Publications by authors named "Ling Shen"

267 Publications

Screening Potential Drugs for COVID-19 Based on Bound Nuclear Norm Regularization.

Front Genet 2021 7;12:749256. Epub 2021 Oct 7.

School of Computer Science, Hunan University of Technology, Zhuzhou, China.

The novel coronavirus pneumonia COVID-19 infected by SARS-CoV-2 has attracted worldwide attention. It is urgent to find effective therapeutic strategies for stopping COVID-19. In this study, a Bounded Nuclear Norm Regularization (BNNR) method is developed to predict anti-SARS-CoV-2 drug candidates. First, three virus-drug association datasets are compiled. Second, a heterogeneous virus-drug network is constructed. Third, complete genomic sequences and Gaussian association profiles are integrated to compute virus similarities; chemical structures and Gaussian association profiles are integrated to calculate drug similarities. Fourth, a BNNR model based on kernel similarity (VDA-GBNNR) is proposed to predict possible anti-SARS-CoV-2 drugs. VDA-GBNNR is compared with four existing advanced methods under fivefold cross-validation. The results show that VDA-GBNNR computes better AUCs of 0.8965, 0.8562, and 0.8803 on the three datasets, respectively. There are 6 anti-SARS-CoV-2 drugs overlapping in any two datasets, that is, remdesivir, favipiravir, ribavirin, mycophenolic acid, niclosamide, and mizoribine. Molecular dockings are conducted for the 6 small molecules and the junction of SARS-CoV-2 spike protein and human angiotensin-converting enzyme 2. In particular, niclosamide and mizoribine show higher binding energy of -8.06 and -7.06 kcal/mol with the junction, respectively. G496 and K353 may be potential key residues between anti-SARS-CoV-2 drugs and the interface junction. We hope that the predicted results can contribute to the treatment of COVID-19.
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http://dx.doi.org/10.3389/fgene.2021.749256DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8529063PMC
October 2021

Sexual dimorphism in intestinal absorption and lymphatic transport of dietary lipids.

J Physiol 2021 Oct 14. Epub 2021 Oct 14.

Department of Pathology and Laboratory Medicine, University of Cincinnati College of Medicine, Cincinnati, OH, 45237, USA.

Key Points: Significant differences in intestinal lipid absorption and lymphatic transport were found between female and male animals. Estrogen treatment significantly reduced [ H]-triacylglycerol (TAG) lymphatic output through suppressing TAG transport in ovariectomized (OVX) rats, and this effect is associated with enhanced vegfa gene expression in the intestine. Progesterone treatment significantly decreased the output of [ C]-cholesterol (Chol) in lymph by inhibiting Chol absorption in the OVX rats. Estrogen treatment also increased lymphatic output of apolipoprotein A-I (apoA-I) in the OVX rats, which may contribute to the reduced risk of atherosclerosis in females.

Abstract: Although the basic process of intestinal lipid absorption and transport is understood, many critical aspects remain unclear. One question, in particular, is whether intestinal lipid absorption and transport differ between the sexes. Using a well-established lymph fistula model, we found that intact female mice exhibited lower lymphatic output of triacylglycerol (TAG) than male mice. Further analysis revealed that the female mice segregated into two groups: the high group having similar lymphatic TAG transport to the males, and the low group having significantly less lymphatic output, implying the impact of cyclical variation of ovarian hormonal levels. These led us to examine whether estradiol (E2) and progesterone (P) affect intestinal absorption and lymphatic transport of dietary lipids. In ovariectomized (OVX) rats, E2 treatment significantly reduced [ H]-TAG lymphatic output through reducing TAG transport; and P-treatment decreased [ C]-cholesterol (Chol) lymphatic output by inhibiting Chol absorption, compared to vehicle treatment. Gene expression data suggested that E2 enhances vascular endothelial growth factor-A (VEGF-A) signaling to reduce the permeability of lacteals, leading to reduced CM transport through the lymphatic system. Interestingly, E2 treatment also increased lymphatic output of apolipoprotein A-I (apoA-I), but not apoB-48 and apoA-IV, in the OVX rats. Collectively, these data suggested that ovarian hormone-induced reductions of intestinal lipid absorption and lymphatic transport, as well as increased lymphatic output of apoA-I, may contribute to a beneficial protection from atherosclerosis in females. This article is protected by copyright. All rights reserved.
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http://dx.doi.org/10.1113/JP281621DOI Listing
October 2021

A Genetically Encoded F-19 NMR Probe Reveals the Allosteric Modulation Mechanism of Cannabinoid Receptor 1.

J Am Chem Soc 2021 Oct 1;143(40):16320-16325. Epub 2021 Oct 1.

Laboratory of RNA Biology, Institute of Biophysics, Chinese Academy of Science, Beijing 100101, China.

Due to the lack of genetically encoded probes for fluorine-19 nuclear magnetic resonance spectroscopy (F NMR), its utility for probing eukaryotic membrane protein dynamics is limited. Here we report an efficient method for the genetic incorporation of an unnatural amino acid (UAA), 3'-trifluoromenthyl-phenylalanine (mtfF), into cannabinoid receptor 1 (CB1) in the Baculovirus Expression System. The probe can be inserted at any environmentally sensitive site, while causing minimal structural perturbation to the target protein. Using F NMR and X-ray crystallography methods, we discovered that the allosteric modulator Org27569 and agonists synergistically stabilize a previously unrecognized pre-active state. An allosteric modulation model is proposed to explain Org27569's distinct behavior. We demonstrate that our site-specific F NMR labeling method is a powerful tool in decoding the mechanism of GPCR allosteric modulation. This new method should be broadly applicable for uncovering conformational states for many important eukaryotic membrane proteins.
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http://dx.doi.org/10.1021/jacs.1c06847DOI Listing
October 2021

Development of a DNAzyme-based colorimetric biosensor assay for dual detection of Cd and Hg.

Anal Bioanal Chem 2021 Sep 29. Epub 2021 Sep 29.

Jiangsu Key Laboratory for Biofunctional Molecules, College of Life Science and Chemistry, Jiangsu Second Normal University, Nanjing, 210013, China.

