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Mimura S, Morishita A, Oura K, Takuma K, Nakahara M, Tadokoro T, Fujita K, Tani J, Kobara H. Galectins and Liver Diseases. Int J Mol Sci 2025; 26:790. [PMID: 39859504 PMCID: PMC11766161 DOI: 10.3390/ijms26020790] [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: 12/18/2024] [Revised: 01/13/2025] [Accepted: 01/15/2025] [Indexed: 01/27/2025] Open
Abstract
Galectins are widely distributed throughout the animal kingdom, from marine sponges to mammals. Galectins are a family of soluble lectins that specifically recognize β-galactoside-containing glycans and are categorized into three subgroups based on the number and function of their carbohydrate recognition domains (CRDs). The interaction of galectins with specific ligands mediates a wide range of biological activities, depending on the cell type, tissue context, expression levels of individual galectin, and receptor involvement. Galectins affect various immune cell processes through both intracellular and extracellular mechanisms and play roles in processes, such as apoptosis, angiogenesis, and fibrosis. Their importance has increased in recent years because they are recognized as biomarkers, therapeutic agents, and drug targets, with many other applications in conditions such as cardiovascular diseases and cancer. However, little is known about the involvement of galectins in liver diseases. Here, we review the functions of various galectins and evaluate their roles in liver diseases.
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Affiliation(s)
- Shima Mimura
- Departments of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Kita-gun, Takamatsu 761-0793, Kagawa Prefecture, Japan
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Liu S, He F, Jin C, Li Q, Zhao G, Ding K. Design and Synthesis of Dual Galectin-3 and EGFR Inhibitors Against Liver Fibrosis. Chem Asian J 2025; 20:e202401078. [PMID: 39504308 DOI: 10.1002/asia.202401078] [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: 08/28/2024] [Revised: 10/29/2024] [Accepted: 11/04/2024] [Indexed: 11/08/2024]
Abstract
Liver fibrosis, mainly arising from chronic viral or metabolic liver diseases, is a significant global health concern. There is currently only one FDA-approved drug (Resmetirom) in the market to combat liver fibrosis. Both galectin-3 and epidermal growth factor receptor (EGFR) play important roles in liver fibrosis, while galectin-3 may interact with EGFR. Galectin-3 inhibitors, typically lactose or galactose derivatives may inhibit liver fibrosis. We hypothesized that targeting both galectin-3 and EGFR may have better effect against liver fibrosis. Here, EGFR inhibitor erlotinib was used in a series of designed galectin-3 inhibitors after hybridization with the pharmacophore structure in reported galectin-3 inhibitors to impede hepatic stellate cells (HSCs) activation by a typical method of click chemistry. Bioactivity test results showed that compound 29 suppressed TGF-β-induced upregulation of fibrotic markers (α-SMA, fibronectin-1, and collagen I). The preferred compound 29 displayed better binding to galectin-3 (KD=52.29 μM) and EGFR protein (KD=3.31 μM) by SPR assay. Further docking studies were performed to clarify the possible binding mode of compound 29 with galectin-3 and EGFR. Taken together, these results suggested that compound 29 could be a potential dual galectin-3 and EGFR inhibitor as leading compound for anti-liver fibrosis new drug development.
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Affiliation(s)
- Shuanglin Liu
- School of Pharmacy, Henan University of Chinese Medicine, Zhengzhou, Henan, 450046, China
- Henan Polysaccharide Research Center, Henan Key Laboratory of Chinese Medicine for Polysaccharides and Drugs Research, Academy of Chinese Medical Sciences, Henan University of Chinese Medicine, Zhengzhou, 450046, China
- Zhongshan Institute for Drug Discovery, Shanghai Institute of Materia Medica, Chinese Academy of Science, SSIP Healthcare and Medicine Demonstration Zone, Zhongshan, Guangdong, Tsuihang New District, 528400, China
| | - Fei He
- Glycochemistry and Glycobiology Lab, CAS Key Laboratory of Receptor Research, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China
- University of Chinese Academy of Science, No.19 A Yuquan Road, Beijing, 100049, China
| | - Can Jin
- Zhongshan Institute for Drug Discovery, Shanghai Institute of Materia Medica, Chinese Academy of Science, SSIP Healthcare and Medicine Demonstration Zone, Zhongshan, Guangdong, Tsuihang New District, 528400, China
- Glycochemistry and Glycobiology Lab, CAS Key Laboratory of Receptor Research, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China
- University of Chinese Academy of Science, No.19 A Yuquan Road, Beijing, 100049, China
| | - Qing Li
- Glycochemistry and Glycobiology Lab, CAS Key Laboratory of Receptor Research, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China
- University of Chinese Academy of Science, No.19 A Yuquan Road, Beijing, 100049, China
- School of Pharmacy, Henan University, Kaifeng, Henan, 475004, China
| | - Guilong Zhao
- Zhongshan Institute for Drug Discovery, Shanghai Institute of Materia Medica, Chinese Academy of Science, SSIP Healthcare and Medicine Demonstration Zone, Zhongshan, Guangdong, Tsuihang New District, 528400, China
- Glycochemistry and Glycobiology Lab, CAS Key Laboratory of Receptor Research, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China
- University of Chinese Academy of Science, No.19 A Yuquan Road, Beijing, 100049, China
| | - Kan Ding
