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Jiang Q, Zhao Q, Li P. Galectin-3 in metabolic disorders: mechanisms and therapeutic potential. Trends Mol Med 2025; 31:424-437. [PMID: 39690058 DOI: 10.1016/j.molmed.2024.11.006] [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: 08/06/2024] [Revised: 11/12/2024] [Accepted: 11/13/2024] [Indexed: 12/19/2024]
Abstract
Galectin-3 (Gal3), a β-galactoside-binding lectin, is expressed predominantly in immunological and inflammatory cells. Gal3 expression is elevated in metabolic diseases, including obesity, diabetes, and metabolic dysfunction-associated steatotic liver disease (MASLD), and plays an important role in the progression of these diseases. In this review, we summarize the structure and post-translational modifications of Gal3 and the cellular functions of Gal3 according to its subcellular localization. We focused on the pathological functions and molecular mechanisms of Gal3 in various cell types. In particular, extracellular Gal3 and intracellular Gal3 may have different physiological and pathological functions. We also discuss promising Gal3 inhibitors or antibodies that are currently in clinical trials and outstanding questions and challenges for future pursuit.
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Affiliation(s)
- Qian Jiang
- State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China; Diabetes Research Center of Chinese Academy of Medical Sciences, Beijing 100050, China; CAMS Key Laboratory of Molecular Mechanism and Target Discovery of Metabolic Disorder and Tumorigenesis, Beijing 100050, China
| | - Qijin Zhao
- State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China; Diabetes Research Center of Chinese Academy of Medical Sciences, Beijing 100050, China; CAMS Key Laboratory of Molecular Mechanism and Target Discovery of Metabolic Disorder and Tumorigenesis, Beijing 100050, China
| | - Pingping Li
- State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China; Diabetes Research Center of Chinese Academy of Medical Sciences, Beijing 100050, China; CAMS Key Laboratory of Molecular Mechanism and Target Discovery of Metabolic Disorder and Tumorigenesis, Beijing 100050, China.
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Venuti MT, Roda E, Brandalise F, Sarkar M, Cappelletti M, Speciani AF, Soffientini I, Priori EC, Giammello F, Ratto D, Locatelli CA, Rossi P. A pathophysiological intersection between metabolic biomarkers and memory: a longitudinal study in the STZ-induced diabetic mouse model. Front Physiol 2025; 16:1455434. [PMID: 40144552 PMCID: PMC11937145 DOI: 10.3389/fphys.2025.1455434] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2024] [Accepted: 02/06/2025] [Indexed: 03/28/2025] Open
Abstract
Diabetes mellitus (DM) is a metabolic disorder characterized by high blood sugar levels due to insufficient insulin production or insulin resistance. Recently, metabolic biomarkers, such as glycated albumin (GA) and methylglyoxal (MGO), have been successfully employed for the management of diabetes and its complications. The main goal of this study was to investigate the relationship between metabolic parameters, related to diabetic conditions, and the recognition memory, a declarative episodic long-term memory, in a streptozotocin (STZ)-induced diabetes mouse model. The longitudinal experimental plan scheduled five experimental timepoints, starting from 9 months and lasting until 19 months of age, and included different evaluations: i) fasting serum glucose, GA, and MGO, ii) recognition memory performance; iii) histological examinations of pancreas and hippocampus. At 13 months of age, mice were randomly divided into two groups, and STZ (50 mg/kg i.p.) or vehicle was administered for 5 consecutive days. Mice were fed with a normal diet but, starting from 14 months, half of them were given water with a high sugar (HS) to explore the potential detrimental effects of HS intake to hyperglycemia. Our main outcomes are as follows: i) HS intake alone does not contribute to worsened diabetic condition/hyperglycemia; ii) GA emerges as a reliable biomarker for monitoring diabetic conditions, consistently increasing with hyperglycemia; iii) diabetic conditions correlate with a worsening of recognition memory; iv) diabetic mice display mild-to-severe insulitis and injured hippocampal cytoarchitecture, detectable in Ammon's horns regions CA1 and CA3; v) correlation among recovered normal fasting glycemic level and recognition memory, partial regaining of physiological pancreatic morphology, and hippocampal cytoarchitecture.
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Affiliation(s)
- Maria Teresa Venuti
- Department of Biology and Biotechnology “L. Spallanzani”, University of Pavia, Pavia, Italy
| | - Elisa Roda
- Laboratory of Clinical and Experimental Toxicology, Pavia Poison Centre, National Toxicology Information Centre, Toxicology Unit, Istituti Clinici Scientifici Maugeri IRCCS, Pavia, Italy
| | - Federico Brandalise
- Department of Biomedical Sciences, Div. Neuroscience and Clinical Pharmacology, University of Cagliari, Cagliari, Italy
| | - Meghma Sarkar
- Department of Biology and Biotechnology “L. Spallanzani”, University of Pavia, Pavia, Italy
| | | | | | - Irene Soffientini
- Department of Biology and Biotechnology “L. Spallanzani”, University of Pavia, Pavia, Italy
| | - Erica Cecilia Priori
- Department of Biology and Biotechnology “L. Spallanzani”, University of Pavia, Pavia, Italy
| | - Francesca Giammello
- Department of Biology and Biotechnology “L. Spallanzani”, University of Pavia, Pavia, Italy
| | - Daniela Ratto
- Department of Biology and Biotechnology “L. Spallanzani”, University of Pavia, Pavia, Italy
| | - Carlo A. Locatelli
- Laboratory of Clinical and Experimental Toxicology, Pavia Poison Centre, National Toxicology Information Centre, Toxicology Unit, Istituti Clinici Scientifici Maugeri IRCCS, Pavia, Italy
| | - Paola Rossi
- Department of Biology and Biotechnology “L. Spallanzani”, University of Pavia, Pavia, Italy
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Bahreiny SS, Ahangarpour A, Aghaei M, Mohammadpour Fard R, Jalali Far MA, Sakhavarz T. A closer look at Galectin-3: its association with gestational diabetes mellitus revealed by systematic review and meta-analysis. J Diabetes Metab Disord 2024; 23:1621-1633. [PMID: 39610475 PMCID: PMC11599495 DOI: 10.1007/s40200-024-01461-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/31/2024] [Accepted: 06/20/2024] [Indexed: 11/30/2024]
Abstract
Purpose Gestational diabetes mellitus (GDM) represents a significant metabolic disorder that affects pregnant women worldwide and has negative consequences for both the mother and her offspring. This research aims to investigate the relation between circulating levels of Galectin-3 and the incidence of GDM, and to evaluate its potential as a biomarker for monitoring and early detection of the disease. Methods A thorough search of the literature has been performed using databases such as Scopus, Web of science, Embase, Cochrane Library and PubMed. The standardized mean difference (SMD) and corresponding confidence intervals (CIs) were used to compute the effect size from individual records and pooled using the Random-effect model. Results Our meta-analysis synthesized data from 9 studies, encompassing 1,286 participants (533 GDM patients and 753 healthy pregnant controls). The findings demonstrated a considerable increase in Galectin-3 levels among individuals diagnosed with GDM as compared to the healthy control (SMD = 0.929; CI: 0.179-1.679; p = 0.015), with observed heterogeneity (I2 = 87%; p < 0.001). Subgroup analyses revealed the influence of factors such as age, BMI, study design, and sample type on Galectin-3 levels. A meta-regression analysis further identified trends indicating that levels of Galectin-3 are linked to gestational age, specific geographical areas, and sample size. Conclusion Increased levels of Galectin-3 exhibit a significant association with GDM, indicating its prospective utility as a biomarker for early detection and risk assessment. Further research is warranted to elucidate its regulation and clinical implications in GDM management. Graphical Abstract Supplementary Information The online version contains supplementary material available at 10.1007/s40200-024-01461-z.
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Affiliation(s)
- Seyed Sobhan Bahreiny
- Medicinal Plant Research Center, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
- Student Research Committee, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
- Department of Physiology, School of Medicine, Physiology Research Center, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Akram Ahangarpour
- Medicinal Plant Research Center, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
- Department of Physiology, School of Medicine, Physiology Research Center, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Mojtaba Aghaei
- Student Research Committee, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
- Thalassemia & Hemoglobinopathy Research Center, Health Research Institute, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Reza Mohammadpour Fard
- Student Research Committee, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Mohammad Ali Jalali Far
- Thalassemia & Hemoglobinopathy Research Center, Health Research Institute, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Tannaz Sakhavarz
- Department of Biochemistry, Faculty of Biological Science, Kharazmi University, Tehran, Iran
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Xia J, Wang Y, Qi BR. In vitro and in vivo effects of Galectin-3 inhibitor TD139 on inflammation and ERK/JNK/p38 pathway in gestational diabetes mellitus. Kaohsiung J Med Sci 2024; 40:916-925. [PMID: 39230472 DOI: 10.1002/kjm2.12890] [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: 06/21/2024] [Revised: 08/11/2024] [Accepted: 08/12/2024] [Indexed: 09/05/2024] Open
Abstract
This study aims to investigate the effects of the Galectin-3 (Gal-3) inhibitor TD139 on inflammation and the extracellular signal-regulated kinase (ERK)/c-Jun N-terminal kinase (JNK)/p38 pathway in gestational diabetes mellitus (GDM). Human placental tissues were treated with TD139 and TNF-α, assessing Gal-3, ERK/JNK/p38 activation, and inflammatory cytokines. GDM was induced in mice via subcutaneous injections of streptozotocin (STZ). After confirming GDM, mice were treated with 15 mg/kg TD139 on GD 10.5 12.5, 14.5, 16.5, and 18.5. Serum inflammatory cytokines were measured on GD 20.5, and post-delivery placental tissues were analyzed. Data were analyzed using one-way or two-way repeated measures ANOVA with post hoc tests. TD139 suppressed TNF-α-induced increases in Gal-3, IL-1β, IL-6, MCP-1, and ERK/JNK/p38 activation in placental tissues. In STZ-induced GDM mice, TD139 reduced glucose levels, weight loss, and food and water intake. TD139 significantly lowered TNF-α, IL-1β, IL-6, and MCP-1 in serum and placental tissues and inhibited the ERK/JNK/p38 pathway. TD139 improved pup numbers in GDM mice compared to untreated ones. TD139 reduces inflammation and inhibits the ERK/JNK/p38 pathway in TNF-α stimulated placental tissues and STZ-induced GDM mice, suggesting its therapeutic potential for managing GDM-related placental inflammation and improving pregnancy outcomes. The study used TNF-α to mimic GDM in placental tissues and an STZ-induced GDM mouse model, which may not fully represent human GDM complexity. Future research should explore alternative models, and broader signaling pathways, and thoroughly evaluate TD139's safety in pregnancy.
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Affiliation(s)
- Ji Xia
- Department of Obstetrics, Hainan Branch, Shanghai Children's Medical Center, School of Medicine, Shanghai Jiao Tong University, Sanya, China
| | - Yan Wang
- Department of Obstetrics, Hainan Branch, Shanghai Children's Medical Center, School of Medicine, Shanghai Jiao Tong University, Sanya, China
| | - Bang-Ruo Qi
- Department of Obstetrics, Hainan Branch, Shanghai Children's Medical Center, School of Medicine, Shanghai Jiao Tong University, Sanya, China
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Touceda V, Fontana Estevez F, Cacciagiú L, Finocchietto P, Bustos R, Vidal A, Berg G, Morales C, González G, Miksztowicz V. Liraglutide improves adipose tissue remodeling and mitochondrial dynamics in a visceral obesity model induced by a high-fat diet. CURRENT RESEARCH IN PHARMACOLOGY AND DRUG DISCOVERY 2024; 6:100185. [PMID: 38846009 PMCID: PMC11153889 DOI: 10.1016/j.crphar.2024.100185] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2024] [Revised: 05/17/2024] [Accepted: 05/22/2024] [Indexed: 06/09/2024] Open
Abstract
Central obesity is characterized by visceral adipose tissue (VAT) expansion, considered one of the main risk factors for metabolic complications. In recent years, new drugs have been studied for obesity treatment. Liraglutide (LGT), a GLP-1 agonist, decreases body weight, however, several mechanisms of action on VAT are still unknown. Aim to study the effect of LGT on factors associated with VAT remodeling and mitochondrial dynamics in mice fed a high-fat diet (HFD). Methods C57BL/6 mice were divided into Control (C) and HFD. After 15 weeks of feeding, each group was subdivided according to LGT administration for 5 weeks: C, C + LGT, HFD, and HFD + LGT. In epididymal AT (EAT) we evaluated histological and mitochondrial characteristics, vascularity, gelatinase activity (MMPs), and galectin-3 expression. Results HFD presented larger adipocytes (p < 0.05), and lower vascular density and MMP-9 activity (p < 0.01) than C, while a major number of smaller adipocytes (p < 0.05) and an increase in vascularity (p < 0.001) and MMP-9 activity (p < 0.01) was observed in HFD + LGT. Collagen content was higher (p < 0.05) in EAT from HFD and decreased in HFD + LGT. In C, C + LGT, and HFD + LGT, mitochondria were predominantly tubular-shaped while in HFD mitochondria were mostly spherical (p < 0.001). Conclusion LGT positively influences VAT behavior by modulating gelatinase activity, enhancing vascularization, and improving adipocyte histological characteristics. Additionally, LGT improves mitochondrial dynamics, a process that would favor VAT functionality.
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Affiliation(s)
- Vanessa Touceda
- Pontificia Universidad Católica Argentina. Facultad de Medicina, Instituto de Investigaciones Biomédicas (UCA-CONICET), Laboratorio de Patología Cardiovascular Experimental e Hipertensión Arterial, Buenos Aires, Argentina
- Universidad de Buenos Aires, Facultad de Odontología, Cátedra de Bioquímica General y Bucal, Buenos Aires, Argentina
| | - Florencia Fontana Estevez
- Pontificia Universidad Católica Argentina. Facultad de Medicina, Instituto de Investigaciones Biomédicas (UCA-CONICET), Laboratorio de Patología Cardiovascular Experimental e Hipertensión Arterial, Buenos Aires, Argentina
| | - Leonardo Cacciagiú
- Universidad de Buenos Aires, Facultad de Odontología, Cátedra de Bioquímica General y Bucal, Buenos Aires, Argentina
- Hospital General de Agudos Teodoro Álvarez, Laboratorio Central, Sección Bioquímica, Buenos Aires, Argentina
| | - Paola Finocchietto
- Universidad de Buenos Aires, Facultad de Medicina. Instituto de Inmunología, Genética y Metabolismo (INIGEM. UBA-CONICET), Laboratorio de Metabolismo del Oxígeno, Buenos Aires, Argentina
| | - Romina Bustos
- Pontificia Universidad Católica Argentina. Facultad de Medicina, Instituto de Investigaciones Biomédicas (UCA-CONICET), Laboratorio de Patología Cardiovascular Experimental e Hipertensión Arterial, Buenos Aires, Argentina
| | - Agustina Vidal
- Pontificia Universidad Católica Argentina. Facultad de Medicina, Instituto de Investigaciones Biomédicas (UCA-CONICET), Laboratorio de Patología Cardiovascular Experimental e Hipertensión Arterial, Buenos Aires, Argentina
| | - Gabriela Berg
- Universidad de Buenos Aires, Facultad de Farmacia y Bioquímica, Departamento de Bioquímica Clínica, Laboratorio de Lípidos y Aterosclerosis, Buenos Aires, Argentina
| | - Celina Morales
- Universidad de Buenos Aires, Facultad de Medicina, Departamento de Patología, Buenos Aires, Argentina
| | - Germán González
- Pontificia Universidad Católica Argentina. Facultad de Medicina, Instituto de Investigaciones Biomédicas (UCA-CONICET), Laboratorio de Patología Cardiovascular Experimental e Hipertensión Arterial, Buenos Aires, Argentina
| | - Veronica Miksztowicz
- Pontificia Universidad Católica Argentina. Facultad de Medicina, Instituto de Investigaciones Biomédicas (UCA-CONICET), Laboratorio de Patología Cardiovascular Experimental e Hipertensión Arterial, Buenos Aires, Argentina
- Universidad de Buenos Aires, Facultad de Odontología, Cátedra de Bioquímica General y Bucal, Buenos Aires, Argentina
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Jiang Q, Zhao Q, Chen Y, Ma C, Peng X, Wu X, Liu X, Wang R, Hou S, Kong L, Wan Y, Wang S, Meng ZX, Cui B, Chen L, Li P. Galectin-3 impairs calcium transients and β-cell function. Nat Commun 2024; 15:3682. [PMID: 38693121 PMCID: PMC11063191 DOI: 10.1038/s41467-024-47959-1] [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: 09/04/2023] [Accepted: 04/15/2024] [Indexed: 05/03/2024] Open
Abstract
In diabetes, macrophages and inflammation are increased in the islets, along with β-cell dysfunction. Here, we demonstrate that galectin-3 (Gal3), mainly produced and secreted by macrophages, is elevated in islets from both high-fat diet (HFD)-fed and diabetic db/db mice. Gal3 acutely reduces glucose-stimulated insulin secretion (GSIS) in β-cell lines and primary islets in mice and humans. Importantly, Gal3 binds to calcium voltage-gated channel auxiliary subunit gamma 1 (CACNG1) and inhibits calcium influx via the cytomembrane and subsequent GSIS. β-Cell CACNG1 deficiency phenocopies Gal3 treatment. Inhibition of Gal3 through either genetic or pharmacologic loss of function improves GSIS and glucose homeostasis in both HFD-fed and db/db mice. All animal findings are applicable to male mice. Here we show a role of Gal3 in pancreatic β-cell dysfunction, and Gal3 could be a therapeutic target for the treatment of type 2 diabetes.
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Grants
- the National Natural Science Foundation China (82104263 to Q.J., 81622010 to P.L., 82104259 to Q.Z., and 82304591 to Y.W.), the National Key R&D Program of China (2017YFA0205400 to P.L.), the Chinese Academy of Medical Sciences (CAMS) Central Public-Interest Scientific Institution Basal Research Fund (2017RC31009 and 2018PT35004), the CAMS Innovation Fund for Medical Sciences (2021-I2M-1-026 to Q.J. and 2021-I2M-1-016), the Beijing Outstanding Young Scientist Program (BJJWZYJH01201910023028 to P.L.), and the Special Research Fund for Central Universities, Peking Union Medical College (3332021041 to Q.Z., 3332022047 Y.W.)
