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2.
Nat Struct Mol Biol ; 28(10): 847-857, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34625747

RESUMO

The protein K-Ras functions as a molecular switch in signaling pathways regulating cell growth. In the human mitogen-activated protein kinase (MAPK) pathway, which is implicated in many cancers, multiple K-Ras proteins are thought to assemble at the cell membrane with Ras effector proteins from the Raf family. Here we propose an atomistic structural model for such an assembly. Our starting point was an asymmetric guanosine triphosphate-mediated K-Ras dimer model, which we generated using unbiased molecular dynamics simulations and verified with mutagenesis experiments. Adding further K-Ras monomers in a head-to-tail fashion led to a compact helical assembly, a model we validated using electron microscopy and cell-based experiments. This assembly stabilizes K-Ras in its active state and presents composite interfaces to facilitate Raf binding. Guided by existing experimental data, we then positioned C-Raf, the downstream kinase MEK1 and accessory proteins (Galectin-3 and 14-3-3σ) on and around the helical assembly. The resulting Ras-Raf signalosome model offers an explanation for a large body of data on MAPK signaling.


Assuntos
Proteínas Proto-Oncogênicas c-raf/química , Proteínas Proto-Oncogênicas c-raf/metabolismo , Proteínas Proto-Oncogênicas p21(ras)/química , Proteínas Proto-Oncogênicas p21(ras)/metabolismo , Proteínas Sanguíneas/química , Proteínas Sanguíneas/metabolismo , Proteínas de Ligação a DNA/química , Proteínas de Ligação a DNA/metabolismo , Transferência Ressonante de Energia de Fluorescência , Proteínas Ativadoras de GTPase/química , Proteínas Ativadoras de GTPase/metabolismo , Galectinas/química , Galectinas/metabolismo , Guanosina Trifosfato/química , Guanosina Trifosfato/metabolismo , Células HEK293 , Humanos , MAP Quinase Quinase 1/metabolismo , Microscopia Eletrônica , Microscopia Eletrônica de Transmissão , Simulação de Dinâmica Molecular , Complexos Multiproteicos/química , Complexos Multiproteicos/metabolismo , Mutagênese , Multimerização Proteica , Proteínas Proto-Oncogênicas c-raf/genética , Proteínas Proto-Oncogênicas p21(ras)/genética , Reprodutibilidade dos Testes , Transdução de Sinais , Fatores de Transcrição/química , Fatores de Transcrição/metabolismo
3.
Stem Cell Res Ther ; 12(1): 541, 2021 10 15.
Artigo em Inglês | MEDLINE | ID: mdl-34654474

RESUMO

BACKGROUND: Autoimmune hepatitis (AIH) is a T cell-mediated immune disease that activates abnormally against hepatic antigens. We have previously reported that endometrial regenerative cells (ERCs) were a novel source of adult stem cells, which exhibiting with powerful immunomodulatory effects. Galectin-9 (Gal-9) is expressed in ERCs and plays an important role in regulating T cell response. This study aims to explore the role of ERCs in attenuation of AIH and to determine the potential mechanism of Gal-9 in ERC-mediated immune regulation. METHODS: ERCs were obtained from menstrual blood of healthy female volunteers. In vitro, ERCs were transfected with lentivirus vectors carrying LGALS9 gene and encoding green fluoresce protein (GFP-Gal-9-LVs) at a MOI 50, Gal-9 expression in ERCs was detected by ELISA and Q-PCR. CD4+ T cells isolated from C57BL/6 mouse spleen were co-cultured with ERCs. The proliferation of CD4+ T cells was detected by CCK-8 kit and the level of Lck/zap-70/LAT protein was measured by western blot. Furthermore, AIH was induced by ConA in C57BL/6 mice which were randomly assigned to untreated, unmodified ERC-treated and Gal-9 high-expressing ERC-treated groups. Histopathological score, liver function, CD4+/CD8+ cell infiltration in liver tissues, the proportion of immune cells in the spleen and liver, and ERC tracking were performed accordingly to assess the progression degree of AIH. RESULTS: After transfecting with GFP-Gal-9-LVs, Gal-9 expression in ERCs was significantly increased. Additionally, Gal-9 high-expressing ERCs effectively inhibited CD4+ T cell proliferation and downregulated CD4+ T cell active related proteins p-Lck/p-ZAP70/p-LAT in vitro. Furthermore, treatment with Gal-9 high-expressing ERCs restored liver function, ameliorated liver pathological damage, inhibit CD4+ and CD8+ T cell proliferation and suppress Th1 and Th17 cell response in the hepatitis mice. In addition, Gal-9 high-expressing ERCs further markedly enhanced the level of IL-10 but reduced the levels of IFN-γ, TNF-α, and IL-4 in mouse sera and liver. Cell tracking also showed that ERCs could migrate to the damaged liver organs. CONCLUSIONS: The results suggested that Gal-9 was an essential modulator, which was required by ERCs in regulating T cell response and attenuating ConA-induced experimental hepatitis. And also, it provides a novel idea for the clinical treatment of AIH.


