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Specht JW, Bailly AR, Garcia S, Klepacz S, Oliveira SAD, Lucero D, McKenna ZJ, Schlader ZJ, Amorim FT. Effect of Ibuprofen on Markers of Acute Kidney Injury, Intestinal Injury, and Endotoxemia after Running in the Heat. Med Sci Sports Exerc 2025; 57:1092-1102. [PMID: 39876077 PMCID: PMC12101219 DOI: 10.1249/mss.0000000000003659] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/30/2025]
Abstract
PURPOSE To test the hypothesis that ibuprofen ingestion exacerbates markers of acute kidney injury (AKI), gastrointestinal (GI) injury, and endotoxemia after running in the heat. METHODS Using a randomized double-blind crossover design, 11 physically active individuals (six women) ingested 600 mg of ibuprofen or placebo 12- and 1-h before running 1 h in a heated chamber (35°C, 20%-60% R.H.) at an intensity of 60% V̇O 2peak . Blood and urine samples were collected preexercise, postexercise, and 1-h postexercise to assess cytokines and markers of AKI, GI injury, and endotoxemia. RESULTS One hour of running in the heat increased markers of AKI (urinary product of IGFBP7•TIMP2 [Placebo: ∆ 1.8 ± 0.8 log 10 (ng·mL 2 )/1000, Ibuprofen: ∆ 1.8 ± 0.9 log 10 (ng·mL 2 )/1000], urinary NGAL, and serum cystatin C), GI damage (I-FABP [Placebo: ∆ 631 ± 446 pg·mL -1 , Ibuprofen: ∆ 576 ± 455 pg·mL -1 ]), and inflammatory cytokines (TNFα [Placebo: ∆ 5.2 ± 3.5 pg·mL -1 , Ibuprofen: ∆ 6.2 ± 4.9 pg·mL -1 ], IL-6, IL-10, and MCP-1), but these changes were not exacerbated by ibuprofen ingestion. There were effects of time ( P < 0.001) and condition ( P = 0.03) for serum IL-8, with greater concentrations in the ibuprofen (pre: 11.4 ± 5.1 pg·mL -1 , post: 15.5 ± 7.3 pg·mL -1 ) trials than placebo (pre: 9.7 ± 4.2 pg·mL -1 , post: 11.7 ± 5.4 pg·mL -1 ). There were no effects of time or condition on markers of endotoxemia (LBP [Placebo: ∆ -1.2 ± 3.2 μg·mL -1 , Ibuprofen: ∆ 1.0 ± 1.6 μg·mL -1 ], sCD14). CONCLUSIONS These findings indicate that ibuprofen ingestion does not worsen intestinal or renal injury experienced during 1 h of exercise in the heat, but increases pro-inflammatory IL-8.
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Affiliation(s)
- Jonathan W. Specht
- Department of Health, Exercise, and Sports Sciences, University of New Mexico, Albuquerque, NM
| | - Alyssa R. Bailly
- Department of Health, Exercise, and Sports Sciences, University of New Mexico, Albuquerque, NM
| | - Serena Garcia
- Department of Health, Exercise, and Sports Sciences, University of New Mexico, Albuquerque, NM
| | - Steven Klepacz
- Department of Health, Exercise, and Sports Sciences, University of New Mexico, Albuquerque, NM
| | | | - David Lucero
- Department of Health, Exercise, and Sports Sciences, University of New Mexico, Albuquerque, NM
| | - Zachary J. McKenna
- Institute for Exercise and Environmental Medicine, Texas Health Presbyterian Hospital, and University of Texas Southwestern Medical Center, Dallas, TX
| | - Zachary J. Schlader
- Department of Kinesiology, Indiana University School of Public Health - Bloomington, IN
| | - Fabiano T. Amorim
- Department of Health, Exercise, and Sports Sciences, University of New Mexico, Albuquerque, NM
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Cecati M, Fumarola S, Vaiasicca S, Cianfruglia L, Vignini A, Giannubilo SR, Emanuelli M, Ciavattini A. Preeclampsia as a Study Model for Aging: The Klotho Gene Paradigm. Int J Mol Sci 2025; 26:902. [PMID: 39940672 PMCID: PMC11817256 DOI: 10.3390/ijms26030902] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2024] [Revised: 01/18/2025] [Accepted: 01/20/2025] [Indexed: 02/16/2025] Open
Abstract
Aging and pregnancy are often considered opposites in a woman's biological timeline. Aging is defined by a gradual decline in the functional capabilities of an organism over its lifetime, while pregnancy is characterized by the presence of the transient placenta, which fosters the cellular fitness necessary to support fetal growth. However, in the context of preeclampsia, pregnancy and aging share common hallmarks, including clinical complications, altered cellular phenotypes, and heightened oxidative stress. Furthermore, women with pregnancies complicated by preeclampsia tend to experience age-related disorders earlier than those with healthy pregnancies. Klotho, a gene discovered fortuitously in 1997 by researchers studying aging mechanisms, is primarily expressed in the kidneys but also to a lesser extent in several other tissues, including the placenta. The Klotho protein is a membrane-bound protein that, upon cleavage by ADAM10/17, is released into the circulation as soluble Klotho (sKlotho) where it plays a role in modulating oxidative stress. This review focuses on the involvement of sKlotho in the development of preeclampsia and age-related disorders, as well as the expression of the recently discovered Mytho gene, which has been associated with skeletal muscle atrophy.
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Affiliation(s)
- Monia Cecati
- Department of Human Sciences and Promotion of the Quality of Life, San Raffaele Roma Open University, 00166 Rome, Italy;
| | - Stefania Fumarola
- Scientific Direction, IRCCS INRCA, 60124 Ancona, Italy; (S.F.); (S.V.); (L.C.)
| | - Salvatore Vaiasicca
- Scientific Direction, IRCCS INRCA, 60124 Ancona, Italy; (S.F.); (S.V.); (L.C.)
| | - Laura Cianfruglia
- Scientific Direction, IRCCS INRCA, 60124 Ancona, Italy; (S.F.); (S.V.); (L.C.)
| | - Arianna Vignini
- Department of Clinical Sciences, Section of Biochemistry, Biology and Physics, Università Politecnica Delle Marche, 60126 Ancona, Italy;
| | - Stefano Raffaele Giannubilo
- Department of Clinical Sciences, Clinic of Obstetrics and Gynaecology, Università Politecnica Delle Marche, 60123 Ancona, Italy;
| | - Monica Emanuelli
- Department of Clinical Sciences, Section of Biochemistry, Biology and Physics, Università Politecnica Delle Marche, 60126 Ancona, Italy;
| | - Andrea Ciavattini
- Department of Clinical Sciences, Clinic of Obstetrics and Gynaecology, Università Politecnica Delle Marche, 60123 Ancona, Italy;
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3
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Zhang W, Pan L, Wu X, Slivano OJ, Dong K, Long X. Functional characterization of human IL-8 in vascular stenosis using a novel humanized transgenic mouse model. Vascul Pharmacol 2024; 157:107438. [PMID: 39486776 PMCID: PMC12044608 DOI: 10.1016/j.vph.2024.107438] [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: 10/09/2024] [Revised: 10/29/2024] [Accepted: 10/29/2024] [Indexed: 11/04/2024]
Abstract
IL-8 (aka interleukin 8, CXCL8) is a prototypic cytokine that is highly expressed in the diseased vessel wall and its plasma concentration is strongly associated with cardiovascular events. However, whether IL-8 plays a causative role in cardiovascular diseases remains largely unknown. In this study we used a human IL-8 transgenic (Tg) mouse strain with a bacterial artificial chromosome (BAC) integrated into its genome. This BAC encompasses 166 kb of sequence encompassing the human IL-8 gene locus as well as upstream and downstream DNA sequences containing regulatory elements. This BAC ensured a pathophysiologically regulated, rather than forced constitutive, expression of human IL-8 in the mouse. Tg mice were subjected to complete carotid ligation injury. IL-8 was highly expressed in the ligation-injured carotid artery from 3 days until 2 weeks after injury. As a result, exacerbated neointimal hyperplasia and increased Mac2 and PCNA positive cells were observed in Tg mice. To further confirm its role in promoting neointimal formation, IL-8 was neutralized by anti-IL8 treatment at the ligation site. Consequently, the size of neointima was significantly reduced. Our results provided new insights into the regulation and function of IL-8 in response to vascular insult and during neointima formation.
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Affiliation(s)
- Wei Zhang
- Lemole Center for Integrated Lymphatic and Vascular Research, Lewis Katz School of Medicine, Temple University, Philadelphia, PA, USA; Vascular Biology Center, Medical College of Georgia at Augusta University, Augusta, GA, USA.
| | - Lihua Pan
- Lemole Center for Integrated Lymphatic and Vascular Research, Lewis Katz School of Medicine, Temple University, Philadelphia, PA, USA; Vascular Biology Center, Medical College of Georgia at Augusta University, Augusta, GA, USA; Department of Cardiology, Affiliated Hospital of Nantong University, Nantong, China
| | - Xiaoliang Wu
- Vascular Biology Center, Medical College of Georgia at Augusta University, Augusta, GA, USA
| | - Orazio J Slivano
- Vascular Biology Center, Medical College of Georgia at Augusta University, Augusta, GA, USA
| | - Kunzhe Dong
- Immunology Center of Georgia, Medical College of Georgia at Augusta University, Augusta, GA, USA
| | - Xiaochun Long
- Vascular Biology Center, Medical College of Georgia at Augusta University, Augusta, GA, USA
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Roser LA, Sakellariou C, Lindstedt M, Neuhaus V, Dehmel S, Sommer C, Raasch M, Flandre T, Roesener S, Hewitt P, Parnham MJ, Sewald K, Schiffmann S. IL-2-mediated hepatotoxicity: knowledge gap identification based on the irAOP concept. J Immunotoxicol 2024; 21:2332177. [PMID: 38578203 DOI: 10.1080/1547691x.2024.2332177] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2023] [Accepted: 03/13/2024] [Indexed: 04/06/2024] Open
Abstract
Drug-induced hepatotoxicity constitutes a major reason for non-approval and post-marketing withdrawal of pharmaceuticals. In many cases, preclinical models lack predictive capacity for hepatic damage in humans. A vital concern is the integration of immune system effects in preclinical safety assessment. The immune-related Adverse Outcome Pathway (irAOP) approach, which is applied within the Immune Safety Avatar (imSAVAR) consortium, presents a novel method to understand and predict immune-mediated adverse events elicited by pharmaceuticals and thus targets this issue. It aims to dissect the molecular mechanisms involved and identify key players in drug-induced side effects. As irAOPs are still in their infancy, there is a need for a model irAOP to validate the suitability of this tool. For this purpose, we developed a hepatotoxicity-based model irAOP for recombinant human IL-2 (aldesleukin). Besides producing durable therapeutic responses against renal cell carcinoma and metastatic melanoma, the boosted immune activation upon IL-2 treatment elicits liver damage. The availability of extensive data regarding IL-2 allows both the generation of a comprehensive putative irAOP and to validate the predictability of the irAOP with clinical data. Moreover, IL-2, as one of the first cancer immunotherapeutics on the market, is a blueprint for various biological and novel treatment regimens that are under investigation today. This review provides a guideline for further irAOP-directed research in immune-mediated hepatotoxicity.
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Affiliation(s)
- Luise A Roser
- Fraunhofer Institute for Translational Medicine and Pharmacology (ITMP), Frankfurt am Main, Germany
| | | | - Malin Lindstedt
- Department of Immunotechnology, Lund University, Lund, Sweden
| | - Vanessa Neuhaus
- Fraunhofer Institute for Toxicology and Experimental Medicine (ITEM), Preclinical Pharmacology and In-Vitro Toxicology, Hannover, Germany
- Biomedical Research in Endstage and Obstructive Lung Disease Hannover (BREATH), Member of the German Center for Lung Research (DZL), Member of the Fraunhofer Cluster of Excellence Immune-Mediated Diseases CIMD, Hannover, Germany
| | - Susann Dehmel
- Fraunhofer Institute for Toxicology and Experimental Medicine (ITEM), Preclinical Pharmacology and In-Vitro Toxicology, Hannover, Germany
- Biomedical Research in Endstage and Obstructive Lung Disease Hannover (BREATH), Member of the German Center for Lung Research (DZL), Member of the Fraunhofer Cluster of Excellence Immune-Mediated Diseases CIMD, Hannover, Germany
| | - Charline Sommer
- Fraunhofer Institute for Toxicology and Experimental Medicine (ITEM), Preclinical Pharmacology and In-Vitro Toxicology, Hannover, Germany
- Biomedical Research in Endstage and Obstructive Lung Disease Hannover (BREATH), Member of the German Center for Lung Research (DZL), Member of the Fraunhofer Cluster of Excellence Immune-Mediated Diseases CIMD, Hannover, Germany
| | | | - Thierry Flandre
- Translational Medicine, Novartis Institutes of Biomedical Research, Basel, Switzerland
| | - Sigrid Roesener
- Chemical and Preclinical Safety, Merck Healthcare KGaA, Darmstadt, Germany
| | - Philip Hewitt
- Chemical and Preclinical Safety, Merck Healthcare KGaA, Darmstadt, Germany
| | - Michael J Parnham
- Fraunhofer Institute for Translational Medicine and Pharmacology (ITMP), Frankfurt am Main, Germany
- EpiEndo Pharmaceuticals ehf, Reykjavík, Iceland
| | - Katherina Sewald
- Fraunhofer Institute for Toxicology and Experimental Medicine (ITEM), Preclinical Pharmacology and In-Vitro Toxicology, Hannover, Germany
- Biomedical Research in Endstage and Obstructive Lung Disease Hannover (BREATH), Member of the German Center for Lung Research (DZL), Member of the Fraunhofer Cluster of Excellence Immune-Mediated Diseases CIMD, Hannover, Germany
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Malheiro LFL, Oliveira CA, Portela FS, Mercês ÉAB, Benedictis LMD, Benedictis JMD, Andrade END, Magalhães ACM, Melo FFD, Oliveira PDS, Soares TDJ, Amaral LSDB. High-intensity interval training alleviates liver inflammation by regulating the TLR4/NF-κB signaling pathway and M1/M2 macrophage balance in female rats with cisplatin hepatotoxicity. Biochem Biophys Res Commun 2024; 733:150712. [PMID: 39317112 DOI: 10.1016/j.bbrc.2024.150712] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2024] [Revised: 09/12/2024] [Accepted: 09/16/2024] [Indexed: 09/26/2024]
Abstract
Cisplatin (CDDP) is an antineoplastic drug whose adverse effects include hepatotoxicity. The inflammatory process is crucial in the progression of liver injuries. Exercise is known for its anti-inflammatory effects, but the influence of different training modalities on hepatoprotection is still unclear. This study aims to compare the impacts between preconditioning with high-intensity interval training (HIIT) and traditional continuous training of low (LT) and moderate (MT) intensities on inflammatory markers in Wistar female rats with CDDP-induced hepatotoxicity. Thirty-five rats were divided into five groups: control and sedentary (C + Sed), treated with CDDP and sedentary (CDDP + Sed), treated with CDDP and subjected to LT (CDDP + LT), treated with CDDP and subjected to MT (CDDP + MT), and treated with CDDP and subjected to HIIT (CDDP + HIIT). The training protocols consisted of treadmill running for 8 weeks before CDDP treatment. The rats were euthanized 7 days after the treatment. Liver samples were collected to evaluate the expression of various inflammatory markers and types of macrophages. Our results indicated that HIIT was the only protocol to prevent the increase in all analyzed pro-inflammatory cytokines and reduce the number of ED-1-positive cells, attenuating the TLR4/NF-κB signaling pathway in the liver. Additionally, HIIT increased the anti-inflammatory cytokine IL-10 and regulated M1/M2 macrophage polarization. Thus, this study suggests that preconditioning with HIIT is more effective in promoting hepatoprotective effects than LT and MT, regulating inflammatory markers through modulation of the TLR4/NF-κB signaling pathway and M2 macrophage polarization in the hepatic tissue of female rats treated with CDDP.
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Affiliation(s)
- Lara Fabiana Luz Malheiro
- Instituto Multidisciplinar em Saúde, Universidade Federal da Bahia, Vitória da Conquista, Bahia, 45029-094, Brazil
| | - Caroline Assunção Oliveira
- Instituto Multidisciplinar em Saúde, Universidade Federal da Bahia, Vitória da Conquista, Bahia, 45029-094, Brazil
| | - Fernanda Santos Portela
- Instituto Multidisciplinar em Saúde, Universidade Federal da Bahia, Vitória da Conquista, Bahia, 45029-094, Brazil
| | - Érika Azenatte Barros Mercês
- Instituto Multidisciplinar em Saúde, Universidade Federal da Bahia, Vitória da Conquista, Bahia, 45029-094, Brazil
| | - Laís Mafra de Benedictis
- Instituto Multidisciplinar em Saúde, Universidade Federal da Bahia, Vitória da Conquista, Bahia, 45029-094, Brazil
| | - Júlia Mafra de Benedictis
- Instituto Multidisciplinar em Saúde, Universidade Federal da Bahia, Vitória da Conquista, Bahia, 45029-094, Brazil
| | | | | | - Fabrício Freire de Melo
- Instituto Multidisciplinar em Saúde, Universidade Federal da Bahia, Vitória da Conquista, Bahia, 45029-094, Brazil
| | - Patrícia da Silva Oliveira
- Instituto Multidisciplinar em Saúde, Universidade Federal da Bahia, Vitória da Conquista, Bahia, 45029-094, Brazil
| | - Telma de Jesus Soares
- Instituto Multidisciplinar em Saúde, Universidade Federal da Bahia, Vitória da Conquista, Bahia, 45029-094, Brazil
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Czaja AJ. Cellular senescence and its pathogenic and therapeutic implications in autoimmune hepatitis. Expert Rev Gastroenterol Hepatol 2024; 18:725-743. [PMID: 39575891 DOI: 10.1080/17474124.2024.2432480] [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: 09/25/2024] [Accepted: 11/18/2024] [Indexed: 12/28/2024]
Abstract
INTRODUCTION Senescent cells are characterized by replicative arrest and phenotypes that produce diverse pro-inflammatory and pro-oxidant mediators. The senescence of diverse hepatic cell types could constitute an unrecognized pathogenic mechanism and prognostic determinant in autoimmune hepatitis. The impact of cellular senescence in autoimmune hepatitis is unknown, and it may suggest adjunctive management strategies. AREAS COVERED This review describes the molecular mechanisms of cellular senescence, indicates its diagnostic features, suggests its consequences, presents possible therapeutic interventions, and encourages investigations of its pathogenic role and management in autoimmune hepatitis. Treatment prospects include elimination or reversal of senescent cells, generation of ectopic telomerase, reactivation of dormant telomerase, neutralization of specific pro-inflammatory secretory products, and mitigation of the effects of mitochondrial dysfunction. EXPERT OPINION The occurrence, nature, and consequences of cellular senescence in autoimmune hepatitis must be determined. The senescence of diverse hepatic cell types could affect the outcome of autoimmune hepatitis by impairing hepatic regeneration, intensifying liver inflammation, and worsening hepatic fibrosis. Cellular senescence could contribute to suboptimal responses during conventional glucocorticoid-based therapy. Interventions that target specific pro-inflammatory products of the senescent phenotype or selectively promote apoptosis of senescent cells may be preferred adjunctive treatments for autoimmune hepatitis depending on the cancer risk.
