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Chronic pancreatitis (CP) is a progressive, irreversible inflammatory and fibrotic disease. The characteristics of this disease are progressive inflammation, acinar atrophy and fibrosis. Numerous factors are involved in CP such as inflammation, and oxidative stress. Recently, it has been noted that fibroblast growth factor 21 (FGF-21) reduced the severity of acute pancreatitis in mice. However, whether FGF-21 has effects on CP remains unclear. Thus, the present study was undertaken to detect the effects of FGF-21 on l-arginine induced chronic pancreatitis/islet fibrosis in mice. We used l-arginine to create a CP model in C57BL/6 mice and treated these mice with FGF-21. Compared to normal mice, blood glucose and intra-peritoneal glucose tolerance test (IPGTT) revealed significant impairment in CP animal model. CP mice also had acinar atrophy, loss of pancreas morphology, inflammatory cells infiltration, extensive deposition of collagen, elevated
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Fatores de Crescimento de Fibroblastos/uso terapêutico , Macrófagos Peritoneais/efeitos dos fármacos , Pancreatite Crônica/tratamento farmacológico , Amilases/sangue , Animais , Arginina/toxicidade , Diferenciação Celular/efeitos dos fármacos , Fatores de Crescimento de Fibroblastos/farmacologia , Fibrose , Teste de Tolerância a Glucose , Humanos , Masculino , Malondialdeído/sangue , Camundongos , Camundongos Endogâmicos C57BL , Estresse Oxidativo/efeitos dos fármacos , Pancreatite Crônica/induzido quimicamente , Pancreatite Crônica/patologia , Peroxidase/sangue , Proteínas Recombinantes/farmacologia , Proteínas Recombinantes/uso terapêutico , Transdução de Sinais/efeitos dos fármacos , Células THP-1 , Serina-Treonina Quinases TOR/fisiologiaRESUMO
Persistent inflammation disrupts functional recovery after spinal cord injury (SCI). Peroxisome proliferator-activated receptor gamma (PPAR-γ) activation promotes functional recovery in SCI rats by inhibiting inflammatory cascades and increasing neuronal survival. We sought to clarify the relationship between PPAR-γ activation and NACHT, LRR and PYD domain-containing protein 3 (NLRP3) inflammasome suppression, and the role of NF-κB in activating the NLRP3 inflammasome in neurons. In SCI rats, we found that rosiglitazone (PPAR-γ agonist) inhibited the expression of caspase-1. In in vitro neurons, G3335 (PPAR-γ antagonist) reversed the rosiglitazone-induced inhibition of caspase-1, interleukin 1 (IL-1ß), and interleukin 6 (IL-6). Rosiglitazone inhibited the expression of NLRP3, caspase-1, IL-1ß, and IL-6. However, the activator of NLRP3 could counteract this inhibition induced by PPAR-γ activation. NF-κB did not participate in the process of rosiglitazone-induced inhibition of NLRP3. Consistent with our in vitro results, we verified that locomotor recovery of SCI rats in vivo was regulated via PPAR-γ, NLRP3, and NF-κB. These results suggest that PPAR-γ activation exerts an anti-inflammatory effect by suppressing the NLRP3 inflammasome-but not NF-κB-in neurons and that PPAR-γ activation is a promising therapeutic target for SCI.
