Biomedical subjects

Yutaka Kawahito

Publications and source records attributed to Yutaka Kawahito.

At least 19 recordsLinked to original sources

PubMed2006

SKL-2841, a dual antagonist of MCP-1 and MIP-1 beta, prevents bleomycin-induced skin sclerosis in mice.

Systemic sclerosis (SSc) is a connective tissue disease characterized by fibrosis and excessive collagen deposition in the skin and various internal organs. In early stages of SSc, the dermis reveals infiltration of inflammatory cells associated with increased collagen synthesis. SKL-2841 was initially synthesized as a novel small molecule antagonist of MCP-1. In this study, we indicated that SKL-2841 also exerts anti-chemotactic activity for MIP-1 beta in mouse spleen cells. In the early stages of bleomycin-induced skin lesions, immunohistochemical analysis showed the expression of both MCP-1 and MIP-1 beta in dermal inflammatory cells. Moreover, intraperitoneal administration of SKL-2841 suppressed the infiltration of inflammatory mononuclear cells and polymorphonuclear cells in the acute phase and also significantly suppressed fibrillization in the chronic phase in bleomycin-induced scleroderma, compared with PBS treatment. These findings suggest that SKL-2841 has potential as a compound for the treatment of conditions associated with skin fibrosis such as SSc.

Animals↗

PubMed2006

A case report of tumor necrosis factor-alpha antibody-induced thrombocytopenia associated with emerging IgM anticardiolipin antibody in patients with scleroderma overlap/rheumatoid arthritis.

It is commonly believed that infliximab-induced anticardiolipin antibody belongs to the IgM subclass but not the IgG subclass and that the IgM subclass could not produce clinical symptoms. However, we had a patient with scleroderma overlap/rheumatoid arthritis who developed thrombocytopenia associated with the appearance of IgM anticardiolipin antibody after treatment with infliximab. This is a report of a rare case that should make us aware of the possibility of the development of thrombocytopenia with the appearance of IgM anticardiolipin antibody induced by infliximab.

Adult↗

PubMed2006

Combination therapy of prednisolone and mizoribine improves cryoglobulinemic vasculitis with purpura and skin ulcers.

Conventional treatment is not standardized for hepatitis C virus-negative cryoglobulinemia, but corticosteroids, immunosuppressive agents, and plasma exchange typically improved the symptoms. Mizoribine is an immunosuppressive agent that was developed in Japan and has been found to inhibit the proliferation of lymphocytes, especially B cells. We have encountered an elder patient who had hepatitis C virus-negative, type II cryoglobulinemic vasculitis with leg purpura and skin ulcers. Her symptoms improved and cryoglobulin disappeared by the combination therapy of prednisolone and mizoribine. We speculate the action mechanism of this therapy is due to immunosuppressive effects including up-regulation of the efficacy of prednisolone by mizoribine.

Aged↗

PubMed2006

Sphingosine 1-phosphate/sphingosine 1-phosphate receptor 1 signaling in rheumatoid synovium: regulation of synovial proliferation and inflammatory gene expression.

OBJECTIVE: Sphingosine 1-phosphate (S1P) is involved in various pathologic conditions and has been implicated as an important mediator of angiogenesis, inflammation, cancer, and autoimmunity. This study was undertaken to examine the role of S1P/S1P1 signaling in the pathogenesis of rheumatoid arthritis (RA). METHODS: We examined S1P1 messenger RNA (mRNA) and protein levels in RA synoviocytes and MH7A cells by reverse transcriptase-polymerase chain reaction and Western blotting. We also performed S1P1 immunohistochemistry analysis in synovial tissue from 28 RA patients and 18 osteoarthritis (OA) patients. We investigated the effects of S1P on proliferation by WST-1 assay, and its effects on tumor necrosis factor alpha (TNFalpha)- or interleukin-1beta (IL-1beta)-induced cyclooxygenase 2 (COX-2) expression and prostaglandin E2 (PGE2) production in RA synoviocytes and MH7A cells by Western blotting and enzyme-linked immunosorbent assay, respectively. Finally, we examined whether these effects of S1P were sensitive to pertussis toxin (PTX), an inhibitor of the Gi/Go proteins. RESULTS: S1P1 mRNA and protein were detected in RA synoviocytes and MH7A cells. S1P1 was more strongly expressed in synovial lining cells, vascular endothelial cells, and inflammatory mononuclear cells of RA synovium compared with OA synovium. S1P increased the proliferation of RA synoviocytes and MH7A cells. S1P alone significantly enhanced COX-2 expression and PGE2 production. Moreover, S1P enhanced expression of COX-2 and production of PGE2 induced by stimulation with TNFalpha or IL-1beta in RA synoviocytes and MH7A cells. These effects of S1P were inhibited by pretreatment with PTX. CONCLUSION: These findings suggest that S1P signaling via S1P receptors plays an important role in cell proliferation and inflammatory cytokine-induced COX-2 expression and PGE2 production by RA synoviocytes. Thus, regulation of S1P/S1P1 signaling may represent a novel therapeutic target in RA.

