Publications by authors named "Xuan Lv"

17 Publications

  • Page 1 of 1

Development of a potential diagnostic monoclonal antibody against capsid spike protein VP27 of the novel goose astrovirus.

Poult Sci 2022 Mar 23;101(3):101680. Epub 2021 Dec 23.

College of Animal Science and Technology, Anhui Agricultural University, Hefei 230036, China; Anhui Province Key Laboratory of Veterinary Pathobiology and Disease Control, Hefei 230036, China. Electronic address:

Goose astrovirus (GAstVs) is an emerging pathogen of goslings that causes fatal gout, kidney hemorrhages, renomegaly, and high mortality. The GAstVs VP27 protein is an important capsid protein and a candidate for the development of diagnostic reagents. The aim of this study was to clone and express the VP27 gene for preparation of a specific monoclonal antibody (mAb). The VP27 protein was expressed and purified in the supernatant of Escherichia coli BL21. Then, the mAb was obtained with the hybridoma technique and named 2AF11. It was differentiated as IgG1 with the help of immunoglobulin subclass tests. This mAb can specifically recognize the VP27 protein in GAstVs-infected cells, as evidenced by western blot analysis and immunofluorescent assay. Furthermore, this mAb could also detect the VP27 protein in GAstVs-infected tissues, as demonstrated by immunohistochemistry. These findings indicate that this mAb has high diagnostic potential. Therefore, the newly produced anti-VP27 mAb, 2AF11, could be a useful tool as a specific diagnostic marker for GAstVs.
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http://dx.doi.org/10.1016/j.psj.2021.101680DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8883067PMC
March 2022

Antiviral and virucidal activities of lycorine on duck tembusu virus in vitro by blocking viral internalization and entry.

Poult Sci 2021 Oct 25;100(10):101404. Epub 2021 Jul 25.

College of Animal Science and Technology, Anhui Agricultural University, Hefei 230036, China; Anhui Province Key Laboratory of Veterinary Pathobiology and Disease Control, Hefei 230036, China. Electronic address:

Duck tembusu virus (DTMUV) was firstly identified in 2010 in China; since then, it has caused enormous economic loss to breeding industry. Great efforts have been made to develop drugs and vaccines against DTMUV. However, current available vaccines or anti-DTMUV drugs are consistently inefficient. Hence, various more broadly effective drugs have become important for the treatment of DTMUV infection; among these, lycorine, one of the important sources of active alkaloids, is a promising example. Nevertheless, it is not known whether lycorine has any antiviral activities against DTMUV. Therefore, the purpose of the present study is to investigate the anti-DTMUV abilities of lycorine. The cytotoxicity of lycorine was evaluated on BHK-21 cells by CCK-8 assay, and its antiviral effect against DTMUV was examined by real-time PCR assays, virus titer determination, Western blot and immunofluorescence (IFA) assays, respectively. Furthermore, the underlying mechanisms of the anti-DTMUV effects of lycorine were also investigated. The results indicated that the highest nontoxicity concentration of lycorine on BHK-21 cells was 5 µM. Lycorine possessed the antiviral ability against DTMUV on BHK-21 cells, as demonstrated by the reduction of virus titers and copy numbers in vitro. Western blot and IFA analysis showed the inhibitory effect of lycorine on DTMUV envelope (E) protein expression. Moreover, using time-of-addition assays, we found that lycorine displays its antivirus and virucidal activities through blocking viral internalization and entry in vitro. Taken together, our findings firstly demonstrate the antiviral activities of lycorine against DTMUV, suggesting that lycorine can be a potential drug for the treatment of DTMUV infection.
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http://dx.doi.org/10.1016/j.psj.2021.101404DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8414183PMC
October 2021

A novel Tembusu virus isolated from goslings in China form a new subgenotype 2.1.1.

Transbound Emerg Dis 2021 May 16. Epub 2021 May 16.

Anhui Province Key Laboratory of Veterinary Pathobiology and Disease Control, Anhui Agricultural University, Hefei, China.

