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Depression is a high-incidence mental illness that seriously affects human health. AQP4 has been reported to be closely associated with depression, while the underlying mechanism is still unclear. This work aimed to investigate the functional role of AQP4 in depression. Depression mouse model was constructed by administration of chronic social defeat stress (CSDS). We found that AQP4 was highly expressed in the hippocampal tissues of CSDS mice. AQP4 knockdown alleviated depression and enhanced the expression of NR2B and PSD95 in CSDS mice. Moreover, primary hippocampal neurons were treated with N-methyl-d-aspartate (NMDA) to induce neuron injury. AQP4 overexpression repressed cell viability and promoted apoptosis of NMDA-treated primary hippocampal neurons. AQP4 up-regulation repressed the expression of NR2B (surface), and enhanced the expression of NR2B (intracellular), P-NR2B, CaMK II and CK2 in the NMDA-treated primary hippocampal neurons. The influence conferred by AQP4 up-regulation was abolished by KN-93 (CaMK II inhibitor) or TBB (CK2 inhibitor) treatment. Rapamycin treatment enhanced the expression of NR2B (surface), and repressed the expression of AQP4, NR2B (intracellular) and P-NR2B in the primary hippocampal neurons by activating autophagy. The activated autophagy alleviated depression in CSDS mice by repressing AQP4 expression. In conclusion, our data demonstrated that autophagy ameliorated depression by repressing AQP4 expression in mice, and AQP4 knockdown promoted membrane trafficking of NR2B and inhibited phosphorylation of NR2B via CaMK II/CK2 pathway. Thus, our work suggests that AQP4 may be a promising molecular target for the development of antidepressant drugs.
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N-Metilaspartato , Receptores de N-Metil-D-Aspartato , Animais , Autofagia , Depressão , Hipocampo , Humanos , CamundongosRESUMO
Cognitive deficits are the core feature of schizophrenia and effective treatment strategies are still missing. Previous studies have reported that fisetin promotes long-term potentiation (LTP) and cognitive function in normal rodents and other model animals of neurological diseases. The aim of this study was to assess the effect of fisetin on synaptic plasticity and cognitive deficits caused by a brief disruption of N-methyl-D-aspartate receptors (NMDARs) with dizocilpine (MK-801) during early development in rats. The cognitive performance was examined by the Morris water maze task and a fear conditioning test. Hippocampal synaptic plasticity was investigated by field potential recording. The expression of α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors (AMPARs) and cognition-related proteins was measured by western blotting. We found that intraperitoneal administration of fisetin rescued hippocampus-dependent spatial and contextual fear memory in MK-801 rats. In parallel with these behavioral results, fisetin treatment in MK-801 rats reversed the impairment of hippocampal LTP. At the molecular level, fisetin treatment selectively increased the phosphorylation and surface expression of AMPA receptor subunit 1 (GluA1) in MK-801-treated rats. Moreover, fisetin restored the phosphorylation levels of calcium-calmodulin-dependent kinaseII (CaMKII), cAMP response element-binding protein (CREB), and the extracellular signal-regulated kinase (ERK1/2) in MK-801-treated rats. Collectively, our findings demonstrate that fisetin treatment can reverse the deficits of hippocampal synaptic plasticity and memory in a male rat model of schizophrenia by restoring the phosphorylation and surface expression of AMPAR GluA1 subunit, suggesting fisetin as a promising therapeutic candidate for schizophrenia-associated cognitive deficits.
