Publications by authors named "Wanhong Liu"

79 Publications

The effect of dipeptidyl peptidase IV on disease-associated microglia phenotypic transformation in epilepsy.

J Neuroinflammation 2021 May 11;18(1):112. Epub 2021 May 11.

Department of Pathophysiology, School of Basic Medical Sciences, Wuhan University, Donghu Road No. 185, Wuchang, Wuhan, 430071, China.

Background: Accumulating evidence suggests that disease-associated microglia (DAM), a recently discovered subset of microglia, plays a protective role in neurological diseases. Targeting DAM phenotypic transformation may provide new therapeutic options. However, the relationship between DAM and epilepsy remains unknown.

Methods: Analysis of public RNA-sequencing data revealed predisposing factors (such as dipeptidyl peptidase IV; DPP4) for epilepsy related to DAM conversion. Anti-epileptic effect was assessed by electroencephalogram recordings and immunohistochemistry in a kainic acid (KA)-induced mouse model of epilepsy. The phenotype, morphology and function of microglia were assessed by qPCR, western blotting and microscopic imaging.

Results: Our results demonstrated that DPP4 participated in DAM conversion and epilepsy. The treatment of sitagliptin (a DPP4 inhibitor) attenuated KA-induced epilepsy and promoted the expression of DAM markers (Itgax and Axl) in both mouse epilepsy model in vivo and microglial inflammatory model in vitro. With sitagliptin treatment, microglial cells did not display an inflammatory activation state (enlarged cell bodies). Furthermore, these microglia exhibited complicated intersections, longer processes and wider coverage of parenchyma. In addition, sitagliptin reduced the activation of NF-κB signaling pathway and inhibited the expression of iNOS, IL-1β, IL-6 and the proinflammatory DAM subset gene CD44.

Conclusion: The present results highlight that the DPP4 inhibitor sitagliptin can attenuate epilepsy and promote DAM phenotypic transformation. These DAM exhibit unique morphological features, greater migration ability and better surveillance capability. The possible underlying mechanism is that sitagliptin can reduce the activation of NF-κB signaling pathway and suppress the inflammatory response mediated by microglia. Thus, we propose DPP4 may act as an attractive direction for DAM research and a potential therapeutic target for epilepsy.
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http://dx.doi.org/10.1186/s12974-021-02133-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8114532PMC
May 2021

The Upregulation of a Novel Long Noncoding RNA AK097647 Promotes Enterovirus 71 Replication and Decreases IFN-λ1 Secretion.

Intervirology 2021 May 5:1-9. Epub 2021 May 5.

Shenzhen Institute of Wuhan University, Shenzhen, China.

Background: Enterovirus 71 (EV71) infects millions of children every year in China and has become a challenge to public health. However, there is no effective treatment for EV71 infection. Long noncoding RNAs (lncRNAs) have been found to play various roles in virus replication and infection.

Objective: We aimed to explore the role of a novel long noncoding RNA AK097647 (lncRNA-AK097647) during EV71 infection.

Methods: To assess the role of lncRNA-AK097647 during EV71 infection, siRNAs were used to silence lncRNA-K097647 expression. RT-qPCR assay and Western blotting were applied to measure the mRNA and protein levels of EV71 VP1 and the phosphorylation of NF-κB. ELISA was used to detect the level of IFN-λ1 expression.

Results: The novel lncRNA-AK097647 was upregulated in human rhabdomyosarcoma cells and the blood of hand, foot, and mouth disease patients infected with EV71, as demonstrated by RT-qPCR. Interestingly, RNAi-mediated knockdown of lncRNA-AK097647 dramatically increased the level of IFN-λ1 expression, resulting in the suppression of EV71 replication. In contrast, overexpression of lncRNA-AK097647 decreased the level of IFN-λ1 expression and resulted in increased EV71 replication. In addition, we found that lncRNA-AK097647 could inhibit the phosphorylation of NF-κB.

Conclusion: These results suggest a novel mechanism by which EV71 evades the IFN-mediated host antiviral response by increasing lncRNA-AK097647 expression.
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http://dx.doi.org/10.1159/000515903DOI Listing
May 2021

Blockade of Kv1.3 potassium channel inhibits CD8 T cell-mediated neuroinflammation via PD-1/Blimp-1 signaling.

FASEB J 2020 11 27;34(11):15492-15503. Epub 2020 Sep 27.

Department of Pathophysiology, School of Basic Medical Sciences, Wuhan University, Wuhan, China.

Kv1.3 potassium channel is considered as a target for the treatment of autoimmune diseases such as multiple sclerosis (MS), since Kv1.3 blockade suppresses memory T cell activation including cytotoxic CD8 T cells. However, the underlying signaling pathway related to autoimmune CD8 T cell inhibition by Kv1.3 channel in neuroinflammatory diseases remains unclear. We found that ImK, a selective Kv1.3 blocker, reduced auto-reactive CD8 T cell infiltration in the spinal cords of experimental autoimmune encephalomyelitis (EAE) rats, an animal model of MS. ImK suppressed transcriptional factor Blimp-1 expression and reduced the cytotoxicity of CD8 T cells on neuronal cells. Furthermore, ImK upregulated co-inhibitory molecule PD-1 to inhibit B lymphocyte-induced maturation protein (Blimp-1) in an IL-2 independent way. In addition, PD-1 inhibitor impaired the suppression of ImK on CD8 T cells and accelerated EAE progression. Our study demonstrated a novel regulatory mechanism of Kv1.3 blockade on modulating CD8 T cell differentiation through PD-1/Blimp-1 signaling. This work expands the understanding of Kv1.3 channel for modulating neuroinflammation.
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http://dx.doi.org/10.1096/fj.202000861RRDOI Listing
November 2020

Inhibition of the NLRP3-inflammasome prevents cognitive deficits in experimental autoimmune encephalomyelitis mice via the alteration of astrocyte phenotype.

Cell Death Dis 2020 05 15;11(5):377. Epub 2020 May 15.

Department of Pathophysiology, School of Basic Medical Sciences, Wuhan University, Wuhan, China.

