ABSTRACT
Background To evaluate the individual and combined effects of enterolactone, vitamin D, free testosterone, Chlamydia trachomatis and HPV-18 on the risk of prostate cancer in a large population-based biochemical material that combined three Nordic serum sample banks. Material and methods A joint cohort of 209 000 healthy men was followed using cancer registry linkages. From this cohort altogether 699 incident cases of prostate cancer were identified. Four controls were selected by incidence density sampling and matching for country, age and date of the blood sampling. Complete data for all investigated exposures was available for 483 eligible cases and 1055 eligible controls. Multivariate regression analyses were performed to investigate the solitary and combined effects. Results The solitary effects were small. Significantly increased risk [rate ratio 1.6 (95% CI 1.0-2.5)] was found in those seronegative for C. trachomatis infection. The joint effect in risk levels of enterolactone and vitamin D was antagonistic [observed rate ratio (RR) 1.4 (1.0-2.1), expected RR 2.0 (1.0-4.1)] as well as that of HPV-18 and C. trachomatis [observed RR 1.9 (0.8-4.5), expected RR 9.9 (1.1-87.0)]. Conclusion A large follow-up study combining data from several previously investigated exposures to investigate joint effects found no evidence that exposure to two risk factors would increase the risk of prostate cancer from that expected on basis of exposure to one risk factor. If anything, the results were consistent with antagonistic interactions.
Subject(s)
Prostatic Neoplasms/etiology , Vitamin D/blood , 4-Butyrolactone/analogs & derivatives , 4-Butyrolactone/blood , Adult , Blood Banks/statistics & numerical data , Case-Control Studies , Chlamydia Infections/complications , Chlamydia trachomatis/pathogenicity , Cohort Studies , Finland/epidemiology , Human papillomavirus 18/pathogenicity , Humans , Lignans/blood , Longitudinal Studies , Male , Middle Aged , Norway/epidemiology , Papillomavirus Infections/complications , Papillomavirus Infections/epidemiology , Prostatic Neoplasms/epidemiology , Risk Factors , Sweden/epidemiology , Testosterone/bloodABSTRACT
1α,25-Dihydroxyvitamin D3 (1α,25(OH)2D3) had earlier been regarded as the only active hormone. The newly identified actions of 25-hydroxyvitamin D3 (25(OH)D3) and 24R,25-dihydroxyvitamin D3 (24R,25(OH)2D3) broadened the vitamin D3 endocrine system, however, the current data are fragmented and a systematic understanding is lacking. Here we performed the first systematic study of global gene expression to clarify their similarities and differences. Three metabolites at physiologically comparable levels were utilized to treat human and mouse fibroblasts prior to DNA microarray analyses. Human primary prostate stromal P29SN cells (hP29SN), which convert 25(OH)D3 into 1α,25(OH)2D3 by 1α-hydroxylase (encoded by the gene CYP27B1), displayed regulation of 164, 171, and 175 genes by treatment with 1α,25(OH)2D3, 25(OH)D3, and 24R,25(OH)2D3, respectively. Mouse primary Cyp27b1 knockout fibroblasts (mCyp27b1 (-/-)), which lack 1α-hydroxylation, displayed regulation of 619, 469, and 66 genes using the same respective treatments. The number of shared genes regulated by two metabolites is much lower in hP29SN than in mCyp27b1 (-/-). By using DAVID Functional Annotation Bioinformatics Microarray Analysis tools and Ingenuity Pathways Analysis, we identified the agonistic regulation of calcium homeostasis and bone remodeling between 1α,25(OH)2D3 and 25(OH)D3 and unique non-classical actions of each metabolite in physiological and pathological processes, including cell cycle, keratinocyte differentiation, amyotrophic lateral sclerosis signaling, gene transcription, immunomodulation, epigenetics, cell differentiation, and membrane protein expression. In conclusion, there are three distinct vitamin D3 hormones with clearly different biological activities. This study presents a new conceptual insight into the vitamin D3 endocrine system, which may guide the strategic use of vitamin D3 in disease prevention and treatment.
