Hubei Province Key Laboratory of Allergy and Immunology

Wuhan, China

Hubei Province Key Laboratory of Allergy and Immunology

Wuhan, China
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Tu X.,Wuhan University | Li S.,Hubei University of Medicine | Zhao L.,Wuhan University | Xiao R.,Wuhan University | And 3 more authors.
Virologica Sinica | Year: 2017

Human endogenous retrovirus W family (HERV-W) envelope (env) has been reported to be related to several human diseases, including autoimmune disorders, and it could activate innate immunity. However, there are no reports investigating whether human leukemia antigen (HLA)-A*0201+ restriction is involved in the immune response caused by HERV-W env in neuropsychiatric diseases. In the present study, HERV-W env-derived epitopes presented by HLA-A*0201 are described with the potential for use in adoptive immunotherapy. Five peptides displaying HLA-A* 0201-binding motifs were predicted using SYFEPITHI and BIMAS, and synthesized. A CCK-8 assay showed peptides W, Q and T promoted lymphocyte proliferation. Stimulation of peripheral blood mononuclear cells from HLA-A*0201+ donors with each of these peptides induced peptide-specific CD8+ T cells. High numbers of IFN-γ-secreting T cells were also detectable after several weekly stimulations with W, Q and T. Besides lysis of HERV-W env-loaded target cells, specific apoptosis was also observed. These data demonstrate that human T cells can be sensitized toward HERV-W env peptides (W, Q and T) and, moreover, pose a high killing potential toward HERV-W env-expressing U251 cells. In conclusion, peptides W Q and T, which are HERV-W env antigenic epitopes, have both antigenicity and immunogenicity, and can cause strong T cell immune responses. Our data strengthen the view that HERV-W env should be considered as an autoantigen that can induce autoimmunity in neuropsychiatric diseases, such as multiple sclerosis and schizophrenia. These data might provide an experimental foundation for a HERV-W env peptide vaccine and new insight into the treatment of neuropsychiatric diseases. [Figure not available: see fulltext.] © 2017 Wuhan Institute of Virology, CAS and Springer Nature Singapore Pte Ltd.

Na S.,Wuhan University | Li J.,Wuhan University | Zhang H.,Wuhan University | Li Y.,Wuhan University | And 6 more authors.
Toxicology | Year: 2017

Ethanol, one of the most commonly abused substances throughout history, is a substrate and potent inducer of cytochrome P450 2E1 (CYP2E1). Our previous study showed that brain CYP2E1 was induced by chronic ethanol treatment and was associated with ethanol-induced neurotoxicity in rats. We therefore investigated the possible mechanism of brain CYP2E1 involvement in ethanol-induced neurodegeneration. Compared with the controls, chronic ethanol treatment (3.0 g/kg, i.g., 160 days) significantly increased CYP2E1 mRNA levels in the rat cortex, but the mRNA levels of peroxisome proliferator–activated receptor α (PPARα) and the pre- and post-synaptic proteins (synaptophysin, SYP, and drebrin1, DBN1) were decreased. Ethanol treatment dose-dependently induced CYP2E1 mRNA expression, and CYP2E1 overexpression exacerbated the ethanol-induced neurotoxicity. Pretreatment with p38 inhibitor (SB202190) and ERK1/2 inhibitor (U0126) attenuated the induction of CYP2E1 mRNA and protein levels by ethanol; however, no change was observed with JNK inhibitor pretreatment. Ethanol exposure or CYP2E1 overexpression significantly decreased PPARα, SYP, and DBN1 expression as indicated by the data from real-time RT-PCR, Western blotting and immunocytochemistry. The activation of PPARα by WY14643 increased the activity of the SYP and DBN1 promoters and attenuated the inhibition of these genes by ethanol. The specific siRNA for CYP2E1 significantly attenuated the ethanol-induced inhibition of PPARα, SYP and DBN1 mRNA levels. These results suggest that the induction of CYP2E1 by ethanol may be mediated via the p38 and ERK1/2 signaling pathways in neurons but not via the JNK pathway. The CYP2E1-PPARα axis may play a role in ethanol-induced neurotoxicity via the alteration of the genes related with synaptic function. © 2017