A colorimetric biosensor assay has been developed for Cd and Hg detection based on Cd-dependent DNAzyme cleavage and Hg-binding-induced conformational switching of the G-quadruplex fragment. Two types of multifunctional magnetic beads (Cd-MBs and Hg-MBs) were synthesized by immobilizing two functionalized DNA sequences on magnetic beads via avidin-biotin chemistry. For Cd detection, Cd-MBs are used as recognition probes, which are modified with a single phosphorothioate ribonucleobase (rA) substrate (PS substrate) and a Cd-specific DNAzyme (Cdzyme). In the presence of Cd, the PS substrate is cleaved by Cdzyme, and single-stranded DNA is released as the signal transduction sequence. After molecular assembly with the other two oligonucleotides, duplex DNA is produced, and it can be recognized and cleaved by FokI endonuclease. Thus, a signal output component consisting of a G-quadruplex fragment is released, which catalyzes the oxidation of ABTS with the addition of hemin and HO, inducing a remarkably amplified colorimetric signal. To rule out false-positive results and reduce interference signals, Hg-MBs modified with poly-T fragments were used as Hg accumulation probes during the course of Cd detection. On the other hand, Hg-MBs can perform their second function in Hg detection by changing the catalytic activity of the G-quadruplex/hemin DNAzyme. In the presence of Hg, the G-quadruplex structure in Hg-MBs is disrupted upon Hg binding. In the absence of Hg, an intensified color change can be observed by the naked eye for the formation of intact G-quadruplex/hemin DNAzymes. The biosensor assay exhibits excellent selectivity and high sensitivity. The detection limits for Cd and Hg are 1.9 nM and 19.5 nM, respectively. Moreover, the constructed sensors were used to detect environmental water samples, and the results indicate that the detection system is reliable and could be further used in environmental monitoring. The design strategy reported in this study could broadly extend the application of metal ion-specific DNAzyme-based biosensors.
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http://dx.doi.org/10.1007/s00216-021-03677-xDOI Listing
September 2021

A novel lncRNA-protein interaction prediction method based on deep forest with cascade forest structure.

Sci Rep 2021 Sep 23;11(1):18881. Epub 2021 Sep 23.

School of Computer Science, Hunan University of Technology, Zhuzhou, 412007, China.

Long noncoding RNAs (lncRNAs) regulate many biological processes by interacting with corresponding RNA-binding proteins. The identification of lncRNA-protein Interactions (LPIs) is significantly important to well characterize the biological functions and mechanisms of lncRNAs. Existing computational methods have been effectively applied to LPI prediction. However, the majority of them were evaluated only on one LPI dataset, thereby resulting in prediction bias. More importantly, part of models did not discover possible LPIs for new lncRNAs (or proteins). In addition, the prediction performance remains limited. To solve with the above problems, in this study, we develop a Deep Forest-based LPI prediction method (LPIDF). First, five LPI datasets are obtained and the corresponding sequence information of lncRNAs and proteins are collected. Second, features of lncRNAs and proteins are constructed based on four-nucleotide composition and BioSeq2vec with encoder-decoder structure, respectively. Finally, a deep forest model with cascade forest structure is developed to find new LPIs. We compare LPIDF with four classical association prediction models based on three fivefold cross validations on lncRNAs, proteins, and LPIs. LPIDF obtains better average AUCs of 0.9012, 0.6937 and 0.9457, and the best average AUPRs of 0.9022, 0.6860, and 0.9382, respectively, for the three CVs, significantly outperforming other methods. The results show that the lncRNA FTX may interact with the protein P35637 and needs further validation.
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http://dx.doi.org/10.1038/s41598-021-98277-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8460650PMC
September 2021

Bipolaquinones A-J, Immunosuppressive Meroterpenoids from a Soil-Derived .

J Nat Prod 2021 Sep 1;84(9):2427-2436. Epub 2021 Sep 1.

Hubei Key Laboratory of Natural Medicinal Chemistry and Resource Evaluation, School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, People's Republic of China.

Ten new meroterpenoids, bipolaquinones A-J (-), and one known congener, isocochlioquinone F (), were isolated and identified from the fermented rice cultures of a soil-derived fungus, . The planar structures of - were elucidated based on extensive spectroscopic analyses (including HRESIMS and 1D and 2D NMR data), and their absolute configurations were determined by single-crystal X-ray diffraction analyses, comparison of experimental electronic circular dichroism (ECD) data, ECD calculations, and hydrolysis reaction. The immunosuppressive activity assay revealed that compounds , , and - showed significant inhibitory activity against concanavalin A (ConA)-induced T lymphocyte proliferation with IC values ranging from 4.1 to 9.4 μM, which furnished potential lead molecules for the design and development of new immunosuppressants for treating autoimmune-associated diseases.
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http://dx.doi.org/10.1021/acs.jnatprod.1c00327DOI Listing
September 2021

Theory of the exterior-interior relationship between the lungs and the large intestine to explore the mechanism of Eriobotrya japonica leaf water extract in the treatment of cough variant asthma.

J Ethnopharmacol 2021 Dec 23;281:114482. Epub 2021 Aug 23.

College of Life Science and Engineering, Southwest Jiaotong University, Chengdu, 610031, China. Electronic address:

Ethnopharmacological Relevance: Eriobotrya japonica (Thunb.) Lindl leaf (EJL) is used as a traditional Chinese medicine. E. japonica is a member of the Rosaceae family. EJL suppresses cough and relieves asthma and is widely used to treat lung diseases. In the present study, guided by the traditional Chinese medicine theory of the exterior-interior relationship between the lungs and the large intestine, the pathogenesis of cough variant asthma (CVA) and the treatment mechanism of EJL on CVA were explored.

Aim Of The Study: This study aimed to explore the airway remodeling effects of EJL in CVA from the perspective of the intestinal flora and the matrix metallopeptidase 9/tissue inhibitor of metalloproteinases-1 (MMP-9/TIMP-1) pathway.