Since 2010, several duck Tembusu viruses (DTMUVs) have been isolated from infected ducks in China, and these virus strains have undergone extensive variation over the years. Although the infection rate is high, the mortality rate is usually relatively low-~5%-30%; however, since fall 2019, an infectious disease similar to DTMUV infection but with a high mortality rate of ~50% in goslings has been prevalent in Anhui Province, China. The present study identified a new Tembusu virus, designated DTMUV/Goose/China/2019/AQ-19 (AQ-19), that is believed to be responsible for the noticeably high mortality in goslings. To investigate the genetic variation of this strain, its entire genome was sequenced and analysed for specific variations, and goslings and mice were challenged with the isolated virus to investigate its pathogenicity. The AQ-19 genome shared only 94.3%-96.9% and 90.9% nucleotide identity with other Chinese and Malaysian DTMUVs, respectively; however, AQ-19 has high homology with Thailand DTMUVs (97.2%-98.1% nucleotide identity). Phylogenetic analysis of the E gene revealed that AQ-19 and most of Thailand DTMUVs form a branch separate from any of the previously reported DTMUV strains in China. After the challenge, some goslings and mice showed typical clinical signs of DTMUV, particularly severe neurological dysfunction. AQ-19 has high virulence in goslings and mice, resulting in 60% and 70% mortality through intramuscular and intracerebral routes, respectively. Pathological examination revealed severe histological lesions in the brain and liver of the infected goslings and mice. Taken together, these results demonstrated the emergence of a novel Tembusu virus with high virulence circulating in goslings in China for the first time, and our findings highlight the high genetic diversity of DTMUVs in China. Further study of the pathogenicity and host range of this novel Tembusu virus is particularly important.
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http://dx.doi.org/10.1111/tbed.14155DOI Listing
May 2021

Epigallocatechin-3-gallate exhibits antiviral effects against the duck Tembusu virus via blocking virus entry and upregulating type I interferons.

Poult Sci 2021 Apr 14;100(4):100989. Epub 2021 Jan 14.

College of Animal Science and Technology, Anhui Agricultural University, Hefei 230036, China; Anhui Province Key Laboratory of Veterinary Pathobiology and Disease Control, Hefei 230036, China. Electronic address:

The duck Tembusu virus (DTMUV) is a novel mosquito-borne Flavivirus which caused huge economic losses for poultry industries in Southeast Asia and China. Currently, no effective antiviral drugs against this virus have been reported. (-)-Epigallocatechin-3-gallate (EGCG), a polyphenol present in abundance in green tea, has recently been demonstrated to have an antiviral activity for many viruses; however, whether EGCG can inhibit DTMUV infection remains unknown. Here, we tried to explore the anti-DTMUV effects and mechanisms of EGCG both in vitro and in vivo. Several EGCG treatment regimens were used to study the comprehensive antiviral activity of EGCG in DTMUV-infected baby hamster kidney cell line (BHK-21). The DTMUV titers of mock- and EGCG-treated infected cell cultures were determined using the tissue culture infective dose assay and the DTMUV mRNA copy number as determined using quantitative Real Time PCR. Moreover, the therapeutic efficacy of EGCG against DTMUV was assessed in DTMUV-infected ducklings. Our results suggested that EGCG significantly reduced the viral infection in BHK-21 cells in a dose-dependent manner, as reflected by the reduction of virus titers, virus copy number, and the expressions of viral E protein. We also observed that EGCG exhibited direct virucidal abilities against DTMUV. Notably, a significant reduction in virus binding ability was also observed, indicating that EGCG possesses excellent inhibitory effects on the viral adsorption step. In addition, DTMUV replication was also suppressed in BHK-21 cells treated with EGCG after viral entry, likely because of upregulation of the levels of interferon alfa and interferon beta. Finally, we also proved that EGCG exhibited anti-DTMUV efficacy in a duckling infection model because the survival rate was significantly improved. This is the first study to demonstrate the protective effect of EGCG against DTMUV, suggesting its potential use as an antiviral drug for DTMUV infection.
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http://dx.doi.org/10.1016/j.psj.2021.01.012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7921876PMC
April 2021

Coinfection of parvovirus and astrovirus in gout-affected goslings.

Transbound Emerg Dis 2020 Nov 15;67(6):2830-2838. Epub 2020 Jun 15.

