Publications by authors named "Wenxin Wu"

43 Publications

Long-term cigarette smoke exposure dysregulates pulmonary T cell response and IFN-γ protection to influenza virus in mouse.

Respir Res 2021 Apr 20;22(1):112. Epub 2021 Apr 20.

Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, University of Oklahoma Health Sciences Center, Room 425, RP1, 800 N. Research Pkwy., Oklahoma City, OK, 73104, USA.

Background: Influenza is a highly contagious, acute, febrile respiratory infection caused by a negative-sense, single-stranded RNA virus, which belongs in the Orthomyxoviridae family. Cigarette smoke (CS) exposure worsens influenza infection in terms of frequency and severity in both human and animal models.

Methods: C57BL/6 mice with or without CS exposure for 6 weeks were inoculated intranasally with a single, non-lethal dose of the influenza A virus (IAV) A/Puerto Rico/8/1934 (PR8) strain. At 7 and 10 days after infection, lung and mediastinal lymph nodes (MLN) cells were collected to determine the numbers of total CD4 + and CD8 + T cells, and IAV-specific CD4 + and CD8 + T cells, using flow cytometry. Bronchoalveolar lavage fluid (BALF) was also collected to determine IFN-γ levels and total protein concentration.

Results: Although long-term CS exposure suppressed early pulmonary IAV-antigen specific CD8 + and CD4 + T cell numbers and IFN-γ production in response to IAV infection on day 7 post-infection, CS enhanced numbers of these cells and IFN-γ production on day 10. The changes of total protein concentration in BALF are consistent with the changes in the IFN-γ amounts between day 7 and 10, which suggested that excessive IFN-γ impaired barrier function and caused lung injury at the later stage of infection.

Conclusions: Our results demonstrated that prior CS exposure caused a biphasic T cell and IFN-γ response to subsequent infection with influenza in the lung. Specifically, the number of IAV antigen-specific T cells on day 10 was greatly increased by CS exposure even though CS decreased the number of the same group of cells on day 7. The result suggested that CS affected the kinetics of the T cell response to IAV, which was suppressed at an early stage and exaggerated at a later stage. This study is the first to describe the different effect of long-term CS on T cell responses to IAV at early and late stages of infection in vivo.
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http://dx.doi.org/10.1186/s12931-021-01713-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8056367PMC
April 2021

Self-produced audio-visual animation introduction alleviates preoperative anxiety in pediatric strabismus surgery: a randomized controlled study.

BMC Ophthalmol 2021 Apr 7;21(1):163. Epub 2021 Apr 7.

Department of Anesthesiology, The First Affiliated Hospital of Wenzhou Medical University, South Baixiang Town, Wenzhou, Zhejiang, China.

Background: Hospital anxiety caused by strabismus surgery has an unpleasant and disturbing feeling for both children and their parents. This study aimed to determine the effect of viewing a self-produced audio-visual animation introduction on preoperative anxiety and emergence agitation of pediatric patients undergoing strabismus surgery.

Methods: In this prospective randomized study, 1 hundred children scheduled for strabismus surgery with aged 3 ~ 6 years. The children were randomly divided into 2 groups (n = 50 for each), Group A: using a self-produced audio-visual animation introduction; Group C: controlled group without audio-visual animation introduction. Children's preoperative anxiety was determined by the modified Yale Preoperative Anxiety Scale (mYPAS) at different time points: the night before surgery(T1), at pre-anesthetic holding room(T2), and just before anesthesia induction(T3). The Spielberger State-Trait Anxiety Inventory (STAI) was used to record the anxiety of parents at T1,T2 and T3. The incidence and the degree of emergence agitation were recorded.

Results: The mYPAS scores at T2 and T3 were higher than T1(p < 0.05) in both groups. The average score of mYPAS in Group A was significantly lower than in Group C at T2 and T3(p < 0.05). The STAI scores in Group A at T2 and T3 were significantly lower than in Group C(p < 0.05). The incidence of agitation in Group A was lower than that in Group C(p < 0.05).

Conclusions: Based on the findings, viewing a self-produced audio-visual animation can effectively alleviate the preoperative anxiety for both children and their parents in pediatric strabismus surgery, and it was effective for reducing emergence agitation as well.

Trial Registration: The trial was prospectively registered before patient enrollment at Chinese Clinical Trial Registry (Clinical Trial Number: ChiCTR1900025116 , Date: 08/12/2019).
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http://dx.doi.org/10.1186/s12886-021-01922-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8028828PMC
April 2021

Long non-coding RNA LINC01137 contributes to oral squamous cell carcinoma development and is negatively regulated by miR-22-3p.

Cell Oncol (Dordr) 2021 Apr 2. Epub 2021 Apr 2.

Department of Pathology, The Second Hospital of Hebei Medical University, Shijiazhuang, China.

Purpose: Long noncoding RNAs (lncRNAs) are emerging as key regulators in cancer initiation and progression. LINC01137 is a recently identified lncRNA of which the functional role in the development of oral squamous cell carcinoma (OSCC) has not been determined yet.

Methods: We analyzed the expression of LINC01137 using a microarray-based OSCC gene expression dataset (GSE31056), and validated the results obtained using RT-qPCR in 26 pairs of primary OSCC tumor tissues and adjacent non-tumor tissues. The proliferative and invasive effects of LINC01137 on OSCC cells were determined using CCK-8, colony formation and transwell assays, respectively. Targeted binding between miR-22-3p and LINC01137 was verified using a dual luciferase reporter assay.