Materials And Methods: The oleanolic acid and ursolic acid contents in EJL were measured by high-performance liquid chromatography (HPLC) to ensure the quality of EJL. BALB/c mice were used to establish a CVA model through ovalbumin (OVA) sensitization and atomization. EJL (at 5, 10, or 20 g/kg/day) was intragastrically administered. The body weight, ratio of total bronchial wall area (WAt) to bronchial basement membrane perimeter (Pbm) (WAt/Pbm), the number of coughs, and cough latency were measured. The pathological changes of the lung tissue were analyzed by hematoxylin and eosin (HE) staining. The expression of α-smooth muscle actin (α-SMA) was measured by immunohistochemistry (IHC). The expressions of MMP-9 and TIMP-1 were detected in the lung tissue by reverse transcription quantitative polymerase chain reaction (RT-PCR) and Western blot analysis. Additionally, an Illumina Hiseq platform was used for 16S ribosomal DNA (16S rDNA) high-throughput sequencing to detect the intestinal flora in feces samples.

Results: The results confirmed the positive effects of EJL on CVA. After administration of EJL, the number of coughs and the WAt/Pbm ratio decreased, the cough latency was prolonged, body weight was increased, and the general status was better than that of the CVA model mice. HE staining revealed that EJL decreased inflammatory cell infiltration and improved the histopathological structure of the lung tissue. EJL also showed significant inhibitory effects on the expression of α-SMA, MMP-9, and TIMP-1 and normalized the intestinal flora to a certain extent.

Conclusions: The results demonstrated that EJL alleviated airway remodeling of CVA mice, which might be related to the inhibition of the MMP-P/TIMP-1 pathway and the regulation of intestinal flora.
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http://dx.doi.org/10.1016/j.jep.2021.114482DOI Listing
December 2021

Online evaluation method of coal mine comprehensive level based on FCE.

PLoS One 2021 16;16(8):e0256026. Epub 2021 Aug 16.

School of Business Administration, Henan Polytechnic University, Henan Jiaozuo, China.

An online evaluation method of coal mine comprehensive level based on Fuzzy Comprehensive Evaluation method (FCE) is proposed. Firstly, following the principles of fairness, systematicness and hierarchy, taking research and development, production, sales, finance, safety and management as the first level indicators, a set of multi-level evaluation indicator system of coal mine comprehensive level combining objective and subjective evaluation indicators is established. Secondly, according to the characteristics of the indicator system, the specific process of FCE of coal mine comprehensive level is given. Then, taking SQL Server as the database management system and C#.NET as the development language, a set of B/S structure online evaluation system of coal mine comprehensive level based on FCE is designed and developed. Finally, the proposed method is applied to Coal group PM for test. The application shows that the method proposed can provide an efficient and convenient online evaluation platform to evaluate the comprehensive level of coal mines for the Coal group, and the horizontal and longitudinal comparison of the evaluation results can urge the coal mines to maintain their advantages and avoid their disadvantages, which is of some significance for improving the overall competitiveness of the Coal group.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0256026PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8366963PMC
August 2021

Involvement of noncoding RNA in blood-brain barrier integrity in central nervous system disease.

Noncoding RNA Res 2021 Sep 9;6(3):130-138. Epub 2021 Jul 9.

School of Medicine, Southeast University, Nanjing, 210009, Jiangsu, China.

Given the important role of the blood-brain barrier (BBB) in the central nervous system (CNS), increasing studies have been carried out to determine how the structural and functional integrity of the BBB impacts the pathogenesis of CNS diseases such as stroke, traumatic brain injuries (TBIs), and gliomas. Emerging studies have revealed that noncoding RNAs (ncRNAs) help to maintain the integrity and permeability of the BBB, thereby mediating CNS homeostasis. This review summarizes recent studies that focus on the effects of ncRNAs on the BBB in CNS diseases, including regulating the biological processes of inflammation, necrosis, and apoptosis of cells, affecting the translational dysfunction of proteins and regulating tight junctions (TJs). A comprehensive and detailed understanding of the interaction between ncRNAs and the BBB will lay a solid foundation for the development of early diagnostic methods and effective treatments for CNS diseases.
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http://dx.doi.org/10.1016/j.ncrna.2021.06.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8327137PMC
September 2021

Genetics and Functional Mechanisms of STAT3 Polymorphisms in Human Tuberculosis.

Front Cell Infect Microbiol 2021 7;11:669394. Epub 2021 Jul 7.

Clinic and Research Center of Tuberculosis, Shanghai Key Laboratory of Tuberculosis, Shanghai Pulmonary Hospital, Institute for Advanced Study, Tongji University School of Medicine, Shanghai, China.

Signal transducer and activator of transcription-3 (STAT3) plays an important role in biological balance. Our and others previous studies implied that STAT3 had a great effect on fast-acting innate immunity against tuberculosis (TB). We hypothesized that SNP down-regulation of STAT3 leads to a change in susceptibility to TB in humans. To test this hypothesis, we investigated STAT3 SNPs using SNP scan™ technique in a case-control study of TB patients (n = 470) and HC subjects (n = 356), and then conducted functional studies of them using cellular models. We found that SNPs in STAT3 3`-UTR of rs1053004 TT and rs1053005 AA genotypes or T-A haplotype were associated with susceptibility to TB or TB severity. While the TT/AA genotype correlated with the low constitutive expression of and in PBMC, the variant of rs1053004-rs1053005 T-A haplotype indeed reduced expression in reporter assays. Interestingly, host PBMC expressing the rs1053005 AA genotype and low constitutive exhibited the reduced ability to mount fast-acting innate immunity against mycobacterial infection in cellular models. Finally, mechanistic experiments showed that the STAT3 down-regulation broadly depressed STAT3 downstream anti-mycobacterial activities involving VDR-related CAMP pathway as well as IL-32, iNOS and autophagy mechanisms, leading to an enhanced mycobacterial infection. The findings of this study suggest that low constitutive stat3 derived from the TT/AA genotype/T-A haplotype acts to down-regulate STAT3, depressing multiple anti-mycobacterial pathways/mechanisms downstream, which leads to an enhanced mycobacterial infection or TB in high-risk individuals.
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http://dx.doi.org/10.3389/fcimb.2021.669394DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8294188PMC
July 2021

Protocol for crystal structure determination of the antagonist-bound human cannabinoid receptor CB2.

