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Yordanov Y, Tzankova V, Stefanova D, Georgieva M, Tzankova D. Exploratory Data Analysis of the In Vitro Effects of Novel Hydrazide-Hydrazone Antioxidants in the Context of In Silico Predictors. Antioxidants (Basel) 2025; 14:566. [PMID: 40427448 PMCID: PMC12108285 DOI: 10.3390/antiox14050566] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2025] [Revised: 04/29/2025] [Accepted: 05/05/2025] [Indexed: 05/29/2025] Open
Abstract
Substantial in vitro experimental data have been produced about the safety, antioxidant, neuro- and hepatoprotective effects of a series of recently synthesized N-pyrrolyl hydrazide-hydrazones (compounds 5, 5a-5g). However, compound activity across multiple assays varies and it is challenging to elucidate the favorable physicochemical characteristics of the studied compounds and guide further lead optimization. The aim of the current study is to apply exploratory data analysis in order to profile the biological effects of the novel hydrazide-hydrazones, gain insights related to their mechanisms of action in the context of in silico predictions and identify key predictor-outcome relationships. We collected a dataset from available in vitro studies of compounds 5, 5a-5g. It included cytotoxicity values, protection against hydrogen peroxide-induced damage in HepG2 and SH-SY5Y cells, two radical scavenging assays and a hemolysis assay across a range of treatment concentrations. SwissADME-based predictions of chemometric and ADME parameters and pro-oxidant enzyme docking data were generated to provide context for the interpretation of in vitro outcome patterns and identify causal relationships. Multiple factor analysis (MFA), followed by hierarchical clustering on principal components (HCPC), was applied to profile compounds' biological behavior. This revealed that differences in the number of H-bond donors, in the permeability coefficient and in the docking scores to two pro-oxidant enzymes could aid in explaining the effects of compounds with similar in vitro profiles. HCPC differentiated 5a as mostly neuroprotective, 5 and 5d as hepatoprotective radical scavengers, 5g with higher docking affinity to 5-lipoxygenase (5-LOX) and myeloperoxidase (MPO) and 5b, 5c and 5f as having less H-bond donors and variable in vitro activity. The consensus application of three variable selection approaches based on standard lasso regression, robust penalized regression and random forest confirmed the relationships between some in vitro outcomes and LogP, pan-assay interference (PAINS) alerts, 5-LOX allosteric site docking and H-bond donor numbers. The exploratory analysis of the combined in vitro and in silico dataset provides useful insights which could help explain the major drivers behind the experimental results. It can be informative in the design of new, improved members of the series of novel N-pyrrolyl hydrazide-hydrazones with better neuroprotective potential and less side effects.
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Affiliation(s)
- Yordan Yordanov
- Department of Pharmacology, Pharmacotherapy and Toxicology, Faculty of Pharmacy, Medical University—Sofia, 2 Dunav Str., 1000 Sofia, Bulgaria (D.S.)
| | - Virginia Tzankova
- Department of Pharmacology, Pharmacotherapy and Toxicology, Faculty of Pharmacy, Medical University—Sofia, 2 Dunav Str., 1000 Sofia, Bulgaria (D.S.)
| | - Denitsa Stefanova
- Department of Pharmacology, Pharmacotherapy and Toxicology, Faculty of Pharmacy, Medical University—Sofia, 2 Dunav Str., 1000 Sofia, Bulgaria (D.S.)
| | - Maya Georgieva
- Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Medical University—Sofia, 2 Dunav Str., 1000 Sofia, Bulgaria
| | - Diana Tzankova
- Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Medical University—Sofia, 2 Dunav Str., 1000 Sofia, Bulgaria
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2
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Capinha F, Carvalhana S, Cortez-Pinto H. Role of Alcohol in Steatotic Liver Disease: Impact on Patients with Cardiometabolic Risk Factors. Dig Dis Sci 2025; 70:1746-1756. [PMID: 40025309 DOI: 10.1007/s10620-025-08912-4] [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: 07/23/2024] [Accepted: 02/03/2025] [Indexed: 03/04/2025]
Abstract
The new definition of steatotic liver disease (SLD), as a broader concept, was a step forward in the increasing recognition of the substantial overlap between alcohol and cardiometabolic risk factors (CMRFs), in a continuum way. The spectrum of pathophysiological aspects, ranging from liver steatosis to fibrosis, has similarities in MASLD and ALD. Also, there is now considerable evidence that the association of metabolic dysfunction with increased alcohol consumption impacts on the risk of severe liver disease and prognosis. The new MetALD class, as recently proposed, shows clear differences in prognosis when comparing with MASLD and ALD groups. However, there is room for improvement, such as considering the role of previous alcohol intake, fluctuations of consumption over time, including binge drinking, refinement of alcohol assessment, and better understanding of the role of biomarkers. In summary, SLD is no doubt a significant improvement, but the new classification needs to be dynamic and adapting to patients needing frequent reassessment. Furthermore, it brings opportunities for research on the interaction between alcohol consumption and CMRFs.
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Affiliation(s)
- Francisco Capinha
- Serviço de Gastrenterologia e Hepatologia, Centro Hospitalar Universitário Lisboa Norte, Lisbon, Portugal
- Clínica Universitária de Gastrenterologia, Faculdade de Medicina, Universidade de Lisboa, Avenida Professor Egas Moniz, 1649-035, Lisbon, Portugal
| | - Sofia Carvalhana
- Serviço de Gastrenterologia e Hepatologia, Centro Hospitalar Universitário Lisboa Norte, Lisbon, Portugal
- Clínica Universitária de Gastrenterologia, Faculdade de Medicina, Universidade de Lisboa, Avenida Professor Egas Moniz, 1649-035, Lisbon, Portugal
| | - Helena Cortez-Pinto
- Serviço de Gastrenterologia e Hepatologia, Centro Hospitalar Universitário Lisboa Norte, Lisbon, Portugal.
- Clínica Universitária de Gastrenterologia, Faculdade de Medicina, Universidade de Lisboa, Avenida Professor Egas Moniz, 1649-035, Lisbon, Portugal.
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Hemeda AA, Zahran SA, Ali-Tammam M, Ewida MA, Kashef MT, Yassin AS, Mitra A, Youssef NH, Elshahed MS. Metagenomic mining unveils a novel GH130 enzyme with exclusive xylanase activity over a wide temperature and pH ranges. J Ind Microbiol Biotechnol 2024; 52:kuaf006. [PMID: 40036345 PMCID: PMC11905756 DOI: 10.1093/jimb/kuaf006] [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: 09/24/2024] [Accepted: 02/25/2025] [Indexed: 03/06/2025]
Abstract
The equine gut harbors a diverse microbial community and represents a rich source of carbohydrate-active enzymes (CAZymes). To identify and characterize potentially novel CAZymes from a horse's hindgut metagenome, shotgun metagenomic sequencing was performed on DNA extracted from a stool sample of a male horse, followed by CAZyme annotation. Here, we report on the characterization of a novel enzyme (AH2) that was identified, synthesized, cloned, and characterized from the obtained CAZyme dataset. AH2 was identified as a GH130 family member and displayed exclusive xylanase activity, a trait hitherto unreported in prior characterization of GH130 CAZymes. AH2 displayed an optimal activity at a pH of 5.6 and a temperature of 50°C. AH2 maintained significant activity across a pH range of 4-10 (62-72%) and temperatures of 30-70°C (77-86%). The enzyme had remarkable stability, with minimal reductions in activity across a temperature range of 4-70°C and pH levels of 3, 7, and 9. Docking studies identified AH2's amino acids (Glu90 and Glu149) to be involved in substrate binding. Molecular dynamics simulation confirmed the structural stability of AH2 at pH 5.6 and 50°C, further supporting its resilience under these conditions. Our results expand on the known activities associated with the GH130 CAZyme family and demonstrate that the horse gut metagenome represents an unexplored source of novel CAZymes. ONE-SENTENCE SUMMARY A novel activity for members of the CAZyme family GH130.
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Affiliation(s)
- Amr A Hemeda
- Department of Microbiology and Immunology, Faculty of Pharmacy, Future University in Egypt, 12311 Cairo, Egypt
| | - Sara A Zahran
- Department of Microbiology and Immunology, Faculty of Pharmacy, Future University in Egypt, 12311 Cairo, Egypt
| | - Marwa Ali-Tammam
- Department of Microbiology and Immunology, Faculty of Pharmacy, Future University in Egypt, 12311 Cairo, Egypt
| | - Menna A Ewida
- Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Future University in Egypt, 12311 Cairo, Egypt
| | - Mona T Kashef
- Department of Microbiology and Immunology, Faculty of Pharmacy, Cairo University, Cairo 11562, Egypt
| | - Aymen S Yassin
- Department of Microbiology and Immunology, Faculty of Pharmacy, Cairo University, Cairo 11562, Egypt
| | - Avishek Mitra
- Department of Microbiology and Molecular Genetics, Oklahoma State University, Stillwater, OK 74074, USA
| | - Noha H Youssef
- Department of Microbiology and Molecular Genetics, Oklahoma State University, Stillwater, OK 74074, USA
| | - Mostafa S Elshahed
- Department of Microbiology and Molecular Genetics, Oklahoma State University, Stillwater, OK 74074, USA
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Shahabi S, Esfarjani F, Zamani S, Rarani FZ, Rashidi B. Evaluating the Efficacy of Irisin Injection in Mimicking the Molecular Responses Induced by Endurance Exercise in Mouse Liver Tissue. Int J Prev Med 2024; 15:66. [PMID: 39742130 PMCID: PMC11687683 DOI: 10.4103/ijpvm.ijpvm_124_23] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2023] [Accepted: 02/20/2024] [Indexed: 01/03/2025] Open
Abstract
Background Physical activity has been found to improve liver health by reducing oxidative stress (OS), possibly through the protein irisin. Heat shock proteins (HSPs) and microRNAs (miRNAs) help regulate the body's response to stress and maintain cellular health. This study aimed to investigate the expression of the HSP70 gene and protein, miR-223a, and serum irisin levels in the liver after 8 weeks of endurance exercise or irisin injection. Methods Twenty-one mice were randomly assigned to a control group, an endurance training group, and an irisin injection group. The expression of the HSP70 gene and miR-223a was analyzed using real-time polymerase chain reaction (PCR), while HSP70 protein levels were measured using immunohistochemistry (IHC) and Western blot analysis. The concentration of irisin in the mouse serum was evaluated using the enzyme-linked immunosorbent assay (ELISA) method. Results The endurance training and irisin injection groups exhibited a significant increase in the HSP70 gene (405.30% and 816.03%, respectively) and protein expression (173.89% in IHC, 36.76% in Western blot for endurance training; 206.73% in IHC, 59.80% in Western blot for irisin injection) as well as elevated serum irisin levels (49.75% for endurance training and 60.65% for irisin injection) compared with the control group. In contrast, miR-223a expression decreased in both the endurance training (21.37%) and irisin injection (52.80%) groups (P < 0.05 in all cases). Mice in the irisin injection group demonstrated higher levels of the HSP70 gene (81.28%) and protein expression (11.99% in IHC and 16.84% in Western blot) and lower miR-223a levels (39.97%) than those in the endurance training group (P < 0.05). Conclusions The study concludes that irisin administration can replicate the effects of long-term endurance exercise on HSP70 and miR-223a and may have a more significant impact on their production than exercise training alone.
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Affiliation(s)
- Shirin Shahabi
- Department of Exercise Physiology, Faculty of Sport Science, University of Isfahan, Isfahan, Iran
| | - Fahimeh Esfarjani
- Department of Exercise Physiology, Faculty of Sport Science, University of Isfahan, Isfahan, Iran
| | - Saeed Zamani
- Department of Anatomical Sciences, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Fahimeh Zamani Rarani
- Department of Anatomical Sciences, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Bahman Rashidi
- Department of Anatomical Sciences, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
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Aboona MB, Danpanichkul P, Chen VL, Rangan P, Kim D, Alkhouri N, Fallon MB, Noureddin M, Arab JP, Wijarnpreecha K. Mortality outcomes in individuals with MASLD versus MASLD and increased alcohol intake. J Gastroenterol Hepatol 2024; 39:2456-2463. [PMID: 39175201 PMCID: PMC11620910 DOI: 10.1111/jgh.16726] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/08/2024] [Revised: 08/03/2024] [Accepted: 08/09/2024] [Indexed: 08/24/2024]
Abstract
BACKGROUND AND AIM Metabolic dysfunction-associated steatotic liver disease (MASLD) has become a leading cause of chronic liver disease worldwide. A new entity termed MetALD has also been described and is defined as individuals with MASLD and increased alcohol intake. However, the natural history of MetALD compared with MASLD is unknown. We aimed to compare longitudinal outcomes in patients with MASLD versus MetALD. METHODS This study was performed using data from the National Health and Nutrition Examination Survey from 2011 to 2018. MASLD patients (defined by the United States Fatty Liver Index > 30) who met cardiometabolic criteria including body mass index (BMI) > 25 (BMI > 23 in Asians), hypertension, diabetes mellitus, dyslipidemia, and hypertriglyceridemia were included. MetALD was defined as MASLD with increased alcohol intake (3-6 standard drinks per day in males; 2-5 standard drinks per day in females). A comparison of overall, cardiovascular, cancer-related, and other causes of mortality in patients with MASLD versus MetALD was performed. RESULTS A total of 2838 individuals with MASLD and 2557 individuals with MetALD were included with a median follow-up time of 56 months. MetALD patients were at increased risk of cancer-related mortality compared with patients with MASLD (hazard ratio 1.32; 95% confidence interval 1.14-1.53; P < 0.01). However, there was no significant difference in overall, cardiovascular, and other causes of mortality. CONCLUSIONS Patients with MetALD were at higher risk for cancer-related mortality than MASLD. Close attention to regular cancer surveillance and accurate classification of alcohol consumption in individuals with diagnosed MASLD is warranted to help improve patient care and outcome.
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Affiliation(s)
- Majd B. Aboona
- Division of Clinical Data Analytics and Decision Support, University of Arizona College of Medicine—Phoenix, Arizona, USA
| | - Pojsakorn Danpanichkul
- Department of Internal Medicine, Texas Tech University Health Sciences Center, Lubbock, USA
- Immunology Unit, Department of Microbiology, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand
| | - Vincent L Chen
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, University of Michigan Health System, Ann Arbor, Michigan, USA
| | - Pooja Rangan
- Division of Clinical Data Analytics and Decision Support, University of Arizona College of Medicine—Phoenix, Arizona, USA
| | - Donghee Kim
- Division of Gastroenterology and Hepatology, Stanford University School of Medicine, Stanford, California, USA
| | - Naim Alkhouri
- Arizona Liver Institute, Banner University Medical Center, Phoenix, Arizona, USA
| | - Michael B. Fallon
- Division of Gastroenterology and Hepatology, Department of Medicine, University of Arizona College of Medicine—Phoenix, Arizona, USA
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Banner University Medical Center, Phoenix, Arizona, USA
| | - Mazen Noureddin
- Houston Research Institute and Houston Methodist Hospital, Houston, Texas, USA
| | - Juan Pablo Arab
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Internal Medicine, Virginia Commonwealth University School of Medicine, Richmond, Virginia, USA
- Departmento de Gastroenterologia, Escuela de Medicina, Pontificia Universidad Catolica de Chile, Santiago, Chile
| | - Karn Wijarnpreecha
- Division of Gastroenterology and Hepatology, Department of Medicine, University of Arizona College of Medicine—Phoenix, Arizona, USA
- BIO5 Institution, University of Arizona College of Medicine—Phoenix, Arizona, USA
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Banner University Medical Center, Phoenix, Arizona, USA
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6
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Tian Y, Ni Y, Zhang T, Cao Y, Zhou M, Zhao C. Targeting hepatic macrophages for non-alcoholic fatty liver disease therapy. Front Cell Dev Biol 2024; 12:1444198. [PMID: 39300994 PMCID: PMC11410645 DOI: 10.3389/fcell.2024.1444198] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2024] [Accepted: 08/26/2024] [Indexed: 09/22/2024] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) and its more advanced form, non-alcoholic steatohepatitis (NASH), have become global health challenges with significant morbidity and mortality rates. NAFLD encompasses several liver diseases, ranging from simple steatosis to more severe inflammatory and fibrotic forms. Ultimately, this can lead to liver cirrhosis and hepatocellular carcinoma. The intricate role of hepatic macrophages, particularly Kupffer cells (KCs) and monocyte-derived macrophages (MoMFs), in the pathogenesis of NAFLD and NASH, has received increasing attention. Hepatic macrophages can interact with hepatocytes, hepatic stellate cells, and endothelial cells, playing a crucial role in maintaining homeostasis. Paradoxically, they also participate in the pathogenesis of some liver diseases. This review highlights the fundamental role of hepatic macrophages in the pathogenesis of NAFLD and NASH, emphasizing their plasticity and contribution to inflammation and fibrosis, and hopes to provide ideas for subsequent experimental research and clinical treatment.
