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Biomedical subjects

Takashi Wada

Publications and source records attributed to Takashi Wada.

At least 19 recordsLinked to original sources
PubMed2026

Polygenic risk scores and lifestyle factors predicting new onset of type 2 diabetes in the Japanese general population.

PURPOSE: This study investigated the association of polygenic risk scores (PRS) and lifestyle factors with type 2 diabetes mellitus development in Japanese populations and evaluated whether PRS can improve diabetes risk prediction beyond traditional risk factors. METHODS: We conducted a cross-sectional and a longitudinal study using the Shika resident cohort (n = 895) and the Toshiba worker cohort (n = 7019), respectively. Participants were categorized into low, intermediate, and high genetic risk groups using PRS constructed with genome-wide association study data from East Asian populations. We defined diabetes based on hemoglobin A1c, fasting blood glucose, self-reported diagnosis, or medication use. The associations of PRS and lifestyle factors with diabetes development were analyzed using multivariate logistic regression and Cox proportional hazards models. RESULTS: Higher PRS were associated with increased diabetes risk in both cohorts (resident cohort: odds ratio 4.51, 95% CI 2.53-8.04; worker cohort: hazard ratio 1.50, 95% CI 1.23-1.83 for high vs low PRS), which remained consistent across age, body mass index, and comorbidities. Regular exercise, absence of hypertension, and absence of dyslipidemia were associated with lower diabetes risk, particularly in the high PRS group. The addition of PRS to conventional prediction models improved the discrimination of diabetes risk. MAIN CONCLUSION: PRS are associated with diabetes risk in Japanese general populations, independent of traditional risk factors. Nonetheless, healthy lifestyle habits may reduce diabetes risk even among genetically susceptible individuals, which support the utility of PRS for personalized diabetes risk assessment and prevention strategies.

Adult↗
PubMed2006

Remission of IgA nephropathy after allogeneic peripheral blood stem cell transplantation followed by immunosuppression for acute lymphocytic leukemia.

We report a case with immunoglobulin A (IgA) nephropathy, showing IgA deposition which disappeared after peripheral blood stem cell transplantation (PBSCT) for acute lymphocytic leukemia (ALL). In 1996, a 28-year-old man was diagnosed with IgA nephropathy by renal biopsy. Steroid therapy improved proteinuria from 3 g/day to 1 g/day. In 2003, he received PBSCT following the initial therapy for ALL. After complete remission, urinary protein and hematuria remained at between (-) and (+/-). In 2004, the second renal biopsy specimen revealed no deposit of IgA or C3. These findings suggested that immune reconstruction with PBSCT following immunosuppression therapy was of benefit to IgA nephropathy.

Adult↗
PubMed2006

Secondary lymphoid tissue chemokine (SLC/CCL21)/CCR7 signaling regulates fibrocytes in renal fibrosis.

Fibrocytes are a distinct population of bloodborne cells that share markers of leukocytes as well as mesenchymal cells. We hypothesized that CCR7-positive fibrocytes migrate into the kidney in response to secondary lymphoid tissue chemokine (SLC/CCL21) and contribute to renal fibrosis. To investigate this hypothesis, renal fibrosis was induced by unilateral ureteral obstruction in mice. A considerable number of fibrocytes dual-positive for CD45 and type I collagen (ColI) or CD34 and ColI infiltrated the interstitium, reaching a peak on day 7. Most fibrocytes were positive for CCR7, and CCL21/CCR7 blockade reduced the number of infiltrating fibrocytes. CCL21 and MECA79 dual-positive vessels were also detected in the interstitium. The blockade of CCL21/CCR7 signaling by anti-CCL21 antibodies reduced renal fibrosis, which was confirmed by a decrease in fibrosis in CCR7-null mice with concomitant reduction in renal transcripts of pro alpha1 chain of ColI and TGF-beta1. The number of F4/80-positive macrophages decreased along with renal transcripts of monocyte chemoattractant protein 1 (MCP-1/CCL2) after the blockade of CCL21/CCR7 signaling. These findings suggest that CCR7-positive fibrocytes infiltrate the kidney via CCL21-positive vessels, thereby contributing to the pathogenesis of renal fibrosis. Thus, the CCL21/CCR7 signaling of fibrocytes may provide therapeutic targets for combating renal fibrosis.

