RESUMEN
BACKGROUND: High infiltration of tumor-associated macrophages (TAMs) is associated with tumor promotion and immunosuppression. The triggering receptor expressed on myeloid cells 2 (TREM2) is emerged as a key immunosuppressive regulator for TAMs, however, how TREM2-expressing TAMs are recruited and what ligands TREM2 interacts with to mediate immunosuppression is unknown. METHODS: Flow cytometry and single-cell RNA sequencing were used to analyze TREM2 expression. Mechanistically, mass spectrometry and immunoprecipitation were employed to identify proteins binding to TREM2. Phagocytosis and co-culture experiments were used to explore the in vitro functions of galectin3-TREM2 pair. Establishment of TREM2f/f-Lyz2-cre mice to validate the role of TREM2 signaling pathway in lung carcinogenesis. GB1107 were further supplemented to validate the therapeutic effect of Galectin3 based on TREM2 signaling regulation. RESULTS: This study identified that abundant TREM2+ macrophages were recruited at the intra-tumor site through the CCL2-CCR2 chemotactic axis. Galectin-3 impaired TREM2-mediated phagocytosis and promoted the conversion of TREM2+ macrophages to immunosuppressive TAMs with attenuated antigen presentation and co-stimulatory functions both in vitro both in vivo, and galectin-3 is a potential ligand for TREM2. Genetic and pharmacological blockade of TREM2 and galectin-3 significantly inhibited lung cancer progression in subcutaneous and orthotopic cancer models by remodeling the tumor immune microenvironment. CONCLUSION: Our findings revealed a previously unknown association between galectin-3 and TREM2 in TAMs of lung cancer, and suggested simultaneous inhibition of galectin3 and TREM2 as potent therapeutic approach for lung cancer therapy.
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Galectina 3 , Neoplasias Pulmonares , Macrófagos , Glicoproteínas de Membrana , Receptores Inmunológicos , Animales , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/inmunología , Neoplasias Pulmonares/patología , Neoplasias Pulmonares/genética , Ratones , Receptores Inmunológicos/metabolismo , Receptores Inmunológicos/genética , Glicoproteínas de Membrana/metabolismo , Humanos , Galectina 3/metabolismo , Galectina 3/genética , Macrófagos/metabolismo , Macrófagos/inmunología , Modelos Animales de EnfermedadRESUMEN
Galectin-3 (Gal-3) is a carbohydrate binding protein that has been implicated in the development and progression of fibrotic diseases. Proof-of-principal animal models have demonstrated that inhibition of Gal-3 is a potentially viable pathway for the treatment of fibrosisâwith small molecule Gal-3 inhibitors advanced into clinical trials. We hereby report the discovery of novel galactose-based monosaccharide Gal-3 inhibitors comprising 2-methyl-4-phenyl-2,4-dihydro-3H-1,2,4-triazole-3-thione (compound 20) and 4-phenyl-4H-1,2,4-triazole (compound 15). Notably, hindered rotation caused by steric interaction between the 3-thione and ortho-trifluoromethyl group of compounds 20, 21 induced formation of thermodynamically stable atropisomers. Distinct X-ray cocrystal structures of 20 and 21 were obtained, which clearly demonstrated that the configuration of 21 proscribes a key halogen bonding σ-hole interaction of 3-chloro with carbonyl oxygen of Gly182, thereby leading to significant loss in potency. Ultimately, 20 and 15 were evaluated in mouse pharmacokinetic studies, and both compounds exhibited oral exposures suitable for further in vivo assessment.
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Galactosa , Galectina 3 , Triazoles , Triazoles/química , Triazoles/farmacología , Triazoles/síntesis química , Triazoles/farmacocinética , Galactosa/química , Galactosa/metabolismo , Animales , Humanos , Galectina 3/antagonistas & inhibidores , Galectina 3/metabolismo , Ratones , Relación Estructura-Actividad , Cristalografía por Rayos X , Tionas/química , Tionas/farmacología , Tionas/síntesis química , Tionas/farmacocinética , Proteínas Sanguíneas/metabolismo , Galectinas/antagonistas & inhibidores , Galectinas/metabolismo , Modelos MolecularesRESUMEN
The study included 40 patients of both genders who underwent skin transplantation after a hand injury. The study aims to evaluate the oxidative stress parameters in patients' blood and serum levels of galectin-3 in order to investigate gender differences pre- and post- skin transplantation. The results of the study suggest a significant increase in superoxide anion radical levels, catalase activity, and reduced glutathione levels in females before skin transplantation. The surgical treatment caused significant increase in superoxide anion radical and hydrogen peroxide levels as prooxidants in males, while superoxide dismutase and catalase activity were also increased 7 days after the procedure. In females, superoxide anion radical and TBARS levels increased after surgical procedure as well as the activity of catalase. Regarding galectin-3 levels, a significant interaction between gender and time was observed (gender×time; p=0.000). Correlation analysis of different oxidative stress markers with gal-3 revealed the existence of a significant negative correlation of superoxide anion radical, catalase, and reduced glutathione with gal-3, but only in female patients. It can be concluded that OS as well as galectin-3 play important roles at least in the first 7 days of the postoperative period.