- Henan Polysaccharide Research Center, Henan Key Laboratory of Chinese Medicine for Polysaccharides and Drugs Research, Academy of Chinese Medical Sciences, Henan University of Chinese Medicine, Zhengzhou, 450046, China
- Zhongshan Institute for Drug Discovery, Shanghai Institute of Materia Medica, Chinese Academy of Science, SSIP Healthcare and Medicine Demonstration Zone, Zhongshan, Guangdong, Tsuihang New District, 528400, China
- Glycochemistry and Glycobiology Lab, CAS Key Laboratory of Receptor Research, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China
- University of Chinese Academy of Science, No.19 A Yuquan Road, Beijing, 100049, China
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Patury CB, Santos BLM, Matos ALC, Slabi J, Gastalho LCC, Kaneto CM. Dysregulation of MiR-21, MiR-221 and MiR-451 During Neoadjuvant Treatment of Breast Cancer: A Prospective Study. Biomolecules 2024; 14:1580. [PMID: 39766287 PMCID: PMC11674781 DOI: 10.3390/biom14121580] [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: 10/22/2024] [Revised: 11/20/2024] [Accepted: 12/03/2024] [Indexed: 01/11/2025] Open
Abstract
BACKGROUND Breast cancer is highly heterogeneous disease in which different responses are observed to the same treatment for different subtypes and extents of similar diseases. Considering this scenario, the search for tumor biomarkers is indispensable, with current evidence suggesting that circulating microRNAs are viable biomarkers. This study evaluated the expression of miR-21, miR-221, miR-195, and miR-451 in patients with breast cancer undergoing neoadjuvant treatment at oncology outpatient facilities in Brazil. METHODS We conducted a prospective and observational study in which blood samples were collected for microRNA expression analysis, comparing control and breast cancer patients who were candidates for neoadjuvant treatment groups. The expression of microRNAs was investigated by qRT-PCR method. For parametric data analysis, one-way ANOVA with Tukey's post hoc test was used. RESULTS Thirty-three participants (all female) were included in the control group and twenty-seven participants were included in the study group. The non-special subtype of breast cancer was found in 96% of the study group participants; 88.9% were locally advanced tumors (T3, T4), 40.7% were luminal tumors, 33.3% were HER-2-positive, and 26% were triple negative tumors. Expression analysis of microRNAs during neoadjuvant treatment, using miR-16 as a normalizer, showed higher expression levels of miR-21 and miR-221 at the end of treatment, and high expression levels for miR-451 were also observed at the beginning of treatment. CONCLUSION This is the first study that evaluates the expression of microRNAs in the context of neoadjuvant treatment of breast cancer in the Brazilian population. Our results suggest that there is a deregulation of miR-21, miR-221, and miR-451 during neoadjuvant treatment in these patients.
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Affiliation(s)
- Carine Bispo Patury
- Department of Health Science, Universidade Estadual de Santa Cruz, Ilhéus 45662-900, BA, Brazil; (C.B.P.); (J.S.)
| | - Brenda Luanny Maia Santos
- Department of Biological Science, Universidade Estadual de Santa Cruz, Ilhéus 45662-900, BA, Brazil; (B.L.M.S.); (A.L.C.M.); (L.C.C.G.)
| | - Anna Lucia Carvalho Matos
- Department of Biological Science, Universidade Estadual de Santa Cruz, Ilhéus 45662-900, BA, Brazil; (B.L.M.S.); (A.L.C.M.); (L.C.C.G.)
| | - José Slabi
- Department of Health Science, Universidade Estadual de Santa Cruz, Ilhéus 45662-900, BA, Brazil; (C.B.P.); (J.S.)
| | - Luciene Cristina Campos Gastalho
- Department of Biological Science, Universidade Estadual de Santa Cruz, Ilhéus 45662-900, BA, Brazil; (B.L.M.S.); (A.L.C.M.); (L.C.C.G.)
| | - Carla Martins Kaneto
- Department of Biological Science, Universidade Estadual de Santa Cruz, Ilhéus 45662-900, BA, Brazil; (B.L.M.S.); (A.L.C.M.); (L.C.C.G.)
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Sotoudeheian M. Galectin-3 and Severity of Liver Fibrosis in Metabolic Dysfunction-Associated Fatty Liver Disease. Protein Pept Lett 2024; 31:290-304. [PMID: 38715329 DOI: 10.2174/0109298665301698240404061300] [Citation(s) in RCA: 5] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2023] [Revised: 03/02/2024] [Accepted: 03/21/2024] [Indexed: 08/13/2024]
Abstract
Metabolic dysfunction-associated Fatty Liver Disease (MAFLD) is a chronic liver disease characterized by the accumulation of fat in the liver and hepatic steatosis, which can progress to critical conditions, including Metabolic dysfunction-associated Steatohepatitis (MASH), liver fibrosis, hepatic cirrhosis, and hepatocellular carcinoma. Galectin-3, a member of the galectin family of proteins, has been involved in cascades that are responsible for the pathogenesis and progression of liver fibrosis in MAFLD. This review summarizes the present understanding of the role of galectin-3 in the severity of MAFLD and its associated liver fibrosis. The article assesses the underlying role of galectin-3-mediated fibrogenesis, including the triggering of hepatic stellate cells, the regulation of extracellular degradation, and the modulation of immune reactions and responses. It also highlights the assessments of the potential diagnostic and therapeutic implications of galectin-3 in liver fibrosis during MAFLD. Overall, this review provides insights into the multifaceted interaction between galectin-3 and liver fibrosis in MAFLD, which could lead to the development of novel strategies for diagnosis and treatment of this prevalent liver disease.