Multiple sclerosis (MS) is a chronic disease that is characterized by demyelination and axonal damage in the central nervous system. Cognitive deficits are recognized as one of the features of MS, and these deficits affect the patients' quality of life. Increasing evidence from experimental autoimmune encephalomyelitis (EAE), the animal model of MS, has suggested that EAE mice exhibit hippocampal impairment and cognitive deficits. However, the underlying mechanisms are still unclear. The NLRP3 inflammasome is a key contributor to neuroinflammation and is involved in the development of MS and EAE. Activation of the NLRP3 inflammasome in microglia is fundamental for subsequent inflammatory events. Activated microglia can convert astrocytes to the neurotoxic A1 phenotype in a variety of neurological diseases. However, it remains unknown whether the NLRP3 inflammasome contributes to cognitive deficits and astrocyte phenotype alteration in EAE. In this study, we demonstrated that severe memory deficits occurred in the late phase of EAE, and cognitive deficits were ameliorated by treatment with MCC950, an inhibitor of the NLRP3 inflammasome. In addition, MCC950 alleviated hippocampal pathology and synapse loss. Astrocytes from EAE mice were converted to the neurotoxic A1 phenotype, and this conversion was prevented by MCC950 treatment. IL-18, which is the downstream of NLRP3 inflammasome, was sufficient to induce the conversion of astrocytes to the A1 phenotype through the NF-κB pathway. IL-18 induced A1 type reactive astrocytes impaired hippocampal neurons through the release of complement component 3 (C3). Altogether, our present data suggest that the NLRP3 inflammasome plays an important role in cognitive deficits in EAE, possibly via the alteration of astrocyte phenotypes. Our study provides a novel therapeutic strategy for hippocampal impairment in EAE and MS.
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http://dx.doi.org/10.1038/s41419-020-2565-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7229224PMC
May 2020

HDAC6, A Novel Cargo for Autophagic Clearance of Stress Granules, Mediates the Repression of the Type I Interferon Response During Coxsackievirus A16 Infection.

Front Microbiol 2020 31;11:78. Epub 2020 Jan 31.

Hubei Province Key Laboratory of Allergy and Immunology, Department of Immunology, School of Basic Medical Sciences, Wuhan University, Wuhan, China.

Autophagic cargoes ensure selective autophagy for the recognition and removal of various cytosolic aggregated proteins, damaged organelles, or pathogens. Stress granules (SGs), as antiviral immune complexes, serve a positive role in the type I interferon (IFN) response and can be targeted by autophagy (termed granulophagy). However, the cargo of granulophagy remains elusive, and it is still unknown whether granulophagy plays a role in viral infection. Here, we found that histone deacetylase 6 (HDAC6), a component of viral RNA-induced SGs, is a novel granulophagic cargo that is recognized by p62/Sequestosome 1 (SQSTM1) and mediates the degradation of SGs in coxsackievirus A16 (CA16)-infected cells. CA16 viral RNA activated the protein kinase RNA-activated (PKR)/eukaryotic translation initiation factor 2-alpha (eIF2α) pathway to promote SG assembly. The SGs were degraded by CA16-triggered autophagy via the interaction between the ubiquitin-associated (UBA) domain of p62 and the ubiquitin-binding domain (UBD) of HDAC6, which was bridged by a poly-ubiquitin chain. We also found that granulophagy repressed the type I interferon response and facilitated viral replication. These results suggest that HDAC6 might be the first identified granulophagic cargo and granulophagy could be a strategy that viruses apply to repress the antiviral immune response.
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http://dx.doi.org/10.3389/fmicb.2020.00078DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7005486PMC
January 2020

The Late Domain of Prototype Foamy Virus Gag Facilitates Autophagic Clearance of Stress Granules by Promoting Amphisome Formation.

J Virol 2020 03 17;94(7). Epub 2020 Mar 17.

Hubei Province Key Laboratory of Allergy and Immunology, Department of Immunology, School of Basic Medical Sciences, Wuhan University, Wuhan, China

Prototype foamy virus (PFV), a complex retrovirus belonging to , maintains lifelong latent infection. The maintenance of lifelong latent infection by viruses relies on the repression of the type I interferon (IFN) response. However, the mechanism involving PFV latency, especially regarding the suppression of the IFN response, is poorly understood. Our previous study showed that PFV promotes autophagic flux. However, the underlying mechanism and the role of PFV-induced autophagy in latent infection have not been clarified. Here, we report that the PFV viral structural protein Gag induced amphisome formation and triggered autophagic clearance of stress granules (SGs) to attenuate type I IFN production. Moreover, the late domain (L-domain) of Gag played a central role in Alix recruitment, which promoted endosomal sorting complex required for transport I (ESCRT-I) formation and amphisome accumulation by facilitating late endosome formation. Our data suggest that PFV Gag represses the host IFN response through autophagic clearance of SGs by activating the endosome-autophagy pathway. More importantly, we found a novel mechanism by which a retrovirus inhibits the SG response to repress the type I IFN response. Maintenance of lifelong latent infection for viruses relies on repression of the type I IFN response. Autophagy plays a double-edged sword in antiviral immunity. However, the role of autophagy in the regulation of the type I IFN response and the mechanism involving virus-promoted autophagy have not been fully elucidated. SGs are an immune complex associated with the antiviral immune response and are critical for type I IFN production. Autophagic clearance of SGs is one means of degradation of SGs and is associated with regulation of immunity, but the detailed mechanism remains unclear. In this article, we demonstrate that PFV Gag recruits ESCRT-I to facilitate amphisome formation. Our data also suggest that amphisome formation is a critical event for autophagic clearance of SGs and repression of the type I IFN response. More importantly, we found a novel mechanism by which a retrovirus inhibits the SG response to repress the type I IFN response.
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http://dx.doi.org/10.1128/JVI.01719-19DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7081917PMC
March 2020

Ferroptosis: A Novel Mechanism of Artemisinin and its Derivatives in Cancer Therapy.

Curr Med Chem 2021 ;28(2):329-345

School of Life Sciences, Southwest University, Chongqing 400715, China.

Background: Artemisinin is a sesquiterpene lactone compound with a special peroxide bridge that is tightly linked to the cytotoxicity involved in fighting malaria and cancer. Artemisinin and its derivatives (ARTs) are considered to be potential anticancer drugs that promote cancer cell apoptosis, induce cell cycle arrest and autophagy, inhibit cancer cell invasion and migration. Additionally, ARTs significantly increase intracellular Reactive Oxygen Species (ROS) in cancer cells, which result in ferroptosis, a new form of cell death, depending on the ferritin concentration. Ferroptosis is regarded as a cancer suppressor and as well as considered a new mechanism for cancer therapy.

Methods: The anticancer activities of ARTs and reference molecules were compared by literature search and analysis. The latest research progress on ferroptosis was described, with a special focus on the molecular mechanism of artemisinin-induced ferroptosis.

Results: Artemisinin derivatives, artemisinin-derived dimers, hybrids and artemisinin-transferrin conjugates, could significantly improve anticancer activity, and their IC50 values are lower than those of reference molecules such as doxorubicin and paclitaxel. The biological activities of linkers in dimers and hybrids are important in the drug design processes. ARTs induce ferroptosis mainly by triggering intracellular ROS production, promoting the lysosomal degradation of ferritin and regulating the System Xc-/Gpx4 axis. Interestingly, ARTs also stimulate the feedback inhibition pathway.

