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Biomedical subjects

Yukio Ikeda

Publications and source records attributed to Yukio Ikeda.

At least 37 records · Page 2Linked to original sources
PubMed2004

Correlation of plasma oxidized low-density lipoprotein levels to vascular complications and human serum paraoxonase in patients with type 2 diabetes.

The oxidative modification of low-density lipoprotein (LDL) plays a central role in the initiation and acceleration of atherosclerosis. Human serum paraoxonase (PON1) is associated with high-density lipoprotein (HDL) and has been shown to reduce the susceptibility of LDL to lipid peroxidation. We investigated whether circulating oxidized LDL (Ox-LDL) levels were associated with diabetic vascular complications, and whether the enzymatic activity and gene polymorphisms of PON1 influenced Ox-LDL concentrations in vivo. There was no difference in the plasma Ox-LDL concentrations between diabetic patients with and without macrovascular diseases. However, Ox-LDL concentrations corrected by LDL-cholesterol (OxLDL/LDL-C) or apolipoprotein B (apoB) concentrations (Ox-LDL/apoB), which probably reflect the proportion of oxidatively modified LDL to total LDL particles, were significantly higher in patients with macrovascular diseases than in those without. In addition, patients with peripheral neuropathy had a significantly higher Ox-LDL/apoB ratio than patients without this complication. The genotype TT of -108C/T polymorphism in the promoter region of the PON1 gene, which is associated with decreased PON1 expression, showed a significantly higher Ox-LDL/apoB ratio than genotypes TC or CC (TT: 0.60 +/- 0.15, CT + CC: 0.55 +/- 0.11, P =.02). Stepwise multiple regression analysis for Ox-LDL concentration revealed that the -108C/T polymorphism, subsequently to apoB concentration, was identified as a significant contributor. In summary, the Ox-LDL/apoB ratio was associated with macrovascular disease and peripheral neuropathy in Japanese patients with type 2 diabetes. Increased Ox-LDL/apoB may result, at least partly, from reduced serum antioxidant capacity in the diabetic state, including the attenuation of PON1 action. Increased Ox-LDL/apoB could be a significant marker for susceptibility to vascular complications in diabetic patients.

Adult↗
PubMed2004

Preoperative evaluation of the venous system for potential interference in the clipping of cerebral aneurysm.

BACKGROUND: Variations of the venous system affecting the surgical treatment of cerebral aneurysm were evaluated using three-dimensional computed tomography angiography (3D-CTA) to evaluate the essential aspects of preoperative diagnosis. METHODS: This study included 50 patients who underwent clipping of cerebral aneurysm through the pterional and trans-sylvan approaches. The 3D-CTA and operative findings were compared to assess the characteristics of cases in which the veins restrict brain retraction, hinder operative manipulations or require sacrifice because of the position in the operative field. RESULTS: Superficial sylvian veins that restricted brain retraction were identified in 8 cases. The veins entered the cavernous sinus in a relatively high position just below either the sphenoid ridge (superior lateral type) or the anterior clinoid process (superior medial type), and the veins entering at a more medial position were closer to the spatula and tended to be compressed or directly excluded (superior medial type). The inferior medial type did not tend to become tense and so did not restrict brain retraction. The inferior lateral type hardly affected the operative manipulation. The first segment of the basal vein of Rosenthal, the uncal vein entering the cavernous sinus, or the sphenoparietal sinus were located in the operative field in six cases, and affected the manipulation of dissecting arteries, and exposure and clipping of the aneurysm. CONCLUSIONS: 3D-CTA provides essential information for operative planning to protect the venous system during the pterional and trans-sylvian approaches.

Brain↗
PubMed2004

Assessment of oxidative stress in the spontaneously hypertensive rat brain using electron spin resonance (ESR) imaging and in vivo L-Band ESR.