Arthritis, Rheumatoid↗

PubMed2005

Retrospective assessment of influenza vaccine effectiveness among the non-institutionalized elderly population in Japan.

To construct a framework for monitoring the effectiveness of influenza vaccine, we retrospectively surveyed elderly (> or = 65 years old) people living in rural areas of Kyoto prefecture, Japan, using a self-administered questionnaire, for their influenza-related symptoms during the peak influenza season of 2003-2004. A total of 2301 elderly individuals responded, of whom 1533 (66.6%) had been vaccinated. The odds ratio (OR) of vaccination for fever of > or = 38 degrees C, adjusted for sex, age and underlying conditions, was 0.77 (95% confidence interval (CI), 0.40-1.47), and the OR for a diagnosis of influenza in clinics was 0.81 (95% CI, 0.41-1.57). These findings suggested that the vaccine was 20% effective, although this effectiveness was not statistically significant.

Adult↗

PubMed2005

Electro-transfer of small interfering RNA ameliorated arthritis in rats.

RNA interference provides the powerful means of sequence-specific gene silencing. Particularly, small interfering RNA (siRNA) duplexes may be potentially useful for therapeutic molecular targeting of human diseases, although novel delivery systems should be devised to achieve efficient and organ-specific transduction of siRNA. In the present study, we demonstrated that electro-transfer of a siRNA-polyamine complex made efficient and specific gene knockdown possible in the articular synovium. Targeted suppression of the tumor necrosis factor-alpha gene through this procedure significantly ameliorated collagen-induced arthritis in rats. Our results suggest the potential feasibility of therapeutic intervention with RNA medicines for treatment of rheumatoid and other locomotor diseases.

Animals↗

PubMed2005

Copper chelation with tetrathiomolybdate suppresses adjuvant-induced arthritis and inflammation-associated cachexia in rats.

Tetrathiomolybdate (TM), a drug developed for Wilson's disease, produces an anti-angiogenic and anti-inflammatory effect by reducing systemic copper levels. TM therapy has proved effective in inhibiting the growth of tumors in animal tumor models and in cancer patients. We have hypothesized that TM may be used for the therapy of rheumatoid arthritis and have examined the efficacy of TM on adjuvant-induced arthritis in the rat, which is a model of acute inflammatory arthritis and inflammatory cachexia. TM delayed the onset of and suppressed the severity of clinical arthritis on both paw volume and the arthritis score. Histological examination demonstrated that TM significantly reduces the synovial hyperplasia and inflammatory cell invasion in joint tissues. Interestingly, TM can inhibit the expression of vascular endothelial growth factor in serum synovial tissues, especially in endothelial cells and macrophages. Moreover, the extent of pannus formation, which leads to bone destruction, is correlated with the content of vascular endothelial growth factor in the serum. There was no mortality in TM-treated rat abnormalities. TM also suppressed inflammatory cachexia. We suggest that copper deficiency induced by TM is a potent approach both to inhibit the progression of rheumatoid arthritis with minimal adverse effects and to improve the well-being of rheumatoid arthritis patients.

Administration, Oral↗

PubMed2005

Malnutrition and disease progression in patients with rheumatoid arthritis.

To examine the changes in nutritional status during the progression of rheumatoid arthritis (RA), we studied anthropometric and biochemical variables in 97 Japanese patients with RA. Anthropometric data included body mass index (BMI), triceps skinfold thickness (TSF), and arm muscle area (AMA). Levels of albumin and cholesterol in serum, and lymphocyte count were studied as biochemical variables. The prevalence of malnutrition defined as hypoalbuminemia less than 3.4 g/dl was 24.7%, similar to the reports in other countries. Analysis of the data according to disease stage showed that malnutrition in RA was characterized by a progressive reduction in body protein. Body mass index and TSF were increased in patients with stage 1 disease, whereas serum albumin and AMA were within normal range. Stage 2 patients had normal BMI with decreased body protein, albumin, and AMA. Progression to stages 3 and 4 was associated with a stepwise decrease in AMA; serum albumin and BMI remained in the same range as stage 2. Albumin values and AMA were significantly lower in patients with poor functional class and high C-reactive protein. The characteristic progression of malnutrition in RA is attributed to excessive protein catabolism evoked by inflammatory cytokines and by disuse atrophy due to functional impairment.