Results: We found that LINC01137 was significantly upregulated in primary OSCCs. LINC01137 knockdown inhibited OSCC cell proliferation, migration and invasion, whereas LINC01137 overexpression induced opposite effects. LINC01137 upregulation along with p53 inhibition enhanced the malignant transformation of oral cells. In addition, we found that miR-22-3p can directly target LINC01137 through interaction with a putative miR-22-3p-binding site present within the LINC01137 sequence. A significant negative correlation was observed between LINC01137 and miR-22-3p expression in primary OSCC specimens. Exogenous overexpression of miR-22-3p markedly reduced the endogenous expression level of LINC01137 in OSCC cells. Additional functional assays showed that miR-22-3p overexpression enhanced the inhibitory effect of siRNA-mediated LINC01137 silencing on OSCC cell proliferation, migration and invasion, whereas miR-22-3p inhibition had the opposite effect.

Conclusions: Our results indicate that LINC01137 functions as an oncogenic lncRNA in OSCC. miR-22-3p can directly target LINC01137 and negatively regulate its expression and function.
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http://dx.doi.org/10.1007/s13402-021-00586-0DOI Listing
April 2021

Hyperdimensional Imaging Contrast Using an Optical Fiber.

Sensors (Basel) 2021 Feb 9;21(4). Epub 2021 Feb 9.

Center for Quantitative Cell Imaging, University of Wisconsin, Madison, WI 53706, USA.

Fluorescence properties of a molecule can be used to study the structural and functional nature of biological processes. Physical properties, including fluorescence lifetime, emission spectrum, emission polarization, and others, help researchers probe a molecule, produce desired effects, and infer causes and consequences. Correlative imaging techniques such as hyperdimensional imaging microscopy (HDIM) combine the physical properties and biochemical states of a fluorophore. Here we present a fiber-based imaging system that can generate hyper-dimensional contrast by combining multiple fluorescence properties into a single fluorescence lifetime decay curve. Fluorescence lifetime imaging microscopy (FLIM) with controlled excitation polarization and temporally dispersed emission can generate a spectrally coded, polarization-filtered lifetime distribution for a pixel. This HDIM scheme generates a better contrast between different molecules than that from individual techniques. This setup uses only a single detector and is simpler to implement, modular, cost-efficient, and adaptable to any existing FLIM microscope. We present higher contrast data from epidermal cells based on intrinsic anthocyanin emission properties under multiphoton excitation. This work lays the foundation for an alternative hyperdimensional imaging system and demonstrates that contrast-based imaging is useful to study cellular heterogeneity in biological samples.
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http://dx.doi.org/10.3390/s21041201DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7914562PMC
February 2021

Ochratoxin A induces reprogramming of glucose metabolism by switching energy metabolism from oxidative phosphorylation to glycolysis in human gastric epithelium GES-1 cells in vitro.

Toxicol Lett 2020 Oct 22;333:232-241. Epub 2020 Aug 22.

Department of Pathology, The Second Hospital, Hebei Medical University, Shijiazhuang, China; Metabolic Disease and Cancer Research Center, Laboratory of Pathology, Hebei Medical University, Shijiazhuang, China. Electronic address:

Ochratoxin A (OTA) is a ubiquitous mycotoxin with potential nephrotoxic, hepatotoxic and immunotoxic effects. We previously demonstrated that OTA could cause mitochondrial function disturbance in GES-1 cells in vitro, which lead to the presumption that the glucose metabolism of GES-1 cells will be altered by OTA. Therefore in the present study, we explored the toxicity of OTA on glucose metabolism of GES-1 cells and the molecular mechanism. We found that OTA could induce aerobic glycolysis, evidenced shown by increase of glucose consumption, lactate production and cellular ATP concentration. We further detected expressions of GLUT1 and glycolytic enzymes including HK2, PFK1, PKM2 and LDHA as well as tricarboxylic acid (TCA) cycle-associated enzymes including IDH1, OGDH and CS. The results showed that expression of GLUT1 as well as the activities and expressions of HK2, PFK1 and LDHA were significantly increased while IDH1 and OGDH were reduced by OTA. As to PKM2, western blot showed that OTA could elevated the phospho-PKM2 Ser37 protein level and induce the nuclear accumulation of PKM2, which was further supported by immunofluorescence analyses, in addition, pyruvate kinase activity was reduced by OTA. In conclusion, these findings suggest that OTA exposure induces the metabolic shift from oxidative phosphorylation to aerobic glycolysis via regulating the activities and expressions of glycolysis and TCA-cycle associated molecules in GES-1 cells.
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http://dx.doi.org/10.1016/j.toxlet.2020.08.008DOI Listing
October 2020

Disturbance mechanisms of lacustrine organic carbon burial: Case study of Cuopu Lake, Southwest China.

Sci Total Environ 2020 Dec 9;746:140615. Epub 2020 Jul 9.