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Cognição/efeitos dos fármacos , Flavonóis/farmacologia , Plasticidade Neuronal/efeitos dos fármacos , Receptores de AMPA/efeitos dos fármacos , Esquizofrenia/tratamento farmacológico , Sinapses/efeitos dos fármacos , Animais , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/metabolismo , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/efeitos dos fármacos , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Maleato de Dizocilpina/farmacologia , Antagonistas de Aminoácidos Excitatórios/farmacologia , Medo/efeitos dos fármacos , Medo/psicologia , Injeções Intraperitoneais , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Desempenho Psicomotor/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Psicologia do EsquizofrênicoRESUMO
BACKGROUND: Alzheimer's disease is a neurodegenerative disease. Previous study has reported that caspase-1/IL-1ß is closely associated with Alzheimer's disease. However, the biological role of caspase-1/IL-1ß in Alzheimer's disease has not been fully elucidated. This study aimed to explore the mechanism of action of caspase-1/IL-1ß in Alzheimer's disease. METHODS: Mouse hippocampal neurones were treated with Aß1-42 to induce Alzheimer's disease cell model. APP/PS1 mice and Aß1-42-induced hippocampal neurones were treated with AC-YVAD-CMK (caspase-1 inhibitor). Spatial learning and memory ability of mice were detected by morris water maze. Flow cytometry, TUNEL staining, Thioflavin S staining and immunohistochemistry were performed to examine apoptosis and senile plaque deposition. Enzyme linked immunosorbent assay and western blot were performed to assess the levels of protein or cytokines. Co-Immunoprecipitation was performed to verify the interaction between Stargazin and GluA1. RESULTS: AC-YVAD-CMK treatment improved spatial learning and memory ability and reduced senile plaque deposition of APP/PS1 mice. Moreover, AC-YVAD-CMK promoted membrane transport of GluA1 in APP/PS1 mice. In vitro, Aß1-42-induced hippocampal neurones exhibited an increase in apoptosis and a decrease in the membrane transport of GluA1, which was abolished by AC-YVAD-CMK treatment. In addition, Stargazin interacted with GluA1, which was repressed by caspase-1. Caspase-1/IL-1ß inhibited membrane transport of GluA1 by inhibiting the interaction between Stargazin and GluA1. CONCLUSIONS: Our data demonstrate that caspase-1/IL-1ß represses membrane transport of GluA1 by inhibiting the interaction between Stargazin in Alzheimer's disease. Thus, caspase-1/IL-1ß may be a target for Alzheimer's disease treatment.
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Doença de Alzheimer/tratamento farmacológico , Clorometilcetonas de Aminoácidos/administração & dosagem , Peptídeos beta-Amiloides/efeitos adversos , Canais de Cálcio/metabolismo , Hipocampo/citologia , Interleucina-1beta/metabolismo , Receptores de AMPA/metabolismo , Doença de Alzheimer/genética , Doença de Alzheimer/metabolismo , Doença de Alzheimer/psicologia , Clorometilcetonas de Aminoácidos/farmacologia , Animais , Caspase 1/metabolismo , Células Cultivadas , Modelos Animais de Doenças , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Humanos , Masculino , Memória/efeitos dos fármacos , Camundongos , Camundongos Transgênicos , Neurônios/citologia , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Aprendizagem Espacial/efeitos dos fármacosRESUMO
Microglia polarization is associated with the pathogenesis of depression. A previous study shows that long non-coding RNA uc.80- is down-regulated in the hippocampus of depressed rats. Thus, this article aims to investigate the role of uc.80- in microglia polarization in depression. We first established depression model rats by chronic unpredictable mild stress (CUMS) regiment. We found that hippocampus of depressed rats exhibited an increase of M1 microglias and a decrease of M2 microglias. uc.80- was down-regulated in hippocampus of depressed rats. Furthermore, the detection of behaviouristics of depressed rats showed that uc.80- overexpression alleviated depression of rats. In addition, uc.80- overexpression promoted M2 polarization of microglias in vivo and in vitro. uc.80- overexpression led to a decrease in apoptosis of hippocampal neurons in vivo and in vitro. In conclusion, our study confirms that lncRNA uc.80- overexpression ameliorates depression in rats by promoting M2 polarization of microglias. Thus, our work suggests that uc.80- may be a target gene for depression treatment.
