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Biomedical subjects

Tetsuya Takahashi

Publications and source records attributed to Tetsuya Takahashi.

At least 19 recordsLinked to original sources
PubMed2006

Siah-1 facilitates ubiquitination and degradation of factor inhibiting HIF-1alpha (FIH).

Hypoxia-inducible factor-1alpha (HIF-1alpha) has a central role in neuroprotective responses to hypoxia in the brain. Hydroxylation of HIF-1alpha by prolyl-hydroxylase PHD and aspargynyl-hydroxylase FIH (factor inhibiting HIF-1alpha) causes proteasomal degradation and transcriptional inhibition of HIF-1alpha. Siah ubiquitin ligases regulate the abundance of PHD via targeting for proteasomal degradation. The present study identified Siah-1 as a binding partner for another hydroxylase FIH. Siah-1 and FIH coimmunoprecipitated each other in mammalian cells. Siah-1 was found both to interact with the JmjC domain of FIH through its substrate-binding domain and to specifically ubiquitinate FIH via its RING finger domain. Siah-1 facilitated FIH degradation via the ubiquitin-proteasome pathway under hypoxic conditions. Such findings suggest that Siah ubiquitin ligases might play a role as up-stream regulators of both hydroxylases for HIF-1alpha, i.e., PHD and FIH, by targeting them for proteasomal degradation, leading to increased HIF-1alpha abundance, and transcriptional activity in hypoxia.

Cell Hypoxia↗
PubMed2006

Association between trait anxiety and endothelial function observed in elderly males but not in young males.

BACKGROUND AND OBJECTIVES: Endothelial function plays a key role in determining the clinical manifestations of atherosclerosis. Recent reports have shown that healthy elderly subjects with higher trait anxiety tend to have heightened risks of atherosclerotic lesions and cardiovascular disease. The present study was intended to examine whether an association exists between trait anxiety and endothelial function in healthy young and elderly subjects. METHODS: This study examined 26 young male and 30 elderly male subjects using brachial artery flow-mediated dilation (FMD) - a non-invasive ultrasound method - to evaluate endothelial function by measuring the dilation responses of vascular smooth muscle to the nitric oxide produced by endothelial cells following hyperemia. RESULTS: A significant negative correlation was observed between the State and Trait Anxiety Inventory (STAI)-trait score as a parameter of anxiety and the percentage change of FMD (%FMD) in the elderly subjects, but not in the young subjects. The elderly subjects showed significantly lower %FMD than the young subjects. CONCLUSION: These results suggest the possibility that trait anxiety is a predisposing risk factor for cardiovascular damage that might, over a long period, induce atherosclerotic lesions.

Adult↗
PubMed2006

Hypoxia-induced upregulation of endothelial small G protein RhoA and Rho-kinase/ROCK2 inhibits eNOS expression.

The small G protein RhoA and its downstream effector Rho-kinase/ROCK2 play an important role in regulation of various vasculature cellular functions. Nitric oxide (NO) produced by endothelial NO synthase (eNOS) is an important mediator of vascular homeostasis and cerebral blood flow. Using the human endothelial cell line HUVEC, the present study investigated the role of RhoA and Rho-kinase in endothelial eNOS protein expression under hypoxic conditions as an in vitro model of ischemia. RhoA protein levels in HUVEC were low under normoxic conditions, but were significantly increased after 5h of hypoxia. Endothelial Rho-kinase expression was not detected until after 3h of hypoxia; such expression remained significantly increased after 5h. On the other hand, endothelial eNOS expression was similar after 3h of hypoxia, but was significantly decreased after 5h. The hypoxia-induced decrease in eNOS expression was significantly enhanced by expression of the constitutively active form of RhoA and significantly inhibited by suppression of RhoA expression by small interfering RNA. The hypoxia-induced decrease in eNOS expression was significantly inhibited when endogenous Rho-kinase activation was inhibited by Rho-binding domain expression. Furthermore, the hypoxia-induced decrease in eNOS expression was significantly enhanced by expression of the constitutively active form of Rho-kinase. Since expression and activation of RhoA and Rho-kinase inhibit eNOS expression in endothelial cells, attempts to down-regulate RhoA and Rho-kinase by multiple drugs, such as statins or Rho-kinase inhibitors, might provide endothelial and cardiovascular benefits through upregulation of eNOS.

