RESUMO

Introdução: Cicatrizes hipertróficas e queloides são tipos de cicatrizes excessivas de cicatrização anormal da pele. Galectina-3 (gal-3) é uma proteína da família das lectinas capaz de identificar carboidratos, que podem se combinar e atuar em diversas moléculas. Na literatura, a ação da gal-3 como principal agente regulador da fibrogênese já foi descrita, sendo atualmente utilizada na terapia antifibrótica de diversos órgãos como pulmão e fígado. O objetivo deste estudo piloto foi mostrar resultados preliminares encontrados na expressão de gal-3 em cicatrizes exacerbadas. Método: Foram coletadas 20 amostras de biópsias de cicatrizes excessivas (16 queloides e 4 cicatrizes hipertróficas) e 9 amostras de cicatrizes normais de 22 mulheres e 7 homens. Essas amostras foram processadas para análise histopatológica de rotina por imuno-histoquímica para detectar gal-3. As células positivas para gal-3 foram quantificadas pelo método estereológico utilizando uma grade de 36 pontos. Resultados: A imuno-histoquímica mostrou alta expressão de gal-3 em células endoteliais e epiteliais de todas as amostras de cicatrizes, bem como expressão em células distribuídas pela derme. Maior expressão de gal-3 foi encontrada em amostras de queloides (28% de células positivas) em comparação com cicatrizes normais (18%) e hipertróficas (22%) (p=0,0075). Os resultados foram obtidos de um pequeno número de pacientes, por se tratar de um estudo piloto. Conclusão: Os dados sugerem que a gal-3 participa do processo de cicatrização e, devido à sua maior presença em amostras de queloides, pode ser um potencial biomarcador para formação de queloides e um alvo terapêutico promissor a ser explorado.

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Introduction: Hypertrophic scars and keloids are types of excessive scars from abnormal skin healing. Galectin-3 (gal-3) is a protein from the lectin family capable of identifying carbohydrates, which can combine and act on different molecules. In the literature, the action of gal-3 as the main regulatory agent of fibrogenesis has already been described and is currently used in anti-fibrotic therapy for various organs such as the lung and liver. The objective of this pilot study was to show preliminary results found in the expression of gal-3 in exacerbated scars. Method: Twenty biopsy samples from excessive scars (16 keloids and 4 hypertrophic scars) and 9 samples from normal scars were collected from 22 women and 7 men. These samples were processed for routine histopathological analysis by immunohistochemistry to detect gal-3. Gal-3 positive cells were quantified by the stereological method using a 36-point grid. Results: Immunohistochemistry showed high expression of gal-3 in endothelial and epithelial cells of all scar samples, as well as expression in cells distributed throughout the dermis. Higher gal-3 expression was found in keloid samples (28% positive cells) compared to normal (18%) and hypertrophic (22%) scars (p=0.0075). The results were obtained from a small number of patients, as this was a pilot study. Conclusion: The data suggest that gal-3 participates in the healing process and, due to its greater presence in keloid samples, it may be a potential biomarker for keloid formation and a promising therapeutic target to be explored.

RESUMO

Spinal cord injury (SCI) results from various mechanisms that damage the nervous tissue and the blood-brain barrier, leading to sensory and motor function loss below the injury site. Unfortunately, current therapeutic approaches for SCI have limited efficacy in improving patients outcomes. Galectin-3, a protein whose expression increases after SCI, influences the neuroinflammatory response by favoring pro-inflammatory M1 macrophages and microglia, while inhibiting pro-regenerative M2 macrophages and microglia, which are crucial for inflammation resolution and tissue regeneration. Previous studies with Galectin-3 knock-out mice demonstrated enhanced motor recovery after SCI. The M1/M2 balance is strongly influenced by the predominant lymphocytic profiles (Th1, Th2, T Reg, Th17) and cytokines and chemokines released at the lesion site. The present study aimed to investigate how the absence of galectin-3 impacts the adaptive immune system cell population dynamics in various lymphoid spaces following a low thoracic spinal cord compression injury (T9-T10) using a 30 g vascular clip for one minute. It also aimed to assess its influence on the functional outcome in wild-type (WT)and Galectin-3 knock-out (GALNEG) mice. Histological analysis with hematoxylin-eosin and Luxol Fast Blue staining revealed that WT and GALNEG animals exhibit similar spinal cord morphology. The absence of galectin-3 does not affect the common neuroanatomy shared between the groups prompting us to analyze outcomes between both groups. Following our crush model, both groups lost motor and sensory functions below the lesion level. During a 42-day period, GALNEG mice demonstrated superior locomotor recovery in the Basso Mouse Scale (BMS) gait analysis and enhanced motor coordination performance in the ladder rung walk test (LRW) compared to WT mice. GALNEG mice also exhibited better sensory recovery, and their electrophysiological parameters suggested a higher number of functional axons with faster nerve conduction. Seven days after injury, flow cytometry of thymus, spleen, and blood revealed an increased number of T Reg and Th2 cells, accompanied by a decrease in Th1 and Th17 cells in GALNEG mice. Immunohistochemistry conducted on the same day exhibited an increased number of Th2 and T Reg cells around the GALNEG's spinal cord lesion site. At 42-day dpi immunohistochemistry analyses displayed reduced astrogliosis and greater axon preservation in GALNEG's spinal cord seem as a reduction of GFAP immunostaining and an increase in NFH immunostaining, respectively. In conclusion, GALNEG mice exhibited better functional recovery attributed to the milder pro-inflammatory influence, compensated by a higher quantity of T Reg and Th2 cells. These findings suggest that galectin-3 plays a crucial role in the immune response after spinal cord injury and could be a potential target for clinical therapeutic interventions.

