cholecalciferol and Disease-Models--Animal

The biologically active form of vitamin D

Topics: Animals; Breast Neoplasms; Cholecalciferol; Disease Models, Animal; Female; Humans; Mice; Mice, Transgenic; Vitamins

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

Topics: Animals; Bone and Bones; Bone Density; Bone Density Conservation Agents; Cholecalciferol; Diphosphonates; Disease Models, Animal; Drug Administration Schedule; Drug Synergism; Drug Therapy, Combination; Durapatite; Haplorhini; Humans; Ibandronic Acid; Infusions, Intravenous; Osteoporosis; Randomized Controlled Trials as Topic; Rats; Spinal Fractures

Vitamin D3 deficiency and insufficiency are common in women of child-bearing age. This may be cause for concern because vitamin D3 is a well known regulator of immune function and epidemiological evidence has suggested that immune disorders, including autoimmune diseases, could have developmental origins. However, it is not known whether a developmental deficiency in vitamin D3 could lead to persistent changes in the immune system in adult offspring. Given the prominence of receptors for vitamin D3 within immune cells we hypothesised that the developmental absence of vitamin D3 may alter thymic development and thus produce associated functional changes in T cells. We have developed a model of developmental vitamin D3 (DVD) deficiency in Sprague-Dawley rats, in which the vitamin D3 deficiency is transient and restricted to gestation. First we demonstrate that DVD deficiency induced an increase in central but not peripheral immune organ size. Second when stimulated, lymphocytes from DVD-deficient rats exhibit a pro-inflammatory phenotype. This is the first study to show that a transient vitamin D3 deficiency restricted to gestation can persistently alter aspects of immune phenotype and function in the adult offspring. Given an increased incidence of vitamin D3 deficiency in women of child-bearing age these findings may be highly relevant for autoimmune disorders with a developmental basis.

Topics: Animals; Autoimmune Diseases; Cholecalciferol; Cytokines; Disease Models, Animal; Female; Immune System; Immunophenotyping; Leukocytes, Mononuclear; Lymphocytes; Models, Biological; Organ Size; Rats; Rats, Sprague-Dawley; Th1 Cells; Vitamin D Deficiency

Topics: Animals; Cholecalciferol; Disease Models, Animal; Drug Resistance, Multiple; Humans; Immunotherapy; Interferon-gamma; Macrophages; Mice; Mycobacterium tuberculosis; Tuberculosis

Topics: Alkaline Phosphatase; Animals; Bone and Bones; Calcifediol; Calcitriol; Calcium; Callitrichinae; Cebidae; Cercopithecidae; Cholecalciferol; Disease Models, Animal; Hypophosphatemia, Familial; Intestinal Mucosa; Kidney; Liver; Parathyroid Hormone; Phosphorus; Receptors, Calcitriol; Receptors, Steroid

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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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; 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YAP-Signaling Proteins; Yogurt; Young Adult; Zebrafish; Zebrafish Proteins; Ziziphus

While vitamin D (VitD) levels are negatively correlated with inflammatory bowel disease (IBD) activity, VitD supplementation does not reduce IBD severity. The probiotic Lactobacillus rhamnosus GG (LGG), which secretes p40, can upregulate colonic VitD receptor (VDR) expression. We therefore evaluated synergy between VitD3 and LGG/p40 in the treatment of mouse colitis.. A dextran sulfate sodium (DSS) colitis model was established in Vdr+/+ and Vdr-/- mice, and mice were treated with VitD3, LGG, or p40 alone or in combination for 7 to 14 days. Colitis severity was assessed by weight loss, disease activity index (DAI), colon length, histology, and inflammatory cytokine expression together with VDR expression, proliferation, and apoptosis. In vitro, VDR expression and cell viability were assessed in HCT116 cells after stimulation with p40.. Total and nuclear VDR protein expression were lower in DSS-treated Vdr+/+ mice compared with control mice (P < .05). Compared with the DSS group, VitD3 + LGG alleviated colitis as assessed by significantly improved DAI and histological scores, increased colon length, decreased colonic Tnf, and increased Il10 expression together with increased colonic VDR gene and protein expression and increased Ki-67 proliferation index (P < .05). In Vdr-/- mice, VitD3 + LGG had no effect on DSS colitis. In Vdr+/+ mice, VitD3 + p40 also reduced colitis severity according to clinicopathological and immunological metrics and increased VDR expression and epithelial proliferation (P < .05). In HCT116 cells, p40 stimulation increased VDR protein expression and viability (P < .05).. VitD3 and LGG/p40 synergistically improve the severity of colitis by increasing colonic VDR expression and promoting colonic epithelial proliferation.. There is increasing evidence that vitamin D and its associated pathways may be a helpful adjunct to inflammatory bowel disease therapies. This experimental study shows that vitamin D may synergize with the probiotic Lactobacillus rhamnosus GG for enhanced therapeutic effect.

Topics: Animals; Cell Proliferation; Cholecalciferol; Colitis; Colon; Dextran Sulfate; Disease Models, Animal; Inflammatory Bowel Diseases; Lacticaseibacillus rhamnosus; Mice; Mice, Inbred C57BL; Receptors, Calcitriol

Autologous fat grafting, although broadly indicated, is limited by unsatisfactory retention and often requires multiple procedures to achieve durable outcomes. Graft survival is strongly influenced by the magnitude and duration of post-engraftment ischemia. Calcitriol is a pleiotropic, safe nutrient with cell-specific influence on viability and metabolic flux.. Evaluate the efficacy of activated vitamin D3 (calcitriol) in improving grafting outcomes and examine its mechanisms.. Lipoaspirate was collected for ex vivo culture (7 unique donors), in vitro bioenergetic analysis (6 unique donors), and in vivo transplantation (5 unique donors). Ex vivo samples were incubated for up to 2 weeks before extraction of the stromal vascular fraction (SVF) for viability or flow cytometry. SVF was collected for Seahorse (Agilent; Santa Clara, CA) analysis of metabolic activity. Human endothelial cell lines were utilized for analyses of endothelial function. In vivo, samples were implanted into athymic mice with calcitriol treatment either (1) once locally or (2) 3 times weekly via intraperitoneal injection. Grafts were assessed photographically, volumetrically, and histologically at 1, 4, and 12 weeks. Hematoxylin and eosin (H&E), Sirius red, perilipin, HIF1α, and CD31 tests were performed.. Calcitriol-treated lipoaspirate demonstrated dose-dependent increases in SVF viability and metabolic reserve during hypoxic stress. Calcitriol treatment enhanced endothelial mobility ex vivo and endothelial function in vitro. In vivo, calcitriol enhanced adipocyte viability, reduced fibrosis, and improved vascularity. Continuous calcitriol was sufficient to improve graft retention at 12 weeks (P < .05).. Calcitriol increased fat graft retention in a xenograft model. Calcitriol has potential to be a simple, economical means of increasing fat graft retention and long-term outcomes.

Topics: Adipocytes; Adipose Tissue; Animals; Calcitriol; Cholecalciferol; Disease Models, Animal; Graft Survival; Heterografts; Humans; Mice

Atopic dermatitis and psoriasis are prevalent chronic inflammatory skin diseases that are characterized by dysfunctional skin barriers and substantially impact patients' quality of life. Vitamin D3 regulates immune responses and keratinocyte differentiation and improves psoriasis symptoms; however, its effects on atopic dermatitis remain unclear. Here, we investigated the effects of calcitriol, an active form of vitamin D3, on an NC/Nga mouse model of atopic dermatitis. We observed that the topical application of calcitriol decreased the dermatitis scores and epidermal thickness of NC/Nga mice with atopic dermatitis compared to untreated mice. In addition, both stratum corneum barrier function as assessed by the measurement of transepidermal water loss and tight junction barrier function as evaluated by biotin tracer permeability assay were improved following calcitriol treatment. Moreover, calcitriol treatment reversed the decrease in the expression of skin barrier-related proteins and decreased the expression of inflammatory cytokines such as interleukin (IL)-13 and IL-33 in mice with atopic dermatitis. These findings suggest that the topical application of calcitriol might improve the symptoms of atopic dermatitis by repairing the dysfunctional epidermal and tight junction barriers. Our results suggest that calcitriol might be a viable therapeutic agent for the treatment of atopic dermatitis in addition to psoriasis.

Topics: Animals; Calcitriol; Cholecalciferol; Cytokines; Dermatitis, Atopic; Disease Models, Animal; Interleukin-13; Mice; Psoriasis; Quality of Life; Skin

Pneumoconiosis patients exhibit significantly more anxiety and depression than healthy individuals. However, the mechanism of coal dust-induced anxiety and depression remains unclear.. A pneumoconiosis mouse model with anxiety- and depression-like behaviors were established after 28 days of exposure to coal dust. Vitamin D3 treatment (1200 IU/kg/week) was administered intraperitoneally for 3 months starting from the first coal exposure. Tail suspension test (TST), open field test (OFT), and elevated plus-maze (EPM) test were used to assess anxiety- and depression-like behaviors. Theserum concentration of 25(OH)D. In coal dust-exposed mice, immobility time decreased in OFT and increased in TST,and the frequency of entering the open arm decreased in the EPM compared with the control mice. Coal dust increased hippocampal GFAP expression and astrocyte activation and reduced neurogenic differentiation factor1 expression (NeuroD1). In addition, Vitamin D3 significantly alleviated anxiety- and depressive-like behaviors in TST and EPM test, decreased GFAP expression level, modified hippocampal astrocyte activation pattern, and advanced brain-derived neurotrophic factor (BDNF) distribution and expression in CA1 and CA3 of the hippocampus.. Taken together, our results suggest that, by inhibiting the over-activation of astrocytes and increasing BDNF and neuron protection, vitamin D treatment ameliorates coal-dust-induced depressive and anxiety-like behavior, which is the first evidence that vitamin D may be a new approach for treating mood disorders caused by particulate matter.

Topics: Animals; Anxiety; Astrocytes; Brain-Derived Neurotrophic Factor; Cholecalciferol; Coal; Depression; Disease Models, Animal; Dust; Hippocampus; Humans; Mice; Mood Disorders; Pneumoconiosis

Previous studies have shown a relationship between vitamin D and celiac disease (CD), however little evidence is available examining the direct effects of vitamin D on pathological features of this disease. In this study we evaluated the effect of oral administration of different doses of native vitamin D3 (cholecalciferol) in enteropathic mice. Female non-obese diabetic (NOD)/ShiLt.J mice were fed standard or gluten-free diet and administered gliadin (5 μg/kg) to induce a celiac pathology. Healthy control (gluten-free diet, without gliadin) and control for pathology (standard diet, with gliadin) were administered olive oil. All other experimental groups received gliadin and standard diet plus oral cholecalciferol (5, 10, 20, 50 and 130 μg/kg). Serum levels of 25(OH)D3, calcium and zonulin and expression of vitamin D receptor (VDR), CD3 and zonula occludens-1 (ZO-1) by immunohistochemistry as well as intestinal histological and histomorphometric analyses were undertaken. Although no difference in serum levels of 25(OH)D3, calcium or zonulin was observed in cholecalciferol-treated mice vs. healthy controls, a significant improvement in intestinal mucosa pathological features in mice administered cholecalciferol was observed by histological analysis. Villi length was also significantly increased by cholecalciferol in a dose-dependent manner. Immunohistochemical staining revealed increased expression of CD3 and ZO-1 in celiac mice compared to mice receiving high dose (130 μg/kg) cholecalciferol. These findings show the effect of oral cholecalciferol on signature features of CD in a mouse model of CD. Further dose-ranging studies to investigate the efficacy of cholecalciferol for the treatment of CD are warranted.

Topics: Animals; Calcifediol; Calcium; Calcium, Dietary; Celiac Disease; Cholecalciferol; Disease Models, Animal; Female; Gliadin; Mice; Mice, Inbred NOD; Vitamin D

Epileptic seizures are associated with the overproduction of free radicals in the brain leading to neuronal cell death. Therefore, reduction of oxidative stress may inhibit seizure- induced neuronal cell damage. The current study evaluated the effects of Vit D3 and melatonin and their combination on pentylenetetrazol (PTZ)-induced tonic-clonic seizures in mice.. Animals were divided into six groups. Group I was administered with normal saline (0.5 ml, intraperitoneally (i.p.)) on the 15th day of the experiment. Group II was injected with PTZ (60 mg/kg dissolved in 0.5 ml normal saline, i.p) on the 15th day. Groups III-IV were treated with diazepam (4 mg/kg/day), Vit D3 (6000 IU/kg/day), melatonin (20 mg/kg/day), and Vit D3 (6000 IU/kg/day)/melatonin (20 mg/kg/day), respectively, and were then injected with PTZ (60 mg/kg) on the 15th day of the experiment. Immediately after the injection of PTZ on the 15th day, mice were observed for a 30-min period to measure seizure latency and duration. For determination of oxidative stress markers, malondialdehyde (MDA) level and superoxide dismutase (SOD) activity were measured in mouse brains.. Treatment with Vit D3, melatonin, and Vit D3/melatonin significantly increased seizure latency and decreased seizure duration. The brain level of MDA was lower, and SOD activity was greater than in the PTZ group. Mice treated with Vit D3/melatonin had lower seizure duration than other treated groups.. The combination of Vit D3 and melatonin may reduce seizure frequency in epileptic patients; this effect may result from various mechanisms, including inhibition of oxidative stress.

Topics: Animals; Anticonvulsants; Cholecalciferol; Disease Models, Animal; Epilepsy; Melatonin; Mice; Pentylenetetrazole; Saline Solution; Seizures; Superoxide Dismutase

This prospective study is aimed at observing the number of nasal itching and sneezing in rats from the macroscopic level and examine the pathological changes of nasal mucosa, Th1 and Th2-related cytokines, and Treg/Th17 by vitamin D3 administration from the microscopic level, in order to explore the role of vitamin D in allergic rhinitis and to provide theoretical guidance for prevention and treatment.. There were significant differences in nasal itching and sneezing between the administration groups and the positive groups. Meanwhile, the level of Th1 and Treg in the administration groups increased, while the level of Th2 and Th17 decreased, indicating that the balance of Th1/Th2 was corrected. Our study revealed that vitamin D3 has preventive and therapeutic effects on allergic rhinitis, which provides theoretical guidance for practical application.

Topics: Animals; Cholecalciferol; Cytokines; Disease Models, Animal; Prospective Studies; Pruritus; Rats; Rhinitis, Allergic; Sneezing; T-Lymphocytes, Regulatory; Vitamin D

Individuals with Down syndrome (DS) exhibit impaired olfactory function and are at a higher risk of developing Alzheimer's disease (AD). Olfactory dysfunction may be an early clinical symptom of AD. Recent studies have demonstrated that vitamin D3 (VD3) exerts neuroprotective effects in mouse models of AD. In this study, we investigated the effects of VD3 on the morphology, immunolocalization, and markers involved in neuropathogenic processes, apoptosis, proliferation, cell survival, and clearance of amyloid peptides, along with neuronal markers in the olfactory bulb (OB) of an adult female mouse model of DS. Morphological and molecular analyses revealed that trisomic mice exhibited a volume reduction in the external plexiform layer, a decrease in the number of mitral and granule cells, and an increase in the expression of amyloid-β 42, caspase-3 p12, and P-glycoprotein. VD3 reversed certain morphological abnormalities in the OB of control trisomic mice (Ts

Topics: Alzheimer Disease; Animals; ATP Binding Cassette Transporter, Subfamily B; Caspase 3; Cholecalciferol; Dietary Supplements; Disease Models, Animal; Down Syndrome; Female; Methylenetetrahydrofolate Reductase (NADPH2); Mice; Mice, Transgenic; Neuroprotective Agents; Olfactory Bulb

A multifaceted approach can be effective for the treatment of dementia including the most common form, Alzheimer's disease (AD). However, currently, it involves only symptomatic treatment with cholinergic drugs. Beneficial effects of high Vitamin D

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Biomarkers; Cholecalciferol; Cognitive Dysfunction; Dietary Supplements; Disease Models, Animal; Hippocampus; Maze Learning; Plaque, Amyloid; Rats; Scopolamine

The aim of the study was to explore the effect of topical vitamin D3 in atopic dermatitis (AD) induced by ovalbumin (OVA) in contrast with topical betamethasone in mice.. 35 BALB/c adult male mice, weighing between 25-30 gm were used to induce AD by topically sensitizing the dorsal surface of the skin with the OVA patch. Subsequently, treatments were performed in each group by application of vitamin D3 cream (0.0003%), betamethasone cream (0.1%), or vehicles (QV cream) on the skin.. Remarkably, vitamin D3 had a marked improvement in the skin of OVA-induced AD mice. Additionally, vitamin D3 revealed a considerable diminution in the levels of IgE, IL-5, filaggrin, and epidermal thickness, whereas a significant augmentation in the levels of IL-4 and IL-13 was observed when compared with the control group, and histopathological studies had further confirmed these findings.. This study essentially highlighted the anti-inflammatory effect of vitamin D3 by effective alteration in the immunological components responsible for AD. Moreover, this pioneer experimental work represents a new paradigm and sheds a light on the importance of vitamin D3 in the implications of AD. A comprehensive creative approach is crucial to concretely establish and further corroborate vitamin D3 for this therapeutic role.

Topics: Animals; Anti-Inflammatory Agents; Betamethasone; Cholecalciferol; Cytokines; Dermatitis, Atopic; Disease Models, Animal; Immunoglobulin E; Interleukin-13; Interleukin-4; Interleukin-5; Male; Mice; Mice, Inbred BALB C; Ovalbumin; Skin

To evaluate the effectiveness of vitamin D. Mice were fed a high fat and sucrose diet for 10 weeks. Afterward, diet was maintained for 15 more weeks and two groups were formed, with and without cholecalciferol supplementation. A control group was fed with normal chow. Glucose homeostasis and cardiac function were assessed at baseline and at the 10th and 24th weeks. Animals were killed at the 10th and 25th weeks for plasma and cardiac sample analysis. Cardiac lipid profile was characterized by LC-MS/MS.. After 10 weeks of diet, mice exhibited pre-diabetes, mild left ventricle hypertrophy, and impaired longitudinal strain, but preserved myocardial circumferential as well as global diastolic and systolic cardiac function. After 15 more weeks of diet, animals presented with well-established type 2 diabetes, pathological cardiac hypertrophy, and impaired regional myocardial function. Cholecalciferol supplementation had no effect on glucose homeostasis but improved cardiac remodeling and regional myocardial function. After 25 weeks, non-supplemented mice exhibited increased myocardial levels of ceramides and diacylglycerol, both of which were normalized by vitamin D. This work brought to light the beneficial effects of cholecalciferol supplementation, in secondary prevention, on cardiac remodeling and function in a mouse model of diet-induced type 2 diabetes. Those cardioprotective effects may be, at least in part, attributed to the modulation of myocardial levels of lipotoxic species by vitamin D.

Topics: Animals; Cholecalciferol; Chromatography, Liquid; Diabetes Mellitus, Type 2; Diet; Dietary Supplements; Disease Models, Animal; Glucose; Mice; Tandem Mass Spectrometry; Ventricular Dysfunction, Left; Ventricular Remodeling

Topics: Alkaline Phosphatase; Animals; Aorta, Thoracic; Benzimidazoles; Cholecalciferol; Disease Models, Animal; Glycerophosphates; Large-Conductance Calcium-Activated Potassium Channels; Male; Mice; Mice, Inbred C57BL; Muscle, Smooth, Vascular; Nephrectomy; Osteocalcin; Osteopontin; Peptide Fragments; Proto-Oncogene Proteins c-akt; Random Allocation; Rats; Rats, Sprague-Dawley; RNA, Messenger; Vascular Calcification

We examined the vasoactive effect of estradiol in a rat model of early PCOS and the influence of vitamin D deficiency (VDD). We created a model of chronic hyperandrogenism and VDD in adolescent female Wistar rats (N = 46) with four experimental groups: vitamin D supplemented (T-D+), VDD (T-D-), hyperandrogenic and vitamin D supplemented (T+D+), and hyperandrogenic and VDD (T+D-). T+ groups received an 8-week-long transdermal Androgel treatment, D-animals were on vitamin D-reduced diet and D+ rats were supplemented orally with vitamin D3. Estrogen-induced vasorelaxation of thoracic aorta segments were measured with a wire myograph system with or without the inhibition of endothelial nitric oxide synthase (eNOS) or cyclooxygenase-2 (COX-2). The distribution of estrogen receptor (ER), eNOS and COX-2 in the aortic wall was assessed by immunohistochemistry. VDD aortas showed significantly lower estradiol-induced relaxation independently of androgenic status that was further decreased by COX-2 inhibition. COX-2 inhibition failed to alter vessel function in D+ rats. Inhibition of eNOS abolished the estradiol-induced relaxation in all groups. Changes in vascular function in VDD were accompanied by significantly decreased ER and eNOS staining. Short-term chronic hyperandrogenism failed to, but VDD induced vascular dysfunction, compromised estrogen-dependent vasodilatation and changes in ER and eNOS immunostaining.

Topics: Animals; Aorta; Cholecalciferol; Disease Models, Animal; Estradiol; Estrogens; Female; Nitric Oxide Synthase Type III; Polycystic Ovary Syndrome; Rats; Rats, Wistar; Vasodilation; Vitamin D Deficiency; Vitamins

Cardiovascular disease (CVD) is a chronic disease and causes the highest rate of death globally. CVD-related deaths account for 80% of all deaths in low and middle-income countries, such as China. Crocetin (CT), a carotenoid phytoconstituent already confirm their anti-inflammatory and antioxidant effects in various diseases animal models. In the study, we make effort to access the cardio-protective effect of Crocetin against vitamin D3 and high fat induced atherosclerosis in rats and scrutinize the underlying mechanism. Sprague Dawley (SD) rats were used in this study and rats were divided into different groups and high fat diet and vitamin D was used for induction the atherosclerosis. The rats were received oral administration of crocetin (5, 10 and 15 mg/kg) and simvastatin (0.5 mg/kg) until 30 days. At the end of the experimental period, lipid, cardiac markers, anti-inflammatory, antioxidant, pro-inflammatory cytokines and atherogenic index were estimated. The mRNA expression of Intercellular adhesion molecule-1 (ICAM-1), Monocyte Chemoattractant Protein-1 (MCP-1) and vascular cell adhesion molecule 1 (VCAM-1) in aortic tissue of the atherosclerotic rats. Crocetin significantly reduced the aortic membrane thickness and platelet aggregation rates. Crocetin also dose-dependently reduced total cholesterol (TC), very low-density lipoprotein (VLDL), triacylglycerol (TG), low-density lipoprotein (LDL) and augmented the level of high-density lipoprotein (HDL) level. Additionally, Crocetin significantly (p < 0.001) abridged the level of malonaldehyde (MDA) and augmented the level of superoxide dismutase (SOD), catalase (CAT), reduced glutathione (GSH) and glutathione peroxidase (GPx). Furthermore, Crocetin significantly (p < 0.001) dose-dependently reduced the levels of pro-inflammatory cytokines and inflammatory mediators. Crocetin attenuated mRNA expression of VCAM-1, ICAM-1 and MCP-1. Crocetin had anti-atherosclerosis and cardio-protective effects on vitamin D3 and high fat induced atherosclerosis in rats through anti-inflammatory and antioxidant mechanisms.

Topics: Administration, Oral; Animals; Anti-Inflammatory Agents; Antioxidants; Aorta; Atherosclerosis; Carotenoids; Chemokine CCL2; Cholecalciferol; Cytokines; Diet, High-Fat; Disease Models, Animal; Inflammation Mediators; Intercellular Adhesion Molecule-1; Lipid Metabolism; Phytotherapy; Rats, Sprague-Dawley; Vascular Cell Adhesion Molecule-1; Vitamin A

Biomarkers are essential tools in osteoarthritis (OA) research, clinical trials, and drug development. Detecting and evaluating biomarkers in OA research can open new avenues for researching and developing new therapeutics. In the present report, we have explored the serological detection of various osteoarthritis-related biomarkers in the preclinical model of OA. In this surgical OA model, we disrupted the medial tibial cartilage's integrity via anterior cruciate ligament transection combined with medial meniscectomy (ACLT+MMx) of a single joint of Wistar rats. The progression of OA was verified, as shown by the microscopic deterioration of cartilage and the increasing cartilage degeneration scoring from 4 to 12 weeks postsurgery. The concentration of serological biomarkers was measured at two timepoints, along with the complete blood count and bone electrolytes, with biochemical analysis further conducted. The panel evaluated inflammatory biomarkers, bone/cartilage biomarkers, and lipid metabolic pathway biomarkers. In chronic OA rats, we found a significant reduction of total vitamin D3 and C-telopeptide fragments of type II (CTX-II) levels in the serum as compared to sham-operated rats. In contrast, the serological levels of adiponectin, leptin, and matrix metallopeptidase (MMP3) were significantly enhanced in chronic OA rats. The inflammatory markers, blood cell composition, and biochemical profile remained unchanged after surgery. In conclusion, we found that a preclinical model of single-joint OA with significant deterioration of the cartilage can lead to serological changes to the cartilage and metabolic-related biomarkers without alteration of the systemic blood and biochemical profile. Thus, this biomarker profile provides a new tool for diagnostic/therapeutic assessment in OA scientific research.

Topics: Adiponectin; Animals; Anterior Cruciate Ligament; Anterior Cruciate Ligament Injuries; Biomarkers; Cartilage, Articular; Cholecalciferol; Collagen Type II; Disease Models, Animal; Leptin; Matrix Metalloproteinase 3; Meniscectomy; Menisci, Tibial; Osteoarthritis; Peptide Fragments; Rats; Rats, Wistar; Tibia

Vitamin D3 is beneficial in ameliorating or preventing inflammation and carcinogenesis. CCL20 is a potential therapeutic target in carcinogenesis, which mediates the protective effect of vitamin D or vitamin D analogue in autoimmune and cancer diseases. Here we aim to evaluate whether vitamin D3 plays a protective role in colitis-associated colorectal cancer (CAC) by affecting CCL20 and the molecular mechanism. Administration of azoxymethane (AOM) followed with dextran sulfate sodium (DSS) was used to simulate CAC in mouse. After 5-day DSS treatment, vitamin D3 supplementation was for 9 weeks at 60 IU/g/w. We found that dietary vitamin D3 significantly reduced the tumor number and tumor burden in mouse. In-vivo and -vitro, vitamin D3 reduced the levels of CCL20, phospho-p38 MAPK (p-p38) and phospho-NF-κB p65 (p-p65), and the transcriptional activity of NF-κB. Further studies showed that CCL20 mediated the inhibition of vitamin D3 in p38MAPK-mediated NF-κB signaling in vitro. Taken together, vitamin D3 effectively suppressed colonic carcinogenesis in AOM-DSS mouse model. Downregulation of CCL20 may contribute to the preventive effect of vitamin D3 on NF-κB activity. It may merit further clinical investigation as a therapeutic agent against CAC in humans.

Topics: Animals; Antineoplastic Agents; Carcinogenesis; Chemokine CCL20; Cholecalciferol; Colitis; Colorectal Neoplasms; Disease Models, Animal; Male; Mice; Mice, Inbred C57BL; NF-kappa B; p38 Mitogen-Activated Protein Kinases; Signal Transduction

Elucidation of the pathogenic mechanisms underlying post-stroke depression (PSD) could aid in the development of effective treatments. The present study explored whether Vitamin D3 (VitD3) can function as an antidepressant in PSD model mice and whether the effect is mediated by upregulation of brain-derived neurotrophic factor (BDNF). Mice were subjected to middle cerebral artery occlusion (MCAO) combined with chronic unpredicted mild stress (CUMS) to established the PSD model. For the mice in each group, Longa and Berderson behavioral tests were performed to evaluate motor function, sucrose preference and forced swimming tests were conducted to assess the cardinal depression-like behaviors anhedonia and helplessness, and western blot and immunohistochemistry were conducted to measure the levels of vitamin D receptor (VDR) and BDNF expression levels in mouse hippocampus. Compared to MCAO alone, subsequent CUMS aggravated motor dysfunction and depression-like behaviors, whereas injection of calcitriol (VitD3) enhanced expression levels of VDR and BDNF in the hippocampus as well as ameliorated both motor dysfunction and depression-like behaviors of PSD model mice, with optimal efficacy at 25 μg/kg. Injection of a BDNF-binding protein (TrkB-IgG) almost completely reversed the antidepressant and neuroprotective effects of VitD3, strongly suggesting that VitD3 improved motor dysfunction and depression-like behaviors in PSD model mice by promoting hippocampal BDNF signaling. Modulation of hippocampal BDNF by VitD3 treatment could be an effective strategy for prevention and treatment of PSD.

Topics: Animals; Brain-Derived Neurotrophic Factor; Cholecalciferol; Depression; Disease Models, Animal; Hippocampus; Mice; Receptors, Calcitriol; Stress, Psychological

Eosinophilic chronic rhinosinusitis (ECRS) is a chronic inflammatory disease, characterized by eosinophilic infiltration, T-helper type 2 (Th2-type) response, and olfactory dysfunction. A master regulator of Th2-type inflammation, thymic stromal lymphopoietin (TSLP), is important for basophil activation. TSLP-elicited basophils are a key factor in the pathogenesis of ECRS.. In order to elucidate the mechanisms of ECRS in humans, we aimed to establish a murine model of ECRS based on TSLP production in response to the topical application of MC903 (a vitamin D3 analog) and the subsequent TSLP-induced basophil activation. Histological analyses were performed to assess immune cell infiltration into the nasal mucosa and to explore the impact of eosinophilic inflammation on the olfactory epithelium. The status of Th2-type inflammation was evaluated by quantitative real-time PCR and enzyme-linked immunosorbent assay (ELISA).. Eosinophils, basophils, and M2 macrophages increased significantly in the nasal mucosa of the mice treated with MC903 and ovalbumin (OVA), compared to those treated with OVA alone or the controls. Quantitative real-time PCR and ELISA revealed elevated expression of interleukin (IL)-4, IL-5, IL-13, TSLP, the chemokine CCL11, and CCL24 in the nasal mucosa of the ECRS mice. In parallel, thinned olfactory epithelium and decreased mature olfactory sensory neurons were observed in the ECRS mice.. Our model of ECRS displayed Th2-type inflammation in the sinonasal region, including both eosinophil infiltration and basophil infiltration. Additionally, olfactory epithelium turned out to be affected by eosinophilic inflammation. These features are consistent with the characteristics of the human ECRS.

Topics: Animals; Cholecalciferol; Chronic Disease; Cytokines; Disease Models, Animal; Eosinophilia; Eosinophils; Mice; Nasal Polyps; Rhinitis; Sinusitis

Lung cancer remains incurable; therefore, novel therapeutical approaches are of great demand. This study was designed to investigate the effectiveness of cisplatin nanoparticles combined with vitamin-D

Topics: Animals; Antineoplastic Agents; Apoptosis; Carcinogens; Cholecalciferol; Cisplatin; Disease Models, Animal; Drug Therapy, Combination; Lung Neoplasms; Male; Nanoparticles; Rats; Rats, Wistar; Signal Transduction; Urethane; Vitamins

In the present study, we assessed the adjunct effect of vitamin D3 in combination with Fluconazole (FLZ) against Vulvovaginal Candidiasis (VVC) in mice.. Prophylactic treatment with vitamin D3 (10 and 20 μg/kg) significantly increased the therapeutic effect of FLZ against VVC. In a therapeutic experiment, mice in the infected control group showed the highest vaginal fungal load of 83627 ± 10058 CFUs. Treatment with FLZ at a dose of 10 mg/kg reduced fungal load to 55523 ± 14823 CFUs, whereas the mice treated with a combination of vitamin D3 and FLZ (10 mg/kg) had the fungal burden of 12156 ± 3219. Similarly, treatment with FLZ (20 mg/kg) reduced fungal load to 36394 ± 5648 CFUs, whereas the addition of vitamin D3 to FLZ (20 mg/kg) further reduced the fungal burden to 2179 ± 1188. The leukocyte numbers in the infected mice increased to 9802 ± 505 as compared to 5152 ± 778 in normal control mice. Whereas, a combination of vitamin D3 with FLZ (10 and 20 mg/kg) reduced leukocyte numbers to 7284 ± 607 and 5739 ± 1126. The histological analysis data revealed epithelial necrosis, shedding and ulceration in the vaginal wall. Treatment with FLZ or a combination of FLZ and vitamin D3 brought regenerative changes in the vaginal epithelium and lamina proparia.. The results of the present work recommend that the addition of vitamin D3 may be considered to increase the efficacy of FLZ against VVC.

Topics: Animals; Antifungal Agents; Candidiasis, Vulvovaginal; Cholecalciferol; Disease Models, Animal; Female; Fluconazole; Humans; Mice

Vitamin D3 is useful for the treatment of peritoneal dialysis (PD)-related peritoneal damage, but its side effects, such as hypercalcemia and vascular calcification, limit its applicability. Thus, we developed vitamin D-loaded magnetic nanoparticles (MNPs) and determined their therapeutic efficacy and side effects in vivo.. Alginate-modified MNPs were combined with 1α, 25 (OH). Vitamin D-loaded MNPs targeted the peritoneum better than vitamin D3, and had the same therapeutic effect as vitamin D3 in ameliorating peritoneal fibrosis and functional deterioration in a PD animal model. Most importantly, the particles reduced the side effects of vitamin D3, such as hypercalcemia and body weight loss, in mice.. Vitamin D-loaded MNPs could be an ideal future therapeutic option to treat PD-related peritoneal damage.

Topics: Alginates; Animals; Antibodies; Cholecalciferol; Disease Models, Animal; Drug Delivery Systems; Drug Liberation; Humans; Magnetite Nanoparticles; Male; Membrane Glycoproteins; Mice, Inbred C57BL; Peritoneal Dialysis; Peritoneal Fibrosis; Peritoneum

The importance of sun exposure on human health is well recognized, and a recent trend in the avoidance of sun exposure has led to the risk of missing the beneficial effects such as vitamin D

Topics: Activities of Daily Living; Animals; Antibody Formation; Biomarkers; Cholecalciferol; Cytokines; Diarrhea; Disease Management; Disease Models, Animal; Disease Susceptibility; Dysbiosis; Environmental Exposure; Fecal Microbiota Transplantation; Female; Food Hypersensitivity; Gastrointestinal Microbiome; Humans; Intestinal Mucosa; Mice; Oxidative Stress; Phototherapy; Sunlight; T-Lymphocytes

The present study aimed to investigate the effects of vitamin D3 (Vit D) administration on memory function, hippocampal level of amyloid-beta (Aβ), brain-derived neurotrophic factor (BDNF) and oxidative stress status in a rat model of unpredictable chronic mild stress (UCMS). Vit D was intraperitoneally administered at doses of 100, 1000, and 10,000 IU/kg. Animals were subjected to UCMS for a total period of 4 weeks. Memory function was assessed using morris water maze (MWM) and passive avoidance (PA) tests. Biochemical markers were measured to reveal the status of oxidative stress and antioxidant defense system. In addition, the levels of Aβ and BDNF were measured in hippocampal region. In the UCMS group, latency to find the platform was greater and the time spent in target quadrant (MWM test) as well as the latency to enter the dark compartment (PA test), were less than the vehicle group. Hippocampal malondialdehyde (MDA) and Aβ concentrations in the UCMS group were higher than the vehicle group. Hippocampal level of thiol and BDNF plus the activities of catalase and superoxide dismutase (SOD) were reduced in UCMS group compared to the control subjects (i.e. vehicle group). Interestingly, Vit D treatment supplementation reversed the mentioned effects of UCMS. Our findings indicated that Vit D administration improves UCMS-induced impairment of learning and memory through prevention of adverse effects on Aβ, BDNF and oxidative stress parameters.

Topics: Amyloid beta-Peptides; Animals; Brain-Derived Neurotrophic Factor; Cholecalciferol; Chronic Disease; Disease Models, Animal; Hippocampus; Injections, Intraperitoneal; Memory Disorders; Morris Water Maze Test; Oxidative Stress; Rats; Severity of Illness Index; Stress, Psychological; Superoxide Dismutase

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Caenorhabditis elegans; Cholecalciferol; Disease Models, Animal; Paralysis; Signal Transduction

Major depressive disorder (or depression) is one of the most frequent psychiatric illnesses in the population, with chronic stress being one of the main etiological factors. Studies have shown that cholecalciferol supplementation can lead to attenuation of the depressive state; however, the biochemical mechanisms involved in the relationship between cholecalciferol and depression are not very well known. The objective of this study was to investigate the effects of the administration of cholecalciferol on behavioral parameters (tail suspension test (TST), open field test (OFT), splash test (ST)) and redox state (dichlorofluorescein (DCF)) in adult female Swiss mice subjected to a model of depression induced by chronic corticosterone treatment. Corticosterone (20 mg/kg, p.o.) was administered once a day for 21 days. For investigation of the antidepressant-like effect, cholecalciferol (100 IU/kg) or fluoxetine (10 mg/kg, positive control) was administered p.o. within the last 7 days of corticosterone administration. After the treatments, the behavioral tests and biochemical analyses in the hippocampus and prefrontal cortex of the rodent samples were performed. Animals submitted to repeated corticosterone administration showed a depressive-like behavior, evidenced by a significant increase in the immobility time in the TST, which was significantly reduced by the administration of cholecalciferol or fluoxetine. In addition, the groups treated with cholecalciferol and fluoxetine showed a significant decrease in the production of reactive oxygen species (ROS) in the hippocampus. These results show that cholecalciferol, similar to fluoxetine, has a potential antidepressant-like effect, which may be related to the lower ROS production.

Topics: Animals; Antidepressive Agents; Behavior, Animal; Cholecalciferol; Corticosterone; Depression; Disease Models, Animal; Female; Hippocampus; Mice; Reactive Oxygen Species

Topics: Acetylcholinesterase; Animals; Behavior, Animal; Cholecalciferol; Choline O-Acetyltransferase; Cognitive Dysfunction; Diet, High-Fat; Dietary Supplements; Disease Models, Animal; Male; Memory, Episodic; Prefrontal Cortex; Rats; Rats, Wistar; Recognition, Psychology

Microglial cell activation is the earliest biomarker of the inflammatory processes that cause central nervous system (CNS) lesions in multiple sclerosis. We hypothesized that 1,25-dihydroxyvitamin D

Topics: 25-Hydroxyvitamin D3 1-alpha-Hydroxylase; Animals; B7-2 Antigen; Calcitriol; CD4-Positive T-Lymphocytes; Cholecalciferol; CTLA-4 Antigen; Disease Models, Animal; Encephalomyelitis, Autoimmune, Experimental; Female; Macrophages; Mice; Microglia; Multiple Sclerosis; Vitamin D Response Element

Vitamin D

Topics: Animals; Brain; Cholecalciferol; Cholesterol; Disease Models, Animal; gamma-Aminobutyric Acid; Glutamic Acid; Inflammation; Male; Membrane Fusion; Mice, Inbred C57BL; Nervous System Diseases; Neural Pathways; Phospholipids; Rats; Rats, Wistar; Reactive Oxygen Species; Receptors, Metabotropic Glutamate; Synapses; Vitamin D Deficiency; Vitamins

Polycystic ovarian syndrome (PCOS) is a disorder characterized by oligomenorrhea, anovulation, and hyperandrogenism. Altered mitochondrial biogenesis can result in hyperandrogenism. The goal of this study was to examine the effect of vitamin D3 on mitochondrial biogenesis of the granulosa cells in the PCOS-induced mouse model. Vitamin D3 applies its effect via the mitogen-activated pathway kinase-extracellular signal-regulated kinases (MAPK-ERK1/2) pathway. The PCOS mouse model was induced by the injection of dehydroepiandrosterone (DHEA). Isolated granulosa cells were subsequently treated with vitamin D3, MAPK activator, and MAPK inhibitor. Gene expression levels were measured using real-time polymerase chain reaction. MAPK proteins were investigated by western blot analysis. We also determined reactive oxygen species (ROS) levels with 2', 7'-dichlorofluorescein diacetate. Mitochondrial membrane potential (mtMP) was also measured by TMJC1. Mitochondrial biogenesis (peroxisome proliferator-activated receptor gamma coactivator 1-α and nuclear respiratory factor), antioxidant (superoxide dismutase, glutathione peroxidase, and catalase), and antiapoptotic (B-cell lymphoma-2) genes were upregulated in the PCOS mice that treated with vitamin D3 compared with the PCOS mice without any treatment. Vitamin D3 and MAPK activator-treated groups also reduced ROS levels compared with the nontreated PCOS group. In summary, vitamin D3 and MAPK activator increased the levels of mitochondrial biogenesis, MAPK pathway, and mtMP markers, while concomitantly decreased ROS levels in granulosa cells of the PCOS-induced mice. This study suggests that vitamin D3 may improve mitochondrial biogenesis through stimulation of the MAPK pathway in cultured granulosa cells of DHEA-induced PCOS mice which yet to be investigated.