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Affiliation(s)
- Albert J Czaja
- Mayo Clinic, Department of Medicine, Division of Gastroenterology and Hepatology, Rochester, MN, USA
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Dyba M, Berezenko V, Zabara D, Bezpala A, Donskoi B. Monocyte subpopulations in children with autoimmune liver disease. Pathol Res Pract 2024; 263:155622. [PMID: 39357182 DOI: 10.1016/j.prp.2024.155622] [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: 06/17/2024] [Revised: 09/16/2024] [Accepted: 09/25/2024] [Indexed: 10/04/2024]
Abstract
BACKGROUND Patients with autoimmune liver diseases require individualized long-term immunosuppressive therapy, whose discontinuation is possible after complete histological remission and that requires repeated liver biopsy. In view of this, the search for non-invasive markers is essential for patients with autoimmune liver disease. PURPOSE The purpose of this research is to assess the possibility of predicting the recurrence of autoimmune liver disease in children. METHOD The biological material used in the study was blood serum from 80 children diagnosed with autoimmune hepatitis and autoimmune sclerosing cholangitis. Patients were divided into four groups according to disease activity and therapeutic approach. RESULTS The percentage of monocyte subpopulations was determined by flow cytometry, and disease activity, inflammation, and fibrosis markers were analyzed to study the relationship and diagnostic value of the parameters studied in detail. The results of the study indicate a significant relationship between disease activity and changes in the distribution of the percentage of monocyte subpopulations in the blood. The percentage of intermediate CD14++/CD16+ monocytes was found to correlate with disease activity, and non-classical CD14lowCD16+ monocytes were found to be of high diagnostic value in the diagnosis of disease relapse. CONCLUSIONS These findings not only expand the understanding of the pathogenesis of autoimmune liver disease but also point to the prospects of using monocyte subpopulations as potential biomarkers for predicting relapse, contributing to the development of more effective clinical management strategies.
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Affiliation(s)
- Maryna Dyba
- Department of Hepatology and Comorbidities in Children, Institute of Pediatrics, Obstetrics and Gynecology of the National Academy of Medical Sciences of Ukraine, Kyiv 04050, Ukraine.
| | - Valentyna Berezenko
- Department of Hepatology and Comorbidities in Children, Institute of Pediatrics, Obstetrics and Gynecology of the National Academy of Medical Sciences of Ukraine, Kyiv 04050, Ukraine
| | - Dariia Zabara
- Laboratory of Immunology, Institute of Pediatrics, Obstetrics and Gynecology of the National Academy of Medical Sciences of Ukraine, Kyiv 04050, Ukraine
| | - Anna Bezpala
- Department of Hepatology and Comorbidities in Children, Institute of Pediatrics, Obstetrics and Gynecology of the National Academy of Medical Sciences of Ukraine, Kyiv 04050, Ukraine
| | - Boris Donskoi
- Laboratory of Immunology, Institute of Pediatrics, Obstetrics and Gynecology of the National Academy of Medical Sciences of Ukraine, Kyiv 04050, Ukraine
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Stonebraker JR, Pace RG, Gallins PJ, Dang H, Aksit M, Faino AV, Gordon WW, MacParland S, Bamshad MJ, Gibson RL, Cutting GR, Durie PR, Wright FA, Zhou YH, Blackman SM, O’Neal WK, Ling SC, Knowles MR. Genetic variation in severe cystic fibrosis liver disease is associated with novel mechanisms for disease pathogenesis. Hepatology 2024; 80:1012-1025. [PMID: 38536042 PMCID: PMC11427593 DOI: 10.1097/hep.0000000000000863] [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: 12/15/2023] [Accepted: 03/11/2024] [Indexed: 05/06/2024]
Abstract
BACKGROUND AND AIMS It is not known why severe cystic fibrosis (CF) liver disease (CFLD) with portal hypertension occurs in only ~7% of people with CF. We aimed to identify genetic modifiers for severe CFLD to improve understanding of disease mechanisms. APPROACH AND RESULTS Whole-genome sequencing was available in 4082 people with CF with pancreatic insufficiency (n = 516 with severe CFLD; n = 3566 without CFLD). We tested ~15.9 million single nucleotide polymorphisms (SNPs) for association with severe CFLD versus no-CFLD, using pre-modulator clinical phenotypes including (1) genetic variant ( SERPINA1 ; Z allele) previously associated with severe CFLD; (2) candidate SNPs (n = 205) associated with non-CF liver diseases; (3) genome-wide association study of common/rare SNPs; (4) transcriptome-wide association; and (5) gene-level and pathway analyses. The Z allele was significantly associated with severe CFLD ( p = 1.1 × 10 -4 ). No significant candidate SNPs were identified. A genome-wide association study identified genome-wide significant SNPs in 2 loci and 2 suggestive loci. These 4 loci contained genes [significant, PKD1 ( p = 8.05 × 10 -10 ) and FNBP1 ( p = 4.74 × 10 -9 ); suggestive, DUSP6 ( p = 1.51 × 10 -7 ) and ANKUB1 ( p = 4.69 × 10 -7 )] relevant to severe CFLD pathophysiology. The transcriptome-wide association identified 3 genes [ CXCR1 ( p = 1.01 × 10 -6 ) , AAMP ( p = 1.07 × 10 -6 ), and TRBV24 ( p = 1.23 × 10 -5 )] involved in hepatic inflammation and innate immunity. Gene-ranked analyses identified pathways enriched in genes linked to multiple liver pathologies. CONCLUSION These results identify loci/genes associated with severe CFLD that point to disease mechanisms involving hepatic fibrosis, inflammation, innate immune function, vascular pathology, intracellular signaling, actin cytoskeleton and tight junction integrity and mechanisms of hepatic steatosis and insulin resistance. These discoveries will facilitate mechanistic studies and the development of therapeutics for severe CFLD.
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Affiliation(s)
- Jaclyn R. Stonebraker
- Marsico Lung Institute/UNC CF Research Center, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, 27599, USA
| | - Rhonda G. Pace
- Marsico Lung Institute/UNC CF Research Center, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, 27599, USA
| | - Paul J. Gallins
- Bioinformatics Research Center, North Carolina State University, Raleigh, North Carolina, 27695, USA
| | - Hong Dang
- Marsico Lung Institute/UNC CF Research Center, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, 27599, USA
| | - M.A. Aksit
- Department of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, 21287, USA
| | - Anna V. Faino
- Children’s Core for Biostatistics, Epidemiology and Analytics in Research, Seattle Children’s Research Institute, Seattle, Washington, 98101, USA
| | - William W. Gordon
- Department of Pediatrics, Division of Genetic Medicine, University of Washington, Seattle, Washington, 98195, USA
| | - Sonya MacParland
- Ajmera Transplant Centre, Toronto General Research Institute, University Health Network, Toronto, Ontario, Canada
| | - Michael J. Bamshad
- Department of Pediatrics, Division of Genetic Medicine, University of Washington, Seattle, Washington, 98195, USA
- Brotman Baty Institute for Precision Medicine, Seattle, Washington, 98195, USA
- Department of Genome Sciences, University of Washington, Seattle, Washington, 98195, USA
| | - Ronald L. Gibson
- Center for Respiratory Biology & Therapeutics, Seattle Children’s Research Institute, Seattle, Washington, 98105, USA
| | - Garry R. Cutting
- Department of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, 21287, USA
| | | | - Fred A. Wright
- Department of Biological Sciences, North Carolina State University, Raleigh, North Carolina, 27695, USA
- Department of Statistics, North Carolina State University, Raleigh, North Carolina, 27695, USA
| | - Yi-Hui Zhou
- Bioinformatics Research Center, North Carolina State University, Raleigh, North Carolina, 27695, USA
- Department of Biological Sciences, North Carolina State University, Raleigh, North Carolina, 27695, USA
| | - Scott M. Blackman
- Department of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, 21287, USA
- Division of Pediatric Endocrinology, Johns Hopkins University School of Medicine, Baltimore, Maryland, 21287, USA
| | - Wanda K. O’Neal
- Marsico Lung Institute/UNC CF Research Center, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, 27599, USA
| | - Simon C. Ling
- Division of Gastroenterology, Hepatology, and Nutrition, The Hospital for Sick Children, University of Toronto, Toronto, ON, Canada
| | - Michael R. Knowles
- Marsico Lung Institute/UNC CF Research Center, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, 27599, USA
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Pehar M, Hewitt M, Wagner A, Sandhu JK, Khalili A, Wang X, Cho JY, Sim VL, Kulka M. Histamine stimulates human microglia to alter cellular prion protein expression via the HRH2 histamine receptor. Sci Rep 2024; 14:25519. [PMID: 39462031 PMCID: PMC11513956 DOI: 10.1038/s41598-024-75982-1] [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: 06/05/2024] [Accepted: 10/09/2024] [Indexed: 10/28/2024] Open
Abstract
Although the cellular prion protein (PrPC) has been evolutionarily conserved, the role of this protein remains elusive. Recent evidence indicates that PrPC may be involved in neuroinflammation and the immune response in the brain, and its expression may be modified via various mechanisms. Histamine is a proinflammatory mediator and neurotransmitter that stimulates numerous cells via interactions with histamine receptors 1-4 (HRH1-4). Since microglia are the innate immune cells of the central nervous system, we hypothesized that histamine-induced stimulation regulates the expression of PrPC in human-derived microglia. The human microglial clone 3 (HMC3) cell line was treated with histamine, and intracellular calcium levels were measured via a calcium flux assay. Cytokine production was monitored by enzyme-linked immunosorbent assay (ELISA). Western blotting and quantitative reverse transcription-polymerase chain reaction were used to determine protein and gene expression of HRH1-4. Flow cytometry and western blotting were used to measure PrPC expression levels. Fluorescence microscopy was used to examine Iba-1 and PrPC localization. HMC3 cells stimulated by histamine exhibited increased intracellular calcium levels and increased release of IL-6 and IL-8, while also modifying PrPC localization. HMC3 stimulated with histamine for 6 and 24 hours exhibited increased surface PrPC expression. Specifically, we found that stimulation of the HRH2 receptor was responsible for changes in surface PrPC. Histamine-induced increases in surface PrPC were attenuated following inhibition of the HRH2 receptor via the HRH2 antagonist ranitidine. These changes were unique to HRH2 activation, as stimulation of HRH1, HRH3, or HRH4 did not alter surface PrPC. Prolonged stimulation of HMC3 decreased PrPC expression following 48 and 72 hours of histamine stimulation. HMC3 cells can be stimulated by histamine to undergo intracellular calcium influx. Surface expression levels of PrPC on HMC3 cells are altered by histamine exposure, primarily mediated by HRH2. While histamine exposure also increases release of IL-6 and IL-8 in these cells, this cytokine release is not fully dependent on PrPC levels, as IL-6 release is only partially reduced and IL-8 release is unchanged under the conditions of HRH2 blockade that prevent PrPC changes. Overall, this suggests that PrPC may play a role in modulating microglial responses.
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Affiliation(s)
- Marcus Pehar
- Quantum and Nanotechnologies Research Centre, National Research Council Canada, Edmonton, AB, Canada
- Neuroscience and Mental Health Institute, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB, Canada
- Centre for Prions and Protein Folding Diseases, University of Alberta, Edmonton, AB, Canada
| | - Melissa Hewitt
- Human Health Therapeutics Research Centre, National Research Council Canada, Ottawa, ON, Canada
| | - Ashley Wagner
- Quantum and Nanotechnologies Research Centre, National Research Council Canada, Edmonton, AB, Canada
| | - Jagdeep K Sandhu
- Human Health Therapeutics Research Centre, National Research Council Canada, Ottawa, ON, Canada
| | - Aria Khalili
- Quantum and Nanotechnologies Research Centre, National Research Council Canada, Edmonton, AB, Canada
- Department of Mechanical Engineering, University of Alberta, Edmonton, AB, Canada
| | - Xinyu Wang
- Quantum and Nanotechnologies Research Centre, National Research Council Canada, Edmonton, AB, Canada
- Department of Mechanical Engineering, University of Alberta, Edmonton, AB, Canada
| | - Jae-Young Cho
- Quantum and Nanotechnologies Research Centre, National Research Council Canada, Edmonton, AB, Canada
- Department of Mechanical Engineering, University of Alberta, Edmonton, AB, Canada
| | - Valerie L Sim
- Neuroscience and Mental Health Institute, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB, Canada
- Centre for Prions and Protein Folding Diseases, University of Alberta, Edmonton, AB, Canada
- Department of Medicine, University of Alberta, Edmonton, AB, Canada
| | - Marianna Kulka
- Quantum and Nanotechnologies Research Centre, National Research Council Canada, Edmonton, AB, Canada.
- Neuroscience and Mental Health Institute, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB, Canada.
- Department of Medical Microbiology and Immunology, University of Alberta, Edmonton, AB, Canada.
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10
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Okamoto Y, Kitakaze K, Takenouchi Y, Matsui R, Koga D, Miyashima R, Ishimaru H, Tsuboi K. GPR176 promotes fibroblast-to-myofibroblast transition in organ fibrosis progression. BIOCHIMICA ET BIOPHYSICA ACTA. MOLECULAR CELL RESEARCH 2024; 1871:119798. [PMID: 39047914 DOI: 10.1016/j.bbamcr.2024.119798] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/31/2024] [Revised: 06/20/2024] [Accepted: 07/14/2024] [Indexed: 07/27/2024]
Abstract
Fibrosis is characterized by excessive deposition of extracellular matrix proteins, particularly collagen, caused by myofibroblasts in response to chronic inflammation. Although G protein-coupled receptors (GPCRs) are among the targets of current antifibrotic drugs, no drug has yet been approved to stop fibrosis progression. Herein, we aimed to identify GPCRs with profibrotic effects. In gene expression analysis of mouse lungs with induced fibrosis, eight GPCRs were identified, showing a >2-fold increase in mRNA expression after fibrosis induction. Among them, we focused on Gpr176 owing to its significant correlation with a myofibroblast marker α-smooth muscle actin (αSMA), the profibrotic factor transforming growth factor β1 (TGFβ1), and collagen in a human lung gene expression database. Similar to the lung fibrosis model, increased Gpr176 expression was also observed in other organs affected by fibrosis, including the kidney, liver, and heart, suggesting its role in fibrosis across various organs. Furthermore, fibroblasts abundantly expressed Gpr176 compared to alveolar epithelial cells, endothelial cells, and macrophages in the fibrotic lung. GPR176 expression was unaffected by TGFβ1 stimulation in rat renal fibroblast NRK-49 cells, whereas knockdown of Gpr176 by siRNA reduced TGFβ1-induced expression of αSMA, fibronectin, and collagen as well as Smad2 phosphorylation. This suggested that Gpr176 regulates fibroblast activation. Consequently, Gpr176 acts in a profibrotic manner, and inhibiting its activity could potentially prevent myofibroblast differentiation and improve fibrosis. Developing a GPR176 inverse agonist or allosteric modulator is a promising therapeutic approach for fibrosis.
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Affiliation(s)
- Yasuo Okamoto
- Department of Pharmacology, Kawasaki Medical School, 577 Matsushima, Kurashiki, Okayama 701-0192, Japan.
| | - Keisuke Kitakaze
- Department of Pharmacology, Kawasaki Medical School, 577 Matsushima, Kurashiki, Okayama 701-0192, Japan
| | - Yasuhiro Takenouchi
- Department of Pharmacology, Kawasaki Medical School, 577 Matsushima, Kurashiki, Okayama 701-0192, Japan
| | - Rena Matsui
- Department of Medical Technology, Kawasaki University of Medical Welfare, Kurashiki, Okayama 701-0192, Japan
| | - Daisuke Koga
- Department of Pharmacology, Kawasaki Medical School, 577 Matsushima, Kurashiki, Okayama 701-0192, Japan
| | - Ryo Miyashima
- Department of Pharmacology, Kawasaki Medical School, 577 Matsushima, Kurashiki, Okayama 701-0192, Japan
| | - Hironobu Ishimaru
- Department of Pharmacology, Kawasaki Medical School, 577 Matsushima, Kurashiki, Okayama 701-0192, Japan
| | - Kazuhito Tsuboi
- Department of Pharmacology, Kawasaki Medical School, 577 Matsushima, Kurashiki, Okayama 701-0192, Japan
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11
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Wupperfeld D, Fricker G, Bois De Fer B, Popovic B. Essential phospholipids impact cytokine secretion and alter lipid-metabolizing enzymes in human hepatocyte cell lines. Pharmacol Rep 2024; 76:572-584. [PMID: 38664334 PMCID: PMC11126482 DOI: 10.1007/s43440-024-00595-4] [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: 11/23/2023] [Revised: 04/03/2024] [Accepted: 04/05/2024] [Indexed: 05/09/2024]
Abstract
BACKGROUND Essential phospholipids (EPL) are hepatoprotective. METHODS The effects on interleukin (IL)-6 and -8 secretion and on certain lipid-metabolizing enzymes of non-cytotoxic concentrations of EPL (0.1 and 0.25 mg/ml), polyenylphosphatidylcholine (PPC), and phosphatidylinositol (PtdIns) (both at 0.1 and 1 mg/ml), compared with untreated controls, were assessed in human hepatocyte cell lines (HepG2, HepaRG, and steatotic HepaRG). RESULTS Lipopolysaccharide (LPS)-induced IL-6 secretion was significantly decreased in HepaRG cells by most phospholipids, and significantly increased in steatotic HepaRG cells with at least one concentration of EPL and PtdIns. LPS-induced IL-8 secretion was significantly increased in HepaRG and steatotic HepaRG cells with all phospholipids. All phospholipids significantly decreased amounts of fatty acid synthase in steatotic HepaRG cells and the amounts of acyl-CoA oxidase in HepaRG cells. Amounts of lecithin cholesterol acyltransferase were significantly decreased in HepG2 and HepaRG cells by most phospholipids, and significantly increased with 0.1 mg/ml PPC (HepaRG cells) and 1 mg/ml PtdIns (steatotic HepaRG cells). Glucose-6-phosphate dehydrogenase activity was unaffected by any phospholipid in any cell line. CONCLUSIONS EPL, PPC, and PtdIns impacted the secretion of pro-inflammatory cytokines and affected amounts of several key lipid-metabolizing enzymes in human hepatocyte cell lines. Such changes may help liver function improvement, and provide further insights into the EPL's mechanism of action.
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Affiliation(s)
- Dominik Wupperfeld
- Department of Pharmaceutical Technology and Biopharmacy, Institute of Pharmacy and Molecular Biotechnology, Ruprecht-Karls University of Heidelberg, Heidelberg, Germany
| | - Gert Fricker
- Department of Pharmaceutical Technology and Biopharmacy, Institute of Pharmacy and Molecular Biotechnology, Ruprecht-Karls University of Heidelberg, Heidelberg, Germany
| | | | - Branko Popovic
- Sanofi, Frankfurt am Main, K607, 65929, Industriepark Hoechst, Germany.
