Geranylgeranylacetone attenuates cisplatin-induced reductions in cell viability by suppressing the elevation of intracellular p53 content without heat shock protein induction.

Geranylgeranylacetone (GGA) was originally used as an anti-ulcer drug to protect gastric mucosa from various stresses, and it is also known to induce heat shock proteins (HSPs), especially HSP70. However, it remains unclear how GGA affects cellular functions in the presence of anti-cancer drugs. We investigated the effects of GGA on cellular viability, caspase-3 activation, HSP induction and p53 content in the presence of cisplatin (CDDP). Rat intestinal epithelium-derived IEC-18 cells and human colon cancer-derived CW-2 cells were incubated with GGA in the presence of CDDP, and we observed that GGA attenuated CDDP-induced viability reductions. GGA also suppressed CDDP-induced caspase-3 activation. However, GGA induced neither HSP70 nor GRP78 expression in the presence of CDDP. We found that GGA suppressed the CDDP-induced elevation of intracellular p53 content. In conclusion, GGA attenuates viability reductions and caspase-3 activation in CDDP-treated cells by suppressing the elevation of intracellular p53 content without HSP induction.

Clinicopathological study of colorectal cancer occurring in patients with ulcerative colitis: results from a single hospital in Japan.

BACKGROUND/AIMS: Colorectal cancer (CRC) was first recognized as a complication of ulcerative colitis (UC) in 1925, and the increased risk has since been confirmed in a multitude of epidemiological studies. To our knowledge, however, all of these studies have been conducted in Western countries. The aim of this study was to identify the clinicopathological features of ulcerative colitis-related CRC in a consecutive series of patients at a single hospital in central Japan. METHODOLOGY: 314 (170 males, 144 females, mean age 30) consecutive patients diagnosed with ulcerative colitis were enrolled and investigated for the development of CRC. 240 patients had relapsing-remitting disease, 54 had chronic continuous disease, 16 had experienced one attack only, 2 had the acute fulminating type, and 2 were unknown. With regard to disease extension, 181 cases were of the pan-colitis type, 84 were left-sided colitis, and 42 were proctitis. Two patients (1%) had a family history of colorectal cancer and 45 (14%) were past or current smokers. RESULTS: Colorectal cancer developed in seven patients (male to female ratio of 1:6), which was 2.2% of the total. Average age at the onset of ulcerative colitis was 28 years. Average age at the onset of cancer was 44 years, and average duration of UC at cancer onset was 192 months. Ulcerative colitis was of the pancolitis type in all cases. Three patients (43%) showed the relapse-remitting type and four (57%) the chronic continuing type. Three patients (43%) had a family history of cancer, in particular colorectal cancer in one patient (14%). None of the patients had a history of smoking. The histological type of cancer was well differentiated tubular adenocarcinoma in three patients (43%) and poorly differentiated adenocarcinoma in three patients (43%) each, and endocrine cell carcinoma in one (14%). CONCLUSIONS: In this group of Japanese patients, development of colorectal cancer was more likely to occur in patients with ulcerative colitis that was long-standing, and more extensive than left-sided colitis, particularly in those with a family history of colorectal cancer, inflammatory polyps, or dysplasia. CRCs in our patients with UC were often poorly differentiated and had a poor prognosis.

Potential role for matrix metalloproteinase-3 in gastric ulcer healing.

