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Alhaddad O, Elsabaawy M, Abedelhai A, Badra G, Elfayoumy M. Impact of age on frailty in liver cirrhosis: a prospective cohort study. Clin Exp Med 2025; 25:203. [PMID: 40514576 PMCID: PMC12166003 DOI: 10.1007/s10238-025-01747-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2025] [Accepted: 05/22/2025] [Indexed: 06/16/2025]
Abstract
Frailty is an emerging predictor of adverse outcomes in liver cirrhosis, yet the interplay between aging and liver disease severity in driving frailty remains insufficiently understood. To evaluate the impact of age on the prevalence, severity, and predictors of frailty in patients with liver cirrhosis. In this prospective observational study, 460 adults with liver cirrhosis were assessed for frailty using the CFS (Clinical Frailty Scale) (CFS). Patients were classified as frail (CFS > 4) (210 cases), or non-frail (CFS ≤ 4) (250 cases). Demographic, clinical, and biochemical data of frail cases were collected. Multivariate and logistic regression analyses were performed to identify independent predictors of frailty. Frailty prevalence increased markedly with age-from 42% in patients aged 50-59 to over 90% in those aged ≥ 70. Age was moderately correlated with frailty (r = 0.40, p < 0.001). In multivariate analysis, both age (β = 0.0636, p < 0.001) and Child-Pugh score (β = 0.7874, p < 0.001) were independent predictors of frailty. Logistic regression (including interaction terms where appropriate) confirmed that each additional year of age increased frailty risk (OR = 1.13; 95% CI: 1.09-1.17, p < 0.001). Frailty in cirrhosis is strongly age-associated but also driven by hepatic dysfunction. These findings highlight the inadequacy of MELD-Na scores alone in capturing patient vulnerability, particularly in older adults. Future longitudinal studies and targeted prehabilitation strategies are warranted to mitigate frailty and improve outcomes in this vulnerable population.
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Affiliation(s)
- Omkolsoum Alhaddad
- Department of Hepatology and Gastroenterology, National Liver Institute, Menoufia University, Shebeen Elkoom, Menoufia, Egypt
| | - Maha Elsabaawy
- Department of Hepatology and Gastroenterology, National Liver Institute, Menoufia University, Shebeen Elkoom, Menoufia, Egypt.
| | - Asmaa Abedelhai
- Department of Hepatology and Gastroenterology, National Liver Institute, Menoufia University, Shebeen Elkoom, Menoufia, Egypt
| | - Gamal Badra
- Department of Hepatology and Gastroenterology, National Liver Institute, Menoufia University, Shebeen Elkoom, Menoufia, Egypt
| | - Marwa Elfayoumy
- Department of Hepatology and Gastroenterology, National Liver Institute, Menoufia University, Shebeen Elkoom, Menoufia, Egypt
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Wang X, Liu X, Zhou P, Feng J, Jia J, Xie B, Chen Y, Zhou J. Treatment with hydrogen-rich water protects against thioacetamide-induced hepatic encephalopathy in rats through stabilizing liver-brain disturbance. Sci Rep 2025; 15:17901. [PMID: 40410340 PMCID: PMC12102331 DOI: 10.1038/s41598-025-02891-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2024] [Accepted: 05/16/2025] [Indexed: 05/25/2025] Open
Abstract
Hepatic encephalopathy (HE), a neuropsychiatric complication secondary to liver cirrhosis and hepatic failure, represents the leading cause of mortality in end-stage liver disease. While hyperammonemia remains the central pathogenic factor in HE progression, emerging evidence implicates oxidative stress, neuroinflammation, and neuronal apoptosis as critical synergistic contributors to HE pathogenesis. Hydrogen-rich water, known for its antioxidant, anti-inflammatory, and anti-apoptotic properties, has not been systematically investigated for therapeutic efficacy in HE management. In the current investigation, we successfully established a HE rat model by administering thioacetamide via intraperitoneal injection. By observing the general state and behavioral changes of the rats, detecting liver function and blood ammonia, and observing the pathological changes of liver and brain tissue, it was discussed whether hydrogen-rich water had a preventive and therapeutic effect on hepatic encephalopathy. Oxidative stress, inflammation and neuronal apoptosis were detected in plasma, prefrontal cortex and hippocampus to explore the possible mechanism of its protective effect. The results showed that hydrogen-rich water can improve the behavioral changes of the HE rats, reduce blood ammonia, reduce liver function damage, alleviate the pathological changes of liver and brain tissue, significantly inhibit the systemic and local oxidative stress and inflammation of the brain tissue of the HE rats, and reduce neuronal apoptosis. In summary, hydrogen-rich water might stabilize liver-brain disturbance in thioacetamide-induced HE rats by anti-inflammation, anti-oxidative stress and reducing neuronal apoptosis.
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Affiliation(s)
- Xujiao Wang
- Zigong Fourth People's Hospital, Zigong, 643000, Sichuan, China
- Anesthesiology and Critical Care Medicine Key Laboratory of Luzhou, Southwest Medical University, No. 25 Taiping Road, Jiangyang District, Luzhou, 646000, Sichuan, China
| | - Xiao Liu
- Zigong Fourth People's Hospital, Zigong, 643000, Sichuan, China
- Anesthesiology and Critical Care Medicine Key Laboratory of Luzhou, Southwest Medical University, No. 25 Taiping Road, Jiangyang District, Luzhou, 646000, Sichuan, China
| | - Peng Zhou
- Department of Anesthesiology, The Affiliated Hospital of Southwest Medical University, Luzhou, 646000, Sichuan, China
- Anesthesiology and Critical Care Medicine Key Laboratory of Luzhou, Southwest Medical University, No. 25 Taiping Road, Jiangyang District, Luzhou, 646000, Sichuan, China
| | - Jianguo Feng
- Department of Anesthesiology, The Affiliated Hospital of Southwest Medical University, Luzhou, 646000, Sichuan, China
- Anesthesiology and Critical Care Medicine Key Laboratory of Luzhou, Southwest Medical University, No. 25 Taiping Road, Jiangyang District, Luzhou, 646000, Sichuan, China
| | - Jing Jia
- Department of Anesthesiology, The Affiliated Hospital of Southwest Medical University, Luzhou, 646000, Sichuan, China
- Anesthesiology and Critical Care Medicine Key Laboratory of Luzhou, Southwest Medical University, No. 25 Taiping Road, Jiangyang District, Luzhou, 646000, Sichuan, China
| | - Bingqing Xie
- Laboratory of Neurological Diseases and Brain Function, The Affiliated Hospital of Southwest Medical University, Luzhou, 646000, China
- Institute of Epigenetics and Brain Science, Southwest Medical University, Luzhou, 646000, China
| | - Ye Chen
- Anesthesiology and Critical Care Medicine Key Laboratory of Luzhou, Southwest Medical University, No. 25 Taiping Road, Jiangyang District, Luzhou, 646000, Sichuan, China
- Department of Traditional Chinese Medicine, The Affiliated Hospital of Southwest Medical University, Luzhou, 646000, Sichuan, China
| | - Jun Zhou
- Department of Anesthesiology, The Affiliated Hospital of Southwest Medical University, Luzhou, 646000, Sichuan, China.
- Anesthesiology and Critical Care Medicine Key Laboratory of Luzhou, Southwest Medical University, No. 25 Taiping Road, Jiangyang District, Luzhou, 646000, Sichuan, China.
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Sparacia G, Colelli G, Parla G, Mamone G, Maruzzelli L, Lo Re V, Avorio F, Miraglia R, Pichiecchio A. Brain Magnetic Resonance Imaging Radiomic Signature and Machine Learning Model Prediction of Hepatic Encephalopathy in Adult Cirrhotic Patients. Life (Basel) 2025; 15:346. [PMID: 40141691 PMCID: PMC11943475 DOI: 10.3390/life15030346] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2024] [Revised: 02/16/2025] [Accepted: 02/20/2025] [Indexed: 03/28/2025] Open
Abstract
BACKGROUND Hepatic encephalopathy (HE) may arise as a possible consequence of cirrhosis. Magnetic resonance imaging (MRI) may reveal a T1-weighted hyperintensity in the globi pallidi, indicating the deposition of paramagnetic substances. The objective of this research was to implement a machine learning-based radiomic model to predict the diagnosis and severity of chronic hepatic encephalopathy in adult patients with cirrhosis. METHODS Between October 2018 and February 2020, brain magnetic resonance imaging (MRI) was conducted on adult patients, both with and without cirrhosis. The control population consisted of individuals who did not have a previous medical record of chronic liver disease. The grade of hepatic encephalopathy (HE) was determined by considering factors such as the presence of underlying liver disease, the severity of clinical symptoms, and the frequency of encephalopathic episodes. Radiomic texture analysis based on five machine learning algorithms was applied to axial T1-weighted MR images of bilateral lentiform nuclei. Using the area under the receiver operating characteristics curve, we determined the accuracy of the five machine learning-based algorithms in predicting the presence of HE and the HE grading. RESULTS The ultimate research cohort included 124 individuals, with 70 being cirrhotic patients and 54 being non-cirrhotic controls. Of the total number of patients, 38 had a previous occurrence of HE and, among them, 22 had a grade of HE greater than 1. The multilayer perceptron algorithm classified patients versus controls with an accuracy of 100%. The k-nearest neighbor (KNN) algorithm classified patients with or without HE with an accuracy of 76.5%. The multilayer perceptron algorithm classified HE grade (HE grade 1, HE grade ≥ 2) with an accuracy of 94.1%. CONCLUSIONS The machine learning algorithms implemented provide a robust modeling technique for deriving valuable insights from brain MR images in cirrhotic patients and this can serve as an imaging tool valuable for the assessment of the burden of hepatic encephalopathy.
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Affiliation(s)
- Gianvincenzo Sparacia
- Radiology Service, Department of Biomedicine, Neuroscience and Advanced Diagnosis (BiND), University of Palermo, 90127 Palermo, Italy
- Radiology Service, IRCCS-ISMETT, 90127 Palermo, Italy (G.M.); (L.M.); (R.M.)
- NeuroLab, Computational Neuroimaging Laboratory, IRCCS-ISMETT, 90127 Palermo, Italy
| | - Giulia Colelli
- Advanced Imaging and Radiomic Center, IRCCS Mondino Foundation, 27100 Pavia, Italy; (G.C.); (A.P.)
| | - Giuseppe Parla
- Radiology Service, IRCCS-ISMETT, 90127 Palermo, Italy (G.M.); (L.M.); (R.M.)
- NeuroLab, Computational Neuroimaging Laboratory, IRCCS-ISMETT, 90127 Palermo, Italy
| | - Giuseppe Mamone
- Radiology Service, IRCCS-ISMETT, 90127 Palermo, Italy (G.M.); (L.M.); (R.M.)
| | - Luigi Maruzzelli
- Radiology Service, IRCCS-ISMETT, 90127 Palermo, Italy (G.M.); (L.M.); (R.M.)
| | - Vincenzina Lo Re
- Neurology Service, IRCCS-ISMETT, 90127 Palermo, Italy; (V.L.R.); (F.A.)
| | - Federica Avorio
- Neurology Service, IRCCS-ISMETT, 90127 Palermo, Italy; (V.L.R.); (F.A.)
| | - Roberto Miraglia
- Radiology Service, IRCCS-ISMETT, 90127 Palermo, Italy (G.M.); (L.M.); (R.M.)
| | - Anna Pichiecchio
- Advanced Imaging and Radiomic Center, IRCCS Mondino Foundation, 27100 Pavia, Italy; (G.C.); (A.P.)
- Department of Brain and Behavioural Disorders, University of Pavia, 27100 Pavia, Italy
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Amirshahrokhi K, Imani M. Edaravone reduces brain injury in hepatic encephalopathy by upregulation of Nrf2/HO-1 and inhibition of NF-κB, iNOS/NO and inflammatory cytokines. Mol Biol Rep 2025; 52:222. [PMID: 39937373 DOI: 10.1007/s11033-025-10343-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2024] [Accepted: 02/05/2025] [Indexed: 02/13/2025]
Abstract
BACKGROUND Brain damage is the most important complication in patients with hepatic encephalopathy (HE). Oxidative stress and inflammation are essential factors in the progression of brain injury caused by HE. The aim of this study was to investigate the potential therapeutic effect of edaravone and its underlying mechanisms against brain injury associated with HE in mice. METHODS AND RESULTS HE was induced by the injection of thioacetamide (200 mg/kg) for 2 days and then mice treated with edaravone (10 or 20 mg/kg/day, ip) for four consecutive days. The brain tissues were dissected for histopathological, biochemical, ELISA, RT-qPCR and immunofluorescence analysis. The results showed that edaravone improved the locomotor function and ameliorated brain histopathological changes in mice with HE. Edaravone inhibited oxidative stress markers by increasing the levels of glutathione, catalase, superoxide dismutase, glutathione reductase and the upregulation of nuclear erythroid 2-related factor (Nrf2)/HO-1 pathway in the brain tissue. Administration of edaravone significantly decreased the expression of p-NF-κB and iNOS. Edaravone treatment reduced the levels of NO, MPO and MMP-9 in the brain of mice. Additionally, the brain levels and expressions of inflammatory cytokines IL-1β, IL-6, TNF-α and IFN-γ were downregulated in mice treated with edaravone. CONCLUSIONS These results suggest that edaravone exerts significant neuroprotection by modulating of inflammatory and oxidative responses in HE and may serve as a promising agent for the treatment of brain injury associated with HE.
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Affiliation(s)
- Keyvan Amirshahrokhi
- Department of Pharmacology, School of Pharmacy, Ardabil University of Medical Sciences, P. O. Box 5618953141, Ardabil, Iran.
- Pharmaceutical Sciences Research Center, Ardabil University of Medical Sciences, Ardabil, Iran.
| | - Mahsa Imani
- School of Medicine, Ardabil University of Medical Sciences, Ardabil, Iran
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Kus C, Acehan S, Satar S, Gulen M, Sevdimbas S, Akdoganlar Aİ, Gorur M. Optic nerve sheath diameters predict mortality and severity in hepatic encephalopathy. Eur J Gastroenterol Hepatol 2024; 36:1426-1436. [PMID: 39373626 DOI: 10.1097/meg.0000000000002858] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/08/2024]
Abstract
OBJECTIVE The aim of this study was to compare the predictive power of optic nerve sheath diameter (ONSD) measured by brain computed tomography (CT) in patients diagnosed with hepatic encephalopathy (HE) in the emergency department, with other factors for mortality and disease severity. MATERIALS AND METHODS A total of 217 patients aged 18 years and older with acute decompensation of cirrhosis diagnosed with HE in the emergency department were included in the study. To compare with patients diagnosed with HE, a total of 217 individuals were included in the study as the healthy control group. ONSD measurements were performed on both the HE patients and the healthy control group in the brain CT. RESULTS The mortality rate of HE patients was 32.7%. Regarding the severity of the disease, 53% of the patients had late-stage HE. The presence of acute-on-chronic liver failure was detected in 51.4% of patients. The mortality rate among acute-on-chronic liver failure patients was 56.6%. According to the study data, ONSD, creatinine, lactate, and procalcitonin were independent predictors of mortality. Meanwhile, Child-Pugh score, direct bilirubin, ONSD, ammonia, and total bilirubin were independent predictors of disease severity. In the receiver operating characteristic curve analysis, the ONSD had the highest predictive power for mortality and disease severity among the determined predictive values. CONCLUSION The data from the study suggests that assessing the ONSD through brain CT scans in individuals diagnosed with HE in the emergency department may provide valuable insights for clinicians, aiding in the prediction of both mortality rates and the severity of the disease.
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Affiliation(s)
- Cumali Kus
- Emergency Medicine Clinic, Adana City Training and Research Hospital, Health Sciences University, Adana, Turkey
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Fernandes LK, Barbosa RC, Godoy MFD. NON-INVASIVE METHOD OF MONITORING INTRACRANIAL PRESSURE FOR THE EVALUATION OF HEPATIC ENCEPHALOPATHY. ARQUIVOS DE GASTROENTEROLOGIA 2024; 61:e24057. [PMID: 39607217 DOI: 10.1590/s0004-2803.24612024-057] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/16/2024] [Accepted: 09/11/2024] [Indexed: 11/29/2024]
Abstract
BACKGROUND Liver diseases often occur with hepatic encephalopathy (HE), whose pathophysiology may involve increased intracranial pressure (ICP). Tools for monitoring ICP and its pulse morphology can be useful for assessing HE. The use of a non-invasive and sensitive procedure would be extremely useful in managing these cases. OBJECTIVE To evaluate the feasibility and performance of a new, non-invasive method of monitoring ICP, as an alternative to invasive methods, and to correlate the clinical diagnosis of HE with the morphological findings of ICP. METHODS This is a cross-sectional analytical study, conducted in a tertiary hospital and pioneer in the application of Brain4Care® BWS equipment. The ICP pulse morphology is parallel to the arterial one, where there are three frequent peaks: percussion peak (P1), due to plasma extravasated by the choroid plexus; tidal wave (P2), due to the degree of intracranial compliance to the reflection of P1, and dicrotic notch (P3), due to the closure of the aortic valve. Normality indicates P1>P2>P3. These peaks determine intracranial compliance through their relationship with cerebral blood volume, where P2/P1 ratio >1 suggests a pathological morphology, with a sustained increase in ICP and decreased compliance. Another way to evaluate this would be by a change in the time-to-peak (TTP). These data were compared between patients with and without clinical signs indicative of HE. The study was approved by the Institution's Research Ethics Committee (number 5.493.775). RESULTS A total of 40 liver disease patients were evaluated, of which, at the time of collection, 20 did not have a clinical picture of HE (59.5±9.3 years; 70.0% male) and 20 had a clinical picture of HE (59.6±11.9 years; 65.0% male). The groups are demographically, clinically and laboratory similar; and statistically significant differences were identified in the morphological patterns of ICP between the groups evaluated, as well as trends in the parameters. The difference in the P2/P1 ratio was not significant (Mann Whitney: two-tailed P=0.2978); however, TTP proved to be a parameter with a statistically significant difference between the groups (Mann Whitney: two-tailed P=0.0282; median difference = 0.04). Analysis using the C statistic, using the ROC curve, suggested P2/P1=1.31 (AUROC: 0.5975) and TTP=0.22 (AUROC: 0.7013) as optimal cutoff points, where the presence of HE in liver disease patients would be associated with obtaining parameters below these thresholds. CONCLUSION The brain4care® BWS system proved to be feasible for use in liver disease patients with or without clinical signs of hepatic encephalopathy and was able to differentiate them. Pathophysiological explanations, however, still require better causality explanation and understanding of the intracerebral hydrodynamic picture in hepatic encephalopathy. Given the low sample power found, new studies need better clinical heterogeneity and longer-term follow-up for definitive conclusions.