Topics: Animals; Apoptosis; Catalase; Cholecalciferol; Dehydroepiandrosterone; Disease Models, Animal; Female; Glutathione Peroxidase; Granulosa Cells; Humans; MAP Kinase Signaling System; Mice; Nuclear Respiratory Factors; Organelle Biogenesis; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; Polycystic Ovary Syndrome; Reactive Oxygen Species; Superoxide Dismutase

Topics: Aging; Animals; Aorta; Cell Transdifferentiation; Cholecalciferol; Disease Models, Animal; Male; Mice; Muscle, Smooth, Vascular; Myocytes, Smooth Muscle; Nicotine; Osteogenesis; Peptide Hormones; Rats; Rats, Sprague-Dawley; Sirtuin 1; Up-Regulation; Vascular Calcification

Peripheral nerve injury (PNI) is a frequent problem among young adults. Hopefully, regeneration can occur in PNI unlike central nervous system. If nerve cut is complete, gold standard treatment is surgery, but incomplete cuts have been tried to be treated by medicines. The aim of the study was to evaluate and compare clinical and histopathological outcomes of independent treatment of each of Vitamin B12 (B12) and Vitamin D3 (D3) and their combination on sciatic nerve injury in an experimental rat model.. Experimental animal study was performed after the approval of BEH Ethics Committee No. 2015/10. 32 rats were grouped into four (n=8) according to treatment procedures, such as Group 1 (controls with no treatment), Group 2 (intraperitoneal 1 mg/kg/day B12), Group 3 (oral 3500 IU/kg/week D3), Group 4 (intraperitoneal 1 mg/kg/day B12+ oral 3500 IU/kg/week D3). Sciatic Functional Index (SFI) and histopathological analysis were performed.. SFIs of Group 2, 3, 4 were statistically significantly higher than controls. Group 2 and 3 were statistically not different, however Group 4 was statistically significantly higher than others according to SFI. Axonal degeneration (AD) in all treatment groups were statistically significantly lower than in Group 1. AD in Group 4 was significantly lower than in Group 2 and 3; there was no significant difference between Group 2 and 3. There was no significant difference between Group 1,2 and 3 in Axonolysis (A). But A of Group 4 was significantly very much lower than all others. Oedema- inflammation (OE-I) in all treatment groups were significantly lower than in Group 1; there was no significant difference between Group 2 and group 4. OE-I in Group 2 and 4 were significantly lower than in Group 3. There were no significant differences between Group 1, 2 and 3 in damage level scores; score of Group 4 was significantly lower than of Group 1.. B12 and D3 were found effective with no statistically significant difference. But combined use of B12 and D3 improve nerve healing synergistically. We recommend combined use of B12 and D3 after PNI as soon as possible.. A perifériás idegsérülés (PNI) gyakori probléma fiatal felnőttek körében. Reménykeltő, hogy a központi idegrendszeri sérülésekkel ellentétben, PNI esetén lehetséges a regeneráció. Teljes idegszakadás esetén sebészi kezelés az aranystandard, részleges PNI esetén gyógy­szeres kezeléssel is érdemes próbálkozni. A vizsgálat célja a B12- és a D3-vitaminnal, illetve kombinációjukkal történő kezelés klinikai és hisztopatológiai eredményének értékelése és összehasonlítása volt kísérleti állatmodell (patkány) csípőidegének sérülése esetén.. Az etikai engedély (No. 2015/10) megszerzése után 32 kísérleti állatot osztottunk be a protokoll szerinti négy csoportba: a kontrollként szolgáló 1. csoport nem részesült kezelésben, a 2. csoport B12-vitamin-kezelésben (1 mg/ttkg/nap intraperitoneali­san), a 3. csoport D3-vitamin-kezelésben (3500 NE/ttkg/hét orálisan), míg a 4. csoport kombinált B12- és D3-vitamin-kezelésben (B12: 1 mg/ttkg/nap intraperitonealisan, D3: 3500 NE/ttkg/hét orálisan) részesült. Mértük a csípő­ideg funkcionális index pontszámot (Sciatic Functional Index, SFI), illetve hisztopatológiai értékelést végeztünk.. Az 1. csoport SFI-értékével összehasonlítva a 2., 3. és 4. csoport SFI-pontszáma szignifikánsan magasabb volt. A 2. és 3. csoport SFI-értékei nem különböztek, a 4. csoporté ezekhez képest szignifikánsan magasabb volt. Az axondegeneráció (AD) mértéke valamennyi kezelt csoport esetében szignifikánsan alacsonyabb volt, mint az 1. csoportnál. A 4. csoport AD-értéke szignifikánsan ala­csonyabb volt, mint a 2. és 3. csoporté. A 2. és 3. csoport AD-értékei nem különböztek. Az axonolysis (A) mértékében az 1., 2. és 3. csoport esetében nem volt szignifikáns kü­lönbség; velük összehasonlítva, a 4. csoport esetében szignifikánsan alacsonyabb volt az axonolysis. Valamennyi kezelt csoport esetében szignifikánsan alacsonyabb volt az oedema-gyulladás (OE-I) mértéke, mint az 1. csoportnál. A 2. és a 4. csoport között az OE-I nem különbözött szignifikánsan, a 2. és 4. csoport OE-I-értékei szignifikánsan alacsonyabbak voltak, mint a 3. csoporté. A sérülés mérté­két tekintve (damage level score) nem volt szignifikáns kü­lönb­ség az 1., 2. és 3. csoport között; a 4. csoport eseté­ben a sérülés mértéke szignifikánsan alacso­nyabb volt, mint az 1. csoport esetén.. A B12- és a D3-vitamin hatása között nem találtunk szignifikáns különbséget. A B12- és a D3-vitamin ideggyógyulást elősegítő hatása együttes alkal­mazás esetén szinergikusan érvényesül, ezért PNI után minél előbbi kombinált alkalmazásukat javasoljuk.

Topics: Animals; Cholecalciferol; Disease Models, Animal; Humans; Neuroprotective Agents; Peripheral Nerve Injuries; Rats; Sciatic Nerve; Vitamin B 12; Young Adult

Cardiovascular disease is the primary cause of mortality in patients with chronic kidney disease. Vascular calcification (VC) in the medial layer of the vessel wall is a unique and prominent feature in patients with advanced chronic kidney disease and is now recognized as an important predictor and independent risk factor for cardiovascular and all-cause mortality in these patients. VC in chronic kidney disease is triggered by the transformation of vascular smooth muscle cells (VSMCs) into osteoblasts as a consequence of elevated circulating inorganic phosphate (P. Using primary mouse and human VSMCs, we found that TDAG51 is induced in VSMCs by P. Our studies highlight TDAG51 as an important mediator of P

Topics: Aged; Animals; Cell Transdifferentiation; Cells, Cultured; Cholecalciferol; Core Binding Factor Alpha 1 Subunit; Disease Models, Animal; Female; Gene Expression Regulation; Humans; Hyperphosphatemia; Male; Mice, Inbred C57BL; Mice, Knockout; Muscle, Smooth, Vascular; Myocytes, Smooth Muscle; Osteogenesis; Phosphates; Signal Transduction; Sodium-Phosphate Cotransporter Proteins, Type III; Transcription Factors; Vascular Calcification

Allergen specific immunotherapy (AIT) can provide long-term alleviation of symptoms for allergic disease but is hampered by suboptimal efficiency. We and others have previously shown that 1,25(OH)2-VitaminD3 (VitD3) can improve therapeutic efficacy of AIT. However, it is unknown whether VitD3 supplementation has similar effects in sublingual and subcutaneous immunotherapy. Therefore, we aimed to test VitD3 supplementation in both grass pollen (GP) subcutaneous-IT (SCIT) and sublingual-IT (SLIT) in a mouse model for allergic airway inflammation. To this end, GP-sensitized BALB/c mice received GP-SCIT or GP-SLIT with or without 10 ng VitD3, followed by intranasal GP challenges and measurement of airway hyperresponsiveness (AHR) and inflammation. VitD3 supplementation of GP-SCIT resulted in enhanced induction of GP-specific (sp)-IgG2a and suppression of spIgE after challenge. In addition, eosinophil numbers were reduced and levels of IL10 and Amphiregulin were increased in lung tissue. In GP-SLIT, VitD3 supplementation resulted in enhanced sp-IgG2a levels in serum, enhanced suppression of eosinophils and increased IL10 levels in lung tissue, as well as suppression of AHR to methacholine. These data show that VitD3 increases efficacy of both SCIT and SLIT, by enhancing induction of blocking antibodies and suppression of airway inflammation, underscoring the relevance of proficient VitD3 levels for successful AIT.

Topics: Administration, Sublingual; Allergens; Animals; Asthma; Calcitriol; Cholecalciferol; Desensitization, Immunologic; Disease Models, Animal; Eosinophils; Hypersensitivity; Hypodermoclysis; Lung; Male; Mice; Mice, Inbred BALB C; Poaceae; Pollen; Respiratory Hypersensitivity

Alzheimer's disease (AD) is the most common neurodegenerative disease across the world. The major cause of AD is extensive oxidative stress and inflammation in central nervous system (CNS). Vitamin D

Topics: Alzheimer Disease; Animals; Behavior, Animal; Cholecalciferol; Disease Models, Animal; Male; Neurons; Oxidative Stress; Rats, Wistar; Vitamin E

Type 2 diabetes is clinically associated with progressive necroinflammation and fibrosis in nonalcoholic steatohepatitis (NASH). Advanced glycation end-products (AGEs) accumulate during prolonged hyperglycemia, but the mechanistic pathways that lead to accelerated liver fibrosis have not been well defined. In this study, we show that the AGEs clearance receptor AGER1 was downregulated in patients with NASH and diabetes and in our NASH models, whereas the proinflammatory receptor RAGE was induced. These findings were associated with necroinflammatory, fibrogenic, and pro-oxidant activity via the NADPH oxidase 4. Inhibition of AGEs or RAGE deletion in hepatocytes in vivo reversed these effects. We demonstrate that dysregulation of NRF2 by neddylation of cullin 3 was linked to AGER1 downregulation and that induction of NRF2 using an adeno-associated virus-mediated approach in hepatocytes in vivo reversed AGER1 downregulation, lowered the level of AGEs, and improved proinflammatory and fibrogenic responses in mice on a high AGEs diet. In patients with NASH and diabetes or insulin resistance, low AGER1 levels were associated with hepatocyte ballooning degeneration and ductular reaction. Collectively, prolonged exposure to AGEs in the liver promotes an AGER1/RAGE imbalance and consequent redox, inflammatory, and fibrogenic activity in NASH.

Topics: Animals; Ascorbic Acid; Cholecalciferol; Dehydroepiandrosterone; Diabetes Mellitus, Type 2; Disease Models, Animal; Down-Regulation; Hepatocytes; Liver Cirrhosis; Mice; Mice, Knockout; NF-E2-Related Factor 2; Nicotinic Acids; Non-alcoholic Fatty Liver Disease; Plant Extracts; Receptor for Advanced Glycation End Products

Medial artery calcification (MAC) significantly contributes to the increased cardiovascular death in patients with chronic kidney disease (CKD). Previous genome-wide association studies have shown that various genetic variants of the histone deacetylase Hdac9 are associated with cardiovascular disease, but the role of Hdac9 in MAC under CKD conditions remains unclear.. High phosphate-induced vascular smooth muscle cell (VSMC) calcification and MAC in mice administered with vitamin D3 (vD) were used in the present study. Alizarin red staining, calcium quantitative assay, qPCR, western blotting and histology were performed.. Hdac9 expression was significantly down-regulated during high phosphate-induced vascular smooth muscle cell (VSMC) calcification and MAC in mice administered with vitamin D. These data suggest that Hdac9 is a novel inhibitor of MAC and may represent a potential therapeutic target for MAC in CKD patients.

Topics: Animals; Cells, Cultured; Cholecalciferol; Disease Models, Animal; Down-Regulation; Histone Deacetylases; Male; Mice, Inbred C57BL; Muscle, Smooth, Vascular; Myocytes, Smooth Muscle; Phosphorylation; Proto-Oncogene Proteins c-akt; Repressor Proteins; Signal Transduction; Sp7 Transcription Factor; Vascular Calcification

Cerebral cavernous malformations (CCMs) are ectatic capillary-venous malformations that develop in approximately 0.5% of the population. Patients with CCMs may develop headaches, focal neurologic deficits, seizures, and hemorrhages. While symptomatic CCMs, depending upon the anatomic location, can be surgically removed, there is currently no pharmaceutical therapy to treat CCMs. Several mouse models have been developed to better understand CCM pathogenesis and test therapeutics. The most common mouse models induce a large CCM burden that is anatomically restricted to the cerebellum and contributes to lethality in the early days of life. These inducible models thus have a relatively short period for drug administration. We developed an inducible CCM3 mouse model that develops CCMs after weaning and provides a longer period for potential therapeutic intervention. Using this new model, three recently proposed CCM therapies, fasudil, tempol, vitamin D

Topics: 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; Acute Disease; Animals; Apoptosis Regulatory Proteins; Brain; Cholecalciferol; Chronic Disease; Cyclic N-Oxides; Disease Models, Animal; Gene Deletion; Hemangioma, Cavernous, Central Nervous System; Hemorrhage; Lipopolysaccharides; Mice, Inbred C57BL; Models, Biological; Phenotype; Spin Labels

Topics: Animals; Anti-Inflammatory Agents; Antioxidants; Aorta; Aortic Diseases; Atherosclerosis; Cholecalciferol; Disease Models, Animal; Fat Emulsions, Intravenous; Flavonoids; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Lamiaceae; Lipids; Male; NF-kappa B; Oxidative Stress; Plant Extracts; Plaque, Atherosclerotic; Proto-Oncogene Proteins c-akt; Rats, Sprague-Dawley; Signal Transduction; Simvastatin; Vascular Endothelial Growth Factor A

Vitamin D deficiency has been associated with human abdominal aortic aneurysm (AAA); however, its role in AAA pathogenesis is unclear. The aim of the present study was to investigate the effect of vitamin D deficiency on AAA development and examine if administering cholecalciferol (CCF) could limit growth of established AAA within the angiotensin-II (AngII) infused apolipoprotein E-deficient mouse model. Mice were rendered vitamin D deficiency through dietary restriction and during AngII infusion developed larger AAAs as assessed by ultrasound and ex vivo morphometry that ruptured more commonly (48% vs. 19%; P=0.028) than controls. Vitamin D deficiency was associated with increased aortic expression of osteopontin and matrix metalloproteinase-2 and -9 than controls. CCF administration to mice with established aortic aneurysms limited AAA growth as assessed by ultrasound (P<0.001) and ex vivo morphometry (P=0.036) and reduced rupture rate (8% vs. 46%; P=0.031). This effect was associated with up-regulation of circulating and aortic sclerostin. Incubation of human aortic smooth muscle cells with 1,25-dihyroxyvitamin D3 (the active metabolite of vitamin D) for 48 h induced up-regulation of sclerostin (P<0.001) and changed the expression of a range of other genes important in extracellular matrix remodeling. The present study suggests that vitamin D deficiency promotes development of large rupture-prone aortic aneurysms in an experimental model. CCF administration limited both growth and rupture of established aneurysms. These effects of vitamin D appeared to be mediated via changes in genes involved in extracellular matrix remodeling, particularly sclerostin.

Topics: Adaptor Proteins, Signal Transducing; Angiotensin II; Animals; Aorta, Abdominal; Aortic Aneurysm, Abdominal; Aortic Rupture; Apolipoproteins E; Blood Pressure; Caloric Restriction; Cholecalciferol; Dietary Supplements; Disease Models, Animal; Disease Progression; Gene Expression Regulation; Humans; Mice, Inbred C57BL; Mice, Knockout; Muscle, Smooth, Vascular; Myocytes, Smooth Muscle; Up-Regulation; Vitamin D Deficiency

BACKGROUND Rifaximin is an antimicrobial agent used to treat inflammatory bowel disease (IBD). Vitamin D3 can control IBD due to its effects on inflammatory cytokines. The purpose of this study was to assess the effect of vitamin D3 on the intestinal flora of a dextran sulfate sodium (DSS)-induced mouse model treated with rifaximin. MATERIAL AND METHODS The mouse model of IBD was developed using DSS (4%) administered via the drinking water. Twenty-four male C57BL6 mice were divided into the control group with a normal diet (N=6), the DSS group with a normal diet (N=6), the DSS group with a normal diet treated with rifaximin (N=6), and the DSS group with a normal diet treated with rifaximin and vitamin D3 (N=6). After 14 days, the colonic tissue was studied histologically. Serum levels of tumor necrosis factor-alpha (TNF-alpha) and interleukin-1ß (IL-1ß) and enzyme-linked immunosorbent assay (ELISA) were used to measure the level of IL-6 and P65, and phospho-p65 was measured by western blot. 16S rRNA gene sequencing was used to analyze fecal samples. RESULTS In the DSS mouse model of IBD, rifaximin reduced the inflammation severity of the colon and reduced the expression of phospho-p65, p65, TNF-alpha, and IL-6. In the DSS+rifaximin+vitamin D3 group, the therapeutic influences of rifaximin, in terms of weight loss and colonic disease activity, were significantly reduced, and the gut microbiota of the mice were completely changed in composition and diversity. CONCLUSIONS In a mouse model of IBD, treatment with vitamin D3 significantly increased the metabolism of rifaximin and reduced its therapeutic effects.

Topics: Animals; Cholecalciferol; Colon; Cytokines; Dextran Sulfate; Disease Models, Animal; Gastrointestinal Microbiome; Inflammation; Inflammatory Bowel Diseases; Male; Mice, Inbred C57BL; Phylogeny; Rifaximin

Topics: Allergens; Animals; Asthma; Bronchoalveolar Lavage Fluid; Cholecalciferol; Cytokines; Desensitization, Immunologic; Disease Models, Animal; Eosinophils; Female; Hypersensitivity; Immunoglobulin E; Immunoglobulin G; Inflammation; Lung; Mice; Mice, Inbred BALB C; Poaceae; Pollen; Respiratory Hypersensitivity

Epidemiological outburst of type 2 diabetes is of great global concern. T2D starts with Insulin Resistance (IR) which arises largely due to environmental factors and to a lesser extent due to genetic factor. IR gradually develops into T2D and encompasses a wide array of conditions including Impaired Glucose Tolerance (IGT), hyperinsulinemia, Impaired Fasting Glucose (IFG), and Impaired Insulin Release (IIR). Initiation of IR increases the risk of Cardiovascular Diseases (CVD). Therefore, early diagnosis and management of IR and its related outcomes (hyperinsulinemia, hyperglycemia, and dyslipidemia) should be the prime focus of intervention therapies. Present research aimed to evaluate the synergistic combination of Magnesium orotate (MOD), Menaquinone- 7 (MK-7), and Cholecalciferol (CHOL) for the management of these therapeutic targets in the Streptozotocin-Nicotinamide-induced T2D Wistar rat model. Synergistic combination was found to be superior over its individual components in management of hyperglycemia, impaired insulin secretion, Homeostatic Model Assessment of Insulin Resistance (HOMA-IR), and dyslipidemia (p < 0.01 or p < 0.05). Its effect was found to be equivalent or better than reference drugs (p < 0.01 or p < 0.05). Histopathological analysis depicted that combination treatment was able to regenerate and preserve pancreatic β-cell mass in diabetic rats. In conclusion, combination studied in present research can be evaluated further under clinical settings for management of IR and its related outcomes.

Topics: Animals; Cholecalciferol; Diabetes Mellitus, Experimental; Disease Models, Animal; Dyslipidemias; Hypoglycemic Agents; Male; Niacinamide; Orotic Acid; Rats; Rats, Wistar; Streptozocin; Vitamin K 2

Vitamin D and sunlight have each been reported to protect against the development of experimental autoimmune encephalomyelitis (EAE), a mouse model of multiple sclerosis (MS). To date, the contribution of each has been unclear as ultra violet (UV) exposure also causes the generation of vitamin D in the skin. To examine whether the UV based suppression of EAE results, at least, in part from the production of vitamin D, we studied the effect of UV light on EAE in mice unable to produce 7-dehydroxycholesterol (7-DHC), the required precursor of vitamin D. Furthermore, we examined UV suppression of EAE in mice devoid of the vitamin D receptor (VDR). Our results demonstrate that UV light suppression of EAE occurs in the absence of vitamin D production and in the absence of VDR. Future investigations will focus on identifying the pathway responsible for the protective action of UV in EAE and presumably human MS.

Topics: Animals; Cholecalciferol; Disease Models, Animal; Encephalomyelitis, Autoimmune, Experimental; Female; Humans; Male; Mice; Mice, Inbred C57BL; Multiple Sclerosis; Phototherapy; Receptors, Calcitriol; Skin; Ultraviolet Rays; Vitamin D

Vitamin D (VitD) hypovitaminosis and androgen excess (AE) are both risk factors for cardiovascular diseases in fertile women. However, the possible early interaction between AE and VitD status is not clear. Our goal was to describe how VitD status influences early changes in the biomechanical reactivity of small coronary arterioles in adult female rats after transdermal testosterone treatment. Forty-six adolescent, 90-110-gram-weighed female Wistar rats were randomly grouped into 4 groups. Twenty-four animals received an optimal VitD-supplemented diet, from which 12 animals underwent transdermal testosterone treatment. Twenty-two animals received a VitD-deficient diet, from which 11 were treated with testosterone. At 8 weeks of treatment, invasive arterial blood pressure was registered after in vivo cannulation of carotid artery. Arteriolar end and side branches (200 μm diameter) of the left anterior descendent coronary artery (LAD) were obtained and examined with pressure arteriography in vitro. Similar segments were removed for histological examination. The inner and outer radii of the arterioles were measured using video-microscopy. Normal myogenic tone, maximal passive vasorelaxation and vasoconstriction of the arterioles were measured and statistically analyzed. The vessels' maximal smooth muscle relaxant potential, thromboxane-induced contraction capacity and normal myogenic tone were significantly influenced by actual VitD status. A lower relaxation capacity and increased wall thickness were observed in VitD-deficient groups, which could cause rigidity of the coronary arterioles and elevate cardiovascular risk. Supplementation of VitD could improve myogenic tone and relaxation and hold cardiovascular benefits.

Topics: Animals; Arterioles; Biomechanical Phenomena; Cholecalciferol; Coronary Vessels; Disease Models, Animal; Elastic Modulus; Elastic Tissue; Female; Hyperandrogenism; Rats, Wistar; Vascular Remodeling; Vascular Stiffness; Vasoconstriction; Vasoconstrictor Agents; Vasodilation; Vasodilator Agents; Vitamin D Deficiency

Vascular calcification, a marker of increased cardiovascular risk, is an active process orchestrated by smooth muscle cells. Observational studies indicate that omega-3 fatty acids protect against vascular calcification, but the mechanisms are unknown. The G-protein coupled receptor ChemR23 transduces the resolution of inflammation induced by the omega-3-derived lipid mediator resolvin E1. ChemR23 also contributes to osteoblastic differentiation of stem cells and bone formation, but its role in vascular calcification is unknown. The aim of this study was to establish the role of ChemR23 in smooth muscle cell fate and calcification.. Gene expression analysis in epigastric arteries derived from patients with chronic kidney disease and vascular calcification revealed that ChemR23 mRNA levels predicted a synthetic smooth muscle cell phenotype. Genetic deletion of ChemR23 in mice prevented smooth muscle cell de-differentiation. ChemR23-deficient smooth muscle cells maintained a non-synthetic phenotype and exhibited resistance to phosphate-induced calcification. Moreover, ChemR23-deficient mice were protected against vitamin D3-induced vascular calcification. Resolvin E1 inhibited smooth muscle cell calcification through ChemR23. Introduction of the Caenorhabditis elegans Fat1 transgene, leading to an endogenous omega-3 fatty acid synthesis and hence increased substrate for resolvin E1 formation, significantly diminished the differences in phosphate-induced calcification between ChemR23+/+ and ChemR23-/- mice.. This study identifies ChemR23 as a previously unrecognized determinant of synthetic and osteoblastic smooth muscle cell phenotype, favouring phosphate-induced vascular calcification. This effect may be of particular importance in the absence of ChemR23 ligands, such as resolvin E1, which acts as a calcification inhibitor under hyperphosphatic conditions.

Topics: Adaptation, Physiological; Adult; Aged; Animals; Cadherins; Cholecalciferol; Disease Models, Animal; Eicosapentaenoic Acid; Female; HEK293 Cells; Humans; Male; Mice, Inbred C57BL; Mice, Knockout; Middle Aged; Muscle, Smooth, Vascular; Myocytes, Smooth Muscle; Osteogenesis; Phosphates; Rats; Receptors, Chemokine; Signal Transduction; Vascular Calcification

Bisphosphonates like risedronate inhibit osteoclast-mediated bone resorption and are therefore used in the prevention and treatment of osteoporosis. Also vitamin D

Topics: Animals; Bone Density; Bone Density Conservation Agents; Cholecalciferol; Disease Models, Animal; Female; Humans; Mice; Osteoporosis, Postmenopausal; Risedronic Acid; Vitamins

Topics: Animals; Calcitriol; Cholecalciferol; Disease Models, Animal; Insulin Resistance; Mice; Obesity; Vascular Calcification; Vascular Remodeling; Vitamin D

The use of animal models of aortic stenosis (AS) remains essential to further elucidate its pathophysiology and to evaluate new therapeutic strategies. The waved-2 mouse AS model has been proposed; data have indicated that while aortic regurgitation (AR) is effectively induced, development of AS is rare. We aimed to evaluate the effect of high-fat diet (HFD) and vitamin D. HFD and subcutaneous vitamin D. Total cholesterol and 1,25(OH). These results suggest that HFD and vitamin D

Topics: Animals; Aortic Valve Stenosis; Cholecalciferol; Cholesterol; Diet, High-Fat; Dietary Supplements; Disease Models, Animal; ErbB Receptors; Female; Humans; Male; Mice

Vitamin D. To test effects of VitD supplementation on the response to cisplatin we analyzed patient serum VitD levels and correlated that with survival. In vivo, VitD deficient mice were treated with cisplatin, with or without pretreatment with the active VitD metabolite, 1,25 dihydroxyvitamin D. In this study, we determined that low serum 25 hydroxyvitamin D. Our data suggest that VitD deficiency could be a biomarker for poor response to cisplatin, and pretreating with VitD can increase the apoptotic response to cisplatin through VDR and TAp73 signaling crosstalk.

Topics: Animals; Apoptosis; Cell Line, Tumor; Cholecalciferol; Cisplatin; Disease Models, Animal; Drug Synergism; Female; Gene Expression; Humans; Immunohistochemistry; Mice; Models, Biological; Prognosis; Receptors, Calcitriol; Signal Transduction; Tumor Protein p73; Urinary Bladder Neoplasms; Vitamin D Deficiency; Xenograft Model Antitumor Assays

Duchenne muscular dystrophy (DMD) is caused by a lack of dystrophin protein. Next to direct effects on the muscles, this has also metabolic consequences. The influence of nutrition on disease progression becomes more and more recognized. Protein intake by DMD patients may be insufficient to meet the increased demand of the constantly regenerating muscle fibers. This led to the hypothesis that improving protein uptake by the muscles could have therapeutic effects. The present study examined the effects of a modified diet, which composition might stimulate muscle growth, on disease pathology in the D2-mdx mouse model. D2-mdx males were fed with either a control diet or modified diet, containing high amounts of branched-chain amino acids, vitamin D3 and ursolic acid, for six weeks. Our study indicates that the modified diet could not ameliorate the muscle pathology. No effects on bodyweight or weight of individual muscles were observed. Neither did the diet affect severity of fibrosis or calcification of the muscles.

Topics: Amino Acids, Branched-Chain; Animals; Calcinosis; Cholecalciferol; Dietary Proteins; Disease Models, Animal; Dystrophin; Fibrosis; Humans; Male; Mice; Mice, Inbred DBA; Mice, Inbred mdx; Muscle, Skeletal; Muscular Dystrophy, Duchenne; Regeneration; Triterpenes; Ursolic Acid

Vitamin D

Topics: Animals; Bacterial Load; Cells, Cultured; Cholecalciferol; Cytokines; Dietary Supplements; Disease Models, Animal; Ethanol; Female; Host-Pathogen Interactions; Macrophages; Mice, Inbred C57BL; Mycobacterium bovis; Tuberculosis; Vitamin D Deficiency

Sporadic colon cancer accounts for approximately 80% of colorectal cancer (CRC) with high incidence in Western societies strongly linked to long-term dietary patterns. A unique mouse model for sporadic CRC results from feeding a purified rodent Western-style diet (NWD1) recapitulating intake for the mouse of common nutrient risk factors each at its level consumed in higher risk Western populations. This causes sporadic large and small intestinal tumors in wild-type mice at an incidence and frequency similar to that in humans. NWD1 perturbs intestinal cell maturation and Wnt signaling throughout villi and colonic crypts and decreases mouse Lgr5hi intestinal stem cell contribution to homeostasis and tumor development. Here we establish that NWD1 transcriptionally reprograms Lgr5hi cells, and that nutrients are interactive in reprogramming. Furthermore, the DNA mismatch repair pathway is elevated in Lgr5hi cells by lower vitamin D3 and/or calcium in NWD1, paralleled by reduced accumulation of relevant somatic mutations detected by single-cell exome sequencing. In compensation, NWD1 also reprograms Bmi1+ cells to function and persist as stem-like cells in mucosal homeostasis and tumor development. The data establish the key role of the nutrient environment in defining the contribution of two different stem cell populations to both mucosal homeostasis and tumorigenesis. This raises important questions regarding impact of variable human diets on which and how stem cell populations function in the human mucosa and give rise to tumors. Moreover, major differences reported in turnover of human and mouse crypt base stem cells may be linked to their very different nutrient exposures.

Topics: Animals; Calcium; Carcinogenesis; Cell Differentiation; Cell Proliferation; Cholecalciferol; Colonic Neoplasms; Diet, Western; Disease Models, Animal; Homeostasis; Humans; Intestinal Mucosa; Intestines; Mice; Nutrition Assessment; Receptors, G-Protein-Coupled; Signal Transduction; Stem Cells; Wnt Signaling Pathway

Renal dysfunction has been reported in individuals with Down syndrome (DS); however, the causes and mechanisms involved remain unknown. Here, we present a proposal for how the triplication of the amyloid beta precursor protein (APP) and, mainly the amyloid β peptide 1-42 (Aβ. Twenty female mice (14-week-old) belonging to the B6EiC3Sn-Rb(12.Ts171665Dn)2Cje/CjeDnJ lineage were divided into four experimental groups (n = 5/group): common diet; trisomy (Ts) and wild-type (Wt); and high doses VD. Our results showed that VD. Finally, the results showed that VD

Topics: Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Animals; ATP Binding Cassette Transporter, Subfamily B, Member 1; Caspase 3; Cholecalciferol; Dietary Supplements; Disease Models, Animal; Down Syndrome; Female; Kidney; Methylenetetrahydrofolate Reductase (NADPH2); Mice; Mice, Inbred BALB C; Peptide Fragments

Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by intracellular neurofibrillary tangles and extracellular Aβ deposition. Growing experimental evidence indicate diverse biological effects of vitamin D

Topics: Alzheimer Disease; Animals; Antioxidants; Behavior, Animal; Cholecalciferol; Cognition; Cognition Disorders; Disease Models, Animal; Hippocampus; Inflammation; Male; Neuroprotective Agents; Oxidative Stress; Rats; Rats, Wistar; Streptozocin

The mixture of Hongqu and gypenosides (HG) is composed of Fermentum Rubrum (Hongqu, in Chinese) and total saponins of Gynostemma pentaphyllum (Thunb.) Makino (Jiaogulan, in Chinese) in a 3.6:1 weight ratio. Both Hongqu and Jiaogulan are considered valuable traditional Chinese medicines (TCMs); they have been commonly used in China for the treatment of hyperlipidemia and related diseases for centuries. The aim of the current study was assess the anti-atherosclerotic effect of HG.. Sixty-four Wistar rats were randomly divided into eight groups: normal, model, positive control (simvastatin, 1 mg/kg), Hongqu-treated (72 mg/kg), gypenoside (total saponin)-treated (20 mg/kg), and three doses HG-treated (50, 100, and 200 mg/kg). All of the rats were fed a basal diet. Additionally, the model group rats were intragastrically administered a high-fat emulsion and intraperitoneally injected with vitamin D. The AS rat model was established after 80 days. Compared to the model group, the HG-treated groups showed an obvious improvement in the serum lipid profiles, oxidative stress, and inflammatory cytokine levels, and showed markedly increased hepatic total antioxidant capacity. Moreover, the expression of genes related to lipid synthesis and inflammation reduced and that of the genes related to lipid oxidation increased in the liver and arterial tissue, which also reflected an improved health condition.. the anti-atherosclerotic effects of HG were superior to those of simvastatin, Hongqu, and the gypenosides. Therefore, HG may be a useful anti-atherosclerotic TCM preparation.

Topics: Animals; Atherosclerosis; Cholecalciferol; Diet, High-Fat; Disease Models, Animal; Emulsions; Gynostemma; Lipids; Liver; Male; Medicine, Chinese Traditional; Monascus; Plant Extracts; Rats; Rats, Wistar

Arterial calcification is a common feature of cardiovascular disease. Sortilin is involved in the development of atherosclerosis, but the specific mechanism is unclear. In this study, we established calcification models in vivo and in vitro by using vitamin D

Topics: Adaptor Proteins, Vesicular Transport; Animals; Atherosclerosis; Calcinosis; Cell Line; Cholecalciferol; Disease Models, Animal; Gene Expression Regulation; Glycerophosphates; Humans; MicroRNAs; Muscle, Smooth, Vascular; Rats; Transfection; Vascular Calcification

Vascular calcification (VC) underlies substantial cardiovascular morbidity and mortality. No clinically therapies have emerged presently. Stellate ganglion block (SGB) is one of the most often used sympathetic blockade procedure, and regulates vascular dilation. However, the effect of SGB on VC is still unknown. Therefore, we aimed to identify the ameliorative effect of SGB on VC.. In vivo VC was induced in rats by administering vitamin D3 plus nicotine (VDN), and in vitro calcification of rat aortic vascular smooth muscle cells (VSMC) was induced by β-glycerophosphate. In VDN rats, alkaline phosphatase (ALP) activity and Calcium contents were higher than that in control rats. The transformation of VSMC from contractile to osteoblast-like phenotype was observed in calcified aorta. SGB ameliorated the increase of ALP activity and Calcium content, and the transformation of VSMC in calcified aorta. The stimulation of endoplasmic reticulum stress (ERS) in calcified aorta was also attenuated by SGB treatment. The inducer of ERS, tunicamycin could block the beneficial effect of SGB on VC, and the ERS inhibitor, 4-PBA could mimic the amelioration of SGB. Furthermore, SGB attenuated the increased plasma levels of norepinephrine in VDN rats. In vitro experiments, norepinephrine exaggerated VSMC calcification, phenotype transformation and ERS.. These results demonstrate that SGB could inhibit sympathetic nervous activity, and then prevent the activation of ERS followed by ameliorating VC. Sympathetic over-activation might play critical role in the pathogenesis of VC, which provides new strategy and target for therapy and prevention of VC.

Topics: Animals; Aorta; Autonomic Nerve Block; Calcium; Cholecalciferol; Disease Models, Animal; Endoplasmic Reticulum; Endoplasmic Reticulum Stress; Glycerophosphates; Male; Muscle, Smooth, Vascular; Myocytes, Smooth Muscle; Nicotine; Nordefrin; Rats; Rats, Sprague-Dawley; Signal Transduction; Stellate Ganglion; Vascular Calcification

Atherosclerosis is a chronic inflammatory disease arising from an imbalance in lipid levels and the accumulation of cholesterol-laden macrophages in the artery wall. Crocin is an active ingredient of Crocus sativus L. This study established a rat coronary atherosclerosis model induced by vitamin D3 (VD3), to explore the effect of Crocin on lipid metabolism, macrophage polarization and the activity of inflammatory proteins. The results revealed that Crocin decreased blood lipid levels by decreasing the levels of endothelin (ET), total cholesterol (TC), triglyceridelow (TG) and low-density lipoprotein cholesterol (LDL-c), elevating the level of high-density lipoprotein cholesterin (HDL-c). Crocin also inhibited lipogenesis by suppressing the expression of lipogenesis-related proteins and elevating lipid catabolism-related proteins. Moreover, Crocin effectively alleviated inflammation by suppressing the expression of pro-inflammatory cytokines and increasing levels of anti-inflammatory cytokines. We further found that Crocin promoted macrophage polarization to the M2 phenotype by reducing M1 markers (CD40

Topics: Animals; Carotenoids; Cell Differentiation; Cholecalciferol; Coronary Artery Disease; Crocus; Cytokines; Diet, High-Fat; Disease Models, Animal; Endothelins; Free Radical Scavengers; Humans; Lipid Metabolism; Lipogenesis; Macrophages; Male; NF-kappa B; Rats; Rats, Wistar; Th2 Cells

Cortistatin (CST) is a newly discovered endogenous active peptide that exerts protective effects on the cardiovascular system. However, the relationship between CST and aortic calcification and the underlying mechanism remain obscure. Therefore, we investigated effects of CST on aortic calcification and its signalling pathways.. Calcium content and alkaline phosphatase (ALP) activity were measured using the o-cresolphthalein colorimetric method and ALP assay kit respectively. Protein expression of smooth muscle (SM)-ɑ-actin, osteocalcin (OCN), β-catenin, glycogen synthase kinase 3β (GSK3β), p-GSK3β, protein kinase C (PKC), p-PKC, c-Jun N-terminal kinase (JNK) and p-JNK was determined using Western blotting.. In aorta from a rat vitamin D3 calcification model, CST abrogated calcium deposition and pathological damage, decreased the protein expression of OCN and β-catenin and increased SM-ɑ-actin expression. In a rat cultured vascular smooth muscular cell (VSMC) calcification model induced by β-glycerophosphate (β-GP), CST inhibited the increase in ALP activity, calcium content and OCN protein and the decrease in SM-α-actin expression. CST also inhibited the β-GP-induced increase in p-GSK3β and β-catenin protein (both P < .05). The inhibitory effects of CST on ALP activity, calcium deposition and β-catenin protein were abolished by pretreatment with lithium chloride, a GSK3β inhibitor. CST promoted the protein expression of p-PKC by 68.5% (P < .01), but not p-JNK. The ability of CST to attenuate β-GP-induced increase in ALP activity, calcium content and OCN expression in the VSMC model was abolished by pretreatment with the PKC inhibitor Go6976.. These results indicate that CST inhibits aortic calcification and osteogenic differentiation of VSMCs likely via the GSK3β/β-catenin and PKC signalling pathways, but not JNK signalling pathway.