Conclusion: Artemisinin and its derivatives could be used in the future as cancer therapies with broader applications due to their induction of ferroptosis. Meanwhile, more attention should be paid to the development of novel artemisinin-related drugs based on the mechanism of artemisinininduced ferroptosis.
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http://dx.doi.org/10.2174/0929867327666200121124404DOI Listing
February 2021

Activation of TRPV1 Contributes to Recurrent Febrile Seizures Inhibiting the Microglial M2 Phenotype in the Immature Brain.

Front Cell Neurosci 2019 11;13:442. Epub 2019 Oct 11.

Department of Physiology, Hubei Provincial Key Laboratory of Developmentally Originated Disease, School of Basic Medical Sciences, Wuhan University, Wuhan, China.

Transient receptor potential vanilloid type 1 (TRPV1) is a nonselective cation channel implicated in the nervous system as a key component of several inflammatory diseases. A massive amount of evidence has demonstrated that TRPV1 is extensively expressed in the central nervous system (CNS) and there might be a close relationship between TRPV1 and neuroinflammation, which is a crucial pathogenic factor in seizure generation, although it's signaling mechanism has been less well characterized. Herein, we identified that TRPV1 is functionally expressed in the primary cultured mouse microglia and the membrane expression of TRPV1 is upregulated in rFS mice brain and specifically in activated microglia. Stimulation of TRPV1 promoted microglia activation and indirectly enhanced seizure susceptibility by inhibiting the neuroprotective effects of microglial transforming growth factor-beta1 (TGF-β1) interaction with Toll-like receptor 4 (TLR4) in mice. Conversely, genetic deletion of TRPV1 alleviated hyperthermia or LPS-induced abnormal microglial activation and restored a balanced inflammatory microenvironment in the brain. Taken together, these findings show that microglial TRPV1, as a potential pro-inflammatory mediator, and participate in neuroinflammatory response, which will provide a novel therapeutic strategy for controlling the neuroinflammation-induced seizure.
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http://dx.doi.org/10.3389/fncel.2019.00442DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6798794PMC
October 2019

Lnc-RP5 Regulates the miR-129-5p/Notch1/PFV Internal Promoter Axis to Promote the Expression of the Prototype Foamy Virus Transactivator Tas.

Virol Sin 2020 Feb 21;35(1):73-82. Epub 2019 Oct 21.

Department of Immunology and Hubei Province Key Laboratory of Allergy and Immunology, School of Basic Medical Sciences, Wuhan University, Wuhan, 430071, China.

Prototype foamy virus (PFV) is a unique retrovirus that infects animals and humans and does not cause clinical symptoms. Long noncoding RNAs (lncRNAs) are believed to exert multiple regulatory functions during viral infections. Previously, we utilized RNA sequencing (RNA-seq) to characterize and identify the lncRNA lnc-RP5-1086D14.3.1-1:1 (lnc-RP5), which is markedly decreased in PFV-infected cells. However, little is known about the function of lnc-RP5 during PFV infection. In this study, we identified lnc-RP5 as a regulator of the PFV transcriptional transactivator (Tas). Lnc-RP5 enhanced the activity of the PFV internal promoter (IP). The expression of PFV Tas was found to be promoted by lnc-RP5. Moreover, miR-129-5p was found to be involved in the lnc-RP5-mediated promotion of PFV IP activity, while the Notch1 protein suppressed the activity of PFV IP and the expression of Tas. Our results demonstrate that lnc-RP5 promotes the expression of PFV Tas through the miR-129-5p/Notch1/PFV IP axis. This work provides evidence that host lncRNAs can manipulate PFV replication by employing miRNAs and proteins during an early viral infection.
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http://dx.doi.org/10.1007/s12250-019-00168-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7035397PMC
February 2020

The Long-Noncoding RNA lnc-NONH Enhances the Early Transcription of Prototype Foamy Virus Via Upregulating Expression of miR-34c-5p and Tas Protein.

Intervirology 2019 20;62(3-4):156-163. Epub 2019 Aug 20.

Hubei Province Key Laboratory of Allergy and Immunology, School of Basic Medical Sciences, Wuhan University, Wuhan, China.

Background: Prototype foamy virus (PFV) is a complex and unique retrovirus with the longest genome among the retroviruses and is used as a vector for gene therapies. The viral Tas protein transactivates the viral long terminal repeat promoter and is required for viral replication. We have utilized RNA sequencing to identify and characterize the long-noncoding RNA NONHSAG000101 (lnc-NONH), which markedly increases in PFV-infected cells. However, little is known about the function of lnc-NONH.

Objectives: We aim to explore the role of lnc-NONH during PFV infection.

Methods: To assess the lnc-NONH role during PFV infection, the siRNAs were used to silence the lnc-NONH expression. The microRNA (miRNA) mimic and inhibitor were employed to explore the function of lnc-NONH-related miRNA miR-34c-5p. Quantitative real-time polymerase chain reaction assay and Western blotting were applied to measure the mRNA and protein levels of PFV transactivator Tas. Luciferase assay was used to determine the transcriptional activity of the PFV unique internal promoter (IP).

Results: lnc-NONH promotes the expression of PFV Tas and miR-34c-5p. The interaction between lnc-NONH and miR-34c-5p enhances the transcriptional activity of the PFV IP.

Conclusions: In the current study, we report a novel mechanism for the lnc-NONH-mediated upregulation of Tas expression. Our findings contribute to the understanding of regulatory network of Tas expression and PFV replication.
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http://dx.doi.org/10.1159/000502038DOI Listing
January 2020

BMP4 and Neuregulin regulate the direction of mouse neural crest cell differentiation.

Exp Ther Med 2019 May 26;17(5):3883-3890. Epub 2019 Mar 26.

State Key Laboratory of Silkworm Genome Biology, Southwest University, Chongqing 400715, P.R. China.

The neural crest is a transient embryonic tissue that initially generates neural crest stem cells, which then migrate throughout the body to give rise to a variety of mature tissues. It was proposed that the fate of neural crest cells is gradually determined via environmental cues from the surrounding tissues. In the present study, neural crest cells were isolated and identified from mouse embryos. Bone morphogenetic protein 4 (BMP4) and Neuregulin (NRG) were employed to induce the differentiation of neural crest cells. Treatment with BMP4 revealed neuron-associated differentiation; cells treated with NRG exhibited differentiation into the Schwann cell lineage, a type of glia. Soft agar clonogenic and neurosphere formation assays were conducted to investigate the effects of N-Myc (MYCN) overexpression in neural crest cells; the number of colonies and neurospheres notably increased after 14 days. These findings demonstrated that the direction of cell differentiation may be affected by altering the factors present in the surrounding environment. In addition, MYCN may serve a key role in regulating neural crest cell differentiation.
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http://dx.doi.org/10.3892/etm.2019.7439DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6468403PMC
May 2019

Molecular Characterization of the Gene Family in .

