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1.
Bioresour Technol ; 304: 122928, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32106020

RESUMO

In order to explore changes in microbial enzyme activity and bacterial community, a 60-day composting experiment was conducted using cattle manure and straw under aeration rates of 0.45, 0.68, and 0.90 L min-1 kg-1 fresh weight. High aeration rate increased the cellulase, urease, alkaline and acid phosphatase activities, but decreased that of invertase and catalase. Cellulase, alkaline phosphatase and catalase were the main enzymes that affected the composting process. Microbial analysis showed that high aeration rate increased the uniformity of bacterial community in thermophilic phase, but decreased that in mature phase. Different aeration rate affected the bacterial community structure and further influenced the relationship between enzyme and functional bacteria. Regulating the temperature, moisture content and EC in specific phases to affect bacterial community succession could provide guidance for improving maturity of composting.


Assuntos
Celulase , Compostagem , Animais , Bactérias , Bovinos , Esterco , Solo , Temperatura Ambiente
2.
Artigo em Inglês | MEDLINE | ID: mdl-31917615

RESUMO

RATIONALE: Vascular remodeling, including smooth muscle cell hypertrophy and proliferation, is the key pathological feature of pulmonary arterial hypertension (PAH). Prostaglandin (PG) I2 analogs (baraprost, iloprost, and treprostinil) are effective in the treatment of PAH. Of note, the clinically favorable effects of treprostinil in severe PAH may be attributable to concomitant activation of PGD2 receptor subtype 1 (DP1). OBJECTIVES: To study the role of DP1 in the progression of PAH and its underlying mechanism. METHODS AND RESULTS: DP1 expression was downregulated in hypoxia-treated PASMCs and in pulmonary arteries (PAs) from rodent PAH models and idiopathic PAH patients. DP1 deletion exacerbated PA remodeling in hypoxia-induced PAH, whereas pharmacological activation or forced expression of DP1 receptor had the opposite effect in different rodent models. DP1 deficiency promoted PASMC hypertrophy and proliferation in response to hypoxia via induction of mammalian target of rapamycin complex (mTORC) 1 activity. Rapamycin, an inhibitor of mTORC1, alleviated the hypoxia-induced exacerbation of PAH in DP1-/- mice. DP1 activation facilitated raptor dissociation from mTORC1 complex and suppressed mTORC1 activity through protein kinase A (PKA)-dependent phosphorylation of raptor at Ser791. Moreover, treprostinil treatment blocked the progression of hypoxia-induced PAH in mice in part by targeting DP1 receptor. CONCLUSION: DP1 activation attenuates hypoxia-induced PA remodeling and PAH through PKA-mediated dissociation of raptor from the mTORC1 complex. These results suggest that DP1 receptor may serve as a therapeutic target for the management of PAH.

3.
Acta Pharmacol Sin ; 41(3): 404-414, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31700088

RESUMO

Xanthatin is a natural sesquiterpene lactone purified from Xanthium strumarium L., which has shown prominent antitumor activity against a variety of cancer cells. In the current study, we investigated the effect of xanthatin on the growth of glioma cells in vitro and in vivo, and elucidated the underlying mechanisms. In both rat glioma C6 and human glioma U251 cell lines, xanthatin (1-15 µM) dose-dependently inhibited cell viability without apparent effect on the cell cycle. Furthermore, xanthatin treatment dose-dependently induced glioma cell apoptosis. In nude mice bearing C6 glioma tumor xenografts, administration of xanthatin (10, 20, 40 mg·kg-1·d-1, ip, for 2 weeks) dose-dependently inhibited the tumor growth, but did not affect the body weight. More importantly, xanthatin treatment markedly increased the expression levels of the endoplasmic reticulum (ER) stress-related markers in both the glioma cell lines as well as in C6 xenografts, including glucose-regulated protein 78, C/EBP-homologous protein (CHOP), activating factor 4, activating transcription factor 6, spliced X-box binding protein-1, phosphorylated protein kinase R-like endoplasmic reticulum kinase, and phosphorylated eukaryotic initiation factor 2a. Pretreatment of C6 glioma cells with the ER stress inhibitor 4-phenylbutyric acid (4-PBA, 7 mM) or knockdown of CHOP using small interfering RNA significantly attenuated xanthatin-induced cell apoptosis and increase of proapoptotic caspase-3. These results demonstrate that xanthatin induces glioma cell apoptosis and inhibits tumor growth via activating the ER stress-related unfolded protein response pathway involving CHOP induction. Xanthatin may serve as a promising agent in the treatment of human glioma.