Assuntos

Galectina 3 , Camundongos Endogâmicos C57BL , Camundongos Knockout , Recuperação de Função Fisiológica , Traumatismos da Medula Espinal , Animais , Traumatismos da Medula Espinal/patologia , Traumatismos da Medula Espinal/metabolismo , Traumatismos da Medula Espinal/fisiopatologia , Recuperação de Função Fisiológica/fisiologia , Galectina 3/metabolismo , Galectina 3/genética , Camundongos , Linfócitos/metabolismo , Feminino , Masculino

RESUMO

BACKGROUND: Biochemical markers and imaging tests have been used with the aim of stratifying the risk and detecting atrial fibrosis. Speckle-tracking echocardiography (STE) is used for the detection of atrial fibrosis and Gal-3 provides an important prognostic value. The objective of the study was to assess the association between atrial fibrosis markers and serum levels, genetic polymorphisms and genic expression of galectin-3. METHODS: 206 patients with permanent AF and 70 patients with paroxysmal AF were included in the study. Real time PCR (TaqMan) system was used to study SNPs rs4652 and 4644 of the gene LGALS3. Serum levels of Gal-3 were determined by ELISA and STE was performed to assess fibrosis. RESULTS: Mean age of individuals with permanent AF was 66.56 ± 12 years. As for the echocardiography results, those patients showed an decrease in the following parameters peak atrial longitudinal strain (PALS) (p = 0.002) when compared to the same parameters from the paroxysmal AF group of patients. There was a correlation between serum levels of Gal-3 and PALS in the group of patients with permanent AF; the lower the levels of gal-3, the lower the LA strain (r = 0.24; p = 0.01). CONCLUSIONS: Echocardiographic findings showed association with the groups, and with serum levels of Gal-3 in patients with permanent AF. The distribution of allelic and genotypic frequencies, and of the haplotypes of polymorphism LGALS3 rs4652 and rs4644 did not present statistical variation, which suggests that those SNPs are not associated with the AF clinical forms (permanent and paroxysmal).

Assuntos

Fibrilação Atrial , Humanos , Pessoa de Meia-Idade , Idoso , Fibrilação Atrial/diagnóstico por imagem , Fibrilação Atrial/genética , Galectina 3/genética , Átrios do Coração/diagnóstico por imagem , Átrios do Coração/patologia , Ecocardiografia/métodos , Fibrose

RESUMO

Melanoma is originated from the malignant transformation of the melanocytes and is characterized by a high rate of invasion, the more serious stage compromising deeper layers of the skin and eventually leading to the metastasis. A high mortality due to melanoma lesion persists because most of melanoma lesions are detected in advanced stages, which decreases the chances of survival. The identification of the principal mechanics implicated in the development and progression of melanoma is essential to devise new early diagnosis strategies. Cell mechanics is related with a lot of cellular functions and processes, for instance motility, differentiation, migration and invasion. In particular, the elastic modulus (Young's modulus) is a very explored parameter to describe the cell mechanical properties; most cancer cells reported in the literature smaller elasticity modulus. In this work, we show that the elastic modulus of melanoma cells lacking galectin-3 is significantly lower than those of melanoma cells expressing galectin-3. More interestingly, the gradient of elastic modulus in cells from the nuclear region towards the cell periphery is more pronounced in shGal3 cells. RESEARCH HIGHLIGHTS: AFM imaging and force spectroscopy were used to investigate the morphology and elasticity properties of healthy HaCaT cells and melanoma cells WM1366, with (shSCR) and without (shGal3) expression of galectin-3. It is shown the effect of galectin-3 protein on the elastic properties of cells: the cells without expression of galectin-3 presents lower elastic modulus. By the results, we suggest here that galectin-3 could be used as an effective biomarker of malignancy in both melanoma diagnostic and prognosis.

Assuntos

Galectina 3 , Melanoma , Humanos , Elasticidade , Módulo de Elasticidade/fisiologia , Diferenciação Celular , Microscopia de Força Atômica/métodos

RESUMO

Prostate cancer remains the most prevalent cancer among men worldwide. This cancer is hormone-dependent; therefore, androgen, estrogen, and their receptors play an important role in development and progression of this disease, and in emergence of the castration-resistant prostate cancer (CRPC). Galectins are a family of ß-galactoside-binding proteins which are frequently altered (upregulated or downregulated) in a wide range of tumors, participating in different stages of tumor development and progression, but the molecular mechanisms which regulate its expression are still poorly understood. This review provides an overview of the current and emerging knowledge on Galectin-3 in cancer biology with focus on prostate cancer and the interplay with estrogen receptor (ER) signaling pathways, present in androgen-independent prostate cancer cells. We suggest a molecular mechanism where ER, Galectin-3 and ß-catenin can modulate nuclear transcriptional events, such as, proliferation, migration, invasion, and anchorage-independent growth of androgen-independent prostate cancer cells. Despite a number of achievements in targeted therapy for prostate cancer, CRPC may eventually develop, therefore new effective drug targets need urgently to be found. Further understanding of the role of Galectin-3 and ER in prostate cancer will enhance our understanding of the molecular mechanisms of prostate cancer development and the future treatment of this disease.

