Background & Aims The Fragile X Mental Retardation Protein (FMRP) affects multiple steps of the mRNA metabolism during brain development and in different neoplastic processes. However, the contribution of FMRP in colon carcinogenesis has not been investigated. Methods FMRP transcripts and proteins expression were analyzed in human colon samples derived from patients with sporadic CRC and healthy subjects

Background & Aims Maintaining endoplasmic reticulum (ER) proteostasis is essential for pancreatic acinar cell function. Under conditions of severe ER stress, activation of pathogenic unfolded protein response pathways plays a central role in the development and progression of pancreatitis. Less is known, however, of the consequence of perturbing ER-associated post-translational protein modifications

Background and aims Non-alcoholic fatty liver disease (NAFLD) is becoming a severe liver disorder worldwide. Autophagy plays a critical role in liver steatosis. However, the role of autophagy in NAFLD remains exclusive and under debate. In this study, we investigated the role of S100 calcium binding protein A11 (S100A11) in the pathogenesis of hepatic steatosis. Methods We performed liver proteomics

Background & Aims Increased vascular permeability (VP) has been indicated to play an important role in the pathogenesis of inflammatory bowel disease (IBD). However, the pathological causes of increased intestinal VP in IBD remain largely unknown. Method Fibrinogen level was measured in dextran sulphate sodium (DSS)-induced colitis and patients with ulcerative colitis. Gly-Pro-Arg-Pro acetate (GPRP)

Background & aims Tight junctions form a barrier to the paracellular passage of luminal antigens. Although most tight junction proteins reside within the apical tight junction complex, claudin-18 localizes mainly to the basolateral membrane where its contribution to paracellular ion transport is undefined. Claudin-18 loss in mice results in gastric neoplasia development and tumorigenesis that may or

Background & Aims Inflammatory bowel disease (IBD) is a polygenic disorder principally characterized by dysregulated inflammation impacting the gastrointestinal tract. However, there is also increasing evidence for a clinical association with stress and depression. Given the role of the hypothalamus in stress responses and in the pathogenesis of depression, useful insights could be gleaned from understanding

Background & Aims Alcohol-associated liver disease (ALD) is a significant cause of liver-related morbidity and mortality worldwide and with limited therapies. Soluble epoxide hydrolase (sEH; Ephx2) is a largely cytosolic enzyme that is highly expressed in the liver and is implicated in hepatic function, but its role in ALD has heretofore remained uncharted. Methods To decipher the role of hepatic sEH

Background and aims Acid hypersensitivity is claimed to be a symptomatic trigger in functional dyspepsia (FD); however, the neuroimmune pathway(s) and the mediators involved in this process have not been systematically investigated. Palmitoylethanolamide (PEA) is an endogenous compound, able to modulate nociception and inflammation, but its role in FD has never been assessed. Methods Duodenal biopsies

Background And Aims Besides prominent respiratory involvement, gastrointestinal manifestations are commonly reported in Coronavirus Disease 2019 (COVID-19) patients. We compared infection of ex vivo human intestinal tissues by SARS-CoV-2 and SARS-CoV with respect to their replication kinetics and immune activation profile. Methods Human intestinal tissues were obtained from patients while undergoing

Background & Aims Adherent-invasive E. coli (AIEC) are implicated in inflammatory bowel disease (IBD), and mitochondrial dysfunction has been observed in IBD-patient biopsies. As a novel aspect of AIEC-epithelial interaction we hypothesized that E. coli (strain LF82) would elicit substantial disruption of epithelial mitochondrial form and function. Methods Monolayers of human colon-derived epithelial

Background and Aims Liver injury due to COVID-19 is being increasingly recognized. Abnormal liver chemistry tests of varying severities occur in a majority of patients. However, there is a dearth of accompanying liver histologic studies in these patients. Methods: The current report details the clinical courses of two patients having severe COVID-19 hepatitis. Liver biopsies were analyzed under light