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Mackinnon AC, Tonev D, Jacoby B, Pinzani M, Slack RJ. Galectin-3: therapeutic targeting in liver disease. Expert Opin Ther Targets 2023; 27:779-791. [PMID: 37705214 DOI: 10.1080/14728222.2023.2258280] [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: 04/27/2023] [Accepted: 09/08/2023] [Indexed: 09/15/2023]
Abstract
INTRODUCTION The rising incidence of liver diseases is a worldwide healthcare concern. However, the therapeutic options to manage chronic inflammation and fibrosis, the processes at the basis of morbidity and mortality of liver diseases, are very limited. Galectin 3 (Gal-3) is a protein implicated in fibrosis in multiple organs. Several Gal-3 inhibitors are currently in clinical development. AREAS COVERED This review describes our current understanding of the role of Gal-3 in chronic liver diseases, with special emphasis on fibrosis. Also, we review therapeutic advances based on Gal-3 inhibition, describing drug properties and their current status in clinical research. EXPERT OPINION Currently, the known effects of Gal-3 point to a direct activation of the NLRP3 inflammasome leading to its activation in liver macrophages and activated macrophages play a key role in tissue fibrogenesis. However, more research is needed to elucidate the role of Gal-3 in the different activation pathways, dissecting the intracellular and extracellular mechanisms of Gal-3, and its role in pathogenesis. Gal-3 could be a target for early therapy of numerous hepatic diseases and, given the lack of therapeutic options for liver fibrosis, there is a strong pharmacologic potential for Gal-3-based therapies.
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Affiliation(s)
| | - Dimitar Tonev
- Galecto Biotech AB, Cobis Science Park, Copenhagen, Denmark
| | - Brian Jacoby
- Galecto Biotech AB, Cobis Science Park, Copenhagen, Denmark
| | - Massimo Pinzani
- Institute for Liver and Digestive Health, University College London, London, UK
| | - Robert J Slack
- Galecto Biotech AB, Cobis Science Park, Copenhagen, Denmark
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Prado MSG, de Jesus ML, de Goes TC, Mendonça LSO, Kaneto CM. Downregulation of circulating miR-320a and target gene prediction in patients with diabetic retinopathy. BMC Res Notes 2020; 13:155. [PMID: 32178730 PMCID: PMC7077016 DOI: 10.1186/s13104-020-05001-9] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2019] [Accepted: 03/10/2020] [Indexed: 12/11/2022] Open
Abstract
Objective To evaluate the expression of a set of miRNAs to identify differentially expressed miRNAs that might be considered reliable biomarkers on Diabetic Retinopathy (DR) blood samples. Results Expression levels of MiR-320a, MiR-342-3p, MiR-155, MiR-99a, MiR-29a and MiR-27b were analyzed in 60 healthy controls, 48 Diabetes Melitus (DM) without DR patients and 62 DR patients by qRT-PCR. MiR-320a was shown to be downregulated in the plasma of DR patients compared with DM patients without DR and healthy subjects. Target genes were predicted using miRWalk3.0, miR targeting data and target gene interaction data were imported to Cytoscape to visualize and merge networks and top ranked predicted genes were run through Ontology Genes to perform enrichment analysis on gene sets and classification system to identify biological processes and reactome pathways associated with DR. Highly scored target genes of miR-320a were categorized for various biological processes, including negative regulation of cell aging, negative regulation of cellular protein metabolic process and regulation of cellular response to stress that are critical to the development of DR. Our findings suggest that MiR-320a may have a role in the pathogenesis of DR and may represent novel biomarkers for this disease.
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Affiliation(s)
| | - Mirthz Lemos de Jesus
- Department of Health Science, Universidade Estadual de Santa Cruz, Ilhéus, BA, Brazil
| | - Thaline Cunha de Goes
- Department of Biological Science, Universidade Estadual de Santa Cruz, Rodovia Jorge Amado, Km16, Ilhéus, BA, 45662-900, Brazil
| | - Lucilla Silva Oliveira Mendonça
- Department of Biological Science, Universidade Estadual de Santa Cruz, Rodovia Jorge Amado, Km16, Ilhéus, BA, 45662-900, Brazil
| | - Carla Martins Kaneto
- Department of Biological Science, Universidade Estadual de Santa Cruz, Rodovia Jorge Amado, Km16, Ilhéus, BA, 45662-900, Brazil.
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The Number of Liver Galectin-3 Positive Cells Is Dually Correlated with NAFLD Severity in Children. Int J Mol Sci 2019; 20:ijms20143460. [PMID: 31337151 PMCID: PMC6679049 DOI: 10.3390/ijms20143460] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2019] [Revised: 07/03/2019] [Accepted: 07/12/2019] [Indexed: 02/07/2023] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is a complex disease ranging from steatosis to non-alcoholic steatohepatitis (NASH). Galectin-3 (Gal-3), which is a β-galactoside binding protein, has been associated with liver fibrosis, but its role in NAFLD remains elusive. We investigated the expression of Gal-3 in liver resident cells and its potential association with liver damage in 40 children with biopsy-proven NAFLD. We found that several liver cells expressed Gal-3. The number of total Gal-3 positive cells decreased with the severity of disease and the cells were correlated with the presence of steatosis and the diagnosis of NASH. CD68 macrophages expressed Gal-3 but the number CD68/Gal-3 positive cells was significantly reduced in patients diagnosed with steatosis and NASH. Triple CD68/CD206/Gal-3, which represented the subpopulation of M2 macrophages, were mainly present in patients without NASH, and clearly reduced in patients with steatosis and NASH. On the contrary, the number of α-smooth muscle actin (SMA)/Gal-3 positive cells increased with the severity of fibrosis in children with NAFLD. Our data demonstrated that the number of Gal-3 positive cells was associated with tissue damage in different ways, which suggests a dual role of this protein in the pathogenesis of pediatric NAFLD, even if the role of Gal-3 deserves further studies.
