Persistent Nausea and Gastrointestinal Distention: A Case Report of Aerophagia.

A 43-year-old woman experienced acute nausea, diarrhea, and abdominal pain, leading her to our hospital. No relevant medical history or physical abnormalities were noted. Symptoms persisted for a month, causing weight loss and abdominal bloating. CT scans revealed distension throughout the gastrointestinal tract without stenosis. Intestinal pseudo-obstruction and aerophagia were suspected. MR enterography confirmed normal gastric and intestinal motility, diagnosing the condition as aerophagia-induced gastrointestinal distention. This case underscores the value of MR enterography in assessing intestinal motility and differentiating between intestinal pseudo-obstruction and aerophagia.

Exosomal microRNAs derived from colon cancer cells promote tumor progression by suppressing fibroblast TP53 expression.

The tumor microenvironment offers favorable conditions for tumor progression, and activated fibroblasts, known as cancer-associated fibroblasts, play a pivotal role. TP53-deficient cancer cells are known to induce strong fibroblast activation. We aimed to elucidate the oncogenic role of exosomes derived from TP53-deficient colon cancer cells in fibroblast proliferation and tumor growth. Cancer cell-derived exosomes (CDEs) were isolated from the conditioned media of cancer cells using a sequential ultracentrifugation method. The effects of exosomes on tumor growth were evaluated using human cell lines (TP53-WT colon cancer, HCT116; TP53-mutant colon cancer, HT29; and fibroblasts, CCD-18Co and WI-38) and an immune-deficient nude mouse xenograft model. HCT116 (HCT116sh p53 ) cells deficient in TP53 accelerated cocultured fibroblast proliferation compared to TP53-WT HCT116 (HCT116sh control ) cells in vitro. Exosomes from HCT116sh p53 cells suppressed TP53 expression of fibroblasts and promoted their proliferation. Xenografts of HCT116sh p53 cells grew significantly faster than those of HCT116sh control cells in the presence of co-injected fibroblasts, but this difference was diminished by CDE inhibition. Microarray analysis identified upregulation of several microRNAs (miR-1249-5p, miR-6737-5p, and miR-6819-5p) in TP53-deficient CDEs, which were functionally proven to suppress TP53 expression in fibroblasts. Exosomes derived from TP53-mutant HT29 cells also suppressed TP53 expression in fibroblasts and accelerated their growth. The proliferative effect of HT29 on cocultured fibroblasts was diminished by inhibition of these miRNAs in fibroblasts. Our results suggest that CDEs play a pivotal role in tumor progression by fibroblast modification. Cancer cell-derived exosomes might, therefore, represent a novel therapeutic target in colon cancer.

Adenoma of colorectal laterally spreading tumor nongranular type with biological phenotypic features similar to cancer.

BACKGROUND AND AIM: Colorectal laterally spreading tumors (LSTs) are morphologically subdivided into granular (LST-G) and nongranular (LST-NG) categories. We aimed to elucidate the differences in oncogenic characteristics between the two types. METHODS: Laterally spreading tumors resected by endoscopic submucosal dissection and surgery from March 2009 to May 2017 were examined for p53 positivity, Ki-67 labeling index (LI), microvessel density, degree of fibrosis, intensities of inducible nitric oxide synthase (iNOS) and nitrotyrosine (NT), and expression of acid mucins. We compared these factors between adenomas, noninvasive cancers, and invasive cancers, both LST-G and LST-NG. RESULTS: Ninety-three LST-G (53 adenomas [LST-GA] and 40 cancers [LST-GC]) and 55 LST-NG (24 adenomas [LST-NGA] and 31 cancers [LST-NGC]) were evaluated. Although p53 positivity was lower in LST-GA than in LST-NGA (P < 0.001), there was no difference between LST-GC and LST-NGC. Ki-67 LI was higher in LST-NGA than in LST-GA (P < 0.001) and higher in LST-NGC than in LST-GC of noninvasive cancers (P < 0.001). Microvessel density and degree of fibrosis were higher in LST-NGA than in LST-GA (P < 0.001), and intensities of iNOS and NT were also higher in LST-NGA than in LST-GA (P < 0.001). Expression of acid mucins was lower in LST-NGA than in LST-GA (P < 0.001). Although there were significant differences in p53 positivity, Ki-67 LI, microvessel density, degree of fibrosis, intensities of iNOS and NT, and expression of acid mucins between LST-GA and LST-NGA, these factors were only slightly different between LST-GC and LST-NGC of invasive cancers. CONCLUSIONS: Unlike LST-GA, LST-NGA possessed phenotypic features similar to cancer.

