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1.
Plant Cell Physiol ; 2020 Jan 22.
Artigo em Inglês | MEDLINE | ID: mdl-31967299

RESUMO

Late embryogenesis abundant (LEA) proteins comprise a large family that play important roles in the regulation of abiotic stresses. No in-depth analysis of LEA genes has been performed in grapevine. In this study, we analyzed a total of 52 putative LEA genes in grapevine at genomic and transcriptomic levels, compiled expression profiles of four selected VamLEA genes under cold and osmotic stress and studied potential function of VamDHN3 gene in grapevine callus. The 52 LEA proteins can be classified into seven phylogenetic groups. RNA-seq and qRT-PCR results demonstrated that a total of 16 and 23 VamLEA genes were upregulated under cold and osmotic stress. Overexpression of VamDHN3 enhances the stability of cell membrane in grapevine callus, suggesting VamDHN3 is involved in osmotic regulation. These results formed fundamental knowledge for further analysis of biological roles of LEA genes in grapevine's adaption to abiotic stresses.

2.
J Org Chem ; 2020 Feb 06.
Artigo em Inglês | MEDLINE | ID: mdl-31994398

RESUMO

A strategy for the synthesis of cis-hydrocarbazole with a C3 quaternary carbon center has been developed through nickel/Lewis acid dual-catalyzed arylcyanation. A wide array of cis-hydrocarbazoles was accessed with high diastereoselectivities and atom economies in a good yield. The rich chemistry of the installed nitrile group was demonstrated in the preparation of tryptamine- and tryptophol-derived cis-hydrocarbazoles.

3.
Sensors (Basel) ; 20(2)2020 Jan 19.
Artigo em Inglês | MEDLINE | ID: mdl-31963786

RESUMO

It is of great significance for the global navigation satellite system (GNSS) service to detect the polar ionospheric total electron content (TEC) and its variations, particularly under disturbed ionosphere conditions, including different phases of solar activity, the polar day and night alternation, the Weddell Sea anomaly (WSA) as well as geomagnetic storms. In this paper, four different models are utilized to map the ionospheric TEC over the Arctic and Antarctic for about one solar cycle: the polynomial (POLY) model, the generalized trigonometric series function (GTSF) model, the spherical harmonic (SH) model, and the spherical cap harmonic (SCH) model. Compared to other models, the SCH model has the best performance with ±0.8 TECU of residual mean value and 1.5-3.5 TECU of root mean square error. The spatiotemporal distributions and variations of the polar ionospheric TEC are investigated and compared under different ionosphere conditions in the Arctic and Antarctic. The results show that the solar activity significantly affects the TEC variations. During polar days, the ionospheric TEC is more active than it is during polar nights. In polar days over the Antarctic, the maximum value of TEC always appears at night in the Antarctic Peninsula and Weddell Sea area affected by the WSA. In the same year, the ionospheric TEC of the Antarctic has a larger amplitude of annual variation than that of the TEC in the Arctic. In addition, the evolution of the ionization patch during a geomagnetic storm over the Antarctic can be clearly tracked employing the SCH model, which appears to be adequate for mapping the polar TEC, and provides a sound basis for further automatic identification of ionization patches.

4.
Chemosphere ; 238: 124602, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31545211

RESUMO

Polybrominated diphenyl ethers (PBDEs) have been known to exhibit neurotoxicity in rats; however, the underlying mechanism remains unknown and there is no available intervention. In this study, we aimed to investigate the role of oxidative and nitrosative stress in the neurotoxicity in the cerebral cortex and primary neurons in rats following the BDE-153 treatment. Compared to the untreated group, BDE-153 treatment significantly induced the neurotoxic effects in rats, as manifested by the increased lactate dehydrogenase (LDH) activities and cell apoptosis rates, and the decreased neurotrophic factor contents and cholinergic enzyme activities in rats' cerebral cortices and primary neurons. When compared to the untreated group, the oxidative and nitrosative stress had occurred in the cerebral cortex or primary neurons in rats following the BDE-153 treatment, as manifested by the increments in levels of reactive oxygenspecies (ROS), malondialdehyde (MDA), nitric oxide (NO), and neuronal nitric oxide synthase (nNOS) mRNA and protein expressions, along with the decline in levels of superoxide dismutase (SOD) activity, glutathione (GSH) content, and peroxiredoxin I (Prx I) and Prx II mRNA and protein expressions. In addition, the ROS scavenger N-acetyl-l-cysteine (NAC) or NO scavenger NG-Nitro-l-arginine (L-NNA) significantly rescued the LDH leakage and cell survival, reversed the neurotrophin contents and cholinergic enzymes, mainly via regaining balance between oxidation/nitrosation and antioxidation. Overall, our findings suggested that oxidative and nitrosative stresses are involved in the neurotoxicity induced by BDE-153, and that the antioxidation is a potential targeted intervention.