4.
Environ Sci Pollut Res Int ; 27(4): 4115-4126, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31828712

RESUMO

The present research developed a direct in situ heterogeneous method to synthesize UiO-66-poly(m-phenylenediamine) core-shell nanostructures by inducing assembly of m-phenylenediamine radical on UiO-66 surfaces. The strong interaction between negative charged UiO-66 and positive radical from the oxidation of monomer is the major driving force. The produced UiO-66-poly(m-phenylenediamine) composites exhibited a distinct core-shell morphology with controllable surface features. The UiO-661-PmPD0.5 showed a uniform PmPD shell with a thickness of 40-60 nm and the nanocomposite exhibited a high specific surface area of 319.77 m2 g-1. Moreover, the Cr(VI) adsorption amount of the polymeric shell in the nanocomposites can reach as high as 745 mg g-1, far beyond the performance of the original PmPD. The adsorption tends to be equilibrium within 300 min. This research opens a hopeful window for facile and large-scale fabrication of core-shell nanostructures with controllable core-shell configuration, exhibiting high prospect in heavy metal removal from water.

6.
Hepatology ; 2019 Aug 30.
Artigo em Inglês | MEDLINE | ID: mdl-31469428

RESUMO

BACKGROUND AND AIMS: Endoplasmic reticulum (ER) stress is associated with liver inflammation and hepatocellular carcinoma (HCC). However, how ER stress links inflammation and HCC remains obscure. Mesencephalic astrocyte-derived neurotrophic factor (MANF) is an ER stress-inducible secretion protein that inhibits inflammation by interacting with the key subunit of nuclear factor kappa light chain enhancer of activated B cells (NF-κB) p65. We hypothesized that MANF may play a key role in linking ER stress and inflammation in HCC. APPROACH AND RESULTS: Here, we found that MANF mRNA and protein levels were lower in HCC tissues versus adjacent noncancer tissues. Patients with high levels of MANF had better relapse-free survival and overall survival rates than those with low levels. MANF levels were also associated with the status of liver cirrhosis, advanced tumor-node-metastasis (TNM) stage, and tumor size. In vitro experiments revealed that MANF suppressed the migration and invasion of hepatoma cells. Hepatocyte-specific deletion of MANF accelerated N-nitrosodiethylamine (DEN)-induced HCC by up-regulating Snail1+2 levels and promoting epithelial-mesenchymal transition (EMT). MANF appeared in the nuclei and was colocalized with p65 in HCC tissues and in tumor necrosis factor alpha (TNF-α)-treated hepatoma cells. The interaction of p65 and MANF was also confirmed by coimmunoprecipitation experiments. Consistently, knockdown of MANF up-regulated NF-κB downstream target genes TNF-α, interleukin (IL)-6 and IL-1α expression in vitro and in vivo. Finally, small ubiquitin-related modifier 1 (SUMO1) promoted MANF nuclear translocation and enhanced the interaction of MANF and p65. Mutation of p65 motifs for SUMOylation abolished the interaction of p65 and MANF. CONCLUSIONS: MANF plays an important role in linking ER stress and liver inflammation by inhibiting the NF-κB/Snail signal pathway in EMT and HCC progression. Therefore, MANF may be a cancer suppressor and a potential therapeutic target for HCC.

7.
Bioresour Technol ; 291: 121752, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31330494

RESUMO

Intensive and unregulated use of feed additives in China has led to high levels of heavy metals such as copper and zinc in fertilizers, considerable quantities of which find their way into the environment. Studies have shown that composting could significantly decrease the bioavailability of heavy metals. This study was to investigate the effects of addition of biochar and a microbial agent on the morphological changes in copper and zinc during composting. Results show that treatment T8 successfully immobilized 70.36% of copper as a result of biochar addition. Treatment T3 successfully immobilized 40.76% of zinc; transformation of zinc to a higher stable state was found to be closely related to the formation of fulvic and humic acids. Results of fluorescence spectrum analysis also corroborate that the conversion of copper and zinc to forms with higher stability was associated with the formation of fulvic and humic acid-like substances.


