Publications by authors named "Dan-Dan Chen"

96 Publications

HSP90 acts as a senomorphic target in senescent retinal pigmental epithelial cells.

Aging (Albany NY) 2021 09 8;13(17):21547-21570. Epub 2021 Sep 8.

The Division of Ophthalmology and Vision Science, Department of Ophthalmology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, China.

The senescence of retinal pigment epithelial (RPE) cells is associated with age-related macular degeneration (AMD), a leading cause of blindness in the world. HSP90 is a predominant chaperone that regulates cellular homeostasis under divergent physio-pathological conditions including senescence. However, the role of HSP90 in senescent RPE cells still remains unclear. Here, we reported that HSP90 acts as a senomorphic target of senescent RPE cells . Using HO-induced senescent ARPE-19 cells and replicative senescent primary RPE cells from rhesus monkey, we found that HSP90 upregulates the expression of IKKα, and HIF1α in senescent ARPE-19 cells and subsequently controls the induction of distinct senescence-associated inflammatory factors. Senescent ARPE-19 cells are more resistant to the cytotoxic HSP90 inhibitor IPI504 (IC50 = 36.78 μM) when compared to normal ARPE-19 cells (IC50 = 6.16 μM). Administration of IPI504 at 0.5-5 μM can significantly inhibit the induction of IL-1β, IL-6, IL-8, MCP-1 and VEGFA in senescent ARPE-19 and the senescence-mediated migration of retinal capillary endothelial cells . In addition, we found that inhibition of HSP90 by IPI504 reduces SA-β-Gal's protein expression and enzyme activity in a dose-dependent manner. HSP90 interacts with and regulates SA-β-Gal protein stabilization in senescent ARPE-19 cells. Taken together, these results suggest that HSP90 regulates the SASP and SA-β-Gal activity in senescent RPE cells through associating with distinctive mechanism including NF-κB, HIF1α and lysosomal SA-β-Gal. HSP90 inhibitors (e.g. IPI504) could be a promising senomorphic drug candidate for AMD intervention.
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http://dx.doi.org/10.18632/aging.203496DOI Listing
September 2021

Cross-cultural adaptation and validation of the caregiver contribution to self-care of chronic illness inventory in China: a cross-sectional study.

BMJ Open 2021 09 7;11(9):e048875. Epub 2021 Sep 7.

Nursing Department, Affiliated Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China

Objective: Caregiver contribution (CC) is important for the self-care behaviors of chronic disease individuals, as it could enhance patient outcomes. Therefore, it is necessary to assess this CC by using a good validity and reliability instrument. The Caregiver Contribution to Self-Care Chronic Illness Inventory (CC-SC-CII) was designed to assess CC to self-care behaviors of patients with chronic illness in Italy. However, it was unclear whether this tool had sound psychometrics properties in the context of Chinese culture. Therefore, we performed the cross-cultural adaption of the CC-SC-CII and we tested its psychometric properties among Chinese caregivers of patients with chronic disease.

Design: A cross-sectional observational design.

Settings: Participants were recruited from communities and institutions in Pingdingshan, Henan Province, China.

Participants: 301 caregivers of care recipients with chronic disease completed the Chinese version of the CC-SC-CII (C-CC-SC-CII).

Primary And Secondary Outcome Measures: The content validity index of items (I-CVI), the scale content validity index-average (S-CVI/Ave), exploratory factor analysis, confirmatory factor analysis (CFA), internal consistency and item analysis were tested.

Results: The range of I-CVI was between 0.833 and 1.00, and the score of S-CVI was 0.991. In CFA, the C-CC to self-care monitoring scale had satisfactory fit indices. However, the C-CC to self-care maintenance and management scales had unsupported fit indices. The reliability coefficients of C-CC-SC-CII were 0.792, 0.880 and 0.870 for its three scales. Item-total correlations were all over 0.590. Test-retest reliability showed that the range of intraclass correlation coefficients was from 0.728 to 0.783.

Conclusion: The C-CC-SC-CII has sound psychometrics characteristics and is a culturally appropriate and reliable instrument for assessing CC to the self-care behaviours of patients with chronic disease in China.
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http://dx.doi.org/10.1136/bmjopen-2021-048875DOI Listing
September 2021

The LAC Score Indicates Significant Fibrosis in Patients With Chronic Drug-Induced Liver Injury: A Large Biopsy-Based Study.

Front Pharmacol 2021 18;12:734090. Epub 2021 Aug 18.

Senior Department of Hepatology, Fifth Medical Center of Chinese PLA General Hospital, Beijing, China.

Currently, there are no satisfactory noninvasive methods for the diagnosis of fibrosis in patients with chronic drug-induced liver injury (DILI). Our goal was to develop an algorithm to improve the diagnostic accuracy of significant fibrosis in this population. In the present study, we retrospectively investigated the biochemical and pathological characteristics of consecutive patients with biopsy-proven chronic DILI, who presented at our hospital from January 2013 to December 2017. A noninvasive algorithm was developed by using multivariate logistic regression, receiver operating characteristic (ROC) curves, and decision curve analysis (DCA) to diagnose significant fibrosis in the training cohort, and the algorithm was subsequently validated in the validation cohort. Totally, 1,130 patients were enrolled and randomly assigned into a training cohort (n = 848) and a validation cohort (n = 282). Based on the multivariate analysis, LSM, CHE, and APRI were independently associated with significant fibrosis. A novel algorithm, LAC, was identified with the AUROC of 0.81, which was significantly higher than LSM (AUROC 0.78), CHE (AUROC 0.73), and APRI (AUROC 0.68), alone. The best cutoff value of LAC in the training cohort was 5.4. When the LAC score was used to diagnose advanced fibrosis and cirrhosis stages, the optimal cutoff values were 6.2 and 6.7, respectively, and the AUROC values were 0.84 and 0.90 in the training cohort and 0.81 and 0.83 in the validation cohort. This study proved that the LAC score can contribute to the accurate assessment of high-risk disease progression and the establishment of optimal treatment strategies for patients with chronic DILI.
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http://dx.doi.org/10.3389/fphar.2021.734090DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8416439PMC
August 2021

Long non-coding RNA ZFAS1 alleviates sepsis-induced myocardial injury via target miR-34b-5p/SIRT1.

Innate Immun 2021 Jul 2;27(5):377-387. Epub 2021 Aug 2.

Department of Pulmonary and Critical Care Medicine, Hainan General Hospital, P.R. China.