School of Geography Science, Nanjing Normal University, Nanjing 210023, PR China; Jiangsu Center for Collaborative Innovation in Geographical Information Resource Development and Application, Nanjing Normal University, Nanjing 210023, PR China; Key Laboratory of Virtual Geographic Environment (Nanjing Normal University), Ministry of Education, Nanjing 210023, PR China; State Key Laboratory Cultivation Base of Geographical Environment Evolution (Jiangsu Province), Nanjing 210023, PR China. Electronic address:

Lakes are important organic carbon (OC) traps in the global carbon cycle. Recent studies have shown that the rate of OC burial in lacustrine sediments is influenced by factors such as climate change, land-use change, and eutrophication. In this study, we use multiproxy methods to reveal the mechanisms of lacustrine sediment OC burial in an alpine lake (Cuopu Lake), in southwest China. Combined with the dating from Pb and n-alkanes distribution analysis using the Positive Matrix Factorization model, the sedimentary history was divided into five stages: religious activity (the 1840s-1880s), earthquake (the 1880s-1910s), garrison (the 1910s-1960s), transition (the 1960s-1990s), and ecotourism (the 1990s-2010s). During the earthquake stage, OC burial was dominated by terrestrial solids (>40%) and co-precipitated algae (>30%), with a rapid deposition rate (>4 mm a) and low OC concentration (<4 mg g). During the other stages, when the level of disturbance was relatively low, a change in nutrient conditions either promoted or inhibited plant growth, which influenced the type of buried OC. The contribution of OC derived from combustion sources varied from stage to stage. Severe anthropogenic disturbances have led to a significant increase in nutritional levels in the lake water, leading to an increase in the OC burial rate. Climate change, which leads to changes in temperature and rainfall, did not significantly influence OC burial, whereas nitrogen deposition (and associated ecological changes) was a significant determinant. When the general mechanism is dominant, the total nitrogen to inorganic phosphorus ratio is an effective indicator of OC burial due to its selective promotion of different plant types. In conclusion, our results suggest that lacustrine sediment OC burial is closely linked to physical and anthropogenic factors in Cuopu Lake, as well as similar montane lakes.
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http://dx.doi.org/10.1016/j.scitotenv.2020.140615DOI Listing
December 2020

Expression, association with clinicopathological features and prognostic potential of CEP55, p-Akt, FoxM1 and MMP-2 in astrocytoma.

Oncol Lett 2020 Aug 17;20(2):1685-1694. Epub 2020 Jun 17.

Department of Pathology, The Second Hospital of Hebei Medical University, Shijiazhuang, Hebei 050000, P.R. China.

Centrosomal protein 55 (CEP55) is a member of the centrosomal-associated protein family and participates in the regulation of cytokinesis during cell mitosis. However, aberrant CEP55 protein expression has been observed in human tumors. In addition, CEP55 regulates the biological functions of tumors by inducing the Akt pathway and upregulating forkhead box protein M1 (FoxM1) and matrix metalloproteinase-2 (MMP-2). In the present study, the levels, clinicopathological features and prognostic potential of CEP55, phosphorylated Akt (p-Akt), FoxM1 and MMP-2 in astrocytoma were evaluated. CEP55, p-Akt, FoxM1 and MMP-2 levels were examined in 27 normal brain tissues and 262 astrocytoma tissues by using immunohistochemistry. Furthermore, Kaplan-Meier analysis and Cox proportional hazards models were applied to predict the prognosis of patients with astrocytoma. The results indicated that expression levels of CEP55 and other proteins were elevated in human astrocytoma compared with those in normal brain tissue. The levels of the selected proteins were increased as the tumor grade increased. Furthermore, CEP55 expression was positively correlated with p-Akt, FoxM1 and MMP-2 levels in astrocytoma. Overall survival analysis revealed that patient prognosis was associated with CEP55, p-Akt, FoxM1 and MMP-2 levels, as well as with the tumor grade and patient age. Furthermore, CEP55, FoxM1, tumor grade and patient age were independent prognostic factors in astrocytoma according to multivariate analysis. Taken together, the present results suggested that CEP55, p-Akt, FoxM1 and MMP-2 have crucial roles in the progression and prognosis of human astrocytoma and that CEP55 and FoxM1 may be potential therapeutic targets.
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http://dx.doi.org/10.3892/ol.2020.11742DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7377175PMC
August 2020

The Role of Type I IFNs in Influenza: Antiviral Superheroes or Immunopathogenic Villains?

J Innate Immun 2020 19;12(6):437-447. Epub 2020 Jun 19.

Department of Medicine, Pulmonary, Critical Care and Sleep Medicine, The University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA.

The important role of interferons (IFNs) in antiviral innate immune defense is well established. Although recombinant IFN-α was approved for cancer and chronic viral infection treatment by regulatory agencies in many countries starting in 1986, no IFNs are approved for treatment of influenza A virus (IAV) infection. This is partially due to the complex effects of IFNs in acute influenza infection. IAV attacks the human respiratory system and causes significant morbidity and mortality globally. During influenza infection, depending on the strain of IAV and the individual host, type I IFNs can have protective antiviral effects or can contribute to immunopathology. In the context of virus infection, the immune system has complicated mechanisms regulating the expression and effects of type I IFN to maximize the antiviral response by both activating and enhancing beneficial innate cell function, while limiting immunopathological responses that lead to exaggerated tissue damage. In this review, we summarize the complicated, but important, role of type I IFNs in influenza infections. This includes both protective and harmful effects of these important cytokines during infection.
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http://dx.doi.org/10.1159/000508379DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7747089PMC
June 2020

IRF7 Is Required for the Second Phase Interferon Induction during Influenza Virus Infection in Human Lung Epithelia.

Viruses 2020 03 29;12(4). Epub 2020 Mar 29.

Pulmonary, Critical Care & Sleep Medicine, Department of Medicine, the University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA.