Anhui Province Key Laboratory of Veterinary Pathobiology and Disease Control, Anhui Agricultural University, Hefei, China.

Outbreaks of gosling gout have occurred in China since 2017 and caused a considerable economic impact on the poultry industry. While gosling astrovirus (GoAstV) is believed to be the main causal pathogen of gout, the full-blown disease of gout cannot be well reproduced by infecting the goslings with GoAstV, suggesting the possibility of other infectious agents being involved with the development of gosling gout. To assess other possible infectious agents, we collected tissues from gout-affected goslings in 12 goose farms in China, followed by PCR detection of GoAstV, goose reovirus (GRV), goose parvovirus (GPV), fowl adenovirus (FAdV), goose circovirus (GcoV), Tembusu virus (TMUV) and goose haemorrhagic polyomavirus (GHPV). Our data showed that all gout-affected goslings carried both of GoAstV and GPV determined by PCRs, and this was further confirmed by fluorescence multiplex immunohistochemical staining, and phylogenetic analysis of ORF2 gene of GoAstV and VP3 gene of GPV. In addition to the haemorrhage in the kidney, liver, spleen and lung of the gout-affected goslings, histological examinations showed also extensive infiltration of heterophil myelocytes in the kidney, liver, spleen, bursa of Fabricius, thymus, lungs and pancreas. Our findings strongly suggest that coinfection of GoAstV and GPV increases the severity of gout. While this is the first study to report GPV in gout-affected goslings, further studies including infection model are warranted to investigate the role of GPV and its coinfection with GoAstV in the development of gosling gout.
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http://dx.doi.org/10.1111/tbed.13652DOI Listing
November 2020

Accurately Predicting Mutation-Caused Stability Changes from Protein Sequences Using Extreme Gradient Boosting.

J Chem Inf Model 2020 04 30;60(4):2388-2395. Epub 2020 Mar 30.

School of Data and Computer Science, Sun Yat-sen University, Guangzhou, Guangdong 510275, China.

Accurately predicting the impact of point mutation on protein stability has crucial roles in protein design and engineering. In this study, we proposed a novel method (BoostDDG) to predict stability changes upon point mutations from protein sequences based on the extreme gradient boosting. We extracted features comprehensively from evolutional information and predicted structures and performed feature selection by a strategy of sequential forward selection. The features and parameters were optimized by homologue-based cross-validation to avoid overfitting. Finally, we found that 14 features from six groups led to the highest Pearson correlation coefficient (PCC) of 0.535, which is consistent with the 0.540 on an independent test. Our method was indicated to consistently outperform other sequence-based methods on three precompiled test sets, and 7363 variants on two proteins (PTEN and TPMT). These results highlighted that BoostDDG is a powerful tool for predicting stability changes upon point mutations from protein sequences.
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http://dx.doi.org/10.1021/acs.jcim.0c00064DOI Listing
April 2020

PP2A Facilitates Porcine Reproductive and Respiratory Syndrome Virus Replication by Deactivating irf3 and Limiting Type I Interferon Production.

Viruses 2019 10 15;11(10). Epub 2019 Oct 15.

State Key Laboratory of Veterinary Biotechnology, Heilongjiang Provincial Key Laboratory of Laboratory Animal and Comparative Medicine, Harbin Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Harbin 150069, China.

Protein phosphatase 2A (PP2A), a major serine/threonine phosphatase in mammalian cells, is known to regulate the kinase-driven intracellular signaling pathways. Emerging evidences have shown that the PP2A phosphatase functions as a bona-fide therapeutic target for anticancer therapy, but it is unclear whether PP2A affects a porcine reproductive and respiratory syndrome virus infection. In the present study, we demonstrated for the first time that inhibition of PP2A activity by either inhibitor or small interfering RNA duplexes in target cells significantly reduced their susceptibility to porcine reproductive and respiratory syndrome virus (PRRSV) infection. Further analysis revealed that inhibition of PP2A function resulted in augmented production of type I interferon (IFN). The mechanism is that inhibition of PP2A activity enhances the levels of phosphorylated interferon regulatory factor 3, which activates the transcription of IFN-stimulated genes. Moreover, inhibition of PP2A activity mainly blocked PRRSV replication in the early stage of viral life cycle, after virus entry but before virus release. Using type I IFN receptor 2 specific siRNA in combination with PP2A inhibitor, we confirmed that the effect of PP2A on viral replication within target cells was an interferon-dependent manner. Taken together, these findings demonstrate that PP2A serves as a negative regulator of host cells antiviral responses and provides a novel therapeutic target for virus infection.
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http://dx.doi.org/10.3390/v11100948DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6832233PMC
October 2019

Dispersion characteristics of a suspended-core optical fiber infiltrated with water.