Assuntos

Neoplasias de Próstata Resistentes à Castração , Masculino , Humanos , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Neoplasias de Próstata Resistentes à Castração/metabolismo , Neoplasias de Próstata Resistentes à Castração/patologia , Receptores de Estrogênio , Galectina 3/genética , Androgênios/uso terapêutico , Receptores Androgênicos/metabolismo , Galectinas

RESUMO

The aim of the present study was to investigate the role of estrogen receptor (ER)α and ERß, and galectin­3 (GAL­3) in migration and invasion of androgen­independent DU­145 prostate cancer cells, and to examine the regulation of the expression of GAL­3 by the activation of these receptors. Wound healing and cell invasion assays were performed using the control (basal level of cellular function) and treated DU­145 cells. At 24 h of treatment, 17ß­estradiol (E2), the ERα­selective agonist, 4,4',4"­(4­propyl­(1H)­pyrazole­1,3,5­triyl)trisphenol (PPT), or the ERß­selective agonist, 2,3­bis(4­hydroxyphenyl)­propionitrile (diarylprepionitrile; DPN), increased the migration and invasion of the DU­145 cells. Pre­treatment with the ERα­ and ERß­selective antagonists blocked these effects, indicating that ERα and ERß are upstream receptors regulating these processes. Western blot analysis and immunofluorescence staining for the detection of the GAL­3 were performed using the control and treated DU­145 cells. Treatment of the DU­145 cells with E2, PPT or DPN for 24 h increased the expression of the GAL­3 compared to the control. Furthermore, a specific inhibitor of GAL­3 (VA03) inhibited the migration and invasion of DU­145 cells, indicating the involvement of the complex ERα/GAL­3 and ERß/GAL­3 in the regulation of these processes. On the whole, the present study demonstrates that the activation of both ERs increases the expression and signaling of GAL­3, and promotes the migration and invasion of DU­145 cells. The findings of the present study provide novel insight into the signatures and molecular mechanisms of ERα and ERß in DU­145 cells.

Assuntos

Neoplasias da Próstata , Receptores de Estrogênio , Masculino , Humanos , Receptor alfa de Estrogênio/metabolismo , Galectina 3 , Androgênios , Receptor beta de Estrogênio/genética , Receptor beta de Estrogênio/metabolismo , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/metabolismo , Estradiol/farmacologia

RESUMO

Galectin-3 (Gal-3) is a carbohydrate-binding protein with multiple functions. Gal-3 regulates cell growth, proliferation, and apoptosis by orchestrating cell-cell and cell-matrix interactions. It is implicated in the development and progression of cardiovascular disease, and its expression is increased in patients with heart failure. In atherosclerosis, Gal-3 promotes monocyte recruitment to the arterial wall boosting inflammation and atheroma. In acute myocardial infarction (AMI), the expression of Gal-3 increases in infarcted and remote zones from the beginning of AMI, and plays a critical role in macrophage infiltration, differentiation to M1 phenotype, inflammation and interstitial fibrosis through collagen synthesis. Genetic deficiency of Gal-3 delays wound healing, impairs cardiac remodeling and function after AMI. On the contrary, Gal-3 deficiency shows opposite results with improved remodeling and function in other cardiomyopathies and in hypertension. Pharmacologic inhibition with non-selective inhibitors is also protective in cardiac disease. Finally, we recently showed that Gal-3 participates in normal aging. However, genetic absence of Gal-3 in aged mice exacerbates pathological hypertrophy and increases fibrosis, as opposed to reduced fibrosis shown in cardiac disease. Despite some gaps in understanding its precise mechanisms of action, Gal-3 represents a potential therapeutic target for the treatment of cardiovascular diseases and the management of cardiac aging. In this review, we summarize the current knowledge regarding the role of Gal-3 in the pathophysiology of heart failure, atherosclerosis, hypertension, myocarditis, and ischemic heart disease. Furthermore, we describe the physiological role of Gal-3 in cardiac aging.

RESUMO

SUMMARY OBJECTIVE: Sepsis and septic shock are clinical conditions with high mortality and an ever-increasing prevalence, and early diagnosis is of great importance in treating these diseases. Increase in serum Galectin-3 protein in septic patients is associated with increased inflammation, which in turn is associated with mortality. This study aimed to investigate the diagnostic importance of serum Galectin-3 levels and its relationship with in-hospital mortality in sepsis and septic shock patients. METHODS: This prospective cohort study included 44 sepsis and 44 septic shock patients. Sequential Organ Failure Assessment score and Acute Physiology and Chronic Health Evaluation 2 score were calculated. In addition, routine clinical and laboratory parameters along with serum Galectin-3 were evaluated. RESULTS: Serum Galectin-3 levels were significantly higher in the septic shock group [4.1 (0.1-10.2) vs. 6.0 (0.1-11.3) ng/mL, respectively; p=0.01]. Moreover, patients with a Galectin-3 level <6.94 ng/mL were associated with longer survival [31.4 vs. 23.1 days; hazards ratio, 1.85; 1.03-3.34, p=0.03]. More importantly, the need for mechanical ventilation, the duration of mechanical ventilation, and serum Galectin-3 levels were independent prognostic factors and predicted poor in-hospital survival in both sepsis and septic shock patients. CONCLUSION: These findings suggest that Galectin-3 levels are higher in septic shock patients and predict mortality. In addition, high serum Galectin-3 levels, together with mechanical ventilation requirement and mechanical ventilation duration, are closely associated with poor in-hospital survival. Therefore, Galectin-3 may be a valuable diagnostic and prognostic biomarker in these patients.