BACKGROUND/AIMS: Matrix metalloproteinases (MMPs) are endopeptidases which perform important functions in extracellular matrix remodeling, cell proliferation, and inflammatory processes. Here, we compared MMP-3 levels with those of tissue inhibitor of metalloproteinases (TIMP)-1 and several inflammatory cytokines in gastric ulcer (GU) patients. METHODS: This study enrolled 50 patients with GU and 6 with functional dyspepsia (FD). Samples of gastric mucosa from the antrum and the ulcer site were harvested from GU patients and of antral mucosa alone from FD patients during upper gastrointestinal endoscopy. Mucosal biopsy tissues were cultured for 24 h, and the culture supernatant was measured for levels of MMP-3, TIMP-1, IL-1beta, IL-6, and IL-8. RESULTS: All GU patients were positive for Helicobacter pylori, while all FD patients were negative. Antral levels of TIMP-1, IL-1beta, IL-6, and IL-8 were significantly higher in GU than FD patients. Further, MMP-3 levels were significantly higher in GU patients at the ulcer site than in the antrum, and had a significantly positive correlation with TIMP-1, IL-1beta, IL-6, and IL-8. CONCLUSION: MMP-3 levels were significantly higher at the ulcer site than in the antrum, suggesting that MMP-3 may perform an important function in gastric ulcer healing.

Relationship between nutritional therapy and surgery in Crohn's disease.

BACKGROUND/AIMS: Crohn's disease is often refractory and some patients require repeated surgical treatment. Nutritional therapy with an elemental diet has been reported effective in improving nutritional state and suppressing inflammation, and might be expected to assist in minimizing the need for surgery. We evaluated the relationship between an elemental diet and the period that patients spent without intestinal resection. METHODOLOGY: A total of 153 patients with Crohn's disease who visited our hospital from July, 1999 to July, 2005 were enrolled. The relationship between the caloric content of an elemental diet and surgery as an endpoint was examined using Cox regression analysis. Cumulative non-operation rates were calculated by the Kaplan-Meier method. Statistical significance was determined using the log-rank test. RESULTS: Among patients with jejunoileal involvement, patients receiving an elemental diet providing 900 kcal or more per day showed a statistically significant improvement in cumulative non-operation rate. Among those without jejunoileal involvement, in contrast, the cumulative non-operation rate did not differ among those receiving an elemental diet of less or more than 900 kcal per day. CONCLUSIONS: The use of an elemental diet of 900 kcal per day may be effective in avoiding surgery in patients with jejunoileal lesions. This diet may be useful in improving long-term convalescence in these patients.

Confocal endomicroscopy in patients with ulcerative colitis.

BACKGROUND: Confocal endomicroscopy is a new technology that provides microscopic images of cellular morphology in the gastrointestinal tract in vivo. In particular, confocal microendoscopy allows histological diagnosis during the endoscopic examination. We examined patients with ulcerative colitis (UC) using confocal endoscopy and investigated the features of confocal endomicroscopic images of inflamed and non-inflamed rectal mucosa. METHODS: Seventeen patients with UC, 12 in the active phase and 5 in the non-active phase, and 14 non-UC control patients who had colon polyps or colon cancer underwent colonoscopy, during which fluorescence images of the rectal mucosa were obtained with confocal endomicroscopy. Histological findings of rectal biopsy specimens were compared with the microendoscopic images. RESULTS: Confocal microendoscopy allowed observation of cellular and subcellular structures. The crypts of normal colonic mucosa were small, round and regularly arranged, and the crypt lumens of the colonic glands were small and round. The crypts of colonic mucosa in non-active UC were small, round and slightly irregular in arrangement and the crypt lumens of the colonic glands were small and round. Inflammatory cells and capillaries were visible in the lamina propria. The crypts of colonic mucosa in active UC were large, variously shaped and irregular in arrangement. The crypt lumens of the colonic glands were large and the crypt structure could not be recognized in some areas. Numerous inflammatory cells and capillaries were visible in the lamina propria. CONCLUSIONS: Images taken with the confocal microendoscope provided information that was equivalent to conventional histology, and improve our understanding of the differences in rectal tissues (crypts, capillaries and inflammatory cells) between normal controls and active and non-active UC patients during ongoing endoscopy.

Relationships between Helicobacter pylori infection status, endoscopic, histopathological findings, and cytokine production in the duodenum of Crohn's disease patients.