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12
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Pellegrino M, Giordano F, De Amicis F, Marra M, Tucci P, Marsico S, Aquaro S. HIV-1 Structural Proteins or Cell-Signaling Factors? That Is the Question! Curr Issues Mol Biol 2024; 46:5100-5116. [PMID: 38920978 PMCID: PMC11202448 DOI: 10.3390/cimb46060306] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2024] [Revised: 05/20/2024] [Accepted: 05/21/2024] [Indexed: 06/27/2024] Open
Abstract
The biological activity of structural HIV-1 proteins is not limited to ensuring a productive viral infection but also interferes with cellular homeostasis through intra- and extracellular signaling activation. This interference induces genomic instability, increases the lifespan of the infected cell by inhibiting apoptosis, and subverts cell senescence, resulting in unrestricted cell proliferation. HIV structural proteins are present in a soluble form in the lymphoid tissues and blood of infected individuals, even without active viral replication. The HIV matrix protein p17, the envelope glycoprotein gp120, the transenvelope protein gp41, and the capsid protein p24 interact with immune cells and deregulate the biological activity of the immune system. The biological activity of HIV structural proteins is also demonstrated in endothelial cells and some tumor cell lines, confirming the ability of viral proteins to promote cell proliferation and cancer progression, even in the absence of active viral replication. This review corroborates the hypothesis that HIV structural proteins, by interacting with different cell types, contribute to creating a microenvironment that is favorable to the evolution of cancerous pathologies not classically related to AIDS.
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Affiliation(s)
| | | | | | | | | | - Stefania Marsico
- Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, 87036 Arcavacata di Rende, Italy; (M.P.)
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13
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Kim W, Chu JO, Kim DY, Lee SH, Choi CH, Lee KH. Mimicking chronic alcohol effects through a controlled and sustained ethanol release device. J Biol Eng 2024; 18:31. [PMID: 38715085 PMCID: PMC11077717 DOI: 10.1186/s13036-024-00428-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2024] [Accepted: 04/26/2024] [Indexed: 05/12/2024] Open
Abstract
Alcohol consumption, a pervasive societal issue, poses considerable health risks and socioeconomic consequences. Alcohol-induced hepatic disorders, such as fatty liver disease, alcoholic hepatitis, chronic hepatitis, liver fibrosis, and cirrhosis, underscore the need for comprehensive research. Existing challenges in mimicking chronic alcohol exposure in cellular systems, attributed to ethanol evaporation, necessitate innovative approaches. In this study, we developed a simple, reusable, and controllable device for examining the physiological reactions of hepatocytes to long-term alcohol exposure. Our approach involved a novel device designed to continuously release ethanol into the culture medium, maintaining a consistent ethanol concentration over several days. We evaluated device performance by examining gene expression patterns and cytokine secretion alterations during long-term exposure to ethanol. These patterns were correlated with those observed in patients with alcoholic hepatitis. Our results suggest that our ethanol-releasing device can be used as a valuable tool to study the mechanisms of chronic alcohol-mediated hepatic diseases at the cellular level. Our device offers a practical solution for studying chronic alcohol exposure, providing a reliable platform for cellular research. This innovative tool holds promise for advancing our understanding of the molecular processes involved in chronic alcohol-mediated hepatic diseases. Future research avenues should explore broader applications and potential implications for predicting and treating alcohol-related illnesses.
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Affiliation(s)
- Wanil Kim
- Department of Biochemistry and Institute of Medical Science, School of Medicine, Gyeongsang National University, Jinju, 52727, Republic of Korea
| | - Jin-Ok Chu
- Department of Cosmetic Science and Technology, Daegu Haany University, Gyeongsan, 38610, Republic of Korea
| | - Do-Yeon Kim
- Department of Pharmacology, School of Dentistry, Kyungpook National University, Daegu, 41940, Republic of Korea
| | - Soo-Hyeon Lee
- Department of Molecular Biology, Pusan National University, Busan, 46241, Republic of Korea
| | - Chang-Hyung Choi
- School of Chemical Engineering, Yeungnam University, Gyeongsan, 38541, Republic of Korea.
| | - Kyung-Ha Lee
- Department of Molecular Biology, Pusan National University, Busan, 46241, Republic of Korea.
- Institute of Systems Biology, Pusan National University, Busan, 46241, Republic of Korea.
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14
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He H, Tang Y, Zhuang L, Zheng Y, Huang X. PINK1/Park2-Mediated Mitophagy Relieve Non-Alcoholic Fatty Liver Disease. Physiol Res 2024; 73:253-263. [PMID: 38710055 PMCID: PMC11081181] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2022] [Accepted: 11/07/2023] [Indexed: 05/08/2024] Open
Abstract
Up to now, there's a limited number of studies on the relationship between PINK1/Park2 pathway and mitophagy in NAFLD. To investigate the effect of Park2-mediated mitophagy on non-alcoholic fatty liver disease (NAFLD). Oleic acid was used for the establishment of NAFLD model. Oil red-dyed lipid drops and mitochondrial alternations were observed by transmission electron microscopy. Enzymatic kit was used to test lipid content. The levels of IL-8 and TNF-alpha were determined by ELISA. Lenti-Park2 and Park2-siRNA were designed to upregulate and downregulate Park2 expression, respectively. The changing expression of PINK and Park2 was detected by RT-qPCR and Western blot. Immunofluorescence staining was applied to measure the amount of LC3. Successful NAFLD modeling was featured by enhanced lipid accumulation, as well as the elevated total cholesterol (TC), triglyceride (TG), TNF-alpha and IL-8 levels. Mitochondria in NAFLD model were morphologically and functionally damaged. Park2 expression was upregulated by lenti-Park2 and downregulated through Park2-siRNA. The PINK1 expression showed the same trend as Park2 expression. Immunofluorescence staining demonstrated that the when Park2 was overexpressed, more LC3 protein on mitochondrial autophagosome membrane was detected, whereas Park2 knockdown impeded LC3' locating on the membrane. The transmission electron microscopy image exhibited that the extent of damage to the mitochondrial in NAFLD model was revered by enhanced Park2 expression but further exacerbated by reduced Park2 expression. Park2-mediated mitophagy could relive NAFLD and may be a novel therapeutic target for NAFLD treatment. Keywords: Non-alcoholic Fatty Liver Disease (NAFLD), Mitophagy, PINK1/Park2, Park2, PINK1.
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Affiliation(s)
- H He
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China.
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15
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Antonucci L, Karin M. The Past and Future of Inflammation as a Target to Cancer Prevention. Cancer Prev Res (Phila) 2024; 17:141-155. [PMID: 38271694 PMCID: PMC10987280 DOI: 10.1158/1940-6207.capr-23-0423] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2023] [Revised: 12/21/2023] [Accepted: 01/23/2024] [Indexed: 01/27/2024]
Abstract
Inflammation is an essential defense mechanism in which innate immune cells are coordinately activated on encounter of harmful stimuli, including pathogens, tissue injury, and toxic compounds and metabolites to neutralize and eliminate the instigator and initiate healing and regeneration. Properly terminated inflammation is vital to health, but uncontrolled runaway inflammation that becomes chronic begets a variety of inflammatory and metabolic diseases and increases cancer risk. Making damaged tissues behave as "wounds that do not heal" and sustaining the production of growth factors whose physiologic function is tissue healing, chronic inflammation accelerates cancer emergence from premalignant lesions. In 1863, Rudolf Virchow, a leading German pathologist, suggested a possible association between inflammation and tumor formation, but it took another 140 years to fully elucidate and appreciate the tumorigenic role of inflammation. Key findings outlined molecular events in the inflammatory cascade that promote cancer onset and progression and enabled a better appreciation of when and where inflammation should be inhibited. These efforts triggered ongoing research work to discover and develop inflammation-reducing chemopreventive strategies for decreasing cancer risk and incidence.
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Affiliation(s)
- Laura Antonucci
- Laboratory of Gene Regulation and Signal Transduction, Departments of Pharmacology and Pathology, University of California San Diego School of Medicine; La Jolla, CA 92093, USA
| | - Michael Karin
- Laboratory of Gene Regulation and Signal Transduction, Departments of Pharmacology and Pathology, University of California San Diego School of Medicine; La Jolla, CA 92093, USA
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16
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Zhang Y, Zhang X, Chen R, Jiao Z, Shen B, Shuai Z. HSCs-derived exosomes regulate the levels of inflammatory cytokines in HIBECs through miR-122-5p mediated p38 MAPK signaling pathway. Genomics 2024; 116:110795. [PMID: 38228248 DOI: 10.1016/j.ygeno.2024.110795] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2023] [Revised: 12/29/2023] [Accepted: 01/13/2024] [Indexed: 01/18/2024]
Abstract
PBC is an autoimmune-mediated liver disease, and intrahepatic biliary epithelial cells (IBECs) are the target cells of early damage. Previous studies found that miRNAs and inflammation is closely related to PBC. In this study, we extracted exosomes from serum and human IBECs supernatant, and RNA-sequence analyzed the expression profiles of miRNAs. Elisa measured the levels of inflammatory cytokines. RT- qPCR and western blot detected the levels of miR-122-5p, p38 and p-p38. The results showed that 263 differentially expressed (DE) miRNAs were identified in serum exosomes of PBC patients. The levels of IL-1β, IL-6, IL-12, IL-17 A, IFN-γ, TNF-α and TGF-β1 in peripheral blood of PBC patients were higher than those of normal controls. According to the validation results and previous literature, exosomal miR-122-5p was finally selected as the study object, and correlated with inflammatory factors. In vitro experiments further found that exosomal miR-122-5p may derive from hepatic stellate cells (HSCs), and can be HIBECs intake, and influence HIBECs inflammatory factor levels though p38 MAPK signaling pathways. This may provide a new strategy for the treatment of PBC.
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Affiliation(s)
- Yaqin Zhang
- Department of Rheumatology, The First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Xiangzhi Zhang
- Department of Rheumatology, The First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Ruofei Chen
- Department of Rheumatology, The First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Ziying Jiao
- Department of Physiology, School of Basic Medicine of Anhui Medical University, Hefei, China
| | - Bing Shen
- Department of Physiology, School of Basic Medicine of Anhui Medical University, Hefei, China.
| | - Zongwen Shuai
- Department of Rheumatology, The First Affiliated Hospital of Anhui Medical University, Hefei, China.
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17
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Campos-Murguia A, Hupa-Breier KL, Hartleben B, Wedemeyer H, Taubert R, Engel B. Elevated Plasma CXCL8 Concentrations in Significant Fibrosis but Not in Subclinical Rejection After Adult Liver Transplantation. Transplant Direct 2024; 10:e1592. [PMID: 39877649 PMCID: PMC11774564 DOI: 10.1097/txd.0000000000001592] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2023] [Revised: 12/27/2023] [Accepted: 12/29/2023] [Indexed: 01/31/2025] Open
Abstract
Background The noninvasive detection of subclinical graft injury including subclinical T cell-mediated rejection (subTCMR) is one of the unresolved challenges after liver transplantation. Recently, serum C-X-C motif chemokine ligand 8 (CXCL8) was proposed as a highly accurate marker of subTCMR in pediatric liver transplant recipients. We aimed to evaluate the accuracy of the quantification of this chemokine for predicting subTCMR in adult liver transplant recipients, as well as its capacity to classify patients who could benefit from immunosuppression reduction. Methods Plasma CXCL8 concentrations were measured retrospectively in a prospectively collected cohort of adult liver transplant recipients with well-characterized histologic phenotypes. Results In total, 78 patients were included. Median plasma CXCL8 concentrations did not differ (P = 0.24) between patients without histological evidence of rejection (3.6 [0.4-22.0] pg/mL), subTCMR (11.5 [0.4-41.0] pg/mL), clinical TCMR (9.4 [0.4-40.5] pg/mL), and other etiologies of graft injury (8.7 [0.4-31.2] pg/mL). Likewise, plasma CXCL8 concentrations did not discriminate between patients within and outside histologic criteria for immunosuppression reduction that were proposed by the 2016 Banff Working Group on Liver Allograft Pathology (cutoff: 10.9 pg/mL, sensitivity: 0.48, and specificity: 0.79). Furthermore, weak correlation was found between plasma CXCL8 and alanine aminotransferase and aspartate aminotransferase (Spearman ρ = 0.18 and 0.25). Patients with significant fibrosis (17.8 [0.4-40.5] pg/mL) showed higher plasma CXCL8 concentrations than patients without fibrosis (8.2 [0.4-41.0] pg/mL; P = 0.05). Conclusions Plasma CXCL8 concentrations are not predictive of subclinical graft injury or of histological criteria for the minimization of immunosuppression in adult liver transplant recipients.
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Affiliation(s)
- Alejandro Campos-Murguia
- Department of Gastroenterology, Hepatology, Infectious Diseases and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Katharina Luise Hupa-Breier
- Department of Gastroenterology, Hepatology, Infectious Diseases and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Björn Hartleben
- Institute for Pathology, Hannover Medical School, Hannover, Germany
| | - Heiner Wedemeyer
- Department of Gastroenterology, Hepatology, Infectious Diseases and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Richard Taubert
- Department of Gastroenterology, Hepatology, Infectious Diseases and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Bastian Engel
- Department of Gastroenterology, Hepatology, Infectious Diseases and Endocrinology, Hannover Medical School, Hannover, Germany
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18
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Thai SF, Jones CP, Robinette BL, Ren H, Vallanat B, Fisher A, Kitchin KT. Effects of multi-walled carbon nanotubes on gene and microRNA expression in human hepatocarcinoma HepG2 cells. MATERIALS EXPRESS : AN INTERNATIONAL JOURNAL ON MULTIDISCIPLINARY MATERIALS RESEARCH 2024; 14:403-415. [PMID: 39022637 PMCID: PMC11251416 DOI: 10.1166/mex.2024.2641] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 07/20/2024]
Abstract
The usage of multi-walled carbon nanotubes (MWCNT) has increased exponentially in the past years, but, potential toxicity mechanisms are not clear. We studied the transcriptomic alterations induced by one multi-walled carbon nanotube (MWCNT) and its -OH and -COOH functionalized derivatives in human HepG2 cells. We showed that all three MWCNT treatments induced alterations in stress-related signaling pathways, inflammation-related signaling pathways, cholesterol synthesis pathways, proliferation-related pathways, senescence-related pathways and cancer-related pathways. In stress-related pathways, the acute phase response was induced in all three MWCNTs and all doses treated and ranked high. Other stress-related pathways were also related to the oxidative-induced signaling pathways, such as NRF-2 mediated oxidative stress response, hepatic fibrosis/Stella cell activation, iNOS signaling, and Hif1α signaling. Many inflammation-related pathways were altered, such as IL-8, IL-6, TNFR1, TNFR2, and NF-κB signaling pathways. These results were consistent with our previous results with exposures to the same three multi-walled carbon nanotubes in human lung BEAS-2B and also with results in mice and rats. From the microRNA target filter analysis, TXNIP & miR-128-3p interaction was present in all three MWCNT treatments, and maybe important for the induction of oxidative stress. CXCL-8 & miR-146-5p and Wee1 & miR-128-3p were only present in the cells treated with the parent and the OH-functionalized MWCNTs. These mRNA-miRNA interactions were involved in oxidative stress, inflammation, cell cycle, cholesterol biosynthesis and cancer related pathways. Target filter analysis also showed altered liver hyperplasia/hyperproliferation and hepatic cancer pathways. In short, target filter analysis complemented the transcriptomic analysis and pointed to specific gene/microRNA interactions that can help inform mechanism of action. Moreover, our study showed that the signaling pathways altered in HepG2 cells correlated well with the toxicity and carcinogenicity observed in vivo, indicating that HepG2 may be a good in vitro predictive model for MWCNT toxicity studies.
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Affiliation(s)
- Sheau-Fung Thai
- Center for Computational Toxicology and Exposure, US Environmental Protection Agency, 109 TW Alexander Dr., Durham NC 27709 USA
| | - Carlton P. Jones
- Center for Computational Toxicology and Exposure, US Environmental Protection Agency, 109 TW Alexander Dr., Durham NC 27709 USA
| | - Brian L. Robinette
- Center for Computational Toxicology and Exposure, US Environmental Protection Agency, 109 TW Alexander Dr., Durham NC 27709 USA
| | | | - Beena Vallanat
- Center for Computational Toxicology and Exposure, US Environmental Protection Agency, 109 TW Alexander Dr., Durham NC 27709 USA
| | - Anna Fisher
- Center for Public Health and Environmental Assessment, US Environmental Production Agency, 109 TW Alexander Dr., Durham NC 27709
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19
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Yang M, Zhang CY. Interleukins in liver disease treatment. World J Hepatol 2024; 16:140-145. [PMID: 38495285 PMCID: PMC10941743 DOI: 10.4254/wjh.v16.i2.140] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/04/2023] [Revised: 12/22/2023] [Accepted: 01/08/2024] [Indexed: 02/27/2024] Open
Abstract
Cytokines play pleiotropic roles in human health and disease by regulating both innate and adaptive immune responses. Interleukins (ILs), a large group of cytokines, can be divided into seven families, including IL-1, IL-2, IL-6, IL-8, IL-10, IL-12, and IL-17 families. Here, we review the functions of ILs in the pathogenesis and resolution of liver diseases, such as liver inflammation (e.g., IL-35), alcohol-related liver disease (e.g., IL-11), non-alcoholic steatohepatitis (e.g., IL-22), liver fibrosis (e.g., Il-17a), and liver cancer (e.g., IL-8). Overall, IL-1 family members are implicated in liver inflammation induced by different etiologies, such as alcohol consumption, high-fat diet, and hepatitis viruses. IL-2 family members mainly regulate T lymphocyte and NK cell proliferation and activation, and the differentiation of T cells. IL-6 family cytokines play important roles in acute phase response in liver infection, liver regeneration, and metabolic regulation, as well as lymphocyte activation. IL-8, also known as CXCL8, is activated in chronic liver diseases, which is associated with the accumulation of neutrophils and macrophages. IL-10 family members contribute key roles to liver immune tolerance and immunosuppression in liver disease. IL-12 family cytokines influence T-cell differentiation and play an essential role in autoimmune liver disease. IL-17 subfamilies contribute to infection defense, liver inflammation, and Th17 cell differentiation. ILs interact with different type I and type II cytokine receptors to regulate intracellular signaling pathways that mediate their functions. However, most clinical studies are only performed to evaluate IL-mediated therapies on alcohol and hepatitis virus infection-induced hepatitis. More pre-clinical and clinical studies are required to evaluate IL-mediated monotherapy and synergistic therapies.
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Affiliation(s)
- Ming Yang
- Department of Surgery, University of Missouri, Columbia, MO 65212, United States.
| | - Chun-Ye Zhang
- Bond Life Sciences Center, University of Missouri, Columbia, MO 65212, United States
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Gu L, Zhao C, Wang Y, Wang C, Yin X, Ye Q, Liu Y, Zou X, Wang L, Zhuge Y, Wu J, Zhang F. Senescence of Hepatic Stellate Cells by Specific Delivery of Manganese for Limiting Liver Fibrosis. NANO LETTERS 2024; 24:1062-1073. [PMID: 38164915 PMCID: PMC10836362 DOI: 10.1021/acs.nanolett.3c03689] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/25/2023] [Revised: 12/17/2023] [Accepted: 12/19/2023] [Indexed: 01/03/2024]
Abstract
Senescence of activated hepatic stellate cells (HSCs) is crucial for the regression of liver fibrosis. However, impaired immune clearance can result in the accumulation of senescent HSCs, exacerbating liver fibrosis. The activation of the cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway is essential for both senescence and the innate immune response. Additionally, the specific delivery to activated HSCs is hindered by their inaccessible anatomical location, capillarization of liver sinusoidal endothelial cells (LSECs), and loss of substance exchange. Herein, we propose an antifibrotic strategy that combines prosenescence with enhanced immune clearance through targeted delivery of manganese (a cGAS-STING stimulator) via albumin-mediated transcytosis, specifically aimed at inducing senescence and eliminating activated HSCs in liver fibrosis. Our findings demonstrate that only albumin efficiently transfers manganese to activated HSCs from LSECs via transcytosis compared to liposomes, resulting in significant antifibrotic effects in vivo while exhibiting negligible toxicity.
