An untargeted metabolomic study using MALDI-mass spectrometry imaging reveals region-specific biomarkers associated with bowel inflammation.

Introduction: Inflammatory bowel diseases (IBDs) are chronic immune driven intestinal disorders with marked metabolic alteration. Mass spectrometry imaging (MSI) enables the direct visualization of biomolecules within tissues and facilitates the study of metabolic changes. Integrating multiple spatial information sources is a promising approach for discovering new biomarkers and understanding biochemical alteration within the context of the disease.

4-Anilinoquinazoline Derivatives as the First Potent NOD1-RIPK2 Signaling Pathway Inhibitors at the Nanomolar Range.

Inflammation is a defense mechanism that restores tissue damage and eliminates pathogens. Among the pattern recognition receptors that recognize danger or pathogenic signals, nucleotide oligomerization domains 1 and 2 (NOD1/2) have been identified to play an important role in innate immunity responses, and inhibition of NOD1 could be interesting to treat severe infections and inflammatory diseases. In this work, we identified the first selective NOD1 versus NOD2 pathway inhibitors at the nanomolar range based on a 4-anilinoquinazoline scaffold.

Chronic Exposure to Both Electronic and Conventional Cigarettes Alters Ileum and Colon Turnover, Immune Function, and Barrier Integrity in Mice.

Although the effects of cigarette smoke (CS) on the development of several intestinal diseases is well documented, the impact of e-cigarette aerosol (e-cig) on digestive health is largely unknown. To compare the effects of e-cig and CS on mouse ileum and colon, animals were chronically exposed for 6 months by nose-only inhalation to e-cig at 18 or 30 W power, or to 3R4F CS. Results showed that e-cig exposure decreased colon cell proliferation.

O-GlcNAcylation controls pro-fibrotic transcriptional regulatory signaling in myofibroblasts.

Tissue injury causes activation of mesenchymal lineage cells into wound-repairing myofibroblasts (MFs), whose uncontrolled activity ultimately leads to fibrosis. Although this process is triggered by deep metabolic and transcriptional reprogramming, functional links between these two key events are not yet understood. Here, we report that the metabolic sensor post-translational modification O-linked β-D-N-acetylglucosaminylation (O-GlcNAcylation) is increased and required for myofibroblastic activation.

Receptor Interacting Ser/Thr-Protein Kinase 2 as a New Therapeutic Target.

Receptor interacting serine/threonine protein kinase 2 (RIPK2) is a downstream signaling molecule essential for the activation of several innate immune receptors, including the NOD-like receptors (NOD1 and NOD2). Recognition of pathogen-associated molecular pattern proteins by NOD1/2 leads to their interaction with RIPK2, which induces release of pro-inflammatory cytokines through the activation of NF-κB and MAPK pathways, among others. Thus, RIPK2 has emerged as a key mediator of intracellular signal transduction and represents a new potential therapeutic target for the treatment of various conditions, including inflammatory diseases and cancer.

Oral exposure to polyethylene microplastics induces inflammatory and metabolic changes and promotes fibrosis in mouse liver.

Accumulating evidence shows widespread contamination of water sources and food with microplastics. Although the liver is one of the main sites of bioaccumulation within the human body, it is still unclear whether microplastics produce damaging effects. In particular, the hepatic consequences of ingesting polyethylene (PE) microplastics in mammals are unknown.

Low dose dietary contamination with deoxynivalenol mycotoxin exacerbates enteritis and colorectal cancer in mice.

Background: The mycotoxin deoxynivalenol (DON) is a frequent contaminant of grain and cereal products worldwide. Exposure to DON can cause gastrointestinal inflammation, disturb gut barrier function, and induce gut dysbiosis in vivo under basal conditions, but little is known about the effects of DON ingestion in individuals with pre-existing gastrointestinal disease.

Objectives: Mice were orally exposed to 10 and 100 μg/kg bw/day of DON, corresponding to 10 to 100-fold human tolerable daily intake concentrations, and to the translation in mice of current human daily intake.

An extended transcription factor regulatory network controls hepatocyte identity.

