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Molecular Advances in Liver Inflammation and Fibrosis

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: 10 July 2024 | Viewed by 5756

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Special Issue Editor

Dr. Sara Ceccarelli

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Guest Editor

Independent Researcher, Macclesfield, UK
Interests: liver fibrosis; inflammation; molecular targets; therapeutics

Special Issue Information

Dear Colleagues,

Liver fibrosis is a complex pathological condition resulting from repeated and long-lasting pro-inflammatory insults. Hepatocyte damage and persistent inflammation initiate and sustain the activation of hepatic stellate cells. Their transdifferentiation into myofibroblasts (MFs) and immune cells infiltration lead to excessive collagen production and extracellular matrix accumulation. The role of MFs in liver fibrogenesis is well described, while the role of adaptive immune cells is less understood. The interplay of the different cell types involved in the pathogenesis and the understanding of key molecular signaling pathways are crucial to develop new therapeutic strategies. Several preclinical models have been proven useful to better understand the anti-fibrotic effect of promising candidate agents. Nevertheless, there are still numerous challenges in the clinical development of anti-fibrotic compounds.

The aim of this Special Issue is to describe advancements in the comprehension of molecular mechanisms that are crucial for the onset and perpetuation of liver inflammation and fibrosis and their significance as possible therapeutic targets for their treatment.

Dr. Sara Ceccarelli
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. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. 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

liver fibrosis
inflammation
molecular targets
therapeutics

Published Papers (4 papers)

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Research

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22 pages, 12353 KiB

Open AccessArticle

Adhesion G Protein-Coupled Receptor G2 Promotes Hepatocellular Carcinoma Progression and Serves as a Neutrophil-Related Prognostic Biomarker

by Qian Wu, Pei Wang, Qihang Peng, Zhongcui Kang, Yiting Deng, Jiayi Li, Ying Chen, Jin Li and Feng Ge

Int. J. Mol. Sci. 2023, 24(23), 16986; https://doi.org/10.3390/ijms242316986 - 30 Nov 2023

Viewed by 1414

Abstract

Adhesion G protein-coupled receptor G2 (ADGRG2) is an orphan adhesion G protein-coupled receptor (GPCR), which performs a tumor-promoting role in certain cancers; however, it has not been systematically investigated in hepatocellular carcinoma (HCC). In the current study, we utilized multiple databases to analyze the expression and diagnostic and prognostic value of ADGRG2 in HCC and its correlation with immune infiltration and inflammatory factors. The function and upstream regulatory miRNA of ADGRG2 were validated through qPCR, Western blot, CCK8, wound healing, and dual luciferase assays. It turned out that ADGRG2 was significantly higher in HCC and had a poor survival rate, especially in AFP ≤ 400 ng/mL subgroups. Functional enrichment analysis suggested that ADGRG2 may be involved in cancer pathways and immune-related pathways. In vitro, siRNA-mediated ADGRG2 silencing could inhibit the proliferation and migration of Huh7 and HepG2 cells. There was a highly significant positive correlation between ADGRG2 and neutrophils. Moreover, NET-related genes were filtered and confirmed, such as ENO1 and S100A9. Meanwhile, the high expression of ADGRG2 was also accompanied by the highest number of inflammatory cytokines, chemokines, and chemokine receptors and good immunotherapy efficacy. Finally, AGDGR2 may be sensitive to two drugs (PIK-93 and NPK76-II-72-1) and can be targeted by miR-326. In conclusion, ADGRG2 may serve as a novel biomarker and drug target for HCC diagnosis, immunotherapy, and prognosis and was related to neutrophils and the inflammatory process of liver cancer development. Full article

(This article belongs to the Special Issue Molecular Advances in Liver Inflammation and Fibrosis)

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22 pages, 6947 KiB

Open AccessArticle

Hepatic NLRP3-Derived Hsp70 Binding to TLR4 Mediates MASLD to MASH Progression upon Inhibition of PP2A by Harmful Algal Bloom Toxin Microcystin, a Second Hit

by Subhajit Roy, Punnag Saha, Dipro Bose, Ayushi Trivedi, Madhura More, Shuo Xiao, Anna Mae Diehl and Saurabh Chatterjee

Int. J. Mol. Sci. 2023, 24(22), 16354; https://doi.org/10.3390/ijms242216354 - 15 Nov 2023

Viewed by 1217

Abstract

Harmful algal bloom toxin microcystin has been associated with metabolic dysfunction-associated steatotic liver disease (MASLD) progression and hepatocellular carcinoma, though the mechanisms remain unclear. Using an established mouse model of MASLD, we show that the NLRP3–Hsp70–TLR4 axis drives in part the inflammation of the liver lobule that results in the progression of MASLD to metabolic dysfunction-associated steatohepatitis (MASH). Results showed that mice deficient in NLRP3 exhibited decreased MASH pathology, blocked Hsp70 expression, and co-binding with NLRP3, a crucial protein component of the liver inflammasome. Hsp70, both in the liver lobule and extracellularly released in the liver vasculature, acted as a ligand to TLR4 in the liver, primarily in hepatocytes to activate the NF-κB pathway, ultimately leading to hepatic cell death and necroptosis, a crucial pathology of MASH progression. The above studies show a novel insight into an inflammasome-triggered Hsp70-mediated inflammation that may have broader implications in MASLD pathology. MASLD to MASH progression often requires multiple hits. One of the mediators of progressive MASLD is environmental toxins. In this research report, we show for the first time a novel mechanism where microcystin-LR, an environmental toxin, advances MASLD to MASH by triggering the release of Hsp70 as a DAMP to activate TLR4-induced inflammation in the liver. Full article