Asunto(s)
Catalasa , Galectina 3 , Glutatión , Traumatismos de la Mano , Estrés Oxidativo , Trasplante de Piel , Adulto , Femenino , Humanos , Masculino , Persona de Mediana Edad , Adulto Joven , Proteínas Sanguíneas , Catalasa/sangre , Catalasa/metabolismo , Galectina 3/sangre , Galectina 3/metabolismo , Galectinas , Glutatión/sangre , Glutatión/metabolismo , Traumatismos de la Mano/cirugía , Traumatismos de la Mano/sangre , Traumatismos de la Mano/metabolismo , Peróxido de Hidrógeno/sangre , Peróxido de Hidrógeno/metabolismo , Caracteres Sexuales , Factores Sexuales , Superóxido Dismutasa/sangre , Superóxido Dismutasa/metabolismo , Superóxidos/metabolismo , Superóxidos/sangre , Sustancias Reactivas al Ácido Tiobarbitúrico/metabolismoRESUMEN
Adverse intrauterine conditions may cause fetal growth restriction (FGR), a pregnancy complication frequently linked to perinatal morbidity and mortality. Although many studies have focused on FGR, the pathophysiological processes underlying this disorder are complex and incompletely understood. We have recently determined that galectin-3 (gal-3), a ß-galactoside-binding protein, regulates pregnancy-associated processes, including uterine receptibility, maternal vascular adaptation and placentation. Because gal-3 is expressed at both sides of the maternal-fetal interface, we unraveled the contribution of maternal- and paternal-derived gal-3 on fetal-placental development in the prenatal window and its effects on the post-natal period. Deficiency of maternal gal-3 induced maternal gut microbiome dysbiosis, resulting in a sex-specific fetal growth restriction mainly observed in female fetuses and offspring. In addition, poor placental metabolic adaptions (characterized by decreased trophoblast glycogen content and insulin-like growth factor 2 (Igf2) gene hypomethylation) were only associated with a lack of maternal-derived gal-3. Paternal gal-3 deficiency caused compromised vascularization in the placental labyrinth without affecting fetal growth trajectory. Thus, maternal-derived gal-3 may play a key role in fetal-placental development through the gut-placenta axis.
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Retardo del Crecimiento Fetal , Galectina 3 , Placenta , Retardo del Crecimiento Fetal/metabolismo , Retardo del Crecimiento Fetal/genética , Embarazo , Femenino , Animales , Placenta/metabolismo , Ratones , Galectina 3/metabolismo , Galectina 3/deficiencia , Galectina 3/genética , Masculino , Microbioma Gastrointestinal , Ratones Endogámicos C57BL , Humanos , Desarrollo Fetal , Factor II del Crecimiento Similar a la Insulina/metabolismo , Factor II del Crecimiento Similar a la Insulina/genética , Factor II del Crecimiento Similar a la Insulina/deficiencia , Trofoblastos/metabolismoRESUMEN
Nearly six million people worldwide have died from the coronavirus disease (COVID-19) outbreak caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Although COVID-19 vaccines are largely successful in reducing the severity of the disease and deaths, the decline in vaccine-induced immunity over time and the continuing emergence of new viral variants or mutations underscore the need for an alternative strategy for developing broad-spectrum host-mediated therapeutics against SARS-CoV-2. A key feature of severe COVID-19 is dysregulated innate immune signaling, culminating in a high expression of numerous pro-inflammatory cytokines and chemokines and a lack of antiviral interferons (IFNs), particularly type I (alpha and beta) and type III (lambda). As a natural host defense, the myeloid differentiation primary response protein, MyD88, plays pivotal roles in innate and acquired immune responses via the signal transduction pathways of Toll-like receptors (TLRs), a type of pathogen recognition receptors (PRRs). However, recent studies have highlighted that infection with viruses upregulates MyD88 expression and impairs the host antiviral response by negatively regulating type I IFN. Galectin-3 (Gal3), another key player in viral infections, has been shown to modulate the host immune response by regulating viral entry and activating TLRs, the NLRP3 inflammasome, and NF-κB, resulting in the release of pro-inflammatory cytokines and contributing to the overall inflammatory response, the so-called "cytokine storm". These studies suggest that the specific inhibition of MyD88 and Gal3 could be a promising therapy for COVID-19. This review presents future directions for MyD88- and Gal3-targeted antiviral drug discovery, highlighting the potential to restore host immunity in SARS-CoV-2 infections.
