[A new cucurbitane glycoside from Picrorhiza scrophulariiflora].

Chemical constituents from the ethanol extract of Picrorhiza scrophulariiflora were isolated and purified by column chromatography. Their structures were identified by HR-MS, 1D and 2D-NMR, and their cytotoxicity was assessed by CCK-8 assay. Four compounds were isolated and identified as follows: 2ß-D-glucosyloxy-3ß,16α,20ß-trihydroxy-9-methyl-19-norlanosterol-5,25-diene-22-one(1), 2ß-D-glucosyloxy-3ß,16α,20ß-trihydroxy-9-methyl-19-norlanosta-5,24-diene-22-one(2), 25-acetoxy-2ß-glucosyloxy-3ß,16α,20ß-trihydroxy-9-methyl-19-norlanosta-5-ene-22-one(3) and 25-acetoxy-2ß-glucosyloxy-3ß,16α,20ß-trihydroxy-9-methyl-19-norlanosta-5,23-(E)-diene-22-one(4). Compound 1 represents a new cucurbitane glycoside. The half inhibitory concentrations of the 4 compounds exceeded 100 µmol·L~(-1) against four tumor cell lines, indicating no significant cytotoxicity.

Comprehensive bibliometric and visualized analysis of research on gut-liver axis published from 1998 to 2022.

Background: The concept of the gut-liver axis was proposed by Marshall in 1998, and since then, this hypothesis has been gradually accepted by the academic community. Many publications have been published on the gut-liver axis, making it important to assess the scientific implications of these studies and the trends in this field. Methods: Publications were retrieved from the Web of Science Core Collection. Microsoft Excel, CiteSpace, VOSviewer, and Scimago Graphica software were used for bibliometric analysis. Results: A total of 776 publications from the Web of Science core database were included in this study. In the past 25 years, the number of publications on the gut-liver axis has shown an upward trend, particularly in the past 3 years (2020-2022). China had the highest number of publications (267 articles, 34.4%). However, the United States was at the top regarding influence and international cooperation in this field. The University of California San Diego had contributed the most publications. Suk, Ki Tae and Schnabl, Bernd were tied for the first rank in most publications. Thematic hotspots and frontiers were focused on gut microbiota, microbial metabolite, intestinal permeability, bacterial translocation, bile acid, non-alcoholic steatohepatitis, and alcoholic liver disease. Conclusion: Our study is the first bibliometric analysis of literature using visualization software to present the current research status of the gut-liver axis over the past 25 years. The damage and repair of intestinal barrier function, as well as the disruption of gut microbiota and host metabolism, should be a focus of attention. This study can provide a reference for later researchers to understand the global research trends, hotspots, and frontiers in this field.

Irritable bowel syndrome: Epidemiology, overlap disorders, pathophysiology and treatment.

Irritable bowel syndrome (IBS) is a common chronic gastrointestinal disease with a significant impact on patients' quality of life and a high socioeconomic burden. And the understanding of IBS has changed since the release of the Rome IV diagnosis in 2016. With the upcoming Rome V revision, it is necessary to review the results of IBS research in recent years. In this review of IBS, we can highlight future concerns by reviewing the results of IBS research on epidemiology, overlap disorders, pathophysiology, and treatment over the past decade and summarizing the latest research.

Overlapping Symptoms of Functional Gastrointestinal Disorders: Current Challenges and the Role of Traditional Chinese Medicine.

Several functional gastrointestinal disorders (FGIDs) have overlapping symptoms, and, consequently, developing treatment strategies based on symptomatology poses a challenge for the clinical management of complex FGIDs. The significant overlap in the symptoms of FGIDs caused by the shared pathophysiological mechanisms is both a challenge and an excellent target for therapeutic development, since treatment strategies focused on shared pathophysiological mechanisms can treat the associated underlying diseases rather than just alleviating the primary symptoms. Owing to its multi-targeted approach, traditional Chinese medicine (TCM) has garnered immense interest worldwide; however, the quality of the data demonstrating its effectiveness is generally weak. Additionally, the causal link between the intrinsic mechanisms of action of TCM and its clinical benefits remains obscure. Systems biology is characterized by holistic and dynamic research, which corresponds to the holistic, multi-targeted, and syndrome-based approach of TCM. Therefore, high-throughput analysis techniques can be employed to describe and comprehend the genesis and progression of diseases, as well as the impacts of TCM on the organism, which may aid in elucidating the pathogenic mechanisms of the diseases as well as the mechanism of action of TCM.