Topics: Animals; beta Catenin; Cholecalciferol; Disease Models, Animal; Glycerophosphates; Glycogen Synthase Kinase 3 beta; Male; MAP Kinase Signaling System; Myocytes, Smooth Muscle; Neuropeptides; Osteogenesis; Primary Cell Culture; Protein Kinase C; Rats, Sprague-Dawley; Vascular Calcification

Vascular calcification and increased cardiovascular morbidity and mortality are closely related in patients with end-stage renal disease and diabetes mellitus. Specific protein 1 (Sp1) is a transactivation molecule that plays a crucial role in the regulation of apoptosis, fibrosis, angiogenesis, and other pathological disorders. There is evidence that specific protein 1 (Sp1) directly stimulates the transcription of bone morphogenetic protein 2 (BMP2) and that BMP2 plays a key role in the calcification process in the BMP2-expressing F9 cell model system. Here, we investigated whether Sp1 plays an important role in vascular calcification and its potential regulatory mechanism in vascular calcification.. In this study, vascular calcification was induced in male Wistar rats by administration of nicotine (25 mg/kg) and vitamin D3 (300 000 IU/kg). These rats were randomly selected for treatment with adenovirus harboring Sp1 knockdown gene or empty virus. The mechanism of Sp1 in vascular smooth muscle cells cultured in high phosphate medium was studied. Based on our findings, the Sp1 gene silencing or inhibition improved calcium deposition, which was partly achieved by inhibiting phenotype switch, apoptosis, and matrix vesicle release of vascular smooth muscle cells. Moreover, Sp1 can activate BMP2 transcription by binding to the Sp1-binding element of the BMP2 promoter.. Overall, elevated Sp1 exerts a pro-apoptotic effect, promoting BMP2 transcription and further accumulating vascular calcification. Proper and timely regulation of Sp1 expression may be a potential strategy for treatment of aging, end-stage renal disease, and diabetic-related macrovascular disease treatment.

Topics: Animals; Apoptosis; Binding Sites; Bone Morphogenetic Protein 2; Cell Transdifferentiation; Cholecalciferol; Disease Models, Animal; Humans; Male; Muscle, Smooth, Vascular; Myocytes, Smooth Muscle; Nicotine; Osteoblasts; Phenotype; Promoter Regions, Genetic; Rats, Wistar; Signal Transduction; Sp1 Transcription Factor; Transcriptional Activation; Vascular Calcification

There was evidence that 1,25(OH)

Topics: Actins; Animals; Aquaporin 2; Aquaporin 4; Calcitriol; Cholecalciferol; Cholesterol; Disease Models, Animal; Down-Regulation; Emulsions; Epithelial Cells; Fibronectins; Fibrosis; Kidney; Male; Mice, Inbred ICR; Necrosis; Plasminogen Activator Inhibitor 1; Receptors, Calcitriol; Signal Transduction; Tissue Culture Techniques; Transforming Growth Factor beta; Ureteral Obstruction

Poor corneal permeability, nasolacrimal drainage and requirement of chronic administration are major drawbacks of existing therapies for ocular inflammation. Hence, we designed topical micelles of PEG. Integrin targeted tacrolimus loaded PEGCCF micelles (TTM) were prepared by solvent diffusion evaporation method and characterized for particle size, osmolality, encapsulation efficiency and drug loading. Therapeutic potential of TTM was evaluated in benzalkonium chloride induced ocular inflammation model in BALB/c mice. Corneal flourescein staining and histopathological analysis of corneal sections was performed.. TTM had a particle size of 45.3 ± 5.3 nm, encapsulation efficiency (88.7 ± 0.9%w/w) and osmolality of 292-296 mOsmol/Kg. TTM significantly reduced the corneal fluorescence as compared to tacrolimus suspension (TACS). H&E staining showed that TTM could restore corneal epithelial thickness, reduce stromal edema (p < 0.05) and decrease number of inflammatory cells (p < 0.01) compared with TACS. Immunohistochemistry analysis demonstrated lower expression of Ki67 + ve cells (p < 0.05) and IL-6 throughout the cornea against TACS (p < 0.01) and the control (p < 0.001).. TTM is an innovative delivery system for improving ocular inflammation due to a) integrin targeting b) PEGCCF in the form of carrier and c) anti-inflammatory and synergistic effect (due to Pgp inhibition) with TAC.

Topics: Administration, Ophthalmic; Animals; Benzalkonium Compounds; Cholecalciferol; Disease Models, Animal; Drug Carriers; Drug Compounding; Eye; Eye Diseases; Female; Humans; Inflammation; Integrins; Mice; Mice, Inbred BALB C; Micelles; Polyethylene Glycols; Tacrolimus

Polycystic ovary syndrome (PCOS) is an endocrine and metabolic disorder in reproductive-aged women. Hormonal abnormality caused by steroidogenesis disturbances appears to be the main culprit of the clinical picture in PCOS. Vitamin D3 could regulate steroidogenesis in granulosa cells, but the mechanism of action of vitamin D3 on steroidogenesis remains unknown. AMP-activated protein kinase (AMPK) has a modulating role in steroid hormone production. We investigated the effect of vitamin D3 on steroidogenesis in cultured granulosa cells of dehydroepiandrosterone-induced PCOS mice and studied the involvement of AMPK signalling pathway in the current process. Immunoblotting assay showed that vitamin D3 could increase phosphorylation of AMPK alpha and acetyl-CoA carboxylase, main substrate of AMPK. Vitamin D3 and 5-aminoimidazole-4-carboxamide-1-β-D-riboside or Aicar (AMPK activator) not only reduced gene expression of steroidogenic enzymes (P450scc or Cyp11a1, StAR, Cyp19a1 and 3B-HSD), but also reduced production of progesterone and 17B-estradiol assessed by radioimmunoassay. Pretreatment with compound C (AMPK inhibitor) decreased APMK phosphorylation and eliminated the effects of vitamin D3 and Aicar on steroidogenic enzymes expression and estradiol and progesterone production. This study showed that vitamin D3 has the main role in regulating of steroidogenesis in granulosa cells of mouse polycystic ovary through activation of the AMPK signalling pathway.. Polycystic ovarian syndrome (PCOS) is an endocrine disorder of women in reproductive age. This disorder is partly related to disruption in steroidogenesis pathway and dysregulation of estradiol and progesterone production in granulosa cells of polycystic ovaries. Previously, we have shown that vitamin D3 could modulate steroidogenesis pathway in PCOS granulosa cells. In this study, we investigate the molecular mechanism of vitamin D3 in regulation of steroidogenesis pathway. We have shown that vitamin D3 has a modulating role in steroidogenesis pathway of granulosa cells by regulation of AMP-activated protein kinase (AMPK) as an underlying molecular mechanism in mouse polycystic ovary.

Topics: AMP-Activated Protein Kinases; Animals; Cells, Cultured; Cholecalciferol; Dehydroepiandrosterone; Disease Models, Animal; Dose-Response Relationship, Drug; Enzyme Activation; Female; Granulosa Cells; Mice; Mice, Inbred BALB C; Polycystic Ovary Syndrome; Steroids; Structure-Activity Relationship

End-stage renal disease is strongly associated with progressive cardiovascular calcification (CVC) and there is currently no therapy targeted to treat CVC. SNF472 is an experimental formulation under development for treatment of soft tissue calcification. We have investigated the pharmacokinetics of SNF472 administration in rats and its inhibitory effects on CVC. SNF472 was studied in three rat models: (1) prevention of vitamin D3-induced CVC with an intravenous SNF472 bolus of 1 mg/kg SNF472, (2) inhibition of progression of vitamin D3-induced CVC with a subcutaneous SNF472 bolus of 10 or 60 mg/kg SNF472, starting after calcification induction, (3) CVC in adenine-induced uremic rats treated with 50 mg/kg SNF472 via i.v. 4h -infusion. Uremic rats presented lower plasma levels of SNF472 than control animals after i.v. infusion. CVC in non-uremic rats was inhibited by 60-70% after treatment with SNF472 and progression of cardiac calcification completely blocked. Development of CVC in uremic rats was inhibited by up to 80% following i.v. infusion of SNF472. SNF472 inhibits the development and progression of CVC in uremic and non-uremic rats in the same range of SNF472 plasma levels but using in each case the required dose to obtain those levels. These results collectively support the development of SNF472 as a novel therapeutic option for treatment of CVC in humans.

Topics: Animals; Calcinosis; Cardiovascular Diseases; Cholecalciferol; Disease Models, Animal; Disease Progression; Humans; Inositol; Kidney Failure, Chronic; Rats; Renal Insufficiency, Chronic; Uremia

Decreased blood flow in the brain leads to a rapid increase in reactive oxygen species (ROS). NADPH oxidase (NOX) is an enzyme family that has the physiological function to produce ROS. NOX2 and NOX4 overexpression is associated with aggravated ischemic injury, while NOX2/4-deficient mice had reduced stroke size. Dysregulation of matrix metalloproteinases (MMPs) contributes to tissue damage. The active form of vitamin D3 expresses neuroprotective, immunomodulatory, and anti-inflammatory effects in the CNS. The present study examines the effects of the vitamin D3 pretreatment on the oxidative stress parameters and the expression of NOX subunits, MMP9, microglial marker Iba1, and vitamin D receptor (VDR), in the cortex and hippocampus of Mongolian gerbils subjected to ten minutes of global cerebral ischemia, followed by 24 hours of reperfusion. The ischemia/reperfusion procedure has induced oxidative stress, changes in the expression of NOX2 subunits and MMP9 in the brain, and increased MMP9 activity in the serum of experimental animals. Pretreatment with vitamin D3 was especially effective on NOX2 subunits, MMP9, and the level of malondialdehyde and superoxide anion. These results outline the significance of the NOX and MMP9 investigation in brain ischemia and the importance of adequate vitamin D supplementation in ameliorating the injury caused by I/R.

Topics: Animals; Brain Ischemia; Cholecalciferol; Disease Models, Animal; Gerbillinae; Male; Matrix Metalloproteinase 9; NADPH Oxidases

Depression is one of the most frequent neuropsychiatric diseases in the western world and its physiological causes are not yet fully understood. Since the available antidepressants failed to provide a complete illness remission, the diversification of the therapy in the management of depression could be a useful contribution. The present study aimed to investigate the cholecalciferol capability to revert depressive-like behavior induced by chronic corticosterone (CORT) treatment in mice and its implication on the oxidative stress modulation. Sixty minutes after having orally received different doses of cholecalciferol, adult male mice were evaluated in the forced swimming and tail suspension tests, whereas in the seven-day treatment they were only tested in tail suspension. Additionally, for 21 days, the animals received CORT (20 mg/kg, p.o.) and cholecalciferol or fluoxetine, once a day for the last 7-days of the CORT treatment. Moreover, the markers of oxidative stress, lipid peroxidation, protein carbonyl and nitrite levels were assessed in the plasma and brain's mice after the splash and tail suspension tests. It was observed that corticosterone treatment resulted in depressive-like behavior with established oxidative stress in mice, while cholecalciferol ameliorated both, behavioral (immobility time and grooming latency) and biochemical (protein carbonyl and nitrite levels) changes induced by CORT model, suggesting that cholecalciferol has antidepressant-like effect with the involvement of the oxidative stress modulation.

Topics: Animals; Antidepressive Agents; Behavior, Animal; Cholecalciferol; Corticosterone; Depression; Disease Models, Animal; Fluoxetine; Humans; Lipid Peroxidation; Male; Mice; Motor Activity; Oxidative Stress; Toxicity Tests, Acute; Toxicity Tests, Subchronic; Treatment Outcome; Vitamins

Reduced sunlight exposure has been associated with an increased incidence of Crohn's disease and ulcerative colitis. The effect of ultraviolet radiation (UVR) on the faecal microbiome and susceptibility to colitis has not been explored. C57Bl/6 female mice were fed three different vitamin D-containing diets for 24 days before half of the mice in each group were UV-irradiated (1 kJ/m²) for each of four days, followed by twice-weekly irradiation of shaved dorsal skin for 35 days. Faecal DNA was extracted and high-throughput sequencing of the 16S RNA gene performed. UV irradiation of skin was associated with a significant change in the beta-diversity of faeces compared to nonirradiated mice, independently of vitamin D. Specifically, members of phylum Firmicutes, including

Topics: Animal Feed; Animals; Bacteria; Cholecalciferol; Colitis; Cytokines; Dextran Sulfate; Disease Models, Animal; Feces; Female; Gastrointestinal Microbiome; Inflammation Mediators; Mice, Inbred C57BL; Skin; Ultraviolet Rays

The chronic use of ethanol causes neuropathy and atrophy of type II fibers and promotes vitamin D decrease. This study evaluated cholecalciferol effects on the deep fibular nerve and extensor digitorum longus (EDL) muscle using an UChB ethanol-preferring rats model. Blood analyses were carried out to measure levels of 25-hydroxycholecalciferol (25(OH)D), calcium (Ca

Topics: Alcoholism; Animals; Cholecalciferol; Dietary Supplements; Disease Models, Animal; Ethanol; Muscle Fibers, Skeletal; Oxidative Stress; Rats; Vitamin D

Polycystic ovarian syndrome (PCOS) is the most common endocrine disorder of women of reproductive age characterized by polycystic ovarian morphology, anovulation or oligomenorrhea, and hyperandrogenism. It is shown that disruption in the steroidogenesis pathway caused by excess androgen in PCOS is a critical element of abnormal folliculogenesis and failure in dominant follicle selection. Vitamin D plays an important role in the regulation of ovulatory dysfunction and can influence genes involved in steroidogenesis in granulosa cells. In the present study, we investigated the effects of vitamin D3 on steroidogenic enzyme expression and activities in granulosa cell using a PCOS mouse model. In our study, the PCOS mouse model was developed by the injection of dehydroepiandrosterone (DHEA) for 20 days. The mRNA and protein expression levels of genes involved in steroidogenesis in granulosa cells were compared between polycystic and normal ovaries using real-time PCR and Western blotting assays. Granulosa cells of DHEA-induced PCOS mice were then cultured with and without vitamin D3 and mRNA and protein expression levels of steroidogenic enzymes and serum 17beta-estradiol and progesterone levels were investigated using qRT-PCR, western blot, and radioimmunoassay, respectively. Steroidogenic enzymes including Cyp11a1, StAR, Cyp19a1, and 3β-HSD were upregulated in granulosa cells of PCOS mice when compared to normal mice. Treatment with vitamin D3 decreased mRNA and protein expression levels of steroidogenic enzymes in cultured granulosa cells. Vitamin D3 also decreased aromatase and 3β-HSD activity that leads to decreased 17beta-estradiol and progesterone release. This study suggests that vitamin D3 could modulate the steroidogenesis pathway in granulosa cells of PCOS mice that may lead to improving follicular development and maturation. This is a step towards a possible conceivable treatment for PCOS.. AMHR-II: anti-müllerian hormone receptor-II; 3β-HSD: 3β-hydroxysteroid dehydrogenase; Cyp11a1: Cytochrome P450 Family 11 Subfamily A Member 1; Cyp19a1: cytochrome P450 aromatase; DHEA: dehydroepiandrosterone; FSH: follicle stimulating hormone; FSHR: follicle stimulating hormone receptor; IVF: in vitro fertilization; 25OHD: 25-hydroxy vitamin D; OHSS: ovarian hyperstimulation syndrome; PCOS: polycystic ovarian syndrome; P450scc: P450 side-chain cleavage enzyme; StAR: steroidogenic acute regulatory protein; VDRs: vitamin D receptors.

Topics: Animals; Cholecalciferol; Disease Models, Animal; Drug Evaluation, Preclinical; Estrous Cycle; Female; Gonadal Steroid Hormones; Granulosa Cells; Mice, Inbred BALB C; Ovary; Polycystic Ovary Syndrome

This study aims to investigate the regulatory mechanism of 1,25-(OH)2D3 on the proliferation of fibroblast-like synoviocytes (FLS) and expressions of pro-inflammatory cytokines in rheumatoid arthritis (RA) rats via microRNA-22 (miR-22).. A rat model of RA was established with a subcutaneous injection of type II collagen. After treated with different concentrations of 1,25-(OH)2D3 the proliferation of FLS was estimated by the MTT method, and the optimal concentration of 1,25-(OH)2D3 was selected for further experiments. Cell proliferation was detected by MTT. Cell cycle and apoptosis were analyzed by FCM. The IL-1β, IL-6, IL-8, and PGE2 protein expressions were determined by ELISA, and MMP-3, INOS, and Cox-2 mRNA expressions were measured by qRT-PCR.. The rat model of RA was successfully established. Compared with the blank group, the 1,25-(OH)2D3 and miR-22 inhibitors groups exhibited higher proliferation inhibition and apoptosis rates, lower levels of pro-inflammatory cytokines (IL-1β, IL-6, IL-8, and PGE2), and decreased mRNA expressions of MMP-3, INOS, and Cox-2. The miR-22 mimics group had lower proliferation inhibition and apoptosis rates, elevated expressions of pro-inflammatory cytokines and MMP-3, INOS, and Cox-2 than the blank group. In contrast to the 1,25-(OH)2D3 group, the proliferation inhibition and apoptosis rates were down-regulated, and the expressions of pro-inflammatory cytokines and MMP-3, INOS, and Cox-2 were up-regulated in the 1,25-(OH)2D3 + miR-22 mimics group.. Our study demonstrated that 1,25-(OH)2D3 inhibits the proliferation of FLS and alleviates inflammatory response in RA rats by down-regulating miR-22.

Topics: Animals; Antagomirs; Apoptosis; Arthritis, Rheumatoid; Cell Proliferation; Cells, Cultured; Cholecalciferol; Cyclooxygenase 2; Cytokines; Dinoprostone; Disease Models, Animal; Down-Regulation; Fibroblasts; Male; Matrix Metalloproteinase 3; MicroRNAs; Nitric Oxide Synthase Type II; Rats; Rats, Sprague-Dawley; Synoviocytes

Vitamin D

Topics: Animals; Aorta; Aortic Diseases; Calcium; Cholecalciferol; Disease Models, Animal; Doxycycline; Gene Expression Profiling; Male; Oligonucleotide Array Sequence Analysis; Rats, Sprague-Dawley; Transcriptome; Vascular Calcification

Vitamin D can be one of the candidate substances that are used as additional supplementation in the treatment of anxiety-related disorders in women with estrogen imbalance.. The aim of the present study was to examine the effects of chronic cholecalciferol administration (1.0, 2.5 or 5.0 mg/kg/day, s.c.) on the anxiety-like behavior and monoamines levels in the rat hippocampus following ovariectomy in female rats. Cholecalciferol was given to ovariectomized (OVX) rats and OVX rats treated with 17β-estradiol (17β-E2, 0.5 μg/rat, s.c.). The anxiety-like behavior was assessed in the elevated plus maze (EPM) and the light-dark tests (LDT), locomotor and grooming activities were assessed in the open-field test (OFT).. Cholecalciferol in high doses alone or in combination with 17β-E2-induced anxiolytic-like effects in OVX and OVX rats treated with 17β-E2 as evidenced in the EPM and LDT tests, and increased grooming activity in the OFT test. We found that DA and 5-HT levels increased while 5-HT turnover in the hippocampus decreased in these groups of OVX rats.. Our results indicate that cholecalciferol in high doses has a marked anxiolytic-like effect due to an increase in the monoamines levels in the experimental rat model of estrogen deficiency.

Topics: Analysis of Variance; Animals; Anxiety; Behavior, Animal; Cholecalciferol; Deficiency Diseases; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Administration Schedule; Estradiol; Estrogens; Female; Ovariectomy; Random Allocation; Rats; Rats, Wistar; Reference Values; Treatment Outcome

Vitamin D3 is beneficial in ameliorating or preventing inflammation and carcinogenesis. Here, we evaluated if vitamin D3 has a preventive effect on colitis-associated carcinogenesis. Administration of azoxymethane (AOM), followed with dextran sulfate sodium (DSS), was used to simulate colitis-associated colon cancer in mice. The supplement of vitamin D3 at different dosages (15, 30, 60 IU·g·w), started before AOM or immediately after DSS treatment (post 60), was sustained to the end of the experiment. Dietary vitamin D3 significantly reduced the number of tumors and tumor burden in a dose-dependent manner. Of note, vitamin D3 in high doses showed significant preventive effects on carcinogenesis regardless of administration before or after AOM-DSS treatment. Cell proliferation decreased in vitamin D3 groups compared with the control group after inhibition of expression of β-catenin and its downstream target gene cyclin D1 in the colon. In vitro, vitamin D3 reduced the transcriptional activity and nuclear level of β-catenin, and it also increased E-cadherin expression and its binding affinity for β-catenin. Moreover, repression of E-cadherin was rescued by supplemental vitamin D3 in mouse colons. Taken together, our results indicate that vitamin D3 effectively suppressed colonic carcinogenesis in the AOM-DSS mouse model. Our findings further suggest that upregulation of E-cadherin contributes to the preventive effect of vitamin D3 on β-catenin activity.

Topics: Animals; Azoxymethane; beta Catenin; Cadherins; Carcinogenesis; Cell Proliferation; Cholecalciferol; Colitis; Colon; Colonic Neoplasms; Dextran Sulfate; Disease Models, Animal; Dose-Response Relationship, Drug; Male; Mice; Mice, Inbred C57BL; Up-Regulation; Vitamins

Despite long use of antiepileptic drugs, it remains a challenge to achieve seizure control while reducing adverse effects and preventing cognitive impairment. Several lines of evidence suggest a role of vitamin D in epilepsy. So this study aimed to investigate the effect of vitamin D on epileptogenesis, cognitive dysfunction and antiepileptic activity of lamotrigine, in a rat model of chemical kindling. Rats were kindled by pentylenetetrazole injections every other day over four weeks, together with daily oral treatment by either vehicle, vitamin D, lamotrigine or combination of vitamin D and lamotrigine. The non-treated kindled rats developed generalized seizures and had poor cognitive performance in water maze, associated with prooxidative status; elevated malondialdehyde and nitric oxide with lowered glutathione levels; in brain tissues. Treatment with either vitamin D, lamotrigine or both leads to significant reduction of seizure activity score, improvement of cognitive performance, and amelioration of the disturbed oxidative stress biomarkers. These findings indicate that, vitamin D has anti-epileptic, cognitive improving and antioxidant effects, on its own and enhance the effects of lamotrigine, in a chronic model of epileptic seizures. Thus, vitamin D supplementation may be a useful addition to antiepileptic drugs improving seizure control and cognitive function in patients with epilepsy.

Topics: Animals; Anticonvulsants; Antioxidants; Cholecalciferol; Chronic Disease; Cognition; Disease Models, Animal; Drug Therapy, Combination; Epilepsy; Glutathione; Kindling, Neurologic; Lamotrigine; Male; Malondialdehyde; Maze Learning; Nitric Oxide; Nootropic Agents; Oxidative Stress; Pentylenetetrazole; Random Allocation; Rats, Wistar; Triazines

Patients with chronic rhinosinusitis with nasal polyps (CRSwNP) have been shown to be vitamin D3 (VD3) deficient, which is associated with more severe disease and increased polyp size. To gain mechanistic insights into these observational studies, we examined the impact of VD3 deficiency on inflammation and VD3 metabolism in an Aspergillus fumigatus (Af) mouse model of chronic rhinosinusitis (Af-CRS).. Balb/c mice were fed control or VD3 deficient diet for 4 weeks. Mice were then sensitized with intraperitoneal Af, and one week later given Af intranasally every three days for four weeks while being maintained on control or VD3 deficient diet. Airway function, sinonasal immune cell infiltrate and sinonasal VD3 metabolism profiles were then examined.. Mice with VD3 deficiency had increased Penh and sRaw values as compared to controls as well as exacerbated changes in sRaw when coupled with Af-CRS. As compared to controls, VD3 deficient and Af-CRS mice had reduced sinonasal 1α-hydroxylase and the active VD3 metabolite, 1,25(OH)2D3. Differential analysis of nasal lavage samples showed that VD3 deficiency alone and in combination with Af-CRS profoundly upregulated eosinophil, neutrophil and lymphocyte numbers. VD3 deficiency exacerbated increases in monocyte-derived dendritic cell (DC) associated with Af-CRS. Conversely, T-regulatory cells were decreased in both Af-CRS mice and VD3 deficient mice, though coupling VD3 deficiency with Af-CRS did not exacerbate CD4 or T-regulatory cells numbers. Lastly, VD3 deficiency had a modifying or exacerbating impact on nasal lavage levels of IFN-γ, IL-6, IL-10 and TNF-α, but had no impact on IL-17A.. VD3 deficiency causes changes in sinonasal immunity, which in many ways mirrors the changes observed in Af-CRS mice, while selectively exacerbating inflammation. Furthermore, both VD3 deficiency and Af-CRS were associated with altered sinonasal VD3 metabolism causing reductions in local levels of the active VD3 metabolite, 1,25(OH)2D3, even with adequate circulating levels.

Topics: Animals; Aspergillus fumigatus; Blood Cell Count; Cholecalciferol; Diet; Dietary Supplements; Disease Models, Animal; Eosinophils; Humans; Inflammation; Lymphocytes; Mice; Nasal Lavage; Nasal Polyps; Neutrophils; Rhinitis; Sinusitis; T-Lymphocytes, Regulatory; Vitamin D Deficiency

Vitamin D (25(OH)D3) is an essential nutrient that plays a role in the immune system. Serum 25(OH)D3 is found to be associated with asthma. However, the role of vitamin D in obese asthma remains unclear. Therefore, we investigated the association between vitamin D levels and asthma outcomes in a murine model of obese asthma. We also evaluated NLRP3 inflammasome activity in the pathogenesis of obese asthma. We divided 20 male Balb/c mice (3-4 weeks old) into 4 groups: normal control, asthma, obese, and obese asthma and developed an obese asthma mouse model. Airway hyperreactivity, cytokine concentrations, 25(OH)D3 levels, NLRP3 mRNA and IL-1β mRNA expressions were measured. Lung histology and bronchoalveolar lavage fluid (BALF) cell count were also determined. Obese asthma mice showed a significant increase in airway hyper-responsiveness, airway inflammation, pro-inflammatory cytokine levels and NLRP3 mRNA, IL-1β mRNA expression. Both asthma and obese groups had lower 25(OH)D3 levels. Vitamin D levels in obese asthma were the lowest among all groups. Vitamin D levels correlated negatively with body weight, lung resistance levels at 25 mg/mL of methacholine, total inflammatory cells, and IL-1β and IL-17 concentrations in BALF. These data demonstrated an association between serum vitamin D levels and outcomes of obese asthma, and indicated that NLRP3 inflammasome may play a role in this disorder.

Topics: Animals; Asthma; Body Weight; Bronchoalveolar Lavage Fluid; Cholecalciferol; Cytokines; Disease Models, Animal; Enzyme-Linked Immunosorbent Assay; Leukocyte Count; Lung; Male; Mice, Inbred BALB C; NLR Family, Pyrin Domain-Containing 3 Protein; Obesity; Real-Time Polymerase Chain Reaction; Time Factors

Immune-modulating drugs that target myeloid-derived suppressor cells or stimulate natural killer T cells have been shown to reduce mycobacterial loads in tuberculosis (TB). We aimed to determine if a combination of these drugs as adjunct immunotherapy to conventional antibiotic treatment could also increase therapeutic efficacy against TB. In our model of pulmonary TB in mice, we applied treatment with isoniazid, rifampicin, and pyrazinamide for 13 weeks alone or combined with immunotherapy consisting of all-trans retinoic acid, 1,25(OH)

Topics: Animals; Anti-Bacterial Agents; Antitubercular Agents; Cholecalciferol; Combined Modality Therapy; Disease Models, Animal; Female; Galactosylceramides; Immunity, Cellular; Immunotherapy; Lung; Mice, Inbred BALB C; Recurrence; Tretinoin; Tuberculosis; Tumor Necrosis Factor-alpha

COPD represents a multifactorial lung disorder with high morbidity and mortality. Despite intensive research concerning the underlying disease mechanisms, the involvement of the CD200/CD200R axis in supporting or preventing the onset of COPD has not yet been addressed. Since the CD200/CD200R axis is crucially implicated in the maintenance of pulmonary immune homeostasis, we hypothesized that it might be involved in controlling the onset of COPD.. To address this, we analyzed the serum samples from COPD patients and normal controls for soluble (s) CD200 and correlated the data to COPD-relevant clinical parameters. In addition, basic studies were conducted in CD200-deficient and wild-type mice in which COPD-like inflammation was induced with elastase/LPS followed by lung and serum component analysis.. We observed a positive correlation between serum sCD200 and IL-6 levels as well as a trend toward a negative correlation of sCD200 with vitamin D3 in COPD patients. Further investigations in mice revealed that despite elevated serum concentration of MMP-9 in CD200KO mice, the early onset of COPD-like lung inflammation was similar in CD200-deficient and wild-type animals in terms of immune cell infiltration, emphysematous changes, and mucus overproduction.. While our murine studies suggest that the co-inhibitory molecule CD200 does not appear to play a prominent role in the early onset of COPD-like features, correlation of sCD200 serum levels with COPD-related parameters in humans with established disease revealed that the CD200/CD200R axis may be mechanistically linked to the disease course in COPD patients.

Topics: Aged; Animals; Antigens, CD; Antigens, Surface; Case-Control Studies; Cholecalciferol; Disease Models, Animal; Female; Humans; Interleukin-6; Lipopolysaccharides; Lymphocytes; Macrophages, Alveolar; Male; Matrix Metalloproteinase 9; Mice; Mice, Inbred C57BL; Mice, Knockout; Middle Aged; Neutrophils; Orexin Receptors; Pancreatic Elastase; Pulmonary Disease, Chronic Obstructive; Receptors, Cell Surface

Active surveillance has emerged as an alternative to immediate treatment for men with low-risk prostate cancer. Accordingly, identification of environmental factors that facilitate progression to more aggressive stages is critical for disease prevention. Although calcium-enriched diets have been speculated to increase prostate cancer risk, their impact on early-stage tumors remains unexplored. In this study, we addressed this issue with a large interventional animal study. Mouse models of fully penetrant and slowly evolving prostate tumorigenesis showed that a high calcium diet dramatically accelerated the progression of prostate intraepithelial neoplasia, by promoting cell proliferation, micro-invasion, tissue inflammation, and expression of acknowledged prostate cancer markers. Strikingly, dietary vitamin D prevented these calcium-triggered tumorigenic effects. Expression profiling and in vitro mechanistic studies showed that stimulation of PC-3 cells with extracellular Ca

Topics: Animals; Calcium; Cell Line, Tumor; Cholecalciferol; Diet; Dietary Supplements; Disease Models, Animal; Humans; Male; Mice; Mice, Inbred C57BL; Prostatic Neoplasms; Receptors, Calcium-Sensing; TRPC Cation Channels; TRPC6 Cation Channel; Up-Regulation

The Angong Niuhuang Pill (ANP) is a well known Chinese traditional therapeutic for the treatment for diseases affecting the Central Nervous System (CNS). Components of the ANP formulation, including Bovis Calculus Sativus, Pulvis Bubali Comus Concentratus, Moschus, Margarita, Cinnabaris, Realgar, Coptidis Rhizoma, Scutellariae Radix, Gardeniae Fructus, Curcumae Radix, and Bomeolum Syntheticum, have been used for the treatment of stroke, encephalitis and emergency meningitis across Asia, especially in China for hundreds of years.. The goal of this study was to investigate the anti-atherosclerosis and cardio-protective effects of ANP administration using a rodent model of atherosclerosis induced by a high fat and vitamin D. Specific Pathogen-Free (SPF) 78 male SD rats were randomly divided into a control group and 5 atherosclerotic model groups. The atherosclerotic groups were divided to receive either Simvastatin (SVTT, 0.005g/kg), Low-dose ANP (0.125g/kg), Medium-dose ANP (0.25g/kg), and High-dose ANP (0.5g/kg). Following adaptive feeding for one week, atherosclerosis was induced and the atherosclerosis model was established. Experimental drugs (either simvastatin or ANP) or normal saline were administered intragastrically once daily for 9 weeks starting from the 8th week. A carotid artery ultrasound was performed at the 17th week to determine whether atherosclerosis had been induced. After the atherosclerosis model was successfully established, platelet aggregation rates, serum biochemical indices, apoptosis-related Bcl-2, Bax proteins levels in the heart were assayed. Pathological and histological analysis was completed using artery tissue from different experimental different groups to assess the effects of ANP.. ANP significantly decreased aortic membrane thickness, the maximum platelet aggregation rates, and the ratio of low density lipoprotein cholesterol (LDL) to high density lipoprotein cholesterol (HDL). In addition, ANP significantly reduced serum contents of total cholesterol, low density lipoprotein, malondialdehyde, troponin I, high-sensitivity C-reactive protein, and lactate dehydrogenase. ANP markedly improved abnormal pathological conditions of the aorta and heart, and helped to prevent myocardial apoptosis.. We have demonstrated that ANP has robust ant-atherosclerosis and cardio-protective effects on a high-fat and vitamin D

Topics: Animals; Anti-Inflammatory Agents; Antioxidants; Aorta, Thoracic; Aortic Diseases; Apoptosis; Atherosclerosis; Biomarkers; Carotid Artery Diseases; Cholecalciferol; Diet, High-Fat; Disease Models, Animal; Drugs, Chinese Herbal; Enzymes; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypolipidemic Agents; Inflammation Mediators; Lipids; Male; Myocardium; Platelet Aggregation; Platelet Aggregation Inhibitors; Rats, Sprague-Dawley; Simvastatin; Tablets; Time Factors

This study aimed to investigate whether ghrelin ameliorated vascular calcification (VC) through improving autophagy.. VC model was induced by nicotine plus vitamin D. Ghrelin treatment attenuated the elevation of calcium deposition and ALP activity in VC model both in vivo and in vitro. Interesting, the protein levels of autophagy markers, LC3 and beclin1 were significantly upregulated by ghrelin in VC model. An autophagy inhibitor, 3-methyladenine blocks the ameliorative effect of ghrelin on VC. Furthermore, protein expressions of phosphate-AMPK were increased by ghrelin treatment both in calcified aorta and VSMC. The effect of ghrelin on autophagy induction and VC attenuation was prevented by AMPK inhibitor, compound C.. Our results suggested that ghrelin improved autophagy through AMPK activation, which was resulted in VC amelioration. These data maybe throw light on prevention and therapy of VC.

Topics: AMP-Activated Protein Kinases; Animals; Aorta; Autophagy; Calcium; Cholecalciferol; Disease Models, Animal; Ghrelin; Glycerophosphates; Male; Muscle, Smooth, Vascular; Nicotine; Rats; Rats, Sprague-Dawley; Vascular Calcification

In vascular smooth muscle, calcium overload is linked to advancing age. The pharmacokinetics of Sulfanilamide (SA), a compound with antibacterial properties, was evaluated in a preclinical model of vascular calcification. SA was used since it is useful to study possible modifications in the renal and hepatic management of drugs. Vascular calcification was induced by administration of a single high dose of vitamin D

Topics: Acetylation; Acetyltransferases; Animals; Anti-Bacterial Agents; Biotransformation; Cholecalciferol; Disease Models, Animal; Liver; Liver Circulation; Male; Models, Biological; Rats, Wistar; Renal Circulation; Renal Elimination; Sulfanilamide; Vascular Calcification

The present preclinical study was created to determine the therapeutic effects of vitamin D hormone treatment as an adjunctive therapy alone or in a combination with low dose of 17β-estradiol (17β-E₂) on anxiety-like behavior in female rats with long-term absence of estrogen. Accordingly, the aim of the current study was to examine the effects of chronic cholecalciferol administration (1.0, 2.5 or 5.0 mg/kg subcutaneously, SC, once daily, for 14 days) on the anxiety-like state after long-term ovariectomy in female rats. Twelve weeks postovariectomy, cholecalciferol was administered to ovariectomized (OVX) rats and OVX rats treated with 17β-E₂ (0.5 µg/rat SC, once daily, for 14 days). Anxiety-like behavior was assessed in the elevated plus maze (EPM) and the light/dark test (LDT), and locomotor and grooming activities were tested in the open field test (OFT). Cholecalciferol at two doses of 1.0 and 2.5 mg/kg alone or in combination with 17β-E₂ produced anxiolytic-like effects in OVX rats as evidenced in the EPM and the LDT, as well as increased grooming activity in the OFT. Our results indicate that cholecalciferol, at two doses of 1.0 and 2.5 mg/kg, has a profound anxiolytic-like effects in the experimental rat model of long-term estrogen deficiency.

Topics: Animals; Anxiety; Behavior, Animal; Cholecalciferol; Disease Models, Animal; Dose-Response Relationship, Drug; Estradiol; Estrogens; Female; Ovariectomy; Rats; Rats, Wistar

Atopic dermatitis (AD) is a chronic relapsing inflammatory skin disease with pruritus and high prevalence. Indeed, 15-30 % of children and 2-10 % of adults from industrialized countries are affected. Acute AD lesions are characterized by epidermal hyperplasia associated with a dominant Th2/Th17 immune response and dermal inflammatory infiltrates. Moreover, the expression of alarmins such as TSLP, IL-33, and IL-25 is upregulated in acute AD lesions. Topical application of vitamin D3 or of its low-calcemic analog MC903 induces changes in skin morphology and inflammation resembling immune perturbations observed in acute lesions of patients with AD. Mice treated with MC903 or vitamin D3 additionally display increased serum IgE levels, as observed in patients with extrinsic AD. Interestingly, these symptoms are not dependent on mouse gender or on genetic background. Thus, the easiness of this mouse model renders it very attractive to study immunologic abnormalities involved in AD development or maintenance. Furthermore, this model might be useful for preclinical studies aiming at unraveling new therapeutic strategies to treat AD. In this chapter, we describe the induction and major features of MC903 and vitamin D3-induced AD-like inflammation in mice.

Topics: Administration, Cutaneous; Animals; Biomarkers; Calcitriol; Cholecalciferol; Dermatitis, Atopic; Disease Models, Animal; Drug Administration Schedule; Ear; Female; Gene Expression; Humans; Immunoglobulins; Keratinocytes; Male; Mice; Mice, Inbred C57BL; Receptors, Cytokine; Skin

Vascular calcification is a risk predictor and common pathological change in cardiovascular diseases that are associated with elastin degradation and phenotypic transformation of vascular smooth muscle cells via gelatinase matrix metalloproteinase-2 (MMP2). However, the mechanisms involved in this process remain unclear. In this study, we investigated the relationships between miR-29b-3p and MMP2, to confirm miR-29b-3p-mediated MMP2 expression at the posttranscriptional level in arterial calcification. In male Sprague Dawley rats, arterial calcification was induced by subcutaneous injection of a toxic dose of cholecalciferol. In vivo, the quantitative real-time polymerase chain reaction (qRT-PCR) showed that MMP2 expression was upregulated in calcified arterial tissues, and miR-29b-3p expression was downregulated. There was a negative correlation between MMP2 mRNA expression and miR-29b-3p levels (

Topics: Animals; Aorta, Thoracic; Base Sequence; Cholecalciferol; Disease Models, Animal; HEK293 Cells; Humans; Male; Matrix Metalloproteinase 2; MicroRNAs; Muscle, Smooth, Vascular; Myocytes, Smooth Muscle; Rats, Sprague-Dawley; Reproducibility of Results; Transfection; Vascular Calcification

Tuberculosis (TB) is a significant human disease caused by inhalation of Mycobacterium tuberculosis. Left untreated, TB mortality is associated with a failure to resolve pulmonary immunopathology. There is currently widespread interest in using vitamin D3 (VitD3) as an adjunct therapy for TB because numerous in vitro studies have shown that VitD3 has direct and indirect mycobactericidal activities. However, to date, there have been no in vivo studies addressing whether VitD3 affects experimental TB outcome. In this study, we used C3HeB/FeJ mice to determine whether dietary VitD3 influences the outcome of experimental TB. We observed that although M. tuberculosis burdens did not differ between mice on a VitD3-replete diet (VitD(HI) mice) and mice on a VitD3-deficient diet (VitD(LO) mice), the inflammatory response in VitD(HI) mice was significantly attenuated relative to VitD(LO) controls. Specifically, the expression of multiple inflammatory pathways was reduced in the lungs at later disease stages as were splenocyte IL12/23p40 and IFN-γ levels following ex vivo restimulation. Dietary VitD3 also suppressed the accumulation of T cells in the mediastinal lymph nodes and lung granulomatous regions while concomitantly accelerating the accumulation of F4/80(+) and Ly6C/Ly6G(+) lineages. The altered inflammatory profile of VitD(HI) mice also associated with reductions in pulmonary immunopathology. VitD receptor-deficient (vdr(-/-)) radiation bone marrow chimeras demonstrate that reductions in pulmonary TB immunopathology are dependent on hematopoietic VitD responsiveness. Collectively, our data support a model wherein the in vivo role of VitD3 during TB is not to promote M. tuberculosis killing but rather to function through hematopoietic cells to reduce M. tuberculosis-elicited immunopathology.