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Affiliation(s)
- Yingxin Tian
- Shanghai Traditional Chinese Medicine Integrated Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
- Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, China
- School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Yiming Ni
- Shanghai Traditional Chinese Medicine Integrated Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
- Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Ting Zhang
- Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Yemin Cao
- Shanghai Traditional Chinese Medicine Integrated Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Mingmei Zhou
- Shanghai Traditional Chinese Medicine Integrated Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
- Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Cheng Zhao
- Shanghai Traditional Chinese Medicine Integrated Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
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Das SK, Nerune SM, Das KK. Antioxidant therapy for hepatic diseases: a double-edged sword. J Basic Clin Physiol Pharmacol 2024; 35:7-14. [PMID: 38234261 DOI: 10.1515/jbcpp-2023-0156] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2023] [Accepted: 01/02/2024] [Indexed: 01/19/2024]
Abstract
Liver diseases are complex conditions, significantly influenced by oxidative stress. This comprehensive review assesses the therapeutic role of antioxidants like l-ascorbic acid and α tocopherol, beta-carotene, various minerals, and plant-based ingredients in mitigating oxidative stress-induced liver diseases. The manuscript delves into the critical influence of genetic and epigenetic factors on disease susceptibility, progression, and response to antioxidant therapy. While animal studies suggest antioxidant efficacy in liver disease treatment, human trials remain inconclusive, and caution is advised due to its possible potential pro-oxidant effects. Moreover, the interactions of antioxidants with other drugs necessitate careful consideration in the management of polypharmacy in liver disease patients. The review underscores the need for further research to establish the clinical benefits of antioxidants with understanding of possible antioxidant toxicities to elucidate the intricate interplay of genetic, epigenetic, and environmental factors in liver diseases. The aim is to foster a better understanding of the knowledge on hepatic disease management with judicial antioxidant therapies.
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Affiliation(s)
- Sayandeep K Das
- Department of Pathology, Shri B. M. Patil Medical College, Hospital and Research Centre, BLDE (Deemed to be University), Vijayapur, Karnataka, India
| | - Savitri M Nerune
- Department of Pathology, Shri B. M. Patil Medical College, Hospital and Research Centre, BLDE (Deemed to be University), Vijayapur, Karnataka, India
| | - Kusal K Das
- Laboratory of Vascular Physiology and Medicine, Department of Physiology, Shri B. M. Patil Medical College, Hospital and Research Centre, BLDE (Deemed to be University), Vijayapur, Karnataka, India
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8
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Hossain KN, Islam MS, Rahman SH, Sarker S, Mondal M, Rahman MA, Alhag SK, Al-Shuraym LA, Alghamdi OA, Islam MT, AL-Farga A, El-Shazly M, Alam MJ, El-Nashar HAS. In Vitro Antioxidant and In Vivo Hepatoprotective Properties of Wissadula periplocifolia Extract. ACS OMEGA 2023; 8:47001-47011. [PMID: 38107893 PMCID: PMC10720299 DOI: 10.1021/acsomega.3c06614] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/08/2023] [Revised: 11/13/2023] [Accepted: 11/16/2023] [Indexed: 12/19/2023]
Abstract
Wissadula periplocifolia (L.) Thwaites is a traditional medicinal plant belonging to the family Malvaceae, used in folk medicine for inflamed snake bites and bee stings. The current study was designed to investigate the in vitro antioxidant and in vivo anti-inflammatory and hepatoprotective activities of 80% ethanol extract of W. periplocifolia and its different fractions. The crude ethanolic extract (CEE) was then serially fractionated with petroleum ether fraction (PEF), chloroform fraction (CHF), and aqueous fraction (AQF). The antioxidant activity was assessed using 1,1-diphenyl-2-picrylhydrazyl (DPPH) radical assay, anti-inflammatory activity was determined in the xylene-induced ear edema model, and hepatoprotective activity was measured in the paracetamol-induced hepatic injury model. PEF showed a significant scavenging effect with an IC50 value of 33.5 μg/mL, followed by CEE (IC50 = 42.2 μg/mL), CHF (IC50 = 77 μg/mL), and AQF (IC50 = 80 μg/mL), compared to standard butylated hydroxytoluene (IC50 = 14.8 μg/mL). Both doses of CEE (250 and 500 mg/kg) could reduce ear edema by 41.3 and 50%, respectively, compared to standard diclofenac sodium (76.09%). Moreover, CEE significantly reduces the elevated liver enzymes (ALT, AST, and ALP), compared to control. Nevertheless, it elevated blood protein and reduced the blood bilirubin level (p < 0.01), compared to control. Histopathological studies also indicated significant protection of the liver from paracetamol-induced liver damage. In conclusion, W. periplocifolia could be a good source of antioxidant and hepatoprotective phytochemicals; meanwhile, toxicological and pharmacokinetic studies are recommended.
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Affiliation(s)
- Kazi Nadim Hossain
- Department
of Pharmacy, Bangabandhu Sheikh Mujibur
Rahman Science and Technology University, Gopalganj 8100, Bangladesh
| | - Md. Shafiqul Islam
- Department
of Pharmacy, Bangabandhu Sheikh Mujibur
Rahman Science and Technology University, Gopalganj 8100, Bangladesh
| | - Sheikh Hasibur Rahman
- Department
of Pharmacy, Bangabandhu Sheikh Mujibur
Rahman Science and Technology University, Gopalganj 8100, Bangladesh
| | - Subroto Sarker
- Department
of Pharmacy, Bangabandhu Sheikh Mujibur
Rahman Science and Technology University, Gopalganj 8100, Bangladesh
| | - Milon Mondal
- Department
of Pharmacy, Bangabandhu Sheikh Mujibur
Rahman Science and Technology University, Gopalganj 8100, Bangladesh
| | | | - Sadeq K. Alhag
- Biology
Department, College of Science and Arts, King Khalid University, Muhayl
Asser 61913, Saudi Arabia
| | - Laila A. Al-Shuraym
- Biology
Department, Faculty of Science, Princess
Nourah bint Abdulrahman University, P.O. Box 84428, Riyadh 11671, Saudi Arabia
| | - Othman A. Alghamdi
- Department
of Biological Sciences, College of Science, University of Jeddah, Jeddah 22233, Saudi Arabia
| | - Muhammad Torequl Islam
- Department
of Pharmacy, Bangabandhu Sheikh Mujibur
Rahman Science and Technology University, Gopalganj 8100, Bangladesh
| | - Ammar AL-Farga
- Department
of Biochemistry, College of Science, University
of Jeddah, Jeddah 23218, Saudi Arabia
| | - Mohamed El-Shazly
- Department
of Pharmacognosy, Faculty of Pharmacy, Ain
Shams University, Abbassia 11566, Cairo, Egypt
| | - Md. Jahir Alam
- Department
of Pharmacy, Jahangirnagar University, Dhaka 1342, Bangladesh
| | - Heba A. S. El-Nashar
- Department
of Pharmacognosy, Faculty of Pharmacy, Ain
Shams University, Abbassia 11566, Cairo, Egypt
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Sawada K, Chung H, Softic S, Moreno-Fernandez ME, Divanovic S. The bidirectional immune crosstalk in metabolic dysfunction-associated steatotic liver disease. Cell Metab 2023; 35:1852-1871. [PMID: 37939656 PMCID: PMC10680147 DOI: 10.1016/j.cmet.2023.10.009] [Citation(s) in RCA: 38] [Impact Index Per Article: 19.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/31/2023] [Revised: 10/13/2023] [Accepted: 10/13/2023] [Indexed: 11/10/2023]
Abstract
Metabolic dysfunction-associated steatotic liver disease (MASLD) is an unabated risk factor for end-stage liver diseases with no available therapies. Dysregulated immune responses are critical culprits of MASLD pathogenesis. Independent contributions from either the innate or adaptive arms of the immune system or their unidirectional interplay are commonly studied in MASLD. However, the bidirectional communication between innate and adaptive immune systems and its impact on MASLD remain insufficiently understood. Given that both innate and adaptive immune cells are indispensable for the development and progression of inflammation in MASLD, elucidating pathogenic contributions stemming from the bidirectional interplay between these two arms holds potential for development of novel therapeutics for MASLD. Here, we review the immune cell types and bidirectional pathways that influence the pathogenesis of MASLD and highlight potential pharmacologic approaches to combat MASLD based on current knowledge of this bidirectional crosstalk.
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Affiliation(s)
- Keisuke Sawada
- Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH 45220, USA; Division of Immunobiology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA; Immunology Graduate Program, University of Cincinnati College of Medicine, Cincinnati, OH 45220, USA; Medical Scientist Training Program, University of Cincinnati College of Medicine, Cincinnati, OH 45220, USA
| | - Hak Chung
- Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH 45220, USA; Division of Immunobiology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA
| | - Samir Softic
- Department of Pediatrics and Gastroenterology, University of Kentucky, Lexington, KY 40536, USA; Department of Pharmacology and Nutritional Sciences, University of Kentucky, Lexington, KY 40536, USA
| | - Maria E Moreno-Fernandez
- Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH 45220, USA; Division of Gastroenterology, Hepatology, and Nutrition, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA.
| | - Senad Divanovic
- Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH 45220, USA; Division of Immunobiology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA; Immunology Graduate Program, University of Cincinnati College of Medicine, Cincinnati, OH 45220, USA; Medical Scientist Training Program, University of Cincinnati College of Medicine, Cincinnati, OH 45220, USA; Center for Inflammation and Tolerance, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA.
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10
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Tourkochristou E, Tsounis EP, Tzoupis H, Aggeletopoulou I, Tsintoni A, Lourida T, Diamantopoulou G, Zisimopoulos K, Kafentzi T, de Lastic AL, Rodi M, Tselios T, Thomopoulos K, Mouzaki A, Triantos C. The Influence of Single Nucleotide Polymorphisms on Vitamin D Receptor Protein Levels and Function in Chronic Liver Disease. Int J Mol Sci 2023; 24:11404. [PMID: 37511164 PMCID: PMC10380285 DOI: 10.3390/ijms241411404] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2023] [Revised: 06/29/2023] [Accepted: 07/11/2023] [Indexed: 07/30/2023] Open
Abstract
Single nucleotide polymorphisms (SNPs) in the vitamin D receptor (VDR) gene have been associated with chronic liver disease. We investigated the role of VDR SNPs on VDR protein levels and function in patients with chronic liver disease. VDR expression levels were determined in peripheral T lymphocytes (CD3+VDR+), monocytes (CD14+VDR+), and plasma from patients (n = 66) and healthy controls (n = 38). Genotyping of SNPs and the determination of expression of VDR/vitamin D-related genes were performed by using qPCR. The effect of FokI SNP on vitamin D-binding to VDR was investigated by molecular dynamics simulations. CD14+VDR+ cells were correlated with the MELD score. The ApaI SNP was associated with decreased CD3+VDR+ levels in cirrhotic patients and with higher liver stiffness in HCV patients. The BsmI and TaqI SNPs were associated with increased VDR plasma concentrations in cirrhotic patients and decreased CD14+VDR+ levels in HCV patients. The FokI SNP was associated with increased CD3+VDR+ levels in cirrhotic patients and controls. VDR polymorphisms were significantly related to the expression of genes critical for normal hepatocyte function and immune homeostasis. VDR expression levels were related to the clinical severity of liver disease. VDR SNPs may be related to the progression of chronic liver disease by affecting VDR expression levels.
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Affiliation(s)
- Evanthia Tourkochristou
- Division of Gastroenterology, Department of Internal Medicine, Medical School, University of Patras, University Hospital of Patras, 26504 Patras, Greece (I.A.); (A.T.)
- Division of Hematology, Department of Internal Medicine, Medical School, University of Patras, 26504 Patras, Greece
| | - Efthymios P. Tsounis
- Division of Gastroenterology, Department of Internal Medicine, Medical School, University of Patras, University Hospital of Patras, 26504 Patras, Greece (I.A.); (A.T.)
| | | | - Ioanna Aggeletopoulou
- Division of Gastroenterology, Department of Internal Medicine, Medical School, University of Patras, University Hospital of Patras, 26504 Patras, Greece (I.A.); (A.T.)
- Division of Hematology, Department of Internal Medicine, Medical School, University of Patras, 26504 Patras, Greece
| | - Aggeliki Tsintoni
- Division of Gastroenterology, Department of Internal Medicine, Medical School, University of Patras, University Hospital of Patras, 26504 Patras, Greece (I.A.); (A.T.)
| | - Theoni Lourida
- Division of Gastroenterology, Department of Internal Medicine, Medical School, University of Patras, University Hospital of Patras, 26504 Patras, Greece (I.A.); (A.T.)
| | - Georgia Diamantopoulou
- Division of Gastroenterology, Department of Internal Medicine, Medical School, University of Patras, University Hospital of Patras, 26504 Patras, Greece (I.A.); (A.T.)
| | - Konstantinos Zisimopoulos
- Division of Gastroenterology, Department of Internal Medicine, Medical School, University of Patras, University Hospital of Patras, 26504 Patras, Greece (I.A.); (A.T.)
| | - Theodora Kafentzi
- Division of Gastroenterology, Department of Internal Medicine, Medical School, University of Patras, University Hospital of Patras, 26504 Patras, Greece (I.A.); (A.T.)
| | - Anne-Lise de Lastic
- Division of Hematology, Department of Internal Medicine, Medical School, University of Patras, 26504 Patras, Greece
| | - Maria Rodi
- Division of Hematology, Department of Internal Medicine, Medical School, University of Patras, 26504 Patras, Greece
| | - Theodore Tselios
- Department of Chemistry, University of Patras, 26504 Patras, Greece
| | - Konstantinos Thomopoulos
- Division of Gastroenterology, Department of Internal Medicine, Medical School, University of Patras, University Hospital of Patras, 26504 Patras, Greece (I.A.); (A.T.)
| | - Athanasia Mouzaki
- Division of Hematology, Department of Internal Medicine, Medical School, University of Patras, 26504 Patras, Greece
| | - Christos Triantos
- Division of Gastroenterology, Department of Internal Medicine, Medical School, University of Patras, University Hospital of Patras, 26504 Patras, Greece (I.A.); (A.T.)