Research trends in the field of the gut-brain interaction: Functional dyspepsia in the spotlight - An integrated bibliometric and science mapping approach.

Objectives: This study aims to perform a bibliometric analysis of functional dyspepsia (FD), which includes visualizing bibliographic information, in order to identify prevailing study themes, topics of interest, contributing journals, countries, institutions, and authors as well as co-citation patterns. Methods: The Web of Science™ Core Collection Database was used to retrieve all peer-reviewed scientific publications related to FD research. The validated search terms were entered into the "title" and "author keywords" fields, and the results were sorted by publication year from 2006 to 2022. There were no restrictions on language. On 12 February 2023, a manual export of the complete metadata for each original publication and review article was performed. CiteSpace was used to reveal co-authorship, publication, and co-citation patterns to find prominent authors, organizations, countries, and journals in FD research as well as to identify author keywords with strong citation bursts, which could indicate an emerging research area. VOSviewer was used to build the co-occurrence indicator (co-word) to identify the main author keywords on which previous studies focused and to induce clustered scientific landscape for two consecutive periods to identify intriguing areas for future research. Results: A search of the database retrieved 2,957 documents. There was a wave-like pattern in the number of publications until 2017, after which there was a spike in publication volume. The USA, China, and Japan provided the majority of contributions. In terms of institution, Mayo Clin, Univ Newcastle, and Katholieke Univ Leuven were found to be the prolific institutions. Additionally, the results indicate that eastern Asian researchers contributed significantly to the global knowledge of literature that led other countries; however, Canada, the USA, Australia, England, and Germany were found to have the highest degree of betweenness centrality. Nicholas J. Talley, Jan Tack, Gerald Holtmann, Michael Camilleri, Ken Haruma, and Paul Moayyedi occupied the top positions based on productivity and centrality indicators. Six thematic clusters emerged (Helicobacter pylori infection; pathophysiological mechanisms of FD; extraintestinal co-morbidities and overlap syndromes associated with FD; herbal medicine in FD; diabetic gastroparesis; and dietary factors in FD). "Acupuncture," "duodenal eosinophilia," "gut microbiota," and others were among the author keywords with rising prevalence. Conclusion: In FD research, eastern Asian countries have established themselves as major contributors with the highest publishing productivity; however, research has primarily been driven by North America, Europe, and Australia, where cooperation is generally more active and highly influential scientific results are produced. Our analysis suggests that increased investments, training of human resources, improved infrastructures, and expanded collaborations are essential to improving the quality of FD research in Asia. The emerging author keyword analysis suggests that eosinophil-mast cell axis, gut microbiota, mental disorders, and acupuncture are the key areas that attract researchers' attention as future research boulevards. There is a highly skewed distribution of research output across Asia, with most focus on complementary and alternative medicine (CAM) coming from Chinese, Japanese, and South Korean centers. However, CAM remains an underexplored area of research in the context of FD, and it deserves greater research efforts in order to obtain quality scientific evidence. Furthermore, we propose that the research framework of CAM should not be limited to dysmotility; rather, it could be interpreted within a more holistic context that includes the brain-gut-microbiota axis, as well as novel concepts such as duodenitis, increased mucosal permeability, and infiltration and activation of eosinophils and mast cells, among others. Overall, we provided bibliometrics-based overviews of relevant literature to researchers from different backgrounds and healthcare professionals to provide an in-depth overview of major trends in FD research.

Small noncoding vault RNA2-1 disrupts gut epithelial barrier function via interaction with HuR.