Front Plant Sci 2018 2;9:952. Epub 2018 Aug 2.

Key Laboratory of Eco-Environments in Three Gorges Reservoir Region (Ministry of Education), Chongqing Key Laboratory of Plant Ecology and Resources Research in Three Gorges Reservoir Region, SWU-TAAHC Medicinal Plant Joint R&D Centre, School of Life Sciences, Southwest University, Chongqing, China.

produces artemisinin, an effective antimalarial drug. In recent decades, the later steps of artemisinin biosynthesis have been thoroughly investigated; however, little is known about the early steps of artemisinin biosynthesis. Comparative transcriptomics of glandular and filamentous trichomes and CO radioisotope study have shown that the 2-C-methyl-D-erythritol-4-phosphate (MEP) pathway, rather than the mevalonate pathway, plays an important role in artemisinin biosynthesis. In this study, we have cloned three () genes from . (, , and ); the DXS enzyme catalyzes the first and rate-limiting enzyme of the MEP pathway. We analyzed the expression of these three genes in different tissues in response to multiple treatments. Phylogenetic analysis revealed that each of the three genes belonged to a distinct clade. Subcellular localization analysis indicated that all three AaDXS proteins are targeted to chloroplasts, which is consistent with the presence of plastid transit peptides in their N-terminal regions. Expression analyses revealed that the expression pattern of in specific tissues and in response to different treatments, including methyl jasmonate, light, and low temperature, was similar to that of artemisinin biosynthesis genes. To further investigate the tissue-specific expression pattern of , the promoter of was cloned upstream of the gene and was introduced in arabidopsis. Histochemical staining assays demonstrated that was mainly expressed in the trichomes of Arabidopsis leaves. Together, these results suggest that might be the only member of the DXS family in that is involved in artemisinin biosynthesis.
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http://dx.doi.org/10.3389/fpls.2018.00952DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6084332PMC
August 2018

Inhibition of DPP4 enhances inhibitory synaptic transmission through activating the GLP-1/GLP-1R signaling pathway in a rat model of febrile seizures.

Biochem Pharmacol 2018 10 4;156:78-85. Epub 2018 Aug 4.

Department of Pathophysiology, School of Basic Medical Sciences, Wuhan University, China.

Dipeptidyl peptidase-IV (DPP4) is a cell surface serine peptidase widely expressed in the brain. Recent studies suggest that DPP4 contributes to the development of febrile seizures (FS); however, the underlying mechanism is still unclear. Thus, we investigated the role of DPP4 in the progression of FS at the molecular and electrophysiological levels using FS models in vivo and in vitro. Herein, we found that both the mRNA and protein levels of DPP4 were upregulated in the FS model. Administration of the pharmacological DPP4 inhibitor sitagliptin suppressed the hyperthermia-induced neuronal excitability as determined via whole-cell patch-clamp recordings in vitro. Interestingly, sitagliptin administration activated the glucagon-like peptide-1 (GLP-1)/GLP-1 receptor (GLP-1R) pathway by increasing the expression of GLP-1 and GLP-1R in a rat model of FS. Moreover, administration of the GLP-1R inhibitor exendin9-39 increased seizure severity, and sitagliptin reversed the effect, as shown in the electroencephalogram (EEG) and patch-clamp results in a rat model of FS. Furthermore, the GLP-1R-mediated reduction in GABAergic transmission was enhanced by sitagliptin and DPP4 knockdown through increasing miniature inhibitory post-synaptic currents (mIPSCs) in vitro accompanied by increased synaptic release of GABA in vivo. Taken together, our results demonstrate a role of DPP4 in regulating GABAergic transmission via the GLP-1/GLP-1R pathway. These findings indicated that DPP4 may represent a novel therapeutic strategy and target for FS.
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http://dx.doi.org/10.1016/j.bcp.2018.08.004DOI Listing
October 2018

Anticonvulsant agent DPP4 inhibitor sitagliptin downregulates CXCR3/RAGE pathway on seizure models.

Exp Neurol 2018 09 6;307:90-98. Epub 2018 Jun 6.

Department of Pathophysiology, School of Basic Medical Sciences, Wuhan University, Wuhan, China. Electronic address:

Epilepsy is a common neurological disorder with a complex etiology. Our previous study demonstrated that dipeptidyl peptidase IV (DPP4) may be associated with the pathogenesis of epilepsy. However, whether the DPP4 inhibitor sitagliptin has an anticonvulsant effect and the underlying mechanism remain to be elucidated. In this study, we determined that sitagliptin remarkably attenuated the severity of seizures in a pentylenetetrazole (PTZ)-induced rat model. In addition, sitagliptin decreased epileptiform activity measured by electroencephalography (EEG) recordings and patch-clamp methods. Interestingly, sitagliptin pretreatment downregulated the RAGE-JAK2/STAT3 pathway and decreased the expression of CXCL4 and CXCR3. Moreover, CXCR3 knockdown decreased the expression of RAGE, JAK2 and STAT3 in cultured neurons, which suggests that CXCR3 is upstream of the RAGE-JAK2/STAT3 pathway. Altogether, our present data suggest that sitagliptin has an anticonvulsant effect, which might act via downregulation of the CXCL4/CXCR3 axis, followed by a decrease in RAGE and JAK2/STAT3 expression. Considering these effects, sitagliptin could be considered as a novel potential anticonvulsant drug.
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http://dx.doi.org/10.1016/j.expneurol.2018.06.004DOI Listing
September 2018

Short Communication: Long Noncoding RNA GAS5 Inhibits HIV-1 Replication Through Interaction with miR-873.

AIDS Res Hum Retroviruses 2018 06 10;34(6):544-549. Epub 2018 May 10.

1 Hubei Province Key Laboratory of Allergy and Immunology, School of Basic Medical Sciences, Wuhan University , Wuhan, China .