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11
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El-Bana MA, Ashour MN, Rasheed WI, Diab YM, Medhat D. Bombax ceiba Linn. leaf extract rich in phenolic compounds to mitigate non-alcoholic fatty liver-related complications in experimental model. JOURNAL OF COMPLEMENTARY & INTEGRATIVE MEDICINE 2023; 20:343-352. [PMID: 36935561 DOI: 10.1515/jcim-2021-0479] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/23/2021] [Accepted: 02/24/2023] [Indexed: 06/16/2023]
Abstract
OBJECTIVES Obesity, diabetes mellitus, insulin resistance (IR), and hypertriglyceridemia are common features observed in non-alcoholic fatty liver diseases (NAFLD). There is a critical medical necessity to find novel therapeutics that can halt the development of NAFLD. METHODS Bombax ceiba Linn. leaf extract was prepared and its phytochemical profile was determined. Standard and high carbohydrate high-fat diets (HCHF) were prepared. Rats were fed HCHF for 18 weeks to induce a non-alcoholic fatty liver (NAFL) model. Forty male rats were divided into control, B. ceiba Linn. leaf extract, NAFL, prophylactic, and treated groups. Serum fasting blood sugar (FBS), insulin, insulin resistance (HOMA-IR), cholesterol, high-density lipoprotein (HDL), triglycerides (TG), low density lipoprotein (LDL), alanine aminotransferase (ALT), aspartate aminotransferase (AST), intelectin-1 (ITLN1), p38 MAP kinase (MAPK), peroxisome proliferator-activated receptor alpha (PPAR-α), and interleukin-6 (IL-6) were evaluated. RESULTS Data obtained showed that HCHF-induced NAFL resulting in a significant increase in FBS, serum insulin, HOMA-IR, cholesterol, LDL, TG, ALT, AST, and IL-6 and a significant decrease in serum levels of HDL, ITLN1, p38 MAP kinase, and PPAR-α compared to the control group. The analysis of B. ceiba Linn. leaf extract showed high content of phenol compounds which may cause a significant decrease in the levels of FBS, insulin, HOMA-IR values, lipid profile, and levels of IL-6 while a significant increase in serum levels of LDL, ITLN1, p38 MAP kinase, and PPAR-α compared to the NAFL group. CONCLUSIONS B. ceiba Linn. Leaf extract is a highly protective and promising therapeutic agent against inflammation and oxidative stress in the NAFLD model induced by HCHF.
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Affiliation(s)
- Mona A El-Bana
- Department of Medical Biochemistry, Medical Research and Clinical Studies Institute, National Research Centre, Dokki, Giza, Egypt
| | - Magdi N Ashour
- Department of Medical Biochemistry, Medical Research and Clinical Studies Institute, National Research Centre, Dokki, Giza, Egypt
| | - Wafaa I Rasheed
- Department of Medical Biochemistry, Medical Research and Clinical Studies Institute, National Research Centre, Dokki, Giza, Egypt
| | - Yasser M Diab
- Department of Biochemistry, Faculty of Agriculture, Fayoum University, Fayoum, Egypt
| | - Dalia Medhat
- Department of Medical Biochemistry, Medical Research and Clinical Studies Institute, National Research Centre, Dokki, Giza, Egypt
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12
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Shinoda H, Watanabe Y, Fukai K, Kasuya K, Furuya Y, Nakazawa S, Honda T, Hayashi T, Nakagawa T, Tatemichi M, Korenaga M. Significance of Fib4 index as an indicator of alcoholic hepatotoxicity in health examinations among Japanese male workers: a cross-sectional and retrospectively longitudinal study. Eur J Med Res 2023; 28:31. [PMID: 36650608 PMCID: PMC9847145 DOI: 10.1186/s40001-022-00976-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2022] [Accepted: 12/29/2022] [Indexed: 01/19/2023] Open
Abstract
BACKGROUND Fib4 index (Fib4) is clinically used as a noninvasive marker of liver fibrosis. In this study, we aimed to preliminarily investigate whether Fib4 can be used to detect individuals who need assessment for alcoholic liver disease (ALD) in the general population by clarifying the detailed association of Fib4 with alcohol consumption and gamma-glutamyl transferase (GGT) among male workers. METHODS We analyzed data sets on the comprehensive medical examinations of male workers as cross-sectional and retrospectively longitudinal studies. We enrolled 10 782 males (mean age: 52.2 ± 10.2 years) in FY2019 and 7845 males (mean follow-up: 12.6 ± 6.7 years) who could be consecutively followed up for 20 years from FY2000 to FY2019. Data were evaluated using logistic regression and COX proportional analysis. RESULTS In the cross-sectional setting, the rate of Fib4 ≥ 2.67 in heavy drinkers (≥ 40 g of ethanol/day) was increased dose dependently in those over 65 years old, and that of body mass index ≥ 30 kg/m2 was increased in those over 60 years old, but not in those with fatty liver. The odds ratio (OR) (95% confidence interval [CI]) for heavy drinking was 4.30 (95% CI = 1.90-9.72), and GGT ≥ 200 IU/L was considerably high (OR = 29.05 [95% CI = 17.03-49.56]). In the longitudinal setting, heavy drinkers and those with GGT ≥ 200 IU/L at 10 years after the baseline showed an increased risk for Fib4 ≥ 2.67 (hazard ratio = 2.17 [95% CI = 1.58-2.98] and 7.65 [95% CI 5.26-11.12], respectively). CONCLUSIONS The development of Fib4 ≥ 2.67 after 10 years was associated with heavy alcohol drinking and GGT level ≥ 200 IU/L. Therefore, Fib4 combined with GGT could indicate high risk of ALD. However, clinical examinations and course observations are essentially needed.
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Affiliation(s)
- Hideki Shinoda
- grid.414178.f0000 0004 1776 0989Hitachi General Hospital, Hitachi, Japan
| | - Yuya Watanabe
- grid.417547.40000 0004 1763 9564Hitachi Health Care Center, Hitachi, Japan
| | - Kota Fukai
- Department of Preventive Medicine, Tokai University School of Medicine, Isehara, Japan.
| | - Kayoko Kasuya
- grid.417547.40000 0004 1763 9564Hitachi Health Care Center, Hitachi, Japan
| | - Yuko Furuya
- grid.265061.60000 0001 1516 6626Department of Preventive Medicine, Tokai University School of Medicine, Isehara, Japan
| | - Shoko Nakazawa
- grid.265061.60000 0001 1516 6626Department of Preventive Medicine, Tokai University School of Medicine, Isehara, Japan
| | - Toru Honda
- grid.417547.40000 0004 1763 9564Hitachi Health Care Center, Hitachi, Japan
| | - Takeshi Hayashi
- grid.417547.40000 0004 1763 9564Present Address: Occupational Hygiene and Promotion Center, Hitachi, Ltd, Tokyo, Japan
| | - Toru Nakagawa
- grid.417547.40000 0004 1763 9564Hitachi Health Care Center, Hitachi, Japan
| | - Masayuki Tatemichi
- grid.265061.60000 0001 1516 6626Department of Preventive Medicine, Tokai University School of Medicine, Isehara, Japan
| | - Masaaki Korenaga
- Hepatitis Information Centre, Research Centre for Hepatitis and Immunology, National Centre for Global Health and Medicine, Ichikawa, Japan
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13
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Alcohol consumption and metabolic syndrome: Clinical and epidemiological impact on liver disease. J Hepatol 2023; 78:191-206. [PMID: 36063967 DOI: 10.1016/j.jhep.2022.08.030] [Citation(s) in RCA: 134] [Impact Index Per Article: 67.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/03/2022] [Revised: 08/04/2022] [Accepted: 08/19/2022] [Indexed: 02/01/2023]
Abstract
Alcohol use and metabolic syndrome are highly prevalent in the population and frequently co-exist. Both are implicated in a large range of health problems, including chronic liver disease, hepatocellular carcinoma, and liver-related outcomes (i.e. decompensation or liver transplantation). Studies have yielded mixed results regarding the effects of mild-moderate alcohol consumption on the risk of metabolic syndrome and fatty liver disease, possibly due to methodological differences. The few available prospective studies have indicated that mild-moderate alcohol use is associated with an increase in liver-related outcomes. This conclusion was substantiated by systems biology analyses suggesting that alcohol and metabolic syndrome may play a similar role in fatty liver disease, potentiating an already existing dysregulation of common vital homeostatic pathways. Alcohol and metabolic factors are independently and jointly associated with liver-related outcomes. Indeed, metabolic syndrome increases the risk of liver-related outcomes, regardless of alcohol intake. Moreover, the components of metabolic syndrome appear to have additive effects when it comes to the risk of liver-related outcomes. A number of population studies have implied that measures of central/abdominal obesity, such as the waist-to-hip ratio, can predict liver-related outcomes more accurately than BMI, including in individuals who consume harmful quantities of alcohol. Many studies even point to synergistic interactions between harmful alcohol use and many metabolic components. This accumulating evidence showing independent, combined, and modifying effects of alcohol and metabolic factors on the onset and progression of chronic liver disease highlights the multifactorial background of liver disease in the population. The available evidence suggests that more holistic approaches could be useful for risk prediction, diagnostics and treatment planning.
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14
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Mei C, Peng F, Yin W, Xu W, Yao R, Li B, Zhou R, Fan X, Li N. Increased suicidal erythrocyte death in patients with hepatitis B-related acute-on-chronic liver failure. Am J Physiol Gastrointest Liver Physiol 2022; 323:G9-G20. [PMID: 35411804 DOI: 10.1152/ajpgi.00050.2020] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Anemia is a common complication of hepatitis B-related acute-on-chronic liver failure (HB-ACLF). Eryptosis, a suicidal erythrocyte death characterized by phosphatidylserine (PS) externalization and red blood cell-derived microparticle (RMP) generation, decreases erythrocyte lifespan. Herein, we investigated whether enhanced eryptosis is involved in the anemia pathophysiology associated with HB-ACLF. PS exposure, cell volume, cytosolic Ca2+, and reactive oxygen species (ROS) production were determined using flow cytometry. RMPs were extracted using a polyethylene glycol (PEG)-based method. We found that hemoglobin (Hb) and hematocrit (Hct) were significantly lower in patients with HB-ACLF than in healthy controls (HC), patients with chronic hepatitis B (CHB), and patients with cirrhosis. The direct antiglobulin test positive rate was 75.9% in patients with HB-ACLF while its intensity was associated with anemia. The ratio of abnormal erythrocytes was higher in patients with HB-ACLF than in HC, CHB, and cirrhosis. The percentage of PS-exposed erythrocytes was higher in patients with HB-ACLF (2.07 ± 0.11%) compared with HC (0.37 ± 0.05%), CHB (0.38 ± 0.03%), and cirrhosis (0.38 ± 0.04%). The cytosolic Ca2+ and ROS abundance were also higher in patients with HB-ACLF compared with HC, patients with CHB, and patients with cirrhosis, and were inversely correlated with the anemia in patients with HB-ACLF. PS exposure of erythrocytes collected from HC was significantly pronounced following incubation in plasma from patients with HB-ACLF compared with incubation in plasma from HC. The protein concentration and RMPs size significantly increased in patients with HB-ACLF compared with HC. Thus, the anemia in patients with HB-ACLF is associated with increased eryptosis, which is partially triggered by increased cytosolic Ca2+ and oxidative stress.NEW & NOTEWORTHY Acute chronic liver failure (ACLF) is a critical syndrome characterized by multiple organ failures and high short-term mortality. A common complication of HB-ACLF is anemia, however, the mechanism of anemia in HB-ACLF remains to be elucidated. We confirm that the accelerated eryptosis is involved in the pathophysiology of anemia associated with HB-ACLF, which progressively aggravates the clinical outcome. Our study illustrates the mechanism regarding the anemia pathogenesis of HB-ACLF, which may be utilized further toward therapeutic ends.
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Affiliation(s)
- Cheng Mei
- Department of Blood Transfusion, Xiangya Hospital, Clinical Transfusion Research Center, Central South University, Changsha, Hunan, China
| | - Fang Peng
- Key Laboratory of Cancer Proteomics of Chinese Ministry of Health, Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Wenyu Yin
- Department of Blood Transfusion, Xiangya Hospital, Clinical Transfusion Research Center, Central South University, Changsha, Hunan, China
| | - Wei Xu
- Department of Blood Transfusion, Xiangya Hospital, Clinical Transfusion Research Center, Central South University, Changsha, Hunan, China
| | - Run Yao
- Department of Blood Transfusion, Xiangya Hospital, Clinical Transfusion Research Center, Central South University, Changsha, Hunan, China
| | - Bijuan Li
- Department of Blood Transfusion, Xiangya Hospital, Clinical Transfusion Research Center, Central South University, Changsha, Hunan, China
| | - Rongrong Zhou
- Department of Infectious Diseases, Key Laboratory of Viral Hepatitis, Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Xuegong Fan
- Department of Infectious Diseases, Key Laboratory of Viral Hepatitis, Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Ning Li
- Department of Blood Transfusion, Xiangya Hospital, Clinical Transfusion Research Center, Central South University, Changsha, Hunan, China.,National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan, China
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Di Ciaula A, Bonfrate L, Krawczyk M, Frühbeck G, Portincasa P. Synergistic and Detrimental Effects of Alcohol Intake on Progression of Liver Steatosis. Int J Mol Sci 2022; 23:2636. [PMID: 35269779 PMCID: PMC8910376 DOI: 10.3390/ijms23052636] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2022] [Revised: 02/24/2022] [Accepted: 02/25/2022] [Indexed: 02/07/2023] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) and alcoholic liver disease (ALD) are the most common liver disorders worldwide and the major causes of non-viral liver cirrhosis in the general population. In NAFLD, metabolic abnormalities, obesity, and metabolic syndrome are the driving factors for liver damage with no or minimal alcohol consumption. ALD refers to liver damage caused by excess alcohol intake in individuals drinking more than 5 to 10 daily units for years. Although NAFLD and ALD are nosologically considered two distinct entities, they show a continuum and exert synergistic effects on the progression toward liver cirrhosis. The current view is that low alcohol use might also increase the risk of advanced clinical liver disease in NAFLD, whereas metabolic factors increase the risk of cirrhosis among alcohol risk drinkers. Therefore, special interest is now addressed to individuals with metabolic abnormalities who consume small amounts of alcohol or who binge drink, for the role of light-to-moderate alcohol use in fibrosis progression and clinical severity of the liver disease. Evidence shows that in the presence of NAFLD, there is no liver-safe limit of alcohol intake. We discuss the epidemiological and clinical features of NAFLD/ALD, aspects of alcohol metabolism, and mechanisms of damage concerning steatosis, fibrosis, cumulative effects, and deleterious consequences which include hepatocellular carcinoma.
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Affiliation(s)
- Agostino Di Ciaula
- Clinica Medica “Augusto Murri”, Department of Biomedical Sciences and Human Oncology, University of Bari Medical School—Piazza Giulio Cesare 11, 70124 Bari, Italy; (A.D.C.); (L.B.)
| | - Leonilde Bonfrate
- Clinica Medica “Augusto Murri”, Department of Biomedical Sciences and Human Oncology, University of Bari Medical School—Piazza Giulio Cesare 11, 70124 Bari, Italy; (A.D.C.); (L.B.)
| | - Marcin Krawczyk
- Department of Medicine II Saarland University Medical Center, Saarland University, 66424 Homburg, Germany;
- Laboratory of Metabolic Liver Diseases, Department of General, Transplant and Liver Surgery, Centre for Preclinical Research, Medical University of Warsaw, 02-091 Warsaw, Poland
| | - Gema Frühbeck
- Department of Endocrinology & Nutrition, Clínica Universidad de Navarra, 31008 Pamplona, Spain;
- Metabolic Research Laboratory, Clínica Universidad de Navarra, 31008 Pamplona, Spain
- CIBER Fisiopatología de la Obesidad y Nutrición (CIBEROBN), ISCIII, 31009 Pamplona, Spain
- Obesity and Adipobiology Group, Instituto de Investigación Sanitaria de Navarra (IdiSNA), 31009 Pamplona, Spain
| | - Piero Portincasa
- Clinica Medica “Augusto Murri”, Department of Biomedical Sciences and Human Oncology, University of Bari Medical School—Piazza Giulio Cesare 11, 70124 Bari, Italy; (A.D.C.); (L.B.)