RESUMO

Crotoxin (CTX) has biological effects both in experimental models and in clinical trials. Our group showed that the antitumor activity of CTX is associated with the modulating actions of the toxin on the secretory activity of inflammatory mediators and on the energy metabolism of macrophages. Furthermore, we demonstrated that CTX, in vivo, interferes with the phenotypic reprogramming of resident peritoneal macrophages and the tumor microenvironment, suggesting a reprogramming or prevalence of the M1 phenotype of macrophages. Among the mechanisms involved with the phenotypic reprogramming of monocytes/macrophages, galectin-3 has been described as an immunoregulatory protein, which may favor the classic pro-inflammatory condition (macrophage-M1) or alternative (macrophage-M2, anti-inflammatory), depending on the pathophysiological condition, with involvement of the PI3K/Akt signaling pathway. Therefore, the objective of this project was to investigate whether CTX is capable of interfering with the expression and secretion of galectin-3 by monocytes and the participation of this lectin in the modulating activity of CTX on the phenotypic condition of these cells by different stimuli. For this purpose, in vitro assays were carried out using cells of the human monocytic lineage (THP-1), pre-incubated in the absence (control) or presence of CTX (0.3; 0.6 and 1.2 μg/mL), by 2 hours and maintained in culture for 72 hours under different microenvironmental stimuli: a) only in fresh RPMI 1640 culture medium (to evaluate the per se activity of CTX on the investigated proteins); b) with culture medium containing 800 μg/mL of LPS; or c) and conditioned medium (CM) from MDA-MB-231 tumor cells. The Western Blotting assay was performed to mark the proteins: PI3Kp110a, Akt (types 1 and 2) and galectin-3. Functional/phenotypic parameters, such as H2O2 release, secretion of pro-(TNF-α) and anti-inflammatory cytokines (IL-10/TGF-β1) and Gal-3, and phenotypic markers (M1- CD80/CD86 and M2-CD163/CD206) was determined in order to associate possible changes in the functional/phenotypic behavior (M1/M2) of these cells and with the expression of signaling proteins involved in the reprogramming of monocytes/macrophages, in the face of different stimuli. The results indicate that CTX modulates the Akt signaling pathway and with the expression and secretion of Gal-3, as well as with the release of H2O2 and against different signals in the microenvironment. Furthermore, a pro-inflammatory and pro-tumor role is attributed to Gal-3 in inflammatory and tumoral conditions and here, the results show the participation of this lectin in the immunomodulatory effect of CTX, both in the action per se of the toxin and in the inflammatory and tumoral microenvironments. Furthermore, particularly the concentration of CTX 0.6 and 1.2 μg/ml seems to promote a THP-1 mixed monocyte/macrophage profile or switch phenotype. This study contributes to knowledge about the immunomodulatory actions of CTX, showing for the first time the participation of Gal-3 in this process.

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A Crotoxina (CTX) apresenta efeitos biológicos tanto em modelos experimentais como em estudos clínicos. Nosso grupo mostrou que a atividade antitumoral da CTX está associada às ações moduladoras da toxina sobre a atividade secretora de mediadores inflamatórios e sobre o metabolismo energético de macrófagos. Ainda, demonstramos que a CTX, in vivo, interfere com a reprogramação fenotípica de macrófagos peritoneais residentes e do microambiente tumoral, sugerindo uma reprogramação ou prevalência do fenótipo M1 de macrófagos. Dentre os mecanismos envolvidos com a reprogramação fenotípica de monócitos/macrófagos, a galectina-3 vem sendo descrita como uma proteína imunorreguladora, podendo favorecer a condição pró- inflamatória clássica (macrófago-M1) ou alternativa (macrófago-M2, anti-inflamatório), conforme a condição fisiopatológica, com envolvimento da via de sinalização PI3K/Akt. Portanto, o objetivo do presente projeto foi investigar se a CTX é capaz de interferir com a expressão e secreção de galectina-3 por monócitos e a participação desta lectina na atividade moduladora da CTX sobre a condição fenotípica dessas células, frente a diferentes estímulos. Para tanto, ensaios in vitro foram realizados utilizando células da linhagem monocítica humana (THP-1), pré-incubadas na ausência (controle) ou presença de CTX (0,3; 0,6 e 1,2 μg/mL), por 2 horas e mantidas em cultura por 72 horas em diferentes estímulos microambientais: a) apenas em meio de cultura RPMI 1640 fresco (para avaliar a atividade per se da CTX sobre as proteínas investigadas); b) com meio de cultura contendo 800 μg/mL de LPS; ou c) e meio condicionado de células tumorais MDA-MB-231. O ensaio de Western Blotting foi realizado para marcação das proteínas: PI3Kp110a, Akt (tipos 1 e 2) e galectina-3. Parâmetros funcionais/fenotípicos, como a liberação de H2O2, secreção de citocinas pró- (TNF-α) e anti-inflamatórias (IL-10/TGF-β1) e Gal-3 e marcadores fenotípicos (M1-CD80/CD86 e M2-CD163/CD206) foi determinado visando associar possíveis alterações sobre o comportamento funcional/fenotípico (M1/M2) dessas células e com a expressão das proteínas sinalizadoras envolvidas com a reprogramação dos monócitos/macrófagos, frente aos diferentes estímulos. Os resultados indicam que a CTX modula a via de sinalização Akt e com a expressão e secreção de Gal-3, bem como, com a liberação de H2O2 e frente a diferentes sinais no microambiente. Ainda, é atribuída a Gal-3 papel pró-inflamatória e pró-tumoral em condições inflamatória e tumoral e aqui, os resultados mostram a participação dessa lectina no efeito imunomodulador da CTX, tanto na ação per se da toxina quanto nos microambientes inflamatório e tumoral. Além disso, particularmente as concentrações de CTX 0,6 e 1,2 μg/mL parece promover um perfil misto de monócito/macrófago THP-1 ou fenótipo switch. Este estudo contribui com o conhecimento sobre as ações imunomoduladoras da CTX, evidenciando pela primeira vez a participação da Gal-3 nesse processo.