Animals↗
PubMed2006

Virological effects and safety of combined double filtration plasmapheresis (DFPP) and interferon therapy in patients with chronic hepatitis C: A preliminary study.

PURPOSE: In patients with chronic genotype 1b hepatitis C and a high viral load, the viral load was reduced by double filtration plasmapheresis (DFPP), followed by combined interferon and ribavirin therapy. The safety and virological effects of this treatment method were preliminarily investigated. METHODS: In nine patients with chronic hepatitis C, DFPP was performed three times on days 1, 2, and 4, and the administration of interferon and ribavirin was initiated immediately after DFPP on day 1. RESULT: The HCV RNA was undetectable in all patients after the plasma was passed through a plasma fractionator (second filter) in the DFPP circuit. After 2 weeks, the HCV RNA tended to decrease in the DFPP group more than in the control group (-2.45+/-1.12 versus -1.57+/-0.95, P=0.073). However, this decrease was not attributable to a sustained virological response (SVR) (22.2% versus 18.2%, P=0.822). Most of the adverse events were caused by the interferon and ribavirin combination therapy. CONCLUSION: DFPP can be safely performed concomitantly with interferon and ribavirin combination therapy in chronic hepatitis C patients. The combination may contribute to an early virological response. The effect of DFPP on the SVR and its significance remain to be clarified.

Journal Article↗
PubMed2006

TAK-603, an anti-inflammatory compound, reduces crescentic glomerulonephritis and preserves renal function in WKY rats.

BACKGROUND: The therapeutic efficacy of the regulation of T helper (Th)-1-predominant immune responses remains to be investigated. Therefore, the effects of the anti-inflammatory compound TAK-603 were investigated in a model of crescentic glomerulonephritis induced by a small dose of nephrotoxic serum in Wistar-Kyoto rats. METHODS: TAK-603 (50 mg/kg body weight) was administered orally, starting at the time of induction of glomerulonephritis. In group 1, the drug was administered daily for the initial 6 days. TAK-603 was administered on day 0 only in group 2, and from day 3 to 5 in group 3. In each group, nephritic rats were killed on days 6 and 56. RESULTS: In group 1 consisting of rats treated with TAK-603 daily from day 0 to 5, glomerular damage, including crescent formation, was improved on day 6, with reductions in the numbers of CD4, CD8 and ED-1 positive cells, as well as in urinary protein excretion. Protein and transcript levels of Th1 cytokines in the diseased kidneys were markedly decreased by TAK-603 treatment. Renal pathology, including glomerulosclerosis and interstitial fibrosis, was ameliorated and proteinuria was markedly decreased. Elevated levels of serum creatinine showed concomitant improvement. In group 3, in which treatment was initiated shortly after the appearance of glomerular abnormalities, glomerular damage was also diminished, resulting in a decrease in urinary protein excretion. Treatment only on the first day in group 2, partially rescued renal dysfunction. CONCLUSIONS: These results suggest the possible therapeutic application of inhibition of Th1-predominant immune responses in progressive crescentic glomerulosclerosis.

Animals↗
PubMed2006

Reduction in chronic allograft nephropathy by inhibition of p38 mitogen-activated protein kinase.

BACKGROUND: Chronic allograft nephropathy (CAN) is the major cause for late graft loss and is therefore a key target for therapy. METHODS: The impact of p38 mitogen-activated kinase (MAPK) on CAN was investigated by administering FR167653 (32 mg/kg/day), a specific inhibitor of p38 MAPK, for 4 weeks in addition to conventional cyclosporine therapy (1.5 mg/kg/day for 5 days) in an established experimental rat transplantation model. RESULTS: Transplanted rats develop glomerulosclerosis, arterial obliteration, interstitial fibrosis and tubular atrophy, all of which are characteristic of CAN, resulting in shortened survival on 32 weeks. However, the inhibition of p38 MAPK by daily subcutaneous treatment with FR167653 resulted in reduced CAN with preserved renal function and prolonged survival. The FR167653-treated rats had fewer phosphorylated p38 MAPK-positive cells in treated kidneys. Concomitantly, the expression of monocyte chemoattractant protein-1/CCL2 and transforming growth factor-beta(1) was markedly reduced. CONCLUSION: These results suggest that p38 MAPK phosphorylation is involved in the pathogenesis of CAN and provide evidence that p38 MAPK is a novel, appealing therapeutic target for combating CAN.