Tissue Drug Concentrations of Anti-tumor Necrosis Factor Agents Are Associated with the Long-term Outcome of Patients with Crohn's Disease.

BACKGROUND: Many reports indicate that a high-serum trough level of anti-tumor necrosis factor (TNF) agents is required for sustained remission in patients with Crohn's disease The pharmacokinetics of anti-TNF agents in inflamed intestinal tissue, however, is not well investigated. We investigated the association between the tissue concentration of anti-TNF agents and long-term disease outcome. METHODS: This was a prospective single-center study that enrolled 25 patients with Crohn's disease who were administered infliximab or adalimumab. All participants underwent endoscopy 2 weeks after administration of the anti-TNF agents, and biopsy samples were obtained from both inflamed and noninflamed intestinal tissue. Tissue concentrations of anti-TNF agents were evaluated and the correlation with serum trough levels was compared. The relation between the tissue drug concentration and clinical course over 24 months was also investigated. RESULTS: Concentrations of anti-TNF agents were significantly higher in inflamed tissue than in noninflamed tissue. Patients with high-serum trough concentrations of anti-TNF agents had significantly higher drug levels in the noninflamed tissue than those with low-serum trough concentrations, but no difference in the levels was detected in the inflamed tissue. Patients with high-drug levels in the noninflamed tissue had a significantly higher sustained response rate than patients with low-drug levels. CONCLUSIONS: Concentrations of anti-TNF agents in the noninflamed tissue can reflect sustained remission and may be a useful biomarker for monitoring therapeutic intensity in patients with Crohn's disease treated with anti-TNF agents (see Video Abstract, Supplemental Digital Content 1, http://links.lww.com/IBD/B623).

p53 functional deficiency in human colon cancer cells promotes fibroblast-mediated angiogenesis and tumor growth.

Cancer-associated fibroblasts (CAFs) create a microenvironment that contributes to tumor growth; however, the mechanism by which fibroblasts are phenotypically altered to CAFs remains unclear. Loss or mutation of the tumor suppressor p53 plays a crucial role in cancer progression. Herein, we analyzed how the p53 status of cancer cells affects fibroblasts by investigating the in vivo and in vitro effects of loss of p53 function in cancer cells on phenotypic changes in fibroblasts and subsequent tumor progression in human colon cancer cell lines containing wild-type p53 and in cells with a p53 functional deficiency. The growth of p53-deficient tumors was significantly enhanced in the presence of fibroblasts compared with that of p53-wild-type tumors or p53-deficient tumors without fibroblasts. p53-deficient cancer cells produced reactive oxygen species, which activated fibroblasts to mediate angiogenesis by secreting vascular endothelial growth factor (VEGF) both in vivo and in vitro Activated fibroblasts significantly contributed to tumor progression. Deletion of fibroblast-derived VEGF or treatment with N-acetylcysteine suppressed the growth of p53-deficient xenograft tumors. The growth effect of blocking VEGF secreted from cancer cells was equivalent regardless of p53 functional status. Human colon cancer tissues also showed a significant positive correlation between p53 cancer cell staining activated fibroblasts and microvessel density. These results reveal that fibroblasts were altered by exposure to p53-deficient epithelial cancer cells and contributed to tumor progression by promoting neovascularization. Thus, p53 acts as a modulator of the tumor microenvironment.

[A case of new-onset refractory status epilepticus (NORSE) with an autoimmune etiology].

