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Background: The intestinal microbiome is involved in the pathogenesis of chronic kidney disease (CKD). Despite its importance, the microbiome of the small intestinal mucosa has been little studied due to sampling difficulties, and previous studies have mainly focused on fecal sources for microbiome studies. We aimed to characterize the small intestinal microbiome of CKD patients by studying the microbiome collected from duodenal and fecal samples of CKD patients and healthy controls. Methods: Overall, 28 stage 5 CKD patients and 21 healthy participants were enrolled. Mucosal samples were collected from the deep duodenum during esophagogastroduodenoscopy and fecal samples were also collected. The 16S ribosomal RNA gene sequencing using Qiime2 was used to investigate and compare the microbial structure and metagenomic function of the duodenal and fecal microbiomes. Results: The duodenal flora of CKD patients had decreased alpha diversity compared with the control group. On the basis of taxonomic composition, Veillonella and Prevotella were significantly reduced in the duodenal flora of CKD patients. The tyrosine and tryptophan metabolic pathways were enhanced in the urea toxin-related metabolic pathways based on the Kyoto Encyclopedia of Genes and Genomes database. Conclusion: The small intestinal microbiome in CKD patients is significantly altered, indicating that increased intestinal permeability and production of uremic toxin may occur in the upper small intestine of CKD patients. [ABSTRACT FROM AUTHOR]

Background: Ferroptosis, a type of programmed cell death triggered by oxidative stress, was suspected to play a role in ulcerative colitis. Indigo naturalis is highly effective against ulcerative colitis, but its mechanism is unclear. This study found that indigo naturalis treatment suppressed ferroptosis. Methods: We analyzed 770 mRNA expressions of patients with ulcerative colitis. Suppression of ferroptosis by indigo naturalis treatment was shown using a cell death assay. Malondialdehyde levels and reactive oxygen species were analyzed in CaCo-2 cells treated with indigo naturalis. Glutathione metabolism was shown by metabolomic analysis. Extraction of the ingredients indigo naturalis from the rectal mucosa was performed using liquid chromatograph—mass spectrometry. Results: Gene expression profiling showed that indigo naturalis treatment increased antioxidant genes in the mucosa of patients with ulcerative colitis. In vitro analysis showed that nuclear factor erythroid-2-related factor 2-related antioxidant gene expression was upregulated by indigo naturalis. Indigo naturalis treatment rendered cells resistant to ferroptosis. Metabolomic analysis suggested that an increase in reduced glutathione by indigo naturalis. The protein expression of CYP1A1 and GPX4 was increased in the rectum by treatment with indigo naturalis. The main ingredients of indigo naturalis, indirubin and indigo inhibited ferroptosis. Indirubin was detected in the rectal mucosa of patients with ulcerative colitis who were treated with indigo naturalis. Conclusions: Suppression of ferroptosis by indigo naturalis in the intestinal epithelium could be therapeutic target for ulcerative colitis. The main active ingredient of indigo naturalis may be indirubin. [ABSTRACT FROM AUTHOR]

Introduction: The proportion of gastroduodenal ulcers caused by drugs is increasing. However, the risk of gastroduodenal ulcer from drugs other than nonsteroidal anti-inflammatory drugs (NSAIDs) and low-dose aspirin is unclear. An association between immunosuppressive drugs and gastroduodenal ulcers has been suggested. We aimed to identify the immunosuppressive drugs and clinical characteristics associated with gastroduodenal ulcers in post-liver transplant patients. Methods: The study investigated 119 patients who underwent esophagogastroduodenoscopy after liver transplantation, and 2 patients were excluded. Clinical characteristics, medications, and endoscopic images were retrospectively reviewed. Results: Among 117 post-living donor liver transplant recipients, gastroduodenal ulcers were found in 10 (9.2%) patients. The ulcer group had endoscopic gastritis more frequently (40%) compared with the non-ulcer group (10%). Logistic regression analysis revealed gastritis, NSAID use, and mycophenolate mofetil were risk factors in the post-liver transplant patients. Among 103 patients not on NSAIDs, 8 (7.8%) had peptic ulcer. The most common ulcer site and ulcer shape were the gastric antrum and a circular shape, respectively. All patients in the ulcer group were taking mycophenolate mofetil, which was the only immunosuppressive drug that showed a significant difference between the two groups. Five out of 8 ulcer patients (63%) were taking gastric acid suppressants, and gastroduodenal ulcers in post-liver transplant recipients were suggested to be refractory. Conclusion: Patients treated with immunosuppressive drugs after liver transplantation can develop gastroduodenal ulcers, even with gastric acid suppressant medication. Mycophenolate mofetil may increase the risk of gastroduodenal ulcers compared with other immunosuppressive drugs. [ABSTRACT FROM AUTHOR]

Background and Aim: The aim of this study was to elucidate the continuous use of antithrombotic medications during the peri‐colorectal endoscopic submucosal dissection (ESD) period. Methods: This study included 468 patients with colorectal epithelial neoplasms treated by ESD, consisting of 82 under antithrombotic medications and 386 patients without the medications. Among patients taking antithrombotic medications, antithrombotic agents were continued during the peri‐ESD period. Clinical characteristics and adverse events were compared after propensity score matching. Results: Before and after propensity score matching, post‐colorectal ESD bleeding rate was higher in patients continuing antithrombotic medications (19.5% and 21.6%, respectively) than in those not taking antithrombotic medications (2.9% and 5.4%, respectively). In the Cox regression analysis, continuation of antithrombotic medications was associated with post‐ESD bleeding risk (hazard ratio, 3.73; 95% confidence interval, 1.2–11.6; P < 0.05) compared with patients without antithrombotic therapy. All patients who experienced post‐ESD bleeding were successfully treated by endoscopic hemostasis procedure or conservative therapy. Conclusions: Continuation of antithrombotic medications during the peri‐colorectal ESD period increases the risk of bleeding. However, the continuation may be acceptable under careful monitoring for post‐ESD bleeding. [ABSTRACT FROM AUTHOR]

