High total Joule heat increases the risk of post-endoscopic submucosal dissection electrocoagulation syndrome after colorectal endoscopic submucosal dissection.

BACKGROUND: We hypothesized that thermal damage accumulation during endoscopic submucosal dissection (ESD) causes the pathogenesis of post-ESD electrocoagulation syndrome (PECS). AIM: To determine the association between Joule heat and the onset of PECS. METHODS: We performed a retrospective cohort study in patients who underwent colorectal ESD from May 2013 to March 2021 in Japan. We developed a novel device that measures swift coagulation time with a sensor adjacent to the electrosurgical coagulation unit foot switch, which enabled us to calculate total Joule heat. PECS was defined as localized abdominal pain (visual analogue scale ≥ 30 mm during hospitalization or increased by ≥ 20 mm from the baseline) and fever (temperature ≥ 37.5 degrees or white blood cell count ≥ 10000 µ/L). Patients exposed to more or less than the median Joule heat value were assigned to the high and low Joule heat groups, respectively. Statistical analyses included Mann-Whitney U and chi-square tests and logistic regression and receiver operating characteristic curve (ROC) analyses. RESULTS: We evaluated 151 patients. The PECS incidence was 10.6% (16/151 cases), and all patients were followed conservatively and discharged without severe complications. In multivariate analysis, high Joule heat was an independent PECS risk factor. The area under the ROC curve showing the correlation between PECS and total Joule heat was high [0.788 (95% confidence interval: 0.666-0.909)]. CONCLUSION: Joule heat accumulation in the gastrointestinal wall is involved in the onset of PECS. ESD-related thermal damage to the peeled mucosal surface is probably a major component of the mechanism underlying PECS.

Early colonoscopy and urgent contrast enhanced computed tomography for colonic diverticular bleeding reduces risk of rebleeding.

BACKGROUND: Colonoscopy within 24 h of hospital admission for colonic diverticular bleeding (CDB) is recommended. However, little is known about rates of rebleeding within 30 d. We posited that a group of patients who underwent contrast-enhanced computed tomography (CT) within 4 h of the last hematochezia and colonoscopy within 24 h would experience fewer incidences of rebleeding. AIM: To evaluate the outcomes of early colonoscopy for CDB among different groups of patients. METHODS: Data from 182 patients with CDB who underwent contrast-enhanced CT and colonoscopy between January 2011 and December 2018 at the study site were retrospectively reviewed. Patients were divided into groups based on the timing of the CT imaging, within or at 4 h were defined as urgent CTs (n = 100) and those performed after 4 h were defined as elective CTs (n = 82). Main outcomes included rebleeding within 30 d and the identification of stigmata of recent hemorrhage (SRH) (i.e., active bleeding, non-bleeding visible vessels, or adherent clots). RESULTS: In total, 182 patients (126 men and 56 women) with median ages of 68.6 (range, 37-92) and 73.7 (range, 48-93) years, respectively, underwent CT imaging and colonoscopy within 24 h of the last hematochezia. Patients for whom CT was performed within 4 h of the last hematochezia were included in the urgent CT group (n = 100) and patients for whom CT was performed after 4 h were included in the elective CT group (n = 82). SRH were identified in 35.0% (35/100) of the urgent CT cases and 7.3% (6/82) of the elective CT cases (P < 0.01). Among all patients with extravasation-positive images on CT, SRH was identified in 31 out of 47 patients (66.0%) in the urgent CT group and 4 out of 20 patients (20.0%) in the elective CT group (P < 0.01). Furthermore, rates of rebleeding within 30 d were significantly improved in the urgent CT and extravasation-positive cases (P < 0.05). Results from the evaluation of early colonoscopy did not show a difference in the ability to detect SRH identification or rebleeding rates. Only cases by urgent CT reduced risk of rebleeding due to the evidence of active bleeding on the image. CONCLUSION: To improve rates of rebleeding, colonoscopy is recommended within 24 h in patients with extravasation-positive CT images within 4 h of the last hema-tochezia. Otherwise, elective colonoscopy can be performed.

Efficacy and safety of short-term therapy with indigo naturalis for ulcerative colitis: An investigator-initiated multicenter double-blind clinical trial.

