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1.
Mater Sci Eng C Mater Biol Appl ; 107: 110311, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31761197

RESUMO

In this study, a small-diameter, double-layered eggshell membrane/thermoplastic polyurethane (ESM/TPU) vascular graft with a wavy structure was developed. The avian eggshell membrane, a fibrous structure similar to the extracellular matrix (ECM), has the potential to yield rapid endothelialization in vitro. The dopamine and heparin modification of the ESM surface not only promoted human umbilical vein endothelial cell (HUVEC) proliferation via cytocompatibility assessment, but also improved its anticoagulation properties as verified in platelet adhesion tests. The biomimetic mechanical properties of the vascular graft were provided by the elastic TPU fibers via electrospinning using a wavy cross-section rotating collector. The advantage of combining these two materials is to make use of the bioactivity of ESM as the internal membrane and the tunable mechanical properties of TPU as the external layer. The circumferentially wavy structure of the vascular graft produced a toe region in the non-linear section of the stress-strain curve similar to that of natural blood vessels. The ESM/TPU graft's circumferential ultimate strength was 2.57 MPa, its strain was 339% mm/mm, and its toe region was found to be around 20% mm/mm. Cyclical tension tests showed that the vascular graft could maintain good mechanical properties and showed no structural damage under repeated extension tests.

2.
J Nanosci Nanotechnol ; 20(4): 2584-2591, 2020 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-31492280

RESUMO

Magnetic iron oxide (Fe3O4) nanoparticles (NPs) have attracted extensive attentions in biomedical fields such as magnetic resonance imaging (MRI). However, the instability and unfavorable dispersity of bare Fe3O4 NPs is a challenge for biomedical applications. Herein, we proposed a strategy using hollow carbon sphere (HCS) as a shell structure to endow Fe3O4 NPs better stability, dispersity, as well as biocompatibility. To verify intracellular behaviors and biosafety of HCSdecorated Fe3O4 nanoparticles (Fe3O4@HCS NPs), the assessment of cellular effects of these NPs based on synchrotron radiation-based techniques were done to explore detailed interaction between Fe3O4@HCS NPs and liver cells, HepG2. We found that a large number of NPs were internalized by cells in a time-dependent manner determined by inductively coupled plasma mass spectrometry (ICP-MS), which was further supported by intracellular accumulation of iron via X-ray fluorescence (XRF) imaging. Moreover, confocal imaging showed that these NPs mainly located in the lysosomes where they remained stable and undissolved within 72 hours, which was verified by chemical form characterization of iron via Fe K-edge X-ray adsorption near edge structure (XANES). With the coating shell of HCS, the release of iron ions was prevented even in acidic lysosome and the integrity of lysosomal membrane remained unchanged during the storage of NPs. As a result, Fe3O4@HCS NPs exhibited low level of oxidative stress and induced negligible cytotoxicity towards HepG2 cells. Based on the powerful techniques, we demonstrated that the carbon outer layer provides a physical barrier that helps remain excellent properties of magnetic Fe3O4 NPs and good dispersity, chemical stability, as well as biocompatibility for potential applications in biomedical fields.

3.
Anal Biochem ; 588: 113474, 2020 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-31614116

RESUMO

With Escherichia coli alkaline phosphatase (ECAP) as the tag fused to the N-terminus of Pseudomonas Aeruginosa arylsulfatase (PAAS) and its mutants via a flexible linker, the comparison of the activity ratios of an applicable enzyme and its mutants to a suitable enzyme tag in cell lysates of their fused forms was tested for high-throughput (HTP) screening of mutants. After both the induced expression of a fused form and alkaline lysis of the transformed cells in microplate wells, HTP assay of the activities of ECAP and PAAS/mutant was realized via spectrophotometric-dual-enzyme-simultaneous-assay to derive their activity ratio. The successful induced expression of fused forms required ECAP activities higher than 5.3 U/L in cell lysates. Of three representative fused PAAS/mutants in cell lysates, there were similar proteolytic fragments and the comparison of their activity ratios greatly enhanced the recognition of weakly positive mutants. After saturation mutagenesis at M72 of the fused PAAS, the activity ratios of PAAS/mutants to ECAP in cell lysates of their fused forms were proportional to specific activities of their non-fused counterparts in cell lysates by an immunoturbidimetric assay. Therefore, the proposed strategy was absorbing for both HTP screening of mutants and HTP elucidation of sequence-activity relationship of applicable enzymes.