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Affiliation(s)
- Lucas Kleebank Fernandes
- Faculdade de Medicina de São José do Rio Preto, Graduação em Medicina, São José do Rio Preto, São Paulo, Brasil
| | - Ricardo Cesar Barbosa
- Faculdade de Medicina de São José do Rio Preto, Programa de Pós-Graduação em Ciências da Saúde, São José do Rio Preto, São Paulo, Brasil
| | - Moacir Fernandes de Godoy
- Faculdade de Medicina de São José do Rio Preto, Departamento de Cardiologia e Cirurgia Cardiovascular, São José do Rio Preto, São Paulo , Brasil
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Albayrak O, Hatipoglu BN, Ozbeyli D, Sen A, Koyuncuoglu T, Cevik O, Ercan F, Kanpalta F, Dogan A, Pazarbasi SE, Sener G. Dodder ( Cuscuta sp.) extract prevents cognitive deficits in a rat model of hepatic encephalopathy. North Clin Istanb 2024; 11:512-519. [PMID: 39650325 PMCID: PMC11622753 DOI: 10.14744/nci.2023.95776] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2023] [Revised: 11/16/2023] [Accepted: 11/28/2023] [Indexed: 12/11/2024] Open
Abstract
OBJECTIVE In our study, the protective effect of dodder plant extract against encephalopathy induced by cholestatic liver disease model was investigated. METHODS Spraque Dawley rats were used in the study. For the cholestatic liver disease model, the bile duct ligation (BDL) was applied. The groups were determined as control, Cuscuta sp. (CUS), BDL and BDL + CUS. Double ligation was performed in the bile duct in the BDL groups. For the applications, saline (SF) was administered to the control and BDL groups for 28 days while 250 mg/kg of Cuscuta sp. extract was given by oral gavage to the CUS and BDL + CUS groups. At the end of the experiment, cognitive evaluations were made by applying new object recognition and Morris water maze tests. After these tests, blood-brain barrier (BBB) measurements were made in half of the groups. In the other half of the groups, brain tissue samples were taken by decapitation and transforming growth factor-beta (TGF-β), 8-hydroxydeoxyguanosine (8-OHdG) and sodium-potassium adenosine triphosphatase (Na+/K+-ATPase) measurements were made in the tissues. Histological examinations of the tissues were also performed. RESULTS Cognitive performance was low, and BBB permeability was found to be increased in the group with bile duct ligation. In addition, TGF-β and 8-OHdG levels were increased in tissues, while Na+/K+-ATPase enzyme activity was suppressed. Treatment with Cuscuta sp. increased cognitive performance and decreased BBB permeability. Other biochemical parameters examined were significantly (p<0.05-0.001) reversed and supported by histological findings. CONCLUSION Our findings in the study suggest that dodder plant may be beneficial for the protection of cognitive performance and brain tissue in encephalopathy caused by cholestasis.
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Affiliation(s)
- Omercan Albayrak
- Department of Research and Development, Anatolia Geneworks, Istanbul, Turkiye
| | - Bilge Nur Hatipoglu
- Department of Pharmacology, Marmara University Faculty of Pharmacy, Istanbul, Turkiye
| | - Dilek Ozbeyli
- Department of Medical Services and Techniques, Marmara University Vocational School of Health Services, Istanbul, Turkiye
| | - Ali Sen
- Department of Pharmacognosy, Marmara University Faculty of Pharmacy, Istanbul, Turkiye
| | - Turkan Koyuncuoglu
- Department of Physiology, Biruni University Faculty of Medicine, Istanbul, Turkiye
| | - Ozge Cevik
- Department of Biochemistry, Adnan Menderes University Faculty of Medicine, Aydin, Turkiye
| | - Feriha Ercan
- Department of Histology and Embryology, Marmara University Faculty of Medicine, Istanbul, Turkiye
| | - Fatma Kanpalta
- Department of Histology and Embryology, Marmara University Faculty of Medicine, Istanbul, Turkiye
| | - Ahmet Dogan
- Department of Pharmaceutical Botany, Marmara University Faculty of Pharmacy, Istanbul, Turkiye
| | - Seren Ede Pazarbasi
- Department of Pharmacy Services, Fenerbahce University Vocational School of Health Services, Istanbul, Turkiye
| | - Goksel Sener
- Department of Pharmacology, Fenerbahce University Faculty of Pharmacy, Istanbul, Turkiye
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Amirshahrokhi K, Imani M. Therapeutic Effect of Levetiracetam Against Thioacetamide-Induced Hepatic Encephalopathy Through Inhibition of Oxidative Stress and Downregulation of NF-κB, NLRP3, iNOS/NO, Pro-Inflammatory Cytokines and Apoptosis. Inflammation 2024; 47:1762-1775. [PMID: 38530519 DOI: 10.1007/s10753-024-02007-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2024] [Revised: 02/29/2024] [Accepted: 03/14/2024] [Indexed: 03/28/2024]
Abstract
Hepatic encephalopathy (HE) is a serious brain disorder which associated with neurological and psychiatric manifestations. Oxidative stress and neuroinflammation and apoptosis play main roles in the development of brain damage in HE. Levetiracetam is an antiseizure drug with established antioxidant and anti-inflammatory activities. In the present study we investigated the therapeutic effects of levetiracetam against brain injury in HE and its underlying mechanisms of action. Male C57BL/6 mice were subjected to the induction of HE by the injection of thioacetamide (200 mg/kg) for 2 days. Mice were treated with levetiracetam at two doses (50 or 100 mg/kg/day) for 3 days in the treatment groups. Animals were subjected to a behavioral test and the brain tissues were dissected for histopathological, biochemical, gene expression and immunofluorescence analysis. The results showed that levetiracetam alleviated body weight loss and improved locomotor activity of mice with HE. Levetiracetam treatment decreased the histopathological changes, lipid peroxidation and protein carbonylation while restored the antioxidants (GSH, SOD and CAT) in the brain. Levetiracetam decreased the expression and activity of NF-κB, NOD-like receptor pyrin domain-containing protein 3 (NLRP3) and pro-inflammatory cytokines (TNF-α, IL-1β, IL-6, and IFN-γ) in the brain tissue. Administration of levetiracetam inhibited iNOS/NO pathway and myeloperoxidase (MPO) activity in the brain. Moreover, caspase-3 was decreased and the ratio of Bcl2/Bax was increased in the brain of mice treated with levetiracetam. These findings suggest that levetiracetam may be a promising therapeutic agent for brain injury in HE through inhibiting the oxidative, inflammatory and apoptotic pathways.
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Affiliation(s)
- Keyvan Amirshahrokhi
- Department of Pharmacology, School of Pharmacy, Ardabil University of Medical Sciences, P. O. Box 5618953141, Ardabil, Iran.
| | - Mahsa Imani
- School of Medicine, Ardabil University of Medical Sciences, Ardabil, Iran
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Karisik A, Bader V, Moelgg K, Buergi L, Dejakum B, Komarek S, Eller MT, Toell T, Mayer-Suess L, Pechlaner R, Granna J, Sollereder S, Rossi S, Schoenherr G, Willeit J, Willeit P, Lang W, Kiechl S, Knoflach M, Boehme C. Comorbidities associated with dysphagia after acute ischemic stroke. BMC Neurol 2024; 24:358. [PMID: 39342159 PMCID: PMC11438413 DOI: 10.1186/s12883-024-03863-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2024] [Accepted: 09/13/2024] [Indexed: 10/01/2024] Open
Abstract
BACKGROUND Pre-existing comorbidities increase the likelihood of post-stroke dysphagia. This study investigates comorbidity prevalence in patients with dysphagia after ischemic stroke. METHODS The data of patients with acute ischemic stroke from two large representative cohorts (STROKE-CARD trial 2014-2019 and STROKE-CARD registry 2020-2022 - both study center Innsbruck, Austria) were analyzed for the presence of dysphagia at hospital admission (clinical swallowing examination). Comorbidities were assessed using the Charlson Comorbidity Index (CCI). RESULTS Of 2054 patients with ischemic stroke, 17.2% showed dysphagia at hospital admission. Patients with dysphagia were older (77.8 ± 11.9 vs. 73.6 ± 14.3 years, p < 0.001), had more severe strokes (NIHSS 7(4-12) vs. 2(1-4), p < 0.001) and had higher CCI scores (4.7 ± 2.1 vs. 3.8 ± 2.0, p < 0.001) than those without swallowing impairment. Dysphagia correlated with hypertension (p = 0.034), atrial fibrillation (p < 0.001), diabetes (p = 0.002), non-smoking status (p = 0.014), myocardial infarction (p = 0.002), heart failure (p = 0.002), peripheral arterial disease (p < 0.001), severe chronic liver disease (p = 0.002) and kidney disease (p = 0.010). After adjusting for relevant factors, the associations with dysphagia remained significant for diabetes (p = 0.005), peripheral arterial disease (p = 0.007), kidney disease (p = 0.014), liver disease (p = 0.003) and overall CCI (p < 0.001). CONCLUSIONS Patients with multiple comorbidities have a higher risk of developing post-stroke dysphagia. Therefore, early and thorough screening for swallowing impairment after acute ischemic stroke is crucial especially in those with multiple concomitant diseases. TRIAL REGISTRATION Stroke Card Registry (NCT04582825), Stroke Card Trial (NCT02156778).
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Affiliation(s)
- Anel Karisik
- VASCage - Centre on Clinical Stroke Research, Adamgasse 23, Innsbruck, Austria
- Department of Neurology, Medical University of Innsbruck, Anichstrasse 35, Innsbruck, Austria
| | - Vincent Bader
- Department of Neurology, Medical University of Innsbruck, Anichstrasse 35, Innsbruck, Austria
| | - Kurt Moelgg
- VASCage - Centre on Clinical Stroke Research, Adamgasse 23, Innsbruck, Austria
- Department of Neurology, Medical University of Innsbruck, Anichstrasse 35, Innsbruck, Austria
| | - Lucie Buergi
- VASCage - Centre on Clinical Stroke Research, Adamgasse 23, Innsbruck, Austria
- Department of Neurology, Medical University of Innsbruck, Anichstrasse 35, Innsbruck, Austria
| | - Benjamin Dejakum
- Department of Neurology, Medical University of Innsbruck, Anichstrasse 35, Innsbruck, Austria
| | - Silvia Komarek
- Department of Neurology, Medical University of Innsbruck, Anichstrasse 35, Innsbruck, Austria
| | - Michael Thomas Eller
- Department of Neurology, Medical University of Innsbruck, Anichstrasse 35, Innsbruck, Austria
| | - Thomas Toell
- Department of Neurology, Medical University of Innsbruck, Anichstrasse 35, Innsbruck, Austria
| | - Lukas Mayer-Suess
- Department of Neurology, Medical University of Innsbruck, Anichstrasse 35, Innsbruck, Austria
| | - Raimund Pechlaner
- Department of Neurology, Medical University of Innsbruck, Anichstrasse 35, Innsbruck, Austria
| | - Julian Granna
- VASCage - Centre on Clinical Stroke Research, Adamgasse 23, Innsbruck, Austria
| | - Simon Sollereder
- VASCage - Centre on Clinical Stroke Research, Adamgasse 23, Innsbruck, Austria
| | - Sonja Rossi
- ICONE - Innsbruck Cognitive Neuroscience, Department for Hearing, Speech and Voice Disorders, Medical University of Innsbruck, Anichstrasse 35, Innsbruck, Austria
| | - Gudrun Schoenherr
- Department of Neurology, Medical University of Innsbruck, Anichstrasse 35, Innsbruck, Austria
| | - Johann Willeit
- Department of Neurology, Medical University of Innsbruck, Anichstrasse 35, Innsbruck, Austria
| | - Peter Willeit
- Institute of Clinical Epidemiology, Public Health, Health Economics, Medical Statistics and Informatics, Medical University of Innsbruck, Anichstrasse 35, Innsbruck, Austria
- Department of Public Health and Primary Care, University of Cambridge, The Old Schools, Trinity Ln, Cambridge, UK
| | - Wilfried Lang
- VASCage - Centre on Clinical Stroke Research, Adamgasse 23, Innsbruck, Austria
- Medical Faculty, Sigmund Freud Private University, Freudplatz 1, Vienna, Austria
| | - Stefan Kiechl
- VASCage - Centre on Clinical Stroke Research, Adamgasse 23, Innsbruck, Austria
- Department of Neurology, Medical University of Innsbruck, Anichstrasse 35, Innsbruck, Austria
| | - Michael Knoflach
- VASCage - Centre on Clinical Stroke Research, Adamgasse 23, Innsbruck, Austria.
- Department of Neurology, Medical University of Innsbruck, Anichstrasse 35, Innsbruck, Austria.
| | - Christian Boehme
- Department of Neurology, Medical University of Innsbruck, Anichstrasse 35, Innsbruck, Austria.
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10
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L'Écuyer S, Charbonney E, Carrier FM, Rose CF. Implication of Hypotension in the Pathogenesis of Cognitive Impairment and Brain Injury in Chronic Liver Disease. Neurochem Res 2024; 49:1437-1449. [PMID: 36635437 DOI: 10.1007/s11064-022-03854-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2022] [Revised: 09/23/2022] [Accepted: 12/26/2022] [Indexed: 01/14/2023]
Abstract
The incidence of chronic liver disease is on the rise. One of the primary causes of hospital admissions for patients with cirrhosis is hepatic encephalopathy (HE), a debilitating neurological complication. HE is defined as a reversible syndrome, yet there is growing evidence stating that, under certain conditions, HE is associated with permanent neuronal injury and irreversibility. The pathophysiology of HE primarily implicates a strong role for hyperammonemia, but it is believed other pathogenic factors are involved. The fibrotic scarring of the liver during the progression of chronic liver disease (cirrhosis) consequently leads to increased hepatic resistance and circulatory anomalies characterized by portal hypertension, hyperdynamic circulatory state and systemic hypotension. The possible repercussions of these circulatory anomalies on brain perfusion, including impaired cerebral blood flow (CBF) autoregulation, could be implicated in the development of HE and/or permanent brain injury. Furthermore, hypotensive insults incurring during gastrointestinal bleed, infection, or liver transplantation may also trigger or exacerbate brain dysfunction and cell damage. This review will focus on the role of hypotension in the onset of HE as well as in the occurrence of neuronal cell loss in cirrhosis.
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Affiliation(s)
- Sydnée L'Écuyer
- Hepato-Neuro Laboratory, Centre de recherche du Centre Hospitalier de l'Université de Montréal (CRCHUM), 900, rue Saint-Denis - Pavillon R, R08.422 Montréal (Québec), Québec, H2X 0A9, Canada
| | - Emmanuel Charbonney
- Department of Medicine, Critical Care Division, Centre Hospitalier de l'Université de Montréal, Montréal, Canada
| | - François Martin Carrier
- Department of Medicine, Critical Care Division, Centre Hospitalier de l'Université de Montréal, Montréal, Canada
- Department of Anesthesiology, Centre Hospitalier de l'Université de Montréal, Montréal, Canada
- Carrefour de l'innovation et santé des populations , Centre de recherche du Centre hospitalier de l'Université de Montréal (CRCHUM), Montréal, Canada
| | - Christopher F Rose
- Hepato-Neuro Laboratory, Centre de recherche du Centre Hospitalier de l'Université de Montréal (CRCHUM), 900, rue Saint-Denis - Pavillon R, R08.422 Montréal (Québec), Québec, H2X 0A9, Canada.
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11
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Xu W, Song Y, Xiao W, Gong Z. Regulatory Effects and Mechanisms of L-Theanine on Neurotransmitters via Liver-Brain Axis Under a High Protein Diet. Mol Neurobiol 2024; 61:783-798. [PMID: 37659037 DOI: 10.1007/s12035-023-03608-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2022] [Accepted: 08/22/2023] [Indexed: 09/05/2023]
Abstract
Excessive protein intake causes liver and brain damage and neurotransmitter disorders, thereby inducing cognitive dysfunction. L-theanine can regulate the neurotransmitter content and show great potential in liver and brain protection. However, it remains unclear whether l-theanine effectively regulates neurotransmitter content under high-protein diet. A 40-day feeding experiment was performed in Sprague Dawley rats to investigate the regulatory effects and mechanisms of l-theanine on neurotransmitters via liver-brain axis in high-protein diets. The results showed that a 30% protein diet increased the liver and brain neurotransmitter content while maintaining the normal structure of liver and the hippocampal CA1 of brain and improving the autonomous behavior of rats. In contrast, 40% and 50% protein diets decreased the content of neurotransmitters, affected autonomous behavior, destroyed the hippocampal CA1 of brain structure, increased hepatic inflammatory infiltration, lipid degeneration, and hepatocyte eosinophilic change in liver, increased liver AST, ALT, MDA, CRP, and blood ammonia level, and decreased liver SOD and CAT level. However, l-theanine improved liver and brain neurotransmitter content, autonomous behavior, liver and hippocampal brain structure, and liver biochemical indicators in 40% and 50% protein diets. To explore how LTA can eliminate the adverse effects of a high-protein diet, we analyzed different metabolites and proteomes and using western blotting for validate quantitatively. We found that l-theanine regulates the activity of PF4 and G protein subunit alpha i2, increases the content of brain-derived neurotrophic factor and dopamine under a 20% protein diet. In addition, l-theanine can activate the adenylate cyclase-protein kinase A pathway through the protein alpha/beta-hydrolase domain protein 12 to regulate the content of neurotransmitters under a 40% protein diet, thereby exerting a neuroprotective effect.