Vault RNAs (vtRNAs) are small noncoding RNAs and highly expressed in many eukaryotes. Here, we identified vtRNA2-1 as a novel regulator of the intestinal barrier via interaction with RNA-binding protein HuR. Intestinal mucosal tissues from patients with inflammatory bowel diseases and from mice with colitis or sepsis express increased levels of vtRNAs relative to controls. Ectopically expressed vtRNA2-1 decreases the levels of intercellular junction (IJ) proteins claudin 1, occludin, and E-cadherin and causes intestinal epithelial barrier dysfunction in vitro, whereas vtRNA2-1 silencing promotes barrier function. Increased vtRNA2-1 also decreases IJs in intestinal organoid, inhibits epithelial renewal, and causes Paneth cell defects ex vivo. Elevating the levels of tissue vtRNA2-1 in the intestinal mucosa increases the vulnerability of the gut barrier to septic stress in mice. vtRNA2-1 interacts with HuR and prevents HuR binding to claudin 1 and occludin mRNAs, thus decreasing their translation. These results indicate that vtRNA2-1 impairs intestinal barrier function by repressing HuR-facilitated translation of claudin 1 and occludin.

Measurement-Error Analysis of Fiber Bragg Grating Flexible Sensor for Displacement-Field Monitoring of Geotechnical Engineering.

Monitoring geotechnical structures and providing real-time early warning is a key measure to mitigate the impacts of disasters (slope slip, subsidence, dam deformation, bridge settlement, etc.). The fiber Bragg grating (FBG) flexible sensor, developed by the combination of flexible material and an FBG sensor, is widely used in geotechnical engineering health monitoring due to its excellent performance. The flexible sensor can perform regional and quasi-distributed measurements of the displacement field of the measured structure, and accurately reflect the operating state of the engineering structure. However, in practical engineering applications, factors such as the strain-transfer rate between the flexible substrate and sensing points, the displacement reconstruction algorithm, and the arrangement interval of the sensing points can cause measurement error, which, in turn, leads to a decrease in the displacement-measurement accuracy. In this paper, the following analysis is performed by means of theoretical derivation and model establishment. The influence of the length, width, and thickness of the cemented layer, the shear modulus of the flexible substrate, and the radius of the groove on the strain-transfer rate were analyzed, and the referential parameters were determined. The displacement reconstruction algorithm is essentially a recursive algorithm, which inevitably introduces cumulative error; the relationship between the layout interval of the sensing points and the measurement error is discussed. Considering the fabrication cost of the sensor and the allowable range of error, a sensing-point-layout interval of 100 mm was chosen. The feasibility and effectiveness of the simulation theory were verified by carrying out deformation-sensing experiments on the developed FBG flexible sensor. The research results can theoretically guide the packaging and fabrication of the FBG flexible sensor, thereby improving the measurement accuracy of the flexible sensor for the measured structure.

Research trends in ulcerative colitis: A bibliometric and visualized study from 2011 to 2021.

Background: Ulcerative colitis (UC) is an idiopathic inflammatory bowel disease with repeated relapses and remissions. Despite decades of effort, numerous aspects, including the initiating event and pathogenesis of UC, still remain ambiguous, which requires ongoing investigation. Given the mass of publications on UC, there are multidimensional challenges to evaluating the scientific impact of relevant work and identifying the current foci of the multifaceted disease. Accordingly, herein, we aim to assess the global growth of UC research production, analyze patterns of research areas, and evaluate trends in this area. Methods: The Web of Science Core Collection of Clarivate Analytics was searched for articles related to UC published from 2011 to 2021. Microsoft Office Excel 2019 was used to visualize the number of publications over time. Knowledge maps were generated using CiteSpace and VOSviewer to analyze collaborations among countries, institutions, and authors and to present the journey of UC research as well as to reveal the current foci of UC research. Results: A total of 5,088 publications were evaluated in the present study. China had the most publications (1,099, 22.5%). Univ Calif San Diego was the most productive institution (126, 2.48%). William J Sandborn published the greatest number of articles (100, 1.97%). Toshifumi Hibi was the most influential author in the field with a betweenness centrality of 0.53. Inflammatory bowel diseases was identified as the most prolific journal (379, 7.45%). Gastroenterology was the most co-cited journal (3,730, 4.02%). "Vedolizumab," "tofacitinib," "Faecalibacterium prausnitzii," "fecal microbiota transplantation (FMT)," "toll-like receptor 4," and "nucleotide-binding oligomerization domain-like receptor protein 3 inflammasome" were considered the hot topics. Conclusion: In UC research, manuscripts that had high impacts on the scientific community provided an evidence base. UC therapy has entered the era of personalized and precision therapy. As research on FMT, anti-integrin antibodies, Janus kinase inhibitors, and anti-tumor necrosis factor drugs continues to grow, their use in the clinical setting may also expand.