INTRODUCTION: Indigo naturalis (IN) is a blue pigment extracted from Assam indigo and other plants and has been confirmed to be highly effective for ulcerative colitis (UC) treatment in several clinical studies. OBJECTIVE: We conducted a multicenter double-blind study to confirm the efficacy and safety of short-term IN administration. METHODS: A multicenter, randomized controlled trial was conducted between December 2015 and October 2018 in our facilities. Forty-six patients with mild to moderate active UC (Lichtiger index: 5-10) were randomly assigned to the IN group or the placebo group and received 5 capsules (500 mg) twice a day for 2 weeks. We investigated the efficacy according to blood tests and the Lichtiger index before and after administration, and we also examined adverse events. RESULTS: The analysis included 42 patients (20 males, 22 females) with an average age of 45 years. Nineteen patients were assigned to the placebo group, and 23 were assigned to the IN group. After treatment administration, in the placebo group, no change in the Lichtiger index was observed (7.47 to 6.95, p = 0.359), and hemoglobin was significantly reduced (12.7 to 12.4, p = 0.031), while in the IN group, the Lichtiger index (9.04 to 4.48, p = 0.001) and albumin (4.0 to 4.12, p = 0.022) improved significantly. Mild headaches were observed in 5 patients and 1 patient in the IN and placebo groups, respectively. CONCLUSIONS: Short-term administration of IN is highly effective without serious adverse events such as pulmonary hypertension or intussusception and may prevent the occurrence of serious adverse events.

PCR analysis and specific immunohistochemistry revealing a high prevalence of non-Helicobacter pylori Helicobacters in Helicobacter pylori-negative gastric disease patients in Japan: High susceptibility to an Hp eradication regimen.

BACKGROUND: The clinical significance of non-Helicobacter pylori Helicobacter (NHPH) is still unknown. There are many reports of NHPH-infected patients suffering from gastric diseases. Here, we investigated the polymerase chain reaction (PCR) positivity of NHPH infection in gastric disease patients who were negative for H. pylori (Hp) by the rapid urease test and by pathological observation. MATERIALS AND METHODS: We collected the 296 endoscopically obtained gastric mucosal samples of Hp-negative gastric disease patients diagnosed based on a rapid urease test and pathology from 17 hospitals in Japan from September 2013 to June 2019, and we analyzed the existence of Hp and NHPH by PCR. The samples were also treated by indirect immunohistochemistry using an anti-Helicobacter suis VacA paralog antibody and were observed by confocal laser microscopy. RESULTS: Among the 236 non-Hp-eradicated cases, 49 cases (20.8%) were positive for NHPH. Among them, 20 cases were positive for Helicobacter suis, 7 cases were positive for Helicobacter heilmannii sensu stricto/ Helicobacter ailurogastricus (Hhss/Ha), and the other 22 cases could not be identified. The regional differences in the infection rates were significant. Forty percent of the nodular gastritis cases, 24% of the MALT lymphoma, 17% of the chronic gastritis cases, and 33% of the gastroduodenal ulcer cases were NHPH positive. Forty-five patients had been treated with one of the four types of combinations of a proton pump inhibitor and two antibiotics, and in all of these cases, the NHPH diagnosed by PCR was successfully eradicated. Immunohistochemistry using the Helicobacter suis-specific HsvA antibody coincided well with the PCR results. Among the 29 post-Hp eradication cases, three were NHPH positive, including one Hhss/Ha-positive case. Thus, approx. 20% of the Hp-negative non-Hp-eradicated gastric disease patients treated at 17 hospitals in Japan were infected with NHPH.

Influence of Living Environment during Childhood on Helicobacter pylori Infection in Japanese Young Adults.

INTRODUCTION: Helicobacter pylori infection is usually established during childhood, for which certain responsible environmental factors have been identified. However, the details of the infection routes remain unclear. OBJECTIVE: To determine the relation between H. pylori infection statuses and living environment of Japanese young adult. METHODS: The subjects were 449 healthy young adult medical students of Tsukuba University (299 men and 150 women, mean age: 22.8 years). The H. pylori infection statuses were investigated using the rapid urease test or urine antibody. Questionnaires regarding sanitary conditions including usage of pit toilet or well water and experience of living with one's grandparents during childhood were surveyed. Each item was compared between the H. pylori-positive and -negative groups. RESULTS: Among all participants, 33 (7.3%) were H. pylori-positive. The usage rates of pit toilets were 12.1 and 3.1% for the H. pylori-positive and -negative groups respectively (p = 0.03; OR 4.35, 95% CI 1.33-14.22). The usage rates of well water were 24.2 and 13.7% for the H. pylori-positive and -negative groups respectively (p = 0.07; OR 2.12, 95% CI 0.91-4.98). The proportion of participants with a history of living with their grandparents was significantly greater in the H. pylori-positive group (46.7%) than in the -negative group (20.9%; p = 0.03; OR 3.28, 95% CI 1.13-9.54). Only a history of living with one's grandparents during childhood showed statistical significance in the multivariate regression analysis (p = 0.04; OR 3.20, 95% CI 1.08-9.49). CONCLUSIONS: These results suggest that H. pylori infection is more strongly related to living with one's grandparents than living in a hygienic environment.

