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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: closed (30 May 2023) | Viewed by 6455

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Dr. Vicente Felipo

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Guest Editor

Laboratory of Neurobiology, Centro de Investigación Príncipe Felipe, 46012 Valencia, Spain
Interests: neuroinflammation; neurotransmission; hepatic encephalopathy; hyperammonemia; cognitive impairment; motor alterations
Special Issues, Collections and Topics in MDPI journals

Dr. Marta Llansola

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Co-Guest Editor

Laboratory of Neurobiology, Centro de Investigacion Principe Felipe, 46012 Valencia, Spain
Interests: hepatic encephalopathy; neuroinflammation; cognitive impairment; cerebellum; hippocampus; motor coordination; cytokines; glutamate receptors; GABA transporters; microbiota metabolits
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Hepatic encephalopathy (HE) is a neuropsychiatric syndrome present in patients with liver diseases. Several million people suffer minimal or clinical HE, which reduce their quality of life and life span. Liver disease leads to hyperammonemia and peripheral inflammation, which act synergistically to induce neuroinflammation, which alters neurotransmission, leading to cognitive and motor impairment.

This Special issue includes articles on the role of hyperammonemia and changes in the gut microbiome, peripheral inflammation, neuroinflammation, neurotransmission, and other cerebral and peripheral alterations in the pathogenesis of HE on the underlying mechanisms and possible new treatments to improve neurological function in clinical or minimal HE.

Dr. Vicente Felipo
Dr. Marta Llansola
Guest Editors

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Published Papers (4 papers)

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Research

18 pages, 9970 KiB

Open AccessArticle

Severe Acute Liver Dysfunction Induces Delayed Hepatocyte Swelling and Cytoplasmic Vacuolization, and Delayed Cortical Neuronal Cell Death

by Kazuhiko Nakadate, Chiaki Sono, Homura Mita, Yuki Itakura and Kiyoharu Kawakami

Int. J. Mol. Sci. 2023, 24(8), 7351; https://doi.org/10.3390/ijms24087351 - 16 Apr 2023

Viewed by 1216

Abstract

Liver dysfunction is the main cause of hepatic encephalopathy. However, histopathological changes in the brain associated with hepatic encephalopathy remain unclear. Therefore, we investigated pathological changes in the liver and brain using an acute hepatic encephalopathy mouse model. After administering ammonium acetate, a transient increase in the blood ammonia level was observed, which returned to normal levels after 24 h. Consciousness and motor levels also returned to normal. It was revealed that hepatocyte swelling, and cytoplasmic vacuolization progressed over time in the liver tissue. Blood biochemistry also suggested hepatocyte dysfunction. In the brain, histopathological changes, such as perivascular astrocyte swelling, were observed 3 h after ammonium acetate administration. Abnormalities in neuronal organelles, especially mitochondria and rough endoplasmic reticulum, were also observed. Additionally, neuronal cell death was observed 24 h post-ammonia treatment when blood ammonia levels had returned to normal. Activation of reactive microglia and increased expression of inducible nitric oxide synthase (iNOS) were also observed seven days after a transient increase in blood ammonia. These results suggest that delayed neuronal atrophy could be iNOS-mediated cell death due to activation of reactive microglia. The findings also suggest that severe acute hepatic encephalopathy causes continued delayed brain cytotoxicity even after consciousness recovery. Full article

(This article belongs to the Special Issue Hepatic Encephalopathy)

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17 pages, 3173 KiB

Open AccessArticle

Tricarboxylic Acid Metabolite Imbalance in Rats with Acute Thioacetamide-Induced Hepatic Encephalopathy Indicates Incomplete Recovery

by Yevgeniya I. Shurubor, Alexander E. Rogozhin, Elena P. Isakova, Yulia I. Deryabina and Boris F. Krasnikov

Int. J. Mol. Sci. 2023, 24(2), 1384; https://doi.org/10.3390/ijms24021384 - 10 Jan 2023

Cited by 2 | Viewed by 1038

Abstract

Exposure to the toxin thioacetamide (TAA) causes acute hepatic encephalopathy (HE), changes in the functioning of systemic organs, and an imbalance in a number of energy metabolites. The deferred effects after acute HE development are poorly understood. The study considers the balance of the tricarboxylic acid (TCA) cycle metabolites in the blood plasma, liver, kidneys, and brain tissues of rats in the post-rehabilitation period. The samples of the control (n = 3) and TAA-induced groups of rats (n = 13) were collected six days after the administration of a single intraperitoneal TAA injection at doses of 200, 400, and 600 mg/kg. Despite the complete physiological recovery of rats by this date, a residual imbalance of metabolites in all the vital organs was noted. The results obtained showed a trend of stabilizing processes in the main organs of the animals and permit the use of these data both for prognostic purposes and the choice of potential therapeutic agents. Full article