Appl Opt 2017 Feb;56(4):1012-1019

In this paper we present a study on the dispersion characteristics in the suspended-core optical fibers made of borosilicate of NC21A glass infiltrated with water. Replacement of air with water results in dramatic improvement of the dispersion characteristics in the fibers, valuable in the process of supercontinuum generation. A near-zero flat dispersion can be achieved in the anomalous or normal dispersion range for various diameters of the core.
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http://dx.doi.org/10.1364/AO.56.001012DOI Listing
February 2017

Effects of triazole fungicides on androgenic disruption and CYP3A4 enzyme activity.

Environ Pollut 2017 Mar 21;222:504-512. Epub 2016 Dec 21.

College of Environmental and Resource Sciences, Zhejiang University, Hangzhou 310058, China; Key Laboratory of Health Risk Factors for Seafood of Zhejiang Province, Zhoushan 316022, China. Electronic address:

Triazole fungicides are widely used as broad-spectrum fungicides, non-steroidal antiestrogens and for various industrial applications. Their residues have been frequently detected in multiple environmental and human matrices. The increasingly reported toxicity incidents have led triazole fungicides as emerging contaminants of environmental and public health concern. However, whether triazole fungicides behave as endocrine disruptors by directly mimicking environmental androgens/antiandrogens or exerting potential androgenic disruption indirectly through the inhibition of cytochrome P450 (CYP450) enzyme activity is yet an unresolved question. We herein evaluated five commonly used triazole fungicides including bitertanol, hexaconazole, penconazole, tebuconazole and uniconazole for the androgenic and anti-androgenic activity using two-hybrid recombinant human androgen receptor (AR) yeast bioassay and comparatively evaluated their effects on enzymatic activity of CYP3A4 by P450-Glo™ CYP3A4 bioassay. All five fungicides showed moderate anti-androgenic activity toward human AR with the IC ranging from 9.34 μM to 79.85 μM. The anti-androgenic activity remained no significant change after the metabolism mediated by human liver microsomes. These fungicides significantly inhibited the activity of CYP3A4 at the environmental relevant concentrations and the potency ranks as tebuconazole > uniconazole > hexaconazole > penconazole > bitertanol with the corresponding IC of 0.81 μM, 0.93 μM, 1.27 μM, 2.22 μM, and 2.74 μM, respectively. We found that their anti-androgenic activity and the inhibition potency toward CYP3A4 inhibition was significantly correlated (R between 0.83 and 0.97, p < 0.001). Our results indicated that the risk assessment of triazole pesticides and structurally similar chemicals should fully consider potential androgenic disrupting effects and the influences on the activity of CYP450s.
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http://dx.doi.org/10.1016/j.envpol.2016.11.051DOI Listing
March 2017

Benzotriazole UV 328 and UV-P showed distinct antiandrogenic activity upon human CYP3A4-mediated biotransformation.

Environ Pollut 2017 Jan 13;220(Pt A):616-624. Epub 2016 Oct 13.

