RESUMO
Metabolic syndrome (MS) is a set of cardio-metabolic risk factors that includes central obesity, hyperglycemia, hypertension, and dyslipidemias. The syndrome affects 25% of adults worldwide. The definition of MS has evolved over the last 80 years, with various classification systems and criteria, whose limitations and benefits are currently the subject of some controversy. Likewise, hypotheses regarding the etiology of MS add more confusion from clinical and epidemiological points of view. The leading suggestion for the pathophysiology of MS is insulin resistance (IR). IR can affect multiple tissues and organs, from the classic "triumvirate" (myocyte, adipocyte, and hepatocyte) to possible effects on organs considered more recently, such as the central nervous system (CNS). Mild cognitive impairment (MCI) and Alzheimer's disease (AD) may be clinical expressions of CNS involvement. However, the association between MCI and MS is not understood. The bidirectional relationship that seems to exist between these factors raises the questions of which phenomenon occurs first and whether MCI can be a precursor of MS. This review explores shared pathophysiological mechanisms between MCI and MS and establishes a hypothesis of a possible MCI role in the development of IR and the appearance of MS.
Assuntos
Sistema Nervoso Central/patologia , Síndrome Metabólica/patologia , Ensaios Clínicos como Assunto , Disfunção Cognitiva/epidemiologia , Disfunção Cognitiva/etiologia , Disfunção Cognitiva/patologia , Humanos , Síndrome Metabólica/complicações , Síndrome Metabólica/epidemiologiaRESUMO
Diabetes mellitus (DM) is considered one of the most massive epidemics of the twenty-first century due to its high mortality rates caused mainly due to its complications; therefore, the early identification of such complications becomes a race against time to establish a prompt diagnosis. The research of complications of DM over the years has allowed the development of numerous alternatives for diagnosis. Among these emerge the quantification of advanced glycation end products (AGEs) given their increased levels due to chronic hyperglycemia, while also being related to the induction of different stress-associated cellular responses and proinflammatory mechanisms involved in the progression of chronic complications of DM. Additionally, the investigation for more valuable and safe techniques has led to developing a newer, noninvasive, and effective tool, termed skin fluorescence (SAF). Hence, this study aimed to establish an update about the molecular mechanisms induced by AGEs during the evolution of chronic complications of DM and describe the newer measurement techniques available, highlighting SAF as a possible tool to measure the risk of developing DM chronic complications.
Assuntos
Produtos Finais de Glicação Avançada , Hiperglicemia , Fluorescência , Humanos , PeleRESUMO
Caveolin-1 (CAV1), is a broadly expressed, membrane-associated scaffolding protein that acts both, as a tumor suppressor and a promoter of metastasis, depending on the type of cancer and stage. CAV1 is downregulated in human tumors, tumor cell lines and oncogene-transformed cells. The tumor suppressor activity of CAV1 is generally associated with its presence at the plasma membrane, where it participates, together with cavins, in the formation of caveolae and also has been suggested to interact with and inhibit a wide variety of proteins through interactions mediated by the scaffolding domain. However, a pool of CAV1 is also located at the endoplasmic reticulum (ER), modulating the secretory pathway in a manner dependent on serine-80 (S80) phosphorylation. In melanoma cells, CAV1 expression suppresses tumor formation, but the protein is largely absent from the plasma membrane and does not form caveolae. Perturbations to the function of the ER are emerging as a central driver of cancer, highlighting the activation of the unfolded protein response (UPR), a central pathway involved in stress mitigation. Here we provide evidence indicating that the expression of CAV1 represses the activation of the UPR in vitro and in solid tumors, reflected in the attenuation of PERK and IRE1α signaling. These effects correlated with increased susceptibility of cells to ER stress and hypoxia. Interestingly, the tumor suppressor activity of CAV1 was abrogated by site-directed mutagenesis of S80, correlating with a reduced ability to repress the UPR. We conclude that the tumor suppression by CAV1 involves the attenuation of the UPR, and identified S80 as essential in this context. This suggests that intracellular CAV1 regulates cancer through alternative signaling outputs.
