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1.
Int J Cardiovasc Imaging ; 36(3): 481-489, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32020410

RESUMO

Previous studies demonstrated that men were more likely to have plaque rupture and are at greater risk for myocardial infarction and stroke than women. We evaluated differences in carotid plaque characteristics by MRI between men and women with mild-moderate atherosclerosis and elevated ApoB levels. One hundred eighty-two subjects (104 men and 78 women) with CAD or carotid stenosis (≥ 15% by ultrasound), ApoB ≥ 120 mg/dL and carotid MRI scan were included. Percent wall volume (%WV) was calculated as (wall volume/total vessel volume) × 100%. Three major plaque compositions, fibrous tissue (FT), calcification (CA) and lipid rich necrotic core (LRNC), were identified and quantified using published MRI criteria. Adventitial and plaque neovascularization as fractional plasma volume (Vp) and permeability as transfer constant (Ktrans) were analyzed using kinetic modeling. These characteristics were compared between men and women. Men, compared to women, were younger (54 ± 8 vs. 58 ± 8 years, p = 0.01), had higher rate of previous MI (46 vs. 26%, p = 0.005) but lower proportions of metabolic syndrome (37 vs. 59%, p = 0.003). After adjusting for between-gender differences, men were significantly more likely to have LRNC (OR 2.22, 95% CI 1.04-4.89, p = 0.04) and showed significantly larger %LRNC than women (diff = 4.3%, 95% CI 1.6-6.9%, p = 0.002), while %WV, FT, and CA were similar between men and women. There were no statistically significant differences in adventitial and plaque Vp or Ktrans. Men were significantly more likely to have LRNC and had larger LRNC than women. However, men and women showed relatively similar levels of adventitial and plaque neovascularization and permeability.Trial registration: NCT00715273 at ClinicalTrials.gov. Registered 15 July 2008, retrospectively registered.

2.
J Hazard Mater ; 392: 122354, 2020 Feb 19.
Artigo em Inglês | MEDLINE | ID: mdl-32097861

RESUMO

In this study, a new phototransformation pathway for perfluorooctane sulfonamide (FOSA) and underlying degradation mechanisms are described. Phototransformation of FOSA in a natural clay mineral (montmorillonite) suspension was compared to that in an aqueous solution. Results showed that the presence of montmorillonite can significantly promote the transformation of FOSA to perfluocarboxylic acids (increasing rate). The phototransformation reaction was found to be initiated by the activation of adsorbed oxygen molecules on the surface of montmorillonite, which generate superoxide anion and hydroxyl radicals. Hydroxyl radicals can then attack FOSA adsorbed onto the surface of montmorillonite, promoting the transformation process. In this reaction, clay minerals played a dual role: providing hydroxyl radicals and concentrating FOSA on their surfaces. This helped to promote the contact and reaction between FOSA and hydroxyl radicals. This study provides the first evidence that heterogeneous oxidation of FOSA at the surface of natural clay minerals may act as an important source of perfluocarboxylic acids (PFCAs), especially short chain PFCAs (i.e. trifluoroacetic acid, TFA).

3.
J Mater Chem B ; 8(5): 1033-1039, 2020 Feb 07.
Artigo em Inglês | MEDLINE | ID: mdl-31939981

RESUMO

Photothermal therapy following microscopic temperature detection can avoid overheating effects or insufficient heating, and thus improve therapeutic efficacy. In this study, biocompatible dual-functional nanoparticles (NPs) are constructed from polypyrrole (PPy) and rhodamine B (RB) by a one-step modified polymerization method. The polypyrrole serves as a photothemal agent, and rhodamine B acts as a temperature-sensing probe. The polypyrrole-rhodamine B (PPy-RB) NPs possess a high photothermal effect on irradiation by 808 nm laser, and a competent temperature sensitivity for the real-time temperature monitoring based on the emission intensity response of rhodamine B. After acting on HepG2 cells, the PPy-RB NPs can effectively induce cancer cell death, and the microscopic temperature is monitored by fluorescence feedback from rhodamine B during PTT by laser confocal microscopy. Hence, the proposed approach can supply a facile and promising way for the fabrication of effective theranostic nanoplatforms assisted by self-monitoring of cancer therapeutic processes.

