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OBJECTIVE: Placenta-derived inflammation plays a vital role in the pathophysiology of gestational diabetes mellitus (GDM). IL-32 is a novel pro-inflammatory cytokine and metabolic regulator involved in the development of metabolic disease. We investigated the effect of IL-32 in GDM. MATERIALS AND METHODS: First-trimester C-reactive protein (CRP) level was monitored in a case-control study of 186 women with GDM and 186 women without. Placental tissue was lysed and analyzed by high-resolution liquid chromatography-tandem mass spectrometry. Circulating level of inflammatory cytokines IL-32, IL-6, and TNF-α were measured by ELISA kits. The expression of placenta-derived macrophages, inflammatory cytokines, and related pathway proteins were assessed by reverse transcriptase-quantitative PCR, western blot, immunohistochemistry, or immunofluorescence. RESULTS: First-trimester CRP level in peripheral blood was closely associated with glucose and insulin resistance index and was an independent correlation with the development of GDM. High-resolution liquid chromatography-tandem mass spectrometry revealed that placenta-derived CRP expression was dramatically elevated in women with GDM. Interestingly, the expression of placenta-derived IL-32 was also increased and located in the macrophages of placental tissue. Meanwhile, the expression of IL-6, TNF-α, and p-p38 were up-regulated in the placental tissues with GDM. Either IL-6 or TNF-α was colocated with IL-32 in the placental tissue. Importantly, circulating IL-32 throughout pregnancy was increased in GDM and was related to placental-derived IL-32 expression, circulating IL-6, and TNF-α, glucose and insulin resistance index. CONCLUSION: Increased circulating IL-32 throughout pregnancy was closely associated with placenta macrophage-derived IL-32 expression and GDM. First trimester IL-32 level in peripheral blood may serve to predict the development of GDM.
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Diabetes Gestacional , Resistência à Insulina , Gravidez , Feminino , Humanos , Interleucina-6/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Estudos de Casos e Controles , Placenta/metabolismo , Citocinas , Insulina , GlucoseRESUMO
Breast cancer (BC) is the most common type of cancer among females. Peroxisome proliferator-activated receptor gamma (PPARG) can regulate the production of adipocyte-related genes and has anti-inflammatory and anti-tumor effects. Our aim was to investigate PPARG expression, its possible prognostic value, and its effect on immune cell infiltration in BC, and explore the regulatory effects of natural drugs on PPARG to find new ways to treat BC. Using different bioinformatics tools, we extracted and comprehensively analyzed the data from the Cancer Genome Atlas, Genotype-Tissue Expression, and BenCaoZuJian databases to study the potential anti-BC mechanism of PPARG and potential natural drugs targeting it. First, we found that PPARG was downregulated in BC and its expression level correlates with pathological tumor stage (pT-stage) and pathological tumor-node-metastasis stage (pTNM-stage) in BC. PPARG expression was higher in estrogen receptor-positive (ER+) BC than in estrogen receptor-negative (ER-) BC, which tends to indicate a better prognosis. Meanwhile, PPARG exhibited a significant positive correlation with the infiltration of immune cells and correlated with better cumulative survival in BC patients. In addition, PPARG levels were shown to be positively associated with the expression of immune-related genes and immune checkpoints, and ER+ patients had better responses to immune checkpoint blocking. Correlation pathway research revealed that PPARG is strongly associated with pathways, such as angiogenesis, apoptosis, fatty acid biosynthesis, and degradation in ER+ BC. We also found that quercetin is the most promising natural anti-BC drug among natural medicines that upregulate PPARG. Our research showed that PPARG may reduce BC development by regulating the immune microenvironment. Quercetin as PPARG ligands/agonists is a potential natural drug for BC treatment.
