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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Biology".

Deadline for manuscript submissions: closed (30 June 2022) | Viewed by 15159

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Dr. Águeda González-Rodríguez

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Guest Editor

Health Research Institute, Hospital Universitario de La Princesa, 28006 Madrid, Spain
Interests: liver; NAFLD; insulin resistance; steatosis; hypoxia

Special Issue Information

Dear Colleagues,

A special issue on the topic of “Impact of Novel Molecules on Liver Pathophysiology” is being prepared for the journal IJMS. The liver is a vital abdominal organ, which detoxifies various metabolites, synthesizes proteins, and produces biochemicals necessary for digestion and growth. metabolic fatty liver disease (MAFLD), acute liver failure, liver fibrosis or cirrhosis, viral hepatitis, hepatocellular carcinoma, and alcoholic fatty liver are included within the liver pathophysiology. The molecules, target cells, and regulatory mechanisms associated with these pathologies are emerging as promising therapeutic targets, able to promote liver repair and restore normal function.

So, this Special Issue focuses on identifying the role of novel molecules in the progression of liver damage and leads to the generation of new direct biomarkers for the non-invasive diagnosis/prognosis of the different evolutionary phases of these pathologies. We warmly welcome original papers and reviews on this widely discussed topic.

Dr. Águeda González-Rodríguez
Guest Editor

Manuscript Submission Information

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Published Papers (4 papers)

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Research

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17 pages, 4176 KiB

Open AccessArticle

Antipsychotic Drug Aripiprazole Protects Liver Cells from Oxidative Stress

by Barbara Kramar, Tinkara Pirc Marolt, Maria Monsalve, Dušan Šuput and Irina Milisav

Int. J. Mol. Sci. 2022, 23(15), 8292; https://doi.org/10.3390/ijms23158292 - 27 Jul 2022

Cited by 2 | Viewed by 2447

Abstract

Antipsychotics used to treat schizophrenia can cause drug-induced liver injury (DILI), according to the Roussel Uclaf Causality Assessment Method. The role of oxidative stress in triggering injury in these DILI cases is unknown. We repeatedly administrated two second-generation antipsychotics, aripiprazole and olanzapine, at laboratory alert levels to study underlying mechanisms in stress prevention upon acute oxidative stress. The drugs were administered continuously for up to 8 weeks. For this, hepatoma Fao cells, which are suitable for metabolic studies, were used, as the primary hepatocytes survive in the culture only for about 1 week. Four stress responses—the oxidative stress response, the DNA damage response and the unfolded protein responses in the endoplasmic reticulum and mitochondria—were examined in H₂O₂-treated cells by antioxidant enzyme activity measurements, gene expression and protein quantification. Oxidant conditions increased the activity of antioxidant enzymes and upregulated genes and proteins associated with oxidative stress response in aripiprazole-treated cells. While the genes associated with DNA damage response, Gadd45 and p21, were upregulated in both aripiprazole- and olanzapine-treated cells, only aripiprazole treatment was associated with upregulation in response to even more H₂O₂, which also coincided with better survival. Endoplasmic reticulum stress-induced Chop was also upregulated; however, neither endoplasmic reticulum nor mitochondrial unfolded protein response was activated. We conclude that only aripiprazole, but not olanzapine, protects liver cells against oxidative stress. This finding could be relevant for schizophrenia patients with high-oxidative-stress-risk lifestyles and needs to be validated in vivo. Full article

(This article belongs to the Special Issue Impact of Novel Molecules on Liver Pathophysiology)

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19 pages, 13634 KiB

Open AccessArticle

Tumor-Suppressor Role of the α1-Na/K-ATPase Signalosome in NASH Related Hepatocellular Carcinoma

by Utibe-Abasi S. Udoh, Moumita Banerjee, Pradeep K. Rajan, Juan D. Sanabria, Gary Smith, Mathew Schade, Jacqueline A. Sanabria, Yuto Nakafuku, Komal Sodhi, Sandrine V. Pierre, Joseph I. Shapiro and Juan R. Sanabria

Int. J. Mol. Sci. 2022, 23(13), 7359; https://doi.org/10.3390/ijms23137359 - 1 Jul 2022