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Depressão/genética , Hipocampo/patologia , Microglia/patologia , RNA Longo não Codificante/genética , Animais , Apoptose/efeitos dos fármacos , Apoptose/genética , Células Cultivadas , Meios de Cultivo Condicionados/farmacologia , Depressão/patologia , Modelos Animais de Doenças , Regulação da Expressão Gênica , Hipocampo/fisiologia , Masculino , Microglia/fisiologia , Neurônios/patologia , Neurônios/fisiologia , Ratos Sprague-Dawley , Estresse Psicológico/genéticaRESUMO
OBJECTIVES: This study evaluated the efficacy and safety of baricitinib, an oral Janus kinase (JAK)1/JAK2 inhibitor, in patients with moderately to severely active rheumatoid arthritis (RA) and inadequate response to methotrexate (MTX) therapy. METHODS: In this phase 3, double-blind, 52-week, placebo-controlled study, 290 patients with moderately to severely active RA and inadequate response to MTX were randomly assigned 1:1 to placebo or baricitinib 4-mg once daily, stratified by country (China, Brazil, Argentina) and presence of joint erosions. Primary endpoint measures included American College of Rheumatology 20% response (ACR20) at week 12. Secondary endpoints included changes in Health Assessment Questionnaire-Disability Index (HAQ-DI) and Disease Activity Score for 28-joint counts (DAS28)-high-sensitivity C-reactive protein (hsCRP), Simplified Disease Activity Index (SDAI) score ≤3.3, mean duration of morning joint stiffness, severity of morning joint stiffness numeric rating scale (NRS 0-10), worst tiredness NRS, and worst joint pain NRS at week 12. RESULTS: Most patients (approximately 80%) were from China. More patients achieved ACR20 response at week 12 with baricitinib than with placebo (58.6% vs. 28.3%; p<0.001). Statistically significant improvements were also seen in HAQ-DI, DAS28-hsCRP, morning joint stiffness, worst tiredness, and worst joint pain in the baricitinib group compared to placebo at week 12. Through week 24, rates of treatment-emergent adverse events, including infections, were higher for baricitinib compared to placebo, while serious adverse event rates were similar between baricitinib and placebo. CONCLUSIONS: In patients with RA who had an inadequate response to MTX, baricitinib was associated with significant clinical improvements as compared with placebo.
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Antirreumáticos/uso terapêutico , Artrite Reumatoide/tratamento farmacológico , Argentina , Azetidinas , Brasil , China , Método Duplo-Cego , Quimioterapia Combinada , Humanos , Metotrexato/uso terapêutico , Purinas , Pirazóis , Sulfonamidas , Resultado do TratamentoRESUMO
The work evaluated the influence of different operating conditions (voltage, ionic strength and mechanical pressure) on algae electro-osmotic dewatering effect and extracellular organic matter (EOM) regionalization. It was found that the algae electro-dewatering effect became better as the voltage and ionic strength increased, but electro-dewatering effect was decreased when ionic strength was more than 0.006gNaCl/gTSS, this indicated that too high ionic strength will reduce algae electro-dewatering effect. In addition, electro-osmosis effect first increases and then weakens when the pressure was increased. The content of dissolved organic materials (DOM) in the filtrate of both electrodes was increased when the voltage and ionic strength enhanced, the DOM content of filtrate at cathode and anode were increased from 42.9 mg/L, 36.7 mg/L to 68.2 mg/L, 85.3 mg/L when ionic strength raised from 0gNaCl/gTSS to 0.01gNaCl/gTSS, this indicated that a large amount of EOM dissolution as the voltage and ionic strength increased. The DOM content of both electrodes did not change significantly when mechanical pressure changed, anodic oxidation can oxidize and decompose macromolecular weight substances into mid-molecular weight and low molecular weight substances.
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Esgotos , Eliminação de Resíduos Líquidos , Eletricidade , Eletrodos , Concentração OsmolarRESUMO
Understanding the composition, transformation and bioactivity of dissolved organic matter (DOM) at the molecular level is crucial for investigating the hydrothermal humification process of wastewater sludge and producing ecological fertilizers. In this study, DOM transformation pathways under alkali-thermal humification treatment (AHT) were characterized by Fourier transform-ion cyclotron resonance mass spectrometry (FT-ICR MS) in conjunction with molecular reaction network analysis. The effects of DOM on plant growth were examined using hydroponics and transcriptomic analysis. In the wastewater sludge humification process, AHT produced maximum amounts of protein (3260.56 mg/L) and humic acid (5788.24 mg/L) after 12 h. FT-ICR MS results indicated that protein-like structures were prone to continuous oxidation and were ultimately transformed into aromatic N-containing compounds resembling humic substances. Several reactive fragments (such as -C2H2O2, -C3H4O2, and -C4H6O2) formed by the Maillard reaction (MR) were identified as potential precursors to humic acid (HA). In terms of biological effects, DOM12h showed the highest rice germination and growth activity, whereas that produced by AHT for a longer period (> 12 h) displayed phytotoxicity owing to the accumulation of toxic substances. Plant biostimulants (such as amino acids and HAs) in DOM improved energy metabolism and carbohydrate storage in rice seedlings by upregulating the "starch and sucrose metabolism" pathways. Toxic substances (such as pyrrole, pyridine, and melanoidin) in DOM can activate cell walls formation to inhibit abiotic stimuli in rice seedlings through the biosynthesis of phenylpropanoid pathway. These findings provide a theoretical basis for optimizing sludge hydrothermal humification and recovering high-quality liquid fertilizers.