A 23-year-old man presented tonic-clonic seizure a week after an episode of antecedent infection. Although several anticonvulsants were used, convulsive attacks were not resolved and intravenous anesthetics were used to stop status epileptics. After combination of immunotherapies (high-dose intravenous methylprednisolone, immune absorbance and intravenous immunoglobulin (IVIg) therapies), frequency of convulsive attacks decreased, however, disturbance of consciousness was not recovered. All anti-neuronal antibodies tested were negative. Indirect immunofluorescence using the serum and rat brain section revealed positive signals in cytoplasm and nucleus in hippocampal neurons, strongly suggesting that this case has an autoimmune pathogenesis. The clinical features and course of this patient are well consistent with those in new-onset refractory status epilepticus (NORSE). The result of immunohistochemical analysis supports the hypothesis that NORSE has an autoimmune pathomechanism.

Integrated diagnostic strategy for the invasion depth of early gastric cancer by conventional endoscopy and EUS.

BACKGROUND: Although conventional endoscopy (CE) and EUS are considered useful for predicting the invasion depth (T-staging) in early gastric cancer (EGC), no effective diagnostic strategy has been established. OBJECTIVE: To produce simple CE criteria and to elucidate an efficient diagnostic method by combining CE and EUS for accurate T-staging. DESIGN: Single-center retrospective analysis. SETTING: Academic university hospital. PATIENTS: Consecutive patients with EGC from April 2007 to March 2012 who underwent CE and EUS before treatment. INTERVENTIONS: Recorded endoscopic images were independently reviewed by 3 observers. The CE criteria for massive invasion were defined, and their utility and the additional value of EUS were assessed. MAIN OUTCOME MEASUREMENTS: The accuracy of CE based on the criteria and the accuracy of EUS. RESULTS: Two hundred thirty patients were enrolled: 195 with mucosal cancer or cancer in the submucosa less than 500 µm from the muscularis mucosae and 35 with invasive cancers. Multivariate analysis of the CE findings by 1 observer revealed that an irregular surface and a submucosal tumor-like marginal elevation were significantly associated with massive invasion. The simple CE criteria, consisting of those 2 features, had an overall accuracy of 73% to 82% and no significant differences in the diagnostic yield compared with EUS in all observers. CE accurately revealed mucosal cancer, and EUS efficiently salvaged the lesions that were over-diagnosed by CE. With our strategy, which involved the CE criteria and the optimal use of EUS, the comprehensive accuracy exceeded 85% in each observer. LIMITATIONS: Retrospective, single-center study. CONCLUSIONS: We demonstrated a practical strategy for T-staging in EGC using simple CE criteria and EUS.

The effectiveness of an anti-human IL-6 receptor monoclonal antibody combined with chemotherapy to target colon cancer stem-like cells.

Recent studies have demonstrated that cancer stem cells (CSCs) can initiate and sustain tumor growth and exhibit resistance to clinical cytotoxic therapies. Therefore, CSCs represent the main target of anticancer therapy. Interleukin-6 (IL-6) promotes cellular proliferation and drug resistance in colorectal cancer, and its serum levels correlate with patient survival. Therefore, IL-6 and its downstream signaling molecule the signal transducer and activator of transcription-3 (STAT3) represent potential molecular targets. In the present study, we investigated the effects of IL-6 and its downstream signaling components on stem cell biology, particularly the chemoresistance of CSCs, to explore potential molecular targets for cancer therapy. The colon cancer cell line WiDr was cultured in serum-free, non-adherent, and three-dimensional spheroid-forming conditions to enrich the stem cell-like population. Spheroid-forming cells slowly proliferated and expressed high levels of Oct-4, Klf4, Bmi-1, Lgr5, IL-6, and Notch 3 compared with adherent cells. Treatment with an anti-human IL-6 receptor monoclonal antibody reduced spheroid formation, stem cell-related gene expression, and 5-fluorouracil (5-FU) resistance. In addition, IL-6 treatment enhanced the levels of p-STAT3 (Tyr705), the expression of Oct-4, Klf4, Lgr5, and Notch 3, and chemoresistance to 5-FU. siRNA targeting Notch 3 suppressed spheroid formation, Oct-4 and Lgr5 expression, and 5-FU chemoresistance, whereas STAT3 inhibition enhanced Oct-4, Klf4, Lgr5, and Notch 3 expression and 5-FU chemoresistance along with reduced spheroid growth. Taken together, these results indicate that IL-6 functions in dichotomous pathways involving Notch 3 induction and STAT3 activation. The former pathway is involved in cancer stem-like cell biology and enhanced chemoresistance, and the latter pathway leads to accelerated proliferation and reduced chemoresistance. Thus, an anti-human IL-6 receptor monoclonal antibody or Notch 3 inhibition may be superior to STAT3 inhibition for CSC-targeting therapies concomitant with anticancer drugs.

