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1.
Nat Commun ; 11(1): 1229, 2020 03 06.
Artigo em Inglês | MEDLINE | ID: mdl-32144274

RESUMO

Liquid-liquid phase separation (LLPS) explains many intracellular activities, but its role in extracellular functions has not been studied to the same extent. Here we report how LLPS mediates the extracellular function of galectin-3, the only monomeric member of the galectin family. The mechanism through which galectin-3 agglutinates (acting as a "bridge" to aggregate glycosylated molecules) is largely unknown. Our data show that its N-terminal domain (NTD) undergoes LLPS driven by interactions between its aromatic residues (two tryptophans and 10 tyrosines). Our lipopolysaccharide (LPS) micelle model shows that the NTDs form multiple weak interactions to other galectin-3 and then aggregate LPS micelles. Aggregation is reversed when interactions between the LPS and the carbohydrate recognition domains are blocked by lactose. The proposed mechanism explains many of galectin-3's functions and suggests that the aromatic residues in the NTD are interesting drug design targets.


Assuntos
Aglutinação , Galectina 3/metabolismo , Proteínas Intrinsicamente Desordenadas/metabolismo , Agregados Proteicos , Glicosilação , Lipopolissacarídeos/metabolismo , Micelas , Domínios Proteicos
2.
Am J Physiol Heart Circ Physiol ; 318(5): H1068-H1079, 2020 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-32216615

RESUMO

The clinical risks and prognosis of diabetic vascular intimal calcification (VIC) and medial calcification (VMC) are different. This study aims to investigate the mechanism of VIC/VMC translocation. Anterior tibial arteries were collected from patients with diabetic foot amputation. The patients were then divided into VIC and VMC groups. There were plaques in all anterior tibial arteries, while the enrichment of galectin-3 in arterial plaques in the VIC group was significantly higher than that in the VMC group. Furthermore, a macrophage/vascular smooth muscle cell (VSMC) coculture system was constructed. VSMC-derived extracellular vesicles (EVs) was labeled with fluorescent probe. After macrophages were pretreated with recombinant galectin-3 protein, the migration of VSMC-derived EVs and VSMC-derived calcification was more pronounced. And anti-galectin-3 antibody can inhibit this process of EVs and calcification translocation. Then, lentivirus (LV)-treated bone marrow cells (BMCs) were transplanted into apolipoprotein E-deficient (ApoE-/-) mice, and a diabetic atherosclerosis mouse model was constructed. After 15 wk of high-fat diet, ApoE-/- mice transplanted with LV-shgalectin-3 BMCs exhibited medial calcification and a concentrated distribution of EVs in the media. In conclusion, upregulation of galectin-3 in macrophages promotes the migration of VSMC-derived EVs to the intima and induces diabetic vascular intimal calcification.NEW & NOTEWORTHY The clinical risk and prognosis of vascular intimal and medial calcification are different. Macrophage galectin-3 regulates the migration of vascular smooth muscle cell-derived extracellular vesicles and mediates diabetic vascular intimal/medial calcification translocation. This study may provide insights into the early intervention in diabetic vascular calcification.


Assuntos
Angiopatias Diabéticas/metabolismo , Cardiomiopatias Diabéticas/metabolismo , Galectina 3/metabolismo , Macrófagos/metabolismo , Túnica Íntima/metabolismo , Calcificação Vascular/metabolismo , Idoso , Idoso de 80 Anos ou mais , Animais , Apolipoproteínas E/genética , Células Cultivadas , Angiopatias Diabéticas/patologia , Cardiomiopatias Diabéticas/genética , Cardiomiopatias Diabéticas/patologia , Vesículas Extracelulares/metabolismo , Feminino , Humanos , Masculino , Camundongos , Pessoa de Meia-Idade , Miócitos de Músculo Liso/metabolismo , Artérias da Tíbia/metabolismo , Artérias da Tíbia/patologia , Túnica Íntima/patologia , Calcificação Vascular/patologia
3.
PLoS One ; 15(3): e0229462, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32119722

RESUMO

Aging is a major risk factor for morbidity and mortality from cardiovascular causes in men. To better understand the cellular processes related to age-related cardiac complications, we undertook research aimed at comparative evaluation of genes expression and distribution of ß-catenin, CacyBP/SIP, galectin-3 and LMP7 in the heart of healthy men in different age groups. The study was conducted on the hearts of 12 men (organ donors) without a history of cardiovascular disease, who were divided into two age groups: men under and men over 45 years of age. On paraffin sections, immunohistochemical reactions were performed to detect ß-catenin, CacyBP/SIP, galectin-3 and immunoproteasome subunit LMP7. The expression of genes coding ß-catenin, CacyBP/SIP, galectin-3 and LMP7 was also evaluated by real-time PCR method. In the heart of men over 45 years old, both gene expression and immunoreactivity of ß-catenin, CacyBP/SIP, galectin-3 and LMP7 were stronger compared to younger individuals. The results of the presented studies suggest that ß-catenin, CacyBP/SIP, galectin-3 and immunoproteasomes might be involved in the internal regulation of heart homeostasis during ageing.