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Affiliation(s)
- Lihong Gu
- Department
of Gastroenterology, Nanjing Drum Tower Hospital, Affiliated Hospital
of Medical School, Nanjing University, Nanjing, Jiangsu 210008, People’s
Republic of China
- State
Key Laboratory of Pharmaceutical Biotechnology, Chemistry and Biomedicine
Innovation Center, Medical School of Nanjing
University, Nanjing, Jiangsu 210093, People’s Republic of China
- Jiangsu
Key Laboratory for Nano Technology, Nanjing
University, Nanjing, Jiangsu 210093, People’s Republic of China
- Wuxi
No. 2 People’s Hospital, Wuxi, Jiangsu 214002, People’s Republic of China
| | - Chenxuan Zhao
- State
Key Laboratory of Pharmaceutical Biotechnology, Chemistry and Biomedicine
Innovation Center, Medical School of Nanjing
University, Nanjing, Jiangsu 210093, People’s Republic of China
- Jiangsu
Key Laboratory for Nano Technology, Nanjing
University, Nanjing, Jiangsu 210093, People’s Republic of China
| | - Yixuan Wang
- State
Key Laboratory of Pharmaceutical Biotechnology, Chemistry and Biomedicine
Innovation Center, Medical School of Nanjing
University, Nanjing, Jiangsu 210093, People’s Republic of China
- Jiangsu
Key Laboratory for Nano Technology, Nanjing
University, Nanjing, Jiangsu 210093, People’s Republic of China
| | - Chao Wang
- State
Key Laboratory of Pharmaceutical Biotechnology, Chemistry and Biomedicine
Innovation Center, Medical School of Nanjing
University, Nanjing, Jiangsu 210093, People’s Republic of China
- Jiangsu
Key Laboratory for Nano Technology, Nanjing
University, Nanjing, Jiangsu 210093, People’s Republic of China
| | - Xiaochun Yin
- Department
of Gastroenterology, Nanjing Drum Tower Hospital, Affiliated Hospital
of Medical School, Nanjing University, Nanjing, Jiangsu 210008, People’s
Republic of China
| | - Qingsong Ye
- State
Key Laboratory of Pharmaceutical Biotechnology, Chemistry and Biomedicine
Innovation Center, Medical School of Nanjing
University, Nanjing, Jiangsu 210093, People’s Republic of China
- Jiangsu
Key Laboratory for Nano Technology, Nanjing
University, Nanjing, Jiangsu 210093, People’s Republic of China
| | - Yan Liu
- Department
of Gastroenterology, Nanjing Drum Tower Hospital, Affiliated Hospital
of Medical School, Nanjing University, Nanjing, Jiangsu 210008, People’s
Republic of China
| | - Xiaoping Zou
- Department
of Gastroenterology, Nanjing Drum Tower Hospital, Affiliated Hospital
of Medical School, Nanjing University, Nanjing, Jiangsu 210008, People’s
Republic of China
| | - Lei Wang
- Department
of Gastroenterology, Nanjing Drum Tower Hospital, Affiliated Hospital
of Medical School, Nanjing University, Nanjing, Jiangsu 210008, People’s
Republic of China
| | - Yuzheng Zhuge
- Department
of Gastroenterology, Nanjing Drum Tower Hospital, Affiliated Hospital
of Medical School, Nanjing University, Nanjing, Jiangsu 210008, People’s
Republic of China
| | - Jinhui Wu
- State
Key Laboratory of Pharmaceutical Biotechnology, Chemistry and Biomedicine
Innovation Center, Medical School of Nanjing
University, Nanjing, Jiangsu 210093, People’s Republic of China
- Jiangsu
Key Laboratory for Nano Technology, Nanjing
University, Nanjing, Jiangsu 210093, People’s Republic of China
| | - Feng Zhang
- Department
of Gastroenterology, Nanjing Drum Tower Hospital, Affiliated Hospital
of Medical School, Nanjing University, Nanjing, Jiangsu 210008, People’s
Republic of China
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Ceccherini E, Michelucci E, Signore G, Coco B, Zari M, Bellini M, Brunetto MR, Cecchettini A, Rocchiccioli S. The Clinical Utility of the Saliva Proteome in Rare Diseases: A Pilot Study for Biomarker Discovery in Primary Sclerosing Cholangitis. J Clin Med 2024; 13:544. [PMID: 38256678 PMCID: PMC10816894 DOI: 10.3390/jcm13020544] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2023] [Revised: 01/08/2024] [Accepted: 01/16/2024] [Indexed: 01/24/2024] Open
Abstract
BACKGROUND Primary sclerosing cholangitis (PSC) is a rare chronic inflammatory liver disease characterized by biliary strictures and cholestasis. Due to the lack of effective serological indicators for diagnosis and prognosis, in the present study, we examined the potentiality of the saliva proteome to comprehensively screen for novel biomarkers. METHODS Saliva samples of PSC patients and healthy controls were processed and subsequently analyzed using a liquid chromatography-tandem mass spectrometry technique. A bioinformatic approach was applied to detect the differentially expressed proteins, their related biological functions and pathways, and the correlation with the clinical evidence in order to identify a possible marker for the PSC group. RESULTS We identified 25 differentially expressed proteins in PSC patients when compared to the healthy control group. Among them, eight proteins exhibited area under the curve values up to 0.800, suggesting these saliva proteins as good discriminators between the two groups. Multiple positive correlations were also identified between the dysregulated salivary proteins and increased serum alkaline phosphatase levels and the presence of ulcerative colitis. Pathway analysis revealed significant enrichments in the immune system, neutrophil degranulation, and in the interleukine-17 signaling pathway. CONCLUSION We demonstrated the potentiality of saliva as a useful biofluid to obtain a fingerprint of the pathology, suggesting disulfide-isomerase A3 and peroxiredoxin-5 as the better discriminating proteins in PSC patients. Hence, analysis of saliva proteins could become, in future, a useful tool in the screening of patients with suspected PSC.
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Affiliation(s)
- Elisa Ceccherini
- Institute of Clinical Physiology, National Research Council, 56124 Pisa, Italy; (E.M.); (G.S.); (A.C.); (S.R.)
| | - Elena Michelucci
- Institute of Clinical Physiology, National Research Council, 56124 Pisa, Italy; (E.M.); (G.S.); (A.C.); (S.R.)
- Institute of Chemistry of Organometallic Compounds, National Research Council, 56124 Pisa, Italy
| | - Giovanni Signore
- Institute of Clinical Physiology, National Research Council, 56124 Pisa, Italy; (E.M.); (G.S.); (A.C.); (S.R.)
- Biochemistry Unit, Department of Biology, University of Pisa, 56123 Pisa, Italy
| | - Barbara Coco
- Hepatology Unit, Reference Centre of the Tuscany Region for Chronic Liver Disease and Cancer, University Hospital of Pisa, 56124 Pisa, Italy; (B.C.); (M.R.B.)
| | - Michela Zari
- Gastrointestinal Unit, Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, 56124 Pisa, Italy; (M.Z.); (M.B.)
| | - Massimo Bellini
- Gastrointestinal Unit, Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, 56124 Pisa, Italy; (M.Z.); (M.B.)
| | - Maurizia Rossana Brunetto
- Hepatology Unit, Reference Centre of the Tuscany Region for Chronic Liver Disease and Cancer, University Hospital of Pisa, 56124 Pisa, Italy; (B.C.); (M.R.B.)
- Department of Clinical and Experimental Medicine, University of Pisa, 56126 Pisa, Italy
| | - Antonella Cecchettini
- Institute of Clinical Physiology, National Research Council, 56124 Pisa, Italy; (E.M.); (G.S.); (A.C.); (S.R.)
- Department of Clinical and Experimental Medicine, University of Pisa, 56126 Pisa, Italy
| | - Silvia Rocchiccioli
- Institute of Clinical Physiology, National Research Council, 56124 Pisa, Italy; (E.M.); (G.S.); (A.C.); (S.R.)
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Pecqueux M, Brückner F, Oehme F, Hempel S, Baenke F, Riediger C, Distler M, Weitz J, Kahlert C. Preoperative IL-8 levels as prognostic indicators of overall survival: an extended follow-up in a prospective cohort with colorectal liver metastases. BMC Cancer 2024; 24:90. [PMID: 38233759 PMCID: PMC10792859 DOI: 10.1186/s12885-023-11787-1] [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: 10/14/2023] [Accepted: 12/21/2023] [Indexed: 01/19/2024] Open
Abstract
INTRODUCTION CRC with liver metastases is a major contributor to cancer-related mortality. Despite advancements in liver resection techniques, patient survival remains a concern due to high recurrence rates. This study seeks to uncover prognostic biomarkers that predict overall survival in patients undergoing curative hepatic resection for CRC liver metastases. METHODS Prospectively collected serum samples from a cohort of 49 patients who received curative hepatic resection for CRC liver metastases were studied. The patients are part of a cohort, previously analyzed for perioperative complications (see methods). Various preoperative serum markers, clinical characteristics, and factors were analyzed. Univariate and multivariate Cox regression analyses were conducted to determine associations between these variables and disease-free survival as well as overall survival. RESULTS For disease-free survival, univariate analysis highlighted the correlation between poor outcomes and advanced primary tumor stage, high ASA score, and synchronous liver metastases. Multivariate analysis identified nodal-positive primary tumors and synchronous metastases as independent risk factors for disease-free survival. Regarding overall survival, univariate analysis demonstrated significant links between poor survival and high preoperative IL-8 levels, elevated neutrophil-lymphocyte ratio (NLR), and presence of metastases in other organs. Multivariate analysis confirmed preoperative IL-8 and having three or more liver metastases as independent risk factors for overall survival. The impact of IL-8 on survival was particularly noteworthy, surpassing the influence of established clinical factors. CONCLUSION This study establishes preoperative IL-8 levels as a potential prognostic biomarker for overall survival in patients undergoing curative liver resection for CRC liver metastases. This study underscores the importance of incorporating IL-8 and other biomarkers into clinical decision-making, facilitating improved patient stratification and tailored treatment approaches. Further research and validation studies are needed to solidify the clinical utility of IL-8 as a prognostic marker.
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Affiliation(s)
- Mathieu Pecqueux
- Department of Visceral, Thoracic and Vascular Surgery, Faculty of Medicine and University Hospital Carl Gustav Carus Technische Universität Dresden, Fetscherstrasse 74, 01307, Dresden, Germany.
- National Center for Tumor Diseases (NCT/UCC), Dresden, Germany: German Cancer Research Center (DKFZ), Heidelberg, Germany; Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany; Helmholtz-Zentrum Dresden - Rossendorf (HZDR), Dresden, Germany.
| | - Frederik Brückner
- Department of Visceral, Thoracic and Vascular Surgery, Faculty of Medicine and University Hospital Carl Gustav Carus Technische Universität Dresden, Fetscherstrasse 74, 01307, Dresden, Germany
- National Center for Tumor Diseases (NCT/UCC), Dresden, Germany: German Cancer Research Center (DKFZ), Heidelberg, Germany; Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany; Helmholtz-Zentrum Dresden - Rossendorf (HZDR), Dresden, Germany
| | - Florian Oehme
- Department of Visceral, Thoracic and Vascular Surgery, Faculty of Medicine and University Hospital Carl Gustav Carus Technische Universität Dresden, Fetscherstrasse 74, 01307, Dresden, Germany
- National Center for Tumor Diseases (NCT/UCC), Dresden, Germany: German Cancer Research Center (DKFZ), Heidelberg, Germany; Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany; Helmholtz-Zentrum Dresden - Rossendorf (HZDR), Dresden, Germany
| | - Sebastian Hempel
- Department of Visceral, Thoracic and Vascular Surgery, Faculty of Medicine and University Hospital Carl Gustav Carus Technische Universität Dresden, Fetscherstrasse 74, 01307, Dresden, Germany
- National Center for Tumor Diseases (NCT/UCC), Dresden, Germany: German Cancer Research Center (DKFZ), Heidelberg, Germany; Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany; Helmholtz-Zentrum Dresden - Rossendorf (HZDR), Dresden, Germany
| | - Franziska Baenke
- Department of Visceral, Thoracic and Vascular Surgery, Faculty of Medicine and University Hospital Carl Gustav Carus Technische Universität Dresden, Fetscherstrasse 74, 01307, Dresden, Germany
- National Center for Tumor Diseases (NCT/UCC), Dresden, Germany: German Cancer Research Center (DKFZ), Heidelberg, Germany; Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany; Helmholtz-Zentrum Dresden - Rossendorf (HZDR), Dresden, Germany
| | - Carina Riediger
- Department of Visceral, Thoracic and Vascular Surgery, Faculty of Medicine and University Hospital Carl Gustav Carus Technische Universität Dresden, Fetscherstrasse 74, 01307, Dresden, Germany
- National Center for Tumor Diseases (NCT/UCC), Dresden, Germany: German Cancer Research Center (DKFZ), Heidelberg, Germany; Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany; Helmholtz-Zentrum Dresden - Rossendorf (HZDR), Dresden, Germany
| | - Marius Distler
- Department of Visceral, Thoracic and Vascular Surgery, Faculty of Medicine and University Hospital Carl Gustav Carus Technische Universität Dresden, Fetscherstrasse 74, 01307, Dresden, Germany
- National Center for Tumor Diseases (NCT/UCC), Dresden, Germany: German Cancer Research Center (DKFZ), Heidelberg, Germany; Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany; Helmholtz-Zentrum Dresden - Rossendorf (HZDR), Dresden, Germany
| | - Jürgen Weitz
- Department of Visceral, Thoracic and Vascular Surgery, Faculty of Medicine and University Hospital Carl Gustav Carus Technische Universität Dresden, Fetscherstrasse 74, 01307, Dresden, Germany
- National Center for Tumor Diseases (NCT/UCC), Dresden, Germany: German Cancer Research Center (DKFZ), Heidelberg, Germany; Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany; Helmholtz-Zentrum Dresden - Rossendorf (HZDR), Dresden, Germany
| | - Christoph Kahlert
- Department of Visceral, Thoracic and Vascular Surgery, Faculty of Medicine and University Hospital Carl Gustav Carus Technische Universität Dresden, Fetscherstrasse 74, 01307, Dresden, Germany
- National Center for Tumor Diseases (NCT/UCC), Dresden, Germany: German Cancer Research Center (DKFZ), Heidelberg, Germany; Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany; Helmholtz-Zentrum Dresden - Rossendorf (HZDR), Dresden, Germany
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Rey I, Effendi-Ys R, Sukatendel K. The Comparison of Serum Interleukin-8 Levels Based on Severity of Liver Cirrhosis. Med Arch 2024; 78:92-94. [PMID: 38566873 PMCID: PMC10983089 DOI: 10.5455/medarh.2024.78.92-94] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2023] [Accepted: 01/28/2024] [Indexed: 04/04/2024] Open
Abstract
Background The molecule known as Interleukin-8 (IL-8), a chemotactic leukocyte, has been found to have a crucial role in the perpetuation of the inflammatory environment that is associated with hepatitis B virus (HBV) infection, as well as in the development of liver cirrhosis and cancer. Objective The aim of this study was to carefully examine the role of IL-8 in the inflammatory reaction and to compare the levels based on the severity of liver cirrhosis. Methods The study was conducted from February 2018 to September 2018 at the Gastroenterohepatology Division, Internal medicine Department, Faculty of Medicine, Universitas Sumatera Utara. The study was designed as an analytic comparative, cross-sectional study. The liver cirrhosis patients who participated in this study met the inclusion criteria and provided informed consent. Results A total of 70 patients were included in the study, from which we identified 1 individual with child-pugh A, 28 individuals with child-pugh B, and 41 individuals with child-pugh C. The serum level of IL-8 was found to be 98 (11-320) (pg/ml). The IL-8 levels between child-pugh B and C patients did not exhibit any noteworthy differences during our analysis (p = 0.109, p>0.05). Conclusion There is no notable inequality in the levels of IL-8 across different stages of liver cirrhosis.
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Affiliation(s)
- Imelda Rey
- Division of Gastroenterohepatology, Department of Internal Medicine, Faculty of Medicine, Universitas Sumatera Utara, Medan, Indonesia
- Haji Adam Malik General Hospital, Medan, Indonesia
| | - Rustam Effendi-Ys
- Division of Gastroenterohepatology, Department of Internal Medicine, Faculty of Medicine, Universitas Sumatera Utara, Medan, Indonesia
- Pirngadi General Hospital, Medan, Indonesia
| | - Khairani Sukatendel
- Department of Obstetric Gynecology, Faculty of Medicine, Universitas Sumatera Utara, Medan, Indonesia
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24
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Cates WT, Denbeigh JM, Salvagno RT, Kakar S, van Wijnen AJ, Eaton C. Inflammatory Markers Involved in the Pathogenesis of Dupuytren's Contracture. Crit Rev Eukaryot Gene Expr 2024; 34:1-35. [PMID: 38912961 DOI: 10.1615/critreveukaryotgeneexpr.2024052889] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/25/2024]
Abstract
Dupuytren's disease is a common fibroproliferative disease that can result in debilitating hand deformities. Partial correction and return of deformity are common with surgical or clinical treatments at present. While current treatments are limited to local procedures for relatively late effects of the disease, the pathophysiology of this connective tissue disorder is associated with both local and systemic processes (e.g., fibrosis, inflammation). Hence, a better understanding of the systemic circulation of Dupuytren related cytokines and growth factors may provide important insights into disease progression. In addition, systemic biomarker analysis could yield new concepts for treatments of Dupuytren that attenuate circulatory factors (e.g., anti-inflammatory agents, neutralizing antibodies). Progress in the development of any disease modifying biologic treatment for Dupuytren has been hampered by the lack of clinically useful biomarkers. The characterization of nonsurgical Dupuytren biomarkers will permit disease staging from diagnostic and prognostic perspectives, as well as allows evaluation of biologic responses to treatment. Identification of such markers may transcend their use in Dupuytren treatment, because fibrotic biological processes fundamental to Dupuytren are relevant to fibrosis in many other connective tissues and organs with collagen-based tissue compartments. There is a wide range of potential Dupuytren biomarker categories that could be informative, including disease determinants linked to genetics, collagen metabolism, as well as immunity and inflammation (e.g., cytokines, chemokines). This narrative review provides a broad overview of previous studies and emphasizes the importance of inflammatory mediators as candidate circulating biomarkers for monitoring Dupuytren's disease.