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Affiliation(s)
- Wei Xu
- Key Laboratory of Tea Science of Ministry of Education, Hunan Agricultural University, Changsha, 410128, Hunan, China
- National Research Center of Engineering and Technology for Utilization of Botanical Functional Ingredients, Hunan Agricultural University, Changsha, 410128, Hunan, China
- Co-Innovation Center of Education Ministry for Utilization of Botanical Functional Ingredients, Changsha, China
| | - Yuxin Song
- Key Laboratory of Tea Science of Ministry of Education, Hunan Agricultural University, Changsha, 410128, Hunan, China
- National Research Center of Engineering and Technology for Utilization of Botanical Functional Ingredients, Hunan Agricultural University, Changsha, 410128, Hunan, China
- Co-Innovation Center of Education Ministry for Utilization of Botanical Functional Ingredients, Changsha, China
| | - Wenjun Xiao
- Key Laboratory of Tea Science of Ministry of Education, Hunan Agricultural University, Changsha, 410128, Hunan, China.
- National Research Center of Engineering and Technology for Utilization of Botanical Functional Ingredients, Hunan Agricultural University, Changsha, 410128, Hunan, China.
- Co-Innovation Center of Education Ministry for Utilization of Botanical Functional Ingredients, Changsha, China.
| | - Zhihua Gong
- Key Laboratory of Tea Science of Ministry of Education, Hunan Agricultural University, Changsha, 410128, Hunan, China.
- National Research Center of Engineering and Technology for Utilization of Botanical Functional Ingredients, Hunan Agricultural University, Changsha, 410128, Hunan, China.
- Co-Innovation Center of Education Ministry for Utilization of Botanical Functional Ingredients, Changsha, China.
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12
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Yuksek A, Acehan S, Satar S, Gulen M, Balcik M, Sevdimbas S, Ince C, Koca AN, Tas A. Predictors of 30-day mortality in patients diagnosed with hepatic encephalopathy on admission to the emergency department. Eur J Gastroenterol Hepatol 2023; 35:1402-1409. [PMID: 37695624 DOI: 10.1097/meg.0000000000002646] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 09/12/2023]
Abstract
BACKGROUND The aim of this study is to compare the laboratory findings and disease severity scores of patients diagnosed with hepatic encephalopathy (HE) in the emergency department (ED) to predict 30-day mortality. METHOD The patients over 18 years old and diagnosed HE in the ED of a tertiary hospital were included in the study. Demographic and clinical characteristics, laboratory parameters, predisposing causes and outcomes of the patients included in the study were recorded in the data form. Severity of liver disease was assessed by Child Pugh Score (CPS), End-stage liver disease model (MELD), MELD-Na and MELD-Lactate scores. RESULTS Two hundred fifty-four patients diagnosed with HE were included in the study. 59.1% of the patients were male. The mean age of the patients was 65.2 ± 12.6 years. The mortality rate of the patients was 47.2%. When the receiver operating characteristic (ROC) analysis, which determines the predictive properties of laboratory parameters and disease severity scores, was examined, the area under curve value of the MELD-Lactate score (0.858 95% CI 0.812-0.904, P < 0.001) was the highest. Binary logistic regression analysis for the estimation of patients' 30-day mortality showed that CPS and MELD-Lactate scores and blood ammonia and B-type natriuretic peptide levels were independent predictors of mortality. CONCLUSION According to the study data, MELD-Lactate and BNP levels in patients diagnosed with HE in the ED may help the clinician in the prediction of 30-day mortality in the early period.
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Affiliation(s)
- Ali Yuksek
- Hatay City Training and Research Hospital, Emergency Medicine Clinic, Hatay
| | - Selen Acehan
- Health Sciences University, Adana City Training and Research Hospital, Emergency Medicine Clinic, Adana
| | - Salim Satar
- Health Sciences University, Adana City Training and Research Hospital, Emergency Medicine Clinic, Adana
| | - Muge Gulen
- Health Sciences University, Adana City Training and Research Hospital, Emergency Medicine Clinic, Adana
| | - Muhammet Balcik
- Ministry of Health Kahramanmaras Necip Fazil City Hospital, Department of Emergency Medicine, Kahramanmaraş
| | - Sarper Sevdimbas
- Health Sciences University, Adana City Training and Research Hospital, Emergency Medicine Clinic, Adana
| | - Cagdas Ince
- Health Sciences University, Adana City Training and Research Hospital, Emergency Medicine Clinic, Adana
| | - Ahmet Naci Koca
- Ministry of Health Samandag Hospital, Department of Emergency Medicine, Hatay
| | - Adnan Tas
- Medipark Hospital, Department of Gastroenterology, Adana, Turkey
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13
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Santos RPC, Toscano ECDB, Rachid MA. Anti-inflammatory strategies for hepatic encephalopathy: preclinical studies. ARQUIVOS DE NEURO-PSIQUIATRIA 2023. [PMID: 37487550 PMCID: PMC10371400 DOI: 10.1055/s-0043-1767819] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 07/26/2023]
Abstract
Hepatic encephalopathy (HE) is a potentially reversible neuropsychiatric syndrome. Often, HE causes cognitive and motor dysfunctions due to an acute or chronic insufficiency of the liver or a shunting between the hepatic portal vein and systemic vasculature. Liver damage induces peripheral changes, such as in the metabolism and peripheral inflammatory responses that trigger exacerbated neuroinflammation. In experimental models, anti-inflammatory strategies have demonstrated neuroprotective effects, leading to a reduction in HE-related cognitive and motor impairments. In this scenario, a growing body of evidence has shown that peripheral and central nervous system inflammation are promising preclinical targets. In this review, we performed an overview of FDA-approved drugs and natural compounds which are used in the treatment of other neurological and nonneurological diseases that have played a neuroprotective role in experimental HE, at least in part, through anti-inflammatory mechanisms. Despite the exciting results from animal models, the available data should be critically interpreted, highlighting the importance of translating the findings for clinical essays.
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Affiliation(s)
- Rafaela Pinto Coelho Santos
- Universidade Federal de Minas Gerais, Instituto de Ciências Biológicas, Departamento de Patologia Geral, Laboratório de Patologia Celular e Molecular, Belo Horizonte MG, Brazil
| | - Eliana Cristina de Brito Toscano
- Universidade Federal de Juiz de Fora, Faculdade de Medicina, Departamento de Patologia, Laboratório Integrado de Pesquisa em Patologia, Juiz de Fora MG, Brazil
- Universidade Federal de Juiz e Fora, Faculdade de Medicina, Programa de Pós-Graduação em Saúde, Juiz de Fora MG, Brazil
| | - Milene Alvarenga Rachid
- Universidade Federal de Minas Gerais, Instituto de Ciências Biológicas, Departamento de Patologia Geral, Laboratório de Patologia Celular e Molecular, Belo Horizonte MG, Brazil
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14
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Zhu R, Liu L, Zhang G, Dong J, Ren Z, Li Z. The pathogenesis of gut microbiota in hepatic encephalopathy by the gut-liver-brain axis. Biosci Rep 2023; 43:BSR20222524. [PMID: 37279097 PMCID: PMC10272964 DOI: 10.1042/bsr20222524] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2022] [Revised: 05/05/2023] [Accepted: 05/31/2023] [Indexed: 06/08/2023] Open
Abstract
Hepatic encephalopathy (HE) is a neurological disease occurring in patients with hepatic insufficiency and/or portal-systemic blood shunting based on cirrhosis. The pathogenesis is not completely clear till now, but it is believed that hyperammonemia is the core of HE. Hyperammonemia caused by increased sources of ammonia and decreased metabolism further causes mental problems through the gut-liver-brain axis. The vagal pathway also plays a bidirectional role in the axis. Intestinal microorganisms play an important role in the pathogenesis of HE through the gut-liver-brain axis. With the progression of cirrhosis to HE, intestinal microbial composition changes gradually. It shows the decrease of potential beneficial taxa and the overgrowth of potential pathogenic taxa. Changes in gut microbiota may lead to a variety of effects, such as reduced production of short-chain fatty acids (SCFAs), reduced production of bile acids, increased intestinal barrier permeability, and bacterial translocation. The treatment aim of HE is to decrease intestinal ammonia production and intestinal absorption of ammonia. Prebiotics, probiotics, antibiotics, and fecal microbiota transplantation (FMT) can be used to manipulate the gut microbiome to improve hyperammonemia and endotoxemia. Especially the application of FMT, it has become a new treated approach to target microbial composition and function. Therefore, restoring intestinal microbial homeostasis can improve the cognitive impairment of HE, which is a potential treatment method.
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Affiliation(s)
- Ruirui Zhu
- Department of Infectious Diseases, the First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China
- Gene Hospital of Henan Province; Precision Medicine Center, the First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China
| | - Liwen Liu
- Department of Infectious Diseases, the First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China
- Gene Hospital of Henan Province; Precision Medicine Center, the First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China
- Jinan Microecological Biomedicine Shandong Laboratory, Jinan 250000, China
| | - Guizhen Zhang
- Department of Infectious Diseases, the First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China
- Gene Hospital of Henan Province; Precision Medicine Center, the First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China
- Jinan Microecological Biomedicine Shandong Laboratory, Jinan 250000, China
| | - Jianxia Dong
- Department of Infectious Diseases, the First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China
- Gene Hospital of Henan Province; Precision Medicine Center, the First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China
| | - Zhigang Ren
- Department of Infectious Diseases, the First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China
- Gene Hospital of Henan Province; Precision Medicine Center, the First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China
- Jinan Microecological Biomedicine Shandong Laboratory, Jinan 250000, China
| | - Zhiqin Li
- Department of Infectious Diseases, the First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China
- Gene Hospital of Henan Province; Precision Medicine Center, the First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China
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15
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Gillespie SL, Hanrahan TP, Rockey DC, Majumdar A, Hayes PC. Review article: controversies surrounding the use of carvedilol and other beta blockers in the management of portal hypertension and cirrhosis. Aliment Pharmacol Ther 2023; 57:454-463. [PMID: 36691947 DOI: 10.1111/apt.17380] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/04/2022] [Revised: 11/03/2022] [Accepted: 12/18/2022] [Indexed: 01/25/2023]
Abstract
BACKGROUND Advanced chronic liver disease is an increasing cause of premature morbidity and mortality in the UK. Portal hypertension is the primary driver of decompensation, including the development of ascites, hepatic encephalopathy and variceal haemorrhage. Non-selective beta blockers (NSBB) reduce portal pressure and are well established in the prevention of variceal haemorrhage. Carvedilol, a newer NSBB, is more effective at reducing portal pressure due to additional α-adrenergic blockade and has additional anti-oxidant, anti-inflammatory and anti-fibrotic effects. AIM To summarise the available evidence on the use of beta blockers, specifically carvedilol, in cirrhosis, focussing on when and why to start METHODS: We performed a comprehensive literature search of PubMed for relevant publications. RESULTS International guidelines advise the use of NSBB in primary prophylaxis against variceal haemorrhage in those with high-risk varices, with substantial evidence of efficacy comparable with endoscopic band ligation (EBL). NSBB are also well established in secondary prophylaxis, in combination with EBL. More controversial is their use in patients without large varices, but with clinically significant portal hypertension. However, there is gathering evidence that NSBB, particularly carvedilol, reduce the risk of decompensation and improve survival. While caution is advised in patients with advanced cirrhosis and refractory ascites, recent evidence suggests that NSBB can continue to be used safely, and that premature discontinuation may be detrimental. CONCLUSIONS With increasing evidence of benefit independent of variceal bleeding, namely retardation of decompensation and improvement in survival, it is time to consider whether carvedilol should be offered to all patients with advanced chronic liver disease.
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Affiliation(s)
| | - Timothy P Hanrahan
- Centre for Liver and Digestive Disorders, Royal Infirmary of Edinburgh, Edinburgh, UK.,Department of Gastroenterology and Hepatology, Austin Health, Melbourne, Australia
| | - Don C Rockey
- Digestive Disease Research Center, Medical University of South Carolina, Charleston, South Carolina, USA
| | - Avik Majumdar
- Department of Gastroenterology and Hepatology, Austin Health, Melbourne, Australia.,The University of Melbourne, Melbourne, Australia
| | - Peter C Hayes
- Centre for Liver and Digestive Disorders, Royal Infirmary of Edinburgh, Edinburgh, UK.,College of Medicine and Veterinary Medicine, University of Edinburgh, Edinburgh, UK
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16
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Kuo NR, Hou MC, Chu WC, Yang YY, Huang CC, Li TH, Lee TY, Liu CW, Liao TL, Hsieh SL, Lin HC. Low lymphocyte-to-monocyte ratio, calcitriol level, and CD206 level predict the development of acute-on-chronic liver failure in patients cirrhosis with acute decompensation. J Chin Med Assoc 2023; 86:265-273. [PMID: 36727703 DOI: 10.1097/jcma.0000000000000867] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/03/2023] Open
Abstract
BACKGROUND Cirrhosis-related acute-on-chronic liver failure (ACLF) is associated with high morbidity and mortality rates. Prognostic models of ACLF have been developed; however, few studies have focused on the occurrence of ACLF. This study aimed to identify the factors that predict the development of ACLF, hepatic encephalopathy (HE), and infection in patients with cirrhosis. METHODS Patients with cirrhosis were enrolled, and the serum levels of calcitriol, Cluster of Differentiation 26 (CD206), and macrophage-inducible lectin receptor (Mincle) were measured, and lymphocyte-to-monocyte ratio (LMR) and neutrophil-to-lymphocyte ratio were calculated; all the patients were tracked for 6 months. A generalized estimating equation (GEE) was used to assess the factors associated with ACLF development, HE, and infection. The aforementioned model was derived based on immunological markers, and receiver operating characteristic analysis with area under the curve (AUC) was adopted to evaluate accuracy. RESULTS After screening 325 patients with cirrhosis, 65 patients were eligible. In the GEE model, low levels of calcitriol (odds ratio [OR] = 3.259; 95% confidence interval [CI] = 1.118-8.929) and CD206 (OR = 2.666; 95% CI = 1.082-6.567) were associated with the development of ACLF, and the LMR was a protective factor (OR = 0.356; 95% CI = 0.147-0.861). Low calcitriol levels were a risk factor for HE (OR = 3.827) and infection (OR = 2.489). LMR was found to be a protective factor against HE (OR = 0.388). An immunological model for the discrimination of ACLF development within 6 months was proposed, with an AUC of 0.734 (95% CI = 0.598-0.869). CONCLUSION Single and combined immunological markers, including low LMR and low levels of calcitriol and CD206, were promising for early prediction of the development of ACLF, HE, and infection in patients with cirrhosis.
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Affiliation(s)
- Nai-Rong Kuo
- Department of Medical Education, Medical Innovation and Research Office, Clinical Innovation Center, Taipei Veterans General Hospital, Taipei, Taiwan, ROC
- Faculty of Medicine, School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan, ROC
| | - Ming-Chih Hou
- Faculty of Medicine, School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan, ROC
- Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan, ROC
| | - Wei-Chi Chu
- Faculty of Medicine, School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan, ROC
- Institute of Clinical Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan, ROC
| | - Ying-Ying Yang
- Department of Medical Education, Medical Innovation and Research Office, Clinical Innovation Center, Taipei Veterans General Hospital, Taipei, Taiwan, ROC
- Faculty of Medicine, School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan, ROC
- Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan, ROC
- Institute of Clinical Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan, ROC
| | - Chia-Chang Huang
- Department of Medical Education, Medical Innovation and Research Office, Clinical Innovation Center, Taipei Veterans General Hospital, Taipei, Taiwan, ROC
- Faculty of Medicine, School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan, ROC
- Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan, ROC
- Institute of Clinical Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan, ROC
| | - Tzu-Hao Li
- Faculty of Medicine, School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan, ROC
- Division of Allergy, Immunology, and Rheumatology, Department of Internal Medicine, Shin Kong Wu Ho-Su Memorial Hospital, Taipei, Taiwan, ROC
| | - Tzung-Yan Lee
- Graduate Institute of Traditional Chinese Medicine, Linkou Chang Guang Memorial Hospital, Taoyuan, Taiwan, ROC
| | - Chih-Wei Liu
- Faculty of Medicine, School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan, ROC
- Institute of Clinical Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan, ROC
| | - Tsai-Ling Liao
- Department of Medical Research, Taichung Veterans General Hospital, Taichung, Taiwan, ROC
| | - Shie-Liang Hsieh
- Faculty of Medicine, School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan, ROC
- Institute of Clinical Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan, ROC
- Genomics Research Center, Academia Sinica, Taipei, Taiwan, ROC
| | - Han-Chieh Lin
- Faculty of Medicine, School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan, ROC
- Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan, ROC
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17
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Nasr M, Ahmed-Farid OAH, Ahmed RF. Curcumin-resveratrol nano-formulation counteracting hyperammonemia in rats. Metab Brain Dis 2023; 38:1365-1377. [PMID: 36696035 PMCID: PMC10110714 DOI: 10.1007/s11011-023-01162-1] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/05/2022] [Accepted: 01/10/2023] [Indexed: 01/26/2023]
Abstract
Malnutrition and low dietary protein intake could be risk factors for developing peripheral and central hyperammonemia, especially in pediatrics. Both curcumin and resveratrol proved to be effective against several hepatic and cerebral injuries. They were reported to be beneficial in lowering circulating ammonia levels, yet both are known for their low bioavailability. The use of pharmaceutical nano-formulations as delivery systems for these two nutraceuticals could solve the aforementioned problem. Hence, the present study aimed to investigate the valuable outcome of using a combination of curcumin and resveratrol in a nanoemulsion formulation, to counteract protein-deficient diet (PDD)-induced hyperammonemia and the consequent complications in male albino rats. Results revealed that using a nanoemulsion containing both curcumin and resveratrol at a dose of (5 + 5 mg/kg) effectively reduced hepatic and brain ammonia levels, serum ALT and AST levels, hepatic and brain nitric oxide levels, oxidative DNA damage as well as disrupted cellular energy performance. In addition, there was a substantial increase in brain levels of monoamines, and a decrease in glutamate content. Therefore, it can be concluded that the use of combined curcumin and resveratrol nanoemulsion is an effective means of ameliorating the hepatic and cerebral adverse effects resulting from PDD-induced hyperammonemia in rats.