Animals↗
PubMed2006

Interspecific pheromone cross-attraction among soybean bugs (Heteroptera): does Piezodorus hybneri (Pentatomidae) utilize the pheromone of Riptortus clavatus (Alydidae) as a kairomone?

The chemical and ecological function of cross-attraction of Piezodorus hybneri (Pentatomidae) to the Riptortus clavatus (Alydidae) pheromone (a mixture of three components) was studied. In a field attraction test using traps with synthetic pheromone components, P. hybneri was attracted to (E)-2-hexenyl (E)-2-hexenoate, a component of the R. clavatus pheromone. Other components had neither an additive nor a synergistic effect on the attraction of P. hybneri. Neither (E)-2-hexenyl (E)-2-hexenoate nor other components of the R. clavatus pheromone were detected in volatiles or whole-body extracts of P. hybneri adults by gas chromatographic analysis. In addition, (E)-2-hexenyl (E)-2-hexenoate could not be found in volatiles of soybean plants. Therefore, it appears that P. hybneri responds to a component of the R. clavatus pheromone that is not emitted by P. hybneri itself. We discuss this interspecific pheromone cross-attraction of the soybean bug and hypothesize that P. hybneri utilizes the pheromone of its competitor as a kairomone for host location.

Animals↗
PubMed2006

MCP-1/CCR2-dependent loop for fibrogenesis in human peripheral CD14-positive monocytes.

Monocyte/macrophage (Momicron) migration to sites of inflammation is a prerequisite cause of organ fibrosis. The recruitment and activation of Mo are regulated by C-C chemokines, especially monocyte chemoattractant protein-1 [(MCP-1)/CC chemokine ligand 2], which interacts with CC chemokine receptor 2 (CCR2). However, the mechanisms leading to fibrosis via MCP-1/CCR2 signaling in Mo remain to be investigated. The effect of MCP-1 on the expression of MCP-1, CCR2, transforming growth factor-beta1 (TGF-beta1), and type I collagen in circulating human CD14-positive Mo was investigated. In addition, the impact of MCP-1-specific or TGF-beta1-specific antisense (AS) phosphorothioate oligodeoxynucleotides (ODN) was examined to explore the involvement of autocrine/paracrine production of MCP-1 and TGF-beta1 by human CD14-positive Mo. Furthermore, specific CCR2 inhibitors were applied to examine the involvement of CCR2 signaling for the promotion of a fibrogenic response. The stimulation of Mo with MCP-1 increased mRNA levels of TGF-beta1 and a pro-alpha1 chain of type I collagen (COL1A1) as well as protein synthesis. Similarly, the expression of MCP-1 and CCR2 was enhanced by the stimulation with MCP-1 in dose- and time-dependent manners. This positive loop via MCP-1 was reduced by pretreatment with MCP-1-specific AS-ODN. It was also noted that pretreatment with TGF-beta1-specific AS-ODN partially reduced COL1A1 mRNA levels. Finally, transcripts of these molecules were suppressed by pretreatment with specific CCR2 inhibitors. The present study demonstrated that human peripheral CD14-positive Mo contribute directly to fibrogenesis by a MCP-1/CCR2-dependent amplification loop. These data suggest that fibrogenic processes in Mo regulated by MCP-1/CCR2 may be novel, therapeutic targets for combating organ fibrosis.

Cells, Cultured↗
PubMed2006

Interleukin-1-dependent sequential chemokine expression and inflammatory cell infiltration in ischemia-reperfusion injury.