Subject(s)
Calcifediol/pharmacology , Calcitriol/pharmacology , Cholecalciferol/metabolism , Fibroblasts/drug effects , Stromal Cells/drug effects , Animals , Cell Cycle/drug effects , Cell Differentiation/drug effects , Cholecalciferol/pharmacology , Fibroblasts/metabolism , Gene Expression/drug effects , Gene Expression Profiling , Humans , Mice , Mice, Knockout , Stromal Cells/metabolismABSTRACT
We found previously that long-chain fatty-acid-CoA ligase 3 (FACL3), a critical enzyme for activation of long-chain fatty acids, was upregulated by 1α, 25(OH)(2)D(3) at an mRNA and enzyme activity levels in prostate cancer cells. Our further study indicated that the FACL3 mediated 1α,25(OH)(2)D(3) inhibition of fatty acid synthase (FAS), which is associated with many cancers, including prostate cancer. In the current study, we investigated an FACL3 protein expression and its regulation by 1α, 25(OH)(2)D(3) and its synthetic analogs EB1089 and CB1093 in prostate cancer cells. The results showed that the expression of an FACL3 protein was upregulated by 1α, 25(OH)(2)D(3), EB1089 and CB1093 in LNCaP cells, consistent with their upregulation of an FACL3 mRNA expression. In addition, the FACL3 expression was found to be markedly low at both mRNA and protein levels in more transformed prostate cancer PC-3 and DU145 cells compared with less transformed LNCaP cells. The data suggest that decreased FACL3 expression might be associated with a more malignant phenotype of prostate cancer.
Subject(s)
Cholecalciferol/pharmacology , Coenzyme A Ligases/biosynthesis , Bone Density Conservation Agents/pharmacology , Calcitriol/analogs & derivatives , Calcitriol/pharmacology , Gene Expression Regulation , Humans , Male , Prostatic Neoplasms , Transcription, Genetic , Tumor Cells, Cultured , Up-RegulationABSTRACT
The objective of the study was to compare Bacillus subtilis spore film dosimeters with a Robertson Berger UV meter (RB meter) and diary records for assessing personal UV-B doses during a 13-day heliotherapy (HT) for atopic dermatitis (AD). In addition, the relationship between the personal UV-B dose and change in serum 25-hydroxyvitamin D (25(OH)D) was studied. Altogether 21 adult patients with AD completed the study arranged in the Canary Islands, either in January or March 2005. The spore film dosimeters were used throughout the day during the HT. Serum 25(OH)D was analyzed using radioimmunoassay. The mean personal UV-B dose measured with the dosimeters was 75 SED in January and 131 SED in March. The respective results gained from the RB meter combined with diary records were 63 SED and 119 SED showing a close correlation with the dosimeter results. Serum 25(OH)D concentration increased by 9.7nmol L(-1) in January and by 26.0 7nmol L(-1) in March. The increase in serum 25(OH)D correlated with the UV-B dose received. The patients complied well to use the dosimeters. We conclude spore films to be a feasible and reliable personal UV dosimeter in vivo in field conditions.
Subject(s)
Bacillus subtilis , Film Dosimetry , Heliotherapy , Spores , Ultraviolet Rays , Adult , Dermatitis, Atopic/radiotherapy , Dose-Response Relationship, Radiation , Female , Film Dosimetry/instrumentation , Humans , MaleABSTRACT
Vitamin D is becoming increasingly recognized as a nontraditional drug target for different brain pathologies. Although widely known for their role in calcium metabolism, vitamin D and its receptor have been linked to several brain disorders, including cognitive decline, epilepsy, affective disorders, and schizophrenia. Here we discuss mounting evidence, and parallel recent clinical and animal behavioral, genetic and pharmacological data to emphasize the emerging role of the neurosteroid vitamin D system in brain function.