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Affiliation(s)
- Qian Jiang
- State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100050, China
- Diabetes Research Center of Chinese Academy of Medical Sciences, Beijing, 100050, China
- CAMS Key Laboratory of Molecular Mechanism and Target Discovery of Metabolic Disorder and Tumorigenesis, Beijing, 100050, China
| | - Qijin Zhao
- State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100050, China
- Diabetes Research Center of Chinese Academy of Medical Sciences, Beijing, 100050, China
- CAMS Key Laboratory of Molecular Mechanism and Target Discovery of Metabolic Disorder and Tumorigenesis, Beijing, 100050, China
| | - Yibing Chen
- State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100050, China
- Diabetes Research Center of Chinese Academy of Medical Sciences, Beijing, 100050, China
- CAMS Key Laboratory of Molecular Mechanism and Target Discovery of Metabolic Disorder and Tumorigenesis, Beijing, 100050, China
| | - Chunxiao Ma
- State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100050, China
- Diabetes Research Center of Chinese Academy of Medical Sciences, Beijing, 100050, China
- CAMS Key Laboratory of Molecular Mechanism and Target Discovery of Metabolic Disorder and Tumorigenesis, Beijing, 100050, China
| | - Xiaohong Peng
- College of Future Technology, Institute of Molecular Medicine, National Biomedical Imaging Center, Peking University, Beijing, 100871, China
- Beijing Key Laboratory of Cardiometabolic Molecular Medicine, Peking University, Beijing, 100871, China
| | - Xi Wu
- State Key Laboratory of Membrane Biology, College of Future Technology, Institute of Molecular Medicine, Peking University, Beijing, 100871, China
- Peking-Tsinghua Center for Life Sciences, Peking University, Beijing, 100871, China
| | - Xingfeng Liu
- State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100050, China
- Diabetes Research Center of Chinese Academy of Medical Sciences, Beijing, 100050, China
- CAMS Key Laboratory of Molecular Mechanism and Target Discovery of Metabolic Disorder and Tumorigenesis, Beijing, 100050, China
| | - Ruoran Wang
- School of Basic Medical Sciences, Zhejiang University, Hangzhou, Zhejiang, China
| | - Shaocong Hou
- State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100050, China
- Diabetes Research Center of Chinese Academy of Medical Sciences, Beijing, 100050, China
- CAMS Key Laboratory of Molecular Mechanism and Target Discovery of Metabolic Disorder and Tumorigenesis, Beijing, 100050, China
| | - Lijuan Kong
- State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100050, China
- Diabetes Research Center of Chinese Academy of Medical Sciences, Beijing, 100050, China
- CAMS Key Laboratory of Molecular Mechanism and Target Discovery of Metabolic Disorder and Tumorigenesis, Beijing, 100050, China
| | - Yanjun Wan
- State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100050, China
- Diabetes Research Center of Chinese Academy of Medical Sciences, Beijing, 100050, China
- CAMS Key Laboratory of Molecular Mechanism and Target Discovery of Metabolic Disorder and Tumorigenesis, Beijing, 100050, China
| | - Shusen Wang
- Organ Transplant Center, Tianjin First Central Hospital, Nankai University, Tianjin, 300192, China
| | - Zhuo-Xian Meng
- School of Basic Medical Sciences, Zhejiang University, Hangzhou, Zhejiang, China
| | - Bing Cui
- State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100050, China
- Diabetes Research Center of Chinese Academy of Medical Sciences, Beijing, 100050, China
- CAMS Key Laboratory of Molecular Mechanism and Target Discovery of Metabolic Disorder and Tumorigenesis, Beijing, 100050, China
| | - Liangyi Chen
- College of Future Technology, Institute of Molecular Medicine, National Biomedical Imaging Center, Peking University, Beijing, 100871, China
- Beijing Key Laboratory of Cardiometabolic Molecular Medicine, Peking University, Beijing, 100871, China
- Peking-Tsinghua Center for Life Sciences, Peking University, Beijing, 100871, China
| | - Pingping Li
- State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100050, China.
- Diabetes Research Center of Chinese Academy of Medical Sciences, Beijing, 100050, China.
- CAMS Key Laboratory of Molecular Mechanism and Target Discovery of Metabolic Disorder and Tumorigenesis, Beijing, 100050, China.
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Iacobini C, Vitale M, Haxhi J, Menini S, Pugliese G. Impaired Remodeling of White Adipose Tissue in Obesity and Aging: From Defective Adipogenesis to Adipose Organ Dysfunction. Cells 2024; 13:763. [PMID: 38727299 PMCID: PMC11083890 DOI: 10.3390/cells13090763] [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: 04/02/2024] [Revised: 04/22/2024] [Accepted: 04/25/2024] [Indexed: 05/13/2024] Open
Abstract
The adipose organ adapts and responds to internal and environmental stimuli by remodeling both its cellular and extracellular components. Under conditions of energy surplus, the subcutaneous white adipose tissue (WAT) is capable of expanding through the enlargement of existing adipocytes (hypertrophy), followed by de novo adipogenesis (hyperplasia), which is impaired in hypertrophic obesity. However, an impaired hyperplastic response may result from various defects in adipogenesis, leading to different WAT features and metabolic consequences, as discussed here by reviewing the results of the studies in animal models with either overexpression or knockdown of the main molecular regulators of the two steps of the adipogenesis process. Moreover, impaired WAT remodeling with aging has been associated with various age-related conditions and reduced lifespan expectancy. Here, we delve into the latest advancements in comprehending the molecular and cellular processes underlying age-related changes in WAT function, their involvement in common aging pathologies, and their potential as therapeutic targets to influence both the health of elderly people and longevity. Overall, this review aims to encourage research on the mechanisms of WAT maladaptation common to conditions of both excessive and insufficient fat tissue. The goal is to devise adipocyte-targeted therapies that are effective against both obesity- and age-related disorders.
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Echouffo‐Tcheugui JB, Zhang S, Florido R, Pankow JS, Michos ED, Goldberg RB, Nambi V, Gerstenblith G, Post WS, Blumenthal RS, Ballantyne CM, Coresh J, Selvin E, Ndumele CE. Galectin-3, Metabolic Risk, and Incident Heart Failure: The ARIC Study. J Am Heart Assoc 2024; 13:e031607. [PMID: 38471823 PMCID: PMC11010020 DOI: 10.1161/jaha.123.031607] [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: 07/21/2023] [Accepted: 01/11/2024] [Indexed: 03/14/2024]
Abstract
BACKGROUND It is unclear how metabolic syndrome (MetS) and diabetes affect Gal-3 (galectin 3) levels and the resulting implications for heart failure (HF) risk. We assessed relationships of MetS and diabetes with Gal-3, and their joint associations with incident HF. METHODS AND RESULTS We included 8445 participants without HF (mean age, 63 years; 59% men; 16% Black race) at ARIC (Atherosclerosis Risk in Communities) study visit 4 (1996-1999). We categorized participants as having MetS only, MetS with diabetes, or neither, and by quartiles of MetS severity Z score. We assessed cross-sectional associations of metabolic risk categories with high Gal-3 level (≥75th percentile) using logistic regression. We used Cox regression to evaluate combined associations of metabolic risk categories and Gal-3 quartiles with HF. In cross-sectional analyses, compared with no MetS and no diabetes, MetS only (odds ratio [OR], 1.24 [95% CI, 1.10-1.41]) and MetS with diabetes (OR, 1.59 [95% CI, 1.32-1.92]) were associated with elevated Gal-3. Over a median follow-up of 20.5 years, there were 1749 HF events. Compared with individuals with neither diabetes nor MetS and with Gal-3 in the lowest quartile, the combination of MetS with diabetes and Gal-3 ≥75th percentile was associated with a 4-fold higher HF risk (hazard ratio, 4.35 [95% CI, 3.30-5.73]). Gal-3 provided HF prognostic information above and beyond MetS, NT-proBNP (N-terminal pro-B-type natriuretic peptide), high-sensitivity cardiac troponin T, and CRP (C-reactive protein) (ΔC statistic for models with versus without Gal-3: 0.003; P=0.004). CONCLUSIONS MetS and diabetes are associated with elevated Gal-3. The HF risk significantly increased with the combination of greater metabolic risk and higher Gal-3.
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Affiliation(s)
- Justin B. Echouffo‐Tcheugui
- Division of Endocrinology, Diabetes and Metabolism, Department of MedicineJohns Hopkins UniversityBaltimoreMD
| | - Sui Zhang
- Department of Epidemiology and Welch Center for Prevention, Epidemiology, and Clinical ResearchJohns Hopkins Bloomberg School of Public HealthBaltimoreMDUnited States
| | - Roberta Florido
- Division of Cardiology, Department of MedicineJohns Hopkins University School of MedicineBaltimoreMD
| | - James S. Pankow
- Department of Epidemiology at the University of MinnesotaMinneapolisMN
| | - Erin D. Michos
- Division of Cardiology, Department of MedicineJohns Hopkins University School of MedicineBaltimoreMD
| | - Ronald B. Goldberg
- Division of Endocrinology, Diabetes and Metabolism, Department of MedicineUniversity of MiamiMiamiFL
| | - Vijay Nambi
- Section of Cardiovascular ResearchBaylor College of Medicine and Houston Methodist DeBakey Heart and Vascular CenterHoustonTX
| | - Gary Gerstenblith
- Division of Cardiology, Department of MedicineJohns Hopkins University School of MedicineBaltimoreMD
| | - Wendy S. Post
- Division of Cardiology, Department of MedicineJohns Hopkins University School of MedicineBaltimoreMD
| | - Roger S. Blumenthal
- Division of Cardiology, Department of MedicineJohns Hopkins University School of MedicineBaltimoreMD
| | - Christie M. Ballantyne
- Section of Cardiovascular ResearchBaylor College of Medicine and Houston Methodist DeBakey Heart and Vascular CenterHoustonTX
| | - Josef Coresh
- Department of Epidemiology and Welch Center for Prevention, Epidemiology, and Clinical ResearchJohns Hopkins Bloomberg School of Public HealthBaltimoreMDUnited States
| | - Elizabeth Selvin
- Department of Epidemiology and Welch Center for Prevention, Epidemiology, and Clinical ResearchJohns Hopkins Bloomberg School of Public HealthBaltimoreMDUnited States
| | - Chiadi E. Ndumele
- Division of Cardiology, Department of MedicineJohns Hopkins University School of MedicineBaltimoreMD
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9
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Shah R, Zhong J, Massier L, Tanriverdi K, Hwang SJ, Haessler J, Nayor M, Zhao S, Perry AS, Wilkins JT, Shadyab AH, Manson JE, Martin L, Levy D, Kooperberg C, Freedman JE, Rydén M, Murthy VL. Targeted Proteomics Reveals Functional Targets for Early Diabetes Susceptibility in Young Adults. CIRCULATION. GENOMIC AND PRECISION MEDICINE 2024; 17:e004192. [PMID: 38323454 PMCID: PMC10940209 DOI: 10.1161/circgen.123.004192] [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: 04/19/2023] [Accepted: 11/05/2023] [Indexed: 02/08/2024]
Abstract
BACKGROUND The circulating proteome may encode early pathways of diabetes susceptibility in young adults for surveillance and intervention. Here, we define proteomic correlates of tissue phenotypes and diabetes in young adults. METHODS We used penalized models and principal components analysis to generate parsimonious proteomic signatures of diabetes susceptibility based on phenotypes and on diabetes diagnosis across 184 proteins in >2000 young adults in the CARDIA (Coronary Artery Risk Development in Young Adults study; mean age, 32 years; 44% women; 43% Black; mean body mass index, 25.6±4.9 kg/m2), with validation against diabetes in >1800 individuals in the FHS (Framingham Heart Study) and WHI (Women's Health Initiative). RESULTS In 184 proteins in >2000 young adults in CARDIA, we identified 2 proteotypes of diabetes susceptibility-a proinflammatory fat proteotype (visceral fat, liver fat, inflammatory biomarkers) and a muscularity proteotype (muscle mass), linked to diabetes in CARDIA and WHI/FHS. These proteotypes specified broad mechanisms of early diabetes pathogenesis, including transorgan communication, hepatic and skeletal muscle stress responses, vascular inflammation and hemostasis, fibrosis, and renal injury. Using human adipose tissue single cell/nuclear RNA-seq, we demonstrate expression at transcriptional level for implicated proteins across adipocytes and nonadipocyte cell types (eg, fibroadipogenic precursors, immune and vascular cells). Using functional assays in human adipose tissue, we demonstrate the association of expression of genes encoding these implicated proteins with adipose tissue metabolism, inflammation, and insulin resistance. CONCLUSIONS A multifaceted discovery effort uniting proteomics, underlying clinical susceptibility phenotypes, and tissue expression patterns may uncover potentially novel functional biomarkers of early diabetes susceptibility in young adults for future mechanistic evaluation.
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Affiliation(s)
- Ravi Shah
- Vanderbilt Translational & Clinical Cardiovascular Research Center, Vanderbilt Univ, Nashville, TN
| | - Jiawei Zhong
- Dept of Medicine (H7), Karolinska Institutet, Stockholm, Sweden
| | - Lucas Massier
- Dept of Medicine (H7), Karolinska Institutet, Stockholm, Sweden
| | - Kahraman Tanriverdi
- Vanderbilt Translational & Clinical Cardiovascular Research Center, Vanderbilt Univ, Nashville, TN
| | - Shih-Jen Hwang
- Population Sciences Branch, Division of Intramural Research, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD
| | | | - Matthew Nayor
- Sections of Preventive Medicine & Epidemiology & Cardiovascular Medicine, Dept of Medicine, Dept of Epidemiology, Boston University Schools of Medicine & Public Health, Boston, MA & Framingham Heart Study, Framingham, MA
| | | | - Andrew S. Perry
- Vanderbilt Translational & Clinical Cardiovascular Research Center, Vanderbilt Univ, Nashville, TN
| | | | - Aladdin H. Shadyab
- Herbert Wertheim School of Public Health & Human Longevity Science, Univ of California, San Diego, La Jolla, CA
| | - JoAnn E. Manson
- Dept of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA
| | - Lisa Martin
- George Washington Univ School of Medicine & Health Sciences
| | - Daniel Levy
- Population Sciences Branch, Division of Intramural Research, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD
| | | | - Jane E. Freedman
- Vanderbilt Translational & Clinical Cardiovascular Research Center, Vanderbilt Univ, Nashville, TN
| | - Mikael Rydén
- Dept of Medicine (H7), Karolinska Institutet, Stockholm, Sweden
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10
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Lee J, An HS, Shin HJ, Jang HM, Im CO, Jeong Y, Eum K, Yoon S, Lee SJ, Jeong EA, Kim KE, Roh GS. Intermittent Fasting Reduces Neuroinflammation and Cognitive Impairment in High-Fat Diet-Fed Mice by Downregulating Lipocalin-2 and Galectin-3. Nutrients 2024; 16:159. [PMID: 38201988 PMCID: PMC10780385 DOI: 10.3390/nu16010159] [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: 11/08/2023] [Revised: 12/27/2023] [Accepted: 01/02/2024] [Indexed: 01/12/2024] Open
Abstract
Intermittent fasting (IF), an alternating pattern of dietary restriction, reduces obesity-induced insulin resistance and inflammation. However, the crosstalk between adipose tissue and the hippocampus in diabetic encephalopathy is not fully understood. Here, we investigated the protective effects of IF against neuroinflammation and cognitive impairment in high-fat diet(HFD)-fed mice. Histological analysis revealed that IF reduced crown-like structures and adipocyte apoptosis in the adipose tissue of HFD mice. In addition to circulating lipocalin-2 (LCN2) and galectin-3 (GAL3) levels, IF reduced HFD-induced increases in LCN2- and GAL3-positive macrophages in adipose tissue. IF also improved HFD-induced memory deficits by inhibiting blood-brain barrier breakdown and neuroinflammation. Furthermore, immunofluorescence showed that IF reduced HFD-induced astrocytic LCN2 and microglial GAL3 protein expression in the hippocampus of HFD mice. These findings indicate that HFD-induced adipocyte apoptosis and macrophage infiltration may play a critical role in glial activation and that IF reduces neuroinflammation and cognitive impairment by protecting against blood-brain barrier leakage.
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Affiliation(s)
- Jaewoong Lee
- Department of Anatomy and Convergence Medical Science, College of Medicine, Institute of Medical Science, Gyeongsang National University, Jinju 52727, Republic of Korea; (J.L.); (H.S.A.); (H.J.S.); (H.M.J.); (S.J.L.); (E.A.J.); (K.E.K.)
| | - Hyeong Seok An
- Department of Anatomy and Convergence Medical Science, College of Medicine, Institute of Medical Science, Gyeongsang National University, Jinju 52727, Republic of Korea; (J.L.); (H.S.A.); (H.J.S.); (H.M.J.); (S.J.L.); (E.A.J.); (K.E.K.)
| | - Hyun Joo Shin
- Department of Anatomy and Convergence Medical Science, College of Medicine, Institute of Medical Science, Gyeongsang National University, Jinju 52727, Republic of Korea; (J.L.); (H.S.A.); (H.J.S.); (H.M.J.); (S.J.L.); (E.A.J.); (K.E.K.)
| | - Hye Min Jang
- Department of Anatomy and Convergence Medical Science, College of Medicine, Institute of Medical Science, Gyeongsang National University, Jinju 52727, Republic of Korea; (J.L.); (H.S.A.); (H.J.S.); (H.M.J.); (S.J.L.); (E.A.J.); (K.E.K.)
| | - Chae Oh Im
- Department of Medicine, College of Medicine, Gyeongsang National University, Jinju 52727, Republic of Korea; (C.O.I.); (Y.J.); (K.E.); (S.Y.)
| | - Yeonjun Jeong
- Department of Medicine, College of Medicine, Gyeongsang National University, Jinju 52727, Republic of Korea; (C.O.I.); (Y.J.); (K.E.); (S.Y.)
| | - Kibaek Eum
- Department of Medicine, College of Medicine, Gyeongsang National University, Jinju 52727, Republic of Korea; (C.O.I.); (Y.J.); (K.E.); (S.Y.)
| | - Sejeong Yoon
- Department of Medicine, College of Medicine, Gyeongsang National University, Jinju 52727, Republic of Korea; (C.O.I.); (Y.J.); (K.E.); (S.Y.)
| | - So Jeong Lee
- Department of Anatomy and Convergence Medical Science, College of Medicine, Institute of Medical Science, Gyeongsang National University, Jinju 52727, Republic of Korea; (J.L.); (H.S.A.); (H.J.S.); (H.M.J.); (S.J.L.); (E.A.J.); (K.E.K.)
| | - Eun Ae Jeong
- Department of Anatomy and Convergence Medical Science, College of Medicine, Institute of Medical Science, Gyeongsang National University, Jinju 52727, Republic of Korea; (J.L.); (H.S.A.); (H.J.S.); (H.M.J.); (S.J.L.); (E.A.J.); (K.E.K.)
| | - Kyung Eun Kim
- Department of Anatomy and Convergence Medical Science, College of Medicine, Institute of Medical Science, Gyeongsang National University, Jinju 52727, Republic of Korea; (J.L.); (H.S.A.); (H.J.S.); (H.M.J.); (S.J.L.); (E.A.J.); (K.E.K.)
| | - Gu Seob Roh
- Department of Anatomy and Convergence Medical Science, College of Medicine, Institute of Medical Science, Gyeongsang National University, Jinju 52727, Republic of Korea; (J.L.); (H.S.A.); (H.J.S.); (H.M.J.); (S.J.L.); (E.A.J.); (K.E.K.)
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11
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Patel NA, Lui A, Trujillo AN, Motawe ZY, Bader D, Schuster J, Burgess A, Alves NG, Jo M, Breslin JW. Female and male obese Zucker rats display differential inflammatory mediator and long non-coding RNA profiles. Life Sci 2023; 335:122285. [PMID: 37995934 PMCID: PMC10760426 DOI: 10.1016/j.lfs.2023.122285] [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: 07/31/2023] [Revised: 11/08/2023] [Accepted: 11/20/2023] [Indexed: 11/25/2023]
Abstract
AIMS The goal of this study was to identify mediators in peri-lymphatic adipose tissue (PLAT) that are altered in obese versus lean Zucker rats, with focus on potential sex differences MAIN METHODS: Mesenteric PLAT was analyzed with protein and lncRNA arrays. Additional RT-PCR confirmation was performed with epididymal/ovarian fat. KEY FINDINGS MCP-1, TCK-1, Galectin-1, Galectin-3, and neuropilin-1 were elevated in PLAT from obese rats of both sexes. However, 11 additional proteins were elevated only in obese males while 24 different proteins were elevated in obese females. Profiling of lncRNAs revealed lean males have elevated levels of NEAT1, MALAT1 and GAS5 compared to lean females. NEAT1, MALAT1, and GAS5 were significantly reduced with obesity in males but not in females. Another lncRNA, HOTAIR, was higher in lean females compared to males, and its levels in females were reduced with obesity. Obese rats of both sexes had similar histologic findings of mesenteric macrophage crown-like structures and hepatocyte fat accumulation. SIGNIFICANCE While obese male and female Zucker rats both have increased inflammation, they have distinct signals. Future studies of the proteome and lncRNA landscape of obese males vs. females in various animal models and in human subjects are warranted to better guide development of therapeutics for obesity-induced inflammation.
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Affiliation(s)
- Niketa A Patel
- Department of Molecular Medicine, Morsani College of Medicine, University of South Florida, United States of America; James A. Haley Veteran's Hospital, United States of America
| | - Ashley Lui
- Department of Molecular Medicine, Morsani College of Medicine, University of South Florida, United States of America; James A. Haley Veteran's Hospital, United States of America
| | - Andrea N Trujillo
- Department of Molecular Pharmacology and Physiology, Morsani College of Medicine, University of South Florida, United States of America
| | - Zeinab Y Motawe
- Department of Molecular Pharmacology and Physiology, Morsani College of Medicine, University of South Florida, United States of America
| | - Deena Bader
- James A. Haley Veteran's Hospital, United States of America
| | - Jane Schuster
- Department of Molecular Pharmacology and Physiology, Morsani College of Medicine, University of South Florida, United States of America
| | - Andrea Burgess
- Department of Molecular Pharmacology and Physiology, Morsani College of Medicine, University of South Florida, United States of America
| | - Natascha G Alves
- Department of Molecular Pharmacology and Physiology, Morsani College of Medicine, University of South Florida, United States of America
| | - Michiko Jo
- Department of Molecular Pharmacology and Physiology, Morsani College of Medicine, University of South Florida, United States of America; Division of Presymptomatic Disease, Institute of Natural Medicine, University of Toyama, Japan
| | - Jerome W Breslin
- Department of Molecular Pharmacology and Physiology, Morsani College of Medicine, University of South Florida, United States of America.