4.
Sci Total Environ ; 713: 136657, 2020 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-31958733

RESUMO

Bromophenols are known as direct precursors of the notorious polybrominated dibenzo-p-dioxin/dibenzofurans (PBDD/Fs). There is a long-held viewpoint that only the more toxic dioxin-type products could be formed from the ortho-disubstituted phenols, totally contrary to the experimental observations that both PBDDs and PBDFs are generated. To tackle the issue, the gaseous formation mechanism of PBDD/Fs from 2,4,6-tribromophenol (TBP), a typical ortho-disubstituted phenol, was investigated in this study. Firstly, the reactions between TBP and the active H radical produce three key radical species including the bromophenoxyl radical, the substituted phenyl radical and phenoxyl diradical. The self- and cross-combinations of these radical species and TBP yield not only the dioxin-type products 1,3,6,8-TeBDD and 1,3,7,9-TeBDD, but also the brominated dibenzofurans 1,3,6,8-TeBDF and 2,4,6,8-TeBDF. Notably, the reactions involving the phenyl C sites in the substituted phenyl and phenoxyl diradicals are demonstrated to be both thermodynamically and kinetically more favorable than those involving the bromophenoxyl radical and the TBP molecule. Most importantly, the findings of the present work are of great importance as it provides feasible pathways to form less toxic dibenzofuran-type products from the ortho-disubstituted phenols. These results will improve the understanding of the PBDD/Fs formation mechanism from phenol precursors.

5.
J Clin Lipidol ; 13(5): 847-853, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31783975

RESUMO

BACKGROUND: Statin therapy can improve plaque stability. However, the time course of effects of statin on adventitial angiogenesis and plaque neovascularization has not been studied. OBJECTIVE: The objective of the study was to investigate whether statin therapy reduces plaque neovascularization, associated with adventitial angiogenesis, over 24 months as assessed by using carotid dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI). METHODS: Forty-three lipid treatment-naïve subjects with asymptomatic carotid atherosclerosis received rosuvastatin (5-20 mg/d) to lower low-density lipoprotein cholesterol to <80 mg/dL for 24 months. Carotid DCE-MRI was performed at baseline, 3, 12 and 24 months. Vascularity (Vp = fractional plasma volume) and vascular permeability (Ktrans = transfer constant) derived from kinetic modeling of DCE-MRI were measured in both adventitia and plaque. RESULTS: Adventitia Vp and adventitia Ktrans were significantly correlated with plaque Vp and plaque Ktrans at baseline. Rosuvastatin significantly reduced both adventitial and plaque Vp significantly at 3 months from 0.121 ± 0.064 to 0.085 ± 0.049 (P = .008) and from 0.096 ± 0.052 to 0.067 ± 0.043 (P = .013). Adventitial and plaque Vp continued to decrease by 43% and 34% at 12 months and by 49% and 45% at 24 months. However, the continued reductions from 3 to 12 months and from 12 to 24 months were not statistically significant. Adventitial and plaque Ktrans showed similar trends, but nonstatistically significant decreases during the 24 months of treatment. CONCLUSIONS: Rosuvastatin therapy rapidly and significantly decreased adventitial and plaque neovascularization at 3 months followed by continued, but nonstatistically significant, decreases at 12 and 24 months.

6.
Opt Express ; 27(23): 32912-32923, 2019 Nov 11.
Artigo em Inglês | MEDLINE | ID: mdl-31878367

RESUMO

An effective diode-side-pumped joule-level square-rod Nd:glass multipass amplifier with 1 Hz repetition rate is developed. A Pockels cell is used to extend the amplification-pass to twelve-pass. The linear depolarization compensation method and adaptive optics based wavefront aberration correction method are used to minimize the thermal effects. Combined with the relay-imaging technology and beam-shaping method, good beam quality is obtained. Under the small-signal gain of 3.23 and the input energy of 50 µJ, the output energy of 1 J and the net gain of 2×104 are realized. The effective energy-extraction efficiency in the whole aperture of Nd:glass rod is 12%. The total wavefront aberration is 1.1 µm (peak valley). The Strehl Ratio is 0.62, and 90% of far-field energy is concentrated in 3 times the diffraction limit. The near-field modulation index of twelve-pass amplification at 1 J is 1.4.