4.
J Affect Disord ; 260: 84-90, 2020 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-31493644

RESUMO

BACKGROUND: Previous studies have investigated the role of cognitive factors in the relationship between stressful life events and depression; however, few studies comprehensively considered cognitive and personality factors. Therefore, this study investigated the multiple mediating roles of fatalism and core self-evaluations in the relationship between stressful life events and depression. METHODS: A cross-sectional survey was conducted with 537 Chinese university students (Mage = 20.20, SD = 1.38) at two universities in Guizhou and Sichuan provinces. The independent variable was stressful life events; mediating variables were fatalism and core self-evaluations; and the dependent variable was extent of depression. Multiple mediation analysis was performed using the PROCESS macro in SPSS. RESULTS: Significant positive correlations were found among stressful life events, fatalism, and depression, while core self-evaluations were significantly negatively correlated with stressful life events, fatalism, and depression. After adjusting for demographic variables, stressful life events directly and positively influenced depression (ß = 0.370, 95% CI = 0.292-0.448). Fatalism and core self-evaluations played multiple mediating roles in the relationship between stressful life events and depression, with stressful life events influencing depression through three mediation pathways (total mediation effect = 0.199, 95% CI = 0.145-0.254), which accounted for 53.85% of the total effect. LIMITATIONS: The data used in this study were self-reported by university students and measureed via cross-sectional designs. CONCLUSIONS: Stressful life events can influence depression either directly or indirectly by simultaneously increasing fatalism and lowering core self-evaluations (parallel mediation) or decreasing core self-evaluations through increasing the level of fatalism (serial mediation).

5.
Am J Forensic Med Pathol ; 40(4): 312-317, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31688052

RESUMO

BACKGROUND: Schizophrenia is a detrimental psychiatric disorder, with an increased mortality from natural and nonnatural causes. METHODS: This study was a retrospective review of autopsy cases of all the individuals with history of schizophrenia investigated by the Office of the Chief Medical Examiner, State of Maryland, for a 5-year period from 2008 to 2012. RESULT: A total of 391 schizophrenia patients were autopsied at the Office of the Chief Medical Examiner because they died suddenly and unexpectedly. Their age ranged from 15 to 100 years with the mean age of 49.5 years. Of the 391 deaths, 191 (48.8%) were white, 185 (47.3%) were African American, and 15 (3.9%) were either Hispanic or Asian. The male and female ratio was 1.5:1. The majority of deaths (64.2%) were caused by natural diseases, 12.0% deaths were accidents, 11.5% deaths were suicides, and 9.7% deaths were homicides. The manner of death remained undetermined in 38 cases (9.7%). Of the 251 natural deaths, 198 cases (78.9%) were owing to cardiovascular diseases. Cause of death was listed as cardiac arrhythmia in 11 cases. This diagnosis of cardiac arrhythmia was made by exclusion based on death scene investigation, review of medical history, complete autopsy, and toxicological tests. Drug intoxication was the second most common cause of death. CONCLUSIONS: The study shows high fatality caused by cardiovascular diseases and drug intoxication among schizophrenia patients, which calls attention of the medical community to closely monitor the high risk factors of sudden death among schizophrenia patients.