Assuntos
Carvão Vegetal/metabolismo , Compostagem , Cobre/metabolismo , Esterco/microbiologia , Zinco/metabolismo , Animais , Suínos
8.
FASEB J ; 33(9): 10207-10217, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31216422

RESUMO

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is an environmental pollutant that causes cardiovascular toxicity. The phenotypic transformation of vascular smooth muscle cells (VSMCs) from the contractile to the synthetic phenotype is a hallmark of vascular response to injury. However, the precise role and molecular mechanism of TCDD in vascular remodeling remains unknown. In the present study, we found that TCDD treatment promoted VSMC phenotypic transition from contractile to synthetic phenotype and exaggerated vascular neointimal hyperplasia after wire injury in mice. TCDD treatment enhanced VSMC entry into cell cycle from G0/G1 phase to S and G2/M phase. The expression of cyclin D1, cyclin-dependent kinase 4 (CDK4), and its phosphorylation were coordinately increased in response to TCDD treatment. Knocking down of aryl hydrocarbon receptor (AHR) inhibited VSMC phenotypic transition induced by TCDD and promoted S/G2 phase cell cycle arrest. TCDD treatment markedly increased oncogenic c-Jun gene expression in VSMCs. ChIP assay revealed the direct binding of AHR on the promoter of c-Jun to up-regulate the mRNA expression of c-Jun. Silencing of c-Jun gene enhanced the expression of p53 and p21, whereas attenuated the expression of CDK4 and cyclin D1 leading to the decrease in the TCDD-stimulated VSMC proliferation and synthetic phenotype transition in vitro. In vivo study showed that genetic ablation of c-Jun in VSMCs restricted injury-induced neointimal hyperplasia in TCDD-treated mice. Thus, TCDD exposure exaggerated injury-induced vascular remodeling by the activation of AHR and up-regulation of the expression of its target gene c-Jun, indicating that inhibition of AHR may be a promising prevention strategy for TCDD-associated cardiovascular diseases.-Guo, S., Zhang, R., Liu, Q., Wan, Q., Wang, Y., Yu, Y., Liu, G., Shen, Y., Yu, Y., Zhang, J. 2,3,7,8-Tetrachlorodibenzo-p-dioxin promotes injury-induced vascular neointima formation in mice.

9.
Bioorg Med Chem Lett ; 29(16): 2398-2404, 2019 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-31201064

RESUMO

Conversion of light energy to heat via photothermal conversion agents (PTCAs) is of great interest and has potential applications. Here, we described a heptamethine cyanine (Cy7) dye nanoparticles (Cy7-PEG NPs) prepared from heptamethine cyanine and poly(ethylene glycol) (PEG400) via a simple solvothermal process as novel PTCA. Cy7-PEG NPs have absorption maximum at about 808 nm and good photothermal conversion ability. Upon irradiation, Cy7-PEG NPs can effectively kill living mosquito larva (Aedes albopictus) through heat generation. Furthermore, Cy7-PEG NPs have excellent phototoxic activity to Sf9, HeLa and MCF-7 cells. Our results indicated that Cy7-PEG NPs can be used as controlling agent for mosquito larvae and cancer cells.

10.
Bioresour Technol ; 284: 56-64, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30925423

RESUMO

Biodrying of kitchen waste amended with different bulking agents was carried out to evaluate performance, heat values and combustion characteristics. Results showed that adding bulking agents produced higher water removal rates of 55.6%-65.4%. Addition of bulking agents also yielded higher volatile solid contents related to slower degradation. Lower heat values of bulking agent treatments increased from 2000-3218 kJ·kg-1 to 8544-9849 kJ·kg-1. Organic degradation did not influence ignition or combustion temperatures during the second combustion stage, but did influence combustion rate. Maximum combustion rate and temperature of the third combustion stage remained stable. Bulking agents produced higher apparent activation energies compared with the control, although biodrying made combustion of kitchen waste easier, because of an overall decrease in apparent activation energy.


Assuntos
Eliminação de Resíduos/métodos , Temperatura Alta , Temperatura Ambiente , Água
11.
J Environ Manage ; 236: 108-117, 2019 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-30721828