Department of Biological and Environmental Sciences, University of Houston-Clear Lake, 2700 Bay Area Blvd., Houston, TX 77058, USA. Electronic address:

Benzotriazole ultraviolet stabilizers (BUVSs) are prominent chemicals widely used in industrial and consumer products to protect against ultraviolet radiation. They are becoming contaminants of emerging concern since their residues are frequently detected in multiple environmental matrices and their toxicological implications are increasingly reported. We herein investigated the antiandrogenic activities of eight BUVSs prior to and after human CYP3A4-mediated metabolic activation/deactivation by the two-hybrid recombinant human androgen receptor yeast bioassay and the in vitro metabolism assay. More potent antiandrogenic activity was observed for the metabolized UV-328 in comparison with UV-328 at 0.25 μM ((40.73 ± 4.90)% vs. (17.12 ± 3.00)%), showing a significant metabolic activation. In contrast, the metabolized UV-P at 0.25 μM resulted in a decreased antiandrogenic activity rate from (16.08 ± 0.95)% to (6.91 ± 2.64)%, indicating a metabolic deactivation. Three mono-hydroxylated (OH) and three di-OH metabolites of UV-328 were identified by ultra-performance liquid chromatography quadrupole time of flight mass spectrometry (UPLC-Q-TOF-MS/MS), which were not reported previously. We further surmised that the hydroxylation of UV-328 occurs mainly at the alicyclic hydrocarbon atoms based on the in silico prediction of the lowest activation energies of hydrogen abstraction from C-H bond. Our results for the first time relate antiandrogenic activity to human CYP3A4 enzyme-mediated hydroxylated metabolites of BUVSs. The biotransformation through hydroxylation should be fully considered during the health risk assessment of structurally similar analogs of BUVSs and other emerging contaminants.
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http://dx.doi.org/10.1016/j.envpol.2016.10.011DOI Listing
January 2017

Mir143-BBC3 cascade reduces microglial survival via interplay between apoptosis and autophagy: Implications for methamphetamine-mediated neurotoxicity.

Autophagy 2016 09 27;12(9):1538-59. Epub 2016 Jul 27.

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

BBC3 (BCL2 binding component 3) is a known apoptosis inducer; however, its role in microglial survival remains poorly understood. In addition to the classical transcription factor TRP53, Mir143 is involved in BBC3 expression at the post-transcriptional level. Here, we identify unique roles of Mir143-BBC3 in mediating microglial survival via the regulation of the interplay between apoptosis and autophagy. Autophagy inhibition accelerated methamphetamine-induced apoptosis, whereas autophagy induction attenuated the decrease in microglial survival. Moreover, anti-Mir143-dependent BBC3 upregulation reversed the methamphetamine-induced decrease in microglial survival via the regulation of apoptosis and autophagy. The in vivo relevance of these findings was confirmed in mouse models, which demonstrated that the microinjection of anti-Mir143 into the hippocampus ameliorated the methamphetamine-induced decrease in microglia as well as that observed in heterozygous Mir143(+/-) mice. These findings provide new insight regarding the specific contributions of Mir143-BBC3 to microglial survival in the context of drug abuse.
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http://dx.doi.org/10.1080/15548627.2016.1191723DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5082785PMC
September 2016

Molecular Mechanisms Involving Sigma-1 Receptor in Cell Apoptosis of BV-2 Microglial Cells Induced by Methamphetamine.

CNS Neurol Disord Drug Targets 2016 ;15(7):857-65

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

It has been well documented that methamphetamine induces microglial activation and death, however, the molecular mechanisms underlying this process remain poorly understood. In the present study, we demonstrated the involvement of sigma-1 receptor (σ-1R) in methamphetamine-mediated microglial apoptosis. Exposure of BV-2 cells to methamphetamine induces cell apoptosis through its cognate receptor σ-1R, followed by activation of the mitogen-activated protein kinases, phosphatidylinositol-3' kinase/Akt as well as the downstream transcription factor p53 pathways. Blockage of σ -1R significantly inhibited the increased pro-apoptotic proteins such as Bax, Caspase-3 and Caspase-9 induced by methamphetamine. In conclusion, these findings underscore the critical role of σ-1R in microglial apoptosis induced by methamphetamine. Understanding the link between σ -1R and apoptosis will lead to development of therapeutic strategies targeting methamphetamine-mediated microglial death/dysfunction.
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http://dx.doi.org/10.2174/1871527315666160518122816DOI Listing
October 2017

The Molecular Recognition Paradigm of Environmental Chemicals with Biomacromolecules.

Curr Protein Pept Sci 2017 ;18(1):41-47

College of Environmental and Resource Sciences, Zhejiang University, Hangzhou 310058, China.

