Biomedical subjects

Pentti Tuohimaa

Publications and source records attributed to Pentti Tuohimaa.

At least 19 recordsLinked to original sources

PubMed2007

Neurosteroid hormone vitamin D and its utility in clinical nutrition.

PURPOSE OF REVIEW: Vitamin D is a seco-steroid hormone with multiple functions in the nervous system. We discuss clinical and experimental evidence of the role of vitamin D in normal and pathological brain functions, and analyze the relative importance of vitamin D-modulated brain mechanisms at different stages of life. We also outline perspectives for the use of vitamin D in clinical nutrition to prevent or treat various brain disorders. RECENT FINDINGS: Numerous brain dysfunctions are linked to vitamin D deficits and/or dysfunctions of its receptors. In both animals and humans, vitamin D serves as an important endogenous and/or exogenous regulator of neuroprotection, antiepileptic and anticalcification effects, neuro-immunomodulation, interplay with neurotransmitters and hormones, modulation of behaviors, brain ageing, and some other, less-explored, brain processes. SUMMARY: Vitamin D emerges as an important neurosteroid hormone in the brain, with a strong potential for age-specific applications in clinical nutrition.

Animals↗

PubMed2006

Influence of paternal genotypes on F1 behaviors: lessons from several mouse strains.

F1 and F2 mouse hybrids derived from different parental strains are becoming a useful tool in behavioral research, underlining the importance of their in-depth behavioral phenotyping. 129S1/SvImJ (S1), C57BL/6 (B6), NMRI (N) and BALB/c (BC) mice are commonly used in behavioral neuroscience, demonstrating marked behavioral differences. Here, we assess behavioral phenotypes of male mice of S1 and several hybrid strains (S1B6, S1N, S1BC) in a battery of behavioral tests, including the open field, novel odor exposure, novelty-induced grooming, horizontal rod (Suok) and the elevated plus maze tests. In addition, we assessed aggression and social barbering in these strains. Overall, the substantial differences observed here between these strains allow us to determine the influence of different genetic backgrounds on mouse behaviors, and more fully understand how different strain-specific behaviors overlap in the F1 progeny. Our results imply complex interplay between parental genotypes in anxiety, activity, grooming, aggression and barbering of their F1 progeny, further confirming the utility of F1 hybrids in behavioral neurogenetics.

Analysis of Variance↗

PubMed2006

Regulation of cholesterol 25-hydroxylase expression by vitamin D3 metabolites in human prostate stromal cells.

Vitamin D3 plays an important role in the control of cell proliferation and differentiation. Cholesterol 25-hydroxylase (CH25H) is an enzyme converting cholesterol into 25-hydroxycholesterol. Vitamin D3 as well as 25-hydroxycholesterol has been shown to inhibit cell growth and induce cell apoptosis. Here we show that 10 nM 1alpha,25(OH)2D3 and 500 nM 25OHD3 upregulate CH25H mRNA expression in human primary prostate stromal cells (P29SN). Protein synthesis inhibitor cycloheximide does not block 1alpha,25(OH)2D3 mediated upregulation of CH25H mRNA. Transcription inhibitor actinomycin D blocks basal level as well as 1alpha,25(OH)2D3 induced CH25H mRNA expression. 1alpha,25(OH)2D3 has no effect on CH25H mRNA stability. 25-Hydroxycholesterol significantly decreased the P29SN cell number. A CH25H enzyme inhibitor, desmosterol, increases basal cell number but has no significant effect on vitamin D3 treated cells. Our data suggest that ch25h could be a vitamin D3 target gene and may partly mediate anti-proliferative action of vitamin D3 in human primary prostate stromal cells.

Apoptosis↗

PubMed2006

Androgen enhances the antiproliferative activity of vitamin D3 by suppressing 24-hydroxylase expression in LNCaP cells.