Assuntos
Hepatite Autoimune , Animais , Endométrio , Feminino , Galectinas/genética , Hepatite Autoimune/genética , Hepatite Autoimune/terapia , Camundongos , Camundongos Endogâmicos C57BL
4.
Molecules ; 26(20)2021 Oct 14.
Artigo em Inglês | MEDLINE | ID: mdl-34684775

RESUMO

Carbohydrate-protein conjugates have diverse applications. They have been used clinically as vaccines against bacterial infection and have been developed for high-throughput assays to elucidate the ligand specificities of glycan-binding proteins (GBPs) and antibodies. Here, we report an effective process that combines highly efficient chemoenzymatic synthesis of carbohydrates, production of carbohydrate-bovine serum albumin (glycan-BSA) conjugates using a squarate linker, and convenient immobilization of the resulting neoglycoproteins on carboxylate-coated fluorescent magnetic beads for the development of a suspension multiplex array platform. A glycan-BSA-bead array containing BSA and 50 glycan-BSA conjugates with tuned glycan valency was generated. The binding profiles of six plant lectins with binding preference towards Gal and/or GalNAc, as well as human galectin-3 and galectin-8, were readily obtained. Our results provide useful information to understand the multivalent glycan-binding properties of human galectins. The neoglycoprotein-immobilized fluorescent magnetic bead suspension multiplex array is a robust and flexible platform for rapid analysis of glycan and GBP interactions and will find broad applications.


Assuntos
Galectinas/metabolismo , Análise Serial de Proteínas/métodos , Proteínas Sanguíneas/química , Proteínas Sanguíneas/metabolismo , Configuração de Carboidratos , Sequência de Carboidratos , Corantes Fluorescentes , Galectinas/química , Glicoproteínas , Humanos , Proteínas Imobilizadas , Fenômenos Magnéticos , Lectinas de Plantas/química , Lectinas de Plantas/metabolismo , Polissacarídeos/química , Ligação Proteica , Proteínas Recombinantes/química , Proteínas Recombinantes/metabolismo , Albumina Sérica , Soroalbumina Bovina
5.
Int J Mol Sci ; 22(19)2021 Sep 30.
Artigo em Inglês | MEDLINE | ID: mdl-34638920

RESUMO

Glycan-lectin interactions play an essential role in different cellular processes. One of their main functions is involvement in the immune response to pathogens or inflammation. However, cancer cells and viruses have adapted to avail themselves of these interactions. By displaying specific glycosylation structures, they are able to bind to lectins, thus promoting pathogenesis. While glycan-lectin interactions promote tumor progression, metastasis, and/or chemoresistance in cancer, in viral infections they are important for viral entry, release, and/or immune escape. For several years now, a growing number of investigations have been devoted to clarifying the role of glycan-lectin interactions in cancer and viral infections. Various overviews have already summarized and highlighted their findings. In this review, we consider the interactions of the lectins MGL, DC-SIGN, selectins, and galectins in both cancer and viral infections together. A possible transfer of ways to target and disrupt them might lead to new therapeutic approaches in different pathological backgrounds.


Assuntos
Lectinas/metabolismo , Neoplasias/metabolismo , Polissacarídeos/metabolismo , Viroses/metabolismo , Animais , Moléculas de Adesão Celular/química , Moléculas de Adesão Celular/metabolismo , Galectinas/química , Galectinas/metabolismo , Humanos , Lectinas/química , Lectinas Tipo C/química , Lectinas Tipo C/metabolismo , Polissacarídeos/química , Ligação Proteica , Receptores de Superfície Celular/química , Receptores de Superfície Celular/metabolismo , Selectinas/química , Selectinas/metabolismo , Viroses/virologia
6.
Biomacromolecules ; 22(11): 4720-4729, 2021 11 08.
Artigo em Inglês | MEDLINE | ID: mdl-34704753