Assuntos
Morte Súbita/epidemiologia , Esquizofrenia/epidemiologia , Acidentes/mortalidade , Adolescente , Adulto , Distribuição por Idade , Idoso , Idoso de 80 Anos ou mais , Doenças Cardiovasculares/mortalidade , Grupos de Populações Continentais/estatística & dados numéricos , Médicos Legistas , Feminino , Homicídio/estatística & dados numéricos , Humanos , Masculino , Maryland/epidemiologia , Pessoa de Meia-Idade , Envenenamento/mortalidade , Estudos Retrospectivos , Distribuição por Sexo , Suicídio/estatística & dados numéricos , Adulto Jovem
6.
J Mater Chem B ; 2019 Nov 28.
Artigo em Inglês | MEDLINE | ID: mdl-31776521

RESUMO

In this report, a novel nanocomposite of highly dispersed Au nanoparticles deposited on NH2-MIL-125(Ti) was designed and proposed as a peroxidase-like mimic. Compared with individual Au nanoparticles and NH2-MIL-125(Ti), the peroxidase-like nanozyme exhibits enhanced peroxidase-like activity. Moreover, kinetic analysis reveals that the as-prepared nanozyme has lower Km values and stronger affinity towards both substrates than the natural horseradish peroxidase (HRP). The detection limits of the multifunctional platform for H2O2, cysteine and Hg2+ are down to 0.24 µM, 0.14 µM and 100 nM, respectively. This work provides rapid and sensitive colorimetric detection strategies for small biomolecules and Hg2+, which have great potential for application in biosensors and biotechnology.

7.
J Nutr Biochem ; 75: 108256, 2019 Oct 24.
Artigo em Inglês | MEDLINE | ID: mdl-31760308

RESUMO

High-fat/high-fructose diet plus intermittent hypoxia exposure (HFDIH) causes metabolic disorders such as insulin resistance, obesity, nonalcoholic fatty liver disease (NAFLD) and type 2 diabetes. The purpose of this study is to examine the effects and understand the mechanism of action of Lactobacillus rhamnosus GG culture supernatant (LGGs) on HFDIH-induced metabolic dysfunction. Mice were fed high-fat:high-fructose diet for 15 weeks. After 3 weeks of feeding, the mice were exposed to chronic intermittent hypoxia for the next 12 weeks (HFDIH), and LGGs was supplemented over the entire experiment. HFDIH exposure significantly led to metabolic disorders. LGGs treatment showed significant improvements in indices of metabolic disorders including fat mass, energy expenditure, glucose intolerance, insulin resistance, increased hepatic steatosis and liver injury. HFDIH mice markedly increased adipose inflammation and adipocyte size, and reduced circulating adiponectin, which was restored by LGGs treatment. LGGs treatment increased hepatic FGF21 mRNA expression and circulating FGF21 protein levels, which were associated with increased hepatic PPARα expression and fecal butyrate concentration. In addition, HFDIH-induced hepatic fat accumulation and apoptosis were significantly reduced by LGGs supplementation. In summary, LGGs treatment increased energy expenditure and insulin sensitivity and prevented metabolic abnormalities in HFDIH mice, and this is associated with the FGF21-adiponectin signaling pathway. LGGs may be a potential prevention/treatment strategy in subjects with the metabolic syndrome.

8.
Cell Death Dis ; 10(12): 888, 2019 Nov 26.
Artigo em Inglês | MEDLINE | ID: mdl-31767834

RESUMO

Activation of nuclear-factor-E2-related factor 2 (Nrf2) cascade can alleviate dexamethasone (DEX)-induced oxidative injury and death of human osteoblasts. A recent study has shown that phosphoglycerate kinase 1 (PGK1) inhibition/depletion will lead to Kelch-like ECH-associated protein 1 (Keap1) methylglyoxal modification, thereby activating Nrf2 signaling cascade. Here, in OB-6 osteoblastic cells and primary human osteoblasts, PGK1 silencing, by targeted shRNA, induced Nrf2 signaling cascade activation, causing Nrf2 protein stabilization and nuclear translocation, as well as increased expression of ARE-dependent genes (HO1, NQO1, and GCLC). Functional studies demonstrated that PGK1 shRNA largely attenuated DEX-induced oxidative injury and following death of OB-6 cells and primary osteoblasts. Furthermore, PGK1 knockout, by the CRISPR/Cas9 method, similarly induced Nrf2 signaling activation and protected osteoblasts from DEX. Importantly, PGK1 depletion-induced osteoblast cytoprotection against DEX was almost abolished by Nrf2 shRNA. In addition, Keap1 shRNA mimicked and nullified PGK1 shRNA-induced anti-DEX osteoblast cytoprotection. At last we show that PGK1 expression is downregulated in human necrotic femoral head tissues of DEX-taking patients, correlating with HO1 depletion. Collectively, these results show that PGK1 depletion protects human osteoblasts from DEX via activation of Keap1-Nrf2 signaling cascade.