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Anti-Inflamatórios/uso terapêutico , Inflamassomos/efeitos dos fármacos , Inflamassomos/metabolismo , Inflamação/tratamento farmacológico , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , PPAR gama/metabolismo , Animais , Caspase 1/metabolismo , Feminino , Imuno-Histoquímica , Inflamação/metabolismo , Interleucina-1/metabolismo , Interleucina-6/metabolismo , Neurônios/citologia , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Ratos , Ratos Sprague-Dawley , Rosiglitazona/uso terapêutico , Medula Espinal/citologia , Medula Espinal/metabolismoRESUMO
Menopausal women appear lipid metabolism disorder with the ovarian function decline and the estrogen levels decreased. Modern clinical usually use estrogen replacement therapy and with long time application with lots of side effect appear. Traditional Chinese medicine has more secure and effective methords,using warming Yang drugs and methods. And the previous study proves the Chinese medicine Astragali Complanati Semen water extraction has a good role in regulation of blood lipids. Because of the liver is the most important organ on regulating metabolism, therefore this study aimed to evaluate the effects of total flavonoids in Astragali Complanati Semen(TFS)on liverlipid level and ERα expressionon liver in hyperlipidemia rats with kidney-Yang deficiency pattern to explore the substance basis and mechanism of Astragali Complanati Semen in regulate lipid effect and clarify traditional Chinese medicine advantages and features. This experiment uses hyperlipidemia rats with kidney-Yang deficiency pattern with bilateral ovariectomized and fed with high fat diet for 6 weeks. And rats of sham operation group and model group rats were intragastrilly(ig) with saline, estrogen group were intragastrilly with estrogen(0.2 mg·kg⻹). And three TFS group were intragastrilly with TFS at dose 28.5, 57, 114 mg·kg⻹ for 8 weeks. At the same time, TC, TG, LDL-C,HDL-C liver weight, liver index, uterine weight, uterine index, serum estrogen level, FSH levels and liver pathology, liver estrogen receptor expression were detected, weighting and calculating their organ index. The experimental results compared with the model group, TFS 114 mg·kg⻹ decreased the level of liver TG (P<0.05), TC (P<0.001) and LDL-C (P<0.001) and increased the level of HDL-C (P<0.05). Compared with the model group, estrogen group increased the level of blood serum (P<0.001) and decreased the level of FSH (P<0.001). In addition, compared with sham operation group,model group decreased the protein expression of ERαï¼P<0.01ï¼. Compared with the model group, estrogen group increased the protein expression of ERα significantlyï¼P<0.001ï¼.TFS mid-dose group and TFS high-dose group is increased the protein expression of ERαï¼P<0.01, P<0.001ï¼.In a conclusion,Flavonoids is the main active ingredient of Astragali Complanati Semen. The mechanism of it maybe is enhancing the estrogen receptor sensitivity or the number of estrogen receptors, amplifying the signal after the receptor conduction, which could result in lipid-lowering effect.
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Astrágalo/química , Medicamentos de Ervas Chinesas/farmacologia , Receptor alfa de Estrogênio/metabolismo , Flavonoides/farmacologia , Hiperlipidemias/tratamento farmacológico , Lipídeos/análise , Animais , Feminino , Fígado , Ratos , Deficiência da Energia Yang/tratamento farmacológicoRESUMO
To study the effect of the combined administration of different doses of Glycyrrhizae Radix et Rhizoma and Atractylodis Macrocephalae Rhizoma on the proliferation of DFMO-treated intestinal epithelial cells (IEC-6) and p53, p21 mRNA and protein expressions, in order to define the molecular basis for the effect of the combined administration of different doses of Glycyrrhizae Radix et Rhizoma and Atractylodis Macrocephalae Rhizoma on the cell proliferation. The effect of the drugs on the cell division rate and cell cycle of IEC-6 cells was detected by FCM. Quantitative Real-time PCR (qRT-PCR) was used to analyze the effect of the drugs on mRNA of p2l and p53 related to IEC-6 proliferation. Western blot was used to analyze the effect of the drugs on p2l and p53 protein expressions of IEC-6 cells. Atractylodis Macrocephalae Rhizoma could increase p53, p21 mRNA and proteins expression in DFMO-treated IEC-6 cells. The combined administration of different ratios of Atractylodis Macrocephalae Rhizoma and Glycyrrhizae Radix et Rhizoma could significantly down-regulate Atractylodis Macrocephalae Rhizoma's effect on p53, p21 mRNA and proteins expression in DFMO-treated IEC-6 cells and promote the proliferation of IEC-6 cells. The combined administration of Atractylodis Macrocephalae Rhizoma and Glycyrrhizae Radix et Rhizoma could down-regulate Atractylodis Macrocephalae Rhizoma's effect on DFMO-treated intestinal epithelial cells (IEC-6).
