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1.
Preprint in English | bioRxiv | ID: ppbiorxiv-252973

ABSTRACT

Severe acute respiratory syndrome corona-virus 2 (SARS-CoV-2), the etiologic agent of the coronavirus disease 2019 (COVID-19), has a catastrophic effect on human health and society. Clinical findings indicated that the suppression of innate antiviral immunity, especially the type I and III interferon (IFN) production, contributes to the pathogenesis of COVID-19. However, how SARS-CoV-2 evades antiviral immunity still needs further investigations. Here, we reported that the open reading frame 9b (ORF9b) protein encoded by the SARS-CoV-2 genome inhibits the activation of type I and III IFN response by targeting multiple molecules of innate antiviral signaling pathways. SARS-CoV-2 ORF9b impaired the induction of type I and III IFNs by Sendai virus or the dsRNA mimic poly (I:C). SARS-CoV-2 ORF9b inhibits the activation of type I and III IFNs induced by the components of cytosolic dsRNA-sensing pathways of RIG-I/MDA5-MAVS signaling, including RIG-I, MDA-5, MAVS, TBK1, and IKK{varepsilon} rather than IRF3-5D, the active form of IRF3. SARS-CoV-2 ORF9b also suppressed the induction of type I and III IFNs by TRIF and STING, the adaptor protein of endosome RNA-sensing pathway of TLR3-TRIF signaling and the adaptor protein of cytosolic DNA-sensing pathway of cGAS-STING signaling, respectively. Mechanistically, SARS-CoV-2 ORF9b protein interacts with RIG-I, MDA-5, MAVS, TRIF, STING, TBK1, and prevents TBK1 phosphorylation, thus impeding the phosphorylation and nuclear trans-localization of IRF3 activation. Overexpression of SARS-CoV-2 ORF9b facilitates the replication of the vesicular stomatitis virus. Therefore, SARS-CoV-2 ORF9b negatively regulates antiviral immunity, thus, facilitate virus replication. This study contributes to our understanding of the molecular mechanism of how SARS-CoV-2 impaired antiviral immunity and providing an essential clue to the pathogenesis of COVID-19.

2.
Preprint in English | bioRxiv | ID: ppbiorxiv-222026

ABSTRACT

The coronavirus disease 2019 (COVID-19) caused by Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has quickly spread worldwide and has infected more than ten million individuals. One of the typical features of COVID-19 is that both type I and III interferon (IFN)-mediated antiviral immunity are suppressed. However, the molecular mechanism by which SARS-CoV-2 evades this antiviral immunity remains elusive. Here, we report that the SARS-CoV-2 membrane (M) protein inhibits the production of type I and III IFNs induced by the cytosolic dsRNA-sensing pathway of RIG-I/MDA-5-MAVS signaling. The SARS-CoV2 M protein also dampens type I and III IFN induction stimulated by Sendai virus infection or poly (I:C) transfection. Mechanistically, the SARS-CoV-2 M protein interacts with RIG-I, MAVS, and TBK1 and prevents the formation of a multi-protein complex containing RIG-I, MAVS, TRAF3, and TBK1, thus impeding IRF3 phosphorylation, nuclear translocation, and activation. Consequently, the ectopic expression of the SARS-CoV2 M protein facilitates the replication of vesicular stomatitis virus (VSV). Taken together, the SARS-CoV-2 M protein antagonizes type I and III IFN production by targeting RIG-I/MDA-5 signaling, which subsequently attenuates antiviral immunity and enhances viral replication. This study provides insight into the interpretation of the SARS-CoV-2-induced antiviral immune suppression and sheds light on the pathogenic mechanism of COVID-19.