Assuntos
Córtex Cerebral/patologia , Éteres Difenil Halogenados/toxicidade , Síndromes Neurotóxicas/patologia , Estresse Nitrosativo/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Bifenil Polibromatos/toxicidade , Acetilcisteína/farmacologia , Animais , Antioxidantes/metabolismo , Apoptose/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Córtex Cerebral/efeitos dos fármacos , Glutationa/metabolismo , Éteres Difenil Halogenados/metabolismo , Masculino , Malondialdeído/metabolismo , Fatores de Crescimento Neural/metabolismo , Neurônios/efeitos dos fármacos , Neurotrofina 3/metabolismo , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase Tipo I/metabolismo , Estresse Nitrosativo/fisiologia , Estresse Oxidativo/fisiologia , Ratos , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacos
5.
Acta Neuropathol ; 2019 Dec 18.
Artigo em Inglês | MEDLINE | ID: mdl-31853635

RESUMO

Neurodegenerative diseases are an enormous public health problem, affecting tens of millions of people worldwide. Nearly all of these diseases are characterized by oligomerization and fibrillization of neuronal proteins, and there is great interest in therapeutic targeting of these aggregates. Here, we show that soluble aggregates of α-synuclein and tau bind to plate-immobilized PrP in vitro and on mouse cortical neurons, and that this binding requires at least one of the same N-terminal sites at which soluble Aß aggregates bind. Moreover, soluble aggregates of tau, α-synuclein and Aß cause both functional (impairment of LTP) and structural (neuritic dystrophy) compromise and these deficits are absent when PrP is ablated, knocked-down, or when neurons are pre-treated with anti-PrP blocking antibodies. Using an all-human experimental paradigm involving: (1) isogenic iPSC-derived neurons expressing or lacking PRNP, and (2) aqueous extracts from brains of individuals who died with Alzheimer's disease, dementia with Lewy bodies, and Pick's disease, we demonstrate that Aß, α-synuclein and tau are toxic to neurons in a manner that requires PrPC. These results indicate that PrP is likely to play an important role in a variety of late-life neurodegenerative diseases and that therapeutic targeting of PrP, rather than individual disease proteins, may have more benefit for conditions which involve the aggregation of more than one protein.

6.
Artigo em Inglês | MEDLINE | ID: mdl-31718102

RESUMO

Aerosol pollution elicits considerable public concern due to the adverse influence on air quality, climate change, and human health. Outside of emissions, haze formation is closely related to meteorological conditions, especially relative humidity (RH). Partly due to insufficient investigations on the aerosol hygroscopicity, the accuracy of pollution prediction in Central China is limited. In this study, taking Wuhan as a sample city, we investigated the response of aerosol pollution to RH during wintertime based on in-situ measurements. The results show that, aerosol pollution in Wuhan is dominated by PM2.5 (aerodynamic particle size not larger than 2.5 µm) on wet days (RH ≥ 60%), with the averaged mass fraction of 0.62 for PM10. Based on the RH dependence of aerosol light scattering (f (RH)), aerosol hygroscopicity was evaluated and shows the high dependence on the particle size distribution and chemical compositions. f (RH = 80%) in Wuhan was 2.18 (±0.73), which is comparable to that measured in the Pearl River Delta and Yangtze River Delta regions for urban aerosols, and generally greater than values in Beijing. Ammonium (NH4+), sulfate (SO42-), and nitrate (NO3-) were enhanced by approximately 2.5-, 2-, and 1.5-fold respectively under wet conditions, and the ammonia-rich conditions in wintertime efficiently promoted the formation of SO42- and NO3-, especially at high RH. These secondary ions play an important role in aggravating the pollution level and aerosol light scattering. This study has important implications for understanding the roles of RH in aerosol pollution aggravation over Central China, and the fitted equation between f (RH) and RH may be helpful for pollution forecasting in this region.