(This article belongs to the Special Issue Hepatic Encephalopathy)

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19 pages, 2496 KiB

Open AccessArticle

Plasma Extracellular Vesicles Play a Role in Immune System Modulation in Minimal Hepatic Encephalopathy

by Juan José Gallego, Alessandra Fiorillo, Franc Casanova-Ferrer, Amparo Urios, María-Pilar Ballester, Lucia Durbán, Javier Megías, Teresa Rubio, Andrea Cabrera-Pastor, Desamparados Escudero-García, Vicente Felipo and Carmina Montoliu

Int. J. Mol. Sci. 2022, 23(20), 12335; https://doi.org/10.3390/ijms232012335 - 15 Oct 2022

Cited by 3 | Viewed by 1801

Abstract

Minimal hepatic encephalopathy (MHE) is associated with changes in the immune system including an increased pro-inflammatory environment and altered differentiation of CD4+ T lymphocytes. The mechanisms remain unknown. Changes in extracellular vesicle (EV) cargo including proteins and miRNAs could play a main role as mediators of immune system changes associated with MHE. The aim was to assess whether plasma EVs from MHE patients played a role in inducing the pro-inflammatory environment and altered differentiation of CD4+ T lymphocyte subtypes in MHE patients. We characterized the miRNA and protein cargo of plasma EVs from 50 cirrhotic patients (27 without and 23 with MHE) and 24 controls. CD4+ T cells from the controls were cultured with plasma EVs from the three groups of study, and the cytokine release and differentiation to CD4+ T-cell subtypes were assessed. Plasma EVs from MHE patients had altered miRNA and protein contents, and were enriched in inflammatory factors compared to the controls and patients without MHE. EVs from MHE patients modulated the expression of pro-inflammatory IL-17, IL-21, and TNF-α and anti-inflammatory TGF-β in cultured CD4+ T lymphocytes, and increased the proportion of Th follicular and Treg cells and the activation of Th17 cells. In conclusion, plasma EVs could play an important role in the induction of immune changes observed in MHE. Full article

(This article belongs to the Special Issue Hepatic Encephalopathy)

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20 pages, 6479 KiB

Open AccessArticle

Enhanced BDNF and TrkB Activation Enhance GABA Neurotransmission in Cerebellum in Hyperammonemia

by Yaiza M. Arenas, Mar Martínez-García, Marta Llansola and Vicente Felipo

Int. J. Mol. Sci. 2022, 23(19), 11770; https://doi.org/10.3390/ijms231911770 - 4 Oct 2022

Cited by 8 | Viewed by 1784

Abstract

Background: Hyperammonemia is a main contributor to minimal hepatic encephalopathy (MHE) in cirrhotic patients. Hyperammonemic rats reproduce the motor incoordination of MHE patients, which is due to enhanced GABAergic neurotransmission in the cerebellum as a consequence of neuroinflammation. In hyperammonemic rats, neuroinflammation increases BDNF by activating the TNFR1–S1PR2–CCR2 pathway. (1) Identify mechanisms enhancing GABAergic neurotransmission in hyperammonemia; (2) assess the role of enhanced activation of TrkB; and (3) assess the role of the TNFR1–S1PR2–CCR2–BDNF pathway. In the cerebellum of hyperammonemic rats, increased BDNF levels enhance TrkB activation in Purkinje neurons, leading to increased GAD65, GAD67 and GABA levels. Enhanced TrkB activation also increases the membrane expression of the γ2, α2 and β3 subunits of GABA_A receptors and of KCC2. Moreover, enhanced TrkB activation in activated astrocytes increases the membrane expression of GAT3 and NKCC1. These changes are reversed by blocking TrkB or the TNFR1–SP1PR2–CCL2–CCR2–BDNF–TrkB pathway. Hyperammonemia-induced neuroinflammation increases BDNF and TrkB activation, leading to increased synthesis and extracellular GABA, and the amount of GABA_A receptors in the membrane and chloride gradient. These factors enhance GABAergic neurotransmission in the cerebellum. Blocking TrkB or the TNFR1–SP1PR2–CCL2–CCR2–BDNF–TrkB pathway would improve motor function in patients with hepatic encephalopathy and likely with other pathologies associated with neuroinflammation. Full article

(This article belongs to the Special Issue Hepatic Encephalopathy)

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