7.
Opt Express ; 27(24): 34937-34951, 2019 Nov 25.
Artigo em Inglês | MEDLINE | ID: mdl-31878672

RESUMO

A hybrid adaptive optics (AO) system with an influence function (IF) optimization method is presented for high precision wavefront correction of a traditional Shack-Hartmann AO system. The hybrid AO system consists of a Shack-Hartmann wavefront sensor (SHWFS) and a deflectometry system (DS) to measure the wavefront of the laser beam and the IF of the deformable mirror, respectively. An IF optimization method is used to generate a hybrid IF (H-IF) through a position-calibration algorithm and a resolution-conversion algorithm by use of the original IFs measured by the SHWFS (S-IF) and the DS (D-IF). Configuration of the hybrid AO system is introduced. Principles and calculation results of the IF optimization method are presented. Comparison of the wavefront correction ability between the H-IF and the original IF is carried out in simulation. Closed-loop performance of the hybrid AO system using the H-IF is investigated in experiment. Simulation and experiment results show that for a traditional Shack-Hartmann AO system, the H-IF has better correction ability than the original S-IF and the IF optimization method could help improve closed-loop performance without sacrificing the simplicity of the system structure and the rapidity of the closed-loop correction.

8.
Virus Res ; 277: 197844, 2019 Dec 19.
Artigo em Inglês | MEDLINE | ID: mdl-31866422

RESUMO

Peste des petits ruminants virus (PPRV) is a highly contagious disease that affects sheep and goats. To better understand PPRV replication and virulence, cyclophilin A (CypA), a multifunctional goat host protein, was selected for further studies. CypA has been reported to inhibit or facilitate viral replication. However, the precise roles of CypA during PPRV infection remain unclear. Our data show for the first time that CypA suppressed PPRV replication by its PPIase activity, and PPRV infection decreased CypA protein levels. Detailed analysis revealed that PPRV H protein was responsible for the reduction of CypA, which was dependent on the lysosome pathway. No interaction was identified between H and CypA. Furthermore, the 35-58 region of H was essential for the reduction of CypA. In conclusion, our findings identify the antiviral role of CypA against PPRV and provide key insights into how PPRV H protein antagonizes host antiviral response.

9.
BMC Cardiovasc Disord ; 19(1): 163, 2019 07 04.
Artigo em Inglês | MEDLINE | ID: mdl-31272376

RESUMO

BACKGROUND: Patients with acute myocardial infarction (AMI) often accompanied by admission hyperglycemia, which usually predicts a poor clinical outcomes for non-diabetes mellitus. Appropriate cut-point to identify high risk individuals in these patients remains controversial. METHODS: One thousand six hundred ninety-eight non-diabetes AMI patients in this retrospective study were divided into 3 groups according to admission glucose levels (euglycemia group≤140 mg/dL, moderate hyperglycemia group 141-179 mg/dL, severe hyperglycemia group≥180 mg/dL). The primary endpoint of this study was all-cause in-hospital mortality rate. In-hospital motality related risk factors was analyzed by multivariate binary logistic regression analyses. RESULTS: All myocardial necrosis markers and Log NT-proBNP in severe hyperglycemia group were significantly higher than those in the other 2 groups. Logistic regression showed that independent predictors of the in-hospital mortality rate in non-diabetic patients with AMI were age (OR = 1.057, 95% CI 1.024-1.091, P < 0.001), logarithm of the N-terminal pro-brain natriuretic peptide (OR = 7.697, 95% CI 3.810-15.550, P < 0.001), insufficient myocardial reperfusion (OR = 7.654, 95% CI 2.109-27.779, P < 0.001), percutaneous coronary intervention (OR = 0.221, 95% CI 0.108-0.452, P < 0.001) and admission glucose (as categorical variable). Patients with moderate hyperglycemia (OR = 1.186, 95% CI 0.585-2.408, P = .636) and severe hyperglycemia (OR = 4.595, 95% CI 1.942-10.873, P = 0.001) had a higher all-cause in-hospital mortality rate compared with those with euglycemia after AMI in non-diabetic patients. CONCLUSIONS: The all-cause in-hospital mortality risk increases remarkably as admission glucose levels elevated in non-diabetic patients with AMI, especially in patients with admission glucose levels ≥180 mg/dL. Severe admission hyperglycemia could be regarded as prospective high-risk marker for non-diabetic AMI patients.