Influenza A virus (IAV) infection is a major cause of morbidity and mortality. Retinoic acid-inducible protein I (RIG-I) plays an important role in the recognition of IAV in most cell types, and leads to the activation of interferon (IFN). We investigated mechanisms of RIG-I and IFN induction by IAV in the BCi-NS1.1 immortalized human airway basal cell line and in the A549 human alveolar epithelial cell line. We found that the basal expression levels of RIG-I and regulatory transcription factor (IRF) 7 were very low in BCi-NS1.1 cells. IAV infection induced robust RIG-I and IRF7, not IRF3, expression. siRNA against IRF7 and mitochondrial antiviral-signaling protein (MAVS), but not IRF3, significantly inhibited RIG-I mRNA expression and IFN induction by IAV infection. Most importantly, even without virus infection, IFN-β alone induced RIG-I, and siRNA against IRF7 did not inhibit RIG-I induction by IFN-β. Similar results were found in the alveolar basal epithelial A549 cell line. RIG-I and IRF7 expression in humans is highly inducible and greatly amplified by IFN produced from virus infected cells. IFN induction can be separated into two phases, that initially induced by the virus with basal RIG-I (the first phase), and that induced by the subsequent virus with amplified RIG-I from the first phase IFN (the second phase). The synthesis of IRF7 is required for the second phase IFN induction during influenza virus infection in human lung bronchial and alveolar epithelial cells.
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http://dx.doi.org/10.3390/v12040377DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7232147PMC
March 2020

Programmable DNA Tweezer-Actuated SERS Probe for the Sensitive Detection of AFB.

Anal Chem 2020 04 18;92(7):4900-4907. Epub 2020 Mar 18.

State Key Laboratory of Agricultural Microbiology, College of Food Science and Technology, Huazhong Agricultural University, Wuhan, Hubei 430070, People's Republic of China.

A DNA tweezer is a dynamic DNA nanomachine that can reversibly switch its state between open and closed. Here, we employed a DNA tweezer for the first time to dynamically control the distance between plasmonic silver nanoparticles (Ag NPs) for a surface enhanced Raman scattering (SERS) biosensing application. Two DNA and 4-nitrothiophenol (4-NTP) modified Ag NPs were linked to the arms of the DNA tweezer (DNA tweezer-Ag NPs probe) by complementary base pairing. Activation of the Raman intensity was achieved by the state transformation of the DNA tweezer-Ag NPs probe from open to closed. The distances between two Ag NPs in open and closed state were 8.1 ± 2.7 nm and 3.2 ± 0.8 nm, respectively. Furthermore, the two Ag NPs were spatially separated in the open state with a low Raman signal, whereas in the closed state, Raman intensity was enhanced because of the proximity of two Ag NPs. The developed biosensing system exhibited a good linear relationship when the concentration of aflatoxin B (AFB) ranged from 1 ng/mL to 0.01 pg/mL, and the limit of detection (LOD) was 5.07 fg/mL. In addition, spike recovery and certificated real foodstuffs were used to examine the feasibility in a real situation. This protocol provides a potential candidate for SERS detection and can be used as a promising technology for biological and chemical sensors.
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http://dx.doi.org/10.1021/acs.analchem.9b04822DOI Listing
April 2020

Clinical significance of AJUBA, YAP1, and MMP14 expression in esophageal squamous cell carcinoma.

Int J Clin Exp Pathol 2018 1;11(12):6018-6024. Epub 2018 Dec 1.

Department of Pathology, The Second Hospital of Hebei Medical University Shijiazhuang, PR China.

Esophageal squamous cell carcinoma (ESCC) is generally known to be a highly fatal cancer, and thus novel molecular targets are needed to improve its diagnosis and treatment. AJUBA has been shown to regulate cell cycle, adhesion, proliferation, apoptosis, and migration in many malignant tumors. However, the clinical significance of AJUBA in ESCC tumor metastasis remains unclear. In this study, we explored the role of AJUBA, Yes-associated protein 1 (YAP1), and matrix metalloproteinase 14 (MMP14) in the clinical presentation and survival of ESCC. Immunohistochemical staining showed higher expression of these proteins in cancer tissues than in paired adjacent tissues, and this upregulation was differently related to lymph node metastasis and TNM stage. AJUBA expression was positively correlated with that of YAP1. High expression of MMP14 was associated with reduced survival. In general, our findings reveal that AJUBA, YAP1, and MMP14 might function as oncoproteins and contribute to novel targeted therapy in ESCC.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6963081PMC
December 2018

Annexin A3 may play an important role in ochratoxin-induced malignant transformation of human gastric epithelium cells.

Toxicol Lett 2019 Oct 2;313:150-158. Epub 2019 Jul 2.

Department of Pathology, The Second Hospital, Hebei Medical University, Shijiazhuang, China. Electronic address:

Ochratoxin A (OTA), one of the most abundant food-contaminating mycotoxins, is a possible carcinogen to humans. We previously demonstrated that long-term (40 weeks) OTA exposure induces the malignant transformation of human gastric epithelium cells (GES-1) in vitro. However, the specific mechanism underlying OTA-induced gastric carcinogenesis is complex. In the present study, we used 2-DE and matrix-assisted laser desorption ionization time-of-flight mass spectrometry (MALDI/TOF MS) combined with bioinformatics and immunoblotting to investigate the differentially expressed proteins between GES-1 and OTA-malignant transformed GES-1 cells (OTA-GES-1 cells) in vitro. We found that four differentially expressed proteins were identified after malignant transformation, including actin, cytoplasmic 1 (ACTB), F-actin-capping protein subunit alpha-1 (CAPZA1), Annexin A3 (ANXA3), thioredoxin peroxidase B from red blood cells (TPx-B) and Fibrinogen beta B (Fibrinogen β). Among the differentially expressed proteins, the effect of Annexin A3 was analyzed by MTT assay, western blot, cell cycle analysis, wound healing assay, Transwell assay, and colony formation assay in OTA-GES-1 cells. The results showed that inhibition of Annexin A3 by siRNA effectively prevented the proliferation, migration, and invasion abilities of OTA-GES-1 cells. Collectively, the results of this study will guide future research on OTA carcinogenicity.
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http://dx.doi.org/10.1016/j.toxlet.2019.07.002DOI Listing
October 2019

RIG-I Signaling via MAVS Is Dispensable for Survival in Lethal Influenza Infection .