9.
Pathol Oncol Res ; 2019 Nov 20.
Artigo em Inglês | MEDLINE | ID: mdl-31748879

RESUMO

Previous studies indicated that cyclin D1 shown the potential as a tumor biomarker. However, the prognostic value of cyclin D1 in renal cell carcinoma (RCC) remains controversial. This study investigated the correlation of cyclin D1 expression with the prognostic and clinicopathological features in RCC patients. We systematically searched the database of PubMed, Embase, Cochrane, and Web of Science updated on November 26, 2017. Eighteen studies with 2282 patients satisfied the inclusion criteria. Results demonstrated that cyclin D1 overexpression in RCC showed significant favorable prognostic impact on disease-free survival (DFS) (HR 0.57, 95% CI: 0.43-0.74) and disease-specific survival (DSS) (HR 0.59, 95% CI 0.41-0.85) without significant heterogeneity. In subgroup of clear cell RCC, the prognostic effect on DFS was robust and the pooled HR was 0.39 (95% CI: 0.27-0.57). However, no association between overall survival (OS) and cyclin D1 expression was observed. Stratified analysis in DFS studies by sample size, staining patterns race and metastasis status showed similar results. Otherwise, cyclin D1 overexpression predicted a reduced prevalence of high TNM stage (T3 + T4) (OR 0.63, 95% CI: 0.40-0.99), high-grade tumor (G3 + G4) (OR 0.51, 95% CI: 0.31-0.81) and large tumor size (OR 0.35, 95% CI: 0.19-0.62). Our meta-analysis indicated that cyclin D1 overexpression could predict the favorable prognosis in patients with RCC.

10.
J Environ Manage ; 254: 109810, 2019 Nov 04.
Artigo em Inglês | MEDLINE | ID: mdl-31698300

RESUMO

In order to predict the effects of climate change on the global carbon cycle, it is crucial to understand the environmental factors that affect soil carbon storage in grasslands. In the present study, we attempted to explain the relationships between the distribution of soil carbon storage with climate, soil types, soil properties and topographical factors across different types of grasslands with different grazing regimes. We measured soil organic carbon in 92 locations at different soil depth increments, from 0 to 100 cm in southwestern China. Among soil types, brown earth soils (Luvisols) had the highest carbon storage with 19.5 ±â€¯2.5 kg m-2, while chernozem soils had the lowest with 6.8 ±â€¯1.2 kg m-2. Mean annual temperature and precipitation, exerted a significant, but, contrasting effects on soil carbon storage. Soil carbon storage increased as mean annual temperature decreased and as mean annual precipitation increased. Across different grassland types, the mean carbon storage for the top 100 cm varied from 7.6 ±â€¯1.3 kg m-2 for temperate desert to 17.3 ±â€¯2.9 kg m-2 for alpine meadow. Grazing/cutting regimes significantly affected soil carbon storage with lowest value (7.9 ±â€¯1.5 kg m-2) recorded for cutting grass, while seasonal (11.4 ±â€¯1.3 kg m-2) and year-long (12.2 ±â€¯1.9 kg m-2) grazing increased carbon storage. The highest carbon storage was found in the completely ungrazed areas (16.7 ±â€¯2.9 kg m-2). Climatic factors, along with soil types and topographical factors, controlled soil carbon density along a soil depth in grasslands. Environmental factors alone explained about 60% of the total variation in soil carbon storage. The actual depth-wise distribution of soil carbon contents was significantly influenced by the grazing intensity and topographical factors. Overall, policy-makers should focus on reducing the grazing intensity and land conversion for the sustainable management of grasslands and C sequestration.

