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Biomedical subjects

Takashi Kuroiwa

Publications and source records attributed to Takashi Kuroiwa.

At least 19 recordsLinked to original sources
PubMed2007

Angiotensin II type 1 receptor blockade inhibits the development and progression of HIV-associated nephropathy in a mouse model.

HIV-associated nephropathy (HIVAN) is characterized by a collapsed glomerular capillary tuft with hyperplasia and hypertrophy of podocytes. Recently generated were conditional transgenic mice (podocin/Vpr) that express one of the HIV-1 accessory genes, vpr, selectively in podocytes using podocin promoter and Tet-on system. These transgenic mice developed renal injury similar to HIVAN when treated with doxycycline for 8 to 12 wk. This study demonstrated that nephron reduction by heminephrectomy markedly enhanced phenotypic changes of podocytes and led to severe FSGS within 4 wk. Nephrotic-range proteinuria was observed already at 2 wk, together with dedifferentiation and dysregulation of podocytes, indicated by decreased expression of nephrin, synaptopodin, and Wilms' tumor 1 protein and increased expression of Ki-67. The acceleration of phenotypic changes of podocytes, proteinuria, and subsequent glomerulosclerosis by heminephrectomy was almost completely inhibited by angiotensin II type 1 receptor (AT1R) blocker olmesartan. In contrast, the renoprotective effect of the calcium channel antagonist azelnidipine was minimal, although it lowered systemic BP to the same level as olmesartan, demonstrating that the inhibitory effect of AT1R blocker was independent of systemic BP. Olmesartan also reduced proteinuria and prevented glomerulosclerosis even by the delayed treatment, which was initiated after the podocyte injury appeared. These data suggest that nephron reduction exaggerates podocyte injury and subsequent glomerulosclerosis, possibly through glomerular hypertension, in the mouse model of HIVAN. AT1R blockade could be beneficial in the treatment of HIVAN by ameliorating podocyte injury by avoiding the vicious cycle of nephron reduction and glomerular hypertension.

AIDS-Associated Nephropathy↗
PubMed2005

Secretion of parathyroid hormone oscillates depending on the change in serum ionized calcium during hemodialysis and may affect bone metabolism.

BACKGROUND: The current study was undertaken to clarify the dynamic response of parathyroid hormone (PTH) during hemodialysis and to determine whether or not such dynamic change of PTH affects bone turnover. METHODS: Serum ionized calcium (iCa) and intact PTH (iPTH) were measured in 66 dialysis patients before (basal) and after each hemodialysis. The changes of iCa (DeltaiCa) and iPTH (DeltaiPTH) were defined as [postdialysis iCa -basal iCa] mM, and [(postdialysis iPTH - basal iPTH)/basal iPTH] x 100%, respectively. We also investigated the data of the patients divided into four groups based on their basal iPTH levels; group 1 (iPTH < 60 pg/ml, n = 17), 2 (> or = 60 to < 150, n = 20), 3 (> or = 150 to < 300, n = 15), and 4 (> or = 300, n = 14). RESULTS: While iCa and iPTH changed variably during each hemodialysis procedure, there was a highly significant inverse correlation between DeltaiCa and DeltaiPTH (r = -0.761, p < 0.0001). Regression coefficients between DeltaiPTH and DeltaiCa were -519.1, -311.2, -268.1, and -194.6%/mM in groups 1-4, respectively. The difference in the regression coefficient was statistically significant between group 1 and 2 (F = 3.69, p < 0.05, ANCOVA), group 1 and 3 (F = 5.599, p < 0.05), and group 1 and 4 (F = 10.853, p < 0.005). This suggested that patients with higher basal iPTH responded poorly to modulate serum PTH levels by sensing the change of iCa. However, after an intensified oral calcitriol therapy to reduce iPTH, the PTH response in group 4 patients was restored to levels comparable with those observed in patients having lower basal iPTH. We also demonstrate that the DeltaiPTH of patients of group 1 but not of other groups was significantly correlated with serum markers for bone metabolism; osteocalcin (r = 0.535, p < 0.05) and collagen type I C-terminal telopeptide (r = -0.575, p < 0.05). CONCLUSIONS: Our findings suggest that secretion of PTH is dynamically regulated by DeltaiCa during hemodialysis and such oscillated PTH secretion may affect bone metabolism in a subset of dialysis patients.