Mediators Inflamm 2018 8;2018:6808934. Epub 2018 Nov 8.

Pulmonary, Critical Care & Sleep Medicine, Department of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA.

Retinoic acid-inducible gene I (RIG-I) is an important regulator of virus-induced antiviral interferons (IFNs) and proinflammatory cytokines. It requires interaction with an adaptor molecule, mitochondrial antiviral-signaling protein (MAVS), to activate downstream signaling pathways. To elucidate the mechanism(s) by which RIG-I-dependent recognition of IAV infection triggers innate immune responses, we infected mutant mice lacking RIG-I or MAVS with influenza A virus (IAV) and measured their innate immune responses. As has previously been demonstrated with isolated deletion of the virus recognition receptors TLR3, TLR7, and NOD2, RIG-I or MAVS knockout (KO) did not result in higher mortality and did not reduce IAV-induced cytokine responses in mice. Infected RIG-I KO animals displayed similar lung inflammation profiles as did WT mice, in terms of the protein concentration, total cell count, and inflammatory cell composition in the bronchoalveolar lavage fluid. RNA-Seq results demonstrated that all types of mice exhibited equivalent antiviral and inflammatory gene responses following IAV infection. Together, the results indicated that although RIG-I is important in innate cytokine responses , individual deletion of the genes encoding RIG-I or MAVS did not change survival or innate responses after IAV infection in mice.
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http://dx.doi.org/10.1155/2018/6808934DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6250004PMC
February 2019

Gene expression profiling of primary human type I alveolar epithelial cells exposed to Bacillus anthracis spores reveals induction of neutrophil and monocyte chemokines.

Microb Pathog 2018 Aug 25;121:9-21. Epub 2018 Apr 25.

Pulmonary and Critical Care Division of the Department of Internal Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA; Department of Microbiology and Immunology, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA. Electronic address:

The lung is the entry site for Bacillus anthracis in inhalation anthrax, the most deadly form of the disease. Spores must escape through the alveolar epithelial cell (AEC) barrier and migrate to regional lymph nodes, germinate and enter the circulatory system to cause disease. Several mechanisms to explain alveolar escape have been postulated, and all these tacitly involve the AEC barrier. In this study, we incorporate our primary human type I AEC model, microarray and gene enrichment analysis, qRT-PCR, multiplex ELISA, and neutrophil and monocyte chemotaxis assays to study the response of AEC to B. anthracis, (Sterne) spores at 4 and 24 h post-exposure. Spore exposure altered gene expression in AEC after 4 and 24 h and differentially expressed genes (±1.3 fold, p ≤ 0.05) included CCL4/MIP-1β (4 h), CXCL8/IL-8 (4 and 24 h) and CXCL5/ENA-78 (24 h). Gene enrichment analysis revealed that pathways involving cytokine or chemokine activity, receptor binding, and innate immune responses to infection were prominent. Microarray results were confirmed by qRT-PCR and multiplex ELISA assays. Chemotaxis assays demonstrated that spores induced the release of biologically active neutrophil and monocyte chemokines, and that CXCL8/IL-8 was the major neutrophil chemokine. The small or sub-chemotactic doses of CXCL5/ENA-78, CXCL2/GROβ and CCL20/MIP-3α may contribute to chemotaxis by priming effects. These data provide the first whole transcriptomic description of the human type I AEC initial response to B. anthracis spore exposure. Taken together, our findings contribute to an increased understanding of the role of AEC in the pathogenesis of inhalational anthrax.
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http://dx.doi.org/10.1016/j.micpath.2018.04.039DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6077097PMC
August 2018

The G phase arrest induced by sterigmatocystin is dependent on hMLH1- ERK/p38-p53 pathway in human esophageal epithelium cells in vitro.

Food Chem Toxicol 2018 May 12;115:205-211. Epub 2018 Mar 12.

Department of Pathology, The Second Hospital, Hebei Medical University, Shijiazhuang, China; Laboratory of Pathology, Hebei Medical University, Shijiazhuang, China. Electronic address:

Sterigmatocystin (ST), being a precursor of aflatoxin, is categorized as Group 2B carcinogen. Our previous studies found that both mismatch repair (MMR) pathways and p53 signaling pathway were involved in ST-induced G cell cycle arrest in human esophageal squamous epithelial cell line, HET-1A, in vitro. Studies showed that ERK, JNK and p38 signaling pathways played important roles in cell cycle arrest induced by several other carcinogens. However, the role of MAPK pathway and the links between the MMR and p53 signaling pathways in ST induced G phase arrest is still not clarified. In the present study, we first explored the role of MAPK pathway upon ST induced G arrest, and found that ST up-regulated the expression of G/M regulatory factors through MAPK signaling pathway (both ERK and p38, but not JNK pathway). The inhibition of ERK and p38 significantly inhibited p53 activation by ST. Blockage of MMR pathway by silencing hMLH1 expression inhibited ERK, p38 and p53 activation and then attenuated G arrest by ST. Thus, in conclusion, the current study demonstrated that in response to ST induced DNA damage, hMLH1 was first activated, then triggered ERK, p38 and p53 activation and finally resulted in G arrest in HET-1A cells.
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http://dx.doi.org/10.1016/j.fct.2018.03.012DOI Listing
May 2018

RIG-I overexpression decreases mortality of cigarette smoke exposed mice during influenza A virus infection.