Purpose: Therapeutic efficacy of ustekinumab in the real-world data is limited in patients with refractory Crohn’s disease (CD). In addition, factors predictive of better therapeutic efficacy of ustekinumab remains unsolved in CD. We aimed to evaluate therapeutic efficacy of ustekinumab in patients with refractory CD and to identify the factors associated with the efficacy of ustekinumab. Methods: We retrospectively analyzed the clinical data of 72 patients treated with ustekinumab for refractory CD. Therapeutic efficacy was assessed at weeks 8, 26, 52, and 104 on the basis of dual remission, defined as the combination of Crohn’s Disease Activity Index < 150 and CRP < 0.3 mg/dL, and factors predictive of the induction and maintenance of dual remission were investigated. The cumulative continuation rates and safety of ustekinumab were assessed. Results: The dual remission rates at weeks 8, 26, 52, and 104 were 31.9%, 37.9%, 47.5%, and 42.6%, respectively. A short disease duration (≤ 2 years) and higher baseline serum albumin levels (≥ 3.1 g/dL) were positively associated with dual remission at weeks 8 and 52. Meanwhile, higher serum CRP levels (≥ 1.19 mg/dL) were negatively associated with dual remission at week 8. The cumulative ustekinumab continuation rate was favorable, and no severe adverse events were found. Conclusion: A short disease duration and higher baseline serum albumin levels might be predictive of favorable therapeutic efficacy of ustekinumab in refractory CD. Induction efficacy appears to be lower in patients with higher serum CRP levels. [ABSTRACT FROM AUTHOR]

Background: Tumour immune microenvironment is related with carcinogenesis and efficacy of immunotherapy. B cells play major roles in humoral immunity, but detailed functions of tumour‐infiltrating B lymphocytes (TIL‐Bs) are unknown. Therefore, our aim was to investigate the functional heterogeneity of TIL‐Bs in oesophageal squamous cell carcinoma (ESCC) and lymph nodes (LNs) during chemotherapy. Methods: Single‐cell transcriptome analysis was performed on 23 specimens. We also performed immunohistochemical analysis of immunoglobulin κ C (IGKC), an antibody‐secreting cell (ASC) marker, in 166 ESCC samples and evaluated the implication of IGKC in 2‐year recurrence free survival (RFS) and 3‐year overall survival (OS). Results: A total of 81,246 cells were grouped into 24 clusters. We extracted B cell clusters based on canonical markers and identified 12 TIL‐B subtypes in ESCC. We found that several functions, such as co‐stimulation and CD40 signalling, were enhanced in TIL‐Bs after chemotherapy. The proportion of naive B cells (NBCs) decreased and B cell activation genes were up‐regulated in NBCs after chemotherapy. The proportion of ASCs in tumours increased with the loss of migratory abilities and antibody production in ASCs was promoted after chemotherapy. Differentially expressed genes up‐regulated with chemotherapy in ASCs correlated with prolonged survival with oesophageal cancer (p =.028). In a metastatic LN, the ASC proportion increased and B cell differentiation was enhanced. In immunohistochemical analysis, RFS and OS of high IGKC expression cases were significantly better than those of low IGKC expression cases (RFS: p <.0001, OS: p <.0001). And in multivariable analysis, the expression of IGKC was an independent favourable prognostic factor for RFS (hazard ratio (HR): 0.23, 95% confidence interval (CI): 0.12–0.45, p <.0001) and OS (HR: 0.20, 95% CI: 0.086–0.47, p =.0002) in ESCC. Conclusions: Our findings provide novel insights for the heterogeneity of TIL‐Bs during chemotherapy and will be useful to understand the clinical importance of TIL‐Bs. [ABSTRACT FROM AUTHOR]

Background: The Inception Cohort Registry Study of Patients with Crohn's Disease aimed to clarify clinical characteristics and disease course of newly diagnosed Crohn's disease patients in Japan throughout a 4-year period. Results from an interim analysis of the largest nation-wide registry study that covers approximately 1% of Crohn's disease patient population in Japan are reported.Methods: This prospective, observational registry study was conducted at 19 tertiary centers in Japan. Patients newly diagnosed with Crohn's disease after June 2016 (age ≥ 16 years at informed consent) were enrolled between December 17, 2018 and June 30, 2020. Patient demographics, diagnostic procedures and categories, disease location and lesion behavior (Montreal classification) at the time of diagnosis were recorded.Results: Of 673 patients enrolled, 672 (99.9%) were analyzed (458: men, 214: women), male-to-female ratio: 2.1, median age at diagnosis 25 (range 13-86) years; peak age of disease diagnosis: 20-24 years. Most common disease location was L3 (ileocolonic; 60.1%). Non-stricturing, non-penetrating (B1) disease was most common behavior (62.8%); 48.9% reported perianal lesions. Notably, age-wise analysis revealed disease phenotypes varied between patients aged < 40 and ≥ 40 years in terms of male-to-female ratio (2.5/1.3)/disease location (L3: 66.3%/37.0%)/disease behavior (B1: 66.4%/50.0%)/perianal lesion: (55.7%/20.5%) at Crohn's disease diagnosis, respectively.Conclusions: Interim analysis of this nation-wide Inception Cohort Registry Study of Patients with Crohn's Disease revealed the demographics and disease characteristics of newly diagnosed Crohn's disease patients in Japan and demonstrated that disease phenotype varied between patients aged < 40 and ≥ 40 years, serving as important information for management of individual patients. [ABSTRACT FROM AUTHOR]

Background: Loss of E-cadherin expression is frequently observed in signet ring carcinoma (SRCC). People with germline mutations in CDH1, which encodes E-cadherin, develop diffuse gastric cancer at a higher rate. Loss of E-cadherin expression is thus assumed to trigger oncogenic development. Methods: To investigate novel therapeutic targets for gastric SRCC, we engineered an E-cadherin-deficient SRCC model in vitro using a human gastric organoid (hGO) with CDH1 knockout (KO). Results: CDH1 KO hGO cells demonstrated distinctive morphological changes similar to SRCC and high cell motility. RNA-sequencing revealed up-regulation of matrix metalloproteinase (MMP) genes in CDH1 KO hGO cells compared to wild type. MMP inhibitors suppressed cell motility of CDH1 KO hGO cells and SRCC cell lines in vitro. Immunofluorescent analysis with 95 clinical gastric cancer tissues revealed that MMP-3 was specifically abundant in E-cadherin-aberrant SRCC. In addition, CXCR4 molecules translocated onto the cell membrane after CDH1 KO. Addition of CXCL12, a ligand of CXCR4, to the culture medium prolonged cell survival of CDH1 KO hGO cells and was abolished by the inhibitor, AMD3100. In clinical SRCC samples, CXCL12-secreting fibroblasts showed marked infiltration into the cancer area. Conclusions: E-cadherin deficient SRCCs might gain cell motility through upregulation of MMPs. CXCL12-positive cancer-associated fibroblasts could serve to maintain cancer-cell survival as a niche. MMPs and the CXCL12/CXCR4 axis represent promising candidates as novel therapeutic targets for E-cadherin-deficient SRCC. [ABSTRACT FROM AUTHOR]