HIV is the causative pathogen of AIDS, which has generated worldwide concern. Long noncoding RNAs (lncRNAs) are a rising star in virus-host cross-talk pathways; they are differentially expressed during many viral infections and are involved in multiple biological processes. Currently, lncRNA growth arrest-specific transcript 5 (GAS5) is known to be downregulated during HIV-1 infection. However, the functions and mechanisms of GAS5 in HIV-1 infection remain largely unknown. In this report, it was found for the first time that GAS5 could inhibit HIV-1 replication. Interestingly, using bioinformatics analyses (with Genomica and starBase.v2.0), GAS5 was found to potentially interact with miR-873. It was further verified that GAS5 could suppress miR-873. Moreover, miR-873 could promote HIV-1 replication. Together, these results not only suggest that GAS5 may inhibit HIV-1 replication through interaction with miR-873 but the results may also provide novel biomarkers for antiviral drugs or potential targets for future therapeutics for HIV/AIDS.
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http://dx.doi.org/10.1089/AID.2017.0177DOI Listing
June 2018

Kv1.3 channel blocker (ImKTx88) maintains blood-brain barrier in experimental autoimmune encephalomyelitis.

Cell Biosci 2017 7;7:31. Epub 2017 Jun 7.

Department of Pathophysiology, School of Basic Medical Sciences, Wuhan University, Wuhan, No. 185, Donghu Road, Wuchang District, Wuhan, 430071 China.

Background: Disruption of blood-brain barrier (BBB) and subsequent infiltration of auto-reactive T lymphocytes are major characteristics of multiple sclerosis (MS) and experimental autoimmune encephalomyelitis (EAE). Kv1.3 channel blockers are demonstrated potential therapeutic effects on MS patients and EAE models, maybe via reducing activation of T cells. However, it remains to be explored whether Kv1.3 channel blockers maintain integrity of BBB in MS model.

Results: In this study, ImKTx88, a highly selective Kv1.3 channel blocker, was used to determine the role of Kv1.3 channel in the pathogenesis of EAE, particularly in the maintenance of BBB. ImKTx88 ameliorated pathological severity in the EAE rats, and reduced extravasation into CNS. ImKTx88 also ameliorated the severity of loss or redistribution of tight junction proteins, and inhibited over-expression of ICAM-1 and VCAM-1 in the brain from EAE rats. Furthermore ImKTx88 protection was associated with activation of Ang-1/Tie-2 axis, and might be due to decreased IL-17 production.

Conclusions: ImKTx88 may be a novel therapeutic agent for MS treatment by stabilizing the BBB.
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http://dx.doi.org/10.1186/s13578-017-0158-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5463463PMC
June 2017

DPP4 regulates the inflammatory response in a rat model of febrile seizures.

Biomed Mater Eng 2017 ;28(s1):S139-S152

Department of Pathophysiology, School of Basic Medical Sciences, Wuhan University, Wuhan, China.

Febrile seizures (FS) are the most common seizure disorders in children aged 6 months to 5 years. Children suffering from complex FS have a high risk of developing subsequent temporal lobe epilepsy (TLE). Neuroinflammation is involved in the pathogenesis of FS although the mechanism remains unknown. Our previous study using the Whole Rat Genome Oligo Microarray determined that Dipeptidyl peptidase IV (DPP4) is potentially a related gene in FS rats. In this study, we demonstrated that DPP4 expression was significantly increased at both the protein and mRNA levels after hyperthermia induction. Sitagliptin, a specific enzyme inhibitor of DPP4, remarkably attenuated the severity of seizures in FS rats, and hyperthermia-induced astrocytosis was suppressed after DPP4 inhibition. Furthermore, sitagliptin significantly decreased the levels of the inflammatory cytokines IL-1β, TNF-α, and IL-6 but not IL-10. In addition, sitagliptin prevented NF-κB activation by decreasing phosphorylation of the p65 subunit. Taken together, our findings demonstrate that DPP4 functions as a critical regulator of neuroinflammation in hyperthermia-induced seizures and the DPP4 inhibitor may be a viable option for FS therapeutics.
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http://dx.doi.org/10.3233/BME-171635DOI Listing
July 2017

Prototype foamy virus elicits complete autophagy involving the ER stress-related UPR pathway.

Retrovirology 2017 03 7;14(1):16. Epub 2017 Mar 7.

Hubei Province Key Laboratory of Allergy and Immunology, School of Basic Medical Sciences, Wuhan University, No. 185, Donghu Road, Wuchang District, Wuhan, 430071, China.

Background: Prototype foamy virus (PFV) is a member of the Spumaretrovirinae subfamily of retroviruses, which maintains lifelong latent infection while being nonpathogenic to their natural hosts. Autophagy is a cell-programmed mechanism that plays a pivotal role in controlling homeostasis and defense against exotic pathogens. However, whether autophagy is the mechanism for host defense in PFV infection has not been investigated.

Findings: Our results revealed that PFV infection induced the accumulation of autophagosomes and triggered complete autophagic flux in BHK-21 cells. PFV infection also altered endoplasmic reticulum (ER) homeostasis. The PERK, IRE1 and ATF6 pathways, all of which are components of the ER stress-related unfolded protein response (UPR), were activated in PFV-infected cells. In addition, accelerating autophagy suppressed PFV replication, and inhibition of autophagy promoted viral replication.

Conclusions: Our data indicate that PFV infection can induce complete autophagy through activating the ER stress-related UPR pathway in BHK-21 cells. In turn, autophagy negatively regulates PFV replication.
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http://dx.doi.org/10.1186/s12977-017-0341-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5341167PMC
March 2017

The fourth central polypurine tract guides the synthesis of prototype foamy virus plus-strand DNA.

Virus Genes 2017 Apr 9;53(2):259-265. Epub 2017 Feb 9.

School of Basic Medical Sciences, Pathogenic Organism and Infectious Diseases Research Institute, Wuhan University, No. 299 Bayi Road, Wuchang District, Wuhan, 430071, Hubei, People's Republic of China.

Foamy virus (FV) is a nonpathogenic retrovirus that has the potential to serve as a gene therapy vector. In retroviral replication, the central polypurine tract (cPPT) is used as a primer to synthesize plus-strand DNA. The cPPT is subsequently degraded to produce a single-stranded gap in the double-stranded viral DNA molecule. In the prototype foamy virus (PFV), four cPPT-like motifs have been previously identified, in which there is a gap with uncertain terminals. In this study, we determined the length of the PFV gap varying from 144 to 731 bp. The 3' terminus of the cleavage sites is located between 6272 bp and 6274 bp from the first base of PFV genome, while the 5' terminus is located within a 465 bp range. The start and terminal nucleotides of the gap are located on either side of the fourth cPPT element. Deletion, mutation, and replacement of the fourth cPPT with the Human immunodeficiency virus 1 (HIV-1) cPPT resulted in a significant reduction in modified PFV virions, indicating that the fourth cPPT ought to be the primer that guides the synthesis of PFV plus-strand DNA. These results improve the theoretical basis for understanding FVs replication and will help construct new FV vectors with simple genome sequences containing only the necessary cis elements.
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http://dx.doi.org/10.1007/s11262-016-1425-8DOI Listing
April 2017

Hsa-let-7c-5p augments enterovirus 71 replication through viral subversion of cell signaling in rhabdomyosarcoma cells.