Respir Res 2017 09 2;18(1):166. Epub 2017 Sep 2.

Pulmonary and Critical Care Division, Department of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA.

Background: Retinoic acid-inducible gene I (RIG-I) is an important regulator of virus-induced antiviral interferons (IFNs) and proinflammatory cytokines which participate in clearing viral infections. Cigarette smoke (CS) exposure increases the frequency and severity of respiratory tract infections.

Methods: We generated a RIG-I transgenic (TG) mouse strain that expresses the RIG-I gene product under the control of the human lung specific surfactant protein C promoter. We compared the mortality and host immune responses of RIG-I TG mice and their litter-matched wild type (WT) mice following challenge with influenza A virus (IAV).

Results: RIG-I overexpression increased survival of IAV-infected mice. CS exposure increased mortality in WT mice infected with IAV. Remarkably, the effect of RIG-I overexpression on survival during IAV infection was enhanced in CS-exposed animals. CS-exposed IAV-infected WT mice had a suppressed innate response profile in the lung compared to sham-exposed IAV-infected WT mice in terms of the protein concentration, total cell count and inflammatory cell composition in the bronchoalveolar lavage fluid. RIG-I overexpression restored the innate immune response in CS-exposed mice to that seen in sham-exposed WT mice during IAV infection, and is likely responsible for enhanced survival in RIG-I TG mice as restoration preceded death of the animals.

Conclusions: Our results demonstrate that RIG-I overexpression in mice is protective for CS enhanced susceptibility of smokers to influenza infection, and that CS mediated RIG-I suppression may be partially responsible for the increased morbidity and mortality of the mice exposed to IAV. Thus, optimizing the RIG-I response may be an important treatment strategy for CS-enhanced lung infections, particularly those due to IAV.
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http://dx.doi.org/10.1186/s12931-017-0649-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5581920PMC
September 2017

Sterigmatocystin induced apoptosis in human pulmonary cells in vitro.

Exp Toxicol Pathol 2017 Oct 22;69(8):695-699. Epub 2017 Jul 22.

Department of Pathology, The Second Hospital, Hebei Medical University, Shijiazhuang, China; Laboratory of Pathology, Hebei Medical University, Shijiazhuang, China. Electronic address:

Sterigmatocystin (ST) is generally recognized as a potential carcinogen, mutagen and teratogen. Studies showed that ST could induce adenocarcinoma of lung in mice in vivo and DNA damage, cell cycle arrest in a human immortalized bronchial epithelial cell line (BEAS-2B cells) and a human lung cancer cell line (A549 cells) in vitro. Besides, ST could induce G arrest (cell cycle arrest in G phase) in several other cells. Cell cycle arrest may be one of the common toxic effects of ST. As cells may undergo apoptosis or death due to cell cycle arrest, we wondered whether apoptosis is another common effect of ST in different cells in vitro. In the present study, we studied the effects of ST on proliferation and apoptosis in A549 cells and BEAS-2B cells with 3-(4,5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide (MTT) assay and flow cytometric analysis (FCM). The MTT results showed that proliferation inhibition following ST treatment for 24h was observed in both A549 and BEAS-2B cells in vitro. And increased apoptosis by FCM was also found after ST treatment. Down-regulation of Bcl-2, up-regulation of Bax and the activation of caspase-3 after ST treatment were detected by western blotting analyses. The results in the present study are consistent with our previous results, which indicated that inducing apoptosis may be a common effect of ST in different cells in vitro.
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http://dx.doi.org/10.1016/j.etp.2017.07.002DOI Listing
October 2017

Effect of Graphene Modified Cu Current Collector on the Performance of LiTiO Anode for Lithium-Ion Batteries.

ACS Appl Mater Interfaces 2016 Nov 2;8(45):30926-30932. Epub 2016 Nov 2.

Jiangsu Key Laboratory of Materials and Technology for Energy Conversion, College of Material Science and Engineering, Nanjing University of Aeronautics and Astronautics , Nanjing 210016, P. R. China.

Interface design between current collector and electroactive materials plays a key role in the electrochemical process for lithium-ion batteries. Here, a thin graphene film has been successfully synthesized on the surface of Cu current collector by a large-scale low-pressure chemical vapor deposition (LPCVD) process. The modified Cu foil was used as a current collector to support spinel LiTiO anode directly. Electrochemical test results demonstrated that graphene coating Cu foil could effectively improve overall Li storage performance of LiTiO anode. Especially under high current rate (e.g., 10 C), the LiTiO electrode using modified current collector maintained a favorable capacity, which is 32% higher than that electrode using bare current collector. In addition, cycling performance has been improved using the new type current collector. The enhanced performance can be attributed to the reduced internal resistance and improved charge transfer kinetics of graphene film by increasing electron collection and decreasing lithium ion interfacial diffusion. Furthermore, the graphene film adhered on the Cu foil surface could act as an effective protective film to avoid oxidization, which can effectively improve chemical stability of Cu current collector.
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http://dx.doi.org/10.1021/acsami.6b10038DOI Listing
November 2016

Human primary airway epithelial cells isolated from active smokers have epigenetically impaired antiviral responses.