Cited by 7 | Viewed by 2980

Abstract

Hepatocellular carcinoma (HCC) is the second leading cause of cancer-related mortality worldwide, with an estimate of 0.84 million cases every year. In Western countries, because of the obesity epidemic, non-alcoholic steatohepatitis (NASH) has become the major cause of HCC. Intriguingly, the molecular mechanisms underlying tumorigenesis of HCC from NASH are largely unknown. We hypothesized that the growing uncoupled metabolism during NASH progression to HCC, manifested by lower cell redox status and an apoptotic ‘switch’ activity, follows a dysregulation of α1-Na/K-ATPase (NKA)/Src signalosome. Our results suggested that in NASH-related malignancy, α1-NKA signaling causes upregulation of the anti-apoptotic protein survivin and downregulation of the pro-apoptotic protein Smac/DIABLO via the activation of the PI3K → Akt pro-survival pathway with concomitant inhibition of the FoxO3 circuit, favoring cell division and primary liver carcinogenesis. Signalosome normalization using an inhibitory peptide resets apoptotic activity in malignant cells, with a significant decrease in tumor burden in vivo. Therefore, α1-NKA signalosome exercises in HCC the characteristic of a tumor suppressor, suggesting α1-NKA as a putative target for clinical therapy. Full article

(This article belongs to the Special Issue Impact of Novel Molecules on Liver Pathophysiology)

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18 pages, 3154 KiB

Open AccessArticle

Immunonano-Lipocarrier-Mediated Liver Sinusoidal Endothelial Cell-Specific RUNX1 Inhibition Impedes Immune Cell Infiltration and Hepatic Inflammation in Murine Model of NASH

by Dinesh Mani Tripathi, Sumati Rohilla, Impreet Kaur, Hamda Siddiqui, Preety Rawal, Pinky Juneja, Vikash Kumar, Anupama Kumari, Vegi Ganga Modi Naidu, Seeram Ramakrishna, Subham Banerjee, Rekha Puria, Shiv K. Sarin and Savneet Kaur

Int. J. Mol. Sci. 2021, 22(16), 8489; https://doi.org/10.3390/ijms22168489 - 6 Aug 2021

Cited by 9 | Viewed by 3197

Abstract

Background: Runt-related transcription factor (RUNX1) regulates inflammation in non-alcoholic steatohepatitis (NASH). Methods: We performed in vivo targeted silencing of the RUNX1 gene in liver sinusoidal endothelial cells (LSECs) by using vegfr3 antibody tagged immunonano-lipocarriers encapsulated RUNX1 siRNA (RUNX1 siRNA) in murine models of methionine choline deficient (MCD) diet-induced NASH. MCD mice given nanolipocarriers-encapsulated negative siRNA were vehicle, and mice with standard diet were controls. Results: Liver RUNX1 expression was increased in the LSECs of MCD mice in comparison to controls. RUNX1 protein expression was decreased by 40% in CD31-positive LSECs of RUNX1 siRNA mice in comparison to vehicle, resulting in the downregulation of adhesion molecules, ICAM1 expression, and VCAM1 expression in LSECs. There was a marked decrease in infiltrated T cells and myeloid cells along with reduced inflammatory cytokines in the liver of RUNX1 siRNA mice as compared to that observed in the vehicle. Conclusions: In vivo LSEC-specific silencing of RUNX1 using immunonano-lipocarriers encapsulated siRNA effectively reduces its expression of adhesion molecules, infiltrate on of immune cells in liver, and inflammation in NASH. Full article

(This article belongs to the Special Issue Impact of Novel Molecules on Liver Pathophysiology)

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Review

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19 pages, 2777 KiB

Open AccessReview

Exosomal microRNAs as Biomarkers and Therapeutic Targets for Hepatocellular Carcinoma

by Andrei Sorop, Diana Constantinescu, Florentina Cojocaru, Anca Dinischiotu, Dana Cucu and Simona Olimpia Dima

Int. J. Mol. Sci. 2021, 22(9), 4997; https://doi.org/10.3390/ijms22094997 - 8 May 2021

Cited by 37 | Viewed by 5467

Abstract

Hepatocellular carcinoma (HCC) is the fifth most common cancer worldwide and the second most common cause of cancer-related death globally. This type of liver cancer is frequently detected at a late stage by current biomarkers because of the high clinical and biological heterogeneity of HCC tumours. From a plethora of molecules and cellular compounds, small nanoparticles with an endosomal origin are valuable cancer biomarkers or cargos for novel treatments. Despite their small sizes, in the range of 40–150 nm, these particles are delimited by a lipid bilayer membrane with a specific lipid composition and carry functional information—RNA, proteins, miRNAs, long non-coding RNAs (lncRNAs), or DNA fragments. This review summarizes the role of exosomal microRNA (miRNA) species as biomarkers in HCC therapy. After we briefly introduce the exosome biogenesis and the methods of isolation and characterization, we discuss miRNA’s correlation with the diagnosis and prognosis of HCC, either as single miRNA species, or as specific panels with greater clinical impact. We also review the role of exosomal miRNAs in the tumourigenic process and in the cell communication pathways through the delivery of cargos, including proteins or specific drugs. Full article

(This article belongs to the Special Issue Impact of Novel Molecules on Liver Pathophysiology)

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