Cell Hypoxia↗
PubMed2006

Interactions of Synphilin-1 with phospholipids and lipid membranes.

Synphilin-1 is an alpha-synuclein binding protein that is involved in the pathogenesis of Parkinson's disease. The present study investigated the phospholipid-binding capacity of Synphilin-1. The C-terminus of Synphilin-1 was found to selectively bind to acidic phospholipids, including phosphatidic acid, phosphatidylserine, and phosphatidylglycerol, but not to naturally charged phospholipids. Synphilin-1 was targeted to cytoplasmic lipid droplets in mammalian cells. The amino acid sequence 610-640 was found to represent the primary determinant site for phospholipid binding. Moreover, the R621C mutation identified in Parkinson's disease abolished Synphilin-1 association with lipid droplets. The lipophilicity of Synphilin-1 might prove relevant to its physiologic function.

Animals↗
PubMed2006

Multifractal analysis of deep white matter microstructural changes on MRI in relation to early-stage atherosclerosis.

Multifractal analysis based on generalized concepts of fractals has been applied to evaluate biological tissues composed of complex structures. This type of analysis can provide a precise quantitative description of a broad range of heterogeneous phenomena. Previously, we applied multifractal analysis to describe heterogeneity in white matter signal fluctuation on T2-weighted MR images as a new method of texture analysis and established Deltaalpha as the most suitable index for evaluating white matter structural complexity (Takahashi et al. J. Neurol. Sci., 2004; 225: 33-37). Considerable evidence suggests that pathophysiological processes occurring in deep white matter regions may be partly responsible for cognitive deterioration and dementia in elderly subjects. We carried out a multifractal analysis in a group of 36 healthy elderly subjects who showed no evidence of atherosclerotic risk factors to examine the microstructural changes of the deep white matter on T2-weighted MR images. We also performed conventional texture analysis, i.e., determined the standard deviation of signal intensity divided by mean signal intensity (SD/MSI) for comparison with multifractal analysis. Next, we examined the association between the findings of these two types of texture analysis and the ultrasonographically measured intima-media thickness (IMT) of the carotid arteries, a reliable indicator of early carotid atherosclerosis. The severity of carotid IMT was positively associated with Deltaalpha in the deep white matter region. In addition, this association remained significant after excluding 12 subjects with visually detectable deep white matter hyperintensities on MR images. However, there was no significant association between the severity of carotid IMT and SD/MSI. These results indicate the potential usefulness of applying multifractal analysis to conventional MR images as a new approach to detect the microstructural changes of apparently normal white matter during the early stages of atherosclerosis.

Aged↗
PubMed2006

Plasma levels of adiponectin and tumor necrosis factor-alpha in patients with remitted major depression receiving long-term maintenance antidepressant therapy.

Adiponectin, an adipose tissue-specific plasma protein, is involved in insulin sensitization and has anti-atherosclerotic properties, whereas tumor necrosis factor-alpha (TNF-alpha), a pro-inflammatory protein, plays important roles in inflammatory endothelial injury and atherosclerotic changes. It has been reported that adiponectin and TNF-alpha inhibit each other's expression and production in adipocytes. Several in vitro studies indicated that antidepressant medications decreased the production of pro-inflammatory cytokines including TNF-alpha, but the effect of antidepressants on the expression of adiponectin is still unknown. We examined the plasma levels of TNF-alpha and adiponectin in patients with remitted depression receiving maintenance antidepressant therapy for longer than half a year, and compared the levels with those in healthy controls. The plasma levels of TNF-alpha and adiponectin in the remitted depression group were significantly lower and higher than those in the control group, respectively. This preliminary cross-sectional study suggests the possibility that maintenance antidepressant therapy may have anti-inflammatory effects and prevent the development of atherosclerosis.

Adiponectin↗
PubMed2006

Interactions among higher trait anxiety, sympathetic activity, and endothelial function in the elderly.