7.
J Clin Invest ; 129(12): 5553-5567, 2019 Dec 02.
Artigo em Inglês | MEDLINE | ID: mdl-31710313

RESUMO

Immune checkpoint inhibitors (ICIs), although promising, have variable benefit in head and neck cancer (HNC). We noted that tumor galectin-1 (Gal1) levels were inversely correlated with treatment response and survival in patients with HNC who were treated with ICIs. Using multiple HNC mouse models, we show that tumor-secreted Gal1 mediates immune evasion by preventing T cell migration into the tumor. Mechanistically, Gal1 reprograms the tumor endothelium to upregulate cell-surface programmed death ligand 1 (PD-L1) and galectin-9. Using genetic and pharmacological approaches, we show that Gal1 blockade increases intratumoral T cell infiltration, leading to a better response to anti-PD1 therapy with or without radiotherapy. Our study reveals the function of Gal1 in transforming the tumor endothelium into an immune-suppressive barrier and that its inhibition synergizes with ICIs.

8.
Chemphyschem ; 20(24): 3271-3275, 2019 12 16.
Artigo em Inglês | MEDLINE | ID: mdl-31654459

RESUMO

Multidrug resistance of cancer cells is a major obstacle for cancer chemotherapy. Herein, we present a nanocarrier that can release chemotherapeutic agents to induce tumor cell death and generate NO under NIR to overcome multidrug resistance in cancer chemotherapy. Owing to the unique structure of the water channel in this controlled release system for chemotherapeutic agents, the nanocarrier surface is equipped with more active sites to graft NO donor molecules. The released NO performs very well in reversing multidrug resistance by inhibiting P-gp expression. Our findings provide new insight into multidrug resistance cancer therapy and controlled release nanocarriers for multiple drugs.


Assuntos
Antineoplásicos/química , Portadores de Fármacos/química , Resistencia a Medicamentos Antineoplásicos , Nanopartículas/química , Antineoplásicos/metabolismo , Antineoplásicos/farmacologia , Sobrevivência Celular/efeitos dos fármacos , Preparações de Ação Retardada , Doxorrubicina/química , Doxorrubicina/metabolismo , Doxorrubicina/farmacologia , Liberação Controlada de Fármacos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Humanos , Concentração de Íons de Hidrogênio , Células MCF-7 , Óxido Nítrico/metabolismo
9.
Chin Med J (Engl) ; 132(19): 2354-2361, 2019 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-31567382