Journal Article↗

PubMed2005

[Autoimmune disease].

Peroxisome proliferator-activated receptors (PPARs) are members for the nuclear hormone receptors superfamily of ligand-activated transcriptional factors. PPARs have diverse function for keeping physiology of the human body, such as fatty acid regulation. In particular, PPAR-alpha and -gamma, have anti-inflammatory function and play an important role in immune system. With these ligands, we can suppress inflammation and regulate abnormal immune reaction in variety of immunocompetent cells and organs. In this review, we show the utility of PPARs ligands in models for autoimmune disease, and also examine that these ligands have the possibility of application for useful treatments of human autoimmune diseases.

Autoimmune Diseases↗

PubMed2005

5-Lipoxygenase inhibitors attenuate growth of human renal cell carcinoma and induce apoptosis through arachidonic acid pathway.

The metabolism of arachidonic acid by either the cyclooxygenase or lipoxygenase (LOX) pathway is believed to play an important role in tumor promotion. We investigated the expression of 5- and 12-LOX in renal cell carcinoma (RCC), as well as the effects of their inhibitors on cell proliferation in 2 RCC cell lines (Caki-1 and A498). Expression of 5- and 12-LOX was detected by immunohistochemistry and RT-PCR. Effects of LOX inhibitors on RCC cell growth were examined by MTT assay, and Hoechst staining was used to determine whether or not the LOX inhibitors induce apoptosis. While 5- and 12-LOX expression levels were slightly detected in NK tissues, marked expressions of 5- and 12-LOX were detected in RCC tissues. 5-LOX inhibitors caused marked reduction of RCC cells in a concentration- and time-dependent manner. The effect of the 5-LOX inhibitor was stronger than the 12-LOX inhibitor. Furthermore, the 5-LOX inhibitor caused a marked reduction of RCC cells through apoptosis. LOX, especially 5-LOX, is induced in RCC, and the results suggest that the 5-LOX inhibitor may mediate potent anti-proliferative effects against RCC cells. Thus, 5-LOX may become a new target in treatment of RCC.

Aged↗

PubMed2004

Identification of two novel female-specific non-major histocompatibility complex loci regulating collagen-induced arthritis severity and chronicity, and evidence of epistasis.

OBJECTIVE: To identify additional sex-specific and epistatic quantitative trait loci (QTL) regulating collagen-induced arthritis (CIA) severity overall, as well as within different stages during the disease course, in an intercross between major histocompatibility complex-identical inbred rat strains DA/Bkl (susceptible) and ACI/Hsd (resistant). METHODS: Arthritic male (DA x ACI)F2 intercross offspring (n = 143) were analyzed separately from the females (n = 184). Phenotypic extremes (maximum arthritis scores [MAS]) were genotyped and used for QTL analysis. All 327 rats were genotyped with the simple sequence-length polymorphism (SSLP) markers closest to the peak of Cia7 and Cia10, the major loci previously identified in this intercross, and with SSLPs covering chromosomes 12 and 18. Phenotypes studied were disease onset, arthritis severity scores on days 14-39, MAS, mean and cumulative arthritis scores, delayed-type hypersensitivity, and antibody responses to rat type II collagen. RESULTS: A new female-specific arthritis-severity recessive locus was identified on rat chromosome 12 (Cia25), with a maximum effect observed on day 28 (logarithm of odds [LOD] 4.7). The homozygous DA genotype at Cia25 was associated with a 45% higher median arthritis score in females. Sequencing analyses of the Cia25 candidate gene Ncf1 revealed polymorphisms between DA and ACI. The previously identified locus, Cia10, was found to be male-specific. A 2-locus interaction model analysis identified a novel recessive chromosome 18 QTL, Cia26, which was dependent on Cia7, with its maximum effect observed at later stages during the disease course (peak LOD score of 3.6 for arthritis scores on day 39). CONCLUSION: This study identified 2 novel female-specific loci, and 1 male-specific locus. Cia25 regulates MAS and disease severity during the mid-to-late stages of the disease course and may be accounted for by Ncf1 polymorphisms. Cia26 is in epistasis with Cia7 and regulates later stages of disease, suggesting an involvement in disease perpetuation and/or chronicity.

Animals↗

PubMed2004

[A case report of Churg-Strauss syndrome combined with various vessel diseases].

