction of 15 to 20 micrograms/dl in circulating vitamin A. At 7% dietary protein, plasma levels of vitamin A remained above 30 micrograms/dl when casein protein was fed or when the rice protein diet was supplemented with dietary vitamin A, but not when the rice protein diet was fed without an exogenous source of the vitamin. A scheme is proposed suggesting possible regulatory mechanisms that might control homeostatic levels of plasma vitamin A.

Topics: Animals; Body Weight; Caseins; Dietary Proteins; Liver; Male; Oryza; Plant Proteins; Rats; Tretinoin; Vitamin A; Vitamin A Deficiency

Experiments were conducted to determine the sequence and reliability of appearance of key signs of vitamin A deficiency. Rapid and essentially synchronous vitamin A deficiency was induced by the withdrawal of retinoic acid from mature (190--210 g) stringently vitamin A-deficient male rats reared by feeding early growth plateau (60--70 g) vitamin A-deprived rats diets first supplemented with and then lacking in 2 micrograms retinoic acid per gram diet in repeating 18 day:10 day supplementation:deprivation cycles. Growth was depressed within 1 to 2 days of the withdrawal of retinoic aicid whether animals were force-fed or were fed ad libitum. Similar patterns were obtained when animals were fed 5 or 10 micrograms retinoic acid per gram diet. Appetite was depressed (1--2 days) whether animals were fed 18% casein diets, or were given 10% dextrose drinking solutions only. Decreased food intake was not due to impaired taste function or to poor palatability of the deficient diet. Bilateral electrolytic lesions in the ventromedial nucleus of the hypothalamus or anterior prepyriform cortex failed to prevent or to delay loss of appetite. Supplementation with antibiotics decreased body weight losses in the late stages of deficiency and increased survival time. Other signs of deficiency (days until onset following retinoate withdrawal; percent incidence) were: decreased intestinal goblet cell numbers (2--3; 80), decreased pilocarpine induced salivation (6--8; 80), tracheal metaplasia (6--8; 80), transient periocular porphyria (6--8; 60), altered salivary gland morphology (9--10; 80), decreased stomach emptying in force-fed animals (12; 70), twisting (12; 5) and leg crippling (12; 5). We conclude that the sequence of appearance of individual signs of deficiency following the induction of synchronous vitamin A deficiency is highly reproducible, and that the more general use of synchronously deficient animals would materially assist studies of cause-effect relationships in vitamin A deficiency.

Topics: Animals; Appetite; Body Weight; Chlortetracycline; Hypothalamus; Male; Rats; Taste; Tretinoin; Vitamin A Deficiency

Topics: Animals; Body Composition; Body Weight; Feedback; Liver; Male; Rats; Retinol-Binding Proteins; Time Factors; Tissue Distribution; Tretinoin; Vitamin A; Vitamin A Deficiency

Studies were conducted to investigate the in vivo and in vitro effects of retinol and retinoic acid on the synthesis of mannolipids and mannopeptides in rat liver. The incorporation of 14C-mannose into glycolipids and glycoproteins showed a decrease in vitamin A-depleted rats as compared with vitamin A-fed rats. By means of DEAE-cellulose, silicic acid and thin-layer chromatography, the mannose-containing lipids were separated into mannosyl retinyl phosphate (MRP, Rf 0.2) and dolichyl mannosyl phosphate (DMP, Rf 0.4), respectively. A rapid increase in the synthesis of labelled MRP was observed, exhibiting a peak between 25 and 60 min after intraperitoneal administration of retinol to vitamin A-depleted rats. Similarly, administration of retinoic acid brought about elevation of 14C-mannolipid (Rf 0.2) synthesis with a peak at 60 min after injection. On the other hand, the incorporation of 14C-mannose into DMP (Rf 0.4) remained unchanged by such treatment. In vitro addition of retinyl phosphate, but not retinoyl phosphate, markedly stimulated the synthesis of 14C-mannolipid (Rf 0.2), using crude membrane of rat liver and GDP-14C-mannose as the donor. These findings strongly suggest that not only retinol but also retinoic acid plays an important biological role in mannosyl transfer reaction in rat liver. However, the molecular participation of a metabolite of retinoic acid in the formation of a mannolipid and the structure of such a metabolite remain to be established.