Adult↗
PubMed2005

Expression of interleukin-22 in rheumatoid arthritis: potential role as a proinflammatory cytokine.

OBJECTIVE: Interleukin-22 (IL-22) is a novel cytokine of the IL-10 family. Although its pathophysiologic function is largely unknown, induction of acute-phase responses by IL-22 has suggested proinflammatory properties. In this study, we sought to examine whether IL-22 plays a role in the pathogenesis of rheumatoid arthritis (RA). METHODS: Expression of IL-22 and IL-22 receptor 1 (IL-22R1) was examined by reverse transcription-polymerase chain reaction (RT-PCR), Western blot, and immunohistochemical analysis. The effects of recombinant IL-22 (rIL-22) on cultured synovial fibroblasts derived from RA patients (RASF), with regard to the proliferation of synovial fibroblasts and production of monocyte chemoattractant protein 1 (MCP-1), were examined by alamer blue assay and enzyme-linked immunosorbent assay, respectively. RESULTS: IL-22 messenger RNA was detected by RT-PCR in RA synovial tissues and mononuclear cells isolated from RA synovial fluid samples. High levels of IL-22 were expressed both in the lining and the sublining layers of RA synovial tissues. Staining for vimentin and CD68, as markers of synovial fibroblasts and macrophages, respectively, showed that the majority of IL-22-positive cells were synovial fibroblasts and macrophages. IL-22R1 was also expressed in both the lining and the sublining layers of RA synovial tissues. The majority of cells expressing IL-22R1 were positive for vimentin, but not for CD68. Expression of IL-22 and IL-22R1 in RASF was confirmed by RT-PCR and Western blot analysis. In vitro, rIL-22 significantly increased proliferation of RASF and production of MCP-1 by RASF above the value of medium controls. Moreover, MAPK activation was induced in RASF in response to IL-22 stimulation. CONCLUSION: These data suggest that IL-22, produced by synovial fibroblasts and macrophages, promotes inflammatory responses in RA synovial tissues by inducing the proliferation and chemokine production of synovial fibroblasts.

Animals↗
PubMed2005

Water intoxication associated with moderate dose of cyclophosphamide pulse therapy in an elderly patient: a case report and literature review.

Intravenous high-dose cyclophosphamide infusion, usually performed to treat malignant neoplasms, is known to cause water intoxication. Intravenous cyclophosphamide pulse therapy (IVCY) is increasingly being employed for the treatment of rheumatic diseases as well. Recently, water intoxication has been reported to occur even after low-to-moderate doses of IVCY. In the present paper, we describe a case of polyarteritis nodosa in a patient in whom water intoxication developed after IVCY at a moderate dose. Hydration is usually performed to maintain sufficient urine flow to avoid cystitis. Based on our case and a review of the literature, it is recommended that hydration should be carefully performed during IVCY in order to avoid water intoxication, especially when treating elderly patients.

Journal Article↗
PubMed2005

Oxidative stress-dependent conversion of hydrogen sulfide to sulfite by activated neutrophils.

Sulfite, which is known as a major constituent of volcanic gas, is endogenously produced in mammals, and its concentration in serum is increased in patients with pneumonia. It has been reported that sulfite is produced by oxidation from hydrogen sulfide (H2S) as an intermediate in the mammalian body. The objective of this study was to investigate the ability of reactive oxygen species from neutrophils to produce sulfite from H2S. Sulfite production from activated neutrophils stimulated with N-formyl-methionyl-leucyl-phenylalanine gradually increased with an increased concentration of sodium hydrosulfide (NaHS) in the medium. The production of sulfite was markedly suppressed with an NADPH oxidase inhibitor, diphenyleneiodonium. When NaHS was added to the supernatant of activated neutrophils, a significant amount of sulfite was synthesized in the test tubes. Furthermore, when a medium containing NaHS was incubated with a water-soluble radical initiator, 2,2'-azobis-(amidinopropane) dihydrochloride, sulfite was formed in the solution and this increase was markedly suppressed by ascorbic acid. Finally, we determined serum concentrations of sulfite and H2S in an in vivo model of neutrophil activation induced by systemic injection of lipopolysaccharide (LPS) into rats. We found a significant increase in serum sulfite and H2S after LPS injection. Importantly, coadministration of ascorbic acid with LPS further increased serum H2S but suppressed sulfite levels. This finding implies that oxidative stress-dependent conversion of H2S to sulfite might occur in vivo. Thus, the oxidation of H2S is a novel sulfite production pathway in the inflammatory condition, and this chemical synthesis might be responsible for the upregulation of sulfite production in inflammatory conditions such as pneumonia.