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de Souza VCA, Moura DMN, de Castro MCAB, Bozza PT, de Almeida Paiva L, Fernandes CJB, Leão RLC, Lucena JP, de Araujo RE, de Melo Silva AJ, Figueiredo RCBQ, de Oliveira SA. Adoptive Transfer of Bone Marrow-Derived Monocytes Ameliorates Schistosoma mansoni -Induced Liver Fibrosis in Mice. Sci Rep 2019; 9:6434. [PMID: 31015492 PMCID: PMC6478942 DOI: 10.1038/s41598-019-42703-y] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2018] [Accepted: 04/04/2019] [Indexed: 12/19/2022] Open
Abstract
Liver diseases are a major health problem worldwide leading to high mortality rates and causing a considerable economic burden in many countries. Cellular therapies as potential treatments for liver diseases have proven beneficial in most of the conditions. In recent years, studies involving therapy with bone marrow cells have been implemented to promote liver regeneration and to reduce hepatic fibrosis, however identifying the cell population present in the bone marrow that is responsible for hepatic improvement after therapy is still necessary. The aim of the present study was the evaluation of the therapeutic efficacy of monocytes obtained from bone marrow in fibrosis resulting from S. mansoni infection in C57BL/6 mice. Monocytes were isolated by immunomagnetic separation and administered to the infected animals. The effects of treatment were evaluated through morphometric, biochemical, immunological and molecular analyzes. Monocyte therapy promoted reduction of liver fibrosis induced by S. mansoni infection, associated with a decrease in production of inflammatory and pro-fibrogenic mediators. In addition, monocyte infusion caused downregulation of factors associated with the M1 activation profile, as well as upregulation of M2reg markers. The findings altogether reinforce the hypothesis that the predominance of M2reg macrophages, producers of immunosuppressive cytokines, may favor the improvement of hepatic fibrosis in a preclinical model, through fibrous tissue remodeling, modulation of the inflammatory response and fibrogenesis.
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Affiliation(s)
| | | | | | - Patrícia Torres Bozza
- Laboratório de Imunofarmacologia, Instituto Oswaldo Cruz, Rio de Janeiro, Rio de Janeiro, Brazil
| | - Ligia de Almeida Paiva
- Laboratório de Imunofarmacologia, Instituto Oswaldo Cruz, Rio de Janeiro, Rio de Janeiro, Brazil
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Kotsiou OS, Gourgoulianis KI, Zarogiannis SG. IL-33/ST2 Axis in Organ Fibrosis. Front Immunol 2018; 9:2432. [PMID: 30405626 PMCID: PMC6207585 DOI: 10.3389/fimmu.2018.02432] [Citation(s) in RCA: 164] [Impact Index Per Article: 23.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2018] [Accepted: 10/02/2018] [Indexed: 12/19/2022] Open
Abstract
Interleukin 33 (IL-33) is highly expressed in barrier sites, acting via the suppression of tumorigenicity 2 receptor (ST2). IL-33/ST2 axis has long been known to play a pivotal role in immunity and cell homeostasis by promoting wound healing and tissue repair. However, it is also involved in the loss of balance between extensive inflammation and tissue regeneration lead to remodeling, the hallmark of fibrosis. The aim of the current review is to critically evaluate the available evidence regarding the role of the IL-33/ST2 axis in organ fibrosis. The role of the axis in tissue remodeling is better understood considering its crucial role reported in organ development and regeneration. Generally, the IL-33/ST2 signaling pathway has mainly anti-inflammatory/anti-proliferative effects; however, chronic tissue injury is responsible for pro-fibrogenetic responses. Regarding pulmonary fibrosis mature IL-33 enhances pro-fibrogenic type 2 cytokine production in an ST2- and macrophage-dependent manner, while full-length IL-33 is also implicated in the pulmonary fibrotic process in an ST2-independent, Th2-independent fashion. In liver fibrosis, evidence indicate that when acute and massive liver damage occurs, the release of IL-33 might act as an activator of tissue-protective mechanisms, while in cases of chronic injury IL-33 plays the role of a hepatic fibrotic factor. IL-33 signaling has also been involved in the pathogenesis of acute and chronic pancreatitis. Moreover, IL-33 could be used as an early marker for ulcer-associated activated fibroblasts and myofibroblast trans-differentiation; thus one cannot rule out its potential role in inflammatory bowel disease-associated fibrosis. Similarly, the upregulation of the IL-33/ST2 axismay contribute to tubular cell injury and fibrosis via epithelial to mesenchymal transition (EMT) of various cell types in the kidneys. Of note, IL-33 exerts a cardioprotective role via ST2 signaling, while soluble ST2 has been demonstrated as a marker of myocardial fibrosis. Finally, IL-33 is a crucial cytokine in skin pathology responsible for abnormal fibroblast proliferation, leukocyte infiltration and morphologic differentiation of human endothelial cells. Overall, emerging data support a novel contribution of the IL-33/ST2 pathway in tissue fibrosis and highlight the significant role of the Th2 pattern of immune response in the pathophysiology of organ fibrosis.