Long non-coding RNA ZFAS1 is down-regulated in sepsis. However, whether ZFAS1 participates in sepsis-induced cardiomyopathy (SIC) remains largely unknown. LPS injection to rats was used to establish an sepsis model, while LPS stimulation with H9C2 cell was used to mimic an sepsis-induced myocardial injury model. Western blots and quantitative RT-PCR were performed to evaluate protein and mRNA levels, respectively. ELISA was conducted to determine cytokine levels in supernatant. Flow cytometry was used to test apoptosis. Dual-luciferase assay was performed to validate binding between ZFAS1 and miR-34b-5p, miR-34b-5p and SIRT1. Our data revealed that ZFAS1 and SIRT1 were down-regulated, while miR-34b-5p was up-regulated in LPS-induced H9C2 cells. Inhibition of miR-34b-5p or overexpression of ZFAS1 alleviated inflammatory response and cell apoptosis in LPS-stimulated H9C2 cells. A mechanism study revealed that ZFAS1 sponged miR-34b-5p and thus elevated expression of SIRT1, which was prohibited by miR-34b-5p. ZFAS1 alleviated inflammatory response and cell apoptosis in LPS-stimulated H9C2 cells via the miR-34b-5p/SIRT1 axis, providing novel potential therapeutic targets for SIC.
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http://dx.doi.org/10.1177/17534259211034221DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8419299PMC
July 2021

Impacts of anti-inflammatory phosphodiesterase inhibitors on a murine model of chronic pulmonary inflammation.

Pharmacol Res Perspect 2021 Aug;9(4):e00840

Department of Emergency Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.

Chronic obstructive pulmonary disease (COPD) often tends to respond poorly to glucocorticoid (GC) therapy. Reduced Histone deacetylase-2 (HDAC-2) activity is an important mechanism behind this GC insensitivity. In this study, we investigated the effects of three phosphodiesterase inhibitors (PDEIs), with an anti-inflammatory propensity, on cigarette smoke (CS)-induced pulmonary inflammation and HDAC-2 activity. Male C57BL/6 mice were exposed to cigarette smoke (CS) over the course of 30 weeks. Administration of the PDEIs commenced from the 29th week and followed a schedule of once daily treatments, 5 days a week, for 2 weeks. Roflumilast (ROF) was administered intragastrically (5 mg·kg ), while pentoxifylline (PTX) (10 mg·kg ) and theophylline (THEO) (10 mg·kg ) were administered intraperitoneally, either alone or in combination with a GC (triamcinolone acetonide or TRI, 5 mg·kg , i.m., single injection). Lung morphometry, as well as the activity of HDAC-2, pro-inflammatory cytokines and reactive oxygen species (ROS) were assessed at the end of the 30-week course. CS exposure was associated with a reduction in HDAC-2 activity and the up-regulation of ROS expression. PTX, ROF, and THEO administration led to the partial restoration of HDAC-2 activity, which was favorably associated with the reduction of ROS expression. However, combining TRI to any of these PDEIs did not synergistically augment HDAC-2 activity. Inactivation of HDAC-2 due to long-term CS exposure is closely related to exaggerated oxidative stress, and this reduced HDAC-2 activity could partially be restored through the use of PDEIs. This finding provides a potential novel approach for further clinical research.
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http://dx.doi.org/10.1002/prp2.840DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8322673PMC
August 2021

cGAS Is a Negative Regulator of RIG-I-Mediated IFN Response in Cyprinid Fish.

J Immunol 2021 08 21;207(3):784-798. Epub 2021 Jul 21.

State Key Laboratory of Agricultural Microbiology, College of Fisheries, Huazhong Agricultural University, Wuhan, China;

In mammals, cyclic GMP-AMP synthase (cGAS) recognizes cytosolic dsDNA to induce the type I IFN response. However, the functional role of cGAS in the IFN response of fish remains unclear or controversial. In this study, we report that cGAS orthologs from crucian carp (cGAS) and grass carp (cGAS) target the dsRNA sensor retinoic acid-inducible gene I (RIG-I) for negative regulation of the IFN response. First, poly(deoxyadenylic-deoxythymidylic) acid-, polyinosinic-polycytidylic acid-, and spring viremia of carp virus-induced IFN responses were impaired by overexpression of cGAS and cGAS. Then, cGAS and cGAS interacted with RIG-I and MAVS and inhibited RIG-I- and MAVS-mediated IFN induction. Moreover, the K63-linked ubiquitination of RIG-I and the interaction between RIG-I and MAVS were attenuated by cGAS and cGAS. Finally, cGAS and cGAS decreased RIG-I-mediated the cellular antiviral response and facilitated viral replication. Taken together, data in this study identify cGAS and cGAS as negative regulators in RIG-I-like receptor signaling, which extends the current knowledge regarding the role of fish cGAS in the innate antiviral response.
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http://dx.doi.org/10.4049/jimmunol.2100075DOI Listing
August 2021

Zebrafish Uba1 Degrades IRF3 through K48-Linked Ubiquitination to Inhibit IFN Production.

J Immunol 2021 Jun 30. Epub 2021 Jun 30.

Institute of Hydrobiology, Chinese Academy of Sciences, Wuhan, China;

Fish IFN regulatory factor 3 (IRF3) is a crucial transcription factor in the IFN activation signaling pathway, which leads to IFN production and a positive cycle. Unrestricted IFN expression results in hyperimmune responses and therefore, IFN must be tightly regulated. In the current study, we found that zebrafish Ub-activating enzyme (Uba1) negatively regulated IRF3 via the K-48 ubiquitin proteasome degradation of IRF3. First, expression stimulated by spring viraemia of carp virus infection was blunted by the overexpression of Uba1 and enhanced by Uba1 knockdown. Afterward, we found that Uba1 was localized in the cytoplasm, where it interacted with and degraded IRF3. Functional domains analysis revealed that the C-terminal ubiquitin-fold domain was necessary for IRF3 degradation by Uba1 and the N-terminal DNA-binding domain of IRF3 was indispensable for the degradation by Uba1.The degradation of IRF3 was subsequently impaired by treatment with MG132, a ubiquitin proteasome inhibitor. Further mechanism analysis revealed that Uba1 induced the K48-linked Ub-proteasomal degradation of IRF3. Finally, the antiviral capacity of IRF3 was significantly attenuated by Uba1. Taken together, our study reveals that zebrafish Uba1 interacts with and activates the ubiquitinated degradation of IRF3, providing evidence of the IFN immune balance mechanism in fish.
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http://dx.doi.org/10.4049/jimmunol.2100125DOI Listing
June 2021

Tea consumption and serum uric acid levels among older adults in three large-scale population-based studies in China.

BMC Geriatr 2021 04 21;21(1):267. Epub 2021 Apr 21.

School of Public Health, Medical College of Soochow University, 199 Ren Ai Road, Suzhou, 215123, China.

Background And Aims: The association between serum uric acid (SUA) and tea consumption has been studied in previous work, and there were arguments among various population group employed as well as different statistical approaches. The aim of this work is to investigate the tea effect on SUA levels among older adults by comparing three large-scale populations with both cross-sectional and longitudinal analyses.