Assuntos
Envelhecimento/genética , Proteínas de Ligação ao Cálcio/genética , Galectina 3/genética , Miocárdio/metabolismo , Complexo de Endopeptidases do Proteassoma/genética , beta Catenina/genética , Adulto , Distribuição por Idade , Idoso , Envelhecimento/metabolismo , Proteínas de Ligação ao Cálcio/metabolismo , Galectina 3/metabolismo , Homeostase , Humanos , Masculino , Pessoa de Meia-Idade , Complexo de Endopeptidases do Proteassoma/metabolismo , Regulação para Cima , Adulto Jovem , beta Catenina/metabolismo
4.
Diabetes Res Clin Pract ; 161: 108082, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32057966

RESUMO

INTRODUCTION: To assess the potential of galectin-3 and growth differentiation factor-15 (GDF-15) biomarkers for the early detection of diabetic kidney disease (DKD). METHODOLOGY: This was a cross-sectional study conducted over a period of 1.2 years. Patients were stratified based on estimated glomerular filtration rate (eGFR) and albuminuria level. The receiver operating characteristic (ROC) curve was plotted to assess the diagnostic potential of biomarkers. RESULTS: A total of 90 patients included in this study. Patients were grouped as normoalbuminuria (30 patients), microalbuminuria (30 patients), and macroalbuminuria (30 patients). Galectin-3 and GDF-15 levels were significantly elevated in T2DM patients with macroalbuminuria (p = <0.05). Higher levels of galectin-3 and GDF-15 were found in patients with poor kidney function (Stage IV-V CKD). Negative correlation was observed between galectin- 3 (r = -0.472) and eGFR (p = 0.000), GDF-15 (r = -0.917) and eGFR (p <0.000). The ROC analysis yielded an area under curve (AUC) of 0.776 (95% CI: 0.677 to 0.875; p = <0.0001) for galectin-3 and an AUC of 0.963 (95% CI: 0.929 to 0.997; p = <0.0001) for GDF-15. CONCLUSION: In DKD patients the galectin-3 and GDF-15 levels were inversely related to the eGFR which was further confirmed by the ROC curve demonstrating the potential of galectin-3 and GDF-15 as a biomarker.


Assuntos
Biomarcadores/metabolismo , Nefropatias Diabéticas/diagnóstico , Galectina 3/metabolismo , Taxa de Filtração Glomerular/imunologia , Fator 15 de Diferenciação de Crescimento/metabolismo , Rim/patologia , Idoso , Estudos Transversais , Diagnóstico Precoce , Feminino , Humanos , Masculino , Pessoa de Meia-Idade
5.
Mar Drugs ; 18(2)2020 Feb 04.
Artigo em Inglês | MEDLINE | ID: mdl-32033203

RESUMO

The mucus of fish skin plays a vital role in innate immune defense. Some mucus proteins have the potential to incapacitate pathogens and/or inhibit their passage through the skin. In this study the aim was to isolate and characterize galectin(s), ß-galactosides binding proteins, present in skin mucus. A novel short form of galectin-3 was isolated from Atlantic salmon skin mucus by α-lactose agarose based affinity chromatography followed by Sephadex G-15 gel filtration. Mass spectrometric analysis showed that the isolated protein was the C-terminal half of galectin-3 (galectin-3C). Galectin-3C showed calcium independent and lactose inhabitable hemagglutination, and agglutinated the Gram-negative pathogenic bacteria Moritella viscosa. Galectin-3 mRNA was highly expressed in skin and gill, followed by muscle, hindgut, spleen, stomach, foregut, head kidney, and liver. Moritella viscosa incubated with galectin-3C had a modified proteome. Proteins with changed abundance included multidrug transporter and three ribosomal proteins L7/12, S2, and S13. Overall, this study shows the isolation and characterization of a novel galectin-3 short form involved in pathogen recognition and modulation, and hence in immune defense of Atlantic salmon.