Epithelial cells in the liver (known as hepatocytes) are high-performance engines of myriad metabolic functions and versatile responders to liver injury. As hepatocytes metabolize amino acids, alcohol, drugs and other substrates, they produce and are exposed to a milieu of toxins and harmful byproducts that can damage themselves. In the healthy liver, hepatocytes generally divide slowly. However, after

Background & Aims YAP (Yap1) and TAZ (Wwtr1) are transcriptional co-activators and downstream effectors of the Hippo pathway, which play crucial roles in organ size control and cancer pathogenesis. Genetic deletion of YAP/TAZ has revealed their critical importance for embryonic development of the heart, vasculature and gastrointestinal mesenchyme. The aim of this study was to determine the functional

Background & Aims Tristetraprolin (TTP) is a key post-transcriptional regulator of inflammatory and oncogenic transcripts. Accordingly, TTP was reported to act as a tumor suppressor in specific cancers. Herein, we investigated how TTP contributes to the development of liver inflammation and fibrosis, which are key drivers of hepatocarcinogenesis, as well as to the onset and progression of hepatocellular

Background & aims Aspirin reduces colorectal cancer (CRC) incidence and mortality. Understanding the biology responsible for this protective effect is key to developing biomarker-led approaches for rational clinical use. Wnt signalling drives CRC development from initiation to progression through regulation of epithelial-mesenchymal transition (EMT) and cancer stem cell populations (CSC). Here, we

Background & Aims The incidence of inflammatory bowel diseases has increased over the last half century, suggesting a role for dietary factors. Fructose consumption has increased in recent years. Recently, a high fructose diet (HFrD) was shown to enhance DSS-induced colitis in mice. The primary objectives of the current study were to elucidate the mechanism(s) underlying the pro-colitic effects of

Background and Aims As the incidence of nonalcoholic steatohepatitis (NASH) continues to rise, understanding how normal liver functions are affected during disease is required before developing novel therapeutics which could reduce morbidity and mortality. However, very little is understood about how the transport of proteins and cells from the liver by the lymphatic vasculature is affected by inflammatory

BACKGROUND AND AIMS The etiology of non-alcoholic fatty liver disease (NAFLD) is poorly understood, with males and certain populations exhibiting markedly increased susceptibility. Using a systems genetics approach, involving multi-omic analysis of ∼100 diverse inbred strains of mice, we recently identified several candidate genes driving NAFLD. We investigated the role of one of these, liver pyruvate

Background & Aims Acetaminophen (APAP)-induced liver injury is one of the most common causes of acute liver failure, however, a clear definition of sensitizing risk factors is lacking. Here, we investigated the role of the ligand-activated transcription factor aryl hydrocarbon receptor (Ahr) in APAP-induced liver injury. We hypothesized that Ahr, which integrates environmental, dietary, microbial and

Background & Aims Cancer associated fibroblasts (CAFs) play a key role in cancer process, but the research progress is hampered by the paucity of preclinical models essential for mechanistic dissection of cancer cell-CAF interactions. Here, we aim to establish a 3D organotypic co-cultures of primary liver tumor-derived organoids with CAFs, and to understand their interactions and the response to treatment

We studied the pathological consequence of long-term hypercholanemia caused by NTCP deficiency, and found that NTCP deficiency leads to gallbladder abnormalities in both mice and humans, thereby pointing to a potentially underappreciated cause for gallbladder diseases encountered by physicians in the clinic.

BACKGROUND & AIMS Notch signaling coordinates cell differentiation processes in the intestinal epithelium. The transcription factor Nrf2 orchestrates defense mechanisms by regulating cellular redox homeostasis, which as shown previously in murine liver, can be amplified through signaling crosstalk with the Notch pathway. However, interplay between these two signaling pathways in the gut is unknown

Background & aims Macrophages are key regulators of inflammation and cancer promotion in the liver, and their recruitment and activation is linked to chemokine receptor signaling. However, the exact roles of the chemokine receptors CCR2 and CCR5 for macrophage functions in the liver is obscure. Methods To study CCR2 and CCR5 in inflammatory liver injury, we used mice with a hepatocyte-specific knock-out

