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Silybin, a natural antioxidant, has been traditionally used against a variety of liver ailments. To investigate its effect and the underlying mechanisms of action on non-alcoholic fatty liver in rats, we used 60 4-6-week-old male Sprague-Dawley rats to establish fatty liver models by feeding a high-fat diet for 6 weeks. Hepatic enzyme, serum lipid levels, oxidative production, mitochondrial membrane fluidity, homeostasis model assessment-insulin resistance index (HOMA-IR), gene and protein expression of adiponectin, and resistin were evaluated by biochemical, reverse transcription polymerase chain reaction (RT-PCR) and Western blot analysis. Compared with the model group, silybin treatment (26.25 mg·kg-1·day-1, started at the beginning of the protocol) significantly protected against high-fat-induced fatty liver by stabilizing mitochondrial membrane fluidity, reducing serum content of alanine aminotransferase (ALT) from 450 to 304 U/L, decreasing hepatic malondialdehyde (MDA) from 1.24 to 0.93 nmol/mg protein, but increasing superoxide dismutase (SOD) and glutathione (GSH) levels from 8.03 to 9.31 U/mg protein and from 3.65 to 4.52 nmol/mg protein, respectively. Moreover, silybin enhanced the gene and protein expression of adiponectin from 215.95 to 552.40, but inhibited that of resistin from 0.118 to 0.018. Compared to rosiglitazone (0.5 mg·kg-1·day-1, started at the beginning of the protocol), silybin was effective in stabilizing mitochondrial membrane fluidity, reducing SOD as well as ALT, and regulating gene and protein expression of adiponectin (P < 0.05). These results suggest that mitochondrial membrane stabilization, oxidative stress inhibition, as well as improved insulin resistance, may be the essential mechanisms for the hepatoprotective effect of silybin on non-alcoholic fatty liver disease in rats. Silybin was more effective than rosiglitazone in terms of maintaining mitochondrial membrane fluidity and reducing oxidative stress.

Abstract Background Nuclear factor of kappa B inhibitor alpha (IκBα) protein is implicated in regulating a variety of cellular process from inflammation to tumorigenesis. The objective of this study was to investigate the susceptibility of rs2233408 T/C genotype in the promoter region of IκBα to gastric cancer and the association of this polymorphism with clinicopathologic variables in gastric cancer patients. Methods A population-based case-control study was conducted between 1999 and 2006 in Guangdong Province, China. A total of 564 gastric cancer patients and 566 healthy controls were enrolled in this study. rs2233408 genotypes in IκBα were analyzed by TaqMan SNP genotyping assay. Results Both rs2233408 T homozygote (TT) and T heterozygotes (TC and TT) had significantly reduced gastric cancer risk (TT: OR = 0.250, 95% CI = 0.069-0.909, P = 0.035; TC and TT: OR = 0.721, 95% CI = 0.530-0.981, P = 0.037), compared with rs2233408 C homozygote (CC). rs2233408 T heterozygotes were significantly associated with reduced risk of intestinal-type gastric cancer with ORs of 0.648 (95% CI = 0.459-0.916, P = 0.014), but not with the diffuse or mix type of gastric cancer. The association between rs2233408 T heterozygotes and gastric cancer appeared more apparent in the older patients (age>40) (OR = 0.674, 95% CI = 0.484-0.939, P = 0.02). rs2233408 T heterozygotes was associated with non-cardiac gastric cancer (OR = 0.594, 95% CI = 0.411-0.859, P = 0.006), but not with cardiac gastric cancer. However, rs2233408 polymorphism was not associated with the prognosis of gastric cancer patients. Conclusions IκBα rs2233408 T heterozygotes were associated with reduced risk of gastric cancer, especially for the development of certain subtypes of gastric cancer in Chinese population.

