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1.
Front Aging Neurosci ; 13: 773797, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34776938

RESUMO

Objective: Type 2 diabetes (T2D) is a risk factor for cognitive impairment and cerebral small vessel disease (CSVD). The relation of metformin use and cognitive impairment or CSVD is not clear. The objective of this study was to investigate the cross-sectional effects of long-term use of metformin on total CSVD burden and cognitive function in patients with T2D. Methods: A total of 234 participants with T2D from the memory clinic in Hebei General Hospital were enrolled in this retrospective study. Duration of metformin use and dosage were recorded. Along with cerebral magnetic resonance imaging (MRI) examination, Mini-Mental State Examination (MMSE) was also performed to assess their cognitive status. We determined the validated total CSVD score (ranging from 0-4) by combining four markers of CSVD that were visually rated. We used binary logistic regression analysis, ordinal logistic regression analysis and mediation analysis to assess the relation of long-term use of metformin with CSVD burden and cognitive function. Results: Binary logistic regression analysis showed long-term use of metformin was associated with reducing the risk of cognitive impairment (OR: 0.446; 95% Confidence Interval (CI): 0.249 to 0.800; P = 0.007), after adjustment of potential confounders, such as total CSVD burden score, age, HbA1c, hypertension, history of stroke, homocysteine, body mass index, TG and HDL-C. Ordinal logistic regression analysis suggested that long-term use of metformin was associated with alleviation of total CSVD burden score (OR: 0.583; 95% CI: 0.359 to 0.943; P = 0.027), after adjusting for age, HbA1c, hypertension, history of stroke, homocysteine, body mass index, TG and HDL-C. Mediation analysis showed significant mediation by the presence of severe CSVD burden score for long-term use of metformin in relation to cognitive impairment. Conclusion: Long-term use of metformin was associated with lower rates of cognitive impairment and lower total CSVD burden score in patients with T2D. A proportion of the relation between long-term use of metformin and cognitive impairment may be attributable to alleviation of CSVD burden.

2.
Environ Pollut ; 290: 118022, 2021 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-34492527

RESUMO

Volatile brominated compounds are important trace gases for stratospheric ozone chemistry. In this study, the spatial variations of dibromomethane (CH2Br2), bromodichloromethane (CHBrCl2), dibromochloromethane (CHBr2Cl) and bromoform (CHBr3) in the seawater and overlying atmosphere were measured in the Yellow Sea (YS) and the East China Sea (ECS) in winter. The air-sea fluxes of CH2Br2, CHBrCl2, CHBr2Cl and CHBr3 ranged from -11.46 to 25.33, -4.68 to 7.91, -8.60 to 4.08 and -88.57 to 8.84 nmol m-2·d-1, respectively. In order to understand the mechanism of halocarbons production, we measured bromoperoxidase (BrPO) activity (39.18-186.74 µU·L-1) in the YS and ECS for the first time using an aminophenyl fluorescein (APF) method and performed in-situ incubation experiments in BrPO-treated seawater. The production rates of CH2Br2, CHBrCl2, CHBr2Cl and CHBr3 ranged from 14.21 to 94.74, 0.00 to 19.74, 0.00 to 30.62 and 6.18-72.75 pmol L-1·h-1, respectively, in BrPO-treated seawater. There were significantly higher production rates in coastal waters compared with the open sea (P = 0.016) because of higher DOC levels near the coast. Moreover, the production rates of halocarbons increased with BrPO activity and H2O2 concentration. The results showed that enzyme-mediated reaction was an important source for the production of halocarbons in seawater. The present research is of great significance for understanding the production mechanisms of halocarbons in seawater and global oceanic halocarbons emissions.


Assuntos
Poluentes Atmosféricos , Monitoramento Ambiental , Poluentes Atmosféricos/análise , China , Peróxido de Hidrogênio , Oceanos e Mares , Peroxidases , Água do Mar
3.
ACS Appl Mater Interfaces ; 13(33): 39806-39818, 2021 Aug 25.
Artigo em Inglês | MEDLINE | ID: mdl-34387459