Role of NRF2 in protection of the gastrointestinal tract against oxidative stress.

The gastrointestinal tract is exposed to a variety of noxious factors, such as Helicobacter pylori, nonsteroidal anti-inflammatory drugs, gastric acid, ischemia-reperfusion, and mental stresses. Theses stressors generate free radicals within gastrointestinal tissues, causing organ injury and functional disturbance. Although the gastrointestinal tract can withstand such oxidative stresses to some extent by enhancing its antioxidant system via nuclear factor erythroid 2-related factor 2-Kelch-like erythroid cell-derived protein with CNC homology-associated protein 1-mediated pathways, acute or chronic exposure to oxidative stress can cause several gastrointestinal tract disorders, such as inflammation, ulcers, cancers, and various functional disturbances. Recent studies have demonstrated that some natural compounds and drugs can upregulate the nuclear factor erythroid 2-related factor 2-mediated antioxidant system, ameliorating or preventing these disorders. Although these compounds may be useful as chemopreventive agents, sufficient evidence for their clinical efficacy has not yet been provided. In addition, it is important to note that excessive nuclear factor erythroid 2-related factor 2 stimulation can be harmful to human health, especially from the standpoint of tumor biology.

Multikinase inhibitor-associated hand-foot skin reaction as a predictor of outcomes in patients with hepatocellular carcinoma treated with sorafenib.

AIM: To investigate the relationship between the onsets of multikinase inhibitor (MKI)-associated hand-foot skin reaction (HFSR) and prognosis under intervention by pharmacists after the introduction of sorafenib. METHODS: We conducted a retrospective study involving 40 patients treated with sorafenib. Intervention by pharmacists began at the time of treatment introduction and continued until the appearance of symptomatic exacerbation or non-permissible adverse reactions. We examined the relationship between MKI-associated HFSR and overall survival (OS) after the initiation of treatment. RESULTS: The median OS was 10.9 mo in the MKI-associated HFSR group and 3.4 mo in the no HFSR group, showing a significant difference in multivariate analysis. A multivariate analysis of the time to treatment failure indicated that the intervention by pharmacists and MKI-associated HFSR were significant factors. The median cumulative dose and the mean medication possession ratio were significantly higher in the intervention group than in the non-intervention group. A borderline significant difference was observed in terms of OS in this group. CONCLUSION: Intervention by pharmacists increased drug adherence. Under increased adherence, MKI-associated HFSR was an advantageous surrogate marker. Intervention by healthcare providers needs to be performed for adequate sorafenib treatment.

Contribution of NRF2 in Gastrointestinal Protection from Oxidative Injury.

The human gastrointestinal tract is exposed to a variety of toxic agents, such as Helicobacter pylori (H.pylori), Nonsteroidal Anti-inflammatory Drugs (NSAIDs), gastric acid, enteric pathogenic bacteria, excessive auto immune reactions, and chronic mental stresses. These stressors generate free radicals within the gastrointestinal tissues, causing chronic inflammatory diseases, ulcers, cancers, and functional disturbances. Recent studies have demonstrated that some natural food compounds upregulate the nuclear factor erythroid 2-related factor 2- mediated antioxidant system, ameliorating or preventing these disorders. We have previously shown that dietary intake of sulforaphane-rich broccoli sprouts, ameliorates gastric inflammation induced by H. pylori, prevents NSAIDs-induced small intestinal injury, and improve functional constipation. There have been many other compounds, which enhance the nuclear factor erythroid 2-related factor 2-mediated antioxidant system, sufficient evidence for their clinical efficacy has not yet been provided. In addition, we have to pay attention to some reports, which have shown that excessive stimulation of nuclear factor erythroid 2-related factor 2 enhance chemoresistance and facilitates growth of cancer cells.

Daily intake of broccoli sprouts normalizes bowel habits in human healthy subjects.