RESUMO

Galectins are galactoside-binding lectins that are functional dimers or higher-order oligomers. Multivalent binding has been shown to augment the relatively low affinity of the galectins for their galactoside-binding partners, enabling the galectins to play an important role in the global remodeling of cells that occurs during the stress conditions of disease states, including heart disease and cancer. The presence of galectins in the nematode Caenorhabditis elegans and their galactoside-binding properties have been demonstrated, but the role of multivalent interactions for C. elegans galectins is unknown. Here, we describe the synthesis of Galß1-4Fuc-functionalized poly(amidoamine) dendrimers and their utility in studies using C. elegans during oxidative stress. C. elegans were fed Galß1-4Fuc-functionalized dendrimers and RNA interference to knock down lectins lec-1 and lec-10 while undergoing oxidative stress. C. elegans that were pretreated with the glycodendrimers were less susceptible to oxidative stress than untreated controls. Worms that were fed fluorescently tagged glycodendrimers and imaged indicated that the dendrimers are primarily present in the digestive tract of the worms, and uptake into the vulva and proximal gonads could also be observed in some instances. This study suggests that multivalently presented Galß1-4Fuc can protect C. elegans from oxidative stress.


Assuntos
Proteínas de Caenorhabditis elegans , Dendrímeros , Animais , Caenorhabditis elegans/metabolismo , Proteínas de Caenorhabditis elegans/metabolismo , Dendrímeros/farmacologia , Fucose , Galactose , Galectinas/metabolismo , Estresse Oxidativo
7.
Anal Chem ; 93(37): 12639-12647, 2021 09 21.
Artigo em Inglês | MEDLINE | ID: mdl-34491716

RESUMO

Lysosomal membrane permeabilization (LMP) engaged in multiple human diseases is accompanied by relocation of cytosolic galectin into LMP+ lysosomes. We herein reported a galectin trafficking-targeted method to image LMP using two kinds of glyco-dendrimers, a sialic acid-terminated dendrimer labeled with pH-inert rhodamine and a lactose-terminated dendrimer labeled with fluorescein that becomes green-emissive in pH-elevated lysosomes. Albeit both accumulated in physiological lysosomes, the former is released from LMP+ lysosomes while the latter binds to galectin accumulated in LMP+ lysosomes and thus trapped in LMP+ lysosomes. Accordingly, LMP+ lysosomes exhibit loss of red fluorescence and turn-on green fluorescence due to loss of lysosomal acidity. This red-to-green color switch enables discernment of LMP+ lysosomes from physiological lysosomes and pH-elevated lysosomes and can be further utilized to detect LMP in distinct cell death pathways. These results suggest the utility of galectin trafficking pathway-integrated synthetic probes for detection of LMP, a key factor for diseased cells.


Assuntos
Galectinas , Lisossomos , Morte Celular , Citosol , Humanos , Membranas Intracelulares
8.
Zhongguo Shi Yan Xue Ye Xue Za Zhi ; 29(4): 1360-1364, 2021 Aug.
Artigo em Chinês | MEDLINE | ID: mdl-34362531

RESUMO

The incidence of hematological malignant tumor is increasing year by year, and seriously affecting the human health. In addition to the traditional radiation and chemotherapy, immunotherapy has achieved a certain effect in the treatment of blood tumor, but it is limited by exhaustion of CD8+ T cell. The exhaustion of CD8+ T cells is mainly related to the activation of some immune checkpoint inhibitors, such as (Tim3), programmed death 1 (PD-1), cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), etc. Among them, Tim3 is getting more and more attention. The combination of Tim3 and its ligand galectin-9 produced a strong cellular immunosuppressive effect. Tim3 has been proved to be associated with CD8+ T cell exhaustion in many tumors. In this review, the application of Tim3/galectin-9 in hematologic tumors is briefly summarized so as to provide theoretical basis for clinical diagnosis and treatment of these diseases.


Assuntos
Neoplasias Hematológicas , Receptor Celular 2 do Vírus da Hepatite A , Linfócitos T CD8-Positivos , Galectinas , Humanos , Imunoterapia
9.
Biomolecules ; 11(8)2021 08 07.
Artigo em Inglês | MEDLINE | ID: mdl-34439833

RESUMO

Galectin-3 is a lectin that binds beta-galactosides. It is involved in cardiac remodeling and fibrosis through the activation of macrophages and fibroblasts. ST2 is secreted by myocardial cells due to cardiac overload. These two biomarkers have been traditionally studied in the field of heart failure to guide medical therapy and detect the progression of the disease. Nevertheless, there are novel evidences that connect galectin-3 and ST2 with coronary heart disease and, specifically, with atrial fibrillation. The aim of this article is to concisely review the diagnostic and prognostic role of galectin-3 and ST2 in different cardiac diseases.