RESUMO

Valorization of corn waste involves synthesis of hydrochar for use as a sorbent for ammonium nitrogen recovery from swine manure compost leachate. However, the inability to directly capture organic nitrogen and insoluble nitrogen, and the low sorption ability of hydrochar remain key issues. To overcome these issues, we used hydrothermal assisted pretreatment of compost leachate to promote the solubilization of nitrogen contained in feces, and the conversion of organic nitrogen into ammonium nitrogen in the compost leachate. The synthesis hydrochar was activated with KOH to enhance its sorption ability, and then characterized by SEM, FTIR, elemental analysis, specific surface area, pore volume and size analysis. The content of ammonium nitrogen in hydrolysis leachate at 210 °C increased by 22.3% compared with raw compost leachate. 3D-EEM analysis indicated that aromatic protein substances were rapidly hydrolyzed to gradually increase the content of ammonium nitrogen and produce considerable humic acids. The maximum adsorption capacity of ammonium nitrogen reached 140.3 mg/g at 45 °C for KOH-activated hydrochar of 260 °C. The Langmuir isotherm and pseudo second order kinetic models were good fit for the adsorption process of ammonium nitrogen at higher temperature (35 °C or 45 °C), and this reaction was mainly dominated by chemisorption. The adsorption of ammonium nitrogen was exothermic, spontaneous, and showed an increase in disorder at the solid-liquid interface. For resource recovery, the total release amount of ammonium nitrogen of five interval extractions could reach 12.2% of maximum adsorption capacity (140.3 mg/g) under alkaline (pH 8.0) condition. The nitrogen mass balance calculation revealed that 8.9% of total nitrogen in the compost leachate could be recovered.


Assuntos
Compostos de Amônio , Compostagem , Adsorção , Animais , Nitrogênio , Suínos , Zea mays
12.
J Neuroinflammation ; 16(1): 35, 2019 Feb 13.
Artigo em Inglês | MEDLINE | ID: mdl-30760285

RESUMO

BACKGROUND: Extracellular accumulation of amyloid ß-peptide (Aß) is one of pathological hallmarks of Alzheimer's disease (AD) and contributes to the neuronal loss. Mesencephalic astrocyte-derived neurotrophic factor (MANF) is an endoplasmic reticulum (ER) stress-inducible neurotrophic factor. Many groups, including ours, have proved that MANF rescues neuronal loss in several neurological disorders, such as Parkinson's disease and cerebral ischemia. However, whether MANF exerts its protective effect against Aß neurotoxicity in AD remains unknown. METHODS: In the present study, the characteristic expressions of MANF in Aß1-42-treated neuronal cells as well as in the brains of APP/PS1 transgenic mice were analyzed by immunofluorescence staining, qPCR, and Western blot. The effects of MANF overexpression, MANF knockdown, or recombination human MANF protein (rhMANF) on neuron viability, apoptosis, and the expression of ER stress-related proteins following Aß1-42 exposure were also investigated. RESULTS: The results showed the increased expressions of MANF, as well as ER stress markers immunoglobulin-binding protein (BiP) and C/EBP homologous protein (CHOP), in the brains of the APP/PS1 transgenic mice and Aß1-42-treated neuronal cells. MANF overexpression or rhMANF treatment partially protected against Aß1-42-induced neuronal cell death, associated with marked decrease of cleaved caspase-3, whereas MANF knockdown with siRNA aggravated Aß1-42 cytotoxicity including caspase-3 activation. Further study demonstrated that the expressions of BiP, ATF6, phosphorylated-IRE1, XBP1s, phosphorylated-eIF2α, ATF4, and CHOP were significantly downregulated by MANF overexpression or rhMANF treatment in neuronal cells following Aß1-42 exposure, whereas knockdown of MANF has the opposite effect. CONCLUSIONS: These findings demonstrate that MANF may exert neuroprotective effects against Aß-induced neurotoxicity through attenuating ER stress, suggesting that an applicability of MANF as a therapeutic candidate for AD.


Assuntos
Peptídeos beta-Amiloides/toxicidade , Apoptose/efeitos dos fármacos , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Fatores de Crescimento Neural/metabolismo , Fatores de Crescimento Neural/uso terapêutico , Neurônios/efeitos dos fármacos , Fragmentos de Peptídeos/toxicidade , Regulação para Cima/efeitos dos fármacos , Precursor de Proteína beta-Amiloide/genética , Precursor de Proteína beta-Amiloide/metabolismo , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Células Cultivadas , Córtex Cerebral/citologia , Embrião de Mamíferos , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Fatores de Crescimento Neural/genética , Neuroblastoma/patologia , Fosfopiruvato Hidratase/metabolismo , Presenilina-1/genética , Presenilina-1/metabolismo , RNA Interferente Pequeno/farmacologia , RNA Interferente Pequeno/uso terapêutico
13.
Environ Sci Process Impacts ; 21(3): 575-583, 2019 Mar 20.
Artigo em Inglês | MEDLINE | ID: mdl-30758007