RESUMO

BACKGROUND/AIMS: Aging is accompanied by progressive and adverse cardiac remodeling characterized by myocardial hypertrophy, fibrosis, and dysfunction. We previously reported that galectin-3 (Gal-3) is a critical regulator of inflammation and fibrosis associated with hypertensive heart disease and myocardial infarction. Nevertheless, the role and mechanism of Gal-3 in age-related cardiac remodeling have not been previously investigated. We hypothesized that Gal-3 plays a critical role in cardiac aging and that its deficiency exacerbates the underlying mechanisms of myocardial hypertrophy and fibrosis. METHODS: Male C57BL/6 (control) (n=24) and Gal-3 knockout (KO) (n=29) mice were studied at 24 months of age to evaluate the role of Gal-3 in cardiac aging. We assessed 1) survival rate; 2) systolic blood pressure (SBP) by plethysmography; 3) myocardial hypertrophy, apoptosis, and fibrosis by quantification of histological and immunohistochemical analysis; 4) cardiac expression of angiotensin (Ang) II, Ang (1-7) by Radioimmunoassay; 5) transforming growth factor-ß (TGF-ß), sirtuin (SIRT) 1, SIRT 7 and metalloproteinase 9 (MMP-9) by RT-qPCR and 6) ventricular remodeling and function by echocardiography. RESULTS: We found that aged Gal-3 KO mice had a lower survival rate and exhibited exacerbated myocardial hypertrophy and fibrosis without changes in SBP. Similarly, myocardial apoptosis and MMP-9 mRNA expression was significantly increased in the hearts of Gal-3 KO mice compared to controls. Additionally, cardiac Ang II and TGF-ß expression were higher in aged Gal-3 KO mice while SIRT1 and SIRT7 expression were reduced. CONCLUSION: Our findings strongly suggest that Gal-3 is involved in age-related cardiac remodeling by regulating critical mechanisms associated with the development of pathological hypertrophy. The gene deletion of Gal-3 reduced the lifespan and markedly increased age-dependent mechanisms of myocardial hypertrophy, apoptosis, and fibrosis, including Ang-II, TGF-ß, and MMP-9. At the same time, there was diminished cardiac-specific expression of SIRT1 and SIRT7, which are extensively implicated in delaying age-dependent cardiomyopathies.

Assuntos

Galectina 3 , Remodelação Ventricular , Angiotensina II/metabolismo , Animais , Cardiomegalia/patologia , Modelos Animais de Doenças , Fibrose , Galectina 3/genética , Galectina 3/metabolismo , Deleção de Genes , Masculino , Metaloproteinase 9 da Matriz/genética , Metaloproteinase 9 da Matriz/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Miocárdio/metabolismo , Sirtuína 1/genética , Sirtuína 1/metabolismo , Fator de Crescimento Transformador beta/metabolismo

RESUMO

Melanoma is a highly metastatic and rapidly progressing cancer, a leading cause of mortality among skin cancers. The melanoma microenvironment, formed from the activity of malignant cells on the extracellular matrix and the recruitment of immune cells, plays an active role in the development of drug resistance and tumor recurrence, which are clinical challenges in cancer treatment. These tumoral metabolic processes are affected by proteins, including Galectin-3 (Gal-3), which is extensively involved in cancer development. Previously, we characterized a partially methylated mannogalactan (MG-Pe) with antimelanoma activities. In vivo models of melanoma were used to observe MG-Pe effects in survival, spontaneous, and experimental metastases and in tissue oxidative stress. Analytical assays for the molecular interaction of MG-Pe and Gal-3 were performed using a quartz crystal microbalance, atomic force microscopy, and contact angle tensiometer. MG-Pe exhibits an additive effect when administered together with the chemotherapeutic agent dacarbazine, leading to increased survival of treated mice, metastases reduction, and the modulation of oxidative stress. MG-Pe binds to galectin-3. Furthermore, MG-Pe antitumor effects were substantially reduced in Gal-3/KO mice. Our results showed that the novel Gal-3 ligand, MG-Pe, has both antitumor and antimetastatic effects, alone or in combination with chemotherapy.

Assuntos

Antineoplásicos , Galectina 3 , Melanoma , Neoplasias Cutâneas , Animais , Antineoplásicos/metabolismo , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Dacarbazina/metabolismo , Dacarbazina/farmacologia , Dacarbazina/uso terapêutico , Galectina 3/metabolismo , Galectina 3/farmacologia , Galectina 3/uso terapêutico , Ligantes , Melanoma/tratamento farmacológico , Melanoma/metabolismo , Camundongos , Recidiva Local de Neoplasia , Neoplasias Cutâneas/tratamento farmacológico , Neoplasias Cutâneas/metabolismo , Microambiente Tumoral/efeitos dos fármacos , Microambiente Tumoral/fisiologia