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Affiliation(s)
- Maha Nasr
- Department of Pharmaceutics and Industrial Pharmacy, Faculty of Pharmacy, Ain Shams University, Cairo, Egypt
| | - Omar A H Ahmed-Farid
- Department of Physiology, National Organization for Drug Control and Research, 12553, Giza, Egypt
| | - Rania F Ahmed
- Department of Pharmacology, Medical Research and Clinical studies Institute, National Research Centre, 12622, Dokki, Giza, Egypt.
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18
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Mangini C, Zarantonello L, Formentin C, Giusti G, Angeli P, Montagnese S. Evolution of hepatic encephalopathy over time: ecological data from a tertiary referral centre for hepatology. Dig Liver Dis 2023; 55:93-98. [PMID: 35725551 DOI: 10.1016/j.dld.2022.06.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/26/2022] [Revised: 05/27/2022] [Accepted: 06/01/2022] [Indexed: 12/31/2022]
Abstract
OBJECTIVES Few data on hepatic encephalopathy (HE) over time are available, thus our aim was to study its evolution in patients with varying degree of HE on first assessment. METHODS Eighty-six patients with cirrhosis (age = 58 ± 11 years; males = 72) were evaluated 2-10 times for liver transplantation selection purposes, differential diagnosis or treatment optimization. The presence/severity of HE was assessed by clinical and neuropsychiatric indices [ Psychometric Hepatic Encephalopathy Score (PHES) and electroencephalography (EEG)] and the severity of liver disease by the Model for End-Stage Liver Disease (MELD) score. Treatment was instituted/modified after each evaluation. RESULTS Amongst 23 unimpaired patients, 56/6% remained unimpaired, 35/3% developed covert HE, 9/0% developed overt HE on second/third evaluation. Amongst 32 patients with covert HE, 25/10% became unimpaired, 44/19% remained covert, 31/13% developed overt HE. Finally, amongst 32 patients with overt HE, 19/16% became unimpaired, 25/13 % became covert and 56/25% remained overt. PHES results improved in patients with overt HE and EEG worsened over time (despite remaining normal) in unimpaired patients. In patients with multiple evaluations, HE evolution was manifold and difficult to predict. CONCLUSIONS HE evolution over time is variable and largely dependent on HE history/management. These data support the concept that HE is an essentially reversible condition.
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Affiliation(s)
- C Mangini
- Department of Medicine, University of Padova, Via Giustiniani 2, Padova 35128, Italy
| | - L Zarantonello
- Department of Medicine, University of Padova, Via Giustiniani 2, Padova 35128, Italy
| | - C Formentin
- Department of Medicine, University of Padova, Via Giustiniani 2, Padova 35128, Italy
| | - G Giusti
- Department of Medicine, University of Padova, Via Giustiniani 2, Padova 35128, Italy
| | - P Angeli
- Department of Medicine, University of Padova, Via Giustiniani 2, Padova 35128, Italy
| | - S Montagnese
- Department of Medicine, University of Padova, Via Giustiniani 2, Padova 35128, Italy.
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19
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Ivnitsky JJ, Schäfer TV, Rejniuk VL, Golovko AI. Endogenous humoral determinants of vascular endothelial dysfunction as triggers of acute poisoning complications. J Appl Toxicol 2023; 43:47-65. [PMID: 35258106 DOI: 10.1002/jat.4312] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2022] [Revised: 02/13/2022] [Accepted: 02/26/2022] [Indexed: 12/16/2022]
Abstract
The vascular endothelium is not only the semipermeable membrane that separates tissue from blood but also an organ that regulates inflammation, vascular tone, blood clotting, angiogenesis and synthesis of connective tissue proteins. It is susceptible to the direct cytotoxic action of numerous xenobiotics and to the acute hypoxia that accompanies acute poisoning. This damage is superimposed on the preformed state of the vascular endothelium, which, in turn, depends on many humoral factors. The probability that an exogenous toxicant will cause life-threatening dysfunction of the vascular endothelium, thereby complicating the course of acute poisoning, increases with an increase in the content of endogenous substances in the blood that disrupt endothelial function. These include ammonia, bacterial endotoxin, indoxyl sulfate, para-cresyl sulfate, trimethylamine N-oxide, asymmetric dimethylarginine, glucose, homocysteine, low-density and very-low-density lipoproteins, free fatty acids and products of intravascular haemolysis. Some other endogenous substances (albumin, haptoglobin, haemopexin, biliverdin, bilirubin, tetrahydrobiopterin) or food-derived compounds (ascorbic acid, rutin, omega-3 polyunsaturated fatty acids, etc.) reduce the risk of lethal vascular endothelial dysfunction. The individual variability of the content of these substances in the blood contributes to the stochasticity of the complications of acute poisoning and is a promising target for the risk reduction measures. Another feasible option may be the repositioning of drugs that affect the function of the vascular endothelium while being currently used for other indications.
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Affiliation(s)
- Jury Ju Ivnitsky
- Golikov Research Clinical Center of Toxicology under the Federal Medical Biological Agency, Saint Petersburg, Russia
| | - Timur V Schäfer
- State Scientific Research Test Institute of the Military Medicine of Defense Ministry of the Russian Federation, Saint Petersburg, Russia
| | - Vladimir L Rejniuk
- Golikov Research Clinical Center of Toxicology under the Federal Medical Biological Agency, Saint Petersburg, Russia
| | - Alexandr I Golovko
- Golikov Research Clinical Center of Toxicology under the Federal Medical Biological Agency, Saint Petersburg, Russia
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20
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Bazo A, Lantero A, Mauleón I, Neri L, Poms M, Häberle J, Ricobaraza A, Bénichou B, Combal JP, Gonzalez-Aseguinolaza G, Aldabe R. Gene Therapy in Combination with Nitrogen Scavenger Pretreatment Corrects Biochemical and Behavioral Abnormalities of Infant Citrullinemia Type 1 Mice. Int J Mol Sci 2022; 23:14940. [PMID: 36499263 PMCID: PMC9736988 DOI: 10.3390/ijms232314940] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2022] [Revised: 11/22/2022] [Accepted: 11/23/2022] [Indexed: 12/02/2022] Open
Abstract
Citrullinemia type I (CTLN1) is a rare autosomal recessive disorder caused by mutations in the gene encoding argininosuccinate synthetase 1 (ASS1) that catalyzes the third step of the urea cycle. CTLN1 patients suffer from impaired elimination of nitrogen, which leads to neurotoxic levels of circulating ammonia and urea cycle byproducts that may cause severe metabolic encephalopathy, death or irreversible brain damage. Standard of care (SOC) of CTLN1 consists of daily nitrogen-scavenger administration, but patients remain at risk of life-threatening decompensations. We evaluated the therapeutic efficacy of a recombinant adeno-associated viral vector carrying the ASS1 gene under the control of a liver-specific promoter (VTX-804). When administered to three-week-old CTLN1 mice, all the animals receiving VTX-804 in combination with SOC gained body weight normally, presented with a normalization of ammonia and reduction of citrulline levels in circulation, and 100% survived for 7 months. Similar to what has been observed in CTLN1 patients, CTLN1 mice showed several behavioral abnormalities such as anxiety, reduced welfare and impairment of innate behavior. Importantly, all clinical alterations were notably improved after treatment with VTX-804. This study demonstrates the potential of VTX-804 gene therapy for future clinical translation to CTLN1 patients.
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Affiliation(s)
- Andrea Bazo
- Division of Gene Therapy and Regulation of Gene Expression, CIMA, University of Navarra, 31008 Pamplona, Spain
| | | | - Itsaso Mauleón
- Division of Gene Therapy and Regulation of Gene Expression, CIMA, University of Navarra, 31008 Pamplona, Spain
| | - Leire Neri
- Vivet Therapeutics, S.L., 31008 Pamplona, Spain
| | - Martin Poms
- Department of Clinical Chemistry and Biochemistry, University Children’s Hospital Zurich, University of Zurich, 8091 Zurich, Switzerland
| | - Johannes Häberle
- Division of Metabolism, Children’s Research Centre (CRC), University Children’s Hospital Zurich, 8091 Zurich, Switzerland
| | - Ana Ricobaraza
- Division of Gene Therapy and Regulation of Gene Expression, CIMA, University of Navarra, 31008 Pamplona, Spain
| | | | | | - Gloria Gonzalez-Aseguinolaza
- Division of Gene Therapy and Regulation of Gene Expression, CIMA, University of Navarra, 31008 Pamplona, Spain
- Vivet Therapeutics, S.L., 31008 Pamplona, Spain
| | - Rafael Aldabe
- Division of Gene Therapy and Regulation of Gene Expression, CIMA, University of Navarra, 31008 Pamplona, Spain
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21
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Liver Enzymes in a Cohort of Community-Dwelling Older Persons: Focus on Sex Contribution. Nutrients 2022; 14:nu14234973. [PMID: 36501002 PMCID: PMC9737251 DOI: 10.3390/nu14234973] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2022] [Revised: 11/16/2022] [Accepted: 11/21/2022] [Indexed: 11/25/2022] Open
Abstract
Dysfunctions in liver metabolic activities may increase the risk of cognitive impairment and dementia. In a cohort of community-dwelling older persons investigated for a suspected cognitive decline, we studied the association between liver status and dementia, considering sex and frailty contribution. Serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) concentrations, and the AST/ALT ratio were used to assess liver function in 419 older adults (248 persons with dementia and 171 age- and sex-matched subjects without cognitive decline). Although the serum concentrations of the liver enzymes were in the physiologic range, patients with dementia showed lower ALT concentrations (p = 0.005) and higher AST/ALT ratios (p = 0.003) compared to controls. The same differences were found when comparing men with and without dementia (ALT, p = 0.009; AST/ALT ratio, p = 0.003) but disappeared in women. Curiously, comparing women and men with the same diagnosis, the ALT concentrations were lower (p = 0.008), and the AST/ALT ratio was higher (p = 0.001) in control women than men, whereas no significant difference was found between persons with dementia. In conclusion, in our cohort of older people living in the community, the association between serum aminotransferases and dementia was remarked. Moreover, our results support attention to sex difference in liver function, suggesting a role in the pathogenesis of dementia.
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22
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Amirshahrokhi K, Niapour A. Carvedilol attenuates brain damage in mice with hepatic encephalopathy. Int Immunopharmacol 2022; 111:109119. [PMID: 35933745 DOI: 10.1016/j.intimp.2022.109119] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2022] [Revised: 07/17/2022] [Accepted: 07/30/2022] [Indexed: 11/17/2022]
Abstract
Brain injury is the most common and serious consequence of hepatic encephalopathy (HE), and its pathophysiology is poorly understood. Excessive inflammatory, oxidative and apoptotic responses are the major mechanisms involved in the progression of brain injury induced by HE. Carvedilol is an adrenergic receptor antagonist with pronouncedantioxidant and anti-inflammatory activity. The present study aimed to investigatethe effects and underlying mechanisms of carvedilol on HE-induced brain damage in mice. Experimental model of HE was induced by the injection of thioacetamide (200 mg/kg) for two consecutive days and then mice were treated with carvedilol (10 or 20 mg/kg/day, orally) for 3 days in treatment groups. After the behavioral test, animals were sacrificed and the brain tissues were collected for biochemical, real time PCR and immunohistochemical analysis. The results showed that carvedilol improved locomotor impairment and reduced mortality rate in mice with HE. Carvedilol treatment decreased the brain levels of oxidative stress markers and induced Nrf2/HO-1 pathway. Carvedilol inhibited the activity of nuclear factor kappa B (NF-κB) and the expression of pro-inflammatory cytokines TNF-α, IL1β and IL-6 in the brain tissues. Treatment of mice with carvedilol caused a significant reduction in the brain levels of iNOS/NO, myeloperoxidase (MPO), cyclooxygenase (COX)-2 and chemokine MCP-1 as proinflammatory mediators in HE. Moreover, the ratio of Bcl2/Bax was increased and apoptotic cell death was decreased in the brain of mice treated with carvedilol. In conclusion, carvedilol exerted protective effect against HE-induced brain injury through increasing antioxidant defense mechanisms and inhibitionof inflammatory and apoptotic pathways.
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Affiliation(s)
- Keyvan Amirshahrokhi
- Department of Pharmacology, School of Pharmacy, Ardabil University of Medical Sciences, Ardabil, Iran; Pharmaceutical Sciences Research Center, Ardabil University of Medical Sciences, Ardabil, Iran.
| | - Ali Niapour
- Department of Anatomical Sciences, School of Medicine, Ardabil University of Medical Sciences, Ardabil, Iran
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23
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Schäfer TV, Vakunenkova OA, Ivnitsky JJ, Golovko AI. Gut Barrier in Critical States of the Body. BIOLOGY BULLETIN REVIEWS 2022. [PMCID: PMC9297268 DOI: 10.1134/s2079086422040077] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Abstract
The intestinal barrier (IB) is a system of diffusion barriers separating the intestinal chyme and blood. The aim of the review is to identify the role of IB dysfunction in the formation of critical states of the body and to substantiate ways to prevent these states. Toxic substances produced by normal intestinal microflora are characterized. The involvement of endotoxin and ammonia in the pathogenesis of sepsis, acute circulatory disorders, secondary acute pulmonary lesions, and acute cerebral insufficiency is shown. Approaches to protect the IB in critical states of the body are proposed.
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Affiliation(s)
- T. V. Schäfer
- State Scientific Research and Testing Institute of Military Medicine, St. Petersburg, Russia
| | - O. A. Vakunenkova
- Golikov Scientific and Clinical Center of Toxicology, St. Petersburg, Russia
| | - Ju. Ju. Ivnitsky
- Golikov Scientific and Clinical Center of Toxicology, St. Petersburg, Russia
| | - A. I. Golovko
- Golikov Scientific and Clinical Center of Toxicology, St. Petersburg, Russia
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24
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Ivnitsky JJ, Schäfer TV, Rejniuk VL, Vakunenkova OA. Secondary Dysfunction of the Intestinal Barrier in the Pathogenesis of Complications of Acute Poisoning. J EVOL BIOCHEM PHYS+ 2022; 58:1075-1098. [PMID: 36061072 PMCID: PMC9420239 DOI: 10.1134/s0022093022040123] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2022] [Revised: 05/23/2022] [Accepted: 05/24/2022] [Indexed: 11/22/2022]
Abstract
The last decade has been marked by an exponential increase
in the number of publications on the physiological role of the normal
human gut microbiota. The idea of a symbiotic relationship between
the human organism and normal microbiota of its gastrointestinal
tract has been firmly established as an integral part of the current
biomedical paradigm. However, the type of this symbiosis varies
from mutualism to parasitism and depends on the functional state
of the host organism. Damage caused to the organism by external
agents can lead to the emergence of conditionally pathogenic properties
in the normal gut microbiota, mediated by humoral factors and affecting
the outcome of exogenous exposure. Among the substances produced
by symbiotic microbiota, there are an indefinite number of compounds
with systemic toxicity. Some occur in the intestinal chyme in potentially
lethal amounts in the case they enter the bloodstream quickly. The quick
entry of potential toxicants is prevented by the intestinal barrier
(IB), a set of structural elements separating the intestinal chyme
from the blood. Hypothetically, severe damage to the IB caused by
exogenous toxicants can trigger a leakage and subsequent systemic
redistribution of toxic substances of bacterial origin. Until recently,
the impact of such a redistribution on the outcome of acute exogenous
poisoning remained outside the view of toxicology. The present review
addresses causal relationships between the secondary dysfunction
of the IB and complications of acute poisoning. We characterize
acute systemic toxicity of such waste products of the normal gut microflora
as ammonia and endotoxins, and demonstrate their involvement in
the formation of such complications of acute poisoning as shock,
sepsis, cerebral insufficiency and secondary lung injuries. The
principles of assessing the functional state of the IB and the approaches
to its protection in acute poisoning are briefly considered.