A 71-year-old man was admitted to our institution complaining of abdominal pain and constipation. Barium enema examination revealed narrowing, cobble stoning, and longitudinal ulcerations in the sigmoid colon and upper rectum. Conventional colonoscopy, magnifying narrow-band imaging endoscopy, and magnifying chromoendoscopy revealed edematous mucosa, longitudinal ulcerations with luminal narrowing, and multiple pseudopolyps. The histologic examination of the biopsy specimens showed thick-walled (arterialized) capillaries and subendothelial fibrin deposits in the mucosa and submucosa. Based on a preoperative diagnosis of idiopathic myointimal hyperplasia of mesenteric veins (IMHMV), he underwent a laparoscopic resection of the sigmoid colon and upper rectum. The histologic examination of the resected specimens showed marked proliferation of venous walls with marked myointimal thickening and luminal occlusion from the submucosa to the mesentery throughout the entire resected tissue section. The final diagnosis was IMHMV. [ABSTRACT FROM AUTHOR]

Introduction: An association has been found between human-gut microbiota and various diseases (e.g., metabolic disease) by analyzing fecal or colonic microbiota. Despite the importance of the small intestinal microbiota, sampling difficulties prevent its full analysis. We investigated the composition and metagenomic functions of microbiota along the small intestine and compared them with the microbiota from feces and from other gastrointestinal (GI) sites. Methods: Mucosal samples from the six GI sites (stomach, duodenum, distal jejunum, proximal ileum, terminal ileum, and rectum) were collected under balloon-assisted enteroscopy. Fecal samples were collected from all participants. The microbial structures and metagenomic functions of the small intestinal mucosal microbiota were compared with those from feces and other GI sites using 16S ribosomal RNA gene sequencing. Results: We analyzed 133 samples from 29 participants. Microbial beta diversity analysis showed that the jejunum and ileum differed significantly from the lower GI tract and the feces (p < 0.001). Jejunal and duodenal microbiotas formed similar clusters. Wide clusters spanning the upper and lower GI tracts were observed with the ileal microbiota, which differed significantly from the jejunal microbiota (p < 0.001). Veillonella and Streptococcus were abundant in the jejunum but less so in the lower GI tract and feces. The metagenomic functions associated with nutrient metabolism differed significantly between the small intestine and the feces. Conclusions: The fact that the compositional structures of small intestinal microbiota differed from those of fecal and other GI microbiotas reveals that analyzing the small intestinal microbiota is necessary for association studies on metabolic diseases and gut microbiota. [ABSTRACT FROM AUTHOR]

This document is a reply to a comment about the lack of a definitive marker in ferroptosis research. The authors discuss their studies, which have shown that indigo naturalis can reverse cell death induced by a ferroptosis inducer. They observed the accumulation of reactive oxygen species and lipid peroxidation, as well as a depletion of glutathione, and found that indigo naturalis can inhibit intracellular iron accumulation. The authors agree with the commenter's perspective on the importance of evaluating antioxidant and iron-chelating activity in ferroptosis inhibitors. They also mention the need for further investigation into iron metabolic abnormalities and gene expression changes in non-responding patients. The authors appreciate the insights provided by the readers. [Extracted from the article]

Purpose: The aim of this investigation was to evaluate the clinical value of barium enema (BE) examination for the management of colorectal epithelial neoplasms. Methods: We reviewed the colonoscopy records at our institution from 2014 to 2019 and identified cases of endoscopically or surgically resected colorectal epithelial neoplasms evaluated by BE, conventional colonoscopy, magnifying narrow-band imaging colonoscopy (M-NBI), and magnifying chromoendoscopy (MCE). The yield of each modality for the diagnosis of massively submucosal invasive (mSM) colorectal cancer was evaluated by a receiver-operating characteristic analysis including the area under the curve (AUC). Results: We analyzed the records of 105 patients (17 adenomas, 53 high-grade dysplasias (HGDs), and 35 cancers). Smooth surface, irregularity in depression, and eccentric deformity on the profile view with BE were observed more frequently in mSM cancers than adenomas/HGDs/slightly submucosal invasive cancers (p < 0.01). The AUC of BE was 0.8355, the value of which was not different from the other three modalities (conventional colonoscopy 0.7678; M-NBI 0.7835; MCE 0.8376). Although the specificity, PPV, and accuracy of BE were lower than those of M-NBI and MCE, the sensitivity and NPV of BE were the highest among the four types of examinations. Conclusion: BE is still available and may serve as a supplementary modality for the diagnosis of mSM cancers. [ABSTRACT FROM AUTHOR]

Background: The mortality and risk factors of severe disease and death due to arterial and venous thromboembolism (ATE and VTE, respectively) in patients with inflammatory bowel disease (IBD) remain unclear, especially in Asia. Aims: This study aimed to reveal the mortality and risk factors of TE in IBD patients in Japan. Methods: In the primary surveillance, responses to questionnaires regarding the number of cases of severe TE and TE-associated death in IBD patients in a span of over the past 10 years were obtained from 32 institutions in Japan. In the secondary surveillance, detailed data about IBD patients with TE were collected. The characteristics, laboratory data, therapy status, and situation at the time of TE development were retrospectively collected, and the data were compared between the patients with and without severe TE and TE-associated death. Results: The incidence of TE was 1.89% among 31,940 IBD patients. The frequencies of severe TE and TE-associated mortality were 10.7% and 1.0% among the total IBD and TE with IBD patients, respectively. The only risk factor for severe ATE and ATE-associated death was ischemic heart disease. The independent risk factors for severe VTE and VTE-associated death were age (≤ 45 years old), the site of VTE, and disease severity, with anti-TNF therapy as a potential negative risk factor. Patients with severe VTE had a high risk of developing persistent VTE and sequelae. Conclusion: Unlike ATE, the incidence of VTE was comparable in Asian and Western countries. Therapeutic and prophylactic strategies for managing IBD-associated TE in Asia are urgently needed. [ABSTRACT FROM AUTHOR]