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12
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Khalaji A, Amirkhani N, Sharifkashani S, Behnoush AH. Role of galectin-3 as a biomarker in obstructive sleep apnea: a systematic review and meta-analysis. Sleep Breath 2023; 27:2273-2282. [PMID: 37129844 DOI: 10.1007/s11325-023-02842-z] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2022] [Revised: 04/17/2023] [Accepted: 04/24/2023] [Indexed: 05/03/2023]
Abstract
BACKGROUND Because obstructive sleep apnea (OSA) is a prevalent condition, biomarkers for OSA would be very useful. Galectin-3 has gained attention as a marker for several diseases. The aim of this study was to investigate the association between circulating galectin-3 levels and OSA. METHODS PubMed, Scopus, Embase, and Web of Science were explored to find the studies evaluating galectin-3 in OSA and controls, within different severities of OSA, or before and after continuous positive airway pressure (CPAP) treatment in cases with OSA. We used random-effect meta-analysis to calculate standardized mean differences (SMD) along with 95% confidence intervals (CI). Newcastle-Ottawa Scale was used assessment of the risk of bias in studies. RESULTS An initial search resulted in 289 results. After exclusion of duplicate studies, screening of titles/abstracts and assessments of full texts, six studies were included comprised of 987 cases with a mean age of 54.4 years. Meta-analysis showed that there were significantly higher galectin-3 circulating levels in patients with OSA than in healthy controls (SMD 0.80, 95% CI 0.30 to 1.31, p value < 0.01). Severe OSA was related to higher levels of galectin-3, in comparison to non-severe OSA (SMD 0.76, 95% CI 0.29 to 1.22, p value < 0.01). CPAP therapy also significantly reduced galectin-3 peripheral levels in patients with OSA (SMD - 3.55, 95% CI - 6.90 to - 0.20, p value = 0.04). CONCLUSION The findings suggest that Galectin-3 may have potential utility as a biomarker in patients with OSA. Further research is needed to demonstrate its role in pathophysiology, as well as its possible use in diagnosis and prognosis.
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Affiliation(s)
- Amirmohammad Khalaji
- School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
- Non-Communicable Diseases Research Center, Endocrinology and Metabolism Population Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Nikan Amirkhani
- School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | | | - Amir Hossein Behnoush
- School of Medicine, Tehran University of Medical Sciences, Tehran, Iran.
- Non-Communicable Diseases Research Center, Endocrinology and Metabolism Population Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran.
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13
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Kim KE, Shin HJ, Ju Y, Jung Y, An HS, Lee SJ, Jeong EA, Lee J, Hwang GS, Roh GS. Intermittent Fasting Attenuates Metabolic-Dysfunction-Associated Steatohepatitis by Enhancing the Hepatic Autophagy-Lysosome Pathway. Nutrients 2023; 15:4574. [PMID: 37960230 PMCID: PMC10649202 DOI: 10.3390/nu15214574] [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: 10/13/2023] [Revised: 10/25/2023] [Accepted: 10/26/2023] [Indexed: 11/15/2023] Open
Abstract
An intermittent fasting (IF) regimen has been shown to protect against metabolic dysfunction-associated steatohepatitis (MASH). However, the precise mechanism remains unclear. Here, we explored how IF reduced hepatic lipid accumulation, inflammation, and fibrosis in mice with MASH. The mice were fed a high-fat diet (HFD) for 30 weeks and either continued on the HFD or were subjected to IF for the final 22 weeks. IF reduced body weight, insulin resistance, and hepatic lipid accumulation in HFD-fed mice. Lipidome analysis revealed that IF modified HFD-induced hepatic lipid composition. In particular, HFD-induced impaired autophagic flux was reversed by IF. The decreased hepatic lysosome-associated membrane protein 1 level in HFD-fed mice was upregulated in HFD+IF-fed mice. However, increased hepatic lysosomal acid lipase protein levels in HFD-fed mice were reduced by IF. IF attenuated HFD-induced hepatic inflammation and galectin-3-positive Kupffer cells. In addition to the increases in hepatic hydroxyproline and lumican levels, lipocalin-2-mediated signaling was reversed in HFD-fed mice by IF. Taken together, our findings indicate that the enhancement of the autophagy-lysosomal pathway may be a critical mechanism of MASH reduction by IF.
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Affiliation(s)
- Kyung Eun Kim
- Department of Anatomy and Convergence Medical Science, College of Medicine, Institute of Medical Science, Gyeongsang National University, Jinju 52727, Republic of Korea; (K.E.K.); (H.J.S.); (H.S.A.); (S.J.L.); (E.A.J.); (J.L.)
| | - Hyun Joo Shin
- Department of Anatomy and Convergence Medical Science, College of Medicine, Institute of Medical Science, Gyeongsang National University, Jinju 52727, Republic of Korea; (K.E.K.); (H.J.S.); (H.S.A.); (S.J.L.); (E.A.J.); (J.L.)
| | - Yeajin Ju
- Integrated Metabolomics Research Group, Western Seoul Center, Korea Basic Science Institute, Seoul 03759, Republic of Korea; (Y.J.); (Y.J.)
| | - Youngae Jung
- Integrated Metabolomics Research Group, Western Seoul Center, Korea Basic Science Institute, Seoul 03759, Republic of Korea; (Y.J.); (Y.J.)
| | - Hyeong Seok An
- Department of Anatomy and Convergence Medical Science, College of Medicine, Institute of Medical Science, Gyeongsang National University, Jinju 52727, Republic of Korea; (K.E.K.); (H.J.S.); (H.S.A.); (S.J.L.); (E.A.J.); (J.L.)
| | - So Jeong Lee
- Department of Anatomy and Convergence Medical Science, College of Medicine, Institute of Medical Science, Gyeongsang National University, Jinju 52727, Republic of Korea; (K.E.K.); (H.J.S.); (H.S.A.); (S.J.L.); (E.A.J.); (J.L.)
| | - Eun Ae Jeong
- Department of Anatomy and Convergence Medical Science, College of Medicine, Institute of Medical Science, Gyeongsang National University, Jinju 52727, Republic of Korea; (K.E.K.); (H.J.S.); (H.S.A.); (S.J.L.); (E.A.J.); (J.L.)
| | - Jaewoong Lee
- Department of Anatomy and Convergence Medical Science, College of Medicine, Institute of Medical Science, Gyeongsang National University, Jinju 52727, Republic of Korea; (K.E.K.); (H.J.S.); (H.S.A.); (S.J.L.); (E.A.J.); (J.L.)
| | - Geum-Sook Hwang
- Integrated Metabolomics Research Group, Western Seoul Center, Korea Basic Science Institute, Seoul 03759, Republic of Korea; (Y.J.); (Y.J.)
- College of Pharmacy, Chung-Ang University, Seoul 06974, Republic of Korea
| | - Gu Seob Roh
- Department of Anatomy and Convergence Medical Science, College of Medicine, Institute of Medical Science, Gyeongsang National University, Jinju 52727, Republic of Korea; (K.E.K.); (H.J.S.); (H.S.A.); (S.J.L.); (E.A.J.); (J.L.)
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14
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Deng Y, Jin H, Ning J, Cui D, Zhang M, Yang H. Elevated galectin-3 levels detected in women with hyperglycemia during early and mid-pregnancy antagonizes high glucose - induced trophoblast cells apoptosis via galectin-3/foxc1 pathway. Mol Med 2023; 29:115. [PMID: 37626284 PMCID: PMC10463409 DOI: 10.1186/s10020-023-00707-5] [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: 04/05/2023] [Accepted: 07/26/2023] [Indexed: 08/27/2023] Open
Abstract
OBJECTIVE This study was to evaluate plasma galectin-3 levels from early pregnancy to delivery and explore the effects of galectin-3 on the function of trophoblast cells under high glucose exposure. METHODS The plasma galectin-3 levels were quantified by enzyme-linked immunosorbent assay (ELISA) in the China National Birth Cohort (CNBC) at Peking University First Hospital, and the underlying signaling pathway was identified by protein-protein interaction (PPI) analysis, gene set enrichment analysis (GSEA), quantitative PCR (qPCR), western blotting, small interfering RNA (siRNA) transfections, and flow cytometry. RESULTS Significantly higher galectin-3 levels were found in patients with gestational diabetes mellitus (GDM group; n = 77) during the first and second trimesters than that in healthy pregnant women (HP group; n = 113) (P < 0.05). No significant differences in plasma galectin-3 levels were detected between GDM and HP groups in maternal third-trimester blood and cord blood. PPI analysis suggested potential interactions between galectin-3 and foxc1. The findings of GSEA showed that galectin-3 was involved in the cytochrome P450-related and complement-related pathways, and foxc1 was associated with type I diabetes mellitus. Additionally, high glucose (25 mM) significantly increased the expression levels of galectin-3 and foxc1 and induced apoptosis in HTR-8/SVneo cells. Further in vitro experiments showed that galectin-3/foxc1 pathway could protect HTR-8/SVneo cells against high glucose - induced apoptosis. CONCLUSION Future studies were required to validate whether plasma galectin-3 might become a potential biomarker for hyperglycemia during pregnancy. Elevated galectin-3 levels might be a vital protective mechanism among those exposed to hyperglycemia during pregnancy.
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Affiliation(s)
- Yu Deng
- Department of Obstetrics and Gynecology, Peking University First Hospital, No. 8 Xishiku Street, Beijing, 100034, China
- Beijing Key Laboratory of Maternal Fetal Medicine of Gestational Diabetes Mellitus, Beijing, 100034, China
| | - Hongyan Jin
- Department of Obstetrics and Gynecology, Peking University First Hospital, No. 8 Xishiku Street, Beijing, 100034, China
| | - Jie Ning
- Department of Obstetrics and Gynecology, Peking University First Hospital, No. 8 Xishiku Street, Beijing, 100034, China
- Beijing Key Laboratory of Maternal Fetal Medicine of Gestational Diabetes Mellitus, Beijing, 100034, China
| | - Dong Cui
- Department of Obstetrics and Gynecology, Peking University First Hospital, No. 8 Xishiku Street, Beijing, 100034, China
- Beijing Key Laboratory of Maternal Fetal Medicine of Gestational Diabetes Mellitus, Beijing, 100034, China
| | - Muqiu Zhang
- Department of Obstetrics and Gynecology, Peking University First Hospital, No. 8 Xishiku Street, Beijing, 100034, China
- Beijing Key Laboratory of Maternal Fetal Medicine of Gestational Diabetes Mellitus, Beijing, 100034, China
| | - Huixia Yang
- Department of Obstetrics and Gynecology, Peking University First Hospital, No. 8 Xishiku Street, Beijing, 100034, China.
- Beijing Key Laboratory of Maternal Fetal Medicine of Gestational Diabetes Mellitus, Beijing, 100034, China.
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15
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Involvement of Galectin-3 in neurocognitive impairment in obstructive sleep apnea via regulating inflammation and oxidative stress through NLRP3. Sleep Med 2023; 101:1-10. [PMID: 36332381 DOI: 10.1016/j.sleep.2022.09.018] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/15/2022] [Revised: 09/08/2022] [Accepted: 09/19/2022] [Indexed: 01/11/2023]
Abstract
OBJECTIVE Accumulated studies have revealed that oxidative stress and inflammation play important roles in the development of OSA related cognitive dysfunction. Galectin-3, a member of the galectin family, has been reported to be involved in the neuroinflammatory diseases. However, the relationship between Galectin-3 and cognitive impairment in OSA remains ambiguous. MATERIALS AND METHODS 47 new diagnosed OSA patients and 18 age-, gender-, education- and body mass index-matched healthy control subjects were enrolled in the present study. All subjects underwent whole-night in-laboratory polysomnography (PSG). Montreal Cognitive Assessment (MoCA) was used to evaluated the cognitive function of OSA patients. Serum Galectin-3, interleukin (IL)-1β and IL-8 were examined by enzyme-linked immunosorbent assay (ELISA). The levels of malonaldehyde (MDA), superoxide dismutase (SOD) and catalase (CAT) were measured to evaluate oxidative stress. Protein level of Galectin-3 and NLRP3 in peripheral blood mononuclear cells (PBMCs) and human microglial clone 3 (HMC3) cells were measured by Western Blot. RESULTS Serum Galectin-3 level in severe OSA patients (2.31 ± 0.43 ng/m) was higher than those in mild-moderate OSA patients (1.87 ± 0.32 ng/m, p < 0.001) and those in the healthy controls (1.56 ± 0.22 ng/ml, p < 0.001). Similarly, Galectin-3 level in PBMCs was increased with disease severity (p < 0.01). In addition, OSA patients also showed higher levels of inflammation and oxidative stress (p < 0.01). Patients with OSA scored significantly lower than healthy controls on the MoCA test after controlling for age, gender, education, and BMI. CPAP treatment for 12 weeks effectively reduced the levels of Galectin-3, inflammation and oxidative stress, as well as improved cognitive function of severe OSA patients. Closed correlations were observed between Galectin-3 with sleep respiratory parameters and cognitive dysfunction. In addition, we explored the underlying mechanism of Galectin-3 in neuroinflammation and oxidative stress. We treated HMC3 cells with LPS to mimic neuroinflammatory response in vitro. The results showed that LPS treatment led to a dose-dependent increase in Galectin-3 expression, meanwhile induced inflammation and oxidative stress. Inhibiting Galectin-3 with a specific Galectin-3 inhibitor, TD139, significantly ameliorated LPS-induced neuroinflammation and oxidative stress via suppressing NLRP3. CONCLUSION Current findings suggest that increased Galectin-3 might be involved in the cognitive impairment of OSA patients by promoting neuroinflammation and oxidative stress via regulating NLRP3. These results suggested that Galectin-3 inhibition may exert a protective role against the neurocognitive dysfunction associated with OSA.
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16
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Intracellular galectin-3 is a lipopolysaccharide sensor that promotes glycolysis through mTORC1 activation. Nat Commun 2022; 13:7578. [PMID: 36481721 PMCID: PMC9732310 DOI: 10.1038/s41467-022-35334-x] [Citation(s) in RCA: 29] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2022] [Accepted: 11/29/2022] [Indexed: 12/13/2022] Open
Abstract
How the carbohydrate binding protein galectin-3 might act as a diabetogenic and tumorogenic factor remains to be investigated. Here we report that intracellular galectin-3 interacts with Rag GTPases and Ragulator on lysosomes. We show that galectin-3 senses lipopolysaccharide (LPS) to facilitate the interaction of Rag GTPases and Ragulator, leading to the activation of mTORC1. We find that the lipopolysaccharide/galectin-3-Rag GTPases/Ragulator-mTORC1 axis regulates a cohort of genes including GLUT1, and HK2, and PKM2 that are critically involved in glucose uptake and glycolysis. Indeed, galectin-3 deficiency severely compromises LPS-promoted glycolysis. Importantly, the expression of HK2 is significantly reduced in diabetes patients. In multiple types of cancer including hepatocellular carcinoma (HCC), galectin-3 is highly expressed, and its level of expression is positively correlated with that of HK2 and PKM2 and negatively correlated with the prognosis of HCC patients. Our study unravels that galectin-3 is a sensor of LPS, an important modulator of the mTORC1 signaling, and a critical regulator of glucose metabolism.
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The Expression of IL-1β Correlates with the Expression of Galectin-3 in the Tissue at the Maternal-Fetal Interface during the Term and Preterm Labor. J Clin Med 2022; 11:jcm11216521. [PMID: 36362749 PMCID: PMC9656499 DOI: 10.3390/jcm11216521] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2022] [Revised: 10/22/2022] [Accepted: 10/24/2022] [Indexed: 11/06/2022] Open
Abstract
The inflammatory processes that occur at the maternal−fetal interface are considered one of the factors that are responsible for preterm birth. The pro-inflammatory roles of the Gal-3-induced activation of NLRP3 inflammasome and the consecutive production of IL-1β have been described in several acute and chronic inflammatory diseases, but the role of this inflammatory axis in parturition has not been studied. The aim of this study was to analyze the protein expression of Gal-3, NLRP3, and IL-1β in the decidua, villi, and fetal membranes, and to analyze their mutual correlation and correlation with the clinical parameters of inflammation in preterm birth (PTB) and term birth (TB). The study included 40 women that underwent a preterm birth (gestational age of 25.0−36.6) and histological chorioamnionitis (PTB) and control subjects, 22 women that underwent a term birth (gestational age of 37.0−41.6) without histological chorioamnionitis (TB). An analysis of the tissue sections that were stained with anti- Gal-3, -NLRP3, and -IL-1β antibodies was assessed by three independent investigators. The expression levels of Gal-3 and IL-1β were significantly higher (p < 0.001) in the decidua, villi, and fetal membranes in the PTB group when they compared to those of the TB group, while there was no difference in the expression of NLRP3. A further analysis revealed that there was no correlation between the protein expression of NLRP3 and the expression of Gal-3 and IL-1β, but there was a correlation between the expression of Gal-3 and IL-1β in decidua (R = 0.401; p = 0.008), villi (R = 0.301; p = 0.042) and the fetal membranes (R = 0.428; p = 0.002) in both of the groups, PTB and TB. In addition, the expression of Gal-3 and IL-1β in decidua and the fetal membranes was in correlation with the parameters of inflammation in the maternal and fetal blood (C-reactive protein, leukocyte number, and fibrinogen). The strong correlation between the expression of Gal-3 and IL-1β in the placental and fetal tissues during labor indicates that Gal-3 may participate in the regulation of the inflammatory processes in the placenta, leading to increased production of IL-1β, a cytokine that plays the main role in both term and preterm birth.
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The Role of Galectin 3 in the Pathogenesis of Diabetes Mellitus: Focus on Β-Cell Function and Survival. SERBIAN JOURNAL OF EXPERIMENTAL AND CLINICAL RESEARCH 2022. [DOI: 10.2478/sjecr-2022-0008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022] Open
Abstract
Abstract
Galectin 3 is a lectin expressed in many tissues with a significant biological role in physiological and pathological processes. Our review aims to sublimate the effects of galectin 3 on the β-cells function and survival. Data about the effect of galectin 3 on β- cells are scarce and contradictory. Several studies have shown that reduced activity of the galectin 3 gene reduces the risk of developing type 1 diabetes in an experimental model of diabetes in galectin 3 deficient mice. On the other side, in an experimental model of type 1 diabetes with mice with selectively enhanced expression of galectin 3 in β-cells, was shown that increased expression of this lectin has a protective role. Unlike type 1 diabetes where the autoimmune process plays a dominant role in pathogenesis, the pathogenesis of type 2 diabetes is multifactorial. One of the main factors which contribute to type 2 diabetes, the insulin resistance, is related to the concentration of soluble galectin 3. The effect of galectin 3 is very important for β-cell function. When a harmful factor acts on a β-cell, its intracellular concentration increases to preserve the function of β-cells and prevent their apoptosis, by blocking the internal path of apoptosis. However, excessive accumulation of galectin 3 inside the cell leads to its secretion, which encourages tissue inflammation. Based on all the above, galectin 3 has a double effect on β-cells.