Respir Res 2016 09 7;17(1):111. Epub 2016 Sep 7.

Pulmonary and Critical Care Division, Department of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA.

Background: Cigarette smoking (CS) is the main risk factor for the development of chronic obstructive pulmonary disease (COPD) and most COPD exacerbations are caused by respiratory infections including influenza. Influenza infections are more severe in smokers. The mechanism of the increased risk and severity of infections in smokers is likely multifactorial, but certainly includes changes in immunologic host defenses.

Methods: We investigated retinoic acid-inducible protein I (RIG-I) and interferon (IFN) induction by influenza A virus (IAV) in human bronchial epithelial cells (HBEC) isolated from smokers or nonsmokers. Subcultured HBEC cells were infected with A/Puerto Rico/8/1934 (PR8) IAV at an MOI of 1. After 24 h of infection, cells and supernatants were collected for qRT-PCR, immunoblot or ELISA to determine RIG-I, Toll-like receptor3 (TLR3) and IFN expression levels.

Results: IAV exposure induced a vigorous IFN-β, IFN-λ 1 and IFN-λ 2/3 antiviral response in HBEC from nonsmokers and significant induction of RIG-I and TLR3. In cells from smokers, viral RIG-I and TLR3 mRNA induction was reduced 87 and 79 % compared to the response from nonsmokers. CS exposure history was associated with inhibition of viral induction of the IFN-β, IFN-λ1 and IFN-λ 2/3 mRNA response by 85, 96 and 95 %, respectively, from that seen in HBEC from nonsmokers. The demethylating agent 5-Aza-2-deoxycytidine reversed the immunosuppressive effects of CS exposure in HBEC since viral induction of all three IFNs was restored. IFN-β induction of RIG-I and TLR3 was also suppressed in the cells from smokers.

Conclusion: Our results suggest that active smoking reduces expression of antiviral cytokines in primary HBEC cells. This effect likely occurs via downregulation of RIG-I and TLR3 due to smoke-induced epigenetic modifications. Reduction in lung epithelial cell RIG-I and TLR3 responses may be a major mechanism contributing to the increased risk and severity of viral respiratory infections in smokers and to viral-mediated acute exacerbations of COPD.
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http://dx.doi.org/10.1186/s12931-016-0428-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5013564PMC
September 2016

Bacillus anthracis spore movement does not require a carrier cell and is not affected by lethal toxin in human lung models.

Microbes Infect 2016 Oct 16;18(10):615-626. Epub 2016 Jun 16.

Pulmonary and Critical Care Division of the Department of Internal Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA; Department of Microbiology and Immunology, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA. Electronic address:

The lung is the entry site for Bacillus anthracis in inhalation anthrax, the most deadly form of the disease. Spores escape from the alveolus to regional lymph nodes, germinate and enter the circulatory system to cause disease. The roles of carrier cells and the effects of B. anthracis toxins in this process are unclear. We used a human lung organ culture model to measure spore uptake by antigen presenting cells (APC) and alveolar epithelial cells (AEC), spore partitioning between these cells, and the effects of B. anthracis lethal toxin and protective antigen. We repeated the study in a human A549 alveolar epithelial cell model. Most spores remained unassociated with cells, but the majority of cell-associated spores were in AEC, not in APC. Spore movement was not dependent on internalization, although the location of internalized spores changed in both cell types. Spores also internalized in a non-uniform pattern. Toxins affected neither transit of the spores nor the partitioning of spores into AEC and APC. Our results support a model of spore escape from the alveolus that involves spore clustering with transient passage through intact AEC. However, subsequent transport of spores by APC from the lung to the lymph nodes may occur.
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http://dx.doi.org/10.1016/j.micinf.2016.06.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5534360PMC
October 2016

Extreme Light Management in Mesoporous Wood Cellulose Paper for Optoelectronics.

ACS Nano 2016 Jan 21;10(1):1369-77. Epub 2015 Dec 21.

Department of Materials Science and Engineering, University of Maryland , College Park, Maryland 20742, United States.

Wood fibers possess natural unique hierarchical and mesoporous structures that enable a variety of new applications beyond their traditional use. We dramatically modulate the propagation of light through random network of wood fibers. A highly transparent and clear paper with transmittance >90% and haze <1.0% applicable for high-definition displays is achieved. By altering the morphology of the same wood fibers that form the paper, highly transparent and hazy paper targeted for other applications such as solar cell and antiglare coating with transmittance >90% and haze >90% is also achieved. A thorough investigation of the relation between the mesoporous structure and the optical properties in transparent paper was conducted, including full-spectrum optical simulations. We demonstrate commercially competitive multitouch touch screen with clear paper as a replacement for plastic substrates, which shows excellent process compatibility and comparable device performance for commercial applications. Transparent cellulose paper with tunable optical properties is an emerging photonic material that will realize a range of much improved flexible electronics, photonics, and optoelectronics.
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http://dx.doi.org/10.1021/acsnano.5b06781DOI Listing
January 2016

Low expression of KLF17 is associated with tumor invasion in esophageal carcinoma.

Int J Clin Exp Pathol 2015 1;8(9):11157-63. Epub 2015 Sep 1.

Cancer Center, The Second Hospital of Hebei Medical University Shijiazhuang, China.