Background: Ustekinumab (UST), an antibody targeting the p40 subunit of interleukin (IL)-12 and IL-23, is effective in treating Crohn's disease (CD). To clarify the mechanism of UST, we investigated T-cell differentiation in CD patients treated with UST. Methods: Twenty-seven patients with active CD were enrolled in this study. Seventeen patients were treated with UST, and 10 patients were treated with anti-tumor necrosis factor (TNF)-alpha therapy. The changes in the proportions of T-cell subsets after these therapies were analyzed by flow cytometry. Comprehensive gene expression changes in the colonic mucosa were also evaluated. Results: The frequency of T helper (Th) 17 cells was significantly decreased in the peripheral blood of patients with active CD after UST therapy. Anti-TNF therapy had a minimal effect on Th17 cells but increased the proportion of regulatory T cells. Enrichment analysis showed the expression of genes involved in the Th17 differentiation pathway was downregulated in the colonic mucosa after UST but not anti-TNF therapy. There were no common differentially expressed genes between CD patients treated with UST and anti-TNF therapy, suggesting a clear difference in their mechanism of action. Conclusion: In patients with active CD, UST therapy suppressed Th17 cell differentiation both in the peripheral blood and colonic tissues. [ABSTRACT FROM AUTHOR]

Background: Although combining thiopurine with infliximab (IFX) is considered to improve the clinical efficacy of IFX when treating Crohn's disease (CD), it also increases the risk of adverse events (AEs). We compared the efficacy and safety of delayed thiopurine addition after loss of response (LOR) to IFX with the efficacy and safety of an earlier combination of thiopurine and IFX. Methods: This retrospective study analyzed patients with CD who started IFX as a first-line biologic at Kyushu University Hospital between June 2002 and July 2018. Patients were assigned to either the early-combination (EC) group, who started IFX and thiopurine simultaneously, or the late-combination (LC) group, who were treated with IFX alone until they developed LOR. We compared the cumulative IFX continuation rates and AE incidence between the two groups. Results: One hundred seventy-six patients were enrolled in this study; 49 were enrolled in the EC group, and 127 were enrolled in the LC group. Disease activity at baseline did not significantly differ between the groups, nor did the cumulative IFX continuation rates differ between the groups (P = 0.30); however, the AE rate was significantly higher in the EC group than in the LC group (38.7% vs. 21.2%; P = 0.02). The severe AE rate was also higher in the EC group than in the LC group (18.3% vs 3.1%; P = 0.001). Conclusion: Considering the risk–benefit balance, delayed addition of thiopurine after LOR to IFX might be an alternative strategy when using IFX to treat CD. [ABSTRACT FROM AUTHOR]

Background: This study aimed to compare the markers of potential pancreatic injury during antegrade double-balloon endoscopy (DBE) using the newly developed ultrathin EN-580XP system and the conventional EN-580T system.Methods: Patients who were scheduled for antegrade DBE during daily clinical practice were enrolled. Clinical background, adverse events, and laboratory data of patients were compared between those who underwent endoscopy using the EN-580XP system and those in whom the EN-580T system was used. The primary end points were pancreatic hyperamylasemia and hyperlipasemia after DBE.Results: A total of 295 cases were registered. Pancreatic hyperamylasemia occurred in 2 of 92 patients (2.2 %) in the EN-580XP group and in 28 of 147 patients (19.1 %) in the EN-580 T diagnosis group (P < 0.001). Hyperlipasemia was significantly different between the two groups (1.1 % [EN-580XP] vs. 13.6 % [EN-580 T diagnosis]; P < 0.001). Acute pancreatitis occurred in four patients (7.1 %) in the EN-580 T therapy group. Multiple logistic regression analyses revealed that the endoscope type EN-580 T was significantly associated with pancreatic hyperamylasemia (adjusted odds ratio [OR] 8.63, 95 % confidence interval [CI] 1.97 - 37.70; P < 0.01) and hyperlipasemia (adjusted OR 13.10, 95 %CI 1.70 - 100.70; P = 0.01).Conclusions: The EN-580XP system seemed less harmful to the pancreas during antegrade DBE. [ABSTRACT FROM AUTHOR]

Background: This multicenter prospective study (UMIN000019958) aimed to evaluate the usefulness of serum leucin-rich alpha-2 glycoprotein (LRG) levels in monitoring disease activity in inflammatory bowel disease (IBD).Methods: Patients with moderate-to-severe IBD initiated on adalimumab therapy were enrolled herein. Serum LRG, C-reactive protein (CRP), and fecal calprotectin (fCal) levels were measured at week 0, 12, 24, and 52. Colonoscopy was performed at week 0, 12, and 52 for ulcerative colitis (UC), and at week 0, 24, and 52 for Crohn's disease (CD). Endoscopic activity was assessed using the Simple Endoscopic Score for Crohn's Disease (SES-CD) for CD and the Mayo endoscopic subscore (MES) for UC.Results: A total of 81 patients was enrolled. Serum LRG levels decreased along with improvements in clinical and endoscopic outcomes upon adalimumab treatment (27.4 ± 12.6 μg/ml at week 0, 15.5 ± 7.7 μg/ml at week 12, 15.7 ± 9.6 μg/ml at week 24, and 14.5 ± 6.8 μg/ml at week 52), being correlated with endoscopic activity at each time point (SES-CD: r = 0.391 at week 0, r = 0.563 at week 24, r = 0.697 at week 52; MES: r = 0.534 at week 0, r = 0.429 at week 12, r = 0.335 at week 52). Endoscopic activity better correlated with LRG compared to CRP and fCal on pooled analysis at all time points (SES-CD: LRG: r = 0.636, CRP: r = 0.402, fCal: r = 0.435; MES: LRG: r = 0.568, CRP: 0.389, fCal: r = 0.426).Conclusions: Serum LRG is a useful biomarker of endoscopic activity both in CD and UC during the adalimumab treatment. [ABSTRACT FROM AUTHOR]

A 67-year old woman with a history of long-term Chinese herb use was admitted to our institution complaining of abdominal pain. Barium enema disclosed rigidity of throughout the proximal colon and a slightly elevated lesion in the transverse colon. Colonoscopy showed diffuse and bronze mucosa in the proximal colon, which was compatible with mesenteric phlebosclerosis. There was also a reddish, elevated lesion in the transverse colon. Magnifying colonoscopy revealed irregular microsurface and microvessels on the surface of the lesion. Under a diagnosis of intramucosal cancer, the elevated lesion was treated by endoscopic submucosal dissection. Histological examination of the resected specimen showed intramucosal well-differentiated adenocarcinoma, and fibrous thickening of the vascular wall together with collagen deposition in the submucosa. The final diagnosis was an intramucosal cancer occurring in mesenteric phlebosclerosis. [ABSTRACT FROM AUTHOR]

