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Molecular Mechanisms of Human Liver Diseases 2.0
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Molecular Mechanisms of Human Liver Diseases 2.0

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: closed (30 June 2024) | Viewed by 15654

Special Issue Editor

Dr. Elena Grossini

E-Mail Website
Guest Editor
Department of Translational Medicine, University Eastern Piedmont, 28100 Novara, Italy
Interests: oxidative stress; cardiac function; mitochondrial function; aging; nitric oxide; physiology; NAFLD; microvesicles
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

There are many known liver diseases, the most prominent of which are virus-induced and autoimmune hepatitis, non-alcoholic fatty liver disease (NAFLD), storage diseases such as Wilson’s disease and hemochromatosis, and acute and chronic liver failure.

NAFLD, which includes steatohepatitis (in particular, non-alcoholic steatohepatitis (NASH), which should be separated from alcoholic steatohepatitis (ASH)) and steatosis, is a rising health problem world-wide. Steatosis, liver fibrosis, and cirrhosis often develop into hepatocellular carcinogenesis, frequently resulting in the need for liver transplantation, which underlines the clinical significance of this disease complex.

Wilson’s disease (which involves morbidly heightened copper accumulation) and hemochromatosis can also both result in cirrhosis. Whereas acute liver failure can have multiple origins over a short period of time, chronic liver failure is preceded by HBV, HCV, or excessive alcohol intake over a long time span.

In this Special Issue, we provide an overview of current knowledge and recent findings regarding the development, progression, molecular pathways, and mechanisms of these diseases.

Dr. Elena Grossini
Guest Editor

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Keywords

  • non-alcoholic fatty liver disease (NAFLD)
  • non-alcoholic steatohepatitis (NASH)
  • alcoholic steatohepatitis (ASH) Wilson’s disease
  • hemochromatosis
  • viral hepatitis
  • autoimmune hepatitis
  • hepatocellular carcinoma
  • signaling pathways
  • molecular mechanisms

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Published Papers (7 papers)