Topics: Animals; Cholecalciferol; Diet; Disease Models, Animal; Flow Cytometry; Image Processing, Computer-Assisted; Immunohistochemistry; Lung; Mice; Mice, Inbred Strains; Real-Time Polymerase Chain Reaction; T-Lymphocytes; Tuberculosis, Pulmonary; Vitamins

Deficiency in α-Klotho is involved in the pathogenesis of vascular calcification. Since intermedin (IMD)1-53 (a calcitonin/calcitonin gene-related peptide) protects against vascular calcification, we studied whether IMD1-53 inhibits vascular calcification by upregulating α-Klotho. A rat model of chronic kidney disease (CKD) with vascular calcification induced by the 5/6 nephrectomy plus vitamin D3 was used for study. The aortas of rats with CKD showed reduced IMD content but an increase of its receptor, calcitonin receptor-like receptor, and its receptor modifier, receptor activity-modifying protein 3. IMD1-53 treatment reduced vascular calcification. The expression of α-Klotho was greatly decreased in the aortas of rats with CKD but increased in the aortas of IMD1-53-treated rats with CKD. In vitro, IMD1-53 increased α-Klotho protein level in calcified vascular smooth muscle cells. α-Klotho knockdown blocked the inhibitory effect of IMD1-53 on vascular smooth muscle cell calcification and their transformation into osteoblast-like cells. The effect of IMD1-53 to upregulate α-Klotho and inhibit vascular smooth muscle cell calcification was abolished by knockdown of its receptor or its modifier protein, or treatment with the protein kinase A inhibitor H89. Thus, IMD1-53 may attenuate vascular calcification by upregulating α-Klotho via the calcitonin receptor/modifying protein complex and protein kinase A signaling.

Topics: Animals; Aorta, Thoracic; Cell Transdifferentiation; Cells, Cultured; Cholecalciferol; Cyclic AMP; Cyclic AMP-Dependent Protein Kinases; Disease Models, Animal; Glucuronidase; Humans; Klotho Proteins; Male; Muscle, Smooth, Vascular; Myocytes, Smooth Muscle; Nephrectomy; Osteoblasts; Peptide Hormones; Phenotype; Rats, Sprague-Dawley; Receptor Activity-Modifying Protein 3; Receptors, Calcitonin; Renal Insufficiency, Chronic; RNA Interference; Signal Transduction; Transfection; Up-Regulation; Vascular Calcification

Atopic dermatitis (AD) is a widespread inflammatory skin disease with an early onset, characterized by pruritus, eczematous lesions and skin dryness. This chronic relapsing disease is believed to be primarily a result of a defective epidermal barrier function associated with genetic susceptibility, immune hyper-responsiveness of the skin and environmental factors. Although the important role of abnormal immune reactivity in the pathogenesis of AD is widely accepted, the role of regulatory T cells (Tregs) remains elusive. We found that the Treg population is expanded in a mouse model of AD, i.e. mice topically treated with vitamin D3 (VitD). Moreover, mice with AD-like symptoms exhibit increased inducible T-cell costimulator (ICOS)-, cytotoxic T-lymphocyte antigen-4 (CTLA-4)- and Glycoprotein-A repetitions predominant receptor (GARP)-expressing Tregs in skin-draining lymph nodes. Importantly, the differentiation of Tregs into thymus-derived Tregs is favoured in our mouse model of AD. Emigrated skin-derived dendritic cells are required for Treg induction and Langerhans cells are responsible for the biased expansion of thymus-derived Tregs . Intriguingly, thymus-derived Tregs isolated from mice with AD-like symptoms exhibit a Th2 cytokine profile. Thus, AD might favour the expansion of pathogenic Tregs able to produce Th2 cytokines and to promote the disease instead of alleviating symptoms.

Topics: Animals; Cell Differentiation; Cell Proliferation; Cholecalciferol; CTLA-4 Antigen; Cytokines; Dermatitis, Atopic; Disease Models, Animal; Epidermis; Gene Expression Regulation; Humans; Inducible T-Cell Co-Stimulator Protein; Langerhans Cells; Lymph Nodes; Membrane Proteins; Mice; Mice, Inbred C57BL; Signal Transduction; T-Lymphocytes, Cytotoxic; T-Lymphocytes, Regulatory; Th1-Th2 Balance; Thymus Gland

Deficiency of vitamin D3, a lipophilic micronutrient, plays a role in the development of some chronic diseases. Vitamin D3 deficiency affects 25-50% of the human population and has been associated with increased risk for development of hypertension. DNA damage induced by reactive oxygen species (ROS) occurs more often in hypertensive than in normotensive individuals, and vitamin D3 status can influence this relationship. The aim of this study was to evaluate whether a diet supplemented with (10,000 IU/kg) or deficient in (0 IU/kg) vitamin D3, compared to a vitamin D3 control diet (1000 IU/kg), would modulate DNA damage and ROS production in spontaneously hypertensive rats (SHR) and normotensive control Wistar-Kyoto (WKY) rats after 12 weeks of treatment. ROS production was assessed by measuring the oxidative burst of neutrophils. DNA damage was evaluated using the comet assay in peripheral blood and the micronucleus test in bone marrow and peripheral blood. Vitamin D3 supplementation did not induce DNA damage and did not change neutrophil ROS production in SHR and WKY rats. Vitamin D3 deficiency induced neutrophil ROS production and a high frequency of micronucleus formation in the bone marrow and peripheral blood of SHR rats only, and induced DNA damage (comet) in peripheral blood of both SHR and WKY rats. In conclusion, vitamin D3 deficiency showed a more pronounced effect on hypertensive animals. Population studies are needed to test whether this relationship also exists in humans.

Topics: Animals; Cholecalciferol; Dietary Supplements; Disease Models, Animal; DNA Damage; Hypertension; Male; Neutrophils; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Reactive Oxygen Species; Respiratory Burst

Reduced homoarginine plasma levels are associated with unfavourable cardiovascular outcome in chronic kidney disease (CKD). Cardiovascular events in CKD are fostered by vascular calcification, an active process promoted by hyperphosphatemia and involving osteo-/chondrogenic transformation of vascular smooth muscle cells (VSMCs). The present study explored the effect of homoarginine on phosphate-induced osteo-/chondrogenic signalling and vascular calcification.. Experiments were performed in hyperphosphatemic klotho-hypomorphic mice (kl/kl), in subtotal nephrectomy and vitamin D3-overload mouse calcification models and in primary human aortic smooth muscle cells (HAoSMCs). As a result, plasma homoarginine levels were lower in kl/kl mice than in wild-type mice and in both genotypes significantly increased by lifelong treatment with homoarginine. Surprisingly, homoarginine treatment of kl/kl mice and of mice with renal failure after subtotal nephrectomy augmented vascular calcification and enhanced the transcript levels of plasminogen activator inhibitor 1 (Pai1) and of osteogenic markers Msx2, Cbfa1, and Alpl. Similarly, homoarginine treatment of HAoSMCs increased phosphate-induced calcium deposition, ALP activity, as well as PAI1, MSX2, CBFA1, and ALPL mRNA levels. Homoarginine alone up-regulated osteo-/chondrogenic signalling and indicators of oxidative stress in HAoSMCs. Furthermore, homoarginine reduced citrulline formation from arginine by nitric oxide (NO) synthase (NOS) isoforms. NO formation by NOS was reduced when using homoarginine as a substrate instead of arginine. The osteoinductive effects of homoarginine were mimicked by NOS inhibitor L-NAME and abolished by additional treatment with the NO donors DETA-NONOate and PAPA-NONOate or the antioxidants TEMPOL and TIRON. Furthermore, homoarginine augmented vascular calcification and aortic osteo-/chondrogenic signalling in mice after vitamin D3-overload, effects reversed by the NO donor molsidomine.. Homoarginine augments osteo-/chondrogenic transformation of VSMCs and vascular calcification, effects involving impaired NO formation from homoarginine.

Topics: Animals; Biomarkers; Calcium; Cell Transdifferentiation; Cells, Cultured; Cholecalciferol; Chondrogenesis; Disease Models, Animal; Dose-Response Relationship, Drug; Gene Expression Regulation; Genetic Predisposition to Disease; Glucuronidase; Homoarginine; Humans; Hyperphosphatemia; Klotho Proteins; Mice, Knockout; Muscle, Smooth, Vascular; Myocytes, Smooth Muscle; Nephrectomy; Nitric Oxide; Nitric Oxide Donors; Nitric Oxide Synthase; Osteogenesis; Phenotype; Renal Insufficiency; Time Factors; Vascular Calcification

In this study, the vitamin D3 plus nicotine (VDN) model of rats was used to prove that H2S alleviates vascular calcification (VC) and phenotype transformation of vascular smooth muscle cells (VSMC). Besides, H2S can also inhibit endoplasmic reticulum stress (ERS) of calcified aortic tissues. The effect of H2S on alleviating VC and phenotype transformation of VSMC can be blocked by TM, while PBA also alleviated VC and phenotype transformation of VSMC that was similar to the effect of H2S. These results suggest that H2S may alleviate rat aorta VC by inhibiting ERS, providing new target and perspective for prevention and treatment of VC.

Topics: Animals; Aorta; Cholecalciferol; Disease Models, Animal; Endoplasmic Reticulum Stress; Hydrogen Sulfide; Male; Muscle, Smooth, Vascular; Myocytes, Smooth Muscle; Nicotine; Rats; Rats, Sprague-Dawley; Vascular Calcification

The effect of vitamin D3 in oral solution (VD3 ) and vitamin D3 -loaded nanocapsules (NC-VD3 ) was analysed in animals with complete Freund's adjuvant (CFA) induced arthritis (AR). For this purpose, we evaluated scores for arthritis, thermal hyperalgesia and paw oedema, as well as histological analyses and measurements of the activity of the ectonucleoside triphosphate diphosphohydrolase (E-NTPDase) and ecto-adenosine deaminase (E-ADA) enzymes in rat lymphocytes. Haematological and biochemical parameters were also determined. The doses administered were 120 UI/day of VD3 and 15.84 UI/day of NC-VD3 . Fifteen days after the induction of AR, the groups were treated for 15 days with vitamin D3 . The results demonstrated that VD3 was able to reduce arthritis scores, thermal hyperalgesia and paw oedema in rats with CFA-induced arthritis. However, treatment with NC-VD3 did not reduce arthritis scores. The histological analyses showed that both formulations were able to reduce the inflammatory changes induced by CFA. The activity of E-NTPDase in rat lymphocytes was higher in the AR compared with the control group, while the activity of E-ADA was lower. This effect was reversed after the 15-day treatment. Data from this study indicates that both forms of vitamin D3 seem to contribute to decreasing the inflammatory process induced by CFA, possibly altering the activities of ectoenzymes. Copyright © 2016 John Wiley & Sons, Ltd.. The effects promoted by both formulations of vitamin D3 , either in oral solution or nanoencapsulated form, strongly suggests the softening of the inflammatory process induced by complete Freund's adjuvant (CFA), possibly altering the E-NTPDase and E-ADA activities. However, it is known that vitamin D has a beneficial effect on the modulation of the immune system components responsible for the inflammatory process. Moreover, the establishment of responses to treatment with vitamin D3 may provide an alternative for inhibiting the proinflammatory response, assisting in our understanding of the immunopathology of this disease and possibly improving the signs and symptoms that hinder the quality of life of patients with rheumatoid arthritis.. Evaluation of the effects on the E-NTPDase and E-ADA activities in an animal model of induced arthritis. Two formulations of vitamin D3 were used: form oral solution and nanoencapsulated. Vitamin D3 seems to contribute to the inflammatory process induced by CFA. Vitamin D3 possibly alters the E-NTPDase and E-ADA activities. Vitamin D3 may be an alternative supplementary treatment for chronic arthritis.

Topics: Adenosine Deaminase; Administration, Oral; Animals; Anti-Inflammatory Agents; Antigens, CD; Apyrase; Arthritis, Rheumatoid; Cholecalciferol; Disease Models, Animal; Female; Freund's Adjuvant; Lymphocytes; Nanocapsules; Nanoparticles; Rats, Wistar; Solutions

Atypical antipsychotics are associated with an increased risk of hyperglycaemia, thus limiting their clinical use. This study focused on finding the molecular mechanism underlying antipsychotic-induced hyperglycaemia. First, we searched for drug combinations in the FDA Adverse Event Reporting System (FAERS) database wherein a coexisting drug reduced the hyperglycaemia risk of atypical antipsychotics, and found that a combination with vitamin D analogues significantly decreased the occurrence of quetiapine-induced adverse events relating diabetes mellitus in FAERS. Experimental validation using mice revealed that quetiapine acutely caused insulin resistance, which was mitigated by dietary supplementation with cholecalciferol. Further database analysis of the relevant signalling pathway and gene expression predicted quetiapine-induced downregulation of Pik3r1, a critical gene acting downstream of insulin receptor. Focusing on the phosphatidylinositol 3-kinase (PI3K) signalling pathway, we found that the reduced expression of Pik3r1 mRNA was reversed by cholecalciferol supplementation in skeletal muscle, and that insulin-stimulated glucose uptake into C2C12 myotube was inhibited in the presence of quetiapine, which was reversed by concomitant calcitriol in a PI3K-dependent manner. Taken together, these results suggest that vitamin D coadministration prevents antipsychotic-induced hyperglycaemia and insulin resistance by upregulation of PI3K function.

Topics: Animals; Antipsychotic Agents; Cell Line; Cholecalciferol; Class Ia Phosphatidylinositol 3-Kinase; Data Mining; Databases, Factual; Disease Models, Animal; Glucose Transporter Type 4; Humans; Hyperglycemia; Insulin Resistance; Mice; Quetiapine Fumarate; Signal Transduction; Vitamin D

Tolerogenic dendritic cells (tolDC) have been postulated as a potent immunoregulatory therapy for autoimmune diseases such as multiple sclerosis (MS). In a previous study, we demonstrated that the administration of antigen-specific vitamin D3 (vitD3) tolDC in mice showing clinical signs of experimental autoimmune encephalomyelitis (EAE; the animal model of MS) resulted in abrogation of disease progression. With the purpose to translate this beneficial therapy to the clinics, we have investigated the effectivity of vitD3-frozen antigen-specific tolDC pulsed with myelin oligodendrocyte glycoprotein 40-55 peptide (f-tolDC-MOG) since it would reduce the cost, functional variability and number of leukapheresis to perform to the patients.. Mice showing EAE clinical signs were treated with repetitive doses of f-tolDC-MOG. Tolerogenic mechanisms induced by the therapy were analysed by flow cytometry and T cell proliferation assays.. Treatment with f-tolDC-MOG was effective in ameliorating clinical signs of mice with EAE, inhibiting antigen-specific reactivity and inducing Treg. In addition, the long-term treatment was well tolerated and leading to a prolonged maintenance of tolerogenicity mediated by induction of Breg, reduction of NK cells and activation of immunoregulatory NKT cells.. The outcomes of this study show that the use of antigen-specific f-tolDC promotes multiple and potent tolerogenic mechanisms. Moreover, these cells can be kept frozen maintaining their tolerogenic properties, which is a relevant step for their translation to the clinic. Altogether, vitD3 f-tolDC-MOG is a potential strategy to arrest the autoimmune destruction in MS patients.

Topics: Animals; Autoantigens; Cell Transplantation; Cholecalciferol; Cryopreservation; Cytokines; Dendritic Cells; Disease Models, Animal; Encephalomyelitis, Autoimmune, Experimental; Female; Follow-Up Studies; Killer Cells, Natural; Mice; Mice, Inbred C57BL; Myelin-Oligodendrocyte Glycoprotein; Peptide Fragments; Polysaccharides; Time Factors

Multiple sclerosis (MS) is an immune-mediated demyelinating disorder of the central nervous system (CNS). We described that Candida albicans (Ca) aggravates experimental autoimmune encephalomyelitis (EAE) that is a model to study MS. We also observed that vaccination with a myelin peptide (MOG) in the presence of vitamin D (VitD) protected mice against EAE. In this work, we investigated whether Ca infection interferes with the efficacy of this vaccine.. EAE was induced in C57BL/6 female mice previously vaccinated with MOG+VitD and then infected 3 days before encephalomyelitis induction.. Vaccination was able to control EAE development in infected mice. These animals gained weight, and only a few progressed to very low clinical scores. Protection was confirmed by a lower inflammatory infiltration in the CNS and was also associated with a reduced production of encephalitogenic cytokines by spleen and CNS cell cultures. The elevated percentage of CD25(+) FoxP3(+) cells suggests that regulatory T cells are involved in the protection. Adoptive transfer of splenocytes from mice vaccinated with MOG+VitD supports the view that protection is mediated by immunoregulatory cells.. Together, these experiments provide evidence demonstrating that EAE can be prevented by the inverse vaccination with MOG+VitD even in the presence of a disease-aggravating infectious agent.

Topics: Animals; Body Weight; Candida albicans; Candidiasis; Cells, Cultured; Central Nervous System; Cholecalciferol; Cytokines; Dendritic Cells; Disease Models, Animal; Down-Regulation; Encephalomyelitis, Autoimmune, Experimental; Female; Forkhead Transcription Factors; Indoleamine-Pyrrole 2,3,-Dioxygenase; Lymph Nodes; Mice; Mice, Inbred C57BL; Myelin-Oligodendrocyte Glycoprotein; Vitamins

To investigate the protective effect of the active form of vitamin D3, 1,25-(OH)2D3, on macrovasculopathy in rats with type 2 diabetes mellitus (T2DM), 8-week-old male Sprague-Dawley rats were randomly divided into control group, T2DM group, and treatment group. The T2DM model was established after 6 weeks by administering an intraperitoneal injection of streptozotocin (30 mg/kg). 1,25-(OH)2D3 was administered by gavage to rats in the treatment group, and an equal volume of peanut oil was administered to rats in the T2DM group. Fasting plasma glucose (FPG), triglyceride (TG), total cholesterol (TC), high-density lipoprotein (HDL-C) and low-density lipoprotein (LDL-C) cholesterols were measured in all rats. The morphology of the thoracic aorta was examined, and the expression of tumor necrosis factor alpha (TNF-α), endothelin (ET), endothelial nitric oxide synthase (eNOS), CD54, and CD106 in the thoracic aorta was determined by immunohistochemistry. The expression of FPG, TG, TC, and LDL-C in rats from the T2DM and treatment groups was significantly elevated compared with rats from the control group (P < 0.05). Compared with that in control group, the expression of TNF-α, ET, eNOS, and CD106 was significantly upregulated in the T2DM group and the treatment group, while the expression of CD54 was increased only in the T2DM group (P < 0.05). Moreover, the levels of TNF-α, CD54, and CD106 in rats from the treatment group were lower than those in the T2DM group (P < 0.05). These data suggest that 1,25-(OH)2D3 may protect the macrovessels from injury in T2DM rats by inhibiting the expression of TNF-α, CD54, and CD106.

Topics: Animals; Blood Glucose; Calcitriol; Cholecalciferol; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Disease Models, Animal; Humans; Intercellular Adhesion Molecule-1; Lipoproteins, HDL; Male; Nitric Oxide Synthase Type III; Rats; Triglycerides; Tumor Necrosis Factor-alpha

Asthma is a common worldwide health burden, the prevalence of which is increasing. Recently, the biologically active form of vitamin D3, 1,25-dihydroxyvitamin D3, has been reported to have a protective role in murine asthma; however, the molecular mechanisms by which vitamin D3 attenuates asthma‑associated airway injury remain elusive. In the present study, BALB/c mice were sensitized to ovalbumin (OVA) and were administered 100 ng 1,25-dihydroxyvitamin D3 (intraperitoneal injection) 30 min prior to each airway challenge. The inflammatory responses were measured by ELISA, airway damage was analyzed by hematoxylin and eosin staining, airway remodeling was analyzed by Masson staining and periodic acid‑Schiff staining, markers of oxidative stress were measured by commercial kits, and the expression levels of α‑smooth muscle actin (α-SMA) and the activity of the NF‑E2‑related factor 2 (Nrf2)/heme oxygenase‑1 (HO‑1) and the transforming growth factor‑β (TGF‑β)/Smad signaling pathways were measured by immunohistochemistry and western blotting. The results demonstrated that OVA‑induced airway inflammation and immunoglobulin E overexpression were significantly reduced by vitamin D3 treatment. In addition, treatment with vitamin D3 decreased α‑SMA expression, collagen deposition and goblet cell hyperplasia, and inhibited TGF‑β/Smad signaling in the asthmatic airway. The upregulated levels of malondialdehyde, and the reduced activities of superoxide dismutase and glutathione in OVA‑challenged mice were also markedly restored following vitamin D3 treatment. Furthermore, treatment with vitamin D3 enhanced activation of the Nrf2/HO‑1 pathway in the airways of asthmatic mice. In conclusion, these findings suggest that vitamin D3 may protect airways from asthmatic damage via the suppression of TGF‑β/Smad signaling and activation of the Nrf2/HO‑1 pathway; however, these protective effects were shown to be accompanied by hypercalcemia.

Topics: Airway Remodeling; Animals; Asthma; Biomarkers; Bronchoalveolar Lavage Fluid; Cholecalciferol; Disease Models, Animal; Female; Heme Oxygenase-1; Immunoglobulin E; Mice; NF-E2-Related Factor 2; Oxidative Stress; Protective Agents; Signal Transduction; Smad Proteins; Transforming Growth Factor beta

In the central nervous system (CNS) the main proteins of myelin are proteolipid protein (PLP), myelin basic protein (MBP), myelin oligodendrocyte glycoprotein (MOG) and CNPase. Myelin oligodendrocyte glycoprotein is a minor component of the myelin sheath, but is an important autoantigen linked to the pathogenesis of multiple sclerosis (MS). CNPase is expressed exclusively by oligodendrocytes in the CNS, and the appearance of CNPase seems to be one of the earliest events of oligodendrocyte differentiation and myelination. In this study the effects of vitamin D on total protein concentration, CNPase and MOG expression in the cerebral cortex of the murine model of cuprizone-induced demyelination was investigated. The mice were treated by cuprizone for five weeks in order to induce demyelination. The mice were then divided into 3 groups. The first group was injected intraperitoneally (IP) with vitamin D diluted in olive oil in the amount of 5 µg/kg/daily body weight. The second group (SHAM) was injected IP with olive oil and the third group was left without any injection as the control group (n = 11 for each group). After five weeks the mice were killed and the cerebral cortex was collected and the expression of CNPase and MOG was studied by Western blot. Total protein concentration in the vitamin D injected, SHAM and control groups were 0.918 ± 0.003, 0917 ± 0.004 and 0.916 ± 0.004 g/l, respectively (p > 0.05). However, a significant increase in the MOG and CNPase expression was seen in vitamin D injected group as compared to SHAM and control groups. It is concluded that vitamin D plays a role in the process of remyelination by increasing MOG and CNPase expression in the cortex.

Topics: Animals; Cerebral Cortex; Cholecalciferol; Cuprizone; Demyelinating Diseases; Disease Models, Animal; Mice; Mice, Inbred BALB C; Myelin Basic Protein; Myelin-Oligodendrocyte Glycoprotein; Oligodendroglia

The lower threshold plasma 25-hydroxy vitamin D (25(OH)D) level for optimal cardiovascular health is unclear, whereas the toxicity threshold is less clear. The aim of this study was to examine the cardiovascular-vitamin D dose-response curve in a normal rat model. Doses of cholecalciferol ranged from deficiency to toxic levels (equivalent to human doses of 0, 0·015, 0·25 and 3·75mg/d) for 4 weeks, and then cardiovascular health was examined using blood pressure telemetry and high-resolution ultrasound in normal male rats (n 16/group, 64 rats total). After 1 month, only the 0·25mg/d group had plasma 25(OH)D that was within current recommended range (100-125 nmol/l), and all groups failed to change plasma Ca or phosphate. Systolic blood pressure increased significantly (10-15 mmHg) in the rat groups with plasma 25(OH)D levels at both 30 and 561 nmol/l (groups fed 0 and 3·75mg/d) compared with the group fed the equivalent to 0·015mg/d (43 nmol/l 25(OH)D). Although not significant, the group fed the equivalent to 0·25mg/d (108 nmol/l 25(OH)D) also showed a 10 mmHg increase in systolic blood pressure. Carotid artery diameter was significantly smaller and wall thickness was larger, leading to higher peak carotid systolic blood velocity in these two groups. Despite these vascular changes, cardiac function did not differ among treatment groups. The key finding in this study is that arterial stiffness and systolic blood pressure both showed a U-shaped dose-response for vitamin D, with lowest values (best cardiovascular health) observed when plasma 25(OH)D levels were 43 nmol/l in normal male rats.

Topics: Animals; Blood Pressure; Calcifediol; Calcium; Cardiac Output; Carotid Arteries; Cholecalciferol; Diet, Vegetarian; Disease Models, Animal; Echocardiography; Heart; Hypertension; Male; Phosphates; Rats, Wistar; Stroke Volume; Time Factors; Ultrasonography, Doppler; Vascular Stiffness; Vitamin D Deficiency

Vitamin D₃ improves portal hypertension (PH) through the activation of vitamin D receptor (VDR) and calcium-sensing receptor (CaSR) in cirrhotic rats. Propranolol is a non-selective β-blocker that is recommended for the treatment of PH. The present study aims to investigate the detail systemic and hepatic mechanisms of vitamin D₃ and propranolol, alone or in combination, in cirrhotic rats.. Common bile duct-ligated and thioacetamide cirrhotic rats were treated with vehicle, propranolol (30 mg/kg/day), vitamin D₃ (0.5 μg/100 g/day, twice weekly), or propranolol + vitamin D₃, separately.. Significantly, propranolol and vitamin D₃ produced a similar magnitude of reduction in portal venous pressure (PVP) in cirrhotic rats through different mechanisms: whereas propranolol decreased PVP by reducing splanchnic hyperemia and cardiac index, vitamin D₃ decreased PVP by decreasing intrahepatic resistance (IHR). However, propranolol + vitamin D₃ did not further decrease PVP in cirrhotic rats. Notably, a marked decrease in hepatic VDR and CaSR expressions was noted in cirrhotic human/rat livers compared with non-cirrhotic human/rat livers. In cirrhotic rats, vitamin D₃ administration decreasing IHR by inhibiting the renin-angiotensin system, hepatic oxidative stress, inflammation/fibrosis, angiotensin II (ANGII) production, CaSR-mediated ANGII hyperresponsiveness, ANGII-induced hepatic stellate cells contraction, and correcting hepatic endothelial dysfunction through upregulation of hepatic VDR, CaSR, and endothelial nitric oxide synthase expressions.. Chronic vitamin D₃ treatment alone results in comparative portal hypotensive effects as propranolol alone in cirrhotic rats with PH. Taken together, chronic vitamin D₃ administration was an ideal alternative strategy to effectively improve PH without unwanted systemic side-effects.

Topics: Adrenergic beta-Antagonists; Animals; Cholecalciferol; Disease Models, Animal; Drug Therapy, Combination; Humans; Hypertension, Portal; Liver Cirrhosis; Propranolol; Rats; Receptors, Calcitriol; Receptors, Calcium-Sensing; Treatment Outcome; Vascular Resistance

Low vitamin D level is a risk factor for various late-onset CNS demyelinating disorders. We investigated whether vitamin D deficiency influences disease in twitcher mice (GALC(twi/twi) ; twi), a murine model of Krabbe disease (KD), an inherited disorder caused by galactocerebrosidase (GALC) deficiency that leads to psychosine accumulation, oligodendrocyte (OL) loss, and CNS demyelination. We found that the in situ 1,25-dihydroxyvitamin D3 level was reduced, with a parallel increase in the expression of inflammatory cytokines and vitamin D-catabolizing enzymes in the brains of KD and twi mice compared with age-matched controls. Pups maintained on milk from lactating heterozygous (GALC(twi/+) ) mothers that were fed a vitamin D3-supplemented diet until weaning and then fed a vitamin D3-supplemented diet demonstrated delayed body weight loss and development of disease in twi mice. This delayed the onset of tremors and locomotor disabilities that eventually impacted the life span of twi mice (50 ± 2 days). Accordingly, the expression of antioxidant enzymes was increased with delayed psychosine accumulation, lipid peroxidation, and inflammatory response that eventually protected CNS myelin and axonal integrity in twi mice. In vitro studies revealed that 1,25-dihydroxyvitamin D3 enhances antioxidant defenses in OLs deficient for GALC or incubated with psychosine. Together these data provide the first evidence that vitamin D deficiency affects disease development in twi mice and that vitamin D3 supplementation has the potential to improve the efficacy of KD therapeutics.

Topics: 25-Hydroxyvitamin D3 1-alpha-Hydroxylase; Age Factors; Animals; Animals, Newborn; Brain; Calcitriol; Cells, Cultured; Cholecalciferol; Cytokines; Disease Models, Animal; Galactosylceramidase; Glutathione; Humans; Leukodystrophy, Globoid Cell; Mice; Mice, Mutant Strains; Myelin Basic Protein; Neuroglia; Superoxide Dismutase; Vitamin D3 24-Hydroxylase

Roles of vitamin D on the immune and nervous systems are increasingly recognized. Two previous studies demonstrated that ergocalciferol (vitamin D2) or cholecalciferol (vitamin D3) induced functional recovery and increased myelination in a rat model of peroneal nerve transection. The current report assessed whether cholecalciferol was efficient in repairing transected rabbit facial nerves. Animals were randomized into two groups of rabbits with an unilateral facial nerve surgery: the vitamin D group included animals receiving a weekly oral bolus of vitamin D3 (200 IU/kg/day), from day 1 post-surgery; the control group included animals receiving a weekly oral bolus of vehicle (triglycerides). Contralateral unsectioned facial nerves from all experimental animals were used as controls for the histological study. The facial functional index was measured every week while the inner diameter of myelin sheath and the G ratio were quantified at the end of the 3 month experiment. The current report indicates that cholecalciferol significantly increases functional recovery and myelination, after 12 weeks of treatment. To the best of our knowledge, this is the first study investigating the therapeutic benefit of vitamin D supplementation in an animal model of facial paralysis. It paves further the way for clinical trials based on the administration of this steroid in individuals with injured facial nerves.

Topics: Animals; Cholecalciferol; Dietary Supplements; Disease Models, Animal; Facial Nerve Injuries; Male; Nerve Fibers, Myelinated; Rabbits; Recovery of Function; Vitamins

Vitamin D3 and metformin are widely used in humans for regulating mineral metabolism and as an antidiabetic drug, respectively; and both of them have been shown to have chemopreventive effects against various tumors. This study was designed to investigate the potential synergistic chemopreventive effects of vitamin D3 and metformin against the development of early colon neoplasia in two models. The first model was a 1,2-dimethylhydrazine dihydrochloride (DMH)-induced colon cancer rat model and the second, a DMH-dextran sodium sulfate (DSS)-induced colitis-associated colon neoplasia mouse model. Compared with either vitamin D3 or metformin alone, combined use of vitamin D3 and metformin showed more pronounced effect in reducing the numbers of aberrant crypt foci (ACF) and tumor in the colon. The most prominent inhibitory effects were observed in the vitamin D3 medium dose (100 IU/kg/d) and metformin medium dose (120 mg/kg/d) combination group. Furthermore, our results showed that enhancement of metformin's chemopreventive effects by vitamin D3 was associated with downregulation of S6P expression, via the AMPK (IGFI)/mTOR pathway. In addition, enhancement of vitamin D3's chemopreventive effects by metformin was associated with inhibition of the protein expressions of c-Myc and Cyclin D1, via the vitamin D receptor/β-catenin pathway. These findings show that the combined use of vitamin D3 and metformin exhibits synergistic effects against the development of early colon neoplasia. They suggest that the combined use of vitamin D3 and metformin may represent a novel strategy for chemoprevention of colorectal cancer.

Topics: Aberrant Crypt Foci; Animals; Anticarcinogenic Agents; Blotting, Western; Cholecalciferol; Colorectal Neoplasms; Disease Models, Animal; Drug Synergism; Enzyme-Linked Immunosorbent Assay; Male; Metformin; Mice; Mice, Inbred ICR; Rats; Rats, Wistar; Signal Transduction

Thyroid hormones (THs) including thyroxine (T4) and triiodothyronine (T3) play critical roles in bone remodeling. However, the role and mechanism of THs in vascular calcification (VC) have been unclear. To explore the pathophysiological roles of T3 on VC, we investigated the changes in plasma and aortas of THs concentrations and the effect of T3 on rat VC induced by vitamin D3 plus nicotine (VDN). VDN-treated rat showed decreased plasma T3 content, increased vascular calcium deposition, and alkaline phosphatase (ALP) activity. Administration of T3 (0.2 mg/kg body weight IP) for 10 days greatly reduced vascular calcium deposition and ALP activity in calcified rat aortas when compared with controls. Concurrently, the loss of smooth muscle lineage markers α-actin and SM22a was restored, and the increased bone-associated molecules, such as runt-related transcription factor2 (Runx2), Osterix, and osteopontin (OPN) levels in calcified aorta, were reduced by administration of T3. The suppression of klotho in calcified rat aorta was restored by T3. Methimazole (400 mg/L) blocked the beneficial effect of T3 on VC. These results suggested that T3 can inhibit VC development.

Topics: Animals; Bone and Bones; Bone Remodeling; Cholecalciferol; Disease Models, Animal; Male; Nicotine; Osteopontin; Rats, Sprague-Dawley; Thyroid Hormones; Vascular Calcification

Cerebral cavernous malformation (CCM) is a hemorrhagic stroke disease affecting up to 0.5% of North Americans that has no approved nonsurgical treatment. A subset of patients have a hereditary form of the disease due primarily to loss-of-function mutations in KRIT1, CCM2, or PDCD10. We sought to identify known drugs that could be repurposed to treat CCM.. We developed an unbiased screening platform based on both cellular and animal models of loss of function of CCM2. Our discovery strategy consisted of 4 steps: an automated immunofluorescence and machine-learning-based primary screen of structural phenotypes in human endothelial cells deficient in CCM2, a secondary screen of functional changes in endothelial stability in these same cells, a rapid in vivo tertiary screen of dermal microvascular leak in mice lacking endothelial Ccm2, and finally a quaternary screen of CCM lesion burden in these same mice. We screened 2100 known drugs and bioactive compounds and identified 2 candidates, cholecalciferol (vitamin D3) and tempol (a scavenger of superoxide), for further study. Each drug decreased lesion burden in a mouse model of CCM vascular disease by ≈50%.. By identifying known drugs as potential therapeutics for CCM, we have decreased the time, cost, and risk of bringing treatments to patients. Each drug also prompts additional exploration of biomarkers of CCM disease. We further suggest that the structure-function screening platform presented here may be adapted and scaled to facilitate drug discovery for diverse loss-of-function genetic vascular disease.

Topics: Animals; Cells, Cultured; Central Nervous System Neoplasms; Cholecalciferol; Disease Models, Animal; Drug Repositioning; Drug Screening Assays, Antitumor; Endothelial Cells; Free Radical Scavengers; Hemangioma, Cavernous, Central Nervous System; Humans; Mice; Mice, Knockout; Mice, Transgenic; Treatment Outcome

Vitamin D and calcium are essential for bone formation, mineralization, and remodeling. Recent studies demonstrated that an increased body mass can be detrimental to bone health. However, whether an increase in dietary vitamin D and calcium intakes in obesity is beneficial to bone health has not been established. The aim of this study was to examine the effects of increased vitamin D and calcium intakes, alone or in combination, on bone status in a high-fat diet-induced obesity (DIO) mouse model. We hypothesized that DIO in growing mice affects bone mineral status and that high vitamin D and calcium intakes will promote mineralization of the growing bone in obesity via Ca(2+) regulatory hormones, 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) and parathyroid hormone (PTH). Male mice were fed high vitamin D3 (10 000 IU/kg), high calcium (1.2%), or high vitamin D3 plus high-calcium diets containing 60% energy as fat for 10 weeks. Bone weight, specific gravity, mineral (Ca and P), and collagen (hydroxyproline) content were measured in the femur and the tibia. Regulators of Ca(2+) metabolism and markers of bone status (PTH, 25-hydroxyvitamin D [25(OH)D], 1,25(OH)2D3, and osteocalcin) were measured in blood plasma. Diet-induced obese mice exhibited lower bone Ca and P content and relative bone weight compared with the normal-fat control mice, whereas collagen (hydroxyproline) content was not different between the two groups. High vitamin D3 and calcium intakes significantly increased bone Ca and P content and relative bone weight in DIO mice, which was accompanied by an increase in 1,25(OH)2D3 and a decrease in PTH and osteocalcin concentrations in blood. The findings obtained indicate that increased vitamin D and calcium intakes are effective in increasing mineral (Ca and P) content in the growing bone of obese mice and that the hormonal mechanism of this effect may involve the vitamin D-PTH axis.

Topics: Animals; Bone and Bones; Calcium; Calcium, Dietary; Cholecalciferol; Diet, High-Fat; Disease Models, Animal; Drug Therapy, Combination; Hydroxyproline; Male; Mice; Obesity; Osteocalcin; Parathyroid Hormone; Phosphorus; Treatment Outcome; Vitamin D

Meningoencephalitis caused by Escherichia coli is associated with high rates of mortality and risk of neurological sequelae in newborns and infants and in older or immunocompromised adults. A high prevalence of neurological disorders has been observed in geriatric populations at risk of hypovitaminosis D.. In vivo, we studied the effects of vitamin D3 on survival and the host's immune response in experimental bacterial meningoencephalitis in mice after intracerebral E. coli infection. To produce different systemic vitamin D3 concentrations, mice received a low, standard, or high dietary vitamin D3 supplementation. Bacterial titers in blood, spleen, and brain homogenates were determined. Leukocyte infiltration was assessed by histological scores, and tissue cytokine or chemokine concentrations were measured.. Mice fed a diet with low vitamin D3 concentration died earlier than control animals after intracerebral infection. Vitamin D deficiency did not inhibit leukocyte recruitment into the subarachnoid space and did not lead to an increased density of bacteria in blood, spleen, or brain homogenates. The release of proinflammatory interleukin (IL)-6 was decreased and the release of anti-inflammatory IL-10 was increased in mice fed a diet with high vitamin D3 supplementation.. Our observations suggest a detrimental role of vitamin D deficiency in bacterial central nervous system infections. Vitamin D may exert immune regulatory functions.