10.
Virol Sin ; 34(6): 610-617, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31359346

RESUMO

Foot-and-mouth disease virus (FMDV) can infect domestic and wild cloven-hoofed animals. The non-structural protein 3D plays an important role in FMDV replication and pathogenesis. However, the interaction partners of 3D, and the effects of those interactions on FMDV replication, remain incompletely elucidated. In the present study, using the yeast two-hybrid system, we identified a porcine cell protein, DEAD-box RNA helicase 1 (DDX1), which interacted with FMDV 3D. The DDX1-3D interaction was further confirmed by co-immunoprecipitation experiments and an indirect immunofluorescence assay (IFA) in porcine kidney 15 (PK-15) cells. DDX1 was reported to either inhibit or facilitate viral replication and regulate host innate immune responses. However, the roles of DDX1 during FMDV infection remain unclear. Our results revealed that DDX1 inhibited FMDV replication in an ATPase/helicase activity-dependent manner. In addition, DDX1 stimulated IFN-ß activation in FMDV-infected cells. Together, our results expand the body of knowledge regarding the role of DDX1 in FMDV infection.

11.
Am J Cardiol ; 124(4): 476-484, 2019 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-31235063

RESUMO

The prognostic value of the CHA2DS2-VASc score in acute coronary syndrome (ACS) patients without atrial fibrillation (AF) who underwent percutaneous coronary intervention remains uncertain. We examine the association of the CHA2DS2-VASc score and major adverse cardiovascular events (MACE) in this population and compared its risk prediction with 2 other commonly used risk scores (Global Registry of Acute Coronary Events [GRACE] and thrombolysis in myocardial infarction [TIMI]). A total of 3,745 consecutive ACS patients without AF who underwent percutaneous coronary intervention during 2013 to 2017 were classified into 4 groups according to the CHA2DS2-VASc score: low (0 to 1), moderate (2 to 3), high (4 to 5), and very high (>5). Incidences of MACE including cardiovascular death, nonfatal myocardial infarction, or stroke in-hospital and during a median follow-up of 33 months were compared among the 4 groups. Receiver-operating characteristic curves were generated to compare CHA2DS2-VASc with GRACE and TIMI for risk prediction. The incidences of in-hospital MACE (3.5%, 6.6%, 7.6%, and 9.1%, p <0.001) and mid-term follow-up MACE (4.5%, 7.1%, 13.1%, and 16.1%, p <0.001) were significantly higher as the CHA2DS2-VASc score increased. The CHA2DS2-VASc score was an independent predictor of subsequent MACE (hazard ratio = 1.31, 95% CI 1.24 to 1.39, p <0.001), and the very high-risk score group showed 3.8-fold increased risk of MACE than the low-risk score group. Receiver-operating characteristic curves showed that the CHA2DS2-VASc score was comparable to the GRACE score and to TIMI-STEMI, but, better than the TIMI-NSTEMI/unstable angina pectoris score in terms of predicting MACE. In conclusion, higher CHA2DS2-VASc score was independently associated with increased risk of MACE in the ACS patients without AF who underwent PCI.


Assuntos
Síndrome Coronariana Aguda/cirurgia , Intervenção Coronária Percutânea , Complicações Pós-Operatórias/epidemiologia , Medição de Risco/métodos , Síndrome Coronariana Aguda/complicações , Síndrome Coronariana Aguda/mortalidade , Idoso , China/epidemiologia , Feminino , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Sistema de Registros , Estudos Retrospectivos
12.
J Biomol Struct Dyn ; : 1-9, 2019 Jul 08.
Artigo em Inglês | MEDLINE | ID: mdl-31244379