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Li Z, Gurung M, Rodrigues RR, Padiadpu J, Newman NK, Manes NP, Pederson JW, Greer RL, Vasquez-Perez S, You H, Hioki KA, Moulton Z, Fel A, De Nardo D, Dzutsev AK, Nita-Lazar A, Trinchieri G, Shulzhenko N, Morgun A. Microbiota and adipocyte mitochondrial damage in type 2 diabetes are linked by Mmp12+ macrophages. J Exp Med 2022; 219:213260. [PMID: 35657352 PMCID: PMC9170383 DOI: 10.1084/jem.20220017] [Citation(s) in RCA: 26] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2022] [Revised: 03/22/2022] [Accepted: 05/05/2022] [Indexed: 01/07/2023] Open
Abstract
Microbiota contribute to the induction of type 2 diabetes by high-fat/high-sugar (HFHS) diet, but which organs/pathways are impacted by microbiota remain unknown. Using multiorgan network and transkingdom analyses, we found that microbiota-dependent impairment of OXPHOS/mitochondria in white adipose tissue (WAT) plays a primary role in regulating systemic glucose metabolism. The follow-up analysis established that Mmp12+ macrophages link microbiota-dependent inflammation and OXPHOS damage in WAT. Moreover, the molecular signature of Mmp12+ macrophages in WAT was associated with insulin resistance in obese patients. Next, we tested the functional effects of MMP12 and found that Mmp12 genetic deficiency or MMP12 inhibition improved glucose metabolism in conventional, but not in germ-free mice. MMP12 treatment induced insulin resistance in adipocytes. TLR2-ligands present in Oscillibacter valericigenes bacteria, which are expanded by HFHS, induce Mmp12 in WAT macrophages in a MYD88-ATF3-dependent manner. Thus, HFHS induces Mmp12+ macrophages and MMP12, representing a microbiota-dependent bridge between inflammation and mitochondrial damage in WAT and causing insulin resistance.
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Affiliation(s)
- Zhipeng Li
- Carlson College of Veterinary Medicine, Oregon State University, Corvallis, OR,Shanghai Mengniu Biotechnology R&D Co., Ltd., Shanghai, China
| | - Manoj Gurung
- Carlson College of Veterinary Medicine, Oregon State University, Corvallis, OR
| | - Richard R. Rodrigues
- College of Pharmacy, Oregon State University, Corvallis, OR,Laboratory of Integrative Cancer Immunology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD,Basic Science Program, Frederick National Laboratory for Cancer Research, Frederick, MD
| | | | | | - Nathan P. Manes
- Laboratory of Immune System Biology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD
| | - Jacob W. Pederson
- Carlson College of Veterinary Medicine, Oregon State University, Corvallis, OR
| | - Renee L. Greer
- Carlson College of Veterinary Medicine, Oregon State University, Corvallis, OR
| | | | - Hyekyoung You
- Carlson College of Veterinary Medicine, Oregon State University, Corvallis, OR
| | - Kaito A. Hioki
- College of Pharmacy, Oregon State University, Corvallis, OR
| | - Zoe Moulton
- Carlson College of Veterinary Medicine, Oregon State University, Corvallis, OR
| | - Anna Fel
- Laboratory of Immune System Biology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD
| | - Dominic De Nardo
- Anatomy and Developmental Biology, Monash Biomedicine Discovery Institute, Monash University, Clayton, Australia
| | - Amiran K. Dzutsev
- Laboratory of Integrative Cancer Immunology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD
| | - Aleksandra Nita-Lazar
- Laboratory of Immune System Biology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD
| | - Giorgio Trinchieri
- Laboratory of Integrative Cancer Immunology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD,Giorgio Trinchieri:
| | - Natalia Shulzhenko
- Carlson College of Veterinary Medicine, Oregon State University, Corvallis, OR,Correspondence to Natalia Shulzhenko:
| | - Andrey Morgun
- College of Pharmacy, Oregon State University, Corvallis, OR,Andrey Morgun:
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20
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Horne BD, Anderson JL, May HT, Le VT, Galenko O, Drakos SG, Bair TL, Knowlton KU, Muhlestein JB. Intermittent fasting and changes in Galectin-3: A secondary analysis of a randomized controlled trial of disease-free subjects. Nutr Metab Cardiovasc Dis 2022; 32:1538-1548. [PMID: 35361560 DOI: 10.1016/j.numecd.2022.03.001] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/20/2021] [Revised: 02/08/2022] [Accepted: 03/01/2022] [Indexed: 11/30/2022]
Abstract
BACKGROUND AND AIMS Intermittent fasting reduces risk of interrelated cardiometabolic diseases, including type 2 diabetes and heart failure (HF). Previously, we reported that intermittent fasting reduced homeostasis model assessment of insulin resistance (HOMA-IR) and Metabolic Syndrome Score (MSS) in the WONDERFUL Trial. Galectin-3 may act to reduce insulin resistance. This post hoc evaluation assessed whether intermittent fasting increased galectin-3. METHODS AND RESULTS The WONDERFUL Trial enrolled adults ages 21-70 years with ≥1 metabolic syndrome features or type 2 diabetes who were not taking anti-diabetic medication, were free of statins, and had elevated LDL-C. Subjects were randomized to water-only 24-h intermittent fasting conducted twice-per-week for 4 weeks and once-per-week for 22 weeks or to a parallel control arm with ad libitum energy intake. The study evaluated 26-week change scores of galectin-3 and other biomarkers. Overall, n = 67 subjects (intermittent fasting: n = 36; control: n = 31) completed the trial and had galectin-3 results. At 26-weeks, the galectin-3 change score was increased by intermittent fasting (median: 0.793 ng/mL, IQR: -0.538, 2.245) versus control (median: -0.332 ng/mL, IQR: -0.992, 0.776; p = 0.021). Galectin-3 changes correlated inversely with 26-week change scores of HOMA-IR (r = -0.288, p = 0.018) and MSS (r = -0.238, p = 0.052). Other HF biomarkers were unchanged by fasting. CONCLUSION A 24-h water-only intermittent fasting regimen increased galectin-3. The fasting-triggered galectin-3 elevation was inversely correlated with declines in HOMA-IR and MSS. This may be an evolutionary adaptive survival response that protects human health by modifying disease risks, including by reducing inflammation and insulin resistance. TRIAL REGISTRATION Clinicaltrials.gov, NCT02770313 (registered on May 12, 2016; first subject enrolled: November 30, 2016; final subject's 26-week study visit: February 19, 2020).
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Affiliation(s)
- Benjamin D Horne
- Intermountain Medical Center Heart Institute, Salt Lake City, UT, USA; Division of Cardiovascular Medicine, Department of Medicine, Stanford University, Stanford, CA, USA.
| | - Jeffrey L Anderson
- Intermountain Medical Center Heart Institute, Salt Lake City, UT, USA; Cardiology Division and Nora Eccles Harrison CVRTI, University of Utah, Salt Lake City, UT, USA
| | - Heidi T May
- Intermountain Medical Center Heart Institute, Salt Lake City, UT, USA
| | - Viet T Le
- Intermountain Medical Center Heart Institute, Salt Lake City, UT, USA; Rocky Mountain University of Health Professions, Provo, UT, USA
| | - Oxana Galenko
- Intermountain Medical Center Heart Institute, Salt Lake City, UT, USA
| | - Stavros G Drakos
- Cardiology Division and Nora Eccles Harrison CVRTI, University of Utah, Salt Lake City, UT, USA
| | - Tami L Bair
- Intermountain Medical Center Heart Institute, Salt Lake City, UT, USA
| | - Kirk U Knowlton
- Intermountain Medical Center Heart Institute, Salt Lake City, UT, USA; Division of Cardiovascular Medicine, Department of Medicine, University of California San Diego, La Jolla, CA, USA
| | - Joseph B Muhlestein
- Intermountain Medical Center Heart Institute, Salt Lake City, UT, USA; Cardiology Division and Nora Eccles Harrison CVRTI, University of Utah, Salt Lake City, UT, USA
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Duan H, Jing L, Xiang J, Ju C, Wu Z, Liu J, Ma X, Chen X, Liu Z, Feng J, Yan X. CD146 Associates with Gp130 to Control a Macrophage Pro-inflammatory Program That Regulates the Metabolic Response to Obesity. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2022; 9:e2103719. [PMID: 35258174 PMCID: PMC9069186 DOI: 10.1002/advs.202103719] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/25/2021] [Revised: 02/17/2022] [Indexed: 06/14/2023]
Abstract
The mechanism of obesity-related metabolic dysfunction involves the development of systemic inflammation, largely mediated by macrophages. Switching of M1-like adipose tissue macrophages (ATMs) to M2-like ATMs, a population of macrophages associated with weight loss and insulin sensitivity, is considered a viable therapeutic strategy for obesity-related metabolic syndrome. However, mechanisms for reestablishing the polarization of ATMs remain elusive. This study demonstrates that CD146+ ATMs accumulate in adipose tissue during diet-induced obesity and are associated with increased body weight, systemic inflammation, and obesity-induced insulin resistance. Inactivating the macrophage CD146 gene or antibody targeting of CD146 alleviates obesity-related chronic inflammation and metabolic dysfunction. Macrophage CD146 interacts with Glycoprotein 130 (Gp130), the common subunit of the receptor signaling complex for the interleukin-6 family of cytokines. CD146/Gp130 interaction promotes pro-inflammatory polarization of ATMs by activating JNK signaling and inhibiting the activation of STAT3, a transcription factor for M2-like polarization. Disruption of their interaction by anti-CD146 antibody or interleukin-6 steers ATMs toward anti-inflammatory polarization, thus attenuating obesity-induced chronic inflammation and metabolic dysfunction in mice. The results suggest that macrophage CD146 is an important determinant of pro-inflammatory polarization and plays a pivotal role in obesity-induced metabolic dysfunction. CD146 could constitute a novel therapeutic target for obesity complications.
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Affiliation(s)
- Hongxia Duan
- Laboratory of Protein and Peptide PharmaceuticalInstitute of BiophysicsChinese Academy of SciencesBeijing100101China
| | - Lin Jing
- Laboratory of Protein and Peptide PharmaceuticalInstitute of BiophysicsChinese Academy of SciencesBeijing100101China
- College of Life SciencesUniversity of Chinese Academy of Sciences19A Yuquan RoadBeijing100049China
| | - Jianquan Xiang
- Laboratory of Protein and Peptide PharmaceuticalInstitute of BiophysicsChinese Academy of SciencesBeijing100101China
- College of Life SciencesUniversity of Chinese Academy of Sciences19A Yuquan RoadBeijing100049China
| | - Chenhui Ju
- Laboratory of Protein and Peptide PharmaceuticalInstitute of BiophysicsChinese Academy of SciencesBeijing100101China
| | - Zhenzhen Wu
- Laboratory of Protein and Peptide PharmaceuticalInstitute of BiophysicsChinese Academy of SciencesBeijing100101China
| | - Jingyu Liu
- Laboratory of Protein and Peptide PharmaceuticalInstitute of BiophysicsChinese Academy of SciencesBeijing100101China
- College of Life SciencesUniversity of Chinese Academy of Sciences19A Yuquan RoadBeijing100049China
| | - Xinran Ma
- Laboratory of Protein and Peptide PharmaceuticalInstitute of BiophysicsChinese Academy of SciencesBeijing100101China
- College of Life SciencesUniversity of Chinese Academy of Sciences19A Yuquan RoadBeijing100049China
| | - Xuehui Chen
- Laboratory of Protein and Peptide PharmaceuticalInstitute of BiophysicsChinese Academy of SciencesBeijing100101China
| | - Zheng Liu
- Laboratory of Protein and Peptide PharmaceuticalInstitute of BiophysicsChinese Academy of SciencesBeijing100101China
| | - Jing Feng
- Laboratory of Protein and Peptide PharmaceuticalInstitute of BiophysicsChinese Academy of SciencesBeijing100101China
| | - Xiyun Yan
- Laboratory of Protein and Peptide PharmaceuticalInstitute of BiophysicsChinese Academy of SciencesBeijing100101China
- College of Life SciencesUniversity of Chinese Academy of Sciences19A Yuquan RoadBeijing100049China
- Joint Laboratory of Nanozymes in Zhengzhou UniversitySchool of Basic Medical SciencesZhengzhou UniversityZhengzhou450001China
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22
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Henry A, Gordillo-Marañón M, Finan C, Schmidt AF, Ferreira JP, Karra R, Sundström J, Lind L, Ärnlöv J, Zannad F, Mälarstig A, Hingorani AD, Lumbers RT. Therapeutic Targets for Heart Failure Identified Using Proteomics and Mendelian Randomization. Circulation 2022; 145:1205-1217. [PMID: 35300523 PMCID: PMC9010023 DOI: 10.1161/circulationaha.121.056663] [Citation(s) in RCA: 87] [Impact Index Per Article: 29.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/21/2021] [Accepted: 02/09/2022] [Indexed: 11/16/2022]
Abstract
BACKGROUND Heart failure (HF) is a highly prevalent disorder for which disease mechanisms are incompletely understood. The discovery of disease-associated proteins with causal genetic evidence provides an opportunity to identify new therapeutic targets. METHODS We investigated the observational and causal associations of 90 cardiovascular proteins, which were measured using affinity-based proteomic assays. First, we estimated the associations of 90 cardiovascular proteins with incident heart failure by means of a fixed-effect meta-analysis of 4 population-based studies, composed of a total of 3019 participants with 732 HF events. The causal effects of HF-associated proteins were then investigated by Mendelian randomization, using cis-protein quantitative loci genetic instruments identified from genomewide association studies in more than 30 000 individuals. To improve the precision of causal estimates, we implemented an Mendelian randomization model that accounted for linkage disequilibrium between instruments and tested the robustness of causal estimates through a multiverse sensitivity analysis that included up to 120 combinations of instrument selection parameters and Mendelian randomization models per protein. The druggability of candidate proteins was surveyed, and mechanism of action and potential on-target side effects were explored with cross-trait Mendelian randomization analysis. RESULTS Forty-four of ninety proteins were positively associated with risk of incident HF (P<6.0×10-4). Among these, 8 proteins had evidence of a causal association with HF that was robust to multiverse sensitivity analysis: higher CSF-1 (macrophage colony-stimulating factor 1), Gal-3 (galectin-3) and KIM-1 (kidney injury molecule 1) were positively associated with risk of HF, whereas higher ADM (adrenomedullin), CHI3L1 (chitinase-3-like protein 1), CTSL1 (cathepsin L1), FGF-23 (fibroblast growth factor 23), and MMP-12 (matrix metalloproteinase-12) were protective. Therapeutics targeting ADM and Gal-3 are currently under evaluation in clinical trials, and all the remaining proteins were considered druggable, except KIM-1. CONCLUSIONS We identified 44 circulating proteins that were associated with incident HF, of which 8 showed evidence of a causal relationship and 7 were druggable, including adrenomedullin, which represents a particularly promising drug target. Our approach demonstrates a tractable roadmap for the triangulation of population genomic and proteomic data for the prioritization of therapeutic targets for complex human diseases.
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Affiliation(s)
- Albert Henry
- Institute of Cardiovascular Science (A.H., M.G.-M., C.F., A.F.S., A.D.H.), University College London, United Kingdom
- British Heart Foundation Research Accelerator (A.H., M.G.-M., C.F., A.F.S., A.D.H., R.T.L.), University College London, United Kingdom
- Institute of Health Informatics (A.H., R.T.L.), University College London, United Kingdom
| | - María Gordillo-Marañón
- Institute of Cardiovascular Science (A.H., M.G.-M., C.F., A.F.S., A.D.H.), University College London, United Kingdom
- British Heart Foundation Research Accelerator (A.H., M.G.-M., C.F., A.F.S., A.D.H., R.T.L.), University College London, United Kingdom
| | - Chris Finan
- Institute of Cardiovascular Science (A.H., M.G.-M., C.F., A.F.S., A.D.H.), University College London, United Kingdom
- British Heart Foundation Research Accelerator (A.H., M.G.-M., C.F., A.F.S., A.D.H., R.T.L.), University College London, United Kingdom
- Department of Cardiology, Division of Heart and Lungs, University Medical Center Utrecht, The Netherlands (C.F., A.F.S.)
| | - Amand F. Schmidt
- Institute of Cardiovascular Science (A.H., M.G.-M., C.F., A.F.S., A.D.H.), University College London, United Kingdom
- British Heart Foundation Research Accelerator (A.H., M.G.-M., C.F., A.F.S., A.D.H., R.T.L.), University College London, United Kingdom
- Department of Cardiology, Division of Heart and Lungs, University Medical Center Utrecht, The Netherlands (C.F., A.F.S.)
| | - João Pedro Ferreira
- Unidade de Investigação e Desenvolvimento Cardiovascular, Rede de Investigação em Saúde, Department of Surgery and Physiology, Faculty of Medicine of the University of Porto, Portugal (J.P.F.)
- Université de Lorraine, Inserm, Centre d’Investigations Cliniques - Plurithématique 14-33, and Inserm U1116, Centre Hospitalier Régional Universitaire, French Clinical Research Infrastructure Network, Investigation Network Initiative - Cardiovascular and Renal Clinical Trialists, Nancy, France (J.P.F., F.Z.)
| | - Ravi Karra
- Division of Cardiology, Department of Medicine (R.K.), Duke University Medical Center, Durham, NC
- Department of Pathology (R.K.), Duke University Medical Center, Durham, NC
| | - Johan Sundström
- Department of Medical Sciences, Uppsala University, Sweden (J.S., L.L.)
- The George Institute for Global Health, University of New South Wales, Sydney, Australia (J.S.)
| | - Lars Lind
- Department of Medical Sciences, Uppsala University, Sweden (J.S., L.L.)
| | - Johan Ärnlöv
- School of Health and Social Studies, Dalarna University, Falun, Sweden (J.Ä.)
- Division of Family Medicine and Primary Care, Department of Neurobiology, Care Science and Society, Karolinska Institutet, Huddinge, Sweden (J.Ä.)
| | - Faiez Zannad
- Université de Lorraine, Inserm, Centre d’Investigations Cliniques - Plurithématique 14-33, and Inserm U1116, Centre Hospitalier Régional Universitaire, French Clinical Research Infrastructure Network, Investigation Network Initiative - Cardiovascular and Renal Clinical Trialists, Nancy, France (J.P.F., F.Z.)
| | - Anders Mälarstig
- Department of Medical Epidemiology and Biostatistics, Karolinska Institute, Solna‚ Sweden (A.M.)
- Emerging Science and Innovation, Pfizer Worldwide Research, Development and Medical, Cambridge, MA (A.M.)
| | - Aroon D. Hingorani
- Institute of Cardiovascular Science (A.H., M.G.-M., C.F., A.F.S., A.D.H.), University College London, United Kingdom
- British Heart Foundation Research Accelerator (A.H., M.G.-M., C.F., A.F.S., A.D.H., R.T.L.), University College London, United Kingdom
| | - R. Thomas Lumbers
- British Heart Foundation Research Accelerator (A.H., M.G.-M., C.F., A.F.S., A.D.H., R.T.L.), University College London, United Kingdom
- Institute of Health Informatics (A.H., R.T.L.), University College London, United Kingdom
- Health Data Research UK London (R.T.L.), University College London, United Kingdom
| | - HERMES and SCALLOP Consortia
- Institute of Cardiovascular Science (A.H., M.G.-M., C.F., A.F.S., A.D.H.), University College London, United Kingdom
- British Heart Foundation Research Accelerator (A.H., M.G.-M., C.F., A.F.S., A.D.H., R.T.L.), University College London, United Kingdom
- Institute of Health Informatics (A.H., R.T.L.), University College London, United Kingdom
- Health Data Research UK London (R.T.L.), University College London, United Kingdom
- Department of Cardiology, Division of Heart and Lungs, University Medical Center Utrecht, The Netherlands (C.F., A.F.S.)
- Unidade de Investigação e Desenvolvimento Cardiovascular, Rede de Investigação em Saúde, Department of Surgery and Physiology, Faculty of Medicine of the University of Porto, Portugal (J.P.F.)
- Université de Lorraine, Inserm, Centre d’Investigations Cliniques - Plurithématique 14-33, and Inserm U1116, Centre Hospitalier Régional Universitaire, French Clinical Research Infrastructure Network, Investigation Network Initiative - Cardiovascular and Renal Clinical Trialists, Nancy, France (J.P.F., F.Z.)
- Division of Cardiology, Department of Medicine (R.K.), Duke University Medical Center, Durham, NC
- Department of Pathology (R.K.), Duke University Medical Center, Durham, NC
- Department of Medical Sciences, Uppsala University, Sweden (J.S., L.L.)
- The George Institute for Global Health, University of New South Wales, Sydney, Australia (J.S.)