11.
Lab Invest ; 2019 Nov 20.
Artigo em Inglês | MEDLINE | ID: mdl-31748682

RESUMO

Tumor-associated macrophages (TAMs) constitute a large population of glioblastoma and facilitate tumor growth and invasion of tumor cells, but the underlying mechanism remains undefined. In this study, we demonstrate that chemokine (C-C motif) ligand 8 (CCL8) is highly expressed by TAMs and contributes to pseudopodia formation by GBM cells. The presence of CCL8 in the glioma microenvironment promotes progression of tumor cells. Moreover, CCL8 induces invasion and stem-like traits of GBM cells, and CCR1 and CCR5 are the main receptors that mediate CCL8-induced biological behavior. Finally, CCL8 dramatically activates ERK1/2 phosphorylation in GBM cells, and blocking TAM-secreted CCL8 by neutralized antibody significantly decreases invasion of glioma cells. Taken together, our data reveal that CCL8 is a TAM-associated factor to mediate invasion and stemness of GBM, and targeting CCL8 may provide an insight strategy for GBM treatment.

12.
Chemistry ; 2019 Nov 20.
Artigo em Inglês | MEDLINE | ID: mdl-31747078

RESUMO

The electrochemical reduction of CO2 presents a promising strategy to mitigate the greenhouse effect and reduce the excess carbon dioxide emission to realize a carbon-neutral energy cycle, but it suffers from the lack of high-performance electrocatalysts. In this work, we precisely anchor catalytic active cobalt porphyrin [TCPP(Co) = (5,10,15,20)-tetrakis(4-carboxyphenyl)porphyrin-Co(II)] onto the water-stable 2-D MOF nanosheets (Zr-BTB) to obtain ultra-thin 2-D MOF nanosheets [TCPP(Co)/Zr-BTB] with accessible catalytic sites for CO2 reduction reaction. Compared with molecular cobalt porphyrin, the TCPP(Co)/Zr-BTB exhibits ultrahigh turnover frequency (TOF = 4768 hr-1 at -0.919 V vs. RHE) due to high active-site utilization. Besides, we obtained three post-modified 2-D MOF nanosheets [TCPP(Co)/Zr-BTB-PABA, TCPP(Co)/Zr-BTB-PSBA, TCPP(Co)/Zr-BTB-PSABA], with the modifiers of p-(aminomethyl)benzoic acid (PABA), p-sulfobenzoic acid potassium (PSBA) and p-sulfamidobenzoic acid (PSABA), respectively, to change the micro-environments around TCPP(Co) through the tuning of steric effect. Among them, the TCPP(Co)/Zr-BTB-PSABA exhibited the best performance with Faradaic efficiency (FECO) of 85.1%, TOF of 5315 hr-1 and jtotal of 6 mA/cm2 at -0.769 V (vs. RHE). In addition, long-term durability of electrocatalysts is evaluated and the role of pH buffer is revealed.

