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1.
Food Chem ; 304: 125446, 2020 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-31491715

RESUMO

Fused coumarins recently attracted strong scientific interest due to their potent pharmacological activities. In this study, density functional theory (DFT) calculations were performed to evaluate the antiradical activities of a series of coumarin-fused coumarins. By calculating the thermodynamic parameters, three primary mechanisms including hydrogen atom transfer (HAT), electron transfer followed by proton transfer (SET-PT) and sequential proton loss electron transfer (SPLET) were examined. It was found that in the gas and benzene phases, the studied compounds prefer to undergo HAT mechanism, while SPLET is more favored in polar media. The results also reveal the possibility of double HAT and double SPLET mechanisms for compound CC-6. Interestingly, a new polycyclic compound was generated by forming a new C5-O5' bond during the second HAT process at the 5'-OH in CC-6-R6 radical. In addition, the SPLHAT mechanism is proposed as a competitive pathway for radical scavenging by CC-4, CC-5 and CC-6.

2.
J Nanosci Nanotechnol ; 20(2): 1098-1108, 2020 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-31383110

RESUMO

In this study, the 2D porous graphitic carbon nitride (g-C3N4) nanosheets were successfully fabricated via a facile thermal decomposition polymerization method without any help of templates, and then novel porous g-C3N4/CdS complex catalysts of different mass fractions were is situ synthesized by a simple solvothermal process. The results of photocatalytic experiments demonstrate that the coupling g-C3N4/CdS cocatalysts exhibit significant enhanced visible-light-driven photocatalytic activity for the decolorization of methyl orange (MO) compared with individual porous g-C3N4 and CdS. In particular, an optimal porous g-C3N4 content in the hybridized composite has been determined to be 70 wt.%, corresponding to pseudo-first-order rate constant of 0.046 min-1, which is 7 and 11 times faster than that of pure porous g-C3N4 and CdS, respectively. Photoluminescence (PL) spectroscopy measurements clearly confirmed that the recombination of photoproduced electrons and holes in g-C3N4/CdS composites was efficiently inhibited due to the formation of heterojunctions. Furthermore, the possible mechanism of enhanced photocatalytic activity and photostability of prous g-C3N4/CdS are also tentatively proposed.

3.
J Ultrasound Med ; 2019 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-31675129

RESUMO

OBJECTIVES: To evaluate the performance of fetal intelligent navigation echocardiography (FINE) applied to spatiotemporal image correlation (STIC) volumes in generating 3 specific abnormal cardiac views (left ventricular outflow tract, right ventricular outflow tract, and 3-vessel and trachea) used to screen for d-transposition of the great arteries (d-TGA). METHODS: In this prospective study, 1 or more STIC volumes were obtained from the 4-chamber view in 34 second- and third-trimester fetuses with d-TGA. Each appropriate STIC volume was evaluated by STICLoop (Samsung Medison, Seoul, Korea) before applying the FINE method. One optimal volume per fetus was selected by observers. The visualization rates of the 3 specific abnormal cardiac views of d-TGA and their diagnostic elements were calculated, and the reliability between 2 observers was verified by the intraclass correlation coefficient. RESULTS: Fetal intelligent navigation echocardiography applied to STIC volume data sets of fetuses with d-TGA successfully generated the 3 specific abnormal cardiac views in the following manner for 2 observers: 75.0% (n = 21) for the left ventricular outflow tract, 89.2% (n = 25) for the right ventricular outflow tract, and 85.7% (n = 24) for the 3-vessel and trachea view. Twenty-four (85.7%) of the STIC volume data sets showed 2 or 3 of the abnormal cardiac views. The interobserver intraclass correlation coefficients between the 2 observers ranged from 0.842 to 1.000 (95% confidence interval), indicating almost perfect reliability for the 2 observers. CONCLUSIONS: In cases of d-TGA, the FINE method has a high success rate in generating 3 specific abnormal cardiac views and therefore can be performed to screen for this congenital defect.