Chronic oxidative stress impairs regular defecation. Sulforaphane (SFN) enhances anti-oxidant systems, ameliorating oxidative injury. SFN inhibits overgrowth of anaerobic microflora and protects small intestine from oxidative injury. We assessed whether daily intake of SFN-rich broccoli sprouts (BS) improves defecation in humans. Forty-eight subjects, with a constipation scoring system (CSS) >2 points, were assigned to either the BS group (n = 24) or the alfalfa sprouts (AS) group (n = 24), and were requested to eat 20 g daily of raw BS or AS, respectively, for 4 weeks. BS contains 4.4 mg/g sulforaphane glucosinolates (SGS), while AS contains no SGS. CSS-based questionnaires were performed to evaluate bowel habit. Stool samples were collected to evaluate intestinal microflora using a terminal restriction fragment length polymorphism flora analysis. Intervention with BS, but not AS, caused a significant decrease in the duration of attempted defecation and the total CSS score. Intervention with BS decreased the percentage of Bifidobacterium in the stool. These results suggest that daily intake of BS improves bowel habit in human subjects. Since BS treatment enhance antioxidant enzyme activities, these effects of BS appear to relate with the SFN-mediated modulation of the intestinal motility during exposure to oxidative stress. (UMIN Clinical Trial Registration Number: UMIN-000021207).

Role of Sulforaphane in Protection of Gastrointestinal Tract Against H. pylori and NSAID-Induced Oxidative Stress.

BACKGROUND: Sulforaphane (SFN), a phytochemical found in abundance in broccoli sprouts, potently induces a variety of antioxidant enzymes, and thereby protects cells from injury induced by various kinds of oxidative stresses. It has been suggested that both H. pylori infection and intake of non-steroidal anti-inflammatory drugs (NSAIDs) induce chronic oxidative stress in gastrointestinal (GI) mucosa, thereby causing mucosal injury in the GI tract. Therefore, it would be a reasonable assumption that SFN protects GI mucosa against oxidative injury induced by H. pylori or NSAIDs. METHODS: We examined the effects of SFN on H. pylori viability in vitro, levels of gastritis in H.pylori-infected mice in vivo, and in H.pylori-infected human subjects. We also examined the effects of SFN on NSAID-induced small intestinal injury in mice. RESULTS: Our data from the H. pylori infection study clearly demonstrated that SFN inhibited H. pylori viability both in vitro and in vivo, and mitigated H. pylori-induced gastritis in mice and humans. Similarly, our study on NSAID-induced small intestinal injury showed that SFN not only mitigated aspirin-induced injury of small intestinal epithelial cells in vitro, but also ameliorated indomethacin-induced small intestinal injury in mice in vivo. CONCLUSIONS: These data strongly suggest that SFN contributes to the protection of GI mucosa against oxidative injury induced by H. pylori or NSAIDs.

The Promoting Effect of the Extracellular Matrix Peptide TNIIIA2 Derived from Tenascin-C in Colon Cancer Cell Infiltration.

The extracellular matrix (ECM) molecule tenascin C (TNC) is known to be highly expressed under various pathological conditions such as inflammation and cancer. It has been reported that the expression of TNC is correlated with the malignant potential of cancer. In our laboratory, it was found that the peptide derived from the alternative splicing domain A2 in TNC, termed TNIIIA2, has been shown to influence a variety of cellular processes, such as survival, proliferation, migration, and differentiation. In this study, we investigated the effect of TNC/TNIIIA2 on the invasion and metastasis of colon cancer cells, Colon26-M3.1, or PMF-Ko14, using an in vitro and in vivo experimental system. The degree of cell invasion was increased by the addition of TNC and TNIIIA2 in a dose-dependent manner. The invasion by TNC and TNIIIA2 were suppressed by an MMP inhibitor or TNIIIA2-blocking antibody. In an in vivo experiment, pulmonary metastasis was promoted conspicuously by the addition of TNIIIA2. In this study, we found that colon cancer cell invasion and metastasis was accelerated by TNC/TNIIIA2 via MMP induction. This result suggests the possibility of a new strategy targeting TNC/TNIIIA2 for colon cancer.

Therapeutic efficacy of the Qing Dai in patients with intractable ulcerative colitis.

