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2.
Sheng Li Xue Bao ; 73(4): 539-550, 2021 Aug 25.
Artigo em Chinês | MEDLINE | ID: mdl-34405210

RESUMO

The article aims to study the effect and mechanism of shear stress on eicosanoids produced by the metabolism of polyunsaturated fatty acids in endothelial cells. First, human umbilical vein endothelial cells were treated by control (Static), laminar shear stress (LSS) and oscillatory shear stress (OSS) for 6 h. Then the endothelial cells were incubated with fresh M199 medium for 3 h, and the cell culture medium was collected. Ultra-performance liquid chromatography-mass spectrometer was used to detect the level of eicosanoid metabolites secreted by endothelial cells. The results showed that under different shear stress, the level of eicosanoid metabolites were changed significantly. We found 10 metabolites were significantly up-regulated by OSS compared with those in LSS group, including PGD2, PGE2, PGF2α and PGJ2 produced by cyclooxygenase; 11-HETE, 15-HETE, 13-HDoHE produced by lipoxygenase or spontaneous oxidation; 12,13-EpOME, 9,10-EpOME, 9,10-DiHOME produced by cytochrome P450 oxidase and soluble epoxide hydrolase. The transcription levels of these up-regulated eicosanoids metabolic enzyme-related genes were also increased in vitro and in vivo. These results indicate that OSS may promote the increase of metabolites by up-regulating the transcription level of metabolic enzyme-related genes, which playing a key role in the development of atherosclerosis. This study reveals the effect of shear stress on eicosanoid metabolism in endothelial cells, which provides a novel supplement to the systems biology approach to study systemic hemodynamics.


Assuntos
Eicosanoides , Metabolômica , Células Cultivadas , Células Endoteliais da Veia Umbilical Humana , Humanos , Estresse Mecânico
3.
Sheng Li Xue Bao ; 73(4): 551-558, 2021 Aug 25.
Artigo em Chinês | MEDLINE | ID: mdl-34405211

RESUMO

Nonalcoholic fatty liver disease (NAFLD) and hyperhomocysteinemia (HHcy) both are major health problems worldwide, whose incidence are closely related with each other. We previously reported the mechanism of HHcy-caused hepatic steatosis, but the role of n-3 polyunsaturated fatty acid (n-3 PUFA) in HHcy-induced hepatic steatosis remains unclear. In this study, 6-week-old C57BL/6 male mice were given a high methionine diet (HMD, 2% methionine diet), and plasma homocysteine levels were measured by ELISA to confirm the establishment of an HHcy model. Meantime, mice were fed HMD with or without n-3 PUFA supplement for 8 weeks to determine the role and mechanism of n-3 PUFA in hepatic steatosis induced by HHcy. Results showed that n-3 PUFA significantly improved hepatic lipid deposition induced by HHcy. qRT-PCR analysis demonstrated that n-3 PUFA inhibited the upregulation of Cd36, a key enzyme of fatty acid uptake, caused by HHcy. Further, the inhibition of hepatic Cd36 expression was associated with the inactivation of aryl hydrocarbon receptor (Ahr) induced by n-3 PUFA. Of note, mass spectrometry revealed that hepatic content of lipoxin A5 (LXA5) was significantly increased in HMD+n-3 PUFA-fed mice compared with that in HMD-fed mice. In primary cultured hepatocytes, LXA5 treatment markedly reversed homocysteine-evoked Cd36 upregulation and Ahr activation, which resulted in reduced lipid accumulation. In conclusion, we demonstrate that n-3 PUFA inactivates HHcy-induced Ahr-Cd36 pathway by increasing hepatic LXA5 content, which alleviates hepatic steatosis. Thus, our results may provide a potential strategy for treatment of NAFLD.