4.
Parasit Vectors ; 12(1): 534, 2019 Nov 11.
Artigo em Inglês | MEDLINE | ID: mdl-31711531

RESUMO

BACKGROUND: Malaria, one of the largest health burdens worldwide, is caused by Plasmodium spp. infection. Upon infection, the host's immune system begins to clear the parasites. However, Plasmodium species have evolved to escape the host's immune clearance. T-cell immunoglobulin and mucin domain 3 (Tim-3), a surface molecule on most immune cells, is often referred to as an exhaustion marker. Galectin (Gal)-9 is a Tim-3 ligand and the T helper (Th) 1 cell response is inhibited when Gal-9 binds to Tim-3. In the present study, dynamic expression of Tim-3 on key populations of lymphocytes during infection periods of Plasmodium berghei and its significance in disease resistance and pathogenesis were explored. METHODS: Tim-3 expression on critical lymphocyte populations and the proportion of these cells, as well as the levels of cytokines in the sera of infected mice, were detected by flow cytometry. Further, in vitro anti-Tim-3 assay using an anti-Tim-3 antibody and in vivo Tim-3-Gal-9 signaling blockade assays using α-lactose (an antagonist of Gal-9) were conducted. An Annexin V Apoptosis Detection Kit with propidium iodide was used to detect apoptosis. In addition, proteins associated with apoptosis in lung and spleen tissues were confirmed by Western blotting assays. RESULTS: Increased Tim-3 expression on splenic CD8+ and splenic CD4+, and circulatory CD4+ T cells was associated with a reduction in the proportion of these cells. Furthermore, the levels of interleukin (IL)-2, IL-4, IL-6, IL-22, and interferon (IFN)-γ, but not that of tumor necrosis factor alpha (TNF-α), IL-10, and IL-9, increased to their highest levels at day 4 post-infection and decreased thereafter. Blocking Tim-3 signaling in vitro inhibited lymphocyte apoptosis. Tim-3-Gal-9 signaling blockade in vivo did not protect the mice, but induced the expression of the immunosuppressive molecule, T cell immunoreceptor with Ig and ITIM domains (TIGIT), in Plasmodium berghei ANKA-infected mice. CONCLUSIONS: Tim-3 on lymphocytes negatively regulates cell-mediated immunity against Plasmodium infection, and blocking Tim-3-galectin 9 signaling using α-lactose did not significantly protect the mice; however, it induced the compensatory expression of TIGIT. Further investigations are required to identify whether combined blockade of Tim-3 and TIGIT signaling could achieve a better protective effect.

5.
Int J Biol Macromol ; 2019 Nov 11.
Artigo em Inglês | MEDLINE | ID: mdl-31726176

RESUMO

Polysaccharides are considered to be promising candidates for non-viral gene delivery because of their molecular diversity, which can be modified to fine-tune their physicochemical properties. In this work, transcriptional activator protein (TAT) functionalized PEI grafted polysaccharide polymer (PRBP) was prepared by using rice bran polysaccharide as the starting material, and characterized by various methods. The potential of TAT functionalized PRBP (PRBP-TAT) as gene vector was studied in vitro, including DNA loading capacity, DNA protection ability and biocompatibility. The cell uptake and transfection efficiency of the PRBP-TAT/pDNA polyplexes were studied. The results showed that PRBP-TAT could completely condense DNA at N/P 2. The PRBP-TAT/pDNA polyplexes could protect DNA from degrading by DNase and were efficiently internalized by cells. Biocompatibility result showed that PRBP-TAT had no significant cytotoxicity and effect on cell proliferation. At low N/P ratios of 1-3.5, PRBP-TAT showed higher transfection efficiency than PEI30k and PEI30k-grafted rice bran polysaccharide. PRBP-TAT and PEI showed the highest transfection efficiency of 42.8% and 28.1% when pDNA is 2 µg and N/P ratio is 1.5, respectively, while PRBP showed the highest transfection efficiency of 37.3% at N/P 2.5. These results indicate that PTA is a promising candidate vector for safe and efficient gene delivery.