Ulcerative colitis (UC) is a chronic inflammatory bowel disease that may become intractable when treated with conventional medications such as aminosalicylates, corticosteroids, and azathioprine. The herbal medicine Qing Dai has traditionally been used in Chinese medicine to treat UC patients, but there is a lack of published data on the efficacy of Qing Dai in UC treatment. We report several cases of patients with intractable UC who take Qing Dai in a retrospective observational study. Furthermore, we explore the mechanisms of action of Qing Dai. Nine patients with active UC who received conventional medications but wished to receive Qing Dai as an alternative medication were included in our analysis. The UC severity level was determined based on the clinical activity index (CAI). Additionally, 5 of the 9 patients were endoscopically evaluated according to the Matts grading system. Each patient received 2 g/d of Qing Dai orally and continued taking other medications for UC as prescribed. Electron spin resonance was applied to explore the mechanisms of action of Qing Dai. After 4 mo of treatment with Qing Dai, the CAI score decreased from 8.3 ± 2.4 to 2.4 ± 3.4 (mean ± SD; P < 0.001). Similarly, the endoscopic Matts grade decreased from 3.4 ± 0.5 to 2.2 ± 0.8 (P = 0.02). Six of 7 patients who were on prednisolone upon enrollment in the study were able to discontinue this corticosteroid. Electron spin resonance revealed that Qing Dai possesses strong hydroxyl radical scavenging activity. Qing Dai showed significant clinical and endoscopic efficacy in patients who failed to respond to conventional medications. Scavenging of hydroxyl radicals appears to be a potential mechanism through which Qing Dai acts, but the significance of the scavenging ability of Qing Dai with respect to the anti-inflammatory effect in UC patients warrants further investigation.

SPECT/CT of lung nodules using 111In-DOTA-c(RGDfK) in a mouse lung carcinogenesis model.

OBJECTIVE: Lung cancer is one of the leading causes of cancer-related deaths worldwide, including Japan. Although computed tomography (CT) can detect small lung lesions such as those appearing as ground glass opacity, it cannot differentiate between malignant and non-malignant lesions. Previously, we have shown that single photon emission computed tomography (SPECT) imaging using (111)In-1,4,7,10-tetraazacyclododecane-N,N',N'',N'''-tetraacetic acid-cyclo-(Arg-Gly-Asp-D-Phe-Lys) (DOTA-c(RGDfK)), an imaging probe of αvß3 integrin, is useful for the early detection of pancreatic cancer in a hamster pancreatic carcinogenesis model. In this study, we aimed to assess the usefulness of SPECT/CT with (111)In-DOTA-c(RGDfK) for the evaluation of the malignancy of lung cancer. METHODS: Lung tumors were induced by a single intraperitoneal injection (250 mg/kg) of urethane in male A/J mice. Twenty-six weeks after the urethane treatment, SPECT was performed an hour after injection of (111)In-DOTA-c(RGDfK). Following this, the radioactivity ratios of tumor to normal lung tissue were measured by autoradiography (ARG) in the excised lung samples. We also examined the expression of αvß3 integrin in mouse and human lung samples. RESULTS: Urethane treatment induced 5 hyperplasias, 41 adenomas and 12 adenocarcinomas in the lungs of 8 A/J mice. SPECT with (111)In-DOTA-c(RGDfK) could clearly visualize lung nodules, though we failed to detect small lung nodules like adenoma and hyperplasias (adenocarcinoma: 66.7%, adenoma: 33.6%, hyperplasia: 0.0%). ARG analysis revealed significant uptake of (111)In-DOTA-c(RGDfK) in all the lesions. Moreover, tumor to normal lung tissue ratios increased along with the progression of carcinogenesis. Histopathological examination using human lung tissue samples revealed clear up-regulation of αvß3 integrin in well-differentiated adenocarcinoma (Noguchi type B and C) rather than atypical adenomatous hyperplasia. CONCLUSION: Although there are some limitations in evaluating the malignancy of small lung tumors using (111)In-DOTA-c(RGDfK), SPECT with (111)In-DOTA-c(RGDfK) might be a useful non-invasive imaging approach for evaluating the characteristics of lung tumors in mice, thus showing potential for use in humans.

Sulforaphane protects small intestinal mucosa from aspirin/NSAID-induced injury by enhancing host defense systems against oxidative stress and by inhibiting mucosal invasion of anaerobic enterobacteria.