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Esgotos , Águas Residuárias , Substâncias Húmicas/análise , Matéria Orgânica Dissolvida , Fertilizantes , Peróxido de Hidrogênio/análise , Compostos OrgânicosRESUMO
Phosphate tailings (PTs) are solid waste, which is produced by phosphate flotation. In this work, PTs were used as raw materials for the preparation of diethylenetriamine pentamethronic acid (DTPMP) intercalated trimetal (Ca-Mg-Al) layered double hydroxides (TM-DTPMP LDHs) by co-precipitation method. TM-DTPMP LDHs were characterized by X-ray diffraction, fourier-transform infrared spectroscopy, scanning electron microscopy, differential thermal gravimetric analysis, X-ray photoelectron spectroscopy and applied as a flame retardant to improve the fire safety of epoxy resin (EP). The results showed that the composite materials exhibited obvious layered structure. After intercalation, layer spacing increased from 0.783 to 1.78 Å. When the amount of TM-DTPMP LDH in EP was 8%, the limitted oxygen index of the composite material increased from the original 19.2% to 30.2%. In addition, Cone calorimeter (CC) and Raman spectrum results indicated that with the addition of TM-DTPMP LDHs, the value of heat release rate peak (pHRR) and total heat release (THR) were reduced by more than 43% and 60%, while the value of smoke formation rate (pSPR) and the total smoke production (TSP) decreased nearly 64% and 83%, respectively. The significant reduction in the release of combustion heat and harmful smoke during EP combustion may be attributed to the synergistic flame-retardant effect between hydrotalcite and DTPMP. This work exhibited great potential for the green recycling of PTs and the enhancement of the fire safety of EP.
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In this work, phosphate tailings (PTs) were used as raw materials for the preparation of Ca-Mg-Al layered double hydroxides (LDHs-1) and Ca-Mg-Al-Fe layered double hydroxides (LDHs-2) by co-precipitation method. The as-prepared samples were characterized by FT-IR, SEM, XRD, and XPS and applied as a flame retardant to improve the fire safety of epoxy resin (EP). The results showed that both LDHs-1 and LDHs-2 exhibited layered structure and high crystallinity. Compared with neat EP, the value of limiting oxygen index (LOI) increased from 25.8 to 29.3 and 29.9 with 8 wt% content of LDHs-1 and LDHs-2, respectively. The flame retardant properties of the composite material were characterized by cone calorimeter (CC), and the results showed that the peak value of the smoke production rate (SPR) decreased more than 45% and 74%, total smoke production (TSP) reduced nearly 64% and 85% with the addition of LDHs-1 and LDHs-2. Meanwhile, the value of the total heat release (THR) reduced more than 28% and 63%. The conversion from LDHs to layered double oxide (LDO) might be conducive to the fire safety of EP. Moreover, the transformation of Fe-OH to Fe-O could promote the early cross-linking of polymer. In summary, LDHs-2 could significantly improve the carbonization process of EP and suppress the smoke released during the combustion process.
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Sludge pyrolysis carbonization has shown potential to convert sludge biomass into multifunctional carbon materials. However, ecological risks of dissolved organic matters (DOMs) with obscure molecular characteristics retaining in sludge-based carbons (SBCs) have received little attention. This study investigated the impact of pyrolysis temperatures on the molecular conversion and biotoxicity effects of DOMs in SBCs. The results revealed that DOMs in SBCs300-400 were mainly derived from depolymerization of biopolymers and the polycondensation and cyclization of small intermediate molecules, which mainly consisted of aromatic CHON compounds with 1-3 N atoms, featuring high unsaturation and molecular weights. High-temperature pyrolysis (500-800 °C) promoted the decomposition and ring-opening of aromatic CHON compounds into saturated aliphatic CHO compounds with 2-4 O atoms in SBCs500-800. Noteworthily, SBCs300-400-derived DOMs showed relatively strong biotoxicity on the growth and development of wild-type zebrafish embryos, pakchoi seeds, and Vibrio qinghaiensis Q67, which was significantly related to aromatic amines, phenols, and heterocyclic-N compounds in DOMs of SBCs300-400. SBCs500-800-derived DOMs were mainly straight-chain fatty acids and showed no observable acute biotoxicity. This study highlights the negative impact of DOMs in SBCs on the ecological environment, and provides the theoretical basis for controlling toxic byproducts in sludge pyrolysis process.