The interactions of ligands with biomacromolecules play a fundamental role in almost all bioprocesses occuring in living organisms. The binding of ligands can cause the conformational changes of biomacromolecules, possibly affecting their physiological functions. The interactions of ligands with biomacromolecules are thus becoming a research hotspot. However, till now, there still lacks a systematic compilation of review with the focus on the interactions between environmental chemicals and biomacromolecules. In this review, we focus on the molecular recognition paradigm of environmental chemicals with biomacromolecules and chemical basis for driving the complex formation. The state-of-the-art review on in vitro and in silico studies on interaction of organic chemicals with transport proteins, nuclear receptors and CYP450 enzymes was provided, and the enantioselective interactions of chiral environmental chemicals was also mentioned.
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http://dx.doi.org/10.2174/1389203717666160421152301DOI Listing
February 2017

Atomic-scale investigation of the interactions between tetrabromobisphenol A, tetrabromobisphenol S and bovine trypsin by spectroscopies and molecular dynamics simulations.

J Hazard Mater 2015 Dec 23;299:486-94. Epub 2015 Jul 23.

Institute of Environmental Science, College of Environmental and Resource Sciences, Zhejiang University, Hangzhou 310058, China; Zhejiang Provincial Key Laboratory of Organic Pollution Process and Control, Hangzhou 310058, China. Electronic address:

Tetrabromobisphenol A (TBBPA) and its replacement alternative tetrabromobisphenol S (TBBPS) are used widely as brominated flame retardants (BFRs). However, the potential risk of their effects on bovine trypsin remains largely unknown. We investigated the effects of TBBPA and TBBPS to bovine trypsin by the fluorescence spectroscopy, circular dichroism and molecular dynamics (MD) simulations. They statically quenched the intrinsic fluorescence of bovine trypsin in a concentration-dependent mode and caused slight red-shifted fluorescence. The short and long fluorescence lifetime decay components of bovine trypsin were both affected, partly due to the disturbed microenvironmental changes of Trp215. The β-sheet content of bovine trypsin was significantly reduced from 82.4% to 75.7% and 76.6% by TBBPA and TBBPS, respectively, possibly impairing the physiological function of bovine trypsin. TBBPA and TBBPS bind at the 8-anilinonaphthalene-1-sulfonate (ANS) binding site with an association constant of 1.09×10(4) M(-1) and 2.41×10(4) M(-1) at 298 K, respectively. MD simulations revealed that van der Waals interactions and hydrogen bond interactions are dominant for TBBPA, whereas electrostatic interactions are critical for TBBPS. Our in vitro and in silico studies are beneficial to the understanding of risk assessment and future design of environmental benign BFRs.
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http://dx.doi.org/10.1016/j.jhazmat.2015.07.050DOI Listing
December 2015

Down regulation of MiR-93 contributes to endometriosis through targeting MMP3 and VEGFA.

Am J Cancer Res 2015 15;5(5):1706-17. Epub 2015 Apr 15.

Department of Obstetrics and Gynecology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University Shanghai 200127, China.

Objective: This study aimed to explore the role of miRNAs in pathogenesis of endometriosis.

Methodology: Endometrial samples from 57 females with endometriosis and 44 non-endometriotic controls were compared for the expression of a selected group of miRNAs. The regulatory function on downstream target was also explored.

Results: The expression of miR-93 and miR106a was significantly reduced in endometriotic samples compared to that in non-endometriotic samples. High levels of MMP3 and VEGFA were detected in more than 50% ectopic endometrium tissues. A negative association was found between the expression of miR-93 and the protein levels of MMP3 (Pearson correlation, r=-0.39, P=0.0025) or VEGFA (Pearson correlation, r=-0.37, P=0.0047) in samples from endometriosis patients. Mechanistically, miR-93 targeted MMP3 and VEGFA by directly binding to the 3'UTR of MMP3 and VEGFA mRNAs, and thereby inhibited the proliferation, migration and invasive capability of endometrial stromal cells (ESCs).

Conclusion: The finding of this study suggests that deregulation of miR-93 contribute to endometriosis by up-regulation of MMP3 and VEGFA and thus provide potential therapeutic targets for the treatment of endometriosis.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4497437PMC
July 2015

NMDA receptor NR2B subunits contribute to PTZ-kindling-induced hippocampal astrocytosis and oxidative stress.