5­FU resistance abrogates the amplified cytotoxic effects induced by inhibiting checkpoint kinase 1 in p53­mutated colon cancer cells.

The emergence of chemoresistance is a major limitation of current cancer therapies, and checkpoint kinase (Chk1) 1 positively correlates with resistance to chemo­ or radio­therapy. Cancer cells lacking p53 pathways are completely dependent on the S and G2/M checkpoints via Chk1; therefore, Chk1 inhibition enhances the cytotoxicity of DNA­damaging agents only in p53­deficient cells. However, little is known about the synergistic effect of Chk1 inhibition with 5­FU, the most frequently used antimetabolite, in chemoresistant colorectal cells. In this study, we found that 5­FU induced S­phase arrest only in p53­deficient colorectal cancer cells. 5­FU treatment induced DNA damage and activation of ataxia telangiectasia mutated (ATM) and Chk1, leading to S­phase arrest, and Chk1 inhibition using SB218078 reduced S­phase arrest and increased apoptosis in the presence of 5­FU. In contrast, in p53­deficient, 5­FU­resistant (5FUR) colon cancer cells that we developed, 5­FU enhanced DNA damage but did not induce Chk1/ATM activation or cell cycle arrest. SB218078 in combination with 5­FU did not induce apoptosis. These results indicate that 5­FU­resistance abrogated the anticancer effect amplified by Chk1 inhibition, even in p53­deficient cancer cells.

Adiponectin inhibits murine pancreatic cancer growth.

BACKGROUND: Adiponectin is an adipose tissue-derived secretory hormone whose plasma concentrations are lower in obese individuals. Obesity is a risk factor for the development and growth of pancreatic cancer, and hypoadiponectinemia was suggested to be involved in the growth of Pan02 murine pancreatic cancer cells that were inoculated into the flanks of congenitally obese mice. AIM: The aim of this study was to clarify the role of adiponectin in the growth of pancreatic cancer cells. METHODS: We examined the effect of adiponectin on the growth of Pan02 cells using recombinant adiponectin and adiponectin knockout mice. RESULTS: The in vitro treatment of Pan02 cells with adiponectin inhibited cellular proliferation that was accompanied by increased apoptosis and caspase-3 and caspase-7 activities. Transplantation of Pan02 cells into the pancreas of knockout mice resulted in a larger tumor volume with fewer terminal deoxyribonucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) positive cells compared with wild-type mice. CONCLUSIONS: The results indicate that adiponectin directly suppresses the proliferation of Pan02 cells.

Gastric Contraction Imaging System Using a 3-D Endoscope.

This paper presents a gastric contraction imaging system for assessment of gastric motility using a 3-D endoscope. Gastrointestinal diseases are mainly based on morphological abnormalities. However, gastrointestinal symptoms are sometimes apparent without visible abnormalities. One of the major factors for these diseases is abnormal gastrointestinal motility. For assessment of gastric motility, a gastric motility imaging system is needed. To assess the dynamic motility of the stomach, the proposed system measures 3-D gastric contractions derived from a 3-D profile of the stomach wall obtained with a developed 3-D endoscope. After obtaining contraction waves, their frequency, amplitude, and speed of propagation can be calculated using a Gaussian function. The proposed system was evaluated for 3-D measurements of several objects with known geometries. The results showed that the surface profiles could be obtained with an error of [Formula: see text] of the distance between two different points on images. Subsequently, we evaluated the validity of a prototype system using a wave simulated model. In the experiment, the amplitude and position of waves could be measured with 1-mm accuracy. The present results suggest that the proposed system can measure the speed and amplitude of contractions. This system has low invasiveness and can assess the motility of the stomach wall directly in a 3-D manner. Our method can be used for examination of gastric morphological and functional abnormalities.

