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Molecular Mechanisms of Hepatotoxicity: New Insights and Therapeutic Challenges

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A special issue of Current Issues in Molecular Biology (ISSN 1467-3045). This special issue belongs to the section "Molecular Medicine".

Deadline for manuscript submissions: closed (31 December 2022) | Viewed by 12345

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Special Issue Editor

Dr. Ahmed Ezat El Zowalaty

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Guest Editor

1. Sahlgrenska Center for Cancer Research, Department of Surgery, Institute of Clinical Sciences, University of Gothenburg, 405 30 Gothenburg, Sweden
2. Wallenberg Centre for Molecular and Translational Medicine, University of Gothenburg, 405 30 Gothenburg, Sweden
Interests: natural compounds; cellular toxicology; pharmacogenomics; toxicogenomics; metabolism
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

The liver is the central organ for detoxification and metabolism of drugs and xenobiotics. Different factors such as lifestyle, environmental changes, high fat diet, obesity, and alcohol drinking lead to liver injury, fibrosis, cirrhosis, fatty liver disease, and liver cancer. While sexual dimorphism defines liver diseases such as fatty liver disease and liver cancer, ligand-activated nuclear receptors such as PPARα, PXR, and CAR, FXR, LXR, and G-protein-coupled receptors (GPCRs) are key regulators of the response to chemical toxicants, nutrient/energy homeostasis and involved in the pathogenesis of liver diseases. Identification of molecular mechanisms of liver injury is therefore essential to identify new therapeutic targets and develop new promising treatments. In this Special Issue, we invite researchers to present primary research papers, reviews, visionary perspectives, or retrospective analyses that address novel findings in deciphering the mechanisms of liver disease development as well as the molecular pharmacology of GPCR, hormone and nuclear receptor signaling at different stages of liver diseases, and hepatocarcinogenesis. Studies addressing targeted pharmacologic intervention at receptor signaling axes during hepatocarcinogenesis, pharmacological interventions including dual/triple agonists, agonist/antagonist combination, tissue-specific agonists/antagonists, and nuclear receptor modulators would be essential for the identification of therapeutic targets. Studies addressing mediators of protection against liver damage, inflammation, and death induced by liver toxic agents are welcome. Studies addressing redox signaling, toxicity mechanisms induced by epigenetic reprogramming, in silico and machine learning methods that advance understanding of mechanisms of toxicity, cytotoxicity mechanisms involving dysregulation of miRNA pathways, RNA metabolism, signal transduction, proliferation, differentiation, cell death pathways, transcriptomics, and toxicogenomics in the context of liver diseases are welcome.

Dr. Ahmed Ezat El Zowalaty
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Current Issues in Molecular Biology is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2200 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

hepatotoxicity
liver steatosis
liver fibrosis
liver cirrhosis
nuclear receptors
GPCR

Published Papers (4 papers)

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Research

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11 pages, 5044 KiB

Open AccessArticle

Development of an Improved Method for the Isolation and Culture of Newborn Sheep Primary Hepatocytes

by Bowen Chen, Xiaoning Dou, Dan Zhang, Tiaoguo Liu, Bohui Yang and Zengkui Lu

Curr. Issues Mol. Biol. 2022, 44(8), 3621-3631; https://doi.org/10.3390/cimb44080248 - 12 Aug 2022

Cited by 1 | Viewed by 2162

Abstract

The liver plays a crucial role in metabolism, synthesis, biotransformation, secretion, and excretion. Hepatocytes are the main cells of the liver and can be used as a cell model to study liver function. The classic method of collagenase perfusion to isolate hepatocytes is a two-step technique that is time-consuming, labor-intensive, and has high technical requirements. Therefore, in this study, we compared different methods for isolating and culturing primary hepatocytes. We found that the 0.25% trypsin and 0.1 mg/mL type IV collagenase mixture at a 1:1 ratio showed the most efficient cell digestion, and William’s Medium E complete medium showed the best growth and proliferation. The isolated cells showed the typical irregular polygonal morphology of hepatocytes. Periodic acid–Schiff staining and immunofluorescence confirmed that the isolated cells were positive for glycogen and hepatocyte-specific markers cytokeratin 18, AFP, and albumin. On subculturing, stable cell lines were obtained. Therefore, we optimized the isolation and in vitro culture method to obtain highly pure (>95%) sheep primary hepatocytes from newborn sheep liver tissue. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Hepatotoxicity: New Insights and Therapeutic Challenges)

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Review

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13 pages, 936 KiB

Open AccessReview

Liver Damage and COVID-19: At Least a “Two-Hit” Story in Systematic Review

by Michele Montori, Gialuca Svegliati Baroni, Pierangelo Santori, Catia Di Giampaolo, Francesca Ponziani, Ludovico Abenavoli and Emidio Scarpellini