BACKGROUND AND AIMS: Recent studies have shown that daily use of NSAIDs, frequently causes small intestinal ulcers and erosions. However, effective drugs to prevent aspirin/NSAIDs-induced small intestinal lesions have not been developed. In the present study, we examined the effects of sulforaphane (SFN), a substance rich in broccoli sprouts, on aspirin/NSAIDs-induced small intestinal injury. METHODS: 1. In vitro study: IEC6 cells, derived from rat small intestinal mucosae, were incubated with or without SFN. The cells were subsequently exposed to aspirin. In some experiments, the effect of zinc protoporphyrin-IX (ZnPP), 0.1 µM, an inhibitor of heme oxygenase- 1 (HO-1), was also examined. 2. In vivo study: IND-induced small intestinal mucosal injury was induced in male ddY mice. SFN glucosinolates (SGS), which is glucosinolates precursor of SFN, was orally administered to the mice, at dose of 17 mg/mouse, before and after the injection of IND. Vascular permeability was assessed by measuring the amount of exudated Evans Blue in the mucosa, which had been injected intravenously. Neutrophil activation was evaluated by myeloperoxidase (MPO) activity. Amount of mucosal anaerobic bacteria was also measured. RESULTS: 1. In vitro study: (1) SFN, 5 µM, significantly attenuated aspirin (20 mM)-induced cell injury. (2) SFN enhanced HO-1 expression in IEC-6 cells. The protective effect of SFN against aspirin-induced injury was attenuated by 0.1 µM ZnPP. 2. In vivo study: (1) IND treatment caused mucosal injury in small intestine, increased vascular permeability, enhanced MPO activity, and augmented mucosal invasion of anaerobic enterobacteria. (2) SGS attenuated the IND-induced small intestinal injury. (3) SGS prevented the IND-induced increase in mucosal invasion of anaerobic enterobacteria. CONCLUSIONS: These results suggest that SFN protects small intestine from aspirin / NSAIDs-induced injury, presumably by up-regulating nrf2-keap1 dependent antioxidant system and by inhibiting invasion of anaerobic bacteria into the mucosa.

Non-invasive X-ray micro-computed tomographic evaluation of indomethacin on urethane-induced lung carcinogenesis in mice.

BACKGROUND: Lung cancer is the leading cause of cancer-related death worldwide. We previously reported that respiration-gated X-ray micro-computed tomography (micro-CT) is a useful tool for analyzing lung tumor development in animal models. MATERIALS AND METHODS: Lung tumors were induced by a single intraperitoneal injection (250 mg/kg) of urethane in male A/J mice, followed by indomethacin treatment at 5 ppm in the diet. The mice were scanned by micro-CT every 4 weeks from 10 to 26 weeks after urethane administration. RESULTS: Total incidence and multiplicity of lung tumors were not significantly reduced by indomethacin treatment, as compared with untreated mice. However, the incidence of adenocarcinoma tended to be reduced by indomethacin treatment. Moreover, the size of lung tumors, especially adenomas, was suppressed by indomethacin treatment. Micro-CT analysis revealed that indomethacin effectively suppressed tumor development after urethane treatment for 10 weeks. CONCLUSION: These findings indicate that indomethacin suppresses lung carcinogenesis in mice and micro-CT is a useful non-invasive imaging approach for evaluating the characteristics and suppression of lung tumors in mice treated with cancer chemopreventive agents.

Suppressive effect of pioglitazone, a PPAR gamma ligand, on azoxymethane-induced colon aberrant crypt foci in KK-Ay mice.

Obesity is an established risk factor for colorectal cancer. Pioglitazone is a peroxisome proliferator- activated receptor γ(PPARγ) agonist that induces differentiation in adipocytes and induces growth arrest and/or apoptosis in vitro in several cancer cell lines. In the present study, we investigated the effect of pioglitazone on the development of azoxymethane-induced colon aberrant crypt foci (ACF) in KK-Ay obesity and diabetes model mice, and tried to clarify mechanisms by which the PPARγ ligand inhibits ACF development. Administration of 800 ppm pioglitazone reduced the number of colon ACF / mouse to 30% of those in untreated mice and improved hypertrophic changes of adipocytes in KK-Ay mice with significant reduction of serum triglyceride and insulin levels. Moreover, mRNA levels of adipocytokines, such as leptin, monocyte chemoattractant protein-1 and plasminogen activator inhibitor-1, in the visceral fat were decreased. PCNA immunohistochemistry revealed that pioglitazone treatment suppressed cell proliferation in the colorectal epithelium with elevation of p27 and p53 gene expression. These results suggest that pioglitazone prevented obesity-associated colon carcinogenesis through improvement of dysregulated adipocytokine levels and high serum levels of triglyceride and insulin, and increase of p27 and p53 mRNA levels in the colorectal mucosa. These data indicate that pioglitazone warrants attention as a potential chemopreventive agent against obesity-associated colorectal cancer.