RESUMO

Perfluorinated compounds (PFCs) have serious impacts on human health, which could interfere with the body's signal pathways and affect the normal hormone balance of humans. PFCs were reported to bind to many proteins causing a series of biological effects. It was quite possible that the in vivo action of PFCs was not a single target or a single pathway, suggesting the toxic effect was due to the disturbance of protein or gene network, not limited to the modification of a single target protein or gene. Thus, a PFCs-targets interaction network was constructed and the significant differences in the characteristics of complex networks between the branched PFCs and linear PFCs were observed. A molecular dynamics simulation proved that binding ability of the branched PFCs to the target protein was much weaker than that of the linear PFCs, explaining why the branched PFCs presented significantly difference from the linear PFCs in terms of complex network characteristics. In addition, four target genes were identified as the central node genes of the network. The four target genes were proved to present certain influences on some diseases, which suggested a high correlation between PFCs to these diseases, including obesity, hepatocellular carcinoma and diabetes. The present work was helpful to develop new approaches to identify the key toxic targets of compounds and to explore the toxicity effects on pathways. Abbreviations AR androgen receptor BPA bisphenol A ESR1 estrogen receptor 1 ESR2 estrogen receptor 2 GLTP glycolipid transfer protein HbF the fetal hemoglobin HBG1 hemoglobin subunit γ-1 hERα human ERα HSD17B1 hydroxysteroid 17-ß dehydrogenase 1 KEGG Kenya encyclopedia of genes and genomes MD molecular dynamics simulation PFCs perfluorinated compounds PFOA perfluorooctanoic acid PFOS perfluorooctane sulfonate POPs persistent organic pollutants RMSD root-mean-square deviation SHBG sex hormone binding globulin SPC/E extended simple point charge model TR thyroid hormone receptor Communicated by Ramaswamy H. Sarma.

13.
Sci Total Environ ; 687: 516-526, 2019 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-31216508

RESUMO

Polyhalogenated carbazoles (PHCZs) are a class of contaminants identified with persistence and bioaccumulation property from previous studies. However, the toxic effect and mechanism of PHCZs are not fully understood. In this study, eleven PHCZs, including four chlorocarbazoles, four bromocarbazoles and two bromo/chlorocarbazoles were screened for their potential aryl hydrocarbon receptor (AhR) activity by using a dioxin responsive element-driven luciferase reporter assay. We found that nine PHCZs significantly activated AhR in a concentration-dependent manner. Their potencies of AhR activation were 1000 to 100,000 folds less than that of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), the most potent AhR ligand. The relative AhR activation potency of the nine PHCZs followed the order 2,3,6,7-tetrachloro-9H-carbazole >2,7-dibromo-9H-carbazole >1,3,6-tribromo-9H-carbazole >1,3,6,8-tetrachloro-9H-carbazole >1,3,6,8-tetrabromo-9H-carbazole >1-bromo-3,6-dichloro-9H-carbazole >3,6-dibromo-9H-carbazole >3-bromo-9H-carbazole >1,8-dibromo-3,6-dichloro-9H-carbazole, which was partly in line with the induction of AhR-mediated CYP1A1 expression. In silico analysis indicated that the nine PHCZs could be docked into the same pocket as TCDD due to their high structural similarity. However, the shrunk size of the heterocyclic moieties in PHCZs relative to that in TCDD dramatically decreased the complex stability provided by inter-molecular interactions. Moreover, two distinguished docking poses adopted by the nine PHCZs were found, in which one was illustrated by 2367-CCZ and 27-BCZ while the other symbolized by TCDD and the left seven agonists. The differential antagonizing effects of CH223191 on PHCZ-induced AhR activity supported such pose differentiation. The present experimental and in silico data provide new direct evidence of PHCZ-AhR interaction which sheds light on AhR-associated toxicological study and risk assessment of PHCZs.

14.
Chem Res Toxicol ; 32(6): 1002-1013, 2019 06 17.
Artigo em Inglês | MEDLINE | ID: mdl-30924335

RESUMO

Numerous chemicals have been reported to exert estrogen-like endocrine disrupting effects via a receptor binding mechanism that directly interacts with the ligand binding domain of estrogen receptor α (ERα). However, not only their binding affinities to ERα but also their interference in specific cell and tissue functions are clearly different. In this regard, significant regulation differences among three representative estrogenic chemicals (diethylstilbestrol (DES), bisphenol A (BPA), and diarylpropionitrile (DPN)), well-known ERα agonists with very similar structures, have been observed. Molecular dynamics simulation is used to explore the underlying mechanism of different regulation effects induced by the similar estrogen-like chemicals. The DES-induced 12 Å motion of the H9-H10 loop markedly expands the negative electrostatic potential surface of the AF-2 domain, which is consistent with the over-regulation effect of the agonist. In comparison, the 3 Å motion induced by BPA and DPN corresponds to the low-regulation effect of the chemicals. Cross-correlation analysis indicates that the different ERα motions and resulting surface feature of AF-2 domain are brought by the distinguished binding modes of the agonists. Moreover, only hydrophobic DES with estrogen-like size and flexibility has a high binding affinity of -23.47 kcal/mol binding free energy. Both the hydrophilic group in DPN and the small molecular size of BPA dramatically decrease the agonist binding ability, and their binding free energies are only -12.43 kcal/mol and -11.82 kcal/mol, respectively. Our study demonstrates that similar chemicals interact differently with ERα and induce different allosteric effects, which explains the observed regulation diversity.

