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Kikuo Kasai

Publications and source records attributed to Kikuo Kasai.

At least 19 recordsLinked to original sources
PubMed2006

Tetrahydrobiopterin prevents endothelial dysfunction and restores adiponectin levels in rats.

Oxidative stress induces endothelial dysfunction and hypoadiponectinemia. We previously reported that supplementation with tetrahydrobiopterin (BH4), one of the most potent naturally occurring reducing agents and an essential cofactor of enzymatic NO synthase (NOS), ameliorates endothelial dysfunction and reverses hypoadiponectinemia as a result of oxidative stress in rats. To further confirm this hypothesis, we investigated the effects of treatment with BH4 on endothelium-dependent relaxation and adiponectin levels during oxidative stress in fructose-fed rats, which provide an animal model for the metabolic syndrome. Ingestion of a fructose diet for 8 weeks significantly impaired endothelium-dependent arterial relaxation in aortic strips and decreased plasma adiponectin levels, as well as adiponectin mRNA levels within adipose tissue. However, oral supplementation with BH4 (10 mg/kg day) over the final 4 weeks leads to a significant partial reversal of impaired endothelium-dependent arterial relaxation, as well as normalization of plasma adiponectin and fat adiponectin mRNA levels. Moreover, BH4 treatment of the fructose-fed rats significantly reduced the lipid peroxidation content of aorta, heart, liver, and kidney tissues, which were increased in fructose-fed rats. This effect of BH4 treatment may be due to its function as a cofactor for eNOS, as well as its anti-oxidative effects. Thus, BH4 might show promise for the treatment of oxidative stress-induced disorders, including the metabolic syndrome.

Adiponectin↗
PubMed2006

[Werner's syndrome].

Explore the source record for details and available documents.

Diabetes Mellitus, Type 2↗
PubMed2006

Haplotype analysis reveals founder effects of thyroglobulin gene mutations C1058R and C1977S in Japan.

CONTEXT: Thyroglobulin (Tg) mutations were previously believed to be rare, resulting in congenital goitrous hypothyroidism. However, an increasing number of patients with Tg mutations, who are euthyroid to mildly hypothyroid, have been identified in Japan. OBJECTIVES: The purpose of this study was to investigate whether the three frequently found Tg mutations, namely C1058R, C1245R, and C1977S, were caused by a founder effect. RESULTS: We found 26 different mutations within the Tg gene in 52 patients from 41 families. Thirty-five patients were homozygous for the mutations, whereas the others were compound heterozygous. The occurrence of Tg mutation within the general Japanese population is one in 67,000. Patients with the C1245R mutation were found throughout Japan, whereas those with the C1058R mutation were confined to a small village on a southern island, and those with the C1977S mutation were restricted to a city. The eight patients with the C1058R mutation and the seven patients with the C1977S mutation all showed the same combinations of 18 single-nucleotide polymorphisms in the coding region of the Tg gene, which would appear in one in 810 million and one in 37 billion, respectively, control subjects. CONCLUSIONS: The frequently found mutations, C1058R and C1977S, were caused by founder effects. This result suggests that Tg mutations may provide a genetic basis for the cause of familial euthyroid goiter.

Founder Effect↗
PubMed2006

Metformin inhibits cytokine-induced nuclear factor kappaB activation via AMP-activated protein kinase activation in vascular endothelial cells.