RESUMO

Silver nanomaterials have attracted a great deal of interest due to their broad-spectrum antimicrobial activity. However, it is still challenging to balance the high antibacterial efficiency with low damage to biological cells of silver nanostructures, especially when the diameter decreases to less than 10 nm. Here, we developed a new type of Ag nanohybrid material via a unimolecular micelle template method, which presents amazing antibacterial activities and almost noncytotoxicity. First, water-soluble multiarm star-shaped brushlike copolymer α-CD-g-[(PEO40-g-PAA50)-b-PEO5]18 was precisely synthesized and its micelle behavior in different solvents was revealed. Then, nanocrystal clusters assembled by Ag grains (Ag@Template NCs) were prepared through an in situ redox route using the unimolecular micelle of α-CD-g-[(PEO40-g-PAA50)-b-PEO5]18 as the soft template, AgNO3 as a precursor, and tetrabutylammonium borohydride (TBAB) as the reducing agent. The overall size of the achieved Ag@Template NCs is controlled by the template structure at around 40 nm (Dh in DMF), and the size of the Ag grain can be easily regulated from ∼1 to ∼5 nm by adjusting the feeding ratio of AgNO3/acrylic acid (AA) units in the template from 1:10 to 1:1. Benefitting from the structural design of the template, all Ag@Template NCs prepared here exhibit excellent dispersibility and chemical stability in different aqueous environments (neutral, pH = 5.5, and 0.9% NaCl physiological saline solution), which play a crucial role in the long-term storage and potential application in a complex physiological environment. The antibacterial and cytotoxicity tests indicate that Ag@Template NCs display much better performance than Ag nanoparticles (Ag NPs), which have a comparable overall size of ∼25 nm. The inhibitory capability of Ag@Template NCs to bacteria strongly depends on the grain size. Specifically, the Ag@Template-1 NC assembled by the smallest grains (1.6 ± 0.3 nm) presents the best antibacterial activity. For E. coli (-), the MIC value is as low as 5 µg/mL (0.36 µg/mL of Ag), while for S. aureus (+), the value is around 10 µg/mL (0.72 µg/mL of Ag). The survival rate of L02 cells and lactate dehydrogenase assay together illustrate the low cytotoxicity possessed by the prepared Ag@Template NCs. Therefore, the proposed Ag@Template NC structure successfully resolves the high reactivity, instability, and fast oxidation issues of the ultrasmall Ag nanoparticles, and integrates high antibacterial efficiency and nontoxicity to biological cells into one platform, which implies its broad potential application in biomedicine.


Assuntos
Antibacterianos/efeitos adversos , Antibacterianos/química , Nanopartículas Metálicas/química , Prata/química , Antibacterianos/metabolismo , Boroidretos/química , Sobrevivência Celular/efeitos dos fármacos , Escherichia coli/efeitos dos fármacos , Humanos , Testes de Sensibilidade Microbiana , Tamanho da Partícula , Polímeros/química , Compostos de Amônio Quaternário/química , Staphylococcus aureus/efeitos dos fármacos , Propriedades de Superfície , Nanomedicina Teranóstica
4.
Food Chem ; 344: 128600, 2021 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-33221101

RESUMO

The contents of phenolic compounds, especially flavonoids, and antioxidant activity of rice (Oryza sativa, Os) and Chinese wild rice (Zizania latifolia, Zl) harvested in China were compared. Zl possessed significantly higher contents of total phenolics, flavonoids, and proanthocyanidins and exhibited higher antioxidant activity than in the Os Xian group, the Os Geng group, and red rice. The flavonoid contents of Os and Zl were compared using a UHPLC-QqQ-MS-based metabolomics approach. A total of 159 flavonoids were identified, among which 78 showed differential expression (72 up-regulated and six down-regulated in the Zl group). The Kyoto Encyclopaedia of Genes and Genomes annotation and classification indicated that the differentially expressed flavonoids were mainly related to anthocyanin biosynthesis. Moreover, candidate genes for flavonoid biosynthesis in Os and Zl were identified in this study. Compared with non-pigmented and red rice, Zl may be more nutritious and is thus considered a better source of natural antioxidants.


Assuntos
Antioxidantes/química , Flavonoides/análise , Oryza/química , Fenóis/análise , Extratos Vegetais/química , Poaceae/química , Área Sob a Curva , China , Cromatografia Líquida de Alta Pressão , Análise Discriminante , Flavonoides/química , Humanos , Análise dos Mínimos Quadrados , Metabolômica/métodos , Oryza/metabolismo , Fenóis/química , Poaceae/metabolismo , Análise de Componente Principal , Curva ROC , Espectrometria de Massas em Tandem
5.
Immunology ; 162(3): 328-338, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33283278

RESUMO

Schistosomiasis is a neglected tropical disease with over 250 million people infected worldwide. The main clinically important species Schistosoma mansoni (S. mansoni) and Schistosoma japonicum (S. japonicum) cause inflammatory responses against tissue-trapped eggs, resulting in formation of granulomas mainly in host liver. Persistent granulomatous response results in severe fibrosis in the liver, leading to irreversible impairment of the liver and even death of the host. CD1d, a highly conserved MHC class I-like molecule, is expressed by both haematopoietic and non-haematopoietic cells. CD1d on antigen-presenting cells (APCs) of haematopoietic origin presents pathogen-derived lipid antigens to natural killer T (NKT) cells, which enables them to rapidly produce large amounts of various cytokines and facilitate CD4+ T helper (Th) cell differentiation upon invading pathogens. Noteworthy, hepatocytes of non-haematopoietic origin have recently been shown to be involved in maintaining liver NKT cell homeostasis through a CD1d-dependent manner. However, whether hepatocyte CD1d-dependent regulation of NKT cell homeostasis also modulates CD4+ Th cell responses and liver immunopathology in murine schistosomiasis remains to be addressed. Here, we show in mice that CD1d expression on hepatocytes was decreased dramatically upon S. japonicum infection, accompanied by increased NKT cells, as well as upregulated Th1 and Th2 responses. Overexpression of CD1d in hepatocytes significantly decreased local NKT numbers and cytokines (IFN-γ, IL-4, IL-13), concomitantly with downregulation of both Th1 and Th2 responses and alleviation in pathological damage in livers of S. japonicum-infected mice. These findings highlight the potential of hepatocyte CD1d-targeted therapies for liver immunopathology control in schistosomiasis.