13.
Mediators Inflamm ; 2019: 3592620, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31686981

RESUMO

Objective: This study is aimed at evaluating the diagnostic value of blood lipid indicators (BLIs) for insulin resistance (IR) among major ethnic groups in Xinjiang, China, to identify the most valuable indicators and appropriate cut-off points for each ethnic group and to lay the foundation for the early detection, diagnosis, and treatment of metabolic diseases in remote rural areas. Methods: Overall, 418 Uygurs, 331 Kazakhs, and 220 Hans were randomly included in our study. The homeostasis model assessment was the gold standard for identifying IR. The receiver operating characteristic (ROC) curve was used to evaluate the diagnostic value, and the nomogram was utilized to analyze the predictive value. The size of the area under the curve (AUC) reflected the accuracy of screening and prediction. Results: Differences in races were observed in terms of IR and BLIs, and the Kazakhs had the highest IR level at 5.27 mmol/L. The correlation between IR and BLIs differed among the three races. For the Kazakhs and Hans, all BLIs, except total cholesterol (TC), were correlated to IR. However, for the Uygurs, only the triglyceride (TG) level, TG/high-density lipoprotein cholesterol (HDL-C) ratio, and TC/HDL-C ratio were associated with IR. After further adjustment of confounding factors, these indicators were still correlated to IR. BLIs that independently correlated to IR in the three nationalities had a certain diagnostic value for IR. In terms of the AUC size, the TG level was the highest in Uygurs, the TG/HDL-C ratio was the highest for Kazakhs and Hans, and the corresponding best cut-off points for IR were 1.515, 1.230, and 1.495 mmol/L, respectively. In addition, for each race, when the indicators with a certain diagnostic value were combined, the diagnostic value for IR was higher. Conclusion: BLIs had a certain diagnostic value for IR and could be used as a screening tool for IR among Uygurs, Kazakhs, and Hans in Xinjiang. These findings are extremely important for the prevention and treatment of IR and metabolic diseases in remote rural areas.

14.
Molecules ; 24(21)2019 Nov 05.
Artigo em Inglês | MEDLINE | ID: mdl-31694145

RESUMO

Carbon fiber mesh reinforced cement-based composites (CMCCs) have received extensive attention in the field of engineering repair and structural reinforcement due to their outstanding properties such as two-way force, rust prevention, high specific strength, and low base surface requirements. However, the development of this material has been slowed down to some extent due to the poor interfacial bonding between the carbon fiber mesh and the cement matrix. In this paper, a novel fabrication strategy was proposed in which the carbon fiber mesh was modified with epoxy resin and silane coupling agent (SCA) to increase its surface chemical activity. Meanwhile, the hydroxymethyl cellulose (HMC) was also filled into the concrete matrix to improve the mechanical strength of the matrix as well as the load transfer behaviors between the mortar and carbon fiber (CF) mesh. The potential to employ SCA and HMC was evaluated for the making of CMCCs via the above methods. The results showed that the longitudinal shear strength of composites with SCA and SCA&HMC increased by 26.6% and 56.1% compared to those of CF with epoxy resin (EP) reinforced composites, respectively. The flexural strength of composite with SCA&HMC increases by 147.6% compared to I-(F) without CF. The novel II-HCM&CF/EP-SCA composites with excellent performance are promised to be applied in practical uses.

15.
Pest Manag Sci ; 2019 Nov 06.
Artigo em Inglês | MEDLINE | ID: mdl-31696614

RESUMO

BACKGROUND: Pydiflumetofen is a new generation succinate dehydrogenase inhibitor currently in the registration process in China for the control of Fusarium head blight in wheat. Resistance risk assessment of Fusarium graminearum to pydiflumetofen was investigated in this study. RESULTS: A total of 75 pydiflumetofen-resistant mutants were generated through spontaneous selection and displayed high resistance with average RF value of 78. Four mutants were generated through UV mutagenesis and displayed very high resistance with RF value > 1000. The sequence analysis results for Sdh genes and fitness studies revealed the existence of four types of mutations. In particular, 32 spontaneous selection mutants (SP-mutants) had an arginine (R) to histidine (H) transition at position 86 in FGSdhC, resulting in seriously reduced fitness. Seven SP-mutants had an R to cysteine (C) transition at position 86 in FGSdhC, resulting in reduced fitness. Thirty-six SP-mutants had an alanine (A) to valine (V) transition at position 83 in FGSdhC and had no fitness penalties. The efficacy of pydiflumetofen to mutant carrying A83V in FGSdhC in vivo was significantly decreased with efficacy of 42.71%. Four UV-mutants had no mutations on all Sdh genes and no fitness penalties. Cross-resistance among pydiflumetofen and boscalid, fluopyram was observed. CONCLUSION: Sdhc mutations were found and other target site resistance may be present in laboratory PR mutants of F. graminearum. An overall moderate risk of resistance development in F. graminearum was recommended for pydiflumetofen. This article is protected by copyright. All rights reserved.

