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Hepatotoxin Exposures, Molecular Mechanisms, and Implications for Liver Diseases

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A special issue of Toxins (ISSN 2072-6651).

Deadline for manuscript submissions: closed (31 July 2021) | Viewed by 14871

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Special Issue Editor

Dr. John Clarke

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Guest Editor

Washington State University, WA, USA

Special Issue Information

Dear Colleagues,

The liver is a major detoxification organ and encounters toxins from many different sources, including but not limited to endotoxins, exotoxins, mycotoxins, and phycotoxins. These hepatotoxins can initiate and propagate various liver diseases through molecular and cellular mechanisms of liver damage (e.g., apoptosis, necrosis, inflammation, steatosis) and repair (e.g., proliferation, collagen deposition, regeneration). These mechanisms are mediated through cell-type specific effects in hepatocytes, stellate cells, Kupffer cells, endothelial cells, and cholangiocytes. Many liver diseases develop over a long period of time and have multifaceted etiology, providing a continual opportunity for toxins to influence disease progression. There is a great need to better understand fundamental pathogenic toxin mechanisms in various species to connect exposures (intermittent or continual) to liver diseases and improve risk assessment for different toxins.

This Special Issue welcomes submissions that span the research spectrum from preclinical to clinical. These include but are not limited to:

Hepatotoxin exposure assessment in model organisms or human populations;
Fundamental mechanisms of hepatotoxin in liver damage in in vitro systems or model organisms;
Roles of hepatotoxin in liver disease etiology and/or progression;
Interaction between hepatotoxins and other liver disease risk factors;
Review articles addressing the established, putative, and unexplored connections between toxins and liver diseases.

Dr. John Clarke
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 double-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Toxins 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 2700 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

exposures
hepatoxicity
alcoholic liver disease
hepatocellular carcinoma
fatty liver disease
preclinical models
clinical evidence

Published Papers (4 papers)

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Research

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9 pages, 1729 KiB

Open AccessArticle

Identification of Decrease in TRiC Proteins as Novel Targets of Alpha-Amanitin-Derived Hepatotoxicity by Comparative Proteomic Analysis In Vitro

by Doeun Kim, Sunjoo Kim, Ann-Yae Na, Chang Hwan Sohn, Sangkyu Lee and Hye Suk Lee

Toxins 2021, 13(3), 197; https://doi.org/10.3390/toxins13030197 - 09 Mar 2021

Cited by 8 | Viewed by 2621

Abstract

Alpha-amanitin (α-AMA) is a cyclic peptide and one of the most lethal mushroom amatoxins found in Amanita phalloides. α-AMA is known to cause hepatotoxicity through RNA polymerase II inhibition, which acts in RNA and DNA translocation. To investigate the toxic signature of α-AMA beyond known mechanisms, we used quantitative nanoflow liquid chromatography–tandem mass spectrometry analysis coupled with tandem mass tag labeling to examine proteome dynamics in Huh-7 human hepatoma cells treated with toxic concentrations of α-AMA. Among the 1828 proteins identified, we quantified 1563 proteins, which revealed that four subunits in the T-complex protein 1-ring complex protein decreased depending on the α-AMA concentration. We conducted bioinformatics analyses of the quantified proteins to characterize the toxic signature of α-AMA in hepatoma cells. This is the first report of global changes in proteome abundance with variations in α-AMA concentration, and our findings suggest a novel molecular regulation mechanism for hepatotoxicity. Full article

(This article belongs to the Special Issue Hepatotoxin Exposures, Molecular Mechanisms, and Implications for Liver Diseases)

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10 pages, 2594 KiB

Open AccessCommunication

Fungi–Bacteria Correlation in Alcoholic Hepatitis Patients

by Bei Gao, Xinlian Zhang and Bernd Schnabl

Toxins 2021, 13(2), 143; https://doi.org/10.3390/toxins13020143 - 14 Feb 2021

Cited by 12 | Viewed by 2798

Abstract

Alcohol-related liver disease is one of the most prevalent types of chronic liver diseases globally. Alcohol-related liver disease begins with fatty liver, which further develops into hepatic inflammation, hepatocyte injury, and progresses to fibrosis and cirrhosis. Compositional changes of gut bacteria and fungi were found in patients with alcohol-related liver disease. However, the functional changes of fungi and correlations between fungi and bacteria have not been investigated. In this study, we first examined the functional capacity of fungi in patients with alcohol-related liver disease using shotgun metagenomics. Among 24 MetaCyc pathways contributed by fungi, superpathway of allantoin degradation in yeast was enriched in patients with alcoholic hepatitis. Furthermore, we compared the predictive power of bacteria versus fungi and found that bacteria performed better than fungi to separate patients with alcoholic hepatitis from non-alcoholic controls and patients with alcohol use disorder. Finally, we investigated the associations between the intestinal fungi and bacteria in alcoholic hepatitis patients. Positive association between fungi and bacteria was found between Cladosporium and Gemmiger, meanwhile negative association was found between Cryptococcus and Pseudomonas in alcoholic hepatitis patients. Full article