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Antivirales , COVID-19 , Galectina 3 , Factor 88 de Diferenciación Mieloide , SARS-CoV-2 , Humanos , Factor 88 de Diferenciación Mieloide/metabolismo , Factor 88 de Diferenciación Mieloide/genética , SARS-CoV-2/fisiología , SARS-CoV-2/inmunología , COVID-19/inmunología , COVID-19/virología , Antivirales/uso terapéutico , Antivirales/farmacología , Galectina 3/metabolismo , Tratamiento Farmacológico de COVID-19 , Inmunidad Innata , Transducción de Señal , AnimalesRESUMEN
Conventional histopathological features of psoriasis and atopic dermatitis often overlap. We aimed to investigate Galectin-3 (Gal-3) expression in psoriatic skin lesions and its potential as an immunohistochemical marker for distinguishing between psoriasis and atopic dermatitis on a pathological basis. Based on immunohistochemical analysis, we assessed Gal-3 expression in formalin-fixed, paraffin-embedded tissue sections from 21 patients with psoriasis and 15 patients with atopic dermatitis. Quantitative analysis of expression intensity was performed using the average density (average optical density) method. We analysed the relationship between Gal-3 expression and clinical characteristics, as well as conventional histopathological features. Patients with psoriasis exhibited significantly decreased Gal-3 expression in the epidermis (0.11±0.05) compared to the atopic dermatitis group (0.36±0.15) and healthy controls (0.49±0.13) (p<0.0001). Reduction in Gal-3 expression in the psoriatic epidermis around areas of neutrophil aggregation was more pronounced than around areas of non-neutrophil aggregation (0.07±0.02 vs 0.16±0.05, p<0.01). In both psoriasis (r=-0.48, p<0.05) and atopic dermatitis groups (r=-0.70, p<0.01), Gal-3 expression negatively correlated with epidermal thickness. When epidermal thickness was matched between the two groups, the decrease in epidermal Gal-3 expression remained significant in the psoriasis group compared to the atopic dermatitis group (0.14±0.05 Vs 0.30±0.07, p<0.01). Patients with psoriasis show specific downregulation of epidermal Gal-3, correlating with epidermal thickness and neutrophil-related factors. Gal-3 may serve as an auxiliary discriminative marker between psoriasis and atopic dermatitis, potentially associated with keratinocyte proliferation and neutrophil function.
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Dermatitis Atópica , Epidermis , Galectina 3 , Psoriasis , Humanos , Psoriasis/metabolismo , Psoriasis/patología , Epidermis/metabolismo , Epidermis/patología , Galectina 3/metabolismo , Galectina 3/análisis , Femenino , Masculino , Dermatitis Atópica/metabolismo , Dermatitis Atópica/patología , Adulto , Persona de Mediana Edad , Biomarcadores/metabolismo , Biomarcadores/análisis , Inmunohistoquímica , Estudios de Casos y Controles , Adulto Joven , Anciano , Diagnóstico DiferencialRESUMEN
Intravascular hemolysis is a central feature of congenital and acquired hemolytic anemias, complement disorders, infectious diseases, and toxemias. Massive and/or chronic hemolysis is followed by the induction of inflammation, very often with severe damage of organs, which enhances the morbidity and mortality of hemolytic diseases. Galectin-3 (Gal-3) is a ß-galactoside-binding lectin that modulates the functions of many immune cells, thus affecting inflammatory processes. Gal-3 is also one of the main regulators of fibrosis. The role of Gal-3 in the development of different kidney and liver diseases and the potential of therapeutic Gal-3 inhibition have been demonstrated. Therefore, the objective of this review is to discuss the possible effects of Gal-3 on the process of kidney and liver damage induced by intravascular hemolysis, as well as to shed light on the potential therapeutic targeting of Gal-3 in intravascular hemolysis.
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Galectina 3 , Hemólisis , Humanos , Galectina 3/metabolismo , Animales , Hepatopatías/metabolismo , Hepatopatías/etiología , Hepatopatías/patología , Enfermedades Renales/metabolismo , Enfermedades Renales/etiología , Enfermedades Renales/patología , Riñón/metabolismo , Riñón/patologíaRESUMEN
Demyelination is characterized by disruption of myelin sheath and disorders in myelin formation. Currently, there are no effective therapeutic treatments available. Microglia, especially anti-inflammatory phenotype microglia are critical for remyelination. Galectin-3 (Gal-3), which is known to modulate microglia activation, is correlated with myelination. In this study, we aimed to elucidate the roles of Gal-3 during myelin formation and explore the efficiency and mechanism of rGal-3 administration in remyelination. We enrolled Gal-3 knockout (Lgals3 KO) mice and demonstrated Lgals3 KO causes demyelination during spontaneous myelinogenesis. We performed a cuprizone (CPZ) intoxication model and found Lgals3 KO aggravates demyelinated lesions and favors microglial pro-inflammatory phenotype polarization. Recombinant Gal-3 (rGal-3) administration alleviates CPZ intoxication and drives microglial towards anti-inflammatory phenotype. Additionally, RNA sequencing results reveal the correlation between Gal-3 and the PPARγ-CD36 axis. Thus, we performed SSO and GW9662 administration to inhibit the activation of the PPARγ-CD36 axis and found that rGal-3 administration modulates microglial phenotype polarization by regulating the PPARγ-CD36 axis. Together, our findings highlight the importance of Gal-3 in myelination and provide insights into rGal-3 administration for modulating microglial anti-inflammatory phenotype polarization through the PPARγ-CD36 axis.