This study examined the blood brain barrier (BBB)-permeable nitroxyl compound, 3-methoxycarbonyl-2,2,5,5-tetramethylpyrrolidine-1-oxyl (MC-PROXYL), as a spin probe for the assessment of oxidative stress in the brain by electron spin resonance (ESR) imaging and in vivo L-band ESR. Preliminary comparisons were made by ESR imaging of MC-PROXYL in the isolated brains of normal Wistar-Kyoto rats (WKY), spontaneously hypertensive rats (SHR), and stroke prone SHR (SHRSP). The decay of the ESR images of MC-PROXYL in the isolated brains was faster in SHR than in normal WKY, but was only moderate in SHRSP. In addition, the decay rate of MC-PROXYL in the heads of live rats, as measured noninvasively by L-band ESR, was faster in SHR than in WKY, and was slower in SHR than in SHRSP. Taken together, our data suggest that the oxidative stress of SHR is not as high as that in high oxidative stress animal models such as SHRSP. This is the first study to present reconstructed 3D images of the distribution of MC-PROXYL in the isolated SHR brain. The ESR technique employed herein appears to be a powerful tool for evaluating oxidative stress and for detecting the region of oxidative stress in the brain of SHR.

Animals↗
PubMed2004

Lack of association between IL-12B gene polymorphism and autoimmune thyroid disease in Japanese patients.

Interleukin (IL)-12 is a key factor in cell-mediated immunity that drives the development of Th1 cells and stimulates T lymphocytes and natural killer cells to produce interferon (INF)-gamma. The IL-12B gene, which encodes the p40 subunit of IL-12, is located at chromosome 5q31-33 and a linkage finding for autoimmune thyroid disease (AITD) on 5q31-33 in a Japanese population has been reported. It is also reported that the A/C polymorphism in the 3' untranslated region (UTR) of the IL-12B gene (1188A/C) is associated with IL12B mRNA expression levels. We attempted to determine whether genetic polymorphisms of the IL-12B gene are associated with AITD. One hundred three patients with Hashimoto's thyroiditis, 90 patients with Graves' disease, and 123 healthy control subjects were recruited. We detected the 1188A/C polymorphism using a PCR-RFLP method and the A/T polymorphism in intron 4 of the IL-12B gene using a cycle sequencing method. These IL-12B gene polymorphisms showed strong linkage disequilibrium, and their genotype and allele frequencies in the patients did not differ from those in the control subjects. Our results suggest that IL-12B gene polymorphisms were unlikely to have an effect on the development of Hashimoto's thyroiditis or Graves' disease in Japanese patients.

3' Untranslated Regions↗
PubMed2004

[Cerebral aneurysms in identical twins].

The hypothesis that genetic factors play a role in the genesis of cerebral aneurysms may be supported by clinical analysis of cerebral aneurysms in identical twins. In addition to reporting the present case, we review the literature on clinical features and genetical considerations in this matter. A forty-two-year-old male presented with subarachnoid hemorrhage (SAH) due to a left MCA aneurysm. At the age of 39, his identical twin brother also had SAH due to a ruptured left MCA aneurysm. This identical twin brother and his father's sisters died of SAH. Venous blood of the patient and his parents was collected to determine apolipoprotein E, angiotensinogen, angiotensin-converting enzyme, and very low density lipoprotein receptor genes. This analysis suggested a strong genetic association of apolipoprotein E epsilon4 with the pathogenesis. Including our cases, 13 cases of cerebral aneurysms in identical twins have been reported. There was a total of 37 aneurysms. Six twins had the same sites of aneurysm. These aneurysms show a tendency to be small in size, and to cause a high frequency of SAH occurring at a similar age. In young adults, cerebral aneurysms in identical twins tend to rupture. A screening diagnosis should be carried out as early as possible on an asymptomatic twin when the other has been discovered to have a ruptured cerebral aneurysm. Preventive treatment and systemic genome-wide linkage study should be conducted.