RESUMO

The considerable spatial and temporal variabilities of nitrogen (N) processing introduce large uncertainties for quantifying N cycles on a large scale, particularly in plain river network regions with complicated hydrographic connections and mixed multiple N sources. In this paper, the dual isotopes δ15N and δ18O and dissolved anions in regularly collected samples (n = 10) from the studied river, which is one of the most seriously polluted rivers in the plain river network regions of the Taihu Lake catchment, were analyzed to ascertain the main nitrate (NO3-) sources and watershed N processing in the context of monsoon climate. The seasonal variations in precipitation, temperature, and hydrology play key roles in the regulation of the river NO3- concentration, NO3- sources, and watershed N processing. Nitrification of N-containing materials in the soil was possibly the major source of NO3- all year round, especially in the rainy season, whereas manure and sewage significantly contributed to the NO3- load in the Taige River in the dry season. Nitrification and denitrification processes within the area were closely related. The significant negative relationship between the water temperature and δ18O-NO3- values indicated the occurrence of nitrification in the soil throughout the year. By contrast, seasonal variations of denitrification were apparent from May to July with the high soil temperature and moisture, thereby indicating the occurrence of denitrification (22.9%) within the watershed. After the assessment of temporal variations of NO3- sources and watershed N processing, improved environmental management practices can be implemented to protect water resources and prevent further water quality deterioration in human-impacted watersheds.


Assuntos
Monitoramento Ambiental/métodos , Nitratos/análise , Ciclo do Nitrogênio , Rios/química , Poluentes Químicos da Água/análise , China , Desnitrificação , Humanos , Hidrologia , Lagos/química , Nitrificação , Isótopos de Nitrogênio/análise , Isótopos de Oxigênio/análise , Estações do Ano , Solo/química
14.
Eur J Pharmacol ; 843: 1-11, 2019 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-30389633

RESUMO

Hepatocellular carcinoma (HCC) has high incidence and mortality in patients with chronic liver diseases worldwide. However, there are limited chemotherapeutic agents for HCC in clinic. Xanthatin, a natural sesquiterpene lactone, has significant antitumor activity against a variety of cancers, but little is known about its effects on HCC and the underlying mechanism. Here, we evaluated the antitumor effects of xanthatin on human hepatoma cells. We found that xanthatin caused morphological changes and reduced cell viability in three HCC cell lines in concentration- and time-dependent manners. Xanthatin at 10 µM significantly arrested cell cycle at the G2/M checkpoint, and at 40 µM significantly arrested cell cycle at the S phase in hepatoma cells. Additionally, xanthatin induced apoptosis associated with activation of caspase-3 in hepatoma cells, but did not apparently induce apoptosis in human normal LO2 hepatocytes. We also demonstrated that the three primary signaling pathways of unfolded protein response (UPR) were activated by xanthatin to different extents. Notably, the PERK/eIF-2α/ATF4 axis was most significantly activated by xanthatin. More importantly, both xanthatin and tunicamycin, an endoplasmic reticulum stress (ERS) inducing compound, increased the levels of CHOP and cleaved-caspase-3 in HepG2 cells, but their effects were significantly abolished by siRNA-mediated knockdown of CHOP. Further experiments validated that xanthatin more potently activated ATF4 by promoting its nuclear translocation in hepatoma cells. Taken together, we discovered that xanthatin induced apoptosis in human hepatoma cells by activating ERS. Our current data revealed a novel mechanism for xanthatin as a promising anti-tumor candidate for HCC therapy.


Assuntos
Antineoplásicos/farmacologia , Carcinoma Hepatocelular/tratamento farmacológico , Furanos/farmacologia , Neoplasias Hepáticas/tratamento farmacológico , Fator 4 Ativador da Transcrição/genética , Fator 4 Ativador da Transcrição/metabolismo , Apoptose/efeitos dos fármacos , Carcinoma Hepatocelular/metabolismo , Linhagem Celular , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Fator de Iniciação 2 em Eucariotos/metabolismo , Hepatócitos/efeitos dos fármacos , Hepatócitos/metabolismo , Humanos , Neoplasias Hepáticas/metabolismo , Fator de Transcrição CHOP/genética , Fator de Transcrição CHOP/metabolismo , eIF-2 Quinase/metabolismo
15.
Acad Radiol ; 26(8): e224-e232, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-30385206