Asunto(s)
Antígenos CD36 , Enfermedades Desmielinizantes , Galectina 3 , Ratones Noqueados , Microglía , PPAR gamma , Animales , PPAR gamma/metabolismo , Microglía/metabolismo , Microglía/efectos de los fármacos , Galectina 3/metabolismo , Ratones , Enfermedades Desmielinizantes/metabolismo , Enfermedades Desmielinizantes/patología , Antígenos CD36/metabolismo , Ratones Endogámicos C57BL , Cuprizona/toxicidad , Vaina de Mielina/metabolismo , Vaina de Mielina/efectos de los fármacos , Masculino , Modelos Animales de EnfermedadRESUMEN
Cervical cancer is still the leading cause of cancer mortality worldwide even after introduction of vaccine against Human papillomavirus (HPV), due to low vaccine coverage, especially in the developing world. Cervical cancer is primarily treated by Chemo/Radiotherapy, depending on the disease stage, with Carboplatin/Cisplatin-based drug regime. These drugs being non-specific, target rapidly dividing cells, including normal cells, so safer options are needed for lower off-target toxicity. Natural products offer an attractive option compared to synthetic drugs due to their well-established safety profile and capacity to target multiple oncogenic hallmarks of cancer like inflammation, angiogenesis, etc. In the current study, we investigated the effect of Bergenin (C-glycoside of 4-O-methylgallic acid), a natural polyphenol compound that is isolated from medicinal plants such as Bergenia crassifolia, Caesalpinia digyna, and Flueggea leucopyrus. Bergenin has been shown to have anti-inflammatory, anti-ulcerogenic, and wound healing properties but its anticancer potential has been realized only recently. We performed a proteomic analysis of cervical carcinoma cells treated with bergenin and found it to influence multiple hallmarks of cancers, including apoptosis, angiogenesis, and tumor suppressor proteins. It was also involved in many different cellular processes unrelated to cancer, as shown by our proteomic analysis. Further analysis showed bergenin to be a potent-angiogenic agent by reducing key angiogenic proteins like Galectin 3 and MMP-9 (Matrix Metalloprotease 9) in cervical carcinoma cells. Further understanding of this interaction was carried out using molecular docking analysis, which indicated MMP-9 has more affinity for bergenin as compared to Galectin-3. Cumulatively, our data provide novel insight into the anti-angiogenic mechanism of bergenin in cervical carcinoma cells by modulation of multiple angiogenic proteins like Galectin-3 and MMP-9 which warrant its further development as an anticancer agent in cervical cancer.
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Benzopiranos , Proliferación Celular , Galectina 3 , Metaloproteinasa 9 de la Matriz , Neoplasias del Cuello Uterino , Humanos , Metaloproteinasa 9 de la Matriz/metabolismo , Benzopiranos/farmacología , Femenino , Neoplasias del Cuello Uterino/tratamiento farmacológico , Neoplasias del Cuello Uterino/metabolismo , Neoplasias del Cuello Uterino/patología , Galectina 3/metabolismo , Proliferación Celular/efectos de los fármacos , Línea Celular Tumoral , Simulación del Acoplamiento Molecular , Galectinas/metabolismo , Galectinas/farmacología , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Apoptosis/efectos de los fármacos , Células HeLa , Proteínas SanguíneasRESUMEN
The association between cardiac fibrosis and galectin-3 was evaluated in patients with acute myocardial infarction (MI). The role of galectin-3 and its association with endoplasmic reticulum (ER) stress activation in the progression of cardiovascular fibrosis was also evaluated in obese-infarcted rats. The inhibitor of galectin-3 activity, modified citrus pectin (MCP; 100 mg/kg/day), and the inhibitor of the ER stress activation, 4-phenylbutyric acid (4-PBA; 500 mg/kg/day), were administered for 4 weeks after MI in obese rats. Overweight-obese patients who suffered a first MI showed higher circulating galectin-3 levels, higher extracellular volume, and LV infarcted size, as well as lower E/e'ratio and LVEF compared with normal-weight patients. A correlation was observed between galectin-3 levels and extracellular volume. Obese-infarcted animals presented cardiac hypertrophy and reduction in LVEF, and E/A ratio as compared with control animals. They also showed an increase in galectin-3 gene expression, as well as cardiac fibrosis and reduced autophagic flux. These alterations were associated with ER stress activation characterized by enhanced cardiac levels of binding immunoglobulin protein, which were correlated with those of galectin-3. Both MCP and 4-PBA not only reduced cardiac fibrosis, oxidative stress, galectin-3 levels, and ER stress activation, but also prevented cardiac functional alterations and ameliorated autophagic flux. These results show the relevant role of galectin-3 in the development of diffuse fibrosis associated with MI in the context of obesity in both the animal model and patients. Galectin-3 in tandem with ER stress activation could modulate different downstream mechanisms, including inflammation, oxidative stress, and autophagy.
