The latest medical research on Gastroenterology

The research magnet gathers the latest research from around the web, based on your specialty area. Below you will find a sample of some of the most recent articles from reputable medical journals about gastroenterology gathered by our medical AI research bot.

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Characterization and Application of Precore/Core-Related Antigens in Animal Models of Hepatitis B Virus Infection.

Hepatology

The hepatitis B core-related antigen (HBcrAg), a composite antigen of precore/core gene including classical hepatitis B core antigen (HBc) and e an...

Reply to Letter to the Editors: "Prognostic value of B-type natriuretic peptide in liver transplant patients".

Hepatology

We appreciate Jin and Li for their interest in our recent research (1), which emphasizes the B-type natriuretic peptide (BNP) screening, rather tha...

Mutational signature analysis reveals widespread contribution of pyrrolizidine alkaloid exposure to human liver cancer.

Hepatology

Mutational signature analyses are effective tool for identifying cancer etiology. Humans are frequently exposed to pyrrolizidine alkaloids (PAs), the most common carcinogenic phytotoxins widely distributed in herbal remedies and foods. However, due to the lack of human epidemiological data, PAs are classified as group II hepatocarcinogens by WHO. This study identified PA mutational signature as the biomarker to investigate the association of PA exposure with human liver cancer.

Pyrrole-protein adducts (PPA), the PA exposure biomarker, were measured and found in 32% of surgically resected specimens from 34 liver cancer patients in Hong Kong. Next, we delineated the mode of mutagenic and tumorigenic actions of retrorsine, a representative PA, in mice and human hepatocytes (HepaRG). Retrorsine induced DNA adduction, DNA damage, and activation of tumorigenic hepatic progenitor cells that initiated hepatocarcinogenesis. PA mutational signature, as the unique molecular fingerprint of PA-induced mutation, was derived from exome mutations in retrorsine-exposed mice and HepaRG cells. Notably, PA mutational signature was validated in genomes of PPA-positive liver cancer patients but not PPA-negative patients, confirming the specificity of this biomarker in revealing PA-associated liver cancers. Further, we examined the established PA mutational signature in 1,513 liver cancer genomes and found that PA-associated liver cancers were potentially prevalent in Asia: Mainland China (48%), Hong Kong (44%), Japan (22%), South Korea (6%), Southeast Asia (25%); but minor in Western countries: North America (3%), and Europe (5%).

This study provides the first clinical indication of PA-associated liver cancer. We discover an unexpectedly extensive implication of PA exposure in liver cancer patients, laying the scientific basis for precautionary approaches and prevention of PA-associated human liver cancers.

Enoxacin upregulates microRNA biogenesis and downregulates cytotoxic CD8 T cell function in autoimmune cholangitis.

Hepatology

Primary biliary cholangitis (PBC) is a prototypical organ specific autoimmune disease, mediated by autoreactive T cell attack and destruction of cholangiocytes. Despite the clear role of autoimmunity in PBC, immune-directed therapies have failed to halt PBC, including biologic therapies effective in other autoimmune disease. MicroRNA (miRNA) dysregulation is implicated in the pathogenesis (PBC). In the dominant negative TGF-β receptor (dnTGFβRII) mouse model of PBC, autoreactive CD8 T cells play a major pathogenic role, and demonstrate a striking pattern of miRNA downregulation. Enoxacin is a small molecule fluoroquinolone that enhances miRNA biogenesis, partly by stabilizing the interaction of trans-activation response RNA binding protein (TRBP) with Argonaute2 (Ago2).

We hypothesized that correcting aberrant T cell miRNA expression with enoxacin in dnTGFβRII mice could modulate autoreactive T cell function and prevent PBC. Here we show that liver-infiltrating dnTGFβRII CD8 T cells have significantly decreased levels of the miRNA biogenesis molecules P4ha1 and Ago2 along with significantly increased levels of granzyme B and perforin. Enoxacin treatment significantly upregulated miRNAs in dnTGFβRII CD8 T cells and effectively treated autoimmune cholangitis in dnTGFβRII mice. Enoxacin treatment directly altered T cells both ex vivo and in vitro, resulting in altered memory subset numbers, decreased proliferation and decreased IFN-γ production. Enoxacin significantly decreased CD8 T cell expression of the transcription factor, Runx3, and significantly decreased perforin expression at both the mRNA and protein levels.

Enoxacin increases miRNA expression in dnTGFβRII CD8 T cells, reduces CD8 T cell pathogenicity, and effectively halted progression of autoimmune biliary disease. Targeting the miRNA pathway is a novel therapeutic approach to autoimmunity that corrects pathological miRNA abnormalities in autoreactive T cells.