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Affiliation(s)
- Ju. Ju. Ivnitsky
- Golikov Research Clinical Center of Toxicology, Federal Medical Biological Agency, St. Petersburg, Russia
| | - T. V. Schäfer
- State Scientific Research Test Institute of Military Medicine, Ministry of Defense of the Russian Federation, St. Petersburg, Russia
| | - V. L. Rejniuk
- Golikov Research Clinical Center of Toxicology, Federal Medical Biological Agency, St. Petersburg, Russia
| | - O. A. Vakunenkova
- Golikov Research Clinical Center of Toxicology, Federal Medical Biological Agency, St. Petersburg, Russia
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Efficacy of rifaximin against covert hepatic encephalopathy and hyperammonemia in Japanese patients. PLoS One 2022; 17:e0270786. [PMID: 35776720 PMCID: PMC9249214 DOI: 10.1371/journal.pone.0270786] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2022] [Accepted: 06/20/2022] [Indexed: 11/23/2022] Open
Abstract
Covert hepatic encephalopathy (CHE) impairs patient quality of life and occurs in approximately 30% of liver cirrhosis (LC) cases. Japanese clinical practice guidelines recommend rifaximin to treat overt HE (OHE). However, the usefulness of rifaximin against CHE is not thoroughly investigated in Japanese patients. We aimed to investigate the efficacy of rifaximin against hyperammonemia and CHE in Japan. We observed 102 patients with HE showing hyperammonemia secondary to LC and examined various biochemical and behavioral parameters following rifaximin treatment. CHE was diagnosed when the patients exhibited two or more abnormal neuropsychological test (NPT) scores but did not indicate OHE symptoms. In the 102 cases, a significant therapeutic effect of rifaximin on hyperammonemia was observed from 2 to 48 weeks after starting treatment. Excluding 10 patients diagnosed with OHE upon starting rifaximin treatment, 12 of the 92 remaining patients (11.8%) transitioned to OHE within 1 year. The 1 year cumulative OHE transition rate was 14.5%. Among the 24 patients with CHE diagnosed by the NPT for whom NPT results could be evaluated at 4 and 12 weeks after starting treatment, 10 (41.6%) had recovered from CHE at 12 weeks. When the factors contributing to recovery from CHE were examined by multivariate analysis, an ammonia level <129 μg/dL was a significant factor. Rifaximin was thus significantly effective against both hyperammonemia and CHE in Japanese patients.
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26
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Lu H, Lei X, Winkler R, John S, Kumar D, Li W, Alnouti Y. Crosstalk of hepatocyte nuclear factor 4a and glucocorticoid receptor in the regulation of lipid metabolism in mice fed a high-fat-high-sugar diet. Lipids Health Dis 2022; 21:46. [PMID: 35614477 PMCID: PMC9134643 DOI: 10.1186/s12944-022-01654-6] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2021] [Accepted: 05/06/2022] [Indexed: 12/15/2022] Open
Abstract
BACKGROUND Hepatocyte nuclear factor 4α (HNF4α) and glucocorticoid receptor (GR), master regulators of liver metabolism, are down-regulated in fatty liver diseases. The present study aimed to elucidate the role of down-regulation of HNF4α and GR in fatty liver and hyperlipidemia. METHODS Adult mice with liver-specific heterozygote (HET) and knockout (KO) of HNF4α or GR were fed a high-fat-high-sugar diet (HFHS) for 15 days. Alterations in hepatic and circulating lipids were determined with analytical kits, and changes in hepatic mRNA and protein expression in these mice were quantified by real-time PCR and Western blotting. Serum and hepatic levels of bile acids were quantified by LC-MS/MS. The roles of HNF4α and GR in regulating hepatic gene expression were determined using luciferase reporter assays. RESULTS Compared to HFHS-fed wildtype mice, HNF4α HET mice had down-regulation of lipid catabolic genes, induction of lipogenic genes, and increased hepatic and blood levels of lipids, whereas HNF4α KO mice had fatty liver but mild hypolipidemia, down-regulation of lipid-efflux genes, and induction of genes for uptake, synthesis, and storage of lipids. Serum levels of chenodeoxycholic acid and deoxycholic acid tended to be decreased in the HNF4α HET mice but dramatically increased in the HNF4α KO mice, which was associated with marked down-regulation of cytochrome P450 7a1, the rate-limiting enzyme for bile acid synthesis. Hepatic mRNA and protein expression of sterol-regulatory-element-binding protein-1 (SREBP-1), a master lipogenic regulator, was induced in HFHS-fed HNF4α HET mice. In reporter assays, HNF4α cooperated with the corepressor small heterodimer partner to potently inhibit the transactivation of mouse and human SREBP-1C promoter by liver X receptor. Hepatic nuclear GR proteins tended to be decreased in the HNF4α KO mice. HFHS-fed mice with liver-specific KO of GR had increased hepatic lipids and induction of SREBP-1C and PPARγ, which was associated with a marked decrease in hepatic levels of HNF4α proteins in these mice. In reporter assays, GR and HNF4α synergistically/additively induced lipid catabolic genes. CONCLUSIONS induction of lipid catabolic genes and suppression of lipogenic genes by HNF4α and GR may mediate the early resistance to HFHS-induced fatty liver and hyperlipidemia.
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Affiliation(s)
- Hong Lu
- Department of Pharmacology, SUNY Upstate Medical University, Syracuse, NY, 13210, USA.
| | - Xiaohong Lei
- Department of Pharmacology, SUNY Upstate Medical University, Syracuse, NY, 13210, USA
| | - Rebecca Winkler
- Department of Pharmacology, SUNY Upstate Medical University, Syracuse, NY, 13210, USA
| | - Savio John
- Department of Medicine, SUNY Upstate Medical University, Syracuse, NY, 13210, USA
| | - Devendra Kumar
- Department of Pharmaceutical Sciences, University of Nebraska Medical Center, Omaha, NE, 68198, USA
| | - Wenkuan Li
- Department of Pharmaceutical Sciences, University of Nebraska Medical Center, Omaha, NE, 68198, USA
| | - Yazen Alnouti
- Department of Pharmaceutical Sciences, University of Nebraska Medical Center, Omaha, NE, 68198, USA
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Yang B, Sun T, Chen Y, Xiang H, Xiong J, Bao S. The Role of Gut Microbiota in Mice With Bile Duct Ligation-Evoked Cholestatic Liver Disease-Related Cognitive Dysfunction. Front Microbiol 2022; 13:909461. [PMID: 35620109 PMCID: PMC9127770 DOI: 10.3389/fmicb.2022.909461] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2022] [Accepted: 04/25/2022] [Indexed: 12/12/2022] Open
Abstract
The pathogenesis of Hepatic Encephalopathy (HE) is complex and multifactorial. The development of metagenomics sequencing technology led to show the significant role of gut microbiota in the pathogenesis of cognitive dysfunction, which paved the way for further research in this field. However, it is unknown whether gut microbiota plays a role in bile duct ligation (BDL)-evoked cholestatic liver disease-related cognitive dysfunction. The aim of this investigation is to assess BDL mice induced cognitive dysfunction and meanwhile to delineate the alteration of gut microbiota in cognitive dysfunction mice, which may underline the role of gut microbiota in BDL mice induced cognitive dysfunction. Our study was carried out in male C57BL/6 J mice with bile duct ligation. The liver functions were assessed via different biochemical markers [alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), total bilirubin (TBIL), and total bile acid (TBA)] and a histopathological examination of the liver tissue. We used the novel object recognition test (NORT) to assess cognitive dysfunction. And BDL mice were divided into BDL with cognitive dysfunction (BDL-CD) or BDL without cognitive dysfunction (BDL-NCD groups) by the result of hierarchical cluster analysis of NORT. Then, 16S ribosomal RNA (rRNA) gene sequencing was used to compare the gut bacterial composition between BDL-CD and BDL-NCD groups. According to our results, we concluded that bile duct ligation can significantly change the gut microbiota composition, and Bacteroides fragilis, Bacteroides ovatus V975, and Bacteroides thetaiotaomicron play a vital role in BDL-evoked cholestatic liver disease-related cognitive dysfunction.
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Affiliation(s)
- Bowen Yang
- Department of Hepatobiliary Surgery, Affiliated Hospital of Guangdong Medical University, Zhanjiang, China
| | - Tianning Sun
- Department of Anesthesiology and Pain Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yingle Chen
- Department of Anesthesiology, The First Affiliated Quanzhou Hospital of Fujian Medical University, Quanzhou, China
| | - Hongbing Xiang
- Department of Anesthesiology and Pain Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Jun Xiong
- Hepatobiliary Surgery Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Shiting Bao
- Department of Hepatobiliary Surgery, Affiliated Hospital of Guangdong Medical University, Zhanjiang, China
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Brain magnetic resonance imaging radiomics features associated with hepatic encephalopathy in adult cirrhotic patients. Neuroradiology 2022; 64:1969-1978. [PMID: 35488097 PMCID: PMC9474333 DOI: 10.1007/s00234-022-02949-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2021] [Accepted: 04/05/2022] [Indexed: 10/28/2022]
Abstract
PURPOSE Hepatic encephalopathy (HE) is a potential complication of cirrhosis. Magnetic resonance imaging (MRI) may demonstrate hyperintense T1 signal in the globi pallidi. The purpose of this study was to evaluate the performance of MRI-based radiomic features for diagnosing and grading chronic HE in adult patients affected by cirrhosis. METHODS Adult patients with and without cirrhosis underwent brain MRI with identical imaging protocol on a 3T scanner. Patients without history of chronic liver disease were the control population. HE grading was based on underlying liver disease, severity of clinical manifestation, and number of encephalopathic episodes. Texture analysis was performed on axial T1-weighted images on bilateral lentiform nuclei at the level of the foramina of Monro. Diagnostic performance of texture analysis for the diagnosis and grading of HE was assessed by calculating the area under the receiver operating characteristics (AUROC) with 95% confidence interval (CI). RESULTS The final study population consisted of 124 patients, 70 cirrhotic patients, and 54 non-cirrhotic controls. Thirty-eight patients had history of HE with 22 having an HE grade > 1. The radiomic features predicted the presence of HE with an AUROC of 0.82 (95% CI: 0.73, 0.90; P < .0001; 82% sensitivity, 66% specificity). Radiomic features predicted grade 1 HE (AUROC 0.75; 95% CI: 0.61, 0.89; P < .0001; 94% sensitivity, 60% specificity) and grade ≥ 2 HE (AUROC 0.82; 95% CI: 0.71, 0.93; P < .0001, 95% sensitivity, 57% specificity). CONCLUSION In cirrhotic patients, MR radiomic is effective in predicting the presence of chronic HE and in grading its severity.
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29
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Arjunan A, Sah DK, Jung YD, Song J. Hepatic Encephalopathy and Melatonin. Antioxidants (Basel) 2022; 11:837. [PMID: 35624703 PMCID: PMC9137547 DOI: 10.3390/antiox11050837] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2022] [Revised: 04/06/2022] [Accepted: 04/24/2022] [Indexed: 11/25/2022] Open
Abstract
Hepatic encephalopathy (HE) is a severe metabolic syndrome linked with acute/chronic hepatic disorders. HE is also a pernicious neuropsychiatric complication associated with cognitive decline, coma, and death. Limited therapies are available to treat HE, which is formidable to oversee in the clinic. Thus, determining a novel therapeutic approach is essential. The pathogenesis of HE has not been well established. According to various scientific reports, neuropathological symptoms arise due to excessive accumulation of ammonia, which is transported to the brain via the blood-brain barrier (BBB), triggering oxidative stress and inflammation, and disturbing neuronal-glial functions. The treatment of HE involves eliminating hyperammonemia by enhancing the ammonia scavenging mechanism in systemic blood circulation. Melatonin is the sole endogenous hormone linked with HE. Melatonin as a neurohormone is a potent antioxidant that is primarily synthesized and released by the brain's pineal gland. Several HE and liver cirrhosis clinical studies have demonstrated impaired synthesis, secretion of melatonin, and circadian patterns. Melatonin can cross the BBB and is involved in various neuroprotective actions on the HE brain. Hence, we aim to elucidate how HE impairs brain functions, and elucidate the precise molecular mechanism of melatonin that reverses the HE effects on the central nervous system.
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Affiliation(s)
- Archana Arjunan
- Department of Anatomy, Chonnam National University Medical School, Hwasun 58128, Korea;
| | - Dhiraj Kumar Sah
- Department of Biochemistry, Chonnam National University Medical School, Hwasun 58128, Korea;
| | - Young Do Jung
- Department of Biochemistry, Chonnam National University Medical School, Hwasun 58128, Korea;
| | - Juhyun Song
- Department of Anatomy, Chonnam National University Medical School, Hwasun 58128, Korea;
- BioMedical Sciences Graduate Program (BMSGP), Chonnam National University, 264 Seoyangro, Hwasun 58128, Korea
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30
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Ochoa-Sanchez R, Tamnanloo F, Rose CF. Hepatic Encephalopathy: From Metabolic to Neurodegenerative. Neurochem Res 2021; 46:2612-2625. [PMID: 34129161 DOI: 10.1007/s11064-021-03372-4] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2021] [Revised: 05/31/2021] [Accepted: 06/03/2021] [Indexed: 12/15/2022]
Abstract
Hepatic encephalopathy (HE) is a neuropsychiatric syndrome of both acute and chronic liver disease. As a metabolic disorder, HE is considered to be reversible and therefore is expected to resolve following the replacement of the diseased liver with a healthy liver. However, persisting neurological complications are observed in up to 47% of transplanted patients. Several retrospective studies have shown that patients with a history of HE, particularly overt-HE, had persistent neurological complications even after liver transplantation (LT). These enduring neurological conditions significantly affect patient's quality of life and continue to add to the economic burden of chronic liver disease on health care systems. This review discusses the journey of the brain through the progression of liver disease, entering the invasive surgical procedure of LT and the conditions associated with the post-transplant period. In particular, it will discuss the vulnerability of the HE brain to peri-operative factors and post-LT conditions which may explain non-resolved neurological impairment following LT. In addition, the review will provide evidence; (i) supporting overt-HE impacts on neurological complications post-LT; (ii) that overt-HE leads to permanent neuronal injury and (iii) the pathophysiological role of ammonia toxicity on astrocyte and neuronal injury/damage. Together, these findings will provide new insights on the underlying mechanisms leading to neurological complications post-LT.
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Affiliation(s)
- Rafael Ochoa-Sanchez
- Hepato-Neuro Laboratory, CRCHUM, Université de Montréal, 900, rue Saint-Denis Pavillon R, R08.422, Montreal, QC, H2X-0A9, Canada
| | - Farzaneh Tamnanloo
- Hepato-Neuro Laboratory, CRCHUM, Université de Montréal, 900, rue Saint-Denis Pavillon R, R08.422, Montreal, QC, H2X-0A9, Canada
| | - Christopher F Rose
- Hepato-Neuro Laboratory, CRCHUM, Université de Montréal, 900, rue Saint-Denis Pavillon R, R08.422, Montreal, QC, H2X-0A9, Canada.
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31
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Ishay Y, Kolben Y, Kessler A, Ilan Y. Role of circadian rhythm and autonomic nervous system in liver function: a hypothetical basis for improving the management of hepatic encephalopathy. Am J Physiol Gastrointest Liver Physiol 2021; 321:G400-G412. [PMID: 34346773 DOI: 10.1152/ajpgi.00186.2021] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Hepatic encephalopathy (HE) is a common, incapacitating complication of cirrhosis that affects many patients with cirrhosis. Although several therapies have proven effective in the treatment and prevention of this condition, several patients continue to suffer from covert disease or episodes of relapse. The circadian rhythm has been demonstrated to be pivotal for many body functions, including those of the liver. Here, we explore the impact of circadian rhythm-dependent signaling on the liver and discuss the evidence of its impact on liver pathology and metabolism. We describe the various pathways through which circadian influences are mediated. Finally, we introduce a novel method for improving patient response to drugs aimed at treating HE by utilizing the circadian rhythm. A digital system that introduces a customization-based technique for improving the response to therapies is presented as a hypothetical approach for improving the effectiveness of current medications used for the treatment of recurrent and persistent hepatic encephalopathy.
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Affiliation(s)
- Yuval Ishay
- Department of Medicine, Faculty of Medicine, Hadassah Medical Center, Hebrew University, Jerusalem, Israel
| | - Yotam Kolben
- Department of Medicine, Faculty of Medicine, Hadassah Medical Center, Hebrew University, Jerusalem, Israel
| | - Asa Kessler
- Department of Medicine, Faculty of Medicine, Hadassah Medical Center, Hebrew University, Jerusalem, Israel
| | - Yaron Ilan
- Department of Medicine, Faculty of Medicine, Hadassah Medical Center, Hebrew University, Jerusalem, Israel
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32
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Kreisel W, Lazaro A, Trebicka J, Grosse Perdekamp M, Schmitt-Graeff A, Deibert P. Cyclic GMP in Liver Cirrhosis-Role in Pathophysiology of Portal Hypertension and Therapeutic Implications. Int J Mol Sci 2021; 22:10372. [PMID: 34638713 PMCID: PMC8508925 DOI: 10.3390/ijms221910372] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2021] [Revised: 09/20/2021] [Accepted: 09/21/2021] [Indexed: 01/10/2023] Open
Abstract
The NO-cGMP signal transduction pathway plays a crucial role in tone regulation in hepatic sinusoids and peripheral blood vessels. In a cirrhotic liver, the key enzymes endothelial NO synthase (eNOS), soluble guanylate cyclase (sGC), and phosphodiesterase-5 (PDE-5) are overexpressed, leading to decreased cyclic guanosine-monophosphate (cGMP). This results in constriction of hepatic sinusoids, contributing about 30% of portal pressure. In contrast, in peripheral arteries, dilation prevails with excess cGMP due to low PDE-5. Both effects eventually lead to circulatory dysfunction in progressed liver cirrhosis. The conventional view of portal hypertension (PH) pathophysiology has been described using the "NO-paradox", referring to reduced NO availability inside the liver and elevated NO production in the peripheral systemic circulation. However, recent data suggest that an altered availability of cGMP could better elucidate the contrasting findings of intrahepatic vasoconstriction and peripheral systemic vasodilation than mere focus on NO availability. Preclinical and clinical data have demonstrated that targeting the NO-cGMP pathway in liver cirrhosis using PDE-5 inhibitors or sGC stimulators/activators decreases intrahepatic resistance through dilation of sinusoids, lowering portal pressure, and increasing portal venous blood flow. These results suggest further clinical applications in liver cirrhosis. Targeting the NO-cGMP system plays a role in possible reversal of liver fibrosis or cirrhosis. PDE-5 inhibitors may have therapeutic potential for hepatic encephalopathy. Serum/plasma levels of cGMP can be used as a non-invasive marker of clinically significant portal hypertension. This manuscript reviews new data about the role of the NO-cGMP signal transduction system in pathophysiology of cirrhotic portal hypertension and provides perspective for further studies.