Asunto(s)
Estrés del Retículo Endoplásmico , Galectina 3 , Obesidad , Animales , Galectina 3/metabolismo , Obesidad/metabolismo , Obesidad/complicaciones , Masculino , Ratas , Humanos , Pectinas/farmacología , Persona de Mediana Edad , Infarto del Miocardio/metabolismo , Infarto del Miocardio/patología , Infarto del Miocardio/complicaciones , Femenino , Fibrosis , Ratas Wistar , Isquemia Miocárdica/metabolismo , Isquemia Miocárdica/patología , Fenilbutiratos/farmacología , Autofagia , Miocardio/metabolismo , Miocardio/patología , Galectinas/metabolismo , Anciano , Proteínas Sanguíneas/metabolismoRESUMEN
OBJECTIVE: Oral lichen planus carries a risk for malignancy. The pathogenesis of the disease is mediated by various inflammatory mediators. Several mediators could be responsible for the oncogenic behavior in certain cases. Hypoxia-inducible factor-1a (HIF-1), and its possible correlation to Galactin-3 (Gal-3) and matrix metalloproteinase-9 (MMP-9) over expression represents an important indicator for malignant transformation. The investigation of these factors may present evidence-based information on malignant transformation of the disease. SUBJECTS AND METHODS: The study investigated the expression of HIF-1, Gla-3 and MMP-9 in tissue samples of OLP compared to control subjects of un-inflamed gingival overgrowth. 20 biospecimen were allocated in each group. RESULTS: Immunohistochemical findings of OLP showed immunoreactivity for Galectin 3, HIF1a and MMP-9 by most of the epithelial cells. There was a positive correlation between HIF1α and MMP-9, r = 0.9301 (P-value < 0.00001). A positive correlation was detected between Galectin 3 and MMP-9, r = 0.7292 (P-value = 0.000264) between Galectin 3 and HIF1α, r = 0.5893 (P-value = 0.006252). CONCLUSION: These findings confirm the hypothesis that the adaptive pathways to hypoxia as Gal 3 and MMP-9 expressions and their HIF-1 may play a crucial role in carcinogenesis of OLP.
Asunto(s)
Galectina 3 , Subunidad alfa del Factor 1 Inducible por Hipoxia , Liquen Plano Oral , Metaloproteinasa 9 de la Matriz , Humanos , Metaloproteinasa 9 de la Matriz/metabolismo , Liquen Plano Oral/metabolismo , Liquen Plano Oral/patología , Galectina 3/metabolismo , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Femenino , Masculino , Persona de Mediana Edad , Galectinas/metabolismo , Adulto , Transformación Celular Neoplásica , Células Epiteliales/metabolismo , Estudios de Casos y Controles , Inmunohistoquímica , Proteínas SanguíneasRESUMEN
Non-enzymatic cascade reactions between amines and reducing sugars are known as Maillard reaction. The late phase of these reactions consists of advanced glycation end products (AGEs), which have been implicated in the pathogenesis of numerous human diseases. Recent evidence suggests that galectin-3 acts as a receptor for AGEs and some early products of the Maillard reaction. The early phase of the Maillard reaction, which consists of 1-amino-1-deoxyketoses (Amadori compounds) and 2-amino-2-deoxyaldoses (Heyns compounds), was the subject of our study. The binding interactions between galectin-3 and the Amadori and Heyns compounds of leucine-enkephalin (YGGFL), leucine-enkephalin methyl ester (YGGFL-OMe), truncated enkephalin (YGG and Y) and tetrapeptide (LSKL) were measured using the AlphaScreen competitive binding assay. The affinity of galectin-3 for Amadori and Heyns compounds depends on both the sugar moiety and the amino acid sequence of the model compounds. The best results were obtained with Leu-enkephalin derivatives of Amadori (IC50 = 6.06 µm) and Heyns (IC50 = 8.6 µm) compound, respectively.
Asunto(s)
Galectina 3 , Galectina 3/química , Galectina 3/metabolismo , Ligandos , Humanos , Péptidos/química , Galectinas/metabolismo , Galectinas/química , Unión Proteica , Encefalinas/química , Encefalinas/metabolismo , Encefalina Leucina/química , Encefalina Leucina/metabolismo , Proteínas SanguíneasRESUMEN
Galectin-3 is a multifunctional protein that is involved in various physiological and pathological events. Emerging evidence suggests that galectin-3 also plays a critical role in the pathogenesis of pulmonary diseases. Galectin-3 can be produced and secreted by various cell types in the lungs, and the overexpression of galectin-3 has been found in acute lung injury/acute respiratory distress syndrome (ALI/ARDS), pulmonary hypertension (PH), pulmonary fibrosis diseases, lung cancer, lung infection, chronic obstructive pulmonary disease (COPD), and asthma. Galectin-3 exerts diverse effects on the inflammatory response, immune cell activation, fibrosis and tissue remodeling, and tumorigenesis in these pulmonary disorders, and genetic and pharmacologic modulation of galectin-3 has therapeutic effects on the treatment of pulmonary illnesses. In this review, we summarize the structure and function of galectin-3 and the underlying mechanisms of galectin-3 in pulmonary disease pathologies; we also discuss preclinical and clinical evidence regarding the therapeutic potential of galectin-3 inhibitors in these pulmonary disorders. Additionally, targeting galectin-3 may be a very promising therapeutic approach for the treatment of pulmonary diseases.