A 73-year-old woman with a three-year history of allergic rhinitis and bronchial asthma was found to have Churg-Strauss syndrome combined with fever, eosinophilia, mononeuritis multiplex, and acute coronary syndrome. After the treatment with a methylprednisolone pulse therapy and a high dose of corticosteroids were initiated, eosinophilia normalized together with decline of fever, but acute superior mesenteric artery occlusion occurred, which improved with conservative therapy. Severe stenosis of bilateral carotid arteries was found, so immunosuppressive drugs were added. In general, Churg-Strauss syndrome is a disease with vasculitis affecting small arteries, arterioles, venules, or capillaries, and cases with arteritis in large and medium-sized arteries, such as this case are rare. This suggested that in cases of Churg-Strauss syndrome of the elderly patients, physicians must be careful about involvement of larger vessels.

Aged↗

PubMed2004

Expression of 12-lipoxygenase in human renal cell carcinoma and growth prevention by its inhibitor.

The metabolism of arachidonic acid (AA) by either the cyclooxygenase (COX) or lipoxygenase (LOX) pathway generates eicosanoids, has been implicated in the pathogenesis of a variety of human diseases, including cancer, and may play important roles in tumor promotion, progression, and metastasis. The involvement of 12-LOX expression and function in tumor growth and metastasis has been reported in both murine and human tumor cell lines. The expression of 12-LOX in human renal cell carcinoma (RCC), normal kidney (NK) tissues and 3 kinds of RCC cell lines (Caki-1, A498, RC-1), and its effects on cell proliferation in 3 RCC cell lines were examined. Expression of 12-LOX protein was detected by immunohistochemistry and 12-LOX mRNA in RCC cell lines was detected by nested RT-PCR. Effects of 12-LOX inhibitor on RCC cell growth was examined by MTT assay, and to determine whether or not 12-LOX inhibitors induce apoptosis, we used Hoechst staining. While 12-LOX expression was detected slightly in NK tissues, a marked expression of 12-LOX was detected in RCC tissues. All human RCC cell lines expressed 12-LOX mRNA. The 12-LOX inhibitor baicalein caused marked inhibition of all three kinds of RCC cells in a concentration- and time-dependent manner. Cells treated with 12-LOX inhibitor showed chromatin condensation, cellular shrinkage, small membrane-bound bodies (apoptotic bodies), and cytoplasmic condensation. These results suggest 12-LOX may play a role in the progression of RCC in human tissue, and its inhibitors may become anticancer agents in human RCC.

Apoptosis↗

PubMed2004

Study of cyclooxygenase-2 in renal cell carcinoma.

Cyclooxygenase (COX)-2 plays an important role in the development of various cancers due to its angiogenetic function. As the expression of COX-2 is up-regulated in human colorectal carcinoma and other cancers, we investigated the expression of COX-2 in human renal cell carcinoma (RCC) tissues. One hundred and eight specimens were obtained from patients with RCC, and 20 from normal kidney (NK) tissues. Immunohistochemistry, using affinity purified anti-bodies against human COX-2, and RT-PCR to study the COX-2 mRNA expression were carried out. We also examined whether or not there was a significant difference in the expression of COX-2 among grades (G1, G2, G3) and stages (pT1, pT2, pT3a, pT3b) in RCC. While no marked expression of COX-2 was observed in the NK tissues, a significantly strong expression of COX-2 was detected in RCC tissues. The extent and intensity of immunoreactive COX-2 polypeptides in cancer cells were statistically greater than those of cells from normal kidney tissues. However, no marked difference was seen among grades or between stages. These results demonstrate that the generated COX-2 in human renal cell carcinoma plays an important role in the proliferation of malignant renal cells.

Adult↗

PubMed2004

Relationship between lipoxygenase and human testicular cancer.

The metabolism of arachidonic acid by either the cyclooxygenase (COX) or lipoxygenase (LOX) pathway generates eicosanoids, which have been implicated in the pathogenesis of a variety of human diseases, including cancer. They are now believed to play important roles in tumor promotion, progression, and metastasis, and the involvement of LOX expression and function in tumor growth and metastasis has been reported in human tumor cell lines. Expressions of 5-LOX and 12-LOX in human testicular cancer (TC), and normal testis (NT) tissues were examined, as well as effects of their inhibitors on cell proliferation in TC cell line. Expressions of 5-LOX and 12-LOX were detected by immunohistochemistry. Effects of LOX inhibitors on TC cell growth were examined by MTT assay. While 5-LOX and 12-LOX expressions were slightly detected in NT tissues, expressions of 5-LOX and 12-LOX were significant detected in TC tissues by immunohistochemistry. The LOX inhibitors inhibited the growth of TC cells. LOX is induced in TC, and results may suggest that LOXs are essential for cell growth of TC cells.