Abstract Background Epidemiological studies suggest considerable overlap between functional dyspepsia (FD) and irritable bowel syndrome (IBS). To date, no surveys have been performed to investigate the clinical overlap between these two disorders using Rome III criteria. Our aim was to investigate the prevalence and risk factors for the overlap of FD and IBS based on Rome III criteria in a large clinical sample. Methods Consecutive patients at the general gastroenterology outpatient clinic were requested to complete a self-report questionnaire. FD and IBS were defined by Rome III criteria. Results Questionnaires were returned by 3014 patients (52.8% female, 89% response rate). FD-IBS overlap was observed in 5.0% of the patients, while 15.2% and 10.9% of the patients were classified as FD alone and IBS alone, respectively. Compared with non-IBS patients, the odds ratio of having FD among IBS patients was 2.09 (95% CI: 1.68–2.59). Patients with FD-IBS overlap had higher severity scores for the postprandial fullness symptom (2.35 ± 1.49 vs. 1.72 ± 1.59, P < 0.001) and overall FD symptom (6.65 ± 2.88 vs. 5.82 ± 2.76, P = 0.002) than those with FD alone. The only independent risk factor for FD-IBS overlap vs. FD alone was the presence of postprandial fullness symptom (OR 2.67, 95% CI: 1.34–5.31). Conclusion Clinical overlap of FD and IBS according to Rome III criteria is very common. One risk factor for FD-IBS overlap is the presence of postprandial fullness symptom. This study provides clues for future pathophysiological studies of FD and IBS.

Introduction: The aim of this study was to investigate the role of circulating regulatory T cells (Tregs) as a novel marker associated with liver metastases and treatment response to transarterial embolization (TAE) in patients with gastroenteropancreatic neuroendocrine tumors (GEP-NETs). Methods: Circulating Tregs, defined as the CD4+CD25+CD127low/− population, were examined by flow cytometry in peripheral blood mononuclear cells from patients with GEP-NETs. Clinicopathological parameters, radiologic response, and hepatic progression-free survival (hPFS) data were collected. Results: The association between circulating Tregs and clinicopathological parameters was analyzed in 139 GEP-NET patients. Higher Treg levels were significantly associated with more progressive clinical features, including a higher WHO grade, more advanced TNM stage, and the presence of liver metastases. A Treg level ≥8.015% distinguished between patients with and without liver metastases. Among a cohort of 51 GEP-NET patients who were subjected to TAE for reducing liver metastasis burden, patients with higher Treg levels depicted unfavorable responses and significantly reduced hPFS after TAE treatment. We also revealed that patients with Treghigh (≥8.975%) displayed significantly shorter median hPFS than patients with Treglow (<8.975%). Additionally, after adjusting for other confounding clinical parameters, the association between Tregs and treatment response as well as hPFS remained significant, suggesting that Tregs may have a strong and independent prognostic impact in GEP-NETs. Conclusion: Our data suggest that circulating Tregs are a novel immunological marker associated with liver metastases and treatment response to TAE in patients with GEP-NETs. [ABSTRACT FROM AUTHOR]

Gut microbiota dysbiosis contributes to the onset and perpetuation of inflammatory bowel disease (IBD). Given that gut microbiotas vary across geography and ethnicity, it remains obscure whether any universal microbial signatures for IBD diagnosis and prognosis evaluation exist irrespective of populations. Here we profiled the fecal microbiota of a series of Chinese IBD patients and combined them with two Western IBD cohorts, PRISM and RISK, for meta-analyses. We found that the gut microbial alteration patterns in IBD are similar among Chinese and Westerners. Our prediction model based on gut microbiome for IBD diagnosis is robust across the cohorts, which showed 87.5% and 79.1% prediction accuracy in Crohn's disease (CD) and ulcerative colitis (UC) patients, respectively. A relative increase in the levels of Actinobacteria and Proteobacteria (Enterobacteriaceae) and a relative decrease in the levels of Firmicutes (Clostridiales) were strongly correlated with IBD severity (P < 0.05). Additionally, restoration of gut microbiota diversity and a significant increase in Clostridiales relative abundance were found in patients responding to infliximab (IFX [Remicade]) treatment compared to those in relapse. Moreover, certain microbes, mainly Clostridiales, predicted the treatment effectiveness with 86.5% accuracy alone and 93.8% accuracy in combination with calprotectin levels and Crohn's disease activity index (CDAI). Taking the results together, we conclude that gut microbiota can offer a set of universal biomarkers for diagnosis, disease activity evaluation, and infliximab treatment response prediction in IBD. IMPORTANCE In the present report, we show that the human fecal microbiota contains promising and universal biomarkers for the noninvasive evaluation of inflammatory bowel disease severity and IFX treatment efficacy, emphasizing the potential ability to mine the gut microbiota as a modality to stratify IBD patients and apply personalized therapy for optimal outcomes.