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Galectina 3 , Enfermedades Pulmonares , Humanos , Galectina 3/metabolismo , Galectina 3/antagonistas & inhibidores , Enfermedades Pulmonares/tratamiento farmacológico , Enfermedades Pulmonares/metabolismo , Animales , Pulmón/metabolismo , Pulmón/fisiopatología , Pulmón/patología , Proteínas Sanguíneas , GalectinasRESUMEN
Acute pancreatitis (AP) is a complex inflammatory condition that can lead to systemic inflammatory responses and multiple organ dysfunction. This study investigates the role of Galectin-3 (Gal-3), a ß-galactoside-binding lectin, in modulating acquired immune responses in AP. Acute pancreatitis was induced by ligation of the bile-pancreatic duct in wild-type and Galectin-3-deficient C57BL/6 mice. We determined the phenotypic and molecular features of inflammatory cells, serum concentrations of amylase, pancreatic trypsin activity, and pancreatic and lung pathology. Galectin-3 deficiency decreased the total number of CD3+CD49- T cells and CD4+ T helper cells, downregulated the production of inflammatory cytokine and IFN-γ, and increased the accumulation of IL-10-producing Foxp3+ T regulatory cells and regulatory CD4+ T cells in the pancreata of diseased animals. The deletion of Galectin-3 ameliorates acute pancreatitis characterized by lowering serum amylase concentration and pancreatic trypsin activity, and attenuating of the histopathology of the lung. These findings shed light on the role of Galectin-3 in acquired immune response in acute pancreatitis and identify Galectin-3 as an attractive target for investigation of the immunopathogenesis of disease and for consideration as a potential therapeutic target for patients with acute inflammatory disease of the pancreas.
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Galectina 3 , Ratones Endogámicos C57BL , Pancreatitis , Linfocitos T Reguladores , Animales , Pancreatitis/inmunología , Pancreatitis/patología , Pancreatitis/metabolismo , Pancreatitis/genética , Galectina 3/metabolismo , Galectina 3/genética , Ratones , Linfocitos T Reguladores/inmunología , Linfocitos T Reguladores/metabolismo , Ratones Noqueados , Enfermedad Aguda , Masculino , Amilasas/sangreRESUMEN
Galectins are a family of beta-galactoside-binding proteins that are characterised by their carbohydrate recognition domain (CRD) and include galectin-1 and galectin-3. These galectins have been implicated in numerous diseases due to their pleiotropic nature, including cancer and fibrosis, with therapeutic inhibitors being clinically developed to block the CRD. One of the early methods developed to characterise these galectins was the hemagglutination of red blood cells. Although it is insightful, this approach has been hampered by a lack of sensitivity and accurate quantification of the agglutination observed. In this study, we aimed to validate a more precise and quantitative method to enable the further investigation of differences between galectins in respect to agglutination induction in different blood groups, as well as the characterisation of small molecule inhibitors. Quantification of hemagglutination was shown to be optimal using U-bottom plates imaged and analysed with FIJI ImageJ rather than flat-bottom plates read for absorbance on an optical density plate reader. Galectin-3-induced red blood cell agglutination efficacy increased significantly from blood group O to A to B. However, for both the galectin-1 monomer and concatemer, a more comparable effect was observed between blood group B and O, but with more potent effects than in blood group A. Inhibition assays for both galectin-3 and galectin-1 induced-hemagglutination were able to demonstrate clear concentration responses and expected selectivity profiles for a set of small-molecule glycomimetics, confirming the historical profiles obtained in biochemical binding and functional cellular assays.