25-Hydroxyvitamin D3-24-hydroxylase (24-hydroxylase, CYP24) is an important inactivating enzyme controlling the concentrations of both active metabolites 25-hydroxyvitamin D3 and 1alpha,25-dihydroxyvitamin D3. In this paper, we demonstrate that 25-hydroxyvitamin D3 at 500 nM significantly increases the expression of 24-hydroxylase mRNA and the increase is significantly decreased by 5alpha-dihydrotestosterone (DHT) at concentrations of 1-100 nM in androgen-sensitive prostate cancer cells LNCaP. 25-Hydroxyvitamin D3 at 500 nM and 1alpha,25-dihydroxyvitamin D3 at 10 nM inhibit LNCaP cell growth, and the growth inhibition is enhanced by 1 nM DHT. Neither 25-hydroxyvitamin D3 nor 1alpha,25-dihydroxyvitamin D3 at physiological concentrations has growth effect. However, in the presence of 1 nM DHT, both 25-hydroxyvitamin D3 and 1alpha,25-dihydroxyvitamin D3 at physiological concentrations are clearly antiproliferative. These data demonstrate that DHT enhances the antiproliferative activity of Vitamin D3 hormones by inhibiting their inactivating enzyme. Most previous studies on Vitamin D3 action in cell cultures have used pharmacological concentrations of 1alpha,25-dihydroxyvitamin D3, the present results demonstrate, for the first time, that both 25-hydroxyvitamin D3 and 1alpha,25-dihydroxyvitamin D3 at physiological concentrations are active in the presence of physiological concentration of androgen. The combined use of androgen and Vitamin D3 metabolites could be a promising treatment for prostate cancer.

Androgens↗

PubMed2006

Temporal stability of novelty exploration in mice exposed to different open field tests.

We investigated behavioural activity and temporal distribution (patterning) of mouse exploration in different open field (OF) arenas. Mice of 129S1 (S1) strain were subjected in parallel to three different OF arenas (Experiment 1), two different OF arenas in two trials (Experiment 2) or two trials of the same OF test (Experiment 3). Overall, mice demonstrated a high degree of similarity in the temporal profile of novelty-induced horizontal and vertical exploration (regardless of the size, colour and shape of the OF), which remained stable in subsequent OF exposures. In Experiments 4 and 5, we tested F1 hybrid mice (BALB/c-S1; NMRI-S1), and Vitamin D receptor knockout mice (generated on S1 genetic background), again showing strikingly similar temporal patterns of their OF exploration, despite marked behavioural strain differences in anxiety and activity. These results suggest that mice are characterised by stability of temporal organization of their exploration in different OF novelty situations.

Animals↗

PubMed2006

Behavioural anomalies in mice evoked by "Tokyo" disruption of the Vitamin D receptor gene.

Vitamin D is a steroid hormone with many important functions in the brain, mediated through the nuclear Vitamin D receptor (VDR). Mounting clinical data link VDR mutations to various psychiatric phenotypes. We have reported previously that mutant mice lacking functional VDR ("Tokyo" VDR mutant mice) display several behavioural anomalies, including high anxiety and aberrant grooming. Given the important role of Vitamin D and VDR in brain development and functioning, we hypothesized that several other important behavioural domains may be affected by disruption of the VDR gene in mice. Here we report that VDR mutants display unaffected depressive-like behaviour, but show abnormal social behaviours, reduced social barbering and aggressiveness, impaired nest building and aberrant maternal (pup neglect, cannibalism) behaviours. Taken together, these findings confirm the important role postulated for the VDR in the regulation of behaviour, and suggest the mice lacking functional VDR may be a useful tool to model different brain disorders.

Aggression↗

PubMed2006

Association between serum 25(OH)D concentrations and bone stress fractures in Finnish young men.