Assuntos
Fibrilação Atrial/sangue , Doença das Coronárias/sangue , Galectinas/sangue , Insuficiência Cardíaca/sangue , Proteína 1 Semelhante a Receptor de Interleucina-1/sangue , Isquemia Miocárdica/sangue , Fibrilação Atrial/diagnóstico , Fibrilação Atrial/mortalidade , Fibrilação Atrial/patologia , Biomarcadores/sangue , Proteínas Sanguíneas , Doença das Coronárias/diagnóstico , Doença das Coronárias/mortalidade , Doença das Coronárias/patologia , Progressão da Doença , Fibroblastos/metabolismo , Fibroblastos/patologia , Coração , Insuficiência Cardíaca/diagnóstico , Insuficiência Cardíaca/mortalidade , Insuficiência Cardíaca/patologia , Humanos , Macrófagos/metabolismo , Macrófagos/patologia , Isquemia Miocárdica/diagnóstico , Isquemia Miocárdica/mortalidade , Isquemia Miocárdica/patologia , Peptídeo Natriurético Encefálico/sangue , Fragmentos de Peptídeos/sangue , Prognóstico , Análise de Sobrevida , Troponina/sangue
10.
Biomolecules ; 11(8)2021 07 28.
Artigo em Inglês | MEDLINE | ID: mdl-34439775

RESUMO

Galectin-3 (gal-3) is a fibrosis marker and may play a role in fibrosis of the left atrium (LA). Left atrial wall fibrosis may influence the transition from paroxysmal to non-paroxysmal atrial fibrillation (AF). In this study, we assessed the correlation of gal-3 concentration with the main echocardio-graphic parameters evaluating dimensions, volume, compliance, and left atrial contractility during AF and after successful electrical cardioversion (DCCV). The study included 63 patients with left atrial enlargement who qualified for DCCV due to persistent AF. The procedure recovered sinus rhythm in 43 (68.3%) patients. The concentration of gal-3 was negatively correlated with the echocardiographic parameters of LA including dimensions (LA length pre, rho = -0.38; p = 0.003), volume (LAV pre, rho = -0.39; p = 0.003), compliance (LASr mean post, rho = -0.33) and contractility (pLASRct mean post, rho = -0.33; p = 0.038). Negative correlations of gal-3 concentration were also observed in relation to the volume and contractility of the left ventricle. The concentration of gal-3 significantly negatively correlates with the size, systolic function, and compliance of the LA wall in patients with persistent AF. Determining gal-3 concentration in patients with persistent AF may help in the assessment of remodeling of the LA wall.


Assuntos
Fibrilação Atrial/metabolismo , Remodelamento Atrial , Proteínas Sanguíneas/metabolismo , Fibrose Endomiocárdica/metabolismo , Galectinas/metabolismo , Átrios do Coração/metabolismo , Idoso , Fibrilação Atrial/diagnóstico por imagem , Fibrilação Atrial/fisiopatologia , Fibrilação Atrial/terapia , Biomarcadores/metabolismo , Proteínas Sanguíneas/genética , Ecocardiografia , Cardioversão Elétrica/métodos , Fibrose Endomiocárdica/diagnóstico por imagem , Fibrose Endomiocárdica/fisiopatologia , Fibrose Endomiocárdica/terapia , Feminino , Galectinas/genética , Expressão Gênica , Átrios do Coração/diagnóstico por imagem , Átrios do Coração/patologia , Átrios do Coração/fisiopatologia , Ventrículos do Coração/diagnóstico por imagem , Ventrículos do Coração/metabolismo , Ventrículos do Coração/patologia , Ventrículos do Coração/fisiopatologia , Humanos , Masculino , Pessoa de Meia-Idade , Contração Miocárdica , Função Ventricular Esquerda
11.
Molecules ; 26(16)2021 Aug 04.
Artigo em Inglês | MEDLINE | ID: mdl-34443300