6.
Asian J Androl ; 2019 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-31696835

RESUMO

Epididymitis can be caused by infectious and noninfectious etiological factors. While microbial infections are responsible for infectious epididymitis, the etiological factors contributing to noninfectious epididymitis remain to be defined. The present study demonstrated that damaged male germ cells (DMGCs) induce epididymitis in mice. Intraperitoneal injection of the alkylating agent busulfan damaged murine male germ cells. Epididymitis was observed in mice 4 weeks after the injection of busulfan and was characterized by massive macrophage infiltration. Epididymitis was coincident with an accumulation of DMGCs in the epididymis. In contrast, busulfan injection into mice lacking male germ cells did not induce epididymitis. DMGCs induced innate immune responses in epididymal epithelial cells (EECs), thereby upregulating the pro-inflammatory cytokines such as tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and interleukin-1ß (IL-1ß), as well as the chemokines such as monocyte chemotactic protein-1 (MCP-1), monocyte chemotactic protein-5 (MCP-5), and chemokine ligand-10 (CXCL10). These results suggest that male germ cell damage may induce noninfectious epididymitis through the induction of innate immune responses in EECs. These findings provide novel insights into the mechanisms underlying noninfectious epididymitis, which might aid in the diagnosis and treatment of the disease.

7.
J Rehabil Med ; 2019 Oct 04.
Artigo em Inglês | MEDLINE | ID: mdl-31583420

RESUMO

OBJECTIVE: To evaluate the efficacy of classical pulsed electromagnetic field therapy on patients with knee osteoarthritis. METHODS: The databases PubMed, EMBASE, Web of Science and Cochrane Library were searched for relevant studies. Randomized controlled trials comparing classical pulsed electromagnetic field with placebo for patients with knee osteoarthritis were included. Data for primary outcomes, including pain, stiffness and physical function, were extracted. Data from 8 randomized controlled trials involving 421 patients were pooled. RESULTS: Pulsed electromagnetic field therapy had an effect on improving physical function (weighted mean difference; WMD = -5.28, 95% confidence interval; 95% CI -9.45 to -1.11, p = 0.01), but showed no advantage in the reduction of Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) total score (WMD = -7.80, 95% CI -16.08 to 0.47, p = 0.06), WOMAC pain score (WMD = -1.06, 95% CI -2.30 to 0.17, p = 0.09), visual analogue scale pain score (WMD=-0.88, 95% CI -2.06 to 0.31, p = 0.15) or WOMAC stiffness score (WMD = -0.50, 95% CI -1.09 to 0.09, p = 0.1). CONCLUSION: Pulsed electromagnetic field therapy is beneficial for improving physical function despite having no advantage in treating pain and stiffness. Further randomized controlled trials are needed to confirm these findings and determine the optimal parameters and treatment regimen for pulsed electromagnetic field therapy.

8.
Cell ; 179(2): 561-577.e22, 2019 Oct 03.
Artigo em Inglês | MEDLINE | ID: mdl-31585088

RESUMO

We performed the first proteogenomic characterization of hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) using paired tumor and adjacent liver tissues from 159 patients. Integrated proteogenomic analyses revealed consistency and discordance among multi-omics, activation status of key signaling pathways, and liver-specific metabolic reprogramming in HBV-related HCC. Proteomic profiling identified three subgroups associated with clinical and molecular attributes including patient survival, tumor thrombus, genetic profile, and the liver-specific proteome. These proteomic subgroups have distinct features in metabolic reprogramming, microenvironment dysregulation, cell proliferation, and potential therapeutics. Two prognostic biomarkers, PYCR2 and ADH1A, related to proteomic subgrouping and involved in HCC metabolic reprogramming, were identified. CTNNB1 and TP53 mutation-associated signaling and metabolic profiles were revealed, among which mutated CTNNB1-associated ALDOA phosphorylation was validated to promote glycolysis and cell proliferation. Our study provides a valuable resource that significantly expands the knowledge of HBV-related HCC and may eventually benefit clinical practice.

9.
Dalton Trans ; 48(39): 14783-14791, 2019 Oct 07.
Artigo em Inglês | MEDLINE | ID: mdl-31552973

RESUMO

Considerable efforts have been directed towards constructing high-efficiency, earth-abundant and low-cost photocatalysts for hydrogen evolution under visible light irradiation. In this work, 2D ultrathin CoP-decorated bimetallic MnxCd1-xS photocatalysts were developed based on the combined strategies of controllable band structure and co-catalyst modification. An optimal H2 production rate of 65 324 µmol g-1 h-1 was obtained for the Mn0.5Cd0.5S/CoP-4% sample under visible light irradiation, which was 4.26 times higher than that of pure Mn0.5Cd0.5S as well as 38.7 times that of pure CdS. UV-vis and MS characterization results showed that the introduction of Mn into CdS could change the band potential towards a more negative direction, which would be beneficial for water reduction. Moreover, the added CoP could act as a co-catalyst to facilitate the electron transfer and restrain the recombination of photogenerated electron-hole pairs, which was testified by photocurrent, PL and EIS analyses. This work paves the way to offer a new direction towards designing efficient photocatalysts for hydrogen evolution.

