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Takashi Wada

Publications and source records attributed to Takashi Wada.

At least 55 records · Page 3Linked to original sources
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↗
PubMed2003

Detecting homozygous deletions in the CDKN2A(p16(INK4a))/ARF(p14(ARF)) gene in urinary bladder cancer using real-time quantitative PCR.

PURPOSE: 9p21 is a major target in the pathogenesis of human urinary bladder cancer. The locus harbors the CDKN2A/ARF tumor suppressor gene, which encodes two cell cycle regulatory proteins cyclin dependent kinase 2A (p16(INK4a)) and alternate reading frame (p14(ARF)). We have designed a real-time quantitative PCR (QPCR) application to study homozygous deletion (HD) of CDKN2A/ARF in 186 urinary bladder cancer patients. EXPERIMENTAL DESIGN: Real-time QPCR, based on simultaneous amplification of ARF and a reference gene, GAPDH, was developed and evaluated in three melanoma cell lines with HDs at the CDKN2A/ARF locus (IGR-1, SK-MEL-5, and WM-266-4). In addition, loss of heterozygosity was analyzed at the D9S942, D9S1748, and D12S99 markers. Mutation analysis of the CDKN2A/ARF gene was performed using single-strand conformational polymorphism and sequencing. Results from the present investigation were combined with previous p53 analysis of the same urinary bladder neoplasms. RESULTS: Real-time QPCR analysis showed 26 (14%) HDs, 22 (12%) hemizygous deletions, and 3 (2%) multiple duplications. Loss of heterozygosity was determined in 30 (22%) cases at the D9S942 locus, which is located between E1alpha and E1beta of the CDKN2A/ARF gene. No association was established between occurrence of genetic aberrations at 9p21 and tumor stage or grade, supporting previous suggestions that CDKN2A/ARF inactivation is an early event in bladder carcinogenesis. CONCLUSIONS: We have established a fast and efficient method for detection of HDs. Our data support the notion that inactivation, including HDs, of CDKN2A/ARF is an early event in transitional cell carcinoma. We observed separate and specific targeting of the CDKN2A and ARF genes, respectively, and that simultaneous inactivation of ARF and p53 occurs.

Carcinoma, Transitional Cell↗
PubMed2002

Structure and catalytic mechanism of 2-C-methyl-D-erythritol 2,4-cyclodiphosphate (MECDP) synthase, an enzyme in the non-mevalonate pathway of isoprenoid synthesis.

Precursors for isoprenoid synthesis are essential in all organisms. These compounds are synthesized by one of two known routes: the well characterized mevalonate pathway or a recently discovered non-mevalonate route which is used in many bacteria and human pathogens. Since the second pathway is both vital and unlike any found in humans, enzymes catalysing reactions along this synthetic route are possible drug targets. The structure of one such enzyme from the thermophilic bacterium Thermus thermophilus has been solved to high resolution in the presence of substrate and with a substrate analogue. Enzyme co-crystallized with substrate shows only one product, cytosine monophosphate (CMP), in the active site. At the high resolution of the refinement (1.6 A) the positions and coordination of the magnesium ions in the active site are clearly seen.

Amino Acid Sequence↗
PubMed2002

Electron-dense deposition patterns and the outcomes of idiopathic membranous nephropathy in Japanese.

A considerable diversity in prognosis is seen with membranous nephropathy (MN). In terms of pathological findings, the presence of tubulointerstitial lesions was emphasized as a poor prognostic factor. However, the glomerular factors affecting the long-term outcome of idiopathic human MN have remained unclear. We reviewed the initial clinicopathological factors affecting the primary and secondary outcomes in 105 patients with primary MN, as well as reviewing previous reports. Based on electron microscopic (EM) findings, we could divide patients into two subtypes and one subgroup; i.e., homogeneous type with a synchronous phase of electron-dense deposits, with large dense deposits (deep subgroup) and heterogeneous type with various phases of dense deposits. The homogeneous type showed no endstage renal failure, and had earlier remission as compared with the heterogeneous type. For the secondary outcome, heterogeneous type and deep subgroup were also independent risk factors. However, there was no significant difference in the final primary or secondary outcome for any treatment subgroups. These results indicated that our category of EM findings was a beneficial marker of the primary and secondary outcomes in MN; the homogeneous type of MN with synchronous phase of electron-dense deposits (except for the "deep" subgroup) had a good outcome.