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CONTEXT: The immune system plays a central role in the pathophysiology of gestational diabetes mellitus (GDM). Monocytes, the main innate immune cells, are especially important in the maintenance of a normal pregnancy. OBJECTIVE: Here, we investigated the potential effect of monocytes in GDM. METHODS: Monocyte count was monitored throughout pregnancy in 214 women with GDM and 926 women without in a case-control and cohort study. Circulating levels of inflammatory cytokines, placenta-derived macrophages, and their products were measured. RESULTS: Throughout pregnancy, monocyte count was significantly decreased in women with GDM, and was closely associated with glucose level, insulin resistance, and newborn weight. First-trimester monocyte count outperformed that of the second and third trimester as a risk factor and diagnostic predictor of GDM and macrosomia both in the case-control and cohort study. In addition, our cohort study showed that as first-trimester monocyte count decreased, GDM and macrosomia incidence, glucose level, and newborn weight increased in a stepwise manner. Risk of GDM started to decrease rapidly when first-trimester monocyte count exceeded 0.48â ×â 109/L. Notably, CD206 and interleukin 10 (IL-10) were significantly lower, whereas CD80, CD86, tumor necrosis factor α (TNF-α), and interleukin 6 (IL-6) were higher both in GDM placental tissue and peripheral blood. First-trimester monocyte count was positively related to IL-10 and CD206, but negatively related to CD80, CD86, TNF-α, and IL-6. CONCLUSION: Decreased monocyte count throughout pregnancy was closely associated with the development of GDM, macrosomia, and the chronic inflammatory state of GDM. First-trimester monocyte count has great potential as an early diagnostic marker of GDM.
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Diabetes Gestacional/epidemiologia , Macrossomia Fetal/epidemiologia , Monócitos/imunologia , Adulto , Peso ao Nascer/imunologia , Glicemia/análise , Estudos de Casos e Controles , Diabetes Gestacional/sangue , Diabetes Gestacional/diagnóstico , Diabetes Gestacional/imunologia , Feminino , Macrossomia Fetal/imunologia , Humanos , Incidência , Recém-Nascido , Inflamação/sangue , Inflamação/epidemiologia , Inflamação/imunologia , Contagem de Leucócitos , Gravidez , Primeiro Trimestre da Gravidez/sangue , Medição de Risco/métodos , Fatores de Risco , Adulto JovemRESUMO
Invasive nonfunctioning pituitary adenomas (NFPAs) grow rapidly and the mechanisms are unclear. Among many complex mechanisms, the role of immunity in the development of NFPAs has not been fully explored. Here, we analyzed the clinical features 146 NFPA patients who underwent trans-sphenoidal surgery or craniotomy and examined the effects of immune tolerance in invasiveness of NFPA patients using fluorescence-activated cell sorting and immunohistochemical methods. We found patients with invasive NFPAs had more visual deficits and defective fields, higher tumor size, and lower white blood cell count compared with patients with noninvasive NFPAs. Additionally, compared with patients with noninvasive NFPAs, patients with invasive NFPAs had conspicuously lower CD3-CD56+ natural killer (NK) cells and significantly higher levels of CD3+CD8+CD28-T cells (CD8+ Tregs) and interleukin-10 (IL-10) in peripheral blood. Moreover, patients with invasive NFPAs had lower infiltrated CD56+ cells, less infiltrated CD28+ cells, and significantly greater IL-10 expression. These results demonstrated that low CD56+ cells infiltration and CD28+ cells infiltration, as well as high IL-10 expression in pituitary tumor tissues, were related with increased invasiveness of NFPAs. Levels of CD3-CD56+ NK cells, CD8+ Tregs and IL-10 in the peripheral blood could be feasible diagnostic markers for invasive NFPAs.
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Adenoma/patologia , Antígeno CD56/metabolismo , Linfócitos T CD8-Positivos/imunologia , Interleucina-10/metabolismo , Células Matadoras Naturais/imunologia , Neoplasias Hipofisárias/patologia , Linfócitos T Reguladores/imunologia , Adenoma/imunologia , Adenoma/metabolismo , Adenoma/cirurgia , Biomarcadores Tumorais/análise , Estudos de Casos e Controles , Craniotomia , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Invasividade Neoplásica , Neoplasias Hipofisárias/imunologia , Neoplasias Hipofisárias/metabolismo , Neoplasias Hipofisárias/cirurgia , PrognósticoRESUMO
Objective: Nanocapsules play a role in the targeted delivery of chemotherapy drugs. However, the traditional technology for preparation of nanocapsules is relatively complex with poor controllability, leading to large differences batch to batch. This study aimed to evaluate the quality of drugs-loaded nanocapsules (Drugs-NCs) fabricated by coaxial capillary microfluidic device, and inhibitory effect on malignant tumors. Materials and Methods: In this study, oxaliplatin, irinotecan, and 5-fluorouracil were selected as chemotherapy drugs, and Drugs-NCs were prepared by coaxial glass capillary microfluidic device. Next, transmission electron microscope was utilized to characterize surface morphology and particle size distribution of Drugs-NCs. Then, high performance liquid chromatography was used to determine the drug loading and encapsulation efficiency. Dialysis method was performed to measure the drug release of Drugs-NCs in vitro. To study the effects of Drugs + NCs on tumor growth in vivo, BALB/c (nu/nu) nude mice were used in vivo experiments. Results: The Drugs-NCs were spherical and uniform in size (103.4 nm). Besides, the encapsulation efficiencies of oxaliplatin, irinotecan, and 5-fluorouracil were 97.0%, 95.7%, and 15.6%, respectively. Moreover, drugs encapsulated in the nanocapsules released less and was pH-dependent, with more rapid release being observed at pH 5.5 group compared with pH 7.4 group. MTT assay and in vivo experiments indicated the inhibitory effect of Drugs-NCs on malignant tumors. Conclusion: The prepared nanocapsules had potential tumor targeting. Furthermore, coaxial capillary microfluidic device could be used as a promising microfluidic technology to fabricate multiple Drug-NCs.