Assuntos
Ácidos Graxos Ômega-3 , Fígado Gorduroso , Hiper-Homocisteinemia , Animais , Fígado Gorduroso/tratamento farmacológico , Hiper-Homocisteinemia/complicações , Hiper-Homocisteinemia/tratamento farmacológico , Fígado , Masculino , Camundongos , Camundongos Endogâmicos C57BL
4.
Free Radic Biol Med ; 173: 7-18, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34252540

RESUMO

Myocardial ischemia/reperfusion injury (MIRI) is closely related to oxidative stress. However, the redox environment of the heart has not been evaluated thoroughly after MIRI, which limits precise redox intervention. In this study, we developed the redox environment metabolomic evaluation (REME) method to analyze the redox metabolites of the heart after MIRI. Based on the targeted metabolomics strategy, we established a detection panel for 22 redox-related molecules, including the major redox couples nicotinamide adenine dinucleotide (NADH/NAD+), nicotinamide adenine dinucleotide phosphate (NADPH/NADP+), and glutathione/glutathione disulfide (GSH/GSSG), reactive oxygen and nitrogen species-related molecules, and some lipid peroxidation products. The high sensitivity and specificity of the method make it suitable for evaluating the endogenous redox environment. The REME method showed that the heart tissue in a MIRI mouse model had a different redox profile from that in the control group. Different redox species changed in different ways. The ratios of GSSG/GSH and NADP+/NADPH increased, but the levels of both NAD+ and NADH decreased in the risk area of the infarcted heart after reperfusion. In addition, some reactive nitrogen species-related metabolites (tetrahydrobiopterin, arginine, and S-nitrosoglutathione) decreased and some lipid peroxides (4-hydroxy-2-nonenal, 4-hydroxy-2-hexenal, and benzaldehyde) increased. The redox metabolites GSH, GSSG, NADPH, NAD+, S-nitrosoglutathione, arginine, and tetrahydrobiopterin had a positive correlation with the ejection fraction and a negative correlation with the level of lactate dehydrogenase in plasma. In summary, we achieved a comprehensive, systemic understanding of the changes in the redox environment after MIRI. Our REME method could be used to evaluate the redox environment in other processes.


Assuntos
Traumatismo por Reperfusão Miocárdica , Animais , Dissulfeto de Glutationa/metabolismo , Metabolômica , Camundongos , NADP/metabolismo , Oxirredução
5.
Hematology ; 26(1): 518-528, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34314648

RESUMO

OBJECTIVE: Hypomethylating agents (HMAs) have been reported to target the Sonic Hedgehog (Shh) signaling pathway in myelodysplastic syndrome (MDS). However, the synergistic inhibitory effect of Smo inhibitor jervine and its combination with decitabine in MUTZ-1 cell lines remains lacking. METHODS: We used a CCK-8 assay to detect the in-vitro proliferation rate of MUTZ-1 cell lines. Besides, the Annexin V-FITC/PI double staining flow cytometry was utilized to detect the apoptosis rate and cell cycle changes. The expression levels of mRNA were quantified by using qRT-PCR, and the western blot was employed to detect the expression of proteins. RESULTS: We found that the single-agent jervine or decitabine can significantly inhibit the proliferation rate of MUTZ-1 cell lines, and this inhibitory effect is time-dependent and concentration-dependent. The combined intervention of the jervine and decitabine can more significantly inhibit cell proliferation, induce cell apoptosis, and block the G1 phase of the cell cycle. The combined intervention of the two drugs significantly reduced Smo and G1i-1 mRNA expression in MUTZ-1 cells. Furthermore, after combining both of the drug treatments, the proteins levels of Smo, G1i-1, PI3K, p-AKT, Bcl2, and Cyclin Dl were significantly downregulated, and Caspase-3 is upregulated, indicating that jervine with its combination of decitabine might be effective for controlling the proliferation, apoptosis, and cell cycle. CONCLUSION: The Smo inhibitor jervine and its combination with decitabine have a synergistic effect on the proliferation, cell cycle, and apoptosis of MUTZ-1 cells, and its mechanism may be achieved by interfering with the Shh signaling pathway.


Assuntos
Decitabina/farmacologia , Proteínas Hedgehog/metabolismo , Transdução de Sinais/efeitos dos fármacos , Receptor Smoothened/antagonistas & inibidores , Alcaloides de Veratrum/farmacologia , Apoptose/efeitos dos fármacos , Ciclo Celular/efeitos dos fármacos , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Relação Dose-Resposta a Droga , Sinergismo Farmacológico , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Síndromes Mielodisplásicas/tratamento farmacológico , Síndromes Mielodisplásicas/metabolismo , Síndromes Mielodisplásicas/patologia , Receptor Smoothened/genética , Receptor Smoothened/metabolismo , Proteína GLI1 em Dedos de Zinco/genética , Proteína GLI1 em Dedos de Zinco/metabolismo
6.
FEBS J ; 2021 Jun 26.
Artigo em Inglês | MEDLINE | ID: mdl-34174031