Adult↗

PubMed2004

Expression of lipoxygenase in human prostate cancer and growth reduction by its inhibitors.

The metabolism of arachidonic acid by either the cyclooxygenase (COX) or lipoxygenase (LOX) pathway generates eicosanoids, which have been implicated in the pathogenesis of a variety of human diseases, including cancer. They are believed to play important roles in tumor promotion, progression, and metastasis. Involvement of LOXs expression and function in tumor growth and metastasis has been reported in human tumor cell lines. Expressions of 5- and 12-LOX in prostate cancer (PC) patients, prostatic intraepithelial neoplasia (PIN), benign prostatic hyperplasia (BPH), and normal prostate (NP) tissues were examined, as well as effects of their inhibitors on cell proliferation in 2 PC cell lines (PC3, DU-145). Expression of 5- and 12-LOX protein was detected by immunohistochemistry. Effects of LOX inhibitors on prostate cancer cell growth were examined by MTT assay, and Hoechst staining was used to determine whether or not the LOX inhibitors induce apoptosis. While 5- and 12-LOX expressions were slightly detected in BPH and NP tissues, marked expressions of 5- and 12-lipoxygenase were detected in PIN and PC tissues. The LOX inhibitors caused marked reduction of prostate cancer cells in a concentration- and time-dependent manner. The LOX inhibitors caused marked inhibition of PC cells through apoptosis. LOX is induced in prostate cancer, and our results suggest that LOX inhibitors may mediate potent antiproliferative effects against prostate cancer cells. Thus, LOX may become a new target in treatment of prostate cancer.

Aged↗

PubMed2004

Lipoxygenase inhibitors prevent urological cancer cell growth.

Recent studies have demonstrated that lipoxygenase (LOX) inhibitor induces growth arrest of cancer cells through apoptosis. In this study, we examined the effects of LOX inhibitors on cell proliferation in renal cell carcinoma (RCC), bladder tumor (BT), and prostate cancer (PC) cell lines. We investigated the inhibitory effect of LOX inhibitors, 5-, 12- and non-specific LOX inhibitor on RCC, BT and PC-derived cell lines using MTT assay and Hoechst staining. All LOX inhibitors induced the reduction of cell viability with the half-maximal concentration of growth inhibition of RCC, BT, and PC cell lines. Furthermore, counting cells at days 1, 2 and 3, clearly showed marked inhibition of cell proliferation by treatment with non-specific and 5-LOX inhibitor. All LOX inhibitors stopped the growth of all RCC, BT and PC cells. The effect of non-specific LOX inhibitor was strongest. The effect of 5-LOX inhibitor was stronger than 12-LOX inhibitor. All LOX inhibitors caused marked inhibition of urological cancer cells through apoptosis. LOX inhibitor may mediate potent antiproliferative effects against RCC, BT and PC cells through differentiation. Thus, LOX inhibitor, especially 5-LOX inhibitor may become a new target in treatment of urological cancers.

Apoptosis↗

PubMed2004

The effects of cyclooxygenase-2 inhibitors on urological cancer cells.

Cyclooxygenase (COX)-2 plays an important role in the development of various cancers due to its angiogenic function. We have demonstrated that the expression of COX-2 was up-regulated in human renal cell carcinoma (RCC), bladder tumor (BT) and prostate cancer (PC). In this study, we examined the effects of COX-2 inhibitors on cell proliferation in RCC, BT and PC-derived cell lines using MTT assay and Hoechst staining. COX-2 inhibitors did not induce a reduction of cell viability with the half-maximal concentration of growth inhibition of RCC, BT and PC cell lines. Furthermore, counting cells at days 1, 2 and 3, showed no inhibition of cell proliferation using COX-2 inhibitors. COX-2 inhibitors could not stop the growth of RCC, BT and PC cells. Typical characteristics of apoptosis, i.e. chromatin condensation, cellular shrinkage, small membrane-bound bodies (apoptotic bodies) and cytoplasmic condensation, did not occur. Although the expression of COX-2 was up-regulated in human RCC, BT and PC tissues, COX-2 inhibitors have only slight anti-proliferative effects against RCC, BT and PC cells through differentiation. Thus, using only down-regulation of arachidonic acid (AA) metabolizing enzyme, COX may be an unsuccessful approach in providing new anti-cancer therapies.

Apoptosis↗