Expression quantitative trait locus (eQTL) analyses have enabled us to predict the function of disease susceptibility SNPs. However, eQTL for the effector memory T cells (TEM) located in the lamina propria mononuclear cells (LPMCs), which play an important role in Crohn's disease (CD), are not yet available. Thus, we conducted RNA sequencing and eQTL analyses of TEM cells located in the LPMCs from IBD patients (n = 20). Genome-wide association study (GWAS) was performed using genotyping data of 713 Japanese CD patients and 2,063 controls. We compared the results of GWAS and eQTL of TEM, and also performed a transcriptome-wide association study using eQTL from Genotype Tissue Expression project. By eQTL analyses of TEM, correlations of possible candidates were confirmed in 22,632 pairs and 2,463 genes. Among these candidates, 19 SNPs which showed significant correlation with tenascin-XA (TNXA) expression were significantly associated with CD in GWAS. By TWAS, TNFSF15 (FDR = 1.35e-13) in whole blood, ERV3-1 (FDR = 2.18e-2) in lymphocytes, and ZNF713 (FDR = 3.04e-2) in the sigmoid colon was significantly associated with CD. By conducting integration analyses using GWAS and eQTL data, we confirmed multiple gene transcripts are involved in the development of CD. [ABSTRACT FROM AUTHOR]

Because the pathogenesis of gastrointestinal follicular lymphoma (GI-FL) remains unclear, no standardized treatment strategy has been established. Of the gastrointestinal lymphomas, gastric mucosa-associated lymphoid tissue lymphomas are strongly associated with Helicobacter pylori; hence, the microbiota may be involved in GI-FL pathogenesis. However, the association between GI-FL and the microbiota remains uninvestigated. Therefore, we compared the mucosal microbiotas of GI-FL patients with those of controls to identify microbiota changes in GI-FL patients. Mucosal biopsy samples were obtained from the second portion of the duodenum from 20 GI-FL patients with duodenal lesions and 20 controls. Subsequent 16S rRNA gene sequencing was performed on these samples. QIIME pipeline and LEfSe software were used to analyze the microbiota. The GI-FL patients had significantly lower alpha diversity (P = .049) than did the controls, with significant differences in the microbial composition (P = .023) evaluated by the beta diversity metrics between the two groups. Comparing the taxonomic compositions indicated that the genera Sporomusa, Rothia, and Prevotella and the family Gemellaceae were significantly less abundant in the GI-FL patients than in the controls. GI-FL patients presented altered duodenal mucosal microbial compositions, suggesting that the microbiota might be involved in the GI-FL pathogenesis. [ABSTRACT FROM AUTHOR]

Background and Aim: Indigo naturalis (IN) is a traditional Chinese herbal medicine reported to be effective in inducing remission in ulcerative colitis (UC). We conducted a retrospective observational study to investigate the efficacy and safety of IN for induction and maintenance therapy in patients with inflammatory bowel disease. Methods: Data were collected from the electric medical records of patients with inflammatory bowel disease who had started IN treatment between March 2015 and April 2017 at Kyushu University Hospital. Clinical response and remission rates were assessed based on the clinical activity index determined by Rachmilewitz index or Crohn's disease (CD) activity index. Cumulative IN continuation rates were estimated using the Kaplan–Meier method. Overall adverse events (AEs) during follow‐up were also analyzed. Results: Seventeen UC patients and eight CD patients were enrolled. Clinical response and remission rates at week 8 were 94.1% and 88.2% in UC patients and 37.5% and 25.0% in CD patients, respectively. Clinical remission rates, as assessed through non‐responders imputation analyses at weeks 52 and 104, were 76.4% and 70.4% in UC patients and 25.0% and 25.0% in CD patients, respectively. Ten patients (40%) experienced AEs during follow‐up. Three patients (12%) experienced severe AEs, including acute colitis requiring hospitalization in two patients and acute colitis with intussusception requiring surgery in one patient. Conclusions: Indigo naturalis showed favorable therapeutic efficacy in UC, whereas its therapeutic efficacy in CD appeared to be modest. The risk of severe AEs should be recognized for IN treatment. [ABSTRACT FROM AUTHOR]

Background: Although capsule endoscopy (CE) is useful to evaluate obscure gastrointestinal bleeding (OGIB), CE does not always identify the responsible lesions in patients with overt OGIB. Objectives: To identify factors predictive of rebleeding after negative CE in patients with overt OGIB. Methods: We retrospectively analyzed the clinical data of 221 patients who underwent CE for overt OGIB. Among 120 patients with negative CE findings, clinical course of 112 patients after CE was followed-up. Clinical factors associated with rebleeding after negative CE and lesions responsible for rebleeding were investigated. Results: Rebleeding was identified in 37 patients (33.0%) during follow-up after negative CE, and 36 patients (32.1%) developed rebleeding within 24 months after negative CE. Multivariate analyses showed that ongoing overt OGIB (OR 2.67; 95% CI 1.07–5.80; p = 0.036) and severe anemia at the initial CE examination (OR 2.54; 95% CI 1.33–4.96; p = 0.005) were independent factors -associated with rebleeding. Rebleeding source was detected in 13 patients. Conclusions: Rebleeding is not a rare condition among patients with overt OGIB after negative CE. Patients with ongoing overt OGIB or severe anemia at the initial CE examination seem to have a higher risk of rebleeding. [ABSTRACT FROM AUTHOR]

This article discusses a case study of a 66-year-old woman with a history of endoscopic submucosal dissection (ESD) for esophageal cancer who was referred for surveillance esophagogastroduodenoscopy (EGD). The EGD revealed a pale reddish lesion and melanosis in the right pyriform sinus. Narrow-band imaging (NBI) endoscopy and magnifying NBI endoscopy were used to further examine the lesion. Texture and color enhancement imaging (TXI) mode 1 was also used, which helped distinguish between the tumor and melanosis and enabled a clear boundary of the tumor. The patient underwent ESD with the use of an esophagogastroduodenoscope and needle- and scissors-type knives. The resected tumor was found to be well-differentiated squamous cell cancer limited to the epithelial layers without lymphovascular invasion. The authors suggest that a combination of TXI and ESD may be valuable for the diagnosis and treatment of hypopharyngeal cancer with melanosis. [Extracted from the article]