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Research

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22 pages, 2138 KiB  
Article
Idiosyncratic Drug-Induced Liver Injury and Amoxicillin–Clavulanate: Spotlight on Gut Microbiota, Fecal Metabolome and Bile Acid Profile in Patients
by Sara Román-Sagüillo, Raisa Quiñones Castro, María Juárez-Fernández, Polina Soluyanova, Camilla Stephens, Mercedes Robles-Díaz, Francisco Jorquera Plaza, Javier González-Gallego, Susana Martínez-Flórez, María Victoria García-Mediavilla, Esther Nistal, Ramiro Jover and Sonia Sánchez-Campos
Int. J. Mol. Sci. 2024, 25(13), 6863; https://doi.org/10.3390/ijms25136863 - 22 Jun 2024
Viewed by 1552
Abstract
Several hepatic disorders are influenced by gut microbiota, but its role in idiosyncratic drug-induced liver injury (iDILI), whose main causative agent is amoxicillin–clavulanate, remains unknown. This pioneering study aims to unravel particular patterns of gut microbiota composition and associated metabolites in iDILI and [...] Read more.
Several hepatic disorders are influenced by gut microbiota, but its role in idiosyncratic drug-induced liver injury (iDILI), whose main causative agent is amoxicillin–clavulanate, remains unknown. This pioneering study aims to unravel particular patterns of gut microbiota composition and associated metabolites in iDILI and iDILI patients by amoxicillin–clavulanate (iDILI-AC). Thus, serum and fecal samples from 46 patients were divided into three study groups: healthy controls (n = 10), non-iDILI acute hepatitis (n = 12) and iDILI patients (n = 24). To evaluate the amoxicillin–clavulanate effect, iDILI patients were separated into two subgroups: iDILI non-caused by amoxicillin–clavulanate (iDILI-nonAC) (n = 18) and iDILI-AC patients (n = 6). Gut microbiota composition and fecal metabolome plus serum and fecal bile acid (BA) analyses were performed, along with correlation analyses. iDILI patients presented a particular microbiome profile associated with reduced fecal secondary BAs and fecal metabolites linked to lower inflammation, such as dodecanedioic acid and pyridoxamine. Moreover, certain taxa like Barnesiella, Clostridia UCG-014 and Eubacterium spp. correlated with significant metabolites and BAs. Additionally, comparisons between iDILI-nonAC and iDILI-AC groups unraveled unique features associated with iDILI when caused by amoxicillin–clavulanate. In conclusion, specific gut microbiota profiles in iDILI and iDILI-AC patients were associated with particular metabolic and BA status, which could affect disease onset and progression. Full article
(This article belongs to the Special Issue Molecular Mechanisms of Human Liver Diseases 2.0)
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19 pages, 6585 KiB  
Article
Receptor Targeting Using Copolymer-Modified Gold Nanoparticles for pCMV-Luc Gene Delivery to Liver Cancer Cells In Vitro
by Mkhuseli Zenze and Moganavelli Singh
Int. J. Mol. Sci. 2024, 25(9), 5016; https://doi.org/10.3390/ijms25095016 - 4 May 2024
Cited by 4 | Viewed by 2190
Abstract
The formulation of novel delivery protocols for the targeted delivery of genes into hepatocytes by receptor mediation is important for the treatment of liver-specific disorders, including cancer. Non-viral delivery methods have been extensively studied for gene therapy. Gold nanoparticles (AuNPs) have gained attention [...] Read more.
The formulation of novel delivery protocols for the targeted delivery of genes into hepatocytes by receptor mediation is important for the treatment of liver-specific disorders, including cancer. Non-viral delivery methods have been extensively studied for gene therapy. Gold nanoparticles (AuNPs) have gained attention in nanomedicine due to their biocompatibility. In this study, AuNPs were synthesized and coated with polymers: chitosan (CS), and polyethylene glycol (PEG). The targeting moiety, lactobionic acid (LA), was added for hepatocyte-specific delivery. Physicochemical characterization revealed that all nano-formulations were spherical and monodispersed, with hydrodynamic sizes between 70 and 250 nm. Nanocomplexes with pCMV-Luc DNA (pDNA) confirmed that the NPs could bind, compact, and protect the pDNA from nuclease degradation. Cytotoxicity studies revealed that the AuNPs were well tolerated (cell viabilities > 70%) in human hepatocellular carcinoma (HepG2), embryonic kidney (HEK293), and colorectal adenocarcinoma (Caco-2) cells, with enhanced transgene activity in all cells. The inclusion of LA in the NP formulation was notable in the HepG2 cells, which overexpress the asialoglycoprotein receptor on their cell surface. A five-fold increase in luciferase gene expression was evident for the LA-targeted AuNPs compared to the non-targeted AuNPs. These AuNPs have shown potential as safe and suitable targeted delivery vehicles for liver-directed gene therapy. Full article