3.
Article in Chinese | WPRIM (Western Pacific) | ID: wpr-864611

ABSTRACT

Objective:To study effect of rehabilitation training self-efficacy and training compliance of stage nursing intervention Based on the Compliance Curve for hemiplegia patients with Cerebral Infarction.Methods:Totally 116 stroke patients with hemiplegia from July 2017 to June 2018 were Divided into observation groups (January 2018 to June 2018) 60 cases, control group (July 2017 to December 2017) 56 cases. The control group given including health education, psychological intervention, basic nursing, rehabilitation training, complications prevention, follow-up management etc received routine nursing interventions. The observation group combined nursing intervention based on the compliance curve. After 6 months of follow-up, the rehabilitation self-efficacy, rehabilitation training compliance, and rehabilitation effects were compared between two groups.Results:The observation group physical exercise self-efficacy, coping self-efficacy, self-efficacy rehabilitation (SER) in rehabilitation self-efficacy scale was (35.36 ± 4.45), (51.24 ± 6.42), (86.60 ± 9.20) points, which was significantly higher than that control group (30.45 ± 4.56), (42.45 ± 6.34), (72.90 ± 8.45) points, and the difference was statistically significant ( t values were 5.658, 7.145, 8.028, P<0.05 or 0.01) ; The 6-24 week rehabilitation training compliance index curve was a flat line, Physical exercise, exercise effect monitoring, active seeking advice, and rehabilitation training total compliance index were (74.26 ± 8.20), (68.36±7.20), (61.45±7.21), (70.26±8.54) points, which was significantly higher than that of the control group (67.06±7.12), (6.12±7.34), (56.12±6.45), (63.23±7.36) points, and the difference was statistically significant ( t values were 4.845, 5.882, 4.030, 4.556, P<0.05) ; Fugl-Meyer Assessment Scale (FMA), Berg Balance Scale (BBS), Barethl index score were (22.32 ± 4.12), (32.72 ± 5.36), (72.45 ± 8.21) points, which were significantly higher than that in the control group (18.45±3.26), (26.45±4.42), (60.65±7.42) points, and the difference was statistically significant ( t values were 5.370, 6.586, 7.801, P<0.05). Conclusion:Staged nursing intervention based on the compliance curve help to promote the development of rehabilitation self-efficacy, and enhance rehabilitation training compliance behavior, then improve rehabilitation training effect.

4.
Article in Chinese | WPRIM (Western Pacific) | ID: wpr-616580

ABSTRACT

Objective To study the association between renal dysfunction and platelet parameters in elderly patients with early heart failure (HF).Methods 637 patients (350 old-aged and 287 middle-aged) with hypertension,CHD,T2DM admitted to our hospital from January 2013 to December 2014 served as a disease group and 464 subjects (229 old-aged and 235 middle-aged) selected from the 973 Aging Project in September 2007-June 2008 served as a healthy group.Their eGFR and platelets (PLT) were calculated,their plateletcrit (PCT) and mean platelet volume (MPV) were measured.Association between platelet parameters and renal dysfunction was analyzed by binary logistic regression analysis.Results The MPV and PCT were significantly lower in the old-aged disease group than in the old aged healthy group (9.78± 1.45 vs 10.66±0.78,P<0.01;19.79 ± 6.21 vs 21.82 ± 6.04,P<0.01).The PLT and PCT were closely associated with the eGFR in two groups (P<0.05,P<0.01).Binary logistic regression analysis indicated that the median and high PLT in disease group and the median PLT in healthy group were independently associated with renal dysfunction (OR=0.560,95%CI:0.315-0.996;OR=0.480,95%CI:0.262-0.879;OR=0.483,95%CI:0.249-0.936,P<0.05).Conclusion Attention should be paid to the effect of PLT and their functional activity on renal function in treatment of early HF patients because aging-induced change of PLT and their functional activity are associated with renal dysfunction.