- School of Health and Social Studies, Dalarna University, Falun, Sweden (J.Ä.)
- Division of Family Medicine and Primary Care, Department of Neurobiology, Care Science and Society, Karolinska Institutet, Huddinge, Sweden (J.Ä.)
- Department of Medical Epidemiology and Biostatistics, Karolinska Institute, Solna‚ Sweden (A.M.)
- Emerging Science and Innovation, Pfizer Worldwide Research, Development and Medical, Cambridge, MA (A.M.)
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Exo-D-Mapps Attenuates Production of Inflammatory Cytokines and Promoted Generation of Immunosuppressive Phenotype in Peripheral Blood Mononuclear Cells. SERBIAN JOURNAL OF EXPERIMENTAL AND CLINICAL RESEARCH 2022. [DOI: 10.2478/sjecr-2019-0045] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
Abstract
Mesenchymal stem cells (MSCs) produce immunomodulatory factors that regulate production of cytokines and chemokines in immune cells affecting their functional properties. Administration of MSCs-sourced secretome, including MSC-derived conditioned medium (MSC-CM) and MSC-derived exosomes (MSC-Exos), showed beneficial effects similar to those observed after transplantation of MSCs. Due to their nano-size dimension, MSC-Exos easily penetrate through the tissue and in paracrine and endocrine manner, may deliver MSC-sourced factors to the target immune cells modulating their function. MSCs derived from amniotic fluid (AF-MSCs) had superior cell biological properties than MSCs derived from bone marrow. We recently developed “Exosomes Derived Multiple Allogeneic Proteins Paracrine Signaling (Exo-d-MAPPS)”, a biological product in which the activity is based on AF-MSC-derived Exos capable to deliver immunomodulatory molecules and growth factors to the target cells. Herewith, we analyzed immunosuppressive capacity of Exo-d-MAPPS against human peripheral blood mononuclear cells (pbMNCs) and demonstrated that Exo-d-MAPPS efficiently suppressed generation of inflammatory phenotype in activated pbMNCs. Exo-d-MAPPS attenuated production of inflammatory cytokines and promoted generation of immunosuppressive phenotype in Lipopolysaccharide-primed pbMNCs. Exo-d-MAPPS treatment reduced expansion of inflammatory Th1 and Th17 cells and promoted generation of immunosuppressive T regulatory cells in the population of Concanavalin A-primed pbMNCs. Similarly, Exod-MAPPS treatment suppressed pro-inflammatory and promoted anti-inflammatory properties of α-GalCer-primed pbMNCs. In summing up, due to its capacity for suppression of activated pbMNCs, Exo-d-MAPPS should be further explored in animal models of acute and chronic inflammatory diseases as a potentially new remedy for the attenuation of detrimental immune response.
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Intracellular Toxic Advanced Glycation End-Products in 1.4E7 Cell Line Induce Death with Reduction of Microtubule-Associated Protein 1 Light Chain 3 and p62. Nutrients 2022; 14:nu14020332. [PMID: 35057513 PMCID: PMC8777741 DOI: 10.3390/nu14020332] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2021] [Revised: 12/17/2021] [Accepted: 01/11/2022] [Indexed: 02/06/2023] Open
Abstract
Background: The death of pancreatic islet β-cells (β-cells), which are the insulin-producing cells, promote the pathology in both Type 1 and Type 2 diabetes mellitus (DM) (T1DM and T2DM), and they are protected by autophagy which is one of the mechanisms of cell survival. Recently, that some advanced glycation end-products (AGEs), such as methylglyoxial-derived AGEs and Nε-carboxymethyllysine, induced the death of β-cells were revealed. In contrast, we had reported AGEs derived from glyceraldehyde (GA, the metabolism intermediate of glucose and fructose) are considered to be toxic AGEs (TAGE) due to their cytotoxicity and role in the pathogenesis of T2DM. More, serum levels of TAGE are elevated in patients with T1 and T2DM, where they exert cytotoxicity. Aim: We researched the cytotoxicity of intracellular and extracellular TAGE in β-cells and the possibility that intracellular TAGE were associated with autophagy. Methods: 1.4E7 cells (a human β-cell line) were treated with GA, and analyzed viability, quantity of TAGE, microtubule-associated protein 1 light chain 3 (LC3)-I, LC3-II, and p62. We also examined the viability of 1.4E7 cells treated with TAGE-modified bovine serum albumin, a model of TAGE in the blood. Results: Intracellular TAGE induced death of 1.4E7 cells, decrease of LC3-I, LC3-II, and p62. Extracellular TAGE didn’t show cytotoxicity in the physiological concentration. Conclusion: Intracellular TAGE induced death of β-cells more strongly than extracellular TAGE, and may suppress autophagy via reduction of LC3-I, LC3-II, and p62 to inhibit the degradation of them.
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Tian L, Ding F, Zhang R. Predictive Value of Galectin-3 and Brachial-Ankle Pulse Wave Velocity for Coronary Artery Calcification in Coronary Arteriography Patients. Int J Clin Pract 2022; 2022:1865736. [PMID: 35685493 PMCID: PMC9159218 DOI: 10.1155/2022/1865736] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/06/2022] [Accepted: 04/27/2022] [Indexed: 11/17/2022] Open
Abstract
OBJECTIVES To study the predictive value for coronary artery calcification (CAC) of plasma galectin-3 and brachial-ankle pulse wave velocity (BaPWV) in coronary arteriography (CAG) patients. METHODS Patients who received coronary arteriography (CAG) examination were recruited. The level of plasma galectin-3 was measured by the enzyme-linked immunosorbent assay. The arterial stiffness was analyzed by BaPWV and ankle-brachial index (ABI) which were measured using a volume-plethysmographic device. Receiver operating characteristic (ROC) curve was used to analyze the prognostic value of galectin-3 or BaPWV for coronary artery calcification (CAC). RESULTS The level of galectin-3 and BaPWV was significantly higher in CAC patients compared with that in control (p < 0.01). The level of plasma galectin-3 was positively correlated with BaPWV (r = -0.296, p < 0.01) and negatively correlated with ABI (r = -0.296, p < 0.01). ROC curve analysis revealed that galectin-3 ≥5.90 ng/ml was the most powerful predictor for CAC with sensitivity of 85.5% and specificity of 83.5%. The area under the curve (AUC) was 0.916. When the level of BaPWV was more than 1909 m/s, the sensitivity and specificity were 61.8% and 69.6%, respectively, for predicting CAC. The AUC was 0.646. CONCLUSIONS The level of plasma galectin-3 increases significantly in CAC patients compared to control, and its level is related to BaPWV and ABI. Galectin-3 and BaPWV can be used to predict CAC, and the diagnosis value (sensitivity and specificity) of galectin-3 for CAC is better than that of BaPWV.
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Affiliation(s)
- Lei Tian
- Department of Cardiovascular Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Fenghua Ding
- Department of Cardiovascular Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Ruiyan Zhang
- Department of Cardiovascular Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
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26
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Luís C, Soares R, Baylina P, Fernandes R. Underestimated Prediabetic Biomarkers: Are We Blind to Their Strategy? Front Endocrinol (Lausanne) 2022; 13:805837. [PMID: 35321333 PMCID: PMC8936175 DOI: 10.3389/fendo.2022.805837] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/31/2021] [Accepted: 01/31/2022] [Indexed: 11/13/2022] Open
Abstract
Type 2 Diabetes (T2D) is currently one of the fastest growing health challenging, a non-communicable disease result of the XXI century lifestyle. Given its growing incidence and prevalence, it became increasingly imperative to develop new technologies and implement new biomarkers for early diagnosis in order to promote lifestyle changes and thus cause a setback of the disease. Promising biomarkers have been identified as predictive of T2D development; however, none of them have yet been implemented in clinical practice routine. Moreover, many prediabetic biomarkers can also represent potential therapeutical targets in disease management. Previous studies have identified the most popular biomarkers, which are being thoroughly investigated. However, there are some biomarkers with promising preliminary results with limited associated studies; hence there is still much to be understood about its mechanisms and associations in T2D pathophysiology. This work identifies and discusses the promising results of Galectin-3, Ophthalmate and Fetuin-A.
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Affiliation(s)
- Carla Luís
- Laboratory of Medical & Industrial Biotechnology (LABMI)-Porto Research, Technology and Innovation Center (PORTIC), Porto, Portugal
- Departamento de Biomedicina, Faculdade de Medicina da Universidade do Porto, Porto, Portugal
- Instituto de Investigação e Inovação em Saúde (i3S), Universidade do Porto, Porto, Portugal
- *Correspondence: Carla Luís, ; Rúben Fernandes,
| | - Raquel Soares
- Departamento de Biomedicina, Faculdade de Medicina da Universidade do Porto, Porto, Portugal
- Instituto de Investigação e Inovação em Saúde (i3S), Universidade do Porto, Porto, Portugal
| | - Pilar Baylina
- Laboratory of Medical & Industrial Biotechnology (LABMI)-Porto Research, Technology and Innovation Center (PORTIC), Porto, Portugal
- Instituto de Investigação e Inovação em Saúde (i3S), Universidade do Porto, Porto, Portugal
- ESS-IPP – Escola Superior de Saúde, Instituto Politécnico do Porto, Porto, Portugal
| | - Rúben Fernandes
- Laboratory of Medical & Industrial Biotechnology (LABMI)-Porto Research, Technology and Innovation Center (PORTIC), Porto, Portugal
- Instituto de Investigação e Inovação em Saúde (i3S), Universidade do Porto, Porto, Portugal
- ESS-IPP – Escola Superior de Saúde, Instituto Politécnico do Porto, Porto, Portugal
- *Correspondence: Carla Luís, ; Rúben Fernandes,
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27
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Cabrera-Reyes F, Parra-Ruiz C, Yuseff MI, Zanlungo S. Alterations in Lysosome Homeostasis in Lipid-Related Disorders: Impact on Metabolic Tissues and Immune Cells. Front Cell Dev Biol 2021; 9:790568. [PMID: 34957117 PMCID: PMC8703004 DOI: 10.3389/fcell.2021.790568] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2021] [Accepted: 11/22/2021] [Indexed: 12/16/2022] Open
Abstract
Lipid-related disorders, which primarily affect metabolic tissues, including adipose tissue and the liver are associated with alterations in lysosome homeostasis. Obesity is one of the more prevalent diseases, which results in energy imbalance within metabolic tissues and lysosome dysfunction. Less frequent diseases include Niemann-Pick type C (NPC) and Gaucher diseases, both of which are known as Lysosomal Storage Diseases (LSDs), where lysosomal dysfunction within metabolic tissues remains to be fully characterized. Adipocytes and hepatocytes share common pathways involved in the lysosome-autophagic axis, which are regulated by the function of cathepsins and CD36, an immuno-metabolic receptor and display alterations in lipid diseases, and thereby impacting metabolic functions. In addition to intrinsic defects observed in metabolic tissues, cells of the immune system, such as B cells can infiltrate adipose and liver tissues, during metabolic imbalance favoring inflammation. Moreover, B cells rely on lysosomes to promote the processing and presentation of extracellular antigens and thus could also present lysosome dysfunction, consequently affecting such functions. On the other hand, growing evidence suggests that cells accumulating lipids display defective inter-organelle membrane contact sites (MCSs) established by lysosomes and other compartments, which contribute to metabolic dysfunctions at the cellular level. Overall, in this review we will discuss recent findings addressing common mechanisms that are involved in lysosome dysregulation in adipocytes and hepatocytes during obesity, NPC, and Gaucher diseases. We will discuss whether these mechanisms may modulate the function of B cells and how inter-organelle contacts, emerging as relevant cellular mechanisms in the control of lipid homeostasis, have an impact on these diseases.
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Affiliation(s)
- Fernanda Cabrera-Reyes
- Department of Cellular and Molecular Biology, Faculty of Sciences, Pontificia Universidad Católica de Chile, Santiago, Chile
- Department of Gastroenterology, Faculty of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Claudia Parra-Ruiz
- Department of Cellular and Molecular Biology, Faculty of Sciences, Pontificia Universidad Católica de Chile, Santiago, Chile
- Department of Gastroenterology, Faculty of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - María Isabel Yuseff
- Department of Cellular and Molecular Biology, Faculty of Sciences, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Silvana Zanlungo
- Department of Gastroenterology, Faculty of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile
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28
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Physical Activity Attenuates the Obesity-Induced Dysregulated Expression of Brown Adipokines in Murine Interscapular Brown Adipose Tissue. Int J Mol Sci 2021; 22:ijms221910391. [PMID: 34638731 PMCID: PMC8508858 DOI: 10.3390/ijms221910391] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2021] [Revised: 09/22/2021] [Accepted: 09/22/2021] [Indexed: 11/17/2022] Open
Abstract
In recent years, brown adipose tissue (BAT), which has a high heat-producing capacity, has been confirmed to exist even in adults, and it has become a focal point for the prevention and the improvement of obesity and lifestyle-related diseases. However, the influences of obesity and physical activity (PA) on the fluid factors secreted from BAT (brown adipokines) are not well understood. In this study, therefore, we focused on brown adipokines and investigated the effects of obesity and PA. The abnormal expressions of gene fluid factors such as galectin-3 (Lgals3) and Lgals3 binding protein (Lgals3bp), whose proteins are secreted from HB2 brown adipocytes, were observed in the interscapular BAT of obese mice fed a high-fat diet for 4 months. PA attenuated the abnormalities in the expressions of these genes. Furthermore, although the gene expressions of factors related to brown adipocyte differentiation such as peroxisome proliferator-activated receptor gamma coactivator 1-α were also down-regulated in the BAT of the obese mice, PA suppressed the down-regulation of these factors. On the other hand, lipogenesis was increased more in HB2 cells overexpressing Lgals3 compared with that in control cells, and the overexpression of Lgals3bp decreased the mitochondrial mass. These results indicate that PA attenuates the obesity-induced dysregulated expression of brown adipokines and suggests that Lgals3 and Lgals3bp are involved in brown adipocyte differentiation.
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Schmitt VH, Prochaska JH, Föll AS, Schulz A, Keller K, Hahad O, Koeck T, Tröbs SO, Rapp S, Beutel M, Pfeiffer N, Strauch K, Lackner KJ, Münzel T, Wild PS. Galectin-3 for prediction of cardiac function compared to NT-proBNP in individuals with prediabetes and type 2 diabetes mellitus. Sci Rep 2021; 11:19012. [PMID: 34561496 PMCID: PMC8463561 DOI: 10.1038/s41598-021-98227-x] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2021] [Accepted: 09/02/2021] [Indexed: 12/21/2022] Open
Abstract
Use of galectin-3 for assessing cardiac function in prediabetes and type 2 diabetes mellitus (T2DM) needs to be established. Within the Gutenberg Health Study cohort (N = 15,010, 35–74 years) patient characteristics were investigated regarding galectin-3 levels. Prognostic value of galectin-3 compared to NT-proBNP concerning cardiac function and mortality was assessed in individuals with euglycaemia, prediabetes and T2DM in 5 years follow-up. Higher galectin-3 levels related to older age, female sex and higher prevalence for prediabetes, T2DM, cardiovascular risk factors and comorbidities. Galectin-3 cross-sectionally was related to impaired systolic (β − 0.36, 95% CI − 0.63/− 0.09; P = 0.008) and diastolic function (β 0.014, 95% CI 0.001/0.03; P = 0.031) in T2DM and reduced systolic function in prediabetes (β − 0.34, 95% CI − 0.53/− 0.15; P = 0.00045). Galectin-3 prospectively related to systolic (β − 0.656, 95% CI − 1.07/− 0.24; P = 0.0021) and diastolic dysfunction (β 0.0179, 95% CI 0.0001/0.036; P = 0.049), cardiovascular (hazard ratio per standard deviation of galectin-3 (HRperSD) 1.60, 95% CI 1.39–1.85; P < 0.0001) and all-cause mortality (HRperSD 1.36, 95% CI 1.25–1.47; P < 0.0001) in T2DM. No relationship between galectin-3 and cardiac function was found in euglycaemia, whereas NT-proBNP consistently related to reduced cardiac function. Prospective value of NT-proBNP on cardiovascular and all-cause mortality was higher. NT-proBNP was superior to galectin-3 to assess reduced systolic and diastolic function.
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Affiliation(s)
- Volker H Schmitt
- Department of Cardiology, Cardiology I, University Medical Center, Johannes Gutenberg University Mainz, Langenbeckstr. 1, 55131, Mainz, Germany.,German Center for Cardiovascular Research (DZHK), Partner Site Rhine-Main, Mainz, Germany
| | - Jürgen H Prochaska
- German Center for Cardiovascular Research (DZHK), Partner Site Rhine-Main, Mainz, Germany.,Preventive Cardiology and Preventive Medicine, Department of Cardiology, University Medical Center, Johannes Gutenberg University Mainz, Langenbeckstr. 1, 55131, Mainz, Germany.,Center for Thrombosis and Hemostasis (CTH), University Medical Center, Johannes Gutenberg University Mainz, Langenbeckstr. 1, 55131, Mainz, Germany
| | - Annegret S Föll
- Preventive Cardiology and Preventive Medicine, Department of Cardiology, University Medical Center, Johannes Gutenberg University Mainz, Langenbeckstr. 1, 55131, Mainz, Germany
| | - Andreas Schulz
- Preventive Cardiology and Preventive Medicine, Department of Cardiology, University Medical Center, Johannes Gutenberg University Mainz, Langenbeckstr. 1, 55131, Mainz, Germany.,Center for Thrombosis and Hemostasis (CTH), University Medical Center, Johannes Gutenberg University Mainz, Langenbeckstr. 1, 55131, Mainz, Germany
| | - Karsten Keller
- Department of Cardiology, Cardiology I, University Medical Center, Johannes Gutenberg University Mainz, Langenbeckstr. 1, 55131, Mainz, Germany.,Center for Thrombosis and Hemostasis (CTH), University Medical Center, Johannes Gutenberg University Mainz, Langenbeckstr. 1, 55131, Mainz, Germany.,Medical Clinic VII, Department of Sports Medicine, University Hospital Heidelberg, Im Neuenheimer Feld 410, 69120, Heidelberg, Germany
| | - Omar Hahad
- Department of Cardiology, Cardiology I, University Medical Center, Johannes Gutenberg University Mainz, Langenbeckstr. 1, 55131, Mainz, Germany.,German Center for Cardiovascular Research (DZHK), Partner Site Rhine-Main, Mainz, Germany
| | - Thomas Koeck
- German Center for Cardiovascular Research (DZHK), Partner Site Rhine-Main, Mainz, Germany.,Center for Thrombosis and Hemostasis (CTH), University Medical Center, Johannes Gutenberg University Mainz, Langenbeckstr. 1, 55131, Mainz, Germany
| | - Sven-Oliver Tröbs
- Department of Cardiology, Cardiology I, University Medical Center, Johannes Gutenberg University Mainz, Langenbeckstr. 1, 55131, Mainz, Germany.,German Center for Cardiovascular Research (DZHK), Partner Site Rhine-Main, Mainz, Germany.,Preventive Cardiology and Preventive Medicine, Department of Cardiology, University Medical Center, Johannes Gutenberg University Mainz, Langenbeckstr. 1, 55131, Mainz, Germany
| | - Steffen Rapp
- Preventive Cardiology and Preventive Medicine, Department of Cardiology, University Medical Center, Johannes Gutenberg University Mainz, Langenbeckstr. 1, 55131, Mainz, Germany.,Center for Thrombosis and Hemostasis (CTH), University Medical Center, Johannes Gutenberg University Mainz, Langenbeckstr. 1, 55131, Mainz, Germany
| | - Manfred Beutel
- Department of Psychosomatic Medicine and Psychotherapy, University Medical Center, Johannes Gutenberg University Mainz, Langenbeckstr. 1, 55131, Mainz, Germany
| | - Norbert Pfeiffer
- Department of Ophthalmology, University Medical Center, Johannes Gutenberg University Mainz, Langenbeckstr. 1, 55131, Mainz, Germany
| | - Konstantin Strauch
- Institute of Medical Biostatistics, Epidemiology and Informatics (IMBEI), University Medical Center, Johannes Gutenberg University Mainz, Obere Zahlbacher Str. 69, 55131, Mainz, Germany
| | - Karl J Lackner
- German Center for Cardiovascular Research (DZHK), Partner Site Rhine-Main, Mainz, Germany.,Institute of Clinical Chemistry and Laboratory Medicine, University Medical Center, Johannes Gutenberg University Mainz, Langenbeckstr. 1, 55131, Mainz, Germany
| | - Thomas Münzel
- Department of Cardiology, Cardiology I, University Medical Center, Johannes Gutenberg University Mainz, Langenbeckstr. 1, 55131, Mainz, Germany. .,German Center for Cardiovascular Research (DZHK), Partner Site Rhine-Main, Mainz, Germany. .,Center for Thrombosis and Hemostasis (CTH), University Medical Center, Johannes Gutenberg University Mainz, Langenbeckstr. 1, 55131, Mainz, Germany.