15.
Cardiovasc J Afr ; 30(2): 79-86, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30882133

RESUMO

AIM: We aimed to study the effect of allocryptopine (All) on the late sodium current (INa,Late) of atrial myocytes in spontaneously hypertensive rats (SHR). METHODS: The enzyme digestion method was used to separate single atrial myocytes from SHR and Wistar-Kyoto (WKY) rats. INa,Late was recorded using the patch-clamp technique, and the effect of All was evaluated on the current. RESULTS: Compared with WKY rat cells, an increase in the INa,Late current in SHR myocytes was found. After treatment with 30 µM All, the current densities were markedly decreased; the ratio of INa,Late/INa,peak of SHR was reduced by 30 µM All. All reduced INa,Late by alleviating inactivation of the channel and increasing the window current of the sodium channel. Furthermore, INa,Late densities of three SCN5A mutations declined substantially with 30 µM All in a concentration-dependent manner. CONCLUSIONS: The results clearly show that an increase in INa,Late in SHR atrial myocytes was inhibited by All derived from Chinese herbal medicine.


Assuntos
Antiarrítmicos/farmacologia , Fibrilação Atrial/prevenção & controle , Alcaloides de Berberina/farmacologia , Átrios do Coração/efeitos dos fármacos , Hipertensão/tratamento farmacológico , Miócitos Cardíacos/efeitos dos fármacos , Canal de Sódio Disparado por Voltagem NAV1.5/efeitos dos fármacos , Sódio/metabolismo , Potenciais de Ação , Animais , Fibrilação Atrial/etiologia , Fibrilação Atrial/metabolismo , Fibrilação Atrial/fisiopatologia , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Células HEK293 , Átrios do Coração/metabolismo , Frequência Cardíaca , Humanos , Hipertensão/complicações , Hipertensão/metabolismo , Hipertensão/fisiopatologia , Masculino , Mutação , Miócitos Cardíacos/metabolismo , Canal de Sódio Disparado por Voltagem NAV1.5/genética , Canal de Sódio Disparado por Voltagem NAV1.5/metabolismo , Ratos Endogâmicos SHR , Ratos Endogâmicos WKY , Fatores de Tempo
16.
J Virol ; 93(11)2019 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-30894473

RESUMO

The role of nucleotide-binding oligomerization domain 2 (NOD2) in foot-and-mouth disease virus (FMDV)-infected cells remains unknown. Here, we showed that FMDV infection activated NOD2-mediated beta interferon (IFN-ß) and nuclear factor-κB (NF-ĸB) signaling pathways. NOD2 inhibited FMDV replication in the infected cells. FMDV infection triggered NOD2 transcription, while it reduced the abundance of NOD2 protein. Our results revealed that FMDV 2B, 2C, and 3C proteinase (3Cpro) were responsible for the decrease in NOD2 protein levels. 3Cpro is a viral proteinase that can cleave multiple host proteins and limit protein synthesis. Our previous studies determined that FMDV 2B suppressed protein expression of RIG-I and LGP2. Here, we found that 3Cpro and 2B also decreased NOD2 expression. However, this is the first report that 2C induced the reduction of NOD2 protein levels. We determined that both 2B- and 2C-induced decreases in NOD2 were independent of the cleavage of host eukaryotic translation initiation factor 4 gamma (eIF4G), induction of cellular apoptosis, or proteasome, lysosome, and caspase pathways. The interactions between NOD2 and 2B or 2C were observed in the context of viral infection. The carboxyl-terminal amino acids 105 to 114 and 135 to 144 of 2B were essential for the reduction of NOD2, while the residues 105 to 114 were required for the interaction. Amino acids 116 to 260 of the carboxyl terminus of 2C were essential for the interaction, while truncated 2C mutants did not reduce NOD2. These data suggested novel antagonistic mechanisms of FMDV that were mediated by 2B, 2C, and 3Cpro proteins.IMPORTANCE NOD2 was identified as a cytoplasmic viral pattern recognition receptor in 2009. Subsequently, many viruses were reported to activate NOD2-mediated signaling pathways. This study demonstrated that FMDV infection activated NOD2-mediated IFN-ß and NF-ĸB signaling pathways. Host cells have developed multiple strategies against viral infection; however, viruses have evolved many strategies to escape host defenses. FMDV has evolved multiple mechanisms to inhibit host type I IFN production. Here, we showed that NOD2 suppressed FMDV replication during viral infection. FMDV 2B, 2C, and 3Cpro decreased NOD2 protein expression by different mechanisms to promote viral replication. This study provided new insight into the immune evasion mechanisms mediated by FMDV and identified 2B, 2C, and 3Cpro as antagonistic factors for FMDV to evade host antiviral responses.