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16
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Khalaf MM, Hassanein EHM, Shalkami AGS, Hemeida RAM, Mohamed WR. Diallyl Disulfide Attenuates Methotrexate-Induced Hepatic Oxidative Injury, Inflammation and Apoptosis and Enhances its Anti-Tumor Activity. Curr Mol Pharmacol 2022; 15:213-226. [PMID: 34042041 DOI: 10.2174/1874467214666210525153111] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2020] [Revised: 01/03/2021] [Accepted: 02/08/2021] [Indexed: 11/22/2022]
Abstract
BACKGROUND Methotrexate (MTX) is used potently for a wide range of diseases. However, hepatic intoxication by MTX hinders its clinical use. OBJECTIVES The present study was conducted to investigate the diallyl disulfide (DADS) ability to ameliorate MTX-induced hepatotoxicity. METHODS Thirty-two rats were randomly divided into four groups: normal control, DADS (50 mg/kg/day, orally), MTX (single i.p. injection of 20 mg/kg) and DADS+MTX. Liver function biomarkers, histopathological examinations, oxidative stress, inflammation, and apoptosis biomarkers were investigated. Besides, an in vitro cytotoxic activity study was conducted to explore the modulatory effects of DADS on MTX cytotoxic activity using Caco-2, MCF-7, and HepG2 cells. RESULTS DADS significantly reduced the increased serum activities of ALT, AST, ALP, and LDH. These results were confirmed by the alleviation of liver histopathological changes. It restored the decreased GSH content and SOD activity, while significantly decreased MTX-induced elevations in both MDA and NO2 - contents. The hepatoprotective effects were mechanistically mediated through the up-regulation of hepatic Nrf-2 and the down-regulation of Keap-1, P38MAPK, and NF- κB expression levels. In addition, an increase in Bcl-2 level with a decrease in the expression of both Bax and caspase-3 was observed. The in vitro study showed that DADS increased MTX antitumor efficacy. CONCLUSION DADS potently alleviated MTX-induced hepatotoxicity through the modulation of Keap-1/Nrf-2, P38MAPK/NF-κB and apoptosis signaling pathways and effectively enhanced the MTX cytotoxic effects, which could be promising for further clinical trials.
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Affiliation(s)
- Marwa M Khalaf
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Beni-Suef University, Beni-Suef,Egypt
| | - Emad H M Hassanein
- Department of Pharmacology & Toxicology, Faculty of Pharmacy, Al-Azhar University, Assiut Branch, Assiut,Egypt
| | - Abdel-Gawad S Shalkami
- Department of Pharmacology & Toxicology, Faculty of Pharmacy, Al-Azhar University, Assiut Branch, Assiut,Egypt
| | - Ramadan A M Hemeida
- Department of Pharmacology & Toxicology, Faculty of Pharmacy, Al-Azhar University, Assiut Branch, Assiut,Egypt
| | - Wafaa R Mohamed
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Beni-Suef University, Beni-Suef,Egypt
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17
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Sugiyama A, Kurisu A, Ouoba S, E B, Ko K, Rakhimov A, Hussain MRA, Akita T, Harakawa T, Sako T, Koshiyama M, Tanaka J. Relationship between drinking frequency and fatty liver prevalence or incidence in Japanese undergoing health checkup in 2008-2019. Liver Int 2021; 41:2914-2923. [PMID: 34523235 PMCID: PMC9292946 DOI: 10.1111/liv.15055] [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] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/29/2021] [Revised: 08/25/2021] [Accepted: 09/05/2021] [Indexed: 12/20/2022]
Abstract
BACKGROUND & AIMS The relationship between the frequency of drinking and fatty liver in the general population is still poorly understood. This study analysed data from a large cohort who underwent health checkups in Japan between 2008 and 2019 to investigate the prevalence and incidence of fatty liver by alcohol consumption and risk factors for fatty liver. METHODS The prevalence of fatty liver diagnosed with ultrasonography was calculated in 75,670 residents. The incidence of fatty liver in 31,062 residents who underwent ultrasonography at least twice during the period without fatty liver at the first time was calculated using the person-year method. Multivariate logistic analysis was performed to investigate risk factors associated with the prevalence and incidence of fatty liver. RESULTS The prevalence of fatty liver was 27.6% (95% confidence interval [CI], 27.2-27.9) in non-drinkers, 28.5% (27.5-29.5) in moderate-drinkers and 28.0% (26.0-29.9) in heavy-drinkers. The incidence of fatty liver was 3,084/100,000 person-years (2,997-3,172/100,000) in non-drinkers, 3,754/100,000 person-years (3,481-4,042/100,000) in moderate-drinkers and 3,861/100,000 person-years (3,295-4,497/100,000) in heavy-drinkers. The prevalence and incidence of fatty liver were not associated with drinking status. Obesity was the most important independent risk factor (prevalence: adjusted odds ratio [AOR], 6.3; 95% CI, 6.0-6.5; incidence: AOR, 2.4; 95% CI, 2.3-2.6). CONCLUSIONS Drinking status does not affect the prevalence or incidence of fatty liver in Japanese residents undergoing health checkups. From a public health perspective, measures for obesity control must be prioritised to reduce the burden of disease of fatty liver in Japan.
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Affiliation(s)
- Aya Sugiyama
- Department of Epidemiology, Infectious Disease Control and PreventionGraduate School of Biomedical and Health SciencesHiroshima UniversityHiroshimaJapan
| | - Akemi Kurisu
- Department of Epidemiology, Infectious Disease Control and PreventionGraduate School of Biomedical and Health SciencesHiroshima UniversityHiroshimaJapan
| | - Serge Ouoba
- Department of Epidemiology, Infectious Disease Control and PreventionGraduate School of Biomedical and Health SciencesHiroshima UniversityHiroshimaJapan,Unité de Recherche Clinique de Nanoro (URCN)Institut de Recherche en Science de la Santé (IRSS)NanoroBurkina Faso
| | - Bunthen E
- Department of Epidemiology, Infectious Disease Control and PreventionGraduate School of Biomedical and Health SciencesHiroshima UniversityHiroshimaJapan,Payment Certification AgencyMinistry of HealthPhnom PenhCambodia
| | - Ko Ko
- Department of Epidemiology, Infectious Disease Control and PreventionGraduate School of Biomedical and Health SciencesHiroshima UniversityHiroshimaJapan
| | - Anvarjon Rakhimov
- Department of Epidemiology, Infectious Disease Control and PreventionGraduate School of Biomedical and Health SciencesHiroshima UniversityHiroshimaJapan
| | - Md Razeen Ashraf Hussain
- Department of Epidemiology, Infectious Disease Control and PreventionGraduate School of Biomedical and Health SciencesHiroshima UniversityHiroshimaJapan
| | - Tomoyuki Akita
- Department of Epidemiology, Infectious Disease Control and PreventionGraduate School of Biomedical and Health SciencesHiroshima UniversityHiroshimaJapan
| | - Takayuki Harakawa
- General AffairsFoundation for Community Health and Medicine Promotion in Hiroshima PrefectureHiroshimaJapan
| | - Toru Sako
- General AffairsFoundation for Community Health and Medicine Promotion in Hiroshima PrefectureHiroshimaJapan
| | - Makoto Koshiyama
- Iwate Prefectural Preventive Medicine AssociationMorioka CityJapan
| | - Junko Tanaka
- Department of Epidemiology, Infectious Disease Control and PreventionGraduate School of Biomedical and Health SciencesHiroshima UniversityHiroshimaJapan
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18
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Arya A, Azarmehr N, Mansourian M, Doustimotlagh AH. Inactivation of the superoxide dismutase by malondialdehyde in the nonalcoholic fatty liver disease: a combined molecular docking approach to clinical studies. Arch Physiol Biochem 2021; 127:557-564. [PMID: 31475569 DOI: 10.1080/13813455.2019.1659827] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
The objective of the present study was to investigate the plasma levels of oxidative stress markers and the activity of antioxidant enzymes in NAFLD and healthy subjects. Furthermore, the interaction behaviors of malondialdehyde (MDA) with Cu/Zn superoxide dismutase (SOD1) enzyme were elucidated by molecular docking. The study involved 60 patients with NAFLD and 25 healthy volunteers. The plasma levels of oxidative stress parameters and antioxidant enzymes activity were determined. NAFLD patients had significantly higher alanine aminotransferase, MDA and nitric oxide metabolites values, as well as significantly lower total thiol and SOD activity than the control group. Based on the molecular docking, MDA could deactivate the enzymatic activity of SOD1. Impaired antioxidant defense systems may be involved in the progression of NAFLD. This study provides direct evidence at a molecular level to explain that MDA may exert its oxidant activity by specific action within the specific molecular pathway.HighlightsImpairing antioxidant defense systems may be a main factor in the progression of nonalcoholic fatty liver disease (NAFLD).Increasing MDA and NO metabolites, as well as decreasing TSH values and SOD activity in NAFLD patients as compared to control subjectsIncreasing MDA level in NAFLD patients may be inactivate SOD activity by reaction with the key residues Cu ion inside active site of the enzyme catalytic site.
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Affiliation(s)
- Arash Arya
- Internal Medicine, Yasuj University of Medical Sciences, Yasuj, Iran
| | - Nahid Azarmehr
- Student Research Committee, Yasuj University of Medical Sciences, Yasuj, Iran
| | - Mahboubeh Mansourian
- Medicinal Plants Research Center, Yasuj University of Medical Sciences, Yasuj, Iran
| | - Amir Hossein Doustimotlagh
- Medicinal Plants Research Center, Yasuj University of Medical Sciences, Yasuj, Iran
- Department of Clinical Biochemistry, Faculty of Medicine, Yasuj University of Medical Sciences, Yasuj, Iran
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Association between telomere length and hepatic fibrosis in non-alcoholic fatty liver disease. Sci Rep 2021; 11:18004. [PMID: 34504179 PMCID: PMC8429461 DOI: 10.1038/s41598-021-97385-2] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2021] [Accepted: 08/25/2021] [Indexed: 12/15/2022] Open
Abstract
Telomere length has been linked to the prevalence and progression of metabolic disease. However, clinical implications of telomere length in biopsy-proven non-alcoholic fatty liver disease (NAFLD) patients remain unclear. Therefore, this study aimed to investigate the association of telomere length with the histological severity of NAFLD. The cross-sectional data derived from the prospectively enrolled Boramae NAFLD registry (n = 91) were analyzed. The liver tissues and clinical information were obtained from both NAFLD patients and non-NAFLD subjects. Binary logistic regression was performed to identify the independent association between telomere length and the histological severity of NAFLD. A total of 83 subjects with or without biopsy-proven NAFLD were included for analysis: non-NAFLD in 23 (27.7%), non-alcoholic fatty liver in 15 (18.1%), and non-alcoholic steatohepatitis (NASH) in 45 (54.2%). Telomere length measured from liver tissues showed a strong negative correlation (p < 0.001) with age, regardless of NAFLD status. Therefore, telomere length was corrected for age. Age-adjusted telomere length than decreased gradually with an increasing severity of fibrosis in patients with NAFLD (p < 0.028). In multivariate analysis, age-adjusted telomere length (odds ratio [OR] 0.59; 95% CI 0.37–0.92; p = 0.019) and high-density lipoprotein cholesterol (OR 0.94; 95% CI 0.80–0.99; p = 0.039) were independently associated with significant fibrosis. The age-adjusted telomere length tends to decrease along with the fibrosis stage of NAFLD. In particular, among the histological components of NAFLD, fibrosis severity seems to be related to telomere length in the liver.
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CYP2E1 in Alcoholic and Non-Alcoholic Liver Injury. Roles of ROS, Reactive Intermediates and Lipid Overload. Int J Mol Sci 2021; 22:ijms22158221. [PMID: 34360999 PMCID: PMC8348366 DOI: 10.3390/ijms22158221] [Citation(s) in RCA: 123] [Impact Index Per Article: 30.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2021] [Revised: 07/09/2021] [Accepted: 07/13/2021] [Indexed: 02/08/2023] Open
Abstract
CYP2E1 is one of the fifty-seven cytochrome P450 genes in the human genome and is highly conserved. CYP2E1 is a unique P450 enzyme because its heme iron is constitutively in the high spin state, allowing direct reduction of, e.g., dioxygen, causing the formation of a variety of reactive oxygen species and reduction of xenobiotics to toxic products. The CYP2E1 enzyme has been the focus of scientific interest due to (i) its important endogenous function in liver homeostasis, (ii) its ability to activate procarcinogens and to convert certain drugs, e.g., paracetamol and anesthetics, to cytotoxic end products, (iii) its unique ability to effectively reduce dioxygen to radical species causing liver injury, (iv) its capability to reduce compounds, often generating radical intermediates of direct toxic or indirect immunotoxic properties and (v) its contribution to the development of alcoholic liver disease, steatosis and NASH. In this overview, we present the discovery of the enzyme and studies in humans, 3D liver systems and genetically modified mice to disclose its function and clinical relevance. Induction of the CYP2E1 enzyme either by alcohol or high-fat diet leads to increased severity of liver pathology and likelihood to develop ALD and NASH, with subsequent influence on the occurrence of hepatocellular cancer. Thus, fat-dependent induction of the enzyme might provide a link between steatosis and fibrosis in the liver. We conclude that CYP2E1 has many important physiological functions and is a key enzyme for hepatic carcinogenesis, drug toxicity and liver disease.
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21
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Bingül İ, Aydın AF, Küçükgergin C, Doğan-Ekici I, Doğru-Abbasoğlu S, Uysal M. The effect of 1,25-dihydroxyvitamin D3 on liver damage, oxidative stress, and advanced glycation end products in experimental nonalcoholic- and alcoholic- fatty liver disease. Turk J Med Sci 2021; 51:1500-1511. [PMID: 33421970 PMCID: PMC8283439 DOI: 10.3906/sag-2007-289] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2020] [Accepted: 01/07/2021] [Indexed: 01/10/2023] Open
Abstract
Background/aim Oxidative stress and advanced glycation end products (AGEs) formation are proposed as effective mechanisms in the pathogenesis of nonalcoholic fatty liver disease (NAFLD) and alcoholic liver disease (ALD). 1,25(OH)2D3 was proposed to have antioxidant, antiinflammatory and antiglycation properties. In this study, the effect of 1,25(OH)2D3 treatment on oxidative stress parameters and AGEs levels together with hepatic histopathology was investigated in high fructose (HFr) or ethanol (EtOH)-treated rats. Materials and methods Rats were treated with fructose (30%) or ethanol (5-20%) in drinking water with and without 1,25(OH)2D3 treatment (5 µg/kg two times a week) for 8 weeks. Insulin resistance (IR), oxidative stress parameters, AGEs, triglyceride (TG), and hydroxyproline (Hyp) levels together with histopathology were investigated in the liver. Results 1,25(OH)2D3 decreased hepatic reactive oxygen species, lipid and protein oxidation products together with histopathological improvements in HFr- and EtOH-treated rats. 1,25(OH)2D3 treatment was observed to decrease significantly serum and hepatic AGEs in HFr group, and hepatic AGEs in EtOH group. Conclusion Our results clearly show that 1,25(OH)2 D3 treatment may be useful in the alleviation of hepatic lesions by decreasing glycooxidant stress in both NAFLD and ALD models created by HFr- and EtOH-treated rats, respectively.