Assuntos
Galectina 3/imunologia , Galectina 3/metabolismo , Moritella/efeitos dos fármacos , Muco/metabolismo , Aglutinação , Animais , Proteínas de Transporte , Proteínas de Peixes , Galectina 3/genética , Bactérias Gram-Negativas/efeitos dos fármacos , Imunidade Inata , Peptídeos , Domínios e Motivos de Interação entre Proteínas , Proteoma , Salmo salar/metabolismo , Pele/metabolismo
6.
Mol Cell Biochem ; 464(1-2): 143-152, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31782085

RESUMO

Heart failure (HF) is considered one of the most common diseases and one of the major causes of death. The latest studies show that HF is associated with an increase in oxidative stress. The use of antioxidants as therapy is effective in animal models, but not in humans. In this review, we analyse some emerging markers related to oxidative stress, evaluating their possible use as therapeutic targets: galectin-3, a ß galactoside associated with myocardial fibrosis, α1-antitrypsin, an antiprotease and lectin-like oxidized low-density-lipoprotein receptor-1, the major receptor for ox-LDL. The up-regulation of galectin-3 appears to be associated with HF, atrial fibrillation, dilated cardiomyopathy, fibrogenesis and mortality, while in other cases it seems that galectin-3 may be protective in ischaemia-reperfusion injury. Serum α1-antitrypsin protein levels may increase in the presence of high concentrations of serum proteases, which are over expressed during reperfusion. The overexpression of α1-antitrypsin or the exogenous α1-antitrypsin treatment exhibits an anti-oxidative stress role, evaluated by increased eNOS expression and by decreased MMP9 expression, implicated in HF. The cardiac lectin-like oxidized low-density-lipoprotein receptor-1 is activated by oxidative stress in ischaemia-reperfusion injury, inducing apoptosis in cardiomyocytes through the deleterious NF-kB pathway, while the administration of anti-lectin-like oxidized low-density-lipoprotein receptor-1 antibody suppresses apoptosis and reduces the extent of myocardial infarction. In conclusion, α1-antitrypsin and lectin-like oxidized low-density-lipoprotein receptor-1 seem to represent two good markers in HF and therapeutic targets, whereas galectin-3 does not.


Assuntos
Galectina 3/metabolismo , Insuficiência Cardíaca/metabolismo , Infarto do Miocárdio/metabolismo , Estresse Oxidativo , Receptores Depuradores Classe E/metabolismo , alfa 1-Antitripsina/metabolismo , Apoptose , Biomarcadores/metabolismo , Insuficiência Cardíaca/patologia , Humanos , Infarto do Miocárdio/patologia
7.
Exp Mol Pathol ; 113: 104363, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-31881201

RESUMO

Non-alcoholic steatohepatitis (NASH) is characterized by immune cell infiltration. Loss of the scaffold protein alpha-syntrophin (SNTA) protected mice from hepatic inflammation in the methionine-choline-deficient (MCD) diet model. Here, we determined increased numbers of macrophages and CD8+ T-cells in MCD diet induced NASH liver of wild type mice. In the mutant animals these NASH associated changes in immune cell composition were less pronounced. Further, there were more γδ T-cells in the NASH liver of the null mice. Galectin-3 protein in the hepatic non-parenchymal cell fraction was strongly induced in MCD diet fed wild type but not mutant mice. Antioxidant enzymes declined in NASH liver with no differences between the genotypes. To identify the target cells responsive to SNTA loss in-vitro experiments were performed. In the human hepatic stellate cell line LX-2, SNTA did not regulate pro-fibrotic or antioxidant proteins like alpha-smooth muscle actin or catalase. Soluble galectin-3 was, however, reduced upon SNTA knock-down and increased upon SNTA overexpression. SNTA deficiency neither affected cell proliferation nor cell death of LX-2 cells. In the macrophage cell line RAW264.7 low SNTA indeed caused higher galectin-3 production whereas release of TNF and cell viability were normal. Moreover, SNTA had no effect on hepatocyte chemerin and CCL2 expression. Overall, SNTA loss improved NASH without causing major effects in macrophage, hepatocyte and hepatic stellate cell lines. SNTA null mice fed the MCD diet had less body weight loss and this seems to contribute to improved liver health of the mutant mice.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Proteínas de Ligação ao Cálcio/deficiência , Galectina 3/metabolismo , Fígado/patologia , Macrófagos/patologia , Proteínas de Membrana/deficiência , Proteínas Musculares/deficiência , Hepatopatia Gordurosa não Alcoólica/imunologia , Hepatopatia Gordurosa não Alcoólica/prevenção & controle , Actinas/metabolismo , Animais , Antioxidantes/metabolismo , Peso Corporal , Proteínas de Ligação ao Cálcio/metabolismo , Catalase/metabolismo , Linhagem Celular , Proliferação de Células , Sobrevivência Celular , Quimiocina CCL2/metabolismo , Quimiocinas/metabolismo , Fator de Crescimento do Tecido Conjuntivo/metabolismo , Ácido Graxo Sintases/metabolismo , Comportamento Alimentar , Heme Oxigenase-1/metabolismo , Humanos , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Interleucina-6/metabolismo , L-Lactato Desidrogenase/metabolismo , Macrófagos/metabolismo , Masculino , Proteínas de Membrana/metabolismo , Camundongos Endogâmicos C57BL , Proteínas Musculares/metabolismo , Hepatopatia Gordurosa não Alcoólica/patologia , Superóxido Dismutase/metabolismo , Fator de Necrose Tumoral alfa/metabolismo
8.
Glia ; 68(2): 435-450, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31626379