Curr. Issues Mol. Biol. 2023, 45(4), 3035-3047; https://doi.org/10.3390/cimb45040199 - 4 Apr 2023

Cited by 3 | Viewed by 2948

Abstract

COVID-19 pandemic waves have hit on our lives with pulmonary and, also, gastrointestinal symptoms. The latter also includes acute liver damage linked to direct SARS-CoV-2 action and/or drug-induced (DILI) in the frame of pre-existing chronic liver disease. We aimed to review literature data regarding liver damage during COVID-19. We conducted a systematic search on the main medical databases for original articles, reviews, meta-analyses, randomized clinical trials and case series using the following keywords and acronyms and their associations: liver disease, COVID-19, acute liver damage, drug-induced liver injury, antivirals. Acute liver damage due to SARS-CoV-2 infection is common among COVID-19 patients and is generally self-limiting. However, chronic hepatic diseases, such as metabolic-associated fatty liver disease (MAFLD), are associated with a less favorable prognosis, especially when alkaline phosphatases show a significant rise. Pathophysiology of COVID-19 liver damage is multifaceted and helps understand differences in liver derangement among patients. Thus, early recognition, monitoring and treatment of liver damage are crucial in these patients. In the frame of a not-ending pandemic sustained by SARS-CoV-2, it is crucial to recognize acute hepatic decompensation due to the virus and/or drugs used for COVID-19 treatment. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Hepatotoxicity: New Insights and Therapeutic Challenges)

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14 pages, 1275 KiB

Open AccessReview

Liver Damage and microRNAs: An Update

by Erika Cione, Diana Marisol Abrego Guandique, Maria Cristina Caroleo, Filippo Luciani, Manuela Colosimo and Roberto Cannataro

Curr. Issues Mol. Biol. 2023, 45(1), 78-91; https://doi.org/10.3390/cimb45010006 - 23 Dec 2022

Cited by 6 | Viewed by 2151

Abstract

One of the major organs in the body with multiple functions is the liver. It plays a central role in the transformation of macronutrients and clearance of chemicals and drugs. The serum biomarkers often used to indicate liver damage are not specifically for drug-induced liver injury (DILI) or liver injury caused by other xenobiotics, nor for viral infection. In this case, microRNAs (miRNAs) could play an exciting role as biomarkers of specific liver damage. In this review, we aimed to update the current literature on liver damage induced by drugs, as acute conditions and viral infections mediated by the hepatitis B virus (HBV) linked these two conditions to advanced research, with a focus on microRNAs as early biomarkers for liver damage. The undoubtable evidence that circulating miR-122 could be used as a human biomarker of DILI came from several studies in which a strong increase of it was linked with the status of liver function. In infancy, there is the possibility of an early miRNA detection for hepatitis B virus infection, but there are a lack of solid models for studying the HVB molecular mechanism of infection in detail, even if miRNAs do hold unrealized potential as biomarkers for early detection of hepatitis B virus infection mediated by HBV. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Hepatotoxicity: New Insights and Therapeutic Challenges)

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10 pages, 860 KiB

Open AccessReview

Mitochondrial Dysfunction and Chronic Liver Disease

by Chunyan Zhang, Yabin Zhao, Mengli Yu, Jianru Qin, Bingyu Ye and Qiwen Wang

Curr. Issues Mol. Biol. 2022, 44(7), 3156-3165; https://doi.org/10.3390/cimb44070218 - 9 Jul 2022

Cited by 18 | Viewed by 3961

Abstract

Mitochondria are generally considered the powerhouse of the cell, a small subcellular organelle that produces most of the cellular energy in the form of adenosine triphosphate (ATP). In addition, mitochondria are involved in various biological functions, such as biosynthesis, lipid metabolism, oxidative phosphorylation, cell signal transduction, and apoptosis. Mitochondrial dysfunction is manifested in different aspects, like increased mitochondrial reactive oxygen species (ROS), mitochondrial DNA (mtDNA) damage, adenosine triphosphate (ATP) synthesis disorder, abnormal mitophagy, as well as changes in mitochondrial morphology and structure. Mitochondrial dysfunction is related to the occurrence and development of various chronic liver diseases, including hepatocellular carcinoma (HCC), viral hepatitis, drug-induced liver injury (DILI), alcoholic fatty liver (AFL), and non-alcoholic fatty liver (NAFL). In this review, we summarize and discuss the role and mechanisms of mitochondrial dysfunction in chronic liver disease, focusing on and discussing some of the latest studies on mitochondria and chronic liver disease. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Hepatotoxicity: New Insights and Therapeutic Challenges)

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