RESUMO

BACKGROUND: In our previous paper, we demonstrated that Connexin 43 (CX43) was highly expressed in bladder cancer (BC) tissues. But the molecular mechanism about microRNAs (miRNAs) regulation upstream of CX43 in BC has not been well elucidated and remains to be further studied. MicroRNA-139-5p (miR-139-5p) is a tumor suppressor in progression of multifarious cancers including BC. Nevertheless, the underlying mechanisms of CX43/miR-139-5p in tumorigenesis of BC are still not well illustrated. The specific objective of our study was to inquiry the effect of CX43/miR-139-5p on BC progression and its underlying mechanism. METHODS: The bioinformatics analysis softwares were applied to predict the miRNAs in the upstream of CX43. First, the expression levels of miR-139-5p in BC tissues (tumor) and paracancer tissues (normal) were investigated using the data from The Cancer Genome Atlas database. Quantitative reverse transcription-polymerase chain reaction (qRT-PCR) was used to detect the mRNA expression level of miR-139-5p in three human BC cell lines 5637, T24, ECV-304 and a human bladder epithelial immortalized cell line SV-HUC-1 (normal control). Then si-CX43, si-control, miR-139-5p mimic, and its negative control (NC) were transfected into BC cell line ECV-304. The relationship of miR-139-5p and CX43 was analyzed by dual-luciferase reporter assay. The qRT-PCR and Western blotting were used to test the mRNA and protein expression level of CX43. The proliferation of ECV-304 and T24 cells were examined by cell counting kit-8. The migration and invasion of ECV-304 cells were tested by transwell assay. To determine whether miR-139-5p would affect cell proliferation, migration and invasion by targeting CX43, we executed the rescue assay. The comparison between two groups was analyzed by Student's t test, and comparisons among multiple samples were performed by one-way analysis of variance and a Bonferroni post hoc test. RESULTS: The expression of miR-139-5p was remarkably down-regulated in BC tissues (tumor vs. normal, 2.286 ±â€Š0.017 vs. 3.211 ±â€Š0.034, t = 11.540, P < 0.0001) and cell lines (P < 0.01 in all BC cell lines). Besides, we also indicated that over-expression of miR-139-5p reduced the proliferation of ECV-304 (P = 0.001) and T24 cells (P = 0.005). Moreover, miR-139-5p over-expression weakened the invasion (P = 0.001) and migration (P = 0.001) of ECV-304 cells. Furthermore, the relative luciferase activity of CX43-wild type construct was distinctly lessened by up-regulation of miR-139-5p (miR-139-5p mimic NC vs. miR-139-5p mimic, 0.916 ±â€Š0.063 vs. 0.356 ±â€Š0.048, t = 7.085, P = 0.002), nevertheless the activity of CX43-mutant type construct was untouched (miR-139-5p mimic NC vs. miR-139-5p mimic, 0.918 ±â€Š0.057 vs. 0.878 ±â€Š0.039, t = 0.577, P = 0.595). Finally, the rescue assay revealed that CX43 deletion enhanced the depressor effect of miR-139-5p on ECV-304 cell proliferation (P < 0.01), invasion (P = 0.028), and migration (P = 0.014). CONCLUSION: MiR-139-5p, as a tumor-suppressor, repressed cell proliferation, invasion, and migration in BC, which might be achieved by regulating CX43.

10.
Org Lett ; 2019 Aug 22.
Artigo em Inglês | MEDLINE | ID: mdl-31436437

RESUMO

Phenols are readily available by degradation of lignin resource. Palladium-catalyzed conversion of phenols to tetrahydro-ß-carboline skeletons bearing a spirocycle at the C-1 position in water is reported. Various substituted phenols are successfully cross-annulated with different tryptamines via sequential C(Ar)-O bond cleavage of phenols, C-H bond activation of tryptamines, and C-N/C-C bond formations. This method provides a new protocol of converting lignin phenols into high-value-added compounds, such as natural product Komavine.

11.
Environ Sci Pollut Res Int ; 26(26): 27330-27337, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31321728

RESUMO

Coprecipitation of humic acid (HA) with ferrihydrite (Fh) has been proposed to reduce the activity of heavy metals in aqueous solutions. The effect of the amount of HA added to the coprecipitates on the stabilization of Cd in soil is unclear. In this research, five different Fh-HA coprecipitates were synthesized to study the impact of different HA additions on the fractionation of Cd in the soil and the optimal addition ratio of C/Fe. Characterization technique as Fourier transform infrared spectroscopy (FT-IR), X-ray diffraction (XRD), specific surface area analyzer, and scanning electron microscopy (SEM) was used in order to test and analyze of the microstructure and physicochemical property of the coprecipitates. The results showed that the Fh-HA coprecipitate is mainly combined by the coordination exchange of -OH on the surface of the Fh with the carboxyl group of the HA. Adding HA could stabilize Fh and increase its surface roughness. Changes in the fractionation of the Cd were used to evaluate the stabilization effect of the coprecipitate. Before treatment, Cd in different contaminated soils was existed only a small amount of residual fraction. After the addition of the Fh-HA coprecipitate, the proportion of residual Cd in each contaminated soil increased. When the C/Fe ratio was 1.5, the maximum residual fraction were 62.94%, 55.67%, and 52.99% respectively. Residual Cd could remain relatively stable indicating that the Fh-HA coprecipitate is a promising amendment for repairing Cd-contaminated soil. The addition of HA has strengthened the active role of Fh on stabilizing heavy metals.