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Affiliation(s)
- Ourania S. Kotsiou
- Department of Respiratory Medicine, Faculty of Medicine, School of Health Sciences, University of Thessaly, BIOPOLIS, Larissa, Greece
- Department of Physiology, Faculty of Medicine, School of Health Sciences, University of Thessaly, BIOPOLIS, Larissa, Greece
| | - Konstantinos I. Gourgoulianis
- Department of Respiratory Medicine, Faculty of Medicine, School of Health Sciences, University of Thessaly, BIOPOLIS, Larissa, Greece
| | - Sotirios G. Zarogiannis
- Department of Respiratory Medicine, Faculty of Medicine, School of Health Sciences, University of Thessaly, BIOPOLIS, Larissa, Greece
- Department of Physiology, Faculty of Medicine, School of Health Sciences, University of Thessaly, BIOPOLIS, Larissa, Greece
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Kaneto CM, Nascimento JS, Moreira MCR, Ludovico ND, Santana AP, Silva RAA, Silva-Jardim I, Santos JL, Sousa SMB, Lima PSP. MicroRNA profiling identifies miR-7-5p and miR-26b-5p as differentially expressed in hypertensive patients with left ventricular hypertrophy. ACTA ACUST UNITED AC 2017; 50:e6211. [PMID: 29069223 PMCID: PMC5649865 DOI: 10.1590/1414-431x20176211] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2017] [Accepted: 06/22/2017] [Indexed: 12/17/2022]
Abstract
Recent evidence suggests that cell-derived circulating miRNAs may serve as biomarkers of cardiovascular diseases. However, a few studies have investigated the potential of circulating miRNAs as biomarkers for left ventricular hypertrophy (LVH). In this study, we aimed to characterize the miRNA profiles that could distinguish hypertensive patients with LHV, hypertensive patients without LVH and control subjects, and identify potential miRNAs as biomarkers of LVH. LVH was defined by left ventricular mass indexed to body surface area >125 g/m2 in men and >110 g/m2 in women and patients were classified as hypertensive when presenting a systolic blood pressure of 140 mmHg or more, or a diastolic blood pressure of 90 mmHg or more. We employed miRNA PCR array to screen serum miRNAs profiles of patients with LVH, essential hypertension and healthy subjects. We identified 75 differentially expressed miRNAs, including 49 upregulated miRNAs and 26 downregulated miRNAs between LVH and control patients. We chose 2 miRNAs with significant differences for further testing in 59 patients. RT-PCR analysis of serum samples confirmed that miR-7-5p and miR-26b-5p were upregulated in the serum of LVH hypertensive patients compared with healthy subjects. Our findings suggest that these miRNAs may play a role in the pathogenesis of hypertensive LVH and may represent novel biomarkers for this disease.
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Affiliation(s)
- C M Kaneto
- Departamento de Ciências Biológicas, Universidade Estadual de Santa Cruz, Ilhéus, BA, Brasil
| | - J S Nascimento
- Departmento de Ciências da Saúde, Universidade Estadual de Santa Cruz, Ilhéus, BA, Brasil
| | - M C R Moreira
- Departmento de Ciências da Saúde, Universidade Estadual de Santa Cruz, Ilhéus, BA, Brasil
| | - N D Ludovico
- Departmento de Ciências da Saúde, Universidade Estadual de Santa Cruz, Ilhéus, BA, Brasil
| | - A P Santana
- Departmento de Ciências Naturais, Universidade Estadual do Sudoeste da Bahia, Vitória da Conquista, BA, Brasil
| | - R A A Silva
- Instituto Multidisciplinar em Saúde, Universidade Federal da Bahia, Vitória da Conquista, BA, Brasil
| | - I Silva-Jardim
- Departamento de Ciências Biológicas, Universidade Estadual de Santa Cruz, Ilhéus, BA, Brasil
| | - J L Santos
- Departamento de Ciências Biológicas, Universidade Estadual de Santa Cruz, Ilhéus, BA, Brasil
| | - S M B Sousa
- Departmento de Ciências Naturais, Universidade Estadual do Sudoeste da Bahia, Vitória da Conquista, BA, Brasil
| | - P S P Lima
- Departmento de Ciências Naturais, Universidade Estadual do Sudoeste da Bahia, Vitória da Conquista, BA, Brasil
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de Souza VCA, Pereira TA, Teixeira VW, Carvalho H, de Castro MCAB, D’assunção CG, de Barros AF, Carvalho CL, de Lorena VMB, Costa VMA, Teixeira ÁAC, Figueiredo RCBQ, de Oliveira SA. Bone marrow-derived monocyte infusion improves hepatic fibrosis by decreasing osteopontin, TGF-β1, IL-13 and oxidative stress. World J Gastroenterol 2017; 23:5146-5157. [PMID: 28811709 PMCID: PMC5537181 DOI: 10.3748/wjg.v23.i28.5146] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/30/2016] [Revised: 02/25/2017] [Accepted: 04/12/2017] [Indexed: 02/06/2023] Open
Abstract
AIM To evaluate the therapeutic effects of bone marrow-derived CD11b+CD14+ monocytes in a murine model of chronic liver damage.
METHODS Chronic liver damage was induced in C57BL/6 mice by administration of carbon tetrachloride and ethanol for 6 mo. Bone marrow-derived monocytes isolated by immunomagnetic separation were used for therapy. The cell transplantation effects were evaluated by morphometry, biochemical assessment, immunohistochemistry and enzyme-linked immunosorbent assay.
RESULTS CD11b+CD14+ monocyte therapy significantly reduced liver fibrosis and increased hepatic glutathione levels. Levels of pro-inflammatory cytokines, including tumor necrosis factor-α, interleukin (IL)-6 and IL-1β, in addition to pro-fibrotic factors, such as IL-13, transforming growth factor-β1 and tissue inhibitor of metalloproteinase-1 also decreased, while IL-10 and matrix metalloproteinase-9 increased in the monocyte-treated group. CD11b+CD14+ monocyte transplantation caused significant changes in the hepatic expression of α-smooth muscle actin and osteopontin.
CONCLUSION Monocyte therapy is capable of bringing about improvement of liver fibrosis by reducing oxidative stress and inflammation, as well as increasing anti-fibrogenic factors.