Assuntos
Antígenos CD1d/metabolismo , Hepatócitos/imunologia , Fígado/imunologia , Schistosoma japonicum/imunologia , Esquistossomose Japônica/imunologia , Animais , Antígenos CD1d/genética , Citocinas/metabolismo , Modelos Animais de Doenças , Hepatócitos/metabolismo , Hepatócitos/patologia , Interações Hospedeiro-Parasita , Fígado/metabolismo , Fígado/patologia , Masculino , Camundongos , Células T Matadoras Naturais/imunologia , Células T Matadoras Naturais/metabolismo , Células T Matadoras Naturais/parasitologia , Schistosoma japonicum/patogenicidade , Esquistossomose Japônica/metabolismo , Esquistossomose Japônica/parasitologia , Células Th1/imunologia , Células Th1/metabolismo , Células Th1/parasitologia , Células Th2/imunologia , Células Th2/metabolismo , Células Th2/parasitologia
6.
Chem Biodivers ; 18(2): e2000804, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33346933

RESUMO

A series of (E)-1-(substituted benzylidene)-4-(3-isopropylphenyl)thiosemicarbazone derivatives were synthesized and characterized by FT-IR spectrum, elemental analysis, NMR spectrum, HR-MS spectrum, and X-ray single crystal diffraction technology. The crystal structures and packing of (E)-1-(4-fluorobenzylidene)-4-(3-isopropylphenyl)thiosemicarbazone and (E)-1-(3-fluorobenzylidene)-4-(3-isopropylphenyl)thiosemicarbazone were maintained through the intramolecular hydrogen bond (N3-H6⋅⋅⋅N1) and intermolecular hydrogen bonds (N2-H4⋅⋅⋅S1, C14-H14⋅⋅⋅F1 and C7-H7⋅⋅⋅S1). The results obtained by employing the DPPH free radicals scavenging assay indicated that (E)-1-(4-methoxylbenzylidene)-4-(3-isopropylphenyl)thiosemicarbazone had a more significant antioxidant activity compared with other compounds. The results measured by adopting the disc diffusion method elucidated that (E)-1-(4-trifluoromethylbenzylidene)-4-(3-isopropylphenyl)thiosemicarbazone possessed a more prominent antifungal activity than other compounds. Molecular docking showed that (E)-1-(4-chlorobenzylidene)-4-(3-isopropylphenyl)thiosemicarbazone had the highest affinity with receptor protein (1NMT). Moreover, the drug-likeness characteristic, physicochemical properties, pharmacokinetic profiles, and bioactivity scores of all the compounds were predicted through in silico studies. The results illustrated that (E)-1-(4-fluorobenzylidene)-4-(3-isopropylphenyl)thiosemicarbazone had the drug-likeness characteristic and all the compounds were considered as moderately biological active molecules.


Assuntos
Compostos de Benzilideno/química , Compostos de Benzilideno/farmacologia , Tiossemicarbazonas/química , Tiossemicarbazonas/farmacologia , Antifúngicos/síntese química , Antifúngicos/química , Antifúngicos/farmacologia , Antioxidantes/síntese química , Antioxidantes/química , Antioxidantes/farmacologia , Compostos de Benzilideno/síntese química , Cristalografia por Raios X , Fungos/efeitos dos fármacos , Humanos , Ligação de Hidrogênio , Modelos Moleculares , Micoses/tratamento farmacológico , Tiossemicarbazonas/síntese química
7.
Nat Commun ; 11(1): 4792, 2020 09 22.
Artigo em Inglês | MEDLINE | ID: mdl-32963238

RESUMO

Natural biomolecules have been used extensively as chiral scaffolds that bind/surround metal complexes to achieve stereoselectivity in catalytic reactions. ATP is ubiquitously found in nature as an energy-storing molecule and can complex diverse metal cations. However, in biotic reactions ATP-metal complexes are thought to function mostly as co-substrates undergoing phosphoanhydride bond cleavage reactions rather than participating in catalytic mechanisms. Here, we report that a specific Cu(II)-ATP complex (Cu2+·ATP) efficiently catalyses Diels-Alder reactions with high reactivity and enantioselectivity. We investigate the substrates and stereoselectivity of the reaction, characterise the catalyst by a range of physicochemical experiments and propose the reaction mechanism based on density functional theory (DFT) calculations. It is found that three key residues (N7, ß-phosphate and γ-phosphate) in ATP are important for the efficient catalytic activity and stereocontrol via complexation of the Cu(II) ion. In addition to the potential technological uses, these findings could have general implications for the chemical selection of complex mixtures in prebiotic scenarios.