Assuntos
Cádmio/química , Compostos Férricos/química , Substâncias Húmicas , Poluentes do Solo/química , Fracionamento Químico , Precipitação Química , China , Recuperação e Remediação Ambiental/métodos , Solo/química , Espectroscopia de Infravermelho com Transformada de Fourier , Difração de Raios X
12.
Toxicol Rep ; 6: 674-682, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31360640

RESUMO

Two-year toxicology and carcinogenesis rodent studies conducted at the National Toxicology Program (NTP) are used to identify potential adverse health effects in humans due to chemical exposure, including cancer. Liver tumor, the most frequently diagnosed tumor type of chemically induced neoplastic effects documented in NTP's carcinogenicity studies, is usually difficult to be detected at early stage due to the inconspicuous symptoms. However, the abnormal growth of liver cells can lead to liver weight increase, so it is hypothesized that liver tumor incidence is associated with early stage liver weight increase. In this study, the association between liver weight increase and liver tumor incidence are quantified by (1) calculating the correlation coefficient of and (2) building quantitative linear relationship between benchmark dose estimates derived from these two types of data collected from NTP studies. Together with 151 chemical/species/sex combinations of liver tumor data showing positive evidence collected from 76 NTP long-term studies, short-term liver weight data reported in the same NTP report were extracted to be paired with the liver tumor data for the analyses. Results show that the estimated correlation coefficients (as high as 0.78) along with the adequately fitted linear models suggest that the association between relative liver weight increase and aggregated liver tumor incidence are relatively strong. Additional analyses focused on some more specific situations (e.g., specific tumor type or specific strain/sex combination) further confirmed the strong association. Given the design of this study, the interpretation of the findings is not that liver weight increase can be used to predict liver tumor incidence, instead, evident increase in liver weight might be used as a reason to prioritize the test article for a two-year toxicology and carcinogenesis study.

13.
BMC Cancer ; 19(1): 536, 2019 Jun 04.
Artigo em Inglês | MEDLINE | ID: mdl-31164094

RESUMO

BACKGROUND: Aerobic exercise has been shown to slow tumor progression in rodents and humans, but the mechanisms behind this effect are still unclear. Here we show that aerobic exercise in the form of chronic endurance training suppresses tumor recruitment of FoxP3+ Treg cells thus enhancing antitumor immune efficiency. METHODS: Adult wild-type and athymic BALB/c female mice were endurance-trained for 8 weeks. Circulating leukocytes as well as muscle and liver mtDNA copy number were compared to aged-matched concurrent sedentary controls to establish systemic effects. 4 T1 murine mammary tumor cells were injected subcutaneously to the 4th mammary pad at the end of the training period. Tumor growth and survival rates were compared, together with antitumor immune response. RESULTS: Exercised wild-type had 17% slower growth rate, 24% longer survival, and 2-fold tumor-CD+ 8/FoxP3+ ratio than sedentary controls. Exercised athymic BALB/c females showed no difference in tumor growth or survival rates when compared to sedentary controls. CONCLUSIONS: Cytotoxic T cells are a significant factor in endurance exercise-induced suppression of tumor growth. Endurance exercise enhances antitumor immune efficacy by increasing intratumoral CD8+/FoxP3+ ratio.


Assuntos
Progressão da Doença , Treino Aeróbico , Neoplasias Mamárias Experimentais/imunologia , Neoplasias Mamárias Experimentais/fisiopatologia , Condicionamento Físico Animal , Linfócitos T Reguladores/metabolismo , Animais , Linhagem Celular Tumoral , Feminino , Fatores de Transcrição Forkhead/metabolismo , Estimativa de Kaplan-Meier , Ácido Láctico/sangue , Neoplasias Mamárias Experimentais/mortalidade , Neoplasias Mamárias Experimentais/prevenção & controle , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Projetos Piloto , Taxa de Sobrevida , Linfócitos T Citotóxicos/metabolismo , Carga Tumoral
14.
Brain ; 142(5): 1441-1457, 2019 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-31032851

RESUMO

The primary structure of canonical amyloid-ß-protein was elucidated more than 30 years ago, yet the forms of amyloid-ß that play a role in Alzheimer's disease pathogenesis remain poorly defined. Studies of Alzheimer's disease brain extracts suggest that amyloid-ß, which migrates on sodium dodecyl sulphate polyacrylamide gel electrophoresis with a molecular weight of ∼7 kDa (7kDa-Aß), is particularly toxic; however, the nature of this species has been controversial. Using sophisticated mass spectrometry and sensitive assays of disease-relevant toxicity we show that brain-derived bioactive 7kDa-Aß contains a heterogeneous mixture of covalently cross-linked dimers in the absence of any other detectable proteins. The identification of amyloid-ß dimers may open a new phase of Alzheimer's research and allow a better understanding of Alzheimer's disease, and how to monitor and treat this devastating disorder. Future studies investigating the bioactivity of individual dimers cross-linked at known sites will be critical to this effort.