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Pirólise , Esgotos , Animais , Carbono , Matéria Orgânica Dissolvida , Temperatura , Peixe-ZebraRESUMO
Klotho is a life extension factor that has the ability to regulate the function of GluN2B-containing N-methyl-D-aspartate receptors (NMDARs), whose dysfunction in the nucleus accumbens (NAc) underlies critical aspects of the pathophysiology of major depression. Here, we study the functional relevance of klotho in the pathogenesis of depression. A chronic social defeat stress paradigm, in which mice are categorized as either susceptible or unsusceptible based on their performance in a social interaction test, was used in this study. We found that the expression of klotho was largely decreased in the NAc of susceptible mice compared to control or unsusceptible mice. Genetic knockdown of klotho in the NAc induced behavioral alterations relevant to depression in naive mice, while overexpression of klotho produced an antidepressive effect in normal mice and ameliorated the behavioral responses to stress in susceptible mice. Molecularly, knockdown of klotho in the NAc resulted in selective decreases in total and synaptic GluN2B expression that were identical to those in susceptible mice. Elevation of klotho in the NAc reversed the reductions in GluN2B expressions and altered synaptic transmission and spine density in the NAc of susceptible mice. Furthermore, blockade of GluN2B with a specific antagonist abolished the beneficial effects of klotho elevation in susceptible mice. Collectively, we demonstrated that klotho in the NAc modulates behavioral responses to stress by regulating the function of GluN2B-containing NMDARs. These results reveal a novel role for klotho in the pathogenesis of depression, providing new insights into the molecular basis of major depression.
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Proteínas Klotho , Expectativa de Vida , Núcleo Accumbens , Receptores de N-Metil-D-Aspartato , Estresse Psicológico , Animais , Antidepressivos/farmacologia , Proteínas Klotho/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Receptores de N-Metil-D-Aspartato/metabolismo , Estresse Psicológico/metabolismoRESUMO
In this work, a novel carbon-based hydrotalcite-like compounds materials (LDO-SBCs) were prepared by coupling layered double hydroxides (LDHs) conditioning and pyrolytic carbonization, and characterized by X-ray diffraction (XRD), Thermogravimetric Analyzer (TGA), X-ray photoelectron spectroscopy (XPS) and Brunner-Emmet-Teller (BET) measurements. The synthesized LDO-SBCs composites were used in wastewater treatment for simultaneous removal of phosphate and dissolved organic matter (DOM). The adsorption of DOM and phosphate were well conformed to pseudo-second-order mode. Adsorption equilibrium was better fitted by Langmuir model for phosphate, while Freundlich model for DOM. Compared with the raw sludge carbon, the removal efficiency of DOM and phosphate by LDO-SBCs were increased by 8% and 13%, respectively. Based on the fluorescence spectrum and parallel factor analysis (PARAFAC), LDO-SBCs performed well in promoting the removal of protein substances (TPN and APN). Pore filling, hydrogen bonding, electrostatic adsorption and surface complexation might be dominant in the adsorption of DOM, while, surface complexation and ion exchange between the LDO layers were mainly responsible for the adsorption of phosphate. The difference of adsorption capacity of LDO-SBCs was related to the superior channel structure of composite materials and the composition of interlayer anions of LDO.