Brain Res Bull 2015 May 17;114:70-8. Epub 2015 Apr 17.

Department of Pharmacology, Medical School of Southeast University, Nanjing, China.

The N-methyl-d-aspartate (NMDA) receptor plays an important role in the pathophysiology of several neurological diseases, including epilepsy. The present study investigated the effect of NMDA receptor NR2B subunits on pentylenetetrazole (PTZ)-kindling-induced pathological and biochemical events in mice. Our results showed that PTZ-kindling up-regulates the expression of NMDA receptor NR2B subunits in the hippocampus and that kindled mice were characterized by significant astrocytosis and neuron loss in the hippocampus. Oxidative stress, including excessive malondialdehyde (MDA) production and decreased enzymatic activities of superoxide dismutase (SOD) and glutathione peroxidase (GSH-PX), were detected in the hippocampus after the mice were fully kindled. Additionally, expression of brain-derived neurotrophic factor (BDNF) in the hippocampus was found to be up-regulated in PTZ-kindled mice. However, selectively blocking NMDA receptor NR2B subunits by ifenprodil significantly suppressed PTZ-kindling-induced hippocampal astrocytosis, oxidative stress and neuron loss. Furthermore, blocking NMDA receptor NR2B subunits also abolished PTZ-kindling-induced BDNF expression. These results indicate that NMDA receptor NR2B subunits contribute to epilepsy-associated pathological and biochemical events, including hippocampal astrocytosis, oxidative stress and neuron loss, and these events might be correlated with up-regulation of BDNF expression.
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http://dx.doi.org/10.1016/j.brainresbull.2015.04.002DOI Listing
May 2015

Involvement of sigma-1 receptor in astrocyte activation induced by methamphetamine via up-regulation of its own expression.

J Neuroinflammation 2015 Feb 17;12:29. Epub 2015 Feb 17.

Department of Pharmacology, Medical School of Southeast University, 87 Dingjiaqiao, Nanjing, Jiangsu, 210009, China.

Background: Although it has been documented that methamphetamine induces astrocyte activation, the mechanism(s) underlying this effect remain poorly understood. We thus sought to examine the molecular mechanisms involved in methamphetamine-mediated activation of astrocytes with a focus on the role of sigma-1 receptor (σ-1R) in this process.

Methods: The expression of σ-1R and glial fibrillary acidic protein (GFAP) was examined by reverse transcription PCR (RT-PCR), real-time PCR, Western blot, and immunofluorescent staining; phosphorylation of cell signaling pathways was detected by Western blot analysis. Immunoprecipitation was used to determine the interaction between σ-1R and p-Src. Chromatin immunoprecipitation (ChIP) assay was employed to discern the binding of cAMP-response element-binding protein (CREB) with the promoter of σ-1R. The role of σ-1R in astrocyte activation was further validated in σ-1R knockout (KO) mice by Western blot combined with immunofluorescent staining.

Results: Exposure of primary rat astrocytes to methamphetamine increased the expression of σ-1R via the activation of Src, ERK mitogen-activated protein kinase, and downstream CREB pathways. Subsequently, CREB translocated into nucleus and interacted with the promoter of σ-1R resulting in increased expression of σ-1R with a concomitant increase in expression of GFAP. This effect was inhibited in cells treated with the σ-1R antagonist-BD1047, thereby implicating the role of σ-1R in the activation of astrocytes. In vivo relevance of these findings was further corroborated in σ-1R KO mice that were administered methamphetamine. In the methamphetamine administered mice, there was a failure of the drug to induce activation of astrocytes, an effect that was evident in wild-type (WT) mice exposed to methamphetamine.

Conclusions: The study presented herein demonstrates that methamphetamine-mediated activation of astrocytes involved up-regulation of σ-1R through a positive-feedback mechanism. Understanding the regulation of σ-1R expression could provide insights into the development of potential therapeutic strategies for astrocyte activation induced by methamphetamine.
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http://dx.doi.org/10.1186/s12974-015-0250-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4340104PMC
February 2015
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