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Affiliation(s)
- William T Cates
- Department of Orthopedic Surgery, Mayo Clinic, Rochester, MN 55905, USA
| | - Janet M Denbeigh
- Department of Orthopedic Surgery, Mayo Clinic, Rochester, MN 55905, USA
| | | | - Sanjeev Kakar
- Department of Orthopedic Surgery, Mayo Clinic, Rochester, MN 55905, USA
| | - Andre J van Wijnen
- Department of Biochemistry, University of Vermont, Burlington, VT 05405, USA
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Lowe KO, Tanase CE, Maghami S, Fisher LE, Ghaemmaghami AM. Inflammatory Network of Liver Fibrosis and How It Can Be Targeted Therapeutically. IMMUNO 2023; 3:375-408. [DOI: 10.3390/immuno3040023] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2025] Open
Abstract
Liver fibrosis is a complex, dynamic process associated with a broad spectrum of chronic liver diseases and acute liver failure, characterised by the dysregulated intrahepatic production of extracellular matrix proteins replacing functional liver cells with scar tissue. Fibrosis progresses due to an interrelated cycle of hepatocellular injury, triggering a persistent wound-healing response. The accumulation of scar tissue and chronic inflammation can eventually lead to cirrhosis and hepatocellular carcinoma. Currently, no therapies exist to directly treat or reverse liver fibrosis; hence, it remains a substantial global disease burden. A better understanding of the intricate inflammatory network that drives the initiation and maintenance of liver fibrosis to enable the rationale design of new intervention strategies is required. This review clarifies the most current understanding of the hepatic fibrosis cellular network with a focus on the role of regulatory T cells, and a possible trajectory for T cell immunotherapy in fibrosis treatment. Despite good progress in elucidating the role of the immune system in liver fibrosis, future work to better define the function of different immune cells and their mediators at different fibrotic stages is needed, which will enhance the development of new therapies.
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Affiliation(s)
- Kirstin O. Lowe
- School of Life Sciences, University of Nottingham, Nottingham NG7 2RD, UK
| | | | - Susan Maghami
- Hull York Medical School, University of York, York YO10 5DD, UK
| | - Leanne E. Fisher
- School of Life Sciences, University of Nottingham, Nottingham NG7 2RD, UK
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26
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Zhu H, Zheng M, He H, Lei H, Tai W, Yang J. High neutrophil-lymphocyte ratio indicates a worse response to ursodeoxycholic acid in primary biliary cholangitis: a retrospective cohort study. BMC Gastroenterol 2023; 23:400. [PMID: 37978445 PMCID: PMC10657125 DOI: 10.1186/s12876-023-03031-8] [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: 09/10/2023] [Accepted: 11/05/2023] [Indexed: 11/19/2023] Open
Abstract
BACKGROUND Primary biliary cholangitis (PBC) is a chronic cholestatic liver disease characterized by inflammation of the interlobular bile ducts. Ursodeoxycholic acid (UDCA) is the only FDA approved first-line therapy for PBC, but up to 40% of patients with PBC have an incomplete response to UDCA. Neutrophil-to-lymphocyte (NLR) has been used to predict prognosis in various liver diseases. There is limited evidence on the treatment response to UDCA in PBC patients. Our study aimed to evaluate the relationship between NRL and the response to UDCA treatment in PBC patients. METHODS A total of 257 primary biliary cholangitis (PBC) patients treated with UDCA (13-15 mg/kg/d) were enrolled in this retrospective study. The response to treatment was evaluated based on alkaline phosphatase levels ≤1.67 times the upper limit of the normal value after 12 months of UDCA treatment. Multivariable logistic regression analysis was performed to investigate the association between NLR at baseline and the response to 12 months of UDCA treatment after adjusting for important confounding variables. The stability of the results was evaluated by unadjusted and adjusted models. RESULTS The results of multiple regression analysis showed that NLR at baseline was positively associated with the nonresponse to UDCA treatment after adjustments for potential confounders (age, sex, BMI, hypertension, arterial plaque, thyroid disease, jaundice, albumin, globulin, total bile acid, ALP, GGT, LDLC, total cholesterol, hemoglobin, and APTT) (OR = 1.370, 95% CI 1.066-1.761). These results reveal that NLR is an independent risk factor for UDCA treatment nonresponse. CONCLUSIONS Our results suggest that PBC patients with a high NLR had a worse response to UDCA therapy.
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Affiliation(s)
- Huiling Zhu
- Department of Gastroenterology, Second Affiliated Hospital of Kunming Medical University, Kunming, China
| | - Mengyao Zheng
- Department of Gastroenterology, Second Affiliated Hospital of Kunming Medical University, Kunming, China
| | - Haiyu He
- Department of Gastroenterology, Second Affiliated Hospital of Kunming Medical University, Kunming, China
| | - Hongtao Lei
- School of Public Health Kunming Medical University, Kunming, China
| | - Wenlin Tai
- Clinical Lab, Second Affiliated Hospital of Kunming Medical University, Kunming, China
| | - Jinhui Yang
- Department of Gastroenterology, Second Affiliated Hospital of Kunming Medical University, Kunming, China.
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Balazs I, Stadlbauer V. Circulating neutrophil anti-pathogen dysfunction in cirrhosis. JHEP Rep 2023; 5:100871. [PMID: 37822786 PMCID: PMC10562928 DOI: 10.1016/j.jhepr.2023.100871] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/18/2023] [Revised: 07/16/2023] [Accepted: 07/22/2023] [Indexed: 10/13/2023] Open
Abstract
Neutrophils are the largest population of leucocytes and are among the first cells of the innate immune system to fight against intruding pathogens. In patients with cirrhosis, neutrophils exhibit altered functionality, including changes in phagocytic ability, bacterial killing, chemotaxis, degranulation, reactive oxygen species production and NET (neutrophil extracellular trap) formation. This results in their inability to mount an adequate antibacterial response and protect the individual from infection. Prognosis and survival in patients with cirrhosis are greatly influenced by the development of infectious complications. Multidrug-resistant bacterial infections in patients with cirrhosis are currently a growing problem worldwide; therefore, alternative methods for the prevention and treatment of bacterial infections in cirrhosis are urgently needed. The prevention and treatment of neutrophil dysfunction could be a potential way to protect patients from bacterial infections. However, the reasons for changes in neutrophil function in cirrhosis are still not completely understood, which limits the development of efficient therapeutic strategies. Both cellular and serum factors have been proposed to contribute to the functional impairment of neutrophils. Herein, we review the current knowledge on features and proposed causes of neutrophil dysfunction in cirrhosis, with a focus on current knowledge gaps and limitations, as well as opportunities for future investigations in this field.
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Affiliation(s)
- Irina Balazs
- Department of Internal Medicine, Division of Gastroenterology and Hepatology, Medical University of Graz, Graz, Austria
- Center for Biomarker Research in Medicine (CBmed), Graz, Austria
| | - Vanessa Stadlbauer
- Department of Internal Medicine, Division of Gastroenterology and Hepatology, Medical University of Graz, Graz, Austria
- Center for Biomarker Research in Medicine (CBmed), Graz, Austria
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El-Mokhtar SA, Afifi NA, Abdel-Malek MO, Hassan WA, Hetta H, El-Badawy O. Aberrant cytokine and VCAM-1 expression in patients with viral and non-viral related liver cirrhosis. Cytokine 2023; 171:156385. [PMID: 37788510 DOI: 10.1016/j.cyto.2023.156385] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2023] [Revised: 08/26/2023] [Accepted: 09/27/2023] [Indexed: 10/05/2023]
Abstract
The study aim was to compare the alterations in the expression levels of proinflammatory and chemotactic cytokines as tumor necrosis factor-alpha (TNF-α), interleukin (IL)-17A and IL-8, the down regulatory cytokine IL-10, in addition to the vascular cell adhesion molecule-1 (VCAM-1) gene in different groups of patients with cirrhosis due to various etiologies. This case-control study included 84 patients suffering from cirrhosis of viral and non-viral etiologies and 20 sex and age-matched healthy controls. All patients were subjected to detailed history taking, clinical examination, and liver function assessment. The expression levels of TNF-α, IL-17A, IL-8, IL-10, and VCAM-1 were assessed in peripheral blood mononuclear cells by real-time PCR. Patients with cirrhosis showed marked changes in the tested gene expression levels relative to the control group. Higher expression levels of all genes except IL-10 were seen in patients of the viral than in the non-viral groups. Most of the significant correlations of liver function parameters were observed with TNF-α in both the viral and non-viral groups, followed by IL-17A. Increased TNF-α and IL-17A presented potential risk factors for disease progression to cirrhosis of Child class C.
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Affiliation(s)
- Sara A El-Mokhtar
- Microbiology & Immunology Department, Faculty of Pharmacy, Assiut University, Assiut, Egypt
| | - Noha A Afifi
- Medical Microbiology & Immunology Department, Faculty of Medicine, Assiut University, Assiut, Egypt
| | - Mohamed O Abdel-Malek
- Tropical Medicine & Gastroenterology Department, Faculty of Medicine, Assiut University, Assiut, Egypt
| | - Waleed A Hassan
- Tropical Medicine & Gastroenterology Department, Faculty of Medicine, Assiut University, Assiut, Egypt
| | - Helal Hetta
- Medical Microbiology & Immunology Department, Faculty of Medicine, Assiut University, Assiut, Egypt
| | - Omnia El-Badawy
- Medical Microbiology & Immunology Department, Faculty of Medicine, Assiut University, Assiut, Egypt.
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Pecqueux M, Brückner F, Bogner A, Oehme F, Hau HM, von Bechtolsheim F, Held HC, Baenke F, Distler M, Riediger C, Weitz J, Kahlert C. Interleukin-8 is superior to CRP for the prediction of severe complications in a prospective cohort of patients undergoing major liver resection. Langenbecks Arch Surg 2023; 408:377. [PMID: 37747507 PMCID: PMC10519863 DOI: 10.1007/s00423-023-03041-w] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2023] [Accepted: 08/02/2023] [Indexed: 09/26/2023]
Abstract
INTRODUCTION Early detection of severe complications may reduce morbidity and mortality in patients undergoing hepatic resection. Therefore, we prospectively evaluated a panel of inflammatory blood markers for their value in predicting postoperative complications in patients undergoing liver surgery. METHODS A total of 139 patients undergoing liver resections (45 wedge resections, 49 minor resections, and 45 major resections) were prospectively enrolled between August 2017 and December 2018. Leukocytes, CRP, neutrophil-lymphocyte ratio (NLR), thrombocyte-lymphocyte ratio (TLR), bilirubin, INR, and interleukin-6 and -8 (IL-6 and IL-8) were measured in blood drawn preoperatively and on postoperative days 1, 4, and 7. IL-6 and IL-8 were measured using standardized immunoassays approved for in vitro diagnostic use in Germany. ROC curve analysis was used to determine predictive values for the occurrence of severe postoperative complications (CDC ≥ 3). RESULTS For wedge and minor resections, leukocyte counts at day 7 (AUC 0.80 and 0.82, respectively), IL-6 at day 7 (AUC 0.74 and 0.73, respectively), and CRP change (∆CRP) at day 7 (AUC 0.72 and 0.71, respectively) were significant predictors of severe postoperative complications. IL-8 failed in patients undergoing wedge resections, but was a significant predictor of severe complications after minor resections on day 7 (AUC 0.79), had the best predictive value in all patients on days 1, 4, and 7 (AUC 0.72, 0.72, and 0.80, respectively), and was the only marker with a significant predictive value in patients undergoing major liver resections (AUC on day 1: 0.70, day 4: 0.86, and day 7: 0.92). No other marker, especially not CRP, was predictive of severe complications after major liver surgery. CONCLUSION IL-8 is superior to CRP in predicting severe complications in patients undergoing major hepatic resection and should be evaluated as a biomarker for patients undergoing major liver surgery. This is the first paper demonstrating a feasible implementation of IL-8 analysis in a clinical setting.
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Affiliation(s)
- Mathieu Pecqueux
- Department of Visceral, Thoracic and Vascular Surgery, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Fetscherstrasse 74, 01307, Dresden, Germany
- National Center for Tumor Diseases (NCT/UCC), Dresden, Germany: German Cancer Research Center (DKFZ), Heidelberg, Germany; Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany; Helmholtz-Zentrum Dresden - Rossendorf (HZDR), Dresden, Germany
| | - Frederik Brückner
- Department of Visceral, Thoracic and Vascular Surgery, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Fetscherstrasse 74, 01307, Dresden, Germany
- National Center for Tumor Diseases (NCT/UCC), Dresden, Germany: German Cancer Research Center (DKFZ), Heidelberg, Germany; Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany; Helmholtz-Zentrum Dresden - Rossendorf (HZDR), Dresden, Germany
| | - Andreas Bogner
- Department of Visceral, Thoracic and Vascular Surgery, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Fetscherstrasse 74, 01307, Dresden, Germany
- National Center for Tumor Diseases (NCT/UCC), Dresden, Germany: German Cancer Research Center (DKFZ), Heidelberg, Germany; Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany; Helmholtz-Zentrum Dresden - Rossendorf (HZDR), Dresden, Germany
| | - Florian Oehme
- Department of Visceral, Thoracic and Vascular Surgery, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Fetscherstrasse 74, 01307, Dresden, Germany
- National Center for Tumor Diseases (NCT/UCC), Dresden, Germany: German Cancer Research Center (DKFZ), Heidelberg, Germany; Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany; Helmholtz-Zentrum Dresden - Rossendorf (HZDR), Dresden, Germany
| | - Hans-Michael Hau
- Department of Visceral, Thoracic and Vascular Surgery, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Fetscherstrasse 74, 01307, Dresden, Germany
- National Center for Tumor Diseases (NCT/UCC), Dresden, Germany: German Cancer Research Center (DKFZ), Heidelberg, Germany; Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany; Helmholtz-Zentrum Dresden - Rossendorf (HZDR), Dresden, Germany
| | - Felix von Bechtolsheim
- Department of Visceral, Thoracic and Vascular Surgery, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Fetscherstrasse 74, 01307, Dresden, Germany
- National Center for Tumor Diseases (NCT/UCC), Dresden, Germany: German Cancer Research Center (DKFZ), Heidelberg, Germany; Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany; Helmholtz-Zentrum Dresden - Rossendorf (HZDR), Dresden, Germany
| | - Hanns-Christoph Held
- Department of Visceral, Thoracic and Vascular Surgery, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Fetscherstrasse 74, 01307, Dresden, Germany
- National Center for Tumor Diseases (NCT/UCC), Dresden, Germany: German Cancer Research Center (DKFZ), Heidelberg, Germany; Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany; Helmholtz-Zentrum Dresden - Rossendorf (HZDR), Dresden, Germany
| | - Franziska Baenke
- Department of Visceral, Thoracic and Vascular Surgery, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Fetscherstrasse 74, 01307, Dresden, Germany
- National Center for Tumor Diseases (NCT/UCC), Dresden, Germany: German Cancer Research Center (DKFZ), Heidelberg, Germany; Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany; Helmholtz-Zentrum Dresden - Rossendorf (HZDR), Dresden, Germany
| | - Marius Distler
- Department of Visceral, Thoracic and Vascular Surgery, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Fetscherstrasse 74, 01307, Dresden, Germany
- National Center for Tumor Diseases (NCT/UCC), Dresden, Germany: German Cancer Research Center (DKFZ), Heidelberg, Germany; Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany; Helmholtz-Zentrum Dresden - Rossendorf (HZDR), Dresden, Germany
| | - Carina Riediger
- Department of Visceral, Thoracic and Vascular Surgery, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Fetscherstrasse 74, 01307, Dresden, Germany
- National Center for Tumor Diseases (NCT/UCC), Dresden, Germany: German Cancer Research Center (DKFZ), Heidelberg, Germany; Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany; Helmholtz-Zentrum Dresden - Rossendorf (HZDR), Dresden, Germany
| | - Jürgen Weitz
- Department of Visceral, Thoracic and Vascular Surgery, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Fetscherstrasse 74, 01307, Dresden, Germany
- National Center for Tumor Diseases (NCT/UCC), Dresden, Germany: German Cancer Research Center (DKFZ), Heidelberg, Germany; Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany; Helmholtz-Zentrum Dresden - Rossendorf (HZDR), Dresden, Germany
| | - Christoph Kahlert
- Department of Visceral, Thoracic and Vascular Surgery, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Fetscherstrasse 74, 01307, Dresden, Germany.
- National Center for Tumor Diseases (NCT/UCC), Dresden, Germany: German Cancer Research Center (DKFZ), Heidelberg, Germany; Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany; Helmholtz-Zentrum Dresden - Rossendorf (HZDR), Dresden, Germany.
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Gylstorff S, Wilke V, Kraft D, Bertrand J, Pech M, Haag F, Relja B. Selective Internal Radiotherapy Alters the Profiles of Systemic Extracellular Vesicles in Hepatocellular Carcinoma. Int J Mol Sci 2023; 24:12512. [PMID: 37569887 PMCID: PMC10419408 DOI: 10.3390/ijms241512512] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2023] [Revised: 08/02/2023] [Accepted: 08/03/2023] [Indexed: 08/13/2023] Open
Abstract
Incidence of hepatocellular carcinoma (HCC) is increasing globally. Radioembolization (RE)/selective internal radiotherapy (SIRT) is a promising treatment for inoperable HCC. RE triggers an immune response, involving extracellular vesicles (EVs) which are crucial for cell communication and tumor development. This study explores EV immune profiles and origins in patients with inoperable HCC before and after SIRT/RE. Blood samples from 50 HCC-patients treated with SIRT/RE were collected before and after therapy to determine cytokines and isolate EVs using size exclusion chromatography. The dynamic range and EV quality required for detecting variations in surface markers were assessed. Thirty-seven EV surface markers were analyzed using flow cytometry and correlated with clinical parameters. Several immunological markers (CD4, CD2, CD40, CD45, CD49e, CD69, CD209-EVs) were present in the circulation of HCC patients. These markers positively correlated with therapy response and survival. Conversely, B cell CD20, endothelial cell CD146, platelet CD49e, and CD41b EV markers negatively correlated with 60-day survival. Elevated levels of IL-6 and IL-8 before therapy correlated negatively with patient survival, coinciding with a positive correlation with CD20-positive EVs. Plasma EVs from HCC patients exhibit immunological, cancer, and coagulation markers, including potential biomarkers (CD4, CD20, CD49e, CD146). These may enhance our understanding of cancer biology and facilitate SIRT therapy monitoring.