RESUMO

Frutalin is a plant lectin with beneficial immunobiological action, although the access to its active form is still restricted. Moreover, there is a knowledge gap on isoform activity and glycosylation impact on its bioactivity, and recombinant production protocols were seen as ineffective. Here, a simpler and faster production and purification protocol was developed, attaining a yield of purified frutalin 3.3-fold higher than that obtained previously. Hemagglutination assays confirmed that this frutalin isoform could not agglutinate rabbit erythrocytes, while maintaining the native tetrameric structure, as indicated by DLS analysis, and strong interaction with methyl-alpha-galactose, in fluorescence spectroscopy studies. The cytotoxicity of the recombinant frutalin isoform was shown in a broad panel of human cancer cells: colon (HCT116), melanoma (A375), triple-negative breast cancer (MDA-MB-231), and ovarian (IGROV-1). Treatment with 8.5-11.8 µM TrxFTL reduced proliferation of all cancer cells to half in 48 h. This anti-proliferative effect encompasses the p53 pathway since it was significantly reduced in p53-null colon cancer cells (HCT116 p53-/-; GI50 of 25.0 ± 3.0 µM), when compared to the isogenic p53-positive cells (HCT116 p53+/+; GI50 of 8.7 ± 1.8 µM; p < 0.002). This recombinantly produced frutalin isoform has relevant cytotoxic effect and its biological activity is not dependent on glycosylation. The developed E. coli production and purification protocol generates high yield of non-glycosylated frutalin isoform with potent cytotoxic activity, enabling the development of novel anticancer p53-targeting therapies.


Assuntos
Galectinas/farmacologia , Neoplasias/patologia , Sequência de Aminoácidos , Animais , Antineoplásicos/farmacologia , Morte Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Difusão Dinâmica da Luz , Escherichia coli/metabolismo , Galactose/metabolismo , Galectinas/química , Galectinas/isolamento & purificação , Glicosilação/efeitos dos fármacos , Hemaglutinação/efeitos dos fármacos , Modelos Moleculares , Peso Molecular , Coelhos , Proteínas Recombinantes/química , Proteínas Recombinantes/isolamento & purificação , Proteínas Recombinantes/farmacologia , Espectrometria de Fluorescência
12.
Elife ; 102021 08 09.
Artigo em Inglês | MEDLINE | ID: mdl-34369876

RESUMO

Despite the mechanisms of central and peripheral tolerance, the mature B cell compartment contains cells reactive for self-antigen. How these cells are poised not to respond and the mechanisms that restrain B cell responses to low-affinity endogenous antigens are not fully understood. Here, we demonstrate a critical role for the glycan-binding protein galectin-9 in setting the threshold of B cell activation and that loss of this regulatory network is sufficient to drive spontaneous autoimmunity. We further demonstrate a critical role for galectin-9 in restraining not only conventional B-2 B cells, but also innate-like B-1a cells. We show that galectin-9-deficient mice have an expanded population of B-1a cells and increased titers of B-1a-derived autoantibodies. Mechanistically, we demonstrate that galectin-9 regulates BCR and distinct TLR responses in B-1a cells, but not B-1b cells, by regulating the interaction between BCR and TLRs with the regulatory molecules CD5 and CD180, respectively. In the absence of galectin-9, B-1a cells are more readily activated and secrete increased titers of autoantibodies that facilitate autoantigen delivery to the spleen, driving autoimmune responses.


Assuntos
Autoimunidade/genética , Linfócitos B/metabolismo , Galectinas/deficiência , Fatores Etários , Animais , Centro Germinativo/metabolismo , Centro Germinativo/patologia , Camundongos , Nefrite/genética , Esplenomegalia/genética
13.
Nutrients ; 13(8)2021 Aug 16.
Artigo em Inglês | MEDLINE | ID: mdl-34444962

RESUMO

Galectin-3 reportedly participates in the inflammatory process that causes insulin resistance in the target tissues. However, the role of high plasma galectin-3 levels as an indicator of protein-energy wasting (PEW) in patients undergoing maintenance hemodialysis remains unclear. This study included 240 hemodialysis patients (64.5 [55.3-74.0] years, 35.8% women) from a tertiary medical center. A baseline assessment of demographic and clinical data, biochemical parameters, and body composition was conducted. Plasma galectin-3 and other biomarkers were measured using a multiplex bead-based immunoassay. Participants were then divided into two subgroups depending on the median value of plasma galectin-3. Malnutrition was identified using the geriatric nutritional risk index (GNRI) and the criteria of the International Society of Renal Nutrition and Metabolism. Independent risk factors for elevated plasma galectin-3 and malnutrition were identified by multivariate logistic regression. The high galectin-3 group was more likely to be older, have lower lean tissue mass and GNRI scores, be diagnosed with PEW, dialyze through a tunneled catheter, and have higher circulating IL-6, TNF-α, and MCP-1 concentrations than the low galectin-3 group. After multivariate adjustment, only low mean arterial pressure, dialyzing with tunneled cuffed catheters, and elevated systemic inflammatory markers correlated with high galectin-3 levels. Plasma galectin-3 concentrations also increased significantly in hemodialysis patients with PEW. However, compared with other commonly used nutritional indicators, galectin-3 did not show superiority in predicting PEW. Although the plasma galectin-3 levels correlated with PEW severity, this correlation disappeared after adjustment for potential confounding variables (OR, 1.000; 95% CI, 0.999-1.001). In conclusion, plasma galectin-3 is a valuable biomarker for systemic inflammation but is less prominent for PEW in patients with maintenance hemodialysis. Further identification of novel biomarkers is required to detect patients at risk for malnutrition and implement appropriate interventions.