Comprehensive bibliometric and visualized analysis of research on fecal microbial transplantation published from 2000 to 2021.

BACKGROUND: Fecal microbial transplantation has emerged in recent years as a method of treating disease by rebuilding the intestinal flora. However, few bibliometric analyses have systematically studied this area of research. We aimed to use bibliometric analysis to visualize trends and topical research in fecal microbial transplantation to help provide insight into future trends in clinical and basic research. MATERIALS AND METHODS: Articles and reviews related to fecal microbial transplantation were collected from the Web of Science Core Collection. Significant information associated with this field was visually analyzed by using Biblioshiny and CtieSpace software. RESULTS: A total of 3144 articles and overviews were included. The number of publications related to fecal microbial transplantation significantly increased yearly. These publications mainly came from 100 countries, led by the US and China, and 521 institutions. The most prolific and influential author is KHORUTS A. The main disciplines and application fields of fecal microbial transplantation included molecular /biology/immunology and medicine/clinical medicine, and the research foundation of fecal microbial transplantation was molecular /biology/genetics and health/nursing/medicine. An alluvial flow visualization showed several landmark articles. New developments were identified in terms of reference and keyword citation bursts. Data analysis showed that different FMT preparation and delivery methods gradually appeared as research hotspots. The main research keywords in the last 3 years were chain fatty acids, Akkermansia muciniphila, and insulin sensitivity, other keywords were current and developing research fields. CONCLUSION: Research on fecal microbial transplantation is flourishing and many new applications of fecal microbial transplantation are emerging. Microbial metabolites such as short-chain fatty acids and the microbiota-gut-brain axis have become the focus of current research and are future research trends.

External therapy of traditional Chinese medicine for treating irritable bowel syndrome with diarrhea: A systematic review and meta-analysis.

Background: Irritable bowel syndrome with diarrhea (IBS-D) is a chronic functional gastrointestinal disorder that has a significant impact on quality of life, work productivity, and healthcare resources. External therapy of traditional Chinese medicine (TCM) has positive effects on IBS-D and is simple, convenient, and low-cost. This study aimed to systematically evaluate the efficacy and safety of external therapy of TCM for IBS-D. Methods: This study was conducted according to Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines. The PubMed, Embase, Cochrane Library, Web of Science, China National Knowledge Infrastructure (CNKI), Chinese Scientific Journals (VIP), Wan Fang, and Chinese Biomedical (CBM) databases were electronically searched to collect randomized controlled trials comparing external therapy of TCM with Western medicine for IBS-D from inception to 31 December 2021. Two authors independently screened, extracted, and assessed the selected studies. The Jadad scale and Cochrane Collaboration Risk of Bias tool were used to evaluate study quality. The certainty of evidence was assessed using the Grading of Recommendations, Assessment, Development, and Evaluations (GRADE). The meta-analysis was performed using the Review Manager software (version 5.3). Results: Twenty-one studies involving 1,862 subjects were included. Acupuncture and moxibustion were the most commonly used external therapies. The meta-analysis showed that based on total effective rate with moderate certainty of evidence (n = 21 studies, n = 1,862 participants, RR = 1.25, 95% CI [1.2, 1.31], I2 = 0%, P < 0.00001), clinical cure rate with low certainty of evidence (n = 17 studies, n = 1,502 participants, RR = 1.66, 95% CI [1.4, 1.96], I2 = 1%, P < 0.00001), recurrence rate with very low certainty of evidence (n = 5 studies, n = 260 participants, RR = 0.44, 95% CI [0.34, 0.58], I2 = 0%, P < 0.00001), total symptom score (MD = -4.9, 95% CI [-7.34, -2.47]), and IBS severity scoring system score (IBS-SSS) with moderate certainty of evidence (MD = -52.72, 95% CI [-63.9, -41.53]), the experimental group had significant advantages compared with the control group. The sensitivity analysis further confirmed the robustness of the primary outcomes. The improvement in quality of life associated with IBS (IBS-QOL) was superior in the experimental group compared to the control group, and the difference was statistically significant; however, the clinical heterogeneity was strong. The inverted funnel plot of the included studies indicated a potential publication bias. Conclusion: External therapy of TCM for IBS-D alleviated abdominal symptoms, improved clinical effectiveness, and reduced recurrence with great safety. However, because of the limitations of publication bias in trials, more rigorous studies with a clinical design are necessary for further verification of the outcomes. Systematic Review Registration: [https://www.crd.york.ac.uk/PROSPERO/], identifier [CRD42020222993].