Animals↗
PubMed2004

Mesangial cells stimulate differentiation of endothelial cells to form capillary-like networks in a three-dimensional culture system.

BACKGROUND: There are conflicting results regarding the role of periendothelial mural cells in angiogenesis. In the current study, we investigated the role of mesangial cells (MCs) in endothelial vascularization by using a three-dimensional co-culture system in basement-membrane reconstruct gel (Matrigel). METHODS: Human umbilical vein endothelial cells (ECs) and human MCs were used. In the contact co-culture system, ECs and MCs were mixed and then plated together onto Matrigel. In the non-contact co-culture system, MCs were cultured within an intercup chamber, which prevented direct physical contact with the ECs on the Matrigel but allowed both cell types to share culture medium. To visualize ECs and MCs, the cells were labelled with two different fluorescent dyes prior to the co-culture. A capillary-like network formation was observed under a fluorescent microscope and confocal microscope, and the length of the network formation was quantified by the image analyzer. RESULTS: ECs barely formed capillary-like networks when cultured alone in growth factor-free medium. However, ECs cultured with MCs in a contact condition remarkably formed capillary-like networks (9.10+/-0.96 vs 0.20+/-0.07 mm/mm2 at 6 h, contact vs ECs alone, P<0.001). Direct contact between ECs and MCs was clearly demonstrated by confocal microscopy. Differentiation into branching capillary-like structures was also observed in the non-contact co-culture system (3.02+/-1.21 mm/mm2 at 6 h, P<0.001 vs ECs alone), but less prominently than in the contact co-culture condition. Vascular endothelial growth factor (VEGF) was secreted from MCs, as determined by enzyme-linked immunosorbent assay and immunofluorescent study. Adding neutralizing antibodies against VEGF into the co-culture system partially inhibited capillary network formation. CONCLUSIONS: Our data indicate that MCs help ECs differentiate toward vascularization, in which the direct cell-cell contact between ECs and MCs plays an important role. VEGF is a mediator in this process.

Analysis of Variance↗
PubMed2004

Aplastic anemia associated with initiation of nizatidine therapy in a hemodialysis patient.

We report on a hemodialysis (HD) patient in whom fatal aplastic anemia developed after the administration of nizatidine, a histamine 2 (H2)-receptor antagonist. The patient was a 55-year old Japanese woman and had been on HD for 2 years due to endstage diabetic nephropathy. The patient had a hemorrhagic duodenal ulcer and had been treated with lansoprazole, a proton pump inhibitor, for 2 months. After improvement, lansoprozole was discontinued and she was subsequently treated with nizatidine. Twelve days after initiation of nizatidine treatment, the patient developed a high-grade fever with symptoms suggestive of upper respiratory infection. Hematological tests showed severe pancytopenia, and drug-induced aplastic anemia was diagnosed. Nizatidine was suggested as the causal drug. Despite intensive therapies, the patient died on the 23rd hospital day from generalized fungal infections. Although hematological adverse events have been reported in HD patients receiving H2-receptor antagonists, few studies of fatal aplastic anemia associated with these drugs have been reported. This case emphasized that careful observation is required after the initiation of H2-receptor antagonist treatment in HD patients.

Anemia, Aplastic↗
PubMed2004

Increased levels of serum sulfite in patients with acute pneumonia.