8.
Exp Ther Med ; 20(4): 3679-3686, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32855720

RESUMO

Hepatitis B virus (HBV) can establish a lifelong chronic infection in humans, leading to liver cirrhosis, liver failure and hepatocellular carcinoma. Patients with chronic hepatitis B (CHB) exhibit a weak virus-specific immune response. Regulatory T cells (Tregs) play a key role in regulating the immune response in patients with CHB. Patients with hepatitis B envelope antigen (HBeAg)-positive CHB harbored a higher percentage of Tregs in their peripheral blood than those with HBeAg-negative CHB. However, whether and how HBeAg manipulates the host immune system to increase the population of Tregs remains to be elucidated. The present manuscript describes a preliminary immunological study of HBeAg in a mouse model. Multiple potential CD4+ T cell epitopes in HBeAg were identified using Immune Epitope Database consensus binding prediction. It was demonstrated that HBeAg treatment increased the numbers of Tregs in mouse spleens in vitro and in vivo. Furthermore, it was indicated that the HBeAg-mediated increase in Tregs occurred through the conversion of CD4+CD25- T cells into CD4+CD25+Foxp3+ Tregs. Additionally, in vitro study illustrated that HBeAg stimulated murine spleen cells to produce increased transforming growth factor-ß, which is required to enable HBeAg to convert T cells into Tregs. The results of the present study may provide further evidence of the effect of HBeAg on Tregs and aid in the development of novel HBeAg-based immunotherapy for CHB.

9.
J Biomater Sci Polym Ed ; 31(11): 1385-1404, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32345136

RESUMO

Herein, we construct a charge - switchable polymer nano micelles poly (2-(hexamethyl eneimino) ethyl methacrylate) - b - poly (ethylene glycol) monomethyl ether methacrylate) - b - poly (diethyl enetriaminepentaacetic acid methacrylate) - b - poly (1-vinyl imidazole) - b - poly (4-vinyl phenylboronic acid) (PC7A-PEG-DTPA-VI-PBA) in different pH solutions. DOX released faster from micelles in a weakly acidic environment (pH 5.0) than at pH 7.4. In order to enhance the anti-tumor effect, the imidazole functional groups in the polymer were used to coordinate CdSeTe quantum dots (QDs) for photodynamic treatment (PDT). In addition, the surfaces of the micelles were further decorated with phenylboronic acidas a targeting group, using DTPA chelating 99mTc for SPECT imaging.It has been successfully demonstrated that the nanoparticles have a good cumulative effect on the tumor site.The structure of the polymer was characterized by 1HNMR. The morphology and particle size of the micelles were characterized by transmission electron microscopy (TEM) and dynamic light scattering (DLS). The drug loading capacity (DLC) and drug loading efficiency (DLE) of the micelles were analyzed by ultraviolet visible spectroscopy. And the pH-sensitive drug release and cytotoxicity of the micelles were verified in vitro. In vitro experiments showed that the nano micelles were noncytotoxic to different cell lines, while DOX@CdSeTe@PC7A-PEG-DTPA-VI-PBA inhibited the proliferation and promoted the apoptosis of B16F10 cells. An in vivo study with C57BL tumor-bearing mice indicated that DOX@CdSeTe@PC7A-PEG-DTPA-VI-PBA nano micelles efficiently inhibited tumor growth. Results showed that the nano micelles had good pH responsibility and biocompatibility, and the loaded DOX could be released in the weak acidic environment of tumor cells, and it was expected to be a good drug delivery system.


Assuntos
Antineoplásicos , Fotoquimioterapia , Animais , Doxorrubicina/farmacologia , Portadores de Fármacos , Sistemas de Liberação de Medicamentos , Concentração de Íons de Hidrogênio , Camundongos , Camundongos Endogâmicos C57BL , Micelas , Polietilenoglicóis
10.
Angew Chem Int Ed Engl ; 59(9): 3444-3449, 2020 02 24.
Artigo em Inglês | MEDLINE | ID: mdl-31825550

RESUMO

The diverse secondary structures of nucleic acids are emerging as attractive chiral scaffolds to construct artificial metalloenzymes (ArMs) for enantioselective catalysis. DNA-based ArMs containing duplex and G-quadruplex scaffolds have been widely investigated, yet RNA-based ArMs are scarce. Here we report that a cyclic dinucleotide of c-di-AMP and Cu2+ ions assemble into an artificial metalloribozyme (c-di-AMP⋅Cu2+ ) that enables catalysis of enantioselective Friedel-Crafts reactions in aqueous media with high reactivity and excellent enantioselectivity of up to 97 % ee. The assembly of c-di-AMP⋅Cu2+ gives rise to a 20-fold rate acceleration compared to Cu2+ ions. Based on various biophysical techniques and density function theory (DFT) calculations, a fine coordination structure of c-di-AMP⋅Cu2+ metalloribozyme is suggested in which two c-di-AMP form a dimer scaffold and the Cu2+ ion is located in the center of an adenine-adenine plane through binding to two N7 nitrogen atoms and one phosphate oxygen atom.


