RESUMO
Retinoic acid-inducible gene I (RIG-I) and melanoma differentiation-associated protein 5 (MDA5) sense viral RNA and activate antiviral immune responses. Herein we investigate their functions in human epithelial cells, the primary and initial target of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). A deficiency in MDA5, RIG-I or mitochondrial antiviral signaling protein (MAVS) enhanced viral replication. The expression of the type I/III interferon (IFN) during infection was impaired in MDA5-/- and MAVS-/-, but not in RIG-I-/-, when compared to wild type (WT) cells. The mRNA level of full-length angiotensin-converting enzyme 2 (ACE2), the cellular entry receptor for SARS-CoV-2, was ~ 2.5-fold higher in RIG-I-/- than WT cells. These data demonstrate MDA5 as the predominant SARS-CoV-2 sensor, IFN-independent induction of ACE2 and anti-SARS-CoV-2 role of RIG-I in epithelial cells.
Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , COVID-19/imunologia , Proteína DEAD-box 58/metabolismo , Helicase IFIH1 Induzida por Interferon/metabolismo , Receptores Imunológicos/metabolismo , SARS-CoV-2/fisiologia , Proteínas Adaptadoras de Transdução de Sinal/genética , Enzima de Conversão de Angiotensina 2/metabolismo , Linhagem Celular , Proteína DEAD-box 58/genética , Humanos , Interferon Tipo I/metabolismo , Helicase IFIH1 Induzida por Interferon/genética , Interferons/metabolismo , Receptores Imunológicos/genética , Transdução de Sinais , Replicação Viral , Interferon lambdaRESUMO
AIMS: High glucose (HG)-induced pancreatic ß-cell apoptosis may be a major contributor to the progression of diabetes mellitus (DM). NADPH oxidase (NOX2) has been considered a crucial regulator in ß-cell apoptosis. This study was designed to evaluate the impact of GLP-1 receptor agonist (GLP-1Ra) liraglutide on pancreatic ß-cell apoptosis in diabetes and the underlying mechanisms involved. METHODS: The diabetic rat models induced by streptozotocin (STZ) and a high fat diet (HFD) received 12â¯weeks of liraglutide treatment. Hyperglycemic clamp test was carried out to evaluate ß-cell function in vivo. Flow cytometry analysis was used to measure apoptosis rates in vitro. DCFH-DA method was used to detected ROS level in vivo and in vitro. RESULTS: Liraglutide significantly improved islet function and morphology in diabetic rats and decreased cell apoptosis rates. Thr183/Thr185 p-JNK1/2 and NOX2 levels reduced in diabetic rats and HG-induced INS-1 cell following liraglutide treatment. In addition, liraglutide upregulated the phosphorylation of AMPKα (p-AMPKα), which prevented NOX2 activation and alleviated HG-induced ß-cell apoptosis. CONCLUSION: The p-AMPKα/NOX2/JNK1/2 pathway is essential for liraglutide to attenuate HG-induced ß-cell apoptosis, which further proves that GLP-1Ras may become promising therapeutics for diabetes mellitus.
Assuntos
Apoptose/efeitos dos fármacos , Diabetes Mellitus Experimental/patologia , Células Secretoras de Insulina/efeitos dos fármacos , Liraglutida/farmacologia , NADPH Oxidase 2/metabolismo , Animais , Células Cultivadas , Citoproteção/efeitos dos fármacos , Diabetes Mellitus Experimental/induzido quimicamente , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Experimental/metabolismo , Regulação para Baixo/efeitos dos fármacos , Células Secretoras de Insulina/fisiologia , Liraglutida/uso terapêutico , Masculino , Camundongos , Ratos , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacos , EstreptozocinaRESUMO
OBJECTIVES: The aim of this study was to determine the effect of obesity, gestational diabetes mellitus (GDM) on circulating chemerin concentrations and chemerin gene expression of adipotissue in pregnancy women. MATERIAL AND METHODS: Totally 42 normal glucose tolerant (NGT) women and 48 women with GDM were included in this study. Their clinical features and biochemical parameters were analyzed. The NGT and GDM women were subgrouped by prepregnancy BMI as normal-weight group, overweight group, and obese group, respectively. Serum chemerin and tumor necrosis factor α (TNF-α) of these individuals were determined by ELISA methods, and subcutaneous adipose tissues' mRNA expressions of chemerin and CMKLR1 (encoding the receptor of chemerin) were analyzed by real-time PCR. RESULTS: Serum chemerin in obese-NGT group and normal-weight-GDM group was significantly higher than that of normal-weight-NGT group. Chemerin and CMKLR1 mRNA expression of subcutaneous adipose tissue was lower in the obese-NGT group than normal-weight-NGT group. There was no significant difference of CMKLR1 mRNA expression between normal-weight-NGT and normal-weight-GDM group. Serum chemerin significantly and positively correlated with triglycerides (TG) and homeostasis model assessment of insulin resistance (HOMA-IR) assessed both by uni- and multivariate. CONCLUSIONS: Gestational obesity, GDM may contribute to the elevating serum chemerin. Serum chemerin in pregnancy was associated with insulin resistance and triglycerides. Chemerin gene may play a role both in obese and GDM patients. CMKLR1 might exert its action only in obese individuals, not in GDM patients before delivery.