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1.
Plant Mol Biol ; 2019 Aug 30.
Artigo em Inglês | MEDLINE | ID: mdl-31471780

RESUMO

KEY MESSAGE: Our study firstly elaborated the underlying mechanism of endogenous CH4-induced abiotic tolerance, along with an alteration of ABA sensitivity by mimicking the endogenous CH4 production in MtMCR transgenic Arabidopsis. Endogenous methane (CH4) production and/or emission have been ubiquitously observed in stressed plants. However, their physiological roles remain unclear. Here, the methyl-coenzyme M reductase gene from Methanobacterium thermoautotrophicum (MtMCR), encoding the enzyme of methanogenesis, was expressed in Arabidopsis thaliana, to mimic the production of endogenous CH4. In response to salinity and osmotic stress, MtMCR expression was up-regulated in transgenic plants, resulting in significant increase of endogenous CH4 levels. Similar results were observed in abscisic acid (ABA) treatment. The functions of endogenous CH4 were characterized by the changes in plant phenotypes related to stress and ABA sensitivity during the germination and post-germination periods. When challenged with osmotic stress, a reduction in water loss and stomatal closure, were observed. Redox homeostasis was reestablished during osmotic and salinity stress, and ion imbalance was also restored in salinity conditions. The expression of several stress/ABA-responsive genes was up-regulated, and ABA sensitivity, in particularly, was significantly altered in the MtMCR transgenic plants. Together, our genetic study for the first time elaborated the possible mechanism of endogenous CH4-enhanced salinity and osmotic tolerance, along with an alteration of ABA sensitivity. These findings thus provided novel cues for understanding the possible roles of endogenous CH4 in plants.

2.
Sci Total Environ ; 695: 133780, 2019 Aug 05.
Artigo em Inglês | MEDLINE | ID: mdl-31416039

RESUMO

BACKGROUND: The identification of constituents of fine particulate matter (PM2.5) air pollution that had key impacts of ischemic stroke (the predominant subtype of stroke) is important to understand the underlying biological mechanisms and develop air pollution control policies. OBJECTIVES: To explore the associations between PM2.5 constituents and hospitalization for ischemic stroke in Shanghai, China. METHODS: We conducted a time-series study to explore the associations between 27 constituents of PM2.5 and hospitalization for ischemic stroke in Shanghai, China from 2014 to 2016. The over-dispersed generalized additive models with adjustment for time, day of week, holidays, and weather conditions were used to estimate the associations. We also evaluated the robustness of the effect estimates for each constituent after adjusting for the confounding effects of PM2.5 total mass and gaseous pollutants and the collinearity (the residual) between this constituent and PM2.5 total mass. We also compared the associations between seasons. RESULTS: In total, we identified 4186 ischemic stroke hospitalizations during the study period. The associations of ischemic stroke were consistently significant with elemental carbon and several elemental constituents (Chromium, Iron, Copper, Zinc, Arsenic, Selenium, and Lead) at lag 1 day in single-constituent models, models adjusting for PM2.5 total mass or gaseous pollutants and models adjusting for collinearity. The associations were much stronger in cool season than in warm season. CONCLUSIONS: The current study provides suggestive evidence that elemental carbon and some metallic elements may be mainly responsible for the risks of ischemic stroke hospitalization induced by short-term PM2.5 exposure.