Assuntos
Reação de Cicloadição , Fosfatos de Dinucleosídeos/química , Água/química , Catálise , Cobre/química , Teoria da Densidade Funcional , Dimerização , Fosfatos de Dinucleosídeos/metabolismo , Quadruplex G , Cinética , Metaloproteínas/química , Metaloproteínas/metabolismo , Estereoisomerismo , Especificidade por Substrato
11.
Braz J Med Biol Res ; 52(11): e8371, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31721903

RESUMO

Oxiracetam (ORC) is a commonly used nootropic drug for improving cognition and memory impairments. The therapeutic effect and underlying mechanism of ORC in vascular dementia (VaD) treatment remain unknown. In this study, 3-month-old male Sprague-Dawley rats with permanent bilateral common carotid artery occlusion-induced VaD were treated orally with low (100 mg/kg) or high (200 mg/kg) dose ORC once a day for 4 weeks. The results of the Morris water maze test and Nissl staining showed that ORC treatment significantly alleviated learning and memory deficits and neuronal damage in rats with VaD. Mechanistically, the protein levels of a panel of genes associated with neuronal apoptosis (Bcl-2, Bax) and autophagy (microtubule-associated protein 1 chain 3, Beclin1, p62) were significantly altered by ORC treatment compared with VaD, suggesting a protective role of ORC against VaD-induced neuronal apoptosis and autophagy. Moreover, the Akt/mTOR pathway, which is known to be the upstream signaling governing apoptosis and autophagy, was found to be activated in ORC-treated rats, suggesting an involvement of Akt/mTOR activation in ORC-rendered protection in VaD rats. Taken together, this study demonstrated that ORC may alleviate learning and memory impairments and neuronal damage in VaD rats by altering the expression of apoptosis/autophagy-related genes and activation of the Akt/mTOR signaling pathway in neurons.


Assuntos
Disfunção Cognitiva/tratamento farmacológico , Demência Vascular/tratamento farmacológico , Fármacos Neuroprotetores/administração & dosagem , Proteínas Proto-Oncogênicas c-akt/metabolismo , Pirrolidinas/administração & dosagem , Transdução de Sinais/fisiologia , Serina-Treonina Quinases TOR/metabolismo , Animais , Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Disfunção Cognitiva/metabolismo , Disfunção Cognitiva/fisiopatologia , Demência Vascular/metabolismo , Demência Vascular/fisiopatologia , Modelos Animais de Doenças , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley
12.
Methods Enzymol ; 625: 41-59, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31455536

RESUMO

So far, four cyclic dinucleotides (CDNs) have been discovered as important second messengers in nature, where three canonical CDNs of c-di-GMP, c-di-AMP and c-AMP-GMP were found in bacteria containing two 3'-5' phosphodiester linkages and one non-canonical CDN 2'3'-c-GMP-AMP was identified in mammals containing mixed 2'-5' and 3'-5' phosphodiester linkages. The CDNs are produced by specific cyclases and degraded by phosphodiesterases (PDEs). All of the known CDNs could bind to the stimulator of interferon genes (STING) to induce type I interferon (IFN) responses and the three bacterial CDNs are sensed by specific riboswitches to regulate gene expression. The emerging physiological functions of bacterial CDNs lead the motivation to investigate other possible canonical CDNs. In recent years, many endeavors have been devoted to develop fast, convenient and cheap strategies for chemically synthesizing CDNs and their analogues. The phosphoramidite approach using commercial starting materials has attracted much attention. Herein, we describe an adapted one-pot strategy that enables fast synthesis of crude 3'-5'-linked canonical CDNs followed by purification of the obtained CDNs using reversed phase high-performance of liquid chromatography (HPLC). Furthermore, we report the full characterization of CDNs by mass spectrometry (MS) and nuclear magnetic resonance (NMR) techniques.


Assuntos
Fosfatos de Dinucleosídeos/metabolismo , Nucleotídeos Cíclicos/metabolismo , Animais , AMP Cíclico/química , AMP Cíclico/metabolismo , Fosfatos de Dinucleosídeos/química , Humanos , Proteínas de Membrana/química , Proteínas de Membrana/metabolismo , Nucleotídeos Cíclicos/química , Nucleotídeos Cíclicos/isolamento & purificação
13.
Behav Brain Res ; 356: 98-106, 2019 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-29885845

RESUMO

Vascular dementia (VD) is a heterogeneous group of brain disorders in which cognitive impairment is attributed to cerebrovascular pathologies. Autophagy, a self-cannibalization mechanism, has been demonstrated to be involved in VD progression. Molecular hydrogen is known for its powerful anti-oxidative, anti-apoptotic, and anti-inflammatory activities, and it is also involved in autophagy. However, the effects of hydrogen on VD remain unclear. The current study found that hydrogen-rich water (HRW) significantly alleviated spatial learning and memory impairments. Similar to donepezil treatment, HRW also inhibited neuron loss and shrinkage in the hippocampal CA1 region. In addition, we found that HRW significantly increased the Bcl-2/Bax expression ratio and decreased cleaved caspase-3 expression levels in the hippocampus of VD rats. Moreover, electron microscopy revealed that HRW decreased the number of autophagosomes. We also observed that HRW reduced the increased ratio of LC3-II/I and Beclin 1 expression and saliently upregulated p62 expression. Furthermore, FoxO1 (a major mediator of autophagy regulation) and Atg7 levels were apparently decreased in the hippocampus of HRW-treated bilateral common carotid artery occlusion (2VO) rats. Taken together, these data show that molecular hydrogen exerts beneficial effects on cognitive impairment induced by chronic cerebral hypoperfusion. FoxO1-mediated autophagy plays an important role in the neuroprotective effects of hydrogen in a rat model of VD. Furthermore, the present findings highlight that HRW should be further investigated as a new therapeutic strategy for VD treatment in the future.