Adult↗
PubMed2004

[Bilateral chronic subdural hematoma in a young adult mimicking subarachnoid hemorrhage].

A 33-year-old man was admitted to our hospital with a sudden severe headache five days after the onset CT scan showed a slight high-density area in the basal cistern, mimicking subarachnoid hemorrhage (SAH), and diffuse brain swelling. However, conventional cerebral angiography and CT angiography failed to demonstrate aneurysms and vascular malformations. MRI showed bilateral subdural hematoma, but no SAH. Irrigation of liquefied subdural hematoma, causing high intracranial pressure, was carried out. Postoperative course was uneventful and his headache resolved within a day. The author presented a case of bilateral chronic subdural hematoma who presented with a sudden severe headache mimicking a SAH. Hyper attenuation in the basal cistern and subarachnoid space in CT, don't always indicate SAH. MRI, including fluid-attenuated inversion recovery (FLAIR) sequences, is useful in differentiating the "pseudo" SAH from "true" SAH, and lead to the right diagnosis.

Adult↗
PubMed2003

Activation of peroxisome proliferator-activated receptor delta induces fatty acid beta-oxidation in skeletal muscle and attenuates metabolic syndrome.

In this study, we defined the role of peroxisome proliferator-activated receptor beta/delta (PPARdelta) in metabolic homeostasis by using subtype selective agonists. Analysis of rat L6 myotubes treated with the PPARdelta subtype-selective agonist, GW501516, by the Affymetrix oligonucleotide microarrays revealed that PPARdelta controls fatty acid oxidation by regulating genes involved in fatty acid transport, beta-oxidation, and mitochondrial respiration. Similar PPARdelta-mediated gene activation was observed in the skeletal muscle of GW501516-treated mice. Accordingly, GW501516 treatment induced fatty acid beta-oxidation in L6 myotubes as well as in mouse skeletal muscles. Administration of GW501516 to mice fed a high-fat diet ameliorated diet-induced obesity and insulin resistance, an effect accompanied by enhanced metabolic rate and fatty acid beta-oxidation, proliferation of mitochondria, and a marked reduction of lipid droplets in skeletal muscles. Despite a modest body weight change relative to vehicle-treated mice, GW501516 treatment also markedly improved diabetes as revealed by the decrease in plasma glucose and blood insulin levels in genetically obese ob/ob mice. These data suggest that PPARdelta is pivotal to control the program for fatty acid oxidation in the skeletal muscle, thereby ameliorating obesity and insulin resistance through its activation in obese animals.

Animals↗
PubMed2003

Human paraoxonase-1 gene expression by HepG2 cells is downregulated by interleukin-1beta and tumor necrosis factor-alpha, but is upregulated by interleukin-6.

Recent studies have demonstrated that human paraoxonase-1 (PON1) associated with HDL, plays a role for anti-atherosclerotic effects of HDL, however, the relationships between PON1 and inflammatory cytokines remain unclear. To clarify this point, we evaluated the transcriptional regulation of PON1 gene by IL-1beta, IL-6 and TNF-alpha in HepG2 cells using luciferase reporter gene assay. We determined the nucleotide sequence of upstream of PON1 gene, and constructed plasmids containing various lengths of upstream region. In the plasmid constructs of U39 (PON1 upstream -1232/-6), U682 (-589/-6), U797 (-472/-6) and U953 (-318/-6), U953 showed a stepwise upregulation in basal promoter activity. The relative promoter activities using U682 plasmid were generally downregulated by IL-1beta and TNF-alpha, but were upregulated by IL-6. By the combination of IL-1beta, IL-6 and/or TNF-alpha, the promoter activities were proportionally regulated. The result of PON1 transcriptional regulation by cytokines in HepG2 cells was confirmed to be concordant with that of regulation of PON1 mRNA expression by cytokines. These results suggest that PON1 mRNA expression by hepatocytes is regulated by proinflammatory cytokines and that proinflammatory cytokines secreted in a disease state, may play a role in the development of atherosclerotic lesion via modification of PON1 mRNA expression affecting on the anti-oxidative property of HDL.