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Atractylodes/química , Inibidor de Quinase Dependente de Ciclina p21/genética , Medicamentos de Ervas Chinesas/farmacologia , Expressão Gênica/efeitos dos fármacos , Glycyrrhiza/química , Proteína Supressora de Tumor p53/genética , Animais , Linhagem Celular , Inibidor de Quinase Dependente de Ciclina p21/metabolismo , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/metabolismo , Mucosa Intestinal/metabolismo , Intestinos/efeitos dos fármacos , Ratos , Rizoma/química , Proteína Supressora de Tumor p53/metabolismoRESUMO
The clearance of host cell DNA is a critical indicator for Vero-cell culture-derived rabies vaccine. In this study, we evaluated the clearance of DNA in Vero-cell culture-derived rabies vaccine by purification process utilizing ultrafiltration, nuclease digestion, and gel filtration chromatography. The results showed that the bioprocess of using nuclease decreased residual DNA. Dot-blot hybridization analysis showed that the residual host cell DNA was <100 pg/ml in the final product. The residual nuclease in rabies vaccine was less than 0.1 ng/ml protein. The residual nuclease could not paly the biologically active role of digestion of DNA. Experiments of stability showed that the freeze-drying rabies virus vaccine was stable and titers were >5.0 IU/ml. Immunogenicity test and protection experiments indicated mice were greatly induced generation of neutralizing antibodies and invoked protective effects immunized with intraperitoneal injections of the rabies vaccine. These results demonstrated that the residual DNA was removed from virus particles and nuclease was removed by gel filtration chromatography. The date indicated that technology was an efficient method to produce rabies vaccine for human use by using nuclease.
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DNA/isolamento & purificação , Endodesoxirribonucleases , Endorribonucleases , Vacina Antirrábica/isolamento & purificação , Animais , Anticorpos Neutralizantes/biossíntese , Anticorpos Antivirais/biossíntese , Chlorocebus aethiops , Cromatografia em Gel , Contaminação de Medicamentos/prevenção & controle , Estabilidade de Medicamentos , Endodesoxirribonucleases/isolamento & purificação , Endorribonucleases/isolamento & purificação , Liofilização , Humanos , Camundongos , Raiva/imunologia , Raiva/prevenção & controle , Vacina Antirrábica/imunologia , Vírus da Raiva/imunologia , Células VeroRESUMO
To investigate the cell-killing effect and its possible mechanism of rClone30-hDR5 in combination with TRAIL on human hepatic carcinoma (HCC) cell line, first of all, recombinant plasmid pee12.4-hDR5 was introduced into HepG2 cells by liposome transfection. After five rounds of screening by flow cytometry, HepG2 cells expressing high levels of DR5 on cell surface were isolated. The cytotoxicity of TRAIL to selected cells was higher than that of TRAIL to HepG2 cells by MTT method (P < 0.01). The result suggested that the cloned hDR5 gene had biological activity. MTT assay showed that, rClone30- hDR5 in combination with TRAIL more efficiently inhibited the tumor growth of HepG2 cells compared to rClone30-hDR5 or TRAIL in vitro. The results of Annexin V-FITC/PI staining and Quantitative Real-time PCR indicated that rClone30-hDR5 in combination with TRAIL significantly increased the mRNA levels of caspase 3 and caspase 8, and induced the apoptosis of tumor cells. HepG2 cells were infected with rClone30-hDR5 or rClone30 at MOI of 1. The expression of hDR5 on tumor surface increased significantly by rClone30-hDR5 compared to that by rClone30, which contributed to the sensitivity to TRAIL. In conclusion, rClone30-hDR5 in combination with TRAIL has potential application value in cancer treatment.