17.
Cells ; 8(2)2019 02 11.
Artigo em Inglês | MEDLINE | ID: mdl-30754684

RESUMO

Breast cancer is the most common malignant tumors in females. Although the conventional treatment has demonstrated a certain effect, some limitations still exist. The Rho guanosine triphosphatase (GTPase) Cdc42 (Cell division control protein 42 homolog) is often upregulated by some cell surface receptors and oncogenes in breast cancer. Cdc42 switches from inactive guanosine diphosphate (GDP)-bound to active GTP-bound though guanine-nucleotide-exchange factors (GEFs), results in activation of signaling cascades that regulate various cellular processes such as cytoskeletal changes, proliferation and polarity establishment. Targeting Cdc42 also provides a strategy for precise breast cancer therapy. In addition, Cdc42 is a potential target for several types of non-coding RNAs including microRNAs and lncRNAs. These non-coding RNAs is extensively involved in Cdc42-induced tumor processes, while many of them are aberrantly expressed. Here, we focus on the role of Cdc42 in cell morphogenesis, proliferation, motility, angiogenesis and survival, introduce the Cdc42-targeted non-coding RNAs, as well as present current development of effective Cdc42-targeted inhibitors in breast cancer.


Assuntos
Neoplasias da Mama/genética , Neoplasias da Mama/terapia , Terapia de Alvo Molecular , RNA não Traduzido/metabolismo , Proteína cdc42 de Ligação ao GTP/metabolismo , Apoptose , Neoplasias da Mama/irrigação sanguínea , Neoplasias da Mama/patologia , Células Epiteliais/metabolismo , Feminino , Humanos , RNA não Traduzido/genética
18.
Talanta ; 194: 960-968, 2019 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-30609629

RESUMO

The free concentration of low molecular weight compounds (LMWCs) in serum play important roles in both the environmental health and pharmacokinetic fields. A novel and broad spectrum method for direct determination of free LMWCs in serum was established by online TurboFlow SPE HPLC-MS/MS. Macromolecules, including proteins and protein-bound LMWCs, were removed by the TurboFlow SPE column. Meanwhile, free LMWCs were retained on the TurboFlow SPE column and eluted by the mobile phase for HPLC-MS/MS detection. 16 representative LMWCs with low, medium and high affinities to serum proteins were selected for method optimization and validation, and their free concentrations in serum detected by present method showed fairly consistent results with the equilibrium dialysis (r = 0.9714, p < 0.01) and ultrafiltration (r = 0.9054, p < 0.01) method. Then, present method was successfully applied to detect free LMWCs in human serum as well as to evaluate the dissociation constants (Kd) of LMWC-HSA complexes. Kd values of some emerging pollutants, such as 9Cl-PF3ONS, PFEtCHxS and 8:2 diPAP, were firstly evaluated by the present method. The rapid processing time (18 min), small sample amount requirement (25 µL) and convenient operation (direct injection) made present method be promising in studies on the bioavailability, bioaccumulation and elimination of LMWCs in serum, real-time detection of free LMWCs for therapeutic drug monitoring during clinical drug research and development, and the degradation kinetic processes of free LMWCs in serum.