Subject(s)
Brain/physiopathology , Drug Delivery Systems , Vitamin D/metabolism , Animals , Brain/metabolism , Brain Diseases/drug therapy , Brain Diseases/physiopathology , Humans , Mental Disorders/drug therapy , Mental Disorders/physiopathology , Receptors, Calcitriol/drug effects , Receptors, Calcitriol/genetics , Receptors, Calcitriol/metabolism , Vitamin D/administration & dosageABSTRACT
Knowledge of the stability of serum samples stored in large biobanks is pivotal for reliable assessment of hormone-dependent disease risks. We studied the effects of sample storage time and season of serum sampling on the stability of 25-hydroxy vitamin D (25-OHD) and androstenedione in a stratified random sample of 402 women, using paired sera from the Finnish Maternity Cohort. Serum samples selected were donated between 6 and 24 yr ago. The storage time did not affect serum 25-OHD and androstenedione levels. However, there was a significant mean difference in the 25-OHD levels of sera withdrawn during winter (first sample) vs. during summer (second sample; -18.4 nmol/l, P Subject(s)
Androstenedione/blood
, Seasons
, Vitamin D/analogs & derivatives
, Adult
, Blood Specimen Collection/methods
, Drug Stability
, Female
, Finland
, Humans
, Pregnancy
, Pregnancy Trimester, First
, Time Factors
, Vitamin D/blood
ABSTRACT
25-Hydroxyvitamin D(3) 1alpha-hydroxylase encoded by CYP27B1 converts 25-hydroxyvitamin D(3) into 1alpha,25-dihydroxyvitamin D(3), a vitamin D receptor ligand. 25-Hydroxyvitamin D(3) has been regarded as a prohormone. Using Cyp27b1 knockout cells and a 1alpha-hydroxylase-specific inhibitor we provide in four cellular systems, primary mouse kidney, skin, prostate cells and human MCF-7 breast cancer cells, evidence that 25-hydroxyvitamin D(3) has direct gene regulatory properties. The high expression of megalin, involved in 25-hydroxyvitamin D(3) internalisation, in Cyp27b1(-/-) cells explains their higher sensitivity to 25-hydroxyvitamin D(3). 25-Hydroxyvitamin D(3) action depends on the vitamin D receptor signalling supported by the unresponsiveness of the vitamin D receptor knockout cells. Molecular dynamics simulations show the identical binding mode for both 25-hydroxyvitamin D(3) and 1alpha,25-dihydroxyvitamin D(3) with the larger volume of the ligand-binding pocket for 25-hydroxyvitamin D(3). Furthermore, we demonstrate direct anti-proliferative effects of 25-hydroxyvitamin D(3) in human LNCaP prostate cancer cells. The synergistic effect of 25-hydroxyvitamin D(3) with 1alpha,25-dihydroxyvitamin D(3) in Cyp27b1(-/-) cells further demonstrates the agonistic action of 25-hydroxyvitamin D(3) and suggests that a synergism between 25-hydroxyvitamin D(3) and 1alpha,25-dihydroxyvitamin D(3) might be physiologically important. In conclusion, 25-hydroxyvitamin D(3) is an agonistic vitamin D receptor ligand with gene regulatory and anti-proliferative properties.
Subject(s)
Calcifediol/metabolism , Receptors, Calcitriol/agonists , 24,25-Dihydroxyvitamin D 3/pharmacology , 25-Hydroxyvitamin D3 1-alpha-Hydroxylase/antagonists & inhibitors , 25-Hydroxyvitamin D3 1-alpha-Hydroxylase/genetics , Animals , Binding Sites , Calcifediol/chemistry , Calcifediol/pharmacology , Calcitriol/chemistry , Calcitriol/pharmacology , Cell Line, Tumor , Cell Proliferation/drug effects , Cells, Cultured , Drug Synergism , Enzyme Inhibitors/pharmacology , Epithelial Cells/cytology , Epithelial Cells/drug effects , Epithelial Cells/metabolism , Gene Expression/drug effects , Gene Expression/genetics , Gene Expression Regulation/drug effects , Gene Expression Regulation/physiology , Humans , Kidney/cytology , Low Density Lipoprotein Receptor-Related Protein-2/genetics , Male , Mice , Mice, Knockout , Molecular Dynamics Simulation , Prostate/cytology , Protein Structure, Tertiary , Receptors, Calcitriol/chemistry , Receptors, Calcitriol/genetics , Skin/cytology , Steroid Hydroxylases/genetics , Steroid Hydroxylases/metabolism , Vitamin D3 24-HydroxylaseABSTRACT
BACKGROUND: Several laboratory and epidemiological studies have inversely linked endogenous vitamin D and the risk of breast cancer. The acquisition of vitamin D over time on the relative risk (RR) of the disease development is not known. In a longitudinal study, we evaluated the association between vitamin D levels at pregnancy over time with the risk of breast cancer, and pregnancy-associated breast cancer. METHOD: The risk for subsequent development of breast cancer associated with serum 25-hydroxyvitamin (25-OHD) levels was assessed for consecutive (1st and 2nd pregnancy) samples of 100 cases, with mean lag times (micro(t)) of 7.4 and 4.6 years between sampling and the diagnosis, and matched (parity, age, year, season) controls. Pregnancy-associated breast cancer (PABC, 111 case-control pairs, micro(t)=1 year) risk was also studied. Odds ratios (ORs) with 95% confidence intervals (CI) were calculated using the lowest quintile as the reference. RESULTS: Serum 25-OHD level was not associated with an increased risk neither at the 1st nor at the 2nd pregnancy samples (OR=1.4, 95%CI 0.6-3.4; OR 1.4, 95%CI 0.7-2.8, respectively), but was associated with an increased risk of PABC (OR=2.7, 95%CI 1.04-6.7). CONCLUSION: Generally, vitamin D may not be related to breast cancer risk but the increased PABC risk fits the association of vitamin D with the most aggressive cancers, and warrants caution with vitamin D supplementation during pregnancy.
