Biomedical subjects

Ken-Ichi Kobayashi

Publications and source records attributed to Ken-Ichi Kobayashi.

8 recordsLinked to original sources

PubMed2003

PPARgamma gene polymorphism is associated with exercise-mediated changes of insulin resistance in healthy men.

Exercise training improves insulin sensitivity, but individual responses vary greatly. Peroxisome proliferator-activated receptor-gamma (PPARgamma) is a regulator of adipose cell differentiation and plays an important role in systemic insulin action. We investigated whether PPARgamma gene polymorphism affects insulin resistance in response to exercise in Japanese healthy men. The exercise program at an individual intensity of 50% of the maximal heart rate was performed for 20 to 60 min/d, and 2 to 3 days per week to attain a level of physical activity of 700 kcal/wk. The program was conducted for 3 months without any dietary intervention, and the clinical and metabolic characteristics were examined before and after the exercise program. Body mass index (BMI) did not change significantly after the exercise program, whereas percentage of body fat (% body fat), fasting plasma glucose (FPG), and serum leptin levels decreased significantly. Pro12Ala polymorphism in PPARgamma gene was performed on genomic DNA isolated from human leukocytes and examined with polymerase chain reaction (PCR) and subsequent restriction enzyme analysis using BstU-I. In this study, the Ala allele did not correlate with fasting immunoreactive insulin (IRI) and homeostasis model assessment-insulin resistance index (HOMA-R) at baseline, but did so with the changes in IRI and HOMA-R after exercise (DeltaIRI, Pro/Pro 0.55 +/- 3.49 microU/mL v Pro/Ala -2.83 +/- 1.47 microU/mL, P <.05; DeltaHOMA-R, Pro/Pro 0.09 +/- 0.86 v Pro/Ala -0.61 +/- 0.32, P <.05). This result suggests that the Ala allele is associated with improvement in insulin resistance after exercise. We conclude that PPARgamma gene polymorphism may be a reliable indicator of whether exercise will have a beneficial effect as part of the treatment of insulin resistance syndrome.

Adult↗

PubMed2003

Gene therapy expressing amino-terminal truncated monocyte chemoattractant protein-1 prevents renal ischemia-reperfusion injury.

Ischemia-reperfusion is closely associated with tissue damage in various organs, including kidney. Despite clinical investigations, useful therapy for renal ischemia-reperfusion injury is not available so far. This study evaluated therapeutic effects of gene therapy expressing an amino-terminal deletion mutant of MCP-1 called 7ND to inhibit monocyte chemoattractant protein (MCP)-1/CCR2 signaling in vivo on renal ischemia-reperfusion injury. 7ND gene was transferred into the femoral muscle of Balb/c mice. Renal artery and vein of the left kidney were occluded with a vascular clamp for 60 min. A large number of infiltrated cells were observed, as was marked acute tubular necrosis in outer medulla after renal ischemia-reperfusion injury in control mice, while these lesions were significantly decreased in 7ND gene-transfected mice. Macrophages in the interstitial region, most of which were CCR2-positive, were markedly decreased in 7ND gene-transfected mice after reperfusion. Although macrophages infiltrated around MCP-1-positive cells in control mice, the smaller number of F4/80-positive cells could infiltrate into the neighbor of MCP-1-positive cells in 7ND-treated mice. These results provide evidence that gene therapy by 7ND is potentially a powerful therapeutic approach to inhibit MCP-1/CCR2 signaling, resulting in rescue from renal ischemia-reperfusion injury.

Animals↗

PubMed2003

CCR2 signaling contributes to ischemia-reperfusion injury in kidney.