RESUMO

BACKGROUND & AIMS: Patients with advanced cirrhosis often have immune dysfunction and are more susceptible to infections. Galectin-3 is a ß-galactoside-binding lectin implicated in inflammation, immune regulation and liver fibrosis. We aim to investigate galectin-3 expression in advanced cirrhosis and its ability to predict post-transplant infectious complications. METHODS: We collected sera and liver samples from 129 cirrhotic patients at the time of liver transplantation and from an external cohort of 37 patients with alcoholic liver disease including alcoholic hepatitis (AH) at the time of diagnosis. Galectin-3 was assessed by ELISA, real-time PCR, immunohistochemistry and RNA-seq. Receiver operating characteristic curves and Cox proportional-hazards regression analysis were performed to assess the predictive power of galectin-3 for disease severity and post-transplant infections. RESULTS: Increased galectin-3 levels were found in advanced cirrhosis. Galectin-3 significantly correlated with disease severity parameters and inflammatory markers. Galectin-3 had significant discriminating power for compensated and advanced cirrhosis (AUC = 0.78/0.84, circulating/liver galectin-3; p < .01), and was even higher to discriminate severe AH (AUC = 0.95, p < .0001). Cox Proportional-hazard model showed that galectin-3, MELD-Na and the presence of SIRS predict the development of post-transplant infectious complications. Patients with circulating galectin-3 (>16.58 ng/ml) were at 2.19-fold 95% CI (1.12-4.29) increased risk, but when combined with MELD-Na > 20.0 and SIRS, the risk to develop post-transplant infectious complications, increased to 4.60, 95% CI (2.38-8.90). CONCLUSION: Galectin-3 is a novel biological marker of active inflammation and disease severity that could be clinically useful alone or in combination with other scores to discriminate advanced cirrhosis and predict post-transplant infectious complications.

Assuntos

Hepatite Alcoólica , Hepatopatias , Transplante de Fígado , Biomarcadores , Proteínas Sanguíneas , Galectina 3 , Galectinas , Hepatite Alcoólica/complicações , Humanos , Inflamação , Cirrose Hepática/complicações , Hepatopatias/complicações , Transplante de Fígado/efeitos adversos , Complicações Pós-Operatórias , Prognóstico , Estudos Retrospectivos , Índice de Gravidade de Doença , Síndrome de Resposta Inflamatória Sistêmica

RESUMO

Molecular imaging (MI) is a non-invasive growing technology that allows the investigation of cellular and molecular processes in basic and clinical research and medicine. Luminescent proteins and radionuclides can be associated to target molecules providing high-definition and real-time image of whole body in few minutes or hours. Several MI studies have enabled the determination of molecular partners, in vivo tracking, and fate of compounds in different disorders. Considering that galectins are multifaceted proteins with great impact in many biological events, here we describe methods and strategies to generate labeled galectins for in vivo non-invasive imaging studies.

Assuntos

Galectinas , Imagem Molecular , Proteínas Luminescentes

RESUMO

Galectin-3 is the only chimeric representative of the galectin family. Although galectin-3 has ubiquitous regulatory and physiological effects, there is a great number of pathological environments where galectin-3 cooperatively participates. Pectin is composed of different chemical structures, such as homogalacturonans, rhamnogalacturonans, and side chains. The study of pectin's major structural aspects is fundamental to predicting the impact of pectin on human health, especially regarding distinct molecular modulation. One of the explored pectin's biological activities is the possible galectin-3 protein regulation. The present review focuses on revealing the structure/function relationship of pectins, their fragments, and their biological effects. The discussion highlighted by this review shows different effects described within in vitro and in vivo experimental models, with interesting and sometimes contradictory results, especially regarding galectin-3 interaction. The review demonstrates that pectins are promissory food-derived molecules for different bioactive functions. However, galectin-3 inhibition by pectin had been stated in literature before, although it is not a fully understood, experimentally convincing, and commonly agreed issue. It is demonstrated that more studies focusing on structural analysis and its relation to the observed beneficial effects, as well as substantial propositions of cause and effect alongside robust data, are needed for different pectin molecules' interactions with galectin-3.

Assuntos

Galectina 3 , Pectinas , Galectina 3/metabolismo , Galectinas , Humanos , Pectinas/química

RESUMO

BACKGROUND: Anthracycline (ANT) is often used for breast cancer treatment but its clinical use is limited by cardiotoxicity (CTX). CECCY trial demonstrated that the ß-blocker carvedilol (CVD) could attenuate myocardial injury secondary to ANT. Mieloperoxydase (MPO) is a biomarker of oxidative stress and galectin-3 (Gal-3) is a biomarker of fibrosis and cardiac remodeling. We evaluated the correlation between MPO and Gal-3 behavior with CTX. MATERIALS AND METHODS: A post hoc analysis was performed in the patients who were included in the CECCY trial. A total of 192 women had her blood samples stored during the study at -80°C until the time of assay in a single batch. Stored blood samples were obtained at baseline, 3 and 6 months after randomization. We excluded samples from 18 patients because of hemolysis. MPO and Gal-3 were measured using Luminex xMAP technology through MILLIPLEX MAP KIT (Merck Laboratories). RESULTS: 26 patients (14.9%) had a decrease of at least 10% in LVEF at 6 months after the initiation of chemotherapy. Among these, there was no significant difference in the MPO and Gal-3 when compared to the group without drop in LVEF (p = 0.85 for both MPO and Gal-3). Blood levels of MPO [baseline: 13.2 (7.9, 24.8), 3 months: 17.7 (11.1, 31.1), 6 months: 19.2 (11.1, 37.8) ng/mL] and Gal-3 [baseline: 6.3 (5.2, 9.6), 3 months: 12.3 (9.8, 16.0), 6 months: 10.3 (8.2, 13.1) ng/mL] increased after ANT chemotherapy, and the longitudinal changes were similar between the placebo and CVD groups (p for interaction: 0.28 and 0.32, respectively). In an exploratory analysis, as there is no normal cutoff value established for Gal-3 and MPO in the literature, the MPO and Gal-3 results were splited in two groups: above and below median. In the placebo group, women with high (above median) baseline MPO blood levels demonstrated a greater increase in TnI blood levels than those with low baseline MPO blood levels (p = 0.041). Compared with placebo, CVD significantly reduced TnI blood levels in women with high MPO blood levels (p < 0.001), but did not reduce the TnI levels in women with low baseline MPO blood levels (p = 0.97; p for interaction = 0.009). There was no significant interaction between CVD treatment and baseline Gal-3 blood levels (p for interaction = 0.99). CONCLUSIONS: In this subanalysis of the CECCY trial, MPO and Gal-3 biomarkers did not predict the development of CTX. However, MPO blood levels above median was associated with more severe myocardial injury and identified women who were most likely to benefit from carvedilol for primary prevention (NCT01724450).