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Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Portadores de Fármacos/química , Composição de Medicamentos/instrumentação , Dispositivos Lab-On-A-Chip , Neoplasias/tratamento farmacológico , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Plásticos Biodegradáveis/química , Linhagem Celular Tumoral , Composição de Medicamentos/métodos , Liberação Controlada de Fármacos , Fluoruracila/administração & dosagem , Fluoruracila/farmacocinética , Humanos , Irinotecano/administração & dosagem , Irinotecano/farmacocinética , Masculino , Camundongos , Nanocápsulas/química , Neoplasias/patologia , Oxaliplatina/administração & dosagem , Oxaliplatina/farmacocinética , Tamanho da Partícula , Polímeros/química , Reprodutibilidade dos Testes , Propriedades de Superfície , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Atorvastatin is a substrate of cytochrome P450 3a (CYP3a), organic anion-transporting polypeptides (OATPs), breast cancer-resistance protein (BCRP), and P-glycoprotein (P-gp). We aimed to develop a semiphysiologically based pharmacokinetic (semi-PBPK) model involving both enzyme and transporters for predicting the contributions of altered function and expression of CYP3a and transporters to atorvastatin transport in diabetic rats by combining high-fat diet feeding and low-dose streptozotocin injection. Atorvastatin metabolism and transport parameters comes from in situ intestinal perfusion, primary hepatocytes, and intestinal or hepatic microsomes. We estimated the expressions and functions of these proteins and their contributions. Diabetes increased the expression of hepatic CYP3a, OATP1b2, and P-gp but decreased the expression of intestinal CYP3a, OATP1a5, and P-gp. The expression and function of intestinal BCRP were significantly decreased in 10-day diabetic rats but increased in 22-day diabetic rats. Based on alterations in CYP3a and transporters by diabetes, the developed semi-PBPK model was successfully used to predict atorvastatin pharmacokinetics after oral and intravenous doses to rats. Contributions to oral atorvastatin PK were intestinal OATP1a5 < intestinal P-gp < intestinal CYP3a < hepatic CYP3a < hepatic OATP1b2 < intestinal BRCP. Contributions of decreased expression and function of intestinal CYP3a and P-gp by diabetes to oral atorvastatin plasma exposure were almost attenuated by increased expression and function of hepatic CYP3a and OATP1b2. Opposite alterations in oral plasma atorvastatin exposure in 10- and 22-day diabetic rats may be explained by altered intestinal BCRP. In conclusion, the altered atorvastatin pharmacokinetics by diabetes was the synergistic effects of altered intestinal or hepatic CYP3a and transporters and could be predicted using the developed semi-PBPK.