10.
Med Sci Monit ; 25: 7169-7174, 2019 Sep 24.
Artigo em Inglês | MEDLINE | ID: mdl-31548540

RESUMO

BACKGROUND The present study assessed and compared the diagnostic accuracy of elastography (acoustic radiation force impulse, ARFI) with that of Wisteria floribunda agglutinin-positive Mac-2-binding protein (WFA⁺-M2BP) for estimating the stage of hepatic fibrosis in chronic liver disease patients. MATERIAL AND METHODS This retrospective cross-sectional study enrolled 70 chronic liver disease patients who underwent hepatectomy for hepatic tumors. ARFI and WFA⁺-M2BP serum level, underlying liver disease, and laboratory data for all patients were recorded. The stage of fibrosis was determined from a surgical specimen. The area under the receiver operating characteristic (ROC) curves (AUC) was measured to compare the diagnostic accuracy. RESULTS The ARFI and serum WFA⁺-M2BP levels had good performances for detecting severe fibrosis (≥F3). The AUC in characterization of fibrosis stage ≥F3 was 0.79 for ARFI and 0.71 for serum WFA⁺-M2BP levels. When comparing the diagnostic performances between ARFI and serum WFA⁺-M2BP levels for the severity of fibrosis stage, no significant differences were found. Then all patients were divided into 2 subgroups, the AUC for serum WFA⁺-M2BP levels was higher in the hepatitis C virus (HCV) subgroup than in the hepatitis B virus (HBV) subgroup when characterizing fibrosis stages ≥F3. CONCLUSIONS WFA⁺-M2BP is an accurate biomarker and is as good as ARFI in detecting severe fibrosis for chronic liver disease patients.

11.
Int Heart J ; 60(5): 1168-1175, 2019 Sep 27.
Artigo em Inglês | MEDLINE | ID: mdl-31484876

RESUMO

The aims of the present study were to investigate the effects of angiotensin receptor neprilysin inhibitors (ARNi) on the susceptibility of ventricular arrhythmias (VAs) in rats with myocardial infarction (MI) and to explore the related mechanisms.A total of 32 adult male Sprague-Dawley rats were divided into 3 groups: a control group, MI group, and MI+ARNi group. MI was generated by ligation of the left anterior descending coronary artery. ARNi was given at 68 mg/kg/day for 4 weeks after MI surgery. At 4 weeks after MI, electrical programmed stimulation (EPS) was performed in all groups for the evaluation of VAs, and echocardiography was used to evaluate cardiac function. Indicators of sympathetic neural remodeling and cardiac remodeling were detected to further explore the related mechanisms.Four weeks after MI, rats in the ARNi group exhibited low susceptibility of VAs in comparison with that in the MI group, which was coincident with the attenuation of sympathetic nerve remodeling, amelioration of cardiac fibrosis, and regulation of Cx43 expression.ARNi is effective in reducing VAs in rats with ischemic cardiomyopathy, which is associated with attenuating sympathetic nerve remodeling and myocardial fibrosis.


Assuntos
Conexina 43/metabolismo , Infarto do Miocárdio/tratamento farmacológico , Neprilisina/farmacologia , Taquicardia Ventricular/tratamento farmacológico , Remodelação Ventricular/efeitos dos fármacos , Animais , Biópsia por Agulha , China , Modelos Animais de Doenças , Ecocardiografia/métodos , Imuno-Histoquímica , Masculino , Contração Miocárdica/efeitos dos fármacos , Infarto do Miocárdio/diagnóstico por imagem , Infarto do Miocárdio/patologia , Distribuição Aleatória , Ratos , Ratos Sprague-Dawley , Fatores de Risco , Taxa de Sobrevida , Sistema Nervoso Simpático/efeitos dos fármacos , Taquicardia Ventricular/diagnóstico por imagem
12.
FASEB J ; 33(11): 12528-12540, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31450968

