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BACKGROUND: Alcohol-associated liver disease (ALD) is one of the most common chronic liver diseases worldwide. Fetuin-A (FetA) is a plasma glycoprotein closely related to fat accumulation in the liver. However, the role of FetA in ALD remains unclear. METHODS: Both National Institute on Alcohol Abuse and Alcoholism (NIAAA) model and ethanol (EtOH) treated cell were used in this study. The effect of FetA deficiency on the progression of ALD was analyzed and the underlying mechanism was explored. RESULTS: The expression of FetA was upregulated in the liver tissues of ethanol-fed mice and ALD patients, as well as in AML12 cells treated with ethanol. FetA deletion reduced hepatic steatosis, oxidative stress, and inflammation in ALD mice. Interestingly, the absence of FetA led to a reduction of TLR4 protein level in liver tissue of EtOH-fed mice, without a corresponding change of its mRNA level. Conversely, the administration of recombinant FetA elevated TLR4 protein level in ethanol-treated RAW264.7 cells. FetA knockout significantly impeded the polarization of M1 macrophage in vivo or in vitro. Mechanistically, FetA deficiency drived the autophagy-lysosomal degradation of TLR4, subsequently inhibiting the activation of NF-kB/NLRP3 inflammasome pathway. Furthermore, knockdown of FetA using an adeno-associated virus 8 (AAV8)-shRNA can effectively prevent the progression of ALD in mice. CONCLUSION: Our results indicate that inhibition of FetA reverses the progression of ALD in mice, implying that FetA can serve as a therapeutic target for the treatment of ALD.
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In contrast to the unipedal DNA walker, a bipedal DNA walker features a broader walking area and exhibits faster walking kinetics, leading to enhanced amplification efficiency. In this study, we designed a stochastic three-dimensional (3D) bipedal DNA walker, capable of navigating AuNP-based 3D tracks, driven by exonuclease III (Exo III). This detection system enables the linear detection of the non-invasive biomarker apurinic/apyrimidinic endonuclease 1 (APE1) activity across a range of 0 to 120 U per mL, with a detection limit of 0.03 U per mL. The platform not only offers a novel DNA walker for sensitive APE1 detection in cell lysate but also facilitates the precise assessment of NCA's inhibitory effect on APE1. This research holds promise for future screening of other potential APE1 inhibitors.
Assuntos
DNA Liase (Sítios Apurínicos ou Apirimidínicos) , DNA , DNA Liase (Sítios Apurínicos ou Apirimidínicos)/metabolismo , Humanos , DNA/química , DNA/análise , Ouro/química , Limite de Detecção , Nanopartículas Metálicas/química , Exodesoxirribonucleases/química , Exodesoxirribonucleases/metabolismo , Técnicas Biossensoriais/métodosRESUMO
Previous studies on Ranunculus sceleratus L. have shown the existence of coumarins and their anti-inflammatory effect. Phytochemical work was conducted to investigate the bioactive compounds, leading to the isolation of two undescribed benzopyran derivatives, namely ranunsceleroside A (1) and B (3), together with two known coumarins (2, 4) from the whole plant of R. sceleratus L. All compounds were structurally identified by extensive spectroscopic analysis and then investigated for their inhibitory effect on nitric oxide (NO), tumor necrosis factor-α (TNF-α), interleukin-1ß (IL-1ß) and interleukin-6 (IL-6) production induced by lipopolysaccharide (LPS) in RAW 264.7 murine macrophages, repectively. As a result, compound 1-4 presented inhibitory effects on the production of NO, TNF-α, IL-1ß, and IL-6 in a concentration-dependent manner, which provides a potential chemical basis for the traditional use of R. sceleratus L. as an anti-inflammatory plant.