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Eritrocitos , Galectina 1 , Galectinas , Hemaglutinación , Humanos , Eritrocitos/metabolismo , Eritrocitos/efectos de los fármacos , Hemaglutinación/efectos de los fármacos , Galectinas/antagonistas & inhibidores , Galectinas/metabolismo , Galectina 1/antagonistas & inhibidores , Galectina 1/metabolismo , Galectina 3/antagonistas & inhibidores , Galectina 3/metabolismo , Pruebas de Aglutinación/métodos , Pruebas de Hemaglutinación , Aglutinación/efectos de los fármacosRESUMEN
The effects of the enzyme N-acetylgalactosamine-4-sulfatase (Arylsulfatase B, ARSB), which removes the 4-sulfate group at the non-reducing end of chondroitin 4-sulfate, on the expression of PD-L1 were determined, and the underlying mechanism of PD-L1 expression was elucidated. Initial experiments in human melanoma cells (A375) showed that PD-L1 expression increased from 357 ± 31 to 796 ± 50 pg/mg protein (p < 10-11) when ARSB was silenced in A375 cells. In subcutaneous B16F10 murine melanomas, PD-L1 declined from 1227 ± 189 to 583 ± 110 pg/mg protein (p = 1.67 × 10-7), a decline of 52%, following treatment with exogenous, bioactive recombinant ARSB. This decline occurred in association with reduced tumor growth and prolongation of survival, as previously reported. The mechanism of regulation of PD-L1 expression by ARSB is attributed to ARSB-mediated alteration in chondroitin 4-sulfation, leading to changes in free galectin-3, c-Jun nuclear localization, HDAC3 expression, and effects of acetyl-H3 on the PD-L1 promoter. These findings indicate that changes in ARSB contribute to the expression of PD-L1 in melanoma and can thereby affect the immune checkpoint response. Exogenous ARSB acted on melanoma cells and normal melanocytes through the IGF2 receptor. The decline in PD-L1 expression by exogenous ARSB may contribute to the impact of ARSB on melanoma progression.
Asunto(s)
Antígeno B7-H1 , Epigénesis Genética , Regulación Neoplásica de la Expresión Génica , Histona Desacetilasas , Melanoma Experimental , Melanoma , N-Acetilgalactosamina-4-Sulfatasa , Animales , Humanos , Ratones , N-Acetilgalactosamina-4-Sulfatasa/metabolismo , N-Acetilgalactosamina-4-Sulfatasa/genética , Antígeno B7-H1/metabolismo , Antígeno B7-H1/genética , Histona Desacetilasas/metabolismo , Histona Desacetilasas/genética , Línea Celular Tumoral , Melanoma Experimental/metabolismo , Melanoma Experimental/patología , Melanoma Experimental/genética , Melanoma/metabolismo , Melanoma/genética , Melanoma/patología , Galectina 3/metabolismo , Galectina 3/genética , Regiones Promotoras Genéticas , Proteínas Sanguíneas , GalectinasRESUMEN
BACKGROUND: The unmet challenge in prostate cancer (PCa) management is to discriminate it from benign prostate hyperplasia (BPH) due to the lack of specific diagnostic biomarkers. Contemporary research on potential PCa biomarkers is directed toward methylated cell-free DNA (cfDNA) from liquid biopsies since epigenetic mechanisms are strongly involved in PCa development. METHODS: In the present research, cfDNA methylation of the LGALS3 gene in blood and seminal plasma of PCa and BPH patients was assessed using pyrosequencing, as well as LGALS3 DNA methylation in tissue biopsies. Liquid biopsy samples were taken from patients with clinical suspicion of PCa, who were subsequently divided into two groups, that is, 42 with PCa and 55 with BPH, according to the histopathological analysis. RESULTS: Statistically significant higher cfDNA methylation of LGALS3 in seminal plasma of BPH than in PCa patients was detected by pyrosequencing. ROC curve analysis showed that it could distinguish PCa and BPH patients with 56.4% sensitivity and 70.4% specificity, while PSA did not differ between the two patient groups. In contrast, there was no statistically significant difference in LGALS3 cfDNA methylation in blood plasma between the two patient groups. In prostate tumor tissue, there was a statistically significant DNA hypermethylation of LGALS3 compared to surrounding nontumor tissue and BPH tissue. CONCLUSIONS: The DNA hypermethylation of the LGALS3 gene represents an event specific to PCa development. In conclusion, LGALS3 cfDNA methylation in seminal fluid discriminates early PCa and BPH presenting itself as a powerful novel PCa biomarker highly outperforming PSA.
Asunto(s)
Biomarcadores de Tumor , Metilación de ADN , Antígeno Prostático Específico , Hiperplasia Prostática , Neoplasias de la Próstata , Semen , Humanos , Masculino , Neoplasias de la Próstata/genética , Neoplasias de la Próstata/diagnóstico , Neoplasias de la Próstata/metabolismo , Neoplasias de la Próstata/patología , Neoplasias de la Próstata/sangre , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/sangre , Anciano , Antígeno Prostático Específico/sangre , Antígeno Prostático Específico/genética , Hiperplasia Prostática/genética , Hiperplasia Prostática/diagnóstico , Hiperplasia Prostática/metabolismo , Hiperplasia Prostática/sangre , Hiperplasia Prostática/patología , Semen/metabolismo , Semen/química , Persona de Mediana Edad , Ácidos Nucleicos Libres de Células/genética , Ácidos Nucleicos Libres de Células/sangre , Galectina 3/genética , Galectina 3/metabolismo , Galectina 3/sangre , Sensibilidad y Especificidad , Proteínas Sanguíneas , GalectinasRESUMEN
OBJECTIVES: Clinical studies have confirmed that galectin-3 (Gal-3) levels are significantly elevated in periodontitis patients. The present study aimed to explore the effects of Gal-3 inhibition on periodontal inflammation in vitro and in vivo. METHODS: Human gingival fibroblasts (HGFs) with or without Gal-3 knockdown were stimulated by lipopolysaccharide (LPS), and a ligation-induced mouse periodontitis model treated with a Gal-3 inhibitor was established. Hematoxylin-eosin (H&E) and immunohistochemistry (IHC) staining were used to evaluate Gal-3 levels in gingival tissues. Quantitative real-time polymerase chain reaction (qRT-PCR) and enzyme-linked immunosorbent assay (ELISA) were used to detect Gal-3, interleukin (IL)-6, IL-8, and C-C motif ligand 2 (CCL2) expression. Immunofluorescence and western blotting were used to detect NF-κB and ERK signaling pathway activation. Micro-computed tomography was used to analyse the degree of bone loss. RESULTS: Gal-3 was significantly up-regulated in inflamed gingival tissues and LPS-induced HGFs. Gal-3 knockdown markedly decreased LPS-induced IL-6, IL-8, and CCL2 expression and blocked NF-κB and ERK signaling pathway activation in HGFs. In the mouse periodontitis model, Gal-3 inhibition significantly alleviated IL-1ß and IL-6 infiltration in gingival tissue and mitigated periodontal bone loss. CONCLUSIONS: Gal-3 inhibition notably alleviated periodontal inflammation partly through blocking NF-κB and ERK signaling pathway activation.