16.
iScience ; 21: 308-327, 2019 Oct 21.
Artigo em Inglês | MEDLINE | ID: mdl-31678913

RESUMO

Plant exosomes protect plants against infection; however, whether edible plant exosomes can protect mammalian hosts against infection is not known. In this study, we show that ginger exosome-like nanoparticles (GELNs) are selectively taken up by the periodontal pathogen Porphyromonas gingivalis in a GELN phosphatidic acid (PA) dependent manner via interactions with hemin-binding protein 35 (HBP35) on the surface of P. gingivalis. Compared with PA (34:2), PA (34:1) did not interact with HBP35, indicating that the degree of unsaturation of PA plays a critical role in GELN-mediated interaction with HBP35. On binding to HBP35, pathogenic mechanisms of P. gingivalis were significantly reduced following interaction with GELN cargo molecules, including PA and miRs. These cargo molecules interacted with multiple pathogenic factors in the recipient bacteria simultaneously. Using edible plant exosome-like nanoparticles as a potential therapeutic agent to prevent/treat chronic periodontitis was further demonstrated in a mouse model.

17.
Artigo em Inglês | MEDLINE | ID: mdl-31721397

RESUMO

Fluorinated ketones are widely prevalent in numerous biologically interesting molecules, and the development of novel transformations to access these structures is an important task in organic synthesis. As an emerging powerful strategy, the concurrent installation of fluorine and ketone moieties into target molecules from simple, variable, and abundant feedstocks remains synthetically challenging and underdeveloped. Here, we report a multicomponent radical acylfluoroalkylation of olefins in the presence of various commercially available aromatic aldehydes and fluoroalkyl reagents through N -heterocyclic carbene organocatalysis. Notably, a broad spectrum of olefin substrates, including styrenes, cyclic internal alkenes, indoles, vinyl ethers, vinyl esters, and the unactivated simple alkenes, could be compatible in this organocatalytic system. With this protocol, over 120 examples of functionalized ketones with diverse fluorine substituents have been facilely synthesized in up to 99% yield with complete regioselectivity. The generality of this catalytic strategy was further highlighted by its successful application in the late-stage functionalization of pharmaceutical skeletons. Interestingly, excellent diastereoselectivity could be achieved in the reactions forging multiple stereocenters. In addition, preliminary results have been achieved on the catalytic asymmetric variant of the olefin difunctionalization process. The reaction mechanism involves a single-electron reduction of fluoroalkyl reagents by deprotonated Breslow intermediates, radical addition to alkenes, and the radical-radical recombination.