Assuntos

Antraciclinas , Galectina 3 , Antraciclinas/efeitos adversos , Antibióticos Antineoplásicos/efeitos adversos , Biomarcadores , Cardiotoxicidade/etiologia , Carvedilol/uso terapêutico , Feminino , Humanos , Estresse Oxidativo

RESUMO

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is one of the most fatal malignant tumors of the digestive system. Many patients are diagnosed at an advanced stage and lose eligibility for surgery. Moreover, there are few effective methods for treating pancreatic ductal cell carcinoma. Increasing attention has been given to microRNAs (miRNAs) and their regulatory roles in tumor progression. In this study, we investigated the effects of exosomes extracted from human umbilical cord mesenchymal stem cells (HUCMSCs) carrying hsa-miRNA-128-3p on pancreatic cancer cells. METHODS: Based on existing experimental and database information, we selected Galectin-3, which is associated with pancreatic cancer, and the corresponding upstream hsa-miRNA-128-3p. We extracted HUCMSCs from a fresh umbilical cord, hsa-miRNA-128-3p was transfected into HUCMSCs, and exosomes containing hsa-miRNA-128-3p were extracted and collected. The effect of exosomes rich in hsa-miRNA-128-3p on pancreatic cancer cells was analyzed. RESULTS: The expression of Galectin-3 in normal pancreatic duct epithelial cells was significantly lower than that in PDAC cell lines. We successfully extracted HUCMSCs from the umbilical cord and transfected hsa-miRNA-128-3p into HUCMSCs. Then we demonstrated that HUCMSC-derived exosomes with hsa-miRNA-128-3p could suppress the proliferation, invasion, and migration of PANC-1 cells in vitro by targeting Galectin-3. CONCLUSION: Hsa-miRNA-128-3p could be considered as a potential therapy for pancreatic cancer. We provided a new idea for targeted therapy of PDAC.

Assuntos

Carcinoma Ductal Pancreático/patologia , Exossomos/fisiologia , Galectina 3/fisiologia , Células-Tronco Mesenquimais/ultraestrutura , Neoplasias Pancreáticas/patologia , Cordão Umbilical/citologia , Humanos , Células Tumorais Cultivadas

RESUMO

ABSTRACT Chronic Chagas Cardiomyopathy (CCC) is the most prevalent type of myocarditis and the main clinical form of the Chagas disease, which has peculiarities such as focal inflammation, structural derangement, hypertrophy, dilation, and intense reparative fibrosis. Many cellular compounds contribute to CCC development. Galectin-3 is a partaker in inflammation and contributes to myocardial fibrosis formation. Some studies showed the connection between Galectin-3 and fibrosis in Chagas disease but are still inconclusive on the guidance for the early implementation of pharmacological therapy. This systematic review evaluated Galectin-3 as a biomarker for fibrosis intensity in CCC. Two independent reviewers have searched five databases (PubMed, EMBASE, Cochrane Library, Scopus, and Lilacs), using the following search terms: galectin-3, biomarkers, fibrosis, Chagas cardiomyopathy, and Chagas disease. Overall, seven studies met the inclusion criteria and made up this review. There were four trials conducted through animal model experiments and three trials with humans. Experimental data in mice indicate an association between Galectin-3 expression and fibrosis in CCC (75% of studies). Data from human studies showed no direct connection between myocardial fibrosis and Galectin-3 expression (80% of studies). Thus, human findings do not provide significant evidence indicating that Galectin-3 is related to fibrosis formation in Chagas disease. Based on the analyzed studies, it is suggested that Galectin-3 might not be a good fibrosis marker in CCC.

