RESUMO
The pathogenesis of recurrent acute tonsillitis (Rtn) is to be further investigated. Polymorphonuclear neutrophils (PMN) often associate with the pathogenesis of acute and chronic inflammation. This study aims to identify the antigen-specific PMNs (sPMNs) isolated from the tonsillar tissues with recurrent acute inflammation. In this study, CD66b+ PMNs were isolated from surgically removed tonsils (40 tonsils were from 20 Rtn patients; 24 tonsils were from 12 tonsil tumour patients) by flow cytometry cell sorting. sPMNs were identified through immunological approaches. We found that compared with the control tonsil samples (from marginal non-tumour tissues of tonsil cancer), Rtn samples showed higher PMN frequency, higher levels of myeloperoxidase (MPO) and neutrophil elastase (NE), in which positive correlation was detected between the inflammatory scores in the Rtn tissues and PMN counts (r = .7352; p = .0002), or MPO (r = .6565, p = .0017), or NE (r = .6687, p = .0013). Upon exposure to tonsillar tissue protein extracts in the culture, a portion of Rtn PMNs was activated and released inflammatory mediators. A complex of tonsillar tissue-specific IgG and FcγRI was observed on the surface of Rtn PMNs; these PMNs could specifically recognize the Rtn tissue extracts and were designated the tonsillar antigen-specific PMNs (sPMNs). A signal transduction pathway of mitogen-activated protein kinase (MAPK)-nuclear factor of T cell activation (NFAT) was activated in sPMNs after exposure to Rtn tissue extracts. In summary, a fraction of sPMN in the Rtn tonsillar tissues was identified and characterized. The sPMNs can be activated upon exposure to tonsil-specific antigens. These sPMNs may contribute to the Rtn pathogenesis.
Assuntos
Antígenos/imunologia , Neutrófilos/imunologia , Tonsila Palatina/imunologia , Tonsilite/imunologia , Adolescente , Adulto , Idoso , Animais , Extratos Celulares/imunologia , Medicamentos de Ervas Chinesas/farmacologia , Feminino , Humanos , Mediadores da Inflamação/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Pessoa de Meia-Idade , Neutrófilos/efeitos dos fármacos , Tonsila Palatina/efeitos dos fármacos , Peroxidase/metabolismo , Receptores de IgG/imunologia , Recidiva , Adulto JovemRESUMO
The immune dysregulation plays an important role in the pathogenesis of ulcerative colitis (UC). Bcl2 like protein-12 (Bcl2L12) and mast cells are involved in immune dysregulation of UC. This study aims to elucidate the role of Bcl2L12 in the contribution to the pathogenesis of T helper (Th)2-biased inflammation in UC patients. The results showed that Bcl2L12 was expressed by peripheral CD4+ T cells that was associated with Th2 polarization in UC patients. Bcl2L12 mediated the protease-activated receptor-2 (PAR2)-induced IL-4 expression in CD4+ cells. Activation of PAR2 increased expression of Bcl2L12 in CD4+ T cells. Bcl2L12 mRNA decayed spontaneously in CD4+ T cells after separated from UC patients which was prevented by activating PAR2. Bcl2L12 mediated the binding between GATA3 and the Il4 promoter in CD4+ T cells. Mice with Bcl2L12 deficiency failed to induce Th2-biased inflammation in the colon mucosa. We conclude that CD4+ T cells from UC patients expressed high levels of Bcl2L12; the latter plays an important role in the development of Th2-biased inflammation in the intestine. Bcl2L12 may be a novel therapeutic target in the treatment of Th2-biased inflammation.
Assuntos
Colite Ulcerativa/etiologia , Proteínas Musculares/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Células Th2/metabolismo , Adulto , Animais , Linfócitos T CD4-Positivos/metabolismo , Colo/metabolismo , Citocinas/metabolismo , Feminino , Fator de Transcrição GATA3/metabolismo , Humanos , Inflamação/metabolismo , Mucosa Intestinal/metabolismo , Masculino , Camundongos Endogâmicos BALB C , Camundongos Knockout , Proteínas Musculares/genética , Regiões Promotoras Genéticas , Proteínas Proto-Oncogênicas c-bcl-2/genética , Receptor PAR-2RESUMO
The Th2-biased inflammation and immune deregulation play a critical role in the pathogenesis of ulcerative colitis (UC). Recent studies indicate that the Bcl2-like protein 12 (Bcl2L12) is associated with immune deregulation of UC. This study aims to investigate the role of Bcl2L12 in the induction of aberrant Th2-biased inflammation. In this study, peripheral blood samples were collected from patients with inflammatory bowel disease. The Th2 cell activities were analyzed by flow cytometry, real-time quantitative RT-PCR, and Western blotting. Mice with Bcl2L12-knockout CD4+ T cells were used in the experiments. The results showed that the expression of Bcl2L12 was detected in peripheral CD4+ T cells, which was significantly higher in UC patients than in healthy subjects. A positive correlation between the expression of Bcl2L12 and Th2 cytokines was detected in CD4+ T cells from UC patients. Naive CD4+ T cells with Bcl2L12 overexpression were prone to differentiate into Th2 cells. Mice with Bcl2L12 deficiency failed to induce the Th2-biased inflammation in the intestine. Bcl2L12 bound GATA3 to form a complex to enhance the binding between GATA3 and the Il4 promoter to enhance the expression of IL-4 in CD4+ T cells. CD4+ T cells with Bcl2L12 overexpression were resistant to apoptosis. In conclusion, the Bcl2L12 is a critical factor in the induction of aberrant Th2 polarization by upregulating Th2 responses and downregulating Th2 cell apoptosis. Bcl2L12 may be a novel therapeutic target in the management of the disorders with Th2-biased inflammation.