BACKGROUND: The chronic inflammatory process in patients with Crohn's disease (CD) may affect any part of the gastrointestinal (GI) tract. The pathogenesis of CD involves immunological abnormalities, including deficient or excessive expression of cytokines. We examined Helicobacter pylori infection status, endoscopic and histopathological findings, and cytokine production in the duodenum of CD patients in comparison with controls. METHODS: Thirty-eight CD patients underwent diagnostic upper GI endoscopy. Twelve age- and sex-matched health checkup examinees were used as controls. H. pylori infection status was assessed by the (13)C-urea breath test. At the time of endoscopy, two biopsy specimens each were obtained from the second portion of the duodenum, one for hematoxylin-eosin staining and immunohistochemical analysis with anti-CD68 antibody, and one for in vitro organ culture. Interleukin (IL)-6 and -8 levels were measured in organ culture supernatant by enzyme-linked immunosorbent assay. RESULTS: H. pylori infection was significantly (P<0.05) more frequent in controls (42%) than in CD patients (8%). In the duodenum, erosions or ulcers were more frequent in CD patients (53%) than in controls (8%). Mononuclear cell infiltration in the duodenum was more severe in CD patients than in controls and IL-6 production was higher, whereas IL-8 production showed no significant difference. CD68+ cells in the duodenum were more prominent in CD patients than in controls. CONCLUSIONS: H. pylori infection is unlikely in CD patients, but they show immunological abnormalities in the duodenum, possibly from innate immune responses.

Immunological status of the stomach in inflammatory bowel disease--comparison between ulcerative colitis and Crohn's disease.

BACKGROUND/AIMS: Ulcerative colitis (UC) mainly affects the colon and rectum, whereas the chronic inflammatory process in Crohn's disease (CD) can affect any part of the gastrointestinal tract. Recently, however, upper gastrointestinal lesions have been reported in UC patients. In this study, we investigated the immunological status of the stomach in UC or CD patients. METHODS: 26 patients each with UC, CD or functional dyspepsia (FD) underwent diagnostic upper gastrointestinal endoscopy, and biopsy specimens were obtained from the gastric antrum. The contents of interleukin (IL)-6 and IL-8 in the organ culture supernatants of antral mucosal tissues were measured with enzyme-linked immunosorbent assay. RESULTS: Endoscopically abnormal findings in the stomach were more frequent in CD than in UC or FD patients. Mononuclear cell infiltration and IL-6 production in the gastric antrum did not significantly differ between UC and FD patients, but were higher in those with CD. There was no significant difference in neutrophil infiltration or IL-8 production between UC, CD, and FD patients. CONCLUSIONS: UC patients did not show the immunological abnormalities in the stomach seen in CD patients.

A case of cytomegalovirus enterocolitis diagnosed by the double-balloon enteroscopy.

A 73-year-old woman presented with massive bloody stools while undergoing hospitalization for multiple myeloma. Colonoscopy and transrectal double-balloon enteroscopy revealed multiple punched-out ulcers throughout the entire colon and in the distal ileum. Cytomegalovirus was detected in the biopsy specimens of both the colonic and ileal mucosa and in the peripheral blood, which lead the diagnosis of CMV enterocolitis. The patient's gastrointestinal bleeding was temporarily improved by the administration of ganciclovir, though she died thereafter due to progression of the primary disease. We herein report the effectiveness of transrectal double-balloon enteroscopy for the diagnosis of cytomegalo-virus enterocolitis.

Magnifying chromoscopy, a novel and useful technique for colonoscopy in ulcerative colitis.