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Fosfatos , Esgotos , Adsorção , Carbono , Hidróxidos , CinéticaRESUMO
INTRODUCTION: To assess the effect of baricitinib on patient-reported outcomes (PROs) in patients with moderately to severely active rheumatoid arthritis (RA) who had an inadequate response to methotrexate (MTX). METHODS: This was a 52-week, randomized, double-blind, placebo controlled, phase III study in patients with RA who had an inadequate response to MTX. Patients (n = 290) receiving stable background MTX were randomly assigned (1:1) to receive placebo or baricitinib 4 mg once daily with a primary endpoint at week 12. PROs assessed included Health Assessment Questionnaire-Disability Index (HAQ-DI), Patient's Global Assessment of Disease Activity, patient's assessment of pain, Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F), European Quality of Life-5 Dimensions-5 Level index scores and visual analogue scale, and measures collected in electronic patient daily diaries: duration of morning joint stiffness, Worst Tiredness, and Worst Joint Pain. Treatment comparisons were made with logistic regression and analysis of covariance models for categorical and continuous variables, respectively. RESULTS: Statistically significant (p ⩽ 0.05) improvements in all PROs were observed in the baricitinib 4 mg group compared to placebo as early as week 1 to week 4; and were sustained to week 24. These improvements were maintained until week 52 for the baricitinib group. A significantly larger proportion of patients met or exceeded the minimum clinically important difference for HAQ-DI (⩾0.22) and FACIT-F (3.56) profiles in the baricitinib group. CONCLUSION: Baricitinib provided significant improvements in PROs compared to placebo to 52 weeks of treatment in patients with RA who had an inadequate response to MTX.Clinicaltrials.gov identifier: https://clinicaltrials.gov/ct2/show/NCT02265705; NCT02265705; RA-BALANCE. Registered 13 October 2014.
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BACKGROUND AND AIMS: Hepatic fibrosis is associated with elevated sinusoidal pressure, which can be transmitted to the hepatic stellate cells (HSCs) in the perisinusoidal space of Disse. Here, we sought to determine the effects of pressure on cellular growth and Src-dependent signaling pathways in the rat HSCs. METHODS: Cultured rat HSCs were exposed to pressures (0 to 80 mmHg) by using a pressure-inducing apparatus. The proliferation of the cells was determined by a 5-bromo-2'-deoxy-uridine (BrdU) incorporation assay. Reverse transcription-PCR and Western-blot analysis were used to examine the mRNA and protein levels of representative molecules in Src-dependent signaling pathways. RESULTS: Pressure at 10 to 20 mmHg applied to the HSCs over 1 h upregulated Brdu incorporation and expression of proliferating cell nuclear antigen (PCNA) and type I collagen, while a higher pressure of 40-80 mmHg did not have noticeable effect. The mRNA level of beta (3) integrin was increased by 1-h application of 5 to 20 mmHg. Immunoblot with phospho-specific antibodies demonstrated the phosphorylation of Src (Tyr418), focal adhesion kinase (FAK) (Tyr397), Akt (Ser473) and extracellular signal-regulated kinases 1 and 2 (ERK1/2) (Thr421/Ser424) was increased in response to 10-mmHg pressure. Herbimycin A, an inhibitor of Src phosphorylation, attenuated the pressure-induced HSC proliferation and phosphorylation of above-mentioned signaling molecules. CONCLUSION: Our data demonstrated that pressure alone induced HSC proliferation involving the activation of Src-dependent signaling pathways.
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Quinase 1 de Adesão Focal/metabolismo , Células Estreladas do Fígado/enzimologia , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Quinases da Família src/metabolismo , Animais , Benzoquinonas/farmacologia , Colágeno Tipo I/metabolismo , Inibidores Enzimáticos/farmacologia , Células Estreladas do Fígado/metabolismo , Integrina beta3/genética , Integrina beta3/metabolismo , Lactamas Macrocíclicas/farmacologia , Fosforilação , Pressão , Antígeno Nuclear de Célula em Proliferação/metabolismo , Ratos , Rifabutina/análogos & derivados , Transdução de Sinais , Quinases da Família src/antagonistas & inibidoresRESUMO
Parkinson's disease (PD) is associated with mitochondrial dysfunction, oxidative stress, and activation of the apoptotic cascade. In the study, we investigated the effects of salvianolic acid B (Sal B) on 1-methyl-4-phenylpyridinium (MPP(+))-treated SH-SY5Y cells, a classic in vitro model for PD. We found Sal B inhibited the loss of cell viability by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. The underlying mechanisms of Sal B action were further studied. Treatment of SH-SY5Y cells with MPP(+) caused a loss of cell viability and mitochondrial membrane potential, condensation of nuclei, elevation in the level of reactive oxygen species (which was associated with cytochrome c release), an increase in the Bax/Bcl-2 mRNA ratio, and activation of caspase-3. Sal B ameliorated the MPP(+)-altered phenotypes. These results indicate that the Sal B protected SH-SY5Y cells against MPP(+)-induced apoptosis by relieving oxidative stress and modulating the apoptotic process. Our findings suggest that salvianolic acid B may be a promising agent to prevent PD.