15.
Toxicol Lett ; 311: 37-48, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31029751

RESUMO

Polybrominated diphenyl ether-153 (BDE-153) has been demonstrated to induce neuronal apoptosis in rat cerebral cortex and primary neurons, however, the roles of mitochondria and endoplasmic reticulum (ER) remain unclear in the BDE-153-induced neuronal apoptosis. To this purpose, we observed the mitochondria and ER ultrastructure changes in the neuronal apoptosis in rats following BDE-153 treatment, detected the mitochondrial membrane potential (MMP), Ca2+-Mg2+-ATP enzyme activity, and the changes of mitochondria and ER apoptosis related molecules in rat cerebral cortex and in primary neurons following BDE-153 treatment. Results showed that compared to the control group, neuronal apoptosis was significantly increased in a dose-dependent manner in rat cerebral cortex and in primary neurons following BDE-153 treatment. In comparison with control, BDE-153 treatment induced remarkable ultrastructural changes in ER rather than in mitochondria, and the severity of ER damage was worse with the increasing BDE-153 dose. Meanwhile, ER apoptosis related molecules including caspase-12 (at mRNA level), cleaved caspase-12 (at protein level), and Tmem132a (at mRNA and protein levels) were significantly increased in the cerebral cortex in rats following BDE-153 treatment, while procaspase-12 protein was significantly decreased, comparing with control. In contrast, mitochondria apoptosis related molecules (MMP, Ca2+-Mg2+-ATP enzyme activity, cyt-C protein, caspase-3, 8, 9 mRNA, caspase-8, 9 enzyme activities) did not significantly changed in the cerebral cortex of rats or in primary neurons following BDE-153 treatment, except for the elevated caspase-3 mRNA and enzyme activity. Therefore, we conclude that BDE-153 induced neuronal apoptosis was dependent on p53, and mediated more by ER than mitochondria in the cerebral cortex of rats and in primary neurons. The findings suggest that ER is a potential sensitive target of BDE-153 neurotoxicity, providing a scientific evidence for the mechanism and intervention study on PBDE's neurotoxicity.


Assuntos
Apoptose/efeitos dos fármacos , Córtex Cerebral/efeitos dos fármacos , Retículo Endoplasmático/efeitos dos fármacos , Mitocôndrias/efeitos dos fármacos , Degeneração Neural , Neurônios/efeitos dos fármacos , Síndromes Neurotóxicas/etiologia , Bifenil Polibromatos/toxicidade , Animais , Proteínas Reguladoras de Apoptose/genética , Proteínas Reguladoras de Apoptose/metabolismo , Células Cultivadas , Córtex Cerebral/metabolismo , Córtex Cerebral/ultraestrutura , Relação Dose-Resposta a Droga , Retículo Endoplasmático/metabolismo , Retículo Endoplasmático/ultraestrutura , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Masculino , Mitocôndrias/metabolismo , Mitocôndrias/ultraestrutura , Neurônios/metabolismo , Neurônios/ultraestrutura , Síndromes Neurotóxicas/metabolismo , Síndromes Neurotóxicas/patologia , Ratos Sprague-Dawley , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismo
16.
Org Lett ; 21(7): 2302-2306, 2019 04 05.
Artigo em Inglês | MEDLINE | ID: mdl-30908058

RESUMO

N-Alkylation of indoles is one of the important pathways for the construction of various biologically active indole molecules. Using ketones as N-alkylation reagent for indoles has been a great challenge not only because of the competing alkylation reaction of C-3 position but also because of the poor nucleophilicity of the nitrogen atom of indole, in addition to the steric hindrance and lower electrophilicity of the ketones. A dearomatization-rearomatization strategy has been developed for reductive cross-coupling of indoles with ketones in water. Various functional groups and other heterocyclic compounds are tolerated.