Method: We examined the relationship between intake and SUA levels among older adults using linear regression. All the studies include the parameters SUA levels, tea intake, age, sex, education level, smoking status, alcohol drinking status, body mass index (BMI), and health history (diabetes, hypertension, and fasting plasma glucose). The cross-sectional analyses were conducted with 4579 older adults in the Weitang Geriatric Diseases Study (WGDS, ≥60 years), 2440 in the China Health and Nutrition Survey (CHNS, ≥60 years) and 1236 in the Chinese Longitudinal Healthy Longevity Survey (CLHLS, ≥62 years); and the longitudinal analyses were performed with 3870 (84.5%) in the WGDS and 420 (34.0%) in the CLHLS. Multivariable linear regression analyses were performed in both cross-sectional and longitudinal studies.

Results: Cross-sectional studies showed that tea consumers tended to have higher SUA levels than non-tea consumers in all the three datasets (P < 0.05). However, longitudinal associations of SUA levels with tea consumption had no statistical significance (P>0.05). The results of sex-stratified analyses were consistent with those of the whole datasets.

Conclusions: This work implied that any possible association between tea consumption and SUA levels could be very weak.
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http://dx.doi.org/10.1186/s12877-021-02216-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8061055PMC
April 2021

Neutrophil functions can be regulated by IL-35, which is mainly expressed in IL-15Rα cells in grass carp (Ctenopharyngodon idella).

Dev Comp Immunol 2021 Aug 20;121:104103. Epub 2021 Apr 20.

Laboratory for Marine Biology and Biotechnology, Qingdao National Laboratory for Marine Science and Technology, Qingdao, 266071, China; State Key Laboratory of Agricultural Microbiology, College of Fisheries, Huazhong Agricultural University, Wuhan, 430070, China; Engineering Research Center of Green Development for Conventional Aquatic Biological Industry in the Yangtze River Economic Belt, Ministry of Education, Wuhan, 430070, China. Electronic address:

IL-35 plays a key role in regulatory T (Treg) and regulatory B (Breg) cell functions in mammals. CD25 has been demonstrated as one of the markers of Treg cells, and CD19CD25CD71 cells have been verified as a type of Breg cells in humans. These results indicate that there is a close relationship between IL-35 and CD25 cells. In mammals, CD25 (alias IL-2Rα) has been identified as having high affinity and specificity for IL-2 binding, and is closely linked and structurally related to IL-15Rα, which having high affinity for IL-15 binding. In teleost, IL-15Rα can bind to both IL-2 and IL-15, with higher affinity to IL-15 than IL-2, and has been termed a CD25-like molecule in some research studies. To date, no studies of IL-35 and IL-15Rα have been documented in fish. In this work, five isoforms of IL-15Rα were cloned from grass carp, and a monoclonal antibody to the protein was developed. The results of flow cytometry and quantitative real-time PCR analyses demonstrated that grass carp IL-35 subunit genes EBI3a and IL-12p35 were mainly expressed in IL-15Rα cells, while the expression levels of IL-10 and TGF-β in IL-15Rα and IL-15Rα cells were insignificant. Recombinant grass carp IL-35 (rgcIL-35) could increase the proportion of IL-15Rα cells in leukocytes, and a certain proportion of IL-15Rα cells also appeared in myeloid cell subset II after stimulation with rgcIL-35. Meanwhile, the migration, phagocytic ability, and bactericidal ability of grass carp neutrophils were significantly decreased after stimulation with certain concentrations of rgcIL-35. Moreover, neutrophil apoptosis could be significantly inhibited by rgcIL-35.
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http://dx.doi.org/10.1016/j.dci.2021.104103DOI Listing
August 2021

[Effects of FABP5-PPARγ signaling pathway on learning-memory ability and lipid metabolism in rats with vascular dementia].

Zhongguo Ying Yong Sheng Li Xue Za Zhi 2020 Sep;36(5):438-443

Department of Neurology, the 983th Hospital of People's Liberation Army, Tianjin 300142, China.

To investigate the effects of fatty acid binding protein 5(FABP5)- peroxisome proliferator-activated receptor gamma(PPARγ) signaling pathway on learning-memory ability and lipid metabolism in rats with vascular dementia(VD) and its mechanisms. ①VD model rats were established by ligating bilateral common carotid artery. These rats were divided into three groups: normal group (WT group), sham-operated group (sham group) and VD model group; ②WT group and FABP5 inhibitor group were set up. After four weeks, Morris water maze test was used to detect spatial learning and memory ability in rats. RT-qPCR and Western blot methods were used to detect the expressions of FABP5, PPARγ, p-PPARγ and lipoprotein lipase (LPL) in the brain at the mRNA and protein levels. The levels of TC, TG and FFA in the brain were detected by assay kits. Compared with the WT group and sham group, the learning-memory ability of the VD model and the FABP5 inhibitor group were significantly decreased, and the expressions of FABP5, PPARγ, p-PPARγ and LPL were significantly decreased at mRNA level and protein level in the brain; and the levels of TC, TG and FFA were increased significantly in the brain. FABP5 can affect the learning-memory ability and lipid metabolism in VD rats through PPARγ and LPL.
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http://dx.doi.org/10.12047/j.cjap.5991.2020.093DOI Listing
September 2020

A novel role of Zebrafish TMEM33 in negative regulation of interferon production by two distinct mechanisms.

PLoS Pathog 2021 02 18;17(2):e1009317. Epub 2021 Feb 18.

Institute of Hydrobiology, Chinese Academy of Sciences, Wuhan, China.

The transmembrane protein 33 (TMEM33) was originally identified as an endoplasmic reticulum (ER) protein that influences the tubular structure of the ER and modulates intracellular calcium homeostasis. However, the role of TMEM33 in antiviral immunity in vertebrates has not been elucidated. In this article, we demonstrate that zebrafish TMEM33 is a negative regulator of virus-triggered interferon (IFN) induction via two mechanisms: mitochondrial antiviral signaling protein (MAVS) ubiquitination and a decrease in the kinase activity of TANK binding kinase 1 (TBK1). Upon stimulation with viral components, tmem33 was remarkably upregulated in the zebrafish liver cell line. The IFNφ1 promoter (IFNφ1pro) activity and mRNA level induced by retinoic acid-inducible gene (RIG)-I-like receptors (RLRs) were significantly inhibited by TMEM33. Knockdown of TMEM33 increased host ifn transcription. Subsequently, we found that TMEM33 was colocalized in the ER and interacted with the RLR cascades, whereas MAVS was degraded by TMEM33 during the K48-linked ubiquitination. On the other hand, TMEM33 reduced the phosphorylation of mediator of IFN regulatory factor 3 (IRF3) activation (MITA)/IRF3 by acting as a decoy substrate of TBK1, which was also phosphorylated. A functional domain assay revealed that the N-terminal transmembrane domain 1 (TM1) and TM2 regions of TMEM33 were necessary for IFN suppression. Finally, TMEM33 significantly attenuated the host cellular antiviral capacity by blocking the IFN response. Taken together, our findings provide insight into the different mechanisms employed by TMEM33 in cellular IFN-mediated antiviral process.
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http://dx.doi.org/10.1371/journal.ppat.1009317DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7891750PMC
February 2021

Transcription factor Sp1 ameliorates sepsis-induced myocardial injury via ZFAS1/Notch signaling in H9C2 cells.