Subject(s)
Biomarkers, Tumor/blood , Breast Neoplasms/blood , Pregnancy/blood , Vitamin D/analogs & derivatives , Adult , Breast Neoplasms/etiology , Epidemiologic Methods , Female , Humans , Middle Aged , Parity , Pregnancy Complications, Neoplastic/blood , Prognosis , Vitamin D/bloodABSTRACT
INTRODUCTION: Ecological and experimental studies suggest that vitamin D may be associated with a reduced risk of ovarian cancer. In this study, we sought to determine the risk of developing ovarian cancer according to serum 25-hydroxyvitamin D (25-OHD) concentrations assessed on average 5 years before the diagnosis. METHODS: We conducted a population-based longitudinal case-control study nested within the Finnish Maternity Cohort (FMC) which contains serum samples of virtually all pregnant women in Finland since 1983. Among them, 201 ovarian cancers diagnosed within 10 years of serum sampling were randomly selected as cases for this study. For each case, we selected two controls matched for age, parity and sampling season (+/-4 weeks) and one control matched for age and parity but for the opposite sampling season (6 months+/-4 weeks). RESULTS: The relative risks (estimated as odds ratio, OR) for ovarian cancer comparing the lowest quintile to the highest quintile of serum 25-OHD concentration were 1.8 (95% CI 0.9-3.5) among controls matched for the same season, and 1.1 (95% CI 0.6-2.2) among controls matched for the opposite season. The OR among women with insufficient (<75 nmol/L) serum 25-OHD concentration was 2.7 (95% CI 1.0-7.9, lower limit, 0.95) compared to that among those with sufficient (75 nmol/L) serum 25-OHD concentration. No differences in the point estimates were observed between serous or mucinous histological subtypes of ovarian cancer. CONCLUSION: Overall, we did not observe a significant association between serum 25-OHD concentrations and the risk of ovarian cancer. However, we found evidence suggestive of an increased risk among women with low to insufficient serum 25-OHD concentrations.
Subject(s)
Ovarian Neoplasms/epidemiology , Vitamin D Deficiency/epidemiology , Vitamin D/analogs & derivatives , Adolescent , Adult , Biomarkers/blood , Case-Control Studies , Female , Finland/epidemiology , Humans , Risk Factors , Vitamin D/blood , Young AdultABSTRACT
Hypervitaminosis vitamin D(3) has been recently implicated in premature aging through the regulation of 1alpha hydroxylase expression by klotho and fibroblast growth factor-23 (Fgf-23). Here we examined whether the lack of hormonal function of vitamin D(3) in mice is linked to aging phenomena. For this, we used vitamin D(3) receptor (VDR) "Tokyo" knockout (KO) mice (fed with a special rescue diet) and analyzed their growth, skin and cerebellar morphology, as well as overall motor performance. We also studied the expression of aging-related genes, such as Fgf-23, nuclear factor kappaB (NF-kappaB), p53, insulin like growth factor 1 (IGF1) and IGF1 receptor (IGF1R), in liver, as well as klotho in liver, kidney and prostate tissues. Overall, VDR KO mice showed several aging related phenotypes, including poorer survival, early alopecia, thickened skin, enlarged sebaceous glands and development of epidermal cysts. There was no difference either in the structure of cerebellum or in the number of Purkinje cells. Unlike the wildtype controls, VDR KO mice lose their ability to swim after 6 months of age. Expression of all the genes was lower in old VDR KO mice, but only NF-kappaB, Fgf-23, p53 and IGF1R were significantly lower. Since the phenotype of aged VDR knockout mice is similar to mouse models with hypervitaminosis D(3), our study suggests that VDR genetic ablation promotes premature aging in mice, and that vitamin D(3) homeostasis regulates physiological aging.