Assuntos
Galectinas/sangue , Inflamação , Falência Renal Crônica , Desnutrição Proteico-Calórica , Diálise Renal/estatística & dados numéricos , Idoso , Proteínas Sanguíneas , Estudos Transversais , Feminino , Humanos , Falência Renal Crônica/complicações , Falência Renal Crônica/epidemiologia , Falência Renal Crônica/terapia , Masculino , Pessoa de Meia-Idade
14.
PLoS Biol ; 19(8): e3001387, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34411088

RESUMO

The interaction of neutrophils with T cells has been the subject of debate and controversies. Previous studies have suggested that neutrophils may suppress or activate T cells. Despite these studies, the interaction between neutrophils and T cells has remained a largely unexplored field. Here, based on our RNA sequencing (RNA-seq) analysis, we found that neutrophils have differential transcriptional and functional profiling depending on the CD4 T-cell count of the HIV-infected individual. In particular, we identified that neutrophils in healthy individuals express surface Galectin-9 (Gal-9), which is down-regulated upon activation, and is consistently down-regulated in HIV-infected individuals. However, down-regulation of Gal-9 was associated with CD4 T-cell count of patients. Unstimulated neutrophils express high levels of surface Gal-9 that is bound to CD44, and, upon stimulation, neutrophils depalmitoylate CD44 and induce its movement out of the lipid raft. This process causes the release of Gal-9 from the surface of neutrophils. In addition, we found that neutrophil-derived exogenous Gal-9 binds to cell surface CD44 on T cells, which promotes LCK activation and subsequently enhances T-cell activation. Furthermore, this process was regulated by glycolysis and can be inhibited by interleukin (IL)-10. Together, our data reveal a novel mechanism of Gal-9 shedding from the surface of neutrophils. This could explain elevated plasma Gal-9 levels in HIV-infected individuals as an underlying mechanism of the well-characterized chronic immune activation in HIV infection. This study provides a novel role for the Gal-9 shedding from neutrophils. We anticipate that our results will spark renewed investigation into the role of neutrophils in T-cell activation in other acute and chronic conditions, as well as improved strategies for modulating Gal-9 shedding.


Assuntos
Galectinas/metabolismo , Infecções por HIV/imunologia , Receptores de Hialuronatos/metabolismo , Ativação Linfocitária , Neutrófilos/fisiologia , Contagem de Linfócito CD4 , Estudos de Casos e Controles , Glicólise , Humanos , Interleucina-10/metabolismo , Cultura Primária de Células
15.
Respir Med ; 187: 106556, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34375925

RESUMO

OBJECTIVES: Galectin-3 is ß-galactoside-binding lectin with several roles in immune-inflammatory response. To date, there is no evidence of Galectin-3 role as a prognostic biomarker in COVID-19 disease. The aim of this study is to clarify the prognostic role of Galectin-3 in patients with COVID 19 acute respiratory failure. METHODS: We enrolled 156 consecutive patients with COVID-19 disease. Routine laboratory test, arterial blood gas, chest X-ray or Computed Tomography and Galectin-3 dosage were performed. The primary outcome was to assess Galectin-3 predictive power for 30-day mortality. Secondary outcomes were 30-day Intensive Care Unit admission and Acute Respiratory Distress Syndrome stratification according to Galectin-3 dosage. We performed Mann-Whitney U and Kruskal-Wallis tests for continuous variables comparison. Fisher's exact test or Chi-square test were used for categorical variables analysis. Receiver Operating Characteristic curves estimated Galectin-3 predictive power for the endpoints. With a fixed cut-off of 35.3 ng/ml, Kaplan-Meier with Log-Rank test and Cox Regression were performed to assess mortality and Intensive Care Unit admission risk. RESULTS: Galectin-3 correlated with many other prognostic predictors tested in our analysis. Moreover, patients with serum levels of Galectin-3 above 35.3 ng/ml had increased risk for mortality, Intensive Care Unit admission and severe Acute Respiratory Distress Syndrome. CONCLUSIONS: Our study demonstrates the role of Galectin-3 as a predictor of mortality, Intensive Care Unit access and ARDS stratification in patients with COVID 19 acute respiratory failure.