5.
Article in Chinese | WPRIM (Western Pacific) | ID: wpr-467191

ABSTRACT

Objective To explore CT and MRI imaging in the application of newly diagnosed esophageal cancer staging.Methods 200 patients with newly diagnosed esophageal cancer were selected as the research object, who voluntarily accepted the chest CT and MRI examination.Newly diagnosed esophageal cancer pathological results and CT,MRI features were observed.Spiral CT,MRI for T staging of esophageal cancer and N staging diagnosis were compared.Results In 200 patients,including 160 cases of squamous cell carcinoma,30 cases of adenocarcinoma, 10 cases of other types,T1 ,T2 ,T3 and T4 clinical staging period were respectively 19 cases,47 cases,81 cases and 53 cases,while N0 and N1 period were 65 cases and 135 cases respectively.The lesion diameter was 10 -22 (16.5 ± 4.6)mm.CT and MRI showed irregular thickening of the esophageal wall,CT showed equal or slightly lower density, T1 WI was MRI or low signal,T2 WI showed a slightly higher signal.Enhanced scanning,a substantial part of lesion enhancement,while the dead part had no enhancement.In T1 ,T2 of the diagnosis of esophageal carcinoma,MRI had higher diagnostic sensitivity and accuracy compared with CT,and the difference was statistically significant (χ2 =4.32,3.89,all P 0.05).By using the joint appli-cation of the two methods,the diagnostic sensitivity and accuracy were significantly higher than that used alone,the difference was statistically significant (χ2 =4.12,3.98,all P 0.05).The combined application of MRI and CT significantly improved the diag-nostic sensitivity and accuracy.Compared with the single application,the difference was statistically significant (χ2 =4.32,4.54,all P <0.05).Conclusion MRI is more sensitive to diagnosis T1 ,T2 stage and N0 ,N1 stage in esopha-geal carcinoma.Combined application of MRI and CT can improve the diagnostic sensitivity and accuracy.

6.
Chinese Circulation Journal ; (12): 910-912, 2014.
Article in Chinese | WPRIM (Western Pacific) | ID: wpr-458663

ABSTRACT

Objective: To study the effect of cytochrome P-450 4F2 (CYP4F2, rs2108622) gene polymorphisms in patients with warfarin for initial doses in 7 days. Methods: A total of 271 patients treated by warfarin were studied. The CYP4F2 gene polymorphisms were assessed by real-time PCR, the average initial warfarin doses in 7 days and the time of international normalized ratio (INR) ifrst arrived to therapeutic range were recorded. The differences of initial warfarin doses and the time of INR ifrst arrived to therapeutic range among CYP4F2 gene polymorphisms of CC, CT and TT genotypes were analyzed by statistical method. Results: The average initial warfarin doses among CYP4F2 polymorphisms of TT and CT/TT were higher than CC, P Conclusion: CYP4F2 polymorphisms inlfuenced the initial warfarin doses in 7 days in relevant patients.

7.
Chinese Medical Journal ; (24): 2571-2577, 2014.
Article in English | WPRIM (Western Pacific) | ID: wpr-241620

ABSTRACT

<p><b>BACKGROUND</b>Whether two clopidogrel pretreatment strategies prior to elective percutaneous coronary intervention (PCI): a 300 mg loading dose (LD) in clopidogrel naїve patients and a 75 mg maintenance dose (MD) once daily in patients on chronic clopidogrel therapy play the same role in the platelet inhibition in Chinese with different CYP2C19 genotypes remains unknown. We aim to evaluate the impact on platelet inhibition by clopidogrel pretreatment strategy and its interaction effect with CYP2C19 genotype.</p><p><b>METHODS</b>Chinese patients undergoing PCI (n = 840) were assigned to 2×2 groups in the trial according to different clopidogrel pretreatment strategies (470 patients in LD, 370 patients in MD) and CYP2C19 genotypes (494 carriers of any CYP2C19 *2 or *3 loss-of-function allele, 346 non-carriers). The primary outcome was platelet aggregation (PA) as measured by the 10 µmol/L adenosine diphosphate induced light transmission aggregation.</p><p><b>RESULTS</b>Compared with MD group, LD strategy showed a significantly higher PA-((59.22 ± 11.67)% vs. (52.83 ± 12.17)%, P < 0.01), similar PA difference was observed in CYP2C19 loss-of-function carriers compared with non-carriers ((59.41 ± 10.91)% vs. (52.10 ± 12.90)%, P < 0.01). LD patients in either the CYP2C19 loss-of-function allele carrier or non-carrier group showed a significantly higher PA compared with MD group ((61.50 ± 10.61)% vs. (56.84 ± 10.74)%, P < 0.01; (56.06 ± 12.34)% vs. (46.88 ± 11.78)%, P < 0.01, respectively). A quantitative interaction effect was observed between clopidogrel pretreatment strategy and CYP2C19 genotype (P = 0.001).</p><p><b>CONCLUSION</b>The 300 mg LD strategy results in a decreased effect on platelet inhibition compared with the 75 mg MD in Chinese patients receiving clopidogrel prior to PCI, especially in the CYP2C19 2 or 3 loss-of-function allele non-carriers. (ClinicalTrials.gov number NCT01710436)</p>