Assuntos
Caveolina 1/metabolismo , Resposta a Proteínas não Dobradas/fisiologia , Animais , Caveolina 1/fisiologia , Linhagem Celular Tumoral , Membrana Celular/metabolismo , Retículo Endoplasmático/metabolismo , Estresse do Retículo Endoplasmático/fisiologia , Endorribonucleases/metabolismo , Feminino , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Fosforilação , Proteínas Serina-Treonina Quinases/metabolismo , Transdução de Sinais/efeitos dos fármacos , eIF-2 Quinase/metabolismoRESUMO
In advanced stages of cancer disease, caveolin-1 (CAV1) expression increases and correlates with increased migratory and invasive capacity of the respective tumor cells. Previous findings from our laboratory revealed that specific ECM-integrin interactions and tyrosine-14 phosphorylation of CAV1 are required for CAV1-enhanced melanoma cell migration, invasion and metastasis in vivo. In this context, CAV1 phosphorylation on tyrosine-14 mediated by non-receptor Src-family tyrosine kinases seems to be important; however, the effect of Src-family kinase inhibitors on CAV1-enhanced metastasis in vivo has not been studied. Here, we evaluated the effect of CAV1 and c-Abl overexpression, as well as the use of the Src-family kinase inhibitors, PP2 and dasatinib (more specific for Src/Abl) in lung metastasis of B16F10 melanoma cells. Overexpression of CAV1 and c-Abl enhanced CAV1 phosphorylation and the metastatic potential of the B16F10 murine melanoma cells. Alternatively, treatment with PP2 or dasatinib for 2â¯h reduced CAV1 tyrosine-14 phosphorylation and levels recovered fully within 12â¯h of removing the inhibitors. Nonetheless, pre-treatment of cells with these inhibitors for 2â¯h sufficed to prevent migration, invasion and trans-endothelial migration in vitro. Importantly, the transient decrease in CAV1 phosphorylation by these kinase inhibitors prevented early steps of CAV1-enhanced lung metastasis by B16F10 melanoma cells injected into the tail vein of mice. In conclusion, this study underscores the relevance of CAV1 tyrosine-14 phosphorylation by Src-family kinases during the first steps of the metastatic sequence promoted by CAV1. These findings open up potential options for treatment of metastatic tumors in patients in which Src-family kinase activation and CAV1 overexpression favor dissemination of cancer cells to secondary sites.
Assuntos
Caveolina 1/metabolismo , Dasatinibe/farmacologia , Neoplasias Pulmonares/secundário , Melanoma Experimental/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Pirimidinas/farmacologia , Neoplasias Cutâneas/metabolismo , Quinases da Família src/antagonistas & inibidores , Animais , Caveolina 1/genética , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Dasatinibe/uso terapêutico , Feminino , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/patologia , Masculino , Melanoma Experimental/patologia , Camundongos , Camundongos Endogâmicos C57BL , Neuropeptídeos/metabolismo , Fosforilação/efeitos dos fármacos , Inibidores de Proteínas Quinases/uso terapêutico , Pirimidinas/uso terapêutico , Neoplasias Cutâneas/patologia , Transfecção , Tirosina/metabolismo , Proteínas rac1 de Ligação ao GTP/metabolismoRESUMO
OBJECTIVE: . The aim of this study is to compare the predictive capacity of different anthropometric indices in multiple risk factors aggregation (MRFA) determination in the adult population from Cuenca city, Ecuador. MATERIALS AND METHODS: . A cross- sectional descriptive study was performed with a random multi-stage sampling in 318 adult subjects who underwent a clinical, anthropometric and laboratory evaluation; being the abdominal circumference, body mass index (BMI) and waist height index (WHtR) evaluated. MRFA was defined as the presence of ≥2 components of the metabolic syndrome (excluding abdominal circumference). ROC curves were plotted to determine the area under the curve (AUC) for each index. RESULTS: . Of the 318 individuals, 54.1% (n=172) presented MRFA. According to ROC curves, the highest predictive capacity in women was observed with BMI and WHtR (AUC: 0.751 and 0.750, respectively), while in men abdominal circumference and WHtR showed a similar predictive power (AUC: 0.762). The multivariate analysis adjusted for sex and age showed that high WHtR (OR: 2.53, 95% CI: 1.12-5.71, p=0.026) was the best predictor of MRFA, followed by BMI (OR: 2.15, 95% CI: 1.19-3.88, p=0.010). CONCLUSIONS: . The predictive capacity of the anthropometric indexes is influenced by gender; nevertheless the WHtR is the best predictor of MRFA in our population.