Global Research Trends in Irritable Bowel Syndrome: A Bibliometric and Visualized Study.

Background: There are about 10-23% of adults worldwide suffering from irritable bowel syndrome (IBS). Over the past few decades, there are many aspects of uncertainty regarding IBS leading to an ongoing interest in the topic as reflected by a vast number of publications, whose heterogeneity and variable quality may challenge researchers to measure their scientific impact, to identify collaborative networks, and to grasp actively researched themes. Accordingly, with help from bibliometric approaches, our goal is to assess the structure, evolution, and trends of IBS research between 2007 and 2022. Methods: The documents exclusively focusing on IBS from 2007 to 2022 were retrieved from the Science Citation Index Expanded of the Web of Science Core Collection. The annual productivity of IBS research, and the most prolific countries or regions, authors, journals and resource-, intellectual- and knowledge-sharing in IBS research, as well as co-citation analysis of references and keywords were analyzed through Microsoft Office Excel 2019, CiteSpace, and VOSviewer. Results: In total, 4,092 publications were reviewed. The USA led the list of countries with the most publications (1,226, 29.96%). Mayo Clinic contributed more publications than any other institution (193, 4.71%). MAGNUS SIMREN stood out as the most active and impactful scholar with the highest number of publications and the greatest betweenness centrality value. The most high-yield journal in this field was Neurogastroenterology and motility: the official journal of the European Gastrointestinal Motility Society (275, 6.72%). Gastroenterology had the most co-citations (3,721, 3.60%). Keywords with the ongoing strong citation bursts were chromogranin A, rat model, peptide YY, gut microbiota, and low-FODMAP diet, etc. Conclusion: Through bibliometric analysis, we gleaned deep insight into the current status of literature investigating IBS for the first time. These findings will be useful to scholars interested in understanding the key information in the field, as well as identifying possible research frontiers.

A Breakthrough Point in Integrative Medical Research: Challenge of Treating Overlapping Symptoms in Functional Gastrointestinal Disorders.

Functional gastrointestinal disorders (FGIDs) are common disorders that are characterized by persistent and recurring gastrointestinal symptoms. Many patients with FGIDs have overlapping symptoms, which impaired the quality of life and ability to work of patients, and left a considerable impact on health-care systems and society. Chinese medicines (CMs) are commonly utilized by many patients with FGIDs. This article discusses the current status of diagnosis and treatment of FGIDs, the advantages and characteristics of CM treatment, and how integrated medicine can make a breakthrough in FGIDs diagnosis and treatment.

A Bibliometric Analysis of Atrophic Gastritis From 2011 to 2021.

BACKGROUND: Atrophic gastritis (AG), which is characterized by a decreased number or disappearance of the glandular structures and secretory dysfunction, is linked to chronically inflamed stomach. It has been estimated that the annual incidence of gastric cancer (GC) is 0.1% for patients with AG. Early eradication of Helicobacter pylori (H. pylori) can reduce the risk of GC development. Additionally, the follow-up and management of AG are necessary to prevent GC. Exploring novel methods of the automatized analysis of data for apprehending knowledge in any medical field is encouraged, especially when a body of literature suggests the necessity of doing so. Accordingly, herein, we aim to systematically review the current foci and status of AG research using bibliometric analysis. METHODS: Articles and reviews related to AG published from 2011 to 2021 in the Web of Science Core Collection were retrieved. Microsoft Office Excel 2019 and GraphPad Prism were used to show the annual number of publications and scientific productivity of authors through time. CiteSpace and VOSviewer were used to generate network maps about the collaborations among countries, institutions, and authors as well as reveal hotspots of AG research. The relationships among the author's keywords, cited references, and the top authors were summarized by a Sankey plot (three-fields plot). RESULTS: A total of 1,432 publications were included in the present study. China remained the most productive country, with the highest number of publications (377, 26.32%). Vanderbilt University contributed the most publications of any single institution (56, 3.91%). James R Goldenring was the most active and influential scholar, with the highest number of publications and greatest centrality. The most prolific journal in this field was World Journal of Gastroenterology (62, 4.32%). Gastroenterology (997, 69.62%) was the most co-cited journal. Exploring the origin of gastric metaplasia, especially spasmolytic polypeptide-expressing metaplasia (SPEM) was a major topic in AG research. CONCLUSIONS: This bibliometric study provides a comprehensive analysis of the scientific progress of AG over the past decade. Metaplasia is a hot topic and could be a promising area of research in the coming years.