RESUMO

Mumps virus (MuV) has high tropism to the testis and may lead to male infertility. Sertoli cells are the major targets of MuV infection. However, the mechanisms by which MuV infection impairs male fertility and Sertoli cell function remain unclear. The present study elucidated the effect of MuV infection on the blood-testis barrier (BTB). The transepithelial electrical resistance of MuV-infected mouse Sertoli cells was monitored, and the expression of major proteins of the BTB was examined. We demonstrated that MuV infection disrupted the BTB by reducing the levels of occludin and zonula occludens 1. Sertoli cells derived from Tlr2-/- and Tnfa-/- mice were analyzed for mediating MuV-induced impairment. TLR2-mediated TNF-α production by Sertoli cells in response to MuV infection impaired BTB integrity. MuV-impaired BTB was not observed in Tlr2-/- and Tnfa-/- Sertoli cells. Moreover, an inhibitor of TNF-α, pomalidomide, prevents the disruption of BTB in response to MuV infection. FITC-labeled biotin tracing assay confirmed that BTB permeability and spermatogenesis were transiently impaired by MuV infection in vivo. These findings suggest that the disruption of the BTB could be one of the mechanisms underlying MuV-impaired male fertility, in which TNF-α could play a critical role.-Wu, H., Jiang, X., Gao, Y., Liu, W., Wang, F., Gong, M., Chen, R., Yu, X., Zhang, W., Gao, B., Song, C., Han, D. Mumps virus infection disrupts blood-testis barrier through the induction of TNF-α in Sertoli cells.

13.
J Matern Fetal Neonatal Med ; : 1-9, 2019 Aug 11.
Artigo em Inglês | MEDLINE | ID: mdl-31402727

RESUMO

Objectives: To explore the feasibility of applying smart-planes fetal heart (S-Planes FH) to 3D volumes to generate and display the outflow tract views (OFTVs) and evaluate its agreement and reliability in determining fetal vessel dimensions. Methods: A total of 147 normal fetuses in the second or third trimester were enrolled. Once conventional 2D sonographic examination was finished, one or more 3D static volumes were then acquired in the 4-chamber view (4CV). The OFTVs automatically generated and displayed via a simple offline operation using S-Planes FH software. Per fetus, a single qualified S-Planes FH image was selected by an expert. The inner diameters of the aorta (AO) and pulmonary artery (PA) were measured in 2D and S-Planes FH images, respectively. The agreement and reliability of the two methods were verified by the Bland-Altman method and the intraclass correlation coefficient (ICC), respectively. Results: A total of 515 3D static volumes were successfully acquired in 147 fetuses. The OFTVs were generated and displayed using S-Planes FH in 138 (93.9%) cases. S-Planes FH had good agreement in measuring the diameters of great arteries (95% CI of limits, -0.9419 to 1.1464 for AO diameter, -0.8871 to 1.7007 for PA diameter). The intraobserver and interobserver ICCs in this study were greater than 0.81, indicating almost perfect reliability of the two methods with regard to observers. Conclusions: S-Planes FH software is a feasible method for generating OFTVs as well as determining vessel dimensions in the second and third trimesters and had good agreement with 2D examination. Therefore, it possesses clinical value in screening for CHD and can be operated by different sonographers.

14.
Ann Palliat Med ; 8(4): 442-450, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31452376

RESUMO

BACKGROUND: To assess the subjective concordance on mental health service needs in hospitalized patients between patients and doctors in China. METHODS: A cross-sectional study was performed in one day. All hospitalized inpatients from selected departments of West China Hospital were recruited as potential participants. A questionnaire set including demographic variables and the Patient Health Questionnaire-9 (PHQ-9) and Generalized Anxiety Disorder 7-item scale (GAD-7) questionnaires were completed by the included patients. They and their doctors in-charge were asked if they perceived that the patients needed mental health services. RESULTS: The overall response rate in patients was 84.25% and the final sample consisted of 1,273 patients. Among those, 605 patients (47.53%) themselves believed that they needed mental health services, whereas only 345 patients (27.10%) were deemed to be in need of mental health services only by their doctors. Kappa statistics showed that the concordance rate between patients and doctors was low in the total patient group (kappa =0.055) and in the group of patients with significant depression or anxiety (kappa =0.080). A logistic regression analysis showed that the ward where the patients were treated was related to a consistent recognition of mental health needs (OR =1.667). CONCLUSIONS: The concordance between Chinese inpatient perception and doctor evaluation of mental health service needs for these patients was low. Therefore, it seems necessary to develop effective strategies to improve the detection rate, such as the use of screening-instruments and the training of health professionals in the detection of psycho-social distress.