3.
Artigo em Inglês | MEDLINE | ID: mdl-31267700

RESUMO

Peripheral human nerves fail to regenerate across long tube implants (>2 cm), and tissue-engineered nerve grafts represent a promising treatment alternative. The present study aims to investigate the testosterone propionate (TP) repair effect of acellular nerve allograft (ANA) seeded with allogeneic bone marrow mesenchymal stem cells (BMSCs) on 3-cm canine sciatic nerve defect. ANA cellularized with allogeneic BMSCs was implanted to the defect, and TP was injected into the lateral crus of the defected leg. The normal group, the autograft group, the ANA + BMSCs group, the ANA group, and the nongrafted group were used as control. Five months postoperatively, dogs in the TP + ANA + BMSCs group were capable of load bearing, normal walking, and skipping, the autograft group and the ANA + BMSCs group demonstrated nearly the same despite a slight limp. The compound muscle action potentials (CMAPs) on the injured side to the uninjured site in the TP + ANA + BMSCs group were significantly higher than that in the ANA + BMSCs group [CMAPs ratio at A: F(3, 20) = 191.40; 0.02, CMAPs ratio at B: F(3, 20) = 43.27; 0.01]. Masson trichrome staining revealed that in the TP + ANA + BMSCs group, both the diameter ratio of the myelinated nerve and the thickness ratio of regenerated myelin sheath were significantly larger than that in the other groups [the diameter of myelinated nerve fibers: F(3, 56) = 13.45; P < .01, the thickness ratio of regenerated myelin sheath: F(3, 56) = 51.25; P < .01]. In conclusion, TP could significantly increase the repairing effects of the ANA + BMSCs group, and their combination was able to repair 3-cm canine sciatic nerve defect. It therefore represents a promising therapeutic approach.

4.
Environ Int ; 131: 105019, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31330363

RESUMO

BACKGROUND: Fine particulate matter (PM2.5) has been widely associated with airway inflammation represented by increased fractional concentration of exhaled nitric oxide (FeNO). However, it remains unclear whether various PM2.5 constituents have different impacts on FeNO and its production process from the arginase (ARG)-nitric oxide synthase (NOS) pathway. OBJECTIVES: To investigate the acute effects of PM2.5 constituents on FeNO and DNA methylation of genes involved. METHODS: We conducted a longitudinal panel study among 43 young adults in Shanghai, China from May to October in 2016. We monitored the concentrations of 25 constituents of PM2.5. We applied the linear mixed-effect model to evaluate the associations of PM2.5 constituents with FeNO and DNA methylation of the ARG2 and NOS2A genes. RESULTS: Following PM2.5 exposure, NOS2A methylation decreased and ARG2 methylation increased only on the concurrent day, whereas FeNO increased most prominently on the second day. Nine constituents (OC, EC, K, Fe, Zn, Ba, Cr, Se, and Pb) showed consistent associations with elevated FeNO and decreased NOS2A methylation or increased ARG2 methylation in single-constituent models and models adjusting for PM2.5 total mass and collinearity. An interquartile range increase of these constituents was associated with respective decrements of 0.27-1.20 in NOS2A methylation (%5mC); increments of 0.48-1.56 in ARG2 methylation (%5mC); and increments of 7.12%-17.54% in FeNO. CONCLUSIONS: Our results suggested that OC, EC, and some metallic elements may be mainly responsible for the development and epigenetic regulation of airway inflammatory response induced by short-term PM2.5 exposure.

5.
Bioorg Med Chem Lett ; 29(14): 1812-1818, 2019 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-31088713

RESUMO

Given the therapeutic efficacy of fasudil hydrochloride (F) and dichloroacetate (DCA) on pulmonary arterial hypertension (PAH), a new salt fasudil dichloroacetate (FDCA) was designed, synthesized and biologically evaluated. FDCA exhibited comparable ROCK II inhibitory activity relative to fasudil hydrochloride, and suppressed the expression of TNF-α and IL-6 in both PDGF-BB and hypoxia-treated pulmonary arterial smooth muscle cells (PASMCs) and endothelial cells (PAECs). Significantly, FDCA lowered mean pulmonary artery pressure (mPAP) and right ventricular systolic pressure (RVSP), and decreased right ventricular hypertrophy (RVH) in monocrotaline (MCT)-induced PAH rats. Meanwhile, FDCA remarkably decreased pulmonary artery medial thickness (PAMT) and hyperplasia, restoring the elasticity of elastic fiber, reduced cardiac hypertrophy, and attenuated fibrosis of heart and lung. Collectively, FDCA exhibited triple activities of pulmonary vasodilation, vascular remodeling inhibition and RVH inhibition, suggesting that it may be a promising agent for PAH intervention.