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Atorvastatina/farmacocinética , Diabetes Mellitus Experimental/metabolismo , Hipercolesterolemia/tratamento farmacológico , Modelos Biológicos , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/metabolismo , Animais , Atorvastatina/uso terapêutico , Células Cultivadas , Citocromo P-450 CYP3A/metabolismo , Diabetes Mellitus Experimental/complicações , Diabetes Mellitus Experimental/etiologia , Dieta Hiperlipídica/efeitos adversos , Hepatócitos/metabolismo , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacocinética , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Hipercolesterolemia/etiologia , Mucosa Intestinal/metabolismo , Masculino , Microssomos Hepáticos/metabolismo , Cultura Primária de Células , Ratos , Membro 1B3 da Família de Transportadores de Ânion Orgânico Carreador de Soluto/metabolismo , Estreptozocina/toxicidadeRESUMO
BACKGROUND The aim of this study was to evaluate the risk factors of gonadal dysfunction among Chinese women of reproductive age with pituitary adenomas (PAs) after trans-sphenoidal surgery. MATERIAL AND METHODS We retrospectively evaluated 317 women (16-44 years old) who underwent gonadal function and hormone testing before and after trans-sphenoidal surgery for PAs during 2003-2012. Gonadal function was assessed on the basis of menstrual status. RESULTS Three women were excluded because of pre-existing gynecological diseases. Before trans-sphenoidal surgery, 34 (10.7%) women were eugonadal and 283 (89.3%) women had gonadal dysfunction. After trans-sphenoidal surgery, 130/189 (68.7%) women with follow-up menstruation data were eugonadal, and 59/189 (31.2%) women exhibited gonadal dysfunction. In addition, 67.4% women of reproductive age with PAs and gonadal dysfunction were restored by trans-sphenoidal surgery (P<0.01). Postoperative gonadal dysfunction was independently associated with high prolactin level at day 1 after trans-sphenoidal surgery (odds ratio (OR)=1.024; 95% confidence interval (CI)=1.005-1.043; P=0.012) and tumor invasion (OR=5.752; 95%CI=1.618-20.447; P<0.01). Based on the receiver operating characteristic (ROC) curve, prediction of gonadal dysfunction in women of reproductive age after trans-sphenoidal surgery for PAs using prolactin >46.82 µg/L on postoperative day 1 had sensitivity of 88%, specificity of 95%, positive predictive value of 98%, and negative predictive value of 76%, and an area under the ROC curve of 0.701. CONCLUSIONS Gonadal dysfunction is very common in Chinese women of reproductive age with PAs and can be effectively restored by trans-sphenoidal surgery. Prolactin >46.82 µg/L at 1 day after trans-sphenoidal surgery and tumor invasion can predict postoperative gonadal dysfunction in these patients.
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Hormônios Gonadais/análise , Neoplasias Hipofisárias/cirurgia , Prolactina/análise , Osso Esfenoide/cirurgia , Adenoma/cirurgia , Adolescente , Adulto , Biomarcadores , Feminino , Humanos , Microcirurgia/métodos , Razão de Chances , Neoplasias Hipofisárias/metabolismo , Período Pós-Operatório , Prognóstico , Curva ROC , Estudos Retrospectivos , Fatores de Risco , Sensibilidade e Especificidade , Adulto JovemRESUMO
Obesity and insulin resistance are associated with overexpression of retinaldehyde dehydrogenase 1 (RALDH1). We aimed to investigate the roles of hepatic RALDH1 induction in glucose metabolism impairment using mice fed with high-fat-diet (HFD). Mice were fed with HFD for 8 weeks and treated with RALDH inhibitor citral for another 4 weeks. Oral glucose tolerance test (OGTT), pyruvate tolerance test (PTT) and insulin tolerance test were performed. Expressions of phosphoenolpyruvate carboxykinase 1 (PCK1), glucokinase (GCK) and RALDH1 were measured. Therapeutic effects of citral were also documented in diabetic rats. Effects of retinaldehyde on PCK1 and GCK expressions were examined in rat primary hepatocytes and HepG2 cells. The results showed that HFD mice were characterized by hyperlipidaemia and insulin resistance, accompanied by significantly increased RALDH1 activity and expression. Citral (10 and 50 mg/kg) ameliorated HFD-induced hyperlipidaemia and insulin resistance, as demonstrated by the improved fasting glucose, insulin levels and lipid profiles. OGTT and PTT demonstrated that citral reversed HFD-induced glucose disposal impairment and glucose production enhancement. Citral also reversed the increased PCK1 expression and decreased GCK expression by HFD. Citral therapeutic effects were reconfirmed in diabetic rats. In vitro data indicated that retinaldehyde had the strongest PCK1 induction in primary hepatocytes of diabetic rats compared with HFD rats and control rats, in line with the increased RALDH1 expression. Citral reversed the retinaldehyde-induced PCK1 expression in primary rat hepatocytes and HepG2 cells. In conclusion, RALDH1 induction impaired glucose metabolism partly via modulating PCK1 and GCK expressions. Citral improved glucose metabolism through inhibiting RALDH activity.