Also, an Appendix listing iCREST-CD Study Group collaborators is included in this correction. Appendix: iCREST-CD Study Group Collaborators Masakazu Nagahori: Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University; Tatsu Yukawa: Inflammatory Bowel Disease Center Yokohama City University Medical Center; Daisuke Saito: Department of Gastroenterology and Hepatology, Kyorin University School of Medicine; Mikio Kawai: Department of Intestinal Inflammation Research, Hyogo College of Medicine; Atsushi Masamune: Division of Gastroenterology, Tohoku University Graduate School of Medicine; Mitsuo Nagasaka: Department of Gastroenterology, Fujita Health University School of Medicine; Tomoe Kazama: Department of Gastroenterology and Hepatology, Sapporo Medical University School of Medicine. [Extracted from the article]

Background: Anti-tumor necrosis factor (TNF) therapy induces and maintains clinical remission in patients with Crohn's disease (CD). However, the effect of anti-TNF therapy on the natural course of CD remains controversial. We aimed to investigate the effect of anti-TNF therapy on the initial intestinal surgery for CD.Methods: In this single-center retrospective cohort study, clinical course of 199 CD patients of inflammatory type at the initial diagnosis (the period between 1973 and 2014) was precisely reviewed until the end of 2016. Patients were divided into TNF and non-TNF groups based on anti-TNF agent use. After comparisons of clinical characteristics and medical treatments, propensity scores were calculated for covariates. Risk of intestinal surgery was compared by a Cox proportional hazards model using the propensity scores. The effect of immunomodulators on initial intestinal surgery was assessed in the TNF group.Results: During the study period, 108 patients received anti-TNF therapy. The patients in the TNF group were diagnosed more recently, and more frequently had isolated colonic involvement, and perianal disease. Immunomodulators were more frequently used in the TNF group. Cumulative probability of initial intestinal surgery was significantly lower in the TNF group (P < 0.0001). The hazard ratio in the TNF group was 0.32 (95% CI 0.13-0.74). Immunomodulators did not decrease the risk of initial intestinal surgery.Conclusions: Anti-TNF therapy can decrease the risk of intestinal surgery among patients with inflammatory-type CD at the initial diagnosis. Further studies should be necessary to determine the additive effect of immunomodulators on the risk of intestinal surgery. [ABSTRACT FROM AUTHOR]

Comprehensive gene expression analysis in this study revealed that B cell signaling was upregulated in non-CR patients, and the up-regulated genes in CR patients were related with tumor micro-environment. Keywords: gastric DLBCL; Helicobacter pylori; MALT; CARD11 EN gastric DLBCL Helicobacter pylori MALT CARD11 145 147 3 02/25/21 20210201 NES 210201 PEER REVIEW The peer review history for this article is available at https://publons.com/publon/10.1002/hon.2816. Helicobacter pylori eradication therapy is effective in the treatment of early-stage H pylori-positive gastric diffuse large B-cell lymphomas. [Extracted from the article]

Abstract: Background and Aim: The gut microbiota is suggested to play an important role in the pathogenesis of ulcerative colitis (UC). However, interindividual and spatial variations hamper the identification of UC‐related changes. We thus investigated paired mucosa‐associated microbiota obtained from both inflamed and non‐inflamed sites of UC patients and corresponding sites of non‐inflammatory bowel disease (IBD) controls. Methods: Mucosal biopsies of both inflamed and non‐inflamed sites were obtained from 14 patients with active UC of the left‐sided or proctitis type. Paired mucosal biopsies of the corresponding sites were obtained from 14 non‐IBD controls. The microbial community structure was investigated using 16S ribosomal RNA gene sequences, followed by data analysis using qiime and LEfSe softwares. Results: Microbial alpha diversity in both inflamed and non‐inflamed sites was significantly lower in UC patients compared with non‐IBD controls. There were more microbes of the genus Cloacibacterium and the Tissierellaceae family, and there were less microbes of the genus Neisseria at the inflamed site when compared with the non‐inflamed site in UC patients. Decreased abundance of the genera Prevotella, Eubacterium, Neisseria, Leptotrichia, Bilophila, Desulfovibrio, and Butyricimonas was evident at the inflamed site of UC patients compared with the corresponding site of non‐IBD controls. Among these taxa, the genera Prevotella and Butyricimonas were also less abundant at the non‐inflamed site of UC patients compared with the corresponding site in non‐IBD controls. Conclusions: Mucosal microbial dysbiosis occurs at both inflamed and non‐inflamed sites in UC patients. The taxa showing altered abundance in UC patients might mediate colonic inflammation. [ABSTRACT FROM AUTHOR]

Genomewide association studies have shown that a nonsynonymous single nucleotide polymorphism in PRKCH is associated with cerebral infarction and atherosclerosis-related complications. We examined the role of PKCη in lipid metabolism and atherosclerosis using apolipoprotein E-deficient ( Apoe −/−) mice. PKCη expression was augmented in the aortas of mice with atherosclerosis and exclusively detected in MOMA2-positive macrophages within atherosclerotic lesions. Prkch +/+ Apoe −/− and Prkch −/− Apoe −/− mice were fed a high-fat diet ( HFD), and the dyslipidemia observed in Prkch +/+ Apoe −/− mice was improved in Prkch −/− Apoe −/− mice, with a particular reduction in serum LDL cholesterol and phospholipids. Liver steatosis, which developed in Prkch +/+ Apoe −/− mice, was improved in Prkch −/− Apoe −/− mice, but glucose tolerance, adipose tissue and body weight, and blood pressure were unchanged. Consistent with improvements in LDL cholesterol, atherosclerotic lesions were decreased in HFD-fed Prkch −/− Apoe −/− mice. Immunoreactivity against 3-nitrotyrosine in atherosclerotic lesions was dramatically decreased in Prkch −/− Apoe −/− mice, accompanied by decreased necrosis and apoptosis in the lesions. ARG2 mRNA and protein levels were significantly increased in Prkch −/− Apoe −/− macrophages. These data show that PKCη deficiency improves dyslipidemia and reduces susceptibility to atherosclerosis in Apoe −/− mice, showing that PKCη plays a role in atherosclerosis development. [ABSTRACT FROM AUTHOR]

The physiological role of autophagic flux within the vascular endothelial layer remains poorly understood. Here, we show that in primary endothelial cells, oxidized and native LDL stimulates autophagosome formation. Moreover, by both confocal and electron microscopy, excess native or modified LDL appears to be engulfed within autophagic structures. Transient knockdown of the essential autophagy gene ATG7 resulted in higher levels of intracellular 125I- LDL and oxidized LDL (Ox LDL) accumulation, suggesting that in endothelial cells, autophagy may represent an important mechanism to regulate excess, exogenous lipids. The physiological importance of these observations was assessed using mice containing a conditional deletion of ATG7 within the endothelium. Following acute intravenous infusion of fluorescently labeled Ox LDL, mice lacking endothelial expression of ATG7 demonstrated prolonged retention of Ox LDL within the retinal pigment epithelium ( RPE) and choroidal endothelium of the eye. In a chronic model of lipid excess, we analyzed atherosclerotic burden in ApoE−/−mice with or without endothelial autophagic flux. The absence of endothelial autophagy markedly increased atherosclerotic burden. Thus, in both an acute and chronic in vivo model, endothelial autophagy appears critically important in limiting lipid accumulation within the vessel wall. As such, strategies that stimulate autophagy, or prevent the age-dependent decline in autophagic flux, might be particularly beneficial in treating atherosclerotic vascular disease. [ABSTRACT FROM AUTHOR]