Cell Biosci 2017 14;7. Epub 2017 Jan 14.

Hubei Province Key Laboratory of Allergy and Immunology, School of Basic Medical Sciences, Wuhan University, No. 185, Donghu Road, Wuchang District, Wuhan, 430071 China ; Hubei Provincial Key Laboratory of Developmentally Originated Disease, School of Basic Medical Sciences, Wuhan University, Wuhan, 430071 China.

Background: Human enterovirus 71 (EV71) causes severe hand, foot and mouse disease, accompanied by neurological complications. During the interaction between EV71 and the host, the virus subverts host cell machinery for its own replication. However, the roles of microRNAs (miRNAs) in this process remain obscure.

Results: In this study, we found that the miRNA hsa-let-7c-5p was significantly upregulated in EV71-infected rhabdomyosarcoma cells. The overexpression of hsa-let-7c-5p promoted replication of the virus, and the hsa-let-7c-5p inhibitor suppressed viral replication. Furthermore, hsa-let-7c-5p targeted mitogen-activated protein kinase kinase kinase kinase 4 (MAP4K4) and inhibited its expression. Interestingly, downregulation of MAP4K4 expression led to an increase in EV71 replication. In addition, MAP4K4 knockdown or transfection with the hsa-let-7c-5p mimic led to activation of the c-Jun NH2-terminal kinase (JNK) signaling pathway, whereas the hsa-let-7c-5p inhibitor inhibited activation of this pathway. Moreover, EV71 infection promoted JNK pathway activation to facilitate viral replication.

Conclusions: Our data suggested that hsa-let-7c-5p facilitated EV71 replication by inhibiting MAP4K4 expression, which might be related to subversion of the JNK pathway by the virus. These results may shed light on a novel mechanism underlying the defense of EV71 against cellular responses. In addition, these findings may facilitate the development of new antiviral strategies for use in future therapies.
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http://dx.doi.org/10.1186/s13578-017-0135-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5237547PMC
January 2017

ACY-1215 accelerates vemurafenib induced cell death of BRAF-mutant melanoma cells via induction of ER stress and inhibition of ERK activation.

Oncol Rep 2017 Feb 28;37(2):1270-1276. Epub 2016 Dec 28.

Department of Dermatology, Zhongnan Hospital of Wuhan University, Wuhan, Hubei 430071, P.R. China.

BRAFV600E mutation is found in ~50% of melanoma patients and BRAFV600E kinase activity inhibitor, vemurafenib, has achieved a remarkable clinical response rate. However, most patients treated with vemurafenib eventually develop resistance. Overcoming primary and secondary resistance to selective BRAF inhibitors remains one of the most critically compelling challenges for these patients. HDAC6 has been shown to confer resistance to chemotherapy in several types of cancer. Few studies focused on the role of HDAC6 in vemurafenib resistance. Here we showed that overexpression of HDAC6 confers resistance to vemurafenib in BRAF-mutant A375 cells. ACY-1215, a selective HDAC6 inhibitor, inhibits the proliferation and induces the apoptosis of A375 cells. Moreover, ACY-1215 sensitizes A375 cells to vemurafenib induced cell proliferation inhibition and apoptosis induction, which occur partly through induction of endoplasmic reticulum (ER) stress and inactivation of extracellular signal-regulated kinase (ERK). Taken together, our results suggest that the inhibition of HDAC6 may be a promising strategy for the treatment of melanoma and overcoming resistance to vemurafenib.
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http://dx.doi.org/10.3892/or.2016.5340DOI Listing
February 2017

Cocaine Withdrawal Reduces Gamma-Aminobutyric Acid-Ergic Transmission and Gephyrin Expression at Medial Prefrontal Cortex in Cocaine-Conditioned Place-Preference Rats, Which Shows Increased Cocaine Seeking.

Eur Addict Res 2017 30;23(1):28-36. Epub 2016 Nov 30.

Department of Neurology, Dongfeng Hospital, Hubei University of Medicine, Shiyan, PR China.

Aims: Chronic cocaine abuse decreases the inhibitory synaptic transmission via unknown mechanisms, while pharmacologically augmenting gamma-aminobutyric acid-ergic (GABAergic) transmission attenuates cocaine craving. Here, we propose that prolonged cocaine withdrawal downregulates GABAergic transmission and its important regulator gephyrin in medial prefrontal cortex (mPFC), in cocaine-conditioned place-preference (CPP) rats.

Methods: CPP test, patch clamp, and Western blot analysis are engaged to test this proposal.

Results: Two-week cocaine withdrawal further increased CPP score, as compared to the 24-hour withdrawn group. The amplitude of GABAergic inhibitory postsynaptic currents (IPSCs) was decreased in 2-week-withdrawn mPFC neurons from cocaine-CPP rats, compared to that of saline-CPP rats. Two-week withdrawal did not alter the amplitude of glutamatergic excitatory postsynaptic currents (EPSCs) in mPFC in cocaine-CPP rats. Two-week withdrawal increased the ratio of EPSCs/IPSCs (E/I) in the same mPFC neuron in cocaine-CPP rats. In addition, Western blots showed 2-week cocaine-withdrawn down-regulated gephyrin at postsynaptic density (PSD) sites of mPFC.

Conclusion: We found decreased GABAergic IPSCs and downregulated gephyrin in PSD at mPFC in 2-week cocaine-withdrawn rats that showed increased CPP, suggesting that an increased E/I ratio and neuron excitability in mPFC may associate with a cocaine-seeking tendency. Strategies aimed at GABAergic synapses in mPFC may therapeutically benefit to cocaine addiction treatment.
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http://dx.doi.org/10.1159/000452657DOI Listing
June 2017

Decreased Methylation Level of H3K27me3 Increases Seizure Susceptibility.

Mol Neurobiol 2017 11 5;54(9):7343-7352. Epub 2016 Nov 5.

Department of Pathophysiology, School of Basic Medical Sciences, Wuhan University, Donghu Road No. 185, Wuchang, Wuhan, 430071, China.