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Glucose/metabolismo , Hepatócitos , Hiperlipidemias , Insulina/sangue , Isoenzimas , Monoterpenos/farmacologia , Retinal Desidrogenase , Monoterpenos Acíclicos , Família Aldeído Desidrogenase 1 , Animais , Diabetes Mellitus Experimental/etiologia , Diabetes Mellitus Experimental/metabolismo , Dieta Hiperlipídica/métodos , Glucoquinase/metabolismo , Teste de Tolerância a Glucose/métodos , Células Hep G2 , Hepatócitos/efeitos dos fármacos , Hepatócitos/metabolismo , Humanos , Hiperlipidemias/etiologia , Hiperlipidemias/metabolismo , Resistência à Insulina , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Isoenzimas/antagonistas & inibidores , Isoenzimas/metabolismo , Metabolismo dos Lipídeos/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C57BL , Fosfoenolpiruvato Carboxiquinase (GTP)/metabolismo , Ratos , Retinal Desidrogenase/antagonistas & inibidores , Retinal Desidrogenase/metabolismoRESUMO
BACKGROUND: Skeletal myoblast transplantation seems a promising approach for the repair of myocardial infarction (MI). However, the low engraftment efficacy and impaired angiogenic ability limit the clinical efficiency of the myoblasts. Gene engineering with angiogenic growth factors promotes angiogenesis and enhances engraftment of transplanted skeletal myoblasts, leading to improved infarction recovery in myocardial ischemia. The present study evaluated the therapeutic effects of hepatocyte growth factor (HGF) gene-engineered skeletal myoblasts on tissue regeneration and restoration of heart function in a rat MI model. METHODS AND RESULTS: The skeletal myoblasts were isolated, expanded, and transduced with adenovirus carrying the HGF gene (Ad-HGF). Male SD rats underwent ligation of the left anterior descending coronary artery. After 2 weeks, the surviving rats were randomized into four groups and treated with skeletal myoblasts by direct injection into the myocardium. The survival and engraftment of skeletal myoblasts were determined by real-time PCR and in situ hybridization. The cardiac function with hemodynamic index and left ventricular architecture were monitored; The adenovirus-mediated-HGF gene transfection increases the HGF expression and promotes the proliferation of skeletal myoblasts in vitro. Transplantation of HGF-engineered skeletal myoblasts results in reduced infarct size and collagen deposition, increased vessel density, and improved cardiac function in a rat MI model. HGF gene modification also increases the myocardial levels of HGF, VEGF, and Bcl-2 and enhances the survival and engraftment of skeletal myoblasts. CONCLUSIONS: HGF engineering improves the regenerative effect of skeletal myoblasts on MI by enhancing their survival and engraftment ability.
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Transplante de Células , Fator de Crescimento de Hepatócito/genética , Mioblastos Esqueléticos/metabolismo , Mioblastos Esqueléticos/transplante , Isquemia Miocárdica/terapia , Adenoviridae/genética , Animais , Sobrevivência Celular/fisiologia , Colágeno/metabolismo , Modelos Animais de Doenças , Feminino , Fibrose/patologia , Fibrose/fisiopatologia , Fibrose/terapia , Engenharia Genética , Vetores Genéticos , Ventrículos do Coração/patologia , Ventrículos do Coração/fisiopatologia , Hemodinâmica/fisiologia , Fator de Crescimento de Hepatócito/metabolismo , Masculino , Isquemia Miocárdica/patologia , Isquemia Miocárdica/fisiopatologia , Neovascularização Fisiológica/fisiologia , Distribuição Aleatória , Ratos Sprague-Dawley , Recuperação de Função Fisiológica/fisiologia , Regeneração/fisiologiaRESUMO