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Affiliation(s)
- Severin Gylstorff
- Experimental Radiology, Department of Radiology and Nuclear Medicine, Otto-von-Guericke-University, 39120 Magdeburg, Germany
- Research Campus STIMULATE, Otto-von-Guericke University, 39120 Magdeburg, Germany
- Translational and Experimental Trauma Research, Department of Trauma, Hand, Plastic and Reconstructive Surgery, University Ulm, 89081 Ulm, Germany
| | - Vanessa Wilke
- Experimental Radiology, Department of Radiology and Nuclear Medicine, Otto-von-Guericke-University, 39120 Magdeburg, Germany
- Research Campus STIMULATE, Otto-von-Guericke University, 39120 Magdeburg, Germany
| | - Daniel Kraft
- Experimental Radiology, Department of Radiology and Nuclear Medicine, Otto-von-Guericke-University, 39120 Magdeburg, Germany
- Research Campus STIMULATE, Otto-von-Guericke University, 39120 Magdeburg, Germany
| | - Jessica Bertrand
- Department of Orthopaedic Surgery, Otto-von-Guericke-University, 39120 Magdeburg, Germany
| | - Maciej Pech
- Experimental Radiology, Department of Radiology and Nuclear Medicine, Otto-von-Guericke-University, 39120 Magdeburg, Germany
- Research Campus STIMULATE, Otto-von-Guericke University, 39120 Magdeburg, Germany
| | - Florian Haag
- Experimental Radiology, Department of Radiology and Nuclear Medicine, Otto-von-Guericke-University, 39120 Magdeburg, Germany
- Research Campus STIMULATE, Otto-von-Guericke University, 39120 Magdeburg, Germany
- Department of Radiology and Nuclear Medicine, University Medical Center Mannheim, Heidelberg University, 68167 Mannheim, Germany
| | - Borna Relja
- Experimental Radiology, Department of Radiology and Nuclear Medicine, Otto-von-Guericke-University, 39120 Magdeburg, Germany
- Research Campus STIMULATE, Otto-von-Guericke University, 39120 Magdeburg, Germany
- Translational and Experimental Trauma Research, Department of Trauma, Hand, Plastic and Reconstructive Surgery, University Ulm, 89081 Ulm, Germany
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Kezer CA, Simonetto DA, Shah VH. Acute on Chronic Liver Failure in Patients with Alcohol-Associated Hepatitis: A Review. Clin Liver Dis 2023; 27:659-670. [PMID: 37380289 DOI: 10.1016/j.cld.2023.03.009] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/30/2023]
Abstract
Acute on chronic liver failure (ACLF) is a unique disease process associated with significant short-term mortality wherein patients with either chronic liver disease or cirrhosis suffer rapid decompensation in hepatic function accompanied by extrahepatic organ failures. Alcohol-associated hepatitis (AH) is a common precipitant of ACLF and has been shown to uniquely affect the pathophysiology of systemic and hepatic immune responses in patients with ACLF. Treatment of AH-associated ACLF includes supportive measures as well as treatment directed at AH; however, AH-directed therapies unfortunately remain limited and are of suboptimal efficacy.
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Affiliation(s)
- Camille A Kezer
- Division of Gastroenterology and Hepatology, Mayo Clinic, 200 First Street Southwest, Rochester, MN, USA
| | - Douglas A Simonetto
- Division of Gastroenterology and Hepatology, Mayo Clinic, 200 First Street Southwest, Rochester, MN, USA
| | - Vijay H Shah
- Division of Gastroenterology and Hepatology, Mayo Clinic, 200 First Street Southwest, Rochester, MN, USA.
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32
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Velikiy DA, Osoblivaya MA, Shevchenko OP. Galectin-3 in solid organ recipients: role in graft pathology and prospects for use. RUSSIAN JOURNAL OF TRANSPLANTOLOGY AND ARTIFICIAL ORGANS 2023; 25:129-139. [DOI: 10.15825/1995-1191-2023-2-129-139] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
Abstract
Galectin-3 (Gal-3) is an important regulator of cell adhesion, migration, proliferation, differentiation and apoptosis under pathophysiological conditions. It plays a crucial role in diseases associated with chronic inflammation and fibrosis. In recent years, there have been reports indicating changes in serum Gal-3 levels in solid organ transplant recipients in the verification of kidney, liver, heart and lung transplant pathologies. Studies on Gal-3 levels and dynamics in solid organ recipients may serve to assess graft conditions using new minimally invasive methods and to identify therapeutic targets for personalized therapy. The first clinical trial data on Gal-3 pharmacological inhibition are emerging. This review summarizes the current understanding of the role of Gal-3 in transplant pathology and the prospects for its use as a diagnostic marker and therapeutic target in solid organ recipients.
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Affiliation(s)
- D. A. Velikiy
- Shumakov National Medical Research Center of Transplantology and Artificial Organs
| | - M. A. Osoblivaya
- Shumakov National Medical Research Center of Transplantology and Artificial Organs
| | - O. P. Shevchenko
- Shumakov National Medical Research Center of Transplantology and Artificial Organs; Sechenov University
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Hoff J, Xiong L, Kammann T, Neugebauer S, Micheel JM, Gaßler N, Bauer M, Press AT. RIPK3 promoter hypermethylation in hepatocytes protects from bile acid-induced inflammation and necroptosis. Cell Death Dis 2023; 14:275. [PMID: 37072399 PMCID: PMC10113265 DOI: 10.1038/s41419-023-05794-0] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2022] [Revised: 03/24/2023] [Accepted: 04/04/2023] [Indexed: 04/20/2023]
Abstract
Necroptosis facilitates cell death in a controlled manner and is employed by many cell types following injury. It plays a significant role in various liver diseases, albeit the cell-type-specific regulation of necroptosis in the liver and especially hepatocytes, has not yet been conceptualized. We demonstrate that DNA methylation suppresses RIPK3 expression in human hepatocytes and HepG2 cells. In diseases leading to cholestasis, the RIPK3 expression is induced in mice and humans in a cell-type-specific manner. Overexpression of RIPK3 in HepG2 cells leads to RIPK3 activation by phosphorylation and cell death, further modulated by different bile acids. Additionally, bile acids and RIPK3 activation further facilitate JNK phosphorylation, IL-8 expression, and its release. This suggests that hepatocytes suppress RIPK3 expression to protect themselves from necroptosis and cytokine release induced by bile acid and RIPK3. In chronic liver diseases associated with cholestasis, induction of RIPK3 expression may be an early event signaling danger and repair through releasing IL-8.
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Affiliation(s)
- Jessica Hoff
- Department of Anesthesiology and Intensive Care Medicine, Nanophysiology Group, Jena University Hospital, Jena, 07747, Germany
- Center for Sepsis Control and Care, Jena University Hospital, Jena, 07743, Germany
| | - Ling Xiong
- Department of Anesthesiology and Intensive Care Medicine, Nanophysiology Group, Jena University Hospital, Jena, 07747, Germany
- Center for Sepsis Control and Care, Jena University Hospital, Jena, 07743, Germany
| | - Tobias Kammann
- Department of Anesthesiology and Intensive Care Medicine, Nanophysiology Group, Jena University Hospital, Jena, 07747, Germany
- Center for Sepsis Control and Care, Jena University Hospital, Jena, 07743, Germany
| | - Sophie Neugebauer
- Center for Sepsis Control and Care, Jena University Hospital, Jena, 07743, Germany
- Department of Clinical Chemistry and Laboratory Diagnostics, Jena University Hospital, Jena, 07747, Germany
| | - Julia M Micheel
- Department of Anesthesiology and Intensive Care Medicine, Nanophysiology Group, Jena University Hospital, Jena, 07747, Germany
- Center for Sepsis Control and Care, Jena University Hospital, Jena, 07743, Germany
| | | | - Michael Bauer
- Department of Anesthesiology and Intensive Care Medicine, Nanophysiology Group, Jena University Hospital, Jena, 07747, Germany
- Center for Sepsis Control and Care, Jena University Hospital, Jena, 07743, Germany
| | - Adrian T Press
- Department of Anesthesiology and Intensive Care Medicine, Nanophysiology Group, Jena University Hospital, Jena, 07747, Germany.
- Center for Sepsis Control and Care, Jena University Hospital, Jena, 07743, Germany.
- Faculty of Medicine, Friedrich Schiller University Jena, Jena, 07747, Germany.
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DHEA and Its Metabolites Reduce the Cytokines Involved in the Inflammatory Response and Fibrosis in Primary Biliary Cholangitis. Int J Mol Sci 2023; 24:ijms24065301. [PMID: 36982376 PMCID: PMC10049419 DOI: 10.3390/ijms24065301] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2023] [Revised: 03/02/2023] [Accepted: 03/08/2023] [Indexed: 03/12/2023] Open
Abstract
Dehydroepiandrosterone (DHEA) is an abundant steroid and precursor of sex hormones. During aging, the reduction in DHEA synthesis causes a significant depletion of estrogens and androgens in different organs, such as the ovaries, brain, and liver. Primary Biliary Cholangitis (PBC) is a cholestatic liver disease that begins with immune-mediated bile duct damage, and is followed by liver fibrosis, and finally, cirrhosis. PBC primarily affects postmenopausal women, with an average age of diagnosis of 65 years, but younger women are also affected. Here, we analyzed the levels of DHEA, estradiol (E2), and estriol (E3) in the PBC sera of females at an age of diagnosis under 40 (n = 37) and above 65 (n = 29). Our results indicate that in PBC patients at an age of diagnosis under 40, E2 was significantly lower compared to that in healthy women. In contrast, the levels of DHEA and E3 were in a normal range. Furthermore, ELISA assays revealed that in PBC patients at an age of diagnosis above 65, the levels of DHEA, E2, and E3 significantly declined in comparison to those in younger patients. In addition, flow cytometry analysis showed that the level of IL-8 significantly decreased while the level of TNF-α increased in older PBC patients compared to younger ones. Moreover, we showed for the first time that the sulfonated form of DHEA, DHEA-S, reduces the levels of both pro-inflammatory interleukins, IL-8 and TNF-α, in PBC-like cholangiocytes (H69-miR506), while it diminishes the level of the pro-fibrotic interleukin, IL-13, in hepatocytes (Hep-G2). Finally, we demonstrated that the expression of the pro-fibrotic agent TGF-β significantly increased in both the early (F0–F3) and cirrhotic (F4) stages of PBC, and this elevation was accompanied by higher α-SMA expression.
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Martinez-Castillo M, Altamirano-Mendoza I, Sánchez-Valle S, García-Islas L, Sánchez-Barragán M, Hernández-Santillán M, Hernández-Barragán A, Pérez-Hernández J, Higuera-de la Tijera F, Gutierrez-Reyes G. Immune dysregulation and pathophysiology of alcohol consumption and alcoholic liver disease. REVISTA DE GASTROENTEROLOGÍA DE MÉXICO (ENGLISH EDITION) 2023; 88:136-154. [PMID: 36973122 DOI: 10.1016/j.rgmxen.2023.03.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/10/2022] [Accepted: 01/13/2023] [Indexed: 03/28/2023] Open
Abstract
Alcoholic liver disease (ALD) is a clinical-pathologic entity caused by the chronic excessive consumption of alcohol. The disease includes a broad spectrum of anomalies at the cellular and tissual level that can cause acute-on-chronic (alcoholic hepatitis) or chronic (fibrosis, cirrhosis, hepatocellular cancer) injury, having a great impact on morbidity and mortality worldwide. Alcohol is metabolized mainly in the liver. During alcohol metabolism, toxic metabolites, such as acetaldehyde and oxygen reactive species, are produced. At the intestinal level, alcohol consumption can cause dysbiosis and alter intestinal permeability, promoting the translocation of bacterial products and causing the production of inflammatory cytokines in the liver, perpetuating local inflammation during the progression of ALD. Different study groups have reported systemic inflammatory response disturbances, but reports containing a compendium of the cytokines and cells involved in the pathophysiology of the disease, from the early stages, are difficult to find. In the present review article, the role of the inflammatory mediators involved in ALD progression are described, from risky patterns of alcohol consumption to advanced stages of the disease, with the aim of understanding the involvement of immune dysregulation in the pathophysiology of ALD.
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Leung DH, Devaraj S, Goodrich NP, Chen X, Rajapakshe D, Ye W, Andreev V, Minard CG, Guffey D, Molleston JP, Bass LM, Karpen SJ, Kamath BM, Wang KS, Sundaram SS, Rosenthal P, McKiernan P, Loomes KM, Jensen MK, Horslen S, Bezerra JA, Magee JC, Merion RM, Sokol RJ, Shneider BL, ChiLDReN. Serum biomarkers correlated with liver stiffness assessed in a multicenter study of pediatric cholestatic liver disease. Hepatology 2023; 77:530-545. [PMID: 36069569 PMCID: PMC10151059 DOI: 10.1002/hep.32777] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/10/2022] [Revised: 07/26/2022] [Accepted: 08/03/2022] [Indexed: 01/28/2023]
Abstract
BACKGROUND AND AIMS Detailed investigation of the biological pathways leading to hepatic fibrosis and identification of liver fibrosis biomarkers may facilitate early interventions for pediatric cholestasis. APPROACH AND RESULTS A targeted enzyme-linked immunosorbent assay-based panel of nine biomarkers (lysyl oxidase, tissue inhibitor matrix metalloproteinase (MMP) 1, connective tissue growth factor [CTGF], IL-8, endoglin, periostin, Mac-2-binding protein, MMP-3, and MMP-7) was examined in children with biliary atresia (BA; n = 187), alpha-1 antitrypsin deficiency (A1AT; n = 78), and Alagille syndrome (ALGS; n = 65) and correlated with liver stiffness (LSM) and biochemical measures of liver disease. Median age and LSM were 9 years and 9.5 kPa. After adjusting for covariates, there were positive correlations among LSM and endoglin ( p = 0.04) and IL-8 ( p < 0.001) and MMP-7 ( p < 0.001) in participants with BA. The best prediction model for LSM in BA using clinical and lab measurements had an R2 = 0.437; adding IL-8 and MMP-7 improved R2 to 0.523 and 0.526 (both p < 0.0001). In participants with A1AT, CTGF and LSM were negatively correlated ( p = 0.004); adding CTGF to an LSM prediction model improved R2 from 0.524 to 0.577 ( p = 0.0033). Biomarkers did not correlate with LSM in ALGS. A significant number of biomarker/lab correlations were found in participants with BA but not those with A1AT or ALGS. CONCLUSIONS Endoglin, IL-8, and MMP-7 significantly correlate with increased LSM in children with BA, whereas CTGF inversely correlates with LSM in participants with A1AT; these biomarkers appear to enhance prediction of LSM beyond clinical tests. Future disease-specific investigations of change in these biomarkers over time and as predictors of clinical outcomes will be important.
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Affiliation(s)
- Daniel H. Leung
- Department of Pediatrics, Division of Gastroenterology, Hepatology, and Nutrition, Baylor College of Medicine and Texas Children’s Hospital, Houston, TX, USA
| | - Sridevi Devaraj
- Department of Pathology and Immunology, Texas Children’s Hospital and Baylor College of Medicine, Houston, TX, USA
| | | | - Xinpu Chen
- Department of Pathology and Immunology, Texas Children’s Hospital and Baylor College of Medicine, Houston, TX, USA
| | - Deepthi Rajapakshe
- Department of Pathology and Immunology, Texas Children’s Hospital and Baylor College of Medicine, Houston, TX, USA
| | - Wen Ye
- Department of Biostatistics, University of Michigan, Ann Arbor, MI, USA
| | - Victor Andreev
- Arbor Research Collaborative for Health, Ann Arbor, MI, USA
| | - Charles G. Minard
- Institute for Clinical and Translational Research, Baylor College of Medicine
| | - Danielle Guffey
- Institute for Clinical and Translational Research, Baylor College of Medicine
| | - Jean P. Molleston
- Department of Pediatrics, Division of Gastroenterology, Hepatology, and Nutrition, Riley Hospital for Children, Indiana University, Indianapolis, IN, USA
| | - Lee M. Bass
- Department of Pediatrics, Ann & Robert H. Lurie Children’s Hospital of Chicago, Northwestern University Feinberg School of Medicine, Chicago, IL, USA
| | - Saul J. Karpen
- Department of Pediatrics, Division of Gastroenterology, Hepatology, and Nutrition, Children’s Healthcare of Atlanta and Emory University School of Medicine, Atlanta, GA, USA
| | - Binita M. Kamath
- Division of Gastroenterology, Hepatology and Nutrition, Hospital for Sick Children and the University of Toronto, Ont, CA
| | - Kasper S. Wang
- Department of Pediatric Surgery, Children’s Hospital Los Angeles, CA, USA
| | - Shikha S. Sundaram
- Pediatric Gastroenterology, Hepatology and Nutrition, Children’s Hospital Colorado and University of Colorado School of Medicine, Aurora, CO, USA
| | - Philip Rosenthal
- Department of Pediatrics, University of California, San Francisco, San Francisco, CA, USA
| | - Patrick McKiernan
- Pediatric Gastroenterology, Hepatology and Nutrition, Children’s Hospital of Pittsburgh, Pittsburg, PA, USA
| | - Kathleen M. Loomes
- Pediatric Gastroenterology, Hepatology and Nutrition, The Children’s Hospital of Philadelphia and Department of Pediatrics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA
| | - M. Kyle Jensen
- Pediatric Gastroenterology, Hepatology and Nutrition, University of Utah School of Medicine, Salt Lake City, Utah, USA
| | - Simon Horslen
- Pediatric Gastroenterology, Hepatology and Nutrition, University of Washington School of Medicine and Seattle Children’s Hospital, Seattle, WA, USA
| | - Jorge A. Bezerra
- Pediatric Gastroenterology, Hepatology and Nutrition, University of Cincinnati School of Medicine and Cincinnati Children’s Medical Center, Cincinnati, OH, USA
| | - John C. Magee
- University of Michigan Hospitals and Health Centers, Ann Arbor, MI, USA
| | | | - Ronald J. Sokol
- Pediatric Gastroenterology, Hepatology and Nutrition, Children’s Hospital Colorado and University of Colorado School of Medicine, Aurora, CO, USA
| | - Benjamin L. Shneider
- Department of Pediatrics, Division of Gastroenterology, Hepatology, and Nutrition, Baylor College of Medicine and Texas Children’s Hospital, Houston, TX, USA
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Bai YM, Liang S, Zhou B. Revealing immune infiltrate characteristics and potential immune-related genes in hepatic fibrosis: based on bioinformatics, transcriptomics and q-PCR experiments. Front Immunol 2023; 14:1133543. [PMID: 37122694 PMCID: PMC10140356 DOI: 10.3389/fimmu.2023.1133543] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2023] [Accepted: 03/28/2023] [Indexed: 05/02/2023] Open
Abstract
Background The occurrence and progression of hepatic fibrosis (HF) is accompanied by inflammatory damage. Immune genes play a pivotal role in fibrogenesis and inflammatory damage in HF by regulating immune cell infiltration. However, the immune mechanisms of HF are inadequately studied. Therefore, this research aims to identify the immune genes and biological pathway which involved in fibrosis formation and inflammatory damage in HF and explore immune target-based therapeutics for HF. Methods The expression dataset GSE84044 of HF was downloaded from the GEO database. The crucial module genes for HF were screened according to weighted gene co-expression network analysis (WGCNA). The crucial module genes were mapped to immune-related genes obtained from the ImmPort database to obtain the hepatic fibrosis immune genes (HFIGs). In addition, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) functional enrichment analyses were performed on HFIGs. Then, the protein-protein interaction (PPI) network was conducted on HFIGs and hub genes were identified from the PPI network. Moreover, immune infiltration analysis was performed to identified correlation between hub gene and immune cell infiltration. To verify the reliability of the GSE84044 expression profile data analysis, a rat model of CCl4-induced HF was established, followed by transcriptome sequencing and immunofluorescence analysis and quantitative reverse transcription (q-PCR) experiments were performed in HF rats and normal rat liver tissues. Finally, CMAP platform was used to explore immune target-based therapeutics for HF. Results In the bioinformatics analysis of GSE84044 data, 98 HFIGs were screened. These genes were mainly involved in inflammation-related biological pathways such as NOD-like receptor signaling pathway, NF-kappa B signaling pathway, Toll-like receptor signaling pathway and PI3K-Akt signaling pathway. From the PPI network, 10 hub genes were identified, including CXCL8, IL18, CXCL10, CD8A, IL7, PTPRC, CCL5, IL7R, CXCL9 and CCL2. Immune infiltration analysis showed that immune cells like neutrophils, natural killer (NK) cells, macrophages M1 and macrophages M2 were significantly correlated with the hepatic fibrosis process and hub gene expression was significantly correlated with these immune cells. Notably, most of the biological pathways HFIGs riched and all the hub gene expression except CXCL8 were validated in subsequent transcriptome and qRCR experiments. Finally, 15 small molecule compounds with the potential to reverse the high expression of hub genes were screen out as potential therapeutic agents for HF. Conclusion The immune genes CXCL8, IL18, CXCL10, CD8A, IL7, PTPRC, CCL5, IL7R, CXCL9 and CCL2 may play an essential role in the fibrosis formation and inflammatory damage in HF. The outcomes of this research provide a basis for the study of the immune mechanisms of HF and contribute to the diagnosis and prevention and treatment of HF in clinical practice.