Epigenetic modifications including histone modifications are associated with seizure development and epileptogenesis; however, its underlying mechanism remains to be elucidated. Dipeptidyl peptidase 4 (DPP4) and IL6 are identified as febrile seizure (FS)-related genes using gene microarray analysis in hyperthermia prone (HP) rats. This purpose of the study focused on exploring whether epigenetic modifications marker histone H3 lysine 27 trimethylation (H3K27me3)-regulated DPP4 and IL6 expression further affected seizures development. Herein, we reported broad between-group differences in the global levels of H3K27me3 with increased seizure severity in vivo. Using chromatin immunoprecipitation (ChIP), we identified markedly decreased H3K27me3 enrichment at their promoters of DPP4 and IL6 in vivo. We further showed that hyperthermia significantly decreased protein levels of H3K27me3, increased mRNA levels of DPP4 and IL6 by decreasing H3K27me3 enrichment at their promoters of DPP4 and IL6 in vitro. Importantly, H3K27me3 loss via enhancer of zeste homolog 2 (EZH2) knockdown promoted expression of DPP4 and IL6 via the same mechanism in vitro. EZH2 knockdown also increased neuronal firing frequency in vitro and FS susceptibility in vivo companied with upregulation expression of DPP4 and IL6. Taken together, our study provided the first evidence that hyperthermia-induced decreased of H3K27me3 promoted seizure susceptibility via regulating the expression pattern of DPP4 and IL6. These findings suggested that the methylation level of H3K27me3 might be a key regulator of seizure susceptibility.
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http://dx.doi.org/10.1007/s12035-016-0197-4DOI Listing
November 2017

The Novel Landscape of Long Non-Coding RNAs in Response to Human Foamy Virus Infection Characterized by RNA-Seq.

AIDS Res Hum Retroviruses 2017 05 14;33(5):452-464. Epub 2016 Nov 14.

1 Hubei Province Key Laboratory of Allergy and Immunology, School of Basic Medical Sciences, Wuhan University , Wuhan, China .

Human foamy virus (HFV) is a complex and unique retrovirus with the longest genomes among retroviruses that are used as vectors for gene therapy. Long non-coding RNAs (lncRNAs) are regarded as key regulators that are involved in diverse biological processes during viral infection. However, the role of lncRNAs in HFV infection remains unknown. In this study, we utilized next-generation sequencing to first characterize lncRNAs in 293T cells after HFV infection, evaluating length distribution, exon number distribution, volcano picture, and lncRNA class distribution. We identified 11,336 lncRNAs (4,729 upregulated lncRNAs and 6,588 downregulated lncRNAs) and 61,367 mRNAs (30,133 upregulated mRNAs and 31,220 downregulated mRNAs), which were differentially expressed in the HFV-infected 293T cells. Subsequently, six differentially expressed lncRNAs characterized using RNA-seq were confirmed by quantitative real-time polymerase chain reaction assays. Interestingly, Gene Ontology (GO)/Gene Ontology Tree Machine (GOTM) and Kyoto Encyclopedia of Gene and Genomes (KEGG) pathway analyses indicated that positive regulation of interleukin 8 (IL8) production and cytokine-cytokine receptor interaction might be involved in the functional enrichment of lncRNAs. Moreover, cis-acting and trans-acting regulatory networks show that NR_028036 may target the fas gene in a cis-acting manner and that ENST00000354838 may target the IL18 gene in a trans-acting manner. Overall, these results not only provide novel insights into the relationship between HFV and lncRNAs in the host response to infection but also have implications for the future wider application of HFV as a vector.
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http://dx.doi.org/10.1089/AID.2016.0156DOI Listing
May 2017

miRNA: A Novel Link Between Rice Ragged Stunt Virus and Oryza sativa.

Indian J Microbiol 2016 Jun 4;56(2):219-24. Epub 2016 Mar 4.

Pathogenic Organism and Infectious Diseases Research Institute, School of Basic Medical Sciences, Wuhan University, Donghu Road No. 185, Wuchang, Wuhan, 430071 China ; State Key Laboratory of Hybrid Rice and College of Life Sciences, Wuhan University, Wuhan, 430072 China ; Hubei Province Key Laboratory of Allergy and Immunology, Wuhan, 430071 China.

Rice ragged stunt disease caused leads to severe loss of rice yield. Recently, rice ragged stunt virus (RRSV) were found to be increasingly common in rice-growing regions of China and Vietnam. RRSV may cause problem by interacting with microRNAs (miRNAs) of host cells and the mechanism is not clear yet. In this study we identified 11 miRNAs in response to RRSV infection and predicted their possible targets to viral RNA segments (S1-S10) through the bioinformatics analysis. Interestingly, we found that Osa-miR-168b might bind to both the CDS region and 3'UTR of S5 and S8 and target eEF-1A to inhibit the activity of host cells to facilitate RRSV replication. These results suggest that miRNAs may be a potential target for developing rice against RRSV infection.
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http://dx.doi.org/10.1007/s12088-016-0572-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4984435PMC
June 2016

Hypothalamic gastrin-releasing peptide receptor mediates an antidepressant-like effect in a mouse model of stress.

Am J Transl Res 2016 15;8(7):3097-105. Epub 2016 Jul 15.

Department of Psychiatry, Renmin Hospital of Wuhan University Wuhan 430060, P. R. China.

Evidence has shown that gastrin-releasing peptide receptor (GRPR) is involved in responses to stress and anxiety. The primary role of GRPR is to stimulate corticotrophin-releasing hormone (CRH) or adrenocorticotropic hormone (ACTH) secretion. Thus, the mechanisms of GRPR signaling should be elucidated to discover novel therapeutic targets for treating depression. This study aimed to investigate GRPR alterations in the C57 mouse hypothalamus after the animals were subjected to stress and fluoxetine treatments. Specifically, we subjected the mice to isolation and chronic unpredictable mild stress (CUMS) for three weeks to establish an experimental model of depression. These mice were subsequently treated with fluoxetine for three weeks. Then, we performed the sucrose preference test and the open field test and measured food intake and body weight to explore the effects of stress and fluoxetine on activity and anhedonia. After fluoxetine treatment, we also assessed changes in the levels of GRPR expression in the hypothalamus using immunohistochemistry, western blotting, and real-time quantitative PCR (RT-PCR). We found that stressed mice showed significant reductions in locomotion, food intake/body weight, and sucrose preference; these reduced parameters indicated a state of anhedonia. Marked increases in mRNA and protein expression of GRPR in the hypothalamus of CUMS-exposed mice were also observed, although treatment with fluoxetine reversed these stress-induced changes. Our results also demonstrated the feasibility and effectiveness of the C57 mouse model of depression established by CUMS and isolation. After fluoxetine treatment was administered, the animals' depression symptoms were alleviated, and these behavioral alterations were accompanied by specific changes in mRNA and protein expression of GRPR in the hypothalamus. These results suggest that GRPR may be implicated in depression; therefore, new therapeutic targets of depression focused on GRPR signaling should be explored.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4969446PMC
August 2016

Molecular cloning and characterization of the promoter of aldehyde dehydrogenase gene from Artemisia annua.