RESUMO

Heart disease, including coronary artery disease, myocardial infarction, heart failure, cardiac hypertrophy, and cardiomyopathies, is the leading causes of death worldwide. The Hippo pathway is a central controller for organ size and tissue growth, which plays a pivotal role in determining cardiomyocytes and nonmyocytes proliferation, regeneration, differentiation, and apoptosis. In this review, we summarize the effects of the Hippo pathway on heart disease and propose potential intervention targets. Especially, we discuss the molecular mechanisms of the Hippo pathway involved in maintaining cardiac homeostasis by regulating cardiomyocytes and nonmyocytes function in the heart. Based on this, we conclude that the Hippo pathway is a promising therapeutic target for cardiovascular therapy, which will bring new perspectives for their treatments.

7.
Cell Transplant ; 30: 963689721999615, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33745341

RESUMO

The number of HLA-haploidentical allogeneic hematopoietic stem-cell transplantation (Haplo-HSCT) is increasing. Comparative studies about Haplo-HSCT versus allo-HSCT with HLA-matched sibling donors (MSD-HSCT) have been tried in leukemias and B-cell lymphomas. Few studies were reported in Peripheral T-cell lymphomas (PTCLs). We performed a multicenter retrospective study about 52 patients with PTCLs undergoing Haplo-HSCT (n = 20) or MSD-HSCT (n = 32). All Haplo-HSCT recipients received antithymocyte globulin (ATG) based graft versus host disease (GVHD) prophylaxis. The median follow-up for all survivors was 38 months. The 100-day cumulative incidence of grade II to IV acute GVHD was similar (19% in the MSD-HSCT group versus 28% in the Haplo-HSCT group, P = 0.52). The 2-year cumulative incidence of chronic GVHD (limited and extensive) after Haplo-HSCT (30%) was also similar with that in the MSD-HSCT group (50%, P = 0.15). The 3-year relapse rates (33% vs 27%, P = 0.84) and non-relapse mortality (21% vs 22%, P = 0.78) did not differ between these two groups. There were also no differences in 3-year overall survival (OS) (48% vs 50%, P = 0.78) and progression-free survival (47% vs 51%, P = 0.95) between these two groups. On multivariate analysis, prognostic index for T-cell lymphoma (PIT) score (higher than 1: hazard ratio [HR], 4.0; P = 0.003) and disease status (stable or progression disease before HSCT: HR, 2.8; P = 0.03) were independent variables associated with worse OS. We concluded that ATG-based haplo-HSCT platform could work as an alternative to MSD-HSCT for patients with PTCLs.

8.
J Leukoc Biol ; 110(1): 53-59, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-33600023

RESUMO

Sphingolipids metabolism is an important cell process and plays critical roles in asthma. However, the involvement of sphingolipids in the pathogenesis of asthma and its subtypes is unknown. The present study aimed to determine the role of sphingolipids in asthma and its subtypes. Clinical data from 51 asthma patients and 9 healthy individuals were collected and serum samples were performed to analyze the levels of serum sphingolipids by liquid chromatography-mass spectrometry-based targeted metabolomics. Results showed that the levels of sphingomyelin (SM) including SM34:2, SM38:1, and SM40:1 were significantly decreased in asthmatic patients compared to healthy controls. Moreover, serum SM levels were obviously decreased in the blood noneosinophilic asthma (bNEA) group compared with blood eosinophilic asthma group. Similar tendencies of serum SM level changes were observed in the early-onset group compared with late-onset group. Correlation analysis revealed that SM 40:1 was negatively related to sputum IL-17A (r = -0.621, P = 0.042). The present study presented that the SM may be a protective factor of asthma and contributes to the mechanism of asthma, especially bNEA. SM may be a potential biomarker and therapeutic target in asthma.