Examined were CCR2-deficient mice to clarify the contribution of macrophages via monocyte chemoattractant protein 1 (MCP-1 or CCL2)/CCR2 signaling to the pathogenesis of renal ischemia-reperfusion injury. Also evaluated was the therapeutic effects via the inhibition of MCP-1/CCR2 signaling with propagermanium (3-oxygermylpropionic acid polymer) and RS-504393. Renal artery and vein of the left kidney were occluded with a vascular clamp for 60 min. A large number of infiltrated cells and marked acute tubular necrosis in outer medulla after renal ischemia-reperfusion injury was observed. Ischemia-reperfusion induced the expression of MCP-1 mRNA and protein in injured kidneys, followed by CCR2-positive macrophages in interstitium in wild-type mice. The expression of MCP-1 was decreased in CCR2-deficient mice compared with wild-type mice. The number of interstitial infiltrated macrophages was markedly smaller in the CCR2-deficient mice after ischemia-reperfusion. CCR2-deficient mice decreased the number of interstitial inducible nitric oxide synthase-positive cells after ischemia-reperfusion. The area of tubular necrosis in CCR2-deficient mice was significantly lower than that of wild-type mice after ischemia-reperfusion. In addition, CCR2-deficient mice diminished KC, macrophage inflammatory protein 2, epithelial cell-derived neutrophil-activating peptide 78, and neutrophil-activating peptide 2 expression compared with wild-type mice accompanied with the reduction of interstitial granulocyte infiltration. Similarly, propagermanium and RS-504393 reduced the number of interstitial infiltrated cells and tubular necrosis up to 96 h after ischemia-reperfusion injury. These results revealed that MCP-1 via CCR2 signaling plays a key role in the pathogenesis of renal ischemia-reperfusion injury through infiltration and activation of macrophages, and it offers a therapeutic target for ischemia-reperfusion.

Animals↗

PubMed2002

Lowered blood concentration of tacrolimus and its recovery with changes in expression of CYP3A and P-glycoprotein after high-dose steroid therapy.

BACKGROUND: In a living-donor liver transplant patient continuously receiving tacrolimus (FK506), pulse steroid therapy for 3 days caused the blood concentration of FK506 to decrease, followed by a gradual recovery to presteroid levels within 2 weeks. We conducted a study in rats to clarify the mechanism of the changes in the blood concentration of FK506 during and after steroid therapy. METHODS: Rats were intraperitoneally treated with a low dose (1 mg/kg per day) or a high dose (75 mg/kg per day) of dexamethasone (DEX) for 4 days and, at 1.5 hours after the last dose, were given FK506 (2 mg/kg) intravenously (IV) or orally (PO). Blood concentrations of FK506 and changes in the expression levels of P-glycoprotein and CYP3A2 in the liver and intestine were monitored. RESULTS: In the low-dose DEX group, the blood concentrations of FK506 after PO administration of FK506 were significantly lowered compared with those in the untreated group, while there was no such difference after IV administration. In the high-dose DEX group, the blood concentrations of FK506 after either IV or PO administration were significantly lowered. Consequently, the bioavailability of FK506 was decreased by DEX treatment, and the total clearance was significantly increased by high-dose DEX treatment. The pharmacokinetic parameters gradually recovered within 2 weeks after high-dose DEX treatment. In the high-dose DEX group, the protein levels of P-glycoprotein and CYP3A2 in the liver and intestine increased just after the treatment then decreased to normal levels within 2 weeks. CONCLUSION: Our results indicate that the decrease in the blood FK506 concentration caused by high-dose steroid therapy is a consequence of the induction of P-glycoprotein and CYP3A in the liver and intestine, and these changes were reversed within 2 weeks after cessation of steroid therapy.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed2002

The beneficial effects of lymphocytapheresis for treatment of nephrotic syndrome.

A considerable permeability factor (or factors) derived from circulating T cells has a crucial role in proteinuria of nephrotic syndrome (NS). We attempted to remove pathogenic T cells through lymphocytapheresis (LCAP) in 6 patients with primary NS, 2 patients with minimal change nephrotic syndrome (MCNS), 2 patients with focal segmental glomerulosclerosis (FSGS), 1 patient with membranous nephropathy (MN), and 1 patient with MN and FSGS using Cellsorba (Asahi Medical Co., Osaka, Japan). LCAP was performed 2 times in 2 consecutive weeks and was followed with corticosteroid therapy with or without cyclosporine A in 5 patients. Two patients with MCNS, 1 with FSGS, and 1 with MN and FSGS showed a dramatic decrease of proteinuria (-30% and -94%) in their urine protein/creatinine ratio. Three out of 4 patients had a complete or partial remission (proteinuria <1g/day) within 8 weeks following immunosuppressive therapy. During the LCAP, T cells, especially activated T cells, decreased significantly in the response group. The other 2 patients, 1 with FSGS and 1 with MN, however, had no response to LCAP and following immunosuppressive therapy or low-density lipoprotein apheresis and suffered from end-stage renal failure or death by pneumonia. These results suggested that LCAP might have a beneficial effect on the treatment of NS, especially MCNS and in some patients with FSGS, despite varying responses to LCAP and concomitant immunosuppressive therapy.