RESUMO

Postnatal subventricular zone (SVZ) neural stem cells generate forebrain glia, namely astrocytes and oligodendrocytes. The cues necessary for this process are unclear, despite this phase of brain development being pivotal in forebrain gliogenesis. Galectin-3 (Gal-3) is increased in multiple brain pathologies and thereby regulates astrocyte proliferation and inflammation in injury. To study the function of Gal-3 in inflammation and gliogenesis, we carried out functional studies in mouse. We overexpressed Gal-3 with electroporation and using immunohistochemistry surprisingly found no inflammation in the healthy postnatal SVZ. This allowed investigation of inflammation-independent effects of Gal-3 on gliogenesis. Loss of Gal-3 function via knockdown or conditional knockout reduced gliogenesis, whereas Gal-3 overexpression increased it. Gal-3 overexpression also increased the percentage of striatal astrocytes generated by the SVZ but decreased the percentage of oligodendrocytes. These novel findings were further elaborated with multiple analyses demonstrating that Gal-3 binds to the bone morphogenetic protein receptor one alpha (BMPR1α) and increases bone morphogenetic protein (BMP) signaling. Conditional knockout of BMPR1α abolished the effect of Gal-3 overexpression on gliogenesis. Gain-of-function of Gal-3 is relevant in pathological conditions involving the human forebrain, which is particularly vulnerable to hypoxia/ischemia during perinatal gliogenesis. Hypoxic/ischemic injury induces astrogliosis, inflammation and cell death. We show that Gal-3 immunoreactivity was increased in the perinatal human SVZ and striatum after hypoxia/ischemia. Our findings thus show a novel inflammation-independent function for Gal-3; it is necessary for gliogenesis and when increased in expression can induce astrogenesis via BMP signaling.


Assuntos
Astrócitos/metabolismo , Galectina 3/metabolismo , Ventrículos Laterais/citologia , Neuroglia/metabolismo , Animais , Diferenciação Celular/fisiologia , Movimento Celular/fisiologia , Ventrículos Cerebrais/citologia , Regulação da Expressão Gênica , Isquemia/metabolismo , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Células-Tronco Neurais/metabolismo , Neurogênese/fisiologia , Oligodendroglia/metabolismo
9.
Molecules ; 24(24)2019 Dec 12.
Artigo em Inglês | MEDLINE | ID: mdl-31842510

RESUMO

Gold(III) porphyrin presents an attractive alternative to the use of, for example, cisplatin in chemotherapy. However, approaches that allow to selectively target cancer cells are highly sought. Many plant and mammalian lectins have been shown to bind oligosaccharide sequences of the aberrant glycosylation pattern found on cancerous tumors. For example human galectin-3, of the galectin family specific for ß-galactoside, is overexpressed in the extracellular matrix of tumorigenous and metastatic tissues. We searched for non-carbohydrate ligands for galectin-3 that can guide a cytotoxic drug to the cancer cells by maintaining its affinity for tumor associated carbohydrate antigens. Previous findings showed that zinc tetrasulfonatophenylporphyrin can bind galectin-3 with sub-micromolar affinity without disturbing lactose binding. Gold(III) porphyrin is not only cytotoxic to cancer cells, it knows also a potential application as photosensitiser in photodynamic therapy. We investigated the binding of gold(III) porphyrin to galectin-3 using different biophysical interaction techniques and demonstrated a low micromolar affinity of human galectin-3 for the cytotoxic compound. Co-crystallization attempts in order to understand the binding mode of gold porphyrin to galectin-3 failed, but molecular docking emphasized a highly populated secondary binding site that does not hinder lactose or Thomsen Friendenreich disaccharide binding. This suggests that gold(III) porphyrin might significantly enhance its concentration and delivery to cancer cells by binding to human galectin-3 that keeps its orientation towards tumor associated carbohydrate antigens.