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Affiliation(s)
- Yan-Ming Bai
- School of Traditional Chinese Medicine, Ningxia Medical University, Yinchuan, China
| | - Shuang Liang
- Yinchuan Hospital of Traditional Chinese Medicine, Ningxia Medical University, Yinchuan, China
| | - Bo Zhou
- School of Traditional Chinese Medicine, Ningxia Medical University, Yinchuan, China
- Ningxia Regional Key Laboratory of Integrated Traditional Chinese and Western Medicine for Prevention and Treatment of High Incidence, Ningxia Medical University, Yinchuan, China
- *Correspondence: Bo Zhou,
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Multi-Omics Analyses Identify Signatures in Patients with Liver Cirrhosis and Hepatocellular Carcinoma. Cancers (Basel) 2022; 15:cancers15010210. [PMID: 36612207 PMCID: PMC9818216 DOI: 10.3390/cancers15010210] [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: 11/30/2022] [Revised: 12/26/2022] [Accepted: 12/26/2022] [Indexed: 12/31/2022] Open
Abstract
Gut bacterial/viral dysbiosis, changes in circulating metabolites, and plasma cytokines/chemokines have been previously associated with various liver diseases. Here, we analyzed the associations between fecal microbial composition, circulating metabolites, and plasma cytokines/chemokines in patients with liver cirrhosis (LC) and hepatocellular carcinoma (HCC). We recruited 10 HCC patients, 18 LC patients, and 17 healthy individuals. Their stool samples were used for gene sequencing of bacterial 16S rRNA and viral genomes, while plasma samples were utilized for the determination of endotoxin, zonulin, metabolite, and cytokine/chemokine levels. Dysbiosis was observed among gut bacteria and viruses, with significant changes in abundance at the genus and species levels, respectively. However, no differences were found between cohorts in the alpha and beta diversity. Plasma lipopolysaccharides and zonulin, but not trimethylamine N-oxide, were progressively increased in LC and HCC subjects. Profiling plasma metabolites and selected cytokines/chemokines revealed differential changes in the LC and HCC cohorts. Following joint correlation and correlation network analyses, regardless of etiology, common network signatures shared by LC and HCC patients were characterized by the gut virus Stenotrophomonas virus DLP5 and the uncultured Caudovirales phage, plasma metabolites pyruvic acid and acetic acid, and plasma cytokines/chemokines eotaxin and PDGF-AB/BB, respectively. Additionally, LC- and HCC-specific correlation networks were also identified. This study provides novel insights into altered gut microbial/viral composition that may contribute to pre-HCC disorders, metabolic reprogramming, or inflammatory microenvironments for hepatocarcinogenesis.
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Gallucci GM, Alsuwayt B, Auclair AM, Boyer JL, Assis DN, Ghonem NS. Fenofibrate Downregulates NF-κB Signaling to Inhibit Pro-inflammatory Cytokine Secretion in Human THP-1 Macrophages and During Primary Biliary Cholangitis. Inflammation 2022; 45:2570-2581. [PMID: 35838934 PMCID: PMC10853883 DOI: 10.1007/s10753-022-01713-1] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2022] [Revised: 05/20/2022] [Accepted: 07/01/2022] [Indexed: 11/05/2022]
Abstract
Chronic liver diseases, e.g., cholestasis, are negatively impacted by inflammation, which further aggravates liver injury. Pharmacotherapy targeting the peroxisome proliferator-activated receptor alpha (PPARα), e.g., fenofibrate, has recently become an off-label therapeutic option for patients with refractory cholestasis. Clinical studies show that fibrates can reduce some pro-inflammatory cytokines in primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC); however, its anti-inflammatory mechanisms have not been established. Numerous cytokines are regulated by the transcription factor nuclear receptor kappa B (NF-κB), and PPARα has been shown to interfere with NF-κB signaling. This study investigates the anti-inflammatory mechanism of fenofibrate by inhibiting NF-κB signaling in human macrophages and clinical outcomes in patients with PBC. For adult patients with PBC and an incomplete biochemical response to ursodiol (13-15 mg/kg/day), the addition of fenofibrate (145-160 mg/day) reduced serum levels of TNF-α, IL-17A, IL-1β, IL-6, IL-8, and MCP-1 and increased IL-10. In THP-1 cells, pretreatment with fenofibrate (125 μM) reduced LPS-stimulated peak concentrations of IL-1β (- 63%), TNF-α (- 88%), and IL-8 (- 54%), in a PPARα-dependent manner. Treatment with fenofibrate prior to LPS significantly decreased nuclear NF-κB p50 and p65 subunit binding by 49% and 31%, respectively. Additionally, fenofibrate decreased nuclear NF-κB p50 and p65 protein expression by 66% and 55% and increased cytoplasmic levels by 53% and 54% versus LPS alone, respectively. Lastly, fenofibrate increased IκBα levels by 2.7-fold (p < 0.001) vs. LPS. These data demonstrate that fenofibrate reduces pro-inflammatory cytokines section by inhibiting in NF-κB signaling, which likely contribute to its anti-inflammatory effects during chronic liver diseases.
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Affiliation(s)
- Gina M Gallucci
- College of Pharmacy, Department of Biomedical and Pharmaceutical Sciences, University of Rhode Island, 7 Greenhouse Road, Avedisian Hall, Kingston, RI 02881, USA
| | - Bader Alsuwayt
- School of Pharmacy, Department of Pharmaceutical Sciences, Massachusetts College of Pharmacy and Health Sciences, Boston, MA, USA
| | - Adam M Auclair
- College of Pharmacy, Department of Biomedical and Pharmaceutical Sciences, University of Rhode Island, 7 Greenhouse Road, Avedisian Hall, Kingston, RI 02881, USA
| | - James L Boyer
- Yale School of Medicine, Liver Center, New Haven, CT, USA
| | - David N Assis
- Yale School of Medicine, Liver Center, New Haven, CT, USA
| | - Nisanne S Ghonem
- College of Pharmacy, Department of Biomedical and Pharmaceutical Sciences, University of Rhode Island, 7 Greenhouse Road, Avedisian Hall, Kingston, RI 02881, USA.
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Ma Y, Bao Y, Wu L, Ke Y, Tan L, Ren H, Song J, Zhang Q, Jin Y. IL-8 exacerbates CCl4-induced liver fibrosis in human IL-8-expressing mice via the PI3K/Akt/HIF-1α pathway. Mol Immunol 2022; 152:111-122. [PMID: 36327908 DOI: 10.1016/j.molimm.2022.10.011] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2022] [Revised: 08/25/2022] [Accepted: 10/24/2022] [Indexed: 11/06/2022]
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Liu N, Bauer M, Press AT. The immunological function of CXCR2 in the liver during sepsis. J Inflamm (Lond) 2022; 19:23. [DOI: 10.1186/s12950-022-00321-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2022] [Accepted: 11/15/2022] [Indexed: 12/02/2022] Open
Abstract
Abstract
Background
The chemokine receptor CXCR2 and its ligands, especially CXCL8, are crucial mediators for the progression of liver inflammation and liver failure in sepsis. Neutrophils have the highest CXCR2 expression in mice and humans, and their activation via CXCL8 facilitates their migration to the inflamed liver for the clearance of the pathogens and, in turn, the inflammation.
Main body
In sepsis, the inflammatory insult causes extensive neutrophil migration to the liver that overwhelms the immune response. To compensate for the strong receptor activation, CXCR2 desensitizes, incapacitating the immune cells to efficiently clear pathogens, causing further life-threatening liver damage and uncontrolled pathogen spread.
Conclusion
CXCR2 function during infection strongly depends on the expressing cell type. It signals pro- and anti-inflammatory effects that may prompt novel cell-type-specific CXCR2-directed therapeutics.
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Beudeker BJB, Groothuismink ZMA, van der Eijk AA, Debes JD, Boonstra A. Circulating Cytokines Reflect the Etiology-Specific Immune Environment in Cirrhosis and HCC. Cancers (Basel) 2022; 14:cancers14194900. [PMID: 36230823 PMCID: PMC9563264 DOI: 10.3390/cancers14194900] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2022] [Revised: 09/24/2022] [Accepted: 10/01/2022] [Indexed: 11/16/2022] Open
Abstract
Background and Aims: Chronic liver disease—from any etiology—can progress to fibrosis, cirrhosis and hepatocellular carcinoma (HCC). The progression of liver cirrhosis to the end stages of disease is influenced by a variety of factors, including inflammatory cytokines. We pursued a study of cytokine-mediated inflammatory responses in hepatitis B (HBV), hepatitis C (HCV), alcoholic liver disease (ALD) and non-alcoholic fatty liver disease (NAFLD) patients with liver cirrhosis. Methods: Immune profiles were determined through the serum multiplex profiling of >100 cytokines in a 188 cirrhotic patients, 35 healthy controls and 196 early-stage HCC patients. Results: Patients with liver cirrhosis exhibited a vast upregulation of proinflammatory cytokines (p < 0.0001), including those with pro-oncogenic features, when compared to healthy individuals. In contrast to prevailing assumptions, each etiological cause of cirrhosis exhibited a unique cytokine profile in blood. Regardless of antiviral therapy, HBV cirrhosis patients had the largest number of upregulated proinflammatory mediators, compared to HCV, ALD and NAFLD (p < 0.0001). To further evaluate the etiology-dependent modulation of cytokine response in relation to liver cancer, we studied cytokine profiles in early-stage HCC patients strictly stratified by underlying liver disease. We observed unique sets of differentially expressed cytokines in each cohort of early-stage HCC patients of different cirrhosis etiologies. Conclusions: Our findings, therefore, underscore the importance of stratification by the etiological cause of liver cirrhosis in immune-based studies.
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Affiliation(s)
- Boris J. B. Beudeker
- Department of Gastroenterology and Hepatology, Erasmus MC University Medical Center, 3015 CN Rotterdam, The Netherlands
| | - Zwier M. A. Groothuismink
- Department of Gastroenterology and Hepatology, Erasmus MC University Medical Center, 3015 CN Rotterdam, The Netherlands
| | - Annemiek A. van der Eijk
- Department of Viroscience, Erasmus MC University Medical Center, 3015 CN Rotterdam, The Netherlands
| | - Jose D. Debes
- Department of Gastroenterology and Hepatology, Erasmus MC University Medical Center, 3015 CN Rotterdam, The Netherlands
- Department of Medicine, University of Minnesota, Minneapolis, MN 55455, USA
| | - Andre Boonstra
- Department of Gastroenterology and Hepatology, Erasmus MC University Medical Center, 3015 CN Rotterdam, The Netherlands
- Correspondence:
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Tu T, Alba MM, Datta AA, Hong H, Hua B, Jia Y, Khan J, Nguyen P, Niu X, Pammidimukkala P, Slarve I, Tang Q, Xu C, Zhou Y, Stiles BL. Hepatic macrophage mediated immune response in liver steatosis driven carcinogenesis. Front Oncol 2022; 12:958696. [PMID: 36276076 PMCID: PMC9581256 DOI: 10.3389/fonc.2022.958696] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2022] [Accepted: 08/17/2022] [Indexed: 12/02/2022] Open
Abstract
Obesity confers an independent risk for carcinogenesis. Classically viewed as a genetic disease, owing to the discovery of tumor suppressors and oncogenes, genetic events alone are not sufficient to explain the progression and development of cancers. Tumor development is often associated with metabolic and immunological changes. In particular, obesity is found to significantly increase the mortality rate of liver cancer. As its role is not defined, a fundamental question is whether and how metabolic changes drive the development of cancer. In this review, we will dissect the current literature demonstrating that liver lipid dysfunction is a critical component driving the progression of cancer. We will discuss the involvement of inflammation in lipid dysfunction driven liver cancer development with a focus on the involvement of liver macrophages. We will first discuss the association of steatosis with liver cancer. This will be followed with a literature summary demonstrating the importance of inflammation and particularly macrophages in the progression of liver steatosis and highlighting the evidence that macrophages and macrophage produced inflammatory mediators are critical for liver cancer development. We will then discuss the specific inflammatory mediators and their roles in steatosis driven liver cancer development. Finally, we will summarize the molecular pattern (PAMP and DAMP) as well as lipid particle signals that are involved in the activation, infiltration and reprogramming of liver macrophages. We will also discuss some of the therapies that may interfere with lipid metabolism and also affect liver cancer development.
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Affiliation(s)
- Taojian Tu
- Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, CA, United States
| | - Mario M. Alba
- Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, CA, United States
| | - Aditi A. Datta
- Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, CA, United States
| | - Handan Hong
- Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, CA, United States
| | - Brittney Hua
- Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, CA, United States
| | - Yunyi Jia
- Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, CA, United States
| | - Jared Khan
- Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, CA, United States
| | - Phillip Nguyen
- Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, CA, United States
| | - Xiatoeng Niu
- Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, CA, United States
| | - Pranav Pammidimukkala
- Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, CA, United States
| | - Ielyzaveta Slarve
- Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, CA, United States
| | - Qi Tang
- Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, CA, United States
| | - Chenxi Xu
- Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, CA, United States
| | - Yiren Zhou
- Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, CA, United States
| | - Bangyan L. Stiles
- Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, CA, United States
- Department of Pathology, Keck School of Medicine, University of Southern California, Los Angeles, CA, United States
- *Correspondence: Bangyan L. Stiles,
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Cervantes-Alvarez E, Limon-de la Rosa N, Vilatoba M, Pérez-Monter C, Hurtado-Gomez S, Martinez-Cabrera C, Argemi J, Alatorre-Arenas E, Yarza-Regalado S, Tejeda-Dominguez F, Lizardo-Thiebaud MJ, Mendez-Guerrero O, Gamboa-Dominguez A, Aguilar-Salinas CA, Huang CA, Kershenobich D, Bataller R, Torre A, Navarro-Alvarez N. Galectin-3 is overexpressed in advanced cirrhosis and predicts post-liver transplant infectious complications. Liver Int 2022; 42:2260-2273. [PMID: 35635536 DOI: 10.1111/liv.15326] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/08/2021] [Revised: 05/12/2022] [Accepted: 05/27/2022] [Indexed: 02/13/2023]
Abstract
BACKGROUND & AIMS Patients with advanced cirrhosis often have immune dysfunction and are more susceptible to infections. Galectin-3 is a β-galactoside-binding lectin implicated in inflammation, immune regulation and liver fibrosis. We aim to investigate galectin-3 expression in advanced cirrhosis and its ability to predict post-transplant infectious complications. METHODS We collected sera and liver samples from 129 cirrhotic patients at the time of liver transplantation and from an external cohort of 37 patients with alcoholic liver disease including alcoholic hepatitis (AH) at the time of diagnosis. Galectin-3 was assessed by ELISA, real-time PCR, immunohistochemistry and RNA-seq. Receiver operating characteristic curves and Cox proportional-hazards regression analysis were performed to assess the predictive power of galectin-3 for disease severity and post-transplant infections. RESULTS Increased galectin-3 levels were found in advanced cirrhosis. Galectin-3 significantly correlated with disease severity parameters and inflammatory markers. Galectin-3 had significant discriminating power for compensated and advanced cirrhosis (AUC = 0.78/0.84, circulating/liver galectin-3; p < .01), and was even higher to discriminate severe AH (AUC = 0.95, p < .0001). Cox Proportional-hazard model showed that galectin-3, MELD-Na and the presence of SIRS predict the development of post-transplant infectious complications. Patients with circulating galectin-3 (>16.58 ng/ml) were at 2.19-fold 95% CI (1.12-4.29) increased risk, but when combined with MELD-Na > 20.0 and SIRS, the risk to develop post-transplant infectious complications, increased to 4.60, 95% CI (2.38-8.90). CONCLUSION Galectin-3 is a novel biological marker of active inflammation and disease severity that could be clinically useful alone or in combination with other scores to discriminate advanced cirrhosis and predict post-transplant infectious complications.
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Affiliation(s)
- Eduardo Cervantes-Alvarez
- Department of Gastroenterology, Hepatology and Liver Transplantation Unit, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico
- PECEM, Facultad de Medicina, Universidad Nacional Autónoma de México, Mexico City, Mexico
| | - Nathaly Limon-de la Rosa
- Department of Gastroenterology, Hepatology and Liver Transplantation Unit, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico
| | - Mario Vilatoba
- Department of Surgery, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico
| | - Carlos Pérez-Monter
- Department of Gastroenterology, Hepatology and Liver Transplantation Unit, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico
| | - Sahara Hurtado-Gomez
- Department of Surgery, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico
| | - Cynthia Martinez-Cabrera
- Department of Surgery, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico
| | - Josepmaria Argemi
- Center for Liver Diseases, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA
- Liver Unit, Clinica Universidad de Navarra, Hepatology Program, Center for Applied Medical Research, Pamplona, Spain
| | - Elisa Alatorre-Arenas
- Department of Gastroenterology, Hepatology and Liver Transplantation Unit, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico
| | - Susana Yarza-Regalado
- Department of Gastroenterology, Hepatology and Liver Transplantation Unit, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico
| | | | | | - Osvely Mendez-Guerrero
- Department of Gastroenterology, Hepatology and Liver Transplantation Unit, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico
| | - Armando Gamboa-Dominguez
- Department of Pathology, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico
| | - Carlos A Aguilar-Salinas
- Department of Endocrinology and Metabolism, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico
| | - Christene A Huang
- Department of Surgery, University of Colorado Anschutz Medical Campus, Denver, Colorado, USA
| | - David Kershenobich
- Department of Gastroenterology, Hepatology and Liver Transplantation Unit, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico
| | - Ramon Bataller
- Center for Liver Diseases, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA
- Liver Unit, Clinica Universidad de Navarra, Hepatology Program, Center for Applied Medical Research, Pamplona, Spain
| | - Aldo Torre
- Department of Gastroenterology, Hepatology and Liver Transplantation Unit, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico
| | - Nalu Navarro-Alvarez
- Department of Gastroenterology, Hepatology and Liver Transplantation Unit, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico
- Universidad Panamericana School of Medicine, Mexico City, Mexico
- Department of Surgery, University of Colorado Anschutz Medical Campus, Denver, Colorado, USA
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Banerjee A, Billey LO, McGarvey AM, Shelver WL. Effects of polystyrene micro/nanoplastics on liver cells based on particle size, surface functionalization, concentration and exposure period. THE SCIENCE OF THE TOTAL ENVIRONMENT 2022; 836:155621. [PMID: 35513145 DOI: 10.1016/j.scitotenv.2022.155621] [Citation(s) in RCA: 31] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/10/2022] [Revised: 04/20/2022] [Accepted: 04/27/2022] [Indexed: 06/14/2023]
Abstract
Micro/nanoplastics (MP/NP) contaminate our food and drinking water but their impact on human health has not been well-documented. The liver is one of the first organs that ingested MP/NP encounter and it has a major role in the clearance of xenobiotics. Therefore, the effects of polystyrene MP/NP on liver HepG2 cells were studied. Cellular responses to particles of various sizes (50-5000 nm) and surface functionalization (aminated, carboxylated or non-functionalized) were determined at different concentrations (0.1-100 μg/mL) and exposure periods (1-24 h). Smaller sized particles were internalized by HepG2 cells more avidly than larger particles regardless of functionalization; the highest uptake being for 50 and 100 nm aminated particles at lower concentrations. Confocal microscopy images of cells corroborated quantitative uptake results. Aminated particles were more toxic to the cells than carboxylated or non-functionalized particles. Among aminated particles smaller particles (50 and 100 nm) were more detrimental to cell viability compared to larger particles (1000 or 5000 nm) with toxicity increasing with concentration. Treatment with the particles for 4 h increased intracellular concentrations of Caspase-3 by 1.5-2.8 fold, but 24 h exposure to the particles attenuated this increase in Caspase-3 concentrations. A slight trend of higher Caspase-3 concentration in cells treated with larger particles (500-5000 nm) compared to smaller particles (50-200 nm) was observed, indicating that larger particles are more likely to direct cells toward apoptotic cell death upon 4 h exposure. Exposure of cells to large PS particles (500-5000 nm) upregulated interleukin-8 and the effect was enhanced at 24 h. Overall, the study demonstrated that smaller aminated particles were most toxic to hepatocytes, but larger particles induced apoptotic cell death or an inflammatory response depending on the length of exposure.