Cytokine 2021 04 28;140:155426. Epub 2021 Jan 28.

Department of Respiratory and Critical Care Medicine, Hainan General Hospital, Haikou 570311, PR China. Electronic address:

Purpose: To investigate whether Sp1 can ameliorate sepsis-induced myocardial injury and explore the potential molecular mechanism.

Methods: The embryonic cardiomyocyte cell line H9C2 and primary cultured mouse neonatal cardiomyocytes (CMNCs) were treated with LPS or phosphate-buffered saline (PBS). A mouse model of LPS-induced sepsis was established using male C57BL/6J mice and their cardiomyocytes were collected. Real-time reverse transcription-PCR (qRT-PCR) assay was used to detect the expression levels of Sp1 and ZFAS1 in cardiomyocytes. Western blotting analysis was used to assess the protein expression levels of Sp1, apoptosis-associated proteins and Notch signaling pathway related proteins. Luciferase assay was used to detect the interaction between Sp1 and ZFAS1. Cell transfection was used to generate H9C2 cells with overexpressed or knocked down of Sp1 or ZFAS1. MTT assay and flow cytometry analysis were used to test the cell proliferation and cell apoptosis ratio.

Results: Our data revealed that the expressions of ZFAS1 and Sp1 were significantly reduced in LPS-treated H9C2 cells and primary CMNCs. The downregulation of ZFAS1 and Sp1 were also found in cardiomyocytes obtained from LPS-challenged mice. LPS induced H9C2 cell apoptosis and depressed cell proliferation was ameliorated by ZFAS1 overexpression and aggravated by ZFAS1 knockdown. Mechanistically, Luciferase assay indicated that Sp1 could bind to ZFAS1, and positively regulated ZFAS1 expression. Moreover, Notch signaling pathway participates in H9C2 cell apoptosis mediated by Sp1.

Conclusion: The present study demonstrates that Sp1 regulates LPS-induced cardiomyocyte apoptosis via ZFAS1/Notch signaling pathway, which may serve as therapeutic targets for sepsis-induced myocardial injury.
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http://dx.doi.org/10.1016/j.cyto.2021.155426DOI Listing
April 2021

Small balloon strategy associated with low pacemaker implantation rate after self-expanding transcatheter valve implantation.

World J Emerg Med 2021 ;12(1):48-53

Department of Cardiology, Shanghai Institute of Cardiovascular Disease, Zhongshan Hospital, Fudan University, Shanghai 200032, China.

Background: This study aims to investigate whether small balloon aortic valvuloplasty (BAV) reduces the need for permanent pacemaker implantation (PPMI) after transcatheter aortic valve implantation (TAVI).

Methods: This was a retrospective analysis using data from our local TAVI database. Small BAV was defined as a small balloon size (=18 mm) pre-dilatation. Normal BAV was defined as a balloon size >18 mm. The primary endpoint was the incidence of new PPMI.

Results: Of 99 consecutive TAVI patients, five patients were excluded due to pre-existing permanent pacemaker. Patients in the small BAV group (=57) had a significantly lower PPMI rate compared with the normal BAV group (=37) (3.5% vs. 18.9%, =0.026). Moderate or severe aortic valve regurgitation post-procedure was similar between the small BAV and normal BAV groups (5.3% vs. 8.1%, =0.480); likewise, the mean aortic gradient post-procedure did not differ significantly (11.5±5.2 mmHg vs. 12.2±7.3 mmHg, 1 mmHg=0.133 kPa, =0.580) between the groups. Device success rates were also similar (94.7% vs. 91.8%, =0.680). In multivariable analysis, small BAV (=0.027), the ratio of prosthesis diameter to annulus diameter (=0.048), and mean aortic gradient by echo in the basement (=0.021) were independent predictors of PPMI.

Conclusions: The small BAV strategy is associated with a low rate of permanent pacemaker implantation after transcatheter self-expanding valve implantation in this single-center observational study.
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http://dx.doi.org/10.5847/wjem.j.1920-8642.2021.01.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7790709PMC
January 2021

Grass Carp Reovirus (GCRV) Giving Its All to Suppress IFN Production by Countering MAVS Signaling Transduction.

Front Immunol 2020 26;11:545302. Epub 2020 Oct 26.

Institute of Hydrobiology, Chinese Academy of Sciences, Wuhan, China.

Viruses typically target host RIG-I-like receptors (RLRs), a group of key factors involved in interferon (IFN) production, to enhance viral infection. To date, though immune evasion methods to contradict IFN production have been characterized for a series of terrestrial viruses, the strategies employed by fish viruses remain unclear. Here, we report that all grass carp reovirus (GCRV) proteins encoded by segments S1 to S11 suppress mitochondrial antiviral signaling protein (MAVS)-mediated IFN expression. First, the GCRV viral proteins blunted the MAVS-induced expression of IFN, and impair MAVS antiviral capacity significantly. Interestingly, subsequent co-immunoprecipitation experiments demonstrated that all GCRV viral proteins interacted with several RLR cascades, especially with TANK-binding kinase 1 (TBK1) which was the downstream factor of MAVS. To further illustrate the mechanisms of these interactions between GCRV viral proteins and host RLRs, two of the viral proteins, NS79 (S4) and VP3 (S3), were selected as representative proteins for two distinguished mechanisms. The obtained data demonstrated that NS79 was phosphorylated by gcTBK1, leading to the reduction of host substrate gcIRF3/7 phosphorylation. On the other hand, VP3 degraded gcMAVS and the degradation was significantly reversed by 3-MA. The biological effects of both NS79 and VP3 were consistently found to be related to the suppression of IFN expression and the promotion of viral evasion. Our findings shed light on the special evasion mechanism utilized by fish virus through IFN regulation, which might differ between fish and mammals.
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http://dx.doi.org/10.3389/fimmu.2020.545302DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7649419PMC
April 2021

Grass carp cGASL negatively regulates interferon activation through autophagic degradation of MAVS.

Dev Comp Immunol 2021 02 26;115:103876. Epub 2020 Sep 26.