Assuntos
Antineoplásicos/química , Galectina 3/química , Ouro/química , Simulação de Acoplamento Molecular , Proteínas de Neoplasias/química , Porfirinas/química , Galectina 3/metabolismo , Humanos , Metástase Neoplásica , Proteínas de Neoplasias/metabolismo
10.
Prog Lipid Res ; 76: 101010, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31682868

RESUMO

Galectin-3 (Gal3) is a multifaceted protein which belongs to a family of lectins and binds ß-galactosides. Gal3 expression is altered in many types of cancer, with increased expression generally associated with poor prognosis. Although the mechanisms remain unknown, Gal3 has been implicated in several biological processes involved in cancer progression, including suppression of T cell-mediated immune responses. Extracellular Gal3 binding to the plasma membrane of T cells alters membrane organization and the formation of an immunological synapse. Its multivalent capacity allows Gal3 to interact specifically with different membrane proteins and lipids, influencing endocytosis, trafficking and T cell receptor signalling. The ability of Gal3 to inhibit T cell responses may provide a mechanism by which Gal3 aids in cancer progression. In this review, we seek to give an overview of the mechanisms by which Gal3 alters the spatial organization of cell membranes and how these processes impact on T cell activation.


Assuntos
Membrana Celular/metabolismo , Galectina 3/metabolismo , Modelos Biológicos , Linfócitos T/citologia , Linfócitos T/metabolismo , Animais , Humanos
11.
Oxid Med Cell Longev ; 2019: 7252943, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31737173

RESUMO

Endothelial progenitor cells (EPCs) have the potential to repair damaged blood vessels and promote angiogenesis. Smoking, an important risk factor for cardiovascular diseases, is associated with impaired functions of EPCs. However, the underlying mechanisms remain unclear. The aim of the study was to investigate the effects of cigarette smoke extract (CSE) on autophagy and dysfunction of EPCs and the involvement of galectin-3 in its effects. EPCs were treated with 8% CSE for 24 h (without affecting cell viability). EPC functions were assessed by tube formation and migration capacity and intracellular ROS and eNOS expression. Autophagy was assessed by autophagic protein expression by Western blotting and immunofluorescence microscopy and autophagosome accumulation by transmission electron microscopy. Galectin-3 expression was measured by real-time PCR, Western blotting, and immunofluorescence microscopy, while phospho-AMPK and phospho-mTOR were measured by Western blotting. EPCs were transfected by shRNA-Gal-3 or shRNA-NC before treatment with CSE to examine the effects of galectin-3 on CSE-induced autophagy and dysfunction of EPCs. CSE-treated EPCs showed decreased tube formation and migration ability and eNOS expression but increased oxidative stress. CSE also induced autophagy which was characterized by a decrease in p62 protein, an increase in LC3B-II/I ratio, and accumulation of autophagosomes. CSE upregulated galectin-3 expression on EPCs. Inhibition of galectin-3 abrogated CSE-induced autophagy and dysfunction of EPCs. CSE activated phospho-AMPK and inhibited phospho-mTOR, and inhibition of galectin-3 abolished CSE's effect on activating phospho-AMPK and inhibiting phospho-mTOR. In conclusion, our results suggest that galectin-3 mediates CSE-induced EPC autophagy and dysfunction, likely via the AMPK/mTOR signaling pathway.


Assuntos
Fumar Cigarros/efeitos adversos , Células Progenitoras Endoteliais/fisiologia , Galectina 3/metabolismo , Produtos do Tabaco/efeitos adversos , Autofagia , Diferenciação Celular , Movimento Celular , Células Cultivadas , Galectina 3/genética , Regulação da Expressão Gênica , Humanos , Neovascularização Fisiológica , Estresse Oxidativo , Proteínas Quinases/metabolismo , RNA Interferente Pequeno/genética , Proteínas de Ligação a RNA/metabolismo , Transdução de Sinais , Serina-Treonina Quinases TOR/metabolismo
13.
Rev. esp. cardiol. (Ed. impr.) ; 72(11): 899-906, nov. 2019. tab, graf
Artigo em Espanhol | IBECS | ID: ibc-190741

RESUMO

Introducción y objetivos Los valores plasmáticos de galectina-3 (Gal-3) están elevados y se correlacionan con la mortalidad total y cardiovascular en pacientes con insuficiencia cardiaca, pero su correlación con el pronóstico tras el trasplante cardiaco (TxC) es desconocida. El objetivo fue describir la tendencia evolutiva y el valor pronóstico de este biomarcador tras el TxC. Métodos Mediante enzimoinmunoensayo, se midieron las concentraciones plasmáticas de Gal-3 en muestras de suero de 122 receptores de TxC, antes y 1, 3, 6 y 12 meses después de este. Mediante regresión de Cox se analizó el valor pronóstico del valor plasmático de Gal-3 a los 12 meses del TxC. El objetivo primario del estudio fue la variable combinada muerte o disfunción del injerto. Resultados: Las concentraciones de Gal-3 disminuyeron progresivamente durante el primer año tras el TxC (medianas: pretrasplante, 19,1 ng/ml; 1 año postrasplante, 14,6 ng/ml; p<0,001). Los valores de Gal-3 1 año tras el TxC se asociaron con mayor riesgo de muerte o disfunción del injerto (HR por 1 ng/ml: 1.04; IC95%: 1,01-1,08; p=0,008). La capacidad predictiva del biomarcardor fue moderada: área bajo la curva ROC, 0,72 (IC95%: 0,60-0,82; p<0,001). Conclusiones Las concentraciones plasmáticas de Gal-3 disminuyeron progresivamente durante el primer año tras el TxC. Un valor plasmático elevado de Gal-3 1 año tras el TxC se correlacionó con un pronóstico adverso