Topics: Analysis of Variance; Animals; Bacterial Load; Body Weight; Central Nervous System; Cholecalciferol; Cytokines; Dietary Supplements; Disease Models, Animal; Escherichia coli; Escherichia coli Infections; Gene Expression Regulation; Meningoencephalitis; Mice; Mice, Inbred C57BL; Spleen; Time Factors; Vitamin D Deficiency

The synergistic effects of vitamin D3 and vitamin K2 on bone loss prevention have been reported. This study evaluates the effects of vitamin D3 and vitamin K2 supplementation in conjunction with conventional periodontal therapy (scaling and root planing [SRP]) on gingival interleukin (IL)-1β and IL-10, serum bone alkaline phosphatase (B-ALP) and tartrate-resistant acid phosphatase 5b (TRAP-5b), and calcium and alveolar bone levels in rats with experimentally induced periodontitis.. Seventy-two rats were divided into the following groups: 1) healthy; 2) periodontitis; 3) SRP; 4) SRP + vitamin D3; 5) SRP + vitamin K2; and 6) SRP + vitamins K2 and D3. Periodontitis was induced by ligature placement for 7 days, and vitamin K2 (30 mg/kg) and/or vitamin D3 (2 μg/kg) were administered for 10 days in the SRP + vitamin D3, SRP + vitamin K2, and SRP + vitamins K2 and D3 groups by oral gavage. On day 18, the animals were sacrificed, serum B-ALP, TRAP-5b, and calcium levels were measured, gingiva specimens were extracted for IL-1β and IL-10 analysis, and distances between the cemento-enamel junction and alveolar bone crest were evaluated.. Alveolar bone levels in the periodontitis group were significantly greater than those in the other five groups. No significant differences were found in gingival IL-1β and IL-10, serum B-ALP and TRAP-5b, and calcium and alveolar bone levels between the groups receiving SRP and vitamins and the group receiving SRP alone.. Within the limitations of this study, vitamin D3 and K2 alone or in combination did not affect gingival IL-1β and IL-10, serum B-ALP and TRAP-5b levels, or alveolar bone compared with conventional periodontal therapy alone.

Topics: Acid Phosphatase; Alkaline Phosphatase; Alveolar Process; Animals; Bone Density Conservation Agents; Calcium; Cholecalciferol; Combined Modality Therapy; Dental Scaling; Disease Models, Animal; Gingiva; Interleukin-10; Interleukin-1beta; Isoenzymes; Male; Periodontitis; Random Allocation; Rats; Rats, Wistar; Root Planing; Tartrate-Resistant Acid Phosphatase; Tooth Cervix; Vitamin K 2; Vitamins

Epidemiologic studies in humans have shown associations between greater sunlight exposure, higher serum 25-hydroxycholecalciferol [25(OH)D3] concentrations, and reduced colon cancer risk. However, results from a limited number of vitamin D supplementation trials in humans have not shown a protective effect.. We sought to determine whether adding to the diet increasing amounts of either 25(OH)D3, the stable metabolite measured in serum and associated with cancer risk, or cholecalciferol (vitamin D3), the compound commonly used for supplementation in humans, could reduce emergent adenomas (chemoprevention) or decrease the growth of existing adenomas (treatment) in the colons of vitamin D-sufficient rats carrying a truncation mutation of adenomatous polyposis coli (Apc), a model of early intestinal cancer.. Apc(Pirc/+) rats were supplemented with either vitamin D3 over a range of 4 doses [6-1500 μg/(kg body weight · d)] or with 25(OH)D3 over a range of 6 doses [60-4500 μg/(kg body weight · d)] beginning after weaning. Rats underwent colonoscopy every other week to assess effects on adenoma number and size. At termination (140 d of age), the number of tumors in the small intestine and colon and the size of tumors in the colon were determined, and serum calcium and 25(OH)D3 measurements were obtained.. At lower doses (those that did not affect body weight), neither of the vitamin D compounds reduced the number of existing or emergent colonic tumors (P-trend > 0.24). By contrast, supplementation at higher doses (those that caused a suppression in body weight gain) with either 25(OH)D3 or vitamin D3 caused a dose-dependent increase in colonic tumor number in both males and females (P-trend < 0.003).. No evidence for protection against colon tumor development was seen with lower dose supplementation with either cholecalciferol or 25-hydroxycholecalciferol. Thus, the association between sunlight exposure and the incidence of colon cancer may involve factors other than vitamin D concentrations. Alternative hypotheses warrant investigation. Furthermore, this study provides preliminary evidence for the need for caution regarding vitamin D supplementation of humans at higher doses, especially in individuals with sufficient serum 25(OH)D3 concentrations.

Topics: Adenoma; Animals; Calcifediol; Calcium, Dietary; Cholecalciferol; Colon; Colonic Neoplasms; Diet; Dietary Supplements; Disease Models, Animal; Dose-Response Relationship, Drug; Female; Male; Rats; Rats, Inbred F344; Vitamin D Deficiency

The Ron receptor is upregulated in human breast cancers and correlates with enhanced metastasis and reduced patient survival. Ron overexpression drives mammary tumorigenesis through direct β-catenin activation and augmented tumor cell proliferation, migration and invasion. Ron and β-catenin are also coordinately elevated in breast cancers. The vitamin D receptor (VDR) antagonizes β-catenin signaling. Herein, we examined mammary tumor onset and progression using a Ron-driven murine model of breast tumorigenesis crossed with VDR deficient mice. VDR ablation accelerated mammary tumor onset and led to tumors that exhibited a desmoplastic phenotype and enhanced metastases. Tumor levels of active β-catenin were markedly increased in the absence of VDR. In vitro, VDR activation in breast cancer cells reduced β-catenin activation and transcriptional activity leading to elevated expression of the extracellular Wnt inhibitor dickkopf-related protein 1, and a reduction in the interaction of β-catenin with the cyclin D1 promoter. Expression of a stabilized form or β-catenin ablated the protective effects of VDR activation.Collectively, these studies delineate a protective role for VDR signaling in Ron-induced mammary tumorigenesis through disruption of β-catenin activation.

Topics: Animals; beta Catenin; Cell Line, Tumor; Cell Movement; Cell Proliferation; Cell Transformation, Neoplastic; Cholecalciferol; Cyclin D1; Disease Models, Animal; Enzyme Activation; Female; Gene Expression Regulation, Neoplastic; Intercellular Signaling Peptides and Proteins; Mammary Neoplasms, Animal; Mammary Tumor Virus, Mouse; Mice; Mice, Knockout; Neoplasm Invasiveness; Promoter Regions, Genetic; Receptor Protein-Tyrosine Kinases; Receptors, Calcitriol; RNA Interference; RNA, Small Interfering; Signal Transduction; Transcription, Genetic; Transcriptional Activation; Wnt Proteins

Vitamin D3 and its analogues have recently been shown to enhance the anti-tumour effects of 5- Fluorouracil (5-FU) both in vitro and in xenograft mouse model of colon cancer. This study measured the potential mechanism(s) by which vitamin D3 could synergise the tumouricidal activities of 5-FU in azoxymethane (AOM) rat model of colon cancer.. Seventy-five male Wistar rats were divided equally into 5 groups: Control, AOM, AOM-treated by 5-FU (5-FU), AOM-treated by vitamin D3 (VitD3), and AOM-treated by 5-FU + vitamin D3 (5-FU/D). The study duration was 15 weeks. AOM was injected subcutaneously for 2 weeks (15 mg/kg/week). 5-FU was injected intraperitoneally in the 9th and 10th weeks post AOM (8 total injections were given: 12 mg/kg/day for 4 successive days, then 6 mg/kg every other day for another 4 doses) and oral vitamin D3 (500 IU/rat/day; 3 days/week) was given from week 7 post AOM till the last week of the study. The colons were collected following euthanasia for gross and histopathological examination. The expression of β-catenin, transforming growth factor-β1 (TGF-β1), TGF-β type 2 receptor (TGF-βR2), smad4, inducible nitric oxide synthase (iNOS), and heat shock protein-90 (HSP-90) proteins was measured by immunohistochemistry. In colonic tissue homogenates, quantitative RT-PCR was used to measure the mRNA expression of Wnt, β-catenin, Dickkopf-1 (DKK-1) and cyclooxygenase-2 (COX-2) genes, while ELISA was used to measure the concentrations of TGF-β1, HSP-90 and COX-2 proteins.. Monotherapy with 5-FU or vitamin D3 significantly decreased the number of grown tumours induced by AOM (P < 0.05); however, their combination resulted in more significant tumouricidal effects (P < 0.05) compared with monotherapy groups. Mechanistically, vitamin D3/5-FU co-therapy significantly decreased the expression of Wnt, β-catenin, iNOS, COX-2 and HSP-90 and significantly increased the expression of DKK-1, TGF-β1, TGF-βR2, smad4 (P < 0.05), in comparison with their corresponding monotherapy groups.. Vitamin D3 and 5-FU synergise together and exhibit better anticancer effects by modulating Wnt/β-catenin pathway, TGF-β1 signals, iNOS, COX-2 and HSP-90. Further studies are required to illustrate the clinical value of vitamin D supplementation during the treatment of colon cancer with 5-FU in human patients.

Topics: Animals; beta Catenin; Cholecalciferol; Colonic Neoplasms; Disease Models, Animal; Fluorouracil; Humans; Male; Mice; Rats; Rats, Wistar; Transforming Growth Factor beta; Xenograft Model Antitumor Assays

Our objective is to explore the effect of curcumin on permeability of coronary artery and expression of related proteins in rat coronary atherosclerosis heart disease model.. 45 healthy male Wistar rats of clean grade were selected and divided into treatment group, model control group and blank control group. The rats in the treatment group and model control group received high-fat diet for 12 weeks and intraperitoneal injection of VD3 to establish rat coronary atherosclerosis heart disease model. After modeling, the rats in the treatment group received gavage of 100 mg/(kg·d) curcimin, and the rats in the model control group and blank control group received gavage of 5 ml/(kg·d) distilled water, the intervention time was 4 weeks. After intervention, the rats were killed, and the hearts were dissected to obtain the samples of coronary artery. After embedding and frozen section, immunofluorescence method was used to detect the change of endarterium permeability in 3 groups, Western blot was used to detect matrix metalloproteinase-9 (MMP-9) and CD40L in coronary artery tissue, and enzyme linked immunosorbent assay (ELISA) was used to detect serum tumor necrosis factor-α (TNF-α) and C reaction protein (CRP).. After modeling, compared with the blank control group, total cholesterol (TC), triglyceride (TG) and low density lipoprotein cholesterin (LDL-c) in the treatment group and model control group were significantly higher (P<0.05), however, high density lipoprotein cholesterin (HDL-c) was significantly lower. The pathological sections showed that there was lipidosis in rat coronary artery in treatment group and model control group, indicating that the modeling was successful. Immunofluorescence showed that there was only a little fluorochrome permeability in artery in blank control group, there was some fluorochrome permeability in artery in the treatment group and there was a lot of fluorochrome permeability in artery in the model control group. MMP-9 and CD40L in coronary artery tissue in the model control group were significantly higher than the treatment group (P<0.05), MMP-9 and CD40L in coronary artery tissue in the treatment group were significantly higher than the blank control group (P<0.05); serum TNF-α and CRP in the model control group were significantly higher than the treatment group (P<0.05), which were significantly higher in the treatment group than the blank control group (P<0.05).. Rat coronary atherosclerosis heart disease model can be successfully established by feeding with high-fat diet and intraperitoneal injection of VD3, the permeability of coronary artery in coronary heart disease rat model is significantly increased, which may be related to up-regulation of MMP-9, CD40L, TNF-α and CRP expression. Application of curcumin can inhibit expression of MMP-9, CD40L, TNF-α and CRP to improve the permeability of coronary artery.

Topics: Animals; Biomarkers; C-Reactive Protein; CD40 Ligand; Cholecalciferol; Cholesterol, HDL; Cholesterol, LDL; Coronary Artery Disease; Coronary Vessels; Curcumin; Diet, High-Fat; Disease Models, Animal; Male; Matrix Metalloproteinase 9; Permeability; Rats, Wistar; Triglycerides; Tumor Necrosis Factor-alpha

The chemopreventive actions of vitamin D were examined in the N-nitroso-tris-chloroethylurea (NTCU) mouse model, a progressive model of lung squamous cell carcinoma (SCC). SWR/J mice were fed a deficient diet (D) containing no vitamin D3, a sufficient diet (S) containing 2,000 IU/kg vitamin D3, or the same diets in combination with the active metabolite of vitamin D, calcitriol (C; 80 μg/kg, weekly). The percentage (%) of the mucosal surface of large airways occupied by dysplastic lesions was determined in mice after treatment with a total dose of 15 or 25 μmol NTCU (N). After treatment with 15 μmol NTCU, the percentages of the surface of large airways containing high-grade dysplastic (HGD) lesions were vitamin D-deficient + NTCU (DN), 22.7% [P < 0.05 compared with vitamin D-sufficient +NTCU (SN)]; DN + C, 12.3%; SN, 8.7%; and SN + C, 6.6%. The extent of HGD increased with NTCU dose in the DN group. Proliferation, assessed by Ki-67 labeling, increased upon NTCU treatment. The highest Ki-67 labeling index was seen in the DN group. As compared with SN mice, DN mice exhibited a three-fold increase (P < 0.005) in circulating white blood cells (WBC), a 20% (P < 0.05) increase in IL6 levels, and a four-fold (P < 0.005) increase in WBC in bronchial lavages. Thus, vitamin D repletion reduces the progression of premalignant lesions, proliferation, and inflammation, and may thereby suppress development of lung SCC. Further investigations of the chemopreventive effects of vitamin D in lung SCC are warranted.

Topics: Animals; Anticarcinogenic Agents; Carcinoma, Squamous Cell; Cholecalciferol; Diet; Disease Models, Animal; Disease Progression; Enzyme-Linked Immunosorbent Assay; Immunohistochemistry; Lung Neoplasms; Mice; Multiplex Polymerase Chain Reaction; Precancerous Conditions; Real-Time Polymerase Chain Reaction; Vitamin D Deficiency

Vitamin D deficiency affects more that 1 billion people worldwide. Although thought to increase risk of bacterial infections, the importance of vitamin D on host defense against intestinal bacterial pathogens is currently unclear since injection of the active form of vitamin D, 1,25(OH)2D3, increased susceptibility to the enteric bacterial pathogen Citrobacter rodentium by suppressing key immune/inflammatory factors. To further characterize the role of vitamin D during bacteria-induced colitis, we fed weanling mice either vitamin D3-deficient or vitamin D3-sufficient diets for 5 wk and then challenged them with C. rodentium. Vitamin D3-deficient mice lost significantly more body weight, carried higher C. rodentium burdens, and developed worsened histological damage. Vitamin D3-deficient mice also suffered greater bacterial translocation to extra-intestinal tissues, including mesenteric lymph nodes, spleen, and liver. Intestinal tissues of infected vitamin D3-deficient mice displayed increased inflammatory cell infiltrates as well as significantly higher gene transcript levels of inflammatory mediators TNF-α, IL-1β, IL-6, TGF-β, IL-17A, and IL-17F as well as the antimicrobial peptide REG3γ. Notably, these exaggerated inflammatory responses accelerated the loss of commensal microbes and were associated with an impaired ability to detoxify bacterial lipopolysaccharide. Overall, these studies show that dietary-induced vitamin D deficiency exacerbates intestinal inflammatory responses to infection, also impairing host defense.

Topics: Animals; Bacterial Load; Bacterial Translocation; Cecum; Cholecalciferol; Citrobacter rodentium; Colitis; Colon; Cytokines; Diet; Disease Models, Animal; Enterobacteriaceae Infections; Feces; Female; Host-Pathogen Interactions; Inflammation Mediators; Intestinal Mucosa; Lipopolysaccharide Receptors; Lipopolysaccharides; Mice, Inbred C57BL; Pancreatitis-Associated Proteins; Phosphorylation; Proteins; Time Factors; Vitamin D Deficiency; Weight Loss

Discrepancies in bone healing between osteoporotic and non-osteoporotic bone remain uncertain. The focus of the current work is to evaluate potential healing discrepancies in a metaphyseal defect model in rat femora. Female Sprague-Dawley rats were either ovariectomized (OVX, n=14) and combined with a calcium-, phosphorus- and vitamin D3-, soy- and phytoestrogen-free diet or received SHAM operation with standard diet rat (SHAM, n=14). Three months post-ovariectomy, DEXA measurement showed a reduction of bone mineral density reflecting an osteoporotic bone status in OVX rats. Rats then underwent a 3 mm wedge-shaped osteotomy at the distal metaphyseal area of the left femur stabilized with a T-shaped mini-plate and allowed to heal for 6 weeks. Biomechanical competence by means of a non-destructive three-point bending test showed significant lower flexural rigidity in the OVX rats at 3 mm lever span compared to SHAM animals (p=0.048) but no differences at 10 mm lever span. Microcomputer tomography (μCT) showed bridging cortices and consolidation of the defect in both groups, however, no measurable differences were found in either total ossified tissue or vascular volume fraction. Furthermore, histology showed healing discrepancies that were characterized by cartilaginous remnant and more unmineralized tissue presence in the OVX rats compared to more mature consolidation appearance in the SHAM group. In summary, bone defect healing in metaphyseal bone slightly differs between osteoporotic and non-osteoporotic bone in the current 3 mm defect model in both 3mm lever span biomechanical testing and histology.

Topics: Animals; Bone Density; Calcium; Cholecalciferol; Disease Models, Animal; Ergocalciferols; Female; Femoral Fractures; Fracture Healing; Osteoporosis; Osteoporotic Fractures; Ovariectomy; Rats; Rats, Sprague-Dawley; Vitamin D Deficiency

Suxiao Jiuxin Pill is composed of Ligusticum wallichii, Borneolum Syntheticum and other drugs; it has qi promoting and blood circulation activating, meridian dredging and pain relieving efficacies. The objective of this paper is to study the effect of Suxiao Jiuxin Pill (quick-acting heart reliever), in atherosclerosis (AS) rat model and explore the mechanism for its prevention and treatment of AS.. AS rat model was established by high cholesterol diet and single intra-peritoneal injection of increased dose of vitamin D3.. Compared with the model group, Suxiao Jiuxin Pill medium-and high-dose groups and atorvastatin group can effectively regulate lipid metabolism.. We conclude that Suxiao Jiuxin Pill has a good hypo-lipidemic effect, and can inhibit the occurrence and development of AS.

Topics: Animals; Atherosclerosis; Cholecalciferol; Cholesterol, Dietary; Disease Models, Animal; Drugs, Chinese Herbal; Hypolipidemic Agents; Ligusticum; Male; Phytotherapy; Rats; Rats, Sprague-Dawley

The aim of this study was to examine the effects of cholecalciferol on systemic inflammation and memory in the setting of fatty liver disease in rats.. To induce the development of fatty liver disease, the rats were fed a 35% fructose solution over 8 weeks. Group I (n=6) was designated as the control group and fed with standard rat chow. Group II (n=6) was provided with, standard rat chow, and 0.3 μg/kg/day of oral cholecalciferol over a duration of 2 weeks. In addition to standard rat chow, group III (n=6) and group IV (n=6) were given 4 mL of the 35% fructose solution per day via oral gavage for 8 weeks. However, group IV was also given 0.3 μg/kg/day of oral cholecalciferol over 2 weeks. After the treatment period, passive avoidance tasks were performed by all groups. The liver and brain were harvested for subsequent biochemical and histopathologic analyses.. The development of fatty liver extends the memory latency period of passively avoiding tasks after 1 trial. Moreover, there were increases in brain TNF-α and plasma MDA levels according to two-way analysis of variance. Cholecalciferol supplementation decreased the latency period of passively avoiding tasks in rats with hepatosteatosis, and also significantly reduced brain TNF-α and plasma MDA levels.. Fatty liver may contribute to the development of systemic inflammation, which affects cognition and causes deficits in memory; however, the anti-inflammatory and antioxidant properties of vitamin D may improve the cognitive function of rats with hepatosteatosis.

Topics: Administration, Oral; Animals; Avoidance Learning; Cholecalciferol; Cognition Disorders; Disease Models, Animal; Fatty Liver; Inflammation; Inflammation Mediators; Male; Metabolic Syndrome; Rats; Rats, Sprague-Dawley

This study investigated the effects of hypertension on regional aortic biomechanical and structural properties in three rat models of vascular calcification: the hypertensive Lewis polycystic kidney (LPK; n = 13) model of chronic kidney disease, spontaneously hypertensive rats (SHRs; n = 12), and calcification in normotensive Lewis rats induced by vitamin D3 and nicotine (VDN; n = 8). Lewis and Wistar-Kyoto rats were controls. Thoracic and abdominal aortic stiffness parameters were assessed by tensile testing. In models where aortic stiffness differences compared with controls existed in both thoracic and abdominal segments, an additional cohort was quantified by histology for thoracic and abdominal aortic elastin, collagen, and calcification. LPK and VDN animals had higher thoracic breaking strain than control animals (P < 0.01 and P < 0.05, respectively) and lower energy absorption within the tensile curve of the abdominal aorta (P < 0.05). SHRs had a lower abdominal breaking stress than Wistar-Kyoto rats. LPK and VDN rats had more elastic lamellae fractures than control rats (P < 0.001), which were associated with calcium deposition (thoracic R = 0.37, P = 0.048; abdominal: R = 0.40, P = 0.046). LPK rats had higher nuclear density than control rats (P < 0.01), which was also evident in the thoracic but not abdominal aorta of VDN rats (P < 0.01). In LPK and VDN rats, but not in control rats, media thickness and cross-sectional area were at least 1.5-fold greater in thoracic than abdominal regions. The calcification models chronic kidney disease and induced calcification in normotension caused differences in regional aortic stiffness not seen in a genetic form of hypertension. Detrimental abdominal aortic remodeling but lower stiffness in the thoracic aorta with disease indicates possible compensatory mechanisms in the proximal aorta.

Topics: Animals; Aorta, Abdominal; Aorta, Thoracic; Biomechanical Phenomena; Cholecalciferol; Collagen; Disease Models, Animal; Elastin; Female; Hemodynamics; Hypertension; Male; Oxazines; Rats; Rats, Inbred Lew; Rats, Inbred SHR; Rats, Inbred WKY; Renal Insufficiency, Chronic; Tensile Strength; Vascular Calcification; Vascular Stiffness

Polycystic ovary syndrome (PCOS) causes vascular damage to arteries; however, there are no data for its effect on veins. Our aim was to clarify the effects of dihydrotestosterone (DHT)-induced PCOS both on venous biomechanics and on pharmacological reactivity in a rat model and to test the possible modulatory role of vitamin D3 (vitD). PCOS was induced in female Wistar rats by DHT treatment (83 μg/day, subcutaneous pellet). After 10 wk, the venous biomechanics, norepinephrine (NE)-induced contractility, and acetylcholine-induced relaxation were tested in saphenous veins from control animals and from animals treated with DHT or DHT with vitD using pressure angiography. Additionally, the expression levels of endothelial nitric oxide synthase (eNOS) and cyclooxygenase (COX-2) were measured using immunohistochemistry. Increased diameter, wall thickness, and distensibility as well as decreased vasoconstriction were detected after the DHT treatment. Concomitant vitD treatment lowered the mechanical load on the veins, reduced distensibility, and resulted in vessels that were more relaxed. Although there was no difference in the endothelial dilation tested using acetylcholine (ACh), the blocking effect of N(G)-nitro-l-arginine methyl ester (l-NAME) was lower and was accompanied by lower COX-2 expression in the endothelium after the DHT treatment. Supplementation with vitD prevented these alterations. eNOS expression did not differ among the three groups. We conclude that the hyperandrogenic state resulted in thicker vein walls. These veins showed early remodeling and altered vasorelaxant mechanisms similar to those of varicose veins. Alterations caused by the chronic DHT treatment were prevented partially by concomitant vitD administration.

Topics: Animals; Cholecalciferol; Cyclooxygenase 2; Dihydrotestosterone; Disease Models, Animal; Female; Lower Extremity; Nitric Oxide Synthase Type III; Polycystic Ovary Syndrome; Rats; Rats, Wistar; Saphenous Vein; Vasoconstriction; Vasoconstrictor Agents; Vasodilation; Vasodilator Agents; Venous Pressure

We previously demonstrated that dietary vitamin D(3) at 10x the adequate intake (AI) attenuates the decline in functional capacity in the G93A mouse model of ALS. We hypothesized that higher doses would elicit more robust changes in functional and disease outcomes.. To determine the effects of dietary vitamin D(3) at 50xAI on functional outcomes (motor performance, paw grip endurance) and disease severity (clinical score), as well as disease onset, disease progression and lifespan in the transgenic G93A mouse model of ALS.. Starting at age 25 d, 100 G93A mice (55 M, 45 F) were provided ad libitum with either an adequate (AI; 1 IU D(3)/g feed) or high (HiD; 50 IU D(3)/g feed) vitamin D(3) diet.. HiD females consumed 9% less food corrected for body weight vs. AI females (P = 0.010). HiD mice had a 12% greater paw grip endurance over time between age 60-141 d (P = 0.015), and a 37% greater score during disease progression (P = 0.042) vs. AI mice. Although HiD females had a non-significant 31% greater CS prior to disease onset vs. AI females, they exhibited a significant 20% greater paw grip endurance AUC (P = 0.020) when corrected for clinical score.. Dietary D(3) supplementation at 50x the adequate intake attenuated the decline in paw grip endurance, but did not influence age at disease onset, hindlimb paralysis or endpoint in the transgenic G93A mouse model of ALS. Furthermore, females may have reached the threshold for vitamin D(3) toxicity as evidence by reduced food intake and greater disease severity prior to disease onset.

Topics: Amyotrophic Lateral Sclerosis; Animals; Body Weight; Cholecalciferol; Dietary Supplements; Disease Models, Animal; Disease Progression; Eating; Female; Hand Strength; Hindlimb; Male; Mice; Mice, Transgenic; Physical Endurance; Psychomotor Performance

Osteoporosis is a widespread disease characterised by low bone mass and structural deterioration of bone resulting in an increased susceptibility to fractures. Osteoporosis affects women more frequently than men; every second woman older than 50 years suffers from an osteoporotic fracture, frequently a vertebral fracture. The aim of this study was to induce osteoporosis in rats to establish an osteoporotic small-animal model that simulates the human pathology particularly in the spine. Therefore, bone density parameters, which are routinely determined in the spine of osteoporotic patients, were investigated by Dual-Energy X-ray Absorptiometry (DEXA).. Fourteen-week-old female Sprague-Dawley rats (n = 50) were either sham-operated (control group: sham) or ovariectomised (experimental group). Ovariectomised rats were further divided into two groups; one received calcium/vitamin D2/D3 deficient diet (OVX + diet), and the other received subcutaneous steroid injections (dexamethasone 0.3 mg/kg body weight) twice a month (OVX + steroid). Rats were scanned by DEXA at three time points (Month = M, 0 M, 1 M and 3 M). DEXA measurement of the spine delivered T-value, Z-value, bone mineral content (BMC), and the scanned area. Fifteen female patients at an age of 57-72 years were scanned in 8-10 regions of the spine (150 measurements). T-values and Z-values were pre-calculated based on patient databases. Statistical analysis was performed using two-way ANOVA followed by Bonferroni correction, with significance considered at p < 0.05.. T-value and Z-value of both rat groups were compared with the patient data as well as with each others. Both treated rat groups revealed significantly lower T- and Z-values than controls. Despite the significant difference, the reference line (-2.5 for T-value and -1.5 for Z-value) was only reached by the OVX + diet group. On the other hand, the sham group showed an increase in BMC over time, while no change was seen in OVX + diet or OVX + steroid. Bone area demonstrated a significant increase up to M3. However, the increase in bone area within the OVX + diet group was notably higher than in both sham and OVX + steroid groups. Patients showed significantly lower T- and Z-values than sham and OVX + steroid but insignificant ones when compared with OVX + diet.. A reproducible vertebral osteoporosis can be generated in a rat model by combination of ovariectomy with administration of a calcium/vitamin D3 deficient diet. T- and Z-values of this experimental group mimicked values obtained from osteoporotic patients, reflecting a simulation of their pathology. Interestingly, the increase in bone area over time with the steady BMC results in lower mineral density (BMD) of the OVX + diet group. Therefore, this rat model presents a reliable experimental set-up that may serve as a tool to better understand and treat osteoporosis.

Topics: Animals; Calcium; Cholecalciferol; Disease Models, Animal; Ergocalciferols; Female; Osteoporosis; Ovariectomy; Radiography; Rats; Rats, Sprague-Dawley; Spinal Diseases

Endometriosis is one of the most frequent gynecological diseases. In addition to their side effects, available medical therapies may decrease fertility. Current understanding of endometriosis focuses on the role of the immune system in its pathophysiology. Recent research shed light on the immunomodulatory effect of vitamin D3. Thus, this study was designed to study the effect of vitamin D3 on regression of endometriotic implants in a rat surgical model. Vitamin D3 reduced cyst cross sectional area by 48.8%. Histologically, vitamin D treatment produced fibrosis as well as apoptosis in the stroma. The results of the present study suggest that vitamin D3 administration may have a beneficial effect in treating endometriosis.

Topics: Animals; Cholecalciferol; Disease Models, Animal; Endometriosis; Endometrium; Female; Rats

Several studies have shown that soy isoflavones have estrogen-like activities and might constitute an alternative to hormone replacement treatment. The present study investigated the effects of soy isoflavones alone and combined with vitamin D3 on prevention of bone loss.. Sprague-Dawley rats were sham-operated (n = 8) or ovariectomized (OVX; n = 40), and then the OVX rats were randomly assigned to five groups that were untreated or treated for 14 wk with vitamin D3, 17β-estradiol, soy isoflavone extract (SIE), or vitamin D3 plus SIE. The effects of the isoflavones and 1α,25(OH)(2)D(3) on cultured osteoblasts and osteoclasts also were investigated.. In OVX rats, the bone mineral density and trabecular bone volume loss were improved by 17β-estradiol, SIE, or SIE plus vitamin D3 treatment. SIE treatment was more effective than vitamin D3 or 17β-estradiol in inhibiting increases in serum tumor necrosis factor-α levels and osteoblast osteoprotegerin expression. SIE plus vitamin D3 was more effective in increasing osterix expression than each alone. Bone cell cultures showed that the isoflavones induced preosteoblasts to differentiate into osteoblasts and increased osteoblast mineralization. Isoflavones inhibited preosteoclasts and osteoclast proliferation and decreased osteoclast resorption. The combination of isoflavones plus 1α,25(OH)(2)D(3) showed additive effects on the increase in cell proliferation of cultured preosteoblasts.. Treatment with soy isoflavones might be an alternative to hormone replacement therapy in decreasing bone loss from postmenopausal estrogen deficiency. In addition, there are further effects on increasing transcription factor osterix expression and preosteoblast proliferation when these were combined with vitamin D3.

Topics: Alkaline Phosphatase; Animals; Bone Density; Cholecalciferol; Disease Models, Animal; Drug Synergism; Estradiol; Female; Glycine max; Humans; Interleukin-1beta; Isoflavones; Osteoblasts; Osteocalcin; Osteoclasts; Osteogenesis; Osteoporosis; Ovariectomy; Phytoestrogens; Rats; Rats, Sprague-Dawley; RNA, Messenger; Tumor Necrosis Factor-alpha

The vitamin D system plays a critical role in inflammatory bowel disease as evidenced by the finding that both vitamin D deficient mice and vitamin D receptor knockout mice are extremely sensitive to dextran sodium sulfate (DSS)-induced colitis. Moreover, the active form of vitamin D, 1α,25-dihydroxyvitamin D3 [1,25(OH)2D3] is an important immunomodulator that ameliorates the pathogenesis of inflammatory bowel disease. However, therapeutic application of 1,25(OH)2D3 is hampered by its calcemic activity. Previous work illustrated that the analog 1α,25(OH)2-19-nor-14,20-bisepi-23-yne-vitamin D3 (TX527) has potent antiproliferative effects with limited calcemic activity. In the present study we demonstrated that TX527 ameliorated disease symptoms in a DSS-induced model of inflammatory bowel disease. TX527 significantly attenuated disease scores, by suppressing bleeding and diarrhea. Colon length was significantly elevated at the end of the experiment. Histological examination indicated that TX527 diminished mucosal damage and crypt loss and suppressed the infiltration of immune cells in DSS-induced colitis mice. Furthermore, transcript levels of inflammatory cytokines such as IL-1, IL-6, IFN-γ and TNF-α were significantly down-regulated in colonic mucosa of mice with colitis. Moreover, transcript levels of the gastrointestinal glutathione peroxidase 2, which acts as a radical scavenger, were significantly down-regulated after TX527 treatment in DSS-colitis mice. These results indicate that TX527 may have a therapeutic value in the setting of inflammatory bowel disease. This article is part of a Special Issue entitled 'Vitamin D Workshop'.

Topics: Alkynes; Animals; Calcium; Cholecalciferol; Colitis; Cytokines; Dextran Sulfate; Disease Models, Animal; Down-Regulation; Female; Glutathione Peroxidase; Inflammatory Bowel Diseases; Mice; Mice, Inbred C57BL; Oxidative Stress

Alcohol is a known teratogen that is estimated to affect 2-5% of the births in the U.S. Prenatal alcohol exposure can produce physical features such as facial dysmorphology, physiological alterations such as cell loss in the central nervous system (CNS), and behavioral changes that include hyperactivity, cognitive deficits, and motor dysfunction. The range of effects associated with prenatal alcohol exposure is referred to as fetal alcohol spectrum disorders (FASD). Despite preventative measures, some women continue to drink while pregnant. Therefore, identifying interventions that reduce the severity of FASD is critical. This study investigated one such potential intervention, vitamin D3, a nutrient that exerts neuroprotective properties. The present study determined whether cholecalciferol, a common vitamin D3 nutritional supplement, could serve as a means of mitigating alcohol-related learning deficits. Using a rat model of FASD, cholecalciferol was given before, during, and after 3rd trimester equivalent alcohol exposure. Three weeks after cholecalciferol treatment, subjects were tested on a serial spatial discrimination reversal learning task. Animals exposed to ethanol committed significantly more errors compared to controls. Cholecalciferol treatment reduced perseverative behavior that is associated with developmental alcohol exposure in a dose-dependent manner. These data have important implications for the treatment of FASD and suggest that cholecalciferol may reduce some aspects of FASD. This article is part of a Special Issue entitled 'Vitamin D Workshop'.

Topics: Animals; Behavior, Animal; Cholecalciferol; Discrimination Learning; Disease Models, Animal; Dose-Response Relationship, Drug; Ethanol; Female; Fetal Alcohol Spectrum Disorders; Maze Learning; Neuroprotective Agents; Pregnancy; Prenatal Exposure Delayed Effects; Rats; Rats, Sprague-Dawley

Angiotensin-(1-7) [Ang-(1-7)] is a new bioactive heptapeptide in the renin-angiotensin-aldosterone system (RAAS) with potent protective effects in cardiovascular diseases, opposing many actions of angiotensin II (Ang II) mediated by Ang II type 1 (AT1) receptor. It is produced mainly by the activity of angiotensin-converting enzyme 2 (ACE2) and acts through the Mas receptor. However, the role of Ang-(1-7) in vascular calcification (VC) is still unclear. In this study, we investigated the protective effects of Ang-(1-7) on VC in an in vivo rat VC model induced by vitamin D3 plus nicotine. The levels of ACE2 and the Mas receptor, as well as ACE, AT1 receptor, Ang II type 2 receptor and angiotensinogen, were significantly increased in calcified aortas, and Ang-(1-7) reversed the increased levels. Ang-(1-7) restored the reduced expression of lineage markers, including smooth muscle (SM) α-actin, SM22α, calponin and smoothelin, in vascular smooth muscle cells (VSMCs) and retarded the osteogenic transition of VSMCs by decreasing the expression of bone-associated proteins. It reduced alkaline phosphatase activity and calcium deposition in VC and alleviated the hemodynamic disorders of rats with VC. We provide the first in vivo evidence that Ang-(1-7) can inhibit the development of VC by inhibiting the osteogenic transition of VSMCs, at least in part by decreasing levels of the ACE/Ang II/AT1 axis. The increased expression of ACE2 and the Mas receptor in calcified aortas suggests the involvement of the ACE2/Ang-(1-7)/Mas axis during VC. Ang-(1-7) might be an efficient endogenous vasoprotective factor for VC.

Topics: Actins; Alkaline Phosphatase; Angiotensin I; Angiotensin II; Angiotensin-Converting Enzyme 2; Animals; Biomarkers; Calcium-Binding Proteins; Calponins; Cholecalciferol; Cytoskeletal Proteins; Disease Models, Animal; Gene Expression Regulation; Male; Microfilament Proteins; Muscle Proteins; Muscle, Smooth, Vascular; Nicotine; Peptide Fragments; Peptidyl-Dipeptidase A; Proto-Oncogene Mas; Proto-Oncogene Proteins; Rats; Rats, Sprague-Dawley; Receptors, G-Protein-Coupled; Vascular Calcification

Multiple sclerosis is a neurological disorder that presents with symptoms including inflammation, neurodegeneration, and demyelination of the central nervous system (CNS). Secondary progressive multiple sclerosis (SPMS) manifests with serious physical disability. To quantitatively analyze differential protein expression in patients with SPMS, we performed two-dimensional fluorescence difference in-gel electrophoresis, followed by mass spectrometry on the cerebrospinal fluid of these patients and patients with other neurological diseases. Vitamin D-binding protein (DBP), gelsolin, albumin, etc. showed more than a 1.5-fold difference between the two groups. Based on these results, an experimental allergic encephalomyelitis (EAE) model of multiple sclerosis in Lewis rats was used to investigate DBP's role in the disease. Protein levels, mRNA transcripts, and ligands of DBP in different regions of the CNS were evaluated under various vitamin D intake levels. Here, DBP levels increased in the experimental rat groups compared to the control groups regardless of vitamin D intake. Moreover, DBP mRNA levels varied in different parts of the CNS including spinal cords in the experimental groups. The observed differences between DBP protein and mRNA levels in the experimental groups' spinal cords could be derived from the disruption of the blood-brain barrier. Furthermore, an interaction between DBP and actin was confirmed using coimmunoprecipitation and western blot. These results indicate a role for DBP in the actin scavenge system. Moreover, in the experimental group that received oral vitamin D3 supplement, we observed both delayed onset and diminished severity of the disease. When DBP was upregulated, however, the benefits from the vitamin D3 supplements were lost. Thus, we inferred that high levels of DBP were adverse to recovery. In conclusion, here we observed upregulated DBP in the cerebrospinal fluid could serve as a specific diagnostic biomarker for the progression of multiple sclerosis. Next, we demonstrate the vital function of increased levels of free vitamin D metabolites for multiple sclerosis treatment. Finally, vitamin D supplements may be particularly beneficial for SPMS patients.

Topics: Adult; Aged; Animals; Biomarkers; Blotting, Western; Cholecalciferol; Disease Models, Animal; Disease Progression; Electrophoresis, Gel, Two-Dimensional; Encephalomyelitis, Autoimmune, Experimental; Female; Humans; Male; Middle Aged; Multiple Sclerosis; Rats; Rats, Inbred Lew; Reproducibility of Results; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; Spinal Cord; Up-Regulation; Vitamin D-Binding Protein

Epidemiological data suggest an important role of vitamin D signaling in cancer development and progression, and experimental studies demonstrate that the active vitamin D metabolite 1α, 25-dihydroxyvitamin D₃ (1,25D₃) has broad spectrum antitumor activity. Hypercalcemia has often been suggested to limit the clinical application of these data. The 14-epi-analog of 1,25D₃, inecalcitol [19-nor-14-epi-23-yne-1,25-(OH)₂D₃; TX522], was developed to have superagonistic antitumor activities but low hypercalcemia potential. We examined the antitumor activity of inecalcitol and the underlying mechanisms in a murine squamous cell carcinoma (SCC) model system. In vitro, compared with 1,25D₃, inecalcitol showed enhanced vitamin D receptor (VDR)-mediated transcriptional activity. Inecalcitol suppressed SCC cell proliferation in a dose-dependent manner with an IC50 value 30 times lower than that of 1,25D₃. Both inecalcitol and 1,25D₃ induced a comparable level of G0/G₁ cell cycle arrest in SCC cells. The level of apoptosis induced by inecalcitol was markedly higher than that of 1,25D₃. Apoptosis was mediated through the activation of the caspase 8/10- caspase 3 pathway. Further, inecalcitol markedly inhibited the mRNA and protein expression of c-IAP1 and XIAP compared with 1,25D₃. In vivo, inecalcitol inhibits SCC tumor growth in a dose-dependent fashion. Notably, inecalcitol induced a significantly higher level of apoptosis in the SCC xenograft model. While in vitro inecalcitol demonstrates apparent enhanced VDR binding and antiproliferative effects compared to 1,25D₃, in vivo these advantages disappear; at doses of inecalcitol that have equivalent antitumor effects, similar hypercalcemia is seen. This may be explained by the pharmacokinetics of 1,25D₃ vs. inecalcitol and attributed to the much shorter serum half-life of inecalcitol.We show that inecalcitol has potent antitumor activity in the SCC model system, and this is associated with a strong induction of apoptosis. These findings support the further development of inecalcitol in cancer treatment.