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1-Metil-4-fenilpiridínio/toxicidade , Antiparkinsonianos/farmacologia , Apoptose/efeitos dos fármacos , Benzofuranos/farmacologia , Antiparkinsonianos/química , Benzofuranos/química , Bioensaio , Caspase 3/biossíntese , Técnicas de Cultura de Células , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Humanos , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Estrutura Molecular , Neuroblastoma , Doença de Parkinson/metabolismo , Doença de Parkinson/patologia , Doença de Parkinson/prevenção & controle , Proteínas Proto-Oncogênicas c-bcl-6/biossíntese , Espécies Reativas de Oxigênio/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Proteína X Associada a bcl-2/biossínteseRESUMO
INTRODUCTION: Baricitinib is an oral selective inhibitor of Janus kinase (JAK) 1 and JAK 2, which has demonstrated significant efficacy in patients with moderately to severely active rheumatoid arthritis (RA). This analysis aims to describe the efficacy and safety of baricitinib in Chinese RA patients with an inadequate response to methotrexate (MTX-IR), and to analyze the effects of baseline characteristics on the efficacy of baricitinib treatment. METHODS: In this 52-week, randomized, double-blind, placebo-controlled study, 231 Chinese patients with moderately to severely active RA who had MTX-IR were randomly assigned to placebo (n = 115) or baricitinib 4 mg once daily (n = 116). The primary endpoint was American College of Rheumatology 20% (ACR20) response at week 12. Other efficacy measures included ACR50, ACR70, Physician's Global Assessment of Disease Activity, Patient's Global Assessment of Disease Activity, patient's assessment of pain, Disease Activity Score in 28 joints using high-sensitivity C-reactive protein, remission and low disease activity rates according to Simplified Disease Activity Index or Clinical Disease Activity Index, Health Assessment Questionnaire-Disability Index, and mean duration and severity of morning joint stiffness, worst tiredness and worst joint pain were analyzed. Additionally, subgroup analyses were performed across baseline characteristics. RESULTS: Statistically significant improvement in ACR20 response was achieved with baricitinib at week 12 (53.4 vs. 22.6%, p = 0.001) in Chinese patients, compared to placebo. Most of the secondary objectives were met with statistically significant improvements. Efficacy of baricitinib was irrespective of patient demographics and baseline characteristics. Safety events were similar between the baricitinib and placebo groups. CONCLUSIONS: The efficacy of baricitinib 4 mg in Chinese patients with moderately to severely active RA and prior MTX-IR was clinically significant compared to placebo regardless of baseline characteristics. Baricitinib was well tolerated with an acceptable safety profile during the full study period. TRIAL REGISTRATION: NCT02265705.
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Sludge treatment and disposal have become critical environmental issues in China. Electro-dewatering (ED) is an attractive technology for enhancing dewaterability and improving the sustainability of waste activated sludge (WAS) handling. However, electrically assisted mechanical dewatering processes consume more energy and the extracellular polymeric substance (EPS) dissolution caused by electrochemical reactions can lead to clogging of the filter cloth. Carbon-based materials (CBMs) such as activated carbon and graphite have electrical conductivity and well-developed pore structures which can adsorb the biopolymers. Therefore, addition of CBMs is expected to improve WAS electro-dewatering performance for fuel treatment by enhancing sludge conductivity and filterability. In this study, we evaluated the effects of the three carbon materials (AC-0, AC-5, and graphite) on sludge electro-dewatering behavior and the flammability of sludge cakes. The results showed that CBMs promote the performance of WAS electro-dewatering, and the promoting effect of the carbon materials on the sludge electro-dewatering is proportional to the electrical conductivity of the carbon material, and carbon materials can increase the electrophoretic mobility of sludge flocs and the electro-osmotic effect. Moreover, CBMs can adsorb the dissolved EPS, thus alleviate the plugging and filtration resistance of the filter medium. The addition of CBMs also decreases the energy consumption for water removal during the electro-dewatering process and improves the calorific value and sustainable combustion time of the sludge cake. Our approach can facilitate the resource utilization of the dewatered sludge cake in electro-dewatering processes.