Exploration of the Potential Mechanisms of Wumei Pill for the Treatment of Ulcerative Colitis by Network Pharmacology.

BACKGROUND: Wumei pill (WMP) has a long history of colitis treatment in China, but the protective mechanisms have not been elucidated. To uncover the potential mechanisms of WMP against ulcerative colitis (UC), the network pharmacology approach was utilized in this study. METHODS: Public databases were utilized to identify the potential targets of WMP and genes related to UC. Based on the identified overlapping common targets, drug-ingredient-target gene network, Gene Ontology (GO) analysis, Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis, and protein-protein interaction (PPI) analysis were conducted. Molecular docking was carried out to verify the selected key active ingredients and core targets. RESULTS: 129 active ingredients and 622 target genes were obtained. The drug-ingredient-target gene network revealed 52 active ingredients of WMP acting on 73 targets related to UC. GO analysis revealed that biological processes were mainly associated with oxidative stress, such as, reactive oxygen species metabolic processes, response to oxidative stress, cellular response to oxidative stress, response to reactive oxygen species, and regulation of reactive oxygen species metabolic processes. KEGG analysis revealed that the immune- and inflammation-related pathways, tumor-related signaling pathways, and microbial infection-related signaling pathways were the most significant. PPI network identified 13 core target genes. The molecular docking results indicated the formation of stable bonds between the active ingredients and core target genes. CONCLUSIONS: The approach of network pharmacology reveals the key ingredients, potential core targets, and biological process of WMP in the treatment of UC. The mechanisms of action of WMP involve anti-inflammation, antioxidation, and modulation of immunity, which provides evidence for the therapeutic role of WMP in UC.

Quality of Evidence Supporting the Role of Acupuncture for the Treatment of Irritable Bowel Syndrome.

OBJECTIVES: To systematically collate, appraise, and synthesize the current evidence on acupuncture for irritable bowel syndrome (IBS). METHODS: Systematic reviews (SRs)/meta-analyses (MAs) of acupuncture for IBS were searched in eight databases. For quality evaluation of the enrolled studies, Assessment of Multiple Systematic Reviews 2 (AMSTAR-2) was used for methodological quality, Preferred Reporting Item for Systematic Reviews and Meta-Analyses (PRISMA) for reporting quality, and Grading of Recommendations Assessment, Development, and Evaluation (GRADE) for evidence quality. RESULTS: Ten studies were included in our review. According to AMSTAR-2, only one study met all the criteria and was rated as high methodological quality, and the rest were rated as low or very low methodological quality. According to the PRISMA checklist, most of the items were fully reported, with the exception of Q5 (protocol and registration), Q8 (search), and Q27 (funding). With the GRADE system, no outcome measure was rated as high quality. CONCLUSIONS: Acupuncture may be a promising therapy for IBS. However, this conclusion must be treated with caution since the quality of SRs/MAs providing evidence is generally low.

Circular RNA CircHIPK3 Promotes Homeostasis of the Intestinal Epithelium by Reducing MicroRNA 29b Function.