Cell identity is specified by a core transcriptional regulatory circuitry (CoRC), typically limited to a small set of interconnected cell-specific transcription factors (TFs). By mining global hepatic TF regulons, we reveal a more complex organization of the transcriptional regulatory network controlling hepatocyte identity. We show that tight functional interconnections controlling hepatocyte identity extend to non-cell-specific TFs beyond the CoRC, which we call hepatocyte identity (Hep-ID) TFs.

Dipalmitoyl-phosphatidylserine-filled cationic maltodextrin nanoparticles exhibit enhanced efficacy for cell entry and intracellular protein delivery in phagocytic THP-1 cells.

Vaccination through the upper respiratory tract is a promising strategy, and particulate antigens, such as antigens associated with nanoparticles, triggered a stronger immune response than the sole antigens. Cationic maltodextrin-based nanoparticles loaded with phosphatidylglycerol (NPPG) are efficient for intranasal vaccination but non-specific to trigger immune cells. Here we focused on phosphatidylserine (PS) receptors, specifically expressed by immune cells including macrophages, to improve nanoparticle targeting through an efferocytosis-like mechanism.

Hepatocyte dedifferentiation profiling in alcohol-related liver disease identifies CXCR4 as a driver of cell reprogramming.

Background & Aims: Loss of hepatocyte identity is associated with impaired liver function in alcohol-related hepatitis (AH). In this context, hepatocyte dedifferentiation gives rise to cells with a hepatobiliary (HB) phenotype expressing biliary and hepatocyte markers and showing immature features. However, the mechanisms and impact of hepatocyte dedifferentiation in liver disease are poorly understood.

Hepatocyte Dedifferentiation Profiling In Alcohol-Related Liver Disease Identifies CXCR4 As A Driver Of Cell Reprogramming.

Background And Aims: Loss of hepatocyte identity is associated with impaired liver function in alcohol-related hepatitis (AH). In this context, hepatocyte dedifferentiation gives rise to cells with a hepatobiliary (HB) phenotype expressing biliary and hepatocytes markers and showing immature features. However, the mechanisms and the impact of hepatocyte dedifferentiation in liver disease are poorly understood.

In vitro and in vivo evaluation of a pH-, microbiota- and time-based oral delivery platform for colonic release.

Several formulation strategies have been proposed for oral colon delivery, particularly for the therapy of inflammatory bowel disease (IBD). However, targeting the large intestine remains a challenging goal. The aim of this study was to develop and evaluate a novel type of drug delivery system, which is based on multiple drug release triggers for reliable performance.

Functional genomics uncovers the transcription factor BNC2 as required for myofibroblastic activation in fibrosis.

Tissue injury triggers activation of mesenchymal lineage cells into wound-repairing myofibroblasts, whose unrestrained activity leads to fibrosis. Although this process is largely controlled at the transcriptional level, whether the main transcription factors involved have all been identified has remained elusive. Here, we report multi-omics analyses unraveling Basonuclin 2 (BNC2) as a myofibroblast identity transcription factor.

Gene/environment interaction in the susceptibility of Crohn's disease patients to aluminum.

Background & Aim: The key role of environmental factors in the pathogenesis of Inflammatory Bowel Diseases (IBD) is recognized. Aluminum is suspected to be a risk factor for IBD. However, mechanisms linking aluminum exposure to disease development are unknown.

Dimerization of kringle 1 domain from hepatocyte growth factor/scatter factor provides a potent MET receptor agonist.

Hepatocyte growth factor/scatter factor (HGF/SF) and its cognate receptor MET play several essential roles in embryogenesis and regeneration in postnatal life of epithelial organs such as the liver, kidney, lung, and pancreas, prompting a strong interest in harnessing HGF/SF-MET signalling for regeneration of epithelial organs after acute or chronic damage. The limited stability and tissue diffusion of native HGF/SF, however, which reflect the tightly controlled, local mechanism of action of the morphogen, have led to a major search of HGF/SF mimics for therapy. In this work, we describe the rational design, production, and characterization of K1K1, a novel minimal MET agonist consisting of two copies of the kringle 1 domain of HGF/SF in tandem orientation.