STAR Protoc 2021 Jun 7;2(2):100584. Epub 2021 Jun 7.

iHuman Institute, ShanghaiTech University, Shanghai 201210, China.

Human cannabinoid receptor CB2 plays an important role in the immune system and is an attractive therapeutic target for pain and for inflammatory and neurodegenerative diseases. However, the structural basis of CB2 agonist selectivity is still elusive. Here, we describe a detailed protocol for the determination of the crystal structure of antagonist AM10257-bound CB2. This methodology could be applied to the structural studies of CB2 with diverse antagonists and agonists or to other class A G-protein-coupled receptors. For complete details on the use and execution of this protocol, please refer to Li et al. (2019).
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http://dx.doi.org/10.1016/j.xpro.2021.100584DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8192724PMC
June 2021

Chest pain variant asthma: a report of two cases.

Authors:
Ling Shen

Chin Med J (Engl) 2021 Jun 1;134(15):1877-1879. Epub 2021 Jun 1.

Department of Respiratory Medicine, Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310000, China.

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http://dx.doi.org/10.1097/CM9.0000000000001495DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8367021PMC
June 2021

Effects of blended versus offline case-centred learning on the academic performance and critical thinking ability of undergraduate nursing students: A cluster randomised controlled trial.

Nurse Educ Pract 2021 May 14;53:103080. Epub 2021 May 14.

School of Nursing, Fujian Medical University, No. 1 Xueyuan Road, Shangjie Town, Minhou County, Fuzhou, China.

Objective: This study aimed to compare the effect of blended and offline case-centred learning on medical nursing education for undergraduate nursing students.

Background: Technological advancements are rapidly changing nursing education in higher educational settings. Educational reform, especially regarding methods of teaching, has been the focus of nursing educators in recent years.

Design: The research was conducted between September 2018 and July 2019 in China.

Methods: Second-year undergraduate nursing students in two classes were enrolled for this study by cluster sampling. The study outcomes were academic performance and critical thinking ability, measured using the Critical Thinking Disposition Inventory-Chinese Version.

Results: Students in the experimental class showed significantly higher improvements in academic performance than those in the control class. Compared with the control class, the pre-post difference in competency in critical thinking self-confidence in the experimental class was significantly greater (p = 0.037). In the experimental class, there was a significant improvement over the baseline in the dimension of critical thinking self-confidence (p = 0.022). In the control class, there was a significant improvement over the baseline in the total score (p = 0.029) and two of the seven dimensions: truth-seeking (p = 0.016) and systematicity (p = 0.005).

Conclusions: The use of blended case-centred learning showed promising results in improving students' academic performance. Both blended and offline case-centred learning were indicated to be effective educational approaches to improve the critical thinking ability of undergraduate nursing students and could be implemented for other nursing subjects in the future.
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http://dx.doi.org/10.1016/j.nepr.2021.103080DOI Listing
May 2021

Hydroxytyrosol alleviates oxidative stress and neuroinflammation and enhances hippocampal neurotrophic signaling to improve stress-induced depressive behaviors in mice.

Food Funct 2021 Jun;12(12):5478-5487

College of Food Science and Technology, Guangdong Ocean University, Zhanjiang, 524088, P.R. China.

Hydroxytyrosol (HT), the main phenolic compound in olives and olive products, has antioxidative, anti-inflammatory, neuroprotective, and other physiological functions. The effects of HT on depression are unclear. The aim of this study was to explore the effects of HT on chronic unpredictable mild stress (CUMS) induced depressive-like behaviors. Mice were exposed to CUMS for 9 weeks and then treated with HT beginning in the second week and continuing for 7 weeks. Behavioral, biochemical, and molecular tests were conducted at the end of the experiment. The sucrose preference was significantly decreased in the CUMS group versus the healthy control group. Also, immobility times in forced swimming and tail suspension tests were increased in CUMS-induced mice, but treatment with HT significantly reversed this change. HT ameliorated oxidative stress in CUMS-exposed mice by enhancing superoxide dismutase activity and reducing reactive oxygen species and malondialdehyde levels in the hippocampus. HT administration significantly suppressed microglia activation and inhibited the expression of tumor necrosis factor alpha and interleukin 1 beta in the hippocampus versus the untreated group. The expression level of glial fibrillary acidic protein (GFAP) and the number of GFAP-immunoreactive astrocytes in the hippocampus were significantly augmented by HT. Furthermore, HT treatment increased the expression of hippocampal brain-derived neurotrophic factor (BDNF), phosphorylated tropomyosin receptor kinase B (p-TrkB), and phosphorylated c-AMP response element binding protein (p-CREB) compared with the untreated CUMS group. Overall, HT improved CUMS-induced depressive-like behaviors in mice by alleviating oxidative stress and neuroinflammation and by enhancing the BDNF/TrkB/CREB signaling pathway.
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http://dx.doi.org/10.1039/d1fo00210dDOI Listing
June 2021

Inhibition of sestrin 1 alleviates polycystic ovary syndrome by decreasing autophagy.

Aging (Albany NY) 2021 04 22;13(8):11774-11785. Epub 2021 Apr 22.

Department of Obstetrics and Gynecology, The First Affiliated Hospital of Shantou University Medical College, Shantou, Guangdong 515041, China.

Polycystic ovary syndrome (PCOS) is the most common endocrine disorder in women of reproductive age, accounting for 50-70% of anovulatory infertility cases. However, the etiology of PCOS at the molecular level remains unclear. Here, bioinformatics analysis was performed to identify differentially expressed genes (DEGs) between adipose tissue of PCOS patients and matched tissues from non-hyperandrogenic women. RT-qPCR, western blot, cell counting kit-8 (CCK-8), EdU (5-Ethynyl-2'-deoxyuridine) staining, LC3 staining, ROS (reactive oxygen species) detection, and apoptosis assays were conducted to explore the effects of sestrin 1 on KGN human granulosa-like tumor cells. Bioinformatics analysis indicated that DEGs in adipose tissue from PCOS patients were enriched in the p53 signaling pathway. Moreover, sestrin 1 was identified as a major target of the p53 gene. Downregulation of sestrin 1 inhibited proliferation of KGN cells by inhibiting autophagy. Additionally, sestrin 1 downregulation increased ROS generation and promoted apoptosis in KGN cells. By contrast, overexpression of sestrin 1 increased cell viability by increasing autophagy in KGN cells. Together, these results suggest that downregulation of sestrin 1 may be a potential novel treatment strategy for PCOS.
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http://dx.doi.org/10.18632/aging.202872DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8109134PMC
April 2021

Structural insights into the activation of chemokine receptor CXCR2.