6.
Emerg Microbes Infect ; 8(1): 734-748, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31130074

RESUMO

Many pathogens infect hosts through various immune evasion strategies. However, the molecular mechanisms by which pathogen proteins modulate and evade the host immune response remain unclear. Enterohemorrhagic Escherichia coli (EHEC) is a pathological strain that can induce mitogen-activated protein (MAP) kinase (Erk, Jnk and p38 MAPK) and NF-κB pathway activation and proinflammatory cytokine production, which then causes diarrheal diseases such as hemorrhagic colitis and hemolytic uremic syndrome. Transforming growth factor ß-activated kinase-1 (TAK1) is a key regulator involved in distinct innate immune signalling pathways. Here we report that EHEC translocated intimin receptor (Tir) protein inhibits the expression of EHEC-induced proinflammatory cytokines by interacting with the host tyrosine phosphatase SHP-1, which is dependent on the phosphorylation of immunoreceptor tyrosine-based inhibition motifs (ITIMs). Mechanistically, the association of EHEC Tir with SHP-1 facilitated the recruitment of SHP-1 to TAK1 and inhibited TAK1 phosphorylation, which then negatively regulated K63-linked polyubiquitination of TAK1 and downstream signal transduction. Taken together, these results suggest that EHEC Tir negatively regulates proinflammatory responses by inhibiting the activation of TAK1, which is essential for immune evasion and could be a potential target for the treatment of bacterial infection.


Assuntos
Escherichia coli Êntero-Hemorrágica/patogenicidade , Infecções por Escherichia coli/fisiopatologia , Proteínas de Escherichia coli/metabolismo , Interações Hospedeiro-Patógeno , Evasão da Resposta Imune , MAP Quinase Quinase Quinases/antagonistas & inibidores , Receptores de Superfície Celular/metabolismo , Fatores de Virulência/metabolismo , Animais , Infecções por Escherichia coli/microbiologia , Células HEK293 , Humanos , Macrófagos Peritoneais , Camundongos , Camundongos Endogâmicos C57BL , Ligação Proteica , Proteína Tirosina Fosfatase não Receptora Tipo 6/metabolismo , Células RAW 264.7
7.
J Biomed Inform ; 93: 103155, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30902596

RESUMO

Candidate gene prioritization for complex non-communicable diseases is essential to understanding the mechanism and developing better means for diagnosing and treating these diseases. Many methods have been developed to prioritize candidate genes in protein-protein interaction (PPI) networks. Integrating functional information/similarity into disease-related PPI networks could improve the performance of prioritization. In this study, a candidate gene prioritization method was proposed for non-communicable diseases considering disease risks transferred between genes in weighted disease PPI networks with weights for nodes and edges based on functional information. Here, three types of non-communicable diseases with pathobiological similarity, Type 2 diabetes (T2D), coronary artery disease (CAD) and dilated cardiomyopathy (DCM), were used as case studies. Literature review and pathway enrichment analysis of top-ranked genes demonstrated the effectiveness of our method. Better performance was achieved after comparing our method with other existing methods. Pathobiological similarity among these three diseases was further investigated for common top-ranked genes to reveal their pathogenesis.

8.
Cancer Res ; 79(13): 3395-3405, 2019 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-30918001

RESUMO

Nitric oxide (NO) has a wide range of potential applications in tumor therapy. However, a targeted delivery system for NO donors has remained elusive, creating a bottleneck that limits its druggability. The antibody-drug conjugate (ADC) is a targeted drug delivery system composed of an antibody linked to an active cytotoxic drug. This design may compensate for the weak targeting ability and various biological functions of the NO donor. In this study, we designed the NO donor HL-2, which had a targeted, cleaved disulfide bond and an attachable maleimide terminal. We conjugated HL-2 with an antibody that targeted CD24 through a thioether bond to generate an ADC-like immunoconjugate, antibody-nitric oxide conjugate (ANC), which we named HN-01. HN-01 showed efficient internalization and significantly increased the release of NO in hepatic carcinoma cells in vitro. HN-01 induced apoptosis of tumor cells and suppressed tumor growth in hepatic carcinoma-bearing nude mice through antibody-dependent co-toxicity; HN-01 also increased NO levels in tumor cells. Collectively, this study expands the concept of ADC and provides an innovative NO donor and ANC to address current challenges in targeted delivery of NO. This new inspiration for an ANC design can also be used in future studies for other molecules with intracellular targets. SIGNIFICANCE: This study is the first to expand the concept of ADC with an antibody-nitric oxide conjugate that suppresses hepatic carcinoma in vitro and in vivo.