Sulfite, a common air pollutant, is toxic for humans, causing hypersensitivity or chronic airway diseases. We previously reported that sulfite is actively produced from neutrophils by stimulation with bacterial endotoxin, lipopolysaccharide (LPS). We also found that the serum sulfite concentration is increased in a rat model of sepsis induced by systemic injection of LPS. However, information on sulfite metabolism in human inflammatory conditions is limited. In the current study, the serum concentration of sulfite was determined in 25 patients with acute pneumonia. Serum sulfite concentration in pneumonia patients was significantly higher than that in control subjects (3.75 +/- 0.88 vs. 1.23 +/- 0.48 microM, respectively, P < 0.05). Among 20 patients, serum sulfite was serially determined before and after antibiotic therapy. The levels of serum sulfite were significantly reduced during the recovery phase compared with those during the acute phase (1.34 +/- 0.56 vs. 3.65 +/- 0.92 microM, respectively, P < 0.05). Moreover, neutrophils obtained from three patients during the acute phase of pneumonia spontaneously produced higher amounts of sulfite in vitro than those obtained after recovery. There was a close positive correlation (r = 0.71, P < 0.05) between serum sulfite and C-reactive protein (CRP) in patients with pneumonia. Taken together, the current findings suggest that serum sulfite increases during systemic inflammation in humans. Activated neutrophils might be responsible, at least in part, for the up-regulation of sulfite. Given various biological effects reported previously, sulfite may act as a mediator in inflammation.

Acute Disease↗
PubMed2004

Fluvastatin reduces renal fibroblast proliferation and production of type III collagen: therapeutic implications for tubulointerstitial fibrosis.

BACKGROUND: Accumulating evidence suggests that hydroxymethylglutaryl-CoA reductase inhibitors have many biological effects beyond reducing cholesterol synthesis. In a mouse model of renal interstitial fibrosis induced by unilateral ureteral obstruction, fluvastatin, one of the lipophilic hydroxymethylglutaryl-CoA reductase inhibitors, was shown to ameliorate fibrosis. METHODS: In the present study, we examined the direct effects of fluvastatin on proliferation, matrix and growth factor production by rat kidney fibroblasts (NRK-49F cells). RESULTS: Treatment with fluvastatin reduced proliferation of NRK-49F cells in a dose-dependent manner. The addition of mevalonate or geranylgeranyl pyrophosphate but not farnesyl pyrophosphate to the culture medium almost completely abolished the effect of fluvastatin. Moreover, fluvastatin treatment decreased the expression of activated Rho in NRK-49F cells suggesting that fluvastatin may decrease cell growth through blocking the activation of Rho. The majority of fluvastatin-treated cells were arrested at the G1 phase, associated with down-regulation of cyclin A and up-regulation of cyclin-dependent kinase inhibitor p27kip1, indicating that cell cycle modulation is an important mechanism. Fluvastatin significantly decreased messenger RNA expression of type III collagen and connective tissue growth factor. CONCLUSIONS: Taken together, it is suggested that fluvastatin may prevent tubulointerstitial fibrosis in a variety of progressive renal diseases by inhibiting proliferation of interstitial fibroblasts and their matrix synthesis.

Acute-Phase Proteins↗
PubMed2003

Improvement of the yield of physiologically active oligosaccharides in continuous hydrolysis of chitosan using immobilized chitosanases.

The continuous production of chitosan oligosaccharides using a packed-bed enzyme reactor was investigated as to the effects of the operation conditions on the yield of pentamers and hexamers of chitosan oligosaccharides. A column reactor packed with immobilized chitosanases prepared by the multipoint attachment method was used for continuous hydrolysis of chitosan. In this reactor, the decrease of the yield of the target intermediate oligosaccharides due to axial mixing was negligible. The surface enzyme density of the support and flow rate of the substrate solution significantly affected the maximum yield of pentamers and hexamers. These effects were summarized as a correlation with the Damköhler number (Da), defined as the ratio of the maximum reaction rate to the maximum mass transfer rate. The optimum condition was determined based on Da. Under the optimized condition (Da = 0.12), pentamers and hexamers could be produced continuously for a month with a yield of over 35% (7 kg/m(3) in concentration).

Bioreactors↗
PubMed2003

Sensitive and specific detection of circulating cancer cells in patients with hepatocellular carcinoma; detection of human telomerase reverse transcriptase messenger RNA after immunomagnetic separation.