| | - Philipp S Wild
- German Center for Cardiovascular Research (DZHK), Partner Site Rhine-Main, Mainz, Germany.,Preventive Cardiology and Preventive Medicine, Department of Cardiology, University Medical Center, Johannes Gutenberg University Mainz, Langenbeckstr. 1, 55131, Mainz, Germany.,Center for Thrombosis and Hemostasis (CTH), University Medical Center, Johannes Gutenberg University Mainz, Langenbeckstr. 1, 55131, Mainz, Germany
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Heusler I, Biron-Shental T, Farladansky-Gershnabel S, Pasternak Y, Kidron D, Vulih-Shuitsman I, Einbinder Y, Cohen-Hagai K, Benchetrit S, Zitman-Gal T. Enhanced expression of Galectin-3 in gestational diabetes. Nutr Metab Cardiovasc Dis 2021; 31:1791-1797. [PMID: 34023181 DOI: 10.1016/j.numecd.2021.03.002] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/15/2020] [Revised: 02/01/2021] [Accepted: 03/01/2021] [Indexed: 02/06/2023]
Abstract
BACKGROUND AND AIMS Gestational diabetes mellitus (GDM), hyperglycemia diagnosed during pregnancy, is one of the most common medical complications of pregnancy, treated primarily by diet and pharmacotherapy, if indicated. It is well-established that GDM increases the risk of adverse pregnancy outcomes and long-term complications in mothers and infants. Galectin-3 (Gal-3) is important in processes of cell growth, differentiation, inflammation, and fibrosis. We evaluated Gal-3 expression in pregnancies complicated by GDM as a parameter that might explain how GDM influences early onset of future complications. METHODS AND RESULTS Forty-four women with GDM and 40 with normal pregnancy (NP) were recruited during delivery admission. Blood samples were obtained from parturients and umbilical cords blood, as well as placental tissue for analysis. Gal-3 mRNA expression was increased in maternal blood samples and placental tissue of women with GDM compared to NP. In GDM, Gal-3 mRNA was decreased in cord blood compared to maternal blood and placental tissue. Gal-3 GDM placental protein expression was increased compared to NP. Immunostaining revealed that Gal-3 is upregulated in GDM placental extravillous trophoblast. ELISA of Gal-3 maternal serum levels between GDM and NP were similar. CONCLUSION Gal-3 is strongly expressed at molecular levels (mRNA and protein expression) in GDM maternal blood and placental tissue, and decreased in cord blood. These findings highlight the role of the placenta in protecting the fetus from potential Gal-3 damage. Gal-3 expression at mRNA and protein levels might be influenced by diabetes, even if blood glucose is balanced by medication or diet.
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Affiliation(s)
- Ishai Heusler
- Department of Obstetrics and Gynecology, Meir Medical Center, Kfar Saba, Israel; Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Tal Biron-Shental
- Department of Obstetrics and Gynecology, Meir Medical Center, Kfar Saba, Israel; Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Sivan Farladansky-Gershnabel
- Department of Obstetrics and Gynecology, Meir Medical Center, Kfar Saba, Israel; Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Yael Pasternak
- Department of Obstetrics and Gynecology, Meir Medical Center, Kfar Saba, Israel; Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Debora Kidron
- Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel; Pathology Department, Meir Medical Center, Kfar Saba, Israel
| | | | - Yael Einbinder
- Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel; Nephrology Laboratory, Department of Nephrology and Hypertension, Meir Medical Center, Kfar Saba, Israel
| | - Keren Cohen-Hagai
- Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel; Nephrology Laboratory, Department of Nephrology and Hypertension, Meir Medical Center, Kfar Saba, Israel
| | - Sydney Benchetrit
- Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel; Nephrology Laboratory, Department of Nephrology and Hypertension, Meir Medical Center, Kfar Saba, Israel
| | - Tali Zitman-Gal
- Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel; Nephrology Laboratory, Department of Nephrology and Hypertension, Meir Medical Center, Kfar Saba, Israel.
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Rehman SU, Schallschmidt T, Rasche A, Knebel B, Stermann T, Altenhofen D, Herwig R, Schürmann A, Chadt A, Al-Hasani H. Alternative exon splicing and differential expression in pancreatic islets reveals candidate genes and pathways implicated in early diabetes development. Mamm Genome 2021; 32:153-172. [PMID: 33880624 PMCID: PMC8128753 DOI: 10.1007/s00335-021-09869-1] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2020] [Accepted: 04/03/2021] [Indexed: 12/29/2022]
Abstract
Type 2 diabetes (T2D) has a strong genetic component. Most of the gene variants driving the pathogenesis of T2D seem to target pancreatic β-cell function. To identify novel gene variants acting at early stage of the disease, we analyzed whole transcriptome data to identify differential expression (DE) and alternative exon splicing (AS) transcripts in pancreatic islets collected from two metabolically diverse mouse strains at 6 weeks of age after three weeks of high-fat-diet intervention. Our analysis revealed 1218 DE and 436 AS genes in islets from NZO/Hl vs C3HeB/FeJ. Whereas some of the revealed genes present well-established markers for β-cell failure, such as Cd36 or Aldh1a3, we identified numerous DE/AS genes that have not been described in context with β-cell function before. The gene Lgals2, previously associated with human T2D development, was DE as well as AS and localizes in a quantitative trait locus (QTL) for blood glucose on Chr.15 that we reported recently in our N2(NZOxC3H) population. In addition, pathway enrichment analysis of DE and AS genes showed an overlap of only half of the revealed pathways, indicating that DE and AS in large parts influence different pathways in T2D development. PPARG and adipogenesis pathways, two well-established metabolic pathways, were overrepresented for both DE and AS genes, probably as an adaptive mechanism to cope for increased cellular stress. Our results provide guidance for the identification of novel T2D candidate genes and demonstrate the presence of numerous AS transcripts possibly involved in islet function and maintenance of glucose homeostasis.
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Affiliation(s)
- Sayeed Ur Rehman
- Institute for Clinical Biochemistry and Pathobiochemistry, German Diabetes Center (DDZ), Leibniz Center for Diabetes Research at Heinrich Heine University, Medical Faculty, Duesseldorf, Germany.,German Center for Diabetes Research (DZD), München-Neuherberg, Germany.,Department of Biochemistry, School of Chemical and Life Sciences, Jamia Hamdard, New Delhi, 110062, India
| | - Tanja Schallschmidt
- Institute for Clinical Biochemistry and Pathobiochemistry, German Diabetes Center (DDZ), Leibniz Center for Diabetes Research at Heinrich Heine University, Medical Faculty, Duesseldorf, Germany.,German Center for Diabetes Research (DZD), München-Neuherberg, Germany
| | - Axel Rasche
- Department of Computational Molecular Biology, Max Planck Institute for Molecular Genetics, Berlin, Germany
| | - Birgit Knebel
- Institute for Clinical Biochemistry and Pathobiochemistry, German Diabetes Center (DDZ), Leibniz Center for Diabetes Research at Heinrich Heine University, Medical Faculty, Duesseldorf, Germany.,German Center for Diabetes Research (DZD), München-Neuherberg, Germany
| | - Torben Stermann
- Institute for Clinical Biochemistry and Pathobiochemistry, German Diabetes Center (DDZ), Leibniz Center for Diabetes Research at Heinrich Heine University, Medical Faculty, Duesseldorf, Germany.,German Center for Diabetes Research (DZD), München-Neuherberg, Germany
| | - Delsi Altenhofen
- Institute for Clinical Biochemistry and Pathobiochemistry, German Diabetes Center (DDZ), Leibniz Center for Diabetes Research at Heinrich Heine University, Medical Faculty, Duesseldorf, Germany.,German Center for Diabetes Research (DZD), München-Neuherberg, Germany
| | - Ralf Herwig
- Department of Computational Molecular Biology, Max Planck Institute for Molecular Genetics, Berlin, Germany
| | - Annette Schürmann
- German Center for Diabetes Research (DZD), München-Neuherberg, Germany.,German Institute of Human Nutrition, Potsdam, Germany
| | - Alexandra Chadt
- Institute for Clinical Biochemistry and Pathobiochemistry, German Diabetes Center (DDZ), Leibniz Center for Diabetes Research at Heinrich Heine University, Medical Faculty, Duesseldorf, Germany.,German Center for Diabetes Research (DZD), München-Neuherberg, Germany
| | - Hadi Al-Hasani
- Institute for Clinical Biochemistry and Pathobiochemistry, German Diabetes Center (DDZ), Leibniz Center for Diabetes Research at Heinrich Heine University, Medical Faculty, Duesseldorf, Germany. .,German Center for Diabetes Research (DZD), München-Neuherberg, Germany.
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32
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Michailidou Z, Gomez-Salazar M, Alexaki VI. Innate Immune Cells in the Adipose Tissue in Health and Metabolic Disease. J Innate Immun 2021; 14:4-30. [PMID: 33849008 DOI: 10.1159/000515117] [Citation(s) in RCA: 76] [Impact Index Per Article: 19.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2020] [Accepted: 02/09/2021] [Indexed: 11/19/2022] Open
Abstract
Metabolic disorders, such as obesity, type 2 diabetes mellitus, and nonalcoholic fatty liver disease, are characterized by chronic low-grade tissue and systemic inflammation. During obesity, the adipose tissue undergoes immunometabolic and functional transformation. Adipose tissue inflammation is driven by innate and adaptive immune cells and instigates insulin resistance. Here, we discuss the role of innate immune cells, that is, macrophages, neutrophils, eosinophils, natural killer cells, innate lymphoid type 2 cells, dendritic cells, and mast cells, in the adipose tissue in the healthy (lean) and diseased (obese) state and describe how their function is shaped by the obesogenic microenvironment, and humoral, paracrine, and cellular interactions. Moreover, we particularly outline the role of hypoxia as a central regulator in adipose tissue inflammation. Finally, we discuss the long-lasting effects of adipose tissue inflammation and its potential reversibility through drugs, caloric restriction, or exercise training.
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Affiliation(s)
- Zoi Michailidou
- Centre for Cardiovascular Sciences, Edinburgh University, Edinburgh, United Kingdom
| | - Mario Gomez-Salazar
- Centre for Cardiovascular Sciences, Edinburgh University, Edinburgh, United Kingdom
| | - Vasileia Ismini Alexaki
- Institute for Clinical Chemistry and Laboratory Medicine, Medical Faculty, Technische Universität Dresden, Dresden, Germany
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Velickovic M, Arsenijevic A, Acovic A, Arsenijevic D, Milovanovic J, Dimitrijevic J, Todorovic Z, Milovanovic M, Kanjevac T, Arsenijevic N. Galectin-3, Possible Role in Pathogenesis of Periodontal Diseases and Potential Therapeutic Target. Front Pharmacol 2021; 12:638258. [PMID: 33815121 PMCID: PMC8017193 DOI: 10.3389/fphar.2021.638258] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2020] [Accepted: 02/11/2021] [Indexed: 12/11/2022] Open
Abstract
Periodontal diseases are chronic inflammatory diseases that occur due to the imbalance between microbial communities in the oral cavity and the immune response of the host that lead to destruction of tooth supporting structures and finally to alveolar bone loss. Galectin-3 is a β-galactoside-binding lectin with important roles in numerous biological processes. By direct binding to microbes and modulation of their clearence, Galectin-3 can affect the composition of microbial community in the oral cavity. Galectin-3 also modulates the function of many immune cells in the gingiva and gingival sulcus and thus can affect immune homeostasis. Few clinical studies demonstrated increased expression of Galectin-3 in different forms of periodontal diseases. Therefore, the objective of this mini review is to discuss the possible effects of Galectin-3 on the process of immune homeostasis and the balance between oral microbial community and host response and to provide insights into the potential therapeutic targeting of Gal-3 in periodontal disease.
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Affiliation(s)
- Milica Velickovic
- Department of Dentistry, Faculty of Medical Sciences, University of Kragujevac, Kragujevac, Serbia
| | - Aleksandar Arsenijevic
- Center for Molecular Medicine and Stem Cell Research, Faculty of Medical Sciences, University of Kragujevac, Kragujevac, Serbia
| | - Aleksandar Acovic
- Department of Dentistry, Faculty of Medical Sciences, University of Kragujevac, Kragujevac, Serbia
| | - Dragana Arsenijevic
- Department of Pharmacy, Faculty of Medical Sciences, University of Kragujevac, Kragujevac, Serbia
| | - Jelena Milovanovic
- Center for Molecular Medicine and Stem Cell Research, Faculty of Medical Sciences, University of Kragujevac, Kragujevac, Serbia.,Department of Histology and Embriology, Faculty of Medical Sciences, University of Kragujevac, Kragujevac, Serbia
| | - Jelena Dimitrijevic
- Center for Molecular Medicine and Stem Cell Research, Faculty of Medical Sciences, University of Kragujevac, Kragujevac, Serbia
| | - Zeljko Todorovic
- Department of Internal Medicine, Faculty of Medical Sciences, University of Kragujevac, Kragujevac, Serbia
| | - Marija Milovanovic
- Center for Molecular Medicine and Stem Cell Research, Faculty of Medical Sciences, University of Kragujevac, Kragujevac, Serbia
| | - Tatjana Kanjevac
- Department of Dentistry, Faculty of Medical Sciences, University of Kragujevac, Kragujevac, Serbia
| | - Nebojsa Arsenijevic
- Center for Molecular Medicine and Stem Cell Research, Faculty of Medical Sciences, University of Kragujevac, Kragujevac, Serbia
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34
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Saeed M, Tapia G, Ariansen I, Stene LC, Seljeflot I, Tell GS, Skrivarhaug T, Joner G. Serum Galectin-3 and Subsequent Risk of Coronary Heart Disease in Subjects With Childhood-Onset Type 1 Diabetes: A Cohort Study. Diabetes Care 2021; 44:810-816. [PMID: 33408220 PMCID: PMC7896257 DOI: 10.2337/dc20-1712] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/08/2020] [Accepted: 12/07/2020] [Indexed: 02/03/2023]
Abstract
OBJECTIVE To study whether serum galectin-3 and other biomarkers of inflammation predict coronary heart disease (CHD) in subjects with long-standing childhood-onset type 1 diabetes. RESEARCH DESIGN AND METHODS A population-based nationwide cohort of 299 subjects with type 1 diabetes diagnosed in Norway at <15 years of age during 1973-1982 was examined in 2002-2003 at a mean age of 33 years (range 21-44), with mean diabetes duration of 24 years (range 19-30). Subjects were followed through 31 December 2017 for their first CHD event registered by a hospitalization or cause of death using nationwide registries. Stored serum samples were available for 296 subjects and analyzed for interleukin-6 (IL-6), IL-6 receptor, IL-18, hs-CRP, matrix metalloproteinase-9, tissue inhibitor of metalloproteinase-1 (TIMP-1), galectin-3, and high-sensitivity troponin T. Adjusted hazard ratios (aHRs) for CHD per SD increase in biomarker were estimated using Cox regression. RESULTS Of 295 subjects, 40 (13.6%) had a documented CHD event during a mean follow-up of 14.4 years (range 0.5-16). IL-6 (aHR 1.32 [95% CI 1.07-1.63]), galectin-3 (aHR 1.44 [95% CI 1.09-1.80]), and TIMP-1 (aHR 1.37 [95% CI 1.04-1.81]) were significant predictors of CHD after adjustment for conventional risk factors. CONCLUSIONS Galectin-3 was significantly associated with future CHD in subjects with type 1 diabetes, and if the results are replicated in larger studies, it may aid in prediction together with conventional risk factors for CHD.
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Affiliation(s)
- Maryam Saeed
- Division of Pediatric and Adolescent Medicine, Oslo University Hospital, Oslo, Norway .,Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway
| | - German Tapia
- Department of Chronic Diseases and Ageing, Norwegian Institute of Public Health, Oslo, Norway
| | - Inger Ariansen
- Department of Chronic Diseases and Ageing, Norwegian Institute of Public Health, Oslo, Norway
| | - Lars C Stene
- Department of Chronic Diseases and Ageing, Norwegian Institute of Public Health, Oslo, Norway
| | - Ingebjørg Seljeflot
- Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway.,Department of Cardiology, Center for Clinical Heart Research, Oslo University Hospital, Oslo, Norway
| | - Grethe S Tell
- Department of Chronic Diseases and Ageing, Norwegian Institute of Public Health, Oslo, Norway.,Department of Global Public Health and Primary Care, University of Bergen, Bergen, Norway
| | - Torild Skrivarhaug
- Division of Pediatric and Adolescent Medicine, Oslo University Hospital, Oslo, Norway.,Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway
| | - Geir Joner
- Division of Pediatric and Adolescent Medicine, Oslo University Hospital, Oslo, Norway.,Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway
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35
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Blasetti Fantauzzi C, Iacobini C, Menini S, Vitale M, Sorice GP, Mezza T, Cinti S, Giaccari A, Pugliese G. Galectin-3 gene deletion results in defective adipose tissue maturation and impaired insulin sensitivity and glucose homeostasis. Sci Rep 2020; 10:20070. [PMID: 33208796 PMCID: PMC7675972 DOI: 10.1038/s41598-020-76952-z] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2019] [Accepted: 10/26/2020] [Indexed: 12/11/2022] Open
Abstract
Adiposopathy is a pathological adipose tissue (AT) response to overfeeding characterized by reduced AT expandability due to impaired adipogenesis, which favors inflammation, insulin resistance (IR), and abnormal glucose regulation. However, it is unclear whether defective adipogenesis causes metabolic derangement also independently of an increased demand for fat storage. As galectin-3 has been implicated in both adipocyte differentiation and glucose homeostasis, we tested this hypothesis in galectin-3 knockout (Lgal3-/-) mice fed a standard chow. In vitro, Lgal3-/- adipocyte precursors showed impaired terminal differentiation (maturation). Two-month-old Lgal3-/- mice showed impaired AT maturation, with reduced adipocyte size and expression of adipogenic genes, but unchanged fat mass and no sign of adipocyte degeneration/death or ectopic fat accumulation. AT immaturity was associated with AT and whole-body inflammation and IR, glucose intolerance, and hyperglycemia. Five-month-old Lgal3-/- mice exhibited a more mature AT phenotype, with no difference in insulin sensitivity and expression of inflammatory cytokines versus WT animals, though abnormal glucose homeostasis persisted and was associated with reduced β-cell function. These data show that adipogenesis capacity per se affects AT function, insulin sensitivity, and glucose homeostasis independently of increased fat intake, accumulation and redistribution, thus uncovering a direct link between defective adipogenesis, IR and susceptibility to diabetes.
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Affiliation(s)
- Claudia Blasetti Fantauzzi
- Department of Clinical and Molecular Medicine, "La Sapienza" University, Via di Grottarossa, 1035-1039, 00189, Rome, Italy
| | - Carla Iacobini
- Department of Clinical and Molecular Medicine, "La Sapienza" University, Via di Grottarossa, 1035-1039, 00189, Rome, Italy
| | - Stefano Menini
- Department of Clinical and Molecular Medicine, "La Sapienza" University, Via di Grottarossa, 1035-1039, 00189, Rome, Italy
| | - Martina Vitale
- Department of Clinical and Molecular Medicine, "La Sapienza" University, Via di Grottarossa, 1035-1039, 00189, Rome, Italy
| | - Gian Pio Sorice
- Centre for Endocrine and Metabolic Diseases, Fondazione Policlinico Universitario A. Gemelli IRCCS, Catholic University, Rome, Italy
| | - Teresa Mezza
- Centre for Endocrine and Metabolic Diseases, Fondazione Policlinico Universitario A. Gemelli IRCCS, Catholic University, Rome, Italy
| | - Saverio Cinti
- Department of Experimental and Clinical Medicine, Center of Obesity, University of Ancona (Politecnica delle Marche), Ancona, Italy
| | - Andrea Giaccari
- Centre for Endocrine and Metabolic Diseases, Fondazione Policlinico Universitario A. Gemelli IRCCS, Catholic University, Rome, Italy
| | - Giuseppe Pugliese
- Department of Clinical and Molecular Medicine, "La Sapienza" University, Via di Grottarossa, 1035-1039, 00189, Rome, Italy.