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Affiliation(s)
- İlknur Bingül
- Department of Medical Biochemistry, İstanbul Medical Faculty, İstanbul University, İstanbul, Turkey
| | - A. Fatih Aydın
- Department of Medical Biochemistry, İstanbul Medical Faculty, İstanbul University, İstanbul, Turkey
| | - Canan Küçükgergin
- Department of Medical Biochemistry, İstanbul Medical Faculty, İstanbul University, İstanbul, Turkey
| | - Işın Doğan-Ekici
- Department of Pathology, Acıbadem University Medical Faculty, İstanbul, Turkey
| | - Semra Doğru-Abbasoğlu
- Department of Medical Biochemistry, İstanbul Medical Faculty, İstanbul University, İstanbul, Turkey
| | - Müjdat Uysal
- Retired Prof. Dr., Tayyareci Nurettin Sokak, Bakırkoy, İstanbul, Turkey
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22
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HbA1c may contribute to the development of non-alcoholic fatty liver disease even at normal-range levels. Biosci Rep 2021; 40:221879. [PMID: 31940026 PMCID: PMC6997109 DOI: 10.1042/bsr20193996] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2019] [Revised: 12/24/2019] [Accepted: 01/13/2020] [Indexed: 02/07/2023] Open
Abstract
Previous clinical studies highlighted nonalcoholic fatty liver disease (NAFLD) as a hepatic facet of metabolic syndrome, which progresses toward Type 2 diabetes along with an elevation of HbA1c in the blood. Longitudinal observations were performed in a cohort of 2811 participants with no liver disease at inception. The rate of the conversion into NAFLD was 15.7% (440/2811), with a steady increase in prevalence observed in sub-cohorts with increasing HbA1c levels. Moreover, regression analysis indicated that HbA1c levels serve as the risk factors for NAFLD after multiple adjustments (odds ratio: 1.58, P-value < 0.004). When HbA1c-related molecular networks were investigated using natural language programming algorithms, multiple genetic/small molecular (SM) pathways were highlighted as connectors between the HbA1c levels and the development of NAFLD, including ones for nitric oxide, hypoxia and receptor for advanced glycation end products (RAGE). Our results suggest that increased levels of HbA1c may contribute to the progression of NAFLD either directly, by stimulating RAGE or indirectly, through the promotion of hypoxia and suppression of the release of NO. Further studies are needed to test the impact of HbA1c on the development of the chronic liver disease.
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Budnar P, Singh NP, Rao CM. HSPB5 (αB-crystallin) confers protection against paraquat-induced oxidative stress at the organismal level in a tissue-dependent manner. Cell Stress Chaperones 2021; 26:229-239. [PMID: 33078332 PMCID: PMC7736594 DOI: 10.1007/s12192-020-01171-4] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2020] [Revised: 09/10/2020] [Accepted: 10/05/2020] [Indexed: 12/20/2022] Open
Abstract
Oxidative stress is one of the major and continuous stresses, an organism encounters during its lifetime. Tissues such as the brain, liver and muscles are more prone to damage by oxidative stress due to their metabolic activity, differences in physiological and adaptive processes. One of the defence mechanisms against continuous oxidative stress is a set of small heat shock proteins. αB-Crystallin/HSPB5, a small heat shock protein, gets upregulated under stress and acts as a molecular chaperone. In addition to acting as a molecular chaperone, HSPB5 is shown to have a role in other cytoprotective functions such as inhibition of apoptosis, prevention of oxidative stress and stabilisation of cytoskeletal system. Such protection in vivo, at the organism level, particularly in a tissue-dependent manner, has not been investigated. We have expressed HSPB5 in fat body (liver), neurons and specifically in dopaminergic and motor neurons in Drosophila and investigated its protective effect against paraquat-induced oxidative stress. We observed that expression of HSPB5 in neurons and fat body confers protection against paraquat-induced oxidative stress. Expression in dopaminergic neurons showed a higher protective effect. Our results clearly establish the protective ability of HSPB5 in vivo; the extent of protection, however, varies depending on the tissue in which it is expressed. Interestingly, neuronal expression of HSPB5 resulted in an improvement in negative geotropic behaviour, whereas specific expression in muscle tissue did not show such a beneficial effect.
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Affiliation(s)
- Prashanth Budnar
- Centre for Cellular and Molecular Biology (CCMB), Council of Scientific and Industrial Research (CSIR), Uppal Road, Hyderabad, 500007, India
| | - Narendra Pratap Singh
- Centre for Cellular and Molecular Biology (CCMB), Council of Scientific and Industrial Research (CSIR), Uppal Road, Hyderabad, 500007, India
- Stowers Institute for Medical Research, Kansas City, MO, 64110, USA
| | - Ch Mohan Rao
- Centre for Cellular and Molecular Biology (CCMB), Council of Scientific and Industrial Research (CSIR), Uppal Road, Hyderabad, 500007, India.
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24
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Hepatoprotective effect of pyrroloquinoline quinone against alcoholic liver injury through activating Nrf2-mediated antioxidant and inhibiting TLR4-mediated inflammation responses. Process Biochem 2020. [DOI: 10.1016/j.procbio.2020.01.023] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
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25
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Abstract
PURPOSE OF REVIEW The proportion of overweight and obese persons with HIV (PWH) has increased since the introduction of antiretroviral therapy (ART). We aim to summarize recent literature on risks of weight gain, discuss adipose tissue changes in HIV and obesity, and synthesize current understanding of how excess adiposity and HIV contribute to metabolic complications. RECENT FINDINGS Recent studies have implicated contemporary ART regimens, including use of integrase strand transfer inhibitors and tenofovir alafenamide, as a contributor to weight gain, though the mechanisms are unclear. Metabolic dysregulation is linked to ectopic fat and alterations in adipose immune cell populations that accompany HIV and obesity. These factors contribute to an increasing burden of metabolic diseases in the aging HIV population. Obesity compounds an increasing burden of metabolic disease among PWH, and understanding the role of fat partitioning and HIV- and ART-related adipose tissue dysfunction may guide prevention and treatment strategies.
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Affiliation(s)
- Samuel S Bailin
- Division of Infectious Diseases, Department of Medicine, Vanderbilt University Medical Center, 1161 21st Avenue South, Nashville, TN, 37232-2582, USA
| | - Curtis L Gabriel
- Division of Gastroenterology, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Celestine N Wanjalla
- Division of Infectious Diseases, Department of Medicine, Vanderbilt University Medical Center, 1161 21st Avenue South, Nashville, TN, 37232-2582, USA
| | - John R Koethe
- Division of Infectious Diseases, Department of Medicine, Vanderbilt University Medical Center, 1161 21st Avenue South, Nashville, TN, 37232-2582, USA.
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Abrahamovych M, Abrahamovych O, Fayura O, Tolopko S. Relation between redox homeostasis blood parameters in cirrhotic patients and endothelial dysfunction development. MINERVA GASTROENTERO 2020; 66:98-105. [PMID: 32218418 DOI: 10.23736/s1121-421x.20.02654-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
BACKGROUND Liver is one of the first organs to be exposed to reactive oxygen species (ROS). But the data about the levels of redox homeostasis parameters in the patients with liver cirrhosis (LC) are contradictory. We hypothesized that the levels of malondialdehyde and catalase should change in accordance with the LC severity causing the endothelial dysfunction. METHODS In a randomized way with the preliminary stratification by the presence of LC 81 patients and 20 healthy volunteers were examined. To determine the contents of catalase, malondialdehyde, cyclic guanosine monophosphate, endothelin-1, renin, aldosterone, natriuretic peptide, the routine standardized methods were used. RESULTS Patients with LC revealed the statistically significant increase of malondialdehyde and decrease of catalase levels in parallel with the increase of cyclic guanosine monophosphate, endothelin-1, renin, aldosterone, natriuretic peptide contents and disease course worsening according to the Child-Pugh criteria. It testifies the huge oxidative stress impact on the organism. Initially, at the stage of LC compensation, it slightly stimulates the activation of antioxidant system, followed by its gradual suppression at the stages of sub- and decompensation. Disorders of redox homeostasis lead to the endothelial dysfunction that becomes the background of extrahepatic comorbid disorders. CONCLUSIONS Cirrhotic patients have significant abnormalities in the redox homeostasis, which become the background of the endothelial dysfunction - common trigger mechanism for the syntrophic comorbid diseases and early pathophysiologic symptom of the unfavorable prognosis for such patients.
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Affiliation(s)
- Maryana Abrahamovych
- Department of Family Medicine, Danylo Halytsky Lviv National Medical University, Lviv, Ukraine
| | - Orest Abrahamovych
- Department of Internal Medicine N. 1, Danylo Halytsky Lviv National Medical University, Lviv, Ukraine
| | - Oksana Fayura
- Department of Internal Medicine N. 1, Danylo Halytsky Lviv National Medical University, Lviv, Ukraine -
| | - Solomiya Tolopko
- Department of Internal Medicine N. 1, Danylo Halytsky Lviv National Medical University, Lviv, Ukraine
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27
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Onnis A, Cassioli C, Finetti F, Baldari CT. Regulation of Selective B Cell Autophagy by the Pro-oxidant Adaptor p66SHC. Front Cell Dev Biol 2020; 8:193. [PMID: 32274384 PMCID: PMC7113388 DOI: 10.3389/fcell.2020.00193] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2020] [Accepted: 03/06/2020] [Indexed: 01/28/2023] Open
Abstract
p66SHC is a pro-oxidant member of the SHC family of protein adaptors that acts as a negative regulator of cell survival. In lymphocytes p66SHC exploits both its adaptor and its reactive oxygen species (ROS)-elevating function to antagonize mitogenic and survival signaling and promote apoptosis. As a result, p66SHC deficiency leads to the abnormal expansion of peripheral T and B cells and lupus-like autoimmunity. Additionally, a defect in p66SHC expression is a hallmark of B cell chronic lymphocytic leukemia, where it contributes to the accumulation of long-lived neoplastic cells. We have recently provided evidence that p66SHC exerts a further layer of control on B cell homeostasis by acting as a new mitochondrial LC3-II receptor to promote the autophagic demise of dysfunctional mitochondria. Here we discuss this finding in the context of the autophagic control of B cell homeostasis, development, and differentiation in health and disease.
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Affiliation(s)
- Anna Onnis
- Department of Life Sciences, University of Siena, Siena, Italy
| | - Chiara Cassioli
- Department of Life Sciences, University of Siena, Siena, Italy
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28
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Kašuba V, Micek V, Pizent A, Lovaković BT, Želježić D, Milić M, Kopjar N. DNA damage in kidney and parenchymal and non-parenchymal liver cells of adult Wistar rats after subchronic oral treatment with tembotrione. ENVIRONMENTAL SCIENCE AND POLLUTION RESEARCH INTERNATIONAL 2020; 27:1800-1807. [PMID: 31758481 DOI: 10.1007/s11356-019-06782-8] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/22/2019] [Accepted: 10/15/2019] [Indexed: 06/10/2023]
Abstract
DNA damage in the liver and kidney cells of adult male Wistar rats was studied using the comet assay after a 28-day oral administration of tembotrione at doses of 0.0007, 0.0013 and 0.7 mg/kg b.w./day [AOEL (acceptable operator exposure level), REL (residual exposure level) and 1000× AOEL]. As a descriptor of DNA damage, tail intensity was used. Antioxidant status was assessed by activity of glutathione peroxidase (GPx). Significant DNA damage was recorded in the kidney cells at all three doses as compared to negative control. In parenchymal liver cells, significant DNA damage was observed in AOEL and 1000× AOEL doses, while in non-parenchymal liver cells, only AOEL-treated group was significantly different compared to negative control. In both types of liver cells, REL and 1000× AOEL doses were significantly different from the AOEL dose. No significant changes in GPx activity compared to control were observed at any exposure level. The results of the present study suggest that repeated in vivo exposure to tembotrione led to low-level DNA instability in kidney and liver cells. Exposure to the highest tembotrione dose showed a relatively weak response with the alkaline comet assay. Further research should focus on the effects of this herbicide in other models along with different exposure scenarios.
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Affiliation(s)
- Vilena Kašuba
- Mutagenesis Unit, Institute for Medical Research and Occupational Health, Ksaverska c.2, 10000, Zagreb, Croatia.
| | - Vedran Micek
- Animal Breeding Unit, Institute for Medical Research and Occupational Health, Ksaverska c.2, Zagreb, Croatia
| | - Alica Pizent
- Analytical Toxicology and Mineral Metabolism Unit, Institute for Medical Research and Occupational Health, Ksaverska c.2, Zagreb, Croatia
| | - Blanka Tariba Lovaković
- Analytical Toxicology and Mineral Metabolism Unit, Institute for Medical Research and Occupational Health, Ksaverska c.2, Zagreb, Croatia
| | - Davor Želježić
- Mutagenesis Unit, Institute for Medical Research and Occupational Health, Ksaverska c.2, 10000, Zagreb, Croatia
| | - Mirta Milić
- Mutagenesis Unit, Institute for Medical Research and Occupational Health, Ksaverska c.2, 10000, Zagreb, Croatia
| | - Nevenka Kopjar
- Mutagenesis Unit, Institute for Medical Research and Occupational Health, Ksaverska c.2, 10000, Zagreb, Croatia
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Crude extract of Camellia oleifera pomace ameliorates the progression of non-alcoholic fatty liver disease via decreasing fat accumulation, insulin resistance and inflammation. Br J Nutr 2019; 123:508-515. [PMID: 31771682 DOI: 10.1017/s0007114519003027] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Consumption of a high-fat diet increases fat accumulation and may further lead to inflammation and hepatic injuries. The aim of the study was to investigate the effects of Camellia oleifera seed extract (CSE) on non-alcoholic fatty liver disease (NAFLD). After a 16-week NAFLD-inducing period, rats were assigned to experimental groups fed an NAFLD diet with or without CSE. At the end of the study, we found that consuming CSE decreased the abdominal fat weight and hepatic fat accumulation and modulated circulating adipokine levels. We also found that CSE groups had lower hepatic cytochrome P450 2E1 and transforming growth factor (TGF)-β protein expressions. In addition, we found that CSE consumption may have affected the gut microbiota and reduced toll-like receptor (TLR)-4, myeloid differentiation primary response gene 88, toll/IL-1 receptor domain-containing adaptor-inducing interferon-β (TRIF) expression and proinflammatory cytokine concentrations in the liver. Our results suggest that CSE may alleviate the progression of NAFLD in rats with diet-induced steatosis through reducing fat accumulation and improving lipid metabolism and hepatic inflammation.
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Curcumin Ameliorates Nonalcoholic Fatty Liver Disease through Inhibition of O-GlcNAcylation. Nutrients 2019; 11:nu11112702. [PMID: 31717261 PMCID: PMC6893521 DOI: 10.3390/nu11112702] [Citation(s) in RCA: 71] [Impact Index Per Article: 11.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2019] [Revised: 10/31/2019] [Accepted: 11/04/2019] [Indexed: 12/24/2022] Open
Abstract
The cause of progression to non-alcoholic fatty liver disease (NAFLD) is not fully understood. In the present study, we aimed to investigate how curcumin, a natural phytopolyphenol pigment, ameliorates NAFLD. Initially, we demonstrated that curcumin dramatically suppresses fat accumulation and hepatic injury induced in methionine and choline-deficient (MCD) diet mice. The severity of hepatic inflammation was alleviated by curcumin treatment. To identify the proteins involved in the pathogenesis of NAFLD, we also characterized the hepatic proteome in MCD diet mice. As a result of two-dimensional proteomic analysis, it was confirmed that thirteen proteins including antioxidant protein were differentially expressed in hepatic steatosis. However, the difference in expression was markedly improved by curcumin treatment. Interestingly, eight of the identified proteins are known to undergo O-GlcNAcylation modification. Thus, we further focused on elucidating how the regulation of O-linked β-N-acetylglucosamine (O-GlcNAc) modification is associated with the progression of hepatic steatosis leading to hepatitis in MCD diet mice. In parallel with lipid accumulation and inflammation, the MCD diet significantly up-regulated hexosamine biosynthetic pathway (HBP) and O-GlcNAc transferase (OGT) via ER stress. Curcumin treatment alleviates the severity of hepatic steatosis by relieving the dependence of O-GlcNAcylation on nuclear factor-κB (NF-κB) in inflammation signaling. Conversely, the expressions of superoxide dismutase 1 (SOD1) and SIRT1 were significantly upregulated by curcumin treatment. In conclusion, curcumin inhibits O-GlcNAcylation pathway, leading to antioxidant responses in non-alcoholic steatohepatitis (NASH) mice. Therefore, curcumin will be a promising therapeutic agent for diseases involving hyper-O-GlcNAcylation, including cancer.