PURPOSE: We evaluated whether detection of human telomerase reverse transcriptase (hTERT) mRNA after immunomagnetic separation is useful to detect circulating cancer (CC) cells. EXPERIMENTAL DESIGN: Two ml of peripheral blood were collected from 55 cases with hepatocellular carcinoma (HCC), 20 cases with chronic liver diseases devoid of cancer, and 20 healthy volunteers. Then 1500 and 500 micro l were subjected to immunomagnetic separations using Ber-EP4 and anti-CD45 antibodies, harvested and supernatant cells were collected as epithelial and nonleukocyte fractions, respectively. Samples of each fraction were subjected to reverse transcription-PCR detecting beta-actin, interleukin-2 receptor (IL-2r), alpha-fetoprotein, and hTERT mRNAs. The cases were judged to be positive, equivocal, or negative for CC cells when hTERT positivity with IL-2r negativity, hTERT positivity with IL-2r positivity, or hTERT negativity was seen in epithelial and/or nonleukocyte fractions, respectively. RESULTS: The dilution experiments revealed that our system could detect 10(0-1) HeLa cells involved in 2 ml of blood. The Ber-EP4-harvested cells from cases with distant metastasis were positive for immunostaining using Hep Par 1 monoclonal antibody. CC cells were judged to be positive in 29 of 55 (53%) HCC cases. On the contrary, no cases without HCC were determined to be positive. The frequency of positivity was significantly correlated with disease extent of HCC. CONCLUSIONS: These results strongly suggest that detection of hTERT mRNA after immunomagnetic separation is a specific and sensitive tool to detect CC cells and that it would provide useful source for further investigation of cancer metastasis.

Aged↗
PubMed2003

Telomere length variation and maintenance in hepatocarcinogenesis.

BACKGROUND: Despite the recent discovery of interchromosomal telomere length variation, a role for heterogeneity in telomere maintenance has yet to be established. This study investigated the significance of telomere length variation between chromosomes with respect to the association of cancer progression and telomere length regulation. METHODS: Terminal restriction fragment (TRF) was evaluated in 20 surgically resected hepatocellular carcinoma specimens (HCC), corresponding noncancerous liver tissue specimens (NCL), and in 10 liver tissue specimens with chronic liver diseases devoid of cancer (DOC). Average TRF length (TRF-A) was defined as the point of maximum intensity. Shorter and longer TRF lengths (TRF-S and TRF-L) were defined as the length above which 90% of TRF distribution was involved. A ratio, (TRF-L-TRF-S)/TRF-A, was defined as telomere length dispersion. RESULTS: The dispersion was significantly larger in HCC than in NCL specimens (P = 0.012) and in NCL than in DOC (P = 0.048). TRF-A and TRF-S were significantly shorter in HCC than in NCL (P = 0.0026, P = 0.0010). In seven patients in whom HCC recurred within 1 year, TRF-A and TRF-S were significantly shorter than in 10 patients in whom recurrence occurred after 1 year (P = 0.018, P = 0.0097). Telomeric repeat binding factor 1 was up-regulated in HCC with elongated TRF-L, whereas expression of human telomerase reverse transcriptase was greater in HCC with a shorter TRF-S. CONCLUSIONS: These results suggest that telomere length varied through chronic liver diseases by preferentially increasing shorter telomeres, whose length is a good indicator for malignant potential of HCC. Telomere length variation may be a crucial code in telomere maintenance through hepatocarcinogenesis.

Aged↗
PubMed2003

Activin A induces cell proliferation of fibroblast-like synoviocytes in rheumatoid arthritis.

OBJECTIVE: To investigate the expression of activin A and its receptors in rheumatoid arthritis (RA) synovial tissues, and to determine the effect of activin A on cultured fibroblast-like synoviocytes (FLS). METHODS: The localization of activin A and activin type II receptor (ARII) in synovial tissues of RA patients was analyzed by immunohistochemistry. The expression of activin A and activin receptors in human cultured FLS was examined by reverse transcriptase-polymerase chain reaction and Western blotting. Enzyme-linked immunosorbent assay was used to measure activin A in culture supernatants. The cell growth of FLS was determined by (3)H-thymidine incorporation and MTT assay. RESULTS: Immunohistochemical analysis confirmed the up-regulation of activin A in rheumatoid synovium as compared with osteoarthritis or normal joint tissues. CD68+ macrophage-lineage cells and vimentin-positive FLS were identified as activin-producing cells in rheumatoid synovium. Both cell types also expressed ARII. The expression of activin A and ARII on cultured FLS was confirmed at the protein and messenger RNA levels. Interleukin-1 beta (IL-1 beta), tumor necrosis factor alpha, and transforming growth factor beta activated FLS to secrete activin A. Recombinant activin A accelerated the proliferation of FLS, while follistatin, an endogenous activin antagonist, partially inhibited FLS proliferation induced by IL-1 beta. CONCLUSION: These results suggest that activin A acts as a growth factor of FLS in RA.