AMP-activated protein kinase (AMPK) is tightly regulated by the cellular AMP:ATP ratio and plays a central role in regulation of energy homeostasis and metabolic stress. Metformin has been shown to activate AMPK. We hypothesized that metformin may prevent nuclear factor kappaB (NF-kappaB) activation in endothelial cells exposed to inflammatory cytokines. Metformin was observed to activate AMPK, as well as its downstream target, phosphoacetyl coenzyme A carboxylase, in human umbilical vein endothelial cells (HUVECs). Metformin also dose-dependently inhibited tumor necrosis factor (TNF)-alpha-induced NF-kappaB activation and TNF-alpha-induced IkappaB kinase activity. Furthermore, metformin attenuated the TNF-alpha-induced gene expression of various proinflammatory and cell adhesion molecules, such as vascular cell adhesion molecule-1, E-selectin, intercellular adhesion molecule-1, and monocyte chemoattractant protein-1, in HUVECs. A pharmacological activator of AMPK, 5-amino-4-imidazole carboxamide riboside (AICAR), dose-dependently inhibited TNF-alpha- and interleukin-1beta-induced NF-kappaB reporter gene expression. AICAR also suppressed the TNF-alpha- and interleukin-1beta-induced gene expression of vascular cell adhesion molecule-1, E-selectin, intercellular adhesion molecule-1, and monocyte chemoattractant protein-1 in HUVECs. The small interfering RNA for AMPKalpha1 attenuated metformin or AICAR-induced inhibition of NF-kappaB activation by TNF-alpha, suggesting a possible role of AMPK in the regulation of cell inflammation. In light of these findings, we suggest that metformin attenuates the cytokine-induced expression of proinflammatory and adhesion molecule genes by inhibiting NF-kappaB activation via AMPK activation. Thus, it might be useful to target AMPK signaling in future efforts to prevent atherogenic and inflammatory vascular disease.

AMP-Activated Protein Kinases↗
PubMed2006

Ventricular fibrillation due to severe hypokalemia induced by steroid treatment in a patient with thyrotoxic periodic paralysis.

We report a 25-year-old Japanese man with ventricular fibrillation associated with severe hypokalemia. He developed arm and leg paralysis. He had received 2 g of methylprednisolone because thoracic epidural hematoma had been suspected in another hospital. His serum potassium was 0.8 mEq/l on arrival at our hospital. Half an hour after arrival ventricular fibrillation occurred. Treatment with electric defibrillation 8 times was successful. Afterward Graves' disease was diagnosed, therefore, his clinical symptom was diagnosed as thyrotoxic periodic paralysis. We considered that the unusual condition of hyperthyroid-related hypokalemia worsened by steroid therapy induced the ventricular fibrillation.

Adult↗
PubMed2006

Expression of thyroid hormone receptor isoforms down-regulated by thyroid hormone in human medulloblastoma cells.

The role of thyroid hormone (T3) in the regulation of growth and development of the central nervous system including the cerebellum has been well established. However, the effects of thyroid hormone on malignant tumors derived from the cerebellum remain poorly understood. Our analysis mainly focused on expression levels of TR isoforms and the effects of thyroid hormone in human medulloblastoma HTB-185 cells. Northern blot analysis revealed TRalpha2 mRNA but not TRalpha1, beta1 or beta2 mRNA in the cell. The TRalpha1 and TRbeta1 mRNAs were detected only by RT-PCR method and TRbeta2 was not expressed. Incubation of T3 for 24 h decreased TRalpha1, TRalpha2 and TRbeta1 mRNA. Addition of actinomycin D caused an acute increase in the basal TR mRNA levels and the rate of decrease of all kinds of TR isoform mRNA was accelerated in the T3-treated groups compared to controls, indicating that the stability of TR mRNA was affected by T3. Incubation with cycloheximide also blocked a decrease in TR mRNA levels in the T3-treated HTB-185 cells suggesting that down-regulation of TR mRNA required the synthesis of new protein. Our data provide novel evidence for the expression of TRs down-regulated by T3 in HTB-185 cells, suggesting that TR expression is post-transcriptionally regulated by T3 at the level of RNA stability.

Brain Neoplasms↗
PubMed2005

Activation of AMP-activated protein kinase enhances angiotensin ii-induced proliferation in cardiac fibroblasts.

AMP-activated kinase (AMPK) is a highly conserved heterotrimeric kinase that functions as a metabolic regulator of cellular enzymes involved in carbohydrate and fat metabolism, which regulate ATP conservation and synthesis. Here, we investigated whether AMPK signaling has a role in the regulation of angiotensin II (Ang II)-induced proliferation in rat cardiac fibroblasts. Aminoimidazole-4-carboxamide-1-beta-ribofuranoside (AICAR) activated AMPK in rat cardiac fibroblasts and increased Ang II-induced extracellular signal-regulated kinase 1/2 phosphorylation and activity. AICAR also increased Ang II-induced c-fos mRNA expression in the cells. [3H]-thymidine and [3H]-proline incorporation by cardiac fibroblasts treated with Ang II was enhanced when the cells were pretreated with AICAR. Inhibition of AMPK by small interfering RNA for AMPKalpha1 suppressed Ang II-induced extracellular signal-regulated kinase activity, c-fos mRNA expression, and cell proliferation. Treatment of rats with AICAR (1 mg/g body weight per day) for 1 week significantly enhanced Ang II-induced hypertrophy of the myocardium. Our findings indicate that AMPK works as a stimulator of the Ang II-induced proliferative pathway in cardiac fibroblasts. Inhibition of AMPK signaling might serve as a new therapeutic target of remodeling of the hypertrophic myocardium.