Negative psychological characteristics have been recognized as independent risk factors of cardiovascular disease (CVD). The purpose of this study was to evaluate the influence of depression and anxiety on cardiac autonomic function and endothelial function in healthy elderly subjects. Forty-six healthy elderly volunteers (mean age 60.8 years) were enrolled in this study. Cardiac autonomic function was assessed by spectral analysis of heart rate variability (HRV) with the head-up tilt test. Brachial artery endothelium-dependent flow-mediated dilation (FMD) was measured using high-resolution ultrasound. A significant positive correlation was observed between the State and Trait Anxiety Inventory (STAI)-trait score as a parameter of anxiety and HRV sympathetic modulation in the supine position (baseline), and a significant negative correlation between this score and the head-up-induced HRV sympathetic response from the baseline. The STAI-trait score also showed a significant negative correlation with the percent change of FMD (%FMD). Analysis using structural equation modeling showed that higher trait anxiety reduced %FMD via abnormalities of sympathetic activity. On the other hand, psychometric parameters of depression were not associated with any HRV component or %FMD. These results suggest that there are specific interactions among higher trait anxiety, abnormalities of sympathetic activity, and endothelial dysfunction. This finding may be useful in clarifying the pathophysiological mechanism by which anxiety is associated with increased risks for atherosclerosis and CVD.

Aged↗
PubMed2006

White coat phenomenon, anxiety and endothelial function in healthy normotensive elderly subjects.

OBJECTIVE: The white coat phenomenon (WCP) is a blood pressure (BP) elevation specifically observed in the clinical setting. Though WCP has been suggested to associate with emotional responses such as anxiety or with cardiovascular complications, its pathogenesis and clinical significance are unclear. We studied the possible association between WCP and anxiety or vascular function in normotensive elderly subjects without major cardiovascular risk factors. METHODS: As a parameter of anxiety, the State and Trait Anxiety Inventory (STAI) was used. WCP was evaluated by calculating the difference between the clinic BP and mean daytime ambulatory BP. As parameters of vascular function, brachial artery endothelium-dependent flow-mediated dilation (FMD) and the endothelium-independent dilation response to sublingual glyceryl trinitrate (GTN) were measured using high-resolution ultrasound. RESULTS: Using confounding factors as covariates, no association was observed between WCP and the STAI-trait or STAI-state score. There was a significant negative association between WCP and the percent change of FMD but no association between WCP and the percent change of GTN. CONCLUSION: WCP in the healthy normotensive elderly subjects may reflect a decrease in endothelial function, i.e. initial stage atherosclerosis, rather than anxiety.

Aged↗
PubMed2006

Embryonic stem cell-derived neuron models of Parkinson's disease exhibit delayed neuronal death.

Establishment of a Parkinson's disease (PD) neuron model was attempted with mouse embryonic stem (ES) cells. ES cell lines over-expressing mouse nuclear receptor-related 1 (Nurr1), together with human wild-type and alanine 30 --> proline (A30P) and alanine 53 --> threonine (A53T) mutant alpha-synuclein were established and subjected to differentiation into dopaminergic neurons. The ES cell-derived dopaminergic neurons expressing wild-type or mutant alpha-synuclein exhibited the fundamental characteristics consistent with dopaminergic neurons in the substantia nigra. The ES cell-derived PD model neurons exhibited increased susceptibility to oxidative stress, proteasome inhibition, and mitochondrial inhibition. Cell viability of PD model neurons and the control neurons was similar until 28 days after differentiation. Nonetheless, after that time, PD model neurons gradually began to undergo neuronal death over the course of 1 month, showing cytoplasmic aggregate formation and an increase of insoluble alpha-synuclein protein. Such delayed neuronal death was observed in a mutant alpha-synuclein protein level-dependent manner, which was slightly inhibited by a c-jun N-terminal kinase inhibitor and a caspase inhibitor. Such cell death was not observed when the same ES cell lines were differentiated into oligodendrocytes. The ES cell-derived PD model neurons are considered as prospective candidates for a new prototype modelling PD that would allow better investigation of the underlying neurodegenerative pathophysiology.

Analysis of Variance↗
PubMed2006

[Changes in autonomic function and EEG power during mental arithmetic task and their mutual relationship].