(This article belongs to the Special Issue Hepatotoxin Exposures, Molecular Mechanisms, and Implications for Liver Diseases)

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15 pages, 512 KiB

Open AccessArticle

Effects of Cassava Juice (Manihot esculenta Crantz) on Renal and Hepatic Function and Motor Impairments in Male Rats

by Eduardo Rivadeneyra-Domínguez, José Eduardo Pérez-Pérez, Alma Vázquez-Luna, Rafael Díaz-Sobac and Juan Francisco Rodríguez-Landa

Toxins 2020, 12(11), 708; https://doi.org/10.3390/toxins12110708 - 09 Nov 2020

Cited by 5 | Viewed by 2531

Abstract

Cassava (Manihot esculenta Crantz) is a plant that contains neurotoxins such as linamarin and lotaustraline. Its long-term consumption is associated with neuronal damage and contributes to the development of motor impairment in humans and rats. We investigated the effects of the consumption of cassava juice on renal and hepatic function and motor impairments in male rats. The rats received the vehicle, non-toxic and toxic doses of cassava juice, or linamarin as a pharmacological control, over 35 consecutive days. The effects were evaluated in an open field test, rotarod, and swim test. The toxic cassava dose and linamarin resulted in motor impairments in the rotarod and swim test from day 7 of treatment. The toxic cassava dose and linamarin increased the parameters that indicate renal and hepatic damage, with the exception of total protein and albumin levels. Behavioral variables that show motor incoordination (i.e., latency to fall in the rotarod) were negatively correlated with biochemical parameters of renal and kidney damage, whereas spin behavior was positively correlated. Our data indicate that chronic oral consumption of cassava juice caused renal and hepatic damage that was correlated with motor coordination impairment in rats, similarly to their principal neurotoxic compound, linamarin. Full article

(This article belongs to the Special Issue Hepatotoxin Exposures, Molecular Mechanisms, and Implications for Liver Diseases)

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Review

Jump to: Research

21 pages, 2071 KiB

Open AccessReview

Microcystin Toxicokinetics, Molecular Toxicology, and Pathophysiology in Preclinical Rodent Models and Humans

by Tarana Arman and John D. Clarke

Toxins 2021, 13(8), 537; https://doi.org/10.3390/toxins13080537 - 29 Jul 2021

Cited by 29 | Viewed by 6086

Abstract

Microcystins are ubiquitous toxins produced by photoautotrophic cyanobacteria. Human exposures to microcystins occur through the consumption of contaminated drinking water, fish and shellfish, vegetables, and algal dietary supplements and through recreational activities. Microcystin-leucine-arginine (MCLR) is the prototypical microcystin because it is reported to be the most common and toxic variant and is the only microcystin with an established tolerable daily intake of 0.04 µg/kg. Microcystin toxicokinetics is characterized by low intestinal absorption, rapid and specific distribution to the liver, moderate metabolism to glutathione and cysteinyl conjugates, and low urinary and fecal excretion. Molecular toxicology involves covalent binding to and inhibition of protein phosphatases, oxidative stress, cell death (autophagy, apoptosis, necrosis), and cytoskeleton disruption. These molecular and cellular effects are interconnected and are commonly observed together. The main target organs for microcystin toxicity are the intestine, liver, and kidney. Preclinical data indicate microcystins may also have nervous, pulmonary, cardiac, and reproductive system toxicities. Recent evidence suggests that exposure to other hepatotoxic insults could potentiate microcystin toxicity and increase the risk for chronic diseases. This review summarizes the current knowledge for microcystin toxicokinetics, molecular toxicology, and pathophysiology in preclinical rodent models and humans. More research is needed to better understand human toxicokinetics and how multifactorial exposures contribute to disease pathogenesis and progression. Full article

(This article belongs to the Special Issue Hepatotoxin Exposures, Molecular Mechanisms, and Implications for Liver Diseases)

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