AMP-Activated Protein Kinases↗
PubMed2005

Hypoadiponectinemia is caused by chronic blockade of nitric oxide synthesis in rats.

Adiponectin is an adipocyte-derived anti-atherogenic protein. Adiponectin levels are decreased in patients and animal models with obesity, diabetes, and coronary artery disease. However, the mechanism by which adiponectin levels are reduced remains unknown. Since hypoadiponectinemia is closely linked to endothelial dysfunction, we examined the regulation of adiponectin in a rat model of chronic blockade of nitric oxide (NO) synthesis by N omega-nitro-L-arginine methyl ester (L-NAME). Decreased production of NO and increased production of O2- were observed in aorta from L-NAME-treated rats. Plasma adiponectin levels and adiponectin mRNA levels of adipose tissue were markedly decreased in L-NAME-treated rats. Cotreatment of pioglitazone (PIO) or allopurinol (ALL) with L-NAME restored plasma adiponectin concentration and fat adiponectin mRNA levels to control levels. Thus, adiponectin levels were decreased in L-NAME-treated rats, however, they returned to normal following administration of PIO due to transcriptional activation of the adiponectin gene, as well as administration of ALL, likely due to elimination of oxidative stress. Oxidative stress appears to be an important cause of hypoadiponectinemia.

Adiponectin↗
PubMed2004

Unliganded RXR acts as an inhibitory factor on troglitazone-induced activation.

Troglitazone (TZ), a thiazolidinedione derivative, is a specific ligand for the peroxisome proliferator-activated receptor (PPAR) gamma and improves insulin sensitivity. PPARgamma regulates the expression of genes by binding to PPAR response element in promoter regions of regulator genes as heterodimers with a retinoid X receptor (RXR). We report here that PPARgamma activation by TZ depends on the expression levels of RXR. A transient transfection study in CV-1 cells revealed that the activation by TZ was suppressed by increasing amounts of expression of RXR, but not PPARgamma. Northern blot analysis revealed that PPARgamma and RXR were not expressed in CV-1 cells, and TZ did not induce PPARgamma or RXR mRNA in CV-1 cells indicating that RXR suppression is not related to these endogenous receptor expressions. Electrophoretic mobility shift assay revealed that the increasing amount of RXR did not compete with the DNA binding of the PPARgamma/RXR heterodimer in the presence or absence of TZ. Transfected co-activators enhanced the TZ-dependent gene transcription, and this activation was inhibited by excessive amounts of RXR, indicating that unliganded RXR may recruit the specific coactivators from the PPARgamma/RXR heterodimer.

Animals↗
PubMed2004

NO suppresses while peroxynitrite sustains NF-kappaB: a paradigm to rationalize cytoprotective and cytotoxic actions attributed to NO.