Meditation is a specific consciousness state in which deep relaxation and increased internalized attention coexist. Autonomic nervous activity during meditation was reported to be characterized by decreased sympathetic activity and increased parasympathetic activity. And concerning EEG power, slow alpha power and fast theta power increased during meditation. On the other hand, mental arithmetic (MA) tasks have been reported to induce an increase in blood pressure and heart rate with enhanced sympathetic activity. However, changes in autonomic nervous activity and EEG power during MA tasks and their mutual relationship have not been adequately studied. In the present study, we quantitatively analyzed the changes in autonomic nervous activity using heart rate variability (HRV) and EEG power during MA task in 30 healthy volunteers. MA task induced significant increases in normalized LF, LF/HF ratio (as a sympathetic index), and a decrease in normalized HF (as a parasympathetic index). On the other hand, significant decrease in EEG power (slow theta: 4-6 Hz and fast alpha: 10-13 Hz in the posterior region and fast theta: 6-8 Hz and slow alpha: 8-10 Hz in all the regions) were induced by MA task. Further evaluation of these changes showed a negative correlation between the change rates (with the control resting condition as the baseline) in fast alpha power and that in LF/HF. These results suggest that specific correlated relationships exist between the change in autonomic nervous activity and EEG power depending on the difference in mental task (i.e., meditation or MA).

Adult↗
PubMed2005

Changes in EEG and autonomic nervous activity during meditation and their association with personality traits.

Meditation is the attainment of a restful yet fully alert physical and mental state practiced by many as a self-regulatory approach to emotion management, but the psychophysiological properties and personality traits that characterize this meditative state have not been adequately studied. We quantitatively analyzed changes in psychophysiological parameters during Zen meditation in 20 normal adults, and evaluated the results in association with personality traits assessed by Cloninger's Temperament and Character Inventory (TCI). During meditation, increases were observed in fast theta power and slow alpha power on EEG predominantly in the frontal area, whereas an increase in the normalized unit of high-frequency (nuHF) power (as a parasympathetic index) and decreases in the normalized unit of low-frequency (nuLF) power and LF/HF (as sympathetic indices) were observed through analyses of heart rate variability. We analyzed the possible correlations among these changes in terms of the percent change during meditation using the control condition as the baseline. The percent change in slow alpha EEG power in the frontal area, reflecting enhanced internalized attention, was negatively correlated with that in nuLF as well as in LF/HF and was positively correlated with the novelty seeking score (which has been suggested to be associated with dopaminergic activity). The percent change in fast theta power in the frontal area, reflecting enhanced mindfulness, was positively correlated with that in nuHF and also with the harm avoidance score (which has been suggested to be associated with serotonergic activity). These results suggest that internalized attention and mindfulness as two major core factors of behaviors of mind during meditation are characterized by different combinations of psychophysiological properties and personality traits.

Adult↗
PubMed2004

The FHA domain of aprataxin interacts with the C-terminal region of XRCC1.

Aprataxin (APTX) is the causative gene product for early-onset ataxia with ocular motor apraxia and hypoalbuminemia (EAOH/AOA1). In our previous study, we found that APTX interacts with X-ray repair cross-complementing group 1 (XRCC1), a scaffold protein with an essential role in single-strand DNA break repair (SSBR). To further characterize the functions of APTX, we determined the domains of APTX and XRCC1 required for the interaction. We demonstrated that the 20 N-terminal amino acids of the FHA domain of APTX are important for its interaction with the C-terminal region (residues 492-574) of XRCC1. Moreover, we found that poly (ADP-ribose) polymerase-1 (PARP-1) is also co-immunoprecipitated with APTX. These findings suggest that APTX, together with XRCC1 and PARP-1, plays an essential role in SSBR.

Amino Acid Sequence↗
PubMed2004

Quantitative evaluation of age-related white matter microstructural changes on MRI by multifractal analysis.

Multifractal analysis has been applied to evaluate biological tissues, which are composed of complex structures. We carried out multifractal analyses in a group of healthy young and elderly subjects to examine age-related white matter microstructural changes on T2-weighted MR images without any visible abnormal intensity, and to correlate such changes with age-related cognitive decline. Comparison between the two age groups showed that Deltaalpha (established as the most suitable index of heterogeneity in our previous report) in the frontal region was significantly higher in the elderly group, but no significant group difference was found in Deltaalpha in the parieto-occipital region. The Trail-Making Test score (a measure of executive dysfunction) was significantly higher in the elderly group. In the elderly group, the Trail-Making Test score was positively correlated with Deltaalpha in the frontal region, but not in the parieto-occipital region. These results suggest that microstructural changes in the white matter preferentially occur in the frontal region with normal aging, and these changes are associated with executive cognitive decline reflective of frontal-subcortical dysfunction.