Assuntos
Asma/sangue , Biomarcadores , Esfingolipídeos/sangue , Asma/diagnóstico , Asma/tratamento farmacológico , Asma/etiologia , Estudos de Casos e Controles , Gerenciamento Clínico , Suscetibilidade a Doenças , Eosinófilos/patologia , Humanos , Contagem de Leucócitos , Metabolismo dos Lipídeos , Terapia de Alvo Molecular , Eosinofilia Pulmonar/patologia
9.
Work ; 68(3): 871-879, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33612530

RESUMO

BACKGROUND: An isolated robot must take account of uncertainty in its world model and adapt its activities to take into account such as uncertainty. In the same way, a robot interaction with security and privacy issues (RISAPI) with people has to account for its confusion about the human internal state, as well as how this state will shift as humans respond to the robot. OBJECTIVES: This paper discusses RISAPI of our original work in the field, which shows how probabilistic planning and system theory algorithms in workplace robotic systems that work with people can allow for that reasoning using a security robot system. The problem is a general way as an incomplete knowledge 2-player game. RESULTS: In this general framework, the various hypotheses and these contribute to thrilling and complex robot behavior through real-time interaction, which transforms actual human subjects into a spectrum of production systems, robots, and care facilities. CONCLUSION: The models of the internal human situation, in which robots can be designed efficiently, are limited, and achieve optimal computational intractability in large, high-dimensional spaces. To achieve this, versatile, lightweight portrayals of the human inner state and modern algorithms offer great hope for reasoning.


Assuntos
Robótica , Algoritmos , Humanos , Privacidade , Local de Trabalho
10.
Sci China Life Sci ; 64(3): 404-418, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32804340

RESUMO

Targeting the white-to-brown fat conversion is important for developing potential strategies to counteract metabolic diseases; yet the mechanisms are not fully understood. Yes-associated-protein (YAP), a transcription co-activator, was demonstrated to regulate adipose tissue functions; however, its effects on browning of subcutaneous white adipose tissue (sWAT) are unclear. We demonstrated that YAP was highly expressed in cold-induced beige fat. Mechanistically, YAP was found as a target gene of miR-429, which downregulated YAP expression in vivo and in vitro. In addition, miR-429 level was decreased in cold-induced beige fat. Additionally, pharmacological inhibition of the interaction between YAP and transcriptional enhanced associate domains by verteporfin dampened the browning of sWAT. Although adipose tissue-specific YAP overexpression increased energy expenditure with increased basal uncoupling protein 1 expression, it had no additional effects on the browning of sWAT in young mice. However, we found age-related impairment of sWAT browning along with decreased YAP expression. Under these circumstances, YAP overexpression significantly improved the impaired WAT browning in middle-aged mice. In conclusion, YAP as a regulator of sWAT browning, was upregulated by lowering miR-429 level in cold-induced beige fat. Targeting the miR-429-YAP pathway could be exploited for therapeutic strategies for age-related impairment of sWAT browning.

11.
J Fluoresc ; 31(1): 63-71, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33070269

RESUMO

Herein, an effective pyrene excimer signaled fluorescent biosensor for the determination of tetracycline based on triple-helix aptamer probe (TAP) and supramolecular inclusion of cyclodextrin was reported. The TAP was devised containing an aptamer loop, two DNA segment stems and a triplex-forming oligonucleotide (signal probe) labeled with pyrenes at 5' and 3' ends. The presence of target could result in its binding towards aptamer with a mighty affinity, leading to a conformation change of the TAP and whereupon the release of the signal probe. This liberty of signal probe enabled the formation of pyrene excimer, generating fluorescence signals. Further, signal amplification was fulfilled through the addition of γ-cyclodextrin which could interact with pyrene dimer, thus leading to an enhanced "on-state" of the sensing ensemble. In contrast, when the target was absent, the sensing ensemble remained "off-state" because of the long distance between two pyrene molecules. When the conditions were properly optimized, the increasing signal kept a linear dependence on target concentrations ranging from 5.0 nM to 100 nM, and the detection limit reached as low as 1.6 nM. In this way, a newly-constructed, simple, and economically affordable protocol enjoys desirable efficiency, sensitivity, specificity in biosensing. Also, its universality as another attractive behalf in assaying diverse targets was envisioned with only the need of matched aptamer replacement.