Topics: Alkynes; Animals; Antineoplastic Agents; Apoptosis; Carcinoma, Squamous Cell; Caspases; Cell Cycle Checkpoints; Cell Line, Tumor; Cell Proliferation; Cholecalciferol; Disease Models, Animal; Drug Screening Assays, Antitumor; Enzyme Activation; Inhibitor of Apoptosis Proteins; Mice; Transcription, Genetic; Vitamin D; X-Linked Inhibitor of Apoptosis Protein

The aim of this study was to develop a rat model that shares the similarities of calcification in diabetes.. Male Wistar rats received a high-fat diet during 8 weeks followed by a low dose of streptozotocin. Half of them were treated with vitamin D3 and nicotine (VDN) 1 week after streptozotocin injection (DM) (DM+VDN). The others were treated with vehicle (DM). Arterial calcification was facilitated by vitamin D3 and nicotine in age-matched rats (VDN). Measurements of metabolic parameters, aortic calcium content, von Kossa staining, alkaline phosphatase activity and immunohistochemistry for osteopontin were performed. The expression of genes and proteins associated with calcification were also examined.. Treatment with VDN alone resulted in a small but not significant elevation of calcium content in aorta. However, in DM+VDN, aortic calcium content increased significantly as compared to the VDN. This calcification had also dramatically increased, as shown by von Kossa staining. Mechanistic studies revealed that addition of VDN treatment in diabetic rats enhanced both activity and mRNA expression of alkaline phosphatase. This treatment in diabetic- rats also enhanced the expression of core binding factor α 1 and its downstream protein osteopontin. In aorta, strong immunostaining for osteopontin was observed in DM+VDN. The result was also confirmed by Western blot analysis.. These results suggest that a model of accelerated arterial calcification in diabetes have been established and this model could be useful to investigate mechanisms related to vascular complication in diabetes.

Topics: Alkaline Phosphatase; Animals; Arteriosclerosis; Blotting, Western; Bone Density Conservation Agents; Calcium; Cholecalciferol; Diabetes Complications; Diabetes Mellitus, Experimental; Diet, High-Fat; Disease Models, Animal; Immunoenzyme Techniques; Male; Nicotine; Nicotinic Agonists; Osteopontin; Rats; Rats, Wistar; Vascular Calcification

Allergen-specific immunotherapy (SIT) is currently the only curative treatment for allergy but the treatment needs to be improved. We hypothesize that covalent coupling of immunomodulating vitamin D3 to the major cat allergen Fel d 1 can enhance the beneficial effects of SIT to cat allergy.. We treated mice sensitized to Fel d 1 with subcutaneous injections of two doses of recombinant Fel d 1 coupled to 1α,25-dihydroxyvitamin D3 (rFel d 1:VD3) and compared to treatment with the same doses of rFel d 1 in a mouse model for cat allergy. Airway hyperresponsiveness (AHR), cytokines and cells in bronchoalveolar lavage (BAL), in vitro activation of splenocytes to rFel d 1, and Fel d 1-specific immunoglobulins were evaluated.. Treatment with both doses of rFel d 1:VD3 decreased AHR, cellular influx and Th2 cytokines in BAL compared to untreated mice. High- and low-dose rFel d 1 treatment also decreased AHR and BAL Th2 cytokines, with less decrease for the low-dose treatment. Importantly, the total number of cells and eosinophils in BAL was markedly reduced at both high- and low-dose rFel d 1:VD3 compared to treatment with rFel d 1 alone. Finally, treatment with both rFel d 1 and rFel d 1:VD3 induced Fel d 1-specific serum IgG.. Our results indicate a beneficial therapeutic effect of rFel d 1:VD3 on airway inflammation, AHR and rFel d 1-specific immune responses and thus suggest that this novel immunomodulatory candidate may improve both the efficacy and safety of SIT.

Topics: Allergens; Animals; Antibodies, Blocking; Bronchoalveolar Lavage; Cats; Chemotaxis, Leukocyte; Cholecalciferol; Desensitization, Immunologic; Disease Models, Animal; Eosinophils; Female; Glycoproteins; Humans; Hypersensitivity; Immunoglobulin A, Secretory; Immunoglobulin G; Inflammation; Interleukin-5; Lymphocyte Activation; Mice; Mice, Inbred BALB C; Spleen

To investigate the vascular dysfunction caused by insulin resistance in polycystic ovary syndrome (PCOS) and the effectiveness of vitamin D in an animal model.. Controlled experimental animal study.. Animal laboratory at a university research institute.. Thirty female Wistar rats.. Rats were divided into groups at age 21-28 weeks. Twenty of them were subjected to dihydrotestosterone (DHT) treatment (83 μg/d); ten of them also received parallel vitamin D treatment (120 ng/100 g/wk). Oral glucose tolerance tests with insulin level measurements were performed. Gracilis arterioles were tested for their contractility as well as their nitric oxide (NO)-dependent and insulin-induced dilation using pressure arteriography.. Several physiologic parameters, glucose metabolism, and pressure arteriography.. DHT treatment increased the passive diameter of resistance arterioles, lowered norepinephrine-induced contraction (30.1 ± 4.7% vs. 8.7 ± 3.6%) and reduced acetylcholine-induced (122.0 ± 2.9% vs. 48.0 ± 1.4%) and insulin-induced (at 30 mU/mL: 21.7 ± 5.3 vs. 9.8 ± 5.6%) dilation. Vitamin D treatment restored insulin relaxation and norepinephrine-induced contractility; in contrast, it failed to alter NO-dependent relaxation.. In DHT-treated rats, in addition to metabolically proven insulin resistance, decreased insulin-induced vasorelaxation was observed and was improved by vitamin D treatment without affecting NO-dependent relaxation. The reduction in insulin-induced dilation of arterioles is an important as yet undescribed pathway of vascular damage in PCOS and might explain the clinical effectiveness of vitamin D treatment.

Topics: Acetylcholine; Animals; Arterioles; Blood Glucose; Cholecalciferol; Dihydrotestosterone; Disease Models, Animal; Enzyme Inhibitors; Female; Glucose Tolerance Test; Insulin; Insulin Resistance; Muscle, Skeletal; NG-Nitroarginine Methyl Ester; Nitric Oxide; Nitric Oxide Synthase; Polycystic Ovary Syndrome; Rats; Rats, Wistar; Vasodilation; Vasodilator Agents

Vitamin D has antioxidant, anti-inflammatory, and neuroprotective properties, and may mitigate amyotrophic lateral sclerosis (ALS) pathology.. To determine the effects of dietary vitamin D(3) (D(3)) at 10-fold the adequate intake (AI) on functional and disease outcomes and lifespan in the transgenic G93A mouse model of ALS.. Starting at age 40 days, 32 G93A mice (21 M, 11 F) were provided ad libitum with either an adequate (AI; 1 IU/g feed) or high (HiD; 10 IU/g feed) D(3) diet. Differences were considered significant at P≤ 0.10, as this was a pilot study.. For paw grip endurance, HiD mice had a 7% greater score between 60-133 d versus AI mice (P= 0.074). For motor performance, HiD mice had a 22% greater score between 60-133 days (P= 0.074) versus AI mice due to changes observed in male mice, where HiD males had a 33% greater score (P= 0.064) versus AI males. There were no significant diet differences in disease onset, disease progression, or lifespan.. Although disease outcomes were not affected, D(3) supplementation at 10-fold the AI improved paw grip endurance and motor performance in the transgenic G93A mouse model of ALS, specifically in males.

Topics: Amyotrophic Lateral Sclerosis; Animals; Cholecalciferol; Dietary Supplements; Disease Models, Animal; Female; Humans; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; Pilot Projects; Recovery of Function; Sex Factors; Superoxide Dismutase; Up-Regulation

The aim of this study was to clarify the effects of dihydrotestosterone (DHT)-induced polycystic ovary syndrome (PCOS) on pharmacological reactivity of a resistance vessel in a rat model and the possible modulatory role of 1,25-(OH)₂-cholecalciferol (vitamin D₃). The PCOS model was induced in adolescent female Wistar rats by a 10-week DHT treatment. Norepinephrine induced contractility and acetylcholine relaxation were tested in arterioles by pressure arteriography in control as well as DHT- and DHT plus vitamin D₃-treated (DHT+D3) animals. Decreased vasoconstriction and dilatation were detected after DHT treatment. Concomitant vitamin D₃ treatment increased the contractile response and resulted in more relaxed vessels. Endothelial dilation tested with acetylcholine was lower after DHT treatment, this effect was not depend on vitamin D₃ supplementation. In conclusion, hyperandrogenic state resulted in reduced endothelium- and smooth muscle-dependent vasorelaxation and constriction with a complete loss of nitric oxide (NO)-dependent relaxation compared with controls. These alterations caused by chronic DHT treatment were partially reversed by concomitant vitamin D₃ administration.

Topics: Animals; Arterioles; Cardiovascular Agents; Cardiovascular Diseases; Cholecalciferol; Dihydrotestosterone; Disease Models, Animal; Drug Implants; Endothelium, Vascular; Female; Injections, Subcutaneous; Muscle, Skeletal; Muscle, Smooth, Vascular; Polycystic Ovary Syndrome; Rats; Rats, Wistar; Thigh; Vascular Resistance; Vasoconstriction; Vasodilation

Anti-CD3 monoclonal antibodies remain the most promising immune therapy for reversing recent-onset type 1 diabetes. However, current clinical trials have revealed their major drawback, namely the narrow therapeutic window in which low doses are ineffective and higher doses that preserve functional beta cell mass cause side effects. Strategies that sidestep these limitations while preserving or improving anti-CD3's therapeutic efficiency are essential. We hypothesised that combining a potent vitamin D(3) analogue (TX527), ciclosporin A (CsA) and anti-CD3 would act to lower the dose while maintaining or even boosting therapeutic efficacy to counteract autoimmune destruction of transplanted islets.. This study involved the use of syngeneic islet transplantation, immunofluorescence microscopy, immune phenotyping by flow cytometry, RT-PCR analysis, and in vitro and in vivo suppression assays.. Combination therapy with TX527, CsA and anti-CD3 was well tolerated on the basis of weight, bone and calcium variables. Remarkably, combining all three agents at sub-therapeutic doses greatly reduced recurrent autoimmune responses to a grafted islet mass (mean ± SEM: 79.5 ± 18.6 days; p < 0.01), by far exceeding the therapeutic efficacy of monotherapy (24.8 ± 7.3 days for anti-CD3) and dual therapy (25.5 ± 12.4 days for anti-CD3+CsA). Combination therapy surpassed anti-CD3 monotherapy in reducing islet infiltration by effector/memory phenotype CD8(+) T cells, as well as by reducing proinflammatory cytokine responses and increasing the frequency of T regulatory cells that were functional in vitro and in vivo, and acted in a cytotoxic T lymphocyte antigen 4-dependent manner.. Combining the immunomodulatory actions of anti-CD3 mAb with CsA and the vitamin D(3) analogue, TX527, delivers therapeutic efficacy in an islet-transplanted NOD mouse model of diabetes.

Topics: Alkynes; Animals; Antibodies, Monoclonal; CD3 Complex; Cell Proliferation; Cholecalciferol; Cyclosporine; Diabetes Mellitus, Type 1; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Synergism; Female; Islets of Langerhans Transplantation; Male; Mice; Mice, Inbred NOD; Secondary Prevention; T-Lymphocytes; Vitamin D

Calcium overload in vascular smooth muscle is a highly pathogenic event, which progresses with advancing age. Old patients are polymedicated, and several pharmacotherapeutic agents circulate in the plasma as organic anions. The organic anion transporters 1 and 3 (Oat1 and Oat3) are present in renal basolateral membranes, which transport organic anions of pharmacological and physiological interest. This study was designed to evaluate the renal expression and function of Oat1 and Oat3 in rats with vascular calcification.. Vascular calcification was induced by administration of a single dose of vitamin D(3) (300,000 UI/ kg b.w., i.m.) to male Wistar rats 10 days before the experiments. Oat1 and Oat3 expression was assessed by immunoblotting, immunohistochemistry and reverse-transcriptase polymerase chain reaction. The renal clearance of p-aminohippurate (PAH, a prototypical organic anion, substrate of Oat1 and Oat3) was measured by conventional clearance techniques.. Oat1 and Oat3 protein levels showed an increase in plasma membranes of renal proximal tubules of treated animals, where both transporters are functional. This could explain the increase observed in the renal clearance of PAH in treated rats.. These results suggest the relevance of considering the existence of vascular calcification, which is common in ageing, when organic anion drugs are prescribed.

Topics: Animals; Aorta, Abdominal; Arterial Pressure; Calcium; Cell Membrane; Cholecalciferol; Disease Models, Animal; Kidney; Male; Muscle, Smooth, Vascular; Organic Anion Transport Protein 1; Organic Anion Transporters, Sodium-Independent; p-Aminohippuric Acid; Rats; Rats, Wistar; RNA, Messenger; Vascular Calcification

To clarify the effects of dihydrotestosterone (DHT)-induced polycystic ovary syndrome (PCOS) on arteriolar biomechanics in a rat model and the possible modulatory role of vitamin D3.. The PCOS model was induced in female Wistar rats by ten-weeks DHT treatment. Arteriolar biomechanics was tested in arterioles by pressure arteriography in control as well as DHT- and DHT with vitamin D3-treated animals in contracted and passive conditions. Increased wall stress and distensibility as well as increased vascular lumen were detected after DHT treatment. Concomitant vitamin D3 treatment lowered the mechanical load of the arterioles and restored the vascular diameter.. The hyperandrogenic state resulted in more rigid, less flexible arteriolar walls with increased vascular lumen compared with controls. DHT treatment caused eutrophic remodelling of gracilis arteriole. These prehypertensive alterations caused by chronic DHT treatment were mostly reversed by concomitant vitamin D3 administration.

Topics: Adaptation, Physiological; Animals; Arterioles; Biomechanical Phenomena; Cholecalciferol; Disease Models, Animal; Elasticity; Female; Muscle, Skeletal; Polycystic Ovary Syndrome; Prehypertension; Rats; Rats, Wistar; Stress, Mechanical; Vitamins

While searching for vitamin D(3) analogues which inhibit neutrophil recruitment in the lung without elevating plasma calcium level, we found that (5Z,7E)-(1S,3R)-20(R)-[(5E)-(2S)-2-hydroxy-2-methyl-cyclopentanone-5-ylidene]methyl-9,10-secopregna-5,7,10(19)-triene-1,3-diol (TEI-A00114) had the best efficacy and calcemic action. TEI-A00114 has a vitamin D receptor affinity 2.5-fold weaker and a vitamin D binding protein affinity 330.9-fold weaker than those of 1α,25(OH)(2)D(3). The estimated effective doses for 40% inhibition (ED(40)) via peroral and intratracheal administration are 7.6 and 0.4 μg/kg, respectively. TEI-A00114 was also tested by inhaled administration, and its ED(40) was calculated as 0.2 μg/kg. The estimated 40% inhibitory concentration (IC(40)) of TEI-A00114 on interleukin (IL)-8 production induced by lipopolysaccharide and on IL-1β in human whole blood cells in vitro were 9.8 × 10(-8) or 1.8 × 10(-9)M, respectively. These levels of TEI-A00114's activities are equal to those of 1α,25(OH)(2)D(3). On the other hand, the calcemic action of TEI-A00114, which was evaluated at day 14 after sequential peroral quaque die administration, was 89-fold weaker (molar ratio) than that of 1α,25(OH)(2)D(3). These results indicate that TEI-A00114 has a dissociated profile between inhibition of neutrophil recruitment in the lung and calcemic action, suggesting its suitability over 1α,25(OH)(2)D(3) as a candidate for the treatment of acute lung injury.

Topics: Acute Lung Injury; Animals; Calcitriol; Calcium; Cholecalciferol; Cricetinae; Disease Models, Animal; Dose-Response Relationship, Drug; HL-60 Cells; Humans; Male; Neutrophil Infiltration; Rats; Rats, Sprague-Dawley

Peripheral arterial occlusive disease (PAOD) is a challenge in peripheral vascular disease. Clinical observations show reperfusion of occluded vessels may cause compartment syndrome or remote organ injury. Less well known is the role of vitamin D3 in tissue injury; therefore, we attempted to determine whether vitamin D3 could alleviate local and remote organ injury induced by reperfusion of occluded vessels in animal models.. Twenty-four male Sprague-Dawley rats were randomized into four groups: saline + sham, saline + I/R, vitamin D3 + sham, and vitamin D3 + I/R group. After pretreatment for 5 d, the animals designed to I/R injury were subjected to 3 h of ischemia induced by bilateral femoral arteries clamp, followed by reperfusion of the vessels for 3 h on d 6. Left lung and left anterior tibial muscle tissue were harvested for wet/dry weight ratio and histopathologic analysis. Blood was collected for analysis of urea nitrogen (BUN), creatinine (Cr), aspartate aminotransferase (AST), alanine aminotransferase (ALT), tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), ionized calcium levels, and heme oxygenase-1 (HO-1).. Compared with the saline + sham group, there was a significant increase in plasma IL-6 level in both saline + I/R and vitamin D3 + I/R groups and muscle, lung wet/dry weight ratio in the saline + I/R group (P < 0.05). Compared with the saline + I/R group, there was a significant decrease in plasma IL-6 level, muscle and lung wet/dry weight ratio in both vitamin D3 + sham and vitamin D3 + I/R groups, and leukocyte HO-1 expression in vitamin D3 + sham group (P < 0.05). Compared with the vitamin D3 + sham group, there was a significant increase in plasma IL-6 levels in the vitamin D3 + I/R group, and leukocyte HO-1 expression in vitamin D3 + sham group (P < 0.05). BUN, Cr, AST, ALT, TNF-α, ionized calcium levels did not differ significantly among the groups.. Pretreatment of vitamin D3 ameliorates the systemic IL-6 levels, lung and muscle injury induced by ischemia followed by reperfusion of bilateral occluded vessels in a rat model.

Topics: Acute Lung Injury; Animals; Arterial Occlusive Diseases; Calcium; Cholecalciferol; Compartment Syndromes; Disease Models, Animal; Femoral Artery; Heme Oxygenase (Decyclizing); Hindlimb; Interleukin-6; Kidney; Liver; Male; Muscle, Skeletal; Organ Size; Rats; Rats, Sprague-Dawley; Reperfusion Injury; RNA, Messenger; Tumor Necrosis Factor-alpha; Vitamins

Non-alcoholic steatohepatitis (NASH) is recognized as the most severe form of non-alcoholic fatty liver disease, with likely progression to liver cirrhosis and hepatocellular carcinoma. However, there is no unified standard for diagnosis and therapeutics. This study aimed to characterize lipid transfer/metabolic proteins as non-invasive diagnostic markers, and to evaluate the therapeutic effects of phototherapy on the progression of NASH in rats.. Lewis rats given a choline-deficient and iron-supplemented l-amino acid-defined (CDAA) diet and Zucker fa/fa rats were used as a diet-induced and an obesity-related NASH models, respectively, with or without phototherapy.. Serum apolipoprotein E and low molecular weight-adiponectin levels were gradually reduced and reached the lowest level at fatty liver/NASH stage both in CDAA diet-induced NASH model and in genetically obese model. Total-adiponectin levels were dramatically elevated after NASH was established in CDAA diet-induced NASH model. Phototherapy ameliorated hepatocyte apoptosis, inflammation, fibrosis, and insulin/leptin resistance caused by CDAA diet with alteration of the levels of lipid transfer/metabolic proteins and elevation of the circulating active form of vitamin D(3). Vitamin D(3) supplementation ameliorated NASH progression in CDAA diet-induced NASH model. However, phototherapy failed to ameliorate the obesity and steatosis, suggesting that phototherapy may possess anti-inflammatory/fibrotic activity rather than anti-obesity/steatotic activity.. These results suggest that serum lipid transfer/metabolic proteins and vitamin D(3) status may be effective biomarkers for non-invasive diagnosis of NASH progression, and that phototherapy may be a good complementary therapy for NASH because of its regulation of lipid transfer/metabolic proteins and vitamin D(3).

Topics: Adiponectin; Animals; Apolipoprotein A-I; Apolipoproteins E; Apoproteins; Carrier Proteins; Cholecalciferol; Cytokines; Disease Models, Animal; Disease Progression; Fatty Liver; Gene Expression; Heliotherapy; Liver; Male; Non-alcoholic Fatty Liver Disease; Obesity; Rats; Rats, Inbred Lew; Rats, Zucker; Receptors, Adiponectin

Vitamin D₃ and nicotine (VDN) serve as an animal model of arterial calcification. The vascular calcification induced by the VDN model is always accompanied by compensatory left ventricular (LV) hypertrophy and impaired cardiac performance. To determine the possible mechanisms that are responsible for the effects of VDN on the LV, a 2-DE based proteomics approach was used to evaluate the changes in protein expression of the left ventricle in VDN rats, to our knowledge, for the first time. We identified sixteen proteins that were markedly altered and involved in mitochondrial function, heat shock protein activity, myocyte cytoskeleton composition and enzyme activity for energy metabolism. We describe, for the first time, a novel pathway (NDPK) that is involved in LV hypertrophy and enzyme activities of three of the sixteen clinical identified proteins: lactate dehydrogenase (LDH), SOD [Mn] and GST.

Topics: Animals; Blood Pressure; Calcinosis; Cardiomyopathies; Cholecalciferol; Disease Models, Animal; Electrophoresis, Gel, Two-Dimensional; Heart Ventricles; Hypertrophy, Left Ventricular; Male; Nicotine; Proteome; Rats; Rats, Sprague-Dawley; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization

Genistein aglycone (GEN) has a favorable effect on bone loss. We investigated the effects of GEN alone or in combination with supplemental calcium and vitamin D(3) in an animal model of bone loss to evaluate if there was additional benefit. Ovariectomized (OVX) and SHAM-OVX rats were used. OVX were divided into 12 groups and randomized to receive: GEN at 27, 54, 200, 500 or 1000 mg (human equivalent dose (HED)/day/ip injection alone or with calcium carbonate (Ca) (360 mg/kg/day/gavages) and vitamin D(3) (D(3)) (50 IU/kg/day/gavages) or Ca/D(3) without GEN or untreated for 6 weeks. SHAM-OVX were randomized into 7 groups and treated with: Ca and D(3) alone or in combination with GEN (same doses as OVX), or left untreated. Bone mineral density (BMD), bone-alkaline phosphatase (b-ALP), collagen C-telopeptides (CTX), osteoprotegerin (OPG) and soluble receptor activator of NFκB ligand (sRANKL) were assessed. Femurs were excised and tested for breaking strength and histology. Uterine weight was analyzed to assess GEN's estrogenic effects on the SHAM-OVX. The most effective dose of GEN, independent of Ca/D(3) supplementation, was 54 mg/day. Higher doses yielded no further improvement in bone biomarkers, histology or strength. Only 1000 mg/day HED of genistein produced statistically significant changes in uterine weight of the SHAM-OVX. This study suggests that 54 mg/day of GEN is the threshold dose for efficacy. In addition, supplemental calcium and vitamin D(3), beyond normal dietary intake do not enhance the effects of genistein on improving measures of bone loss. This observation has implications regarding the use of calcium and vitamin D(3) supplementation.

Topics: Alkaline Phosphatase; Animals; Bone Density; Bone Density Conservation Agents; Bone Diseases, Metabolic; Calcium Carbonate; Cholecalciferol; Compressive Strength; Disease Models, Animal; Drug Therapy, Combination; Female; Femur; Genistein; Osteoprotegerin; Ovariectomy; Plant Extracts; Random Allocation; RANK Ligand; Rats; Rats, Sprague-Dawley; Sophora; Uterus

In addition to its function in calcium and bone metabolism, vitamin D is neuroprotective and important for mitigating inflammation. Alzheimer's disease (AD) is a progressive neurodegenerative disorder of the central nervous system, characterized by neuronal loss in many areas of the brain, and the formation of senile (neuritic) plaques, which increase in number and size over time. The goal of this project was to investigate whether vitamin D3 supplementation would affect amyloid plaque formation in amyloid-β protein precursor (AβPP) transgenic mice that spontaneously develop amyloid plaques within 3-4 months of birth. AβPP mice were fed control, vitamin D3-deficient or vitamin D3-enriched diets for five months, starting immediately after weaning. At the end of the study, the animals were subjected to behavioral studies, sacrificed, and examined for bone changes and brain amyloid load, amyloid-β (Aβ) peptide levels, inflammatory changes, and nerve growth factor (NGF) content. The results obtained indicate that a vitamin D3-enriched diet correlates with a decrease in the number of amyloid plaques, a decrease in Aβ peptides, a decrease in inflammation, and an increase in NGF in the brains of AβPP mice. These observations suggest that a vitamin D3-enriched diet may benefit AD patients.

Topics: Amyloid beta-Protein Precursor; Animals; Bone and Bones; Brain; Cholecalciferol; Disease Models, Animal; Dose-Response Relationship, Drug; Enzyme-Linked Immunosorbent Assay; Humans; Learning Disabilities; Male; Maze Learning; Memory Disorders; Mice; Mice, Transgenic; Nerve Growth Factor; NFI Transcription Factors; Plaque, Amyloid; Presenilin-1; Tumor Necrosis Factor-alpha

We previously demonstrated that vitamin D₂ (ergocalciferol) triggers axon regeneration in a rat model of peripheral nerve transection. In order to confirm the regenerative potential of this neuroactive steroid, we performed a study in which vitamin D₃ (cholecalciferol) was delivered at various doses to paralytic rats. After spinal cord compression at the T10 level, rats were given orally either vehicle or vitamin D₃ at the dose of 50 IU/kg/day or 200 IU/kg/day. Three months later, M and H-waves were recorded from rat Tibialis anterior muscle in order to quantify the maximal H-reflex (H(max)) amplitude. We also monitored the ventilatory frequency during an electrically induced muscle fatigue known to elicit the muscle metaboreflex and an increase in respiratory rate. Spinal cords were then collected, fixed and immunostained with an anti-neurofilament antibody. We show here that vitamin D-treated animals display an increased number of axons within the lesion site. In addition, rats supplemented with vitamin D₃ at the dose of 200 IU/kg/day exhibit (i) an improved breathing when hindlimb was electrically stimulated; (ii) an H-reflex depression similar to control animals and (iii) an increased number of axons within the lesion and in the distal area. Our data confirm that vitamin D is a potent molecule that can be used for improving neuromuscular adaptive mechanisms and H-reflex responses.

Topics: Animals; Cholecalciferol; Disease Models, Animal; Electromyography; Female; H-Reflex; Immunohistochemistry; Muscle Fatigue; Nerve Regeneration; Paraplegia; Pulmonary Ventilation; Rats; Rats, Sprague-Dawley; Spinal Cord; Vitamins

Cardiovascular calcifications are frequently found in the aging population and are independent predictors of future cardiovascular events. Integrated backscatter (IB) of ultrasound reflectivity can easily quantify calcifications. For this purpose, 30 male Wistar rats received 25,000 IU/kg/day of vitamin D(3) (group 1, n = 8), 18,800 IU/kg/day (group 2, n = 8), or injections with the vehicle only (group 3, n = 14), for 10 weeks. Echocardiographic calibrated IB (cIB) was measured and calculated at baseline and after 10 weeks, followed by ex vivo micro-CT and histopathology of the aortic valve, ascending aorta, and myocardium. After 10 weeks, the mean cIB value of the aortic valve was significantly higher for vitamin D(3)-dosed animals compared to controls. The mean cIB value of the ascending aorta and the myocardium was also significantly higher in group 1 compared to group 3. In vivo IB results were confirmed by ex vivo micro-CT and histopathology. In conclusion, IB is a non-ionizing, feasible, and reproducible tool to quantify cardiovascular calcifications in an in vivo rat model. The integration of IB in the standard echocardiographic examination for the quantification of cardiovascular calcifications could be useful for serial evaluation of treatment efficacy and for prognosis assessment.

Topics: Animals; Aorta; Aortic Valve; Calcinosis; Cardiomyopathies; Cholecalciferol; Disease Models, Animal; Echocardiography, Doppler, Color; Feasibility Studies; Heart Ventricles; Image Interpretation, Computer-Assisted; Male; Myocardium; Predictive Value of Tests; Rats; Rats, Wistar; Time Factors; Ventricular Function, Left; X-Ray Microtomography

Xuezhikang, extract of red yeast rice, is a traditional Chinese medicine with multiple cardioprotective effect. It contains a family of naturally occurring statins, such as lovastatin. Tissue factor (TF) is overexpressed in macrophages of lipid core plaques, which display high procoagulant activity and seem to be a potentially target for anti-atherothrombosis. Therefore, the purpose of this study was to explore the effect and possible molecular mechanisms of xuezhikang on inhibiting TF expression and hypercoagulable state and the differences compared with lovastatin. Our results showed that xuezhikang significantly suppressed oxidized low-density lipoprotein-induced TF expression in macrophages in a concentration-dependent manner. Xuezhikang reduced nicotinamide adenine dinucleotide phosphate oxidase activity by decreasing membrane translocation of p47 through inhibition of extracellular signal-regulated kinase 1/2 activation. Nicotinamide adenine dinucleotide phosphate inhibitor (diphenyleneiodonium) also inhibited the oxidized low-density lipoprotein-induced TF expression, similar to the effects of xuezhikang. Furthermore, consistent with the severity of aortic atherosclerosis, xuezhikang (300 mg·kg·d) significantly reduced blood coagulation activation and TF expression in high-cholesterol diet-induced atherosclerotic rats. In addition, xuezhikang was more potent than lovastatin on inhibiting the expression of TF and nicotinamide adenine dinucleotide phosphate oxidase activation. These observations provide evidences that inhibition of xuezhikang on hypercoagulation and TF expression may partly account for its cardioprotective benefits.

Topics: Animals; Aorta; Biological Products; Blood Coagulation Tests; Cell Survival; Cholecalciferol; Cholesterol; Diet, High-Fat; Disease Models, Animal; Drugs, Chinese Herbal; Enzyme Activation; Extracellular Signal-Regulated MAP Kinases; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Lipoproteins, LDL; Lovastatin; Macrophages; Male; Mice; NADPH Oxidases; Oryza; Random Allocation; Rats; Rats, Wistar; Reactive Oxygen Species; Thrombophilia; Thromboplastin; Vitamins

To compare the anti-atherosclerotic effects of two different extracts from the leaves of Mallotus furetianus by using rat model of atherosclerosis.. The air-dried powdered Mallotus furetianus leaves were extracted with ethanol and then evaporated. The ethanol extract was experienced Diaion HP-20 CC with a gradient of MeOH and H2O (50:50, 100:0, v/v) and two fractions, Mallotus furetianus A (Mf A) and Mallotus furetianus B (Mf B) were obtained. Rats were divided into control, atherosclerosis and vitamin E, Mf A and Mf B treated groups. Atherosclerotic model was established by administering a loading dose of vitamin D3 and feeding standard diet enriched with 2% cholesterol, 0.5% porcine cholate, 0.2% methimazole, 5% sugar, 10% pork fat. Vitamin E (0.20 g/kg), Mf A (0.053 g/kg), Mf B (0.057 g/kg) (with the potential) were administered to interfere with the development of atherosclerosis. After 9 weeks, rats were sacrificed and the blood lipid as well as composition of bile was examined. In addition, the thoracic aorta was harvested to evaluate histological changes and the intima-media thickness ratio.. Atherosclerosis model was successfully established, administration of vitamin E, Mf A and Mf B increased excretion of total bilirubin in bile, decreased triglyeride (TG), total cholesterol (TC), low density lipoprotein-cholesterol (LDL-C) level, enhanced ratio of high density lipoprotein-cholesterol and LDL-C in blood, improved histological changes and diminished intima-media thickness ratio of thoracic aorta in atherosclerotic rats. As for the difference in anti-atherosclerotic effects betweenMf A and Mf B, Mf A may be more powerful in declining TG level and Mf B may be more effective in decreasing TC level.. The two different extracts, Mf A and Mf B can prevent the development of atherosclerosis, In detail, Mf A is more effective in regulating TG level and Mf B is more powerful in modulating TC level in atherosclerotic rats.

Topics: Animals; Aorta, Thoracic; Atherosclerosis; Bile; Bilirubin; Case-Control Studies; Cholecalciferol; Cholesterol; Cholesterol, HDL; Cholesterol, LDL; Disease Models, Animal; Mallotus Plant; Phytotherapy; Plant Extracts; Plant Leaves; Rats; Rats, Wistar; Treatment Outcome; Triglycerides

Amyotrophic lateral sclerosis (ALS) is a neuromuscular disease characterized by motor neuron death in the central nervous system. Vitamin D supplementation increases antioxidant activity, reduces inflammation and improves motor neuron survival. We have previously demonstrated that vitamin D(3) supplementation at 10× the adequate intake improves functional outcomes in a mouse model of ALS.. To determine whether vitamin D deficiency influences functional and disease outcomes in a mouse model of ALS.. At age 25 d, 102 G93A mice (56 M, 46 F) were divided into two vitamin D(3) groups: 1) adequate (AI; 1 IU D(3)/g feed) and 2) deficient (DEF; 0.025 IU D(3)/g feed). At age 113 d, tibialis anterior (TA), quadriceps (quads) and brain were harvested from 42 mice (22 M and 20 F), whereas the remaining 60 mice (34 M and 26 F) were followed to endpoint.. During disease progression, DEF mice had 25% (P=0.022) lower paw grip endurance AUC and 19% (P=0.017) lower motor performance AUC vs. AI mice. Prior to disease onset (CS 2), DEF mice had 36% (P=0.016) lower clinical score (CS) vs. AI mice. DEF mice reached CS 2 six days later vs. AI mice (P=0.004), confirmed by a logrank test which revealed that DEF mice reached CS 2 at a 43% slower rate vs. AI mice (HR= .57; 95% CI: 0.38, 1.74; P=0.002). Body weight-adjusted TA (AI: r=0.662, P=0.001; DEF: r=0.622, P=0.006) and quads (AI: r=0.661, P=0.001; DEF: r=0.768; P<0.001) weights were strongly correlated with age at CS 2.. Vitamin D(3) deficiency improves early disease severity and delays disease onset, but reduces performance in functional outcomes following disease onset, in the high-copy G93A mouse.

Topics: Amyotrophic Lateral Sclerosis; Animals; Cholecalciferol; Disease Models, Animal; Male; Mice; Polymerase Chain Reaction; Treatment Outcome; Vitamin D Deficiency

The objective of the present study was to test the hypothesis that Calcidiol derivative B3CD qualifies as a potential anti-cancer drug in vivo employing an ovarian cancer xenograft model in mice. In addition, the selectivity of B3CD on viability and proliferation of platinum-resistant human ovarian cancer cell lines in comparison to control cell lines was analyzed in vitro. B3CD displayed cell line-specific cytotoxicity screened against a panel of ovarian and other carcinoma cell lines, endothelial and control cells. B3CD, at sub-cytotoxic concentrations, revealed stronger effects on the proliferation of SKOV-3 ovarian cancer cells vs. primary fibroblasts as determined by BrdU incorporation analysis. Treatment with B3CD at 0.5 microM resulted in highly condensed chromatin and fragmented nuclei in SKOV-3 cells but not in primary fibroblasts. B3CD induced cell death at low drug concentrations (< or = 0.5 microM) in SKOV-3 ovarian cancer cells is mediated by the p38 MAPK signaling pathway: B3CD induced p38 MAPK expression and activation in SKOV-3 cells and inhibition of p38 signaling counteracted B3CD induced cell death in vitro. An ovarian cancer cell animal model (human SKOV-3 cell derived xenografts in nude mice) revealed that tumor growth in few B3CD treated mice accelerated while the majority of B3CD treated mice displayed delayed tumor growth or full tumor regression. B3CD possesses anti-ovarian cancer properties in vitro and in vivo. We propose the further development of non-calcemic bromoacetoxy derivatives of vitamin D(3) as potential anti-cancer therapeutics.

Topics: Animals; Antineoplastic Agents; Calcifediol; Calcitriol; Cell Death; Cell Line, Tumor; Cell Proliferation; Cell Shape; Cholecalciferol; Disease Models, Animal; Enzyme Activation; Female; Fibroblasts; Humans; Kaplan-Meier Estimate; Mice; Ovarian Neoplasms; p38 Mitogen-Activated Protein Kinases; Xenograft Model Antitumor Assays

Plant-derived estrogen-like compounds such as isoflavones (IF) especially daidzein and genistein are said to be preserving the bone in the osteoporotic conditions. However, it is not known whether a combination of IF and calcium (Ca) supplementation attenuates losses in bone mass and prevents the loss of vitamin D (VD). The present study addresses the role of phytoestrogens (PE) and Ca supplementation in low Ca and low VD diet induced osteoporosis (OSP). Cowpea (CP) which has high amount of the IF was selected to study its effect on diet induced osteoporotic conditions. Female weanling WNIN rats (total of 68) were divided into five groups and fed for five weeks on semisynthetic diet with low Ca (0.15%) and low VD (0.1IU/day/rat) in combination with low (10 mg/kg) or high (25 mg/kg) concentrations of PEs derived from CPIF. The study groups are: (I) normal Ca(0.47%) and normal VD (25IU/day/rat), (II) low Ca+low VD, (III) low Ca+low VD+low CPIF (10 mg/kg diet), (IV) low Ca+low VD+high CPIF (25 mg/kg diet) and (V) low Ca+low VD+17-(-estradiol (3.2 mg/kg diet). After the development of OSP the group II was subgrouped into: (SG I) continued on low Ca+VD, (SG II) low CPIF, (SG III) high CPIF, (SG IV) 17-beta-estradiol and (SG V) normal Ca and VD. Serum 25-VD levels were in the range of 14-38 ng/ml in groups I, III, IV and V, where as the values were very low in the group II (5.8 ng/ml). These were partially reversed upon supplementation of CPIF. The results correlated with altered Ca levels, body weight, bone mineral density and content and other related biochemical parameters. The paper further explains the possibility of protective and therapeutic role of VD in the presence of CPIF in osteoporotic health manifestations.