Assuntos
Demência Vascular/metabolismo , Hidrogênio/farmacologia , Proteínas do Tecido Nervoso/metabolismo , Animais , Apoptose/efeitos dos fármacos , Autofagia/fisiologia , Proteína Beclina-1/metabolismo , Isquemia Encefálica/patologia , Região CA1 Hipocampal/efeitos dos fármacos , Região CA1 Hipocampal/metabolismo , Caspase 3/metabolismo , Disfunção Cognitiva/tratamento farmacológico , Demência Vascular/fisiopatologia , Modelos Animais de Doenças , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Hidrogênio/metabolismo , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Proteínas do Tecido Nervoso/fisiologia , Neurônios/metabolismo , Fármacos Neuroprotetores/farmacologia , Ratos , Ratos Sprague-Dawley , Aprendizagem Espacial/efeitos dos fármacos
14.
Braz. j. med. biol. res ; 52(11): e8371, 2019. graf
Artigo em Inglês | LILACS | ID: biblio-1039257

RESUMO

Oxiracetam (ORC) is a commonly used nootropic drug for improving cognition and memory impairments. The therapeutic effect and underlying mechanism of ORC in vascular dementia (VaD) treatment remain unknown. In this study, 3-month-old male Sprague-Dawley rats with permanent bilateral common carotid artery occlusion-induced VaD were treated orally with low (100 mg/kg) or high (200 mg/kg) dose ORC once a day for 4 weeks. The results of the Morris water maze test and Nissl staining showed that ORC treatment significantly alleviated learning and memory deficits and neuronal damage in rats with VaD. Mechanistically, the protein levels of a panel of genes associated with neuronal apoptosis (Bcl-2, Bax) and autophagy (microtubule-associated protein 1 chain 3, Beclin1, p62) were significantly altered by ORC treatment compared with VaD, suggesting a protective role of ORC against VaD-induced neuronal apoptosis and autophagy. Moreover, the Akt/mTOR pathway, which is known to be the upstream signaling governing apoptosis and autophagy, was found to be activated in ORC-treated rats, suggesting an involvement of Akt/mTOR activation in ORC-rendered protection in VaD rats. Taken together, this study demonstrated that ORC may alleviate learning and memory impairments and neuronal damage in VaD rats by altering the expression of apoptosis/autophagy-related genes and activation of the Akt/mTOR signaling pathway in neurons.


Assuntos
Animais , Masculino , Ratos , Pirrolidinas/administração & dosagem , Demência Vascular/tratamento farmacológico , Transdução de Sinais/fisiologia , Fármacos Neuroprotetores/administração & dosagem , Proteínas Proto-Oncogênicas c-akt/metabolismo , Disfunção Cognitiva/tratamento farmacológico , Autofagia/efeitos dos fármacos , Demência Vascular/fisiopatologia , Demência Vascular/metabolismo , Ratos Sprague-Dawley , Apoptose/efeitos dos fármacos , Aprendizagem em Labirinto/efeitos dos fármacos , Modelos Animais de Doenças , Serina-Treonina Quinases TOR/metabolismo , Disfunção Cognitiva/fisiopatologia , Disfunção Cognitiva/metabolismo
15.
Eur J Immunol ; 48(8): 1302-1307, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-29729112

RESUMO

Hepatic Foxp3+ Treg cells are crucial for maintaining local immune homeostasis in the liver. However, the environmental cues required for hepatic Treg cell homeostasis are unclear. In this study, we showed that the IL-33 receptor ST2 was preferentially expressed on Treg cells in the mouse liver, but it was more lowly expressed in the spleen, mesenteric lymph nodes, and blood. More importantly, we found that IL-33 promoted the proliferation of hepatic Treg cells through myeloid differentiation factor MyD88 signaling concomitant with increased cyclin-dependent kinase 4 and cyclin D1 expression. These results suggest that IL-33 is a potential tissue-specific factor controlling Treg cell homeostasis via increased Treg proliferation in the liver.