Assuntos
Aptâmeros de Nucleotídeos/química , Ciclodextrinas/química , Limite de Detecção , Espectrometria de Fluorescência , Tetraciclina/análise , Tetraciclina/química
12.
Diagn Microbiol Infect Dis ; 99(3): 115263, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33248418

RESUMO

This study aimed to characterize molecular mechanism of 3 Salmonella enterica strains and novel mobile genetic elements identified in them. The strains, designated SW1, SW39, and SW109084, were obtained from diarrhea patients. The results of susceptibility testing showed SW39 was nonsusceptible to imipenem and cefotaxime. Whole genome sequencing was performed on Illumina HiSeq platform. Multilocus-sequence typing revealed SW1 belonged to ST2529 which was first confirmed in S. enterica, SW109084 was ST34 which was first reported in Enteritidis and SW39 was ST19. Resistome analysis showed SW1, SW109084, and SW39 carried 14, 19, and 17 antibiotic resistance genes. Seven transposons and 4 integrons were confirmed in these strains. Notably, a novel In6- and In7-like class 1 integron designated InSW39 and a novel transposon Tn5393k were identified in plasmid pSW39. The study of genomics and resistance in S. enterica plays a significant role in prevention and treatment of Salmonella infections.


Assuntos
Antibacterianos/farmacologia , Elementos de DNA Transponíveis/genética , Imipenem/farmacologia , Integrons/genética , Salmonella typhimurium/efeitos dos fármacos , Salmonella typhimurium/genética , Técnicas de Tipagem Bacteriana , China , DNA Bacteriano/genética , Diarreia/microbiologia , Farmacorresistência Bacteriana Múltipla/genética , Humanos , Testes de Sensibilidade Microbiana , Tipagem de Sequências Multilocus , Plasmídeos/genética , Infecções por Salmonella/microbiologia , Sequenciamento Completo do Genoma
13.
Zhongguo Zhong Yao Za Zhi ; 45(18): 4349-4357, 2020 Sep.
Artigo em Chinês | MEDLINE | ID: mdl-33164362

RESUMO

The plants of genus Clinopodium are perennial herbs of Labiatae, which are widely distributed in the world and have a promising medicinal value. Modern researches have shown flavonoids, triterpenoid saponins, terpene glycosides, terpenoids, volatile oils and phenylpropanoids are the main compounds in the plants, presenting various pharmacological effects such as hemostasis, anti-bacteria, anti-inflammation, immunoregulation, reducing blood glucose, antioxidation, and anti-tumor effects. The preparations made of those plants are mainly used for treatment of various bleeding diseases in clinical application. In this review, we systematically summarized the research progress on taxonomy, resource distribution, chemical compositions, pharmacological activities, and clinical application of the medicinal plants of genus Clinopodium. This review provides references and scientific basis for further research and development of genus Clinopodium.


Assuntos
Lamiaceae , Plantas Medicinais , Flavonoides , Compostos Fitoquímicos , Extratos Vegetais
14.
Zhongguo Shi Yan Xue Ye Xue Za Zhi ; 28(5): 1637-1642, 2020 Oct.
Artigo em Chinês | MEDLINE | ID: mdl-33067966

RESUMO

OBJECTIVE: To study the expression of Shh singaling related gene, including Shh, Ptch1, Smo and Gli1 in bone marrow CD34+ cells of patients with myelodysplastic syndrome(MDS) and acute myeloid leukemia with myelodysplasia-related changes(AML-MRC), and to explore their clinical significance. METHODS: The count of CD34+ cells in bone marrow was detected by flow cytometry in 53 patients with MDS and 30 patients with AML-MRC. Magnetic beads were used to separate CD34+ cells. The expression of Shh, Ptch1,Smo and Gli1 on CD34+ cells was detected by qRT-PCR, the effect of the 4 gene expression on prognosis of patients in MDS and AML-MRC group was compared, 25 patients with iron-deficiency anemia were used as controls. RESULTS: The expression levels of Shh, Smo and Gli1 of patients in MDS and AML-MRC group were significantly higher than those in control group (P<0.05), moreover increased with disease progression(P<0.05). The expression of Ptch1 was not statistically significantly different between 3 groups(P>0.05). In comparison of prognosis, the expression of Smo and Gli1 in the patients of relatively high risk groups and AML-MRC groups were significantly increased (P<0.05). The median overall survival time of patients in MDS and AML-MRC groups was 12(7.5,16.5) and 6(3.0,9.0) months (P=0.000) respectively. The median survival time of MDS and AML-MRC patients with high expression of Smo and Gli1 was significantly shorter than that of MDS and AML-MRC patients with low expression of Smo and Gli1(P<0.05). CONCLUSION: Shh signaling pathway in the patients with MDS is activated, which is involved in the progress and prognosis of MDS.