(This article belongs to the Special Issue Molecular Advances in Liver Inflammation and Fibrosis)

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19 pages, 2902 KiB

Open AccessArticle

Hepatic SPARC Expression Is Associated with Inflammasome Activation during the Progression of Non-Alcoholic Fatty Liver Disease in Both Mice and Morbidly Obese Patients

by Agostina M. Onorato, Lucía Lameroli Mauriz, Juan Bayo, Esteban Fiore, María José Cantero, Barbara Bueloni, Mariana García, Cecilia Lagües, Pedro Martínez-Duartez, Gabriel Menaldi, Nicolas Paleari, Catalina Atorrasagasti and Guillermo D. Mazzolini

Int. J. Mol. Sci. 2023, 24(19), 14843; https://doi.org/10.3390/ijms241914843 - 02 Oct 2023

Viewed by 1003

Abstract

The severity of non-alcoholic fatty liver disease (NAFLD) ranges from simple steatosis to steatohepatitis, and it is not yet clearly understood which patients will progress to liver fibrosis or cirrhosis. SPARC (Secreted Protein Acidic and Rich in Cysteine) has been involved in NAFLD pathogenesis in mice and humans. The aim of this study was to investigate the role of SPARC in inflammasome activation, and to evaluate the relationship between the hepatic expression of inflammasome genes and the biochemical and histological characteristics of NAFLD in obese patients. In vitro studies were conducted in a macrophage cell line and primary hepatocyte cultures to assess the effect of SPARC on inflammasome. A NAFLD model was established in SPARC knockout (SPARC^−/−) and SPARC^+/+ mice to explore inflammasome activation. A hepatic RNAseq database from NAFLD patients was analyzed to identify genes associated with SPARC expression. The results were validated in a prospective cohort of 59 morbidly obese patients with NAFLD undergoing bariatric surgery. Our results reveal that SPARC alone or in combination with saturated fatty acids promoted IL-1β expression in cell cultures. SPARC^−/− mice had reduced hepatic inflammasome activation during the progression of NAFLD. NAFLD patients showed increased expression of SPARC, NLRP3, CASP1, and IL-1β. Gene ontology analysis revealed that genes positively correlated with SPARC are linked to inflammasome-related pathways during the progression of the disease, enabling the differentiation of patients between steatosis and steatohepatitis. In conclusion, SPARC may play a role in hepatic inflammasome activation in NAFLD. Full article

(This article belongs to the Special Issue Molecular Advances in Liver Inflammation and Fibrosis)

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Review

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15 pages, 707 KiB

Open AccessReview

MicroRNAs and Nonalcoholic Steatohepatitis: A Review

by Asahiro Morishita, Kyoko Oura, Tomoko Tadokoro, Koji Fujita, Joji Tani, Hideki Kobara, Masafumi Ono, Takashi Himoto and Tsutomu Masaki

Int. J. Mol. Sci. 2023, 24(19), 14482; https://doi.org/10.3390/ijms241914482 - 23 Sep 2023

Cited by 2 | Viewed by 1488

Abstract

Non-alcoholic fatty liver disease (NAFLD) is a clinicopathologic syndrome caused by fat deposition in hepatocytes. Patients with nonalcoholic steatohepatitis (NASH), an advanced form of NAFLD with severe fibrosis, are at high risk for liver-related complications, including hepatocellular carcinoma (HCC). However, the mechanism of progression from simple fat deposition to NASH is complex, and previous reports have linked NAFLD to gut microbiota, bile acids, immunity, adipokines, oxidative stress, and genetic or epigenetic factors. NASH-related liver injury involves multiple cell types, and intercellular signaling is thought to be mediated by extracellular vesicles. MicroRNAs (miRNAs) are short, noncoding RNAs that play important roles as post-transcriptional regulators of gene expression and have been implicated in the pathogenesis of various diseases. Recently, many reports have implicated microRNAs in the pathogenesis of NALFD/NASH, suggesting that exosomal miRNAs are potential non-invasive and sensitive biomarkers and that the microRNAs involved in the mechanism of the progression of NASH may be potential therapeutic target molecules. We are interested in which miRNAs are involved in the pathogenesis of NASH and which are potential target molecules for therapy. We summarize targeted miRNAs associated with the etiology and progression of NASH and discuss each miRNA in terms of its pathophysiology, potential therapeutic applications, and efficacy as a NASH biomarker. Full article

(This article belongs to the Special Issue Molecular Advances in Liver Inflammation and Fibrosis)

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