Assuntos
Esgotos , Eliminação de Resíduos Líquidos , China , Matriz Extracelular de Substâncias Poliméricas , Águas Residuárias , ÁguaRESUMO
In this work, a novel core-shell structured magnetic polyimide@layered double oxides (LDO) composites coating a porous polyimide (PI)-coated Fe3O4 magnetic core and layered double hydroxide (LDH) has been successfully synthesized by solve-thermal synthesis and co-precipitation process. The magnetic PI@LDO composites were characterized by scanning and transmission electron microscopy (SEM and TEM), X-ray diffraction (XRD), thermogravimetry analysis (TGA) and magnetic properties analysis. The composite materials displayed core-shell structure with flower-like morphology. The magnetic PI@LDO composites were applied to remove tetracycline (TC), 2,4-dichlorophenol (2,4-DCP) and glyphosate (GP) from aqueous solution. The action pH value was ranged from 5 to 9 for TC and GP and 3 to 7 for 2,4-DCP, respectively. Cl- showed a weak competitive adsorption effect to TC, 2, 4-DCP and GP. In addition, the presence of humic acid (HA) could slightly reduce the adsorption capacity of magnetic PI@LDO composites. The adsorption process could be well described by pseudo-second-order model for TC and GP, while pseudo-first-order model for 2,4-DCP. The experimental data of TC and 2,4-DCP could be fitted better with Freundlich model, while that of GP were fitted better with Langmuir model. The adsorptions of TC, 2,4-DCP and GP were both spontaneous and endothermic. The adsorption capacity decreased slightly after adsorption-desorption cycles repeated five times. This study demonstrated that magnetic PI@LDO exhibited great potential to be a mild and cost-effective adsorbent for the removal of various organic contaminants from wastewater.
Assuntos
Hidróxidos/química , Magnetismo , Óxidos , Purificação da Água/métodos , Adsorção , Clorofenóis/isolamento & purificação , Glicina/análogos & derivados , Glicina/isolamento & purificação , Substâncias Húmicas , Imidas/química , Óxidos/química , Tetraciclina/química , GlifosatoRESUMO
In this work, calcined chitosan-supported layered double hydroxides (CSLDO) were synthesized through a co-precipitation method that restrained the particles' aggregation of LDHs and exhibited huge specific surface areas, which can enhance the fluoride adsorption capacity. CSLDOs were characterized by physical and chemical methods and used for fluoride adsorption in an aqueous solution. The results indicated that the nanoparticles were constructed first and then assembled to form a porous and layered structure, and chitosan-supported layered double hydroxides (CSLDHs) calcined at 400 °C (CSLDO400) showed the highest specific surface area of 116.98 m²·g-1 and the largest pore volume of 0.411 cm³·g-1. CSLDO400 exhibited excellent adsorption performance at a wide pH range from 5 to 9 for fluoride. The adsorption kinetics indicated that the adsorption reached equilibrium after 120 min, and followed a pseudo-first-order model. It agreed well with the Langmuir isotherm with maximum adsorption amounts of 27.56 mg·g-1. The adsorption of fluoride ions was spontaneous and endothermic. Furthermore, CSLDO400 showed a high stability for fluoride removal; it could still achieve 68% removal for fluoride after repeating five times of adsorption-desorption cycles. This study demonstrated that CSLDO400 is a promising functional material to remove fluoride from surface/ground water.
RESUMO
Early diagnosis of liver fibrosis is critical for early intervention and prognosis of various chronic liver diseases. Conventional repeated histological assessment is impractical due to the associated invasiveness. In the current study, we evaluated circulating miR-185 as a potential biomarker to predict initiation and progression of liver fibrosis. We found that miR-185 was significantly up-regulated in blood specimens from patients with HBV-liver fibrosis and rats with liver fibrosis, the miR-185 levels were correlated with liver fibrosis progression, but not with the different viral loads in HBV-infected patients. miR-185 was observed in collagen deposition regions during advanced liver fibrosis. We found that differences in miR-185 levels facilitated the discrimination between early-staged or advanced-staged liver fibrosis and the healthy controls with high specificity, sensitivity, and likelihood ratio using receiver-operator characteristic analysis. miR-185 targeted SREBF1, and increased expression of COL1A1 and a-SMA genes that are hallmarks of liver fibrosis. Our data supported that circulating miR-185 levels could be used as potential biomarkers for the early diagnosis of liver fibrosis.