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Carcinoma Hepatocelular/patologia , Neoplasias Hepáticas/patologia , Receptores do Ligante Indutor de Apoptose Relacionado a TNF/farmacologia , Ligante Indutor de Apoptose Relacionado a TNF/farmacologia , Apoptose , Caspase 3/metabolismo , Caspase 8/metabolismo , Sinergismo Farmacológico , Células Hep G2 , Humanos , Reação em Cadeia da Polimerase em Tempo Real , TransfecçãoRESUMO
The polymorphism of microphthalmia-associated transcription factor (MITF) and tyrosinase (TYR) genes have been proposed to play a vital role in coat colour genesis in mammals, but their role remains ambiguous in geese at best. Here, we cloned and sequenced 1,397 bp coding region of MITF gene and a 588 bp fragment of TYR exon 1 for polymorphism analysis among 157 domestic geese showing three types of plumage colour. We detected a total of three SNPs (c.280T>C, c.345G>A, and c.369G>A) in TYR and six haplotypes (H1-H6). Among them, haplotypes H1, H2, H3, and H5 were significantly associated with white plumage trait of Zhedong White Geese. However, only diplotype H1H1 and H3H5 were significantly associated with white plumage trait of Zhedong White Geese (p<0.01). We only detected one SNP (c.1109C>T) for MITF gene and found that genotype CT and TT were significantly associated with white plumage trait of Zhedong White Geese. Briefly, our study suggested an association between polymorphisms of TYR and MITF genes and the plumage colour trait in domestic geese.
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The progress in integrative medicine (IM) of coronary heart disease (CHD) in 2013 was summarized in this paper. Gratifying progress has taken place both in clinical studies and basic research of IM on CHD during 2013. We got some innovation in Chinese medical etiologies and pathogeneses of CHD. We also got some improvement in researches on Chinese medical syndromes in various fields. Many clinical studies have proved Chinese medicine and pharmacy is playing a role in preventing and improving CHD patients. In-depth basic researches on preventing and treating CHD by IM are gradually undergoing. Acting targets and mechanism are further clarified. Besides, we also pointed out the developing tendency of CHD researches and the current deficiency in CHD researches, hoping to provide reference for further studies in this field.
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Doença das Coronárias/tratamento farmacológico , Medicamentos de Ervas Chinesas/uso terapêutico , Medicina Integrativa , HumanosRESUMO
Heart failure is a continuously developing syndrome of cardiac insufficiency caused by diseases, which becomes a major disease endangering human health as well as one of the main causes of death in patients with cardiovascular diseases. The occurrence of heart failure is related to hemodynamic abnormalities, neuroendocrine hormones, myocardial damage, myocardial remodeling etc, lead to the clinical manifestations including dyspnea, fatigue and fluid retention with complex pathophysiological mechanisms. Currently available drugs such as cardiac glycoside, diuretic, angiotensin-converting enzyme inhibitor, vasodilator and ß receptor blocker etc are widely used for the treatment of heart failure. In particular, natural products and related active ingredients have the characteristics of mild efficacy, low toxicity, multi-target comprehensive efficacy, and have obvious advantages in restoring cardiac function, reducing energy disorder and improving quality of life. In this review, we mainly focus on the recent advance including mechanisms and active ingredients of natural products for the treatment of heart failure, which will provide the inspiration for the development of more potent clinical drugs against heart failure.
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Drawing upon the perspective of state rescaling in city-region governance, this paper explores the transformation of cross-boundary governance in the Greater Pearl River Delta (GPRD), a cross-boundary region on the South China coast consisting of the PRD under the jurisdiction of Guangdong Province, and Hong Kong and Macao Special Administrative Regions (SARs). Based on updated field investigation and in-depth interviews between 2008 and 2012, the study argues that the Greater PRD has undergone dramatic restructuring of regional governance since mid 2000s, reflected by rescaling attempts initiated by Guangdong provincial government and bottom-up resistance from local residents in Hong Kong. The interaction of the rescaling dynamics has engendered the contested geopolitics of the cross-boundary governance as the regional integration intensified. Notably, the complexity of cross-boundary governance has been heightened by emerging conflicts, resulted from the increasing number of mainlanders as 'individual visitors' to Hong Kong since the implementation of the Closer Economic Partnership Arrangement (CEPA), the first bilateral free trade agreement between Hong Kong and China effective from 2004. By examining the Greater PRD as a salient mega city-region, the present study enriches the growing literature on state rescaling and cross-border governance in contemporary globalization.