(This article belongs to the Special Issue Molecular Mechanisms of Human Liver Diseases 2.0)
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11 pages, 4127 KiB  
Article
Beta-Hydroxyisovaleryl-Shikonin Eradicates Epithelial Cell Adhesion Molecule-Positive Liver Cancer Stem Cells by Suppressing dUTP Pyrophosphatase Expression
by Yoshiro Asahina, Hajime Takatori, Kouki Nio, Hikari Okada, Takehiro Hayashi, Tomoyuki Hayashi, Tomomi Hashiba, Tsuyoshi Suda, Masaki Nishitani, Saiho Sugimoto, Masao Honda, Shuichi Kaneko and Taro Yamashita
Int. J. Mol. Sci. 2023, 24(22), 16283; https://doi.org/10.3390/ijms242216283 - 14 Nov 2023
Cited by 1 | Viewed by 1603
Abstract
Cancer stem cells (CSCs) play an essential role in tumorigenesis, chemoresistance, and metastasis. Previously, we demonstrated that the development of hepatocellular carcinoma (HCC) is dictated by a subset of epithelial cell adhesion molecule-positive (EpCAM+) liver CSCs with the activation of Wnt signaling. In [...] Read more.
Cancer stem cells (CSCs) play an essential role in tumorigenesis, chemoresistance, and metastasis. Previously, we demonstrated that the development of hepatocellular carcinoma (HCC) is dictated by a subset of epithelial cell adhesion molecule-positive (EpCAM+) liver CSCs with the activation of Wnt signaling. In this study, we evaluated the expression of dUTP pyrophosphatase (dUTPase), which plays a central role in the development of chemoresistance to 5-fluorouracil, in EpCAM+ HCC cells. We further evaluated the effect of beta-hydroxyisovaleryl-shikonin (β-HIVS), an ATP-noncompetitive inhibitor of protein tyrosine kinases, on HCC CSCs. EpCAM and dUTPase were expressed in hepatoblasts in human fetal liver, hepatic progenitors in adult cirrhotic liver, and a subset of HCC cells. Sorted EpCAM+ CSCs from HCC cell lines showed abundant nuclear accumulation of dUTPase compared with EpCAM-negative cells. Furthermore, treatment with the Wnt signaling activator BIO increased EpCAM and dUTPase expression. In contrast, β-HIVS treatment decreased dUTPase expression. β-HIVS treatment decreased the population of EpCAM+ liver CSCs in a dose-dependent manner in vitro and suppressed tumor growth in vivo compared with the control vehicle. Taken together, our data suggest that dUTPase could be a good target to eradicate liver CSCs resistant to 5-fluorouracil. β-HIVS is a small molecule that could decrease dUTPase expression and target EpCAM+ liver CSCs. Full article
(This article belongs to the Special Issue Molecular Mechanisms of Human Liver Diseases 2.0)
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25 pages, 6849 KiB  
Article
Plasma Pattern of Extracellular Vesicles Isolated from Hepatitis C Virus Patients and Their Effects on Human Vascular Endothelial Cells
by Elena Grossini, Carlo Smirne, Sakthipriyan Venkatesan, Stelvio Tonello, Davide D’Onghia, Rosalba Minisini, Vincenzo Cantaluppi, Pier Paolo Sainaghi, Cristoforo Comi, Adele Tanzi, Benedetta Bussolati and Mario Pirisi
Int. J. Mol. Sci. 2023, 24(12), 10197; https://doi.org/10.3390/ijms241210197 - 15 Jun 2023
Cited by 8 | Viewed by 2222
Abstract
Hepatitis C virus (HCV) patients are at increased risk of cardiovascular disease (CVD). In this study, we aimed to evaluate the role of extracellular vesicles (EVs) as pathogenic factors for the onset of HCV-related endothelial dysfunction. Sixty-five patients with various stages of HCV-related [...] Read more.
Hepatitis C virus (HCV) patients are at increased risk of cardiovascular disease (CVD). In this study, we aimed to evaluate the role of extracellular vesicles (EVs) as pathogenic factors for the onset of HCV-related endothelial dysfunction. Sixty-five patients with various stages of HCV-related chronic liver disease were enrolled in this case series. Plasma EVs were characterized and used to stimulate human vascular endothelial cells (HUVEC), which were examined for cell viability, mitochondrial membrane potential, and reactive oxygen species (ROS) release. The results showed that EVs from HCV patients were mainly of endothelial and lymphocyte origin. Moreover, EVs were able to reduce cell viability and mitochondrial membrane potential of HUVEC, while increasing ROS release. Those harmful effects were reduced by the pretreatment of HUVEC with the NLR family pyrin domain containing 3 (NLRP3)/AMP-activated protein kinase and protein kinase B blockers. In conclusion, in HCV patients, we could highlight a circulating pattern of EVs capable of inducing damage to the endothelium. These data represent a novel possible pathogenic mechanism underlying the reported increase of CVD occurrence in HCV infection and could be of clinical relevance also in relation to the widespread use of antiviral drugs. Full article
(This article belongs to the Special Issue Molecular Mechanisms of Human Liver Diseases 2.0)
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Review