Female↗
PubMed2002

Fibroepithelioma-like changes occurring in perianal Paget's disease with rectal mucinous carcinoma: case report and review of 49 cases of extramammary Paget's disease.

BACKGROUND: Anogenital Paget's disease (PD) may be accompanied by varying degrees of epidermal hyperplasia. The histological changes can be reminiscent of fibroepithelioma of Pinkus. METHODS: We present a case of perianal PD associated with fibroepitheliomatous epidermal hyperplasia in a 76-year-old-man with an underlying rectal mucinous carcinoma. We also carried out a retrospective analysis of 51 biopsies from 49 cases of extramammary PD to see whether particular epidermal changes occur in association with PD in different anatomic locations. RESULTS: A tumor, 3 cm in diameter, was noted in the patient's perianal skin. Histologically, it was composed of anastomosing thin epithelial strands with follicular differentiation. Paget's cells were distributed in the epithelial strands of this tumor as well as in the surrounding epidermis and anal epithelia. In our series of extramammary PD, epidermis was hyperplastic in two of two perianal cases, 26 of 43 genital skin samples, and one of six axillary PD biopsies. The stroma beneath the hyperplastic epidermis tended to be rich in thin collagen fibers and fibroblasts. CONCLUSIONS: Anogenital PD was more frequently associated with epidermal hyperplasia than axillary PD. Fibroepitheliomatous hyperplasia may be induced by the altered stroma associated with PD.

Adenocarcinoma, Mucinous↗
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

Renal cell carcinoma: allelic loss at chromosome 9 using the fluorescent multiplex-polymerase chain reaction technique.

Loss of tumor-suppressor genes on both arms of chromosome 9 appears to be common in many types of cancer. Chromosome 9q is often partially deleted in bladder cancer, lung cancer, and basal cell carcinoma. However, little data are available on allelic loss on chromosome 9 in renal cell carcinoma (RCC). One hundred and nine nonpapillary RCCs were studied for loss of heterozygosity (LOH) at 13 loci on chromosome 9 by using the fluorescent multiplex-polymerase chain reaction method to compare DNA from tumor samples and peripheral blood lymphocytes. At the loci tested, LOH was found in from 2.3% (9q31, D9S938) to 17% (9q22, 1AJL) of informative cases, and 27 (24.8%) of the 109 RCCs had LOH at 1 or more loci of chromosome 9. LOH was more often detected at 9q22 within the PTCH gene (17%) when compared with LOH at the other 12 loci (P = 0.0172). Regarding the relationship with clinical parameters, however, there were no statistically significant associations between this LOH and tumor stage or grade. Among the 109 tumors, 6 (5.5%) showed replication errors. Our results suggest that LOH of the PTCH gene may be related to the development of nonpapillary RCC, although the clinical relevance has not been not clarified.

Adult↗
PubMed2002

Administration of FR167653, a new anti-inflammatory compound, prevents renal ischaemia/reperfusion injury in mice.

BACKGROUND: Various types of chemokines/cytokines play important roles in ischaemia/reperfusion injury in kidneys. However, the roles of p38 mitogen-activated protein kinase (MAPK) in the inflammatory processes of renal ischaemia/reperfusion injury remain to be investigated. We explored the effect of FR167653, a specific inhibitor of p38 MAPK, on renal ischaemia/reperfusion injury in mice. METHODS: The renal artery and vein of the left kidney were occluded with a vascular clamp for 60 min. FR167653 was injected 2 h before or 24 h after renal vessel clamp. Renal tissues were removed for pathological examination 4, 24 or 48 h after reperfusion. RESULTS: We observed a large number of infiltrated cells and marked acute tubular necrosis in outer medulla after renal ischaemia/reperfusion injury in mice. FR167653 significantly decreased cell infiltration into outer medulla, and the extent of acute tubular necrosis 24 and 48 h after reperfusion. FR167653 markedly decreased the transcription of interleukin-1beta, tumour necrosis factor-alpha, monocyte chemoattractant protein-1 and regulated upon activation, normal T cell expression and secreted in diseased kidneys. Moreover, FR167653 decreased the number of phosphorylated p38 MAPK-positive cells 4 h after reperfusion. CONCLUSION: These results suggest that FR167653 markedly ameliorated renal ischaemia/reperfusion injury, possibly by inhibiting cytokine/chemokine expression and consequent phosphorylation of p38 MAPK in renal tissue.