RESUMO

RATIONALE AND OBJECTIVES: To investigate the feasibility of determining quantitative parameters for evaluating tumor hypoxia in the C6 glioma model by dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI). MATERIALS AND METHODS: Thirty male Sprague-Dawley rats were inoculated to establish C6 brain glioma models. DCE-MRI scans were performed 14, 21, and 28 days after transplantation. Quantitative parameters comprising Ktrans, Ve, Kep, and Vp were calculated and analyzed. At the end of each scan, 10 rats were randomly selected for immunohistochemical (IHC) staining of hypoxia-inducible factor-17αl (HIF-1α), proliferating cell nuclear antigen (PCNA), and CD34. Correlations between quantitative parameters and IHC scores were analyzed. RESULTS: The tumor volumes increased with time. The Ktrans values on days 14, 21, and 28 were 0.03 ± 0.009 min-1, 0.084 ± 0.010 min-1, and 0.050 ± 0.016 min-1, while the Ve values were 0.17 ± 0.070, 0.46 ± 0.159, and 0.51 ± 0.193, the Kep values were 0.18 ± 0.070%, 0.220 ± 0.049%, and 0.06 ± 0.035%, and these three parameters all differed significantly among the three time points. The Vp values on days 14, 21, and 28 were 0.09 ± 0.040%, 0.120 ± 0.034%, and 0.06 ± 0.010%, but the values did not differ among the three time points (P = 0.073). Ktrans had significant negative correlations with the HIF-1α scores on days 14 and 21 when there was also a positive correlation between Ktrans and CD34. Ve had negative correlations with the HIF-1α score on days 14 and 21, and there was a negative correlation between Ve and PCNA on day 21. Kep had a negative correlation with the HIF-1α score and a positive correlation with MVD on day 21. CONCLUSIONS: DCE-MRI may be a useful method for the noninvasive evaluation of the hypoxia status in a glioma model.

16.
Mol Med Rep ; 18(6): 5765-5774, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30365109

RESUMO

Mesencephalic astrocyte­derived neurotrophic factor (MANF) is an endoplasmic reticulum stress­inducible protein, which has been suggested to be upregulated in inflammatory diseases; however, how inflammation regulates its transcription remains unclear. Activator protein­1 (AP­1), which is a transcription factor complex composed of c­Fos and c­Jun, is activated during the inflammatory process. The present study aimed to investigate whether the AP­1 complex regulates MANF transcription. The results of a luciferase reporter assay revealed that one of three putative AP­1 binding sites in the MANF promoter region is essential for enhancement of MANF transcription. Mechanistically, AP­1 was revealed to directly bind to the promoter region of the MANF gene by chromatin immunoprecipitation assay. Furthermore, MANF was strongly expressed in the liver tissues of patients with hepatitis B virus (HBV) infection, compared with in normal liver tissues from patients with hepatic hemangioma. Furthermore, c­Fos and c­Jun were also upregulated in the nuclei of hepatocytes from patients with HBV infection. In mice treated with carbon tetrachloride, the expression patterns of MANF, c­Fos and c­Jun were similar to those in patients with HBV. These results suggested that the AP­1 complex may be a novel regulator of MANF transcription, which may be involved in liver inflammation and fibrosis.


Assuntos
Regulação da Expressão Gênica , Fatores de Crescimento Neural/genética , Fator de Transcrição AP-1/metabolismo , Transcrição Genética , Animais , Sequência de Bases , Sítios de Ligação , Células Cultivadas , Modelos Animais de Doenças , Feminino , Humanos , Imuno-Histoquímica , Hepatopatias/etiologia , Hepatopatias/metabolismo , Hepatopatias/patologia , Masculino , Camundongos , Pessoa de Meia-Idade , Regiões Promotoras Genéticas , Ligação Proteica
17.
J Exp Med ; 215(8): 2175-2195, 2018 08 06.
Artigo em Inglês | MEDLINE | ID: mdl-29970474

RESUMO

Pulmonary arterial hypertension (PAH) is a life-threatening disease characterized by progressive pulmonary artery (PA) remodeling. T helper 2 cell (Th2) immune response is involved in PA remodeling during PAH progression. Here, we found that CRTH2 (chemoattractant receptor homologous molecule expressed on Th2 cell) expression was up-regulated in circulating CD3+CD4+ T cells in patients with idiopathic PAH and in rodent PAH models. CRTH2 disruption dramatically ameliorated PA remodeling and pulmonary hypertension in different PAH mouse models. CRTH2 deficiency suppressed Th2 activation, including IL-4 and IL-13 secretion. Both CRTH2+/+ bone marrow reconstitution and CRTH2+/+ CD4+ T cell adoptive transfer deteriorated hypoxia + ovalbumin-induced PAH in CRTH2-/- mice, which was reversed by dual neutralization of IL-4 and IL-13. CRTH2 inhibition alleviated established PAH in mice by repressing Th2 activity. In culture, CRTH2 activation in Th2 cells promoted pulmonary arterial smooth muscle cell proliferation through activation of STAT6. These results demonstrate the critical role of CRTH2-mediated Th2 response in PAH pathogenesis and highlight the CRTH2 receptor as a potential therapeutic target for PAH.