Assuntos
COVID-19/sangue , COVID-19/mortalidade , Galectinas/sangue , Síndrome do Desconforto Respiratório/sangue , Síndrome do Desconforto Respiratório/virologia , Idoso , Idoso de 80 Anos ou mais , Biomarcadores/sangue , Proteínas Sanguíneas , COVID-19/complicações , Cuidados Críticos , Feminino , Hospitalização , Humanos , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Prognóstico , Síndrome do Desconforto Respiratório/mortalidade , Estudos Retrospectivos , Taxa de Sobrevida
16.
Cells ; 10(7)2021 07 05.
Artigo em Inglês | MEDLINE | ID: mdl-34359869

RESUMO

The recent emergence of anti-immunoglobulin E (IgE) drugs and their candidates for humans has endorsed the significance of IgE-dependent pathways in allergic disorders. IgE is distributed locally in the tissues or systemically to confer a sensory mechanism in a domain of adaptive immunity to the otherwise innate type of effector cells, namely, mast cells and basophils. Bound on the high-affinity IgE receptor FcεRI, IgE enables fast memory responses against revisiting threats of venoms, parasites, and bacteria. However, the dysregulation of IgE-dependent reactions leads to potentially life-threatening allergic diseases, such as asthma and anaphylaxis. Therefore, reactivity of the IgE sensor is fine-tuned by various IgE-associating molecules. In this review, we discuss the mechanistic basis for how IgE-dependent mast cell activation is regulated by the IgE-associating molecules, including the newly developed therapeutic candidates.


Assuntos
Imunoglobulina E/metabolismo , Mastócitos/imunologia , Animais , Galectinas/metabolismo , Glicosilação , Histamina/metabolismo , Humanos , Imunoglobulina E/química , Receptores de IgE/metabolismo
17.
Biomolecules ; 11(8)2021 07 22.
Artigo em Inglês | MEDLINE | ID: mdl-34439744

RESUMO

Galectins are one of the critical players in the tumor microenvironment-tumor crosstalk and the regulation of local immunity. Galectin-9 has been in the limelight in tumor immunology. Galectin-9 possesses its multiplex biological functions both extracellularly and intracellularly, plays a pivotal role in the modulation of adaptive and innate immunity, and induces immune tolerance. NK-92MI cell lines against different malignancies were extensively studied, and recently published trials used genetically chimeric antigen receptor-transfected NK-92MI cells in tumor immunotherapy. Besides the intensive research in tumor immunotherapy, limited information is available on their immune-checkpoint expression and the impact of checkpoint ligands on their effector functions. To uncover the therapeutic potential of modulating Galectin-9-related immunological pathways in NK-cell-based therapy, we investigated the dose-dependent effect of soluble Galectin-9 on the TIM-3 checkpoint receptor and NKG2D, CD69, FasL, and perforin expression of NK-92MI cells. We also examined how their cytotoxicity and cytokine production was altered after Gal-9 treatment and in the presence of different serum supplements using flow cytometric analysis. Our study provides evidence that the Galectin-9/TIM-3 pathway plays an important role in the regulation of NK cell function, and about the modulatory role of Galectin-9 on the cytotoxicity and cytokine production of NK-92MI cells in the presence of different serum supplements. We hope that our results will aid the development of novel NK-cell-based strategies that target Galectin-9/TIM-3 checkpoint in tumors resistant to T-cell-based immunotherapy.


Assuntos
Galectinas/metabolismo , Linfoma não Hodgkin/patologia , Soro/química , Imunidade Adaptativa , Animais , Antígenos CD/metabolismo , Antígenos de Diferenciação de Linfócitos T/metabolismo , Linhagem Celular Tumoral , Citocinas/metabolismo , Proteína Ligante Fas/metabolismo , Expressão Gênica , Receptor Celular 2 do Vírus da Hepatite A/metabolismo , Humanos , Imunidade Inata , Imunoterapia/métodos , Células K562 , Células Matadoras Naturais/metabolismo , Lectinas Tipo C/metabolismo , Linfoma não Hodgkin/metabolismo , Camundongos , Subfamília K de Receptores Semelhantes a Lectina de Células NK/metabolismo , Neoplasias/imunologia , Neoplasias/patologia , Perforina/metabolismo , Fenótipo , Proteínas Recombinantes/química , Microambiente Tumoral
18.
Biomed Pharmacother ; 139: 111713, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34243634