Animals↗
PubMed2002

p38 MAPK phosphorylation and NF-kappa B activation in human crescentic glomerulonephritis.

BACKGROUND: p38 mitogen-activated protein kinase (p38 MAPK) followed by the activation of NF-kappa B participates in the intracellular signal transduction and production of cytokines and chemokines. The pathophysiological roles of p38 MAPK and NF-kappa B in human glomerulonephritis, however, remain to be investigated. METHODS: We investigated the phosphorylated p38 MAPK (p-p38 MAPK) and activated NF-kappa B immunohistochemically in the kidneys of 34 patients with crescentic glomerulonephritis and 26 control patients with thin basement membrane disease and minimal change nephrotic syndrome. We also explored the co-localization of p-p38 MAPK with CCR5, the signal of which leads to p38 MAPK activation. Furthermore, urinary levels of MIP-1 alpha, the cognate ligand for CCR5, were determined by enzyme-linked immunosorbent assay. RESULTS: p-p38 MAPK-positive cells and activated NF-kappa B-positive cells were mainly detected in crescentic lesions, tubular epithelial cells, and interstitial mononuclear infiltrates. The number of p-p38 MAPK-positive cells in patients with crescentic glomerulonephritis was higher than that in control patients. The number of p-p38 MAPK-positive cells in glomeruli was well correlated with the percentage of cellular crescents, the number of CD68-positive cells, and urinary MIP-1 alpha levels. In addition, the number of activated NF-kappa B-positive cells was well correlated with the number of p-p38 MAPK-positive cells in glomeruli. Dual staining revealed that most of CCR5-positive cells were positive for p-p38 MAPK. Finally, p-p38 MAPK-positive cells and activated NF-kappa B-positive cells decreased during glucocorticoid therapy-induced convalescence. CONCLUSIONS: We conclude that the phosphorylation of p38 MAPK associated with the activation of NF-kappa B may be involved in the upregulation of intrarenal MIP-1 alpha and the utilization of CCR5 signalling, which may result in human crescentic glomerulonephritis.

Female↗
PubMed2002

A disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS)-1 null mutant mice develop renal lesions mimicking obstructive nephropathy.

BACKGROUND: A disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS)-1 is distinguished from other a disintegrin and metalloproteinase molecules by the presence of thrombospondin type 1 motifs at its C-terminus and anchors to the extracellular matrix. We studied the biological role of ADAMTS-1 in the kidney. METHODS: We developed ADAMTS-1 null mice by replacing exons 2-4, which encode most of the metalloproteinase domain, with the neomycin resistance gene. RESULTS: In normal mice, ADAMTS-1 was detected in the epithelial cells of collecting ducts, and more intensely in the urinary epithelium at the ureteropelvic junction in kidney. We found that targeted disruption of the mouse ADAMTS-1 gene resulted in enlarged renal calices accompanied by bilateral hydronephrosis and papillary atrophy approximately 4 weeks after birth. Electron microscopic examination revealed the fibrotic changes and hypervascularity of capillaries between the urinary epithelial cell layer and smooth muscle cell layer at the ureteropelvic junction. CONCLUSION: ADAMTS-1 appears necessary for normal kidney morphology and function. Moreover, the resemblance of the renal phenotype to human ureteropelvic junction obstruction may provide a clue to the pathogenesis of this common congenital disease.

ADAM Proteins↗
PubMed2002

Renal metastasis from squamous cell carcinoma of the hypopharynx.

We present a rare case of metastatic renal tumor originating from squamous cell carcinoma of the hypopharynx. A 67-year-old man treated with irradiation for hypopharyngeal carcinoma was referred to our hospital with gross hematuria and a left renal mass, which was delineated as a heterogeneously enhanced mass by CT scan. Left nephrectomy was performed, and the non-encapsulated mass was gray in color macroscopically. Histological examination of the specimen revealed alveolar proliferation of small cancer cells, which was consistent with the original tumor of the hypopharynx. The left renal tumor was diagnosed as poorly differentiated squamous cell carcinoma metastasized from the hypopharynx. The patient remains alive, with no evidence of disease, 8 months following left nephrectomy. This case was thought to be the first report of a renal metastasis from a hypopharyngeal carcinoma that was diagnosed clinically and treated with nephrectomy.

Aged↗
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

[Clinical evaluation of the effect of tamsulosin hydrochloride and cernitin pollen extract on urinary disturbance associated with benign prostatic hyperplasia in a multicentered study].