Endothelial secretion of von Willebrand factor (VWF) from intracellular organelles known as Weibel-Palade bodies (WPBs) is required for platelet adhesion to the injured vessel wall. Here we demonstrate that WPBs are often found near or within autophagosomes and that endothelial autophagosomes contain abundant VWF protein. Pharmacological inhibitors of autophagy or knockdown of the essential autophagy genes Atg5 or Atg7 inhibits the in vitro secretion of VWF. Furthermore, although mice with endothelial-specific deletion of Atg7 have normal vessel architecture and capillary density, they exhibit impaired epinephrine-stimulated VWF release, reduced levels of high-molecular weight VWF multimers and a corresponding prolongation of bleeding times. Endothelial-specific deletion of Atg5 or pharmacological inhibition of autophagic flux results in a similar in vivo alteration of hemostasis. Thus, autophagy regulates endothelial VWF secretion, and transient pharmacological inhibition of autophagic flux may be a useful strategy to prevent thrombotic events. [ABSTRACT FROM AUTHOR]

Abstract: Background and aims: The effects of maintenance infliximab for Crohn''s disease vary widely among patients. The aim of this study was to examine the cytokine profiles and to identify possible markers predictive of therapeutic effect of maintenance infliximab. Methods: Cytokine profiles of 35 Crohn''s disease patients under maintenance infliximab therapy were analyzed prospectively. Blood samples were obtained prior to, and 2 and 6weeks after infliximab infusion. Circulating cytokine values of interleukin (IL)-23, IL-17A, IL-12, IL-6, interferon gamma (IFN-γ), and tumor necrosis factor alpha (TNF-α) were compared according to the disease activity and therapeutic efficacy. Patients were classified into either the active or quiescent phase according to their disease activity at baseline. Patients were also divided into a sustained response group and non-sustained response group according to therapeutic efficacy of infliximab determined 2 and 6weeks after infliximab infusion. Results: At baseline, serum levels of IL-23 (p<0.05), IL-17A (p<0.01), IFN-γ (p<0.05), and IL-6 (p<0.01) were significantly higher in active Crohn''s disease than in quiescent disease. These cytokine levels remained unchanged during the follow-up period. When serum cytokine levels were compared between groups classified by therapeutic efficacy of infliximab, patients in the non-sustained response group had a significantly higher level of serum IL-17A than those in the sustained response group (p<0.05). There were also trends toward higher serum IL-23 and IL-12 in the former than in the latter. Conclusion: Higher levels of IL-17A, IL-23, and IL-12 at baseline may be predictive markers for poor therapeutic response to maintenance infliximab therapy. [Copyright &y& Elsevier]

Background and aims: Although serum albumin levels are associated with mortality in non-institutionalized elderly people under 80 years old, as well as in the institutionalized very elderly, little is known about the relationship in community-dwelling very elderly people. We, therefore, examined the association in a Japanese population of 80-year-old community residents. Methods: Serum albumin levels were measured in 672 (267 men, 405 women) out of 1282 80-year-old individuals. Over the following 4 years, the dates and causes of death were recorded from resident registration cards and official death certificates. Results: Of the above individuals, 107 subjects died (58 men, 49 women: 27 due to cancer, 27 cardiovascular disease, and 22 pneumonia). Survival rates were compared among 4 groups (highest >45 g/L, higher than 43-44 g/L, lower than 41-42 g/L, lowest <40 g/L). After adjustment for confounding factors, total death or cardiovascular death in the lowest albumin group was 3.1 times and 10.7 times more incident than in the highest albumin group, but there were no differences among groups as regards deaths due to cancer or pneumonia. Conclusion: Serum albumin levels are an independent predictor of mortality due to all-cause or cardiovascular disease, but not of mortality due to cancer or pneumonia in very elderly Japanese community residents. [ABSTRACT FROM AUTHOR]

Background: Findings from several studies suggest associations between tooth loss and health outcomes, including malnutrition, poor quality of life, and mortality, in older individuals. However, limited information is available regarding whether those associations remain true in very elderly subjects after adequately considering confounding factors such as sex and smoking status. Herein, we determined whether the number of teeth in 80-year-old subjects is an independent predictor of mortality.Methods: We initially contacted 1282 80-year-old community-dwelling individuals born in 1917, of whom 697 responded and participated in a baseline study, with follow-up examinations conducted 4 and 5.5 years later. Data from interviews and medical and oral examinations were obtained, and oral health was determined according to the number of teeth remaining in the oral cavity.Results: A total of 108 and 157 subjects died in 4 years and 5.5 years, respectively, after the baseline study. Tooth loss was significantly associated with mortality at age 85.5, but not at age 84, after adjusting for potential confounders. When the analysis was stratified by sex, we found a stronger association in females in follow-up examinations conducted at both 4- and 5.5 years. On the other hand, the effect of tooth loss on mortality was not significantly different between smokers and non-smokers.Conclusion: Tooth loss is a significant predictor of mortality independent of health factors, socio-economic status, and lifestyle in octogenarians, with a stronger association in females. [ABSTRACT FROM AUTHOR]

Hypertension is one of the greatest risk factors for cardiovascular disease, but its contribution to cardiovascular mortality weakens with aging. We have previously demonstrated that at the age of 80, higher systolic blood pressure (SBP) is not correlated with increased mortality in Japan. However, we did not examine in detail whether diastolic blood pressure (DBP) independently affects mortality. In the present study, 639 participants, who were 80 years old in 1997, were enrolled. The subjects were divided by their DBP [below 70 mmHg (group 1, n = 136), from 70 mmHg to 80 mmHg (group 2, n = 200), from 80 mmHg to 90 mmHg (group 3, n = 194), over 90 mmHg (group 4, n = 109)]. During the 4-year follow-up period, 90 individuals died. Cox multivariate regression analysis revealed that group 1 showed a significantly higher mortality rate than group 4 [relative risk (RR) 2.47, confidence interval (CI) 1.07–5.70, p = 0.03)]. The relative risks of deaths from cardiovascular diseases, pneumonia, and cancer tended to be higher in group 1 than in group 4, but the difference did not reach statistical significance. These results suggest that decreased DBP is associated with higher mortality in the Japanese elderly. [ABSTRACT FROM AUTHOR]