UNLABELLED: Low vitamin D level may predict rickets, osteomalacia, or osteoporosis. We examined serum 25(OH)D concentration as a predisposing factor for bone stress fracture in 756 military recruits. The average serum 25(OH)D concentration was significantly lower in the group with fracture, suggesting a relationship between vitamin D and fatigue bone stress fracture. INTRODUCTION: Low vitamin D level may predict rickets, osteomalacia, or osteoporosis. Fatigue bone stress fracture is one of the most frequently seen types of overuse injuries in athletes and military recruits. An association was recently shown between vitamin D and BMC. A correlation has also been found between low femoral BMD and stress fractures. We measured serum 25(OH)D concentration in a population sample of military recruits to determine if vitamin D is a predisposing factor for fatigue bone stress fracture. MATERIALS AND METHODS: We prospectively followed 800 randomly selected, healthy Finnish military recruits with a mean age of 19 years for developing stress fractures in homogenous circumstances. Blood for serum 25(OH)D concentration was drawn at entry into military service, and the weight, height, body mass index (BMI), muscle strength, and 12-minute running were measured for all subjects. Serum 25(OH)D concentrations were measured with enzyme immunoassay. At end of the 90-day follow-up, 756 subjects completed the study. Subjects without fracture constituted controls. RESULTS: Twenty-two recruits with stress fracture were identified (2.9%), the incidence being 11.6 (95% CI: 6.8-16.5) per 100 person-years. In the final multivariate analysis, the significant risk factor for stress fracture in conscripts was a below median serum 25(OH)D level (75.8 nM), OR being 3.6 (95% CI: 1.2-11.1). No significant associations between BMI (p = 0.255), age (p = 0.216), or smoking (p = 0.851) and bone stress fracture were found in this study population. CONCLUSIONS: A lower level of serum 25(OH)D concentration may be a generally predisposing element for bone stress fractures. Considering the obvious need of additional vitamin D in prevention of stress fractures, the effects of vitamin D fortification of foods and supplementation will be subjects of interest for future research.

Adolescent↗

PubMed2005

Retinoic acid via RARalpha inhibits the expression of 24-hydroxylase in human prostate stromal cells.

25-Hydroxyvitamin D(3)-24-hydroxylase (24-hydroxylase) is an important inactivating enzyme and its expression is induced by 25-hydroxyvitamin D3 (25OHD3) and 1alpha,25-dihydroxyvitamin D3 (1alpha,25-(OH)2D3) through action of heterodimers of vitamin D receptor (VDR) and retinoid X receptor (RXR). RXRs also act as heterodimer partners for retinoic acid receptors (RARs), mediating the action of all-trans-retinoic acid (ATRA). Prostate stroma plays a crucial role in prostate cancer development and benign prostatic hyperplasia. We demonstrate here that ATRA markedly reduced the expression of 24-hydroxylase mRNA induced by 25OHD3 and 1alpha,25-(OH)2D3 in human prostatic stromal cells P29SN and P32S but not in epithelial cells PrEC or cancer cells LNCaP. By using transfection and RAR-selective ligands, we found that the inhibitory effect of ATRA on 24-hydroxylase expression in stromal cells was mediated by RARalpha but not by RARbeta. Moreover, the ATRA-induced expression of RARbeta was also mediated by RARalpha. The combined treatment of 1alpha,25-(OH)2D3 and RARalpha agonist Am80 at 10 nM exhibited strong growth-inhibitory effect whereas either alone had no effect. Our data suggest that ATRA suppresses 24-hydroxylase expression through RARalpha-dependent signaling pathway and can enhance vitamin D action in suppression of cell growth.

Benzoates↗

PubMed2005

Increased severity of chemically induced seizures in mice with partially deleted Vitamin D receptor gene.

Vitamin D is a neuroactive steroid hormone with multiple functions in the brain. Numerous clinical and experimental data link various Vitamin D-related dysfunctions to epilepsy. Here, we study the role of Vitamin D receptors (VDRs) in experimental epilepsy in mice. To examine this problem, we assessed the seizure profiles in VDR knockout mice following a systemic injection of pentylenetetrazole (70 mg/kg). Overall, compared to the wild-type (WT) 129S1 mice (n=10 in each group), the VDR knockout group significantly demonstrated shorter latencies to the onset, higher Racine scores and increased mortality rates. Our findings suggest that VDRs modulate seizure susceptibility in mice, and that the Vitamin D/VDR endocrine system may be involved in the pathogenesis of epilepsy.

Animals↗

PubMed2005

Anticonvulsant effects of 1,25-dihydroxyvitamin D in chemically induced seizures in mice.