Institute of Hydrobiology, Chinese Academy of Sciences, Wuhan, China; Laboratory for Marine Biology and Biotechnology, Qingdao National Laboratory for Marine Science and Technology, Qingdao, China; State Key Laboratory of Agricultural Microbiology, College of Fisheries, Huazhong Agricultural University, Wuhan, China. Electronic address:

In mammals, cyclic GMP-AMP synthase (cGAS) is a crucial cytosolic DNA sensor responsible for activating the interferon (IFN) response. A cGAS-like (cGASL) gene was previously identified from grass carp Ctenopharyngodon idellus, which is evolutionarily closest to cGAS but not a true ortholog of cGAS. Here, we found that grass carp cGASL targets mitochondrial antiviral signaling protein (MAVS) for autophagic degradation to negatively regulate fish IFN response. Firstly, the transcriptional level of cellular cgasl was upregulated by poly I:C stimulation, and overexpression of cGASL significantly decreased poly I:C- and MAVS-induced promoter activities and transcriptional levels of IFN and IFN-stimulated genes (ISGs). In addition, cGASL associated with MAVS and prompted autophagic degradation of MAVS in a dose-dependent manner. Finally, overexpression of cGASL attenuated MAVS-mediated cellular antiviral response. These results collectively indicate that cGASL negatively regulates fish IFN response by triggering autophagic degradation of MAVS.
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http://dx.doi.org/10.1016/j.dci.2020.103876DOI Listing
February 2021

miR-149 contributes to resistance of 5-FU in gastric cancer via targeting TREM2 and regulating β-catenin pathway.

Biochem Biophys Res Commun 2020 11 22;532(3):329-335. Epub 2020 Sep 22.

Cancer Institute, The Affiliated People's Hospital of Jiangsu University, Zhenjiang, Jiangsu, 212002, China. Electronic address:

Drug resistance remains the unresolved obstacle for gastric cancer (GC) treatment. Recently more and more studies have shown that microRNAs are involved in cancer resistance and could apply to drug resistance therapy in tumors. The relationship between miR-149 and 5-fluorouracil (5-FU) resistance in GC remains unclear. Here we detected miR-149 expression in 5-FU resistance tumor tissues and cell lines, and found that miR-149 expression is upregulated in AGS/5-FU cells compared with AGS cells. Further experiments indicated that overexpression of miR-149 can alleviate 5-FU-induced apoptosis and proliferation inhibition by targeting TREM2. It was also confirmed that TREM2 regulated 5-FU resistance through β-catenin pathway. Generally speaking, our results indicated that miR-149 contributes to resistance of 5-FU in gastric cancer via targeting TREM2 and regulating β-catenin pathway.
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http://dx.doi.org/10.1016/j.bbrc.2020.05.135DOI Listing
November 2020

The effectiveness of massage on peri-operative anxiety in adults: A meta-analysis of randomized controlled trials and controlled clinical trials.

Complement Ther Clin Pract 2020 Nov 17;41:101240. Epub 2020 Sep 17.

Nursing School, Jilin University, Changchun, Jilin province, 130021, China. Electronic address:

Background And Purpose: and purpose: Massage has gained increasing attention for reducing peri-operative anxiety. We aimed to investigate the effectiveness of massage for peri-operative anxiety in adults.

Methods: Six English electronic databases were comprehensively searched from their inception to February 2020. Subgroup analysis, quality assessment, sensitivity analysis, meta-regression and publication bias assessment were performed.

Results: Twenty-five controlled trials comprising 2494 participants were included. The meta-analysis indicated that massage could significantly reduce peri-operative anxiety for most types of surgical patients. Specifically, it was effective for pre-, intra- and post-operative anxiety. Acupoint or specific body reflex area massage showed a larger effect than general massage did. Massage delivered by professionals and non-professionals were both effective. Massage lasting 10-20 min per session was the most worthy of recommendation. Massage was concomitant with the improvement of peri-operative vital signs and post-operative pain.

Conclusion: Massage is a promising complementary therapy for ameliorating peri-operative anxiety in adults.
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http://dx.doi.org/10.1016/j.ctcp.2020.101240DOI Listing
November 2020

Effects of exercise on pregnancy and postpartum fatigue: A systematic review and meta-analysis.

Eur J Obstet Gynecol Reprod Biol 2020 Oct 27;253:285-295. Epub 2020 Aug 27.

Nursing School of Jilin University, Changchun, Jilin Province, China. Electronic address:

Objective: Fatigue is a common adverse experience in pregnant and postpartum women and is associated with poor outcomes and can seriously affect maternal and infant health and quality of life. However, data from existing studies are inconsistent, and no studies have examined the effects of exercise on pregnancy and postpartum fatigue. The aim of this review is to evaluate the effects of exercise on pregnancy and postpartum fatigue.

Study Design: PubMed, EMBASE, Web of Science and the Cochrane Library database were used to retrieve literature. Eligible studies were clinical trials that reported the effects of exercise on pregnancy and postpartum fatigue in women. The methodological quality of the included studies was assessed using the Cochrane Collaboration Risk of Bias Assessment Tool. A fixed-effect model was used to analyse the pooled results. Subgroup analyses were used to explore sources of heterogeneity. Sensitivity analysis was used to validate the robustness of the pooled results.

Results: Seven studies were included. The results of meta-analysis of five studies showed that exercise during pregnancy and the postpartum period may have beneficial effects on women's fatigue ([SMD = 0.29, 95 % CI (0.10, 0.47), P = 0.003]). Subgroup analyses reported that compared with the control, long exercise programmes, postpartum exercise and supervised exercise significantly improved fatigue levels.

Conclusions: Postpartum exercise in a supervised programme lasting more than eight weeks may be beneficial for reducing postpartum fatigue. More available data from large-scale and high-quality trials are needed to demonstrate the effects of exercise on pregnant and postpartum fatigue.
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http://dx.doi.org/10.1016/j.ejogrb.2020.08.013DOI Listing
October 2020

Zebrafish RBM47 Promotes Lysosome-Dependent Degradation of MAVS to Inhibit IFN Induction.

J Immunol 2020 10 28;205(7):1819-1829. Epub 2020 Aug 28.

Institute of Hydrobiology, Chinese Academy of Sciences, Wuhan 430072, China;

IFN is essential for hosts to defend against viral invasion, whereas it must be tightly regulated to prevent hyperimmune responses. Fish mitochondrial antiviral signaling protein (MAVS) is a vital factor for IFN production, but until now, there have been few studies on the regulation mechanisms of fish MAVS enabling IFN to be properly controlled. In this study, we show that zebrafish RNA-binding motif protein 47 (RBM47) promotes MAVS degradation in a lysosome-dependent manner to suppress IFN production. First, the transcription of IFN activated by polyinosinic/polycytidylic acid (poly I:C), spring viremia of carp virus, or retinoic acid-inducible gene I (RIG-I)-like receptor pathway components were significantly suppressed by RBM47. Second, RBM47 interacted with MAVS and promoted lysosome-dependent degradation of MAVS, changing the cellular location of MAVS from the cytoplasm to the lysosome region. Finally, RBM47 inhibited downstream MITA and IRF3/7 activation, impairing the host antiviral response. Collectively, these data suggest that zebrafish RBM47 negatively regulates IFN production by promoting lysosome-dependent degradation of MAVS, providing insights into the role of RBM47 in the innate antiviral immune response in fish.
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http://dx.doi.org/10.4049/jimmunol.1901387DOI Listing
October 2020

Molecular characterization of a cyprinid fish (Ancherythroculter nigrocauda) TBK1 and its kinase activity in IFN regulation.