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Egg-ceasing is a phenomenon that occurs in most avian species and significantly reduces productivity. Although several factors are reported to regulate the reproduction progress, the underlying molecular mechanism of egg-ceasing remains obscure. Herein, we identified and explored the differentially expressed miRNAs and mRNAs involved in ovarian atrophy via high throughput sequencing. We identified a total of 901 mRNAs and 50 miRNAs that were differentially expressed in egg-laying and atrophic ovaries. Among them, numerous differentially expressed gene (DEG) transcripts and target genes for miRNAs were significantly enriched in Gene Ontology terms such as reproductive processes, cell proliferation, and apoptosis pathways. In addition, an interaction network was constructed by considering target relationships and correlation of the expression levels between ovary development-related genes, miRNAs and pathways. We discovered mRNA and miRNAs transcripts that are candidate regulators of ovary development in egg-ceased geese. Our findings expanded our understanding of the functional of miRNAs in ovarian atrophy and demonstrated that RNA-Seq is a powerful tool for examining the molecular mechanism in regulating egg-ceasing.
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Gansos , MicroRNAs , Animais , Atrofia/metabolismo , Atrofia/veterinária , Feminino , Gansos/genética , Gansos/metabolismo , Perfilação da Expressão Gênica/veterinária , MicroRNAs/genética , MicroRNAs/metabolismo , Ovário/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Estações do AnoRESUMO
Purpose: This study aimed to develop a nomogram model based on multiparametric magnetic resonance imaging (MRI) radiomics features, clinicopathological characteristics, and blood parameters to predict the progression-free survival (PFS) of patients with nasopharyngeal carcinoma (NPC). Methods: A total of 462 patients with pathologically confirmed nonkeratinizing NPC treated at Sichuan Cancer Hospital were recruited from 2015 to 2019 and divided into training and validation cohorts at a ratio of 7:3. The least absolute shrinkage and selection operator (LASSO) algorithm was used for radiomics feature dimension reduction and screening in the training cohort. Rad-score, age, sex, smoking and drinking habits, Ki-67, monocytes, monocyte ratio, and mean corpuscular volume were incorporated into a multivariate Cox proportional risk regression model to build a multifactorial nomogram. The concordance index (C-index) and decision curve analysis (DCA) were applied to estimate its efficacy. Results: Nine significant features associated with PFS were selected by LASSO and used to calculate the rad-score of each patient. The rad-score was verified as an independent prognostic factor for PFS in NPC. The survival analysis showed that those with lower rad-scores had longer PFS in both cohorts (p < 0.05). Compared with the tumor-node-metastasis staging system, the multifactorial nomogram had higher C-indexes (training cohorts: 0.819 vs. 0.610; validation cohorts: 0.820 vs. 0.602). Moreover, the DCA curve showed that this model could better predict progression within 50% threshold probability. Conclusion: A nomogram that combined MRI-based radiomics with clinicopathological characteristics and blood parameters improved the ability to predict progression in patients with NPC.