Here, we study the role of a neurosteroid hormone Vitamin D in epilepsy. To examine this problem, we used 1,25-dihydroxyvitamin D, an active form of Vitamin D, injected subcutaneously to NMRI mice (33 microg/20 microl) 40 min prior to seizures induced by systemic injection of pentylenenetrazole (PTZ, 70 mg/kg). Overall, compared to the vehicle-treated control animals (n=11 in each group), the Vitamin D-treated mice demonstrated reduced severity of PTZ-induced seizures (longer latency, shorter duration and lower mortality). In a separate experiment, we assessed the time-course of antiepileptic effects of 1,25-dihydroxyvitamin D. For this, we injected this compound (33 microg/20 microl) to NMRIx129S1 mice (n=11) 40 min, 3, 6, 12 and 24 h prior to seizures, showing that antiepileptic effects were short-term, almost disappearing 3h after administration. Our findings show that Vitamin D plays a direct anticonvulsant role in the brain and suggest that the Vitamin D endocrine system may represent a new target for the development of anticonvulsant drugs.

Animals↗

PubMed2005

Behavioural characterization in rats using the elevated alley Suok test.

Exploration of the long elevated alley (the rat Suok test) enables behavioural characterisation of anxiety, activity and neurological phenotypes in rats. Here we show that this new test is sensitive to different types of anxiety in rats, including drugs (pentylenetetrazole)-induced, light-induced and socially induced (encounter with an unfamiliar male) anxiety, as assessed by reduced Suok test horizontal, vertical, directed exploration and stops. High anxiety also leads to higher motor incoordination (as assessed by the number of falls and hind-paw slips), suggesting that this test may be used for combined profiling of anxiety, motor-vestibular anomalies and anxiety-induced motor incoordination in rats. This new behavioural paradigm may be widely used in neurobehavioural stress research, including modelling of stress-evoked states and pharmacological screening of psychotropic drugs.

Animals↗

PubMed2005

5alpha-dihydrotestosterone inhibits 1alpha,25-dihydroxyvitamin D3-induced expression of CYP24 in human prostate cancer cells.

BACKGROUND: A cross-talk between 1alpha,25-dihydroxyvitamin D(3) [1alpha,25-(OH)(2)D(3)] and 5alpha-dihydrotestosterone (DHT) in the growth inhibition has been demonstrated, but the mechanism is unknown. METHODS: The expression of 25-hydroxyvitamin D(3) 24-hydroxylase (24-hydroxylase) was measured using a real-time quantitative RT-PCR assay and the catabolism of 1alpha,25-(OH)(2)D(3) was measured using a radioreceptor assay. RESULTS: Real-time RT-PCR showed that DHT at 1-100 nM significantly inhibited 1alpha,25-(OH)(2)D(3)-induced expression of 24-hydroxylase in LNCaP cells. Furthermore, the catabolism of 1alpha,25-(OH)(2)D(3) was decreased by 10 nM DHT. An androgen receptor (AR) antagonist, Casodex antagonized the DHT effect, whereas an AR agonist (due to the mutant AR in LNCaP cells) hydroxyflutamide did not. CONCLUSIONS: We demonstrated, for the first time, that DHT reduces the ability of 1alpha,25-(OH)(2)D(3) to induce 24-hydroxylase expression. Our results not only support the earlier finding of a cross-talk between androgen and vitamin D in human prostate cancer cells but also provide a possible mechanism how androgen and vitamin D signaling pathways may interact.

Androgen Receptor Antagonists↗

PubMed2005

Vitamin D-induced up-regulation of tumour necrosis factor alpha (TNF-alpha) in prostate cancer cells.