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36
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ASC, IL-18 and Galectin-3 as Biomarkers of Non-Alcoholic Steatohepatitis: A Proof of Concept Study. Int J Mol Sci 2020; 21:ijms21228580. [PMID: 33203036 PMCID: PMC7698245 DOI: 10.3390/ijms21228580] [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: 09/25/2020] [Revised: 11/11/2020] [Accepted: 11/12/2020] [Indexed: 12/14/2022] Open
Abstract
Non-alcoholic steatohepatitis (NASH) is a severe form of non-alcoholic fatty liver disease that is growing in prevalence. Symptoms of NASH become apparent when the disease has progressed significantly. Thus, there is a need to identify biomarkers of NASH in order to detect the disease earlier and to monitor disease severity. The inflammasome has been shown to play a role in liver diseases. Here, we performed a proof of concept study of biomarker analyses (cut-off points, positive and negative predictive values, receiver operating characteristic (ROC) curves, and likelihood ratios) on the serum of patients with NASH and healthy controls on apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC), interleukin (IL)-18, Galectin-3 (Gal-3), and C-reactive protein (CRP). ASC, IL-18, and Gal-3 were elevated in the serum of NASH patients when compared to controls. The area under the curve (AUC) for ASC was the highest (0.7317) with an accuracy of 68%, followed by IL-18 (0.7036) with an accuracy of 66% and Gal-3 (0.6891) with an accuracy of 61%. Moreover, we then fit a stepwise multivariate logistic regression model using ASC, IL-18, and Gal-3 to determine the probability of patients having a NASH diagnosis, which resulted in an AUC of 0.71 and an accuracy of 79%, indicating that combining these biomarkers increases their diagnostic potential for NASH. These results indicate that ASC, IL-18, and Gal-3 are reliable biomarkers of NASH and that combining these analytes increases the biomarker potential of these proteins.
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37
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Diniz Pereira J, Gomes Fraga V, Morais Santos AL, Carvalho MDG, Caramelli P, Braga Gomes K. Alzheimer's disease and type 2 diabetes mellitus: A systematic review of proteomic studies. J Neurochem 2020; 156:753-776. [PMID: 32909269 DOI: 10.1111/jnc.15166] [Citation(s) in RCA: 52] [Impact Index Per Article: 10.4] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2020] [Revised: 07/15/2020] [Accepted: 08/25/2020] [Indexed: 12/16/2022]
Abstract
Similar to dementia, the risk for developing type 2 diabetes mellitus (T2DM) increases with age, and T2DM also increases the risk for dementia, particularly Alzheimer's disease (AD). Although T2DM is primarily a peripheral disorder and AD is a central nervous system disease, both share some common features as they are chronic and complex diseases, and both show involvement of oxidative stress and inflammation in their progression. These characteristics suggest that T2DM may be associated with AD, which gave rise to a new term, type 3 diabetes (T3DM). In this study, we searched for matching peripheral proteomic biomarkers of AD and T2DM based in a systematic review of the available literature. We identified 17 common biomarkers that were differentially expressed in both patients with AD or T2DM when compared with healthy controls. These biomarkers could provide a useful workflow for screening T2DM patients at risk to develop AD.
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Affiliation(s)
- Jessica Diniz Pereira
- Departamento de Análises Clínicas e Toxicológicas, Faculdade de Farmácia, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil
| | - Vanessa Gomes Fraga
- Departamento de Análises Clínicas e Toxicológicas, Faculdade de Farmácia, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil
| | - Anna Luiza Morais Santos
- Departamento de Análises Clínicas e Toxicológicas, Faculdade de Farmácia, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil
| | - Maria das Graças Carvalho
- Departamento de Análises Clínicas e Toxicológicas, Faculdade de Farmácia, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil
| | - Paulo Caramelli
- Departamento de Clínica Médica, Faculdade de Medicina, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil
| | - Karina Braga Gomes
- Departamento de Análises Clínicas e Toxicológicas, Faculdade de Farmácia, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil
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38
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Li J, Guo Y, Chen YY, Liu Q, Chen Y, Tan L, Zhang SH, Gao ZR, Zhou YH, Zhang GY, Feng YZ. miR-124-3p increases in high glucose induced osteocyte-derived exosomes and regulates galectin-3 expression: A possible mechanism in bone remodeling alteration in diabetic periodontitis. FASEB J 2020; 34:14234-14249. [PMID: 32833280 DOI: 10.1096/fj.202000970rr] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2020] [Revised: 07/26/2020] [Accepted: 07/29/2020] [Indexed: 12/19/2022]
Abstract
The mechanisms underlying the two-way relationship between diabetes mellitus (DM) and periodontitis are unclear. We examined a possible effect of galectin-3 (Gal-3), a factor in DM and bone metabolism, on periodontitis with or without DM. Using enzyme-linked immunosorbent assay, we detected saliva Gal-3 in patients with periodontitis, with or without type 2 diabetes mellitus (T2DM). In animal models, we measured periodontal bone microarchitecture via micro computed tomography, and detected Gal-3, Runt-related transcription factor 2 (Runx2), and interleukin-6 (IL-6) expression in alveolar bone. Applying dual luciferase reporter assay, we explored the target binding of miR-124-3p and Gal-3. We examined osteocyte-derived exosomes with transmission electron microscopy and detected miR-124-3p, Gal-3, and IL-6 expression in exosomes. Saliva Gal-3 was increased in DM compared with controls but decreased in patients with moderate periodontitis and DM compared with those who had moderate periodontitis only. Alveolar bone mass was increased in DM and exacerbated in DM with periodontitis. Gal-3 and Runx2 were both increased in periodontitis and DM compared with controls, but decreased in DM with periodontitis compared with DM alone. MiR-124-3p targeted and inhibited Gal-3 expression in vitro. Osteocytes secreted exosomes carrying miR-124-3p, Gal-3, and IL-6, which were influenced by high glucose. These findings indicate that osteocyte-derived exosomes carrying miR-124-3p may regulate Gal-3 expression of osteoblasts, especially under high-glucose conditions, suggesting a possible mechanism for DM-related alveolar bone pathologies.
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Affiliation(s)
- Jun Li
- Department of Stomatology, The Second Xiangya Hospital, Central South University, Changsha, China
| | - Yue Guo
- Department of Stomatology, The Second Xiangya Hospital, Central South University, Changsha, China
| | - Ying-Yi Chen
- Department of Stomatology, The Second Xiangya Hospital, Central South University, Changsha, China
| | - Qiong Liu
- Department of Stomatology, The Second Xiangya Hospital, Central South University, Changsha, China
| | - Yun Chen
- Department of Stomatology, The Second Xiangya Hospital, Central South University, Changsha, China
| | - Li Tan
- Department of Stomatology, The Second Xiangya Hospital, Central South University, Changsha, China
| | - Shao-Hui Zhang
- Department of Stomatology, The Second Xiangya Hospital, Central South University, Changsha, China
| | - Zheng-Rong Gao
- Department of Stomatology, The Second Xiangya Hospital, Central South University, Changsha, China
| | - Ying-Hui Zhou
- Department of Endocrinology, The Second Xiangya Hospital, Central South University, Changsha, China
| | - Gui-Ying Zhang
- Department of Dermatology, The Second Xiangya Hospital, Central South University, Changsha, China
| | - Yun-Zhi Feng
- Department of Stomatology, The Second Xiangya Hospital, Central South University, Changsha, China
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39
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Åkra S, Aksnes TA, Flaa A, Eggesbø HB, Opstad TB, Njerve IU, Seljeflot I. Markers of remodeling in subcutaneous adipose tissue are strongly associated with overweight and insulin sensitivity in healthy non-obese men. Sci Rep 2020; 10:14055. [PMID: 32820223 PMCID: PMC7441176 DOI: 10.1038/s41598-020-71109-4] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2020] [Accepted: 08/06/2020] [Indexed: 12/21/2022] Open
Abstract
Alteration in extracellular matrix (ECM) in adipose tissues (AT) has been associated with insulin resistance, diabetes and obesity. We investigated whether selected biomarkers of ECM remodeling in AT in healthy subjects associated with the amount and distribution of AT and with glucometabolic variables. Subcutaneous AT and fasting blood samples from 103 middle-aged healthy non-obese men were used. AT gene expression and circulating levels of the biomarkers were quantified. Distribution of AT was assessed by computed tomography, separated into subcutaneous, deep subcutaneous and visceral AT. Insulin sensitivity was measured by glucose clamp technique. Metalloproteinase (MMP)-9, tissue inhibitor of MMP (TIMP)-1 and plasminogen activator inhibitor (PAI)-1 expression in AT correlated significantly to the amount of AT in all compartments (rs = 0.41-0.53, all p ≤ 0.01), and to insulin sensitivity, insulin, C-peptide, waist circumference and body mass index (BMI) (rs = 0.25-0.57, all p ≤ 0.05). MMP-9 was 5.3 fold higher in subjects with insulin sensitivity below median (p = 0.002) and 3.1 fold higher in subjects with BMI above median level (p = 0.013). In our healthy non-obese middle-aged population AT-expressed genes, central in remodeling of ECM, associated strongly with the amount of abdominal AT, overweight and insulin sensitivity, indicating AT-remodeling to play a role also in non-obese individuals. The remodeling process seems furthermore to associate significantly with glucometabolic disturbances.Trial registration: ClinicalTrials.gov, NCT01412554. Registered 9 August 2011, https://clinicaltrials.gov/ct2/show/NCT01412554?term=NCT01412554 .
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Affiliation(s)
- Sissel Åkra
- Department of Cardiology, Center for Clinical Heart Research, Oslo University Hospital, Ullevål, Pb 4956 Nydalen, 0424, Oslo, Norway.
| | - Tonje A Aksnes
- Section of Cardiovascular and Renal Research, Oslo University Hospital, Oslo, Norway.,Section for Interventional Cardiology, Department of Cardiology, Heart-, Lung-, and Vascular-Disease Clinic, Oslo University Hospital, Oslo, Norway
| | - Arnljot Flaa
- Section of Cardiovascular and Renal Research, Oslo University Hospital, Oslo, Norway.,Department of Cardiology, Oslo University Hospital, Ullevål, Oslo, Norway
| | - Heidi B Eggesbø
- Division of Radiology and Nuclear Medicine, Oslo University Hospital, Oslo, Norway
| | - Trine Baur Opstad
- Department of Cardiology, Center for Clinical Heart Research, Oslo University Hospital, Ullevål, Pb 4956 Nydalen, 0424, Oslo, Norway.,Faculty of Medicine, University of Oslo, Oslo, Norway
| | - Ida U Njerve
- Department of Cardiology, Center for Clinical Heart Research, Oslo University Hospital, Ullevål, Pb 4956 Nydalen, 0424, Oslo, Norway
| | - Ingebjørg Seljeflot
- Department of Cardiology, Center for Clinical Heart Research, Oslo University Hospital, Ullevål, Pb 4956 Nydalen, 0424, Oslo, Norway.,Department of Cardiology, Oslo University Hospital, Ullevål, Oslo, Norway.,Faculty of Medicine, University of Oslo, Oslo, Norway
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40
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Freitag N, Tirado-González I, Barrientos G, Cohen M, Daher S, Goldman-Wohl D, Mincheva-Nilsson L, John CM, Jeschke U, Blois SM. The chimera-type galectin-3 is a positive modulator of trophoblast functions with dysregulated expression in gestational diabetes mellitus. Am J Reprod Immunol 2020; 84:e13311. [PMID: 32691950 DOI: 10.1111/aji.13311] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2020] [Revised: 07/15/2020] [Accepted: 07/16/2020] [Indexed: 12/24/2022] Open
Abstract
PROBLEM From conception, a delicate regulation of galectins, a family of carbohydrate-binding proteins, is established to ensure maternal immune tolerance in pregnancy. Though galectin-3 (gal-3), the only chimera-type galectin, is abundantly expressed at the feto-maternal interface; the physiological role of this lectin during pregnancy remains to be fully elucidated and requires further investigation. METHOD OF STUDY In this study, we analyzed serum gal-3 levels during the course of healthy gestation. Trophoblast functions were evaluated upon gal-3 exogenous stimulation using trophoblastic cell lines (e.g. , HIPEC65, SGHPL-4, and BeWo cells). Finally, we investigated variations in peripheral gal-3 levels associated with the development of spontaneous abortion and gestational diabetes mellitus (GDM). RESULTS Gal-3 circulating levels increased as normal pregnancy progressed. In vitro experiments showed that exogenous gal-3 positively regulated trophoblast functions inducing invasion, tube formation, and fusion. Compared with normal pregnant women, circulating gal-3 levels were significantly decreased in patients who developed GDM. CONCLUSION Our results reveal a physiological role for gal-3 during pregnancy, promoting proper trophoblast functions associated with healthy gestation. GDM is associated with a failure to increase circulating gal-3 levels late in gestation. Thus, dysregulation of gal-3 may indicate a contribution of the chimera-type lectin to this adverse pregnancy outcome.
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Affiliation(s)
- Nancy Freitag
- Experimental and Clinical Research Center, a Cooperation between the Max Delbrück Center for Molecular Medicine in the Helmholtz Association, AG GlycoImmunology, the Charité - Universitätsmedizin Berlin, Berlin, Germany.,Division of General Internal and Psychosomatic Medicine, Corporate Member of Freie Universität Berlin, Humboldt- Universität zu Berlin, and Berlin Institute of Health, Charité- Universitätsmedizin Berlin, Berlin, Germany
| | - Irene Tirado-González
- Experimental and Clinical Research Center, a Cooperation between the Max Delbrück Center for Molecular Medicine in the Helmholtz Association, AG GlycoImmunology, the Charité - Universitätsmedizin Berlin, Berlin, Germany
| | - Gabriela Barrientos
- Laboratory of Experimental Medicine, Hospital Alemán, CONICET, Buenos Aires, Argentina
| | - Marie Cohen
- Department of Paediatrics, Gynaecology and Obstetrics, Geneva University Hospitals, Geneva, Switzerland
| | - Silvia Daher
- Department of Obstetrics, Universidade Federal de São Paulo, São Paulo, Brazil
| | - Debra Goldman-Wohl
- Department of Obstetrics and Gynecology, The Magda and Richard Hoffman Center for Human Placenta Research, Hadassah-Hebrew University Medical Center, Jerusalem, Israel
| | - Lucia Mincheva-Nilsson
- Department of Clinical Microbiology, Infection and Immunology, Umeå University, Umeå, Sweden
| | | | - Udo Jeschke
- Department of Obstetrics and Gynecology, University Hospital, LMU Munich, Munich, Germany
| | - Sandra M Blois
- Experimental and Clinical Research Center, a Cooperation between the Max Delbrück Center for Molecular Medicine in the Helmholtz Association, AG GlycoImmunology, the Charité - Universitätsmedizin Berlin, Berlin, Germany.,Department of Obstetrics and Fetal Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
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41
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Sun MJ, Cao ZQ, Leng P. The roles of galectins in hepatic diseases. J Mol Histol 2020; 51:473-484. [PMID: 32734557 DOI: 10.1007/s10735-020-09898-1] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2020] [Accepted: 07/14/2020] [Indexed: 12/24/2022]
Abstract
Hepatic diseases include all diseases that occur in the liver, including hepatitis, cirrhosis, hepatocellular carcinoma, etc. Hepatic diseases worldwide are characterized by high incidences of digestive system diseases, which present with subtle symptoms, are difficult to treat and have high mortality. Galectins are β-galactoside-binding proteins that have been found to be aberrantly expressed during hepatic disease progression. An increasing number of studies have shown that abnormal expression of galectins is extensively involved in hepatic diseases, such as hepatocellular carcinoma (HCC), liver cirrhosis, hepatitis and liver fibrosis. Galectins function as intracellular and extracellular hepatic disease regulators mainly through the binding of their carbohydrate recognition domain to glycoconjugates expressed in hepatocytes. In this review, we summarize current research on the various roles of galectins in cirrhosis, hepatitis, liver fibrosis and HCC, which may provide a preliminary theoretical basis for the exploration of new targets for the treatment of hepatic diseases.
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Affiliation(s)
- Mei-Juan Sun
- Department of Pharmacy, The Affiliated Hospital of Qingdao University, No. 16 Jiang Su Road, Qingdao, 266003, People's Republic of China
| | - Zhan-Qi Cao
- Department of Pharmacy, The Affiliated Hospital of Qingdao University, No. 16 Jiang Su Road, Qingdao, 266003, People's Republic of China
| | - Ping Leng
- Department of Pharmacy, The Affiliated Hospital of Qingdao University, No. 16 Jiang Su Road, Qingdao, 266003, People's Republic of China.
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42
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Menini S, Iacobini C, Vitale M, Pugliese G. The Inflammasome in Chronic Complications of Diabetes and Related Metabolic Disorders. Cells 2020; 9:E1812. [PMID: 32751658 PMCID: PMC7464565 DOI: 10.3390/cells9081812] [Citation(s) in RCA: 54] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2020] [Revised: 07/24/2020] [Accepted: 07/28/2020] [Indexed: 12/14/2022] Open
Abstract
Diabetes mellitus (DM) ranks seventh as a cause of death worldwide. Chronic complications, including cardiovascular, renal, and eye disease, as well as DM-associated non-alcoholic fatty liver disease (NAFLD) account for most of the morbidity and premature mortality in DM. Despite continuous improvements in the management of late complications of DM, significant gaps remain. Therefore, searching for additional strategies to prevent these serious DM-related conditions is of the utmost importance. DM is characterized by a state of low-grade chronic inflammation, which is critical in the progression of complications. Recent clinical trials indicate that targeting the prototypic pro-inflammatory cytokine interleukin-1β (IL-1 β) improves the outcomes of cardiovascular disease, which is the first cause of death in DM patients. Together with IL-18, IL-1β is processed and secreted by the inflammasomes, a class of multiprotein complexes that coordinate inflammatory responses. Several DM-related metabolic factors, including reactive oxygen species, glyco/lipoxidation end products, and cholesterol crystals, have been involved in the pathogenesis of diabetic kidney disease, and diabetic retinopathy, and in the promoting effect of DM on the onset and progression of atherosclerosis and NAFLD. These metabolic factors are also well-established danger signals capable of regulating inflammasome activity. In addition to presenting the current state of knowledge, this review discusses how the mechanistic understanding of inflammasome regulation by metabolic danger signals may hopefully lead to novel therapeutic strategies targeting inflammation for a more effective treatment of diabetic complications.
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Affiliation(s)
| | | | | | - Giuseppe Pugliese
- Department of Clinical and Molecular Medicine, “La Sapienza” University, 00189 Rome, Italy; (S.M.); (C.I.); (M.V.)
