Biomedical subjects
Publications and source records attributed to N Matsuhashi.
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Gastric cancer cell lines express peroxisome proliferator-activated receptor gamma (PPARgamma), and treatment with PPARgamma ligands suppresses growth of subgroup of these cell lines. However, expression and subcellular distribution of PPARgamma in human gastric cancer tissues is still unknown. Therefore, expression and subcellular localization of PPARgamma were examined among different histological types of gastric cancer tissues. Immunohistochemical staining for PPARgamma was performed using biopsy specimens of human gastric cancer of various histological types, gastric adenomas, and intestinal metaplasia. All samples of intestinal metaplasia and most samples of gastric tumors, except for signet ring cell carcinoma, expressed PPARgamma in the epithelial cells. Most samples of signet ring cell cancer lacked PPARgamma expression. All samples of intestinal metaplasia expressed PPARgamma only in the cytosol. For adenoma, 90% was positive for PPARgamma in cytosol, and 40% was positive in nuclei, for well-differentiated adenocarcinoma, 80% was positive in cytosol, and 20% was positive in nuclei. For moderately differentiated adenocarcinomas, 70% was positive for cytosol, and 80% was positive for nuclei; for poorly differentiated adenocarcinoma, 30% was positive in cytosol, and 70% was positive in nuclei. The frequency of samples with positive cytosolic staining decreased as the differentiation stage turned from intestinal metaplasia to adenoma, well-, moderately-, and poorly-differentiated cancers. Simultaneously, there was a tendency toward an increased frequency of samples with positive nuclear PPARgamma staining as the differentiation stage transformed from intestinal metaplasia to poorly-differentiated cancer. There was a striking difference in subcellular localization according to the differentiation levels of gastric dysplastic cells. The findings also supported an intestinal metaplasia-adenoma-well-differentiated gastric cancer sequence, and signet ring cell cancer was suggested to be of a different lineage from other types of gastric cancers.
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A 52-year-old male was diagnosed with Crohn's disease at the age of 25 years. Thereafter, he underwent three operations for intestinal strictures or fistula. A self-expanding metallic stent was inserted into the sigmoid colon stricture endoscopically in November 1999. Thirty two months later, he presented left lower abdominal pain. Endoscopic and radiographic examinations demonstrated perforation of the stent and ileosigmoid fistula. Laparotomy revealed an inflammatory mass around the sigmoid colon, and the wire frame of the metallic stent had penetrated the colonic wall and had fistulized to the ileum. The affected sigmoid colon was resected and low anterior resection and ileostomy were performed. Metallic stent for intestinal stricture of Crohn's disease with active ulceration may postpone surgery temporarily but can be a potentially dangerous procedure.
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BACKGROUND & AIMS: Peroxisome proliferator-activated receptor gamma (PPAR gamma) is a nuclear receptor whose activation has been linked to several physiologic pathways including those related to the regulation of intestinal inflammation. We sought to determine whether PPAR gamma could function as an endogenous anti-inflammatory pathway in a murine model of intestinal ischemia-reperfusion (I/R) injury. METHODS: PPAR gamma-deficient and wild-type mice were examined for their response to I/R procedure. Treatment with a PPAR gamma-specific ligand was also performed. RESULTS: In a murine model of intestinal I/R injury, we observed more severe injury in PPAR gamma-deficient mice and protection against local and remote tissue injury in mice treated with a PPAR gamma-activating ligand, BRL-49653. Activation of PPAR gamma resulted in down-regulation of intercellular adhesion molecule 1 expression by intestinal endothelium and tissue tumor necrosis factor alpha messenger RNA levels most likely by inhibition of the NF-kappa B pathway. CONCLUSIONS: These data strongly suggest that an endogenous PPAR gamma pathway exists in tissues that may be amenable to therapeutic manipulation in I/R-related injuries.
We report a case of pseudomembranous colitis that developed in a patient with liver cirrhosis during anti-tuberculosis therapy with rifampicin and isoniazid. The association between rifampicin and pseudomembranous colitis has been controversial; this report, however, supports the association. Colonoscopy performed 3 days after the onset of the pseudomembranous colitis revealed only reddish patches and a few aphthoid lesions, but 4 days later pseudomembranes were apparent. The pseudomembranous colitis was successfully controlled by discontinuation of the anti-tuberculosis agents, along with the administration of lactic acid bacteria, without vancomycin or metronidazole. Possible predisposing factors for the development of pseudomembranous colitis in this patient are also discussed.