OBJETIVOS.: El objetivo de este estudio es comparar la capacidad predictiva de diferentes índices antropométricos en la determinación de la agregación de múltiples factores de riesgo (AMFR) en la población adulta de la ciudad de Cuenca, Ecuador. MATERIALES Y MÉTODOS .: Se realizó un estudio descriptivo transversal con un muestreo aleatorio multietápico en 318 sujetos adultos a quienes se les realizó una evaluación clínica, antropométrica y de laboratorio; siendo la circunferencia abdominal, índice de masa corporal (IMC) e índice cintura altura (ICA) los índices evaluados. La AMFR se definió como la presencia de ≥ dos componentes del síndrome metabólico (excluyendo circunferencia abdominal). Se realizaron curvas COR para determinar el área bajo la curva (ABC) para cada índice. RESULTADOS.: De los 318 individuos, un 54,1% (n=172) presentaron AMFR. Según los resultados obtenidos por curvas COR, la mayor capacidad predictiva en mujeres se observó con el IMC y el ICA (ABC: 0,751 y 0,750, respectivamente) mientras que en hombres la circunferencia abdominal y el ICA mostraron una capacidad predictiva similar (ABC=0,762). El análisis multivariante ajustado por sexo y edad mostró que el ICA elevado (OR: 2,53; IC95%: 1,12-5,71; p=0,026) fue el mejor predictor de AMFR, seguido por el IMC (OR: 2,15; IC95%: 1,19-3,88; p=0,010). CONCLUSIONES.: La capacidad predictiva de los índices antropométricos está influenciada por el sexo, no obstante, el ICA es el mejor predictor de la AMFR en la población de Cuenca.
Assuntos
Estatura , Índice de Massa Corporal , Circunferência da Cintura , Adulto , Estudos Transversais , Equador , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Medição de Risco , Fatores de RiscoRESUMO
RESUMEN Objetivos. El objetivo de este estudio es comparar la capacidad predictiva de diferentes índices antropométricos en la determinación de la agregación de múltiples factores de riesgo (AMFR) en la población adulta de la ciudad de Cuenca, Ecuador. Materiales y métodos . Se realizó un estudio descriptivo transversal con un muestreo aleatorio multietápico en 318 sujetos adultos a quienes se les realizó una evaluación clínica, antropométrica y de laboratorio; siendo la circunferencia abdominal, índice de masa corporal (IMC) e índice cintura altura (ICA) los índices evaluados. La AMFR se definió como la presencia de ≥ dos componentes del síndrome metabólico (excluyendo circunferencia abdominal). Se realizaron curvas COR para determinar el área bajo la curva (ABC) para cada índice. Resultados. De los 318 individuos, un 54,1% (n=172) presentaron AMFR. Según los resultados obtenidos por curvas COR, la mayor capacidad predictiva en mujeres se observó con el IMC y el ICA (ABC: 0,751 y 0,750, respectivamente) mientras que en hombres la circunferencia abdominal y el ICA mostraron una capacidad predictiva similar (ABC=0,762). El análisis multivariante ajustado por sexo y edad mostró que el ICA elevado (OR: 2,53; IC95%: 1,12-5,71; p=0,026) fue el mejor predictor de AMFR, seguido por el IMC (OR: 2,15; IC95%: 1,19-3,88; p=0,010). Conclusiones. La capacidad predictiva de los índices antropométricos está influenciada por el sexo, no obstante, el ICA es el mejor predictor de la AMFR en la población de Cuenca.
ABSTRACT Objective . The aim of this study is to compare the predictive capacity of different anthropometric indices in multiple risk factors aggregation (MRFA) determination in the adult population from Cuenca city, Ecuador. Materials and Methods . A cross- sectional descriptive study was performed with a random multi-stage sampling in 318 adult subjects who underwent a clinical, anthropometric and laboratory evaluation; being the abdominal circumference, body mass index (BMI) and waist height index (WHtR) evaluated. MRFA was defined as the presence of ≥2 components of the metabolic syndrome (excluding abdominal circumference). ROC curves were plotted to determine the area under the curve (AUC) for each index. Results . Of the 318 individuals, 54.1% (n=172) presented MRFA. According to ROC curves, the highest predictive capacity in women was observed with BMI and WHtR (AUC: 0.751 and 0.750, respectively), while in men abdominal circumference and WHtR showed a similar predictive power (AUC: 0.762). The multivariate analysis adjusted for sex and age showed that high WHtR (OR: 2.53, 95% CI: 1.12-5.71, p=0.026) was the best predictor of MRFA, followed by BMI (OR: 2.15, 95% CI: 1.19-3.88, p=0.010). Conclusions . The predictive capacity of the anthropometric indexes is influenced by gender; nevertheless the WHtR is the best predictor of MRFA in our population.