Assuntos
Proteína 1 Semelhante a Receptor de Interleucina-1/imunologia , Interleucina-33/imunologia , Fator 88 de Diferenciação Mieloide/imunologia , Linfócitos T Reguladores/imunologia , Animais , Proliferação de Células/genética , Ciclina D1/metabolismo , Quinase 4 Dependente de Ciclina/metabolismo , Interleucina-33/genética , Fígado/citologia , Fígado/imunologia , Linfonodos/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fator 88 de Diferenciação Mieloide/genética , Transdução de Sinais/imunologia , Baço/imunologia
16.
Immunol Cell Biol ; 96(9): 958-968, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-29697865

RESUMO

CD4+ CD25+ Foxp3+ regulatory T cells (Tregs) play a pivotal role in limiting immunopathological damage to host organs after schistosome infection. Transforming growth factor-ß (TGF-ß) is an essential factor for the periphery conversion of CD4+ CD25- T cells into CD4+ CD25+ Foxp3+ Tregs by inducing the key transcription factor Foxp3. Antigen presenting cells (APCs), which highly express TGF-ß, are involved in parasite antigen-induced Treg conversion in peripheral. However, the mechanisms underlying high TGF-ß induction in APCs by parasite antigens remain to be clarified during schistosome infection. Here, we demonstrated that Schistosoma japonicum stress protein, heat shock protein 60 (SjHSP60), promoted TGF-ß production in macrophages (Mφ). Furthermore, we showed that activation of TLR4-Mal (MyD88 adaptor-like protein) signaling by SjHSP60 is necessary for induction of TGF-ß expression in Mφ, which subsequently promoted Treg induction. Our results not only demonstrate a novel mechanism of TGF-ß production in Mφ for inducing Tregs in mice with schistosomiasis, but also allude to the possibility of targeting parasite stress protein for potential therapeutics.


Assuntos
Antígenos de Helmintos/imunologia , Chaperonina 60/imunologia , Macrófagos/imunologia , Esquistossomose Japônica/imunologia , Linfócitos T Reguladores/imunologia , Receptor 4 Toll-Like/imunologia , Fator de Crescimento Transformador beta/imunologia , Animais , Feminino , Proteínas de Helminto/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Células RAW 264.7 , Schistosoma japonicum
17.
Math Biosci ; 300: 102-114, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29571814

RESUMO

In the reality, the lake system will be disturbed by stochastic factors including the external and internal factors. By adding the additive noise and the multiplicative noise to the right-hand sides of the model equation, the additive stochastic model and the multiplicative stochastic model are established respectively in order to reduce model errors induced by the absence of some physical processes. For both the two kinds of stochastic ecosystems, the authors studied the bifurcation characteristics with the FPK equation and the Lyapunov exponent method based on the Stratonovich-Khasminiskii stochastic average principle. Results show that, for the additive stochastic model, when control parameter (i.e., nutrient loading rate) falls into the interval [0.388644, 0.66003825], there exists bistability for the ecosystem and the additive noise intensities cannot make the bifurcation point drift. In the region of the bistability, the external stochastic disturbance which is one of the main triggers causing the lake eutrophication, may make the ecosystem unstable and induce a transition. When control parameter (nutrient loading rate) falls into the interval (0, 0.388644) and (0.66003825, 1.0), there only exists a stable equilibrium state and the additive noise intensity could not change it. For the multiplicative stochastic model, there exists more complex bifurcation performance and the multiplicative ecosystem will be broken by the multiplicative noise. Also, the multiplicative noise could reduce the extent of the bistable region, ultimately, the bistable region vanishes for sufficiently large noise. What's more, both the nutrient loading rate and the multiplicative noise will make the ecosystem have a regime shift. On the other hand, for the two kinds of stochastic ecosystems, the authors also discussed the evolution of the ecological variable in detail by using the Four-stage Runge-Kutta method of strong order γ=1.5. The numerical method was found to be capable of effectively explaining the regime shift theory and agreed with the realistic analyze. These conclusions also confirms the two paths for the system to move from one stable state to another proposed by Beisner et al. [3], which may help understand the occurrence mechanism related to the lake eutrophication from the view point of the stochastic model and mathematical analysis.


Assuntos
Ecossistema , Eutrofização , Lagos , Modelos Biológicos , Modelos Estatísticos , Processos Estocásticos
18.
Cell Death Dis ; 9(2): 218, 2018 02 13.
Artigo em Inglês | MEDLINE | ID: mdl-29440630

RESUMO

Although accumulating evidence has linked mesenchymal stem cells (MSCs) with tumor growth, the underlying mechanisms are poorly understood. Here, we demonstrated for the first time that human umbilical cord MSCs (hUCMSCs) dramatically increased the growth of lung adenocarcinoma (LUAD) cancer cells in a xenograft tumor model. Then, we observed that hUCMSC-derived extracellular vesicles (hUCMSC-EVs) contribute to the hUCMSC-promoted LUAD cell growth through a direct effect on LUAD cells. Furthermore, we showed that hUCMSC-EV-mediated LUAD growth is associated with increased proliferation and decreased apoptosis in LUAD cells, concomitant with reduced PTEN expression mediated by the hUCMSC-EV-transmitted miR-410. Our findings provide novel insights into the intercellular communications between cancer cells and MSCs through MSC-EV-miRNA and suggest that modification of hUCMSC-EVs might be an attractive therapeutic option for the clinical application of hUCMSC-EVs that would reduce unwanted side effects.