Dev Comp Immunol 2021 01 2;114:103805. Epub 2020 Aug 2.

Key Laboratory of Aquaculture Disease Control, Ministry of Agriculture, Institute of Hydrobiology, Chinese Academy of Sciences, Wuhan, China. Electronic address:

TANK-binding kinase 1 (TBK1) plays a vital role in activating interferon (IFN) production and positively regulating antiviral response in mammals. Research on more species of fish is necessary to clarify whether the function of fish TBK1 is conserved compared to that in mammals. Here, a cyprinid fish (Ancherythroculter nigrocauda) TBK1 (AnTBK1) was functionally identified and characterized. The full-length open reading frame (ORF) of AnTBK1 consists of 2184 nucleotides encoding 727 amino acids and contains a conserved Serine/Threonine protein kinase catalytic domain (S_TKc) in the N-terminal, similar to TBK1 in other species. The transcripts of AnTBK1 were found in all the tissues evaluated and the cellular distribution indicated that AnTBK1 was localized in the cytoplasm. In terms of functional identification, AnTBK1 induced a variety of IFN promoter activities as well as the expression of downstream IFN-stimulated genes (ISGs). In addition, AnTBK1 interacted with and significantly phosphorylated IFN regulatory factor 3 (IRF3), exhibiting the canonical kinase activity of TBK1. Finally, AnTBK1 presented strong antiviral activity against spring viremia of carp virus (SVCV) infection. Taken together, our research on the features and functions of AnTBK1 demonstrated that AnTBK1 plays a central role in IFN induction against SVCV infection.
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http://dx.doi.org/10.1016/j.dci.2020.103805DOI Listing
January 2021

Ca plays an antiviral role by increasing p53 expression to achieve protection against spring viraemia of carp virus infection.

Fish Shellfish Immunol 2020 Jul 11;102:449-459. Epub 2020 May 11.

Institute of Hydrobiology, Chinese Academy of Sciences, Wuhan, China. Electronic address:

Calcium (Ca) is a messenger that regulates a multitude of physiological processes, but its functions in antiviral progress remain undefined. In this study, we found that Ca enhances fish survival to defend against spring viraemia of carp virus (SVCV) infection by reversing the instability of p53 mediated by the viral protein. First, Ca significantly protected cells and fish against SVCV infection by inducing early apoptosis. Additionally, p53 expression, which was inhibited by SVCV N protein, was upregulated by Ca treatment. Then, the mechanism underlying the reduction of K63-linked p53 ubiquitination by SVCV N protein via the K358 site was completely prevented by Ca. These findings reveal the role of Ca in lower vertebrates in the antiviral response, which is connected to and corresponds with viral immune evasion, providing a solution to fish diseases caused by pathogens.
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http://dx.doi.org/10.1016/j.fsi.2020.05.023DOI Listing
July 2020

Serum High-Density Lipoprotein Cholesterol is Significantly Associated with the Presence and Severity of Pulmonary Arterial Hypertension: A Retrospective Cross-Sectional Study.

Adv Ther 2020 05 1;37(5):2199-2209. Epub 2020 Apr 1.

Department of Cardiology, Shanghai Institute of Cardiovascular Disease, Zhongshan Hospital, Fudan University, Shanghai, China.

Introduction: To explore the relationship between serum high-density lipoprotein cholesterol (HDL-C) levels and the presence and severity of pulmonary arterial hypertension (PAH).

Methods: A total of 177 patients with PAH and 103 patients without pulmonary hypertension (PH) were enrolled in this study. All patients underwent right heart catheterization (RHC) for diagnosing and assessing the severity of PAH. Demographics, comorbidities, and laboratory data including serum HDL-C levels were collected.

Results: Plasma HDL-C levels in patients with PAH were significantly lower compared with patients without PH (1.08 ± 0.36 vs 1.49 ± 0.36, p < 0.001). HDL-C levels positively correlated with cardiac output (r = 0.360, p < 0.001), cardiac index (r = 0.337, p < 0.001), and mixed venous oxygen saturation (r = 0.426, p < 0.001), and negatively with mean pulmonary arterial pressure (r = - 0.529, p < 0.001), right atrial pressure (r = - 0.421, p < 0.001), and pulmonary vascular resistance (r = - 0.583, p < 0.001). Multivariate logistic regression analysis indicated that HDL-C was a significant independent predictor of PAH (OR 0.042, 95% CI 0.006-0.304, p = 0.002). The receiver operating characteristic curve analysis showed that the optimal cutoff value of the serum HDL-C concentration for predicting PAH was 1.32 mmol/L, with a sensitivity of 83.6% and a specificity of 72.8% (area under the curve 0.803, 95% confidence interval 0.750-0.856, p < 0.001).

Conclusions: Serum HDL-C is a simple biomarker that might be used for prediction and assessment of PAH in Chinese Han ethnicity, and the mechanism underlying the association needs further study.
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http://dx.doi.org/10.1007/s12325-020-01304-2DOI Listing
May 2020

Psychometric properties of the Breast Cancer Awareness Measurement among Chinese women: a cross-sectional study.

BMJ Open 2020 03 9;10(3):e035911. Epub 2020 Mar 9.

Nursing School of Jilin University, Jilin University, Changchun, Jilin, China

Objectives: To perform the cross-cultural adaption of the Breast Cancer Awareness Measurement (BCAM) and to test its psychometric properties among Chinese women.

Design: This is a cross-sectional study.

Settings: This study was conducted in communities, schools and institutions in Changchun, Jilin Province, China.

Participants: A total of 328 women voluntarily participated in and completed the Chinese version of the BCAM (C-BCAM), resulting in an effective response rate of 91.1%.

Primary And Secondary Outcome Measures: Psychometric properties, including item analysis (the extreme group comparison and item-total correlations), content validity (item-level content validity index (I-CVI) and scale-level content validity index (S-CVI)), construct validity (exploratory factor analysis (EFA) and confirmatory factor analysis (CFA)) and internal consistency (Cronbach's α and test-retest reliability), were measured.

Results: The C-BCAM has excellent internal consistency (Cronbach's α=0.90), with alpha coefficients of 0.88, 0.84 and 0.94 for its three domains. The test-retest reliability coefficient was 0.72. The I-CVI ranged from 0.86 to 1.00, and the S-CVI was 0.92. CFA showed that the three-factor model explained 51.56% of the total variance, with a good model fit (likelihood ratio χ/df=1.86, incremental fit index=0.94, comparative fit index=0.94, goodness-of-fit index=0.84, adjusted goodness-of-fit index=0.80, standardised root mean square error of approximation=0.06 and root mean square residual=0.05).