Endoscopic Cyanoacrylate Injection vs BRTO for Prevention of Gastric Variceal Bleeding: A Randomized Controlled Trial.

Hepatology

The optimal treatment for gastric varices (GVs) has not yet been fully determined. This study compared the efficacy and safety of endoscopic cyanoa...

Mast Cells Promote Non-Alcoholic Fatty Liver Disease Phenotypes and Microvesicular Steatosis in Mice Fed Western Diet.

Hepatology

Non-alcoholic fatty liver disease (NAFLD) is simple steatosis, but can develop into non-alcoholic steatohepatitis (NASH) characterized by liver inflammation, fibrosis and microvesicular steatosis. Mast cells (MCs) infiltrate the liver during cholestasis and promote ductular reaction (DR), biliary senescence and liver fibrosis. We aimed to determine the effects of MC depletion during NAFLD/NASH.

Wild-type (WT) and KitW-sh (MC-deficient) mice were fed control (CD) or a Western diet (WD) for 16 wks; select WT and KitW-sh WD mice received tail vein injections of MCs 2X/wk for 2 wks prior to sacrifice. Human samples were collected from normal, NAFLD or NASH. Cholangiocytes from WT WD mice and human NASH have increased insulin-like growth factor (IGF)-1 expression that promotes MC migration/activation. Enhanced MC presence was noted in WT WD mice and human NASH, along with increased DR. WT WD mice had significantly increased steatosis, DR/biliary senescence, inflammation, liver fibrosis and angiogenesis compared to WT CD mice, which was significantly reduced in KitW-sh WD mice. Loss of MCs prominently reduced microvesicular steatosis in zone 1 hepatocytes. MC injection promoted WD-induced biliary and liver damage, and specifically upregulated microvesicular steatosis in zone 1 hepatocytes. Aldehyde dehydrogenase 1 family, member A3 (ALDH1A3) expression is reduced in WT WD mice and human NASH, but increased in KitW-sh WD mice. miR-144-3p expression was increased in WT WD mice and human NASH, but reduced in KitW-sh WD mice, and was found to target ALDH1A3.

MCs promote WD-induced biliary and liver damage, and may promote microvesicular steatosis development during NAFLD progression to NASH via miR-144-3p/ALDH1A3 signaling. Inhibition of MC activation may be a therapeutic option for NAFLD/NASH treatment.

Dual Agonist of Farnesoid X Receptor and G Protein-coupled Receptor TGR5 Inhibits Hepatitis B Virus Infection in Vitro and in Vivo.

Hepatology

Chronic hepatitis B virus (HBV) infection is a major health problem worldwide. Currently, the first-line treatment for HBV is nucleos(t)ide analogs (NAs) or interferons (IFNs); however, efficient therapeutic approaches that enable cure are lacking. Therefore, novel anti-HBV agents with mechanisms distinct from those of current drugs are needed. Sodium taurocholate cotransporting polypeptide (NTCP) was previously identified as an HBV receptor that is inhibited by several compounds. Farnesoid X receptor (FXR) activation also inhibits NTCP function.

In this study, we investigated the inhibitory effect of bile acid (BA) derivatives ---namely obeticholic acid (OCA), INT-767 (a dual agonist of FXR and Takeda G protein-coupled receptor [TGR5]), and INT-777 (a TGR5 agonist) --- GW4064 (an FXR agonist), cyclosporin A, and irbesartan. OCA and INT-777 suppressed HBV infection in HepG2-hNTCP-C4 cells. Interestingly, INT-767 showed potent inhibition by attaching to HBV particles rather than binding to NTCP. As an entry inhibitor, INT-767 was stronger than various natural BAs. Further, in chimeric mice with humanized liver, INT-767 markedly delayed the initial rise of hepatitis B surface antigen (HBsAg), hepatitis B e antigen (HBeAg), and HBV DNA, and reduced covalently closed circular DNA (cccDNA). The strong inhibitory effect of INT-767 may be due to the cumulative effect of its ability to inhibit the entry of HBV and to stimulate FXR downstream signaling, which affects the post-entry step.

Our results suggest that BA derivatives, particularly INT-767, are prospective candidate anti-HBV agents. Clarifying the underlying mechanisms of BA derivatives would facilitate the development of novel anti-HBV agents.

Immune Checkpoint Inhibitors in Novel Combinations for Hepatocellular Carcinoma.