Introduction and Objectives: Circulating galectin-3 (Gal-3) is elevated and significantly correlates with all-cause and cardiovascular mortality in patients with heart failure. However, the relationship between serum Gal-3 and heart transplant (HT) outcomes is unclear. The aim of this study was to describe the longitudinal trend and prognostic value of Gal-3 levels after HT. Methods: Banked serum samples were available from 122 HT recipients, collected before transplant and at 1, 3, 6, and 12 months posttransplant. Gal-3 levels in these serum samples were measured by enzyme immune assay. Multivariable Cox regression was performed to determine the prognostic value of 12-month posttransplant Gal-3 serum levels. The primary endpoint was the composite variable all-cause death or graft failure over long-term posttransplant follow-up. Results: Circulating Gal-3 concentration steadily decreased during the first year after HT (median values: pretransplant, 19.1 ng/mL; 1-year posttransplant, 14.6 ng/mL; P<.001). Circulating Gal-3 levels 1-year posttransplant were associated with an increased risk of all-cause death or graft failure (adjusted HR per 1 ng/mL, 1.04; 95%CI, 1.01-1.08; P=.008). The predictive accuracy of this biomarker was moderate: (area under the ROC curve, 0.72 (95%CI, 0.60-0.82; P<.001). Conclusions: Circulating Gal-3 steadily decreased during the first year after HT. However, 1-year posttransplant Gal-3 serum levels that remained elevated were associated with increased long-term risk of death and graft failure


Assuntos
Humanos , Masculino , Feminino , Pessoa de Meia-Idade , Galectina 3/metabolismo , Insuficiência Cardíaca/cirurgia , Transplante de Coração/estatística & dados numéricos , Rejeição de Enxerto/imunologia , Biomarcadores/análise , Galectina 3/análise , Prognóstico , Estudos Retrospectivos , Seguimentos , Curva ROC , Fatores de Risco , Indicadores de Morbimortalidade
14.
Expert Opin Ther Targets ; 23(10): 819-828, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31575307

RESUMO

Introduction: The discoveries that sugars are a highly versatile platform to generate biochemical messages and that glycan-specific receptors (lectins) are a link between these signals and their bioactivity explain the interest in endogenous lectins such as galectins. Their analysis is a highly dynamic field. It is often referred to as being promising for innovative drug design. Area covered: We present a primer to the concept of the sugar code by glycan-(ga)lectin recognition, followed by a survey on galectin-3 (considering common and distinct features within this family of multifunctional proteins expressed at various cellular sites and cell types). Finally, we discuss strategies capable of blocking (ga)lectin activity, with an eye on current challenges and inherent obstacles. Expert opinion: The emerging broad profile of homeostatic and pathophysiological bioactivities stimulates further efforts to explore galectin (Gal-3) functionality, alone and then in mixtures. Like thoroughly assessing the pros and cons of blocking approaches for a multifunctional protein active at different sites, identifying a clinical situation, in which the galectin is essential in the disease process, will be critical.


Assuntos
Desenho de Fármacos , Galectina 3/metabolismo , Terapia de Alvo Molecular , Animais , Galectinas/metabolismo , Humanos
15.
Glycobiology ; 30(1): 49-57, 2019 12 12.
Artigo em Inglês | MEDLINE | ID: mdl-31529034

RESUMO

Glycan interactions with glycan-binding proteins (GBPs) play essential roles in a wide variety of cellular processes. Currently, the glycan specificities of GBPs are most often inferred from binding data generated using glycan arrays, wherein the GBP is incubated with oligosaccharides immobilized on a glass surface. Detection of glycan-GBP binding is typically fluorescence-based, involving the labeling of the GBP with a fluorophore or with biotin, which binds to fluorophore-labeled streptavidin, or using a fluorophore-labeled antibody that recognizes the GBP. While it is known that covalent labeling of a GBP may influence its binding properties, these effects have not been well studied and are usually overlooked when analyzing glycan array data. In the present study, electrospray ionization mass spectrometry (ESI-MS) was used to quantitatively evaluate the impact of GBP labeling on oligosaccharide affinities and specificities. The influence of three common labeling approaches, biotinylation, labeling with a fluorescent dye and introducing an iodination reagent, on the affinities of a series of human milk and blood group oligosaccharides for a C-terminal fragment of human galectin-3 was evaluated. In all cases labeling resulted in a measurable decrease in oligosaccharide affinity, by as much as 90%, and the magnitude of the change was sensitive to the nature of the ligand. These findings demonstrate that GBP labeling may affect both the absolute and relative affinities and, thereby, obscure the true glycan binding properties. These results also serve to illustrate the utility of the direct ESI-MS assay for quantitatively evaluating the effects of protein labeling on ligand binding.


