RESUMO
Objective The aim of this study was to unravel the mechanisms by which thyroxine affects skeletal growth by evaluating proliferative activity and angiogenic profile of growth cartilage of neonatal and weanling rats. Methods Sixteen adult Wistar rats were equally divided into 2 groups: control and treated with thyroxine during pregnancy and lactation. The weight, measurement of plasma free T4 and thyroids, femurs' histomorphometric analysis, and proliferative activity and angiogenic profile by immunohistochemical or real-time reverse transcriptase-polymerase chain reaction in growth cartilage was performed. Data were analyzed using Student's t test. Results The free T4 was significantly higher in the treated rats. However, the height of the follicular epithelium of the thyroid in newborns was significantly lower in the treated group. The excess maternal thyroxine significantly reduced the body weight and length of the femur in the offspring but significantly increased the thickness of trabecular bone and changed the height of the zones of the growth plate. Furthermore, excess maternal thyroxine reduced cell proliferation and vascular endothelial growth factor (VEGF) expression in the growth cartilage of newborn and 20-day-old rats ( P < 0.05). There was also a reduction in the immunohistochemical expression of Tie2 in the cartilaginous epiphysis of the newborns and FLK-1 in the articular cartilage of 20-day-old rats. No significant difference was observed in Ang2 expression. Conclusions The excess maternal thyroxine during pregnancy and lactation reduced endochondral bone growth in the progeny and reduced the proliferation rate and VEGF, Flk-1, and Tie2 expression in the cartilage of growing rats without altering the mRNA expression of Ang1 and Ang2.
Assuntos
Cartilagem/metabolismo , Lactação/metabolismo , Osteogênese/efeitos dos fármacos , Glândula Tireoide/metabolismo , Tiroxina/farmacologia , Angiopoietinas/metabolismo , Animais , Feminino , Fêmur/efeitos dos fármacos , Fêmur/metabolismo , Fêmur/patologia , Lâmina de Crescimento/metabolismo , Hipertireoidismo/metabolismo , Neovascularização Fisiológica , Gravidez , Ratos , Ratos Wistar , Receptor TIE-2/metabolismo , Glândula Tireoide/patologia , Tiroxina/administração & dosagem , Tiroxina/efeitos adversos , Tiroxina/sangue , Fator A de Crescimento do Endotélio Vascular/metabolismo , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismo , DesmameRESUMO
Angiogenesis in inflammation are hallmarks for adipose tissue expansion in obesity. The role of angiopoietin/Tie-2 system in adipose tissue expansion and immune cell recruitment is unclear. We studied the effect of sleeve gastrectomy and the influence of FTO rs9930506 polymorphism on Tie-2, angiopoietin-1 and angiopoietin-2 expression in morbid obesity. Fifteen morbidly obese subjects (4 men and 11 women) aged 24-55 years were followed-up 3 and 6 months after sleeve gastrectomy. Serum sTie-2, angiopoietin-1, angiopoietin-2, and hypoxia-inducible factor-1α concentrations were determined by ELISA. Tie-2 and its ligands in visceral and subcutaneous adipose tissue were localized by immunohistochemistry. Tie-2 expression was measured by flow cytometry in circulating monocytes and infiltrated macrophages. Comparisons before and after sleeve gastrectomy were carried out using ANOVA for repeated measures. rs9930506FTO genotyping was performed by PCR-RFLP. Circulating sTie-2 and angiopoietin-2 were higher before sleeve gastrectomy. Tie-2 and angiopoietin-2 mRNA levels were higher in subcutaneous adipose tissue than visceral and both decreased after surgery. Monocytes and infiltrated macrophages showed a pro-inflammatory phenotype, with increased Tie-2 expression that decreased 3 and 6 months after sleeve gastrectomy. Baseline sTie-2 correlated inversely with adiponectin levels. At baseline the rs9930506FTO AG ó GG genotypes carriers had more 34 kg than genotype carriers of rs9930506 AA. Weight and body mass index decreased at 6 months. We found that angiopoietin/Tie-2 system is mainly expressed in subcutaneous adipose tissue, contributing to expandability, fat accumulation, and monocytes attachment in obesity. Bariatric surgery favorably modifies the pro-angiogenic profile, allowed a reduced angiogenic expression in the circulation and adipose tissue.