Novel compound SK-1009 suppresses interleukin-6 expression through modulation of activation of nuclear factor-kappaB pathway.

Although interleukin-6 (IL-6) is an important biological mediator playing an indispensable role in inflammation and cancer, few inhibitors and suppressors are known. In the present study, the underlying mechanisms of a novel chemically synthesized compound SK-1009, which has suppressive properties on IL-6 production in human macrophage cells, were examined. SK-1009 suppressed IL-6 mRNA levels in human colon cancer cells. Thus, the influence of SK-1009 on transcription factor, nuclear factor-kappaB (NF-κB), which is involved in expression of the IL-6 gene was assessed. SK-1009 was found to suppress degradation of I-κB, an NF-κB inhibitory factor, and consequently inhibited the NF-κB activation pathway. The inhibitory property was almost the same as other NF-κB inhibitors, such as 5HPP-33. Thus, SK-1009 exerts a potent inhibitory effect on IL-6 expression, apparently mediated by modulation of activation of NF-κB transcription factor.

Sulforaphane enhances protection and repair of gastric mucosa against oxidative stress in vitro, and demonstrates anti-inflammatory effects on Helicobacter pylori-infected gastric mucosae in mice and human subjects.

Helicobacter pylori infection induces oxidative stress on gastric mucosa, thereby causing mucosal damage, retarding mucosal repair, and eventually inducing gastric cancer. Cells can survive against chronic oxidative stress by enhancing activities of antioxidant enzymes, thereby protecting cells from DNA damage. Recent studies have clearly shown that the genes encoding nrf2 (NF-E2 p45-related factor-2) and keap1 (Kelch-like ECH-associated protein 1) play an important role in the induction of antioxidant enzymes against oxidative stress. In this paper, we will first describe the cellular mechanisms by which the nrf2-keap1 system contributes to induction of a variety of antioxidant enzymes during exposure to oxidative stress. Secondly, we will also mention beneficial effects of a natural compound sulforaphane, an isothiocyanate family, rich in broccoli sprouts, on gastric mucosa. Sulforaphane stimulates nrf2 gene-dependent antioxidant enzyme activities, thereby protecting cells from oxidative injury. Finally, we will show our data on the effect of sulforaphane, a natural chemical compound rich in broccoli sprouts, on protection and repair of gastric mucosa against oxidative stress, and anti-inflammatory effects on gastric mucosa during H. pylori infection, which appears to be closely related to chemoprotection against gastric cancer induced by .H. pylori-infection.

Suppression of expression of endoplasmic reticulum chaperones by Helicobacter pylori and its role in exacerbation of non-steroidal anti-inflammatory drug-induced gastric lesions.

Both the use of non-steroidal anti-inflammatory drugs (NSAIDs), such as indomethacin, and infection with Helicobacter pylori are major causes of gastric ulcers. Although some clinical studies suggest that infection with H. pylori increases the risk of developing NSAID-induced gastric lesions, the molecular mechanism governing this effect is unknown. We recently found that in cultured gastric cells, expression of endoplasmic reticulum (ER) chaperones (such as 150-kDa oxygen-regulated protein (ORP150) and glucose-regulated protein 78 (GRP78)) is induced by NSAIDs and confers protection against NSAID-induced apoptosis, which is important in the development of NSAID-induced gastric lesions. In this study we have found that co-culture of gastric cells with H. pylori suppresses the expression of ER chaperones. This suppression was regulated at the level of transcription and accompanied by a reduction in the level of activating transcription factor 6 (ATF6), one of the transcription factors for ER chaperone genes. In vivo, inoculation of mice with H. pylori suppressed the expression of ER chaperones at gastric mucosa both with and without administration of indomethacin. Inoculation with H. pylori also stimulated formation of indomethacin-induced gastric lesions and mucosal cell death. In addition, we found that heterozygous ORP150-deficient mice are sensitive to the development of indomethacin-induced gastric lesions and mucosal cell death. The results of this study suggest that H. pylori exacerbates NSAID-induced gastric lesions through suppression of expression of ER chaperones, which stimulates NSAID-induced mucosal cell death.