Asunto(s)
Fibroblastos , Galectina 3 , Encía , Lipopolisacáridos , Periodontitis , Animales , Humanos , Masculino , Ratones , Células Cultivadas , Modelos Animales de Enfermedad , Fibroblastos/metabolismo , Fibroblastos/efectos de los fármacos , Galectina 3/metabolismo , Galectina 3/antagonistas & inhibidores , Galectina 3/genética , Encía/metabolismo , Encía/patología , Ratones Endogámicos C57BL , FN-kappa B/metabolismo , Periodontitis/metabolismo , Periodontitis/tratamiento farmacológico , Transducción de Señal/efectos de los fármacosRESUMEN
Pulmonary hypertension is a cardiovascular disease with a low survival rate. The protein galectin-3 (Gal-3) binding ß-galactosides of cellular glycoproteins plays an important role in the onset and development of this disease. Carbohydrate-based drugs that target Gal-3 represent a new therapeutic strategy in the treatment of pulmonary hypertension. Here, we present the synthesis of novel hydrophilic glycopolymer inhibitors of Gal-3 based on a polyoxazoline chain decorated with carbohydrate ligands. Biolayer interferometry revealed a high binding affinity of these glycopolymers to Gal-3 in the subnanomolar range. In the cell cultures of cardiac fibroblasts and pulmonary artery smooth muscle cells, the most potent glycopolymer 18 (Lac-high) caused a decrease in the expression of markers of tissue remodeling in pulmonary hypertension. The glycopolymers were shown to penetrate into the cells. In a biodistribution and pharmacokinetics study in rats, the glycopolymers accumulated in heart and lung tissues, which are most affected by pulmonary hypertension.
Asunto(s)
Galectina 3 , Hipertensión Pulmonar , Animales , Galectina 3/antagonistas & inhibidores , Galectina 3/metabolismo , Hipertensión Pulmonar/tratamiento farmacológico , Hipertensión Pulmonar/metabolismo , Ratas , Humanos , Distribución Tisular , Masculino , Biomarcadores , Células Cultivadas , Fibroblastos/efectos de los fármacos , Fibroblastos/metabolismo , Polímeros/química , Polímeros/farmacología , Arteria Pulmonar/efectos de los fármacos , Arteria Pulmonar/metabolismoRESUMEN
Respiratory infection by Pseudomonas aeruginosa, common in hospitalized immunocompromised and immunocompetent ventilated patients, can be life-threatening because of antibiotic resistance. This raises the question of whether the host's immune system can be educated to combat this bacterium. Here we show that prior exposure to a single low dose of lipopolysaccharide (LPS) protects mice from a lethal infection by P. aeruginosa. LPS exposure trained the innate immune system by promoting expansion of neutrophil and interstitial macrophage populations distinguishable from other immune cells with enrichment of gene sets for phagocytosis- and cell-killing-associated genes. The cell-killing gene set in the neutrophil population uniquely expressed Lgals3, which encodes the multifunctional antibacterial protein, galectin-3. Intravital imaging for bacterial phagocytosis, assessment of bacterial killing and neutrophil-associated galectin-3 protein levels together with use of galectin-3-deficient mice collectively highlight neutrophils and galectin-3 as central players in LPS-mediated protection. Patients with acute respiratory failure revealed significantly higher galectin-3 levels in endotracheal aspirates (ETAs) of survivors compared to non-survivors, galectin-3 levels strongly correlating with a neutrophil signature in the ETAs and a prognostically favorable hypoinflammatory plasma biomarker subphenotype. Taken together, our study provides impetus for harnessing the potential of galectin-3-expressing neutrophils to protect from lethal infections and respiratory failure.