RESUMO

Resumo Fundamento: A estratificação de risco continua sendo clinicamente desafiadora em pacientes com insuficiência cardíaca (IC) de etiologia não isquêmica. A galectina-3 é um marcador sérico de fibrose que pode ajudar no prognóstico. Objetivo: Determinar o papel da galectina-3 como preditora de eventos arrítmicos graves e mortalidade total. Métodos: Este é um estudo de coorte prospectivo que incluiu 148 pacientes com IC não isquêmica. Todos os pacientes foram submetidos a uma avaliação clínica e laboratorial abrangente para coleta de dados de referência, incluindo níveis de galectina-3 sérica. O desfecho primário foi a ocorrência de síncope arrítmica, intervenções apropriadas do cardioversor desfibrilador implantável, taquicardia ventricular sustentada ou morte súbita cardíaca. O desfecho secundário foi a morte por todas as causas. Para todos os testes estatísticos, considerou-se significativo o valor p<0,05 (bicaudal). Resultados: Em seguimento mediano de 941 dias, os desfechos primário e secundário ocorreram em 26 (17,5%) e 30 (20%) pacientes, respectivamente. A galectina-3 sérica>22,5 ng/mL (quartil mais alto) não foi preditora de eventos arrítmicos graves (HR: 1,98; p=0,152). Os preditores independentes do desfecho primário foram diâmetro diastólico final do ventrículo esquerdo (DDFVE)>73 mm (HR: 3,70; p=0,001), ventilação periódica durante o exercício (VPE) no teste de esforço cardiopulmonar (HR: 2,67; p=0,01) e taquicardia ventricular não sustentada (TVNS)>8 batimentos na monitorização por Holter (HR: 3,47; p=0,027). Os preditores de morte por todas as causas foram: galectina-3>22,5 ng/mL (HR: 3,69; p=0,001), DDFVE>73 mm (HR: 3,35; p=0,003), VPE (HR: 3,06; p=0,006) e TVNS>8 batimentos (HR: 3,95; p=0,007). A ausência de todos os preditores de risco foi associada a um valor preditivo negativo de 91,1% para o desfecho primário e 96,6% para a mortalidade total. Conclusões: Em pacientes com IC não isquêmica, níveis elevados de galectina-3 não foram preditores de eventos arrítmicos graves, mas foram associados à mortalidade total. A ausência de preditores de risco revelou um subgrupo prevalente de pacientes com IC com excelente prognóstico.

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Abstract Background: Risk stratification remains clinically challenging in patients with heart failure (HF) of non-ischemic etiology. Galectin-3 is a serum marker of fibrosis that might help in prognostication. Objective: To determine the role of galectin-3 as a predictor of major arrhythmic events and overall mortality. Methods: We conducted a prospective cohort study that enrolled 148 non-ischemic HF patients. All patients underwent a comprehensive baseline clinical and laboratory assessment, including levels of serum galectin-3. The primary outcome was the occurrence of arrhythmic syncope, appropriate implantable cardioverter defibrillator therapy, sustained ventricular tachycardia, or sudden cardiac death. The secondary outcome was all-cause death. For all statistical tests, a two-tailed p-value<0.05 was considered significant. Results: In a median follow-up of 941 days, the primary and secondary outcomes occurred in 26 (17.5%) and 30 (20%) patients, respectively. Serum galectin-3>22.5 ng/mL (highest quartile) did not predict serious arrhythmic events (HR: 1.98, p=0.152). Independent predictors of the primary outcome were left ventricular end-diastolic diameter (LVEDD)>73mm (HR: 3.70, p=0.001), exercise periodic breathing (EPB) on cardiopulmonary exercise testing (HR: 2.67, p=0.01), and non-sustained ventricular tachycardia (NSVT)>8 beats on Holter monitoring (HR: 3.47, p=0.027). Predictors of all-cause death were galectin-3>22.5 ng/mL (HR: 3.69, p=0.001), LVEDD>73mm (HR: 3.35, p=0.003), EPB (HR: 3.06, p=0.006), and NSVT>8 beats (HR: 3.95, p=0.007). The absence of all risk predictors was associated with a 91.1% negative predictive value for the primary outcome and 96.6% for total mortality. Conclusions: In non-ischemic HF patients, elevated galectin-3 levels did not predict major arrhythmic events but were associated with total mortality. Absence of risk predictors revealed a prevalent subgroup of HF patients with an excellent prognosis.

Assuntos

Humanos , Desfibriladores Implantáveis , Galectina 3/sangue , Insuficiência Cardíaca , Prognóstico , Valor Preditivo dos Testes , Estudos Prospectivos , Fatores de Risco , Morte Súbita Cardíaca

Assuntos

Humanos , Morte Súbita Cardíaca/etiologia , Insuficiência Cardíaca/complicações

RESUMO

Cryptococcus neoformans, the causative agent of cryptococcosis, is the primary fungal pathogen that affects the immunocompromised individuals. Galectin-3 (Gal-3) is an animal lectin involved in both innate and adaptive immune responses. The present study aimed to evaluate the influence of Gal-3 on the C. neoformans infection. We performed histopathological and gene profile analysis of the innate antifungal immunity markers in the lungs, spleen, and brain of the wild-type (WT) and Gal-3 knockout (KO) mice during cryptococcosis. These findings suggest that Gal-3 absence does not cause significant histopathological alterations in the analyzed tissues. The expression profile of the genes related to innate antifungal immunity showed that the presence of cryptococcosis in the WT and Gal-3 KO animals, compared to their respective controls, promoted the upregulation of the pattern recognition receptor (PRR) responsive to mannose/chitin (mrc1) and a gene involved in inflammation (ccr5), as well as the downregulation of the genes related to signal transduction (card9, fos, ikbkb, jun) and PRRs (cd209a, colec12, nptx1). The absence of Gal-3, in fungal infection, a positively modulated gene involved in phagocytosis (sftpd) and negatively genes involved in signal transduction (syk and myd88), proinflammatory cytokines il-1ß and il-12b and cd209a receptor. Therefore, our results suggest that Gal-3 may play an essential role in the development of antifungal immune responses against cryptococcosis.