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Affiliation(s)
- Amrita Banerjee
- USDA-Agricultural Research Service, Edward T. Schafer Agricultural Research Center, Biosciences Research Laboratory, 1616 Albrecht Blvd N, Fargo, ND 58102, USA
| | - Lloyd O Billey
- USDA-Agricultural Research Service, Edward T. Schafer Agricultural Research Center, Biosciences Research Laboratory, 1616 Albrecht Blvd N, Fargo, ND 58102, USA
| | - Amy M McGarvey
- USDA-Agricultural Research Service, Edward T. Schafer Agricultural Research Center, Biosciences Research Laboratory, 1616 Albrecht Blvd N, Fargo, ND 58102, USA
| | - Weilin L Shelver
- USDA-Agricultural Research Service, Edward T. Schafer Agricultural Research Center, Biosciences Research Laboratory, 1616 Albrecht Blvd N, Fargo, ND 58102, USA.
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Listopad S, Magnan C, Asghar A, Stolz A, Tayek JA, Liu ZX, Morgan TR, Norden-Krichmar TM. Differentiating between liver diseases by applying multiclass machine learning approaches to transcriptomics of liver tissue or blood-based samples. JHEP Rep 2022; 4:100560. [PMID: 36119721 PMCID: PMC9472076 DOI: 10.1016/j.jhepr.2022.100560] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/15/2022] [Revised: 07/21/2022] [Accepted: 07/22/2022] [Indexed: 02/08/2023] Open
Abstract
Background & Aims Liver disease carries significant healthcare burden and frequently requires a combination of blood tests, imaging, and invasive liver biopsy to diagnose. Distinguishing between inflammatory liver diseases, which may have similar clinical presentations, is particularly challenging. In this study, we implemented a machine learning pipeline for the identification of diagnostic gene expression biomarkers across several alcohol-associated and non-alcohol-associated liver diseases, using either liver tissue or blood-based samples. Methods We collected peripheral blood mononuclear cells (PBMCs) and liver tissue samples from participants with alcohol-associated hepatitis (AH), alcohol-associated cirrhosis (AC), non-alcohol-associated fatty liver disease, chronic HCV infection, and healthy controls. We performed RNA sequencing (RNA-seq) on 137 PBMC samples and 67 liver tissue samples. Using gene expression data, we implemented a machine learning feature selection and classification pipeline to identify diagnostic biomarkers which distinguish between the liver disease groups. The liver tissue results were validated using a public independent RNA-seq dataset. The biomarkers were computationally validated for biological relevance using pathway analysis tools. Results Utilizing liver tissue RNA-seq data, we distinguished between AH, AC, and healthy conditions with overall accuracies of 90% in our dataset, and 82% in the independent dataset, with 33 genes. Distinguishing 4 liver conditions and healthy controls yielded 91% overall accuracy in our liver tissue dataset with 39 genes, and 75% overall accuracy in our PBMC dataset with 75 genes. Conclusions Our machine learning pipeline was effective at identifying a small set of diagnostic gene biomarkers and classifying several liver diseases using RNA-seq data from liver tissue and PBMCs. The methodologies implemented and genes identified in this study may facilitate future efforts toward a liquid biopsy diagnostic for liver diseases. Lay summary Distinguishing between inflammatory liver diseases without multiple tests can be challenging due to their clinically similar characteristics. To lay the groundwork for the development of a non-invasive blood-based diagnostic across a range of liver diseases, we compared samples from participants with alcohol-associated hepatitis, alcohol-associated cirrhosis, chronic hepatitis C infection, and non-alcohol-associated fatty liver disease. We used a machine learning computational approach to demonstrate that gene expression data generated from either liver tissue or blood samples can be used to discover a small set of gene biomarkers for effective diagnosis of these liver diseases.
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Key Words
- AC, alcohol-associated cirrhosis
- AH, alcohol-associated hepatitis
- AKR1B10, aldo-keto reductase family 1 member B10
- BTM, blood transcription module
- Classification
- DE, differential expression
- FPKM, fragments per kilobase of exon model per million reads mapped
- GSEA, gene set-enrichment analysis
- IG, information gain
- IPA, Ingenuity Pathway Analysis
- LR, logistic regression
- LTCDS, liver tissue cell distribution system
- LV, liver tissue
- ML, machine learning
- MMP, matrix metalloproteases
- NAFLD, non-alcohol-associated fatty liver disease
- PBMCs, peripheral blood mononuclear cells
- RNA sequencing
- RNA-seq, RNA sequencing
- SCAHC, Southern California Alcoholic Hepatitis Consortium
- SVM, support vector machine
- TNF, tumor necrosis factor
- alcohol-associated liver disease
- biomarker discovery
- kNN, k-nearest neighbors
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Affiliation(s)
- Stanislav Listopad
- Department of Computer Science, University of California, Irvine, CA 92697, USA
| | - Christophe Magnan
- Department of Computer Science, University of California, Irvine, CA 92697, USA
| | - Aliya Asghar
- Medicine and Research Services, VA Long Beach Healthcare System, Long Beach, CA 90822, USA
| | - Andrew Stolz
- Division of Gastrointestinal & Liver Diseases, Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA
| | - John A. Tayek
- Division of General Internal Medicine, Harbor-UCLA Medical Center, University of California Los Angeles, Torrance, CA 90509, USA
| | - Zhang-Xu Liu
- Division of Gastrointestinal & Liver Diseases, Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA
| | - Timothy R. Morgan
- Medicine and Research Services, VA Long Beach Healthcare System, Long Beach, CA 90822, USA
| | - Trina M. Norden-Krichmar
- Department of Computer Science, University of California, Irvine, CA 92697, USA,Department of Epidemiology and Biostatistics, University of California, Irvine, CA 92697, USA,Corresponding author. Address: Department of Epidemiology and Biostatistics, University of California, Irvine, CA 92697 USA; Tel.: 949-824-8802.
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Abdelaziz RR, Abdelrahman RS, Abdelmageed ME. SB332235, a CXCR2 antagonist, ameliorates thioacetamide-induced hepatic encephalopathy through modulation of the PI3K/AKT pathways in rats. Neurotoxicology 2022; 92:110-121. [PMID: 35961375 DOI: 10.1016/j.neuro.2022.08.005] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2022] [Revised: 06/27/2022] [Accepted: 08/08/2022] [Indexed: 11/29/2022]
Abstract
RATIONALE Hepatic encephalopathy (HE) is a neuropsychiatric disorder that results from either acute or chronic liver failure. CXCR2 plays an essential role in the pathophysiology of liver and brain diseases. In the present study, the potential beneficial effects of SB332235, a selective inhibitor of CXCR2, against HE were evaluated. METHODS HE was induced in male rats by thioacetamide injection (200 mg/kg, i.p.) at three alternative days. SB332235 was injected in rats 1 h before TAA at a dose of 1 and 3 mg/kg i.p. RESULTS SB332235 alleviated oxidative stress as shown by the decreased serum NO and reduced MDA, elevated GSH and SOD levels, and reduced TNF-α and NF-κB levels in both brain and liver tissues of rats. Additionally, SB332235 suppressed brain ASK-1, JNK, IL-8, and caspase-3 expression, and activated PI3K/AKT expression in brain tissues. Markers of brain dysfunction, such as ammonia, and markers of hepatic injury, such as LDH, albumin, bilirubin, γGT, AST, ALT, and ALP, were significantly ameliorated. Also, the protective effect of SB332235 was confirmed by histological examination of both brain and liver tissues. CONCLUSIONS Both doses (1 and 3 mg/kg) of SB332235 revealed significant hepatic/neuroprotective effects due to their anti-inflammatory, antioxidant, and antiapoptotic activities via activation of the PI3K/AKT pathway. Between the two, the 1 mg/kg dose provided significantly improved outcomes.
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Affiliation(s)
- Rania R Abdelaziz
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Mansoura University, 35516 Mansoura, Egypt
| | - Rehab S Abdelrahman
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Mansoura University, 35516 Mansoura, Egypt; Department of Pharmacology and Toxicology, Faculty of Pharmacy, Taibah University, Al-Madina Al-Munawwarah, 30001, Saudi Arabia
| | - Marwa E Abdelmageed
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Mansoura University, 35516 Mansoura, Egypt.
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Suriguga S, Li M, Luangmonkong T, Boersema M, de Jong KP, Oosterhuis D, Gorter AR, Beljaars L, Olinga P. Distinct responses between healthy and cirrhotic human livers upon lipopolysaccharide challenge: possible implications for acute-on-chronic liver failure. Am J Physiol Gastrointest Liver Physiol 2022; 323:G114-G125. [PMID: 35727919 DOI: 10.1152/ajpgi.00243.2021] [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
Patients with acute-on-chronic liver failure (ACLF) are at risk of developing acute hepatic decompensation and organ failures with an unraveled complex mechanism. An altered immune response toward insults in cirrhotic compared with healthy livers may contribute to the ACLF development. Therefore, we aim to investigate the differences in inflammatory responses between cirrhotic and healthy livers using human precision-cut liver slices (PCLSs) upon the lipopolysaccharide (LPS) challenge. PCLSs prepared from livers of patients with cirrhosis or healthy donors of liver transplantation were incubated ex vivo with or without LPS for up to 48 h. Viability test, qRT-PCR, and multiplex cytokine assay were performed. Regulation of the LPS receptors during incubation or with LPS challenge differed between healthy versus cirrhotic PCLSs. LPS upregulated TLR-2 in healthy PCLSs solely (P < 0.01). Culturing for 48 h induced a stronger inflammatory response in the cirrhotic than healthy PCLS. Upon LPS stimulation, cirrhotic PCLSs secreted more proinflammatory cytokines (IL-8, IL-6, TNF-α, eotaxin, and VEGF) significantly and less anti-inflammatory cytokine (IL-1ra) than those of healthy. In summary, cirrhotic PCLSs released more proinflammatory and less anti-inflammatory cytokines after LPS stimuli than healthy, leading to dysregulated inflammatory response. These events could possibly resemble the liver immune response in ACLF.NEW & NOTEWORTHY Precision-cut liver slices (PCLSs) model provides a unique platform to investigate the different immune responses of healthy versus cirrhotic livers in humans. Our data show that cirrhotic PCLSs exhibit excessive inflammatory response accompanied by a lower anti-inflammatory cytokine release in response to LPS; a better understanding of this alteration may guide the novel therapeutic approaches to mitigate the excessive inflammation during the onset of acute-on-chronic liver failure.
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Affiliation(s)
- Su Suriguga
- Key Laboratory of Clinical Diagnosis and Treatment Technology in Animal Disease, Ministry of Agriculture, College of Veterinary Medicine, Inner Mongolia Agricultural University, Hohhot, People's Republic of China.,Division of Pharmaceutical Technology and Biopharmacy, Department of Pharmacy, University of Groningen, Groningen, The Netherlands
| | - Mei Li
- Division of Pharmaceutical Technology and Biopharmacy, Department of Pharmacy, University of Groningen, Groningen, The Netherlands
| | - Theerut Luangmonkong
- Division of Pharmaceutical Technology and Biopharmacy, Department of Pharmacy, University of Groningen, Groningen, The Netherlands.,Department of Pharmacology, Faculty of Pharmacy, Mahidol University, Bangkok, Thailand
| | - Miriam Boersema
- Division of Pharmaceutical Technology and Biopharmacy, Department of Pharmacy, University of Groningen, Groningen, The Netherlands
| | - Koert P de Jong
- Department of Hepato-Pancreato-Biliary Surgery and Liver Transplantation, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
| | - Dorenda Oosterhuis
- Division of Pharmaceutical Technology and Biopharmacy, Department of Pharmacy, University of Groningen, Groningen, The Netherlands
| | - A R Gorter
- Division of Pharmaceutical Technology and Biopharmacy, Department of Pharmacy, University of Groningen, Groningen, The Netherlands
| | - Leonie Beljaars
- Division of Pharmaceutical Technology and Biopharmacy, Department of Pharmacy, University of Groningen, Groningen, The Netherlands
| | - Peter Olinga
- Division of Pharmaceutical Technology and Biopharmacy, Department of Pharmacy, University of Groningen, Groningen, The Netherlands
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Baboota RK, Rawshani A, Bonnet L, Li X, Yang H, Mardinoglu A, Tchkonia T, Kirkland JL, Hoffmann A, Dietrich A, Boucher J, Blüher M, Smith U. BMP4 and Gremlin 1 regulate hepatic cell senescence during clinical progression of NAFLD/NASH. Nat Metab 2022; 4:1007-1021. [PMID: 35995996 PMCID: PMC9398907 DOI: 10.1038/s42255-022-00620-x] [Citation(s) in RCA: 43] [Impact Index Per Article: 14.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/07/2021] [Accepted: 07/13/2022] [Indexed: 11/09/2022]
Abstract
The role of hepatic cell senescence in human non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) is not well understood. To examine this, we performed liver biopsies and extensive characterization of 58 individuals with or without NAFLD/NASH. Here, we show that hepatic cell senescence is strongly related to NAFLD/NASH severity, and machine learning analysis identified senescence markers, the BMP4 inhibitor Gremlin 1 in liver and visceral fat, and the amount of visceral adipose tissue as strong predictors. Studies in liver cell spheroids made from human stellate and hepatocyte cells show BMP4 to be anti-senescent, anti-steatotic, anti-inflammatory and anti-fibrotic, whereas Gremlin 1, which is particularly highly expressed in visceral fat in humans, is pro-senescent and antagonistic to BMP4. Both senescence and anti-senescence factors target the YAP/TAZ pathway, making this a likely regulator of senescence and its effects. We conclude that senescence is an important driver of human NAFLD/NASH and that BMP4 and Gremlin 1 are novel therapeutic targets.
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Affiliation(s)
- Ritesh K Baboota
- Lundberg Laboratory for Diabetes Research, Department of Molecular and Clinical Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Aidin Rawshani
- Wallenberg Laboratory for Cardiovascular and Metabolic Research, Institute of Medicine, University of Gothenburg, Gothenburg, Sweden
| | - Laurianne Bonnet
- Lundberg Laboratory for Diabetes Research, Department of Molecular and Clinical Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
- Wallenberg Centre for Molecular and Translational Medicine, University of Gothenburg, Gothenburg, Sweden
| | - Xiangyu Li
- Science for Life Laboratory, KTH Royal Institute of Technology, Stockholm, Sweden
| | - Hong Yang
- Science for Life Laboratory, KTH Royal Institute of Technology, Stockholm, Sweden
| | - Adil Mardinoglu
- Science for Life Laboratory, KTH Royal Institute of Technology, Stockholm, Sweden
- Centre for Host-Microbiome Interactions, Faculty of Dentistry, Oral & Craniofacial Sciences, King's College London, London, UK
| | - Tamar Tchkonia
- Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, MN, USA
| | - James L Kirkland
- Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, MN, USA
| | - Anne Hoffmann
- Helmholtz Institute for Metabolic, Obesity and Vascular Research (HI-MAG), University of Leipzig and University Hospital Leipzig, Leipzig, Germany
| | - Arne Dietrich
- Department of Visceral, Transplantation, Thoracic and Vascular Surgery, Section of Bariatric Surgery, University Hospital Leipzig, Leipzig, Germany
| | - Jeremie Boucher
- Lundberg Laboratory for Diabetes Research, Department of Molecular and Clinical Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
- Wallenberg Centre for Molecular and Translational Medicine, University of Gothenburg, Gothenburg, Sweden
- Bioscience Metabolism, Research and Early Development, Cardiovascular, Renal and Metabolism (CVRM), BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden
| | - Matthias Blüher
- Helmholtz Institute for Metabolic, Obesity and Vascular Research (HI-MAG), University of Leipzig and University Hospital Leipzig, Leipzig, Germany
| | - Ulf Smith
- Lundberg Laboratory for Diabetes Research, Department of Molecular and Clinical Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
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Evaluation of the Mechanism of Jiedu Huazhuo Quyu Formula in Treating Wilson's Disease-Associated Liver Fibrosis by Network Pharmacology Analysis and Molecular Dynamics Simulation. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE 2022; 2022:9363131. [PMID: 35707473 PMCID: PMC9192323 DOI: 10.1155/2022/9363131] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/23/2021] [Revised: 03/28/2022] [Accepted: 05/14/2022] [Indexed: 12/23/2022]
Abstract
The Jiedu Huazhuo Quyu formula (JHQ) shows significant beneficial effects against liver fibrosis caused by Wilson's disease (WD). Hence, this study aimed to clarify the mechanisms of the JHQ treatment in WD-associated liver fibrosis. First, we collected 103 active compounds and 527 related targets of JHQ and 1187 targets related to WD-associated liver fibrosis from multiple databases. Next, 113 overlapping genes (OGEs) were obtained. Then, we built a protein-protein interaction (PPI) network with Cytoscape 3.7.2 software and performed the Gene Ontology (GO) term and Kyoto Encyclopedia of Gene and Genome (KEGG) pathway enrichment analyses with GENE DENOVO online sites. Furthermore, module analysis was performed, and the core target genes in the JHQ treatment of WD-associated liver fibrosis were obtained. Pathway and functional enrichment analyses, molecular docking studies, molecular dynamic (MD) simulation, and Western blot (WB) were then performed. The results indicated that 8 key active compounds including quercetin, luteolin, and obacunone in JHQ might affect the 6 core proteins including CXCL8, MAPK1, and AKT1 and 107 related signaling pathways including EGFR tyrosine kinase inhibitor resistance, Kaposi sarcoma-associated herpesvirus infection, and human cytomegalovirus infection signaling pathways to exhibit curative effects on WD-associated liver fibrosis. Mechanistically, JHQ might inhibit liver inflammatory processes and vascular hyperplasia, regulate the cell cycle, and suppress both the activation and proliferation of hepatic stellate cells (HSCs). This study provides novel insights for researchers to systematically explore the mechanism of JHQ in treating WD-associated liver fibrosis.
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