9.
Nano Lett ; 19(4): 2731-2738, 2019 04 10.
Artigo em Inglês | MEDLINE | ID: mdl-30919635

RESUMO

Nitric oxide (NO) induces a multitude of antitumor activities, encompassing the induction of apoptosis, sensitization to chemo-, radio-, or immune-therapy, and inhibition of metastasis, drug resistance, angiogenesis, and hypoxia, thus attracting much attention in the area of cancer intervention. To improve the precise targeting and treatment efficacy of NO, a glutathione (GSH)-sensitive NO donor (1,5-bis[(l-proline-1-yl)diazen-1-ium-1,2-diol- O2-yl]-2,4-dinitrobenzene, BPDB) coordinates with iron ions to form the nanoscale coordination polymer (NCP) via a simple precipitation and then partial ion exchange process. The obtained Fe(II)-BNCP shows desirable solubility, biocompatibility, and circulation stability. Quick NO release triggered by high concentrations of GSH in tumor cells improves the specificity of NO release in situ, thus avoiding side effects in other tissues. Meanwhile, under high concentrations of H2O2 in tumors, Fe2+ ions in BPDB-based NCP, named Fe(II)-BNCP, exert Fenton activity to generate hydroxyl radicals (·OH), which is the main contribution for chemodynamic therapy (CDT). In addition, ·O2- generated by the Haber-Weiss reaction of Fe2+ ions with H2O2 can quickly react with NO to produce peroxynitrite anion (ONOO-) that is more cytotoxic than ·O2- or NO only. This synergistic NO-CDT effect has been proved to retard the tumor growth in Heps xenograft ICR mouse models. This work not only implements a synergistic effect of NO-CDT therapy but also offers a simple and efficient strategy to construct a coordination polymer nanomedicine via rationally designed prodrug molecules such as NO donors.


Assuntos
Neoplasias Hepáticas/tratamento farmacológico , Nanomedicina/métodos , Doadores de Óxido Nítrico/química , Óxido Nítrico/química , Animais , Apoptose/efeitos dos fármacos , Hipóxia Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Dinitrobenzenos/química , Glutationa/química , Humanos , Peróxido de Hidrogênio/química , Neoplasias Hepáticas/patologia , Óxido Nítrico/biossíntese , Polímeros/administração & dosagem , Polímeros/síntese química , Polímeros/química , Pró-Fármacos/administração & dosagem , Pró-Fármacos/síntese química , Pró-Fármacos/química , Ratos
10.
BMC Med Imaging ; 19(1): 17, 2019 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-30767773

RESUMO

BACKGROUND: The clinical and research value of Computed Tomography (CT) volumetry of esophageal cancer tumor size remains controversial. Development in CT technique and image analysis has made CT volumetry less cumbersome and it has gained renewed attention. The aim of this study was to assess esophageal tumor volume by semi-automatic measurements as compared to manual. METHODS: A total of 23 esophageal cancer patients (median age 65, range 51-71), undergoing CT in the portal-venous phase for tumor staging, were retrospectively included between 2007 and 2012. One radiology resident and one consultant radiologist measured the tumor volume by semiautomatic segmentation and manual segmentation. Reproducibility of the respective measurements was assessed by intraclass correlation coefficients (ICC) and by average deviation from mean. RESULTS: Mean tumor volume was 46 ml (range 5-137 ml) using manual segmentation and 42 ml (range 3-111 ml) using semiautomatic segmentation. Semiautomatic measurement provided better inter-observer agreement than traditional manual segmentation. The ICC was significantly higher for semiautomatic segmentation in comparison to manual segmentation (0.86, 0.56, p < 0.01). The average absolute percentage difference from mean was reduced from 24 to 14% (p < 0.001) when using semiautomatic segmentation. CONCLUSIONS: Semiautomatic analysis outperforms manual analysis for assessment of esophageal tumor volume, improving reproducibility.


