RESUMO
BACKGROUNDS: In inflammatory bowel disease microenvironment, transdifferentiation of myeloid-derived suppressor cells (MDSCs) and M2 macrophage accumulation are crucial for the transition of colitis-to-cancer. New insights into the cross-talk and the underling mechanism between MDSCs and M2 macrophage during colitis-to-cancer transition are opening new avenues for colitis-associated cancer (CAC) prevention and treatment. METHODS: The role and underlying mechanism that granulocytic MDSCs (G-MDSCs) or exosomes (Exo) regulates the differentiation of monocytic MDSCs (M-MDSCs) into M2 macrophages were investigated using immunoï¬uorescence, FACS, IB analysis, etc, and employing siRNA and antibodies. In vivo efficacy and mechanistic studies were conducted with dextran sulfate sodium-induced CAC mice, employed IL-6 Abs and STAT3 inhibitor. RESULTS: G-MDSCs promote the differentiation of M-MDSC into M2 macrophages through exosomal miR-93-5 p which downregulating STAT3 activity in M-MDSC. IL-6 is responsible for miR-93-5 p enrichment in G-MDSC exosomes (GM-Exo). Mechanistically, chronic inflammation-driven IL-6 promote the synthesis of miR-93-5 p in G-MDSC via IL-6R/JAK/STAT3 pathway. Early use of IL-6 Abs enhances the effect of STAT3 inhibitor against CAC. CONCLUSIONS: IL-6-driven secretion of G-MDSC exosomal miR-93-5 p promotes the differentiation of M-MDSC into M2 macrophages and involves a STAT3 signaling mechanism that promote colitis-to-cancer transition. Combining STAT3 inhibitors with strategies that inhibit IL-6-mediated G-MDSC exosomal miR-93-5 p production is beneficial for the prevention and treatment of CAC.
Assuntos
Colite , Exossomos , MicroRNAs , Células Supressoras Mieloides , Neoplasias , Animais , Camundongos , Exossomos/metabolismo , Interleucina-6/metabolismo , Neoplasias/metabolismo , Macrófagos/metabolismo , Diferenciação Celular , MicroRNAs/genética , MicroRNAs/metabolismo , Microambiente TumoralRESUMO
Insulin-like growth factor-1 (IGF-1) is a growth factor of the thyroid that has been shown in our previous study to possess proliferative and antiapoptotic effects in FRTL-5 cell lines through the upregulation of cyclin D and Fas-associated death domain-like interleukin-1-converting enzyme (FLICE)-inhibitory protein (FLIP). Diosgenin, a natural steroid sapogenin from plants, has been shown to induce apoptosis in many cell lines, with the exception of thyroid cells. In this report, we investigated the apoptotic effect and mechanism of diosgenin in IGF-1-stimulated primary human thyrocytes. Primary human thyrocytes were preincubated with or without IGF-1 for 24h and subsequently exposed to varying concentrations of diosgenin for different times. We found that diosgenin induced apoptosis in human thyrocytes pretreated with IGF-1 in a dose-dependent manner through the activation of caspase cascades. Moreover, diosgenin inhibited FLIP and activated caspase-8 in the FAS-related apoptotic pathway. Diosgenin increased the production of ROS, regulated the balance of Bax and Bcl-2 and cleaved caspase-9 in the mitochondrial apoptotic pathway. These results indicate that diosgenin induces apoptosis in IGF-1-stimulated primary human thyrocytes through two caspase-dependent pathways.
Assuntos
Apoptose/efeitos dos fármacos , Caspases/biossíntese , Diosgenina/farmacologia , Fator de Crescimento Insulin-Like I/farmacologia , Glândula Tireoide/efeitos dos fármacos , Benzimidazóis/química , Proteína Reguladora de Apoptosis Semelhante a CASP8 e FADD/biossíntese , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Corantes Fluorescentes/química , Humanos , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Coloração e Rotulagem , Glândula Tireoide/citologia , Glândula Tireoide/enzimologia , Proteína X Associada a bcl-2/metabolismoRESUMO
The different effects of ethanol on insulin sensitivity may be due to complex reasons. Here, we focus on the various daily ethanol consumption frequencies in rats fed a high-fat (HF) diet and explore the possible mechanism mediated by adiponectin and AMP-activated protein kinase (AMPK). A total of thirty-six male Wistar rats were fed a HF diet and were randomly divided into three groups: those that received tap water (C); those that received ethanol via a gastric tube twice per d (E1); those that received free access to ethanol for drinking (E2). The total daily ethanol dosage in groups E1 and E2 were the same (5 g/kg per d). At the end of 18 weeks, insulin sensitivity was evaluated. Adiponectin AMPK and GLUT4 levels were determined. We found that the different administration frequencies led to markedly different plasma ethanol concentrations and there were intimate relationships between plasma ethanol concentration and insulin sensitivity. Insulin resistance was markedly improved in group E1, whereas only a slight improvement was observed in group E2. Accordingly, adiponectin, phosphorylated AMPK and GLUT4 levels were significantly increased in group E1. Based on these findings, we propose that ethanol concentration might be the major influencing factor mediating the effect of ethanol on insulin sensitivity. At a total daily dosage of 5 g/kg per d, twice daily administration of ethanol was more beneficial than continuous drinking. The protective effect of ethanol might be mediated by increased adiponectin levels, which subsequently improve the activation of AMPKα and GLUT4 expression in adipose tissue.