Assuntos
Leucemia Mieloide Aguda , Síndromes Mielodisplásicas , Medula Óssea , Células da Medula Óssea , Proteínas Hedgehog , Humanos , Transdução de Sinais
15.
Zhongguo Shi Yan Xue Ye Xue Za Zhi ; 28(4): 1298-1302, 2020 Aug.
Artigo em Chinês | MEDLINE | ID: mdl-32798415

RESUMO

OBJECTIVE: To study the effect of SMO inhibitor (Jervine) on proliferation, apoptosis and cell cycle of MDS cell line MUTZ-1, and its mechanism. METHODS: The effect of different concentrations Jervine on proliferation of MUTZ-1 cells was detected by CCK-8 method. Apoptosis and cell cycle of MUTZ-1 cells were detected by flow cytometry. Western blot was used to detect the changes of Shh signaling pathway effecting proteins BCL2 and CyclinD1. The expression levels of Smo and Gli1 gene were detected by real-time fluorescent quantitative polymerase chain reaction (RT-qPCR). RESULTS: Jervine inhibited MUTZ-1 cell proliferation in a concentration dependent manner (24 h, r=-0.977), the apoptosis rate of MUTZ-1 cells increased with the enhancement of concentration of Jervine in MUTZ-1 cells (P<0.001), the cell proportion of G1 phase increased and the cell number of S phase decreased with enhancement of concentration (P<0.001). The result of RT-qPCR and Western blot showed that the expression of Smo, Gli1 mRNA and BCL2, CyclinD1 proteins decreased (P<0.05). CONCLUSION: SMO inhibitor can effectively inhibit the growth of MDS cell line MUTZ-1 improve the cell apoptosis and induce cell cycle arrest. Its action mechanism may be related with dowm-regulating the expression of BCL2 and CyclinD1.


Assuntos
Proteínas Hedgehog , Síndromes Mielodisplásicas , Apoptose , Linhagem Celular Tumoral , Proliferação de Células , Humanos , Transdução de Sinais , Alcaloides de Veratrum
16.
Preprint em Inglês | medRxiv | ID: ppmedrxiv-20021584

RESUMO

BackgroundSevere ill patients with 2019 novel coronavirus (2019-nCoV) infection progressed rapidly to acute respiratory failure. We aimed to select the most useful prognostic factor for severe illness incidence. MethodsThe study prospectively included 61 patients with 2019-nCoV infection treated at Beijing Ditan Hospital from January 13, 2020 to January 31, 2020. Prognostic factor of severe illness was selected by the LASSO COX regression analyses, to predict the severe illness probability of 2019-CoV pneumonia. The predictive accuracy was evaluated by concordance index, calibration curve, decision curve and clinical impact curve. ResultsThe neutrophil-to-lymphocyte ratio (NLR) was identified as the independent risk factor for severe illness in patients with 2019-nCoV infection. The NLR had a c-index of 0.807 (95% confidence interval, 0.676-0.38), the calibration curves fitted well, and the decision curve and clinical impact curve showed that the NLR had superior standardized net benefit. In addition, the incidence of severe illness was 9.1% in age [≥] 50 and NLR < 3.13 patients, and half of patients with age [≥] 50 and NLR [≥] 3.13 would develop severe illness. Based on the risk stratification of NLR with age, the study developed a 2019-nCoV pneumonia management process. ConclusionsThe NLR was the early identification of risk factors for 2019-nCoV severe illness. Patients with age [≥] 50 and NLR [≥] 3.13 facilitated severe illness, and they should rapidly access to intensive care unit if necessary.

17.
J Cardiovasc Transl Res ; 13(2): 131-141, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-31823221

RESUMO

Deubiquitinases (DUBs) are a major component of the ubiquitin-proteasome system in eukaryotic cells; the system plays a crucial role in many biological processes, such as inflammation, oxidative stress, and cell apoptosis, which are important in vascular biology and pathology. DUBs have drawn significant attention in recent years, and their function is increasingly linked with vascular diseases. In this review, we summarize the indirect and direct evidence for the effects of DUBs on atherosclerosis, abdominal aortic aneurysm, angiogenesis, and hypertension, and point out pathways that could be pursued for investigating DUBs. Intervention in the function of DUBs in vascular diseases has potential therapeutic value.