Adult↗
PubMed2004

Hydrodynamically induced chemical oscillation at a water/nitrobenzene interface.

By measuring a time course of interfacial tension and interfacial electrical potential, we successfully observed oscillatory phenomena that were based on alternatively appearing adsorption and desorption processes of anionic surfactant molecules (sodium dodecyl sulfate (SDS)) at the water/nitrobenzene interface. These oscillation patterns were drastically modified by slightly changing the rate of SDS aqueous solution injection into the water phase. When 10 mM of SDS aqueous solution was injected at a low rate, for example, at less than 1 microl/min, abrupt adsorption was repeatedly followed by slow desorption of DS- ions; in other words, the sequence of the oscillation and relaxation processes was repeated. However, when it was injected at a higher rate, no remarkable periodic phenomenon occurred after the first oscillation. In addition, the rapid adsorption process was observed to be accompanied by a flip motion of the liquid/liquid interface and a flow along the interface. This is caused by a Marangoni convection that is brought about by the generation of heterogeneity of interfacial tension. Furthermore, by estimating the flow speed, it was determined that the faster flow tends to quench the periodic oscillation patterns.

Journal Article↗
PubMed2004

Safe and permissible limits of hepatectomy in obstructive jaundice patients.

The safe and permissible limits of hepatectomy in obstructive jaundice patients and the usefulness of preoperative portal embolization (PE) for increasing the limit for safe hepatectomy were examined. We classified 416 patients with hepatectomy performed over 9 years under the following headings: normal liver function (n = 242); chronic hepatitis (n = 71); liver cirrhosis (n = 64); and liver after relief of obstructive jaundice (n = 39). Hepatectomy was done after the total bilirubin level was reduced below 3 mg/dl by preoperative biliary drainage. Factors influencing the maximum total bilirubin level measured within 2 weeks after hepatectomy were investigated, and this level was taken to reflect the degree of surgical stress. PE was carried out in 18 patients with obstructive jaundice. The maximum total bilirubin, expressed as a logarithm, was significantly correlated with the percent of liver resected in all groups. Hepatectomy followed by a maximum total bilirubin of less than 8.5 mg/dl was accepted as safe, and hepatectomy followed by a bilirubin level of 14.4 mg/dl was deemed the maximum permissible resection. On the basis of these results, the safe and permissible limits of hepatectomy in patients with obstructive jaundice were 48.7% and 71.6%, respectively. PE decreased the maximum total bilirubin from 8.5 mg/dl to 3.9 mg/dl when 48.7% of the liver (a safe proportion in all cases) was resected; PE increased the safe limit of hepatectomy from 48.7% to 67.4% when a maximum posthepatectomy total bilirubin level of 8.5 mg/dl was accepted as safe.

Bilirubin↗
PubMed2004

Hepatic resection for colorectal metastases in the caudate lobe of the liver.

Although hepatic resections for colorectal metastases have become established procedures, there is still only a small number of reports of hepatic resections for such metastases in the caudate lobe. From 1993 to 2001, seven patients underwent eight hepatic resections for colorectal metastases in the caudate lobe at our department. The patients were five men and two women, and their ages were from 53 to 73 years. The ratio of synchronous to metachronous liver metastases was 2 : 5. Solitary metastasis was observed in one patient. One patient with a metastasis in the Spiegel lobe and three patients with metastasis in the caudate process underwent partial resection of the site. The other patients underwent resection of the Spiegel lobe (two times), resection of the right-sided caudate lobe, and total caudate lobe resection. The mean (+/-SE) operative time was 315.9 +/- 30.6 min. Mean intraoperative blood loss was 1325.9 +/- 421.1 ml, and mean postoperative hospital stay was 21 +/- 3.7 days. One patient, who underwent sigmoidectomy and hepatectomy as an emergency operation due to ileus, experienced wound infection. No patient died within 12 months after the surgery. Five patients were alive at 24 months, and three at 36 months. The outcome of these patients encourages us to continue performing hepatic resection for colorectal metastases in the caudate lobe, as it is assumed to be a safe and effective procedure.

Aged↗