OBJECTIVE: To assess the effects of berberine (BBR) on high-molecular weight (HMW) adiponectin and adiponectin receptors (adipoR1/adipoR2) expressions in high-fat (HF) diet fed rats. METHODS: Forty Wistar male rats were randomly assigned into a normal diet fed group and three HF diet (fat for 45% calories) fed groups (n=10 for each group). All rats underwent 12 weeks of feeding. After 4 weeks feeding, rats in the two of three HF diet fed groups were treated with 150 mg·kg-1·day-1 BBR (HF+LBBR group) and 380 mg·kg-1·day-1 BBR (HF+HBBR group) by gavage once a day respectively for the next 8 weeks while the rats in other groups treated with vehicle (NF+Veh and HF+Veh). Body weight and food intake were observed and recorded on daily basis. At the end of 12 weeks, the blood, liver, epididymal fat tissues and quadriceps femoris muscles were collected. Fasting insulin, plasma fasting glucose, serum free fatty acid (FFA), total adiponectin and HMW adiponectin levels were measured by enzyme linked immunosorbent assay method. Glucose tolerance test (GTT) and insulin tolerance test (ITT) were performed to determine the insulinsensitizing. Meanwhile the homeostasis model assessment (HOMA) method was used to determine insulin resistance (HOMA-IR). The expressions of adipoR1, adipoR2 and adenosine monophophate activated protein kinase (AMPK) phosphorylation level in skeletal muscle and liver tissue were detected by Western blot. Liver and kidney toxicity were evaluated during treatment. RESULTS: The body weight of rats in high- or low-dose BBR group reduced as well as HOMA-IR, FFA concentrations and fasting insulin levels decreased compared with HF+Veh group (P<0.05). BBR also increased the ratio of HMW to total adiponectin in high fat-fed rats compared with rats in the HF+Veh group. High- and low-dose BBR increased adipoR1 expression in skeletal muscle by over 6- and 2-fold (P<0.05), respectively, and high-dose BBR also increased adipoR2 expression in liver tissue by over 2-fold (P<0.05). BBR significantly increased AMPK phosphorylation in HF diet rats compared with normal diet rats (P<0.05). The ratio of HMW to total adiponectin was inversely correlated with HOMA-IR (r=-0.52, P=0.001). Meantime, no liver and kidney toxicity was found in high fat-fed rats that treated by BBR. CONCLUSION: Berberine may improve insulin resistance by increasing the expression of adiponectin receptors and the ratio of HMW to total adiponectin.
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OBJECTIVE: To explore the dynamic changes of transforming growth factor-α (TGF-α) and transforming growth factor-ß1 (TGF-ß1) of liver cirrhosis induced by multiple pathogenic factors in rats. METHODS: Animals in the cirrhosis group were fed a mixture of maize flour, lard, cholesterol and alcohol plus subcutaneously injection with carbon tetrachloride (CCl4), the CCl4(0.5 ml/100 g · w) was injected at the first day of experiment and the 40% CCl4oil solution (0.3 ml /100 g · w) was injected at an interval of three days. The thirty-six male SD rats were randomly divided into liver cirrhosis group of the 4th, 6th and 8 th week, and normal control group of the 4th, 6th and 8th week. The contents of alanine transferase (ALT), endotoxin, tumor necrosis factor-α (TNF-α) and homocysteine (Hcy) in plasma were evaluated. Histopathological changes of the liver were observed under microscope with the staining of HE. The expressions of TGF-α and TGF-ß1 were analyzed by the method of immunohistochemistry. RESULTS: Compared with the corresponding normal control group, the levels of ALT, endotoxin, TNF-α and Hcy in plasma were gradually significantly increased in liver cirrhosis group of the 4th, 6th and 8th week (P < 0.05); the expression of TGF-α in the liver tissues was significantly increased at the 4th week (P < 0.05); the expression of TGF-ß1 in the liver tissues was gradually significantly increased in every model group (P < 0.05). CONCLUSION: In the formation process of cirrhosis, the expression of TGF-α was increased in liver of cirrhosis group at the 4th week, and later it was suppressed; the expression of TGF-ß1 was continuously increased. The characteristic dynamic changes of TGF-α and TGF-ß1 might be related to sustained endotoxemia, the high level of TNF-α and hyperhomocysteinemia.
