International Journal of Molecular Sciences

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Dr. Antonietta Messina

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Guest Editor

UMR_S 1193, INSERM/Université Paris-Saclay, Fédération Hospitalo-Universitaire (FHU) Hépatinov, F-94807 Villejuif, France
Interests: organoids; human pluripotent stem cells; hepatic differentiation; biomaterials; biohybrid systems; bioartificial liver; bioengineering; bio-printing; imaging; light-sheet microscopy; biochemistry; pharmacology; organ-on-chip

Prof. Dr. Jean-Charles Duclos-Vallée

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Guest Editor

UMR_S 1193, INSERM/Université Paris-Saclay, Fédération Hospitalo-Universitaire (FHU) Hépatinov, F-94807 Villejuif, France
Interests: end stage liver disease; rare liver disorders; liver regenerative medicine; liver transplantation; liver bioconstruction; bioengineering

Special Issue Information

Dear Colleagues,

This is a continued collection of the hot topic of Molecular Mechanisms of Hepatotoxicity. We already have done a successful special issue which received interesting contributions and discussions (https://www.mdpi.com/journal/ijms/special_issues/molecula_hepatotoxicity).

Liver toxicity is the leading cause of the removal of approved drugs from the market as well as the constant increase in patients suffering from acute liver failure. Drug-induced liver injury (DILI) can be caused by numerous pharmaceutical agents, as well as dietary or herbal supplements. Moreover, with a few exceptions, the mechanisms by which these drugs and molecules cause hepatic injury are elusive. Since there is no real treatment available apart from orthotopic liver transplantation for the most severe cases, the characterization of the specific mechanisms that lead to hepatotoxicity, the identification of potential novel targets for the development of new therapeutic strategies, as well as the development of new devices for improving drug screening and pharmacological responses are major priorities in this field.

The aim of this Special Issue is to provide an overview of the main cellular and molecular mechanisms; to elucidate the causes and sources of hepatoxicity, which leads to the onset and progression of hepatic disorders, highlighting both the common and specific pathways involved in each one of them; and to propose new bio-technological approaches for studying toxicity.

Dr. Antonietta Messina
Prof. Dr. Jean-Charles Duclos-Vallée
Guest Editors

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Keywords

hepatotoxicity
drug-induced liver injury (DILI)
epidemiology of liver toxicity
organoids
organ-on-chip
acute liver failure (ALF)' drugs
paracetamol
antibiotics
mitochondria
drug-screening
immuno-toxicity

Published Papers (2 papers)

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Research

18 pages, 1605 KiB

Open AccessArticle

IL-23/IL-17 Axis in Chronic Hepatitis C and Non-Alcoholic Steatohepatitis—New Insight into Immunohepatotoxicity of Different Chronic Liver Diseases

by Ankica Vujovic, Andjelka M. Isakovic, Sonja Misirlic-Dencic, Jovan Juloski, Milan Mirkovic, Andja Cirkovic, Marina Djelic and Ivana Milošević

Int. J. Mol. Sci. 2023, 24(15), 12483; https://doi.org/10.3390/ijms241512483 - 05 Aug 2023

Cited by 2 | Viewed by 1645

Abstract

Considering the relevance of the research of pathogenesis of different liver diseases, we investigated the possible activity of the IL-23/IL-17 axis on the immunohepatotoxicity of two etiologically different chronic liver diseases. A total of 36 chronic hepatitis C (CHC) patients, 16 with (CHC-SF) and 20 without significant fibrosis (CHC-NSF), 19 patients with non-alcoholic steatohepatitis (NASH), and 20 healthy controls (CG) were recruited. Anthropometric, biochemical, and immunological cytokines (IL-6, IL-10, IL-17 and IL-23) tests were performed in accordance with standard procedure. Our analysis revealed that a higher concentration of plasma IL-23 was associated with NASH (p = 0.005), and a higher concentration of plasma IL-17A but a lower concentration of plasma IL-10 was associated with CHC in comparison with CG. A lower concentration of plasma IL-10 was specific for CHC-NSF, while a higher concentration of plasma IL-17A was specific for CHC-SF in comparison with CG. CHC-NSF and CHC-SF groups were distinguished from NASH according to a lower concentration of plasma IL-17A. Liver tissue levels of IL-17A and IL-23 in CHC-NSF were significantly lower in comparison with NASH, regardless of the same stage of the liver fibrosis, whereas only IL-17A tissue levels showed a difference between the CHC-NSF and CHC-SF groups, namely, a lower concentration in CHC-NSF in comparison with CHC-SF. In CHC-SF and NASH liver tissue, IL17-A and IL-23 were significantly higher in comparison with plasma. Diagnostic accuracy analysis showed significance only in the concentration of plasma cytokines. Plasma IL-6, IL-17A and IL-23 could be possible markers that could differentiate CHC patients from controls. Plasma IL-23 could be considered a possible biomarker of CHC-NSF patients in comparison with controls, while plasma IL-6 and IL-17-A could be biomarkers of CHC-SF patients in comparison with controls. The most sophisticated difference was between the CHC-SF and CHC-NSF groups in the plasma levels of IL-10, which could make this cytokine a useful biomarker of liver fibrosis. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Hepatotoxicity 2.0)

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18 pages, 5110 KiB

Open AccessArticle

Involvement of the p38/MK2 Pathway in MCLR Hepatotoxicity Revealed through MAPK Pharmacological Inhibition and Phosphoproteomics in HepaRG Cells

by Katherine D. Lynch, Dayne T. Iverson, Namrata K. Bachhav, Michael Ridge Call, Guihua Eileen Yue, Bhagwat Prasad and John D. Clarke

Int. J. Mol. Sci. 2023, 24(13), 11168; https://doi.org/10.3390/ijms241311168 - 06 Jul 2023

Viewed by 1856

Abstract

Microcystin-leucine arginine (MCLR) is one of the most common and toxic microcystin variants, a class of cyanotoxins produced by cyanobacteria. A major molecular mechanism for MCLR-elicited liver toxicity involves the dysregulation of protein phosphorylation through protein phosphatase (PP) inhibition and mitogen-activated protein kinase (MAPK) modulation. In this study, specific pharmacological MAPK inhibitors were used in HepaRG cells to examine the pathways associated with MCLR cytotoxicity. SB203580 (SB), a p38 inhibitor, rescued HepaRG cell viability, whereas treatment with SP600125 (JNK inhibitor), MK2206 (AKT inhibitor), or N-acetylcysteine (reactive oxygen species scavenger) did not. Phosphoproteomic analysis revealed that phosphosites—which were altered by the addition of SB compared to MCLR treatment alone—included proteins involved in RNA processing, cytoskeletal stability, DNA damage response, protein degradation, and cell death. A closer analysis of specific proteins in some of these pathways indicated that SB reversed the MCLR-mediated phosphorylation of the necroptosis-associated proteins, the mixed lineage kinase domain-like protein (MLKL), receptor-interacting serine/threonine kinase 1 (RIP1), DNA damage response proteins, ataxia telangiectasia and Rad3-related kinase (ATR), and checkpoint kinase 1 (CHK1). Overall, these data implicate p38/MK2, DNA damage, and necroptosis in MCLR-mediated hepatotoxicity, and suggest these pathways may be targets for prevention prior to, or treatment after, MCLR toxicity. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Hepatotoxicity 2.0)

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