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Benzopiranos , Ranunculus , Animais , Camundongos , Benzopiranos/farmacologia , Células RAW 264.7 , Lipopolissacarídeos/farmacologia , Interleucina-6 , Fator de Necrose Tumoral alfa , Cumarínicos/farmacologia , Anti-Inflamatórios/farmacologia , Interleucina-1beta , Óxido NítricoRESUMO
BACKGROUND: Nonalcoholic steatohepatitis (NASH) is an advanced form of chronic fatty liver disease, which is a driver of hepatocellular carcinoma. However, the roles of the C5aR1 in the NASH remain poorly understood. Here, we aimed to investigate the functions and mechanisms of the C5aR1 on hepatic inflammation and fibrosis in murine NASH model. METHODS: Mice were fed a normal chow diet with corn oil (ND + Oil), a Western diet with corn oil (WD + Oil) or a Western diet with carbon tetrachloride (WD + CCl4) for 12 weeks. The effects of the C5a-C5aR1 axis on the progression of NASH were analyzed and the underlying mechanisms were explored. RESULTS: Complement factor C5a was elevated in NASH mice. C5 deficiency reduced hepatic lipid droplet accumulation in the NASH mice. The hepatic expression levels of TNFα, IL-1ß and F4/80 were decreased in C5-deficient mice. C5 loss alleviated hepatic fibrosis and downregulated the expression levels of α-SMA and TGFß1. C5aR1 deletion reduced inflammation and fibrosis in NASH mice. Transcriptional profiling of liver tissues and KEGG pathway analysis revealed that several pathways such as Toll-like receptor signaling, NFκB signaling, TNF signaling, and NOD-like receptor signaling pathway were enriched between C5aR1 deficiency and wild-type mice. Mechanistically, C5aR1 deletion decreased the expression of TLR4 and NLRP3, subsequently regulating macrophage polarization. Moreover, C5aR1 antagonist PMX-53 treatment mitigated the progression of NASH in mice. CONCLUSIONS: Blockade of the C5a-C5aR1 axis reduces hepatic steatosis, inflammation, and fibrosis in NASH mice. Our data suggest that C5aR1 may be a potential target for drug development and therapeutic intervention of NASH.
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Hepatite , Neoplasias Hepáticas , Hepatopatia Gordurosa não Alcoólica , Camundongos , Animais , Hepatopatia Gordurosa não Alcoólica/patologia , Receptor 4 Toll-Like/metabolismo , Óleo de Milho/metabolismo , Óleo de Milho/uso terapêutico , Camundongos Knockout , Fígado/patologia , Fibrose , Cirrose Hepática/patologia , Modelos Animais de Doenças , Inflamação/tratamento farmacológico , Inflamação/patologia , Transdução de Sinais , Neoplasias Hepáticas/patologia , Macrófagos/metabolismo , Macrófagos/patologia , Camundongos Endogâmicos C57BLRESUMO
To achieve carbon neutrality and carbon reduction goals, China needs to consider industrial structure and trade. This study aims to test the validity of environmental Kuznets curve (EKC) hypothesis at the industry level in China and study the different impact of Sino-US trade in intermediate goods and trade in final goods on China's environment. To do so, we used the annual data of China's 25 sectors in 1990-2015 and classified 25 sectors into three main industries. Based on the Stochastic Impacts by Regression on Population, Affluence and Technology framework, we investigated the validity of EKC hypothesis and the driving factors of greenhouse gas (GHG) emissions. The results show that (1) EKC hypothesis is verified for the country and the tertiary industry. (2) Compared with the primary industry and the secondary industry, the economic growth of the tertiary industry brings less GHG emissions. (3) Intermediate goods exported to all sectors in the USA will increase GHG emissions in the country and the three main industries, but final goods exported to consumers in the USA will reduce GHG emissions except the tertiary industry. From our results, the EKC hypothesis is a suitable model for environmental policy in tertiary industry, but it does not apply to the primary industry and the secondary industry. Environmental policy in the primary industry and the secondary industry needs to focus on reducing energy intensity. In the case of exports to the USA, intermediate goods pollute the environment, while final improve the environment. Thus, China needs to increase controls on exports of intermediate goods with low added value and high pollution and gradually shift to the production of environmentally friendly final goods.
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Dióxido de Carbono , Gases de Efeito Estufa , Carbono , Dióxido de Carbono/análise , China , Desenvolvimento Econômico , IndústriasRESUMO
Aims. To assess the concentrations of serum CXCL13 and intrarenal ectopic lymphoid tissue (ELT) profiles and their correlation in the patients with lupus nephritis (LN). Methods. Serum CXCL13 levels were measured using enzyme-linked immunosorbent assays (ELISA). The expression of CD3, CD20, and CD21 in renal biopsy specimens was tested using immunohistochemical methods. Results. Serum CXCL13 levels were significantly higher in the LN group than those in the SLE group without LN and also in the type III and IV LN patients than in type V LN patients. LN patients with positive CD20 expression (CD20+ LN) had a longer disease course and poorer response to combination therapy and higher serum CXCL13 levels than CD20- LN patients. Moreover, the serum CXCL13 level was positively correlated with the number of B cells/HP in the renal tissue of LN patients. The coexpression patterns of CD3, CD20, and CD21 in the renal tissue of LN patients with different WHO pathological types were significantly different. Serum CXCL13 levels were significantly higher in ELT-2 type LN patients than in 0 or 1 type LN patients. Conclusions. This study suggested that increased serum levels of CXCL13 might be involved in renal ELT formation and renal impairment process in LN.