RESUMO

Galectins, are ß-galactoside binding lectins expressed in numerous cells and are known to regulate various immune responses and cellular physiological functions. Galectins have been reported to participate in the regulation of several viral infections via carbohydrate­dependent/independent manner. Galectins have displayed various regulatory functions on viral infection, however, the detailed mechanism remains unclear. More recently, some members of galectins have been reported to regulate influenza A virus (IAV) infection. In this review, we aim to analyze and summarize current findings regarding the role of galectins in IAV infection and their antiviral potential therapeutic application in the treatment of IAVs. The eligible articles were selected according to the PRISMA guidelines. Results indicate that Galectin-1(Gal-1), Galectin-3(Gal-3) and Galectin-9 (Gal-9) were found as the predominant galectins reported to participate in the regulation of IAVs infection. The inhibitory regulation of IAVs by these galectins occurred mainly through extracellular binding to glycosylated envelope proteins, further blocking the interaction between influenza envelope and sialic acid receptor, interacting with ligands or receptors on immune cells to trigger immunol or cellular response against IAVs, and endogenously interacting cellular components in the cytoplasm to activate inflammasome and autophagy. This study offers information regarding the multiple roles of galectins observed in IAVs infection and suggest that galectins has the potential to be used as therapeutic agents for IAVs.


Assuntos
Antivirais/farmacologia , Galectinas/farmacologia , Vírus da Influenza A/efeitos dos fármacos , Influenza Humana/tratamento farmacológico , Infecções por Orthomyxoviridae/tratamento farmacológico , Animais , Autofagia/efeitos dos fármacos , Citoplasma/efeitos dos fármacos , Humanos , Inflamassomos/efeitos dos fármacos
19.
Int J Mol Sci ; 22(11)2021 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-34206141

RESUMO

The interaction of multi-LacNAc (Galß1-4GlcNAc)-containing N-(2-hydroxypropyl) methacrylamide (HPMA) copolymers with human galectin-1 (Gal-1) and the carbohydrate recognition domain (CRD) of human galectin-3 (Gal-3) was analyzed using NMR methods in addition to cryo-electron-microscopy and dynamic light scattering (DLS) experiments. The interaction with individual LacNAc-containing components of the polymer was studied for comparison purposes. For Gal-3 CRD, the NMR data suggest a canonical interaction of the individual small-molecule bi- and trivalent ligands with the lectin binding site and better affinity for the trivalent arrangement due to statistical effects. For the glycopolymers, the interaction was stronger, although no evidence for forming a large supramolecule was obtained. In contrast, for Gal-1, the results indicate the formation of large cross-linked supramolecules in the presence of multivalent LacNAc entities for both the individual building blocks and the polymers. Interestingly, the bivalent and trivalent presentation of LacNAc in the polymer did not produce such an increase, indicating that the multivalency provided by the polymer is sufficient for triggering an efficient binding between the glycopolymer and Gal-1. This hypothesis was further demonstrated by electron microscopy and DLS methods.


Assuntos
Proteínas Sanguíneas/química , Galectina 1/química , Galectinas/química , Metacrilatos/química , Polímeros/química , Acrilamidas/química , Acrilamidas/farmacologia , Sítios de Ligação/efeitos dos fármacos , Proteínas Sanguíneas/genética , Carboidratos/química , Microscopia Crioeletrônica , Galectina 1/genética , Galectinas/genética , Humanos , Ligantes , Metacrilatos/farmacologia , Polímeros/farmacologia , Ligação Proteica/efeitos dos fármacos
20.
Chemistry ; 27(51): 13040-13051, 2021 Sep 09.
Artigo em Inglês | MEDLINE | ID: mdl-34216419

RESUMO

Galectins are widely expressed galactose-binding lectins implied, for example, in immune regulation, metastatic spreading, and pathogen recognition. N-Acetyllactosamine (Galß1-4GlcNAc, LacNAc) and its oligomeric or glycosylated forms are natural ligands of galectins. To probe substrate specificity and binding mode of galectins, we synthesized a complete series of six mono-deoxyfluorinated analogues of LacNAc, in which each hydroxyl has been selectively replaced by fluorine while the anomeric position has been protected as methyl ß-glycoside. Initial evaluation of their binding to human galectin-1 and -3 by ELISA and 19 F NMR T2 -filter revealed that deoxyfluorination at C3, C4' and C6' completely abolished binding to galectin-1 but very weak binding to galectin-3 was still detectable. Moreover, deoxyfluorination of C2' caused an approximately 8-fold increase in the binding affinity towards galectin-1, whereas binding to galectin-3 was essentially not affected. Lipophilicity measurement revealed that deoxyfluorination at the Gal moiety affects log P very differently compared to deoxyfluorination at the GlcNAc moiety.


Assuntos
Amino Açúcares , Galectinas , Carboidratos , Humanos , Espectroscopia de Ressonância Magnética
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