Choroidal and cutaneous metastasis from gastric adenocarcinoma.

Choroidal or cutaneous metastasis of gastric cancer is rare. Gastrointestinal cancer was found in only 4% in patients with uveal metastasis. Choroidal metastasis from gastric cancer was reported in two cases in earlier literature. The frequency of gastric cancer as a primary lesion was 6% in cutaneous metastasis of men, and cutaneous metastasis occurs in 0.8% of all gastric cancers. We report a patient with gastric adenocarcinoma who presented with visual disorder in his left eye and skin pain on his head as his initial symptoms. These symptoms were diagnosed to be caused by choroidal and cutaneous metastasis of gastric adenocarcinoma. Two cycles of chemotherapy consisted of oral S-1 and intravenous cisplatin (SPIRITS regimen); this was markedly effective to reduce the primary gastric lesion and almost all the metastatic lesions.

Adiponectin negatively correlates with alcoholic and non-alcoholic liver dysfunction: Health check-up study of Japanese men.

AIM: Central obesity, insulin resistance and alcohol consumption are thought to be major risk factors for fatty liver formation. Adiponectin (APN) prevents fatty liver formation, and its serum levels are lower in subjects with central obesity and/or insulin resistance. The aim of this study was to explore the association among serum APN levels, central obesity, insulin resistance and liver dysfunction with or without fatty liver classified by alcohol consumption in healthy subjects. METHODS: A total of 5588 Japanese male subjects who underwent a health check-up were classified into three groups according to alcohol consumption: non- or light drinkers (15 g/day ≥ ethanol); mild drinkers (15 g/day < ethanol ≤ 30 g/day); and moderate- or heavy drinkers (30 g/day < ethanol). Central obesity and insulin resistance were assessed by waist circumference (WC) and Homeostasis Model of Assessment - Insulin Resistance (HOMA-IR), respectively. RESULTS: WC was significantly increased, while HOMA-IR was significantly decreased according to the extent of alcohol consumption. Serum alanine aminotransferase levels were significantly lower and serum APN levels were significantly higher in mild drinkers than in the other two groups. Multiple linear regression analysis showed that serum APN level served as the significant and independent determinant for liver dysfunction in the subjects with fatty liver, irrespective of alcohol consumption. However, WC became a non-significant determinant of liver dysfunction as alcohol consumption increased. CONCLUSION: Hypoadiponectinemia is a significant determinant for steatotic dysfunction for all levels of alcohol consumption, but central obesity was not a significant determinant for alcoholic fatty liver-induced liver dysfunction.

Protective role of adiponectin against ethanol-induced gastric injury in mice.

Adiponectin is an anti-inflammatory molecule released from adipocytes, and serum adiponectin concentrations are reduced in obesity. We previously reported that gastric erosion occurs in association with obesity and low serum adiponectin levels. In the present study, we examined adiponectin-knockout (APN-KO) mice to elucidate the role of adiponectin in gastric mucosal injury. Gastric injury was induced by oral administration of ethanol in wild-type (WT) and APN-KO mice. Ethanol treatment induced severe gastric injury in APN-KO mice compared with WT mice. In APN-KO mice, increased apoptotic cells and decreased expression of prostaglandin E(2) (PGE(2)) were detected in the injured stomach. We next assessed the effect of adiponectin on the cellular response to ethanol treatment and wound repair in rat gastric mucosal cells (RGM1). Adiponectin induced the expression of PGE(2) and cyclooxygenase 2 (COX-2) in ethanol-treated RGM1 cells. RGM1 cells exhibited efficient wound repair accompanied by increased PGE(2) expression in the presence of adiponectin. Coadministration of adiponectin with celecoxib, a COX-2 inhibitor, inhibited efficient wound repair. These findings indicate that adiponectin has a protective role against ethanol-induced gastric mucosal injury in mice. This effect may be partially mediated by the efficient wound repair of epithelial cells via increased PGE(2) expression.