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OBJECTIVE: To assess whether an adjunctive therapy of Sodium Tanshinone II A Sulfonate Injection (STS) is effective and safe in improving clinical outcomes in patients with coronary heart disease (CHD). METHODS: A literature search was conducted through PubMed, the Cochrane Library, Knowledge Infrastructure Databases (CNKI), Chinese Biomedical Literature Database (SinoMed), Chinese Science and Technology Periodical Database (VIP) and Wanfang Database up to August 2017. Randomized controlled trials (RCTs) comparing STS with placebo or no additional treatments on the basis of standard conventional medicine therapies were included. The outcomes were all-cause mortality, major acute cardiovascular events (MACEs), cardiac function and inflammatory factors. The risk of bias assessment according to the Cochrane Handbook was used to evaluate the methodological quality of the included trials. Revman 5.3 software was used for data analyses. RESULTS: A total of 22 RCTs involving 1,873 participants were included. All of the trials used STS as adjunctive treatment to standard conventional medicine therapy. Due to the poor quality of methodologies of most trials, only limited evidence showed that a combination of STS with percutaneous coronary intervention (PCI) or thrombolytic therapy (TT) might be more effective on reduction of all cause death rate than TT alone [risk ratio (RR) 0.25, 95% confidence interval (CI) 0.07 to 0.87] or PCI alone (RR 0.42, 95% CI 0.04 to 4.36). The results of 6 trials comparing STS plus TT with TT alone showed that the addition of STS significantly reduced the incidence of cardiac shock (RR 0.35, 95% CI 0.14 to 0.86), heart failure (RR 0.41, 95% CI 0.20 to 0.83) and arrhythmia (RR 0.21, 95% CI 0.12 to 0.46). STS combined with TT also showed a superior effect on cardiac function and inflammatory factor. No severe adverse event was reported related to STS. CONCLUSIONS: As an adjunctive therapy, STS combined with standard conventional medicine seems to be more effective on all-cause mortality or MACEs than conventional medicine treatment alone with less side effects. However, we cannot make a firm conclusion due to low quality of inclusion trials. Well-designed trials with high methodological quality are needed to validate the effect of STS for CHD patients.
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Doença das Coronárias/tratamento farmacológico , Fenantrenos/uso terapêutico , Doença das Coronárias/mortalidade , Quimioterapia Combinada , Humanos , Injeções , Qualidade de Vida , Ensaios Clínicos Controlados Aleatórios como AssuntoRESUMO
Inflammation, which plays a critical role in atherosclerosis and the occurrence of acute cardiovascular events, may be a new target for treatment of coronary artery disease (CAD) to reduce residual cardiovascular risk. Recently, Antiinflammatory Therapy with Canakinumab for Atherosclerotic Disease (CANTOS), the largest scale clinical trial that targeted inflammation but not lipids, has affirmed for the first time the inflammatory hypothesis of artherosclerosis and marked the advent of an exciting era of targeting inflammation for the prevention and treatment of cardiovascular diseases. Chinese medicine (CM) is a promising adjuvant therapy for CAD in light of its safety and pleiotropic effect of anti-inflammation, anti-platelet, lipid-regulating, endothelium-protection, microcirculation-improving, etc. In recent years, exploration of anti-inflammatory treatment of CAD with CM has been going on from theory to practice. Taking CANTOS as an example, the design strategy to combine CM and Western medicine to inhibit inflammation were discussed in this paper, which might provide a new perspective for CM intervention on CAD.
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Anti-Inflamatórios/uso terapêutico , Doença da Artéria Coronariana/tratamento farmacológico , Medicina Tradicional Chinesa , Anticorpos Monoclonais/uso terapêutico , Anticorpos Monoclonais Humanizados , HumanosRESUMO
BACKGROUND: Upper gastrointestinal bleeding (UGIB) after an acute myocardial infarction (AMI) is not an uncommon complication. Acute UGIB caused by Mallory-Weiss syndrome (MWS) is usually a dire situation with massive bleeding and hemodynamic instability. Acute UGIB caused by MWS after an AMI has not been previously reported. CASE SUMMARY: A 57-year-old man with acute inferior wall ST elevation myocardial infarction underwent a primary coronary intervention of the acutely occluded right coronary artery. Six hours after the intervention, the patient had a severe UGIB, followed by vomiting. His hemoglobin level dropped from 15.3 g/dL to 9.7 g/dL. In addition to blood transfusion and a gastric acid inhibition treatment, early endoscopy was employed and MWS was diagnosed. Bleeding was stopped by endoscopic placement of titanium clips. CONCLUSION: Bleeding complications after stent implantation can pose a dilemma. MWS is a rare but severe cause of acute UGIB after an AMI that requires an early endoscopic diagnosis and a hemoclip intervention to stop bleeding.