Aryldialkylphosphatase↗
PubMed2003

Measurement of oxidative stress in the rodent brain using computerized electron spin resonance tomography.

The strategy of this study was to improve the electronic spin resonance (ESR) application used to detect free radical-induced oxidative stress in animal models. We have developed an in vivo ESR imaging system with high-quality ESR-computed tomography (CT) images by using a nitroxyl spin probe--BBB-permeable, 3-methoxycarbonyl-2,2,5,5-tetramethyl-pyrrolidine-1-yloxy (MC-PROXYL)--in living small animals. We first measured the distribution of MC-PROXYL in the head region of a living mouse by using ESR-CT imaging after treatment with MC-PROXYL. In the ESR-CT experiments, it was clearly observed that MC-PROXYL was well distributed in the brain of head region of a living mouse. The ESR-CT images taken after treatment with MC-PROXYL demonstrate that the decay of MC-PROXYL in the isolated brain of a spontaneously hypertensive rat (SHR) was more rapid than that in a Wister Kyoto rat. ESR-CT analysis revealed that the region of rapid decay might be located in the cerebral cortex of the isolated brain of an SHR. These results suggest that the present study of ESR-CT imaging would be a useful tool for monitoring and detecting the locations of oxidative stress in the brains of rodent animal models.

Animals↗
PubMed2003

Serum paraoxonase activity decreases in rheumatoid arthritis.

OBJECTIVE: To estimate the alterations of paraoxonase 1 (PON1) and high-density lipoprotein (HDL) in rheumatoid arthritis (RA). DESIGN AND METHODS: We investigated the serum enzyme activity and concentration of PON1 and their relationship with serum lipids, high-density lipoprotein (HDL) parameters, and acute phase reactants of serum amyloid A (SAA) and C-reactive protein (CRP) in patients with RA. RESULTS: Serum paraoxonase (PON) activity was significantly decreased in RA patients (n = 64, 131 +/- 53 micro mol/min/L) compared with healthy subjects (n = 155, 164 +/- 59) despite the absence of any difference in serum lipid levels between the two groups. This decrease of serum PON activity in RA patients was found in every genotype (Q/Q, Q/R, R/R) of PON1 at 192 Q/R. There was a different distribution in PON1 Q/R genotypes between RA patients and healthy subjects, and RA patients exhibited less (44%) positive PON1-Q than did the healthy subjects (66%). In a further investigation of age- and gender-matched subgroups of RA (n = 25) and healthy subjects (n = 25), not only serum PON activity, but also lecithin-cholesterol acyltransferase (LCAT) was found to be significantly decreased in RA patients (125 +/- 61 micro mol/min/L, 63.2 +/- 17.2 nmol/ml/hr/37 degrees C) than in healthy subjects (169 +/- 67, 74.7 +/- 19.5), respectively. PON1 and LCAT as well as HDL constituent apolipoprotein (apo) AI and apo AII, were altered significantly in RA patients. CONCLUSIONS: Acute-phase HDL, which is remodeled structurally and functionally in RA, might be less anti-atherogenic due to the impairment of original HDL function. These alterations of HDL in RA patients may explain in part the reported increase in cardiovascular mortality in patients with RA.

Aged↗
PubMed2003

Relationships between polymorphisms of the human serum paraoxonase gene and insulin sensitivity in Japanese patients with type 2 diabetes.