Conclusions: The C-BCAM has satisfactory validity and reliability and is a culturally appropriate and reliable tool for evaluating breast cancer awareness among Chinese women. This reliable instrument can help researchers and health professionals evaluate women's knowledge about the symptoms and risk factors of breast cancer and identify their barriers to seeking medical help. It also helps healthcare providers identify women with poor breast cancer awareness and encourage them to perform screening practice.
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http://dx.doi.org/10.1136/bmjopen-2019-035911DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7064072PMC
March 2020

Grass carp reovirus VP56 represses interferon production by degrading phosphorylated IRF7.

Fish Shellfish Immunol 2020 Apr 4;99:99-106. Epub 2020 Feb 4.

Institute of Hydrobiology, Chinese Academy of Sciences, Wuhan, China; State Key Laboratory of Agricultural Microbiology, College of Fisheries, Huazhong Agricultural University, Wuhan, China. Electronic address:

Grass carp reovirus (GCRV) is an efficient pathogen causing high mortality in grass carp, meanwhile, fish interferon (IFN) is a powerful cytokine enabling host cells to establish an antiviral state; therefore, the strategies used by GCRV to escape the cellular IFN response need to be investigated. Here, we report that GCRV VP56 inhibits host IFN production by degrading the transcription factor IFN regulatory factor 7 (IRF7). First, overexpression of VP56 inhibited the IFN production induced by the polyinosinic-polycytidylic acid (poly I:C) and mitochondrial antiviral signaling protein (MAVS), while the capacity of IRF7 on IFN induction was unaffected. Second, VP56 interacted with RLRs but did not affect the stabilization of the proteins in the normal state, while the phosphorylated IRF7 activated by TBK1 was degraded by VP56 through K48-linked ubiquitination. Finally, overexpression of VP56 remarkably reduced the host cellular ifn transcription and facilitated viral proliferation. Taken together, our results demonstrate that GCRV VP56 suppresses the host IFN response by targeting phosphorylated IRF7 for ubiquitination and degradation.
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http://dx.doi.org/10.1016/j.fsi.2020.02.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7111710PMC
April 2020

Effect of the complete replacement of dietary fish meal by soybean meal on histopathology and immune response of the hindgut in grass carp (Ctenopharyngodon idellus).

Vet Immunol Immunopathol 2020 Mar 8;221:110009. Epub 2020 Jan 8.

Institute of Hydrobiology, Chinese Academy of Sciences, No.7 Donghu South Road, Wuhan 430072, Hubei Province, China.

A 14-day experiment was conducted to explore the pathological process and immune response of soybean meal (SBM) induced enteritis (SBMIE) in grass carp (Ctenopharyngodon idellus). The complete replacement of dietary fish meal (FM) with SBM resulted in a remarkable reduction in final body weight, weight gain ratio, and feed conversion efficiency (p < 0.05). The typical histopathological changes of SBMIE appeared starting at day 4, and progressively increased in severity until day 8, then gradually subsided after day 11. The course of SBMIE could be divided into incubation period (days 1-2), prodromal period (days 3-6), symptomatic period (days 7-10), and convalescent period (days 11-14). Transcription levels of pro-inflammatory cytokines, including IL-1β, TNF-α, IL-6, IL-8, IL-17A/F1 and IFN-γ2, were up-regulated during the prodromal period, and then down-regulated during the convalescent period. Transcript levels of anti-inflammatory cytokines (IL-10 and TGFβ1) and their receptors (IL-10R1 and TβRII), were up-regulated during the prodromal and convalescent periods. Transcript levels of MHCIIβ, Igμ, Igτ, TCRδ, TCRβ, CD4, and CD8α were altered in SBMIE. Furthermore, expression levels of T-bet, IFN-γ2, RORγ2 and IL-17A/F1 were significantly increased in the initiation of enteritis, whereas the transcript levels of Foxp3 and IL-2/15Ra were significantly up-regulated in the repair of enteritis. In conclusion, grass carp SBMIE is regulated by the adjustment of SBM-based diet intake, and the changes of the above-mentioned genes expression suggest that these genes may be involved in SBMIE.
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http://dx.doi.org/10.1016/j.vetimm.2020.110009DOI Listing
March 2020

Polyaniline modified MIL-100(Fe) for enhanced photocatalytic Cr(VI) reduction and tetracycline degradation under white light.

Chemosphere 2020 Apr 14;245:125659. Epub 2019 Dec 14.

Beijing Key Laboratory of Functional Materials for Building Structure and Environment Remediation, Beijing University of Civil Engineering and Architecture, Beijing, 100044, China. Electronic address:

The Z-scheme MIL-100(Fe)/PANI composite photocatalysts were facilely prepared from MIL-100(Fe) and polyaniline (PANI) by ball-milling, and were characterized by powder X-ray diffraction (PXRD), Fourier transform infrared spectroscopy (FTIR), thermogravimetric analysis (TGA), transmission electron microscopy (TEM), UV-visible diffuse-reflectance spectrometry (UV-vis DRS), X-ray photoelectron spectroscopy (XPS) and photoluminescence emission spectrometry (PL). The photocatalytic activities of MIL-100(Fe)/PANI composites were investigated via tetracycline degradation and hexavalent chromium reduction in aqueous solution under the irradiation of white light. The results revealed that the MIL-100(Fe)/PANI composite photocatalysts exhibited outstanding photocatalytic activities toward Cr(VI) reduction and tetracycline decomposition. The effects of pH and coexisting ions on the photocatalytic Cr(VI) reduction were investigated. As well, the primary active species were identified via electron spin resonance (ESR) determination. A possible Z-scheme photocatalyst mechanism was proposed and verified. Finally, MIL-100(Fe)/PANI composites demonstrated good reusability and stability in water solution, implying potentially practical applications for real wastewater treatment.
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http://dx.doi.org/10.1016/j.chemosphere.2019.125659DOI Listing
April 2020

[Mutation and Clinical Feature of IL-7R in Adult Patients with Acute Lymphoblastic Leukemia].

Zhongguo Shi Yan Xue Ye Xue Za Zhi 2019 Oct;27(5):1416-1423

Department of Hematology, The First Affiliated Hospital of Zhengzhou University, Zhenzhou 450052, Henan Province,

Objective: To investigate the IL-7R gene mutation and clinical features of adult patients with acute lymphoblastic leukemia (ALL).

Methods: One hundred sixty-four cases of newly treated adults with ALL from May 2016 to December 2018 were selected. Targeted and specific next-generation sequencing technology was used to detected a total of 16 types of Ph-like ALL mutations, which include IL-7R mutation, and the cilinical features, rate, types and sites of IL-7R were analyzed.