Background: Immunoglobulin levels are elevated in the older people. However, it is unknown whether these levels are related to mortality. Object: To evaluate the association between immunoglobulin levels and mortality. Methods: The study population included 697 individuals (277 males and 420 females) of 1,282 eighty-year-old individuals residing in the Fukuoka prefecture, Japan. The participants were followed for 4 years after the baseline examination. Results: The hyper-IgA group, defined as a serum IgA level >400 mg/dl, had high mortality using Kaplan-Meier analysis (log rank, p = 0.037). Multivariate Cox regression analyses revealed a high risk of mortality (hazard rate = 1.233, 95% confidence interval 1.109–1.491, p = 0.031) after adjusting for covariates. The high risk of mortality in the hyper-IgA group was significant in males, but not in females. Moreover, Kaplan-Meier analysis revealed that IgA was related to cancer mortality in males (log rank, p = 0.031), but not to pneumonia or cardiovascular disease. IgM and IgG levels were not related to high risk of mortality. Conclusion: Serum IgA levels appear to be a predictor of mortality, especially cancer mortality in males. Copyright © 2008 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

The relationship between Helicobacter pylori (HP) infection and body mass index (BMI) is controversial. Several reports have indicated that eradication of HP infection induces an increase in BMI. In contrast, epidemiological case-control studies have failed to show an association between HP infection and BMI. Therefore, we investigated whether HP and atrophic gastritis (AG) were associated with BMI. A total of 617 individuals were recruited for the measurements of BMI, serum leptin, pepsinogens (PGs) I and II, and IgG antibody to HP (HP-IgG). BMI and leptin of the subjects were compared when the subjects were stratified by HP-IgG and PGs. The subjects were divided into AG-positive and AG-negative groups according to PGs (AG-positive: PG I ≤ 70 ng/ml and PG I/II ratio ≤3.0). BMI after adjusting for sex and age was significantly lower in the AG-positive group than in the AG-negative group (23.47 ± 3.05 vs. 24.18 ± 3.25, P = 0.010). When the subjects were divided into two groups according to HP-IgG, BMI tended to be lower in the HP-IgG-positive group, though the difference was not large. When the subjects were divided into four groups for different combinations of AG and HP-IgG, BMI was the lowest in the AG-positive and HP-IgG-negative group. BMI was associated with AG, as diagnosed by PGs, but not with HP infection status. These results mean that HP infection affects BMI via atrophic gastritis. [ABSTRACT FROM AUTHOR]

Objectives: To evaluate the association between high-level functional capacity and chewing in a middle-old community-based population. Background: Although basic and instrumental activities of daily living are known to be associated with chewing ability in the elderly, an association between higher levels of competence and chewing ability has not been evaluated in the elderly. Materials and methods: The association between chewing ability using a number of different foods and high-level functional capacity by the Tokyo Metropolitan Institute of Gerontology was evaluated in 694, 80-year-old people residing in Fukuoka Prefecture, Japan. Results: A significant correlation was found, using multiple regression or logistic regression analyses adjusted for various confounding factors, between the number of total chewable foods, hard foods or moderately hard foods, and total functional capacity, instrumental activity, intellectual activity or social role ability. In contrast, the number of slightly hard foods, easily chewable foods and remaining teeth were only partly related to total functional capacity and intellectual activity. Conclusion: High-level functional capacity including intellectual activity and social role in middle-old elderly was associated with the ability to chew hard foods than to chew easily chewable foods. Maintenance of chewing ability in elderly might result in better intellectual activity and social role. [ABSTRACT FROM AUTHOR]

Inflammation associates with insulin resistance, which dysregulates nutrient homeostasis and leads to diabetes. The suppressor of cytokine signaling 3 (SOCS3), which is induced by pro-inflammatory cytokines, such as TNFα and IL-6, has been implicated in inflammation-mediated insulin resistance in the liver and adipocytes. However, no genetic evidence has been provided for the involvement of SOCS3 on insulin resistance. Here, we generated hepatocyte-specific SOCS3-deficient (L-SOCS3 cKO) mice and examined insulin sensitivity. Being consistent with a previous idea, the loss of SOCS3 in the liver apparently improved insulin sensitivity. However, unexpectedly, L-SOCS3 cKO mice exhibited obesity and systemic insulin resistance with age. Insulin signaling was rather suppressed in muscles, suggesting that deletion of the SOCS3 gene in the liver modulates insulin sensitivity in other organs. Anti-inflammatory reagent, sodium salicylate, partial improved insulin resistance of aged L-SOCS3 cKO mice, suggesting that enhanced inflammatory status is associated with the phenotype of these mice. STAT3 was hyperactivated and acute-phase proteins were elevated in L-SOCS3 cKO mice liver, which were reduced by sodium salicylate treatment. We conclude that hepatic SOCS3 is a mediator of insulin resistance in the liver; however, lack of SOCS3 in the liver promotes systemic insulin resistance by mimicking chronic inflammation. [ABSTRACT FROM AUTHOR]

Leptin is an adipocyte-derived hormone that plays a key role in energy homeostasis, yet resistance to leptin is a feature of most cases of obesity in humans and rodents. In vitro analysis suggested that the suppressor of cytokine signaling-3 (Socs3) is a negative-feedback regulator of leptin signaling involved in leptin resistance. To determine the functional significance of Socs3 in vivo, we generated neural cell-specific SOCS3 conditional knockout mice using the Cre-loxP system. Compared to their wild-type littermates, Socs3-deficient mice showed enhanced leptin-induced hypothalamic Stat3 tyrosine phosphorylation as well as pro-opiomelanocortin (POMC) induction, and this resulted in a greater body weight loss and suppression of food intake. Moreover, the Socs3-deficient mice were resistant to high fat diet-induced weight gain and hyperleptinemia, and insulin-sensitivity was retained. These data indicate that Socs3 is a key regulator of diet-induced leptin as well as insulin resistance. Our study demonstrates the negative regulatory role of Socs3 in leptin signaling in vivo, and thus suppression of Socs3 in the brain is a potential therapy for leptin-resistance in obesity. [ABSTRACT FROM AUTHOR]