Assuntos
Hipertensão Pulmonar/imunologia , Ativação Linfocitária/imunologia , Receptores Imunológicos/metabolismo , Receptores de Prostaglandina/metabolismo , Células Th2/imunologia , Transferência Adotiva , Adulto , Animais , Anticorpos/farmacologia , Pressão Sanguínea/efeitos dos fármacos , Medula Óssea/efeitos dos fármacos , Medula Óssea/metabolismo , Proliferação de Células/efeitos dos fármacos , Quimera , Doença Crônica , Modelos Animais de Doenças , Feminino , Deleção de Genes , Humanos , Hipertensão Pulmonar/fisiopatologia , Hipóxia/complicações , Hipóxia/fisiopatologia , Imunidade/efeitos dos fármacos , Indóis , Pulmão/efeitos dos fármacos , Pulmão/patologia , Pulmão/fisiopatologia , Masculino , Camundongos , Ovalbumina , Artéria Pulmonar/efeitos dos fármacos , Artéria Pulmonar/patologia , Artéria Pulmonar/fisiopatologia , Pirróis , Receptores Imunológicos/deficiência , Receptores de Prostaglandina/deficiência , Fator de Transcrição STAT6/metabolismo , Regulação para Cima/efeitos dos fármacos
18.
World Neurosurg ; 117: e117-e129, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-29883817

RESUMO

BACKGROUND: Our previous studies have shown that mesencephalic astrocyte-derived neurotrophic factor (MANF) provides a neuroprotective effect against ischemia/reperfusion injury and is also involved in inflammatory disease models. This study investigates the potential role and mechanism of MANF in acute brain damage after traumatic brain injury (TBI). METHODS: The model of TBI was induced by Feeney free falling methods with male Sprague-Dawley rats. The expression of MANF, 24 hours after TBI, was detected by the immunohistochemistry, immunofluorescence, Western blot, and reverse transcription polymerase chain reaction techniques. After treatment with recombinant human MANF after TBI, assessment was conducted 24 hours later for brain water content, cerebral edema volume in magnetic resonance imaging, neurobehavioral testing, and Evans blue extravasation. Moreover, by the techniques of Western blot and reverse transcription polymerase chain reaction, the expression of inflammatory cytokines (interleukin 1ß and tumor necrosis factor α) and P65 was also analyzed to explore the underlying protective mechanism of MANF. RESULTS: At 24 hours after TBI, we found that endogenous MANF was widely expressed in the rat's brain tissues and different types of cells. Treatment with a high dose of recombinant human MANF (20 µg/20 µL) significantly increased the modified Garcia score, and reduced brain water content as well as cerebral edema volume on magnetic resonance imaging. Furthermore, MANF alleviated not only the permeability of the blood-brain barrier (BBB) but also the expressions of interleukin 1ß and tumor necrosis factor α messenger RNA and protein. Besides, the activation of P65 was also inhibited. CONCLUSIONS: These results suggest that MANF provides a neuroprotective effect against acute brain injury after TBI, via attenuating blood-brain barrier disruption and intracranial neuroinflammation; the inhibition of the NF-κB signaling pathway might be a potential mechanism.


Assuntos
Barreira Hematoencefálica/efeitos dos fármacos , Lesões Encefálicas Traumáticas/prevenção & controle , Fatores de Crescimento Neural/farmacologia , Fármacos Neuroprotetores/farmacologia , Animais , Masculino , Doenças do Sistema Nervoso/etiologia , Distribuição Aleatória , Ratos Sprague-Dawley , Proteínas Recombinantes/farmacologia
19.
FASEB J ; 32(10): 5413-5425, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-29723062