Assuntos
Tomografia Computadorizada de Feixe Cônico/métodos , Neoplasias Esofágicas/diagnóstico por imagem , Neoplasias Esofágicas/patologia , Idoso , Feminino , Humanos , Processamento de Imagem Assistida por Computador , Masculino , Pessoa de Meia-Idade , Estudos Multicêntricos como Assunto , Estadiamento de Neoplasias , Ensaios Clínicos Controlados Aleatórios como Assunto , Estudos Retrospectivos
11.
Int J Mol Sci ; 20(4)2019 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-30781401

RESUMO

Trichophyton mentagrophytes is a common fungal pathogen that causes human and animal dermatophytosis. Previous studies have shown that zinc deficiency inhibits T. mentagrophytes growth, and the ZafA gene of T. mentagrophytes can code the functionally similar zinc finger transcriptional factor that can promote zinc ion absorption; however, the impact of ZafA on virulence and pathogenicity remains undetermined. To assess its gene function, the ZafA mutant, ZafA-hph, and the ZafA complemented strain, ZafA+bar, were constructed via Agrobacterium tumefaciens-mediated transformation. Polymerase chain reaction and Southern blot analyses were used to confirm the disruption. In vitro growth capacity and virulence analyses comparing ZafA-hph with wild-type T. mentagrophytes and ZafA+bar showed that ZafA-hph's growth performance, reproduction ability, and zinc ion absorption capacity were significantly lower than the wild-type T. mentagrophytes and ZafA+bar. ZafA-hph also showed weak hair biodegradation ability and animal pathogenicity. Thus, the significant decrease in T. mentagrophytes' growth ability and virulence was due to a lack of the zinc-responsive activity factor rather than the transformation process. This study confirmed that the T. mentagrophytes' zinc-responsive activity factor plays important roles in the pathogen's growth, reproduction, zinc ion absorption, and virulence. This factor is important and significant for effectively preventing and controlling T. mentagrophytes infections.


Assuntos
Genes Fúngicos , Trichophyton/crescimento & desenvolvimento , Trichophyton/patogenicidade , Animais , Cabelo , Humanos , Mutação/genética , Pele/microbiologia , Pele/patologia , Trichophyton/genética , Zinco/metabolismo
12.
Environ Sci Pollut Res Int ; 26(8): 7497-7511, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30659487

RESUMO

Herein we investigated the morphology, chemical characteristics, and source apportionment of fine particulate matter (PM2.5) samples collected from five sites in Jiaxing. Scanning electron microscopy (SEM) and transmission electron microscopy (TEM) showed that soot aggregates and coal-fired fly ash were generally the most abundant components in the samples. All the samples were analyzed gravimetrically for mass concentrations and their various compositions were determined. Our results revealed that the PM2.5 concentrations in the samples were in the following order: winter > spring > autumn > summer. The PM2.5 concentrations in winter and spring were higher than those in autumn and summer, except for inorganic elements. Carbonaceous species and water-soluble inorganic ions were the most abundant components in the samples, accounting for 26.17-50.44% and 34.27-49.6%, respectively. The high secondary organic carbon/organic carbon ratio indicated that secondary organic pollution in Jiaxing was severe. The average ratios of NO3-/SO42-, ranging from 1.01 to 1.25 at the five sites, indicated that mobile pollution sources contributed more to the formation of PM2.5 than stationary sources. The BeP/(BeP + BaP) ratio (0.52-0.71) in samples reflected the influence of transportation from outside of Jiaxing. The positive matrix factorization (PMF) model identified eight main pollution sources: secondary nitrates (26.95%), secondary sulfates (15.49%), secondary organic aerosol (SOA) (19.64%), vehicle exhaust (15.67%), coal combustion (8.6%), fugitive dust (7.7%), ships and heavy oil (5.23%), biomass burning, and other sources (0.91%). Therefore, PM2.5 pollution in Jiaxing during the winter and spring seasons was more severe than that in the summer and autumn. Secondary aerosols were the most important source of PM2.5 pollution; therefore, focus should be placed on controlling gaseous precursors.