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14 pages, 921 KiB  
Review
Amanita phalloides-Associated Liver Failure: Molecular Mechanisms and Management
by Tahrima Kayes and Vincent Ho
Int. J. Mol. Sci. 2024, 25(23), 13028; https://doi.org/10.3390/ijms252313028 - 4 Dec 2024
Viewed by 1709
Abstract
Amanita phalloides is well-established as one of the most poisonous mushrooms; toxicity from ingestion was reported as early as the first century. Although native to Europe, this ectomycorrhizal fungus has been widely spread and is responsible for liver toxicity in many parts of [...] Read more.
Amanita phalloides is well-established as one of the most poisonous mushrooms; toxicity from ingestion was reported as early as the first century. Although native to Europe, this ectomycorrhizal fungus has been widely spread and is responsible for liver toxicity in many parts of the world. Toxicity is characterized by delayed gastrointestinal symptoms mimicking acute gastroenteritis followed by severe hepatotoxicity and liver failure with consequent multi-organ failure. The primary mechanism of liver toxicity is considered to be the inhibition of RNA polymerase II with consequent hepatocyte apoptosis. Treatment measures include supportive measures such as rehydration and correction of electrolytes on initial presentation, activated charcoal and lavage to decrease absorption, extracorporeal purification methods such as plasmapheresis, fractionated plasma separation and adsorption, and molecular adsorbent recirculating system, as well as drug therapies including antibiotics, N-acetylcysteine, and silibinin. Liver transplantation is required in those with acute liver failure and poor prognostic features. Here, we reviewed the basic biology, pathophysiology, and molecular mechanisms of Amanita phalloides liver toxicity, as well as available treatments. Full article
(This article belongs to the Special Issue Molecular Mechanisms of Human Liver Diseases 2.0)
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14 pages, 1049 KiB  
Review
Involvement of Lipophagy and Chaperone-Mediated Autophagy in the Pathogenesis of Non-Alcoholic Fatty Liver Disease by Regulation of Lipid Droplets
by Eleftheria M. Mastoridou, Anna C. Goussia, Panagiotis Kanavaros and Antonia V. Charchanti
Int. J. Mol. Sci. 2023, 24(21), 15891; https://doi.org/10.3390/ijms242115891 - 2 Nov 2023
Cited by 7 | Viewed by 3227
Abstract
Non-alcoholic fatty liver disease (NAFLD) is defined as the accumulation of lipids in the form of lipid droplets in more than 5% of hepatocytes. It is regarded as a range of diverse pathologies, including simple steatosis and steatohepatitis. The structural characteristics of lipid [...] Read more.
Non-alcoholic fatty liver disease (NAFLD) is defined as the accumulation of lipids in the form of lipid droplets in more than 5% of hepatocytes. It is regarded as a range of diverse pathologies, including simple steatosis and steatohepatitis. The structural characteristics of lipid droplets, along with their protein composition, mainly including perilipins, have been implicated in the etiology of the disease. These proteins have garnered increasing attention as a pivotal regulator since their levels and distinct expression appear to be associated with the progression from simple steatosis to steatohepatitis. Perilipins are target proteins of chaperone-mediated autophagy, and their degradation is a prerequisite for lipolysis and lipophagy to access the lipid core. Both lipophagy and chaperone-mediated autophagy have significant implications on the development of the disease, as evidenced by their upregulation during the initial phases of simple steatosis and their subsequent downregulation once steatosis is established. On the contrary, during steatohepatitis, the process of chaperone-mediated autophagy is enhanced, although lipophagy remains suppressed. Evidently, the reduced levels of autophagic pathways observed in simple steatosis serve as a defensive mechanism against lipotoxicity. Conversely, in steatohepatitis, chaperone-mediated autophagy fails to compensate for the continuous generation of small lipid droplets and thus cannot protect hepatocytes from lipotoxicity. Full article
(This article belongs to the Special Issue Molecular Mechanisms of Human Liver Diseases 2.0)
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13 pages, 947 KiB  
Review
Role of Oxidative Stress and Carcinoembryonic Antigen-Related Cell Adhesion Molecule 1 in Nonalcoholic Fatty Liver Disease
by Plator Memaj, Zayd Ouzerara and François R. Jornayvaz
Int. J. Mol. Sci. 2023, 24(14), 11271; https://doi.org/10.3390/ijms241411271 - 10 Jul 2023
Cited by 5 | Viewed by 1980
Abstract
Nonalcoholic fatty liver disease (NAFLD) has become a widely studied subject due to its increasing prevalence and links to diseases such as type 2 diabetes and obesity. It has severe complications, including nonalcoholic steatohepatitis, cirrhosis, hepatocellular carcinoma, and portal hypertension that can lead [...] Read more.
Nonalcoholic fatty liver disease (NAFLD) has become a widely studied subject due to its increasing prevalence and links to diseases such as type 2 diabetes and obesity. It has severe complications, including nonalcoholic steatohepatitis, cirrhosis, hepatocellular carcinoma, and portal hypertension that can lead to liver transplantation in some cases. To better prevent and treat this pathology, it is important to understand its underlying physiology. Here, we identify two main factors that play a crucial role in the pathophysiology of NAFLD: oxidative stress and the key role of carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1). We discuss the pathophysiology linking these factors to NAFLD pathophysiology. Full article
(This article belongs to the Special Issue Molecular Mechanisms of Human Liver Diseases 2.0)
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