FEBS J 2021 Apr 9. Epub 2021 Apr 9.

iHuman Institute, ShanghaiTech University, China.

The C-X-C motif chemokine CXCL8 (interleukin-8, IL-8) and its receptor chemokine receptor 2 (CXCR2) mediate neutrophil migration during cell development and inflammatory responses and thus are related to numerous inflammatory diseases and cancers. We have determined the cryo-electron microscopy structure of CXCL8 bound CXCR2 coupled to G protein, as well as the crystal structure of inactive CXCR2 in complex with a designed allosteric antagonist. These results reveal the binding modes between CXCL8 and CXCR2, CXCR2 and G protein, and the detailed binding pattern of the allosteric antagonist, 00767013. Further structural analysis of the inactive- and active- states of CXCR2 reveals the unique shallow-pocket activation mechanism of C-X-C chemokine receptors and promotes our understanding on how a G protein-coupled receptor (GPCR) is activated by an endogenous protein molecule. In addition, the cholesterol molecule is observed in the activated CXCR2 structure, providing the structural basis of the potential allosteric modulation role of cholesterol in chemokine receptors.
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http://dx.doi.org/10.1111/febs.15865DOI Listing
April 2021

UCPSO: A Uniform Initialized Particle Swarm Optimization Algorithm with Cosine Inertia Weight.

Comput Intell Neurosci 2021 18;2021:8819333. Epub 2021 Mar 18.

Shanghai University of Medicine & Health Sciences, Shanghai 201318, China.

The particle swarm optimization algorithm (PSO) is a meta-heuristic algorithm with swarm intelligence. It has the advantages of easy implementation, high convergence accuracy, and fast convergence speed. However, PSO suffers from falling into a local optimum or premature convergence, and a better performance of PSO is desired. Some methods adopt improvements in PSO parameters, particle initialization, or topological structure to enhance the global search ability and performance of PSO. These methods contribute to solving the problems above. Inspired by them, this paper proposes a variant of PSO with competitive performance called UCPSO. UCPSO combines three effective improvements: a cosine inertia weight, uniform initialization, and a rank-based strategy. The cosine inertia weight is an inertia weight in the form of a variable-period cosine function. It adopts a multistage strategy to balance exploration and exploitation. Uniform initialization can prevent the aggregation of initial particles. It distributes initial particles uniformly to avoid being trapped in a local optimum. A rank-based strategy is employed to adjust an individual particle's inertia weight. It enhances the swarm's capabilities of exploration and exploitation at the same time. Comparative experiments are conducted to validate the effectiveness of the three improvements. Experiments show that the UCPSO improvements can effectively improve global search ability and performance.
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http://dx.doi.org/10.1155/2021/8819333DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7997771PMC
July 2021

Involvement of HECTD1 in LPS-induced astrocyte activation via σ-1R-JNK/p38-FOXJ2 axis.

Cell Biosci 2021 Mar 30;11(1):62. Epub 2021 Mar 30.

Department of Pharmacology, School of Medicine, Southeast University, Nanjing, 210009, Jiangsu, China.

Background: Astrocytes participate in innate inflammatory responses within the mammalian central nervous system (CNS). HECT domain E3 ubiquitin protein ligase 1 (HECTD1) functions during microglial activation, suggesting a connection with neuroinflammation. However, the potential role of HECTD1 in astrocytes remains largely unknown.

Results: Here, we demonstrated that HECTD1 was upregulated in primary mouse astrocytes after 100 ng/ml lipopolysaccharide (LPS) treatment. Genetic knockdown of HECTD1 in vitro or astrocyte-specific knockdown of HECTD1 in vivo suppressed LPS-induced astrocyte activation, whereas overexpression of HECTD1 in vitro facilitated LPS-induced astrocyte activation. Mechanistically, we established that LPS activated σ-1R-JNK/p38 pathway, and σ-1R antagonist BD1047, JNK inhibitor SP600125, or p38 inhibitor SB203580 reversed LPS-induced expression of HECTD1, thus restored LPS-induced astrocyte activation. In addition, FOXJ2 functioned as a transcription factor of HECTD1, and pretreatment of primary mouse astrocytes with BD1047, SB203580, and SP600125 significantly inhibited LPS-mediated translocation of FOXJ2 into the nucleus.

Conclusions: Overall, our present findings suggest that HECTD1 participates in LPS-induced astrocyte activation by activation of σ-1R-JNK/p38-FOXJ2 pathway and provide a potential therapeutic strategy for neuroinflammation induced by LPS or any other neuroinflammatory disorders.
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http://dx.doi.org/10.1186/s13578-021-00572-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8008527PMC
March 2021

Comorbidities and functional impairments in children with attention deficit hyperactivity disorder in China: a hospital-based retrospective cross-sectional study.

BMJ Open 2021 03 22;11(3):e042196. Epub 2021 Mar 22.

Department of Child and Adolescent Healthcare, Children's Hospital of Soochow University, Suzhou, China

Objectives: The aim of this study was to assess comorbidity patterns and functional impairment in children with and without attention deficit hyperactivity disorder (ADHD).

Design: Hospital-based retrospective cross-sectional study; data collection occurred between 2016 and 2019.

Settings And Patients: A total of 8256 children and adolescents, 6-17 years of age, with suspected ADHD agreed to participate in this hospital-based cross-sectional study over a 4-year period in China. Comorbidities and social functions were assessed according to the scales Vanderbilt ADHD Diagnostic Parent Rating Scale and Weiss Functional Impairment Rating Scale-Parent Form, which were completed by the parents of the study participants.