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31
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Fang TJ, Guo JT, Lin MK, Lee MS, Chen YL, Lin WH. Protective effects of Lactobacillus plantarum against chronic alcohol-induced liver injury in the murine model. Appl Microbiol Biotechnol 2019; 103:8597-8608. [PMID: 31515596 DOI: 10.1007/s00253-019-10122-8] [Citation(s) in RCA: 31] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2019] [Revised: 08/26/2019] [Accepted: 09/04/2019] [Indexed: 02/07/2023]
Abstract
Long-term alcohol consumption causes liver injuries such as alcoholic hepatitis, fatty liver, and endotoxemia. Some probiotics were demonstrated to exert beneficial effects in the gastrointestinal tract. The present study was aimed to evaluate the protective effects of Lactobacillus plantarum CMU995 against alcohol-induced liver injury. The mice were orally administered L. plantarum CMU995 for 1 week, followed by the administration of alcohol and different tested substances daily for 6 weeks. The liver injury was examined by measuring the levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT), malondialdehyde (MDA), anti-oxidative enzyme, endotoxin, inflammatory cytokines, and lipid accumulation in the liver or serum among different groups. L. plantarum CMU995 exhibited beneficial effects on alcohol-induced liver injury via reduction in the serum concentration of AST, ALT, cholesterol, triglycerides, endotoxin, TNF-α, IL-1β, and oxidative stress. Furthermore, we also found that the levels of glutathione (GSH), superoxide dismutase (SOD), and intestinal tight junction protein zonula occludens-1 (ZO-1) were considerably higher in L. plantarum CMU995-fed groups when compared with placebo group. Meanwhile, the protective effects were demonstrated biological gradients as controversial dose-dependent. We speculate that L. plantarum CMU995 inhibited the migration of alcohol-derived endotoxin into the blood and liver, thereby improving the intestinal barrier. The present evidence may provide a novel microbiota-based strategy to prevent the alcohol-induced liver injury.
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Affiliation(s)
- Tony J Fang
- Department of Food Science and Biotechnology, National Chung Hsing University, Taichung, Taiwan, Republic of China
| | - Jiun-Ting Guo
- Department of Food Science and Biotechnology, National Chung Hsing University, Taichung, Taiwan, Republic of China.,Department of Pharmacy, China Medical University, Taichung, Taiwan, Republic of China
| | - Ming-Kuem Lin
- Department of Chinese Pharmaceutical Sciences and Chinese Medicine Resources, College of Pharmacy, China Medical University, Taichung, Taiwan, Republic of China
| | - Meng-Shiou Lee
- Department of Chinese Pharmaceutical Sciences and Chinese Medicine Resources, College of Pharmacy, China Medical University, Taichung, Taiwan, Republic of China
| | - Yen-Lien Chen
- Department of Food Science and Biotechnology, National Chung Hsing University, Taichung, Taiwan, Republic of China
| | - Wen-Hsin Lin
- Department of Pharmacy, China Medical University, Taichung, Taiwan, Republic of China. .,College of Pharmacy, China Medical University, No. 91, Hsueh Shih Road, Taichung, 404, Taiwan, Republic of China.
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Abstract
PURPOSE OF REVIEW We aim to provide an in-depth review of recent literature highlighting the role of inflammation involving the adipose tissue, liver, skeletal muscles, and gastrointestinal tract in the development of metabolic complications among persons living with HIV (PLWH). RECENT FINDINGS Recent studies in PLWH have demonstrated a significant association between circulating inflammatory markers and development of insulin resistance and metabolic complications. In adipose tissue, pro-inflammatory cytokine expression inhibits adipocyte insulin signaling, which alters lipid and glucose homeostasis. Increased lipolysis and lipogenesis elevate levels of circulating free fatty acids and promote ectopic fat deposition in liver and skeletal muscles. This leads to lipotoxicity characterized by a pro-inflammatory response with worsening insulin resistance. Finally, HIV is associated with gastrointestinal tract inflammation and changes in the gut microbiome resulting in reduced diversity, which is an additional risk factor for diabetes. Metabolic complications in PLWH are in part due to chronic, multisite tissue inflammation resulting in dysregulation of glucose and lipid trafficking, utilization, and storage.
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Abdelmegeed MA, Ha SK, Choi Y, Akbar M, Song BJ. Role of CYP2E1 in Mitochondrial Dysfunction and Hepatic Injury by Alcohol and Non-Alcoholic Substances. Curr Mol Pharmacol 2019; 10:207-225. [PMID: 26278393 DOI: 10.2174/1874467208666150817111114] [Citation(s) in RCA: 68] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2015] [Revised: 08/07/2015] [Accepted: 08/07/2015] [Indexed: 12/17/2022]
Abstract
Alcoholic fatty liver disease (AFLD) and non-alcoholic fatty liver disease (NAFLD) are two pathological conditions that are spreading worldwide. Both conditions are remarkably similar with regard to the pathophysiological mechanism and progression despite different causes. Oxidative stressinduced mitochondrial dysfunction through post-translational protein modifications and/or mitochondrial DNA damage has been a major risk factor in both AFLD and NAFLD development and progression. Cytochrome P450-2E1 (CYP2E1), a known important inducer of oxidative radicals in the cells, has been reported to remarkably increase in both AFLD and NAFLD. Interestingly, CYP2E1 isoforms expressed in both endoplasmic reticulum (ER) and mitochondria, likely lead to the deleterious consequences in response to alcohol or in conditions of NAFLD after exposure to high fat diet (HFD) and in obesity and diabetes. Whether CYP2E1 in both ER and mitochondria work simultaneously or sequentially in various conditions and whether mitochondrial CYP2E1 may exert more pronounced effects on mitochondrial dysfunction in AFLD and NAFLD are unclear. The aims of this review are to briefly describe the role of CYP2E1 and resultant oxidative stress in promoting mitochondrial dysfunction and the development or progression of AFLD and NAFLD, to shed a light on the function of the mitochondrial CYP2E1 as compared with the ER-associated CYP2E1. We finally discuss translational research opportunities related to this field.
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Affiliation(s)
- Mohamed A Abdelmegeed
- Section of Molecular Pharmacology and Toxicology, Laboratory of Membrane Biochemistry and Biophysics, National Institute on Alcohol Abuse and Alcoholism, 9000 Rockville Pike, Bethesda, MD 20892. United States
| | - Seung-Kwon Ha
- Section of Molecular Pharmacology and Toxicology, Laboratory of Membrane, Biochemistry and Biophysics, National Institute on Alcohol Abuse and Alcoholism, Bethesda, MD. United States
| | - Youngshim Choi
- Section of Molecular Pharmacology and Toxicology, Laboratory of Membrane, Biochemistry and Biophysics, National Institute on Alcohol Abuse and Alcoholism, Bethesda, MD. United States
| | - Mohammed Akbar
- Section of Molecular Pharmacology and Toxicology, Laboratory of Membrane, Biochemistry and Biophysics, National Institute on Alcohol Abuse and Alcoholism, Bethesda, MD. United States
| | - Byoung-Joon Song
- Section of Molecular Pharmacology and Toxicology, Laboratory of Membrane, Biochemistry and Biophysics, National Institute on Alcohol Abuse and Alcoholism, Bethesda, MD. United States
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Dornas W, Lagente V. Intestinally derived bacterial products stimulate development of nonalcoholic steatohepatitis. Pharmacol Res 2019; 141:418-428. [PMID: 30658094 DOI: 10.1016/j.phrs.2019.01.026] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/06/2018] [Revised: 01/12/2019] [Accepted: 01/14/2019] [Indexed: 02/08/2023]
Abstract
Fatty livers are susceptible to factors that cause inflammation and fibrosis, but fat deposition and the inflammatory response can be dissociated. While nonalcoholic fatty liver disease (NAFLD), caused by pathologic fat accumulation inside the liver, can remain stable for several years, in other cases NAFLD progresses to nonalcoholic steatohepatitis (NASH), which is characterized by fat accumulation and inflammation and is not a benign condition. In this review, we discuss the NASH host cells and microbial mechanisms that stimulate inflammation and predispose the liver to hepatocyte injury and fibrotic stages via increased lipid deposition. We highlight the interactions between intestine-derived bacterial products, such as lipopolysaccharide, and nutritional models of NAFLD and/or obese individuals. The results of modulating enteric microbiota suggest that gut-derived endotoxins may be essential determinants of fibrotic progression and regression in NASH.
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Affiliation(s)
- Waleska Dornas
- NuMeCan Institute (Nutrition, Metabolism and Cancer), Université de Rennes, INSERM, INRA, F-35000 Rennes, France.
| | - Vincent Lagente
- NuMeCan Institute (Nutrition, Metabolism and Cancer), Université de Rennes, INSERM, INRA, F-35000 Rennes, France.
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Zhao C, Fan J, Liu Y, Guo W, Cao H, Xiao J, Wang Y, Liu B. Hepatoprotective activity of Ganoderma lucidum triterpenoids in alcohol-induced liver injury in mice, an iTRAQ-based proteomic analysis. Food Chem 2019; 271:148-156. [PMID: 30236660 DOI: 10.1016/j.foodchem.2018.07.115] [Citation(s) in RCA: 34] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2017] [Revised: 07/14/2018] [Accepted: 07/17/2018] [Indexed: 02/05/2023]
Abstract
The hepatoprotective activity of ethanol extract of Ganoderma lucidum (GLE) in alcohol-induced liver injury in mice was investigated. HPLC coupled with photo-diode array detector and electrospray ionization-mass spectrometry was used to analyze the major triterpenoids in GLE. The effects of GLE on hepatoprotection were evaluated through histopathology and biochemical analysis of serum enzymes. We used isobaric tag for relative and absolute quantitation (iTRAQ) coupled with tandem mass spectrometry to identify differentially expressed liver proteome in mice. There were more than 4000 differentially expressed proteins; 40 proteins with the most significant changed proteins were applied for further bioinformatics analysis. Expression levels of cytochrome P450 2E1 and alcohol dehydrogenase 1, proteins that are closely associated with these processes, were validated by western blotting. Triterpenoids, major components of GLE, protected alcohol-induced liver injury through inhibiting lipid peroxidation, elevating activity of antioxidant enzymes, and suppressing apoptotic cell death and immune inflammatory response.
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Affiliation(s)
- Chao Zhao
- College of Food Science, Fujian Agriculture and Forestry University, Fuzhou, Fujian 350002, China
| | - Jinlin Fan
- College of Life Science, Fujian Agriculture and Forestry University, Fuzhou, Fujian 350002, China; National Engineering Research Center of JUNCAO, Fuzhou 350002, China
| | - Yuanyuan Liu
- College of Food Science, Fujian Agriculture and Forestry University, Fuzhou, Fujian 350002, China
| | - Weiling Guo
- College of Food Science, Fujian Agriculture and Forestry University, Fuzhou, Fujian 350002, China
| | - Hui Cao
- Institute of Chinese Medical Sciences and State Key Laboratory of Quality Control in Chinese Medicine, University of Macau, Macau
| | - Jianbo Xiao
- Institute of Chinese Medical Sciences and State Key Laboratory of Quality Control in Chinese Medicine, University of Macau, Macau
| | - Ying Wang
- Institute of Chinese Medical Sciences and State Key Laboratory of Quality Control in Chinese Medicine, University of Macau, Macau.
| | - Bin Liu
- College of Food Science, Fujian Agriculture and Forestry University, Fuzhou, Fujian 350002, China; National Engineering Research Center of JUNCAO, Fuzhou 350002, China.
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Lv H, Fan X, Wang L, Feng H, Ci X. Daphnetin alleviates lipopolysaccharide/d-galactosamine-induced acute liver failure via the inhibition of NLRP3, MAPK and NF-κB, and the induction of autophagy. Int J Biol Macromol 2018; 119:240-248. [PMID: 30031824 DOI: 10.1016/j.ijbiomac.2018.07.101] [Citation(s) in RCA: 31] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2018] [Revised: 07/14/2018] [Accepted: 07/16/2018] [Indexed: 01/31/2023]
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Muñoz S, Méndez L, Dasilva G, Torres JL, Ramos-Romero S, Romeu M, Nogués MR, Medina I. Targeting Hepatic Protein Carbonylation and Oxidative Stress Occurring on Diet-Induced Metabolic Diseases through the Supplementation with Fish Oils. Mar Drugs 2018; 16:E353. [PMID: 30261666 PMCID: PMC6213247 DOI: 10.3390/md16100353] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2018] [Revised: 09/20/2018] [Accepted: 09/25/2018] [Indexed: 01/01/2023] Open
Abstract
The present study addressed the ability of long-chain ω-3 polyunsaturated fatty acids (ω-3 PUFA), i.e., eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), to ameliorate liver protein damage derived from oxidative stress and induced by consumption of high-caloric diets, typical of Westernized countries. The experimental design included an animal model of Sprague-Dawley rats fed high-fat high-sucrose (HFHS) diet supplemented with ω-3 EPA and DHA for a complete hepatic proteome analysis to map carbonylated proteins involved in specific metabolic pathways. Results showed that the intake of marine ω-3 PUFA through diet significantly decreased liver protein carbonylation caused by long-term HFHS consumption and increased antioxidant system. Fish oil modulated the carbonylation level of more than twenty liver proteins involved in critical metabolic pathways, including lipid metabolism (e.g., albumin), carbohydrate metabolism (e.g., pyruvate carboxylase), detoxification process (e.g., aldehyde dehydrogenase 2), urea cycle (e.g., carbamoyl-phosphate synthase), cytoskeleton dynamics (e.g., actin), or response to oxidative stress (e.g., catalase) among others, which might be under the control of diet marine ω-3 PUFA. In parallel, fish oil significantly changed the liver fatty acid profile given by the HFHS diet, resulting in a more anti-inflammatory phenotype. In conclusion, the present study highlights the significance of marine ω-3 PUFA intake for the health of rats fed a Westernized diet by describing several key metabolic pathways which are protected in liver.
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Affiliation(s)
- Silvia Muñoz
- Instituto de Investigaciones Marinas, Consejo Superior de Investigaciones Científicas (IIM-CSIC), E-36208 Vigo, Spain.
| | - Lucía Méndez
- Instituto de Investigaciones Marinas, Consejo Superior de Investigaciones Científicas (IIM-CSIC), E-36208 Vigo, Spain.
| | - Gabriel Dasilva
- Instituto de Investigaciones Marinas, Consejo Superior de Investigaciones Científicas (IIM-CSIC), E-36208 Vigo, Spain.
| | - Josep Lluís Torres
- Instituto de Química Avanzada de Catalunya, Consejo Superior de Investigaciones Científicas (IQAC-CSIC) Jordi Girona 18-26, E-08034 Barcelona, Spain.
| | - Sara Ramos-Romero
- Instituto de Química Avanzada de Catalunya, Consejo Superior de Investigaciones Científicas (IQAC-CSIC) Jordi Girona 18-26, E-08034 Barcelona, Spain.
| | - Marta Romeu
- Unidad de Farmacología, Facultad de Medicina, Universidad Rovira i Virgili, Sant Llorenç 21, E-43201 Reus, Spain.
| | - María Rosa Nogués
- Unidad de Farmacología, Facultad de Medicina, Universidad Rovira i Virgili, Sant Llorenç 21, E-43201 Reus, Spain.
| | - Isabel Medina
- Instituto de Investigaciones Marinas, Consejo Superior de Investigaciones Científicas (IIM-CSIC), E-36208 Vigo, Spain.