The precise etiology of hyperplastic polyps of the stomach is unknown, but recent studies suggest that they arise as a consequence of inflammation occurring in intimate association with Helicobacter pylori infection. The process of polyp regression after anti-H. pylori therapy, however, is unclear. Here we report a patient with large hyperplastic polyps of the stomach that regressed markedly after anti-H. pylori therapy. Histological examination of the regressed polyps revealed a decrease in the height of the hyperplastic foveolar epithelium and a decrease in the amount of inflammatory cell infiltration in the stroma. In addition, the percentage of Ki-67-positive hyperplastic epithelial cells markedly decreased after anti-H. pylori therapy, indicating that the epithelial cell proliferation rate had markedly decreased after treatment. At the same time, the degree of cyclooxygenase-2 expression in epithelial cells in the polyps decreased after treatment. Because cyclooxygenase-2 is expressed at sites of inflammation or neoplasm, these findings are consistent with a decrease in inflammatory cell infiltration, and represent resolving inflammation.
We report a case of protein-losing enteropathy associated with an autoimmune disorder, presumably systemic lupus erythematosus. Although typical manifestations of systemic lupus erythematosus were lacking, a high serum cholesterol level, a low serum complement level, positivity for anti-nuclear antibody, and positivity for anti-single-strand DNA antibody suggested an autoimmune mechanism as the cause of the condition. Although immunohistological examination of duodenal and ileal biopsy specimens failed to reveal deposits of immune complex or complement in the vessels, capillary hyperpermeability was suspected as the mechanism of the condition.
We report a case of refractory ulcerative colitis treated with tacrolimus. The patient was a 73-year-old woman with a 45-year history of ulcerative colitis. An attack unresponsive to intravenous corticosteroid therapy occurred when she was age 73. Leukocytapheresis therapy was attempted, but was discontinued because of the patient's poor general condition. Cyclosporine A therapy brought about fair control of the disease. A liver injury that was suspected to be associated with this agent, however, occurred within 5 weeks of its initiation. At that time, the cyclosporine A was discontinued and azathioprine treatment was started. Within 6 weeks, signs of exacerbation of the ulcerative colitis became apparent. Tacrolimus administered at that time brought about remission of the disease, and the corticosteroid dose was then reduced. Tacrolimus, like cyclosporine A, appears to be effective for the treatment of attacks of ulcerative colitis.
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In order to investigate structure-activity relationships between antimycobacterial activities and basic substituents at the C-10 position of levofloxacin (LVFX), we synthesized a series of pyridobenzoxazine derivatives by replacement of the N-methylpiperazinyl group of LVFX with various basic substituents. A compound with a 3-aminopyrrolidinyl group had one-half the activity of LVFX against Mycobacterium avium, M. intracellulare, and M. tuberculosis. Mono- and dimethylation of the 3-amino moiety of the pyrrolidinyl group increased the activities against M. avium and M. intracellulare but not those against M. tuberculosis. On the other hand, dialkylation at the C-4 position of the 3-aminopyrrolidinyl group enhanced the activities against M. avium, M. intracellulare, and M. tuberculosis. Thus, introduction of an N-alkyl or a C-alkyl group(s) into the 3-aminopyrrolidinyl group may contribute to an increase in potency against M. avium, M. intracellulare, and/or M. tuberculosis, probably through elevation of the lipophilicity. However, among the compounds synthesized, compound VII, which was a 2,8-diazabicyclo[4.3.0]nonanyl derivative with relatively low lipophilicity, showed the most potent activity against mycobacterial species: the activity was 4- to 32-fold more potent than that of LVFX and two to four times as potent as that of gatifloxacin. These results suggested that an increase in the lipophilicity of LVFX analogues in part contributed to enhancement of antimycobacterial activities but that lipophilicity of the compound was not a critical factor affecting the potency.
Apoptosis of cells must be regulated both positively and negatively in response to a variety of stimuli in the body. Various environmental stresses are known to initiate apoptosis via differential signal transduction cascades. However, induction of signals that may inhibit apoptosis is poorly understood, although a number of intracellular molecules that mediate inhibition of apoptosis have been identified. Here we present a novel murine macrophage-specific 54-kD secreted protein which inhibits apoptosis (termed AIM, for apoptosis inhibitor expressed by macrophages). AIM belongs to the macrophage scavenger receptor cysteine-rich domain superfamily (SRCR-SF), members of which share a highly homologous conserved cysteine-rich domain. In AIM-deficient mice, the thymocyte numbers were diminished to half those in wild-type mice, and CD4/CD8 double-positive (DP) thymocytes were strikingly more susceptible to apoptosis induced by both dexamethasone and irradiation in vivo. Recombinant AIM protein significantly inhibited cell death of DP thymocytes in response to a variety of stimuli in vitro. These results indicate that in the thymus, AIM functions in trans to induce resistance to apoptosis within DP cells, and thus supports the viability of DP thymocytes before thymic selection.