Assuntos
Dioxigenase FTO Dependente de alfa-Cetoglutarato/genética , Angiopoietinas/metabolismo , Gastrectomia , Obesidade Mórbida/metabolismo , Receptor TIE-2/metabolismo , Adulto , Antropometria , Feminino , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Macrófagos/metabolismo , Masculino , Pessoa de Meia-Idade , Obesidade Mórbida/imunologia , Obesidade Mórbida/cirurgia , Polimorfismo de Nucleotídeo Único , Gordura Subcutânea/imunologia , Gordura Subcutânea/metabolismo , Adulto JovemRESUMO
The development of the syndrome of cancer cachexia and that of metastasis are related with a poor prognostic for cancer patients. They are considered multifactorial processes associated with a proinflammatory environment, to which tumour microenvironment and other tissues from the tumour bearing individuals contribute. The aim of the present review is to address the role of ghrelin, myostatin, leptin, HIF, IL-6, TNF-α, and ANGPTL-4 in the regulation of energy balance, tumour development, and tumoural cell invasion. Hypoxia induced factor plays a prominent role in tumour macro- and microenvironment, by modulating the release of proinflammatory cytokines.
Assuntos
Caquexia/patologia , Neoplasias/patologia , Proteína 4 Semelhante a Angiopoietina , Angiopoietinas/metabolismo , Animais , Citocinas/metabolismo , Grelina/metabolismo , Humanos , Hipóxia , Fator 1 Induzível por Hipóxia/metabolismo , Inflamação , Interleucina-6/metabolismo , Leptina/biossíntese , Leptina/metabolismo , Miostatina/metabolismo , Metástase Neoplásica , Prognóstico , Síndrome , Microambiente Tumoral , Fator de Necrose Tumoral alfa/metabolismoRESUMO
The gut microbiota obtained after birth is composed of a large range of bacteria that play different roles in the human host, such as nutrient uptake, protection against pathogens and immune modulation. The intestinal bacterial content is not completely known, but it is influenced by internal, and mainly by external factors, which modulate its composition and function. Studies indicate that the gut microbiota differs in lean and obese individuals, and in individuals with different food habits. There is evidence that the relationship between diet, inflammation, insulin resistance, and cardiometabolic risk are, in part, mediated by the composition of intestinal bacteria. Knowledge about the gut microbiota may result in different strategies to manipulate bacterial populations and promote health. This review discusses the relevance of understanding the role of dietary factors or patterns in the composition of the microbiota, as well as pathophysiological mechanisms of chronic metabolic diseases, and the potential of prebiotics and probiotics on the cardiometabolic risk profile.
Assuntos
Comportamento Alimentar/fisiologia , Intestinos/microbiologia , Microbiota/fisiologia , Proteína 4 Semelhante a Angiopoietina , Angiopoietinas/metabolismo , Animais , Dieta Hiperlipídica/efeitos adversos , Transtornos do Metabolismo de Glucose/etiologia , Humanos , Hipertensão/etiologia , Transtornos do Metabolismo dos Lipídeos/etiologia , Lipopolissacarídeos/metabolismo , Obesidade/etiologia , Prebióticos , Probióticos , Fatores de RiscoRESUMO
A microbiota intestinal, adquirida no período pós-natal, é composta por grande diversidade de bactérias que desempenham diferentes funções no hospedeiro humano, entre elas a absorção de nutrientes, proteção contra patógenos e modulação do sistema imune. O conteúdo bacteriano intestinal ainda não é totalmente conhecido, mas sabe-se que é influenciado por fatores internos e principalmente externos que modulam sua composição e função. Estudos indicam que a microbiota intestinal difere em indivíduos magros e obesos e ainda naqueles que mantêm hábitos alimentares diferentes. Há evidências de que as relações entre dieta, inflamação, resistência à insulina e risco cardiometabólico são em parte mediadas pela composição de bactérias intestinais. Conhecimentos sobre a microbiota poderão reverter em diferentes estratégias para manipular as populações bacterianas e promover saúde. Esta revisão aborda a relevância do conhecimento sobre o papel de fatores ou padrões alimentares na composição da microbiota, assim como mecanismos fisiopatológicos de doenças metabólicas crônicas e as potencialidades de prebióticos e probióticos sobre o perfil de risco cardiometabólico.