Assuntos
Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estatura , Índice de Massa Corporal , Circunferência da Cintura , Estudos Transversais , Fatores de Risco , Medição de Risco , EquadorRESUMO
Introducción: El índice de adiposidad visceral (VAI) es un método sencillo y costo-efectivo en la determinación de adiposidad visceral. El objetivo de este estudio es evaluar la relación entre el VAI con diversos factores de riesgo cardiovascular, variables sociodemográficas y hábitos psicobiológicos en la población adulta de la ciudad de Cuenca, Ecuador. Materiales y métodos: Se realizó un estudio descriptivo transversal en 318 individuos adultos seleccionados mediante muestreo aleatorio y multietápico, a quienes se les realizó evaluación clínica, evaluación antropométrica y de laboratorio. El VAI se determinó utilizando las fórmulas propuestas que emplean circunferencia abdominal, el índice de masa corporal, los triacilglicéridos y HDL-C. Se realizó un modelo de regresión logística múltiple para determinar los principales factores asociados a adiposidad visceral en sus valores más elevados. Resultados: En los 318 individuos, el promedio del VAI fue 2,57 (1,66-3,94), con valores más elevados para el sexo femenino. En el modelo de regresión logística múltiple, los factores de riesgo significativos para VAI moderado-alto fueron: la edad (> 60 años: OR = 3,87; IC del 95%: 1,15-12,96; p = 0,03), el consumo calórico, la glucemia alterada en ayuno y la actividad física en ocio. Conclusión: El VAI es un método útil para definir a aquellos sujetos con adiposidad visceral en nuestra región. La edad, el consumo calórico diario y la glucemia alterada en ayuno son los principales factores asociados con los valores más elevados delíndice, mientras que la actividad física durante el ocio representó un factor protector para clasificar a los sujetos en los estadios más avanzados.
Introduction: The visceral adiposity index (VAI) is a simple and cost effective method for the determination of visceral adiposity. The objective of this study is to evaluate the relationship between VAI and different cardiovascular risk factors, sociodemographic variables, and psychobiological habits in the adult population of the city of Cuenca, Ecuador. Materials and methods: A descriptive cross-sectional study was performed on 318 adult individuals selected by multistage random sampling, who underwent a clinical, anthropometric and laboratory evaluation. VAI was determined using the proposed formula that used abdominal circumference, body mass index, triglycerides, and HDL-Cholesterol. A multiple logistic regression model was used to determine the main factors associated with the highest values of visceral adiposity. Results: The mean VAI was 2.57 (1.66-3.94) in the 318 individuals studied, with higher values for females. In the multiple logistic regression model, significant risk factors for moderatehigh VAI were: age (>60 years: OR = 3.87, 95% CI: 1.15-12.96, P=.03), calorie intake, impaired fasting glucose, and leisure time physical activity. Conclusion: VAI is a useful method to define those subjects with visceral adiposity in our region. Age, daily calorie intake, and impaired fasting glucose are the main factors associated with higher index values, while leisure time physical activity was a protective factor for classifying subjects in the more advanced stages.
Assuntos
Humanos , Masculino , Feminino , Adulto , Pessoa de Meia-Idade , Idoso , Idoso de 80 Anos ou mais , Distribuição da Gordura Corporal/estatística & dados numéricos , Obesidade Abdominal/complicações , Ingestão de Energia/fisiologia , Exercício Físico/fisiologia , Equador/epidemiologia , Obesidade Abdominal/diagnósticoRESUMO
Expression of the scaffolding protein Caveolin-1 (CAV1) enhances migration and invasion of metastatic cancer cells. Yet, CAV1 also functions as a tumor suppressor in early stages of cancer, where expression is suppressed by epigenetic mechanisms. Thus, we sought to identify stimuli/mechanisms that revert epigenetic CAV1 silencing in cancer cells and evaluate how this affects their metastatic potential. We reasoned that restricted tissue availability of anti-neoplastic drugs during chemotherapy might expose cancer cells to sub-therapeutic concentrations, which activate signaling pathways and the expression of CAV1 to favor the acquisition of more aggressive traits. Here, we used in vitro [2D, invasion] and in vivo (metastasis) assays, as well as genetic and biochemical approaches to address this question. Colon and breast cancer cells were identified where CAV1 levels were low due to epigenetic suppression and could be reverted by treatment with the methyltransferase inhibitor 5'-azacytidine. Exposure of these cells to anti-neoplastic drugs for short periods of time (24-48 h) increased CAV1 expression through ROS production and MEK/ERK activation. In colon cancer cells, increased CAV1 expression enhanced migration and invasion in vitro via pathways requiring Src-family kinases, as well as Rac-1 activity. Finally, elevated CAV1 expression in colon cancer cells following exposure in vitro to sub-cytotoxic drug concentrations increased their metastatic potential in vivo. Therefore exposure of cancer cells to anti-neoplastic drugs at non-lethal drug concentrations induces signaling events and changes in transcription that favor CAV1-dependent migration, invasion and metastasis. Importantly, this may occur in the absence of selection for drug-resistance.