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Pejnovic N, Jeftic I, Jovicic N, Arsenijevic N, Lukic ML. Galectin-3 and IL-33/ST2 axis roles and interplay in diet-induced steatohepatitis. World J Gastroenterol 2016; 22:9706-9717. [PMID: 27956794 PMCID: PMC5124975 DOI: 10.3748/wjg.v22.i44.9706] [Citation(s) in RCA: 45] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/28/2016] [Revised: 09/02/2016] [Accepted: 09/14/2016] [Indexed: 02/06/2023] Open
Abstract
Immune reactivity and chronic low-grade inflammation (metaflammation) play an important role in the pathogenesis of obesity-associated metabolic disorders, including type 2 diabetes and nonalcoholic fatty liver disease (NAFLD), a spectrum of diseases that include liver steatosis, nonalcoholic steatohepatitis (NASH), fibrosis, and cirrhosis. Increased adiposity and insulin resistance contribute to the progression from hepatic steatosis to NASH and fibrosis through the development of proinflammatory and profibrotic processes in the liver, including increased hepatic infiltration of innate and adaptive immune cells, altered balance of cytokines and chemokines, increased reactive oxygen species generation and hepatocellular death. Experimental models of dietary-induced NAFLD/NASH in mice on different genetic backgrounds or knockout mice with different immune reactivity are used for elucidating the pathogenesis of NASH and liver fibrosis. Galectin-3 (Gal-3), a unique chimera-type β-galactoside-binding protein of the galectin family has a regulatory role in immunometabolism and fibrogenesis. Mice deficient in Gal-3 develop pronounced adiposity, hyperglycemia and hepatic steatosis, as well as attenuated liver inflammation and fibrosis when fed an obesogenic high-fat diet. Interleukin (IL)-33, a member of the IL-1 cytokine family, mediates its effects through the ST receptor, which is present on immune and nonimmune cells and participates in immunometabolic and fibrotic disorders. Recent evidence, including our own data, suggests a protective role for the IL-33/IL-33R (ST2) signaling pathway in obesity, adipose tissue inflammation and atherosclerosis, but a profibrotic role in NASH development. The link between Gal-3 and soluble ST2 in myocardial fibrosis and heart failure progression has been demonstrated and we have recently shown that Gal-3 and the IL-33/ST2 pathway interact and both have a profibrotic role in diet-induced NASH. This review discusses the current evidence on the roles of Gal-3 and the IL-33/ST2 pathway and their interplay in obesity-associated hepatic inflammation and fibrogenesis that may be of interest in the development of therapeutic interventions to prevent and/or reverse obesity-associated hepatic inflammation and fibrosis.
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Gajalakshmi P, Majumder S, Viebahn CS, Swaminathan A, Yeoh GC, Chatterjee S. Interleukin-6 secreted by bipotential murine oval liver stem cells induces apoptosis of activated hepatic stellate cells by activating NF-κB-inducible nitric oxide synthase signaling. Biochem Cell Biol 2016; 95:263-272. [PMID: 28177770 DOI: 10.1139/bcb-2016-0011] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023] Open
Abstract
Liver fibrosis is now well recognized as the causative factor for increased mortality from complications associated with liver pathologies. Activated hepatic stellate cells (HSCs) play a critical role in the progression of liver fibrosis. Therefore, targeting these activated HSCs to prevent and (or) treat liver disease is a worthwhile approach to explore. In the present in vitro study, we investigated the use of bipotential murine oval liver cells (BMOL) in regulating the functions of activated HSCs to prevent progression of liver fibrosis. We used a conditioned medium-based approach to study the effect of BMOL cells on activated HSC survival and function. Our data showed that BMOL cells block the contraction of activated HSCs by inducing apoptosis of these cells. We demonstrated that BMOL cells secrete soluble factors, such as interleukin-6 (IL-6), which induced apoptosis of activated HSCs. Using both pharmacological and molecular inhibitor approaches, we further identified that IL-6-mediated activation of NF-κB-iNOS-NO-ROS signaling in activated HSCs plays a critical role in BMOL-cell-mediated apoptosis of activated HSCs. Thus, the present study provides an alternative cell-based therapeutic approach to treat liver fibrosis.
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Affiliation(s)
| | - Syamantak Majumder
- b Keenan Research Centre for Biomedical Science and Li Ka Shing Knowledge Institute of St. Michael's Hospital, Toronto, Ontario, Canada
| | - Cornelia S Viebahn
- c Centre for Medical Research, Harry Perkins Institute of Medical Research, University of Western Australia, Nedlands, Australia
| | - Akila Swaminathan
- a Life Sciences Division, AU-KBC Research Centre, Anna University, Chennai, India
| | - George C Yeoh
- c Centre for Medical Research, Harry Perkins Institute of Medical Research, University of Western Australia, Nedlands, Australia
| | - Suvro Chatterjee
- a Life Sciences Division, AU-KBC Research Centre, Anna University, Chennai, India.,d Department of Biotechnology, Anna University, Chennai, India
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Noya-Rabelo MM, Larocca TF, Macêdo CT, Torreão JA, Souza BSDF, Vasconcelos JF, Souza LE, Silva AM, Ribeiro dos Santos R, Correia LCL, Soares MBP. Evaluation of Galectin-3 as a Novel Biomarker for Chagas Cardiomyopathy. Cardiology 2016; 136:33-39. [DOI: 10.1159/000447529] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/26/2016] [Accepted: 06/10/2016] [Indexed: 11/19/2022]
Abstract
Objectives: Chagas cardiomyopathy has worse long-term outcomes than other cardiomyopathies. A biomarker strategy to refer subjects for noninvasive cardiac imaging may help in the early identification of cardiac damage in subjects with Chagas disease. Galectin-3 (Gal-3) is a mediator of cardiac fibrosis shown to be upregulated in animal models of decompensated heart failure. Here we assessed the correlation of Gal-3 with myocardial fibrosis in patients with Chagas disease. Methods: This study comprised 61 subjects with Chagas disease. All subjects underwent clinical assessments, Doppler echocardiography and magnetic resonance imaging. Plasmatic Gal-3 was determined by ELISA. Results: Delayed enhancement (DE) was identified in 37 of 61 subjects (64%). The total amount of myocardial fibrosis was 9.4% [interquartile interval (IQI): 2.4-18.4]. No differences were observed in Gal-3 concentration according to the presence or absence of myocardial fibrosis, with a median Gal-3 concentration of 11.7 ng/ml (IQI: 9.4-15) in subjects with DE versus 12.9 ng/ml (IQI: 9.2-14) in subjects without DE (p = 0.18). No correlation was found between myocardial fibrosis and Gal-3 concentration (r = 0.098; p = 0.47). Conclusions: There is no correlation between the degree of myocardial fibrosis and the concentration of Gal-3 in subjects with Chagas disease.