OBJECTIVE: Ischemia-reperfusion injury is known to cause organ failure, but the mechanisms of pathogenesis remain unclear. Inflammation is a factor in tissue destruction in ischemia reperfusion injury, and interleukin (IL)-1 is a key promoter of inflammation. DESIGN: Prospective, randomized, and controlled study. SETTING: University laboratory. SUBJECTS: Male mice 6-8 wks of age, in which genes for IL-1alpha and IL-1beta (IL-1alpha/beta deficient) and IL-1 receptor antagonist (IL-1RA deficient) are deleted by homologous recombination, and wild-type controls on a Balb/c background. INTERVENTIONS: In this study, the role of IL-1 on inflammatory cascades, including chemokine expression, inflammatory cell infiltration, and tissue destruction, was investigated in 45 mins of unilateral renal ischemic injury using IL-1alpha/beta-deficient mice and IL-1RA-deficient mice. In addition, the effects of IL-1 on chemokine expression in cultured tubular epithelial cells were investigated. MEASUREMENTS AND MAIN RESULTS: In vivo study revealed that the number of interstitial infiltrated neutrophils and macrophages, which accompanied the increase of the serum levels of keratinocyte-derived chemokine (KC) and macrophage inflammatory protein (MIP)-1alpha, respectively, significantly increased in IL-1RA-deficient mice. The number of interstitial infiltrated neutrophils correlated well with serum levels of KC at 24 hrs after reperfusion, whereas the number of interstitial infiltrated macrophages correlated well with the serum levels of MIP-1alpha and monocyte chemoattractant protein (MCP)-1 at 24 and 48 hrs after reperfusion, respectively. Likewise, in vitro study revealed that stimulation of tubular epithelial cells by IL-1beta and/or H2O2 sequentially induced KC, MIP-1alpha, and MCP-1 in both protein and messenger RNA levels, which is consistent with in vivo results. CONCLUSION: IL-1-dependent inflammatory cascades, followed by inflammatory cell infiltration and subsequent tissue destruction, may affect pathogenesis of renal ischemia-reperfusion injury.

Animals↗
PubMed2006

Role for macrophage metalloelastase in glomerular basement membrane damage associated with alport syndrome.

Alport syndrome is a glomerular basement membrane (GBM) disease caused by mutations in type IV collagen genes. A unique irregular thickening and thinning of the GBM characterizes the progressive glomerular pathology. The metabolic imbalances responsible for these GBM irregularities are not known. Here we show that macrophage metalloelastase (MMP-12) expression is >40-fold induced in glomeruli from Alport mice and is markedly induced in glomeruli of both humans and dogs with Alport syndrome. Treatment of Alport mice with MMI270 (CGS27023A), a broad spectrum MMP inhibitor that blocks MMP-12 activity, results in largely restored GBM ultrastructure and function. Treatment with BAY-129566, a broad spectrum MMP inhibitor that does not inhibit MMP-12, had no effect. We show that inhibition of CC chemokine receptor 2 (CCR2) receptor signaling with propagermanium blocks induction of MMP-12 mRNA and prevents GBM damage. CCR2 receptor is expressed in glomerular podocytes of Alport mice, suggesting MCP-1 activation of CCR2 on podocytes may underlie induction of MMP-12. These data indicate that the irregular GBM that characterizes Alport syndrome may be mediated, in part, by focal degradation of the GBM due to MMP dysregulation, in particular, MMP-12. Thus, MMP-12/CCR2 inhibitors may provide a novel and effective therapeutic stra-tegy for Alport glomerular disease.

Animals↗
PubMed2006

Interferon-gamma plays protective roles in sodium arsenite-induced renal injury by up-regulating intrarenal multidrug resistance-associated protein 1 expression.

Subcutaneous injection of sodium arsenite (NaAs, 12.5 mg/kg) into BALB/c [wild-type (WT)] mice causes acute renal dysfunction characterized by severe hemorrhages, acute tubular necrosis, and cast formation, with increases in serum blood urea nitrogen and creatinine levels. Concomitant enhancement in intrarenal interferon (IFN)-gamma expression prompted us to examine its roles in this pathology. IFN-gamma-deficient (IFN-gamma-/-) mice exhibited higher serum blood urea nitrogen and creatinine levels and exaggerated histopathological changes, compared with WT mice. Eventually, IFN-gamma-/- mice exhibited a high mortality (87.5%) within 24 hours after NaAs challenge, whereas most WT mice survived. The intrarenal arsenic concentration was significantly higher in IFN-gamma-/- mice later than 10 hours after NaAs treatment, with attenuated intrarenal expression of multidrug resistance-associated protein (MRP) 1, a main transporter for NaAs efflux, compared with WT mice. NF-E2-related factor (Nrf) 2 protein, a transcription factor crucial for MRP1 gene expression, was similarly increased in the kidneys of both strains of mice after NaAs treatment. In contrast, the absence of IFN-gamma augmented transforming growth factor-beta-Smad3 signal pathway and eventually enhanced the expression of activating transcription factor 3, which is presumed to repress Nrf2-mediated MRP1 gene expression. Thus, IFN-gamma can protect against NaAs-induced acute renal injury, probably by maintaining Nrf2-mediated intrarenal MRP1 gene expression.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2005