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Affiliation(s)
- Wolfgang Kreisel
- Department of Medicine II, Gastroenterology, Hepatology, Endocrinology, and Infectious Diseases, Faculty of Medicine, Medical Center, University of Freiburg, 79106 Freiburg, Germany
| | - Adhara Lazaro
- Institute for Exercise and Occupational Medicine, Faculty of Medicine, Medical Center, University of Freiburg, 79106 Freiburg, Germany; (A.L.); (P.D.)
| | - Jonel Trebicka
- Translational Hepatology, Department of Internal Medicine I, Goethe University Clinic Frankfurt, 60590 Frankfurt, Germany;
| | - Markus Grosse Perdekamp
- Institute of Forensic Medicine, Faculty of Medicine, Medical Center, University of Freiburg, 79106 Freiburg, Germany;
| | | | - Peter Deibert
- Institute for Exercise and Occupational Medicine, Faculty of Medicine, Medical Center, University of Freiburg, 79106 Freiburg, Germany; (A.L.); (P.D.)
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33
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Ferrell JM, Chiang JY. Bile acid receptors and signaling crosstalk in the liver, gut and brain. LIVER RESEARCH 2021; 5:105-118. [PMID: 39957847 PMCID: PMC11791822 DOI: 10.1016/j.livres.2021.07.002] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/20/2021] [Revised: 06/18/2021] [Accepted: 07/14/2021] [Indexed: 02/06/2023]
Abstract
Bile acids are physiological detergents derived from cholesterol that aid in digestion and nutrient absorption, and they play roles in glucose, lipid, and energy metabolism and in gut microbiome and metabolic homeostasis. Bile acids mediate crosstalk between the liver and gut through bactericidal modulation of the gut microbiome, while gut microbes influence the composition of the circulating bile acid pool. Recent research indicates bile acids may also be important mediators of neurological disease by acting as peripheral signaling molecules that activate bile acid receptors in the blood-brain barrier and in the brain itself. This review highlights the role of bile acids in maintaining liver and gut microbe homeostasis, as well as their function as mediators of cellular signaling in the liver-gut-brain axis.
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Affiliation(s)
- Jessica M. Ferrell
- Integrative Medical Sciences, Northeast Ohio Medical University, Rootstown, OH, USA
| | - John Y.L. Chiang
- Integrative Medical Sciences, Northeast Ohio Medical University, Rootstown, OH, USA
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34
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Zhang Y, Kang JD, Zhao D, Ghosh SS, Wang Y, Tai Y, Gonzalez-Maeso J, Sikaroodi M, Gillevet PM, Lippman HR, Hylemon PB, Zhou H, Bajaj JS. Hepatic Branch Vagotomy Modulates the Gut-Liver-Brain Axis in Murine Cirrhosis. Front Physiol 2021; 12:702646. [PMID: 34248683 PMCID: PMC8268007 DOI: 10.3389/fphys.2021.702646] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2021] [Accepted: 06/02/2021] [Indexed: 02/05/2023] Open
Abstract
BACKGROUND Cirrhosis and hepatic encephalopathy (HE) are linked with an altered gut-liver-brain axis, however, the relative contribution of hepatic vagal innervation is unclear. We aimed to determine the impact of hepatic vagotomy on the gut microbiome, brain, and liver in murine cirrhosis. METHODS 10-15-week-old male C57BL/6 mice with and without hepatic vagotomy underwent carbon tetrachloride (CCl4) gavage for 8 weeks. Frontal cortex [inflammation, glial/microglial activation, BDNF (brain-derived neurotrophic factor)], liver [histology including inflammation and steatosis, fatty acid synthesis (sterol-responsive binding protein-1) SREBP-1, insulin-induced gene-2 (Insig2) and BDNF], and colonic mucosal microbiota (16srRNA microbial sequencing) were evaluated on sacrifice. Conventional mice with and without cirrhosis were compared to vagotomized counterparts. RESULTS Conventional control vs. cirrhosis: Cirrhosis resulted in dysbiosis, hepatic/neuro-inflammation with glial/microglial activation, and low brain BDNF vs. controls. Conventional control vs. vagotomy controls: Vagotomized control mice had a lower colonic dysbiosis than conventional mice but the rest of the hepatic/brain parameters were similar. Conventional cirrhosis vs. vagotomized cirrhosis: After vagotomy + cirrhosis, we found lower dysbiosis but continuing neuroinflammation in the absence of glial/microglial activation vs. conventional cirrhosis. Vagotomy + Cirrhosis groups showed higher hepatic steatosis due to higher SREBP1 and low Insig2 protein and altered activation of key genes involved in hepatic lipid metabolism and inflammation. BDNF levels in the brain were higher but low in the liver in vagotomy + cirrhosis, likely a protective mechanism. CONCLUSIONS Hepatic vagal innervation affects the gut microbial composition, hepatic inflammation and steatosis, and cortical inflammation and BDNF expression and could be a critical modulator of the gut-liver-brain axis with consequences for HE development.
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Affiliation(s)
- Yuan Zhang
- Division of Microbiology and Immunology, Central Virginia Veterans Health Care System, Virginia Commonwealth University, Richmond, VA, United States
| | - Jason D. Kang
- Division of Microbiology and Immunology, Central Virginia Veterans Health Care System, Virginia Commonwealth University, Richmond, VA, United States
| | - Derrick Zhao
- Division of Microbiology and Immunology, Central Virginia Veterans Health Care System, Virginia Commonwealth University, Richmond, VA, United States
| | - Siddartha S. Ghosh
- Division of Nephrology, Virginia Commonwealth University, Richmond, VA, United States
| | - Yanyan Wang
- Division of Microbiology and Immunology, Central Virginia Veterans Health Care System, Virginia Commonwealth University, Richmond, VA, United States
| | - Yunling Tai
- Division of Microbiology and Immunology, Central Virginia Veterans Health Care System, Virginia Commonwealth University, Richmond, VA, United States
| | - Javier Gonzalez-Maeso
- Department of Physiology and Biophysics, Virginia Commonwealth University, Richmond, VA, United States
| | - Masoumeh Sikaroodi
- Microbiome Analysis Center, George Mason University, Manassas, VA, United States
| | - Patrick M. Gillevet
- Microbiome Analysis Center, George Mason University, Manassas, VA, United States
| | - H. Robert Lippman
- Department of Pathology, Central Virginia Veterans Health Care System, Richmond, VA, United States
| | - Phillip B. Hylemon
- Division of Microbiology and Immunology, Central Virginia Veterans Health Care System, Virginia Commonwealth University, Richmond, VA, United States
| | - Huiping Zhou
- Division of Microbiology and Immunology, Central Virginia Veterans Health Care System, Virginia Commonwealth University, Richmond, VA, United States
| | - Jasmohan S. Bajaj
- Division of Gastroenterology, Hepatology, and Nutrition, Central Virginia Veterans Health Care System, Virginia Commonwealth University, Richmond, VA, United States
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López-Cervantes M, Quintanar-Stephano A, Alcauter-Solórzano S, Hernández-Pando R, Aguilar-Roblero R, Gasca-Martínez D, Ortíz JJ, Vázquez-Martínez O, Ximénez-Camilli C, Díaz-Muñoz M. Cerebellar spongiform degeneration is accompanied by metabolic, cellular, and motor disruption in male rats with portacaval anastomosis. J Neurosci Res 2021; 99:2287-2304. [PMID: 34061383 DOI: 10.1002/jnr.24853] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2020] [Revised: 04/14/2021] [Accepted: 04/22/2021] [Indexed: 12/12/2022]
Abstract
The episodes of cerebral dysfunction, known as encephalopathy, are usually coincident with liver failure. The primary metabolic marker of liver diseases is the increase in blood ammonium, which promotes neuronal damage. In the present project, we used an experimental model of hepatic encephalopathy in male rats by portacaval anastomosis (PCA) surgery. Sham rats had a false operation. After 13 weeks of surgery, the most distinctive finding was vacuolar/spongiform neurodegeneration exclusively in the molecular layer of the cerebellum. This cerebellar damage was further characterized by metabolic, histopathological, and behavioral approaches. The results were as follows: (a) Cellular alterations, namely loss of Purkinje cells, morphological changes, such as swelling of astrocytes and Bergmann glia, and activation of microglia; (b) Cytotoxic edema, shown by an increase in aquaporin-4 and N-acetylaspartate and a reduction in taurine and choline-derivate osmolytes; (c) Metabolic adjustments, noted by the elevation of circulating ammonium, enhanced presence of glutamine synthetase, and increase in glutamine and creatine/phosphocreatine; (d) Inflammasome activation, detected by the elevation of the marker NLRP3 and microglial activation; (e) Locomotor deficits in PCA rats as assessed by the Rotarod and open field tests. These results lead us to suggest that metabolic disturbances associated with PCA can generate the cerebellar damage that is similar to morphophysiological modifications observed in amyloidogenic disorders. In conclusion, we have characterized a distinctive cerebellar multi-disruption accompanied by high levels of ammonium and associated with spongiform neurodegeneration in a model of hepatic hypofunctioning.
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Affiliation(s)
- Mayra López-Cervantes
- Departamento de Neurobiología Celular y Molecular, Instituto de Neurobiología, Campus UNAM-Juriquilla, Querétaro, Mexico
| | - Andrés Quintanar-Stephano
- Departmento de Fisiología y Farmacología, Centro de Ciencia Básica, Universidad Autónoma de Aguascalientes, Aguascalientes, Mexico
| | - Sarael Alcauter-Solórzano
- Laboratorio Nacional de Imagenología por Resonancia Magnética, Instituto de Neurobiología, Campus UNAM-Juriquilla, Querétaro, Mexico
| | - Rogelio Hernández-Pando
- Seccion de Patología Experimental, Departamento de Patología, Instituto Nacional de Ciencias Médicas y Nutrición "Salvador Zubirán", Ciudad de México, Mexico
| | - Raúl Aguilar-Roblero
- División de Neurociencias, Instituto de Fisiología Celular, UNAM, Ciudad de México, Mexico
| | - Deisy Gasca-Martínez
- Unidad de Análisis Conductual, Instituto de Neurobiología, Campus UNAM-Juriquilla, Querétaro, Mexico
| | - Juan J Ortíz
- Laboratorio Nacional de Imagenología por Resonancia Magnética, Instituto de Neurobiología, Campus UNAM-Juriquilla, Querétaro, Mexico
| | - Olivia Vázquez-Martínez
- Departamento de Neurobiología Celular y Molecular, Instituto de Neurobiología, Campus UNAM-Juriquilla, Querétaro, Mexico
| | - Cecilia Ximénez-Camilli
- Departamento de Neurobiología Celular y Molecular, Instituto de Neurobiología, Campus UNAM-Juriquilla, Querétaro, Mexico
| | - Mauricio Díaz-Muñoz
- Departamento de Neurobiología Celular y Molecular, Instituto de Neurobiología, Campus UNAM-Juriquilla, Querétaro, Mexico
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36
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Formentin C, Zarantonello L, Mangini C, Frigo AC, Montagnese S, Merkel C. Clinical, neuropsychological and neurophysiological indices and predictors of hepatic encephalopathy (HE). Liver Int 2021; 41:1070-1082. [PMID: 33411388 DOI: 10.1111/liv.14785] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/16/2020] [Revised: 12/30/2020] [Accepted: 01/01/2021] [Indexed: 12/13/2022]
Abstract
BACKGROUND AND AIMS The occurrence of overt hepatic encephalopathy (HE) marks a significant progression in the natural history of liver disease. The aims of the present study were to: 1) describe a large cohort of patients with cirrhosis in terms of neuropsychological or neurophysiological HE indices, and 2) test if the severity of liver disease and/or any such indices [Psychometric Hepatic Encephalopathy Score (PHES), Scan test, electroencephalography (EEG)] predicted mortality/HE risk in a subgroup of such cohort. METHOD Four hundred and sixty-one patients with cirrhosis (59 ± 10 years; 345 males) were included; information on previous overt HE episodes was available in 407. Follow-up information on mortality/HE-related hospitalization in 134/127 respectively. Information on previous overt HE episodes and both mortality and HE-related hospitalization over the follow-up in 124. RESULTS Patients with a history of overt HE (60%) had poorer liver function, worse neuropsychiatric indices, higher ammonia levels and higher prevalence of portal-systemic shunt. The risk of HE-related hospitalization over the follow-up was higher in patients with higher MELD score and worse Scan performance. Mortality was higher in those with higher MELD. Among patients without a history of overt HE, those with worse PHES had higher HE risk. Among patients with a history, those with higher MELD, better PHES and worse Scan performance had higher HE risk. CONCLUSIONS In patients without previous overt HE episodes, neuropsychological and neurophysiological tests predict HE, while in those with previous overt HE episodes, HE development largely depends on the severity of liver dysfunction.
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Affiliation(s)
- Chiara Formentin
- Department of Medicine, and Department of Cardiac-Thoracic-Vascular Sciences and Public Health, University of Padova, Padova, Italy
| | - Lisa Zarantonello
- Department of Medicine, and Department of Cardiac-Thoracic-Vascular Sciences and Public Health, University of Padova, Padova, Italy
| | - Chiara Mangini
- Department of Medicine, and Department of Cardiac-Thoracic-Vascular Sciences and Public Health, University of Padova, Padova, Italy
| | - Anna C Frigo
- Department of Medicine, and Department of Cardiac-Thoracic-Vascular Sciences and Public Health, University of Padova, Padova, Italy
| | - Sara Montagnese
- Department of Medicine, and Department of Cardiac-Thoracic-Vascular Sciences and Public Health, University of Padova, Padova, Italy
| | - Carlo Merkel
- Department of Medicine, and Department of Cardiac-Thoracic-Vascular Sciences and Public Health, University of Padova, Padova, Italy
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37
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Ochoa-Sanchez R, Oliveira MM, Tremblay M, Petrazzo G, Pant A, Bosoi CR, Perreault M, Querbes W, Kurtz CB, Rose CF. Genetically engineered E. coli Nissle attenuates hyperammonemia and prevents memory impairment in bile-duct ligated rats. Liver Int 2021; 41:1020-1032. [PMID: 33548108 DOI: 10.1111/liv.14815] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/17/2020] [Revised: 12/30/2020] [Accepted: 01/28/2021] [Indexed: 12/12/2022]
Abstract
UNLABELLED Hyperammonemia associated with chronic liver disease (CLD) is implicated in the pathogenesis of hepatic encephalopathy (HE). The gut is a major source of ammonia production that contributes to hyperammonemia in CLD and HE and remains the primary therapeutic target for lowering hyperammonemia. As an ammonia-lowering strategy, Escherichia coli Nissle 1917 bacterium was genetically modified to consume and convert ammonia to arginine (S-ARG). S-ARG was further modified to additionally synthesize butyrate (S-ARG + BUT). Both strains were evaluated in bile-duct ligated (BDL) rats; experimental model of CLD and HE. METHODS One-week post-surgery, BDLs received non-modified EcN (EcN), S-ARG, S-ARG + BUT (3x1011 CFU/day) or vehicle until sacrifice at 3 or 5 weeks. Plasma (ammonia/pro-inflammatory/liver function), liver fibrosis (hydroxyproline), liver mRNA (pro-inflammatory/fibrogenic/anti-apoptotic) and colon mRNA (pro-inflammatory) biomarkers were measured post-sacrifice. Memory, motor-coordination, muscle-strength and locomotion were assessed at 5 weeks. RESULTS In BDL-Veh rats, hyperammonemia developed at 3 and further increased at 5 weeks. This rise was prevented by S-ARG and S-ARG + BUT, whereas EcN was ineffective. Memory impairment was prevented only in S-ARG + BUT vs BDL-Veh. Systemic inflammation (IL-10/MCP-1/endotoxin) increased at 3 and 5 weeks in BDL-Veh. S-ARG + BUT attenuated inflammation at both timepoints (except 5-week endotoxin) vs BDL-Veh, whereas S-ARG only attenuated IP-10 and MCP-1 at 3 weeks. Circulating ALT/AST/ALP/GGT/albumin/bilirubin and gene expression of liver function markers (IL-10/IL-6/IL-1β/TGF-β/α-SMA/collagen-1α1/Bcl-2) were not normalized by either strain. Colonic mRNA (TNF-α/IL-1β/occludin) markers were attenuated by synthetic strains at both timepoints vs BDL-Veh. CONCLUSION S-ARG and S-ARG + BUT attenuated hyperammonemia, with S-ARG + BUT additional memory protection likely due to greater anti-inflammatory effect. These innovative strategies, particularly S-ARG + BUT, have potential to prevent HE.