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Azevedo CM, Solano de Freitas Souza B, Andrade de Oliveira S, Paredes BD, Barreto ES, Neto HA, Ribeiro dos Santos R, Pereira Soares MB. Bone marrow-derived cells migrate to the liver and contribute to the generation of different cell types in chronic Schistosoma mansoni infection. Exp Parasitol 2015; 159:29-36. [PMID: 26297681 DOI: 10.1016/j.exppara.2015.08.005] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2014] [Revised: 07/10/2015] [Accepted: 08/16/2015] [Indexed: 12/12/2022]
Abstract
The main pathogenic event caused by Schistosoma mansoni infection is characterized by a granulomatous inflammatory reaction around parasite eggs and fibrosis in the liver. We have previously shown that transplantation of bone marrow cells (BMC) promotes a reduction in liver fibrosis in chronically S. mansoni-infected mice. Here we investigated the presence and phenotype of bone marrow-derived cells in livers of S. mansoni-infected mice. During the chronic phase of infection, C57BL/6 mice had an increased number of circulating mesenchymal stem cells and endothelial progenitor cells in the peripheral blood when compared to uninfected controls. In order to investigate the fate of BMC in the liver, we generated bone marrow chimeric mice by transplanting BMC from transgenic green fluorescent protein (GFP) mice into lethally irradiated wild-type C57BL/6 mice. S. mansoni-infected chimeric mice did not demonstrate increased mortality and developed similar liver histopathological features, when compared to wild-type S. mansoni-infected mice. GFP(+) bone marrow-derived cells were found in the liver parenchyma, particularly in periportal regions. CD45(+)GFP(+) cells were found in the granulomas. Flow cytometry analysis of digested liver tissue characterized GFP(+) cells as lymphocytes, myeloid cells and stem cells. GFP(+) cells were also found in areas of collagen deposition, although rare GFP(+) cells expressed the myofibroblast cell marker α-SMA. Additionally GFP(+) endothelial cells (co-stained with von Willebrand factor) were frequently observed, while BMC-derived hepatocytes (GFP(+) albumin(+) cells) were sparsely found in the liver of chimeric mice chronically infected with S. mansoni. In conclusion, BMC are recruited to the liver during chronic experimental infection with S. mansoni and contribute to the generation of different cell types involved, not only in disease pathogenesis, but possibly in liver regeneration and repair.
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Affiliation(s)
- Carine Machado Azevedo
- Centro de Pesquisas Gonçalo Moniz, Fundação Oswaldo Cruz, Rua Waldemar Falcão, 121, Candeal, 40296-710, Salvador, BA, Brazil; Centro de Biotecnologia e Terapia Celular, Hospital São Rafael, Av. São Rafael, 2152, São Marcos, 41253-190, Salvador, BA, Brazil
| | - Bruno Solano de Freitas Souza
- Centro de Pesquisas Gonçalo Moniz, Fundação Oswaldo Cruz, Rua Waldemar Falcão, 121, Candeal, 40296-710, Salvador, BA, Brazil; Centro de Biotecnologia e Terapia Celular, Hospital São Rafael, Av. São Rafael, 2152, São Marcos, 41253-190, Salvador, BA, Brazil
| | - Sheilla Andrade de Oliveira
- Centro de Pesquisas Aggeu Magalhães, Fundação Oswaldo Cruz, Av. Professor Moraes Rego, s/n, Cidade Universitária, 50.740-465, Recife, PE, Brazil
| | - Bruno Diaz Paredes
- Centro de Biotecnologia e Terapia Celular, Hospital São Rafael, Av. São Rafael, 2152, São Marcos, 41253-190, Salvador, BA, Brazil
| | - Elton Sá Barreto
- Centro de Pesquisas Gonçalo Moniz, Fundação Oswaldo Cruz, Rua Waldemar Falcão, 121, Candeal, 40296-710, Salvador, BA, Brazil
| | - Hélio Almeida Neto
- Centro de Pesquisas Gonçalo Moniz, Fundação Oswaldo Cruz, Rua Waldemar Falcão, 121, Candeal, 40296-710, Salvador, BA, Brazil
| | - Ricardo Ribeiro dos Santos
- Centro de Biotecnologia e Terapia Celular, Hospital São Rafael, Av. São Rafael, 2152, São Marcos, 41253-190, Salvador, BA, Brazil
| | - Milena Botelho Pereira Soares
- Centro de Pesquisas Gonçalo Moniz, Fundação Oswaldo Cruz, Rua Waldemar Falcão, 121, Candeal, 40296-710, Salvador, BA, Brazil; Centro de Biotecnologia e Terapia Celular, Hospital São Rafael, Av. São Rafael, 2152, São Marcos, 41253-190, Salvador, BA, Brazil.
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Abstract
Fibrotic diseases occur in a variety of organs and lead to continuous organ injury, function decline, and even failure. Currently effective treatment options are limited. Galectin-3 (Gal-3) is a pleiotropic lectin that plays an important role in cell proliferation, adhesion, differentiation, angiogenesis, and apoptosis. Accumulating evidence indicates that Gal-3 activates a variety of profibrotic factors, promotes fibroblast proliferation and transformation, and mediates collagen production. Recent studies have defined key roles for Gal-3 in fibrogenesis in diverse organ systems, including liver, kidney, lung, and myocardial. To help set the stage for future research, we review recent advances about the role played by Gal-3 in fibrotic diseases. Herein we discuss the potential profibrotic role of Gal-3, inhibition of which may represent a promising therapeutic strategy against tissue fibrosis.