MRP-1 expression levels determine strain-specific susceptibility to sodium arsenic-induced renal injury between C57BL/6 and BALB/c mice.

To clarify the pathophysiological mechanism underlying acute renal injury caused by acute exposure to arsenic, we subcutaneously injected both BALB/c and C57BL/6 mice with sodium arsenite (NaAs; 13.5 mg/kg). BALB/c mice exhibited exaggerated elevation of serum blood urea nitrogen (BUN) and creatinine (CRE) levels, compared with C57BL/6 mice. Moreover, half of BALB/c mice died by 24 h, whereas all C57BL/6 mice survived. Histopathological examination on kidney revealed severe hemorrhages, acute tubular necrosis, neutrophil infiltration, cast formation, and disappearance of PAS-positive brush borders in BALB/c mice, later than 10 h. These pathological changes were remarkably attenuated in C57BL/6 mice, accompanied with lower intrarenal arsenic concentrations, compared with BALB/c mice. Among heavy metal inducible proteins including multidrug resistance-associated protein (MRP)-1, multidrug resistance gene (MDR)-1, metallothionein (MT)-1, and arsenite inducible, cysteine- and histidine-rich RNA-associated protein (AIRAP), intrarenal MDR-1, MT-1, and AIRAP gene expression was enhanced to a similar extent in both strains, whereas NaAs challenge augmented intrarenal MRP-1 mRNA and protein expression levels in C57BL/6 but not BALB/c mice. Moreover, the administration of a specific inhibitor of MRP-1, MK-571, significantly exaggerated acute renal injury in C57BL/6 mice. Thus, MRP-1 is crucially involved in arsenic efflux and eventually prevention of acute renal injury upon acute exposure to NaAs.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2005

Macular abnormalities and optic disk anomaly associated with a new PAX2 missense mutation.

PURPOSE: To report a family with macular abnormalities accompanied by anomalies of the optic disk and kidney associated with a new PAX2 missense mutation. DESIGN: Observational case report. METHODS: A 34-year-old female presented with horizontal nystagmus, poor visual acuity, and chronic renal failure. She had bilateral colobomatous disk anomaly and foveal hypoplasia. Her mother also had renal dysfunction and bilaterally impaired vision. Besides the optic disk dysplasia, the fovea was hypoplastic in the right eye, whereas pigmented macular atrophy was observed in the left eye. The entire coding regions of PAX2 and PAX6 were screened for mutations. RESULTS: A heterozygous mutation G755C in exon 2 of PAX2 that results in a missense mutation, R71T, was identified in the proband and her mother. No mutations were detected in PAX6. CONCLUSIONS: A new PAX2 missense mutation, R71T, may cause macular abnormalities in addition to anomalies of the optic disk and the kidney.

Abnormalities, Multiple↗
PubMed2005

Involvement of extracellular signal-regulated kinase and p38 in human diabetic nephropathy.