Background: H2S imbalances in the intestinal tract trigger Crohn's disease (CD), a chronic inflammatory gastrointestinal disorder characterized by microbiota dysbiosis and barrier dysfunction. However, a comprehensive understanding of H2S generation in the gut, and the contributions of both microbiota and host to systemic H2S levels in CD, remain to be elucidated. This investigation aimed to enhance comprehension regarding the sulfidogenic potential of both the human host and the gut microbiota. Results: Our analysis of a treatment-naive CD cohorts' fecal metagenomic and biopsy metatranscriptomic data revealed reduced expression of host endogenous H2S generation genes alongside increased abundance of microbial exogenous H2S production genes in correlation with CD. While prior studies focused on microbial H2S production via dissimilatory sulfite reductases, our metagenomic analysis suggests the assimilatory sulfate reduction (ASR) pathway is a more significant contributor in the human gut, given its high prevalence and abundance. Subsequently, we validated our hypothesis experimentally by generating ASR-deficient E. coli mutants ∆cysJ and ∆cysM through the deletion of sulfite reductase and L-cysteine synthase genes. This alteration significantly affected bacterial sulfidogenic capacity, colon epithelial cell viability, and colonic mucin sulfation, ultimately leading to colitis in murine model. Further study revealed that gut microbiota degrade sulfopolysaccharides and assimilate sulfate to produce H2S via the ASR pathway, highlighting the role of sulfopolysaccharides in colitis and cautioning against their use as food additives. Conclusions: Our study significantly advances understanding of microbial sulfur metabolism in the human gut, elucidating the complex interplay between diet, gut microbiota, and host sulfur metabolism. We highlight the microbial ASR pathway as an overlooked endogenous H2S producer and a potential therapeutic target for managing CD. Dka3P5uGJeBhH66pkNJcog Video Abstract [ABSTRACT FROM AUTHOR]

Purpose: Accurately and early detection of intestinal fibrosis in Crohn's disease (CD) is crucial for clinical management yet remains an unmet need. Fibroblast activation protein inhibitor (FAPI) PET/CT has emerged as a promising tool to assess fibrosis. We aimed to investigate the diagnostic capability of [18F]F-FAPI PET/CT in detecting intestinal fibrosis and compared it with[18F]F-FDG PET/CT and magnetization transfer MR imaging (MTI). Methods: Twenty-two rats underwent TNBS treatment to simulate fibrosis development, followed by three quantitative imaging sessions within one week. Mean and maximum standardized uptake values (SUVmean and SUVmax) were calculated on[18F]F-FAPI and [18F]F-FDG PET/CT, along with normalized magnetization transfer ratio on MTI. Intestinal fibrosis was assessed pathologically, with MTI serving as imaging standard for fibrosis. The diagnostic efficacy of imaging parameters in fibrosis was compared using pathological and imaging standards. Ten patients with 34 bowel strictures were prospectively recruited to validate their diagnostic performance, using the identical imaging protocol. Results: In CD patients, the accuracy of FAPI uptake (both AUCs = 0.87, both P ≤ 0.01) in distinguishing non-to-mild from moderate-to-severe fibrosis was higher than FDG uptake (both AUCs = 0.82, P ≤ 0.01) and comparable to MTI (AUCs = 0.90, P ≤ 0.001). In rats, FAPI uptake responded earlier to fibrosis development than FDG and MTI; consistently, during early phase, FAPI uptake showed a stronger correlation (SUVmean: R = 0.69) with pathological fibrosis than FDG (SUVmean: R = 0.17) and MTI (R = 0.52). Conclusion: The diagnostic efficacy of [18F]F-FAPI PET/CT in detecting CD fibrosis is superior to [18F]F-FDG PET/CT and comparable to MTI, exhibiting great potential for early detection of intestinal fibrosis. [ABSTRACT FROM AUTHOR]