Subject(s)
Aging, Premature , Mice, Knockout , Receptors, Calcitriol , Aging, Premature/genetics , Aging, Premature/metabolism , Animals , Body Weight , Cerebellum/cytology , Cholecalciferol/metabolism , Female , Fibroblast Growth Factor-23 , Fibroblast Growth Factors/genetics , Fibroblast Growth Factors/metabolism , Glucuronidase/genetics , Glucuronidase/metabolism , Humans , Insulin-Like Growth Factor I/genetics , Insulin-Like Growth Factor I/metabolism , Klotho Proteins , Male , Mice , NF-kappa B/genetics , NF-kappa B/metabolism , Phenotype , Receptor, IGF Type 1/genetics , Receptor, IGF Type 1/metabolism , Receptors, Calcitriol/genetics , Receptors, Calcitriol/metabolism , Skin/anatomy & histology , Skin/metabolism , Skin/pathology , Survival Rate , Swimming , Tumor Suppressor Protein p53/genetics , Tumor Suppressor Protein p53/metabolismABSTRACT
Recent studies using genetically modified mice, such as FGF23-/- and Klotho-/- mice that exhibit altered mineral homeostasis due to a high vitamin D activity showed features of premature aging that include retarded growth, osteoporosis, atherosclerosis, ectopic calcification, immunological deficiency, skin and general organ atrophy, hypogonadism and short lifespan. The phenotype reversed by normalizing vitamin D and/or mineral homeostasis. Thus, hypervitaminosis D due to an increased 1alpha-hydroxylase activity seems to be a cause of the premature aging. In several studies, we have described that a complete or partial lack of vitamin D action (VDR-/- mice and CYP27B1-/-) show almost similar phenotype as FGF23-/- or Klotho-/- mice. VDR mutant mice have growth retardation, osteoporosis, kyphosis, skin thickening and wrinkling, alopecia, ectopic calcification, progressive loss of hearing and balance as well as short lifespan. CYP27B1-/- mice do not show alopecia nor balance deficit, which might be apoVDR-dependent or calcidiol-dependent. The features are typical to premature aging. The phenotype is resistant to a normalization of the mineral homeostasis by a rescue diet containing high calcium and phosphate. Taken together, aging shows a U-shaped dependency on hormonal forms of vitamin D suggesting that there is an optimal concentration of vitamin D in delaying aging phenomena. Our recent study shows that calcidiol is an active hormone. Since serum calcidiol but not calcitriol is fluctuating in physiological situations, calcidiol might determine the biological output of vitamin D action. Due to its high serum concentration and better uptake of calcidiol-DBP by the target cells through the cubilin-megalin system, calcidiol seems to be an important circulating hormone. Therefore, serum calcidiol might be associated with an increased risk of aging-related chronic diseases more directly than calcitriol. Aging and cancer seem to be tightly associated phenomena. Accumulation of damage on DNA and telomeres cause both aging and cancer, moreover the signalling pathways seem to converge on tumour suppressor protein, p53, which seems to be regulated by vitamin D. Also, the insulin-like growth factor signalling pathway (IGF-1, IGFBPs, IGFR) and fibroblast growth factor-23 (FGF-23) regulate growth, aging and cancer. Vitamin D can regulate these signalling pathways, too. Also NF-kappaB and telomerase reverse transcriptase (TERT) might be molecular mechanisms mediating vitamin D action in aging and cancer. Calcidiol serum concentrations show a U-shaped risk of prostate cancer suggesting an optimal serum concentration of 40-60 nmol/L for the lowest cancer risk. Therefore, it is necessary to study several common aging-associated diseases such as osteoporosis, hypertension and diabetes known to be vitamin D-dependent before any recommendations of an optimal serum concentration of calcidiol are given.
Subject(s)
Aging, Premature/metabolism , Aging/physiology , Calcifediol/metabolism , Neoplasms/metabolism , Vitamin D/metabolism , Animals , Calcitriol/metabolism , Fibroblast Growth Factor-23 , Fibroblast Growth Factors/genetics , Fibroblast Growth Factors/metabolism , Glucuronidase/genetics , Glucuronidase/metabolism , Humans , Klotho Proteins , Nutrition Disorders/metabolism , Vitamin D Deficiency/metabolismABSTRACT
Vitamin D insufficiency has been reported to be associated with increased blood cholesterol concentrations. Here we used two strains of VDR knock-out (VDR-KO) mice to study whether a lack of vitamin D action has any effect on cholesterol metabolism. In 129S1 mice, both in male and female VDR-KO mice serum total cholesterol levels were significantly higher than those in wild type (WT) mice (20.7% (P=0.05) and 22.2% (P=0.03), respectively). In addition, the serum high-density lipoprotein-bound cholesterol (HDL-C) level was 22% (P=0.03), respectively higher in male VDR-KO mice than in WT mice. The mRNA expression levels of five cholesterol metabolism related genes in livers of 129S1 mice were studied using quantitative real-time PCR (QRT-PCR): ATP-binding cassette transporter A1 (ABCA1), regulatory element binding protein (SREBP2), apolipoprotein A-I (ApoAI), low-density lipoprotein receptor (LDLR) and liver X receptor beta (LXRbeta). In the mutant male mice, the mRNA level of ApoAI and LXRbeta were 49.2% (P=0.005) and 38.8% (P=0.034) higher than in the WT mice. These changes were not observed in mutant female mice, but the female mutant mice showed 52.5% (P=0.006) decrease of SREBP2 mRNA expression compared to WT mice. Because the mutant mice were fed with a special rescue diet, we wanted to test whether the increased cholesterol levels in mutant mice were due to the diet. Both the WT and mutant NMRI mice were given the same diet for 3 weeks before the blood sampling. No difference in cholesterol or in HDL-C between WT and mutant mice was found. The results suggest that the food, gender and genetic background have an effect on the cholesterol metabolism. Although VDR seems to regulate some of the genes involved in cholesterol metabolism, its role in the regulation of serum cholesterol seems to be minimal.