15.
Fish Shellfish Immunol ; 93: 871-878, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31400510

RESUMO

Edwardsiella piscicida is an important pathogen that infects a wide range of hosts, from fish to human. Its infection leads to extensive losses in a diverse array of commercially important fish, like Japanese flounder, turbot, and tilapia. During the infection, type III secretion system (T3SS) and type VI secretion system (T6SS) of E. piscicida play significant roles, but how T3SS and T6SS cooperatively contribute to its virulence is still unknown. In this study, we first examined the roles of T3SS and T6SS in different processes during E. piscicida infection of host cells, and revealed that T3SS of E. piscicida is responsible for promoting bacterial invasion, the following intracellular replication and inducing cell death in host cells, while T6SS restrains E. piscicida intracellular replication and cell death in J774A.1 cells, which suggested that T3SS and T6SS antagonistically concert E. piscicida infection. Furthermore, we found an significant decrease in transcription level of IL-1ß in zebrafish kidney infected with T3SS mutant and an drastically increase in transcription level of TNF- α infected with T6SS mutant when compared with the wild-type. Interestingly, both T3SS and T6SS mutants showed significant attenuated virulence in the zebrafish infection model when compared with the wild-type. Finally, considering the cooperative role of T3SS and T6SS, we generated a mutant strain WEDΔT6SS based on the existing live attenuated vaccine (LAV) WED which showed improved vaccine safety and comparable immune protection. Therefore, WEDΔT6SS could be used as an optimized LAV in the future. Taken together, this work suggested a bilateral role of T3SS and T6SS which respectively act as spear and shield during E. piscicida infection, together contribute to E. piscicida virulence.

16.
Small ; 15(38): e1902686, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31271518

RESUMO

The clustered regularly interspaced short palindromic repeats (CRISPR)/associated nuclease (Cas) system is an efficient gene editing tool. In this study, it is found that both single guide RNA (gRNA) and Cas9 protein could be exported from the CRISPR/Cas9-expressing cells by endogenous exosomes independently. Further experiments demonstrate that these naturally produced endogenous exosomes could be used as a vehicle to deliver the functional Cas9 and hepatitis B virus (HBV)-specific gRNA to cut HBV DNA transfected in HuH7 cells or human papilloma virus (HPV)-specific gRNA to cut the integrated HPV DNA in HeLa cells, respectively. In conclusion, this study indicates the potential of endogenous exosomes as a safe and effective delivery vehicle of the functional gRNA and Cas9 protein. Meanwhile, the endogenous exosomes-mediated delivery of gene editing activity to adjacent and distant cells or tissues may further complicate the off-target and safety concerns about the CRISPR/Cas9 system.

17.
Biomed Pharmacother ; 118: 109243, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31349140

RESUMO

BACKGROUND: Myocardial remodeling is the key step in the development of ischemic cardiomyopathy. We aimed to compare effects of renal denervation (RDN) with those of angiotensin receptor neprilysin inhibitors (ARNi) on cardiac remodeling after myocardial infarction (MI), and explore underlying mechanism. METHODS: Sprague-Dawley rats (n = 40; male) were subjected to ligation of left anterior descending coronary artery to induce MI; six rats served as controls. ARNi was administered at a dose of 60 mg/kg/day for 4 weeks starting 1 week after MI. An RDN/Sham-RDN procedure was performed 1 week after MI. Rats in all groups were studied 5 weeks after MI. Echocardiography was used to evaluate cardiac function. Masson staining and TUNEL staining were used to determine the extent of cardiac remodeling. Indicators of oxidative stress in heart and brain were used to analyze the potential mechanisms involved. RESULTS: Five weeks after MI, both RDN and ARNi significantly improved cardiac function and cardiac remodeling; however, RDN was superior to ARNi at attenuating myocardial apoptosis. Compared to ARNi, RDN was also more effective at decreasing the abnormal oxidative stress caused by MI; this was especially true in case of the brain and was confirmed by evaluating the changes in reactive oxygen species (ROS) levels and other oxidative stress parameters following MI. CONCLUSIONS: RDN is not inferior to ARNi with respect to the improvement of cardiac remodeling in rats with ischemic cardiomyopathy. The effect of RDN might be associated with effective inhibition of oxidative stress in both the heart and brain.