Background & Aims Pancreatic ductal adenocarcinoma (PDA) initiation and progression is accompanied by an immunosuppressive inflammatory response. Here, we evaluated the immunomodulatory role of chemosensory signaling in metaplastic tuft cells (MTCs) by analyzing the role of GNAT3, a gustatory pathway G-protein expressed by MTCs, during PDA progression. Methods Gnat3-null (Gnat3-/-) mice were crossbred

Background Infection with hepatitis C virus (HCV) remains to be a major cause of morbidity and mortality worldwide despite the recent advent of highly effective direct-acting antivirals. The envelope glycoproteins of HCV are heavily glycosylated with a high proportion of high-mannose glycans (HMGs), which serve as a shield against neutralizing antibodies and assist in the interaction with cell-entry

Background & Aims Inflammatory bowel diseases (IBD) are chronic inflammatory disorders where predictive biomarkers for the disease development and clinical course are sorely needed for development of prevention and early intervention strategies that can be implemented to improve clinical outcomes. Since gut microbiome alterations can reflect and/or contribute to impending host health changes, we examined

Objective TNFSF15 genetic variants leading to increased TNFSF15 expression confer risk for IBD and TNFSF15 is being explored as a therapeutic target in IBD patients. While the focus for TNFSF15-mediated inflammatory outcomes has been predominantly on its action on T cells, TNFSF15 also promotes inflammatory outcomes in human macrophages. Given the critical role for macrophages in bacterial clearance

Background & Aim Pancreatic ductal adenocarcinoma (PDAC) is resistant to most therapeutics due to dense fibrotic stroma orchestrated by Cancer Associated Pancreatic Stellate Cells (CAPaSC). CAPaSC also support cancer cell growth, metastasis, and resistance to apoptosis. Currently, there is no effective therapy for PDAC that specifically targets CAPaSC. We previously reported a rationally designed protein

Background & Aims The human gut microbiota can regulate production of serotonin (5-HT) from enterochromaffin cells. However, the mechanisms underlying microbial-induced serotonin signaling are not well understood. Methods Adult germ-free mice were treated with sterile media, live Bifidobacterium dentium, heat killed B. dentium, or live Bacteroides ovatus. Mouse and human enteroids were used to assess

Background and Aims Characterization of cell specific transcriptional responses to hepatotoxicants is lost in the averages of bulk RNA-sequencing (RNA-seq). Single-cell/nuclei RNA-seq technologies enable the transcriptomes of individual cell (sub)types to be assessed within the context of in vivo models. Methods Single-nuclei RNA-sequencing (snSeq) of frozen liver samples from male C57BL/6 mice gavaged

BACKGROUND & AIMS Gastric dysfunction in the elderly may cause reduced food intake, frailty and increased mortality. The pacemaker and neuromodulator cells interstitial cells of Cajal (ICC) decline with age in humans and their loss contributes to gastric dysfunction in progeric klotho mice hypomorphic for the anti-aging Klotho protein. The mechanisms of ICC depletion remain unclear. Klotho attenuates

Background & Aims Chronic amino acid (AA) deficiency, as in kwashiorkor, reduces the size of the pancreas through an effect on mTORC1. Because of the physiological importance of AAs and their role as a substrate, a stimulant of mTORC1 and protein synthesis, we studied the effect of acute protein and AA deficiency on the response to feeding. Methods CR mice were fasted overnight and refed for 2 h with

Background & Aims Systemic retinol (vitamin A) homeostasis is controlled by the liver, involving close collaboration between hepatocytes and hepatic stellate cells (HSC). Genetic variants in retinol metabolism (PNPLA3 and HSD17B13) are associated with non-alcoholic fatty liver disease (NAFLD) and disease progression. Still, little mechanistic details are known about hepatic vitamin A metabolism in

Background and aims Mouse models of colitis have been used to study the pathogenesis of inflammatory bowel disease (IBD) and for pre-clinical development of therapeutic agents. Various epigenetic pathways have been shown to play important regulatory roles in IBD. Reversible N6-methyladenosine (m6A) methylation represents a new layer of post-transcriptional gene regulation that affects a variety of