17.
J Mech Behav Biomed Mater ; 93: 170-182, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30802774

RESUMO

Sandwich structures are widely used in aviation and aerospace fields because they can absorb vast energy due to their excellent continuous compression behaviors. And in this work, the light-weight bio-inspired sandwich structure of titanium alloy was designed based on cybister elytra and produced by selective laser melting (SLM). The results show that bio-inspired structures can realize the light-weight effectively by increasing the core height. The specific and ultimate flatwise compressive strengths first increase and then decrease when core height increases. The load-displacement curves of bio-inspired structures during flatwise compression consists of elastic deformation, buffer and compaction zone. Comparatively, the edgewise compression lacks buffer zone. And the bio-inspired structure has an excellent flatwise comprehensive performance when its core height is 6 mm, whose peak flatwise compressive strength and specific volume energy absorption are 84.30 MPa, 101.30 MJ/m3, respectively. The specific ultimate strength of bio-inspired structures is optimized at the core height of 4 mm on the edgewise compression tests. And the fracture of the side arc damaged area shows an obviously ductile fracture and the panel and core of the middle area are brittle fracture in the flatwise compressive tests. Finally, The ANSYS simulation results are consistent with experimental results during the whole compressions, which will provide an accurate guidance in next researches.

18.
Toxicology ; 416: 1-14, 2019 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-30711707

RESUMO

Non-alcoholic fatty liver disease (NAFLD) is affecting up to one-third of the general population in western countries. While the major cause of NAFLD is related to an unhealthy lifestyle, recent evidence has shown a role of chemical exposure in the induction and progression of NAFLD. Perfluorooctanoate (PFOA) is a ubiquitous environmental contaminant that exerts its hepatotoxicity mainly through the activation of peroxisome proliferator-activated receptor α (PPARα). We examined how PFOA might affect the progression of NAFLD and whether a preexisting fatty liver intensified or alleviated the effects of PFOA in the livers. As such, male C57BL/6 mice were fed with a low-fat control diet (CD) or a high fat diet (HFD) for 16 weeks to model normal or steatotic livers, respectively. Mice were then administered with PFOA (1mg/kg/d) by oral gavage for an additional 2, 8, and 16 weeks. Dietary treatment was continued throughout the whole study. We found HFD induced hepatic steatosis, lobular inflammation, and progressive fibrosis in mice. As expected, PFOA activated PPARα, constitutive androstane receptor (CAR) and pregnane X receptor (PXR), regardless of the diet. Gene expression analysis showed the interactions between HFD and PFOA on hepatic nuclear receptors were time-dependent. Hepatocytes growth as measured by DNA synthesis and cell growth genes induced by PFOA were exacerbated in the HFD group after 2 weeks, along with the enhanced activation of PPARα. In contrast, PFOA decreased the severity of hepatic steatosis. In HFD-fed mice, the hepatic triglyceride levels were reduced to 75%, 47%, and 40%, after 2, 8, and 16 weeks of PFOA treatment, respectively, compared to vehicle controls. Transcriptomic analysis showed the preexisting NAFLD enhanced PFOA related lipid oxidation pathways in mice. HFD induced hepatic fibrosis as measured by collagen staining and fibrosis gene markers were also attenuated by PFOA. Taken together, this study demonstrated that the preexisting NAFLD might impact on many biological effects induced by PFOA and thus need to be carefully considered as a factor in risk assessment.


Assuntos
Caprilatos/toxicidade , Doença Hepática Induzida por Substâncias e Drogas/etiologia , Dieta Hiperlipídica , Poluentes Ambientais/toxicidade , Fluorcarbonetos/toxicidade , Fígado/efeitos dos fármacos , Hepatopatia Gordurosa não Alcoólica/etiologia , Animais , Proliferação de Células/efeitos dos fármacos , Doença Hepática Induzida por Substâncias e Drogas/genética , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Doença Hepática Induzida por Substâncias e Drogas/patologia , Sistema Enzimático do Citocromo P-450/genética , Sistema Enzimático do Citocromo P-450/metabolismo , Modelos Animais de Doenças , Progressão da Doença , Regulação da Expressão Gênica , Metabolismo dos Lipídeos/efeitos dos fármacos , Fígado/metabolismo , Fígado/patologia , Masculino , Camundongos Endogâmicos C57BL , Hepatopatia Gordurosa não Alcoólica/metabolismo , Hepatopatia Gordurosa não Alcoólica/patologia , Hepatopatia Gordurosa não Alcoólica/prevenção & controle , PPAR alfa/genética , PPAR alfa/metabolismo , Receptor de Pregnano X/genética , Receptor de Pregnano X/metabolismo , Receptores Citoplasmáticos e Nucleares/genética , Receptores Citoplasmáticos e Nucleares/metabolismo , Medição de Risco , Transdução de Sinais , Fatores de Tempo
19.
Sci Total Environ ; 658: 1256-1264, 2019 Mar 25.
Artigo em Inglês | MEDLINE | ID: mdl-30677988