1alpha,25-dihydroxyvitamin D3 (1alpha,25(OH)2D3 or calcitriol) is an active hormone that regulates cellular proliferation and induces apoptosis in cancer cells. Here we report on a new calcitriol target gene in prostate cancer cells, tumour necrosis factor alpha (TNF-alpha). Calcitriol and its analogue CB1093 up-regulate TNF-alpha mRNA expression in LNCaP and PC-3 cells. The stimulation is dose-dependent in both of these cell lines, demonstrated by the quantitative real-time polymerase chain reaction. Calcitriol and CB1093 act synergistically with human recombinant TNF-alpha in activation of TNF-alpha mRNA expression in LNCaP but not in PC-3 cells. Transcriptional activation of TNF-alpha gene by calcitriol or CB1093 does not lead to TNF-alpha protein secretion, however calcitriol and CB1093 enhance TPA-stimulated TNF-alpha production in LNCaP cells. We did not observe any significant effect of calcitriol on regulation of TNFR1 at the level of gene expression. Nor does calcitriol affect transcriptional regulation of cytokine (IL-1, IL-6) and cytokine receptor genes in LNCaP and PC-3 prostate cancer cell lines. Calcitriol and its analogue CB1093 at 10 nM concentration induce programmed cell death in LNCaP cells. Combined addition of human recombinant TNF-alpha with calcitriol or CB1093 cause enhanced effect in induction of apoptosis. We conclude that under physiological conditions vitamin D activates only the transcription of TNF-alpha gene, for TNF-alpha protein synthesis additional cofactors are required. Therefore a cooperation of vitamin D and TNF-alpha may play an important role in the control of cell growth in prostate cancer.

Adenocarcinoma↗

PubMed2005

Calcitriol inhibits growth response to Platelet-Derived Growth Factor-BB in human prostate cells.

Calcitriol, a hormonal form of Vitamin D, regulates growth of normal and cancer cells of various origins by modulation of peptide growth factors signaling. Platelet-Derived Growth Factor (PDGF) signaling pathway is involved in prostate cancer progression. We studied the expression of PDGF receptors in human prostate primary stromal cells and cancer epithelial cell lines and growth response to PDGF-BB isoform. We found that the expression of PDGF receptors and PDGF-BB-mediated cell growth are regulated by calcitriol in prostate cells. Quantitative RT-PCR analysis revealed a lower level of mRNA for PDGF receptors in LNCaP and PC-3 cells than in primary stromal cells. Western blotting showed a high amount of PDGFRalpha and beta proteins in primary stromal cells that could not be detected in LNCaP, which may explain the resistance of LNCaP cells to growth-promoting effect of PDGF-BB. Addition of Epidermal Growth Factor (EGF) to the culture medium induces the expression of PDGFRbeta and restores responsiveness of LNCaP to PDGF-BB to some extent. Calcitriol down-regulates PDGFRbeta expression and negatively regulates PDGF-mediated cell growth. Calcitriol does not affect PDGFRalpha and PDGF-B mRNA expression. We suggest that inhibition of PDGFRbeta expression by calcitriol might reduce responsiveness of prostate cells to mitogenic action of PDGF-BB.

Base Sequence↗

PubMed2005

A20 gene expression is regulated by TNF, Vitamin D and androgen in prostate cancer cells.

A20 is a TNF-inducible primary response gene and its product, a zinc finger protein, has antiapoptotic function in several cancer cells. We studied A20 gene expression in the Vitamin D- and TNF-sensitive LNCaP cell line and in the Vitamin D- and TNF-resistant PC-3 cell line. The results of the quantitative real-time RT-PCR analyses demonstrated that the basal level of A20 mRNA production in PC-3 cells was considerably higher than in LNCaP cells that is associated with the resistance of PC-3 cells. TNF induced A20 gene expression in both cell lines, but with different effect. A20 mRNA expression was down-regulated by 10nM calcitriol within 3-9h after treatment and up-regulated by androgen reaching maximal values by 6h after stimulation in LNCaP cells. We conclude that A20 may be involved in the regulation of cell proliferation by TNF, Vitamin D, and androgen in prostate cancer.

Androgens↗

PubMed2005

Regulation of aromatase and 5alpha-reductase by 25-hydroxyvitamin D(3), 1alpha,25-dihydroxyvitamin D(3), dexamethasone and progesterone in prostate cancer cells.