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Affiliation(s)
| | - Mariana M Oliveira
- Hepato-Neuro Laboratory, CRCHUM, Université de Montréal, Montréal, Canada
| | - Mélanie Tremblay
- Hepato-Neuro Laboratory, CRCHUM, Université de Montréal, Montréal, Canada
| | - Grégory Petrazzo
- Hepato-Neuro Laboratory, CRCHUM, Université de Montréal, Montréal, Canada
| | | | - Cristina R Bosoi
- Hepato-Neuro Laboratory, CRCHUM, Université de Montréal, Montréal, Canada
| | | | | | | | - Christopher F Rose
- Hepato-Neuro Laboratory, CRCHUM, Université de Montréal, Montréal, Canada
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38
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Mikkelsen ACD, Thomsen KL, Vilstrup H, Aamann L, Jones H, Mookerjee RP, Hamilton-Dutoit S, Frystyk J, Aagaard NK. Potassium deficiency decreases the capacity for urea synthesis and markedly increases ammonia in rats. Am J Physiol Gastrointest Liver Physiol 2021; 320:G474-G483. [PMID: 33404376 DOI: 10.1152/ajpgi.00136.2020] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/21/2020] [Accepted: 12/07/2020] [Indexed: 01/31/2023]
Abstract
Our study provides novel findings of experimental hypokalemia reducing urea cycle functionality and thereby severely increasing plasma ammonia. This is pathophysiologically interesting because plasma ammonia increases during hypokalemia by a hitherto unknown mechanism, which may be particular important in relation to the unexplained link between hypokalemia and hepatic encephalopathy. Potassium deficiency decreases gene expression, protein synthesis, and growth. The urea cycle maintains body nitrogen homeostasis including removal of toxic ammonia. Hyperammonemia is an obligatory trait of liver failure, increasing the risk for hepatic encephalopathy, and hypokalemia is reported to increase ammonia. We aimed to clarify the effects of experimental hypokalemia on the in vivo capacity of the urea cycle, on the genes of the enzymes involved, and on ammonia concentrations. Female Wistar rats were fed a potassium-free diet for 13 days. Half of the rats were then potassium repleted. Both groups were compared with pair- and free-fed controls. The following were measured: in vivo capacity of urea-nitrogen synthesis (CUNS); gene expression (mRNA) of urea cycle enzymes; plasma potassium, sodium, and ammonia; intracellular potassium, sodium, and magnesium in liver, kidney, and muscle tissues; and liver sodium/potassium pumps. Liver histology was assessed. The diet induced hypokalemia of 1.9 ± 0.4 mmol/L. Compared with pair-fed controls, the in vivo CUNS was reduced by 34% (P < 0.01), gene expression of argininosuccinate synthetase 1 (ASS1) was decreased by 33% (P < 0.05), and plasma ammonia concentrations were eightfold elevated (P < 0.001). Kidney and muscle tissue potassium contents were markedly decreased but unchanged in liver tissue. Protein expressions of liver sodium/potassium pumps were unchanged. Repletion of potassium reverted all the changes. Hypokalemia decreased the capacity for urea synthesis via gene effects. The intervention led to marked hyperammonemia, quantitatively explainable by the compromised urea cycle. Our findings motivate clinical studies of patients with liver disease.
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Affiliation(s)
| | - Karen Louise Thomsen
- Department of Hepatology and Gastroenterology, Aarhus University Hospital, Aarhus, Denmark
- UCL Institute of Liver and Digestive Health, University College London, London, United Kingdom
| | - Hendrik Vilstrup
- Department of Hepatology and Gastroenterology, Aarhus University Hospital, Aarhus, Denmark
| | - Luise Aamann
- Department of Hepatology and Gastroenterology, Aarhus University Hospital, Aarhus, Denmark
| | - Helen Jones
- UCL Institute of Liver and Digestive Health, University College London, London, United Kingdom
| | - Rajeshwar P Mookerjee
- Department of Hepatology and Gastroenterology, Aarhus University Hospital, Aarhus, Denmark
- UCL Institute of Liver and Digestive Health, University College London, London, United Kingdom
| | | | - Jan Frystyk
- Department of Endocrinology and Internal Medicine, Aarhus University Hospital, Aarhus, Denmark
| | - Niels Kristian Aagaard
- Department of Hepatology and Gastroenterology, Aarhus University Hospital, Aarhus, Denmark
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Waterman BL, Ramsey SU, Whitsett MP, Patel AA, Radcliff JA, Kotler DL, Winters AC, Woodrell CD, Ufere NN, Serper M, Walling AM, Jones CA, Kelly SG. Top Ten Tips Palliative Care Clinicians Should Know About End-Stage Liver Disease. J Palliat Med 2021; 24:924-931. [PMID: 33733875 DOI: 10.1089/jpm.2021.0097] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
End-stage liver disease (ESLD) is an increasingly prevalent condition with high morbidity and mortality, especially for those ineligible for liver transplantation. Patients with ESLD, along with their family caregivers, have significant needs related to their quality of life, and there is increasing attention being paid to integration of palliative care (PC) principles into routine care throughout the disease spectrum. To provide upstream care for these patients and their family caregivers, it is essential for PC providers to understand their complex psychosocial and physical needs and to be aware of the unique challenges around medical decision making and end-of-life care for this patient population. This article, written by a team of liver and PC experts, shares 10 high-yield tips to help PC clinicians provide better care for patients with advanced liver disease.
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Affiliation(s)
- Brittany L Waterman
- Division of Palliative Medicine, The Ohio State University Wexner Medical Center, Columbus, Ohio, USA
| | - Sinthana U Ramsey
- Division of Palliative Medicine, The Ohio State University Wexner Medical Center, Columbus, Ohio, USA
| | - Maureen P Whitsett
- Division of Gastroenterology and Hepatology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Arpan A Patel
- Division of Digestive Diseases, David Geffen School of Medicine at University of California, Los Angeles, California, USA.,Veterans Affairs Greater Los Angeles Healthcare System, Los Angeles, California, USA
| | - Jacob A Radcliff
- Department of Pharmacy and Palliative Care Program, Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Drew L Kotler
- Division of Palliative Care, Department of Medicine, Main Line Health, Radnor, Pennsylvania, USA
| | - Adam C Winters
- Division of Digestive Diseases, David Geffen School of Medicine at University of California, Los Angeles, California, USA
| | - Christopher D Woodrell
- Brookdale Department of Geriatrics and Palliative Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, USA.,Geriatric Research, Education, and Clinical Center, James J. Peters VA Medical Center, Bronx, New York, USA
| | - Nneka N Ufere
- Division of Gastroenterology, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA
| | - Marina Serper
- Division of Gastroenterology and Hepatology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Anne M Walling
- Veterans Affairs Greater Los Angeles Healthcare System, Los Angeles, California, USA.,Division of General Internal Medicine and Health Services Research, David Geffen School of Medicine University of California, Los Angeles, USA
| | - Christopher A Jones
- Department of Medicine and Palliative Care Program, Duke University School of Medicine, Durham, North Carolina, USA
| | - Sean G Kelly
- Division of Gastroenterology, Hepatology, and Nutrition, The Ohio State University Wexner Medical Center, Columbus, Ohio, USA
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40
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Matyas C, Haskó G, Liaudet L, Trojnar E, Pacher P. Interplay of cardiovascular mediators, oxidative stress and inflammation in liver disease and its complications. Nat Rev Cardiol 2021; 18:117-135. [PMID: 32999450 DOI: 10.1038/s41569-020-0433-5] [Citation(s) in RCA: 71] [Impact Index Per Article: 17.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 08/11/2020] [Indexed: 12/11/2022]
Abstract
The liver is a crucial metabolic organ that has a key role in maintaining immune and endocrine homeostasis. Accumulating evidence suggests that chronic liver disease might promote the development of various cardiac disorders (such as arrhythmias and cardiomyopathy) and circulatory complications (including systemic, splanchnic and pulmonary complications), which can eventually culminate in clinical conditions ranging from portal and pulmonary hypertension to pulmonary, cardiac and renal failure, ascites and encephalopathy. Liver diseases can affect cardiovascular function during the early stages of disease progression. The development of cardiovascular diseases in patients with chronic liver failure is associated with increased morbidity and mortality, and cardiovascular complications can in turn affect liver function and liver disease progression. Furthermore, numerous infectious, inflammatory, metabolic and genetic diseases, as well as alcohol abuse can also influence both hepatic and cardiovascular outcomes. In this Review, we highlight how chronic liver diseases and associated cardiovascular effects can influence different organ pathologies. Furthermore, we explore the potential roles of inflammation, oxidative stress, vasoactive mediator imbalance, dysregulated endocannabinoid and autonomic nervous systems and endothelial dysfunction in mediating the complex interplay between the liver and the systemic vasculature that results in the development of the extrahepatic complications of chronic liver disease. The roles of ageing, sex, the gut microbiome and organ transplantation in this complex interplay are also discussed.
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Affiliation(s)
- Csaba Matyas
- Laboratory of Cardiovascular Physiology and Tissue Injury, National Institutes of Health/NIAAA, Bethesda, MD, USA
| | - György Haskó
- Department of Anesthesiology, Columbia University, New York, NY, USA
| | - Lucas Liaudet
- Department of Intensive Care Medicine and Burn Center, University Hospital Medical Center, Faculty of Biology and Medicine, Lausanne, Switzerland
| | - Eszter Trojnar
- Laboratory of Cardiovascular Physiology and Tissue Injury, National Institutes of Health/NIAAA, Bethesda, MD, USA
| | - Pal Pacher
- Laboratory of Cardiovascular Physiology and Tissue Injury, National Institutes of Health/NIAAA, Bethesda, MD, USA.
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Limón ID, Angulo-Cruz I, Sánchez-Abdon L, Patricio-Martínez A. Disturbance of the Glutamate-Glutamine Cycle, Secondary to Hepatic Damage, Compromises Memory Function. Front Neurosci 2021; 15:578922. [PMID: 33584185 PMCID: PMC7873464 DOI: 10.3389/fnins.2021.578922] [Citation(s) in RCA: 41] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2020] [Accepted: 01/06/2021] [Indexed: 12/13/2022] Open
Abstract
Glutamate fulfils many vital functions both at a peripheral level and in the central nervous system (CNS). However, hyperammonemia and hepatic failure induce alterations in glutamatergic neurotransmission, which may be the main cause of hepatic encephalopathy (HE), an imbalance which may explain damage to both learning and memory. Cognitive and motor alterations in hyperammonemia may be caused by a deregulation of the glutamate-glutamine cycle, particularly in astrocytes, due to the blocking of the glutamate excitatory amino-acid transporters 1 and 2 (EAAT1, EAAT2). Excess extracellular glutamate triggers mechanisms involving astrocyte-mediated inflammation, including the release of Ca2+-dependent glutamate from astrocytes, the appearance of excitotoxicity, the formation of reactive oxygen species (ROS), and cell damage. Glutamate re-uptake not only prevents excitotoxicity, but also acts as a vital component in synaptic plasticity and function. The present review outlines the evidence of the relationship between hepatic damage, such as that occurring in HE and hyperammonemia, and changes in glutamine synthetase function, which increase glutamate concentrations in the CNS. These conditions produce dysfunction in neuronal communication. The present review also includes data indicating that hyperammonemia is related to the release of a high level of pro-inflammatory factors, such as interleukin-6, by astrocytes. This neuroinflammatory condition alters the function of the membrane receptors, such as N-methyl-D-aspartate (NMDA), (α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) AMPA, and γ-aminobutyric acid (GABA), thus affecting learning and spatial memory. Data indicates that learning and spatial memory, as well as discriminatory or other information acquisition processes in the CNS, are damaged by the appearance of hyperammonemia and, moreover, are associated with a reduction in the production of cyclic guanosine monophosphate (cGMP). Therefore, increased levels of pharmacologically controlled cGMP may be used as a therapeutic tool for improving learning and memory in patients with HE, hyperammonemia, cerebral oedema, or reduced intellectual capacity.
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Affiliation(s)
| | - Isael Angulo-Cruz
- Laboratorio de Neurofarmacología, Benemérita Universidad Autónoma de Puebla, Puebla, Mexico
| | - Lesli Sánchez-Abdon
- Laboratorio de Neurofarmacología, Benemérita Universidad Autónoma de Puebla, Puebla, Mexico
| | - Aleidy Patricio-Martínez
- Laboratorio de Neurofarmacología, Benemérita Universidad Autónoma de Puebla, Puebla, Mexico
- Facultad de Ciencias Biológicas, Benemérita Universidad Autónoma de Puebla, Puebla, Mexico
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Chen Z, Ruan J, Li D, Wang M, Han Z, Qiu W, Wu G. The Role of Intestinal Bacteria and Gut-Brain Axis in Hepatic Encephalopathy. Front Cell Infect Microbiol 2021; 10:595759. [PMID: 33553004 PMCID: PMC7859631 DOI: 10.3389/fcimb.2020.595759] [Citation(s) in RCA: 37] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2020] [Accepted: 12/04/2020] [Indexed: 12/12/2022] Open
Abstract
Hepatic encephalopathy (HE) is a neurological disorder that occurs in patients with liver insufficiency. However, its pathogenesis has not been fully elucidated. Pharmacotherapy is the main therapeutic option for HE. It targets the pathogenesis of HE by reducing ammonia levels, improving neurotransmitter signal transduction, and modulating intestinal microbiota. Compared to healthy individuals, the intestinal microbiota of patients with liver disease is significantly different and is associated with the occurrence of HE. Moreover, intestinal microbiota is closely associated with multiple links in the pathogenesis of HE, including the theory of ammonia intoxication, bile acid circulation, GABA-ergic tone hypothesis, and neuroinflammation, which contribute to cognitive and motor disorders in patients. Restoring the homeostasis of intestinal bacteria or providing specific probiotics has significant effects on neurological disorders in HE. Therefore, this review aims at elucidating the potential microbial mechanisms and metabolic effects in the progression of HE through the gut-brain axis and its potential role as a therapeutic target in HE.
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Affiliation(s)
| | | | | | | | | | | | - Guobin Wu
- Guangxi Medical University Cancer Hospital, Nanning, China
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Hassouneh R, Bajaj JS. Gut Microbiota Modulation and Fecal Transplantation: An Overview on Innovative Strategies for Hepatic Encephalopathy Treatment. J Clin Med 2021; 10:330. [PMID: 33477417 PMCID: PMC7830387 DOI: 10.3390/jcm10020330] [Citation(s) in RCA: 31] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2020] [Revised: 01/07/2021] [Accepted: 01/09/2021] [Indexed: 02/06/2023] Open
Abstract
Hepatic encephalopathy (HE) is a major complication of cirrhosis, which is associated with gut microbial composition and functional alterations. Current treatments largely focus on gut microbiota using lactulose, rifaximin and other agents. However, despite these treatments, patients with HE have a high rate of readmission, morbidity and cognitive impairment. Fecal microbiota transplant (FMT) involves introduction of a donor microbiota into a recipient and is currently mainly used for recurrent C. difficile infection (rCDI). The role of FMT in cirrhosis and HE is evolving. There have been two randomized clinical trials (RCT) and several case reports/series in cirrhosis. Both RCTs were safety-focused phase 1 trials. One involved pre-FMT antibiotics and FMT enema versus standard of care, while the other involved 15 FMT capsules versus placebo without pre-FMT antibiotics. There was evidence of safety in both trials and the FMT group demonstrated reduction in hospitalizations compared to the non-FMT group. Changes in microbial function centered around short-chain fatty acids, bile acids and brain function showed improvement in the FMT groups. Long-term follow-up demonstrated continued safety and reduction in the antibiotic-resistance gene carriage. However, larger trials of FMT in HE are needed that can refine the dose, duration and route of FMT administration.
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Affiliation(s)
- Ramzi Hassouneh
- Department of Internal Medicine, Virginia Commonwealth University Medical Center, Richmond, VA 23298, USA;
| | - Jasmohan S. Bajaj
- Division of Gastroenterology, Hepatology and Nutrition Virginia Commonwealth University and Central Virginia Veterans Healthcare System, 1201 Broad Rock Blvd, Richmond, VA 23249, USA
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Chen B, Yang Y, Li S, Zhu X, Qi Y, Hong F. The critical role of hippocampal dopamine in the pathogenesis of hepatic encephalopathy. Physiol Res 2021; 70:101-110. [PMID: 33453721 DOI: 10.33549/physiolres.934563] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022] Open
Abstract
The pathogenesis of hepatic encephalopathy (HE) has been generally linked to blood ammonia, gamma-aminobutyric acid and serotonin. However, the exact mechanism remains unclear. In the present study, we aimed to explore the role of hippocampal dopamine (DA) and its receptors in the pathogenesis of HE through the use of behavioral testing, western blotting, and immunofluorescence staining in normal rats, HE model rats and rats treated with the DA precursor-levodopa (L-DOPA). HE model rats manifested fibrotic livers and showed serious behavioral disorders. They also had significantly lower hippocampal DA content and increased expression of both D1 and D2 receptors relative to normal rats. After treatment with L-DOPA, the HE model rats showed normal behavior and expression of D1 returned to normal levels. Furthermore, pretreatment with the D1 antagonist SCH23390 blocked the therapeutic effect of L-DOPA on behavior in HE model rats. Taken together, these results clarify that the decrease in hippocampal DA plays a role in the pathogenesis of HE and that this effect is mediated by D1. These findings provide new evidence for the pathogenesis of HE.