Topics: Animals; Bone Density; Calcium; Cholecalciferol; Dietary Supplements; Disease Models, Animal; Female; Genistein; Isoflavones; Osteoporosis; Phosphorus; Phytoestrogens; Plants; Rats; Vitamin D

To explore the effect of age on vascular calcification induced by vitamin D3 and nicotine.. Vascular calcification in rats was induced by administration of vitamin D3 plus nicotine (VDN treatment). After six weeks, Von Kossa staining, calcium content, alkaline phosphatase activity, phosphorus and calcium content in plasma were assayed. Carotid blood pressure, cardiac function and the relative amounts of osteopontin (OPN), osteoprotegerin (OPG), matrix Gla protein (MGP), bone morphogenetic protein-2 (BMP2) mRNA level and smooth muscle actin-alpha (alpha-SMA)protein level were measured.. Compared with control group, the systolic blood pressure(SBP)of the rats of 2,8 and 16 months with vascular calcification respectively increased by 20.7%, 29.4% and 22.2% (P<0.05); the left ventricular systolic pressure (LVSP) respectively increased by 13.6%, 21.1% and 16.2% (P<0.05); + LVdP/dtmax respectively increased by 49.1% (P<0.01), 21.4% and 13.1% (P<0.05); -LVdP/dtmax respectively increased by 56.3% (P<0.01), 24.4% and 11.3% (P<0.05). Aortic calcium contents of the 2-, 8- and 16-month calcified rats were respectively 2.62-fold (P<0.05), 24.87-fold (P<0.01) and 10.01-fold (P<0.05) of the age-matched control group. As compared with the aortic calcium contents of calcified groups at different ages, the calcification group of 8 months had higher aortic calcium content than those of 2 and 16 months, which were respectively, 5.28-fold and 2.63-fold (P<0.05). Compared with the control groups, alkaline phosphatases activity (ALP) of calcification groups increased respectively by 126.6%, 115.2% and 227.9% (P<0.01) in the 2-, 8- and 16-month rats. As compared with the ALP activity of calcified groups at different ages, ALP activity of aortic calcification group of the 8-month-old rats was higher than that of the 2-month-old and 16-month-old rats, which increased by 176% and 75% respectively (all P<0.01). Von kossa staining for calcification showed positive staining as black/brown areas within the main, large, nodular structures as shown in extracellular matrix and cytoplasma in VDN groups at different ages, especially in the 8-month-old VDN group, with the most dispersed calcific nodules deposited and a few of the elastic fibers of the medial layer collapse. The mRNA expressions of OPN, OPG, MGP, BMP2 were up-regulated (P<0.01 or P<0.05) and protein levels of alpha-SMA were down-regulated in different calcification groups(P<0.05). The mRNA levels of OPN in 8-month-old calcification group increased by 3.41-fold (P<0.01) and 1.34-fold (P<0.05) respectively compared with the 2-month-old and 16-month-old calcification groups. And the alpha-SMA protein expression levels were lower at calcification groups in different ages, which were respectively equivalent to 17.6% of the 2-month-old control group (P<0.01), 11% of the 8-month-old control group (P<0.05) and 41.7% of 16-month-old control group (P<0.01).. SD rats of 2, 8 and 16 months can all be used to duplicate vascular calcification model induced by vitamin D3 plus nicotine and the 8-month-old rat has the most sensitivity to the calcification treatment, which means that the 8-month-old rat may be the most appropriate age for the study of vascular calcification.

Topics: Aging; Animals; Aorta, Thoracic; Aortic Diseases; Calcinosis; Cholecalciferol; Disease Models, Animal; Male; Nicotine; Rats; Rats, Sprague-Dawley

Calcitriol has been reported to have antitumor efficacy in several cancers. In this study, we hypothesized that calcitriol may potentially function as a cryosensitizer that can enhance cryoablation, and we investigated several molecular marker changes in a murine model of prostate cancer.. Murine prostate tumors (RM-9) were grown in male C57BL/6J mice subcutaneously with neoadjuvant intratumoral injection of calcitriol followed by cryoablation. The microenvironmental changes after cryoablation alone and in combination with calcitriol were analyzed in a comparative fashion using immunohistochemistry and Western blot analyses.. Both cryoablation and the combination group could suppress tumor growth after treatment compared with the control. At final pathologic assessment, a larger necrotic area was seen in the combination group (P = .026). Although microvessel density (CD31) and the area of hypoxia (pimonidazole) was not different between the control and combination groups, cell proliferation (Ki-67) significantly decreased in the combination treatment (P = .035). In Western blot analyses, several markers for apoptosis were expressed significantly higher with the combination treatment.. The synergistic effect of calcitriol with cryoablation was demonstrated because of enhanced antitumor efficacy by increasing necrosis and apoptosis and reduced cell proliferation. This study suggests that calcitriol is a potentially applicable reagent as a freeze sensitizer to cryoablation.

Topics: Animals; Cholecalciferol; Cryosurgery; Disease Models, Animal; Male; Mice; Mice, Inbred C57BL; Preoperative Care; Prostatic Neoplasms; Vitamins

The aim of this study is to determine the protective effects of vitamin D(3) and dehydroascorbic acid (DHA), a blood-brain barrier transportable form of vitamin C, against ischemia/reperfusion (I/R) injury on a middle cerebral artery occlusion/reperfusion model of brain since reactive oxygen species play an important role in the pathophysiology of I/R injury in brain. In order to examine antioxidant status and lipid peroxidation, we assayed malondialdehyde (MDA) levels as a marker of lipid peroxidation, and reduced glutathione (GSH) and superoxide dismutase (SOD) enzyme activities as free radical scavenging enzymes in cortex and corpus striatum (CS). Wistar albino rats were divided into five equal groups of each consisting of seven rats: control, I/R, I/R + DHA, I/R + vitamin D(3), and I/R + vitamin D(3) + dehydroascorbic acid groups. MDA levels were found to be increased in the I/R group, I/R + DHA, and I/R + vitamin D(3) groups compared with the control group in both cortex and corpus striatum. However, MDA level were found to be significantly decreased in only I/R + vitamin D(3) + DHA group compared with the I/R group in cortex (P < 0.0001). MDA levels were not significantly different in I/R + DHA, and I/R + vitamin D(3) groups compared with the I/R group. GSH and SOD enzyme activities were significantly decreased in I/R, I/R + DHA, and I/R + vitamin D(3) groups compared with the control group in both cortex and corpus striatum (CS) (P < 0.0001). Whereas, both GSH and SOD activity were increased in I/R + vitamin D(3) + DHA group compared with the I/R group in both cortex and CS (P < 0.001 in cortex, P < 0.001 in CS for SOD P < 0.002 in cortex P < 0.03 in CS for GSH). Our results demonstrate that the combination of vitamin D(3) and DHA treatment prevent free radical production and dietary supplementation of vitamin D(3) and DHA which may be useful in the ischemic cerebral vascular diseases.

Topics: Analysis of Variance; Animals; Brain Ischemia; Cerebral Cortex; Cholecalciferol; Corpus Striatum; Dehydroascorbic Acid; Disease Models, Animal; Drug Combinations; Glutathione; Male; Malondialdehyde; Neuroprotective Agents; Oxidative Stress; Rats; Rats, Wistar; Reactive Oxygen Species; Reperfusion Injury; Superoxide Dismutase

Chronic non bacterial prostatitis is a chronic inflammatory syndrome. Its etiology and physiopathology are unclear and treatments are empirical and ineffective in most cases. Autoimmunity has been proposed as an etiology. In the present report, we investigated the impact of vitamin D receptor silencing, by use of VDR-KO NOD mice and the immune-modulating effect of the vitamin D3 analog TX527 on the development of Experimental Autoimmune Prostatitis in NOD mice. VDR-KO NOD mice developed a more aggressive form of autoimmune prostatitis characterized by a greater lymphoproliferative response against prostate antigen in vitro (6.92+/-4.77 vs. 2.47+/-0.41 21 days after disease induction, p<0.05) and higher levels of specific INFgamma secretion (471+/-6 vs. 386+/-5pg/ml, p<0.01). This was accompanied in vivo by more severe lesions and augmented mononuclear cell infiltration in the prostate gland. On the other hand, although analog-treated mice showed a significant reduction in the spleen T-cell specific proliferative response against prostate antigen in vitro, no effect on disease development was observed. We conclude that vitamin D receptor modulation holds the promise of interfering with autoimmune prostatitis. Introduction of more powerful analogs, or combinations with anti-T-cell reagents may represent therapeutic solutions for these group of patients.

Topics: Alkynes; Animals; Autoimmune Diseases; Cells, Cultured; Cholecalciferol; Disease Models, Animal; Male; Mice; Mice, Inbred NOD; Mice, Knockout; Prostatitis; Receptors, Calcitriol

Various complications consequent on disordered calcium and phosphate homeostasis occur frequently in chronic kidney disease (CKD) patients. Particularly, vascular calcification has high morbidity and mortality rates. There is a clear need for a better CKD model to examine various aspects of this disordered homeostasis.. Oral dosing with adenine induced CKD in rats in only 10 days. Serum calcium, phosphate and parathyroid hormone were measured and calcification in aorta was assessed histologically. The effects of varying phosphorus content of diet or treatment with phosphate binders or active vitamin D(3) on these parameters were examined.. After adenine dosing, significant hyperphosphatemia, hypocalcemia and secondary hyperparathyroidism (2HPT) were observed during the experimental period of 15 weeks. Aortic calcification was detected in only some of the animals even at 15 weeks (approximately 40%). Treatment with vitamin D(3) for 18 days, even at a low dose (100 ng x kg(-1), 3-4 times week(-1), p.o), caused aortic calcification in all animals and increases in serum calcium levels up to the normal range. The vitamin D(3)-induced calcification was significantly inhibited by phosphate binders which lowered serum phosphate levels and the calcium x phosphate product, although serum calcium levels were elevated.. These data suggest that rats dosed orally with adenine provide a more useful model for analysing calcium/phosphate homeostasis in severe CKD. Controlling serum calcium/phosphate levels with phosphate binders may be better than vitamin D(3) treatment in hyperphosphatemia and 2HPT, to avoid vascular calcification.

Topics: Adenine; Animals; Aortic Diseases; Biomarkers; Blood Urea Nitrogen; Calcinosis; Calcium; Calcium Carbonate; Chelating Agents; Cholecalciferol; Chronic Disease; Creatinine; Disease Models, Animal; Disease Progression; Hyperparathyroidism, Secondary; Hyperphosphatemia; Hypocalcemia; Kidney Diseases; Male; Parathyroid Hormone; Phosphates; Polyamines; Rats; Rats, Wistar; Sevelamer; Severity of Illness Index; Time Factors

Although immune-mediated pathogenesis in adriamycin (ADR)-induced nephropathy has been proposed recently, studies are lacking about the effects of immunmodulators, such as vitamin D, on ADR-induced nephrotoxicity. We hypothesized that vitamin D(3) (cholecalciferol) would be beneficial on ADR-induced nephropathy because of its immunmodulatory properties. Eighteen male Wistar rats were divided into three groups (n = 6): group 1 (control), group 2 (single ADR injection intravenously), and group 3 (similar single ADR injection intravenously + daily oral cholecalciferol for 21 days) were used in the study. A single high dose of ADR resulted in increased urinary protein: creatinine ratio for all three weeks of the experiment in both groups 2 and 3 compared with the controls. Histological examination of the kidney tissue revealed distinct tubular lesions as tubular necrosis, hyaline casts in tubular lumen, tubular degeneration, tubular dilatation, and tubular vacuolization in group 2 compared with group 1. These tubular lesions were significantly reduced in group 3 compared to group 2. The results of this study indicate that cholecalciferol causes satisfactory tubulointerstitial recovery in ADR-induced nephrotoxicity in rats.

Topics: Analysis of Variance; Animals; Antioxidants; Cholecalciferol; Disease Models, Animal; Dose-Response Relationship, Drug; Doxorubicin; Immunohistochemistry; Injections, Intravenous; Kidney Failure, Chronic; Kidney Function Tests; Male; Probability; Random Allocation; Rats; Rats, Wistar; Reference Values

Both epidemiological and experimental findings have indicated that components of Western diets influence colonic tumorigenesis. Among dietary constituents, calcium and cholecalciferol have emerged as promising chemopreventive agents. We have demonstrated that a Western-style diet (WD) with low levels of calcium and cholecalciferol and high levels of (n-6) PUFA, increased the incidence of neoplasia in mouse intestine compared with a standard AIN-76A diet; models included wild-type mice and mice with targeted mutations. In the present study, adenomatous polyposis coli (Apc)(1638N/+) mice carrying a heterozygous Apc mutation were fed either an AIN-76A diet, a WD, or a WD supplemented with calcium and cholecalciferol (WD/Ca/VitD3). Diets were fed for 24 wk and effects on cellular and molecular events were assessed by performing immunohistochemistry in colonic epithelium along the crypt-to-surface continuum. Feeding WD to Apc(1638N/+) mice not only enhanced cyclin D1 expression in colonic epithelium compared with AIN-76A treatment as previously reported but also significantly increased the expression of the antiapoptotic protein B-cell lymphoma 2 (Bcl-2) concomitantly with a decrease in the proapoptotic Bcl2-associated X protein and the number of apoptotic epithelial cells. WD treatment enhanced mutant Apc-driven small intestinal carcinogenesis and also resulted in the formation of a small number of colonic adenomas (0.16 +/- 0.09; P < 0.05). By contrast, the WD/Ca/VitD3 diet reversed WD-induced growth, promoting changes in colonic epithelium. Importantly, Apc(1638N/+) mice fed the WD/Ca/VitD3 diet did not develop colonic tumors, further indicating that dietary calcium and cholecalciferol have a key role in the chemoprevention of colorectal neoplasia in this mouse model of human colon cancer.

Topics: Adenomatous Polyposis Coli; Adenomatous Polyposis Coli Protein; Animals; Apoptosis; bcl-2-Associated X Protein; Body Weight; Calcium, Dietary; Carcinogenicity Tests; Cholecalciferol; Colon; Cyclin D1; Diet; Disease Models, Animal; Female; Gene Expression Regulation, Neoplastic; Male; Mice; Mutation; Proto-Oncogene Proteins c-bcl-2; Random Allocation

Epidemiological studies have reported an association between arterial calcification and bone loss after menopause. However, the underlying mechanism of the association remains unclear. Therefore, to explore the possible mechanisms of the association, we tried to develop a new combined model rat of ovariectomy (OVX, an animal model of osteoporosis) and vitamin D(3) plus nicotine (VDN rat, an animal model of arterial calcification). We tested them by using sham-operated control rats (SC), OVX control rats (OC), and OVX plus VDN-treated rats (OVN). Dissections were performed twice at 4 (4SC, 4OC, and 4OVN) and 8 (8SC, 8OC, and 8OVN) weeks after treatment. 8OVN showed bone loss and arterial calcification, although 8OC showed only bone loss. Moreover, arterial calcium content was associated with indexes of bone loss at 8 weeks. Thus, the OVN rat is considered a good model to examine the relationship of the two disorders after menopause. Additionally, the arterial endothelin-1 (ET-1, a potent regulator of arterial calcification) levels increased in both 4OVN and 8OVN, and the level was associated with arterial calcium content at 8 weeks. Furthermore, the arterial endothelial nitric oxide synthase (eNOS) protein, which is an enzyme that produces nitric oxide (an antiatherosclerotic substance), was significantly reduced in only 8OVN. Estrogens affect the alterations of the eNOS and ET-1 proteins. Therefore, we suggest that impairment of the ET-1- and NO-producing system in arterial tissue during periods of rapid bone loss by estrogen deficiency might be a mechanism of the relationship between the two disorders seen in postmenopausal women.

Topics: Animals; Arteries; Calcinosis; Calcium; Cholecalciferol; Disease Models, Animal; Endothelin-1; Estradiol; Female; Femur; Nicotine; Nitric Oxide Synthase Type III; Osteoporosis; Ovariectomy; Rats; Rats, Sprague-Dawley; Receptors, Estrogen; Tibia

Differentiation therapy with the hormonal form of vitamin D, 1alpha,25-dihydroxyvitamin D(3) (1,25D(3)), is a promising approach to treatment of acute myeloid leukemia (AML); however, 1,25D(3) induces hypercalcemia at pharmacologically active doses. We investigated the in vitro and in vivoantileukemic efficacy of combined treatment with non-toxic doses of a low-calcemic 1,25D(3) analogue, 1,25-dihydroxy-21(3-hydroxy-3-methyl-butyl)-19-nor-cholecalciferol (19-nor-Gemini; Ro27-5646), and rosemary plant agents in a mouse model of AML.. Proliferation and differentiation of WEHI-3B D- (WEHI) murine myelomonocytic leukemia cellsin vitro were determined by standard assays. Reactive oxygen species, glutathione and protein expression levels were measured by flow cytometry, enzymatic assay and Western blotting, respectively. Systemic AML was developed by intravenous injection of WEHI cells in syngeneic Balb/c mice.. 19-nor-Gemini had a higher potency than its parent compounds, Gemini (Ro27-2310) and 1,25D(3), in the induction of differentiation (EC(50) = 0.059 +/- 0.011, 0.275 +/- 0.093 and 0.652 +/- 0.085 nM, respectively) and growth arrest (IC(50) = 0.072 +/- 0.018, 0.165 +/- 0.061 and 0.895 +/- 0.144 nM, respectively) in WEHI cells in vitro, and lower in vivo toxicity. Combined treatment of leukemia-bearing mice with 19-nor-Gemini (injected intraperitoneally) and standardized rosemary extract (mixed with food) resulted in a synergistic increase in survival (from 42.2 +/- 2.5 days in untreated mice to 66.5 +/- 4.2 days, n = 3) and normalization of white blood cell and differential counts. This was consistent with strong cooperative antiproliferative and differentiation effects of low concentrations of 19-nor-Gemini or 1,25D(3) combined with rosemary extract or its major polyphenolic component, carnosic acid, as well as with the antioxidant action of rosemary agents and vitamin D derivatives in WEHI cell cultures.. Combined effectiveness of 1,25D(3) analogues and rosemary agents against mouse AML warrants further exploration of this therapeutic approach in translational models of human leukemia.

Topics: Abietanes; Animals; Antioxidants; Bone Marrow; Calcitriol; Cell Differentiation; Cell Proliferation; Cholecalciferol; Disease Models, Animal; Drug Synergism; Humans; Immunoblotting; Leukemia, Experimental; Leukemia, Myeloid, Acute; Mice; Mice, Inbred BALB C; Plant Extracts; Reactive Oxygen Species; Rosmarinus; Survival Rate; Tumor Cells, Cultured

This study examined whether dietary supplementation can be used to protect against ischemic stroke. Two groups of adult male Sprague-Dawley rats initially received NT-020, a proprietary formulation of blueberry, green tea, Vitamin D3, and carnosine (n = 8), or vehicle (n = 7). Dosing for NT-020 and vehicle consisted of daily oral administration (using a gavage) over a 2-week period. On day 14 following the last drug treatment, all animals underwent the stroke surgery using the transient 1-hour suture occlusion of middle cerebral artery (MCAo). To reveal the functional effects of NT-020, animals were subjected to established behavioral tests just prior to stroke surgery and again on day 14 post-stroke. ANOVA revealed significant treatment effects (p < 0.05), characterized by reductions of 11.8% and 24.4% in motor asymmetry and neurologic dysfunction, respectively, in NT-020-treated stroke animals compared to vehicle-treated stroke animals. Evaluation of cerebral infarction revealed a significant 75% decrement in mean glial scar area in the ischemic striatum of NT-020-treated stroke animals compared to that of vehicle-treated stroke animals (p < 0.0005). Quantitative analysis of subventricular zone's cell proliferative activity revealed at least a one-fold increment in the number of BrdU-positive cells in the NT-020-treated stroke brains compared to vehicle-treated stroke brains (p < 0.0005). Similarly, quantitative analysis of BrdU labeling in the ischemic striatal penumbra revealed at least a three-fold increase in the number of BrdU-positive cells in the NT-020-treated stroke brains compared to vehicle-treated stroke brains (p < 0.0001). In addition, widespread double labeling of cells with BrdU and doublecortin was detected in NT-020-treated stroke brains (intact side 17% and ischemic side 75%), which was significantly higher than those seen in vehicle-treated stroke brains (intact side 5% and ischemic side 13%) (p < 0.05). In contrast, only a small number of cells in NT-020-treated stroke brains double labeled with BrdU and GFAP (intact side 1% and ischemic side 2%), which was significantly lower than those vehicle-treated stroke brains (intact side 18% and ischemic side 35%) (p < 0.0001). Endogenous neurogenic factors were also significantly upregulated in the ischemic brains of NT-020-treated stroke animals. These data demonstrate the remarkable neuroprotective effects of NT-020 when given prior to stroke, possibly acting via its neurogenic potential

Topics: Animals; Blueberry Plants; Brain Ischemia; Carnosine; Cell Differentiation; Cholecalciferol; Dietary Supplements; Disease Models, Animal; Doublecortin Protein; Drugs, Chinese Herbal; Male; Nervous System Diseases; Neurons; Neuroprotective Agents; Plant Extracts; Rats; Rats, Sprague-Dawley; Stroke; Tea

Non-hypercalcemic analogs of vitamin D(3) modulate the immune response through antigen-presenting cells (APCs) and activated T-cells. A large population-base case-control showed that vitamin D(3) intake significantly decreases the risk of type 1 diabetes development. The aim of this study was, therefore, to observe the in vivo effects of a vitamin D(3) analog administered to Bio Breeding (BB) rats. 1,25-Dihydroxy-16,23Z-diene-26,27-hexafluoro-19-nor vitamin D(3) (BXL-219, formerly Ro 26-2198) (BioXell, Milan, Italy) was administered in vivo to BB rats from days 42 to 110 of life at 0.2 microg/Kg BW. Control animals received only vehicle (olive oil, 4.8 microl/100 g BW). The animals of these two groups were subjected to insulin treatment as they became diabetic. Insulin (Humulin, 28.6 UI/day) was administered irrespective of diabetes occurrence to another group of rats for comparison. Blood glucose, insulin levels, glycosuria, degree of islet infiltration, and the expression of some antigens were observed. Results showed that the vitamin D(3) analog reduced diabetes incidence, although limitedly, in BB rats while administration of oral insulin increased diabetes incidence. In addition, the vitamin D(3) analog did not stimulate an enhancement in the expression of CD4 and CD25 in BB rats as it does in NOD mice, which may explain the failure of this as well as other antidiabetic treatments in the BB animal model of type 1 diabetes.

Topics: Animals; Calcium; Cholecalciferol; Diabetes Mellitus, Experimental; Disease Models, Animal; Female; Immunohistochemistry; Male; Rats; Rats, Inbred BB

Topics: Aldosterone; Animals; Blood Pressure; Cholecalciferol; Disease Models, Animal; Hypertension; Potassium; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Sodium

The azoxymethane (AOM) model recapitulates many features of human colon cancer, lacking an inflammatory component. Dextran sulfate sodium (DSS) induces colitis and promotes AOM-induced colon cancer in mice. Vitamin D analogues are anti-inflammatory and chemopreventive in models of colon cancer. Our aim was to evaluate the anti-inflammatory and chemopreventive efficacy of the vitamin D analogue Ro26-2198 in the AOM/DSS model and in vitro in HCA-7 colon cancer cells.. A/J mice received Ro26-2198 (0.01 microg/kg body wt/day x 28 days) or vehicle by mini-osmotic pump. Animals were treated with a single dose of AOM (5 mg/kg body wt) or vehicle 1 week after pump insertion. Mice received 3% DSS or water x 7 days beginning week 3. Animals were sacrificed after 8 weeks and colon segments were fixed in formalin or flash-frozen. Hematoxylin and eosin colonic sections were examined for dysplasia and colonic lysates were assessed for c-Myc, cyclooxygenase 2, and phospho-(active) extracellular signal regulated kinase (ERK) by Western blotting. For in vitro studies, HCA-7 cells were treated with Ro26-2198 followed by interleukin-1beta (IL-1beta). Proliferation was measured by WST-1 assay.. Ro26-2198 delayed the onset of clinical colitis. Several dysplastic foci were present in the AOM/DSS group; none were found in the Ro26-2198 group. Compared with control, AOM/DSS significantly increased c-Myc (15-fold), cyclooxygenase 2 (COX-2) (2.5-fold), and pERK (10-fold), and Ro26-2198 abolished these increases. In vitro, Ro26-2198 inhibited IL-1beta-induced ERK activation and COX-2 induction and decreased HCA-7 cell proliferation.. Ro26-2198 inhibited proliferative (ERK, c-Myc) and pro-inflammatory (COX-2) signals and progression to dysplasia, suggesting chemopreventive efficacy in this model of colitis-associated carcinogenesis.

Topics: Adenocarcinoma; Animals; Anti-Inflammatory Agents; Cell Division; Cell Line, Tumor; Cholecalciferol; Colitis; Colon; Colonic Neoplasms; Cyclooxygenase 2; Disease Models, Animal; Extracellular Signal-Regulated MAP Kinases; Humans; Interleukin-1beta; Male; MAP Kinase Signaling System; Mice; Mice, Inbred A; Proto-Oncogene Proteins c-myc; Up-Regulation

The vitamin D(3) and nicotine (VDN) model is a model of isolated systolic hypertension (ISH) due to arterial calcification raising arterial stiffness and vascular impedance similar to an aged and stiffened arterial tree. We therefore analyzed the impact of this aging model on normal and diseased hearts with myocardial infarction (MI). Wistar rats were treated with VDN (n = 9), subjected to MI by coronary ligation (n = 10), or subjected to a combination of both MI and VDN treatment (VDN/MI, n = 14). A sham-treated group served as control (Ctrl, n = 10). Transthoracic echocardiography was performed every 2 wk, whereas invasive indexes were obtained at week 8 before death. Calcium, collagen, and protein contents were measured in the heart and the aorta. Systolic blood pressure, pulse pressure, thoracic aortic calcium, and end-systolic elastance as an index of myocardial contractility were highest in the aging model group compared with MI and Ctrl groups (P(VDN) < 0.05, 2-way ANOVA). Left ventricular wall stress and brain natriuretic peptide (P(VDNxMI) = not significant) were highest, while ejection fraction, stroke volume, and cardiac output were lowest in the combined group versus all other groups (P(VDNxMI) < 0.05). The combination of ISH due to this aging model and MI demonstrates significant alterations in cardiac function. This model mimics several clinical phenomena of cardiovascular aging and may thus serve to further study novel therapies.

Topics: Aging; Animals; Cardiomyopathies; Cardiovascular System; Cholecalciferol; Disease Models, Animal; Hypertension; Male; Myocardial Contraction; Myocardial Infarction; Nicotine; Rats; Rats, Wistar; Stroke Volume; Ventricular Dysfunction, Left

Among the changes which occur in the brain with age is an increase in hippocampal concentration of proinflammatory cytokines like interleukin-1beta (IL-1beta) and an increase in IL-1beta-induced signaling. Here we demonstrate that the increase in IL-1beta concentration is accompanied by an increase in expression of IL-1 type I receptor (IL-1RI) and an age-related increase in microglial activation, as shown by increased expression of the cell surface marker, major histocompatibility complex II (MHCII) and increased MHCII staining. The evidence indicates that these age-related changes were abrogated in hippocampus of aged rats treated with dexamethasone and vitamin D3. Similarly, the age-related increases in activation of the stress-activated protein kinase, c-Jun N-terminal kinase (JNK), as well as caspase-3 and PARP were all attenuated in hippocampal tissue prepared from rats that received dexamethasone and vitamin D3. The data indicate that dexamethasone and vitamin D3 ameliorated the age-related increase in IFNgamma and suggest that IFNgamma may be the trigger leading to microglial activation, since it increases MHCII mRNA and IL-1beta release from cultured glia. In parallel with its ability to decrease microglial activation in vivo, we report that treatment of cultured glia with dexamethasone and vitamin D3 blocked the lipopolysaccharide increased MHCII mRNA and IL-1beta concentration, while the IL-1beta-induced increases in activation of JNK and caspase 3 in cultured neurons were also reversed by treatment with dexamethasone and vitamin D3. The data suggest that the antiinflammatory effect of dexamethasone and vitamin D3 derives from their ability to downreguate microglial activation.

Topics: Aging; Animals; Animals, Newborn; Anti-Inflammatory Agents; Caspase 3; Cells, Cultured; Cholecalciferol; Cytokines; Dexamethasone; Disease Models, Animal; Encephalitis; Enzyme Activation; Hippocampus; Lipopolysaccharides; Male; MAP Kinase Kinase 4; Neuroglia; Neurons; Rats; Rats, Wistar; Time Factors

The interactions between cholecalciferol, a precursor of the active form of Vitamin D(3), and conventional antiepileptic drugs (valproate, carbamazepine, phenytoin, and phenobarbital) were studied in the maximal electroshock test in mice. Vitamin D(3) applied i.p. at doses of 37.5 and 75 mug/kg, but not at 18.75 mug/kg, significantly raised the electroconvulsive threshold. Furthermore, cholecalciferol (at its highest subthreshold dose of 18.75 mug) potentiated the anticonvulsant activity of phenytoin and valproate. The action of carbamazepine and phenobarbital was also enhanced by Vitamin D(3), but when it was given at the higher dose of 37.5 mug/kg. Cholecalciferol, antiepileptic drugs, and their combinations did not produce significant adverse effects evaluated in the chimney test (motor coordination) and passive-avoidance task (long-term memory). Cholecalciferol did not significantly increase the brain concentrations of conventional antiepileptics, indicating a pharmacodynamic nature of revealed interactions. Our findings show that cholecalciferol may play an anticonvulsant role in the brain and can influence the efficacy of antiepileptic drugs, at least in experimental conditions.

Topics: Animals; Anticonvulsants; Avoidance Learning; Carbamazepine; Cholecalciferol; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Synergism; Electroshock; Injections, Intraperitoneal; Male; Mental Recall; Mice; Motor Activity; Phenobarbital; Phenytoin; Seizures; Valproic Acid; Vitamins

Immature dendritic cells (DC) can promote long-term transplant survival in rodents. We assessed the impact of stably immature, donor-derived DC on alloimmune reactivity in rhesus macaques.. CD14 monocytes isolated from leukapheresis products of Macacca mulatta were cultured in granulocyte-macrophage colony stimulating factor plus interleukin (IL)-4+/-vitamin (vit) D3, and IL-10. Major histocompatibility complex class II and cosignaling molecule expression was determined on CD11c cells by flow cytometry. T-cell allostimulatory capacity of the DC, including DC exposed to proinflammatory cytokines, was determined in mixed leukocyte reaction. To test their influence in vivo, purified DC were infused intravenously into allogeneic recipients, either alone or followed by CTLA4Ig, 24 hr later. Proliferative responses of recipient CFSE-labeled T cells to donor or third party DC, cytokine production by stimulated T cells, and circulating alloantibody levels were determined by flow cytometry, up to 100 days postinfusion.. VitD3/IL-10-conditioned, monocyte-derived DC were resistant to maturation and failed to induce allogeneic T cell proliferation in vitro. After their infusion, an increase in anti-donor and anti-third party T-cell reactivity was observed, that subsequently subsided to fall significantly below pretreatment levels (by day 56) only in animals also given CTLA4Ig. No increase in circulating immunoglobulin (Ig) M or IgG anti-donor alloantibody titers compared with pretreatment values was detected. With DC+CTLA4Ig infusion, alloreactive IL-10-producing T cells were prevalent in the circulation after day 28.. Maturation-resistant rhesus DC infusion is well-tolerated. DC+CTLA4Ig infusion modulates allogeneic T-cell responses and results in hyporesponsiveness to donor and third party alloantigens.

Topics: Animals; Antibodies, Anti-Idiotypic; Autoimmunity; Cell Transplantation; Cells, Cultured; Cholecalciferol; Culture Media, Conditioned; Dendritic Cells; Disease Models, Animal; Flow Cytometry; Graft Rejection; Immunoglobulin M; Interleukin-10; Leukapheresis; Lipopolysaccharide Receptors; Lymphocyte Activation; Macaca mulatta; Macrophages; Phenotype; T-Lymphocytes; Transplantation, Homologous

Inactivating mutations of the PHEX (phosphate-regulating gene with homologies to endopeptidases on the X chromosome) endopeptidase, the disease-causing gene in X-linked hypophosphatemia (XLH), results in increased circulating levels of fibroblastic growth factor-23 (FGF23), a bone-derived phosphaturic factor. To determine the causal role of FGF23 in XLH, we generated a combined Fgf23-deficient enhanced green fluorescent protein (eGFP) reporter and Phex-deficient Hyp mouse model (Fgf23(+/-)/Hyp). eGFP expression was expressed in osteocytes embedded in bone that exhibited marked upregulation of eGFP in response to Phex deficiency and in CD31-positive cells in bone marrow venules that expressed low eGFP levels independently of Phex. In bone marrow stromal cells (BMSCs) derived from Fgf23(-/-)/Hyp mice, eGFP expression was also selectively increased in osteocyte-like cells within mineralization nodules and detected in low levels in CD31-positive cells. Surprisingly, eGFP expression was not increased in cell surface osteoblasts, indicating that Phex deficiency is necessary but not sufficient for increased Fgf23 expression in the osteoblast lineage. Additional factors, associated with either osteocyte differentiation and/or extracellular matrix, are necessary for Phex deficiency to stimulate Fgf23 gene transcription in bone. Regardless, the deletion of Fgf23 from Hyp mice reversed the hypophosphatemia, abnormal 1,25(OH)(2)D(3) levels, rickets, and osteomalacia associated with Phex deficiency. These results suggest that Fgf23 acts downstream of Phex to cause both the renal and bone phenotypes in Hyp mice.

Topics: Animals; Body Weight; Bone Density; Bone Marrow Cells; Calcium; Cholecalciferol; Disease Models, Animal; Female; Femur; Fibroblast Growth Factor-23; Fibroblast Growth Factors; Gene Expression Regulation; Green Fluorescent Proteins; Hypophosphatemia, Familial; Male; Membrane Glycoproteins; Metalloendopeptidases; Mice; Mice, Inbred C57BL; Mice, Knockout; Microscopy, Fluorescence; Osteocytes; Parathyroid Hormone; PHEX Phosphate Regulating Neutral Endopeptidase; Phosphorus; Promoter Regions, Genetic

There is growing evidence that Vitamin D(3) (1,25-dihydroxyvitamin D(3)) is involved in brain development. We have recently shown that the brains of newborn rats from Vitamin D(3) deficient dams were larger than controls, had increased cell proliferation, larger lateral ventricles, and reduced cortical thickness. Brains from these animals also had reduced expression of nerve growth factor (NGF) and glial cell line-derived neurotrophic factor. The aim of the current study was to examine if there were any permanent outcomes into adulthood when the offspring of Vitamin D(3) deficient dams were restored to a normal diet. The brains of adult rats were examined at 10 weeks of age after Vitamin D(3) deficiency until birth or weaning. Compared to controls animals that were exposed to transient early Vitamin D(3) deficiency had larger lateral ventricles, reduced NGF protein content, and reduced expression of a number genes involved in neuronal structure, i.e. neurofilament or MAP-2 or neurotransmission, i.e. GABA-A(alpha4). We conclude that transient early life hypovitaminosis D(3) not only disrupts brain development but leads to persistent changes in the adult brain. In light of the high incidence of hypovitaminosis D(3) in women of child-bearing age, the public health implications of these findings warrant attention.

Topics: Aging; Animals; Atrophy; Brain; Cholecalciferol; Disease Models, Animal; Female; Fetal Nutrition Disorders; Gene Expression Regulation, Developmental; Lateral Ventricles; Microtubule-Associated Proteins; Nerve Growth Factor; Nerve Tissue Proteins; Pregnancy; Rats; Rats, Sprague-Dawley; Receptors, GABA-A; RNA, Messenger; Vitamin D Deficiency

Vitamin D might have an influence on glucose concentrations, due to the presence of VDR receptors on the pancreas. We established an experimental model of type 2 diabetes in spontaneously hypertensive rats (SHR) and Wistar rats in order to investigate the glycemic response.. SHR males (n=6) and Wistar rats (n=6) weighing approximately 89+/-5.5 g and 123.5+/-6.5 g, respectively, after 7 days of basal period, had the chow pattern substituted (350 kcal/100 g) for a hypercaloric/hyperlipidic (HC/HL) diet (490 kcal/100g) and then injected with 40 mg/kg (SHR) and 20 mg/kg (Wistar) streptozotocin I.P. After the creation of diabetes, the rats suffered daily gavage of cholecalciferol (12.5 microg/kg(-) (1)) for 14 days. The blood glucose was assessed twice a week with a glucometer. The data were analyzed by ANOVA.. SHR and Wistar rats fed on a HC/HL diet gained 60 g and 32 g in once week, vs. the basal period, where they only gained 23 g and 13 g, respectively. The cholecalciferol supplementation did not change the glucose concentration in all of the SHR animals. About 40% of the group responded by treatment with reduction of about 60% in glucose concentrations. We did find a 40% of the blood glucose levels in all Wistar rats.. Cholecalciferol is able to reduce blood glucose in this experimental diabetes model.

Topics: Animals; Blood Glucose; Body Weight; Cholecalciferol; Diabetes Mellitus, Type 2; Dietary Supplements; Disease Models, Animal; Male; Rats; Rats, Inbred SHR; Rats, Wistar; Streptozocin

We investigated the relationship between cardiac dysfunction and Ca2+ transport in the myocardial sarcoplasmic reticulum (SR) during the pathogenesis of cardiovascular calcification in rats. The possible mechanism of SR dysfunction was explored by detecting the alteration of the nitric oxide/nitric oxide synthase (NO/NOS) pathway in the SR. Using the vitamin D plus nicotine (VDN treatment for 2 week and 6 week) experimental model of cardiac calcification, cardiac function and sarcoplasmic reticulum function were measured. Inhibition of cardiac functions in vivo (peak rate of contraction and peak rate of relaxation, P < 0.05 or P < 0.01) were observed in all calcification groups, simultaneously, Ca2+ release and uptake in the SR as well as the Ca2+ release channel and Ca2+ pump activity were inhibited. Myocardial Ca2+ concentration and cardiac and SR dysfunction were inversely related (P < 0.05). The specific NO/NOS pathway (NO production, NOS activity and nNOS expression in the SR) was upregulated in the SR and associated with calcification (both 2- and 6 week VDN groups). These results indicate that cardiac dysfunction associated with myocardial calcification might be mediated by SR dysfunction, which may result from an impaired SR-specific NO/NOS pathway.

Topics: Animals; Calcinosis; Calcium; Cardiomyopathies; Cholecalciferol; Disease Models, Animal; Heart; Male; Nicotine; Nitric Oxide; Nitric Oxide Synthase; Rats; Rats, Wistar; Ryanodine Receptor Calcium Release Channel; Sarcoplasmic Reticulum; Up-Regulation

One of the major challenges in neuroscience is to identify the changes which accompany aging and which contribute to the well-documented age-related deterioration in cognitive function. This is a particular challenge in the light of the vast array of reported changes, which include morphological changes like synaptic and perhaps cell loss, alteration in membrane composition and the resultant changes in function of membrane proteins, modulation of the hypothalamo-pituitary axis, impaired calcium homoeostatic mechanisms, alteration in enzyme function and decreased neurotransmitter release. In the past few years, evidence suggesting that an aged brain exhibits signs of oxidative stress and inflammatory stress has been accumulating, and recent evidence using microarray analysis has added support to this view. In this paper, we provide evidence to suggest that vitamin D3 acts as an anti-inflammatory agent and reverses the age-related increase in microglial activation and the accompanying increase in IL-1beta (interleukin-1beta) concentration.

Topics: Aging; Animals; Anti-Inflammatory Agents; Cholecalciferol; Disease Models, Animal; Hippocampus; Inflammation; Interleukin-1; Interleukin-10; Rats; Synapses

D-hormone [1,25(OH)2 D3] is an important immune system regulator that has been shown to inhibit development of autoimmune diseases including experimental inflammatory bowel disease (IBD), rheumatoid arthritis (RA), multiple sclerosis (MS), and type 1 diabetes. Paradoxically, other immune mediated diseases (experimental asthma) and immunity to infectious organisms were not found to be affected by D-hormone treatment. The effectiveness of D-hormone treatment of autoimmune diseases is due to inhibition of the development and function of Th1 cells and the induction of other Th cells including Th2 cells. We report results of microarray analysis of colons from D-hormone treated mice with experimental IBD. Two hundred thirty-nine genes were inhibited and 298 genes were upregulated in the colon by D-hormone treatment of mice with IBD. Of interest was the D-hormone mediated inhibition of 3 tumor necrosis factor-alpha (TNF-alpha, lipopolysaccharide-induced TNF-alpha factor, and TNF receptor) related genes in the colon. It is likely that the effectiveness of D-hormone treatment of experimental autoimmunity is due in part to the inhibition of the TNF family of genes. D-hormone is a selective regulator of the immune system, and the outcome of D-hormone treatment depends on the nature (infectious disease, asthma, autoimmune disease, etc.) of the immune response.