OBJECTIVE: NO has both cytoprotective and cytotoxic effects. A key cytoprotective action of NO is attributed to inhibition of nuclear factor-kappaB (NF-kappaB)-mediated gene expression; this potentially endows NO with ubiquitous anti-inflammatory activity. Since immunostimulant-induced iNOS gene expression is itself dependent on NF-kappaB, NO is expected to limit its own synthesis. On the other hand, many cytotoxic actions of NO have been attributed to the chemical reactivity of peroxynitrite (ONOO-) formed from NO by near diffusion-limited reaction with O2-. To assess whether ONOO- shares the ability of NO to inhibit NF-kappaB activation and consequent iNOS gene expression, we compared effects of NO donors (NOR3 and SNAP), an ONOO- donor (SIN-1), and pure ONOO- on LPS-induced responses in vascular smooth muscle cells (VSMC). METHODS AND RESULTS: NO donors, but not ONOO-, suppressed LPS-induced NF-kappaB activation and expression of a murine iNOS promoter/reporter construct. An NO donor also suppressed NF-kappaB activation when induced by IL-1beta or TNFalpha. Northern blot and RT-PCR analyses showed that NO, but not ONOO- or 8-bromo-cGMP, decreases LPS-induced expression of iNOS mRNA. Electrophoretic mobility shift assays (EMSA) and immunocytochemical analyses confirmed that NO but not ONOO- inhibits nuclear translocation of NF-kappaB. Although ONOO- generation from SIN-1 did not inhibit NF-kappaB activation, conversion of SIN-1 to a pure NO donor (by addition of excess superoxide dismutase) resulted in potent inhibition of NF-kappaB activation. Dose-response analyses suggest that the inhibitory effect of NO on iNOS gene transcription results specifically from inhibition of NF-kappaB activation, and is mediated by a G-cyclase-independent mechanism that is unavailable to ONOO-. LPS stimulates IkappaB-alpha phosphorylation by inducing IkappaB kinase (IKK) activity, and NO, but not ONOO-, inhibits LPS-induced IkappaB-alpha phosphorylation and IKK activity. CONCLUSION: We demonstrate that only NO inhibits the activation of NF-kappaB and suppresses iNOS gene expression. This distinction provides a novel paradigm to rationalize cytoprotective and cytotoxic actions attributed to NO.

Animals↗
PubMed2004

Disruption of the actin cytoskeleton up-regulates iNOS expression in vascular smooth muscle cells.

Cytokines and bacterial lipopolysaccharide (LPS) induce the expression of inducible nitric oxide synthase (iNOS), resulting in the release of nitric oxide (NO) from vascular smooth muscle cells. We here demonstrated that disruption of F-actin formation by sequestration of G-actin with the toxin latrunculin B (Lat B) dramatically potentiated LPS-induced iNOS mRNA and protein expression. We also showed that Lat B enhanced interleukin-1beta- andbgr;- and TNFalpha-induced NO production. Lat B by itself had little or no effect on iNOS expression. Cytochalasin D also enhanced LPS-induced NO production. Lat B dose-dependently enhanced LPS-induced iNOS promoter activity but had no effect on the stability of iNOS mRNA. Staining of F-actin with nitrobenzoxadiazole (NBD)-phallacidin demonstrated that Lat B significantly impaired F-actin stress fiber formation. These data indicate that disruption of the actin cytoskeleton up-regulates cytokine-induced iNOS expression via transcriptional regulation. Further analysis of the signaling pathway from the actin cytoskeleton to iNOS expression may yield new insight into the mechanism of iNOS regulation.

Actins↗
PubMed2003

Lipopolysaccharide activates Akt in vascular smooth muscle cells resulting in induction of inducible nitric oxide synthase through nuclear factor-kappa B activation.

Bacterial lipopolysaccharide and other immunostimulants induce gene expression of an isoform of nitric oxide synthase (iNOS) in vascular smooth muscle cells. This process is dependent on nuclear factor-kappa B (NF-kappa B) activation. The aim of this study was to investigate whether the NF-kappa B and Akt signaling pathways converge to induce iNOS in lipopolysaccharide-stimulated vascular smooth muscle cells. Treatment of vascular smooth muscle cells with lipopolysaccharide plus interferon-gamma (LPS/IFN) caused activation of Akt and NF-kappa B. LPS/IFN caused activation of the iNOS promoter and transcription of iNOS mRNA/protein, resulting in NO production. A pharmacological inhibitor of the phosphoinositide 3-kinase (PI3K)-Akt pathway, 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one (LY294002), inhibited phosphorylation of Akt and suppressed activation of NF-kappa B by attenuating the phosphorylation and degradation of I kappa B. LY294002 thereby inhibited LPS/IFN-induced iNOS expression and NO production. Another inhibitor of the PI3K-Akt pathway, wortmannin, also inhibited NO production in VSMC. LY294002 similarly inhibited interleukin-1 beta- or tumor necrosis factor-alpha-induced NO production. The data indicate that lipopolysaccharide or cytokine stimulation of vascular smooth muscle cells leads to activation of the PI3K-Akt pathway, which then activates the NF-kappa B pathway. Thus, the PI3K-Akt pathway controls the expression of iNOS in lipopolysaccharide- and cytokine-stimulated vascular smooth muscle cells.

Animals↗