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Affiliation(s)
- B Chen
- School of Preclinical Medicine, Wannan Medical College, Wuhu, China.
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Jiménez-Torres C, El-Kehdy H, Hernández-Kelly LC, Sokal E, Ortega A, Najimi M. Acute Liver Toxicity Modifies Protein Expression of Glutamate Transporters in Liver and Cerebellar Tissue. Front Neurosci 2021; 14:613225. [PMID: 33488353 PMCID: PMC7815688 DOI: 10.3389/fnins.2020.613225] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2020] [Accepted: 11/27/2020] [Indexed: 12/24/2022] Open
Abstract
Glutamate is the main excitatory amino acid acting at the level of pre and postsynaptic neurons, as well as in glial cells. It is involved in the coordinated modulation of energy metabolism, glutamine synthesis, and ammonia detoxification. The relationship between the functional status of liver and brain has been known for many years. The most widely recognized aspect of this relation is the brain dysfunction caused by acute liver injury that manifests a wide spectrum of neurologic and psychiatric abnormalities. Inflammation, circulating neurotoxins, and impaired neurotransmission have been reported in this pathophysiology. In the present contribution, we report the effect of a hepatotoxic compound like CCl4 on the expression of key proteins involved in glutamate uptake and metabolism as glutamate transporters and glutamine synthetase in mice liver, brain, and cerebellum. Our findings highlight a differential expression pattern of glutamate transporters in cerebellum. A significant Purkinje cells loss, in parallel to an up-regulation of glutamine synthetase, and astrogliosis in the brain have also been noticed. In the intoxicated liver, glutamate transporter 1 expression is up-regulated, in contrast to glutamine synthetase which is reduced in a time-dependent manner. Taken together our results demonstrate that the exposure to an acute CCl4 insult, leads to the disruption of glutamate transporters expression in the liver-brain axis and therefore a severe alteration in glutamate-mediated neurotransmission might be present in the central nervous system.
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Affiliation(s)
- Catya Jiménez-Torres
- Laboratorio de Neurotoxicología, Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional (Cinvestav-IPN), Departamento de Toxicología, Mexico City, Mexico
| | - Hoda El-Kehdy
- Laboratory of Pediatric Hepatology and Cell Therapy, UCLouvain, Institut de Recherche Expérimentale et Clinique (IREC), Brussels, Belgium
| | - Luisa C Hernández-Kelly
- Laboratorio de Neurotoxicología, Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional (Cinvestav-IPN), Departamento de Toxicología, Mexico City, Mexico
| | - Etienne Sokal
- Laboratory of Pediatric Hepatology and Cell Therapy, UCLouvain, Institut de Recherche Expérimentale et Clinique (IREC), Brussels, Belgium
| | - Arturo Ortega
- Laboratorio de Neurotoxicología, Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional (Cinvestav-IPN), Departamento de Toxicología, Mexico City, Mexico
| | - Mustapha Najimi
- Laboratory of Pediatric Hepatology and Cell Therapy, UCLouvain, Institut de Recherche Expérimentale et Clinique (IREC), Brussels, Belgium
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Effects of an Aquaporin 4 Inhibitor, TGN-020, on Murine Diabetic Retina. Int J Mol Sci 2020; 21:ijms21072324. [PMID: 32230876 DOI: 10.3390/ijms21072324] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2020] [Revised: 03/20/2020] [Accepted: 03/26/2020] [Indexed: 12/13/2022] Open
Abstract
PURPOSE To investigate the effect of a selective aquaporin 4 (AQP4) inhibitor, 2-(nicotinamide)-1,3,4-thiadiazole (TGN-020), on the expression of vascular endothelial growth factor (VEGF) and reactive oxygen species (ROS) production, as well as on the retinal edema in diabetic retina. METHODS Intravitreal injections of bevacizumab, TGN-020, or phosphate-buffered saline (PBS) were performed on streptozotocin-induced diabetic rats. Retinal sections were immunostained for anti-glial fibrillary acidic protein (GFAP), anti-AQP4, and anti-VEGF. Protein levels of VEGF from collected retinas were determined by Western blot analysis. In addition, retinal vascular leakage of Evans Blue was observed in the flat-mounted retina from the diabetic rats in the presence or absence of TGN-020. Volumetric changes of rat retinal Müller cells (TR-MUL5; transgenic rat Müller cells) and intracellular levels of ROS were determined using flow cytometry analysis of ethidium fluorescence in the presence or absence of TGN-020 or bevacizumab under physiological and high glucose conditions. RESULTS In the diabetic retina, the immunoreactivity and protein levels of VEGF were suppressed by TGN-020. AQP4 immunoreactivity was higher than in the control retinas and the expressions of AQP4 were co-localized with GFAP. Similarly to VEGF, AQP4 and GFAP were also suppressed by TGN-020. In the Evans Blue assay, TGN-020 decreased leakage in the diabetic retinas. In the cultured Müller cells, the increase in cell volumes and intracellular ROS production under high glucose condition were suppressed by exposure to TGN-020 as much as by exposure to bevacizumab. CONCLUSION TGN-020 may have an inhibitory effect on diabetic retinal edema.
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Liu R, Kang JD, Sartor RB, Sikaroodi M, Fagan A, Gavis EA, Zhou H, Hylemon PB, Herzog JW, Li X, Lippman RH, Gonzalez-Maeso J, Wade JB, Ghosh S, Gurley E, Gillevet PM, Bajaj JS. Neuroinflammation in Murine Cirrhosis Is Dependent on the Gut Microbiome and Is Attenuated by Fecal Transplant. Hepatology 2020; 71:611-626. [PMID: 31220352 PMCID: PMC6923631 DOI: 10.1002/hep.30827] [Citation(s) in RCA: 73] [Impact Index Per Article: 14.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/30/2019] [Accepted: 06/16/2019] [Indexed: 12/14/2022]
Abstract
Cirrhosis and hepatic encephalopathy (HE) is associated with an altered gut-liver-brain axis. Fecal microbial transplant (FMT) after antibiotics improves outcomes in HE, but the impact on brain function is unclear. The aim of this study is to determine the effect of colonization using human donors in germ-free (GF) mice on the gut-liver-brain axis. GF and conventional mice were made cirrhotic using carbon tetrachloride and compared with controls in GF and conventional state. Additional GF mice were colonized with stool from controls (Ctrl-Hum) and patients with cirrhosis (Cirr-Hum). Stools from patients with HE cirrhosis after antibiotics were pooled (pre-FMT). Stools from the same patients 15 days after FMT from a healthy donor were also pooled (post-FMT). Sterile supernatants were created from pre-FMT and post-FMT samples. GF mice were colonized using stools/sterile supernatants. For all mice, frontal cortex, liver, and small/large intestines were collected. Cortical inflammation, synaptic plasticity and gamma-aminobutyric acid (GABA) signaling, and liver inflammation and intestinal 16s ribosomal RNA microbiota sequencing were performed. Conventional cirrhotic mice had higher degrees of neuroinflammation, microglial/glial activation, GABA signaling, and intestinal dysbiosis compared with other groups. Cirr-Hum mice had greater neuroinflammation, microglial/glial activation, and GABA signaling and lower synaptic plasticity compared with Ctrl-Hum mice. This was associated with greater dysbiosis but no change in liver histology. Pre-FMT material colonization was associated with neuroinflammation and microglial activation and dysbiosis, which was reduced significantly with post-FMT samples. Sterile pre-FMT and post-FMT supernatants did not affect brain parameters. Liver inflammation was unaffected. Conclusion: Fecal microbial colonization from patients with cirrhosis results in higher degrees of neuroinflammation and activation of GABAergic and neuronal activation in mice regardless of cirrhosis compared with those from healthy humans. Reduction in neuroinflammation by using samples from post-FMT patients to colonize GF mice shows a direct effect of fecal microbiota independent of active liver inflammation or injury.
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Affiliation(s)
- Runping Liu
- Division of Microbiology and Immunology, Virginia Commonwealth University and McGuire VA Medical Center, Richmond, VA
| | - Jason D. Kang
- Division of Microbiology and Immunology, Virginia Commonwealth University and McGuire VA Medical Center, Richmond, VA
| | - R. Balfour Sartor
- National Gnotobiotic Rodent Resource Center, Departments of Medicine, Microbiology, and Immunology, University of North Carolina, Chapel Hill, NC
| | | | - Andrew Fagan
- Division of Gastroenterology, Hepatology, and Nutrition, Virginia Commonwealth University and McGuire VA Medical Center, Richmond, VA
| | - Edith A. Gavis
- Division of Gastroenterology, Hepatology, and Nutrition, Virginia Commonwealth University and McGuire VA Medical Center, Richmond, VA
| | - Huiping Zhou
- Division of Microbiology and Immunology, Virginia Commonwealth University and McGuire VA Medical Center, Richmond, VA
| | - Phillip B. Hylemon
- Division of Microbiology and Immunology, Virginia Commonwealth University and McGuire VA Medical Center, Richmond, VA
| | - Jeremy W. Herzog
- National Gnotobiotic Rodent Resource Center, Departments of Medicine, Microbiology, and Immunology, University of North Carolina, Chapel Hill, NC
| | - Xiaojiaoyang Li
- Division of Microbiology and Immunology, Virginia Commonwealth University and McGuire VA Medical Center, Richmond, VA
| | - Robert H. Lippman
- Department of Pathology, Virginia Commonwealth University and McGuire VA Medical Center, Richmond, VA
| | - Javier Gonzalez-Maeso
- Department of Physiology and Biophysics, Virginia Commonwealth University and McGuire VA Medical Center, Richmond, VA
| | - James B. Wade
- Department of Psychiatry, Virginia Commonwealth University and McGuire VA Medical Center, Richmond, VA
| | - Siddhartha Ghosh
- Division of Nephrology, Virginia Commonwealth University and McGuire VA Medical Center, Richmond, VA
| | - Emily Gurley
- Division of Microbiology and Immunology, Virginia Commonwealth University and McGuire VA Medical Center, Richmond, VA
| | | | - Jasmohan S. Bajaj
- Division of Gastroenterology, Hepatology, and Nutrition, Virginia Commonwealth University and McGuire VA Medical Center, Richmond, VA
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cGMP signaling pathway in hepatic encephalopathy neuroinflammation and cognition. Int Immunopharmacol 2019; 79:106082. [PMID: 31869775 DOI: 10.1016/j.intimp.2019.106082] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2019] [Revised: 11/05/2019] [Accepted: 11/24/2019] [Indexed: 12/25/2022]
Abstract
Hepatic encephalopathy (HE) is a complex neuropsychiatric syndrome that results from liver failure and is characterized by a wide range of symptoms such as alteration in the sleep-waking cycle, neuromuscular coordination, mood, and cognition. The deregulation of nitric oxide (NO)/cyclic guanosine monophosphate (cGMP)/protein kinase G (PKG) signaling pathway is thought to play an important role in the etiology and progression of neurodegenerative diseases, and several studies pointed that the cGMP signaling is impaired in patients with HE and experimental models of chronic hyperammonemia. This review aimed to briefly present the current knowledge of the cGMP signaling pathways in neuroinflammation, neurogenesis, and memory in hepatic encephalopathy and its potential therapeutic role.
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Ferreira MDF, Salavati Schmitz S, Schoenebeck JJ, Clements DN, Campbell SM, Gaylor DE, Mellanby RJ, Gow AG, Salavati M. Lactulose drives a reversible reduction and qualitative modulation of the faecal microbiota diversity in healthy dogs. Sci Rep 2019; 9:13350. [PMID: 31527716 PMCID: PMC6746952 DOI: 10.1038/s41598-019-50090-7] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2018] [Accepted: 09/03/2019] [Indexed: 02/07/2023] Open
Abstract
Hepatic encephalopathy is a frequent and debilitating complication of liver disorders. Lactulose is an established and reasonably effective treatment, yet with incompletely understood mechanisms of action. The aims of this study were to examine how the faecal microbiota composition changed before, during and after lactulose treatment in a large animal model. Healthy, privately owned dogs (n = 18) completed a prospective cohort study. Faecal samples were collected weekly, while the subjects were either on their usual diet (week 1), or a standardised diet (weeks 2-9), with added oral lactulose in weeks 6-7. DNA extraction and 16S rRNA gene sequencing were undertaken. Faecal samples from week 7 had a significantly lower microbiota richness/diversity, based on observed operational taxonomic units, Shannon/Chao1 indexes and Pielou's Evenness. Beta diversity based on UniFrac distances was significantly different in week 7 compared to weeks 1, 5 and 9. At the phylum level, week 7 was associated with a significant increase of Firmicutes and Actinobacteria, and a decrease of Bacteroidetes and Fusobacteria, when compared to weeks 5 and 9. In summary, we have shown that lactulose induces a reversible qualitative and quantitative change of the faecal microbiota, which may explain its clinical efficacy in the management of hepatic encephalopathy.
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Affiliation(s)
- Marisa da Fonseca Ferreira
- The Royal (Dick) School of Veterinary Studies and The Roslin Institute, The University of Edinburgh, Easter Bush Campus, Roslin, Midlothian, EH25 9RG, United Kingdom.
| | - Silke Salavati Schmitz
- The Royal (Dick) School of Veterinary Studies and The Roslin Institute, The University of Edinburgh, Easter Bush Campus, Roslin, Midlothian, EH25 9RG, United Kingdom
| | - Jeffrey Joseph Schoenebeck
- The Royal (Dick) School of Veterinary Studies and The Roslin Institute, The University of Edinburgh, Easter Bush Campus, Roslin, Midlothian, EH25 9RG, United Kingdom
| | - Dylan Neil Clements
- The Royal (Dick) School of Veterinary Studies and The Roslin Institute, The University of Edinburgh, Easter Bush Campus, Roslin, Midlothian, EH25 9RG, United Kingdom
| | - Susan Mary Campbell
- The Royal (Dick) School of Veterinary Studies and The Roslin Institute, The University of Edinburgh, Easter Bush Campus, Roslin, Midlothian, EH25 9RG, United Kingdom
| | - Donna Elaine Gaylor
- The Royal (Dick) School of Veterinary Studies and The Roslin Institute, The University of Edinburgh, Easter Bush Campus, Roslin, Midlothian, EH25 9RG, United Kingdom
| | - Richard J Mellanby
- The Royal (Dick) School of Veterinary Studies and The Roslin Institute, The University of Edinburgh, Easter Bush Campus, Roslin, Midlothian, EH25 9RG, United Kingdom
| | - Adam George Gow
- The Royal (Dick) School of Veterinary Studies and The Roslin Institute, The University of Edinburgh, Easter Bush Campus, Roslin, Midlothian, EH25 9RG, United Kingdom
| | - Mazdak Salavati
- The Royal (Dick) School of Veterinary Studies and The Roslin Institute, The University of Edinburgh, Easter Bush Campus, Roslin, Midlothian, EH25 9RG, United Kingdom
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Campion D, Giovo I, Ponzo P, Saracco GM, Balzola F, Alessandria C. Dietary approach and gut microbiota modulation for chronic hepatic encephalopathy in cirrhosis. World J Hepatol 2019; 11:489-512. [PMID: 31293718 PMCID: PMC6603507 DOI: 10.4254/wjh.v11.i6.489] [Citation(s) in RCA: 32] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/15/2019] [Revised: 05/15/2019] [Accepted: 05/20/2019] [Indexed: 02/06/2023] Open
Abstract
Hepatic encephalopathy (HE) is a common and serious neuropsychiatric complication of cirrhosis, acute liver failure, and porto-systemic shunting. HE largely contributes to the morbidity of patients with liver disease, severely affecting the quality of life of both patients and their relatives and being associated with poor prognosis. Its presentation is largely variable, manifesting with a broad spectrum of cognitive abnormalities ranging from subtle cognitive impairment to coma. The pathogenesis of HE is complex and has historically been linked with hyperammonemia. However, in the last years, it has become evident that the interplay of multiple actors, such as intestinal dysbiosis, gut hyperpermeability, and neuroinflammation, is of crucial importance in its genesis. Therefore, HE can be considered a result of a dysregulated gut-liver-brain axis function, where cognitive impairment can be reversed or prevented by the beneficial effects induced by "gut-centric" therapies, such as non-absorbable disaccharides, non-absorbable antibiotics, probiotics, prebiotics, and fecal microbiota transplantation. In this context dietary modifications, by modulating the intestinal milieu, can also provide significant benefit to cirrhotic patients with HE. This review will provide a comprehensive insight into the mechanisms responsible for gut-liver-brain axis dysregulation leading to HE in cirrhosis. Furthermore, it will explore the currently available therapies and the most promising future treatments for the management of patients with HE, with a special focus on the dietary approach.
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Affiliation(s)
- Daniela Campion
- Division of Gastroenterology and Hepatology, Città della Salute e della Scienza di Torino Hospital, University of Turin, 10126 Turin, Italy
| | - Ilaria Giovo
- Division of Gastroenterology and Hepatology, Città della Salute e della Scienza di Torino Hospital, University of Turin, 10126 Turin, Italy
| | - Paola Ponzo
- Division of Gastroenterology and Hepatology, Città della Salute e della Scienza di Torino Hospital, University of Turin, 10126 Turin, Italy
| | - Giorgio M Saracco
- Division of Gastroenterology and Hepatology, Città della Salute e della Scienza di Torino Hospital, University of Turin, 10126 Turin, Italy
| | - Federico Balzola
- Division of Gastroenterology and Hepatology, Città della Salute e della Scienza di Torino Hospital, University of Turin, 10126 Turin, Italy
| | - Carlo Alessandria
- Division of Gastroenterology and Hepatology, Città della Salute e della Scienza di Torino Hospital, University of Turin, 10126 Turin, Italy.
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