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Cirrose Hepática/metabolismo , Fator de Crescimento Transformador alfa/metabolismo , Fator de Crescimento Transformador beta1/metabolismo , Alanina Transaminase/sangue , Animais , Tetracloreto de Carbono , Endotoxinas/sangue , Homocisteína/sangue , Masculino , Ratos , Ratos Sprague-Dawley , Fator de Necrose Tumoral alfa/sangue , Fator de Necrose Tumoral alfa/metabolismoRESUMO
AIM: To evaluate the effect of artesunate (AS) supplementation on bacterial translocation (BT) and gut microbiota in a rat model of liver cirrhosis. METHODS: Fifty-four male Sprague-Dawley rats were randomly divided into a normal control group (N), a liver cirrhosis group (M) and a liver cirrhosis group intervened with AS (MA). Each group was sampled at 4, 6 and 8 wk. Liver cirrhosis was induced by injection of carbon tetrachloride (CCl4), intragastric administration of 10% ethanol, and feeding a high fat diet. Rats in the MA group were intragastrically administered with AS (25 mg/kg body weight, once daily). Injuries of the liver and intestinal mucosa were assessed by hematoxylin-eosin or Masson's trichrome staining. Liver index was calculated as a ratio of the organ weight (g) to body weight (g). The gut microbiota was examined by automated ribosomal intergenic-spacer analysis of fecal DNA. BT was assessed by standard microbiological techniques in the blood, mesenteric lymph nodes (MLNs), liver, spleen, and kidney. RESULTS: Compared to group N, the body weight was reduced significantly in groups M and MA due to the development of liver cirrhosis over the period of 8 wk. The body weight was higher in group MA than in group M. The liver indices were significantly elevated at 4, 6 and 8 wk in groups M and MA compared to group N. AS supplementation partially decreased the liver indices in group MA. Marked histopathologic changes in the liver and small intestinal mucosa in group M were observed, which were alleviated in group MA. Levels of pro-inflammatory interleukin-6 and tumor necrosis factor-α were significantly elevated at 8 wk in ileal homogenates in group M compared to group N, which were decreased after AS supplementation in group MA. The dysbiosis of gut microbiota indicated by the mean diversity (Shannon index) and mean similarity (Sorenson index) was severe as the liver cirrhosis developed, and AS supplementation had an apparent intervention effect on the dysbiosis of gut microbiota at 4 wk. The occurrence of BT was increased in the liver of group M compared to that of group N. AS supplementation reduced BT in group MA at 8 wk. BT also occurred in the MLNs, spleen, and kidney, which was reduced by AS supplementation. BT was not detected in the blood in any group. CONCLUSION: Dysbiosis of gut microbiota, injury of intestinal mucosal barrier and BT occurred as liver cirrhosis progressed, which might enhance inflammation and aggravate liver injury. AS may have other non-antimalarial effects that modulate gut microbiota, inhibit BT and alleviate inflammation, resulting in a reduction in CCl4, alcohol and high fat-caused damages to the liver and intestine.
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Anti-Inflamatórios/farmacologia , Artemisininas/farmacologia , Bactérias/efeitos dos fármacos , Translocação Bacteriana/efeitos dos fármacos , Disbiose , Microbioma Gastrointestinal/efeitos dos fármacos , Intestinos/efeitos dos fármacos , Cirrose Hepática Experimental/tratamento farmacológico , Animais , Artesunato , Bactérias/imunologia , Bactérias/metabolismo , Tetracloreto de Carbono , Citocinas/imunologia , Citocinas/metabolismo , Progressão da Doença , Fezes/microbiologia , Mediadores da Inflamação/imunologia , Mediadores da Inflamação/metabolismo , Mucosa Intestinal/metabolismo , Intestinos/imunologia , Intestinos/microbiologia , Cirrose Hepática Experimental/induzido quimicamente , Cirrose Hepática Experimental/imunologia , Cirrose Hepática Experimental/microbiologia , Masculino , Ratos Sprague-Dawley , Fatores de TempoRESUMO
Berberine (BBR) has been reported in several studies in cell and animal models. However, the mechanism of actions is not fully understood. The present study was therefore aimed to explore the effects of berberine on insulin sensitivity and kidney damage in a high fat diet rat model. Impaired glucose tolerance rats induced by injection of berberine while fed with high fat laboratory chow. After rats were treated for 4 weeks, OGTT and IPITT were determined. Mass and PAS were used to study the kidney tissue. ELISA was used to detect the protein concentration of CRP and TNF-α. Western blot was used to detect the proteins adiponectin, adipoR1, adipoR2 and p-AMPK expression level. These encouraging findings suggest that berberine has excellent pharmacological potential to prevent kidney damage.