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Xu M, Chen L, Li J, Wu H, Xia Q, Kong X. Emerging roles of DJ-1 in liver diseases through regulation of oxidative stress and immune response. LIVER RESEARCH 2018. [DOI: 10.1016/j.livres.2018.06.001] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/16/2023]
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Gupta A. A Tale of Two Diseases or A Story of Co-Existence: Are Obese Individuals' Immune To Alcoholic Liver Disease? J Clin Exp Hepatol 2018; 8:212. [PMID: 29892187 PMCID: PMC5992312 DOI: 10.1016/j.jceh.2017.09.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/13/2017] [Indexed: 12/12/2022] Open
Affiliation(s)
- Ankur Gupta
- Address for correspondence: Ankur Gupta, Department of Gastroenterology, Max Super Speciality Hospital, Dehradun 248001, India. Tel.: +91 9450274612
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Coia H, Ma N, He AR, Kallakury B, Berry DL, Permaul E, Makambi KH, Fu Y, Chung FL. Detection of a lipid peroxidation-induced DNA adduct across liver disease stages. Hepatobiliary Surg Nutr 2018; 7:85-97. [PMID: 29744335 DOI: 10.21037/hbsn.2017.06.01] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Background Oxidative stress and chronic inflammation can increase cellular levels of reactive oxygen species and lipid peroxidation (LPO) when associated with the pathogenesis of hepatocellular carcinoma (HCC), which can develop following the progression of steatosis, fibrosis and cirrhosis. Using a monoclonal antibody for cyclic γ-hydroxy-1, N2 -propanodeoxyguanosine (γ-OHPdG), a promutagenic DNA adduct formed endogenously by LPO, we examined its formation across liver disease stages to understand it's potential role in HCC development. Methods Formalin-fixed paraffin embedded (FFPE) liver tissue samples from 49 patients representing normal, steatosis, fibrosis, cirrhosis and HCC were stained for γ-OHPdG and 8-hydroxydeoxyguanosine (8-oxo-dG), an oxidative damage biomarker. Quantification of immunohistochemical (IHC) staining was performed using histological scoring of intensity and distribution. Using primary human hepatocytes (HH) and a stellate cell (SC) co-culture, immunocytochemical staining of γ-OHPdG and Nile Red was performed to determine if the formation of γ-OHPdG was consistent between the clinical sample disease stages and the in vitro steatotic and fibrotic conditions. Results γ-OHPdG levels varied significantly between the stages of normal and steatosis, steatosis and fibrosis, and steatosis and cirrhosis (P≤0.005). There was a trend, although not significant, of increased levels of γ-OHPdG in HCC compared to the other groups. A strong correlation was observed (Pearson's, R2 =0.85) between levels of γ-OHPdG and 8-oxo-dG across the disease spectrum. The increase of γ-OHPdG in steatosis and decrease in fibrosis was a pattern confirmed in an in vitro model using primary HH co-cultured with human SCs. Conclusions γ-OHPdG was detected in FFPE liver tissues of patients with different stages of liver disease and in vitro studies, demonstrating that its formation is consistent with LPO in early stages of liver disease and suggesting that it may be a source of mutagenic DNA damage in liver disease progression.
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Affiliation(s)
- Heidi Coia
- Department of Biochemistry & Molecular Biology, Georgetown University Medical Center, Washington, DC, USA
| | - Ning Ma
- Department of Biochemistry & Molecular Biology, Georgetown University Medical Center, Washington, DC, USA
| | - Aiwu Ruth He
- Department of Oncology, Bioinformatics, and Biomathematics, Georgetown University, Washington, DC, USA
| | - Bhaskar Kallakury
- Department of Pathology, Lombardi Comprehensive Cancer Center, Bioinformatics, and Biomathematics, Georgetown University, Washington, DC, USA
| | - Deborah L Berry
- Department of Oncology, Bioinformatics, and Biomathematics, Georgetown University, Washington, DC, USA
| | - Eva Permaul
- Department of Oncology, Bioinformatics, and Biomathematics, Georgetown University, Washington, DC, USA
| | - Kepher H Makambi
- Department of Biostatistics, Bioinformatics, and Biomathematics, Georgetown University, Washington, DC, USA
| | - Ying Fu
- Department of Oncology, Bioinformatics, and Biomathematics, Georgetown University, Washington, DC, USA
| | - Fung-Lung Chung
- Department of Biochemistry & Molecular Biology, Georgetown University Medical Center, Washington, DC, USA.,Department of Oncology, Bioinformatics, and Biomathematics, Georgetown University, Washington, DC, USA
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Boyle M, Masson S, Anstee QM. The bidirectional impacts of alcohol consumption and the metabolic syndrome: Cofactors for progressive fatty liver disease. J Hepatol 2018; 68:251-267. [PMID: 29113910 DOI: 10.1016/j.jhep.2017.11.006] [Citation(s) in RCA: 117] [Impact Index Per Article: 16.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/13/2017] [Revised: 10/30/2017] [Accepted: 11/01/2017] [Indexed: 12/12/2022]
Abstract
Current medical practice artificially dichotomises a diagnosis of fatty liver disease into one of two common forms: alcoholic liver disease (ALD) and non-alcoholic fatty liver disease (NAFLD). Together, these account for the majority of chronic liver diseases worldwide. In recent years, there has been a dramatic increase in the prevalence of obesity and metabolic syndrome within the general population. These factors now coexist with alcohol consumption in a substantial proportion of the population. Each exposure sensitises the liver to the injurious effects of the other; an interaction that drives and potentially accelerates the genesis of liver disease. We review the epidemiological evidence and scientific literature that considers how alcohol consumption interacts with components of the metabolic syndrome to exert synergistic or supra-additive effects on the development and progression of liver disease, before discussing how these interactions may be addressed in clinical practice.
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Affiliation(s)
- Marie Boyle
- Institute of Cellular Medicine, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, United Kingdom; Liver Unit, Newcastle Upon Tyne Hospitals NHS Trust, Freeman Hospital, Newcastle upon Tyne, United Kingdom
| | - Steven Masson
- Institute of Cellular Medicine, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, United Kingdom; Liver Unit, Newcastle Upon Tyne Hospitals NHS Trust, Freeman Hospital, Newcastle upon Tyne, United Kingdom
| | - Quentin M Anstee
- Institute of Cellular Medicine, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, United Kingdom; Liver Unit, Newcastle Upon Tyne Hospitals NHS Trust, Freeman Hospital, Newcastle upon Tyne, United Kingdom.
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Montes-Cortés DH, Novelo-Del Valle JL, Olivares-Corichi IM, Rosas-Barrientos JV, Jara LJ, Cruz-Domínguez MP. Impact of intestinal mannitol on hyperammonemia, oxidative stress and severity of hepatic encephalopathy in the ED. Am J Emerg Med 2018; 36:1570-1576. [PMID: 29352675 DOI: 10.1016/j.ajem.2018.01.032] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2017] [Revised: 01/07/2018] [Accepted: 01/08/2018] [Indexed: 12/20/2022] Open
Abstract
Hyperammonemia results from hepatic inability to remove nitrogenous products generated by protein metabolism of intestinal microbiota, which leads to hepatic encephalopathy (HE) in chronic liver disease (CLD). In ammonium neurotoxicity, oxidative stress (OxS) plays a pathogenic role. Our objective was to evaluate if intestinal mannitol is as effective and safe as conventional treatment for diminishing hyperammonemia, OxS, and HE in patients with CLD. MATERIAL AND METHODS We included 30 patients with HE classified by "Haven Criteria for Hepatic Encephalopathy". They were randomized into two groups: 1) Mannitol Group (MG) with mannitol 20% administered into the intestine by an enema, 2) conventional group (CG) with lactulose 40 g enema both substances were diluted in 800 mL of double distilled solution every 6 h; all patients received neomycin. We evaluated ammonia concentration, plasma oxidative stress, HE severity, intestinal discomfort and adverse effects. RESULTS Hyperammonemia (171 ± 104 vs 79 ± 49 μmol ammonia/L, p < 0.01), and oxidative stress (MDA 29 vs 27%, formazan 15 vs 11%, carbonyls 16 vs 9% and dityrosines 10 vs 5%) were reduced in MG and CG respectively. The HE severity decreased by two degrees compared to baseline values in both groups. Intestinal discomfort and electrolyte plasma alterations were less frequent (p < 0.05) in MG than CG. CONCLUSIONS Intestinal mannitol is as effective and safe as conventional treatment for reducing hyperammonemia, oxidative stress, and hepatic encephalopathy of CLD patients in the emergency room. Likewise, mannitol is better tolerated than conventional treatment.
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Affiliation(s)
- Daniel H Montes-Cortés
- Urgencias Adultos. Hospital General, Centro Médico Nacional "La Raza", Instituto Mexicano del Seguro Social, 02990 Ciudad de México, Mexico; Coordinación de Enseñanza e Investigación. Hospital Regional 1° de Octubre, Instituto de Seguridad y Servicios Sociales de los Trabajadores del Estado, 07760 Ciudad de México, Mexico
| | - José L Novelo-Del Valle
- Urgencias Adultos. Hospital General, Centro Médico Nacional "La Raza", Instituto Mexicano del Seguro Social, 02990 Ciudad de México, Mexico
| | - Ivonne M Olivares-Corichi
- Sección de Estudios y Posgrado en Investigación. Escuela Superior de Medicina, Instituto Politécnico Nacional, 11340 Ciudad de México, Mexico
| | - José V Rosas-Barrientos
- Coordinación de Enseñanza e Investigación. Hospital Regional 1° de Octubre, Instituto de Seguridad y Servicios Sociales de los Trabajadores del Estado, 07760 Ciudad de México, Mexico
| | - Luis J Jara
- División de Investigación en Salud. Hospital Especialidades, Centro Médico Nacional "La Raza", Instituto Mexicano del Seguro Social, 02990 Ciudad de México, Mexico
| | - María Pilar Cruz-Domínguez
- División de Investigación en Salud. Hospital Especialidades, Centro Médico Nacional "La Raza", Instituto Mexicano del Seguro Social, 02990 Ciudad de México, Mexico.
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Gao B, Zakhari S. Epidemiology and Pathogenesis of Alcoholic Liver Disease. ZAKIM AND BOYER'S HEPATOLOGY 2018:334-344.e3. [DOI: 10.1016/b978-0-323-37591-7.00022-7] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 09/01/2023]
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Carpino G, Pastori D, Baratta F, Overi D, Labbadia G, Polimeni L, Di Costanzo A, Pannitteri G, Carnevale R, Del Ben M, Arca M, Violi F, Angelico F, Gaudio E. PNPLA3 variant and portal/periportal histological pattern in patients with biopsy-proven non-alcoholic fatty liver disease: a possible role for oxidative stress. Sci Rep 2017; 7:15756. [PMID: 29150621 PMCID: PMC5693899 DOI: 10.1038/s41598-017-15943-z] [Citation(s) in RCA: 48] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2017] [Accepted: 11/05/2017] [Indexed: 12/13/2022] Open
Abstract
Pathogenesis of non-alcoholic fatty liver disease (NAFLD) is influenced by predisposing genetic variations, dysmetabolism, systemic oxidative stress, and local cellular and molecular cross-talks. Patatin-like phospholipase domain containing 3 (PNPLA3) gene I148M variant is a known determinant of NAFLD. Aims were to evaluate whether PNPLA3 I148M variant was associated with a specific histological pattern, hepatic stem/progenitor cell (HpSC) niche activation and serum oxidative stress markers. Liver biopsies were obtained from 54 NAFLD patients. The activation of HpSC compartment was evaluated by the extension of ductular reaction (DR); hepatic stellate cells, myofibroblasts (MFs), and macrophages were evaluated by immunohistochemistry. Systemic oxidative stress was assessed measuring serum levels of soluble NOX2-derived peptide (sNOX2-dp) and 8-isoprostaglandin F2α (8-iso-PGF2α). PNPLA3 carriers showed higher steatosis, portal inflammation and HpSC niche activation compared to wild-type patients. DR was correlated with NAFLD activity score (NAS) and fibrosis score. Serum 8-iso-PGF2α were significantly higher in I148M carriers compared to non-carriers and were correlated with DR and portal inflammation. sNox2-dp was correlated with NAS and with HpSC niche activation. In conclusion, NAFLD patients carrying PNPLA3 I148M are characterized by a prominent activation of HpSC niche which is associated with a more aggressive histological pattern (portal fibrogenesis) and increased oxidative stress.
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Affiliation(s)
- Guido Carpino
- Department of Movement, Human and Health Sciences, University of Rome "Foro Italico", Rome, Italy
| | - Daniele Pastori
- Department of Internal Medicine and Medical Specialties, I Clinica Medica, Sapienza University of Rome, Rome, Italy
- Department of Anatomical, Histological, Forensic Medicine and Orthopaedics Sciences, Sapienza University, Rome, Italy
| | - Francesco Baratta
- Department of Internal Medicine and Medical Specialties, I Clinica Medica, Sapienza University of Rome, Rome, Italy
- Department of Anatomical, Histological, Forensic Medicine and Orthopaedics Sciences, Sapienza University, Rome, Italy
| | - Diletta Overi
- Department of Anatomical, Histological, Forensic Medicine and Orthopaedics Sciences, Sapienza University, Rome, Italy
| | - Giancarlo Labbadia
- Department of Internal Medicine and Medical Specialties, I Clinica Medica, Sapienza University of Rome, Rome, Italy
| | - Licia Polimeni
- Department of Internal Medicine and Medical Specialties, I Clinica Medica, Sapienza University of Rome, Rome, Italy
| | - Alessia Di Costanzo
- Department of Internal Medicine and Medical Specialties, I Clinica Medica, Sapienza University of Rome, Rome, Italy
| | - Gaetano Pannitteri
- Department of Cardiovascular, Respiratory, Nephrologic, Anaesthesiologic and Geriatric Sciences, Sapienza University of Rome, Rome, Italy
| | - Roberto Carnevale
- Department of Internal Medicine and Medical Specialties, I Clinica Medica, Sapienza University of Rome, Rome, Italy
- Department of Medical-Surgical Sciences and Biotechnologies, Sapienza University of Rome, Latina, Italy
| | - Maria Del Ben
- Department of Internal Medicine and Medical Specialties, I Clinica Medica, Sapienza University of Rome, Rome, Italy
| | - Marcello Arca
- Department of Internal Medicine and Medical Specialties, I Clinica Medica, Sapienza University of Rome, Rome, Italy
| | - Francesco Violi
- Department of Internal Medicine and Medical Specialties, I Clinica Medica, Sapienza University of Rome, Rome, Italy
| | - Francesco Angelico
- Department of Public Health and Infectious Diseases, Sapienza University, Rome, Italy.
| | - Eugenio Gaudio
- Department of Anatomical, Histological, Forensic Medicine and Orthopaedics Sciences, Sapienza University, Rome, Italy
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Liebig M, Hassanzada A, Kämmerling M, Genz B, Vollmar B, Abshagen K. Microcirculatory disturbances and cellular changes during progression of hepatic steatosis to liver tumors. Exp Biol Med (Maywood) 2017; 243:1-12. [PMID: 29065724 DOI: 10.1177/1535370217738730] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Non-alcoholic fatty liver disease is closely associated with metabolic syndrome and comprises a pathological spectrum of liver disease ranging from steatosis to steatohepatitis and can progress to fibrosis/cirrhosis and hepatocellular carcinoma. In 2013, a mouse model was described that mimics non-alcoholic fatty liver disease progression from steatohepatitis to tumors in a short time span and with high incidence. As microcirculatory disturbances play a crucial role in liver disease, the suitability of the steatosis-inflammation-tumor model for microcirculatory studies was assessed. Herein, we present a comprehensive view on morphological, microvascular, cellular, and functional aspects of non-alcoholic fatty liver disease progression in the steatosis-inflammation-tumor model using intravital microscopy, biochemical, and histological techniques. Mice develop steatohepatitis, mild fibrosis, and liver tumors at ages of 6, 12, and 20 weeks, respectively. Non-alcoholic fatty liver disease progression was accompanied by several general aspects of disease severity like increasing liver/body weight index, non-alcoholic fatty liver disease activity score, and hepatocellular apoptosis. Intravital microscopic analysis revealed significant changes in hepatic microcirculation with increasing structural alterations, elevated leukocyte adherence, and impaired nutritive perfusion. Non-alcoholic fatty liver disease was further characterized by a lower sinusoidal density with a striking rise at 20 weeks. The characteristic microcirculatory changes make the model a convenient tool for analysis of microcirculation during progression from steatosis to liver tumor. Impact statement Significant alterations of microcirculation contribute to progression of NAFLD, a chronic liver disease with increasing medical and socio-economic impact. Characterization of microcirculation in a NAFLD model reflecting all relevant stages of disease progression was still missing. Thus, we evaluated microcirculatory and cellular changes in a steatosis-inflammation-tumor model using in vivo microscopy. Analyses revealed increasing structural alterations, elevated leukocyte-endothelial interaction, and impaired nutritive perfusion. Thus, this model is suitable for further studies investigating therapeutic approaches targeting these progressive microcirculatory disturbances.