Human serum paraoxonase (PON1), which is associated with HDL, is an esterase and has been shown to reduce the susceptibility of LDL to lipid peroxidation. The objective of the study was to determine whether genetic polymorphisms of the PON1 gene are associated with insulin sensitivity. Forty-eight Japanese patients with type 2 diabetes were recruited, and euglycemic hyperinsulinemic clamp was performed to assess insulin sensitivity. The PON1 promoter polymorphism C(-108)T was determined by direct sequencing, and the coding region polymorphism Q192R was determined by polymerase chain reaction and digestion of the amplified fragments. No association was observed between the Q192R polymorphism and the glucose infusion rate (GIR), whereas GIR increased with the following order of genotypes: -108TT < -108CT < and -108CC (4.2+/-1.6, 5.1+/-2.5, and 6.9+/-2.5 mg kg(-1) min(-1), respectively; P<0.02, ANCOVA). Stepwise regression analysis revealed that the C(-108)T polymorphism significantly contributed to the GIR. It has been reported that oxidative stress attenuates insulin signaling in vitro. The PON1 promoter polymorphism C(-108)T may influence insulin sensitivity by modulating serum antioxidant capacity.

Amino Acid Substitution↗
PubMed2003

Venous infarction resulting from sacrifice of a bridging vein during clipping of a cerebral aneurysm: preoperative evaluation using three-dimensional computed tomography angiography--case report.

A 67-year-old woman presented with a ruptured aneurysm of the left internal carotid artery bifurcation. Three-dimensional computed tomography angiography (3D-CTA) demonstrated the first segment of the basal vein of Rosenthal passing in front of the internal carotid artery and the anastomosis with the cavernous sinus, the partially hypoplastic second segment, and the superficial sylvian vein entering the lateral side of the sphenoparietal sinus. Dissection of the sylvian fissure toward the distal direction enabled transfer of the superficial sylvian vein to the temporal side, but the bridging vein had to be sacrificed to secure adequate operating space. Postoperative CT demonstrated hemorrhagic infarction at the left caudate head and surrounding region. Postoperative venous infarction is not an uncommon complication of various approaches. 3D-CTA can provide important information about the venous anatomy indispensable for avoiding postoperative venous infarction.

Aged↗
PubMed2002

Low-density lipoprotein receptor-related protein 5 (LRP5) is essential for normal cholesterol metabolism and glucose-induced insulin secretion.

A Wnt coreceptor low-density lipoprotein receptor-related protein 5 (LRP5) plays an essential role in bone accrual and eye development. Here, we show that LRP5 is also required for normal cholesterol and glucose metabolism. The production of mice lacking LRP5 revealed that LRP5 deficiency led to increased plasma cholesterol levels in mice fed a high-fat diet, because of the decreased hepatic clearance of chylomicron remnants. In addition, when fed a normal diet, LRP5-deficient mice showed a markedly impaired glucose tolerance. The LRP5-deficient islets had a marked reduction in the levels of intracellular ATP and Ca(2+) in response to glucose, and thereby glucose-induced insulin secretion was decreased. The intracellular inositol 1,4,5-trisphosphate (IP3) production in response to glucose was also reduced in LRP5-- islets. Real-time PCR analysis revealed a marked reduction of various transcripts for genes involved in glucose sensing in LRP5-- islets. Furthermore, exposure of LRP5++ islets to Wnt-3a and Wnt-5a stimulates glucose-induced insulin secretion and this stimulation was blocked by the addition of a soluble form of Wnt receptor, secreted Frizzled-related protein-1. In contrast, LRP5-deficient islets lacked the Wnt-3a-stimulated insulin secretion. These data suggest that WntLRP5 signaling contributes to the glucose-induced insulin secretion in the islets.

Animals↗
PubMed2002

Transcription suppression of thromboxane receptor gene by peroxisome proliferator-activated receptor-gamma via an interaction with Sp1 in vascular smooth muscle cells.