Assuntos
Galectina 3/química , Biotinilação , Corantes Fluorescentes/química , Galectina 3/metabolismo , Humanos , Estrutura Molecular , Espectrometria de Massas por Ionização por Electrospray
16.
Cells ; 8(9)2019 09 13.
Artigo em Inglês | MEDLINE | ID: mdl-31540324

RESUMO

Endoglin is a 180-kDa glycoprotein receptor primarily expressed by the vascular endothelium and involved in cardiovascular disease and cancer. Heterozygous mutations in the endoglin gene (ENG) cause hereditary hemorrhagic telangiectasia type 1, a vascular disease that presents with nasal and gastrointestinal bleeding, skin and mucosa telangiectases, and arteriovenous malformations in internal organs. A circulating form of endoglin (alias soluble endoglin, sEng), proteolytically released from the membrane-bound protein, has been observed in several inflammation-related pathological conditions and appears to contribute to endothelial dysfunction and cancer development through unknown mechanisms. Membrane-bound endoglin is an auxiliary component of the TGF-ß receptor complex and the extracellular region of endoglin has been shown to interact with types I and II TGF-ß receptors, as well as with BMP9 and BMP10 ligands, both members of the TGF-ß family. To search for novel protein interactors, we screened a microarray containing over 9000 unique human proteins using recombinant sEng as bait. We find that sEng binds with high affinity, at least, to 22 new proteins. Among these, we validated the interaction of endoglin with galectin-3, a secreted member of the lectin family with capacity to bind membrane glycoproteins, and with tripartite motif-containing protein 21 (TRIM21), an E3 ubiquitin-protein ligase. Using human endothelial cells and Chinese hamster ovary cells, we showed that endoglin co-immunoprecipitates and co-localizes with galectin-3 or TRIM21. These results open new research avenues on endoglin function and regulation.


Assuntos
Endoglina/metabolismo , Galectina 3/metabolismo , Ribonucleoproteínas/metabolismo , Animais , Células CHO , Cricetulus , Células Endoteliais da Veia Umbilical Humana , Humanos , Análise Serial de Proteínas/métodos , Ligação Proteica
17.
Pathol Res Pract ; 215(10): 152612, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31474314

RESUMO

Galectin-3 has an important function in the development of tumors. The purpose of this meta-analysis was to explore the relationships between the expression of galectin-3 on clinicopathological features and prognosis of colorectal cancer (CRC). A comprehensive literature search was used to identify eligible studies, and Stata software was conducted using in this meta-analysis. A total of 15 studies, including 1661 cases, were matched in the inclusion criteria. The pooled analysis indicated that galectin-3 expression was related to the poor overall survival (OS) in CRC patients (HR: 1.77, 95% CI: 1.36-2.31, P < 0.0001). Our meta-analysis also showed that cancerous tissues have higher levels of galectin-3 expression than normal tissues. Besides, positive galectin-3 expression was also related to advanced TNM stages(III/IV vs. I/II: OR 5.30, 95% CI: 2.42-11.61, P < 0.0001), higher Duke's stages (C/D vs. A/B: OR 4.00, 95% CI: 2.22-7.22, P < 0.0001), venous invasion (venous invasion vs. not: OR 3.02, 95%CI: 1.75-5.22, P < 0.0001) and higher CEA level (CEA≥5 ng/ml vs. ≤ 5 ng/ml: OR 2.09, 95% CI: 1.09-4.03, P = 0.03). In summary, our results indicated that overexpression of galectin-3 is significantly related to the tumor progression and could be a efficient in predicting the prognosis of patients with CRC.


Assuntos
Neoplasias Colorretais/metabolismo , Galectina 3/metabolismo , Biomarcadores Tumorais/metabolismo , Neoplasias Colorretais/mortalidade , Neoplasias Colorretais/patologia , Progressão da Doença , Humanos , Prognóstico , Taxa de Sobrevida
18.
Wiad Lek ; 72(7): 1281-1287, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31398156