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OBJECTIVE: Obesity-related, chronic, low-grade inflammation has been identified as a key factor in the development of many metabolic diseases, such as type 2 diabetes and cardiovascular diseases. Adipocytes, preadipocytes, and macrophages have been implicated in initiating inflammation in adipose tissue. This study aims to investigate the effects of fibroblast growth factor-21 (FGF-21) on obesity-related inflammation and its mechanisms in vivo and in vitro. METHODS: Monosodium glutamate (MSG) was used to induce obesity in mice and subsequently treated the mice with or without FGF-21. Primary adipocytes and stromal vascular fraction cells were isolated from MSG-obesity mice for additional experiments. RESULTS: Results obtained by ELISA and real-time polymerase chain reaction showed that FGF-21 efficiently ameliorated obesity-related inflammation in MSG-obesity mice. This study demonstrated that preadipocytes and adipocytes responded to anti-inflammatory effects of FGF-21. In vitro, 3 T3-L1 preadipocytes lacking ß-klotho did not respond to FGF-21 under glucose uptake. Interestingly, the treatment of 3 T3-L1 preadipocytes with FGF-21 significantly attenuated lipopolysaccharide-induced inflammatory response. CONCLUSIONS: Our study showed that FGF-21-induced glucose uptake and FGF-21-related anti-inflammatory effects are mediated by different signaling pathways. Moreover, FGF-21 showed anti-inflammatory effects on preadipocytes; these effects are mediated by the fibroblast growth factor receptor substrate 2/ERK1/2 signaling pathway.
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Tecido Adiposo/efeitos dos fármacos , Anti-Inflamatórios/uso terapêutico , Fatores de Crescimento de Fibroblastos/uso terapêutico , Inflamação/tratamento farmacológico , Obesidade/tratamento farmacológico , Animais , Anti-Inflamatórios/farmacologia , Fatores de Crescimento de Fibroblastos/farmacologia , Humanos , CamundongosRESUMO
Monocytes display a gradual change in metabolism during inflammation. When activated, the increase in glucose utilization is important for monocytes to participate in immune and inflammatory responses. Further studies on the mechanism underlying this biological phenomenon may provide a new understanding of the relationship between immune response and metabolism. The THP-1 cells were used as a monocyte model. The cells were activated with lipopolysaccharide (LPS). Glucose uptake was measured using flow cytometry. The expression of fibroblast growth factor 21 (FGF-21), glucose transporter 1 (GLUT-1), and other FGF-21 signaling pathway-related factor mRNAs was determined by real-time polymerase chain reaction. Further, the relationship between FGF-21 expression in monocytes and phosphatidylinositol-3-kinase (PI3K)-protein kinase B (Akt) signaling pathway was determined by Western blotting. LPS elevated FGF-21 expression in monocytic THP-1 cells in vitro. Functional assays showed that the phenomenon in which LPS and FGF-21 stimulated glucose uptake in monocytic THP-1 cells could be inhibited by FGFR inhibitor. The mechanism of elevation of FGF-21 was found to involve the PI3K/Akt signaling pathway. This study indicated that FGF-21 could regulate the immune response indirectly by influencing the glucose uptake of activated monocytes cells.
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Fatores de Crescimento de Fibroblastos/metabolismo , Glucose/metabolismo , Monócitos/metabolismo , Transporte Biológico , Transportador de Glucose Tipo 1/metabolismo , Humanos , Proteínas Klotho , Lipopolissacarídeos/farmacologia , Proteínas de Membrana/metabolismo , Monócitos/efeitos dos fármacos , Monócitos/imunologia , Fosfatidilinositol 3-Quinase/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/metabolismo , Transdução de Sinais , Células THP-1 , Fatores de TempoRESUMO
Type 2 diabetes mellitus (T2DM) is accompanied by abnormal glucose metabolism and low-grade chronic inflammation. Fibroblast growth factor 21 (FGF-21) is a novel metabolic regulator and can function as an endocrine hormone to regulate glucose and lipid metabolism. Recently, FGF-21 was found to have anti-inflammatory effect, to our knowledge, the effect of FGF-21 on inflammatory state in diabetes has not been elucidated. Here, we use db/db mice as a Type 2 diabetes model to determine whether FGF-21 alleviates inflammatory state while improves hyperglycemia. Our results demonstrated that FGF-21 not only showed potent long lasting hypoglycemic effect, but also demonstrated strong anti-inflammatory effect in the serum and white adipose tissue. Besides, in vitro experiments, insulin resistance (IR) was induced in 3T3-L1 adipocytes by treating with TNF-α. Our results showed that TNF-α impaired glucose metabolism of 3T3-L1 adipocytes but FGF-21 repressed gene expression of inflammatory factors caused by IR and consequently improved the glucose metabolism in 3T3-L1 adipocytes. Furthermore, FGF-21 ameliorated glucose uptake of TNF-α-induced IR in 3T3-L1 adipocytes by inhibiting NF-κB signaling pathway.