Results: IL-7R mutation was determined in 10 cases of 164 adult patients with ALL and the total mutation frequency was 13 times (6.1%). Out of 10 cases 5 cases were male (50%), 5 cases were female (50%). 6 cases of B-ALL ( 60% ) and 4 cases of T-ALL (40%). The mutation site of all cases was located at exon 6, among which 6 cases had replacement mutations, 3 cases had deletion mutations and 4 cases had insertion mutations. In addition, 1 triple and 1 double mutation of IL-7R were found. Besides, six mutation sites were newly identified, including: c.720_724del, c.723_726del, c.721_722insAGTG, c.727_728insTAACGGCCCCCTGCT, c.727_728insATGCAGGGAGCGAA and c.728_729insAAGTGTCA.

Conclusion: Six novel mutation sites and a poor manifestation of IL-7R have been explored in this research. Thus more samples are required to study the effects of IL-7R mutation on ALL treatment.
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http://dx.doi.org/10.19746/j.cnki.issn.1009-2137.2019.05.010DOI Listing
October 2019

Aeromonas hydrophila suppresses complement pathways via degradation of complement C3 in bony fish by metalloprotease.

Fish Shellfish Immunol 2019 Nov 24;94:739-745. Epub 2019 Sep 24.

Institute of Hydrobiology, Chinese Academy of Sciences, Wuhan, China; State Key Laboratory of Agricultural Microbiology, College of Fisheries, Huazhong Agricultural University, Wuhan, China. Electronic address:

Aeromonas hydrophila is a pathogen that causes high mortality in the grass carp. The complement system, as a frontline defence of innate immunity, plays an important role in the immune response against pathogens. However, the immunity evasion mechanism of A. hydrophila against the complement system of grass carp remains unclear. In this study, we described an additional mechanism used by A. hydrophila GD18 to evade the complement system and survive in grass carp serum. First, A. hydrophila evaded the bactericidal activity of grass carp serum. Second, the haemolytic activity assays showed that A. hydrophila obviously suppressed the alternative pathway, which depended on preventing the formation or disabling the function of the membrane-attack complex (MAC). Further research indicated that A. hydrophila targeted complement C3, the central component of the three complement pathways, and degraded it in the grass carp serum, leading to the inhibition of the complement pathways, which resulted in the serum-resistance of A. hydrophila. Furthermore, cleavage analyses showed that extracellular proteases (ECPases) of A. hydrophila efficiently cleaved purified C3 as well as C3 in grass carp serum. Finally, protease inhibitor studies and mass spectrum analysis identified the secreted metalloprotease elastase (AhE), which was present in large amounts in crude ECPases, as the central molecule responsible for C3 cleavage. Compared to wild strain GD18, the AhE knockout, Δahe was dramatically reduced in the ability of serum resistance. Our findings suggested that A. hydrophila escaped serum-killing by suppressing the complement pathways via the degradation of complement C3 in bony fish, which was related to secreted metalloproteases.
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http://dx.doi.org/10.1016/j.fsi.2019.09.057DOI Listing
November 2019

Dexmedetomidine-mediated protection against septic liver injury depends on TLR4/MyD88/NF-κB signaling downregulation partly via cholinergic anti-inflammatory mechanisms.

Int Immunopharmacol 2019 Nov 11;76:105898. Epub 2019 Sep 11.

Department of Critical Care Medicine, Affiliated Haikou Hospital, Xiangya School of Medicine, Central South University, Haikou 570208, China.

Background: Uncontrolled inflammatory responses exacerbate the pathogenesis of septic acute liver injury (ALI), posing a lethal threat to the host. Dexmedetomidine (DEX) has been reported to possess protective properties in inflammatory conditions. This study aimed to investigate whether DEX pretreatment exhibits hepatoprotection against ALI induced by lipopolysaccharide (LPS) in rats and determine its possible molecular mechanism.

Methods: Septic ALI was induced by intravenous injection of LPS. The rats received DEX intraperitoneally 30 min before LPS administration. α-Bungarotoxin (α-BGT), a specific α7 nicotinic acetylcholine receptor (α7nAChR) antagonist, was administered intraperitoneally 1 h before LPS exposure. The role of the vagus nerve was verified by performing unilateral cervical vagotomy or sham surgery before sepsis.

Results: The expression of α7nAChR, toll-like receptor 4 (TLR4), high mobility group box 1 (HMGB1), and cleaved caspase-3 increased, peaking 24 h during sepsis. DEX enhanced α7nAChR activation and reduced TLR4 expression upon challenge with LPS. DEX significantly prevented LPS-induced ALI, which was associated with increased survival, the mitigation of pathological changes, the attenuation of inflammatory cytokine expression and apoptosis, and the downregulation of TLR4/MyD88/NF-κB pathway. Moreover, the hepatoprotective effect of DEX was abolished by α-BGT. Further investigation established that vagotomy, compared to sham surgery, triggered more severe pathogenic manifestations and higher proinflammatory cytokine levels. The inhibitory effects of DEX were shown in sham-operated rats but not in vagotomized rats.

Conclusions: Our data highlight the pivotal function of α7nAChR and intact vagus nerves in protecting against LPS-induced ALI through inhibiting the TLR4/MyD88/NF-κB signaling pathway upon pretreatment with DEX.
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http://dx.doi.org/10.1016/j.intimp.2019.105898DOI Listing
November 2019

Identification and characterization of two mannan-binding lectin associated proteins in lectin complement pathway of grass carp.

Dev Comp Immunol 2020 02 10;103:103497. Epub 2019 Sep 10.

Institute of Hydrobiology, Chinese Academy of Sciences, Wuhan, China; State Key Laboratory of Agricultural Microbiology, College of Fisheries, Huazhong Agricultural University, Wuhan, China. Electronic address:

The lectin pathway of complement activation is an important component of the innate immune response, which must be tightly controlled to maintain immune homeostasis. However, its control mechanisms have not been investigated in detail in bony fish. In this study, we identified and characterized two novel, phylogenetically conserved mannan-binding lectin (MBL)-associated proteins (MAps) of grass carp (Ctenopharyngodon idella), CiMAp27 and CiMAp39, which were truncated, alternatively-spliced forms of grass carp MBL-associated serine proteases (MASPs), CiMASP1 and CiMASP2, respectively. Gene expression profiling showed that both CiMAp27 and CiMAp39 were upregulated by low doses of Aeromonas hydrophila, and inhibited by high doses, which lead to the inference that these genes acted as immune factors in antibacterial defense. Sequence analysis showed that CiMAp27 lack a catalytic domain but retains two domains (CUB1-EGF) involved in the association with MBL, while CiMAp39 retained four domains (CUB1-EGF-CUB2-CCP1). Not only the two CiMASPs but also the CiMAps were detected in grass carp serum. Furthermore, both recombinant CiMASPs (rCiMASPs) and recombinant rCiMAps (rCiMAps) interacted with recombinant MBL and the two CiMAps competed with CiMASPs for binding to MBL, and hence inhibited downstream C4 binding. These results indicated that CiMAps acted as competitive inhibitors in the lectin complement pathway of grass carp.
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http://dx.doi.org/10.1016/j.dci.2019.103497DOI Listing
February 2020
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