Starch-based NP act as antigen delivery systems without immunomodulating effect.

The nasal route of immunization has become a real alternative to injections. It is indeed described as more efficient at inducing immune protection, since it initiates both mucosal and systemic immunity, thus protecting against both the infection itself and the transmission of pathogens by the host. However, the use of immunomodulators should be limited since they induce inflammation.

MicroRNAs, Tristetraprolin Family Members and HuR: A Complex Interplay Controlling Cancer-Related Processes.

MicroRNAs represent the most characterized post-transcriptional regulators of gene expression. Their altered expression importantly contributes to the development of a wide range of metabolic and inflammatory diseases but also cancers. Accordingly, a myriad of studies has suggested novel therapeutic approaches aiming at inhibiting or restoring the expression of miRNAs in human diseases.

Murine in utero exposure to simulated complex urban air pollution disturbs offspring gut maturation and microbiota during intestinal suckling-to-weaning transition in a sex-dependent manner.

Background: Emerging data indicate that prenatal exposure to air pollution may lead to higher susceptibility to several non-communicable diseases. Limited research has been conducted due to difficulties in modelling realistic air pollution exposure. In this study, pregnant mice were exposed from gestational day 10-17 to an atmosphere representative of a 2017 pollution event in Beijing, China.

Oral exposure to polyethylene microplastics alters gut morphology, immune response, and microbiota composition in mice.

The ubiquitous and growing presence of microplastics (MPs) in all compartments of the environment raises concerns about their possible harmful effects on human health. Human exposure to MPs occurs largely through ingestion. Polyethylene (PE) is widely employed for reusable bags and food packaging and found to be present in drinking water and food.

Exposure to atmospheric Ag, TiO, Ti and SiO engineered nanoparticles modulates gut inflammatory response and microbiota in mice.

The development of nanotechnologies is leading to greater abundance of engineered nanoparticles (EN) in the environment, including in the atmospheric air. To date, it has been shown that the most prevalent EN found in the air are silver (Ag), titanium dioxide (TiO), titanium (Ti), and silicon dioxide (SiO). As the intestinal tract is increasingly recognized as a target for adverse effects induced by inhalation of air particles, the aim of this study was to assess the impact of these 4 atmospheric EN on intestinal inflammation and microbiota.

Starch nanoparticles improve curcumin-induced production of anti-inflammatory cytokines in intestinal epithelial cells.

Inflammatory bowel disease (IBD), encompassing Crohn's disease and ulcerative colitis, is a long-term condition resulting from self-sustained intestinal inflammation. Curcumin (Cur), a powerful, naturally occurring antioxidant and anti-inflammatory polyphenol, has been investigated as a therapeutic for IBD, but its poor stability and low bioavailability limits its efficacy. We investigated the use of crosslinked starch nanocarrier (NPL) on the intracellular delivery and the anti-inflammatory efficiency of curcumin.

Loss of hepatocyte identity following aberrant YAP activation: A key mechanism in alcoholic hepatitis.

Background & Aims: Alcoholic hepatitis (AH) is a life-threatening disease with limited therapeutic options, as the molecular mechanisms leading to death are not well understood. This study evaluates the Hippo/Yes-associated protein (YAP) pathway which has been shown to play a role in liver regeneration.

Method: The Hippo/YAP pathway was dissected in explants of patients transplanted for AH or alcohol-related cirrhosis and in control livers, using RNA-seq, real-time PCR, western blot, immunohistochemistry and transcriptome analysis after laser microdissection.

Severe SARS-CoV-2 patients develop a higher specific T-cell response.

Objectives: Assessment of the adaptive immune response against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is crucial for studying long-term immunity and vaccine strategies. We quantified IFNγ-secreting T cells reactive against the main viral SARS-CoV-2 antigens using a standardised enzyme-linked immunospot assay (ELISpot).

Methods: Overlapping peptide pools built from the sequences of M, N and S viral proteins and a mix (MNS) were used as antigens.