Assuntos
Adenocarcinoma de Pulmão/patologia , Vesículas Extracelulares/metabolismo , Células-Tronco Mesenquimais/metabolismo , MicroRNAs/metabolismo , Cordão Umbilical/metabolismo , Cordão Umbilical/patologia , Adenocarcinoma de Pulmão/genética , Adenocarcinoma de Pulmão/metabolismo , Animais , Diferenciação Celular/fisiologia , Vesículas Extracelulares/genética , Feminino , Xenoenxertos , Humanos , Masculino , Células-Tronco Mesenquimais/patologia , Camundongos , MicroRNAs/genética
19.
Neurol Res ; 40(1): 1-10, 2018 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-29125058

RESUMO

Objectives The potential protective effects and mechanisms of edaravone have not been well elucidated in vascular dementia (VaD) induced by chronic cerebral hypoperfusion (CCH). The aim of this study was to investigate whether edaravone could improve cognitive damage in rats induced by CCH, and whether the effects of edaravone were associated with ERK/Nrf2/HO-1 signaling pathway. Methods CCH was induced by bilateral common carotid arteries occlusion (BCCAO). Sprague-Dawley (SD) rats were randomly divided into four groups: sham (sham-operated) group, vehicle (BCCAO + normal saline) group, edaravone3.0 group and edaravone6.0 group. The edaravone3.0 and edaravone6.0 group rats were provided 3.0 mg/kg and 6.0 mg/kg of edaravone, respectively, intraperitoneal (i.p.) injection twice daily following the first day after BCCAO. In this experiment, the spatial learning and memory were assessed using the Morris water maze. The malondialdehyde (MDA) contents and superoxide dismutase (SOD) activities in the hippocampus were measured biochemically. And, the levels of total ERK1/2 (t-ERK1/2), Phospho-ERK1/2 (p-ERK1/2), total Nrf2 (t-Nrf2), nuclear Nrf2 (n-Nrf2), and HO-1 were assessed by western blot. Results The results showed that the treatment with edaravone significantly improved CCH-induced cognitive damage, and boosted endogenous antioxidants SOD activity and HO-1 level, decreased MDA contents in the hippocampus by activating Nrf2 signaling pathway which was related to ERK1/2. We also found that the neuronal morphology of the hippocampal CA1 area significantly improved and the number of Nrf2 positive cells markedly increased in the edaravone treatment groups. Conclusion Our results demonstrated a neuroprotective effect of edaravone on hippocampus against oxidative stress and cognitive deficit induced by CCH. The mechanism may be related to the enhancement of antioxidant defense system by activating ERK/Nrf2/HO-1 signaling pathway.


Assuntos
Antipirina/análogos & derivados , Isquemia Encefálica/tratamento farmacológico , Isquemia Encefálica/fisiopatologia , Sequestradores de Radicais Livres/uso terapêutico , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Animais , Antipirina/química , Antipirina/uso terapêutico , Isquemia Encefálica/patologia , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Edaravone , Sequestradores de Radicais Livres/química , Heme Oxigenase-1/metabolismo , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Masculino , Malondialdeído/metabolismo , Aprendizagem em Labirinto/efeitos dos fármacos , Fator 2 Relacionado a NF-E2/metabolismo , Ratos , Ratos Sprague-Dawley , Estatísticas não Paramétricas , Superóxido Dismutase/metabolismo
20.
Immunology ; 153(1): 84-96, 2018 01.
Artigo em Inglês | MEDLINE | ID: mdl-28799262

RESUMO

CD4+ CD25+ Foxp3+ regulatory T (Treg) cells play an important role in maintaining immune homeostasis. Interleukin-10 (IL-10), a cytokine with anti-inflammatory capacities, also has a critical role in controlling immune responses. In addition, it is well known that production of IL-10 is one of the suppression mechanisms of Treg cells. However, the action of IL-10 on Treg cells themselves remains insufficiently understood. In this study, by using a Schistosoma japonicum-infected murine model, we show that the elevated IL-10 contributed to Treg cell induction but impaired their immunosuppressive function. Our investigations further suggest that this may relate to the up-regulation of serum transforming growth factor (TGF-ß) level but the decrease in membrane-bound TGF-ß of Treg cells by IL-10 during S. japonicum infection. In addition, similar IL-10-mediated regulation on Treg cells was also confirmed in the murine model of asthma. In general, our findings identify a previously unrecognized opposing regulation of IL-10 on Treg cells and provide a deep insight into the precise regulation in immune responses.


Assuntos
Asma/imunologia , Asma/metabolismo , Imunomodulação , Esquistossomose Japônica/imunologia , Esquistossomose Japônica/metabolismo , Animais , Anticorpos Monoclonais/farmacologia , Asma/sangue , Asma/patologia , Biomarcadores , Citocinas/metabolismo , Modelos Animais de Doenças , Feminino , Expressão Gênica , Imunomodulação/efeitos dos fármacos , Imunossupressores/farmacologia , Interleucina-10/antagonistas & inibidores , Interleucina-10/sangue , Interleucina-10/metabolismo , Interleucina-10/farmacologia , Contagem de Linfócitos , Camundongos , Esquistossomose Japônica/sangue , Esquistossomose Japônica/parasitologia , Linfócitos T Reguladores/efeitos dos fármacos , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/metabolismo , Fator de Crescimento Transformador beta/genética , Fator de Crescimento Transformador beta/metabolismo
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