Qin C.,Wuhan University | Li S.,Hubei University of Medicine | Yan Q.,Wuhan University | Wang X.,Wuhan University | And 5 more authors.
Neuroscience Letters | Year: 2016

Human endogenous retrovirus W family (HERV-W) envelope (env) is known to be associated with neurological and psychiatric disorders, such as multiple sclerosis and schizophrenia. Previous studies showed that overexpression of HERV-W env could induce brain-derived neurotrophic factor (BDNF) gene expression. In human and rat cells, BDNF-mediated signal transduction might be modulated by glycogen synthase kinase 3β (GSK3β). Both BDNF and GSK3β are schizophrenia-related genes. In this paper, we investigated whether GSK3β was involved in the HERV-W env-induced expression of BDNF. We found that HERV-W env increased phosphorylation of GSK3β at Ser9 (p-GSK3β (Ser9)) and the ratio of p-GSK3β (Ser9) to total GSK3β (p < 0.05) in U251 cells. Overexpression of HERV-W env led to a 36.2% reduction in GSK3β activity compared to control (p < 0.05). The levels of β-catenin, cyclin D1 and TSC2 mRNAs were upregulated (p < 0.05). These data suggested that overexpression of HERV-W env might activate the GSK3β signaling pathway in U251 cells. Further, knockdown of GSK3β reduced the expression of total GSK3β, p-GSK3β (Ser9), and the ratio of p-GSK3β (Ser9) to total GSK3β by 28.6%, 50.4%, and 30.2%, respectively (p < 0.05). Levels of β-catenin, cyclin D1 and TSC2 mRNAs were also reduced (p < 0.05). Interestingly, GSK3β activity increased (p < 0.05). Knockdown of GSK3β also decreased mRNA and protein expression of BDNF by 49.9% and 48.5% respectively (p < 0.05). These results indicated that phosphorylation of GSK3β at Ser9 might be involved in HERV-W env-induced BDNF expression, and will hopefully improve our understanding of the role of HERV-W env in neurological and psychiatric diseases (schizophrenia, etc). © 2016 Elsevier Ireland Ltd.

Xiao R.,Wuhan University | Li S.,Hubei University of Medicine | Cao Q.,Wuhan University | Wang X.,Wuhan University | And 5 more authors.
Virologica Sinica | Year: 2017

Human endogenous retrovirus W env (HERV-W env) plays a critical role in many neuropsychological diseases such as schizophrenia and multiple sclerosis (MS). These diseases are accompanied by immunological reactions in the central nervous system (CNS). Microglia are important immunocytes in brain inflammation that can produce a gasotransmitter–nitric oxide (NO). NO not only plays a role in the function of neuronal cells but also participates in the pathogenesis of various neuropsychological diseases. In this study, we reported increased NO production in CHME-5 microglia cells after they were transfected with HERV-W env. Moreover, HERV-W env increased the expression and function of human inducible nitric oxide synthase (hiNOS) and enhanced the promoter activity of hiNOS. Microglial migration was also enhanced. These data revealed that HERV-W env might contribute to increase NO production and microglial migration ability in neuropsychological disorders by regulating the expression of inducible NOS. Results from this study might lead to the identification of novel targets for the treatment of neuropsychological diseases, including neuroinflammatory diseases, stroke, and neurodegenerative diseases. [Figure not available: see fulltext.]. © 2017, Wuhan Institute of Virology, CAS and Springer Nature Singapore Pte Ltd.

Liu C.,Wuhan University | Liu L.,Wuhan University | Wang X.,Wuhan University | Liu Y.,Wuhan University | And 3 more authors.
Virus Genes | Year: 2017