Estrogens and androgens are proposed to play a role in the pathogenesis of prostate cancer. The effective metabolites, estradiol and 5alpha-dihydrotestosterone are produced from testosterone by aromatase and 5alpha-reductase, respectively. Metabolites of vitamin D have shown to inhibit the growth of prostate cancer cells. The aim of the present study was to verify whether 25-hydroxyvitamin D(3) (25OHD(3)), 1alpha,25-dihydroxyvitamin D(3) [1alpha,25-(OH)(2)D(3)], dexamethasone, and progesterone regulate the expression of aromatase and 5alpha-reductase in human prostate cancer cells. LNCaP and PC3 cells were treated with 25OHD(3), 1alpha,25-(OH)(2)D(3), dexamethasone, or progesterone. Aromatase and 5alpha-reductase mRNA was quantified by real-time RT-PCR and aromatase enzyme activity was measured by the [(3)H] water assay. Aromatase enzyme activity in LNCaP and PC3 cells was increased by both 10nM dexamethasone, 1-100 nM 1alpha,25-(OH)(2)D(3) and 100 nM-10 microM progesterone. The induction was enhanced when hormones were used synergistically. Real-time RT-PCR analysis showed no regulation of the expression of aromatase mRNA by any steroids tested in either LNCaP or PC3 cells. The expression of 5alpha-reductase type I mRNA was not regulated by 1alpha,25-(OH)(2)D(3) and no expression of 5alpha-reductase type II was detected in LNCaP.

3-Oxo-5-alpha-Steroid 4-Dehydrogenase↗

PubMed2005

Mouse grooming microstructure is a reliable anxiety marker bidirectionally sensitive to GABAergic drugs.

Grooming is an important part of rodent behavioural repertoire, representing a complex hierarchically ordered cephalo-caudal sequence of patterns sensitive to stress and various drugs. Gamma-aminobutyric acid (GABA) is involved in the regulation of both anxiety and grooming behaviours. This study investigated the predictive validity of grooming behavioural microstructure as a marker of anxiety, by examining the effects of two GABAergic reference compounds, anxiolytic diazepam (0.1 and 0.5 mg/kg i.p.) and anxiogenic pentylenetetrazole (5 and 10 mg/kg i.p.) on mouse grooming. Our data suggest that the percentage of pattern transitions not fitting to the cephalo-caudal progression, and the percentage of interrupted grooming bouts are more reliable behavioural markers of stress bidirectionally sensitive to GABAergic anxiogenic and anxiolytic drugs, compared to the frequency and duration scores. Our study also confirms that detailed ethological analyses of grooming microstructure can be a useful tool in behavioural pharmacology of anxiety.

Animals↗

PubMed2005

The Suok ("ropewalking") murine test of anxiety.

In the present study, we suggest that long elevated horizontal rod (Suok test, ST) and its light-dark modification (LDST) may be used for behavioral characterization in mice, including simultaneous assessment of their anxiety, activity, and neurological phenotypes. To establish the ST and the LDST as murine models of anxiety, we used several different mouse strains which differ markedly in their anxiety and activity (C57BL/6, 129S1/SvImJ, NMRI, and BALB/c). Here we show that our tests are able to ethologically discriminate between high and low anxiety mouse strains, as assessed by horizontal and directed exploration, stops, and defecation boli. The spatial distribution of the LDST behaviors is also sensitive to these strain-specific anxiety phenotypes, showing clear avoidance of the brightly lit part of the test in stressed (rat exposed) vs. control NMRI mice. In addition, we validated the ST in 129S1/SvImJ and BALB/c mice by assessing the behavioral consequences of acute stress such as rat exposure. Finally, we showed that our test is able to detect high anxiety and poorer motor coordination in 129S1/SvImJ (vs. C57BL/6) mice. The results of our study show that the ST emerges as an experimental tool to analyze anxiety, motor-vestibular anomalies, as well as anxiety-induced motor impairments in mice. Overall, we suggest that the ST can be a useful protocol in neurobehavioral stress research including modeling stress-evoked states, pharmacological screening of potential anti-stress drugs, or behavioral phenotyping of genetically modified animals.

Animals↗