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Affiliation(s)
- Liu-cheng Li
- School of Pharmacy, Anhui Medical University, Hefei, P. R. China (L.L., J.L.); and Pharmaceutical Preparation Section, The First Affiliated Hospital of Anhui Medical University, Hefei, P. R. China (J.G.)
| | - Jun Li
- School of Pharmacy, Anhui Medical University, Hefei, P. R. China (L.L., J.L.); and Pharmaceutical Preparation Section, The First Affiliated Hospital of Anhui Medical University, Hefei, P. R. China (J.G.)
| | - Jian Gao
- School of Pharmacy, Anhui Medical University, Hefei, P. R. China (L.L., J.L.); and Pharmaceutical Preparation Section, The First Affiliated Hospital of Anhui Medical University, Hefei, P. R. China (J.G.)
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Abstract
Liver disease is a rising cause of mortality and morbidity, and treatment options remain limited. Liver transplantation is curative but limited by donor organ availability, operative risk and long-term complications. The contribution of bone marrow (BM)-derived stem cells to tissue regeneration has been recognised and there is considerable interest in the potential benefits of BM stem cells in patients with liver disease. In chronic liver disease, deposition of fibrous scar tissue inhibits hepatocyte proliferation and leads to portal hypertension. Although initial reports had suggested transdifferentiation of stem cells into hepatocytes, the beneficial effects of BM stem cells are more likely derived from the ability to breakdown scar tissue and stimulate hepatocyte proliferation. Studies in animal models have yielded promising results, although the exact mechanisms and cell type responsible have yet to be determined. Small-scale clinical studies have quickly followed and, although primarily designed to examine safety and feasibility of this approach, have reported improvements in liver function in treated patients. Well-designed, controlled studies are required to fully determine the benefits of BM stem cell therapy.
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Affiliation(s)
- Andrew King
- NIHR Liver Biomedical Research Unit and Centre for Liver Research, University of Birmingham, Birmingham, UK
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Pellicori P, Torromeo C, Calicchia A, Ruffa A, Di Iorio M, Cleland JGF, Merli M. Does cirrhotic cardiomyopathy exist? 50 years of uncertainty. Clin Res Cardiol 2013; 102:859-64. [PMID: 23995321 DOI: 10.1007/s00392-013-0610-1] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/21/2013] [Accepted: 08/14/2013] [Indexed: 02/08/2023]
Abstract
Subtle abnormalities of cardiac structure or function are often identified in patients with liver cirrhosis and have been termed cirrhotic cardiomyopathy. However, in the absence of a precise definition, its diagnosis remains a challenge. Cardiac dysfunction in patients with cirrhosis can often be attributed to concomitant diseases such as hypertension, ischaemic heart disease or excess alcohol consumption in many patients. Further research is required to identify the existence, origin and importance of abnormal cardiac function due specifically to liver disease. Cardiac dysfunction may be masked by treatments given to cirrhotic patients, such as mineral-corticoid receptor antagonists, or by co-existing conditions, such as anaemia. New imaging tests or plasma biomarkers might be able to detect abnormal cardiac function at an early stage of its development.
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Affiliation(s)
- Pierpaolo Pellicori
- Department of Academic Cardiology, Hull and East Yorkshire Medical Research and Teaching Centre MRTDS (Daisy) Building, Entrance 2 Castle Hill Hospital, Cottingham, Kingston upon Hull, HU16 5JQ, UK,
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de Freitas Souza BS, Nascimento RC, de Oliveira SA, Vasconcelos JF, Kaneto CM, de Carvalho LFPP, Ribeiro-Dos-Santos R, Soares MBP, de Freitas LAR. Transplantation of bone marrow cells decreases tumor necrosis factor-α production and blood-brain barrier permeability and improves survival in a mouse model of acetaminophen-induced acute liver disease. Cytotherapy 2012; 14:1011-21. [PMID: 22809224 DOI: 10.3109/14653249.2012.684445] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023]
Abstract
BACKGROUND AIMS Acute liver failure (ALF), although rare, remains a rapidly progressive and frequently fatal condition. Acetaminophen (APAP) poisoning induces a massive hepatic necrosis and often leads to death as a result of cerebral edema. Cell-based therapies are currently being investigated for liver injuries. We evaluated the therapeutic potential of transplantation of bone marrow mononuclear cells (BMC) in a mouse model of acute liver injury. METHODS ALF was induced in C57Bl/6 mice submitted to an alcoholic diet followed by fasting and injection of APAP. Mice were transplanted with 10(7) BMC obtained from enhanced green fluorescent protein (GFP) transgenic mice. RESULTS BMC transplantation caused a significant reduction in APAP-induced mortality. However, no significant differences in serum aminotransferase concentrations, extension of liver necrosis, number of inflammatory cells and levels of cytokines in the liver were found when BMC- and saline-injected groups were compared. Moreover, recruitment of transplanted cells to the liver was very low and no donor-derived hepatocytes were observed. Mice submitted to BMC therapy had some protection against disruption of the blood-brain barrier, despite their hyperammonemia, and serum metalloproteinase (MMP)-9 activity similar to the saline-injected group. Tumor necrosis factor (TNF)-α concentrations were decreased in the serum of BMC-treated mice. This reduction was associated with an early increase in interleukin (IL)-10 mRNA expression in the spleen and bone marrow after BMC treatment. CONCLUSIONS BMC transplantation protects mice submitted to high doses of APAP and is a potential candidate for ALF treatment, probably via an immunomodulatory effect on TNF-α production.
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Affiliation(s)
- Bruno Solano de Freitas Souza
- Laboratório de Engenharia Tecidual e Imunofarmacologia, Centro de Pesquisas Gonçalo Moniz, Fundação Oswaldo Cruz, Salvador, BA, Brazil
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