Results: Of the 8256 children, 5640 were diagnosed with ADHD. Other 2616 children who did not meet the ADHD diagnostic criteria were classified as the N-ADHD group . The proportion of comorbidities (47.4%) and functional impairments (84.5%) in the ADHD group were higher than the N-ADHD group (p≤0.001). The functional impairment scores in all of the six domains, including family, academic, life skills, self-concept, social activities and risky activities, were significantly higher in the ADHD group than the N-ADHD group (p≤0.001). The functional impairment in ADHD group with comorbidities was more severe than those without comorbidities (p≤0.001). Comorbidities and core symptoms both can affect the functions of children with ADHD. Logistics regression analysis indicated that in all of the six functional domains, the effect of comorbidities on functional impairment exceeded the effects of ADHD core symptoms.

Conclusions: Comorbidities had the greatest influence on different areas of adaptive functioning in children with ADHD. Clinical management of children suspected to have ADHD should address multiple comorbidities and functional impairments assessment, as well as core symptom analysis.
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http://dx.doi.org/10.1136/bmjopen-2020-042196DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7986753PMC
March 2021

Prioritizing antiviral drugs against SARS-CoV-2 by integrating viral complete genome sequences and drug chemical structures.

Sci Rep 2021 03 18;11(1):6248. Epub 2021 Mar 18.

School of Computer Science, Hunan University of Technology, Zhuzhou, 412007, China.

The outbreak of a novel febrile respiratory disease called COVID-19, caused by a newfound coronavirus SARS-CoV-2, has brought a worldwide attention. Prioritizing approved drugs is critical for quick clinical trials against COVID-19. In this study, we first manually curated three Virus-Drug Association (VDA) datasets. By incorporating VDAs with the similarity between drugs and that between viruses, we constructed a heterogeneous Virus-Drug network. A novel Random Walk with Restart method (VDA-RWR) was then developed to identify possible VDAs related to SARS-CoV-2. We compared VDA-RWR with three state-of-the-art association prediction models based on fivefold cross-validations (CVs) on viruses, drugs and virus-drug associations on three datasets. VDA-RWR obtained the best AUCs for the three fivefold CVs, significantly outperforming other methods. We found two small molecules coming together on the three datasets, that is, remdesivir and ribavirin. These two chemical agents have higher molecular binding energies of - 7.0 kcal/mol and - 6.59 kcal/mol with the domain bound structure of the human receptor angiotensin converting enzyme 2 (ACE2) and the SARS-CoV-2 spike protein, respectively. Interestingly, for the first time, experimental results suggested that navitoclax could be potentially applied to stop SARS-CoV-2 and remains to further validation.
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http://dx.doi.org/10.1038/s41598-021-83737-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7973547PMC
March 2021

Ultralong PtPd Alloyed Nanowires Anchored on Graphene for Efficient Methanol Oxidation Reaction.

Chem Asian J 2021 May 30;16(9):1130-1137. Epub 2021 Mar 30.

State Key Laboratory of Advanced Technology for Materials Synthesis and Processing & School of Materials Science and Engineering & International School of Materials Science and Engineering, Wuhan University of Technology, 122, Luoshi Road, Wuhan, 430070, P. R. China.

The rational synthesis of Pt-based alloyed nanowires still remains a great challenge because of the different reduction potentials between Pt and another metal and the intrinsic feature of isotropic growth in face-centered cubic (fcc) structured Pt. In this work, PtPd alloyed nanowires with ultrahigh aspect ratio anchored on graphene (PtPd NWs/graphene) were synthesized by a facile solvothermal method without the use of any templates or surfactants. Due to the integration of ultralong PtPd nanowires and stable graphene support, PtPd NWs/graphene exhibited outstanding electrochemical activity toward methanol oxidation reaction (MOR) in comparison with pure Pt NWs/graphene and commercial Pt/C catalysts. Meanwhile, PtPd NWs/graphene had a much higher current density than Pt NWs/graphene and commercial Pt/C catalysts at a constant potential for 7200s in alkaline methanol solution. Moreover, after 1000 cycles of durability testing, PtPd NWs/graphene retained 89.2% of its initial mass activity, much superior to the 63.7% retained for commercial Pt/C.
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http://dx.doi.org/10.1002/asia.202100156DOI Listing
May 2021

A CD4+CD161+ T-Cell Subset Present in Unexposed Humans, Not Tb Patients, Are Fast Acting Cells That Inhibit the Growth of Intracellular Mycobacteria Involving CD161 Pathway, Perforin, and IFN-γ/Autophagy.

Front Immunol 2021 26;12:599641. Epub 2021 Feb 26.

Department of Microbiology and Immunology, Center for Primate Biomedical Research, University of Illinois College of Medicine, Chicago, IL, United States.

It remains undefined whether a subset of CD4+ T cells can function as fast-acting cells to control (Mtb) infection. Here we show that the primary CD4+CD161+ T-cell subset, not CD4+CD161-, in unexposed healthy humans fast acted as unconventional T cells capable of inhibiting intracellular Mtb and BCG growth upon exposure to infected autologous and allogeneic macrophages or lung epithelial A549 cells. Such inhibition coincided with the ability of primary CD4+CD161+ T cells to rapidly express/secrete anti-TB cytokines including IFN-γ, TNF-α, IL-17, and perforin upon exposure to Mtb. Mechanistically, blockades of CD161 pathway, perforin or IFN-γ by blocking mAbs abrogated the ability of CD4+CD161+ T cells to inhibit intracellular mycobacterial growth. Pre-treatment of infected macrophages with inhibitors of autophagy also blocked the CD4+CD161+ T cell-mediated growth inhibition of mycobacteria. Furthermore, adoptive transfer of human CD4+CD161+ T cells conferred protective immunity against mycobacterial infection in SCID mice. Surprisingly, CD4+CD161+ T cells in TB patients exhibited a loss or reduction of their capabilities to produce perforin/IFN-γ and to inhibit intracellular growth of mycobacteria in infected macrophages. These immune dysfunctions were consistent with PD1/Tim3 up-regulation on CD4+CD161+ T cells in active tuberculosis patients, and the blockade of PD1/Tim3 on this subset cells enhanced the inhibition of intracellular mycobacteria survival. Thus, these findings suggest that a fast-acting primary CD4+CD161+T-cell subset in unexposed humans employs the CD161 pathway, perforin, and IFN-γ/autophagy to inhibit the growth of intracellular mycobacteria, thereby distinguishing them from the slow adaptive responses of conventional CD4+ T cells. The presence of fast-acting CD4+CD161+ T-cell that inhibit mycobacterial growth in unexposed humans but not TB patients also implicates the role of these cells in protective immunity against initial Mtb infection.
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http://dx.doi.org/10.3389/fimmu.2021.599641DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7959736PMC
July 2021

Empyema associated with vegetable foreign body aspiration.