18.
Cancer Res ; 79(17): 4387-4398, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31289136

RESUMO

Gastric cancer is the third leading cause of cancer-related death worldwide. The regulatory mechanisms underlying gastric cancer cell proliferation are largely unclear. Here, we show that the transcription factor GFI1 is associated with advanced clinical gastric cancer progression and promoted gastric cancer cell proliferation partially through inhibition of gastrokine-2 (GKN2) transcription. GFI1 was a degrading substrate of FBXW7, whose loss was observed in gastric cancer. Mechanistically, GSK3ß-mediated GFI1 S94/S98 phosphorylation triggered its interaction with FBXW7, resulting in SCFFBXW7-mediated ubiquitination and degradation. A nondegradable GFI1 S94A/S98A mutant was more potent in driving gastric cancer cell proliferation and tumorigenesis than wild-type GFI1. Overall, this study reveals the oncogenic role of GFI1 in gastric cancer and provides mechanistic insights into the tumor suppressor function of FBXW7. SIGNIFICANCE: These findings demonstrate the oncogenic role of the transcription factor GFI1 and the tumor suppressive function of FBXW7 in gastric cancer.

19.
Int J Biol Sci ; 15(7): 1440-1451, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31337974

RESUMO

Chronic obstructive pulmonary disease (COPD) is a common disease characterized by persistent airflow limitation. Pulmonary vascular endothelial barrier injury and inflammation are increasingly considered to be important pathophysiological processes in cigarette smoke extract (CSE)-induced COPD, but the mechanism remains unclear. To identify the cellular mechanism of endothelial barrier injury and inflammation in CSE-treated human umbilical vein endothelial cells (HUVECs), we investigated the effect of the mitochondrion-targeting antioxidant mitoquinone (MitoQ) on endothelial barrier injury and inflammation. We demonstrated that MitoQ restored endothelial barrier integrity by preventing VE-cadherin disassembly and actin cytoskeleton remodeling, as well as decreased inflammation by the NF-κB and NLRP3 inflammasome pathways in endothelial cells. In addition, MitoQ also maintained mitochondrial function by reducing the production of ROS and excess autophagy. Inhibition of autophagy by 3-MA protected against cytotoxicity that was induced by CSE in HUVECs. Overall, our study indicated that mitochondrial damage is a key promoter in the induction of endothelial barrier dysfunction and inflammation by CSE. The protective effect of MitoQ is related to the inhibition of ROS and excess autophagy in CSE-induced HUVEC injury.

20.
ACS Infect Dis ; 5(8): 1306-1316, 2019 Aug 09.
Artigo em Inglês | MEDLINE | ID: mdl-31267737

RESUMO

Toxin-antitoxin (TA) modules widely exist in bacteria, and their activities are associated with the persister phenotype of the pathogen Mycobacterium tuberculosis (M. tb). M. tb causes tuberculosis, a contagious and severe airborne disease. There are 10 MazEF TA systems in M. tb that play important roles in stress adaptation. How the antitoxins antagonize toxins in M. tb or how the 10 TA systems crosstalk to each other are of interest, but the detailed molecular mechanisms are largely unclear. MazEF-mt9 is a unique member among the MazEF family due to its tRNase activity, which is usually carried out by the VapC toxins. Here, we present the cocrystal structure of the MazEF-mt9 complex at 2.7 Å. By characterizing the association mode between the TA pairs through various techniques, we found that MazF-mt9 bound not only its cognate antitoxin but also the noncognate antitoxin MazE-mt1, a phenomenon that could be also observed in vivo. Based on our structural and biochemical work, we propose that the cognate and heterologous interactions among different TA systems work together in vivo to relieve the toxicity of MazF-mt9 toward M. tb cells.

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