Assuntos
Poluentes Atmosféricos/análise , Monitoramento Ambiental , Material Particulado/análise , Aerossóis , Biomassa , China , Carvão Mineral , Poeira , Nitratos , Estações do Ano , Emissões de Veículos , Água
13.
Plant Cell Rep ; 38(3): 377-389, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30617541

RESUMO

KEY MESSAGE: Pharmacological and molecular evidence reveals a novel role of methane (CH4) gas in root organogenesis, the induction of lateral root (LR) formation, and this response might require hydrogen peroxide (H2O2) synthesis. Although plants can produce CH4 and release this to atmosphere, the beneficial role(s) of CH4 are not fully elucidated. In this study, the fumigation with CH4 not only increased NADPH oxidase activity and H2O2 production, but also induced tomato lateral root primordial formation and thereafter LR development. However, exogenously applied argon and nitrogen failed to influence LR formation. Above responses triggered by CH4 were sensitive to the removal of endogenous H2O2 with dimethylthiourea (DMTU; a membrane-permeable scavenger of H2O2), suggesting the hypothesis that CH4's effect on LR formation could be mediated by endogenous H2O2. Diphenylene iodonium (DPI) inhibition of the H2O2 generating enzyme NADPH oxidase attenuated H2O2 synthesis and impaired LR formation in response to CH4, confirming the requirement of NADPH oxidase-dependent H2O2. Meanwhile, the alterations of endogenous H2O2 concentrations failed to influence CH4 production in tomato seedlings. Molecular evidence revealed that CH4-induced SlCDKA1, SlCYCA2;1, and SlCYCA3;1 transcripts, and -decreased SlKRP2 mRNA were impaired by DMTU or DPI. Contrasting changes in LR formation-related miR390a and miR160 transcripts and their target genes, including SlARF4 and SlARF16, were observed. Together, our pharmacological and molecular evidence suggested the requirement of H2O2 synthesis in CH4-triggered tomato LR formation, partially via the regulation of cell cycle regulatory genes, miRNA-, and tasiRNA-modulated gene expression.


Assuntos
Peróxido de Hidrogênio/metabolismo , Lycopersicon esculentum/metabolismo , Metano/metabolismo , Raízes de Plantas/metabolismo , Regulação da Expressão Gênica de Plantas/fisiologia , NADPH Oxidases/metabolismo , Proteínas de Plantas , Plântula/metabolismo , Tioureia/análogos & derivados , Tioureia/metabolismo
14.
Nutrition ; 59: 50-55, 2018 Aug 09.
Artigo em Inglês | MEDLINE | ID: mdl-30419500

RESUMO

OBJECTIVE: Although computed tomography (CT) is frequently used to determine body composition, the effects of using different CT protocols is not well known. The aim of this study was to determine whether contrast media phase, radiation dose, and slice thickness in CT affect body composition segmentation. METHODS: Clinically indicated perfusion CTs of the upper abdomen in 20 patients (seven women) between 40 and 87 y of age with high suspicion of hepatocellular carcinoma were analyzed retrospectively. Axial images from the L3 level with varying imaging delay were reconstructed after contrast media injection (18 images per patient), slice thickness (5 images, 2-10 mm), and radiation dose (4 images with one-third to four-thirds of standard dose). Muscle and fat areas were segmented semiautomatically by drawing regions of interests and using established cutoff thresholds. Skeletal muscle index (SMI), steatotic muscle area, and adipose tissue index, as well as muscle attenuation and fat attenuation, were evaluated. RESULTS: Average SMI increased by up to 2.8% after contrast media injection. Steatotic muscle area decreased by ≤13.8%, and adipose tissue index decreased by ≤6.5%. Muscle attenuation increased after contrast media injection, whereas fat attenuation decreased (all P < 0.001). SMI decreased by 1.9% on average when increasing slice thickness from 2 to 10 mm. Steatotic muscle area increased by ≤3.3%, and adipose tissue index increased by ≤1.5% (all P < 0.05). Muscle attenuation did not change significantly with reconstruction thickness. Radiation dose had no effect on estimated area of spinal muscle, fatty spinal muscle, or visceral fat. CONCLUSIONS: Contrast media have a strong effect on the evaluation of body composition, whereas the influence of slice thickness is less pronounced. Radiation dose can be reduced by ≥66% without significantly affecting segmentation.