Authors:
Ling Shen

World J Emerg Med 2021 ;12(2):162-164

Department of Respiratory Medicine, Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou 310000, China.

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http://dx.doi.org/10.5847/wjem.j.1920-8642.2021.02.015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7947564PMC
January 2021

Nicotine withdrawal induces hyperalgesia via downregulation of descending serotonergic pathway in the nucleus raphe magnus.

Neuropharmacology 2021 05 17;189:108515. Epub 2021 Mar 17.

Department of Anesthesiology, Shanghai Eastern Hepatobiliary Surgery Hospital, Shanghai, 200438, China. Electronic address:

Patients deprived of cigarettes exhibit increased pain sensitivity during perioperative periods, yet the underlying neuroanatomical and molecular bases of this hypersensitivity are unclear. The present study showed that both the mechanical withdrawal threshold (MWT) and thermal withdrawal latency (TWL) were significantly decreased in a rat model of nicotine withdrawal. These rats showed less tryptophan hydroxylase 2 (TPH2) positive neurons and reduced TPH2 expression in the nucleus raphe magnus (NRM), and thus resulted in decreased 5-hydroxytryptamine (5-HT) levels in cerebrospinal fluid. Intrathecal injection of 5-HT or NRM microinjection of TPH-overexpression adeno-associated virus alleviated nicotine withdrawal-induced hyperalgesia, whereas 5-HT receptor pharmacological blockade by methysergide (a 5-HT receptor antagonist) exacerbated hypersensitivity and diminished the difference between the two groups. Together, these data indicate that hyperalgesia after nicotine withdrawal is mediated by declined descending serotonergic pathways in the NRM. This provides a new perspective to improve the postoperative pain management of patients, especially the smokers.
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http://dx.doi.org/10.1016/j.neuropharm.2021.108515DOI Listing
May 2021

Circular RNA TRAPPC6B inhibits intracellular growth while inducing autophagy in macrophages by targeting microRNA-874-3p.

Clin Transl Immunology 2021 18;10(2):e1254. Epub 2021 Feb 18.

Department of Clinical Immunology Institute of Laboratory Medicine Guangdong Provincial Key Laboratory of Medical Molecular Diagnostics Guangdong Medical University Dongguan China.

Objectives: Genetic and epigenetic mechanisms regulate antimicrobial immunity against (Mtb) infection.

Methods: The present study assessed circular RNA TRAPPC6B (circTRAPPC6B) for antimicrobial immune functions and defined mechanisms wherein circTRAPPC6B regulates Mtb growth, autophagy and microRNA in macrophages.

Results: The Mtb infection of monocytes/macrophages resulted in a significantly decreased level of circTRAPPC6B that inhibited intracellular Mtb growth in macrophages. Conversely, circTRAPPC6B expression enhanced autophagy or autophagy-associated protein LC3-II production in Mtb-infected macrophages. circTRAPPC6B-enhanced autophagy aggregation or sequestration was also observed in fluorescence hybridisation (FISH) analysis and confocal imaging. Mechanistically, circTRAPPC6B targets an inhibiting element miR-874-3p, as shown by bioinformatics, dual-luciferase reporter gene analysis and pull-down assay, respectively. Notably, miR-874-3p prohibited autophagy via suppressing autophagy protein ATG16L1 by binding to its 3'-untranslated region (UTR) in Mtb-infected macrophages and thus promoting intracellular Mtb growth. Concurrently, circTRAPPC6B enhanced autophagy in Mtb-infected macrophages by blocking the ability of miR-874-3p to inhibit ATG16L1. Thus, circTRAPPC6B antagonises the ability of to suppress expression and activate and enhance autophagy sequestration to restrict Mtb growth in macrophages.

Conclusion: The current findings suggested that both circTRAPPC6B and miR-874-3p mechanisms can be explored as potential therapeutics against Mtb infection.
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http://dx.doi.org/10.1002/cti2.1254DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7890665PMC
February 2021

Investigating rare pathogenic/likely pathogenic exonic variation in bipolar disorder.

Mol Psychiatry 2021 Jan 22. Epub 2021 Jan 22.

HudsonAlpha Institute for Biotechnology, Huntsville, AL, 35806, USA.

Bipolar disorder (BD) is a serious mental illness with substantial common variant heritability. However, the role of rare coding variation in BD is not well established. We examined the protein-coding (exonic) sequences of 3,987 unrelated individuals with BD and 5,322 controls of predominantly European ancestry across four cohorts from the Bipolar Sequencing Consortium (BSC). We assessed the burden of rare, protein-altering, single nucleotide variants classified as pathogenic or likely pathogenic (P-LP) both exome-wide and within several groups of genes with phenotypic or biologic plausibility in BD. While we observed an increased burden of rare coding P-LP variants within 165 genes identified as BD GWAS regions in 3,987 BD cases (meta-analysis OR = 1.9, 95% CI = 1.3-2.8, one-sided p = 6.0 × 10), this enrichment did not replicate in an additional 9,929 BD cases and 14,018 controls (OR = 0.9, one-side p = 0.70). Although BD shares common variant heritability with schizophrenia, in the BSC sample we did not observe a significant enrichment of P-LP variants in SCZ GWAS genes, in two classes of neuronal synaptic genes (RBFOX2 and FMRP) associated with SCZ or in loss-of-function intolerant genes. In this study, the largest analysis of exonic variation in BD, individuals with BD do not carry a replicable enrichment of rare P-LP variants across the exome or in any of several groups of genes with biologic plausibility. Moreover, despite a strong shared susceptibility between BD and SCZ through common genetic variation, we do not observe an association between BD risk and rare P-LP coding variants in genes known to modulate risk for SCZ.
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http://dx.doi.org/10.1038/s41380-020-01006-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8295400PMC
January 2021

Coinfection by and in a human immunodeficiency virus-negative patient with anti-interferon-γ autoantibody: a case report.