Like adenomatous polyps in familial adenomatous polyposis, some sporadic colorectal polyps have been reported to regress in response to sulindac administration. However, a rapidly growing invasive rectal cancer developed in one of 15 patients with sulindac-treated sporadic adenomatous colorectal polyps 16 months after sulindac treatment. In this patient, both the adenomatous polyp that responded partially to sulindac and the rectal cancer developing after sulindac therapy showed immunostaining for cyclooxygenase-2. Although short term sulindac therapy seems to be able to cause some adenomatous colorectal polyps to regress, 4 months of sulindac therapy may not reliably prevent colorectal cancer development in these patients.
To evaluate the role of the histamine H2 receptor C terminus in signaling, desensitization, and agonist-induced internalization, canine H2 receptors with truncated C termini were generated. Wild-type (WT) and truncated receptors were tagged at their N termini with a hemagglutinin (HA) epitope and expressed in COS7 cells. Most of the C-terminal intracellular tail could be truncated (51 of 70 residues, termed T308 mutant) without loss of functions: cAMP production, tiotidine binding, and plasma membrane targeting. In fact, the T308 mutant produced more cAMP than the WT when cell-surface expression per cell was equivalent. Pretreatment of cells with 10(-5) M histamine desensitized cAMP productions via WT and T308 receptors to similar extents. Incubation of cells expressing WT receptors with 10(-5) M histamine reduced cell-surface anti-HA antibody binding by approximately 30% (by 30 min, t1/2 approximately 15 min), but did not affect the Bmax of tiotidine in membrane fractions, which represents total receptor amounts, suggesting that WT receptors were internalized from the cell surface. In contrast, no internalization was observed with T308 receptors following histamine treatment. A mutant with a deletion of the 30 C-terminal amino acids, termed T329, was functional but was as potent as the WT in terms of cAMP production. Apart from being desensitized by histamine, the internalization of the receptor was indistinguishable from that of the WT. Internalization was observed in the T320 but not in T313 mutant, narrowing the region involved in internalization to that between Glu314 and Asn320 (ETSLRSN). Of these seven residues, either Thr315, Ser316, or both, were replaced with Ala. Thr315 and Ser316 are conserved among species. The mutation at Thr315 (but not that at Ser316) abolished internalization. Taken together, these results demonstrate that Thr315 is involved in agonist-induced internalization. Furthermore, the finding that T308 receptors were desensitized in the absence of internalization suggests that internalization and desensitization are meditated by independent mechanisms.
A histamine H2 receptor, which had been mutated at its glycosylation site and tagged at its N-terminus with an HA tag (HA-H2 receptor), was expressed in Sf9 cells and COS7 cells. Immunoprecipitation and immunoblotting of HA-H2 receptors with alphaHA antibody revealed four bands of 31.5 +/- 2.5 kDa, 59.0 +/- 6.0 kDa, 80.5 +/- 4.5 kDa and 120 kDa. These bands were also detected by immunoblot using anti-H2 receptor serum (C-terminus). In addition, H2 receptors without the HA-tag coimmunoprecipitated with HA-tagged H2 receptors devoid of the 51 C-terminal amino acids, via immunoprecipitation with alphaHA antibody, when the two receptors were coexpressed. These results suggest that H2 receptors are present as receptor oligomers and that the C-terminal portion is not involved in the formation of these oligomers.
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BACKGROUND: Although sulindac is known to cause regression of colorectal adenomatous polyps in familial adenomatous polyposis, less is known about the effect of sulindac on sporadic adenomas. The precise mechanisms of these effects also remain to be determined. AIMS: Sulindac was given to patients with sporadic colorectal adenomatous polyps to evaluate its effects on them, and histological analysis was performed to elucidate the mechanism of the polyp regression, as well the kind of adenomatous polys that are susceptible to the agent. SUBJECTS: 20 adenomatous polyps in 15 patients were studied. METHODS: Sulindac (300 mg daily) was given for four months, followed by colonoscopy with removal of the residual polyps. Polyp size, degree of atypia, inflammatory cell infiltration in the polyps, and immunostaining for mutant p53 product were evaluated before and after treatment. RESULTS: 13 of the 20 polyps shrank or disappeared. Patient sex, polyp location, size, degree of atypia, or p53 mutation did not affect the response, but polyps in older patients were more sensitive to sulindac. The degree of atypia or inflammatory cell infiltration was not affected by the treatment. A polyp containing a focal cancer was unresponsive. CONCLUSIONS: Sulindac can cause regression of sporadic colorectal adenomatous polyps.