Hepatology

Until May 29, 2020, the multikinase inhibitors (MKIs) sorafenib and lenvatinib comprised the only first-line treatment standards for unresectable h...

Prevalence and risk factors of gastroesophageal reflux disease in a rural Indian population.

Indian Journal of Gastroenterology

Studies on frequency and risk factors of gastroesophageal reflux disease (GERD) in the rural Indian population are scanty.

This household survey was undertaken by the trained interviewers in the adult population (≥ 18 years) in four villages in northern India using translated-validated Enhanced Asian Rome III and hospital anxiety and depression questionnaires.

Of 2774 subjects, 2019 (72.8%) had no heartburn. Heartburn frequency was as follows: 314 (11.3%) once/week, 143 (5.2%) twice/week, 85 (3.1%) thrice/week, 69 (2.5%) four times/week, 48 (1.7%) five times/week, 18 (0.6%) six times/week, 41 (1.5%) daily, 37 (1.4%) > once daily. A total of 298 (10.7%) had GERD (definition: heartburn > twice/week). Older age (36.5 vs. 35 years), non-Hindu religion (7, 2.4% vs. 30, 1.2%), lower education (127, 42.6% vs. 789, 31.9%), lower socioeconomic class (94, 31.5% vs. 517, 20.9%) and income (below Indian National Rupees [INR] 458; 105, 35.2% vs. 599, 24.2%), non-vegetarian diet (15, 5% vs. 105, 4.2%), intake of tea/coffee (260, 87.2% vs. 1687, 68.1%), carbonated soft drinks (216, 72.5% vs. 1234, 49.8%), and alcohol (48, 16.1% vs. 313, 12.6%), tobacco chewing (116, 38.9% vs. 681, 27.5%), and smoking (105, 35.2% vs. 672, 27.1%) were associated with GERD on univariate analysis. On multivariate analysis, body mass index > 25 kg/m2 (odds ratio [OR] 1.23; 95% CI 0.88-1.71), predominant rice eating (1.13; 0.74-1.74), tobacco chewing and smoking (1.68; 1.24-2.30 and 1.36; 0.99-1.88), and alcohol (1.2; 0.78-1.83) and carbonated soft drinks (2.48; 1.79-3.44) intake were associated with GERD. A total of 122 (41%) had associated functional dyspepsia. Psychological comorbidities were commoner among those with than without GERD.

In this rural Indian population, 10.7% had GERD and predominant rice eating, tobacco chewing, and carbonated soft drink intake were the risk factors. Psychological comorbidities were common.

Combined High Dose CRRT and PLEX in the Management of Severe Multi-Organ System Dysfunction Associated with ALF.

Hepatology

Acute liver failure (ALF) can lead to severe hepatic and extrahepatic organ dysfunction and is associated with high morbidity and mortality. Recent...

Dynamic transcriptional and epigenetic changes drive cellular plasticity in the liver.

Hepatology

Following liver injury, a fraction of hepatocytes adopt features of biliary epithelial cells (BECs) in a process known as biliary reprogramming. The aim of this study was to elucidate the molecular events accompanying this dramatic shift in cellular identity. Approach and Results We applied the techniques of bulk RNA-sequencing (RNA-seq), single cell RNA-sequencing (scRNA-seq), and assay for transposase-accessible chromatin with high-throughput sequencing (ATAC-seq) to define the epigenetic and transcriptional changes associated with biliary reprogramming. In addition, we examined the role of TGFβ signaling by profiling cells undergoing reprogramming in mice with hepatocyte-specific deletion in the downstream TGFβ signaling component Smad4. Biliary reprogramming followed a stereotyped pattern of altered gene expression consisting of robust induction of biliary genes and weaker repression of hepatocyte genes. These changes in gene expression were accompanied by corresponding modifications at the chromatin level. While some reprogrammed cells had molecular features of "fully differentiated" BECs, most lacked some biliary characteristics and retained some hepatocyte characteristics. Surprisingly, single cell analysis of Smad4 mutant mice revealed a dramatic increase in reprogramming.

Hepatocytes undergo widespread chromatin and transcriptional changes during biliary reprogramming, resulting in epigenetic and gene expression profiles that are similar to, but distinct from, native BECs. Reprogramming involves a progressive accumulation of biliary molecular features without discrete intermediates. Paradoxically, canonical TGFβ signaling through Smad4 appears to constrain biliary reprogramming, indicating that TGFβ can either promote or inhibit biliary differentiation depending on which downstream components of the pathway are engaged. This work has implications for the formation of new BECs and bile ducts in the adult liver.