BACKGROUND: The involvement of mitogen-activated protein kinase (MAPK) in human diabetic nephropathy has not been fully investigated. METHODS: The presence of cells positive for the phosphorylated MAPK family (phosphorylated extracellular signal-regulated kinase [p-ERK], phosphorylated p38MAPK [p-p38MAPK]) was investigated immunohistochemically in kidneys of 30 patients with diabetic nephropathy. In addition, 10 patients with minimal change nephrotic syndrome, 10 patients with thin basement membrane disease, and 5 patients with benign nephrosclerosis were studied as disease controls. The presence of activated nuclear factor-kappaB (p65)-positive cells also was evaluated in kidney specimens. RESULTS: In patients with diabetic nephropathy, p-ERK, p-p38MAPK, and p65 were observed in mesangial cells, endothelial cells, podocytes, tubular epithelial cells, and mononuclear infiltrates in interstitium. Numbers of p-ERK-, p-p38MAPK-, and p65-positive cells in both glomeruli and interstitium in patients with diabetic nephropathy were higher than those in controls. In particular, the number of glomerular p-ERK-positive cells in patients with diabetic nephropathy increased in accordance with the progression of glomerular lesions and correlated well with the number of glomerular p65-positive cells (r = 0.654; P < 0.01; n = 30). Conversely, the number of p-p38MAPK-positive cells in glomeruli did not correlate with glomerular lesions. However, the number of tubulointerstitial p-p38MAPK-positive cells in patients with diabetic nephropathy reflected the severity of tubulointerstitial lesions, and numbers of those in the interstitium increased with good correlation to numbers of tubulointerstitial p65-positive cells (r = 0.757; P < 0.01; n = 30) and interstitial CD68-positive macrophages (r = 0.647; P < 0.05; n = 30) and urinary monocyte chemoattractant protein-1 levels (r = 0.605; P < 0.05; n = 30). CONCLUSION: These results suggest that MAPK phosphorylation contributes to human diabetic nephropathy. In particular, ERK and p38MAPK may be distinctly involved in glomerular and tubulointerstitial lesions in human diabetic nephropathy.

Antigens, CD↗
PubMed2005

Clinical significance of lymph node dissection in renal cell carcinoma.

OBJECTIVE: To identify the role of lymph node dissection in renal cell carcinoma (RCC). MATERIAL AND METHODS: A total of 100 patients (66 males, 34 females) were enrolled in the study. The mean age and tumor size were 61.4 years and 5.8 cm, respectively. A total of 41 patients (41%) had tumors <4 cm in diameter. The pathological status was pT1, pT2 and pT3 in 60, 11 and 29 patients, respectively. RESULTS: In total, lymph node metastases were found in seven cases (7%). Of 40 patients with pT1a tumors (tumor size <4 cm), one (2.5%) had lymph node metastasis. Patients with lymph node metastases had significantly larger tumors than those without (8.9 vs 5.5 cm; p<0.05). Regarding patient outcome, 33 (33%) had tumor progression (alive with disease, n=14; disease-specific death, n=19) after a median follow-up period of 54.0 months. In univariate analysis, 15/18 prognostic markers [tumor size, tumor grade, pT, pN and M categories, stage, microscopic venous invasion (V category), microscopic lymphatic invasion (Ly category), pathological tumor infiltration pattern (INF category), plasma fibrinogen, C-reactive protein, immunosuppressive acidic protein, alpha-2 globulin and erythrocyte sedimentation rates at 1 and 2 h] were common significant predictors of tumor progression. A Cox hazard model revealed tumor size, tumor grade and pathological stage to be independent prognostic factors. CONCLUSIONS: Tumor size is a crucial prognostic factor for tumor progression, and lymph node dissection may be omitted in T1a tumors.

Carcinoma, Renal Cell↗
PubMed2005

Effective prevention of diabetes mellitus: a motto for healthy habits--"none of one, less of two, more of three".

OBJECTIVE: To demonstrate the correlation of six healthy habits with plasma glucose. METHODS: Our mnemonic or motto for promoting healthy habits is "none of one, less of two, more of three". The 'one' behavior is smoking. The two things are intake of food and alcohol. The three things are exercise, rest and enjoyable activities. SUBJECTS: A questionnaire recording compliance with this motto was completed by 8,113 subjects undergoing medical health check-ups. Subjects under medication were excluded. Fasting plasma glucose was measured. RESULTS: Fasting plasma glucose decreased significantly in relation to the number of healthy habits practiced (5.57 mmol/l for one, 5.51 for two, 5.49 for three, 5.41 for four, 5.38 for five, and 5.31 for six) . CONCLUSION: Practicing these six healthy habits contributes to the prevention of diabetes mellitus.

Attitude to Health↗