Human endogenous retrovirus W family (HERV-W) envelope (env) at chromosome 7 is highly expressed in the placenta and possesses fusogenic activity in trophoblast development. HERV-W env has been found to be overexpressed in some cancers and immune diseases. Viral transactivators can induce the overexpression of HERV-W env in human cell lines. Hepatitis B virus X protein (HBx) is believed to be a multifunctional oncogenic protein. Here, we reported that HBx could increase the promoter activity of HERV-W env and upregulate the mRNA levels of non-spliced and spliced HERV-W env and also its protein in human hepatoma HepG2 cells. Interestingly, we found that the inhibition of nuclear factor κB (NF-κB) using shRNA targeting NF-κB/p65 or PDTC (an inhibitor of NF-κB) could attenuate the upregulation of HERV-W env induced by HBx. These suggested that HBx might upregulate the expression of HERV-W env through NF-κB in HepG2 cells. This study might provide a new insight in HBV-associated liver diseases including HCC. © 2017 Springer Science+Business Media, LLC

Liu L.,Wuhan University | Liu Y.,Wuhan University | Chen X.,Wuhan University | Wang M.,Wuhan University | And 5 more authors.
Oncotarget | Year: 2017

Hepatocellular carcinoma (HCC) is one of the most lethal malignant tumors worldwide and effective therapies, including molecular therapy, remain elusive. Our previous work demonstrates that oncogenic KIAA0101 transcript variant (tv) 1 promotes HCC development and might be a HCC therapeutic target. However, the function of another KIAA0101 variant, KIAA0101 tv2, remains unknown. In this study, we reported that KIAA0101 tv2 was highly expressed in adjacent non-tumorous liver tissues (NTs) compared to HCC tissues. In vivo and in vitro results showed that KIAA0101 tv2 decreased cell survival, colony formation, tumor xenografts, migration, and invasion, as well as induced cell cycle arrest and apoptosis. Interestingly, it could inhibit the function of KIAA0101 tv1 by partially down-regulating KIAA0101 tv1, acting similar to KIAA0101 tv1 short hairpin RNA (shRNA). Further studies illustrated that KIAA0101 tv2 could increase the activity of p53 by competing with KIAA0101 tv1 for P53 binding. In conclusion, KIAA0101 tv2 exerts anti-tumor activity in HCC and acts as an endogenous competitor of tumor-associated KIAA0101 tv1. KIAA0101 tv2 has a potential to work as a therapeutic drug targeting the KIAA0101 tv1 in HCC. © Liu et al.

Liu L.-J.,Hubei University of Medicine | Xie S.-X.,Gannan Medical University | Chen Y.-T.,Hubei University of Medicine | Xue J.-L.,Hubei University of Medicine | And 3 more authors.
World Journal of Gastroenterology | Year: 2016

Hepatocellular carcinoma (HCC) is one of the most lethal malignancies in the world. Several signaling pathways, including the wingless/int-1 (Wnt) signaling pathway, have been shown to be commonly activated in HCC. The Wnt signaling pathway can be triggered via both catenin β1 (CTNNB1)-dependent (also known as "canonical") and CTNNB1-independent (often referred to as "non-canonical") pathways. Specifically, the canonical Wnt pathway is one of those most frequently reported in HCC. Aberrant regulation from three complexes (the cell-surface receptor complex, the cytoplasmic destruction complex and the nuclear CTNNB1/T-cell-specific transcription factor/lymphoid enhancer binding factor transcriptional complex) are all involved in HCC. Although the non-canonical Wnt pathway is rarely reported, two main non-canonical pathways, Wnt/planar cell polarity pathway and Wnt/Ca2+ pathway, participate in the regulation of hepatocarcinogenesis. Interestingly, the canonical Wnt pathway is antagonized by non-canonical Wnt signaling in HCC. Moreover, other signaling cascades have also been demonstrated to regulate the Wnt pathway through crosstalk in HCC pathogenesis. This review provides a perspective on the emerging evidence that the aberrant regulation of Wnt signaling is a critical mechanism for the development of HCC. Furthermore, crosstalk between different signaling pathways might be conducive to the development of novel molecular targets of HCC. © The Author(s) 2016. Published by Baishideng Publishing Group Inc. All rights reserved.