RESUMO

OBJECTIVE: Introduction: Speed myocardial indicators and estimation of galectin-3 presented for estimation of myocardial dysfunction in children with congenital heart defects (CHD). The aim: Evaluate myocardial function while using tissue Doppler imaging (TDI) and galectin-3 in children with CHD after surgical correction. PATIENTS AND METHODS: Materials and methods: We examined 184 children. The study assessed both ventricle systolic and diastolic performance by TDI in combination with tricuspid annular plane systolic excursion (TAPSE). Additionally, systolic (S') and diastolic (ratio E/E') TDI measurements were obtained at the lateral part of mitral annular, interventricular part, and lateral part of tricuspid valve (S`ma lateral, S` ma septal, S`ta lateral та E/E' malateral, E/E' maseptal, E/E' talateral). Galectin-3 amount in serum was detected by immune enzyme method by kit «HumanGalectin-3¼. RESULTS: Results: Compared to results of the healthy children systolic TDI measurements in patients with CHD were significantly lower: S` ma lateral 7,81±0,10 сm/s vs 9,85±0,28 сm/s, S` ta lateral 9,70±0,12 сm/s vs 12,8±0,17 сm/s and TAPSE, 1,48±0,02 vs 2,14±0,03 сm/s (р<0,01). Ratio E/E' in patients with CHD were different from results of the healthy children in all myocardial segments: E/Е` ma lateral 7,45±0,21 vs 6,17±0,12, E/Е` ma septal 9,17±0,22 vs 7,54±0,13, E/Е` ta lateral 6,42 ± 0,14 vs 4,64±0,12, (р<0,05). Patients with CHD got galectin-3 content in serum 7,04±0,21 ng/ml vs 4,17±0,17 ng/ml (р<0,01) results of the healthy children. CONCLUSION: Conclusions: Analyze of TDI measurements and galectin-3 content allows evaluate myocardial dysfunction in asymptomatic patients with CHD after surgical correction.


Assuntos
Galectina 3/metabolismo , Cardiopatias Congênitas , Biomarcadores , Criança , Fibrose , Humanos , Sístole
19.
An Bras Dermatol ; 94(3): 348-354, 2019 Jul 29.
Artigo em Inglês | MEDLINE | ID: mdl-31365668

RESUMO

Galectin 3 is a unique ~31 kDa protein that recognizes the N-acetyl-lactosamine structure of several glycoconjugates. It mainly occurs in epithelial and myeloid cells, but is also found in a variety of human cell types. In view of the crucial role played by galectin 3 in the regulation of cellular processes of essential importance and in the pathogenetic mechanisms of diverse disorders, it is not surprising that, particularly in the last three decades, the attention of the scientific community has been increasingly drawn to this extraordinary and multifunctional galectin. In this paper the authors summarize current knowledge on the expression of galectin 3 in normal and diseased human skin, its implications in the pathogenesis, diagnosis and prognosis of cutaneous disorders, and the perspectives of a novel approach to the treatment of the latter using galectin 3 or its inhibitors/antagonists.


Assuntos
Dermatite/metabolismo , Dermatite/terapia , Galectina 3/uso terapêutico , Amino Açúcares , Dermatite/tratamento farmacológico , Galectina 3/metabolismo , Humanos
20.
Nat Commun ; 10(1): 3473, 2019 08 02.
Artigo em Inglês | MEDLINE | ID: mdl-31375685

RESUMO

Huntington's disease (HD) is a neurodegenerative disorder that manifests with movement dysfunction. The expression of mutant Huntingtin (mHTT) disrupts the functions of brain cells. Galectin-3 (Gal3) is a lectin that has not been extensively explored in brain diseases. Herein, we showed that the plasma Gal3 levels of HD patients and mice correlated with disease severity. Moreover, brain Gal3 levels were higher in patients and mice with HD than those in controls. The up-regulation of Gal3 in HD mice occurred before motor impairment, and its level remained high in microglia throughout disease progression. The cell-autonomous up-regulated Gal3 formed puncta in damaged lysosomes and contributed to inflammation through NFκB- and NLRP3 inflammasome-dependent pathways. Knockdown of Gal3 suppressed inflammation, reduced mHTT aggregation, restored neuronal DARPP32 levels, ameliorated motor dysfunction, and increased survival in HD mice. Thus, suppression of Gal3 ameliorates microglia-mediated pathogenesis, which suggests that Gal3 is a novel druggable target for HD.


Assuntos
Encéfalo/patologia , Galectina 3/metabolismo , Doença de Huntington/patologia , Microglia/patologia , Adulto , Animais , Encéfalo/citologia , Encéfalo/ultraestrutura , Modelos Animais de Doenças , Progressão da Doença , Feminino , Galectina 3/sangue , Galectina 3/genética , Técnicas de Silenciamento de Genes , Humanos , Doença de Huntington/sangue , Doença de Huntington/diagnóstico , Inflamassomos/metabolismo , Lisossomos/metabolismo , Lisossomos/ultraestrutura , Masculino , Camundongos , Microglia/citologia , Microglia/ultraestrutura , Microscopia Eletrônica de Transmissão , Pessoa de Meia-Idade , Índice de Gravidade de Doença , Regulação para Cima
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