Subject(s)
Aged , Female , Humans , Male , Middle Aged , Blood Platelets , Coronary Artery Disease , General Surgery , Cytochrome P-450 CYP2C19 , Genetics , Genotype , Percutaneous Coronary Intervention , Methods , Platelet Aggregation , Prospective Studies , Ticlopidine , Therapeutic Uses
8.
Article in Chinese | WPRIM (Western Pacific) | ID: wpr-291770

ABSTRACT

<p><b>OBJECTIVE</b>To evaluate the effect of VKORC1, CYP2C9, GGCX, PROC, EPHX1 and CYP4F2 gene polymorphisms on Warfarin maintenance dose variation in Chinese Han Population.</p><p><b>METHODS</b>Four hundred eighty-eight patients with prosthetic heart valves, atrial fibrillation or pulmonary thromboembolism and achieved stable Warfarin dose were enrolled. TaqMan probe or direct sequencing were used to genotype Y9VKORC1, CYP2C9, GGCX, EPHX1 and CYP4F2 gene polymorphisms. Demographic characteristics, stable therapeutic dose of Warfarin and concomitant medications were collected for all patients. The effect of VKORC1, CYP2C9, GGCX, PROC, EPHX1 and CYP4F2 gene polymorphisms, demographic characteristics and concomitant medications on Warfarin daily maintenance dose were analyzed with statistical method.</p><p><b>RESULTS</b>VKORC1 and CYP2C9 gene polymorphisms could explain more than 50% Warfarin maintenance dose variation in recruited patients, while CYP4F2 gene polymorphisms could only explain 1%. GGCX, PROC and EPHX1 gene polymorphisms had no impact no Warfarin maintenance dose. VKORC1 and CYP2C9 gene polymorphisms have a greater impact on Warfarin maintenance dose compared with demographic characteristics and concomitant medications.</p><p><b>CONCLUSION</b>VKORC1 and CYP2C9 gene polymorphisms have a significant impact on Warfarin maintenance dose in Chinese Han population.</p>


Subject(s)
Adult , Aged , Female , Humans , Male , Middle Aged , Young Adult , Aryl Hydrocarbon Hydroxylases , Genetics , Asian People , Ethnology , Genetics , Atrial Fibrillation , Drug Therapy , Ethnology , Genetics , Cytochrome P-450 CYP2C9 , Cytochrome P-450 Enzyme System , Genetics , Cytochrome P450 Family 4 , Dose-Response Relationship, Drug , Epoxide Hydrolases , Genetics , Polymorphism, Single Nucleotide , Protein C , Genetics , Pulmonary Embolism , Drug Therapy , Ethnology , Genetics , Treatment Outcome , Vitamin K Epoxide Reductases , Genetics , Warfarin
9.
Chinese Journal of Cardiology ; (12): 384-388, 2014.
Article in Chinese | WPRIM (Western Pacific) | ID: wpr-316452