18.
Viruses ; 11(11)2019 Nov 13.
Artigo em Inglês | MEDLINE | ID: mdl-31766138

RESUMO

Traditional pathogenesis studies of alphaviruses involves monitoring survival, viremia, and pathogen dissemination via serial necropsies; however, molecular imaging shifts this paradigm and provides a dynamic assessment of pathogen infection. Positron emission tomography (PET) with PET tracers targeted to study neuroinflammation (N,N-diethyl-2-[4-phenyl]-5,7-dimethylpyrazolo[1,5-a]pyrimidine-3-acetamide, [18F]DPA-714), apoptosis (caspase-3 substrate, [18F]CP-18), hypoxia (fluormisonidazole, [18F]FMISO), blood-brain barrier (BBB) integrity ([18F]albumin), and metabolism (fluorodeoxyglucose, [18F]FDG) was performed on C3H/HeN mice infected intranasally with 7000 plaque-forming units (PFU) of Venezuelan equine encephalitis virus (VEEV) TC-83. The main findings are as follows: (1) whole-brain [18F]DPA-714 and [18F]CP-18 uptake increased three-fold demonstrating, neuroinflammation and apoptosis, respectively; (2) [18F]albumin uptake increased by 25% across the brain demonstrating an altered BBB; (3) [18F]FMISO uptake increased by 50% across the whole brain indicating hypoxic regions; (4) whole-brain [18F]FDG uptake was unaffected; (5) [18F]DPA-714 uptake in (a) cortex, thalamus, striatum, hypothalamus, and hippocampus increased through day seven and decreased by day 10 post exposure, (b) olfactory bulb increased at day three, peaked day seven, and decreased day 10, and (c) brain stem and cerebellum increased through day 10. In conclusion, intranasal exposure of C3H/HeN mice to VEEV TC-83 results in both time-dependent and regional increases in brain inflammation, apoptosis, and hypoxia, as well as modest decreases in BBB integrity; however, it has no effect on brain glucose metabolism.

19.
Biosci Rep ; 2019 Nov 26.
Artigo em Inglês | MEDLINE | ID: mdl-31769476

RESUMO

To observe changes in AMPK activity and phosphorylation changes in AMPK signaling pathway in gastric smooth muscle cells of rats with diabetic gastroparesis (DGP), investigate the effect of AMPK on apoptosis and explore the underlying mechanism. After establishing rat model of DGP, rats were divided into normal control (NC) and DGP groups. The phosphorylation changes in AMPK pathway were detected by AMPK Signaling Phospho-Antibody Array, and the apoptosis-related proteins were determined. Rat gastric smooth muscle cells were cultured in vitro under different glucose condition, and divided into normal and high glucose groups. The AMPK activity and intracellular Ca2+ changes in cells were observed. After AMPK silencing, cells were divided into high glucose-24h, high glucose-48h and high glucose 48h+siRNA groups. Changes in expression of apoptosis-related proteins were observed. AMPK activity and apoptosis rates were both increased in gastric smooth muscle tissues in DGP rats (P<0.05, P<0.001, respectively). A total of 14 apoptosis-related differentially phosphorylated proteins were identified. Under high glucose condition, AMPK activity and intracellular Ca2+ concentrations in rat gastric smooth muscle cells were increased (both P<0.05). After AMPK silencing, p53 expression was decreased, Akt and p70S6K activities were were increased , Bcl-2 expression was increased, CaMKII activity was decreased in the high-glucose-48h group. Under high glucose condition, activated AMPK can directly or indirectly promote cells apoptosis by regulating the expression and activity of p53, Akt, p70S6K, PKA, PLC-ß3, CaMKII, CaMKIV and 4E-BP1 in rat gastric smooth muscle cells.

20.
Neuroscience ; 419: 72-82, 2019 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-31682827

RESUMO

Previous studies reported that long-term nociceptive stimulation could result in neurovascular coupling (NVC) dysfunction in brain, but these studies were based mainly on unimodal imaging biomarkers, thus could not comprehensively reflect NVC dysfunction. We investigated the potential NVC dysfunction in chronic migraine by exploring the relationship between neuronal activity and cerebral perfusion maps. The Pearson correlation coefficients between these 2 maps were defined as the NVC biomarkers. NVC biomarkers in migraineurs were significantly lower in left inferior parietal gyrus (IPG), left superior marginal gyrus (SMG) and left angular gyrus (AG), but significantly higher in right superior occipital gyrus (SOG), right superior parietal gyrus (SPG), and precuneus. These brain regions were located mainly in parietal or occipital lobes and were related to visual or sensory information processing. ALFF-CBF in right SPG was positively correlated with disease history and that in right precuneus was negatively correlated with migraine persisting time. fALFF-CBF in left SMG and AG were negatively related to headache frequency and positively related to health condition and disease history. In conclusion, multi-modal MRI could be used to detect NVC dysfunction in chronic migraine patients, which is a new method to assess the impact of chronic pain on the brain.

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