Assuntos
Vasos Sanguíneos/enzimologia , Enzimas Desubiquitinantes/metabolismo , Doenças Vasculares/enzimologia , Animais , Vasos Sanguíneos/patologia , Vasos Sanguíneos/fisiopatologia , Humanos , Lisina , Transdução de Sinais , Ubiquitinação , Doenças Vasculares/patologia , Doenças Vasculares/fisiopatologia
18.
Hypertension ; 74(4): 936-946, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31378107

RESUMO

Endothelial cells regulate vascular tone by producing both relaxing and contracting factors to control the local blood flow. Hypertension is a common side effect of mTORC1 (mammalian target of rapamycin complex 1) inhibitors. However, the role of endothelial mTORC1 in hypertension remains elusive. The present study aimed to determine the role of endothelial mTORC1 in Ang II (angiotensin II)-induced hypertension and the underlying mechanism. Endothelial mTORC1 activity was increased by Ang II both in vitro and in vivo. Blood pressure was higher in Tie-2-Cre-mediated regulatory associated protein of mTOR (mammalian target of rapamycin; Raptor) heterozygous-deficient (Tie2Cre-RaptorKD) mice than control mice both before and after Ang II infusion. Acetylcholine-evoked endothelium-dependent relaxation of mesenteric arteries was impaired in Tie2Cre-RaptorKD mice. Treatment with indomethacin or a specific COX (cyclooxygenase)-2 inhibitor, NS-398, but not L-NG-nitroarginine methyl ester reduced endothelium-dependent relaxation in Raptorflox/- mice to a similar extent as in Tie2Cre-RaptorKD mice. Metabolomic profiling revealed that the plasma content of prostaglandin E2 was reduced in Tie2Cre-RaptorKD mice with or without Ang II infusion. In endothelial cells, reduction of the protein level of YAP (yes-associated protein) with siRNA-mediated RPTOR deficiency was autophagy dependent and transcriptionally regulated the expression of COX-2 and mPGES-1 (microsomal prostaglandin E synthase-1). Hence, overexpression of YAP in endothelial cells enhanced the mRNA and protein levels of COX-2 and mPGES-1 and reversed the endothelial dysfunction and hypertension in Tie2Cre-RaptorKD mice. The present results demonstrate that suppression of mTORC1 activity in endothelial cells reduces prostaglandin E2 production and causes hypertension by reducing YAP-mediated COX-2/mPGES-1 expression.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Pressão Sanguínea/fisiologia , Endotélio Vascular/metabolismo , Hipertensão/metabolismo , Alvo Mecanístico do Complexo 1 de Rapamicina/metabolismo , Fosfoproteínas/metabolismo , Transdução de Sinais/fisiologia , Angiotensina II , Animais , Pressão Sanguínea/efeitos dos fármacos , Proteínas de Ciclo Celular , Ciclo-Oxigenase 2/metabolismo , Inibidores de Ciclo-Oxigenase/farmacologia , Dinoprostona/metabolismo , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/metabolismo , Endotélio Vascular/efeitos dos fármacos , Hipertensão/induzido quimicamente , Indometacina/farmacologia , Artérias Mesentéricas/efeitos dos fármacos , Artérias Mesentéricas/metabolismo , Camundongos , Prostaglandina-E Sintases/metabolismo , Transdução de Sinais/efeitos dos fármacos , Vasodilatação/efeitos dos fármacos , Vasodilatação/fisiologia
19.
Biosens Bioelectron ; 143: 111613, 2019 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-31450095