Cheng Q.,Wuhan University | Cheng Q.,Hubei Province Key Laboratory of Allergy and Immunology | Dong L.,Wuhan University | Dong L.,Hubei Province Key Laboratory of Allergy and Immunology | And 11 more authors.
AIDS Research and Human Retroviruses | Year: 2015

RNA interference has shown great potential for the treatment of HIV-1. Vectors derived from prototype foamy viruses (PFVs) with a nonpathogenic nature are very promising gene transfer vehicles in anti-HIV gene therapy. In this article, three short hairpin RNAs (shRNAs) targeting the conserved regions of the HIV-1NL4-3 5′ long terminal repeat (LTR) were first designed. We then constructed novel recombinant PFV vector plasmids, pΦ-H1-shRNAs, expressing these shRNAs under the control of the H1 RNA promoter. To detect the efficacy of these ΔΦ-H1-shRNAs for the inhibition of HIV-1 replication, we performed a dual-luciferase reporter assay, RT-qPCR, ELISA, western blotting, and a lactate dehydrogenase (LDH) assay by transient transfection in 293T cells. The results suggest that these novel shRNAs driven by PFV vectors inhibit HIV-1 replication efficiently without cytotoxicity, with shRNA3 being the most effective. In addition, we analyzed the shRNA target sites in the 5′ LTR of HIV-1 strains other than HIV-1NL4-3 and found that these shRNAs may possibly inhibit other HIV-1 strains. © Mary Ann Liebert, Inc. 2015.

Chen X.,Wuhan University | Zhang Y.,Wuhan University | Shi Y.,Wuhan University | Lian H.,Wuhan University | And 10 more authors.
Oncotarget | Year: 2016

Abnormalities of autophagy have been implicated in an increasing number of human cancers, including glioma. To date, there is a wealth of evidence indicating that microRNAs (miRNAs) contribute significantly to autophagy in a variety of cancers. Previous studies have suggested that miR-129 functioned as an important inhibitor of the cell cycle and could promote the apoptosis of many cancer cell lines in vitro. Here, we reported that miR-129 acted as a potent inducer of autophagy. Forced expression of miR-129 could induce autophagic flux by targetedly suppressing Notch-1 in glioma cells. The autophagy induced by miR-129 could restrain the activity of mammalian target of rapamycin (mTOR) and upregulate Beclin-1. Moreover, we demonstrated that E2F transcription factor 7 (E2F7) could also trigger autophagic flux by upregulating Beclin-1 and mediating miR-129-induced autophagy. Additionally, knockdown of Notch-1 could upregulate the expression of E2F7, whereas downregulation of E2F7 alleviated shNotch-1-induced autophagic flux. In particular, knockdown of endogenous Beclin-1 could effectively reduce autophagic flux stimulated by miR-129 and E2F7. Interestingly, upon attenuation of miR-129- or E2F7-triggered autophagic flux rescued cell viability suppressed by them. More importantly, intratumoral injection of pHAGEmiR- 129 lentivirus in a nude mouse xenograft model significantly restrained tumor growth and triggered autophagy. In conclusion, these findings identify a new function for miR-129 as a potent inducer of autophagy through a novel Notch-1/E2F7/Beclin-1 axis in glioma.

Zhang L.,Wuhan University | Chen X.,Wuhan University | Shi Y.,Wuhan University | Shi Y.,Hubei Province Key Laboratory of Allergy and Immunology | And 11 more authors.
Virus Genes | Year: 2014

Enterovirus 71 (EV71), a major causative agent of hand, foot, and mouth disease, has broken out several times and was accompanied by neurological disease. microRNAs, a class of small non-coding RNAs that are approximately 20 nucleotides long, play important roles in the regulation of various biological processes, including antiviral defense. However, the roles of miRNAs in EV71 replication and pathogenesis are not well understood. In this study, we found that the expression of miR-27a was significantly decreased in EV71-infected cells. Interestingly, the over-expression of miR-27a could inhibit EV71 replication, as measured by virus titration, qPCR, and Western blotting. We identified EGFR mRNA is a bona fide target of miR-27a by computational analysis and luciferase reporter assays. Furthermore, miR-27a could decrease EGFR expression, as measured by qPCR and Western blotting. Moreover, the inhibition of EGFR expression by miR-27a decreased the phosphorylation of Akt and ERK, which facilitate EV71 replication. These results suggest that miR-27a may have antiviral activity against EV71 by inhibiting EGFR. © 2014, Springer Science+Business Media New York.

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