Topics: Animals; Autoimmune Diseases; Autoimmunity; Cholecalciferol; Colon; Disease Models, Animal; DNA-Binding Proteins; Down-Regulation; Gene Expression Profiling; Gene Expression Regulation; Humans; Immune System; Inflammatory Bowel Diseases; Interleukin-10; Mice; Mice, Knockout; Nuclear Proteins; Receptors, Calcitriol; Receptors, Tumor Necrosis Factor; RNA; Transcription Factors; Tumor Necrosis Factor-alpha; Vitamins

Background tumor growth results in the mobilization of immune inhibitory CD34(+) progenitor cells. However, vitamin D(3) can differentiate the CD34(+) cells into immune stimulatory dendritic cells. This study determined if docetaxel treatment could increase the impact of the vitamin D(3) to generate dendritic cells.. The murine squamous cell carcinoma model, SCC VII/SF, which is often used as a head and neck cancer model, was used to determine the immunological effects of two cycles of docetaxel plus vitamin D(3).. Vitamin D(3) with or without docetaxel was similarly effective in reducing CD34(+) cell levels within the spleen, lymph nodes, and tumor. Dendritic cell levels were similarly enhanced in the lymph nodes by vitamin D(3) alone or combined with docetaxel. However, the combination treatment caused a prominent increase in intratumoral levels of active T cells, which was not observed by the individual treatments.. Incorporating docetaxel treatment with vitamin D(3) differentiation-inducing treatment enhances intratumoral immune responsiveness.

Topics: Animals; Antigens, CD; Antineoplastic Agents, Phytogenic; Carcinoma, Squamous Cell; Cell Count; Cholecalciferol; Dendritic Cells; Disease Models, Animal; Docetaxel; Drug Therapy, Combination; Interferon-gamma; Lymph Nodes; Mice; Spleen; Stem Cells; T-Lymphocytes; Taxoids; Vitamins

We have previously demonstrated in vitro that 1alpha,25-dihydroxyvitamin D3 (calcitriol) treatment increases p27 expression and decreases cell proliferation in cultured thyroid carcinoma cell lines. We hypothesized that in vivo treatment with calcitriol would have a beneficial effect on thyroid carcinoma growth and progression. Five x 10(6) WRO (human thyroid follicular carcinoma derived) cells were implanted in the neck in 4- to 5-wk-old female SCID mice in an orthotopic xenograft model. Animals (n = 15) were treated i.p. three times a week for 21 d with 0.75 microg/kg calcitriol or vehicle. Mice were killed 21 d after tumor implantation, tumor volume was measured, and excised tumor tissue was examined by light microscopy and immunohistochemistry for p27 and thyroglobulin reactivity. Average tumor volume in control mice after 21 d of vehicle treatment was 2002 +/- 207 mm3 compared with a mean tumor volume of 1241 +/- 115 mm3 in animals receiving calcitriol, reflecting a 38% reduction in tumor volume size (P < 0.003). Tumors from vehicle-treated animals demonstrated morphological features of epithelial malignancies with characteristics of insular carcinoma and multiple metastases to the lungs. Tumors excised from calcitriol-treated animals demonstrated signs of differentiation with restoration of thyroglobulin staining. This was associated with a marked accumulation of p27 immunoreactivity in the nuclear compartment. These studies demonstrate that in vivo calcitriol administration can effectively restore p27 accumulation in thyroid carcinoma cells, an effect associated with appreciably enhanced cellular differentiation, reduction in tumor burden, and prevention of metastatic growth.

Topics: Adenocarcinoma, Follicular; Animals; Cell Differentiation; Cell Line, Tumor; Cholecalciferol; Disease Models, Animal; Humans; Immunohistochemistry; Lung Neoplasms; Mice; Proliferating Cell Nuclear Antigen; Thyroglobulin; Thyroid Neoplasms; Xenograft Model Antitumor Assays

In vascular smooth muscle, calcium overload is a highly pathogenic event, which increases with advancing age. An increase in the calcium content of arterial wall may be produced in rats by treatment with vitamin D3. The aim of this study was to evaluate the renal clearance of sulfanilamide (a model organic anion, preferentially eliminated by the kidneys) and other parameters of global renal function in rats with arterial calcinosis. Arterial calcinosis was produced in adult rats by means of a single dose of vitamin D3 (300,000 UI/kg bw, i.m.) 5 days before the experiment. Treated rats showed a large increase in calcium content of aortic tissue and an increase in systolic arterial pressure. No modifications were observed in plasma calcium levels and in plasma lipid profiles. Statistically significant decrements were observed in renal clearance of sulfanilamide, in renal blood flow, in fractional excretion of sodium and potassium. A slight decrease, not statistically different, was observed in the glomerular filtration rate. Rats with arterial calcinosis also showed an increment of total calcium levels in renal tissue, in fractional excretion of calcium and in the expression of organic anion transporter 1 (OAT1). Histological studies revealed tubular alterations. In summary, modifications in hemodynamics and tubular parameters are early manifestations of nephropathy in rats with arterial calcinosis, some of which may account for the changes observed in organic anions renal depuration. It is important to mention that the decrease in clearance of organic anions were seen in spite of the increase in expression of OAT1.

Topics: Animals; Aorta, Abdominal; Aortic Diseases; Blood Pressure; Calcinosis; Calcium; Cholecalciferol; Disease Models, Animal; Glomerular Filtration Rate; Kidney Diseases; Kidney Function Tests; Male; Organic Anion Transport Protein 1; Randomized Controlled Trials as Topic; Rats; Rats, Wistar; Renal Circulation; Sulfanilamide; Sulfanilamides; Systole; Time Factors

FK228 [(E)-(1S,4S,10S,21R)-7-[(Z)-ethylidene]-4,21-diisopropyl-2-oxa-12,13-dithia-5,8,20,23-tetraazabicyclo-[8,7,6]-tricos-16-ene-3,6,9,19,22-pentanone; FR901228, depsipeptide] is a novel histone deacetylase inhibitor that shows therapeutic efficacy in Phase I trials of patients with malignant lymphoma. However, its mechanism of action has not been characterized. In this study, we examined the in vitro and in vivo effects of FK228 on human lymphoma U-937 cells. FK228 very strongly inhibited the growth of U-937 cells with an IC(50) value of 5.92 nM. In a scid mouse lymphoma model, mice treated with FK228 once or twice a week survived longer than control mice, with median survival times of 30.5 (0.56 mg/kg) and 33 days (0.32 mg/kg), respectively (vs. 20 days in control mice). Remarkably, 2 out of 12 mice treated with FK228 (0.56 mg/kg once or twice a week) survived past the observation period of 60 days. The apoptotic population of U-937 cells time-dependently increased to 37.7% after 48 hr of treatment with FK228. In addition, FK228 induced G1 and G2/M arrest and the differentiation of U-937 cells to the CD11b(+)/CD14(+) phenotype. Expression of p21(WAF1/Cip1) and gelsolin mRNA increased up to 654- and 152-fold, respectively, after 24hr of treatment with FK228. FK228 caused histone acetylation in p21(WAF1/Cip1) promoter regions, including the Sp1-binding sites. In conclusion, (i) FK228 prolonged the survival time of scid mice in a lymphoma model, and (ii) the beneficial effects of FK228 on human lymphoma may be exerted through the induction of apoptosis, cell cycle arrest, and differentiation via the modulation of gene expression by histone acetylation.

Topics: Acetylation; Animals; Anti-Bacterial Agents; Antibiotics, Antineoplastic; Apoptosis; Cell Cycle; Cell Differentiation; Cholecalciferol; Cyclin-Dependent Kinase Inhibitor p21; Cyclins; Depsipeptides; Disease Models, Animal; Gelsolin; Histone Deacetylase Inhibitors; Histones; Humans; Leukemia; Lymphoma; Mice; Mice, SCID; Neoplasm Transplantation; Peptides, Cyclic; Promoter Regions, Genetic; RNA, Messenger; Tretinoin; U937 Cells; Xenograft Model Antitumor Assays

We have previously demonstrated that ursodeoxycholic acid(UDCA) and a fluorinated analogue of vitamin D(3), F(6)-D(3),inhibited colonic carcinogenesis in the azoxymethane (AOM) model. Generalized colonic mucosal hyperproliferation and aberrant crypt foci (ACF) are intermediate biomarkers of colon cancer. Using these biomarkers, in this study we examined the anticarcinogenic mechanisms of these chemopreventive agents. Rats were maintained on AIN-76A chow or supplemented with 0.4% UDCA or F(6)-D(3) (2.5 nmol/kg chow) and treated weekly with AOM 20 mg i.p./kg wt or saline x 2 weeks. F(6)-D(3) was continued for an additional 2 weeks and UDCA for the duration of the study. At 40 weeks, animals received bromodeoxyuridine (BrdUrd) i.p. 2 h before sacrifice. A portion of each tumor was fixed in formalin and the remainder flash frozen. Colons were divided longitudinally and half-fixed in formalin and half in ethanol. The size and location of methylene blue-stained ACF were recorded. Cell proliferation (BrdUrd labeling) and apoptosis (terminal deoxynucleotidyl transferase-mediated nick end labeling assay) were measured in colonic crypts and tumors. Protein expression levels of several regulators of cell proliferation were analyzed by immunostaining and Western blotting. Colonic crypt cyclin D1 and E-cadherin mRNA levels were measured by real-time PCR. In saline injected controls, neither UDCA nor F(6)-D(3) alone had any effect on cytokinetic parameters or on the expression of mitogenic regulators. AOM significantly increased the proliferation (percentage of BrdUrd-positive cells) of both ACF (23.1 +/- 1.7%) and non-ACF crypts (17.6 +/- 1.6%), compared with normal colonic crypts (4.5 +/- 0.8%; P < 0.05). This hyperproliferation was accompanied by a 5-fold increase in cyclin D1 and >50% decrease in E-cadherin protein (P < 0.05) in ACF, both of which are predicted to be growth-enhancing alterations. UDCA and F(6)-D(3) significantly (P < 0.05) inhibited AOM-induced crypt cell hyperproliferation, ACF development, and tumor burden. These chemopreventive agents also significantly blocked AOM-induced alterations in cyclin D1 and E-cadherin protein in ACF and tumors. In ACF, changes in mRNA levels of cyclin D1, but not E-cadherin, paralleled alterations in protein expression. Cyclooxygenase-2 and inducible nitric oxide synthase were increased in AOM tumors but not in ACF, and these changes were blocked by UDCA and F(6)-D(3). UDCA and F(6)-D(3) significantly inhibited ACF de

Topics: Animals; Azoxymethane; Base Sequence; Biomarkers, Tumor; Biopsy, Needle; Blotting, Western; Cadherins; Cell Division; Cholecalciferol; Colonic Neoplasms; Cyclin D1; Disease Models, Animal; Immunohistochemistry; Injections, Intraperitoneal; Intestinal Mucosa; Male; Molecular Sequence Data; Neoplasms, Experimental; Polymerase Chain Reaction; Random Allocation; Rats; Rats, Inbred F344; Reference Values; RNA, Messenger; Sensitivity and Specificity; Ursodeoxycholic Acid

1Alpha,25-dihydroxyvitamin D3 (active form of vitamin D3; vitamin D3) has been reported to induce the upregulation of thrombomodulin and downregulation of tissue factor (TF) on monocytes. The possibility exists that vitamin D3 prevents the development of disseminated intravascular coagulation (DIC). In particular, monocyte TF production plays an important role in the pathophysiology of DIC in septic patients. We have attempted to determine whether vitamin D3 is effective against DIC in a rat model induced by lipopolysaccharides (LPS) (30 mg/kg, 4 h) or TF (3.75 U/kg, 4 h) using selective hemostatic parameters, markers of organ dysfunction and pathological findings (assessment of glomelular fibrin deposition). Vitamin D3 was administered orally each day at a dose of 2.0 mg/kg/day for 3 days, or low molecular weight heparin (LMWH 200 u/kg; i.v.) was given 10 min before the injection of TF or LPS in each treatment group. Vitamin D3 was effective against DIC in the rat model induced by LPS only, whereas LMWH was effective against DIC in both rat models induced by either TF or LPS. The anti-DIC effect of vitamin D3 was equal to (or more potent than) that of LMWH. The results suggested that vitamin D3 was useful for the treatment of LPS-induced DIC, and that the assessment of a drug's efficacy should be done carefully given the markedly different results obtained according to the agents used to induce DIC.

Topics: Administration, Oral; Animals; Anticoagulants; Cholecalciferol; Coagulants; Disease Models, Animal; Disseminated Intravascular Coagulation; Fibrin; Heparin; Kidney Diseases; Kidney Glomerulus; Lipopolysaccharides; Male; Rats; Rats, Wistar; Sepsis; Thromboplastin; Thrombosis

Previous studies have described the inhibitory effects of citrate on calcium oxalate crystallization in place of crystal growth, but the effects of citrate on matrix proteins of stones has not been studied in vivo. To examine the effect of citrate on the matrix, we investigated the effect of citrate on osteopontin (OPN) expression, which we had previously identified as an important stone matrix protein. Control rats were treated with saline while rats of the stone group were treated with ethylene glycol (EG) and vitamin D3, and the citrate groups (low-dose and high-dose groups) were treated with a citrate reagent compound of sodium citrate and potassium citrate, in addition to EG and vitamin D3. The rate of renal stone formation was lower in the citrate groups than in the stone group. This was associated with a low expression of OPN mRNA in citrate-treated rats relative to that in the stone group. Citrate was effective in preventing calcium oxalate stone formation and reduced OPN expression in rats. Our results suggest that citrate prevents renal stone formation by acting against not only the crystal aggregation and growth of calcium oxalate but also OPN expression.

Topics: Animals; Blotting, Northern; Chelating Agents; Cholecalciferol; Citric Acid; Disease Models, Animal; Ethylene Glycol; Gene Expression; Immunohistochemistry; In Situ Hybridization; Male; Osteopontin; Oxalates; Rats; Rats, Wistar; RNA, Messenger; Sialoglycoproteins; Urinary Calculi

The chronotherapeutic effects of 1-alpha-(OH) vitamin D3, a pro-drug of 1,25(OH)2 vitamin D3 (1,25(OH)2D3), were evaluated by repeated dosing of the drug in aged stroke-prone spontaneously hypertensive male rats, a model of osteoporosis. Animals (7 months old) were kept in rooms with a 12-h light/dark cycle. Drug (0.5 microg/kg) or vehicle was given once daily at 2 or 14 h after lights on for 3 months. The severity of adverse effects such as body weight loss, hypercalcemia and hyperphosphatemia was significantly less when the drug was given at 14 h after lights on (14 HALO). Serum 1,25(OH)2 vitamin D3 concentrations of 2 h after lights on (2 HALO) group and 14 HALO group did not differ significantly after dosing. The decrease in parathyroid hormone (PTH) level 12 weeks after the start of the study was greater in the 14 HALO group than in the 2 HALO group. Urinary excretion of inorganic Ca and P in the 2 HALO group was greater than that in the 14 HALO group. Urinary excretion of deoxypyridiniline, an index of the bone resorption capacity of osteoclasts, was much suppressed in the 14 HALO group, suggesting that the efficacy of vitamin D3 for suppressing bone resorption might vary with the dosing time. The increase in bone density of both femurs, determined by dual-energy X-ray absorption at the end of the study, was greater in the 14 HALO group than in the 2 HALO group. This is the first study to show the dosing time-dependent efficacy and toxicity of active vitamin D3 in an animal model of osteoporosis. These results indicate that a chronopharmacological approach is beneficial for establishing a more effective and/or safer regimen of active vitamin D3 for the treatment of osteoporosis.

Topics: Aging; Amino Acids; Animals; Body Weight; Bone Density; Calcium; Cholecalciferol; Chronotherapy; Disease Models, Animal; Hypercalcemia; Hypertension; Male; Osteoporosis; Parathyroid Hormone; Phosphates; Rats; Rats, Inbred SHR; Steroid Hydroxylases; Time Factors; Weight Loss

Bisphosphonates, potent inhibitors of bone resorption, have been used clinically to correct the continued loss of bone mass in osteoporosis and in other conditions. However, there has been some concern that long-term treatment with these compounds, as well as more recently developed drugs, may also decrease the rate of bone formation. Bisphosphonates, which are strongly bound to hydroxyapatite crystals, may alter the structure and reactivity of the crystals, interfere with new crystal nucleation and growth, as well as alter the short-range order of newly formed crystals. We have investigated the chemistry and structure of the solid calcium-phosphate mineral phase of lumbar vertebrae of ovariectomized, 6.5-month-old rats treated with bisphosphonates for 1 year after onset of osteopenia. Appropriate control groups were used for comparison. The techniques used to assess the mineral phase were chemical analyses, Fourier transform-infrared (FT-IR) and FT-Raman spectroscopy, FT-IR microspectroscopy, and phosphorus-31 magic-angle-sample spinning nuclear magnetic resonance spectroscopy ((31)P MAS NMR). The (31)P MAS NMR spectra of trabecular bone of lumbar vertebrae of control, ovariectomized, and treated animals were similar. However, there were several significant differences in the results obtained by FT-IR spectroscopy of the whole tissue samples, FT-IR microspectroscopy of sections of bone, and chemical analyses. For example, whereas chemical analyses demonstrated that the CO(3) content of the mineral phase of the ovariectomized animals was decreased compared with controls, FT-IR microspectroscopy of bone sections showed no changes in the relative CO(3) content, but some changes in the environment of the CO(3) groups. However, chemical analyses of the crystals, combined with data from all three spectroscopic methods and with data from serum analysis, did indicate small changes in the mineral phase after ovariectomy, corrected after treatment with bisphosphonates. In any event, the chemical and structural data in the present studies demonstrate that the bisphosphonate, tiludronate, does not significantly alter the mineral components of bone after 1 year of treatment during the course of which bone loss was reversed.

Topics: Animals; Apatites; Bone Diseases, Metabolic; Bone Resorption; Calcium; Cholecalciferol; Diphosphonates; Disease Models, Animal; Female; Lumbar Vertebrae; Magnetic Resonance Spectroscopy; Ovariectomy; Parathyroid Hormone; Phosphorus; Phosphorus Radioisotopes; Rats; Rats, Sprague-Dawley; Spectroscopy, Fourier Transform Infrared; Weight Loss

The aim of the present work was to gain insight into a putative anticancer effect of dietary vitamin D3 (cholecalciferol) in a rat model of colon carcinogenesis. Male rats were assigned to three different dietary groups. The dietary regimens were based on a standard murine-defined diet (AIN-76A) or a stress diet containing 20% fat, reduced Ca2+ concentration, a high phosphorus-to-Ca2+ ratio, and either low or high vitamin D3 content. Colorectal cancer was induced by administration of the procarcinogen 1,2-dimethylhydrazine (DMH). Blood Ca2+, 1,25-dihydroxyvitamin D3 [1,25(OH)2D3], and 25-hydroxyvitamin D3 [25(OH)D3] levels were measured in DMH-treated rats and in respective weight- and age-matched dietary control groups. Colonic epithelial proliferation was assessed by determining thymidine kinase (TK) activity, bromodeoxyuridine (BrdUrd) incorporation into crypt cell DNA, and the mean labeling index along the colonic crypt continuum. Maintenance of rats on the stress diet either unmodified or supplemented with vitamin D3 in the absence of carcinogen treatment provoked a time-dependent rise in colonic TK activity and hyperproliferation of colonic epithelium. DMH treatment of rats maintained on the standard diet caused a marked increase in the proliferative indexes of colonic epithelium and in expansion of the crypt proliferative compartment. TK activity and the crypt mitotic zone were significantly augmented in the animal group fed the stress diet. Supplementary vitamin D3 abrogated the stress diet-enhanced colonic responses to the carcinogenic insult. Colon tumor multiplicity was fourfold higher in animals fed the stress diet than in animals maintained on a standard diet. The marked rise in colonic tumor multiplicity and adenocarcinoma incidence in rats fed the stress diet was obliterated by supplemental dietary vitamin D3. Cumulatively, the present results indicate that dietary vitamin D3 impedes the neoplastic process in murine large intestine and strengthen the view that inappropriate changes in dietary components and micronutrients are contributory determinants of colorectal cancer.

Topics: 1,2-Dimethylhydrazine; Adenocarcinoma; Animals; Body Weight; Bromodeoxyuridine; Calcifediol; Calcitriol; Calcium; Calcium, Dietary; Cell Division; Cholecalciferol; Colon; Colonic Neoplasms; Disease Models, Animal; Male; Random Allocation; Rats; Thymidine Kinase

Kampo medicine is a traditional Japanese therapeutic system which originated in China and was used to treat various diseases for hundreds of years. Kampo medicine had been also used for the cure and the prevention of urinary calculi for many years, but the effect and the mechanism of this use of kampo medicine are unclear. We examined the inhibitory effect of the kampo medicine takusha on the formation of calcium oxalate renal stones induced by ethylene glycol (EG) and vitamin D3 in rats. We also investigated the effect of takusha on osteopontin (OPN) expression, which we previously identified as an important stone matrix protein. The control group rats were non-treated; the stone group rats were administered EG and vitamin D3, and the takusha group was administered takusha in addition to EG and vitamin D3. The rate of renal stone formation was lower in the takusha group than in the stone group; thus, the OPN expression in the takusha group was smaller than in the stone group. Takusha was effective in preventing oxalate calculi formation and OPN expression in rats. These findings suggest that takusha prevents stone formation including not only calcium oxalate aggregation but also proliferation.

Topics: Animals; Calcium Oxalate; Cholecalciferol; Disease Models, Animal; Drugs, Chinese Herbal; Ethylene Glycol; Gene Expression; Kidney Calculi; Male; Osteopontin; Rats; Rats, Wistar; Sialoglycoproteins

Urinary calcium stones are a pathological substance, and they show similarities to physiological mineralization and other pathological mineralizations. The expression of messenger (m) RNAs of osteopontin (OPN), matrix Gla protein (MGP), osteonectin (ON) and osteocalcin (OC) in bones and teeth has been described. We previously identified OPN as an important stone matrix protein. In addition, the spontaneous calcification of arteries and cartilage in mice lacking MGP was recently reported, a finding which indicates that MGP has a function as an inhibitor of mineralization. Here, we examined the mRNA expressions of OPN, MGP, ON, and OC in the kidneys of stone-forming model rats administered an oxalate precursor, ethylene glycol (EG) for up to 28 days. The Northern blotting showed that the mRNA expressions of OPN and MGP were markedly increased with the administration of EG, but their expression patterns differed. The OPN mRNA expression reached the maximal level at day 7 after the initiation of the EG treatment and showed no significant difference after 14 and 28 days, whereas the MGP mRNA expression rose gradually to day 28. The in situ hybridization demonstrated that the cell type expressing OPN mRNA was different from that expressing MGP. We suggest that OPN acts on calcification and MGP acts on suppression.

Topics: Animals; Blood Urea Nitrogen; Blotting, Northern; Calcium Oxalate; Calcium-Binding Proteins; Cholecalciferol; Disease Models, Animal; Ethylene Glycol; Extracellular Matrix Proteins; In Situ Hybridization; Kidney; Male; Matrix Gla Protein; Osteocalcin; Osteonectin; Osteopontin; Oxalic Acid; Rats; Rats, Wistar; RNA, Messenger; Sialoglycoproteins; Time Factors; Urinary Calculi

Analogs related to 1 alpha,25-dihydroxy-2 beta-(3-hydroxypropoxy)vitamin D3 (ED-71) (4), oxa-type and carba-type analogs of vitamin D3 bearing substituents at the 2 beta-position of 1 alpha,25-dihydroxyvitamin D3 (1), were synthesized from the alpha-epoxides (6 and 13). Three analogs, ED-71 (4) and two carba-type analogs (16 and 26), showed potent preventive effects on bone mineral loss in pre-osteoporosis model rats. ED-71 (4) was concluded to be an optimized analog and a promising candidate for the treatment of osteoporosis.

Topics: Absorptiometry, Photon; Animals; Bone Density; Calcitriol; Cholecalciferol; Disease Models, Animal; Drug Design; Female; Humans; Osteoporosis, Postmenopausal; Ovariectomy; Rats; Rats, Wistar; Receptors, Calcitriol; Vitamin D

1. The aim of the present study was to test whether the vitamin D-dependent Ca(2+)-binding protein calbindin-D9k could function as an important cytosolic Ca2+ buffer in duodenal enterocytes while facilitating transepithelial active transport of Ca2+ ions. For the investigations we used dual-wavelength, fluorescence ratio imaging, with fura-2 as the Ca(2+)-sensitive dye, to measure changes in cytosolic concentrations of free Ca2+ ions ([Ca2+]i) in isolated pig duodenal enterocytes affected by different cytosolic calbindin-D9k concentrations. 2. Epithelial cells were obtained from weaned piglets with normal calbindin-D9k concentrations (con-piglets), from piglets with low calbindin-D9k levels due to inherited calcitriol deficiency caused by defective renal 25-hydroxycholecalciferol D3-1 alpha-hydroxylase activity (def-piglets), and from piglets with reconstituted calbindin-D9k concentrations, i.e. def-animals treated with high doses of vitamin D3 which elevated plasma calcitriol levels by extrarenal production (def-D3-piglets). Basal levels of [Ca2+]i ranged between 170 and 205 nM and did not differ significantly between the groups. 3. After addition of 5 mM theophylline, the [Ca2+]i in enterocytes from con-piglets doubled during the 10 min incubation. This effect, however, was three times higher in enterocytes from def-piglets compared with those from con-piglets. Similar results were obtained after 4 min incubation of enterocytes from con- and def-piglets in the presence of 1 microM ionomycin. In preparations from def-D3-piglets, ionomycin-induced increases in [Ca2+]i were significantly lower compared with enterocytes from def-piglets and were not different from the control values. 4. From the results, substantial support is given for the hypothesis that one of the major functions of mucosal calbindin-D9k is the effective buffering of Ca2+ ions.

Topics: Animals; Biological Transport, Active; Calbindins; Calcitriol; Calcium; Cell Survival; Cholecalciferol; Cytosol; Disease Models, Animal; Duodenum; Female; Intestinal Mucosa; Ionomycin; Ionophores; Male; Microvilli; S100 Calcium Binding Protein G; Swine; Theophylline; Vitamin D Deficiency

Topics: Animals; Bone Resorption; Cholecalciferol; Depression, Chemical; Diphosphonates; Disease Models, Animal; Female; Hypercalcemia; Imidazoles; Ovariectomy; Pamidronate; Parathyroidectomy; Rats; Thyroidectomy; Zoledronic Acid

To determine whether 24R,25-dihydroxyvitamin D3 [24R,25(OH)2D3] exerts unique biologic effects on bone, we examined the effects of the vitamin D metabolites, 24R,25(OH)2D3 and 1 alpha,25-dihydroxyvitamin D3 [1 alpha,25(OH)2D3], on the hypophosphatemic (Hyp) mouse, a model for X-linked hypophosphatemic rickets in humans. The Hyp mice were administered 1-10,000 micrograms/kg/day of 24R,25(OH)2D3, 0.01-10 micrograms/kg/day of 1 alpha,25(OH)2D3, or vehicle alone, given daily for 28 days by intraperitoneal injection. 24R,25(OH)2D3 at doses of 1-1000 micrograms/kg/day had dose-dependent effects in increasing bone size, dry bone weight, and bone mineral content without causing hypercalcemia. 1 alpha,25(OH)2D3 at doses of 1 or 10 micrograms/kg/day, which we considered to have activity similar to that of 1000 micrograms/kg/day of 24R,25(OH)2D3 with respect to cell differentiation activity, caused severe bone resorption and hypercalcemia. At 0.1 microgram/kg/day, 1 alpha,25(OH)2D3 increased bone size, similarly to a dose of 1000 micrograms/kg/day of 24R,25(OH)2D3, without significantly affecting dry bone weight or bone mineral content, as did 1000 micrograms/kg/day of 24R,25(OH)2D3. These findings suggest that 24R,25(OH)2D3 exerts unique activity in the Hyp mouse rather than merely mimicking the activity of 1 alpha,25(OH)2D3.

Topics: Animals; Bone Density; Bone Development; Calcitriol; Cholecalciferol; Disease Models, Animal; Drug Administration Schedule; Hypercalcemia; Hypophosphatemia; Injections, Intraperitoneal; Male; Mice; Mice, Inbred C57BL; Radiography

According to chemical analyses, the development of conventional human coronary artery plaques from "fatty streaks" to "fibrous plaques" and "complicated lesions" is dominated by progressive mural calcium (Ca) incorporation. The atherogenic significance of Ca ions and arterial Ca overload was examined under the influence of nicotine, oxidatively modified low-density lipoproteins, spontaneous hypertension, and an elevated extracellular Ca concentration or vitamin D3. Experiments were carried out either in vitro on cultured medial cells of rats or in vivo on various types of experimental arteriosclerosis of rats. Suitable Ca antagonists (verapamil, diltiazem, nifedipine, or nitrendipine) prevented experimental Ca overload of arterial walls and transmembrane Ca uptake into cultured medial cells produced by risk factors. Thus they protected, in vivo and/or in vitro, against the atherogenic potential of Ca ions, i.e., migration, proliferation, matrix production and intracellular Ca overload of vascular smooth-muscle cells, as well as calcification of elastic fibers. The data indicate that various Ca-consuming processes demand a progressive uptake of Ca into arterial walls if Ca-dominated types of arteriosclerosis develop. Under experimental conditions, specific Ca antagonists inhibit Ca-mediated arteriosclerotic alterations by preventing progressive mural Ca incorporation.

Topics: Adult; Aged; Aged, 80 and over; Animals; Arteriosclerosis; Calcium; Calcium Channel Blockers; Cells, Cultured; Cholecalciferol; Cholesterol; Coronary Vessels; Diltiazem; Disease Models, Animal; Humans; Hypertension; Middle Aged; Muscle, Smooth, Vascular; Nicotine; Nifedipine; Nitrendipine; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Rats, Sprague-Dawley; Risk Factors; Verapamil

During the course of chronic renal failure (CRF) in man, renal osteodystrophy (osteitis fibrosa and/or osteomalacia) gradually develops. The present study aimed to establish a similar type of CRF leading to renal osteodystrophy in rats. During progressive CRF development over 225 days after 5/6 nephrectomy, the following serum variables were measured: creatinine, immunoreactive parathyroid hormone (iPTH), 1,25-dihydroxyvitamin D3 (1,25(OH)2D3), a25-hydroxyvitamin D3, (25(OH)D3), alkaline phosphatase, albumin, phosphate, urea nitrogen, total calcium, and other blood electrolytes. Subsequent to sacrifice, mechanical properties of the rat femur, bone histomorphometry (osteoid and eroded surfaces) and bone contents of calcium, phosphate and hydroxyproline were also examined. Serum creatinine in rats with CRF gradually escalated by some 70%, while circulating 1,25(OH)2D3 was reduced beneath detection level. Total plasma calcium and phosphate concentrations were, however, almost unchanged indicating that PTH-induced bone remodeling due to moderate hyperparathyroidism sustained calcium homeostasis. Alkaline phosphatase levels were reduced by some 50%, which reflects chronically impeded bone formation. Bone histomorphometry assessment revealed substantial elevation of resorption with moderate accompanying fibrosis in about 70% of afflicted animals. Bone calcium, phosphate and hydroxypyrroline contents remained unaltered. However, hydroxyproline/calcium ratio was marginally reduced. These results, together with altered mechanical bending stress characteristics and diminished diaphysis cross section area, confirm development of mixed bone lesions in the uremic animals. Our results are compatible with the early development of CRF in man. The established rat model is therefore useful in elucidating the precipitation and early treatment of renal osteodystrophy in humans.

Topics: Alkaline Phosphatase; Animals; Biomarkers; Bone and Bones; Calcium; Cholecalciferol; Chronic Kidney Disease-Mineral and Bone Disorder; Disease Models, Animal; Female; Hydroxyproline; Hyperparathyroidism, Secondary; Nephrectomy; Parathyroid Hormone; Rats; Rats, Wistar; Second Messenger Systems; Stress, Mechanical; Uremia

The common marmoset, a New World monkey, requires a large amount of cholecalciferol (110 i.u./day per 100g body wt.) to maintain its normal growth. In a previous report, we demonstrated that the circulating levels of 1 alpha, 25-dihydroxycholecalciferol [1 alpha,25(OH)2D3] in the marmosets are much higher than those in rhesus monkeys and humans, but the marmosets are not hypercalcaemic [Shinki, Shiina, Takahashi, Tanioka, Koizumi & Suda (1983) Biochem. Biophys. Res. Commun. 14, 452-457]. To compare the effect of the daily intake of cholecalciferol, two rhesus monkeys were given a large amount of cholecalciferol (900 i.u./day per 100g body wt). Their serum levels of calcium, 25-hydroxycholecalciferol and 24R,25-dihydroxycholecalciferol were markedly elevated, but the serum 1 alpha,25(OH)2D3 levels remained within a range similar to those in the rhesus monkeys fed the normal diet (intake of cholecalciferol 5 i.u./day per 100g body wt). Intestinal cytosols prepared from both monkeys contained similar 3.5 S macromolecules to which 1 alpha,25(OH)2D3 was bound specifically. However, the cytosols from the marmosets contained only one-sixth as many 1 alpha,25(OH)2D3 receptors as those from the rhesus monkeys. Furthermore, the activity of the 1 alpha,25(OH)2D3-receptor complex in binding to DNA-cellulose was very low in the marmosets. These results suggest that the marmoset possesses an end-organ resistance to 1 alpha,25(OH)2D3 and is a useful animal model for studying the mechanism of vitamin D-dependent rickets, type II.

Topics: Animals; Calcitriol; Calcium; Callithrix; Callitrichinae; Centrifugation, Density Gradient; Cholecalciferol; Chromatography, Ion Exchange; Cytosol; Disease Models, Animal; Drug Resistance; Female; Macaca mulatta; Male; Phosphorus; Receptors, Calcitriol; Receptors, Steroid

The following mechanisms for inactivating excessive Ca++ are found in the vessel wall (e.g. in old age, arteriosclerosis, hypertension, or overdosage with Vitamin D3): 1. The production of Matrix Vesicles, which reduce biologically active extracellular Ca++ by precipitating it during the initial stage of calcification. 2. An increase in the number of muscle cells changed from the "k" to the "m" form. These also possess a mechanism for reducing the intracellular Ca++ level. If in spite of these mechanisms the extracellular Ca++ concentration remains raised, this can result in calcification of the interzellular substance, particularly the elastic material.

Topics: Aged; Animals; Aorta, Thoracic; Calcinosis; Calcium; Cholecalciferol; Coronary Disease; Coronary Vessels; Disease Models, Animal; Elastic Tissue; Humans; Lipids; Microscopy, Electron; Muscle, Smooth, Vascular; Rats; Risk

The comparative effectiveness of vitamin D3 and its derivatives in curing hyperparathyroidism and osteodystrophic bone lesions was examined in a laboratory model of renal osteodystrophy associated with marked secondary hyperparathyroidism in rats. The experimental model was prepared by a single injection of homologous glycopeptide. Plasma levels of 1 alpha,25-dihydroxyvitamin D3 [1 alpha,25(OH)2D3] appeared to decrease in the rats receiving glycopeptide. Various doses of vitamin D3 derivatives [2 or 10 microgram/kg D3, 2 microgram/kg 25-hydroxyvitamin D3 (25OHD3), 0.1 microgram/kg 1 alpha,25(OH)2D3, and 0.1 or 0.2 microgram/kg 1 alpha-hydroxyvitamin D3 (1 alpha OHD3)] were daily administered orally to the nephritic rats for 23 days before sacrifice. 1 alpha,25(OH)2D3 and 1 alpha OHD3 were much more potent than 25OHD3 and D3 in reducing the hyperplasia of parathyroir glands. The potency of 1 alpha OHD3 in curing the histological changes of osteodystrophy appeared to be greater than that of 1 alpha,25(OH)2D3. The same dose level of 1 alpha OHD3 was more effective than 1 alpha,25(OH)2D3 in enhancing plasma 1 alpha,25(OH)2D3 levels.

Topics: Animals; Bone and Bones; Calcium; Cholecalciferol; Chronic Kidney Disease-Mineral and Bone Disorder; Dihydroxycholecalciferols; Disease Models, Animal; Glycopeptides; Hydroxycholecalciferols; Parathyroid Glands; Parathyroid Hormone; Rats; Structure-Activity Relationship

Coronary atherosclerosis developed in normolipemic swine fed a basal ration supplemented with 125,000 IU, 62,500 IU and 31,250 IU of vitamin D3/kg of diet for 3 months and subsequently only the basal ration for the following 3 months. Lesions consisted of intimal atheromata and calcified internal elastica and caused luminal narrowing. The incidence of atherosclerotic lesions was proportional to the vitamin D3 doses. The present experimentally induced lesions had many morphological features resembling those in coronary arteries from human subjects.

Topics: Adult; Aged; Animals; Arteries; Arteriosclerosis; Calcinosis; Calcium; Cholecalciferol; Cholesterol; Coronary Disease; Coronary Vessels; Disease Models, Animal; Humans; Middle Aged; Swine

Topics: Acute Disease; Animals; Blood Urea Nitrogen; Calcium; Cholecalciferol; Dihydroxycholecalciferols; Disease Models, Animal; Hydroxycholecalciferols; Intestinal Mucosa; Male; Phosphorus; Rats; Uremia; Vitamin D; Vitamin D Deficiency

Chronic renal disease in man and animals is associated with disturbances in calcium homeostasis which are resistant to vitamin D-therapy. Partially nephrectomized and intact rats were used to evaluate the effect of uremia on the response of bone to vitamin D. Serum calcium, serum phosphorus and blood urea nitrogen levels were higher in uremic rats than in intact rats, both given vitamin D. Metaphyseal bone in uremic rats was resistant to vitamin D-induced bone resorption; osteoblasts and osteocytes appeared less active ultrastructurally and osteoclass were infrequent. Calcitonin synthesis and release evaluated electron microscopically was greater in uremic rats. It is suggested that the altered response of bone to vitamin D in uremic rats was due in part to elevated serum phosphorus and increased calcitonin release. The present model does not refute experimental and clinical data that metabolism of vitamin D is altered in renal disease. It does, however, emphasize that in chronic renal failure other parameters (phosphorus levels, calcitonin release, uremia) are operating which may influence end organ response to pharmacologic doses of vitamin D. The partially nephrectomized rat may be a useful model for evaluating end-organ resistance to vitamin D in uremia.

Topics: Animals; Blood Urea Nitrogen; Bone and Bones; Calcitonin; Calcium; Cholecalciferol; Disease Models, Animal; Kidney Failure, Chronic; Male; Parathyroid Glands; Phosphates; Rats; Uremia; Vitamin D Deficiency

Topics: Animals; Bone Diseases; Calcium; Chemical Phenomena; Chemistry; Cholecalciferol; Dihydrotachysterol; Dihydroxycholecalciferols; Disease Models, Animal; Humans; Hydroxycholecalciferols; Isomerism; Kidney Failure, Chronic; Microradiography; Osteitis Fibrosa Cystica; Osteomalacia; Phosphates; Rats; Renal Dialysis; Uremia; Vitamin D

Topics: Animals; Cholecalciferol; Dactinomycin; Disease Models, Animal; Rabbits; Renal Aminoacidurias; RNA; Vitamin D Deficiency

Topics: Animals; Calcinosis; Calciphylaxis; Cholecalciferol; Disease Models, Animal; Ear, Middle; Granulation Tissue; Guinea Pigs; Histocytochemistry; Male; Ossification, Heterotopic; Otosclerosis; Tympanic Membrane

Topics: Animals; Calcinosis; Calciphylaxis; Cholecalciferol; Disease Models, Animal; Ear, Middle; Guinea Pigs; Male; Mucous Membrane; Ossification, Heterotopic; Otosclerosis; Tympanic Membrane

Topics: Alcohols; Animals; Cholecalciferol; Disease Models, Animal