Thromboxane (TX) A(2) exerts contraction and proliferation of vascular smooth muscle cells (VSMCs) via its specific membrane TX receptor (TXR), possibly leading to the progression of atherosclerosis. A nuclear hormone receptor, peroxisome proliferator-activated receptor (PPAR)-gamma, has recently been reported to be expressed in VSMCs. Here we examined a role of PPAR-gamma in TXR gene expression in VSMCs. PPAR-gamma ligands 15-deoxy-Delta(12,14)-prostaglandin J(2) and troglitazone reduced TXR mRNA expression levels as well as cell growth as assessed by [(3)H]thymidine incorporation. Transcriptional activity of the TXR gene promoter was suppressed with PPAR-gamma ligands, and the suppression was augmented further by PPAR-gamma overexpression. By deletion and mutation analyses, the transcription suppression was shown to be the result of a -22/-7 GC box-related sequence (upstream of transcription start site). Electrophoretic mobility shift assays also showed that the sequence was bound by Sp1 but not by PPAR-gamma, and the formation of a Sp1 small middle dotDNA complex was inhibited either by coincubation with PPAR-gamma or PPAR-gamma ligand treatment of VSMCs. Moreover, glutathione S-transferase pull-down assays demonstrated a direct interaction between PPAR-gamma and Sp1. In conclusion, PPAR-gamma suppresses TXR gene transcription via an interaction with Sp1. PPAR-gamma may possibly have an antiatherosclerotic action by inhibiting TXR gene expression in VSMCs.

Animals↗
PubMed2002

Sumatriptan scavenges superoxide, hydroxyl, and nitric oxide radicals: in vitro electron spin resonance study.

BACKGROUND: The molecular mechanisms of migraine have not yet been clarified. Oxygen free radicals have been implicated in the genesis of many pathological processes, including migraine. Sumatriptan succinate is known to be a very effective drug for acute relief of migraine attack. OBJECTIVE: To investigate the direct scavenging activities of sumatriptan for superoxide, hydroxyl, and nitric oxide (NO) radicals using electron spin resonance (ESR) spectroscopy. METHODS: Measurement of superoxide and hydroxyl radical scavenging activities was performed by ESR using 5,5-dimethyl-1-pyrroline-N-oxide as a spin trap. NO was generated from 1-hydroxy-2-oxo-3-(N-3-methyl-3-aminopropyl)-3-methyl-1-triazene and analyzed by 2-(4-carboxyphenyl)-4,4,5,5-tetramethylimidazoline-1-oxyl produced from the reaction between 2-(4-carboxyphenyl)-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide and NO. RESULTS: The ESR study demonstrated that sumatriptan scavenged superoxide, hydroxyl, and NO in a dose-dependent manner. CONCLUSIONS: Sumatriptan has direct scavenging activity on free radicals and NO. Acute migraine drugs with antioxidant properties may provide heretofore unheralded benefits via this mechanism.

Electron Spin Resonance Spectroscopy↗
PubMed2002

Edarabone scavenges nitric oxide.

Oxygen free radicals have been proposed to be major causative agents in secondary brain damage in traumatic and ischemic brain injury. Edarabone (3-methyl-1-phenyl-2-pyrazolin-5-one), a powerful antioxidative radical scavenger, is the only drug currently available in clinical practice for the treatment of cerebral infarction. There has been increasing interest in the role of nitric oxide (NO(*)) as a causative agent in brain injury. In the present study, we investigated the scavenging effect of Edarabone on nitric oxide (NO(*)), using an electron spin resonance (ESR) method. NO(*) was generated from 1-hydroxy-2-oxo-3-(N-3-methyl-3-aminopropyl)-3-methyl-1-triazene (NOC-7), and analyzed by 2-(4-carboxyphenyl)-4,4,5,5-tetramethylimidazoline-1-oxy (carboxy-PTI) produced from the reaction between 2-(4-carboxyphenyl)-4,4,5,5-tetramethylimidazoline-1-oxy-3-oxide (carboxy-PTIO) and NO(*). Edarabone directly scavenged NO(*) in a dose-dependent manner. These ESR studies indicate that Edarabone has a direct NO(*) scavenging activity and the additional possibility of novel neuroprotective activities against brain injury and focal cerebral ischemia.

Antioxidants↗