15.
Molecules ; 23(11)2018 Oct 31.
Artigo em Inglês | MEDLINE | ID: mdl-30384445

RESUMO

The inflammatory response mediated by microglia plays a critical role in the progression of ischemic stroke. Phosphoinositide 3-kinase gamma (PI3Kγ) has been implicated in multiple inflammatory and autoimmune diseases, making it a promising target for therapeutic intervention. The aim of this study was to evaluate the efficacy of 8e, a hydrogen sulfide (H2S) releasing derivative of 3-n-butylphthalide (NBP), on brain damage and PI3Kγ signaling following cerebral ischemia injury. 8e significantly reduced sensorimotor deficits, focal infarction, brain edema and neural apoptosis at 72 h after transient middle cerebral artery occlusion (tMCAO). The NOX2 isoform of the NADPH oxidase family is considered a major enzymatic source of superoxide. We found that the release of superoxide, together with the expression of NOX2 subunits p47phox, p-p47phox, and the upstream PI3Kγ/AKT signaling were all down-regulated by 8e, both in the penumbral region of the rat brain and in the primary cultured microglia subjected to oxygen-glucose deprivation (OGD). With the use of siRNA and pharmacological inhibitors, we further demonstrated that 8e regulates the formation of superoxide in activated microglia through the PI3Kγ/AKT/NOX2 signaling pathway and subsequently prevents neuronal death in neighboring neurons. Our experimental data indicate that 8e is a potential candidate for the treatment of ischemic stroke and PI3Kγ-mediated neuroinflammation.

16.
Eur J Med Chem ; 162: 650-665, 2018 Oct 04.
Artigo em Inglês | MEDLINE | ID: mdl-30481687

RESUMO

Glucose intolerance is associated with metabolic syndrome and type 2 diabetes mellitus (T2DM) while some new therapeutic drugs, such as rosiglitazone (Rosi), for T2DM can cause severe cardiovascular side effects. Herein we report the synthesis of Rosi-ferulic acid (FA)-nitric oxide (NO) donor trihybrids to improve glucose tolerance and minimize the side effects. In comparison with Rosi, the most active compound 21 exhibited better effects on improving glucose tolerance, which was associated with its NO production, antioxidant and anti-inflammatory activities. Furthermore, 21 displayed relatively high stability in the simulated gastrointestinal environments and human liver microsomes, and released Rosi in plasma. More importantly, 21, unlike Rosi, had little stimulatory effect on the membrane translocation of aquaporin-2 (AQP2) in kidney collecting duct epithelial cells. These, together with a better safety profile, suggest that the trihybrids, like 21, may be promising candidates for intervention of glucose intolerance-related metabolic syndrome and T2DM.

17.
BMC Plant Biol ; 18(1): 207, 2018 Sep 24.
Artigo em Inglês | MEDLINE | ID: mdl-30249185

RESUMO

BACKGROUND: Osmotic stress is a major abiotic stress limiting crop production by affecting plant growth and development. Although previous reports discovered that methane (CH4) has a beneficial effect on osmotic stress, the corresponding downstream signal(s) is still elusive. RESULTS: Polyethylene glycol (PEG) treatment progressively stimulated the production of CH4 in germinating mung bean seeds. Exogenous CH4 and sodium nitroprusside (SNP) not only triggered nitric oxide (NO) production in PEG-stressed plants, but also alleviated the inhibition of seed germination. Meanwhile, amylase activity was activated, thus accelerating the formation of reducing sugar and total soluble sugar. Above responses could be impaired by NO scavenger(s), suggesting that CH4-induced stress tolerance was dependent on NO. Subsequent tests showed that CH4 could reestablish redox balance in a NO-dependent fashion. The addition of inhibitors of the nitrate reductase (NR) and NO synthase in mammalian (NOS), suggested that NR and NOS-like protein might be partially involved in CH4-alleviated seed germination inhibition. In vitro and scavenger tests showed that NO-mediated S-nitrosylation might be associated with above CH4 responses. CONCLUSIONS: Together, these results indicated an important role of endogenous NO in CH4-enhanced plant tolerance against osmotic stress, and NO-regulated redox homeostasis and S-nitrosylation might be involved in above CH4 action.