Subject(s)
Apolipoprotein A-I/metabolism , Cholesterol/blood , DNA-Binding Proteins/metabolism , Mice, Knockout , Receptors, Calcitriol , Receptors, Cytoplasmic and Nuclear/metabolism , Sterol Regulatory Element Binding Protein 2/metabolism , ATP Binding Cassette Transporter 1 , ATP-Binding Cassette Transporters/genetics , ATP-Binding Cassette Transporters/metabolism , Animals , Apolipoprotein A-I/genetics , Cholesterol/chemistry , DNA-Binding Proteins/genetics , Female , Liver X Receptors , Male , Mice , Orphan Nuclear Receptors , Receptors, Calcitriol/genetics , Receptors, Calcitriol/metabolism , Receptors, Cytoplasmic and Nuclear/genetics , Sterol Regulatory Element Binding Protein 2/geneticsABSTRACT
The vitamin D endocrine system is essential for calcium and bone homeostasis. Vitamin D deficits are associated with muscle weakness and osteoporosis, whereas vitamin D supplementation may improve muscle function, body sway and frequency of falls, growth and mineral homeostasis of bones. The loss of muscle strength and mass, as well as deficits in bone formation, lead to poor balance. Poor balance is one of the main causes of falls, and may lead to dangerous injuries. Here we examine balance functions in vitamin D receptor deficient (VDR-/-) mice, an animal model of vitamin D-dependent rickets type II, and in 1alpha-hydroxylase deficient (1alpha-OHase-/-) mice, an animal model of pseudovitamin D-deficiency rickets. Recently developed methods (tilting box, rotating tube test), swim test, and modified accelerating rotarod protocol were used to examine whether the absence of functional VDR, or the lack of a key vitamin D-activating enzyme, could lead to mouse vestibular dysfunctions. Overall, VDR-/- mice, but not 1alpha-OHase-/- mice, showed shorter latency to fall from the rotarod, smaller fall angle in the tilting box test, and aberrant poor swimming. These data suggest that VDR deficiency in mice is associated with decreased balance function, and may be relevant to poorer balance/posture control in humans with low levels of vitamin D.
Subject(s)
Receptors, Calcitriol/deficiency , Vestibular Diseases/etiology , Animals , Disease Models, Animal , Mice , Mice, Knockout , Mice, Mutant Strains , Postural Balance , Posture , Rickets , Steroid Hydroxylases , Vitamin D Deficiency/complicationsABSTRACT
We propose a new hypothesis pointing of a functional hypoxia in vasa vasorum, which might explain the initiation and the early development of the atherosclerosis in the deep layer of intima. Since vasa vasorum are end arteries, they easily develop hypoxia and/or ischemia in the cells of intima or media of arterial wall. The most vulnerable sites for hypoxia are the arterial bifurcations due to the anatomical and physiological reasons. They are also known to be the most common sites of atherosclerosis. The known risk factors for atherosclerosis, high blood pressure and nicotine, reduce the blood flow in the end branches of the vasa vasorum. The local ischemia will affect the endothelial cell structure and causes a local inflammation, which, in turn, makes it permeable to large particles such as microbes and LDL-lipoproteins and other fatty acids, which are phagocytozed by macrophages transforming them into foam cells. The present hypothesis explains most problems of the previous theories and offers a logical sequence of the events involved in the development of atherosclerosis.