The gut microbiota obtained after birth is composed of a large range of bacteria that play different roles in the human host, such as nutrient uptake, protection against pathogens and immune modulation. The intestinal bacterial content is not completely known, but it is influenced by internal, and mainly by external factors, which modulate its composition and function. Studies indicate that the gut microbiota differs in lean and obese individuals, and in individuals with different food habits. There is evidence that the relationship between diet, inflammation, insulin resistance, and cardiometabolic risk are, in part, mediated by the composition of intestinal bacteria. Knowledge about the gut microbiota may result in different strategies to manipulate bacterial populations and promote health. This review discusses the relevance of understanding the role of dietary factors or patterns in the composition of the microbiota, as well as pathophysiological mechanisms of chronic metabolic diseases, and the potential of prebiotics and probiotics on the cardiometabolic risk profile.
Assuntos
Animais , Humanos , Comportamento Alimentar/fisiologia , Intestinos/microbiologia , Microbiota/fisiologia , Angiopoietinas/metabolismo , Dieta Hiperlipídica/efeitos adversos , Transtornos do Metabolismo de Glucose/etiologia , Hipertensão/etiologia , Transtornos do Metabolismo dos Lipídeos/etiologia , Lipopolissacarídeos/metabolismo , Obesidade/etiologia , Prebióticos , Probióticos , Fatores de RiscoRESUMO
Here, we discuss potential explanations for the higher prevalence of hypertriglyceridemia in populations with an Amerindian background. Although environmental factors are the triggers, the search for the ethnic related factors that explain the increased susceptibility of the Amerindians is a promising area for research. The study of the genetics of hypertriglyceridemia in Hispanic populations faces several challenges. Ethnicity could be a major confounding variable to prove genetic associations. Despite that, the study of hypertriglyceridemia in Hispanics has resulted in significant contributions. Two GWAS reports have exclusively included Mexican mestizos. Fifty percent of the associations reported in Caucasians could be generalized to the Mexicans, but in many cases the Mexican lead SNP was different than that reported in Europeans. Both reports included new associations with apo B or triglycerides concentrations. The frequency of susceptibility alleles in Mexicans is higher than that found in Europeans for several of the genes with the greatest effect on triglycerides levels. An example is the SNP rs964184 in APOA5. The same trend was observed for ANGPTL3 and TIMD4 variants. In summary, we postulate that the study of the genetic determinants of hypertriglyceridemia in Amerindian populations which have major changes in their lifestyle, may prove to be a great resource to identify new genes and pathways associated with hypertriglyceridemia.