Assuntos
Análise Química do Sangue/métodos , Cromatografia Líquida de Alta Pressão/métodos , Extração em Fase Sólida/métodos , Espectrometria de Massas em Tandem/métodos , Humanos , Peso Molecular , Controle de Qualidade , Albumina Sérica Humana/metabolismo
19.
Ecotoxicol Environ Saf ; 169: 623-630, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30496994

RESUMO

Environmentally persistent free radicals (EPFRs) in atmospheric fine particulate matters (PM2.5) possess high bioactivity and result in severe health problems. The facile transformation of aromatic pollutants into EPFRs on montmorillonite (MMT), an important solid component in PM2.5, is an activation of air pollutants into more toxic chemical species and also attributes to the secondary source of EPFRs in PM2.5. In this study, the interfacial reactions of pentachlorophenol (PCP), a typical EPFR precursor in air pollution, on the Fe(III)-, Ca- and Na-MMT surfaces have been explored by the density functional theory (DFT) calculations using the periodic slab models. The PCP molecule is found to be exothermically adsorbed on the three MMT surfaces. Moreover, significant charge transfer from PCP to Fe takes place and finally leads to the surface-bound phenoxyl radical formation on the Fe(III)-MMT surface since the half-filled 3d orbital of Fe3+ in Fe(III)-MMT could act as electron acceptor allowing the electron transferring from the 2p orbital of the phenolic O in PCP to Fe ion. However, similar charge transfer is not found in the Ca- and Na-MMTs, and the PCP transformation reaction is hindered on the Ca- and Na-MMT surfaces. Namely, the PCP activation to the corresponding EPFRs is impossible on the Ca-MMT and Na-MMT surfaces, while the catalytically active Fe(III)-MMT in PM2.5 can transform the chlorinated phenols into more toxic phenoxy-type EPFRs at ambient temperatures. Accordingly, more attention should be paid on the effect of MMT with catalytical capacity on the toxicity of PM2.5.


Assuntos
Poluentes Atmosféricos/análise , Bentonita/química , Compostos Férricos/química , Radicais Livres/análise , Material Particulado/química , Pentaclorofenol/análise , Adsorção , Oxirredução , Tamanho da Partícula , Propriedades de Superfície
20.
Ecotoxicol Environ Saf ; 170: 427-435, 2019 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-30553920

RESUMO

Regional haze episode has already caused overwhelming public concern. Unraveling the health effects of the representative composition mixtures of atmospheric fine particulate matters (PM2.5) becomes a top priority. In this study, a novel computational solution integrating chemical-induced genomic residual effect prediction with in vitro-based risk assessment is proposed to obtain the cumulative health risk of typical chemical mixtures of particulate matters (PM). The joint toxicity of binary mixtures is estimated by analyzing both genomic similarity and dose-response curve of relevant pollutants for the chemical-induced genomic residual effect. Specifically, the modified relative potency factor (mRPF) of mixtures is introduced for this purpose, and the ratio of activation (RA) value is defined to assess the corresponding health risks of the mixtures. As a methodology demonstration, the health risk of typical binary polycyclic aromatic hydrocarbon (PAH) mixtures in PM, containing Benzo[a]pyrene (BaP) as a component, is assessed using the proposed solution. Our results indicate that the combined effect of pairwise PAHs of BaP with Benzo[b]fluoranthene (BbF) and Benz[a]anthracene (BaA) is synergistic on p53 pathway, and that the health risk of the such mixtures increases compared to that of the individual ones. Obviously, the cumulative health risk of environmental mixtures will be underestimated when the synergistic effect is wrongly assumed to be additive. To our knowledge, this is the first study ever report on a computational solution to the health risk assessment of environmental pollution via joint toxicity prediction. The novel methodology proposed here makes full use of the open-access in vitro assay data and transcriptomic information in literatures and provides a successful demonstration of the concept of systems biology and translational science.


Assuntos
Poluição do Ar/efeitos adversos , Material Particulado/toxicidade , Hidrocarbonetos Policíclicos Aromáticos/toxicidade , Benzo(a)pireno/toxicidade , Simulação por Computador , Humanos , Modelos Teóricos , Medição de Risco , Testes de Toxicidade
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