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Adipócitos/fisiologia , Tecido Adiposo Branco/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Fatores de Crescimento de Fibroblastos/metabolismo , Glucose/metabolismo , Inflamação/metabolismo , Animais , Linhagem Celular , Hiperglicemia , Resistência à Insulina , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Mutantes , NF-kappa B/metabolismo , Transdução de Sinais , Fator de Necrose Tumoral alfa/metabolismoRESUMO
Recently, FGF21 was reported to play an important role in anti-inflammation. The aim of the study is to explore the mechanism for FGF21 alleviating inflammation of CIA. CIA mice were injected with FGF21 once a day for 28 days after first booster immunization. The results showed that FGF21 alleviates arthritis severity and decreases serum anti-CII antibodies levels in CIA mice. Compared with CIA model, the number of the splenic TH17 cells was significantly decreased in FGF21-treated mice. FGF21 treatment reduced the mRNA expression of IL-17, TNF-α, IL-1ß, IL-6, IL-8, and MMP3 and increased level of IL-10 in the spleen tissue. The expression of STAT3 and phosphorylated STAT3 was suppressed in FGF21-treated group. The mRNA expression of RORγt and IL-23 also decreased. In conclusion, these findings suggest that the beneficial effects of FGF21 on CIA mice were achieved by down-regulating Th17-IL-17 axis through STAT3/RORγt pathway. Modulating of Th17-mediated inflammatory response may be one of the mechanisms for FGF21 attenuating inflammation in CIA.
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Artrite Experimental/tratamento farmacológico , Fatores de Crescimento de Fibroblastos/uso terapêutico , Interleucina-17/biossíntese , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/metabolismo , Fator de Transcrição STAT3/metabolismo , Células Th17/imunologia , Animais , Regulação para Baixo , Fatores de Crescimento de Fibroblastos/genética , Inflamação/imunologia , Interleucina-10/biossíntese , Interleucina-1beta/biossíntese , Subunidade p19 da Interleucina-23/genética , Interleucina-6/biossíntese , Interleucina-8/biossíntese , Masculino , Metaloproteinase 3 da Matriz/biossíntese , Camundongos , Camundongos Endogâmicos DBA , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/genética , Fosforilação , RNA Mensageiro/biossíntese , Fator de Transcrição STAT3/biossíntese , Baço/imunologia , Fator de Necrose Tumoral alfa/biossínteseRESUMO
Calorie restriction is known to extend lifespan among organisms by a debating mechanism underlying nitric oxide-driven mitochondrial biogenesis. We report here that nitric oxide generators including artemisinin, sodium nitroprusside, and L-arginine mimics calorie restriction and resembles hydrogen peroxide to initiate the nitric oxide signaling cascades and elicit the global antioxidative responses in mice. The large quantities of antioxidant enzymes are correlated with the low levels of reactive oxygen species, which allow the down-regulation of tumor suppressors and accessory DNA repair partners, eventually leading to the compromise of telomere shortening. Accompanying with the up-regulation of signal transducers and respiratory chain signatures, mitochondrial biogenesis occurs with the elevation of adenosine triphosphate levels upon exposure of mouse skeletal muscles to the mimetics of calorie restriction. In conclusion, calorie restriction-triggered nitric oxide provides antioxidative protection and alleviates telomere attrition via mitochondrial biogenesis, thereby maintaining chromosomal stability and integrity, which are the hallmarks of longevity.