Assuntos
Inflamação/imunologia , Doenças Inflamatórias Intestinais/imunologia , Mucosa Intestinal/imunologia , Proteínas Musculares/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Células Th2/imunologia , Adulto , Animais , Células Cultivadas , Citocinas/metabolismo , Feminino , Humanos , Ativação Linfocitária , Masculino , Camundongos , Camundongos Endogâmicos BALB C , RNA Interferente Pequeno/genética , Adulto JovemRESUMO
BACKGROUND/AIMS: Salvianolic acid B (Sal B), a major polyphenolic compound of Salvia miltiorrhiza Bunge, has been shown to possess potential antidiabetic activities. However, the action mechanism of SalB in type 2 diabetes has not been investigated extensively. The present study was designed to investigate the effects of Sal B on diabetes-related metabolic changes in a spontaneous model of type 2 diabetes, as well as its potential molecular mechanism. METHODS: Male C57BL/KsJ-db/db mice were orally treated with Sal B (50 and 100 mg/kg) or metformin (positive drug, 300 mg/kg) for 6 weeks. RESULTS: Both doses of Sal B significantly decreased fasting blood glucose, serum insulin, triglyceride and free fatty acid levels, reduced hepatic gluconeogenic gene expression and improved insulin intolerance in db/db mice. High dose Sal B also significantly improved glucose intolerance, increased hepatic glycolytic gene expression and muscle glycogen content, and ameliorated histopathological alterations of pancreas, similar to metformin. Sal B treatment resulted in increased phosphorylated AMP-activated protein kinase (p-AMPK) protein expression in skeletal muscle and liver, increased glucose transporter 4 (GLUT4) and glycogen synthase protein expressions in skeletal muscle, and increased peroxisome proliferator-activated receptor alpha (PPARα) and phosphorylated acetyl CoA carboxylase (p-ACC) protein expressions in liver. CONCLUSION: Our data suggest that Sal B displays beneficial effects in the prevention and treatment of type 2 diabetes at least in part via modulation of the AMPK pathway.
Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Benzofuranos/uso terapêutico , Dislipidemias/tratamento farmacológico , Hiperglicemia/tratamento farmacológico , Transdução de Sinais , Animais , Benzofuranos/química , Benzofuranos/farmacologia , Peso Corporal/efeitos dos fármacos , Dislipidemias/sangue , Dislipidemias/complicações , Dislipidemias/genética , Regulação da Expressão Gênica/efeitos dos fármacos , Gluconeogênese/efeitos dos fármacos , Glucose/metabolismo , Intolerância à Glucose/sangue , Intolerância à Glucose/complicações , Intolerância à Glucose/tratamento farmacológico , Intolerância à Glucose/genética , Transportador de Glucose Tipo 4/metabolismo , Glicogênio/metabolismo , Glicogênio Sintase/metabolismo , Glicólise/efeitos dos fármacos , Hiperglicemia/sangue , Hiperglicemia/complicações , Hiperglicemia/genética , Hiperinsulinismo/sangue , Hiperinsulinismo/complicações , Hiperinsulinismo/tratamento farmacológico , Lipídeos/sangue , Fígado/efeitos dos fármacos , Fígado/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Músculo Esquelético/efeitos dos fármacos , Músculo Esquelético/enzimologia , PPAR alfa/metabolismo , Pâncreas/efeitos dos fármacos , Pâncreas/patologia , Fosforilação/efeitos dos fármacos , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Transdução de Sinais/efeitos dos fármacosRESUMO
AIM OF THE STUDY: Dietary obesity is usually characterized by leptin resistance and abnormal lipid metabolism. Lithocarpus polystachyus Rehd.(Sweet Tea) leaf is a kind of Chinese folkloric medicine, and it has been widely used for obesity, diabetes, and hypertension in South China. The present study is aimed at investigating the pharmacological mechanism of the anti-hyperleptinaemia effects of Sweet Tea leaves extract in high fat diet-induced obese rats. MATERIALS AND METHODS: We induced high fat diet obesity for 14 weeks to test the corrective effects of three ST doses (75, 150 and 300 mg/kg per day) for 8 weeks. At the end of the experiment, body weight, fasting blood glucose and serum lipids, superoxide dismutase (SOD), malondialdehyde (MDA), fasting serum insulin and leptin, C-reactive protein, adiponectin and resistin levels were measured, Homeostasis Model Assessment for Insulin Resistance (HOMA-IR) was also calculated. mRNA gene expression of PPARγ (peroxisome proliferator-activated receptor γ) and C/EBPα(CCAAT/enhancer-binding protein α) in epididymal adipose tissue of DIO control and experimental groups were evaluated. RESULTS: Sweet Tea leaves extract could significantly decrease the levels of serum lipids, attenuate body weight gain and lower circulating leptin and insulin levels, ameliorate the state of oxidative stress, raise serum adiponectin, reduce circulating CRP and resistin levels, and depress the expression of PPARγ and C/EBPα in epididymal adipose tissue of obese rats. CONCLUSION: The present findings suggest that ST can effectively attenuate the leptin resistance at least through anti-hyperlipidemic activity and thus has the therapeutic potential in treating hyperlipidemia and hyperleptinaemia related to dietary obesity.