We evaluated the clinical efficacy and safety of tamsulosin hydrochloride and cernitin pollen extract in 243 patients with urinary disturbance associated with benign prostatic hyperplasia. They were assigned randomly to 3 groups, oral tamsulosin hydrochloride, cernitin pollen extract and their combination were administered for 12 weeks. The international prostate symptom score, post-voided residual urine and uroflowmetrogram were obtained before and after treatment. The international prostate symptom score improved in each group and then the maximum flow rate and average flow rate also increased significantly in the tamsulosin hydrochloride-administered groups. In conclusion, the administration of only tamsulosin hydrochloride and the combination of tamsulosin hydrochloride and cernitin pollen extract seemed more effective then the administration of only cernitin pollen extract in the treatment of urinary disturbance associated with benign prostatic hyperplasia.

Adrenergic alpha-Antagonists↗
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↗
PubMedDate not supplied

High endothelial venule-like vessels in the interstitial lesions of human glomerulonephritis.

To clarify the characteristics of high endothelial venule (HEV) -like vessels in the interstitium of human glomerulonephritis, we investigated the expression of HEVs related molecules such as P-selectin and L-selectin ligands; MECA-79 epitope and variant sulfated forms of sialyl Lewis X (variant sLe(X), clones 2H5, 2F3, GS-13 and GS-36) in kidney specimens by means of immunohistochemical studies, and P-selectin and hevin mRNA signals by using in situ hybridization analyses. In lymphoid organs, HEVs strongly expressed P-selectin, MECA-79, variant sLe(X) and hevin mRNA signals. In normal kidneys (n = 4), only P-selectin was faintly positive in the vessels of interstitium, but other molecules could not be detected. Interstitial P-selectin expression was upregulated in patients with tubulointerstitial diseases (n = 4) and proliferative glomerulonephritis (n = 51) such as IgA-related nephropathy (n = 39), membranoproliferative glomerulonephritis (n = 4) and crescentic glomerulonephritis (n = 2), but not in nonproliferative glomerular diseases (n = 39) such as minimal change nephrotic syndrome (n = 18) (1.00 +/- 0.41, 0.64 +/- 0.11, 0.21 +/- 0.05, respectively). Interstitial P-selectin expression also correlated with interstitial local cellular infiltration (r = 0.60, p < 0.0001). In addition, P-selectin mRNA signals were detected on the peritubular capillaries and HEV-like vascular endothelial cells. MECA-79 and variant sLe(X) (2H5 and 2F3) were weakly expressed on the HEV-like vessels located at the corticomedullary regions in three cases (7%) and in nine cases (27%) with interstitial cellular infiltration, respectively. However, we could not detect GS-13, GS-36 or hevin mRNA signals in the diseased kidney specimens. In conclusion, HEV-like vessels in renal interstitium expressed molecules somewhat different from HEVs in lymphoid organs and were associated with interstitial leukocyte accumulation in human proliferative glomerulonephritis possibly through the de novo expression of P-selectin and partly L-selectin ligands (MECA-79 epitope and variant sLe(X)) in the interstitial lesions.

Endothelium, Vascular↗
PubMedDate not supplied

In vitro antitumor activity of bropirimine against urinary bladder tumor cells.

BACKGROUND: Bropirimine is an orally-active immunostimulant that has an antitumor effect on superficial transitional cell carcinoma of the bladder. The mechanism of its antitumor effect has not yet been clarified. MATERIALS AND METHODS: The cytokine-mediated antiproliferative activity of bropirimine was tested against cultured KK-47 and 724 cells using a modified human clonogenic tumor assay. Perpheral blood mononuclear cells (PBMCs) obtained from five healthy volunteers were co-cultured with bropirimine and the levels of various cytokines, including IFN-alpha, gamma, IL-1beta and TNF-alpha in the supernatants, were quantified. RESULTS: Colony formation by both cell lines was directly inhibited by bropirimine in a dose-dependent manner. In co-cultures of bropirimine and PBMCs, the inhibition of colony formation by both cell lines was not enhanced compared with the effect of bropirimine alone. No significant elevation of cytokines was detected in the presence of PBMCs. CONCLUSION: The results obtained suggest that bropirimine is like to have direct antitumor activity rather than a cytokine-mediated antitumor effect.

Antineoplastic Agents↗