Topics: Animals; Body Weight; Dolichol Monophosphate Mannose; Glycolipids; Glycopeptides; Glycoproteins; In Vitro Techniques; Liver; Male; Mannose; Mannosyltransferases; Polyisoprenyl Phosphate Monosaccharides; Polyisoprenyl Phosphate Sugars; Rats; Tretinoin; Vitamin A; Vitamin A Deficiency

Topics: Amino Acids; Animals; Body Weight; Eye Proteins; In Vitro Techniques; Palmitates; Rats; Retina; Tretinoin; Trichloroacetic Acid; Vitamin A; Vitamin A Deficiency

An aromatic analog of retinoic acid, all-trans-9-(4-methoxy-2,3,6-trimethylphenyl)-3,7-dimethyl-2,4,6,8-nonatetraenoic acid (Ro 10-1670), its ethyl esther (Ro 10-9359), and ethyl amide (Ro 11-1430) have been shown to inhibit the growth of a transplantable rat chondrosarcoma. The inhibition observed occurred over a range of tolerated doses. At the higher tolerated dose levels, significant regressions of already established tumors were observed. All three compounds were active when administered ip for 2 or 4 weeks. The ethyl ester, Ro 10-9359, and the etyl amide, Ro 11-1430, were also active when administered for 4 weeks as dietary admixes. In the latter experiments, both compounds were equally effective at tolerated doses, but Ro 11-1430 was less toxic than Ro 10-9359 at higher doses.

Topics: Animals; Body Weight; Chondrosarcoma; Dose-Response Relationship, Drug; Drug Evaluation, Preclinical; Female; Neoplasms, Experimental; Rats; Time Factors; Tretinoin; Vitamin A

Topics: Animals; Body Weight; Liver; Male; Organ Size; Rats; Testis; Tretinoin; Vitamin A; Vitamin A Deficiency; Xerophthalmia

Topics: Animals; Antibody Formation; Body Weight; Chickens; Immune Adherence Reaction; Liver; Male; Poultry Diseases; Tretinoin; Vitamin A; Vitamin A Deficiency

A new analogue of vitamin A, viz., retinoic acid anhydride was prepared, for the first time, by the action of thionyl chloride on retinoic acid in benzene containing pyridine. The amhydride was charcterised by its chromatographic properties, elemental analysis, ultraviolet absorption, infrared and nuclear magnetic resonance spectral characteristics. The compound could be readily hydrolysed to retinoic acid both by acid and alkali treatments and reduced by lithium aluminium hydride to vitamin A alcohol (retinol). The spectral changes with antimony trichloride reagent were similar to those observed for retinoic acid. The metabolism of retinoic acid anhydride was found to be similar to that of retinoic acic. When administered either orally or intraperitoneally, the compound promotes growth in vitamin A-deficient rats. Time-course experiments revealed that retinoic acid anhydride is converted into retinoic acid by non-enzymatic hydrolysis and thereby exerts its biological activity. The biopotency of the anhydride was found to be nearly the same as that of the acid. A new method of preparing esters of retinoic acid employing retinoic acid anhydride as an intermediate, has been described.

Topics: Absorption; Animals; Body Weight; Esters; Male; Rats; Stimulation, Chemical; Tretinoin; Vitamin A; Vitamin A Deficiency

Topics: Animals; Biological Assay; Body Weight; Carotenoids; Fatty Acids, Unsaturated; Intestinal Mucosa; Ketones; Liver; Magnetic Resonance Spectroscopy; Male; Oxidation-Reduction; Rats; Spectrophotometry, Infrared; Spectrophotometry, Ultraviolet; Tretinoin; Vitamin A; Vitamin A Deficiency