Emerging role of ferroptosis in metabolic dysfunction-associated steatotic liver disease: revisiting hepatic lipid peroxidation

Summary: Metabolic dysfunction-associated steatohepatitis (MASH) is characterised by cell death of parenchymal liver cells which interact with their microenvironment to drive disease activity and liver fibrosis. The identification of the major death type could pave the way towards pharmacotherapy for MASH. To date, increasing evidence suggest a type of regulated cell death, named ferroptosis, which occurs through iron-catalysed peroxidation of polyunsaturated fatty acids (PUFA) in membrane phospholipids. Lipid peroxidation enjoys renewed interest in the light of ferroptosis, as druggable target in MASH. This review recapitulates the molecular mechanisms of ferroptosis in liver physiology, evidence for ferroptosis in human MASH and critically appraises the results of ferroptosis targeting in preclinical MASH models. Rewiring of redox, iron and PUFA metabolism in MASH creates a proferroptotic environment involved in MASH-related hepatocellular carcinoma (HCC) development. Ferroptosis induction might be a promising novel approach to eradicate HCC, while its inhibition might ameliorate MASH disease progression

Effect of GTS-21, An Alpha7 Nicotinic Acetylcholine Receptor Agonist, on Clp-Induced Inflammatory, Gastrointestinal Motility and Colonic Permeability Changes in Mice

During abdominal sepsis, the inhibition of gastrointestinal (GI) motility together with mucosal barrier dysfunction will lead to increased bacterial translocation and maintenance of sepsis. The activation of the vagal anti-inflammatory pathway remains an appealing therapeutic strategy in sepsis. In this respect, selective alpha7 nicotinic acetylcholine receptor (α7nAChR) agonists have shown anti-inflammatory properties in several animal models of inflammation.status: publishe

Beneficial Effects of Anti-Interleukin-6 Antibodies on Impaired Gastrointestinal Motility, Inflammation and Increased Colonic Permeability in a Murine Model of Sepsis Are Most Pronounced When Administered in a Preventive Setup - Fig 2

<p><b>Effect of</b><u><b><i>preventive</i></b></u><b>treatment with anti-IL-6 antibodies on sepsis-induced clinical signs of disease 24h (A) and 48h (B) following CLP or sham-surgery, percentage of weight loss at day 1 (C), percentage of gastric emptying (D), geometric center of GI transit (E) and colonic permeability as measured by the <i>Evans blue</i> method (F).</b> Two-way ANOVA followed by One-way ANOVA and SNK <i>post-hoc</i> testing when appropriate, or its non-parametric equivalent for ordinal data; n = 7–10/group for A, B and C; n = 9–12/group for D; *p ≤ 0.05, ***p ≤ 0/001, # significant effect of CLP, § significant effect of anti-IL-6. CDS: clinical disease score; CLP: caecal ligation and puncture; GC: geometric center; %GE: percentage of gastric emptying; GI: gastrointestinal.</p

Cytokine levels in serum (A) and supernatants of homogenized colons (B) measured by CBA or ELISA (IL-1α), and determined by RT-PCR in colon (C) during the <i>preventive</i> set-up (administration of anti-IL-6 antibodies simultaneously with the CLP- or sham-procedure).

<p>Cytokine levels in serum (A) and supernatants of homogenized colons (B) measured by CBA or ELISA (IL-1α), and determined by RT-PCR in colon (C) during the <u><i>preventive</i></u> set-up (administration of anti-IL-6 antibodies simultaneously with the CLP- or sham-procedure).</p

Cytokine levels in serum (A) and supernatants of homogenized colons (B) measured by CBA, and determined by RT-PCR in colon (C) during the <i>curative</i> set-up (administration of anti-IL-6 antibodies 24h following the CLP- or sham-procedure).

<p>Cytokine levels in serum (A) and supernatants of homogenized colons (B) measured by CBA, and determined by RT-PCR in colon (C) during the <u><i>curative</i></u> set-up (administration of anti-IL-6 antibodies 24h following the CLP- or sham-procedure).</p

Kaplan-Meier survival analysis.

<p>Kaplan-Meier curve displaying survival of sham and CLP-mice treated with anti-IL-6 antibodies or IgG isotype control up until 48h following the CLP-procedure. Log rank test p = 0.011.</p

RT-PCR of cell adhesion molecules.

<p>RT-PCR of cell adhesion molecules.</p

Experimental design of the study.

<p>In a first experimental setup (A), mice received anti-interleukin-6 antibodies (1 mg/kg) or the vehicle (IgG1 kappa isotype) simultaneously with the CLP- or sham-procedure. In a second setup (B), mice furthermore received a repeated injection with the antibodies 24h following the procedure. In a third setup (C), mice only received anti-IL-6 or vehicle 24h following the CLP- or sham-procedure. 48h post-CLP, mice received a gavage of colored solid beads and 2h later mice were sacrificed for measurement gastrointestinal transit, prelevation of serum and tissue samples, measurement of colonic permeability and quantification of cell adhesion molecules at the mRNA and protein level. CBA: cytometric bead array; CDS: clinical disease score; CLP: caecal ligation and puncture; MLN: mesenteric lymph nodes; mRNA: messenger ribonucleic acid; RT-PCR: reverse transcriptase real-time polymerase chain reaction.</p

Cultures of blood and homogenized mesenteric lymph nodes.

<p>Cultures of blood and homogenized mesenteric lymph nodes.</p