Assuntos
Angiopoietinas/genética , Apolipoproteínas A/genética , Apolipoproteínas B/genética , Interação Gene-Ambiente , Hipertrigliceridemia/etiologia , Proteínas de Membrana/genética , Polimorfismo Genético , Proteína 3 Semelhante a Angiopoietina , Proteínas Semelhantes a Angiopoietina , Angiopoietinas/metabolismo , Apolipoproteína A-V , Apolipoproteínas A/metabolismo , Apolipoproteínas B/metabolismo , Suscetibilidade a Doenças , Predisposição Genética para Doença , Hispânico ou Latino , Humanos , Hiperlipidemia Familiar Combinada/etiologia , Hiperlipidemia Familiar Combinada/genética , Hiperlipidemia Familiar Combinada/metabolismo , Hiperlipoproteinemia Tipo III/etiologia , Hiperlipoproteinemia Tipo III/genética , Hiperlipoproteinemia Tipo III/metabolismo , Hiperlipoproteinemia Tipo IV/etiologia , Hiperlipoproteinemia Tipo IV/genética , Hiperlipoproteinemia Tipo IV/metabolismo , Hipertrigliceridemia/genética , Hipertrigliceridemia/metabolismo , Indígenas Centro-Americanos , Indígenas Norte-Americanos , Proteínas de Membrana/metabolismo , México/etnologia , Herança Multifatorial , Estados UnidosRESUMO
Cancer cell extravasation resembles the leukocyte recruitment during inflammation. Evidence suggests that cancer cells need to weaken the interendothelial junctions in order to cross the endothelial barrier. Several tumor-derived vasoactive compounds have been pointed out to drive this increase in vascular permeability: VEGF, Angptl4, CCL2, SDF-1, etc. Therefore, tumor cells have a wide repertoire of soluble factors to increase vascular permeability in order to colonize new tissues. Tumor soluble factors activate different signaling pathways to induce interendothelial junction disassembly, one common element is Src kinase. Here we summarize the relevant current knowledge about vascular permeability changes involved in tumor metastasis.
Assuntos
Permeabilidade Capilar , Endotélio Vascular/metabolismo , Metástase Neoplásica , Neoplasias/irrigação sanguínea , Migração Transendotelial e Transepitelial , Proteína 4 Semelhante a Angiopoietina , Angiopoietinas/metabolismo , Animais , Movimento Celular , Quimiocina CCL2/metabolismo , Quimiocina CXCL12/metabolismo , Células Endoteliais , Humanos , Junções Intercelulares , Camundongos , Neoplasias/patologia , Neutrófilos/metabolismo , Transdução de Sinais , Fator A de Crescimento do Endotélio Vascular/metabolismoRESUMO
Polycystic ovary syndrome (PCOS) is the most common endocrinological pathology among women of reproductive age. It is characterized by anovulation, oligo- or amenorrhea, hyperandrogenism, obesity, and insulin resistance. PCOS patients present with elevated levels of vascular endothelial growth factor (VEGF) in serum and follicular fluid. In this study, we examined the ovarian expression of angiopoietins (ANGPT) and their receptor tyrosine kinase receptor (TIE2), involved in the stabilization of blood vessels, in a rat model of dehydroepiandrosterone-induced PCOS. We also analyzed the effect of ovarian VEGF inhibition on ANGPT/TIE2, follicular development, and vascular stability. VEGF levels were increased in the PCOS ovaries, whereas the levels of its receptor fetal liver kinase-1 were decreased. In addition, the periendothelial cell area and the ANGPT1 to ANGPT2 ratio in the ovary were increased in the PCOS group. Percentage of primary follicles was increased and the percentage of preantral follicles and corpora lutea was decreased in the PCOS group. VEGF inhibition decreased the percentage of primary follicles close to control values. Interestingly, despite the presence of cysts in the ovaries from VEGF inhibitor-treated PCOS rats, its percentage was lower than the PCOS group without treatment. In summary, this study describes an alteration not only in the VEGF/fetal liver kinase-1 system but also in the ANGPT/TIE2 system in a dehydroepiandrosterone-induced PCOS rat model. This leads to an increase in periendothelial cell recruitment. We also demonstrated that ovarian VEGF inhibition can partially restore the accumulation of small follicles in PCOS rats and reduces cyst formation, improving ovulation and follicular development. Therefore, the inhibition of VEGF could be considered, in addition to other currently applied treatments, as a new strategy to be studied in PCOS patients to restore ovarian function.