RESUMO
Caveolin-1 (CAV1) is a scaffolding protein that plays a dual role in cancer. In advanced stages of this disease, CAV1 expression in tumor cells is associated with enhanced metastatic potential, while, at earlier stages, CAV1 functions as a tumor suppressor. We recently implicated CAV1 phosphorylation on tyrosine 14 (Y14) in CAV1-enhanced cell migration. However, the contribution of this modification to the dual role of CAV1 in cancer remained unexplored. Here, we used in vitro [2D and transendothelial cell migration (TEM), invasion] and in vivo (metastasis) assays, as well as genetic and biochemical approaches to address this question in B16F10 murine melanoma cells. CAV1 promoted directional migration on fibronectin or laminin, two abundant lung extracellular matrix (ECM) components, which correlated with enhanced Y14 phosphorylation during spreading. Moreover, CAV1-driven migration, invasion, TEM and metastasis were ablated by expression of the phosphorylation null CAV1(Y14F), but not the phosphorylation mimicking CAV1(Y14E) mutation. Finally, CAV1-enhanced focal adhesion dynamics and surface expression of beta1 integrin were required for CAV1-driven TEM. Importantly, CAV1 function as a tumor suppressor in tumor formation assays was not altered by the Y14F mutation. In conclusion, our results provide critical insight to the mechanisms of CAV1 action during cancer development. Specific ECM-integrin interactions and Y14 phosphorylation are required for CAV1-enhanced melanoma cell migration, invasion and metastasis to the lung. Because Y14F mutation diminishes metastasis without inhibiting the tumor suppressor function of CAV1, Y14 phosphorylation emerges as an attractive therapeutic target to prevent metastasis without altering beneficial traits of CAV1.
Assuntos
Caveolina 1/metabolismo , Melanoma/metabolismo , Neoplasias Cutâneas/metabolismo , Tirosina/química , Animais , Carcinogênese , Caveolina 1/química , Adesão Celular , Movimento Celular , Feminino , Fibroblastos/metabolismo , Fibronectinas/química , Humanos , Integrina beta1/metabolismo , Laminina/química , Neoplasias Pulmonares/secundário , Masculino , Melanoma Experimental , Camundongos , Camundongos Endogâmicos C57BL , Invasividade Neoplásica , Metástase Neoplásica , FosforilaçãoRESUMO
Migration and invasion are essential steps associated with tumor cell metastasis and increasing evidence points towards endosome trafficking being essential in this process. Indeed, the small GTPase Rab5, a crucial regulator of early endosome dynamics, promotes cell migration in vitro and in vivo. Precisely how Rab5 participates in these events remains to be determined. Considering that focal adhesions represent structures crucial to cell migration, we specifically asked whether Rab5 activation promoted focal adhesion disassembly and thereby facilitated migration and invasion of metastatic cancer cells. Pulldown and biosensor assays revealed that Rab5-GTP loading increased at the leading edge of migrating tumor cells. Additionally, targeting of Rab5 by different shRNA sequences, but not control shRNA, decreased Rab5-GTP levels, leading to reduced cell spreading, migration and invasiveness. Re-expression in knockdown cells of wild-type Rab5, but not the S34N mutant (GDP-bound), restored these properties. Importantly, Rab5 association with the focal adhesion proteins vinculin and paxillin increased during migration, and expression of wild-type, but not GDP-bound Rab5, accelerated focal adhesion disassembly, as well as FAK dephosphorylation on tyrosine 397. Finally, Rab5-driven invasiveness required focal adhesion disassembly, as treatment with the FAK inhibitor number 14 prevented Matrigel invasion and matrix metalloproteinase release. Taken together, these observations show that Rab5 activation is required to enhance cancer cell migration and invasion by promoting focal adhesion disassembly.