Is obesity a new risk factor for gastritis?

Obesity has become a major concern among gastroenterologists due to its large influence on gastrointestinal and hepatic diseases: reflux esophagitis, pancreatitis, gallstone disease, liver fibrosis, and neoplastic tumors of the esophagus, pancreas, and colon. Studies of morbid obese subjects undergoing bariatric surgery have revealed that obesity is related with an increased prevalence of endoscopic and histologic gastritis. A recent study of health check-up subjects demonstrated an association of obesity with endoscopic gastritis and gastric ulcers. We recently investigated the underlying mechanisms of the effects of obesity on endoscopic gastritis in subjects undergoing health check-up examination, and demonstrated that adiponectin, a bioactive molecule released from visceral fat, could be a protective factor of endoscopic gastritis. We would like to propose a new category of gastritis, obesity-related gastritis, which could become dominant in the near future.

Association of low serum adiponectin levels with erosive esophagitis in men: an analysis of 2405 subjects undergoing physical check-ups.

BACKGROUND: Obesity is a risk factor for gastro-esophageal reflux disease (GERD). It is generally considered that intra-abdominal pressure in obese subjects is involved in the pathogenesis of GERD through acid exposure to the esophagus. Recently, visceral fat has been recognized as an endocrine organ that secretes various adipocytokines including adiponectin. The aim of this study was to elucidate the relation between adiponectin and erosive esophagitis. METHODS: This was a cross-sectional retrospective observational study: 2405 consecutive subjects who underwent screening esophago-gastro-duodenoscopy with serum adiponectin measurement as part of their physical check-up programs were analyzed. Clinical factors were compared between subjects with and without erosive esophagitis. The association between adiponectin and erosive esophagitis was assessed using a bootstrapping re-sampling method after adjustment for factors that tended to be different in univariate analysis. RESULTS: Serum adiponectin levels were significantly lower in those with erosive esophagitis (8.17 µg/ml) than in those without (10.1). The erosive esophagitis group had a greater body mass index (BMI) and waist circumference (WC) and a higher prevalence of hiatal hernia. Using the bootstrap method, with a lower adiponectin cut-off value of 3-7 µg/ml, the lower limit of the 95% confidence interval of the adjusted odds ratio consistently exceeded 1 after adjustment for BMI and hiatal hernia in men. When adjusting for WC instead of BMI, the effect of adiponectin was reduced but remained significant at a lower cut-off value (3-3.5 µg/ml). CONCLUSIONS: Low serum adiponectin levels may be associated with an increased risk for erosive esophagitis in men.

[Bronchogenic cyst in the abdomen--a case report].

A man in his thirties with epigastric pain was referred to our hospital for detailed examinations. Abdominal computed tomography showed an abdominal cystic lesion with a longest dimension of 7 cm, located behind the stomach. Endoscopic ultrasonography through the stomach showed a cystic lesion and the wall of the lesion revealed continuity to the proper muscle layer of the gastric wall. Therefore, gastric duplication was suspected and the cystic lesion was resected because of the possibility of malignancy and also for a definitive diagnosis. The cystic lesion consisted of columnar ciliated epithelium, seromucous glands, smooth muscle and cartilage and was diagnosed as a bronchogenic cyst. Bronchogenic cysts are sometimes encountered in the thoracic or mediastinal area, but abdominal bronchogenic cysts, such as the present case, are extremely rare.

Lower serum level of adiponectin is associated with increased risk of endoscopic erosive gastritis.