ABSTRACT

<p><b>OBJECTIVES</b>To establish an algorithm to predict the warfarin maintenance dose in Chinese Han population and validate the accuracy of this algorithm.</p><p><b>METHODS</b>A total of 488 Chinese Han patients, hospitalized in Fuwai hospital and had a stable dose of warfarin and a target international normalized ratio (INR) of 1.5 to 3.0, were recruited. Indications for warfarin use included prosthetic heart valve, atrial fibrillation and pulmonary embolism. These patients were divided into derivation group (n = 323) and validation group (n = 165) according to the enrollment time. A warfarin maintenance dose algorithm was established based on genetic information, demographic characteristics and concomitant medications by multiple linear regression analysis in derivation group. In the validation group, we evaluated the accuracy of our algorithm by comparing the predicted dose with the actual dose.</p><p><b>RESULTS</b>Our algorithm included VKORC1-1639G > A, CYP2C9*3 and CYP4F2 genotype, age, Body hight, body weight, amiodarone and digoxin use (R(2) = 0.652, P < 0.001) .In the validation group, the average predicted dose by our algorithm had no statistical difference with the actual dose [(3.51 ± 1.03) mg vs. (3.53 ± 1.41) mg, P = 0.779]. Our algorithm identified 100 out of 165 (60.6%) patients in the validation group, whose predicted dose of warfarin was within 20% of the actual dose, and predicted warfarin dose was underestimated in 17.6% (29/165) patients and overestimated in 21.8% (36/165) patients.</p><p><b>CONCLUSION</b>Our algorithm based on VKORC1, CYP2C9 and CYP4F2 polymorphisms can help to predict the warfarin maintenance dose in Chinese Han Population.</p>


Subject(s)
Adult , Aged , Female , Humans , Male , Middle Aged , Algorithms , Asian People , Genetics , China , Cytochrome P-450 CYP2C9 , Genetics , Cytochrome P-450 Enzyme System , Genetics , Cytochrome P450 Family 4 , International Normalized Ratio , Models, Theoretical , Polymorphism, Genetic , Vitamin K Epoxide Reductases , Genetics , Warfarin , Therapeutic Uses
10.
FEBS J ; 280(3): 855-66, 2013 Feb.
Article in English | MEDLINE | ID: mdl-23176145

ABSTRACT

In this study, we found that the expression of miR-15a was positively correlated with neuroblastoma (NB) clinical pathological stage and was negatively correlated with reversion-inducing cysteine-rich protein with Kazal motifs (RECK) expression. Using the enhanced green fluorescent protein (EGFP) reporter construct carrying the 3'-UTR of RECK, we identified RECK as a direct target of miR-15a. Suppression of miR-15a significantly decreased the migration ability of GI-LA-N and SK-N-SH cell lines, whereas overexpression of miR-15a increased the migration ability; these effects could be partly reversed by RECK inhibition or ectopic expression. Moreover, inhibition of miR-15a significantly increased secreted matrix metalloproteinase-9 expression in culture medium through regulating the expression of RECK. These findings provide new insights into the characteristics of the miR-15a-RECK-matrix metalloproteinase-9 axis in NB progression, especially in NB migration and invasion.


Subject(s)
GPI-Linked Proteins/genetics , Matrix Metalloproteinase 9/genetics , MicroRNAs/genetics , Neuroblastoma/genetics , 3' Untranslated Regions/genetics , Blotting, Western , Cell Line, Tumor , Cell Movement/genetics , GPI-Linked Proteins/metabolism , Gene Expression Regulation, Neoplastic , Green Fluorescent Proteins/genetics , Green Fluorescent Proteins/metabolism , HEK293 Cells , HeLa Cells , Humans , Matrix Metalloproteinase 9/metabolism , Models, Genetic , Neoplasm Invasiveness , Neoplasm Metastasis , Neoplasm Staging , Neuroblastoma/metabolism , Neuroblastoma/pathology , RNA Interference , Reverse Transcriptase Polymerase Chain Reaction , Spectrometry, Fluorescence
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