BACKGROUND & AIMS: Circular RNAs (circRNAs) are a class of endogenous noncoding RNAs that form covalently closed circles. Although circRNAs influence many biological processes, little is known about their role in intestinal epithelium homeostasis. We surveyed circRNAs required to maintain intestinal epithelial integrity and identified circular homeodomain-interacting protein kinase 3 (circHIPK3) as a major regulator of intestinal epithelial repair after acute injury. METHODS: Intestinal mucosal tissues were collected from mice exposed to cecal ligation and puncture for 48 hours and patients with inflammatory bowel diseases and sepsis. We isolated primary enterocytes from the small intestine of mice and derived intestinal organoids. The levels of circHIPK3 were silenced in intestinal epithelial cells (IECs) by transfection with small interfering RNAs targeting the circularization junction of circHIPK3 or elevated using a plasmid vector that overexpressed circHIPK3. Intestinal epithelial repair was examined in an in vitro injury model by removing part of the monolayer. The association of circHIPK3 with microRNA 29b (miR-29b) was determined by biotinylated RNA pull-down assays. RESULTS: Genome-wide profile analyses identified ∼300 circRNAs, including circHIPK3, differentially expressed in the intestinal mucosa of mice after cecal ligation and puncture relative to sham mice. Intestinal mucosa from patients with inflammatory bowel diseases and sepsis had reduced levels of circHIPK3. Increasing the levels of circHIPK3 enhanced intestinal epithelium repair after wounding, whereas circHIPK3 silencing repressed epithelial recovery. CircHIPK3 silencing also inhibited growth of IECs and intestinal organoids, and circHIPK3 overexpression promoted intestinal epithelium renewal in mice. Mechanistic studies revealed that circHIPK3 directly bound to miR-29b and inhibited miR-29 activity, thus increasing expression of Rac1, Cdc42, and cyclin B1 in IECs after wounding. CONCLUSIONS: In studies of mice, IECs, and human tissues, our results indicate that circHIPK3 improves repair of the intestinal epithelium at least in part by reducing miR-29b availability.

Tojapride Reverses Esophageal Epithelial Inflammatory Responses on Reflux Esophagitis Model Rats.

OBJECTIVE: To investigate the mechanism of Tojapride, a Chinese herbal formula extract, on strengthening the barrier function of esophageal epithelium in rats with reflux esophagitis (RE). METHODS: Ten out of 85 SD rats were randomly selected as the sham group (n10), and 75 rats were developed a reflux esophagitis model (RE) by the esophageal and duodenal side-to-side anastomosis. Fifty successful modeling rats were divided into different medicated groups through a random number table including the model, low-, medium-, and high-dose of Tojapride as well as omeprazole groups (n10). Three doses of Tojapride [5.73, 11.46, 22.92 g/(kg•d)] and omeprazole [4.17 mg/(kg•d)] were administrated intragastrically twice daily for 3 weeks. And the rats in the sham and model groups were administered 10 mL/kg distilled water. Gastric fluid was collected and the supernatant was kept to measure for volume, pH value and acidity. Esophageal tissues were isolated to monitor the morphological changes through hematoxylin-eosin (HE) staining, and esophageal epithelial ultrastructure was observed by transmission electron microscopy. The expressions of nuclear factor kappa-light-chain-enhancer of activated B cells p65 (NF-KBp65), κB kinase beta (IKKß), occludin, and zonula occludens-1 (ZO-1) in the esophageal tissues were measured by immunohistochemistry and Western blot, respectively. RESULTS: The gastric pH value in the model group was significantly lower than the sham group (P<0.05). Compared with the model group, gastric pH value in the omeprazole and medium-dose of Tojapride groups were significantly higher (P<0.05). A large area of ulceration was found on the esophageal mucosa from the model rats, while varying degrees of congestion and partially visible erosion was observed in the remaining groups. Remarkable increase in cell gap width and decrease in desmosome count was seen in RE rats and the effect was reversed by Tojapride treatment. Compared with the sham group, the IKKß levels were significantly higher in the model group (P<0.05). However, the IKKß levels were down-regulated after treatment by all doses of Tojapride (P<0.01 or P<0.05). The occluding and ZO-1 levels decreased in the model group compared with the sham group (Ps0.01 or Ps0.05), while both indices were significantly up-regulated in the Tojapride-treated groups (P<0.01 or P<0.05). CONCLUSIONS: Tojapride could improve the pathological conditions of esophageal epithelium in RE rats. The underlying mechanisms may involve in down-regulating the IKKß expression and elevating ZO-1 and occludin expression, thereby alleviating the inflammation of the esophagus and strengthening the barrier function of the esophageal epithelium.

RNA-binding protein HuR regulates translation of vitamin D receptor modulating rapid epithelial restitution after wounding.