Adolescent↗

PubMed2002

Role of Cytokines and Chemokines in Renal Ischemia-Reperfusion Injury.

Cytokines and chemokines produced by renal tubular epithelial cells and infiltrated cells are critical factors in inflammatory processes of renal ischemia-reperfusion injury. In vitro studies reveal that renal tubular epithelial cells have the potential to produce diverse cytokines, chemokines and other mediators, such as tumor necrosis factor-alpha, interleukin-1 (IL-1), monocyte chemoattractant protein-1, IL-8, platelet-derived growth factor, regulated upon activation, normal T cell expressed and secreted, endothelin-1 and vascular endothelial growth factor (VEGF). Huge numbers of in vivo studies show that cytokines, chemokines and adhesion molecules in diseased kidney together govern critical aspects of ischemia-reperfusion injury. Leukocyteendothelial cell interactions are critical processes of leukocytic infiltration, which are pathologically key factors in inflammatory processes of renal ischemia-reperfusion injury. Leukocyteendothelial interactions are regulated by a cascade of molecular steps of cytokines, chemokines and adhesion molecules. In contrast, the intracellular cascades of cytokine and chemokine expression in the renal ischemia-reperfusion injury remain to be investigated. p38 mitogen-activated protein kinase is one of the essential mediators in cytokine and chemokine expression through the activation of nuclear factor-kappaB and activating protein-1. Moreover, hypoxia-inducible factor-1 (HIF-1) is a transcription factor activated by reductions in oxygen concentration. HIF-1related gene expression, such as erythropoietin or VEGF, results in protection of ischemia reperfusion injury. This review focuses on the contribution of cytokines, chemokines and their related molecules to the inflammatory cascade in renal ischemia-reperfusion injury. (c) 2002 Prous Science. All rights reserved.

Journal Article↗

PubMed2002

[Soluble VCAM-1].

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Biomarkers↗

PubMed2000

A new anti-inflammatory compound, FR167653, ameliorates crescentic glomerulonephritis in Wistar-Kyoto rats.

The pathophysiologic effects of FR167653 were investigated in a model of crescentic glomerulonephritis induced by a small dose of nephrotoxic serum in Wistar-Kyoto rats. The rats developed crescentic glomerulonephritis by 6 d after the administration of serum. The subcutaneous administration of FR167653 (32 mg/kg) markedly decreased the severity of the renal damage. In a group of rats treated with FR167653 daily from day 0 to day 6, glomerular damage, including crescent formation and proteinuria, was virtually absent. FR167653 markedly decreased urinary levels of monocyte chemoattractant protein-1 (MCP-1). In addition, FR167653 reduced production of MCP-1 protein and transcripts in the diseased kidneys. In a group of rats for which treatment was initiated on day 3, shortly after the appearance of glomerular abnormalities, the progression of renal disease was appreciably retarded, with partial inhibition of MCP-1. In contrast, when rats were treated only on the first day, no beneficial effects were observed and severe proliferative and necrotizing glomerulonephritis, with crescent formation, was induced by day 6, with the upregulation of MCP-1. These results suggest that FR167653 may be effective against crescentic glomerulonephritis, possibly via the inhibition of MCP-1. In addition, there was marked reduction in renal injury even when FR167653 treatment was initiated after glomerular inflammation was established, suggesting that the therapeutic application of FR167653 may be clinically useful for human renal diseases.

Animals↗