Assuntos
Alcoolismo/metabolismo , Dieta Hiperlipídica/efeitos adversos , Resistência à Insulina , Proteínas Quinases Ativadas por AMP/genética , Proteínas Quinases Ativadas por AMP/metabolismo , Adiponectina/sangue , Adiponectina/metabolismo , Tecido Adiposo Branco/metabolismo , Alcoolismo/sangue , Animais , Etanol/administração & dosagem , Etanol/sangue , Regulação Enzimológica da Expressão Gênica , Transportador de Glucose Tipo 4/genética , Transportador de Glucose Tipo 4/metabolismo , Masculino , PPAR gama/genética , PPAR gama/metabolismo , Fosforilação , Processamento de Proteína Pós-Traducional , RNA Mensageiro/metabolismo , Distribuição Aleatória , Ratos , Ratos Wistar , Fatores de TempoRESUMO
Farnesoid X receptor (FXR) has been considered as a promising target for nonalcoholic steatohepatitis (NASH), while existing FXR agonists suffer from serious side effects. Thus, it is very necessary to identify novel FXR agonists with good safety. Auraptene (AUR) is a new FXR agonist with excellent safety and extensive pharmacological activities, while the lactone of AUR is vulnerable to esterolysis. In this study, the lactone of AUR was converted to metabolically stable amide moiety, and the obtained analog SU5 revealed comparable activity and better metabolic stability than that of AUR. In NASH model, SU5 showed stronger efficacy than AUR on fatty liver by upregulating gene expressions related to FXR in vivo. Moreover, SU5 improved lipid metabolism by downregulating the gene expressions of lipid synthesis, while upregulating the gene expressions of fatty acid ß-oxidation and triglyceride metabolism. Besides, the inflammation-related genes were significantly decreased in SU5-treated group. These positive results highlighted the pharmacological potential of SU5 for the treatment of NASH.
Assuntos
Cumarínicos/uso terapêutico , Dieta , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Animais , Colina/metabolismo , Cumarínicos/química , Cumarínicos/metabolismo , Cumarínicos/farmacologia , Dieta/veterinária , Modelos Animais de Doenças , Regulação para Baixo/efeitos dos fármacos , Meia-Vida , Humanos , Metabolismo dos Lipídeos/efeitos dos fármacos , Metabolismo dos Lipídeos/genética , Fígado/efeitos dos fármacos , Fígado/metabolismo , Fígado/patologia , Metionina/metabolismo , Camundongos , Camundongos Obesos , Hepatopatia Gordurosa não Alcoólica/patologia , Ratos , Receptores Citoplasmáticos e Nucleares/agonistas , Receptores Citoplasmáticos e Nucleares/genética , Receptores Citoplasmáticos e Nucleares/metabolismo , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/metabolismo , Regulação para Cima/efeitos dos fármacosRESUMO
Loss of pancreatic ß cells is involved in pathogenesis of gestational diabetes mellitus (GDM). Recently, several studies have elucidated the connection between microRNAs (miRNAs) and diabetes mellitus (DM), but the role of miRNAs in GDM remains unclear. The aim of this study was to evaluate the potential functions of miRNAs in GDM and to investigate the underlying mechanisms of action. First, we explored the expression profile of miRNAs in placenta tissue from GDM patients using microarray. Validation analysis was performed in peripheral blood specimens using quantitative reverse transcription PCR (qRT-PCR). Then the role and regulating mechanism of miR-503 in weaken the function of pancreatic ß cell was investigated. We found that miR-503 was markedly upregulated in placenta tissue from GDM patients, as elevated in peripheral blood specimens, and the high level was positively correlated to blood glucose concentration. Knockdown of miR-503 enhanced insulin secretion of pancreatic ß-cells, promoted cell proliferation and protected cells from apoptosis, whereas overexpression of miR-503 showed the opposite effects. Furthermore, mammalian target of rapamycin (mTOR) was identified as a direct target of miR-503 and mTOR silencing could reverse the improving effects of miR-503 knockdown on insulin secretion and pancreatic ß-cells proliferation. High expression of miR-503 in peripheral blood may be acted as a diagnosis biomarker of GDM. MiR-503 regulated functions of pancreatic ß-cells by targeting the mTOR pathway, suggesting that targeting miR-503/mTOR axis could serve as a novel therapeutic target for GDM.
RESUMO
Others and our previous studies showed that the increase of IGF-1 was involved in the formation of goiter. Our aim here was to evaluate the possible effects of diosgenin on cell proliferation induced by IGF-1 in primary human thyroid cells. The cells were treated with or without different concentrations of diosgenin in the present or absent of IGF-1 for 24, 48 and 72 h, respectively. Cell viability was determined by MTT, and cell proliferation was tested by EdU assay, and cell cycle analysis was performed by FACS. In addition, Cyclin D1 and B1 protein expression was tested by Western Blotting, respectively. We found that IGF-1 promoted cell cycle progression to S phase and increased the primary human thyroid cells proliferation. Diosgenin decreased the protein expression of cyclin D1 and resulted in cell G(0)/G(1) arrest. Importantly, when the human thyrocytes were exposed to diosgenin in the present of IGF-1, the IGF-1 inducing proliferation was significantly decreased and the proportion of the cells in G(0)/G(1) phase was increased, while that of S phase was decreased. This study shows that diosgenin inhibited cell proliferation, caused G(0)/G(1) arrest, and could inhibit cell proliferation induced by IGF-1 in primary human thyroid cells.