Homeostasis of the intestinal epithelium is tightly regulated by numerous extracellular and intracellular factors including vitamin D and the vitamin D receptor (VDR). VDR is highly expressed in the intestinal epithelium and is implicated in many aspects of gut mucosal pathophysiology, but the exact mechanism that controls VDR expression remains largely unknown. The RNA-binding protein human antigen R (HuR) regulates the stability and translation of target mRNAs and thus modulates various cellular processes and functions. Here we report a novel role of HuR in the posttranscriptional control of VDR expression in the intestinal epithelium. The levels of VDR in the intestinal mucosa decreased significantly in mice with ablated HuR, compared with control mice. HuR silencing in cultured intestinal epithelial cells (IECs) also reduced VDR levels, whereas HuR overexpression increased VDR abundance; neither intervention changed cellular Vdr mRNA content. Mechanistically, HuR bound to Vdr mRNA via its 3'-untranslated region (UTR) and enhanced VDR translation in IECs. Moreover, VDR silencing not only inhibited IEC migration over the wounded area in control cells but also prevented the increased migration in cells overexpressing HuR, although it did not alter IEC proliferation in vitro and growth of intestinal organoids ex vivo. The human intestinal mucosa from patients with inflammatory bowel diseases exhibited decreased levels of both HuR and VDR. These results indicate that HuR enhances VDR translation by directly interacting with its mRNA via 3'-UTR and that induced VDR by HuR is crucial for rapid intestinal epithelial restitution after wounding.

Interaction between HuR and circPABPN1 Modulates Autophagy in the Intestinal Epithelium by Altering ATG16L1 Translation.

Intestinal epithelial autophagy is crucial for host defense against invasive pathogens, and defects in this process occur frequently in patients with inflammatory bowel disease (IBD) and other mucosal disorders, but the exact mechanism that activates autophagy is poorly defined. Here, we investigated the role of RNA-binding protein HuR (human antigen R) in the posttranscriptional control of autophagy-related genes (ATGs) in the intestinal epithelium. We found that targeted deletion of HuR in intestinal epithelial cells (IECs) specifically decreased the levels of ATG16L1 in the intestinal mucosa. Intestinal mucosa from patients with IBD exhibited reduced levels of both HuR and ATG16L1. HuR directly interacted with Atg16l1 mRNA via its 3' untranslated region and enhanced ATG16L1 translation, without affecting Atg16l1 mRNA stability. Circular RNA circPABPN1 blocked HuR binding to Atg16l1 mRNA and lowered ATG16L1 production. HuR silencing in cultured IECs also prevented rapamycin-induced autophagy, which was abolished by overexpressing ATG16L1. These findings indicate that HuR regulates autophagy by modulating ATG16L1 translation via interaction with circPABPN1 in the intestinal epithelium.

Tojapride prevents CaSR-mediated NLRP3 inflammasome activation in oesophageal epithelium irritated by acidic bile salts.

Impairment of the oesophageal epithelium in patients with reflux oesophagitis (RE) is a cytokine-mediated injury rather than a chemical burn. The present study was conducted to explore CaSR/NLRP3 inflammasome pathway activation and cytokines IL-1ß and IL-18 release in oesophageal epithelia injured by refluxates and the effects of Tojapride on that signal regulation. Using a modified RE rat model with Tojapride administration and Tojapride-pretreated SV40-immortalized human oesophageal epithelial cells (HET-1A) exposed to acidic bile salts pretreated with Tojapride, we evaluated the therapeutic effects of Tojapride on oesophageal epithelial barrier function, the expression of CaSR/NLRP3 inflammasome pathway-related proteins and the release of downstream cytokines in response to acidic bile salt irritation. In vivo, Tojapride treatment ameliorated the general condition and pathological lesions of the oesophageal epithelium in modified RE rats. In addition, Tojapride effectively blocked the CaSR-mediated NLRP3 inflammasome activation in modified RE rats. In vitro, Tojapride treatment can reverse the harmful effect of acidic bile salts, which reduced transepithelial electrical resistance (TEER), up-regulated the CaSR-mediated NLRP3 inflammasome pathway and increased caspase-1 activity, LDH release and cytokines secretion. Taken together, these data show that Tojapride can prevent CaSR-mediated NLRP3 inflammasome activation and alleviate oesophageal epithelial injury induced by acidic bile salt exposure.