Subject(s)
Atherosclerosis/immunology , Cell Hypoxia/immunology , Fatty Acids/immunology , Lipoproteins, LDL/immunology , Models, Cardiovascular , Models, Immunological , Vasa Vasorum/immunology , HumansABSTRACT
Deficiency of the prohormone calcidiol (25OH vitamin D(3)) seems to be associated with several aging-related chronic diseases including cancer. Our results suggest that calcidiol is mainly responsible for differentiation homeostasis, whereas calcitriol might be more involved in calcium homeostasis. Therefore, an imbalance of calcidiol rather than calcitriol is a risk factor for cancer and chronic diseases. Calcidiol insufficiency, as well as insufficient solar exposure, is associated with increased risk of several solid cancers. Both a vitamin D(3) deficiency and a high concentration of calcidiol may increase cancer risk. Similarly, aging phenomena show a U-shaped association with vitamin D bioactivity. Therefore, the chronic diseases and cancers related to aging might be prevented by an optimal concentration of serum calcidiol, which remains to be determined.
Subject(s)
Aging/physiology , Calcifediol/deficiency , Calcifediol/physiology , Neoplasms/metabolism , Vitamin D Deficiency/physiopathology , Vitamin D/physiology , Calcifediol/metabolism , Calcitriol/metabolism , Calcitriol/physiology , Humans , Neoplasms/prevention & control , Vitamin D/analogs & derivativesABSTRACT
BACKGROUND: Both hypo- and hypervitaminosis D can cause sensorineural hearing loss, and aural symptoms due to vitamin D insufficiency are especially common during gravidity. Hormonal forms of vitamin D regulate transcription by binding with the high-affinity vitamin D receptor (VDR). OBJECTIVE: To assess the effects of impaired vitamin D action in VDR knockout (KO) mice on hearing, cochlear morphology, and cochlear gene expression. MATERIALS AND METHODS: Eighteen young male and female mice (10 VDR KO and 8 wild type, WT, < or =6 months old), 33 adult male and female mice (16 VDR KO and 17 WT, between 7 and 14 months old), and 11 aged male and female mice (5 VDR KO and 6 WT, > or =15 months old) on 129S1 genetic background were studied. Auditory thresholds were evaluated by auditory brain stem response. Morphological changes were analyzed using plastic embedding and light microscopy. The expression of key genes (known to play a role in the regulation of cochlear function), and caspase 3 activity, were assessed using immunofluorescent confocal microscopy. RESULTS: There was a statistically significant difference between the young and the adult groups, and between the adult and aged groups of WT mice. There was also a statistically significant difference between the adult and aged groups in VDR KO mice, and between the young WT group and the young VDR KO group. Spiral ganglion cell loss was observed in the basal turn of adult VDR KO mice, a phenomenon infrequently found in WT mice. Expression of connexin 26, KCNJ10, and transient receptor potential channel vanilloid subfamily 4/6 was not affected by VDR KO-mediated hearing loss. Caspase 3 activation was detected in the spiral ganglion cell and its satellite cells, stria vascularis, spiral ligament fibrocytes, and the organ of Corti in both genotypes. However, the percentage of positive cells and the staining intensity were lower in the VDR KO (compared to the WT) mice. CONCLUSION: These data suggest that sensorineural hearing loss progressively developed at an earlier age in VDR KO mice. While the fundamental gene expressions in the cochlea were not influenced by VDR mutation, it resulted in decrease of caspase 3 activation, which may be one of the factors underlying accelerating age-related hearing loss observed in VDR KO mice.
Subject(s)
DNA Mutational Analysis , Deafness/genetics , Presbycusis/genetics , Receptors, Calcitriol/genetics , Age Factors , Animals , Auditory Threshold/physiology , Calcinosis/genetics , Calcinosis/pathology , Calcium/metabolism , Calcium Channels/genetics , Caspase 3/genetics , Cochlea/pathology , Connexin 26 , Connexins/genetics , Deafness/pathology , Disease Progression , Enzyme Activation/genetics , Female , Male , Mice , Mice, Knockout , Microscopy, Confocal , Microscopy, Fluorescence , Presbycusis/pathology , TRPV Cation Channels/geneticsABSTRACT
Animal behavioral models are crucial for neurobiological research, allowing for the thorough investigation of brain pathogenesis to be performed. In both animals and humans, anxiety has long been linked to vestibular disorders. However, although there are many tests of anxiety and vestibular deficits, there are few protocols that address the interplay between these two domains. The Suok test and its light-dark modification presented here appear to be suitable for testing this pathogenetic link in laboratory rodents. This protocol adds a new dimension to previously used tests by assessing animal anxiety and balancing simultaneously, resulting in efficient, high-throughput screens for testing psychotropic drugs, phenotyping genetically modified animals, and modeling clusters of human disorders related to stress/anxiety and balancing.