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Affiliation(s)
- Marie Liebig
- 1 Institute for Experimental Surgery, University Medicine Rostock, Rostock 18057, Germany
| | - Alireza Hassanzada
- 1 Institute for Experimental Surgery, University Medicine Rostock, Rostock 18057, Germany
| | - Malte Kämmerling
- 1 Institute for Experimental Surgery, University Medicine Rostock, Rostock 18057, Germany
| | - Berit Genz
- 1 Institute for Experimental Surgery, University Medicine Rostock, Rostock 18057, Germany.,2 QIMR Berghofer Medical Research Institute, Brisbane QLD 4006, Australia
| | - Brigitte Vollmar
- 1 Institute for Experimental Surgery, University Medicine Rostock, Rostock 18057, Germany
| | - Kerstin Abshagen
- 1 Institute for Experimental Surgery, University Medicine Rostock, Rostock 18057, Germany
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Hepatic Immune Microenvironment in Alcoholic and Nonalcoholic Liver Disease. BIOMED RESEARCH INTERNATIONAL 2017; 2017:6862439. [PMID: 28852648 PMCID: PMC5567444 DOI: 10.1155/2017/6862439] [Citation(s) in RCA: 42] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/12/2017] [Accepted: 07/06/2017] [Indexed: 01/18/2023]
Abstract
Many types of innate (natural killer cells, natural killer T cells, and Kupffer cells/macrophages) and adaptive (T cells and B cells) immune cells are enriched within the liver and function in liver physiology and pathology. Liver pathology is generally induced by two types of immunologic insults: failure to eliminate antigens derived from the gastrointestinal tract which are important for host defense and an impaired tissue protective tolerance mechanism that helps reduce the negative outcomes of immunopathology. Accumulating evidence from the last several decades suggests that hepatic immune cells play an important role in the pathogenesis of alcoholic and nonalcoholic liver injury and inflammation in humans and mice. Here, we focus on the roles of innate and adaptive immune cells in the development and maintenance of alcoholic liver disease and nonalcoholic fatty liver disease/nonalcoholic steatohepatitis. Additionally, the pathogenesis of liver disease and new therapeutic targets for preventing and treating alcoholic liver disease and nonalcoholic fatty liver disease/nonalcoholic steatohepatitis are discussed.
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Patouraux S, Rousseau D, Bonnafous S, Lebeaupin C, Luci C, Canivet CM, Schneck AS, Bertola A, Saint-Paul MC, Iannelli A, Gugenheim J, Anty R, Tran A, Bailly-Maitre B, Gual P. CD44 is a key player in non-alcoholic steatohepatitis. J Hepatol 2017; 67:328-338. [PMID: 28323124 DOI: 10.1016/j.jhep.2017.03.003] [Citation(s) in RCA: 96] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/27/2016] [Revised: 02/01/2017] [Accepted: 03/02/2017] [Indexed: 02/08/2023]
Abstract
BACKGROUND & AIMS Cluster of differentiation (CD)44 regulates adipose tissue inflammation in obesity and hepatic leukocyte recruitment in a lithogenic context. However, its role in hepatic inflammation in a mouse model of steatohepatitis and its relevance in humans have not yet been investigated. We aimed to evaluated the contribution of CD44 to non-alcoholic steatohepatitis (NASH) development and liver injury in mouse models and in patients at various stages of non-alcoholic fatty liver disease (NAFLD) progression. METHODS The role of CD44 was evaluated in CD44-/- mice and after injections of an αCD44 antibody in wild-type mice challenged with a methionine- and choline-deficient diet (MCDD). In obese patients, hepatic CD44 (n=30 and 5 NASH patients with a second liver biopsy after bariatric surgery) and serum sCD44 (n=64) were evaluated. RESULTS Liver inflammation (including inflammatory foci number, macrophage and neutrophil infiltration and CCL2/CCR2 levels), liver injury and fibrosis strongly decreased in CD44-/- mice compared to wild-type mice on MCDD. CD44 deficiency enhanced the M2 polarization and strongly decreased the activation of macrophages by lipopolysaccharide (LPS), hepatocyte damage-associated molecular patterns (DAMPs) and saturated fatty acids. Neutralization of CD44 in mice with steatohepatitis strongly decreased the macrophage infiltration and chemokine ligand (CCL)2 expression with a partial correction of liver inflammation and injury. In obese patients, hepatic CD44 was strongly upregulated in NASH patients (p=0.0008) and correlated with NAFLD activity score (NAS) (p=0.001), ballooning (p=0.003), alanine transaminase (p=0.005) and hepatic CCL2 (p<0.001) and macrophage marker CD68 (p<0.001) expression. Correction of NASH was associated with a strong decrease in liver CD44+ cells. Finally, the soluble form of CD44 increased with severe steatosis (p=0.0005) and NASH (p=0.007). CONCLUSION Human and experimental data suggest that CD44 is a marker and key player of hepatic inflammation and its targeting partially corrects NASH. LAY SUMMARY Human and experimental data suggest that CD44, a cellular protein mainly expressed in immune cells, is a marker and key player of non-alcoholic steatohepatitis (NASH). Indeed, CD44 enhances the non-alcoholic fatty liver (NAFL) (hepatic steatosis) to NASH progression by regulating hepatic macrophage polarization (pro-inflammatory phenotype) and infiltration (macrophage motility and the MCP1/CCL2/CCR2 system). Targeting CD44 partially corrects NASH, making it a potential therapeutic strategy.
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Affiliation(s)
- Stéphanie Patouraux
- INSERM, U1065, C3M, Team 8 "Hepatic Complications in Obesity", Nice, France; Université Côte d'Azur, Nice, France; CHU of Nice, Biological Center, Pasteur Hôpital, Nice, France
| | - Déborah Rousseau
- INSERM, U1065, C3M, Team 8 "Hepatic Complications in Obesity", Nice, France; Université Côte d'Azur, Nice, France
| | - Stéphanie Bonnafous
- INSERM, U1065, C3M, Team 8 "Hepatic Complications in Obesity", Nice, France; Université Côte d'Azur, Nice, France; CHU of Nice, Digestive Center, Nice, France
| | - Cynthia Lebeaupin
- INSERM, U1065, C3M, Team 8 "Hepatic Complications in Obesity", Nice, France; Université Côte d'Azur, Nice, France
| | - Carmelo Luci
- INSERM, U1065, C3M, Team 8 "Hepatic Complications in Obesity", Nice, France; Université Côte d'Azur, Nice, France
| | - Clémence M Canivet
- INSERM, U1065, C3M, Team 8 "Hepatic Complications in Obesity", Nice, France; Université Côte d'Azur, Nice, France; CHU of Nice, Digestive Center, Nice, France
| | - Anne-Sophie Schneck
- INSERM, U1065, C3M, Team 8 "Hepatic Complications in Obesity", Nice, France; Université Côte d'Azur, Nice, France; CHU of Nice, Digestive Center, Nice, France
| | - Adeline Bertola
- INSERM, U1065, C3M, Team 8 "Hepatic Complications in Obesity", Nice, France; Université Côte d'Azur, Nice, France
| | - Marie-Christine Saint-Paul
- INSERM, U1065, C3M, Team 8 "Hepatic Complications in Obesity", Nice, France; Université Côte d'Azur, Nice, France; CHU of Nice, Biological Center, Pasteur Hôpital, Nice, France
| | - Antonio Iannelli
- INSERM, U1065, C3M, Team 8 "Hepatic Complications in Obesity", Nice, France; Université Côte d'Azur, Nice, France; CHU of Nice, Digestive Center, Nice, France
| | - Jean Gugenheim
- INSERM, U1065, C3M, Team 8 "Hepatic Complications in Obesity", Nice, France; Université Côte d'Azur, Nice, France; CHU of Nice, Digestive Center, Nice, France
| | - Rodolphe Anty
- INSERM, U1065, C3M, Team 8 "Hepatic Complications in Obesity", Nice, France; Université Côte d'Azur, Nice, France; CHU of Nice, Digestive Center, Nice, France
| | - Albert Tran
- INSERM, U1065, C3M, Team 8 "Hepatic Complications in Obesity", Nice, France; Université Côte d'Azur, Nice, France; CHU of Nice, Digestive Center, Nice, France
| | - Béatrice Bailly-Maitre
- INSERM, U1065, C3M, Team 8 "Hepatic Complications in Obesity", Nice, France; Université Côte d'Azur, Nice, France
| | - Philippe Gual
- INSERM, U1065, C3M, Team 8 "Hepatic Complications in Obesity", Nice, France; Université Côte d'Azur, Nice, France.
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Sangodele JO, Olaleye MT, Monsees TK, Akinmoladun AC. The para isomer of dinitrobenzene disrupts redox homeostasis in liver and kidney of male wistar rats. Biochem Biophys Rep 2017; 10:297-302. [PMID: 28955757 PMCID: PMC5614678 DOI: 10.1016/j.bbrep.2017.04.017] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2016] [Revised: 03/24/2017] [Accepted: 04/26/2017] [Indexed: 02/07/2023] Open
Abstract
Background Para-Dinitrobenzene (p-DNB) is one of the isomers of dinitrobenzene which have been detected as environmental toxicants. Skin irritation and organ toxicities are likely for industrial workers exposed to p-DNB. This study evaluated the effect of sub-chronic exposure of rats to p-DNB on cellular redox balance, hepatic and renal integrity. Methods Forty eight male Wistar rats weighing 160–180 g were administered 50, 75, 1000 and 2000 mg/kg b.wt (body weight) of p-DNB or an equivalent volume of vehicle (control) orally and topically for 14 days. After the period of treatment, the activities of kidney and liver catalase (CAT), alkaline phosphatase (ALP) and superoxide dismutase (SOD) as well as extent of renal and hepatic lipid peroxidation (LPO) were determined. Serum ALP activity and plasma urea concentration were also evaluated. Results Compared with control animals, p-DNB -administered rats showed decrease in the body and relative kidney and liver weights as well as increased renal and hepatic hydrogen peroxide and lipid peroxidation levels accompanied by decreased superoxide dismutase and catalase activities. However, p-DNB caused a significant increase in plasma urea concentration and serum, liver and kidney ALP activities relative to control. In addition, p-DNB caused periportal infiltration, severe macro vesicular steatosis and hepatic necrosis in the liver. Conclusions Our findings show that sub-chronic oral and sub-dermal administration of p-DNB may produce hepato-nephrotoxicity through oxidative stress.
Activities of kidney and liver catalase and superoxide dismutase were decreased by p-DNB. p-DNB increased serum, liver and kidney activity of alkaline phosphatase. Plasma urea concentration was increased by p-DNB. Lipid peroxidation and H2O2 level were increased by p-DNB. p-DNB caused histopathological changes in liver and kidney tissues.
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Key Words
- ALP, alanine phosphatase
- CAT, Catalase
- Environmental toxicants
- GSH, glutathione
- GST, glutathione –s –transferase, GPX, glutathione reductase, NIH, national institute of health
- H&E, hamatoxilin eosin
- Kidney
- LPO, lipid peroxidation
- Liver
- MDA, malodialdehyde
- OECD, Organisation for economic co-operation and Development
- Oxidative stress
- PHS, public health service
- SOD, Superoxide dismutase
- SPSS, Statistical Pucteage for Social Sciences
- Sub-dermal
- TBA, thiobarbituric acid
- TNB, trinitrobenzene
- o-DNB, ortho-dinitrobenzene, m-DNB, meta-dinitrobenzene
- p-DNB, para-dinitrobenzene
- p‐DNB
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Affiliation(s)
- Janet Olayemi Sangodele
- Phytomedicine, Biochemical Pharmacology and Toxicology Laboratories, Department of Biochemistry, School of Sciences, PMB 704, The Federal University of Technology, Zip code: 340001, Akure, Nigeria.,Department of Medical Biosciences, 4th floor, Life Science Building, Faculty of Natural Science, University of the Western Cape, Bellville, Cape Town, South Africa
| | - Mary Tolulope Olaleye
- Phytomedicine, Biochemical Pharmacology and Toxicology Laboratories, Department of Biochemistry, School of Sciences, PMB 704, The Federal University of Technology, Zip code: 340001, Akure, Nigeria
| | - Thomas K Monsees
- Department of Medical Biosciences, 4th floor, Life Science Building, Faculty of Natural Science, University of the Western Cape, Bellville, Cape Town, South Africa
| | - Afolabi Clement Akinmoladun
- Phytomedicine, Biochemical Pharmacology and Toxicology Laboratories, Department of Biochemistry, School of Sciences, PMB 704, The Federal University of Technology, Zip code: 340001, Akure, Nigeria
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Khalsa J, Duffy LC, Riscuta G, Starke-Reed P, Hubbard VS. Omics for Understanding the Gut-Liver-Microbiome Axis and Precision Medicine. Clin Pharmacol Drug Dev 2017; 6:176-185. [PMID: 28263462 DOI: 10.1002/cpdd.310] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2016] [Accepted: 09/15/2016] [Indexed: 12/14/2022]
Affiliation(s)
- Jag Khalsa
- National Institute on Drug Abuse; National Institutes of Health; Bethesda MD USA
| | - Linda C. Duffy
- National Center for Complementary and Integrative Health; National Institutes of Health; Bethesda MD USA
| | - Gabriela Riscuta
- National Cancer Institute; National Institutes of Health; Bethesda MD USA
| | - Pamela Starke-Reed
- Agricultural Research Service; United States Department of Agriculture; Washington DC USA
| | - Van S. Hubbard
- Formerly National Institute of Diabetes and Digestive and Kidney Diseases; National Institutes of Health; Bethesda MD
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The Role of Tissue Macrophage-Mediated Inflammation on NAFLD Pathogenesis and Its Clinical Implications. Mediators Inflamm 2017; 2017:8162421. [PMID: 28115795 PMCID: PMC5237469 DOI: 10.1155/2017/8162421] [Citation(s) in RCA: 130] [Impact Index Per Article: 16.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2016] [Revised: 11/22/2016] [Accepted: 12/04/2016] [Indexed: 02/06/2023] Open
Abstract
The obese phenotype is characterized by a state of chronic low-grade systemic inflammation that contributes to the development of comorbidities, including nonalcoholic fatty liver disease (NAFLD). In fact, NAFLD is often associated with adipocyte enlargement and consequent macrophage recruitment and inflammation. Macrophage polarization is often associated with the proinflammatory state in adipose tissue. In particular, an increase of M1 macrophages number or of M1/M2 ratio triggers the production and secretion of various proinflammatory signals (i.e., adipocytokines). Next, these inflammatory factors may reach the liver leading to local M1/M2 macrophage polarization and consequent onset of the histological damage characteristic of NAFLD. Thus, the role of macrophage polarization and inflammatory signals appears to be central for pathogenesis and progression of NAFLD, even if the heterogeneity of macrophages and molecular mechanisms that govern their phenotype switch remain incompletely understood. In this review, we discuss the role of adipose and liver tissue macrophage-mediated inflammation in experimental and human NAFLD. This focus is relevant because it may help researchers that approach clinical and experimental studies on this disease advancing the knowledge of mechanisms that could be targeted in order to revert NAFLD-related fibrosis.
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