BACKGROUND: Obesity is recently known as a risk factor for endoscopic gastritis. Adiponectin is an anti-inflammatory cytokine secreted from fat tissue, and its serum concentrations are reduced in obesity. The relation between adiponectin and gastritis remains unclear. AIMS: The aim of this study was to determine whether lower serum adiponectin level is associated with the risk of endoscopic gastritis. METHODS: We analyzed medical records of participants of a routine health check-up examination. Association among endoscopic findings, serum adiponectin level, and other clinical factors including age, sex, alcohol habit, smoking habit, body mass index (BMI), blood pressure, cholesterol, triglyceride, glucose, and insulin were investigated. Endoscopic erosive gastritis was defined as a flat or minimally depressed white spot surrounded by a reddish area or small elevation with central umbilications mimicking octopus' suckers. RESULTS: A total of 2,400 participants were enrolled. BMI was significantly higher in gastritis-positive participants than in gastritis-negative participants. Serum adiponectin levels were significantly lower in gastritis-positive participants than in gastritis-negative participants. Multivariate logistic regression analysis revealed that lower serum adiponectin level (OR 0.96; 95% CI 0.93-0.99), smoking (OR 0.50; 95% CI 0.30-0.80), higher blood pressure (OR 1.02; 95% CI 1.01-1.03), and duodenitis (OR 1.8; 95% CI 1.00-3.09) were significantly associated with endoscopic erosive gastritis. CONCLUSIONS: Lower serum level of adiponectin may increase the risk of endoscopic erosive gastritis, independently of BMI. Our findings facilitate further study to clarify the role of hypoadiponectinemia in erosive gastritis.

Lack of adiponectin promotes formation of cholesterol gallstones in mice.

Plasma adiponectin levels are reduced in obese people, and hypoadiponectinemia is recently reported to associate with cholesterol gallstone formation in human. The aim of this study was to examine the role of adiponectin in gallstone formation using adiponectin knockout mice. We analyzed male knockout and C57BL6J mice fed normal or lithogenic diet for 6 weeks. On lithogenic diet, the prevalence rate of gallstone was significantly greater in knockout mice than C57BL6J mice. The molar percentages of beta and omega-muricholic acid were significantly higher and hepatic sterol 12 alpha-hydroxylase expression (cyp8b1) was significantly lower in knockout mice than C57BL6J mice fed normal diet. The bile apolipoprotein A-I protein levels were decreased in knockout mice. Histological examination showed gallbladder wall thickening and accumulation of glycoprotein in the gallbladder of knockout mice. Gallbladder phospholipase A2-IVA expression was significantly higher in knockout mice than in C57BL6J mice fed lithogenic diet. Our results indicate that lack of adiponectin promotes gallstone formation in mice.

Adiponectin deficiency enhanced the severity of cerulein-induced chronic pancreatitis in mice.

BACKGROUND: Adiponectin is recognized as an antiinflammatory and antifibrotic protein derived from adipocytes, and low serum adiponectin levels are present in obesity. Recent studies have highlighted the relationship between obesity and pancreatic diseases. However, the role of adiponectin in chronic pancreatitis remains uncertain. The aim of this study was to determine the effects of adiponectin in chronic pancreatitis. METHODS: We investigated the effects of adiponectin in experimental chronic pancreatitis by using adiponectin-knockout (APN-KO) mice. Chronic pancreatitis was induced by repeated hourly (6 times) intraperitoneal injections of 50 microg/kg cerulein three times per week for 4 weeks in wild-type (WT) and APN-KO mice. We evaluated the severity of chronic pancreatitis biochemically and morphologically. RESULTS: In cerulein-treated mice, macroscopically and histologically, severe pancreatic damage was observed in APN-KO mice compared with findings in WT mice. The histological scores for chronic pancreatitis, including glandular atrophy, pseudotubular complex, fibrosis, and total scores, were significantly higher in APN-KO mice than in WT mice. Activated pancreatic stellate cells and F4/80-positive pancreatic macrophages accumulated in the pancreas of APN-KO mice but not in WT mice. Overexpression of the mRNAs of transforming growth factor-beta1, CD68, and monocyte chemoattractant protein-1 was noted in APN-KO mice but not in WT mice. The gene expression level of collagen1 (alpha1) tended to be higher in APN-KO mice than in WT mice, albeit insignificantly. CONCLUSIONS: Adiponectin deficiency enhanced the severity of cerulein-induced chronic pancreatitis in mice. Hypoadiponectinemia could enhance the severity of chronic pancreatitis.