RESUMO

Particulates smaller than 1.0 µm (PM1.0) have strong associations with public health and environment, and considerable exposure data should be obtained to understand the actual environmental burden. This study presented a PM1.0 estimation strategy based on the generalised regression neural network model. The proposed strategy combined ground-based observations of PM2.5 and satellite-derived aerosol optical depth (AOD) to estimate PM1.0 concentrations in China from July 2015 to June 2017. Results indicated that the PM1.0 estimates agreed well with the ground-based measurements with an R2 of 0.74, root mean square error of 19.0 µg/m3 and mean absolute error of 11.4 µg/m3 as calculated with the tenfold cross-validation method. The diurnal estimation performance displayed remarkable single-peak variation with the highest R2 of 0.80 at noon, and the seasonal estimation performance showed that the proposed method could effectively capture high-pollution events of PM1.0 in winter. Spatially, the most polluted areas were clustered in the North China Plain, where the average estimates presented a bimodal distribution during daytime. In addition, the quality of satellite-derived AOD, the robustness of the interpolation algorithm and the proportion of PM1.0 in PM2.5 were confirmed to affect the estimation accuracy of the proposed model.

20.
Drug Deliv ; 26(1): 12-22, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30691317

RESUMO

Despite the development of treatment options in breast cancer, many patients die of recurrence and metastasis. Owing to enhanced permeability and retention in solid tumor tissue, nanoparticle (NP) delivery systems have been emerged as novel strategy in cancer chemotherapy. As extracellular matrix, glycosaminoglycan hyaluronan (HA) could bind its surface receptor adhesion molecule CD44 which is strongly expressed on breast cancer. We have previously reported a doxorubicin (DOX)-loaded HA-Lys-LA X-NPs (X-NP-DOX) NP delivery system for breast cancer treatment. In this study, we further investigated the antitumor effect of X-NP-DOX NP delivery system using low-dose DOX in both in vitro and in vivo systems. We demonstrated that low-dose X-NP-DOX possessed the ability for inhibiting MCF-7 breast cancer cell growth, invasion, and migration, and inducing apoptosis in vitro. In in vivo experiments, injection of low-dose X-NP-DOX into tumor-bearing mouse resulted in significant reduction of tumor size. Terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling staining further revealed that low-dose X-NP-DOX induced higher percentage of apoptotic cells compared with free DOX or saline. Furthermore, our study demonstrated that low-dose X-NP-DOX inhibited Notch1 and Ras/MAPK pathways, decreased cancer stem cell population, and reduced tumorigenesis compared to free DOX in both in vitro and in vivo settings. Owing to its enhanced efficacy and higher targetability compared to free DOX, low-dose DOX delivered by NP system may be a promising novel strategy for breast cancer treatment.


Assuntos
Antibióticos Antineoplásicos/administração & dosagem , Neoplasias da Mama/tratamento farmacológico , Doxorrubicina/administração & dosagem , Sistemas de Liberação de Medicamentos/métodos , Ácido Hialurônico/administração & dosagem , Nanopartículas/administração & dosagem , Animais , Antibióticos Antineoplásicos/metabolismo , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Relação Dose-Resposta a Droga , Doxorrubicina/metabolismo , Feminino , Células HCT116 , Humanos , Ácido Hialurônico/metabolismo , Células MCF-7 , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Nanopartículas/metabolismo , Invasividade Neoplásica/patologia , Resultado do Tratamento , Ensaios Antitumorais Modelo de Xenoenxerto/métodos
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