RESUMO

Mechanical insults, such as stent implantation, can induce endothelial injury, vascular inflammation, and ultimately lead to vascular neointimal hyperplasia. Resolvin E1 (RvE1), derived from the ω3 fatty acid eicosapentaenoic acid, can facilitate the resolution of inflammation in many settings. We therefore aimed to determine if there was a role for RvE1 in preventing neointimal formation after arterial injury and to understand the underlying mechanisms. Vascular inflammation and neointimal hyperplasia were induced by wire injury in the femoral arteries of mice. Administration of exogenous RvE1 and endogenously generated RvE1 via dietary supplementation with eicosapentaenoic acid and aspirin markedly reduced vascular neointima formation in this model. Mechanistically, RvE1 was found to inhibit vascular neutrophil infiltration, promote macrophage polarization toward an M2-like phenotype, suppress T-cell trafficking by reducing RANTES secretion from vascular smooth muscle cells, and inhibit vascular smooth muscle cell migration. In summary, RvE1 demonstrated a protective role against vascular inflammation and remodeling in response to mechanical injury, suggesting that it may serve as an adjuvant therapeutic agent for percutaneous coronary interventions, such as stent implantation.-Liu, G., Gong, Y., Zhang, R., Piao, L., Li, X., Liu, Q., Yan, S., Shen, Y., Guo, S., Zhu, M., Yin, H., Funk, C. D., Zhang, J., Yu, Y. Resolvin E1 attenuates injury-induced vascular neointimal formation by inhibition of inflammatory responses and vascular smooth muscle cell migration.


Assuntos
Movimento Celular/efeitos dos fármacos , Ácido Eicosapentaenoico/análogos & derivados , Artéria Femoral , Músculo Liso Vascular/metabolismo , Miócitos de Músculo Liso/metabolismo , Neointima/prevenção & controle , Animais , Modelos Animais de Doenças , Ácido Eicosapentaenoico/farmacologia , Artéria Femoral/lesões , Artéria Femoral/metabolismo , Artéria Femoral/patologia , Inflamação/metabolismo , Inflamação/patologia , Inflamação/prevenção & controle , Masculino , Camundongos , Músculo Liso Vascular/patologia , Miócitos de Músculo Liso/patologia , Neointima/metabolismo , Neointima/patologia
20.
Diabetes ; 67(9): 1748-1760, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-29773555

RESUMO

Gluconeogenesis is drastically increased in patients with type 2 diabetes and accounts for increased fasting plasma glucose concentrations. Circulating levels of prostaglandin (PG) F2α are also markedly elevated in diabetes; however, whether and how PGF2α regulates hepatic glucose metabolism remain unknown. Here, we demonstrated that PGF2α receptor (F-prostanoid receptor [FP]) was upregulated in the livers of mice upon fasting- and diabetic stress. Hepatic deletion of the FP receptor suppressed fasting-induced hepatic gluconeogenesis, whereas FP overexpression enhanced hepatic gluconeogenesis in mice. FP activation promoted the expression of gluconeogenic enzymes (PEPCK and glucose-6-phosphatase) in hepatocytes in a FOXO1-dependent manner. Additionally, FP coupled with Gq in hepatocytes to elicit Ca2+ release, which activated Ca2+/calmodulin-activated protein kinase IIγ (CaMKIIγ) to increase FOXO1 phosphorylation and subsequently accelerate its nuclear translocation. Blockage of p38 disrupted CaMKIIγ-induced FOXO1 nuclear translocation and abrogated FP-mediated hepatic gluconeogenesis in mice. Moreover, knockdown of hepatic FP receptor improved insulin sensitivity and glucose homeostasis in ob/ob mice. FP-mediated hepatic gluconeogenesis via the CaMKIIγ/p38/FOXO1 signaling pathway, indicating that the FP receptor might be a promising therapeutic target for type 2 diabetes.


Assuntos
Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/metabolismo , Dinoprosta/metabolismo , Proteína Forkhead Box O1/metabolismo , Gluconeogênese , Fígado/metabolismo , Obesidade/metabolismo , Receptores de Prostaglandina/agonistas , Transporte Ativo do Núcleo Celular/efeitos dos fármacos , Animais , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/química , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/genética , Células Cultivadas , Cruzamentos Genéticos , Dieta Hiperlipídica/efeitos adversos , Jejum/metabolismo , Proteína Forkhead Box O1/agonistas , Proteína Forkhead Box O1/genética , Regulação da Expressão Gênica/efeitos dos fármacos , Gluconeogênese/efeitos dos fármacos , Humanos , Resistência à Insulina , Fígado/citologia , Fígado/efeitos dos fármacos , Fígado/patologia , Camundongos Endogâmicos C57BL , Camundongos Obesos , Camundongos Transgênicos , Obesidade/etiologia , Obesidade/patologia , Inibidores de Proteínas Quinases/farmacologia , Interferência de RNA , Receptores de Prostaglandina/antagonistas & inibidores , Receptores de Prostaglandina/genética , Receptores de Prostaglandina/metabolismo , Transdução de Sinais/efeitos dos fármacos , Proteínas Quinases p38 Ativadas por Mitógeno/antagonistas & inibidores , Proteínas Quinases p38 Ativadas por Mitógeno/genética , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
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