Activin Receptors↗
PubMed2003

Monocyte response to Th1 stimulation and effector function toward human mesangial cells are not impaired in patients with lupus nephritis.

Monocytes/macrophages activated by Th1 stimulation such as interferon-gamma (IFN-gamma) and CD40 ligand (CD40L) infiltrate the kidney and play a critical role in the progression of lupus nephritis (LN). We examined the monocyte response to Th1 stimulation and their effector function toward activating renal resident cells in patients with LN. Following stimulation with IFN-gamma granulocyte macrophage-colony stimulating factor (GM-CSF)/recombinant CD40L the production of tumor necrosis factor-alpha and IL-12 p70 by PBMC was significantly higher in LN patients. In coculture experiments employing activated monocytes and human mesangial cells, there was a trend toward higher monocyte chemoattractant protein-1 production by lupus monocytes compared to normal controls. Basal expression of CD40, ICAM-1, and STAT-1 was significantly higher in monocytes from LN patients, suggesting ongoing activation. Monocyte response to IFN-gamma, as accessed by intercellular adhesion molecule-1 upregulation and phosphorylation of STAT-1, was comparable between the two groups. Thus, in contrast to earlier reports, Th1-dependent monocyte activation is not impaired. In this disease activated monocytes appear to be fully capable of inducing renal injury.

Adult↗
PubMed2003

Salazosulfapyridine-induced remission of Felty's syndrome along with significant reduction in neutrophil-bound immunoglobulin G.

Felty's syndrome is characterized by neutropenia, splenomegaly, and leg ulcers in patients with rheumatoid arthritis. The pathogenesis of the neutropenia is an immune-mediated process that involves immune complexes, antineutrophil antibodies, and abnormal white cell kinetics. We prescribed salazosulfapyridine to a 65-year-old woman with this syndrome. The neutropenia improved along with a reduction in neutrophil-bound IgG, demonstrated by flow cytometric analysis. Salazosulfapyridine may be of benefit for the treatment of Felty's syndrome, and flow cytometry can be used to monitor disease activity and therapeutic efficacy.

Aged↗
PubMed2003

Kikuchi's disease accompanied by lupus-like butterfly rash.

Kikuchi's disease (KD) is a benign and self-limiting lymphadenitis, particularly affecting young women. KD is often associated with fever, arthralgia, and leukopenia, features also found in systemic lupus erythematosus (SLE). Lymphadenitis associated with SLE is indistinguishable from that in KD, and the association of KD and SLE has been previously reported. We describe a case of KD who developed a typical butterfly rash, reminiscent of SLE. However, histological and laboratory findings excluded the diagnosis of SLE. This case emphasizes that careful differential diagnosis between KD and SLE is required.

Adolescent↗
PubMed2002

Sulfite induces adherence of polymorphonuclear neutrophils to immobilized fibrinogen through activation of Mac-1 beta2-integrin (CD11b/CD18).

Sulfite is a major air pollutant which can cause respiratory tract inflammation characterized by an influx of polymorphonuclear neutrophils (PMN). We have previously shown that human PMN can produce sulfite either spontaneously or in response to stimulation with lipopolysaccharide. We now demonstrate that sulfite activates PMN to adhere to immobilized fibrinogen via the beta2-integrin Mac-1 (CD11b/CD18). Mac-1 expression is not altered by treatment with this agent. Although unaffected by pertussis toxin, sulfite-triggered PMN adhesion was abrogated by pretreating cells with the membrane-impermeant sulfhydryl reagent 5,5'-dithiobis(2-nitrobenzoic acid) (DTNB), a modifier of thiol groups on the cell surface. These results suggest that sulfite-induced PMN adhesion is dependent on a modification of thiols at the cell surface. Given its potent antioxidant and antimicrobial activities, sulfite may act as an endogenous mediator in host defense and/or inflammation.

CD18 Antigens↗