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Meng F, Hao P, Du H, Zhou Z. Effects of Adenovirus-Mediated Overexpression of JAZF1 on Chronic Inflammation: An In Vitro and In Vivo Study. Med Sci Monit Basic Res 2020; 26:e924124. [PMID: 32655126 PMCID: PMC7377004 DOI: 10.12659/msmbr.924124] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022] Open
Abstract
BACKGROUND Insulin sensitivity and inflammation can be affected by juxtaposition with another zinc finger gene 1 (JAZF1), but its precise role in chronic inflammation is unclear. In this study, JAZF1-overexpression adenovirus plasmids were transfected into macrophages, CD4⁺ T cells, and C57BL/6J mice to assess the role of JAZF1 in chronic inflammation. MATERIAL AND METHODS JAZF1 was cloned into an adenovirus skeleton plasmid and transfected in HEK293 cells to package and enrich the virus particles. In vitro, the JAZF1 overexpression adenovirus vector (PAD-JAZF1) was cultured with peritoneal macrophages and peripheral blood CD4⁺ T cells of C57BL/6J mice, and samples were evaluated using flow cytometry. In vivo, PAD-JAZF1 was introduced into C57BL/6J mice, and livers were collected to evaluate factors related to inflammation by hematoxylin & eosin and immunohistochemical staining. RESULTS In vitro, PAD-JAZF1 decreased total macrophages, CD11c⁺ macrophages, and the secretion of proinflammatory cytokines, but increased CD206⁺ macrophages. It also decreased total CD4⁺T cells, active T cells, memory T cells, and the secretion of IL-6, IL-10, and IFN-γ, but increased Treg cells and restrictive T cells. In vivo, compared to those in the control group transfected with the adenovirus skeleton vector, mice transfected with the PAD-JAZF1 recombinant adenovirus had fewer CD11c⁺ ATMs and CD4⁺ T cells, lower levels of TNF-alpha and IL-6, and higher IL-10 concentrations in the liver. CONCLUSIONS These findings indicate that JAZF1 limits chronic inflammation by reducing macrophage and CD4⁺T cell populations, altering subtype differentiation, and regulating the secretion of immune-related factors.
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Affiliation(s)
- Fanping Meng
- Gene Diagnostics Center of Medical Laboratory, Chongqing Three Gorges Central Hospital, Chongqing, China (mainland)
| | - Po Hao
- Department of Medical Technology, Chongqing Three Gorges Medical College, Chongqing, China (mainland)
| | - Hongxin Du
- Gene Diagnostics Center of Medical Laboratory, Chongqing Three Gorges Central Hospital, Chongqing, China (mainland)
| | - Zheng Zhou
- Gene Diagnostics Center of Medical Laboratory, Chongqing Three Gorges Central Hospital, Chongqing, China (mainland)
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Weber M, Söder S, Sander J, Ries J, Geppert C, Kesting M, Wehrhan F. Craniofacial Osteosarcoma-Pilot Study on the Expression of Osteobiologic Characteristics and Hypothesis on Metastasis. Front Oncol 2020; 10:745. [PMID: 32656074 PMCID: PMC7325581 DOI: 10.3389/fonc.2020.00745] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2019] [Accepted: 04/20/2020] [Indexed: 02/05/2023] Open
Abstract
Background: Craniofacial osteosarcomas (COS) and extracranial osteosarcomas (EOS) show distinct clinical differences. COS show a remarkably lower incidence of metastases and a better survival. However, in contrast to EOS, they show a poor response to neoadjuvant chemotherapy. Tumor-associated macrophages and their polarization as well as developmental biological signaling pathways are possible candidates for explaining the clinical differences between COS and EOS. The aim of the study was to analyze differential expression of macrophage markers and important regulators of these pathways. Methods: Twenty osteosarcoma cases (10 COS and 10 EOS) were immunohistochemically stained to assess CD68, CD11c, CD163, MRC1, Gli1, and Gli2 expression. Statistical differences between COS and EOS were tested using the Mann–Whitney U test. Additionally, the paper describes an example of multidisciplinary treatment of a patient suffering from COS and discusses the surgical challenges in treatment and rehabilitation of COS. Results: COS showed a significantly (p < 0.05) increased infiltration of CD11c-positive M1 macrophages and a shift toward M1 polarization compared to EOS. Additionally, COS revealed a significantly (p < 0.05) lower Gli1 expression than EOS. Conclusion: The reduced Gli1 expression in COS can be interpreted as reduced activation of the Hedgehog (Hh) signaling pathway. The increased M1 polarization and reduced Hh activation in COS could explain the low incidence of metastases in these osteosarcomas.
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Affiliation(s)
- Manuel Weber
- Department of Oral and Maxillofacial Surgery, Friedrich-Alexander University Erlangen-Nürnberg (FAU), Erlangen, Germany
| | | | - Janina Sander
- Department of Oral and Maxillofacial Surgery, Friedrich-Alexander University Erlangen-Nürnberg (FAU), Erlangen, Germany
| | - Jutta Ries
- Department of Oral and Maxillofacial Surgery, Friedrich-Alexander University Erlangen-Nürnberg (FAU), Erlangen, Germany
| | - Carol Geppert
- Institute of Pathology, Friedrich-Alexander University Erlangen-Nürnberg (FAU), Erlangen, Germany
| | - Marco Kesting
- Department of Oral and Maxillofacial Surgery, Friedrich-Alexander University Erlangen-Nürnberg (FAU), Erlangen, Germany
| | - Falk Wehrhan
- Department of Oral and Maxillofacial Surgery, Friedrich-Alexander University Erlangen-Nürnberg (FAU), Erlangen, Germany
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Sun J, Zhang L, Fang J, Yang S, Chen L. Galectin-3 mediates high-glucose-induced cardiomyocyte injury by the NADPH oxidase/reactive oxygen species pathway. Can J Physiol Pharmacol 2020; 98:826-833. [PMID: 32311288 DOI: 10.1139/cjpp-2019-0708] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/20/2023]
Abstract
Galectin-3 is a member of the β-galactoside-binding lectin family taking part in the regulation of inflammation, angiogenesis, and fibrosis. This study was designed to study the improved effect of galectin-3 inhibition on diabetic cardiomyopathy (DCM). Sprague-Dawley rats were randomized into the control, DCM, and DCM + modified citrus pectin (MCP) (a galectin-3 pharmacological inhibitor) groups. After 8 weeks, streptozotocin-induced DCM led to high blood glucose level, oxidative stress, cardiac injury, and dysfunction accompanied by suppressed body mass. On the contrary, MCP (100 mg·kg-1·day-1) administration improved body mass and blood glucose level and attenuated cardiac injury and dysfunction in DCM rats. Additionally, MCP attenuated pathological changes in plasma and myocardial tissue markers of oxidative stress, such as hydrogen peroxide and malonyldialdehyde, although it did not change superoxide dismutase activities, which were decreased in the DCM group. The levels of oxidative stress associated proteins evaluated by Western blot, such as p67phox and NADPH oxidase 4, were obviously increased in the DCM group, while they were reversed by MCP treatment. Therefore, galectin-3-mediated high-glucose-induced cardiomyocyte injury and galectin-3 inhibition attenuated DCM by suppressing NADPH oxidase. These findings suggested that galectin-3 could be a potential target for treatment of patients with DCM.
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Affiliation(s)
- Jingang Sun
- Linyi Central Hospital, Linyi, China, 276400
| | | | | | - Shuguo Yang
- Linyi Central Hospital, Linyi, China, 276400
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Le Bagge S, Fotheringham AK, Leung SS, Forbes JM. Targeting the receptor for advanced glycation end products (RAGE) in type 1 diabetes. Med Res Rev 2020; 40:1200-1219. [PMID: 32112452 DOI: 10.1002/med.21654] [Citation(s) in RCA: 30] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2019] [Revised: 11/09/2019] [Accepted: 11/12/2019] [Indexed: 12/18/2022]
Abstract
Type 1 diabetes (T1D) is one of the most common chronic diseases manifesting in early life, with the prevalence increasing worldwide at a rate of approximately 3% per annum. The prolonged hyperglycaemia characteristic of T1D upregulates the receptor for advanced glycation end products (RAGE) and accelerates the formation of RAGE ligands, including advanced glycation end products, high-mobility group protein B1, S100 calcium-binding proteins, and amyloid-beta. Interestingly, changes in the expression of RAGE and these ligands are evident in patients before the onset of T1D. RAGE signals via various proinflammatory cascades, resulting in the production of reactive oxygen species and cytokines. A large number of proinflammatory ligands that can signal via RAGE have been implicated in several chronic diseases, including T1D. Therefore, it is unsurprising that RAGE has become a potential therapeutic target for the treatment and prevention of disease. In this review, we will explore how RAGE might be targeted to prevent the development of T1D.
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Affiliation(s)
- Selena Le Bagge
- Glycation and Diabetes, Translational Research Institute (TRI), Mater Research Institute-The University of Queensland (MRI-UQ), Brisbane, Queensland, Australia.,School of Biomedical Sciences, The University of Queensland, Brisbane, Queensland, Australia
| | - Amelia K Fotheringham
- Glycation and Diabetes, Translational Research Institute (TRI), Mater Research Institute-The University of Queensland (MRI-UQ), Brisbane, Queensland, Australia.,School of Biomedical Sciences, The University of Queensland, Brisbane, Queensland, Australia
| | - Sherman S Leung
- Glycation and Diabetes, Translational Research Institute (TRI), Mater Research Institute-The University of Queensland (MRI-UQ), Brisbane, Queensland, Australia.,School of Biomedical Sciences, The University of Queensland, Brisbane, Queensland, Australia
| | - Josephine M Forbes
- Glycation and Diabetes, Translational Research Institute (TRI), Mater Research Institute-The University of Queensland (MRI-UQ), Brisbane, Queensland, Australia.,Baker IDI Heart and Diabetes Institute, Melbourne, Victoria, Australia.,Mater Clinical School, The University of Queensland, Brisbane, Queensland, Australia
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Galectin-3 Is a Potential Mediator for Atherosclerosis. J Immunol Res 2020; 2020:5284728. [PMID: 32149158 PMCID: PMC7042544 DOI: 10.1155/2020/5284728] [Citation(s) in RCA: 73] [Impact Index Per Article: 14.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2019] [Revised: 01/13/2020] [Accepted: 02/04/2020] [Indexed: 12/22/2022] Open
Abstract
Atherosclerosis is a multifactorial chronic inflammatory arterial disease forming the pathological basis of many cardiovascular diseases such as coronary heart disease, heart failure, and stroke. Numerous studies have implicated inflammation as a key player in the initiation and progression of atherosclerosis. Galectin-3 (Gal-3) is a 30 kDa β-galactose, highly conserved and widely distributed intracellularly and extracellularly. Gal-3 has been demonstrated in recent years to be a novel inflammatory factor participating in the process of intravascular inflammation, lipid endocytosis, macrophage activation, cellular proliferation, monocyte chemotaxis, and cell adhesion. This review focuses on the role of Gal-3 in atherosclerosis and the mechanism involved and several classical Gal-3 agonists and antagonists in the current studies.
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Petrovic I, Pejnovic N, Ljujic B, Pavlovic S, Miletic Kovacevic M, Jeftic I, Djukic A, Draginic N, Andjic M, Arsenijevic N, Lukic ML, Jovicic N. Overexpression of Galectin 3 in Pancreatic β Cells Amplifies β-Cell Apoptosis and Islet Inflammation in Type-2 Diabetes in Mice. Front Endocrinol (Lausanne) 2020; 11:30. [PMID: 32117058 PMCID: PMC7018709 DOI: 10.3389/fendo.2020.00030] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/17/2019] [Accepted: 01/15/2020] [Indexed: 12/23/2022] Open
Abstract
Aims/Hypothesis: Galectin 3 appears to play a proinflammatory role in several inflammatory and autoimmune diseases. Also, there is evidence that galectin 3 plays a role in both type-1 and type-2 diabetes. During obesity, hematopoietic cell-derived galectin 3 induces insulin resistance. While the role of galectin 3 expressed in islet-invading immune cells in both type-1 and type-2 diabetes has been studied, the importance of the expression of this molecule on the target pancreatic β cells has not been defined. Methods: To clarify the role of galectin 3 expression in β cells during obesity-induced diabetogenesis, we developed transgenic mice selectively overexpressing galectin 3 in β cells and tested their susceptibility to obesity-induced type-2 diabetes. Obesity was induced with a 16-week high-fat diet regime. Pancreatic β cells were tested for susceptibility to apoptosis induced by non-esterified fatty acids and cytokines as well as parameters of oxidative stress. Results: Our results demonstrated that overexpression of galectin 3 increases β-cell apoptosis in HFD conditions and increases the percentage of proinflammatory F4/80+ macrophages in islets that express galectin 3 and TLR4. In isolated islets, we have shown that galectin 3 overexpression increases cytokine and palmitate-triggered β-cell apoptosis and also increases NO2--induced oxidative stress of β cells. Also, in pancreatic lymph nodes, macrophages were shifted toward a proinflammatory TNF-α-producing phenotype. Conclusions/Interpretation: By complementary in vivo and in vitro approaches, we have shown that galectin 3-overexpression facilitates β-cell damage, enhances cytokine and palmitate-triggered β-cell apoptosis, and increases NO2--induced oxidative stress in β cells. Further, the results suggest that increased expression of galectin 3 in the pancreatic β cells affects the metabolism of glucose and glycoregulation in mice on a high-fat diet, affecting both fasting glycemic values and glycemia after glucose loading.
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Affiliation(s)
- Ivica Petrovic
- Center for Molecular Medicine and Stem Cell Research, Faculty of Medical Sciences, University of Kragujevac, Kragujevac, Serbia
- Department of Pathophysiology, Faculty of Medical Sciences, University of Kragujevac, Kragujevac, Serbia
| | - Nada Pejnovic
- Center for Molecular Medicine and Stem Cell Research, Faculty of Medical Sciences, University of Kragujevac, Kragujevac, Serbia
- Department of Pathophysiology, Faculty of Medical Sciences, University of Kragujevac, Kragujevac, Serbia
| | - Biljana Ljujic
- Department of Genetics, Faculty of Medical Sciences, University of Kragujevac, Kragujevac, Serbia
| | - Sladjana Pavlovic
- Center for Molecular Medicine and Stem Cell Research, Faculty of Medical Sciences, University of Kragujevac, Kragujevac, Serbia
| | - Marina Miletic Kovacevic
- Department of Histology and Embryology, Faculty of Medical Sciences, University of Kragujevac, Kragujevac, Serbia
| | - Ilija Jeftic
- Center for Molecular Medicine and Stem Cell Research, Faculty of Medical Sciences, University of Kragujevac, Kragujevac, Serbia
- Department of Pathophysiology, Faculty of Medical Sciences, University of Kragujevac, Kragujevac, Serbia
| | - Aleksandar Djukic
- Department of Pathophysiology, Faculty of Medical Sciences, University of Kragujevac, Kragujevac, Serbia
| | - Nevena Draginic
- Department of Pharmacy, Faculty of Medical Sciences, University of Kragujevac, Kragujevac, Serbia
| | - Marijana Andjic
- Department of Pharmacy, Faculty of Medical Sciences, University of Kragujevac, Kragujevac, Serbia
| | - Nebojsa Arsenijevic
- Center for Molecular Medicine and Stem Cell Research, Faculty of Medical Sciences, University of Kragujevac, Kragujevac, Serbia
| | - Miodrag L. Lukic
- Center for Molecular Medicine and Stem Cell Research, Faculty of Medical Sciences, University of Kragujevac, Kragujevac, Serbia
| | - Nemanja Jovicic
- Department of Histology and Embryology, Faculty of Medical Sciences, University of Kragujevac, Kragujevac, Serbia
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Troullinaki M, Chen LS, Witt A, Pyrina I, Phieler J, Kourtzelis I, Chmelar J, Sprott D, Gercken B, Koutsilieris M, Chavakis T, Chatzigeorgiou A. Robo4-mediated pancreatic endothelial integrity decreases inflammation and islet destruction in autoimmune diabetes. FASEB J 2020; 34:3336-3346. [PMID: 31916652 DOI: 10.1096/fj.201900125rr] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2019] [Revised: 12/23/2019] [Accepted: 12/24/2019] [Indexed: 12/18/2022]
Abstract
In Type 1 Diabetes Mellitus (T1DM), leukocyte infiltration of the pancreatic islets and the resulting immune-mediated destruction of beta cells precede hyperglycemia and clinical disease symptoms. In this context, the role of the pancreatic endothelium as a barrier for autoimmunity- and inflammation-related destruction of the islets is not well studied. Here, we identified Robo4, expressed on endothelial cells, as a regulator of pancreatic vascular endothelial permeability during autoimmune diabetes. Circulating levels of Robo4 were upregulated in mice subjected to the Multiple Low-Dose Streptozotocin (MLDS) model of diabetes. Upon MLDS induction, Robo4-deficiency resulted in increased pancreatic vascular permeability, leukocyte infiltration to the islets and islet apoptosis, associated with reduced insulin levels and faster diabetes development. On the contrary, in vivo administration of Slit2 in mice modestly delayed the emergence of hyperglycaemia and ameliorated islet inflammation in MLDS-induced diabetes. Thus, Robo4-mediated endothelial barrier integrity reduces insulitis and islet destruction in autoimmune diabetes. Our findings highlight the importance of the endothelium as gatekeeper of pancreatic inflammation during T1DM development and may pave the way for novel Robo4-related therapeutic approaches for autoimmune diabetes.
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Affiliation(s)
- Maria Troullinaki
- Institute for Clinical Chemistry and Laboratory Medicine, University Clinic Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany
| | - Lan-Sun Chen
- Institute for Clinical Chemistry and Laboratory Medicine, University Clinic Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany
| | - Anke Witt
- Institute for Clinical Chemistry and Laboratory Medicine, University Clinic Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany
| | - Iryna Pyrina
- Institute for Clinical Chemistry and Laboratory Medicine, University Clinic Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany
| | - Julia Phieler
- Institute for Clinical Chemistry and Laboratory Medicine, University Clinic Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany
| | - Ioannis Kourtzelis
- Institute for Clinical Chemistry and Laboratory Medicine, University Clinic Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany
| | - Jindrich Chmelar
- Faculty of Science, University of South Bohemia, České Budějovice, Czech Republic
| | - David Sprott
- Institute for Clinical Chemistry and Laboratory Medicine, University Clinic Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany
| | - Bettina Gercken
- Institute for Clinical Chemistry and Laboratory Medicine, University Clinic Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany
| | - Michael Koutsilieris
- Department of Physiology, Medical School, National and Kapodistrian University of Athens, Athens, Greece
| | - Triantafyllos Chavakis
- Institute for Clinical Chemistry and Laboratory Medicine, University Clinic Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany
- Paul Langerhans Institute Dresden of the Helmholtz Center Munich, University Hospital and Faculty of Medicine, TU Dresden, Dresden, Germany
- German Center for Diabetes Research (DZD), Neuherberg, Germany
| | - Antonios Chatzigeorgiou
- Institute for Clinical Chemistry and Laboratory Medicine, University Clinic Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany
- Department of Physiology, Medical School, National and Kapodistrian University of Athens, Athens, Greece
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Malignant transformation of oral leukoplakia is associated with macrophage polarization. J Transl Med 2020; 18:11. [PMID: 31910881 PMCID: PMC6945578 DOI: 10.1186/s12967-019-02191-0] [Citation(s) in RCA: 38] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2019] [Accepted: 12/23/2019] [Indexed: 12/13/2022] Open
Abstract
Background Most oral squamous cell carcinomas (OSCC) occur on the basis of oral leukoplakias (OLP). The histologic degree of dysplasia is insufficient for the prediction of OLP malignant transformation. Immunologic parameters are gaining importance for prognostic assessment and therapy of cancer. M2 polarized macrophages were shown to be associated with OSCC progression and inferior prognosis. The current study aims to answer the question if OLP with malignant transformation into OSCC within 5 years differ from OLP without transformation regarding macrophage infiltration and polarization. Methods 201 specimens (50 transforming OLP, 53 non-transforming OLP, 49 corresponding OSCC and 49 healthy oral mucosa controls) were processed for immunohistochemistry. Samples were stained for CD68, CD163 and CD11c expression, completely digitalized and computer-assisted cell counting was performed. Epithelial and subepithelial compartments were differentially assessed. Groups were statistically compared using the Mann–Whitney U-test. A cut-off point for the discrimination of transforming and non-transforming OLP was determined and the association between macrophage infiltration and malignant transformation was calculated using the Chi-square test (χ2 test). Results Macrophage infiltration and M2 polarization in OLP with malignant transformation within 5 years was significantly increased compared to OLP without malignant transformation (p < 0.05). OSCC samples showed the highest macrophage infiltration and strongest M2 polarization (p < 0.05). Additionally, transforming OLP revealed a significant shift of macrophage infiltration towards the epithelial compartment (p < 0.05). χ2 test revealed a significant association of increased macrophage infiltration with malignant transformation (p < 0.05). Conclusion Immunological changes precede malignant transformation of OLP. Increased macrophage infiltration and M2 polarization was associated with the development of oral cancer in OLP. Macrophage infiltration could serve as predictive marker for malignant transformation.
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