Ulcerative colitis (UC) is a chronic inflammatory bowel disorder characterized by exacerbations and remissions. The degree of inflammation as assessed by conventional colonoscopy is a reliable parameter of disease activity. However, even when conventional colonoscopy suggests remission and normal mucosal findings, microscopic abnormalities may persist, and relapse may occur later. Patients with long-standing, extensive ulcerative colitis have an increased risk of developing colorectal cancer. Ulcerative colitis-associated colorectal cancer is characterized by an early age at onset, poorly differentiated tumor cells, mucinous carcinoma, and multiple lesions. Early detection of dysplasia and colitic cancer is thus a prerequisite for survival. A relatively new method, magnifying chromoscopy, is thought to be useful for the early detection and diagnosis of dysplasia and colitic cancer, as well as the prediction of relapse.

Helicobacter pylori infection upregulates interleukin-18 production from gastric epithelial cells.

BACKGROUND: Helicobacter pylori infection induces a biased T helper type 1 (Th1) response that produces IFN-gamma and Fas ligand (FasL). Th1 cytokines are associated with apoptosis in the gastric epithelial cells. AIM: We aimed to define the role of the recently cloned IL-18, a IFN-gamma inducing factor, in gastric mucosal injury induced by H. pylori infection. METHODS: Twenty-seven gastric ulcer (GU) patients and 20 functional dyspepsia (FD) patients were enrolled in this study. Mucosal biopsy samples were obtained from the gastric antrum and GU site during endoscopy. Samples were used for histological examination, H. pylori culture and in-situ stimulation for 48 h in the presence of 10 microg/ml phytohemagglutinin-P. IL-18, IFN-gamma, and soluble FasL (sFasL) levels in culture supernatants were assayed by the enzyme-linked immunosorbent assay method. IL-18, IL-1beta-converting enzyme (ICE) and caspase-3 were evaluated by western blotting in gastric cancer cell lines (MKN45) cocultured with H. pylori. RESULTS: All 27 GU patients and ten out of 20 FD patients were found to be H. pylori-positive, whereas ten FD patients were H. pylori-negative. Antral mucosal tissues from H. pylori-positive FD patients contained (P<0.01) higher levels of IL-18, IFN-gamma, and sFasL than those from uninfected FD patients. IL-18, IFN-gamma, and sFasL levels at the ulcer site were significantly (P<0.01) higher than those at distant sites in the antrum. A significant relationship was seen between IL-18 and IFN-gamma levels at the ulcer site (r=0.7, P<0.01). H. pylori eradication led to a significant decrease in the levels of IL-18, IFN-gamma, and sFasL at the ulcer site. Western blotting showed that IL-18, ICE, and caspase-3 were activated in gastric cancer cell lines cocultured with H. pylori. CONCLUSION: This study suggests that H. pylori infection enhanced mucosal injury by stimulating a Th1 response, which was mediated by IL-18 upregulation as well as activation of ICE and caspase-3.

Paeonol attenuates TNBS-induced colitis by inhibiting NF-kappaB and STAT1 transactivation.

Paeonol, a major phenolic component of Moutan Cortex, is known to have anti-inflammatory activity. However, the effect of Paeonol on colitis has not been evaluated and the molecular mechanism of its anti-inflammatory action remains unknown. The aim of this study was to determine if Paeonol enema attenuates trinitrobenzene sulfonic acid (TNBS)-induced colitis in mice. We also investigated the effects of Paeonol in colon cancer-derived CW-2 cells and T cell leukemia-derived Jurkat cells treated with tumor necrosis factor alpha (TNFalpha) and/or interferon gamma (IFNgamma), which play critical roles in TNBS-induced colitis. Paeonol enema attenuated TNBS-induced colitis judging by body weigh reduction, colon length and histological score. Myeloperoxidase activity and inducible nitric oxide synthase (iNOS) production in the colon were also reduced with Paeonol enema. In CW-2 cells, Paeonol inhibited iNOS protein and mRNA expression induced by costimulation of TNFalpha and IFNgamma. Furthermore, Paeonol reduced TNFalpha-induced NF-kappaB transactivation and IFNgamma-induced STAT1 transactivation in CW-2 cells and also in Jurkat cells. These findings suggest that Paeonol enema may be useful for the treatment of colitis.