J Int Med Res 2021 Jan;49(1):300060520976471

Department of Respiratory Medicine, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, P.R. China.

Patients with anti-interferon (IFN)-γ autoantibodies have weakened immune defenses against intracellular pathogens. Because of its low incidence and non-specific symptoms, diagnosis of anti-IFN-γ autoantibody syndrome is difficult to establish during the early stages of infection. Here, we report a patient with high titers of serum anti-IFN-γ autoantibodies suffering from opportunistic infections. The patient presented with intermittent fever for 2 weeks. During his first hospitalization, he was diagnosed with pulmonary infection and successfully treated with antifungal therapy. However, multiple cervical lymph nodes subsequently became progressively enlarged. infection was confirmed by positive cervical lymph node tissue cultures. High-titer serum anti-IFN-γ antibodies were also detected. Following anti- therapy, both his symptoms and lymph node lymphadenitis gradually improved. Anti-IFN-γ autoantibody syndrome should be considered in adult patients with severe opportunistic coinfections in the absence of other known risk factors.
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http://dx.doi.org/10.1177/0300060520976471DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7809313PMC
January 2021

Estradiol Enhances Anorectic Effect of Apolipoprotein A-IV through ERα-PI3K Pathway in the Nucleus Tractus Solitarius.

Genes (Basel) 2020 12 12;11(12). Epub 2020 Dec 12.

Department of Pathology and Laboratory Medicine, University of Cincinnati College of Medicine, Cincinnati, OH 45237, USA.

Estradiol (E2) enhances the anorectic action of apolipoprotein A-IV (apoA-IV), however, the intracellular mechanisms are largely unclear. Here we reported that the phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathway was significantly activated by E2 and apoA-IV, respectively, in primary neuronal cells isolated from rat embryonic brainstem. Importantly, the combination of E2 and apoA-IV at their subthreshold doses synergistically activated the PI3K/Akt signaling pathway. These effects, however, were significantly diminished by the pretreatment with LY294002, a selective PI3K inhibitor. E2-induced activation of the PI3K/Akt pathway was through membrane-associated ERα, because the phosphorylation of Akt was significantly increased by PPT, an ERα agonist, and by E2-BSA (E2 conjugated to bovine serum albumin) which activates estrogen receptor on the membrane. Centrally administered apoA-IV at a low dose (0.5 µg) significantly suppressed food intake and increased the phosphorylation of Akt in the nucleus tractus solitarius (NTS) of ovariectomized (OVX) rats treated with E2, but not in OVX rats treated with vehicle. These effects were blunted by pretreatment with LY294002. These results indicate that E2's regulatory role in apoA-IV's anorectic action is through the ERα-PI3K pathway in the NTS. Manipulation of the PI3K/Akt signaling activation in the NTS may provide a novel therapeutic approach for the prevention and the treatment of obesity-related disorders in females.
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http://dx.doi.org/10.3390/genes11121494DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7764025PMC
December 2020

PARP14 inhibits microglial activation via LPAR5 to promote post-stroke functional recovery.

Autophagy 2021 Oct 15;17(10):2905-2922. Epub 2020 Dec 15.

Department of Pharmacology, School of Medicine, Southeast University, Nanjing, Jiangsu, China.

Stroke is a major public health problem leading to high rates of death and disability worldwide, but no effective pharmacological therapy is currently available except for the use of PLAT (plasminogen activator, tissue). Here we show that PARP14 (poly (ADP-ribose) polymerase family, member 14) level was significantly increased in the peri-infarct zone of photothrombotic stroke (PT) mice. Genetic knockdown and pharmacological inhibition of PARP14 aggravated functional impairment and increased infarct volume in PT mice, while overexpression of PARP14 displayed the opposite effects. Furthermore, PARP14 was abundant in microglia, and downregulation of PARP14 increased post-stroke microglial activation, whereas overexpression of PARP14 alleviated microglial activation, possibly through microglial macroautophagy/autophagy modulation. Mechanistically, overexpression of PARP14 suppressed (lysophosphatidic acid receptor 5) gene transcription to inhibit microglial activation post stroke. Taken together, PARP14 is a stroke-induced signal that restricts microglial activation and promotes functional recovery, and can serve as a novel target to develop new therapeutic agents for stroke. Moreover, these findings may be conducive to proper use of various PARP inhibitors.: 3-MA: 3-methyladenine; AIF1/Iba-1: allograft inflammatory factor 1; CNS: central nervous system; CQ: chloroquine; DAPI: 4',6-diamidino-2-phenylindole; DMEM: Dulbecco's modified Eagle's medium; DMSO: dimethyl sulfoxide; ELISA: enzyme-linked immunosorbent assay; FBS: fetal bovine serum; GFAP: glial fibrillary acidic protein; IL1B/IL-1β: interleukin 1 beta; IL6/IL-6: interleukin 6; LPAR5: lysophosphatidic acid receptor 5; MAP1LC3B: microtubule-associated protein 1 light chain 3 beta; NOS2/iNOS: nitric oxide synthase 2, inducible; OGD: oxygen glucose deprivation; PAR: polymer of poly (ADP ribose); PARP: poly (ADP-ribose) polymerase family; PBS: phosphate-buffered saline; PLAT/tPA: plasminogen activator, tissue; PT: photothrombotic stroke; qPCR: quantitative polymerase chain reaction; Rap: rapamycin; RBFOX3/NeuN: RNA binding protein, fox-1 homolog (C. elegans) 3; SQSTM1: sequestosome 1; TNF/TNF-α: tumor necrosis factor.
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http://dx.doi.org/10.1080/15548627.2020.1847799DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8525999PMC
October 2021
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