Subject(s)
Anxiety , Behavior, Animal , Behavioral Research/methods , Light , Psychomotor Performance , Acclimatization , Animals , Behavioral Research/instrumentation , Darkness , Mice , Models, Animal , Postural Balance , RatsABSTRACT
Vitamin D receptor (VDR) and liver X receptor (LXR) are nuclear receptors, which regulate gene transcription upon binding of their specific ligands. VDR seems to play a role in the regulation of prostate cancer cell proliferation. ATP-binding cassette transporter A1 (ABCA1) is known to be a target gene of LXR and it has been reported to be inhibited by androgen and to be involved in the regulation of LNCaP proliferation. We find that calcitriol (1 alpha,25(OH)(2)D(3)) inhibits both basal and a LXR agonist, TO-901317, induced ABCA1 mRNA expression but has no effect on the mRNA expression of ATP-binding cassette transporter G1 (ABCG1), LXR alpha nor LXR beta. TO-901317 increases both basal and calcitriol induced 25-hydroxyvitamin D(3)-24-hydroxylase (CYP24) mRNA expression and it slightly but significantly inhibits VDR mRNA expression. The inhibition of ABCA1 by calcitriol appears to be androgen-independent. Cell growth assay shows that when each of calcitriol and 5 alpha-dihydrotestosterone (DHT) was co-treated with ABCA1 blocker, glybenclamide, cell-growth is significantly decreased compared to their own treatments respectively. Our study suggests a possible interaction between calcitriol and TO-901317 in LNCaP cells. Alike DHT, the inhibition of ABCA1 by calcitriol may be involved in its regulation of LNCaP growth.
ABSTRACT
Grooming is a commonplace, robust behavior in rodent species. It has been shown to be highly sensitive to a number of experimental factors, making it an ideal target for manipulation. The complex patterning of grooming in rodents, which usually proceeds in a cephalo-caudal direction and involves several distinct stages, can be dissected into its constituent parts and microstructures. Several grooming patterning analysis methods are described in the protocol that allow for an assessment of this behavior based on measurements of grooming activity and its sequencing. Additionally, grooming can be evaluated in reference to the regional distribution and syntax in which it occurs. Owing to the ever-increasing number of rodent models that have strong grooming phenotypes, this high-throughput in-depth analysis is becoming crucial for biomedical research.
Subject(s)
Behavioral Research/methods , Grooming , Mice , 2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine/pharmacology , Acclimatization , Algorithms , Animals , Dopamine Agonists/pharmacology , Grooming/drug effects , Quinpirole/pharmacologyABSTRACT
BACKGROUND: The effects of vitamin D in regulating bone mineralization are well documented. The action of vitamin D as a key link between Toll-like receptor activation and antibacterial responses in innate immunity has recently been shown. The data suggest that differences in the ability of human populations to produce vitamin D may contribute to susceptibility to microbial infection. OBJECTIVE: We aimed to explore whether an association exists between vitamin D insufficiency and acute respiratory tract infection in young Finnish men. DESIGN: Young Finnish men (n = 800) serving on a military base in Finland were enrolled for this study. Their serum 25-hydroxyvitamin [25(OH)D] concentrations were measured in July 2002. They were followed for 6 mo, and the number of days of absence from duty due to respiratory infection were counted. RESULTS: The mean (+/- SD) serum 25(OH)D concentrations were 80.2 +/- 29.3 nmol/L (n = 756). Subjects with serum 25(OH)D concentrations < 40 nmol/L (n = 24) had significantly (P = 0.004) more days of absence from duty due to respiratory infection (median: 4; quartile 1-quartile 3: 2-6) than did control subjects (2; 0-4; n = 628; incidence rate ratio 1.63; 95% CI: 1.15, 2.24). We found a significant (P = 0.004) association between serum 25(OH)D concentrations and the amount of physical exercise before induction into military service. We also found significantly (P < 0.001) lower serum 25(OH)D concentrations in subjects who smoked (72.8 +/- 26.6 nmol/L; n = 192) than in control subjects (82.9 +/- 29.7 nmol/L; n = 537). CONCLUSION: Clinical trials of vitamin D supplementation are needed to investigate whether it enhances immunity to microbial infections.