Biotechnol Appl Biochem 2017 Nov 7;64(6):902-910. Epub 2017 Sep 7.

Key Laboratory of Eco-Environments in Three Gorges Reservoir Region (Ministry of Education), SWU-TAAHC Medicinal Plant Joint R&D Centre, School of Life Sciences, Southwest University, Chongqing 400715, People's Republic of China.

In recent years, although several related genes had been cloned and characterized, the role of aldehyde dehydrogenase 1 (ALDH1), the newly cloned gene involved in artemisinin biosynthesis pathway, is still not clear. In this study, a 2,100-bp ALDH1 promoter region fused with GUS reporter gene was stably transferred into Arabidopsis thaliana. Histochemical staining showed the methyl jasmonate (MeJA) and wounding treatment induced the GUS gene expression specifically in the trichomes of transgenic A. thaliana, consistent with the results that the expression level of ALDH1 gene was increased in the A. annua under MeJA and wounding treatments. Two RAA motifs (AP2/ERF binding site) but no W box (WRKY binding site) motif were identified in the ALDH1 promoter by the analysis through PLACE and plantCARE. Through the dual luciferase reporter assay, we revealed that both AaORA and AaERF2, rather than AaWRKY1, could activate the expression of ALDH1 promoter. Our study shed light on the in-depth understanding of the role of ALDH1 in artemisinin biosynthesis.
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http://dx.doi.org/10.1002/bab.1520DOI Listing
November 2017

HDAC6 promotes cell proliferation and confers resistance to temozolomide in glioblastoma.

Cancer Lett 2016 08 3;379(1):134-42. Epub 2016 Jun 3.

Department of Radiation and Medical Oncology, Zhongnan Hospital of Wuhan University, Wuhan, China. Electronic address:

Histone deacetylases are considered to be among the most promising targets in drug development for cancer therapy. Histone deacetylase 6 (HDAC6) is a unique cytoplasmic enzyme that regulates many biological processes involved in tumorigenesis through its deacetylase and ubiquitin-binding activities. Here, we report that HDAC6 is overexpressed in glioblastoma tissues and cell lines. Overexpression of HDAC6 promotes the proliferation and spheroid formation of glioblastoma cells. HDAC6 overexpression confers resistance to temozolomide (TMZ) mediated cell proliferation inhibition and apoptosis induction. Conversely, knockdown of HDAC6 inhibits cell proliferation, impairs spheroid formation and sensitizes glioblastoma cells to TMZ. The inhibition of HDAC6 deacetylase activity by selective inhibitors inhibits the proliferation of glioblastoma cells and induces apoptosis. HDAC6 selective inhibitors can sensitize glioblastoma cells to TMZ. Moreover, we showed that HDAC6 mediated EGFR stabilization might partly account for its oncogenic role in glioblastoma. TMZ resistant glioblastoma cells showed higher expression of HDAC6 and more activation of EGFR. HDAC6 inhibitors decrease EGFR protein levels and impair the activation of the EGFR pathway. Taken together, our results suggest that the inhibition of HDAC6 may be a promising strategy for the treatment of glioblastoma.
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http://dx.doi.org/10.1016/j.canlet.2016.06.001DOI Listing
August 2016

The long non-coding RNA expression profile of Coxsackievirus A16 infected RD cells identified by RNA-seq.

Virol Sin 2016 Apr 31;31(2):131-41. Epub 2016 Mar 31.

Pathogenic Organism and Infectious Diseases Research Institute, School of Basic Medical Sciences, Wuhan University, Wuhan, 430071, China.

Coxsackievirus A16 (CVA16) is one of major pathogens of hand, foot and mouth disease (HFMD) in children. Long non-coding RNAs (IncRNAs) have been implicated in various biological processes, but they have not been associated with CVA16 infection. In this study, we comprehensively characterized the landscape of IncRNAs of normal and CVA16 infected rhabdomyosarcoma (RD) cells using RNA-Seq to investigate the functional relevance of IncRNAs. We showed that a total of 760 IncRNAs were upregulated and 1210 IncRNAs were downregulated. Out of these dysregulated IncRNAs, 43.64% were intergenic, 22.31% were sense, 15.89% were intronic, 8.67% were bidirectional, 5.59% were antisense, 3.85% were sRNA host IncRNAs and 0.05% were enhancer. Six dysregulated IncRNAs were validated by quantitative PCR assays and the secondary structures of these IncRNAs were projected. Moreover, we conducted a bioinformatics analysis of an IncRNAs (ENST00000602478) to elucidate the diversity of modification and functions of IncRNAs. In summary, the current study compared the dysregulated IncRNAs profile upon CVA16 challenge and illustrated the intricate relationship between coding and IncRNAs transcripts. These results may not only provide a complete picture of transcription in CVA16 infected cells but also provide novel molecular targets for treatments of HFMD.
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http://dx.doi.org/10.1007/s12250-015-3693-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7090472PMC
April 2016

Cold stress improves the production of artemisinin depending on the increase in endogenous jasmonate.

Biotechnol Appl Biochem 2017 May 10;64(3):305-314. Epub 2016 Oct 10.

Key Laboratory of Eco-Environments in Three Gorges Reservoir Region (Ministry of Education), SWU-TAAHC Medicinal Plant Joint R&D Centre, School of Life Sciences, Southwest University, Chongqing, People's Republic of China.

Previous publications reported that the artemisinin level was increased in Artemisia annua following a night-frost period. However, the molecular mechanism was not clear. In this study, we found that exogenous jasmonate (JA) effectively enhanced the freezing tolerance of A. annua. The JA biosynthetic genes (LOX1, LOX2, allene oxide cyclase [AOC], and jasmonate resistant 1 [JAR1]) were induced by cold stress, leading to an increase in endogenous JA in cold-treated A. annua. Increased endogenous JA enhanced the expression of three JA-responsive transcription factors, ethylene response factor 1, ethylene response factor 2, and octadecanoid-responsive AP2/ERF, all of which were reported to transcriptionally activate the expression of artemisinin biosynthetic genes, such as amorpha-4,11-diene synthase (ADS), CYP71AV1, DBR2, and aldehyde dehydrogenase 1 (ALDH1). Furthermore, the expression levels of the four artemisinin biosynthetic genes were also significantly increased under cold stress. Consequently, the levels of artemisinin and related secondary metabolites, such as dihydroartemisinic acid, artemisinin B, and artemisinic acid, were increased in A. annua under cold stress. Our study points to a molecular mechanism in which the production of artemisinin is regulated by cold stress in A. annua.
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http://dx.doi.org/10.1002/bab.1493DOI Listing
May 2017