Assuntos
Metano/metabolismo , Óxido Nítrico/metabolismo , Pressão Osmótica/fisiologia , Vigna/fisiologia , Benzoatos/farmacologia , Óxidos N-Cíclicos/farmacologia , Germinação/efeitos dos fármacos , Imidazóis/farmacologia , Metano/farmacologia , NG-Nitroarginina Metil Éster/farmacologia , Nitroprussiato/farmacologia , Oxirredução , Polietilenoglicóis/farmacologia , Amido/metabolismo , Compostos de Tungstênio/farmacologia , Vigna/efeitos dos fármacos
18.
Chem Sci ; 9(34): 6893-6898, 2018 Sep 14.
Artigo em Inglês | MEDLINE | ID: mdl-30210764

RESUMO

Currently, there is no effective therapy for the treatment of highly metastatic triple-negative breast cancer (TNBC). Microvesicle (MV) formation is crucial for the metastasis of TNBC. Here we report a novel strategy to inhibit the generation of MVs for the intervention of TNBC. O2-3-Aminopropyl diazeniumdiolates 3a-f are designed and synthesized, which can be activated by lysyloxidase over-expressed in TNBC cells. The most active compound 3f is able to selectively release high levels of NO in TNBC cells, inhibit the cell proliferation, and reduce the adhesion, invasion and migration of TNBC cells in vitro. Furthermore, 3f significantly suppresses the growth and metastasis of implanted TNBC in vivo through attenuating MV formation by an epigenetic modification of miR-203/RAB22A expression in an NO-dependent manner, providing the first evidence of NO donor(s) acting as epigenetic modulators to fight highly metastatic TNBC.

19.
Adv Mater ; 30(30): e1704490, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-29889325

RESUMO

Chemotherapy suffers numbers of limitations including poor drug solubility, nonspecific biodistribution, and inevitable adverse effects on normal tissues. Tumor-targeted delivery and intratumoral stimuli-responsive release of drugs by nanomedicines are considered to be highly promising in solving these problems. Compared with traditional chemotherapeutic drugs, high concentration of nitric oxide (NO) exhibits unique anticancer effects. The development of tumor-targeting and intratumoral microenvironment-responsive NO-releasing nanomedicines is highly desired. Here a novel kind of organic-inorganic composite nanomedicine (QM-NPQ@PDHNs) is presented by encapsulating a glutathione S-transferases π (GSTπ)-responsive drug O2 -(2,4-dinitro-5-{[2-(ß-d-galactopyranosyl olean-12-en-28-oate-3-yl)-oxy-2-oxoethyl] piperazine-1-yl} phenyl) 1-(methylethanolamino)diazen-1-ium-1,2-dilate (NPQ) as NO donor and an aggregation-induced-emission (AIE) red fluorogen QM-2 into the cores of the hybrid nanomicelles (PEGylated disulfide-doped hybrid nanocarriers (PDHNs)) with glutathione (GSH)-responsive shells. The QM-NPQ@PDHN nanomedicine is able to respond to the intratumoral over-expressed GSH and GSTπ, resulting in the responsive biodegradation of the protective organosilica shell and NPQ release, and subsequent NO release within the tumor, respectively, and thus normal organs remain unaffected. This work demonstrates a paradigm of dual intratumoral redox/enzyme-responsive NO-release nanomedicine for tumor-specific and high-efficacy cancer therapy.

20.
Nutrition ; 53: 9-13, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-29625351

RESUMO

OBJECTIVES: Our purpose was to investigate whether tube potential in contrast-enhanced computed tomography (CT) affects body composition analysis. METHODS: Images from dual-source, dual-energy CT from the abdomen with intravenous contrast media administration were used. A total of 17 patients (11 women, mean age 52) with a mean body mass index of 20.8 kg/cm2 were included. Simultaneously acquired images with a tube voltage of 80 kV and 140 kV were compared. Body composition was analyzed on a single slice at the L3 level. Parameters evaluated included muscle and fat attenuation (Hounsfield units [HU]), skeletal muscle index (cm2/m2), muscle area (cm2), and steatotic muscle area (cm2). Significant differences between 80 kV and 140 kV series were compared using the paired Student's t test. RESULTS: Tube potential affected muscle attenuation with an average difference of 17% between 80 kV and 140 kV series (48 HU versus 41 HU, P < 0.01), fat attenuation (-84 HU versus -69 HU, P < 0.01), skeletal muscle index of 5.2% (40.1 cm2/m2 versus 42.2 cm2/m2, P < 0.01), muscle area of 5.1% (117 cm2 versus 123 cm2, P < 0.01), and steatotic muscle area of 12.9% (31 cm2 versus 35 cm2, P < 0.01). CONCLUSION: Tube potential significantly affects body segmentation in contrast-enhanced CT.

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