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Adiponectina/sangue , Berberina/farmacologia , Dieta Hiperlipídica , Resistência à Insulina , Nefropatias/prevenção & controle , Rim/efeitos dos fármacos , Proteínas Quinases Ativadas por AMP/metabolismo , Animais , Glicemia/efeitos dos fármacos , Glicemia/metabolismo , Proteína C-Reativa/metabolismo , Citoproteção , Modelos Animais de Doenças , Insulina/sangue , Rim/metabolismo , Rim/patologia , Nefropatias/sangue , Nefropatias/patologia , Nefropatias/fisiopatologia , Masculino , Ratos Wistar , Receptores de Adiponectina/metabolismo , Fatores de Tempo , Fator de Necrose Tumoral alfa/sangue , Regulação para CimaRESUMO
OBJECTIVE: To explore the mechanism of tanshinol on alleviate the inflammatory injury of lung tissue in rat hepatopulmonary syndrome (HPS). METHODS: SD rats were randomly divided into normal control group (n = 8), hepatopulmonary syndrome (HPS) group (n = 11) and tanshinol intervention group (n = 9). HE staining was used to observe the histopathology changes of pulmonary and hepatic tissues, and to count the number of macrophages in lung tissues. The activity of alanine transferase (ALT) and concentrations of endotoxin, tumor necrosis factor-a (TNF-alpha) and homocystein (Hcy) in plasma were detected. The concentrations of TNF-alpha, nitric oxide (NO) and malondialdehyde (MDA) and the activity of inducible nitric oxide synthase (iNOS) in the lung tissues were measured, respectively. RESULTS: Thickened alveolar septum and increased macrophages were observed in lungs in HPS rat. After administered with tanshinol, the pulmonary pathological changes were alleviated and the number of macrophages in lung tissue was decreased compared with HPS group. The activity of ALT and the concentrations of endotoxin, TNF-alpha and Hcy in plasma ,and TNF-alpha, iNOS, NO and MDA in lung tissue in HPS group were higher than those of normal control group; meanwhile, those tanshinol group were less those that of HPS group. CONCLUSION: Tanshinol may play an important role in delaying the development of HPS through protecting liver or directly antagonizing the effect of intestinal endotoxemia so as to alleviate the inflammatory reaction in lung tissue.
Assuntos
Ácidos Cafeicos/farmacologia , Síndrome Hepatopulmonar/tratamento farmacológico , Alanina Transaminase/metabolismo , Animais , Modelos Animais de Doenças , Endotoxinas/sangue , Síndrome Hepatopulmonar/patologia , Homocisteína/sangue , Fígado/efeitos dos fármacos , Fígado/patologia , Pulmão/efeitos dos fármacos , Pulmão/patologia , Macrófagos/efeitos dos fármacos , Macrófagos/patologia , Masculino , Malondialdeído/metabolismo , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase Tipo II/metabolismo , Ratos , Ratos Sprague-Dawley , Fator de Necrose Tumoral alfa/sangueRESUMO
IL-10-producing B cells (B10 cells) have been shown to play a suppressive role in the peripheral blood of humans, with their numbers and function altered in several autoimmune diseases. However, the role of B10 cells in Graves' disease (GD) remains unknown. In this study, we demonstrated that B10 cells in human peripheral blood belonged to a CD24(hi)CD27(+) B cell subpopulation. The proportion of B10 cells along with the CD19(+)CD24(hi)CD27(+) B cell subset was significantly lower in new-onset patients compared with healthy individuals. In recovered patients, these proportions were restored to levels similar to those seen in healthy individuals. Additionally, we found that CD19(+)CD24(hi)CD27(+) B cells from healthy individuals inhibited proliferation and TNF-α production of CD4(+) T cells via an IL-10-independent pathway. They also inhibited IFN-γ production by CD4(+) T cells, through an IL-10-dependent pathway. In contrast, their suppressive function on CD4(+) T cell proliferation and cytokine production was impaired in new-onset and recovered patients compared with healthy individuals. Our study provides evidence that CD19(+)CD24(hi)CD27(+) B cells may possess the capacity to downregulate immune responses, partially by production of IL-10 in human peripheral blood. Impairment of their immunosuppressive function may contribute to GD pathogenesis and relapse.