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Quimiocina CXCL13/sangue , Rim/imunologia , Nefrite Lúpica/imunologia , Estruturas Linfoides Terciárias/fisiopatologia , Adulto , Antígenos CD20/genética , Biópsia , Complexo CD3/genética , Progressão da Doença , Ensaio de Imunoadsorção Enzimática , Feminino , Humanos , Imuno-Histoquímica , Rim/citologia , Rim/patologia , Nefrite Lúpica/sangue , Nefrite Lúpica/fisiopatologia , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Receptores de Complemento 3d/genéticaRESUMO
BACKGROUND: Human chorionic gonadotropin-beta (ß-hCG) is an important index used to monitor embryonic development following embryo transfer. Architect i2000sr and Cobas e601 are widely used automated immunoassay systems used to measure serum ß-hCG concentrations; however, the correlations between serum ß-hCG levels measured with these two immunoassays and the accuracy of the immunoassays have not been fully evaluated. METHODS: Serum ß-hCG levels were measured in 133 serum samples using the Architect i2000sr and Cobas e601 automated immunoassay systems. Passing-Bablok regression analysis was used to compare the correlation in serum ß-hCG levels obtained using the two immunoassays. A Bland-Altman plot analysis was used to identify mean ratios and 95% CIs of the mean ratios of the ß-hCG results between the two immunoassays. In this graphical method the mean ratios between the two techniques were plotted against the averages of the two techniques. RESULTS: The total coefficients of variations (CVs) of serum ß-hCG ranged from 3.12 - 4.66% for Cobas e601 and 3.18 - 4.99% for Architect i2000sr. The measured value of serum ß-hCG detected by the two immunoassays was statistically significant (p < 0.001). The Passing-Bablok regression analysis showed good correlation between the serum ß-hCG values measured using the two systems. At a low concentration of serum ß-hCG (< 10000 IU/L, n = 52), the correlation coefficient r was 0.9628. At a high concentration of serum ß-hCG (> 10000 IU/L, n = 81), the correlation coefficient r was 0.8076. The Bland-Altman plot analysis showed that the measured value of serum ß-hCG detected by Architect i2000sr was about 1.25 times higher than that of Cobas e601. The mean ratio was 1.12 at a low concentration of serum ß-hCG, and it was 1.33 at a high concentration. CONCLUSIONS: Architect i2000sr and Cobas e601 have good concordance for determining serum ß-hCG. However, the ß-hCG values measured with Architect i2000sr were 25% higher than those obtained using Cobas e601.
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Gonadotropina Coriônica Humana Subunidade beta/sangue , Desenvolvimento Embrionário , Imunoensaio/métodos , Adulto , Biomarcadores/sangue , Transferência Embrionária , Feminino , Humanos , Gravidez , Análise de RegressãoRESUMO
Naringin, a well-known flavanone glycoside of grapefruit and citrus fruits, was found to be as an effective anti-inflammatory compound in our previous lipopolysaccharide-induced acute lung injury mouse model via blockading activity of nuclear factor κB. The current study sought to explore the anti-inflammatory effects of naringin on chronic pulmonary neutrophilic inflammation in cigarette smoke (CS)-induced rats. Seventy Sprague-Dawley rats were randomly divided into seven groups to study the effects of CS with or without various concentrations of naringin or saline for 8 weeks. The results revealed that naringin supplementation at 20, 40, and 80 mg/kg significantly increased body weight of CS-induced rats as compared to that in the CS group. Moreover, naringin of 20, 40, and 80 mg/kg prevented CS-induced infiltration of neutrophils and activation of myeloperoxidase and matrix metalloproteinase-9, in parallel with suppression of the release of cytokines, such as tumor necrosis factor-α and interleukin-8 (IL-8). IL-10 in bronchoalveolar lavage fluid was significantly suppressed after CS exposure, but dose dependently elevated by naringin. The results from hematoxylin and eosin staining revealed that naringin dose dependently reduced CS-induced infiltration of inflammatory cells, thickening of the bronchial wall, and expansion of average alveolar airspace. In conclusion, our data suggest that naringin is an effective anti-inflammatory compound for attenuating chronic pulmonary neutrophilic inflammation in CS-induced rats.