RESUMO

Incorporating elements of triple-helix aptamer probes (TAP), catalyzed hairpin assembly (CHA) signal amplification and host-guest recognition, a novel "signal-on" sensing strategy for sensitive electrochemical quantification of tetracycline (TC) was reported unprecedentedly. TAP was formed involving an aptamer loop, two-segment stems and a triplex oligonucleotide serving as trigger probe. Then, the trigger probe would be released from TAP once the target presented due to the conformational variation of TAP induced by aptamer binding event, sparking off the upcoming CHA amplification reaction, in which two coexisting DNA hairpins (H1 and H2 both modified with the electroactive molecules) would hybridize into plentiful H1-H2 double helices. Afterwards, the Exonuclease III was added, demolishing double helices and simultaneously releasing plentiful electroactive molecules which were capable of diffusing onto the electrode surface under the assistance of ß-cyclodextrin due to host-guest recognition, where appreciable signals were enriched and generated. As thus, considerably slight amounts of targets though, emitted trigger probes, yet efficiently engining spectacular CHA cycles of reactions through which amplified signals were yielded, and in turn progressively enabling the sensitive target detection done. Under optimal conditions, the growing signal stayed a linear relation along with the logarithm of the target concentrations ranging from 0.2 nM to 100 nM, the detection limit reaching as low as 0.13 nM. This approach was desirable regarding to sensitivity, detection limit and range, prospectively rendering a service for diverse targets detection by easily replacing the matched aptamer loop of TAP.


Assuntos
Antibacterianos/isolamento & purificação , Técnicas Biossensoriais , Técnicas Eletroquímicas , Tetraciclina/isolamento & purificação , Antibacterianos/química , Aptâmeros de Nucleotídeos/química , DNA/química , Eletrodos , Exodesoxirribonucleases/química , Técnicas de Amplificação de Ácido Nucleico , Tetraciclina/química
20.
Am J Physiol Gastrointest Liver Physiol ; 316(4): G527-G538, 2019 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-30789748

RESUMO

Hepatic steatosis is the beginning phase of nonalcoholic fatty liver disease, and hyperhomocysteinemia (HHcy) is a significant risk factor. Soluble epoxide hydrolase (sEH) hydrolyzes epoxyeicosatrienoic acids (EETs) and other epoxy fatty acids, attenuating their cardiovascular protective effects. However, the involvement of sEH in HHcy-induced hepatic steatosis is unknown. The current study aimed to explore the role of sEH in HHcy-induced lipid disorder. We fed 6-wk-old male mice a chow diet or 2% (wt/wt) high-metnionine diet for 8 wk to establish the HHcy model. A high level of homocysteine induced lipid accumulation in vivo and in vitro, which was concomitant with the increased activity and expression of sEH. Treatment with a highly selective specific sEH inhibitor (0.8 mg·kg-1·day-1 for the animal model and 1 µM for cells) prevented HHcy-induced lipid accumulation in vivo and in vitro. Inhibition of sEH activated the peroxisome proliferator-activated receptor-α (PPAR-α), as evidenced by elevated ß-oxidation of fatty acids and the expression of PPAR-α target genes in HHcy-induced hepatic steatosis. In primary cultured hepatocytes, the effect of sEH inhibition on PPAR-α activation was further confirmed by a marked increase in PPAR-response element luciferase activity, which was reversed by knock down of PPAR-α. Of note, 11,12-EET ligand dependently activated PPAR-α. Thus increased sEH activity is a key determinant in the pathogenesis of HHcy-induced hepatic steatosis, and sEH inhibition could be an effective treatment for HHcy-induced hepatic steatosis. NEW & NOTEWORTHY In the current study, we demonstrated that upregulation of soluble epoxide hydrolase (sEH) is involved in the hyperhomocysteinemia (HHcy)-caused hepatic steatosis in an HHcy mouse model and in murine primary hepatocytes. Improving hepatic steatosis in HHcy mice by pharmacological inhibition of sEH to activate peroxisome proliferator-activated receptor-α was ligand dependent, and sEH could be a potential therapeutic target for the treatment of nonalcoholic fatty liver disease.


Assuntos
Inibidores Enzimáticos/farmacocinética , Epóxido Hidrolases , Ácidos Graxos/metabolismo , Fígado Gorduroso , Hiper-Homocisteinemia , PPAR alfa/metabolismo , Animais , Modelos Animais de Doenças , Descoberta de Drogas , Epóxido Hidrolases/antagonistas & inibidores , Epóxido Hidrolases/metabolismo , Fígado Gorduroso/tratamento farmacológico , Fígado Gorduroso/enzimologia , Fígado Gorduroso/etiologia , Fígado Gorduroso/metabolismo , Hiper-Homocisteinemia/complicações , Hiper-Homocisteinemia/metabolismo , Ligantes , Camundongos , Camundongos Endogâmicos C57BL , Regulação para Cima
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