Purpose: KLF17 belongs to the Sp/KLF zinc-finger protein family as a regulator in tumor development. However, its expression and biologic function has remained unclear in EC.

Methods: The esophageal carcinoma tissue samples and adjacent normal tissues were obtained from the Second Hospital of Hebei Medical University. Immunohistochemistry, Western blot, and transfection were applied to evaluate the expression and clinical significance of KLF17 in esophageal cancer.

Results: In this study, we showed that KLF17 was overexpressed in esophageal normal samples compared to the cancer. Moreover, KLF17 was upregulated at lymph node non-metastatic cancer tissues when compared to metastatic cancer tissues. KLF17 overexpression decreased EC cell proliferation, migration and invasion ability. In contrast, the knockdown of KLF17 increased EC cell proliferation, migration and invasion ability.

Conclusion: These results suggest that KLF17 inhibits tumor development and may serve as a potential therapeutic target.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4637651PMC
September 2016

RIG-I and TLR3 are both required for maximum interferon induction by influenza virus in human lung alveolar epithelial cells.

Virology 2015 Aug 11;482:181-8. Epub 2015 Apr 11.

Pulmonary and Critical Care Division, Department of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA; Department of Microbiology and Immunology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA; Veterans Affairs Medical Center, Oklahoma City, OK, USA. Electronic address:

Pattern recognition receptors, such as retinoic acid-inducible protein I (RIG-I), Toll-like receptors 3 and 7 (TLR3 and 7), and nucleotide-binding oligomerization domain containing protein 2 (NOD2), play important roles in the recognition of influenza A virus (IAV), but their role in interferon (IFN) induction is still unclear, particularly in human lung. We investigated IFN induction by IAV in the A549 cell line as well as in primary human alveolar epithelial cells (AEC). TLR3/7, NOD2, RIG-I, and IFN expression levels were measured by qRT-PCR and ELISA in cells infected with IAV PR8. We found that TLR7 and NOD2 were not involved in IFN induction by IAV in these cells. Neither RIG-I nor TLR3 siRNA alone completely blocked IFN induction. However, double knockdown of RIG-I and TLR3 completely inhibited IFN induction by influenza. Thus, signaling through both RIG-I and TLR3 is important for IFN induction by IAV in human lung AEC.
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http://dx.doi.org/10.1016/j.virol.2015.03.048DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4461467PMC
August 2015

Inhibition of beclin1 affects the chemotherapeutic sensitivity of osteosarcoma.

Int J Clin Exp Pathol 2014 15;7(10):7114-22. Epub 2014 Sep 15.

Department of Osteology, Third Xiangya Hospital, Central South University Changsha 410013, Hunan, China.

This study was conducted to explore the role of autophagy in cisplatin-resistant osteosarcoma. Cisplatin-resistant osteosarcoma cell line (MG63/DDP) was obtained from parental MG63 by treating cisplatin with an intermittent stepwise selection protocol. The autophagy in MG63/DDP and MG63 was fully analyzed by immunofluorescence and western blot analysis. Meanwhile, the autophagy and the sensitivity to cisplatin for MG63/DDP and MG63 after inhibition of beclin1 were analyzed in vitro and in vivo. Increased autophagy was observed in cisplatin resistant MG63/DDP cells and in the cisplatin-treated MG63 and MG63/DDP cells. Meanwhile, inhibition the beclin1 significantly inhibited the formation of autophagosome and resulted in the increase in the sensitivity to cisplatin for both MG63 and MG63/DDP cells in vitro and in vivo. In conclusion, autophagy is implicated in the cisplatin resistant osteosarcoma, and inhibition of beclin1 could be a target for improving osteosarcoma therapy.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4230152PMC
July 2015

Cigarette smoke attenuates the RIG-I-initiated innate antiviral response to influenza infection in two murine models.

Am J Physiol Lung Cell Mol Physiol 2014 Dec 26;307(11):L848-58. Epub 2014 Sep 26.

Pulmonary and Critical Care Division, Department of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma; Department of Microbiology and Immunology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma; and Veterans Affairs Medical Center, Oklahoma City, Oklahoma

Cigarette smoke (CS) exposure increases the frequency and severity of respiratory tract infections. Despite this association, the mechanisms underlying the increased susceptibility to respiratory virus infection are poorly understood. Retinoic acid-inducible gene I (RIG-I) is an important regulator of influenza virus-induced expression of antiviral cytokines, mainly interferons (IFNs), which are necessary to clear viral infections. In this study, we compared the innate cytokine responses of two mouse CS exposure models following a challenge with influenza A virus (IAV): 1) exposure of the mice to cigarette smoke extract (CSE) intratracheally and 2) exposure of the mice to CS in a whole body exposure chamber. Both intratracheal CSE treatment and whole body CS exposure caused antiviral immunosuppression in these mice, and both CS exposure methods inhibited RIG-I induction. CS attenuated influenza-induced antiviral IFNs and IP-10 expression in vivo. However, we did not find that CS inhibited induction of the proinflammatory cytokines IL-6 and TNF-α, whose expression was induced by IAV. Interestingly, IAV infection also increased Toll-like receptor 3 (TLR3) expression in mouse lung, but CS exposure did not impact TLR3 induction in these mice. Together, the results support our previous finding in a human lung organ culture model that the suppression of RIG-I induction and antiviral cytokine responses by CS are likely important in the enhanced susceptibility of smokers to influenza infection in the lung.
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http://dx.doi.org/10.1152/ajplung.00158.2014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4254961PMC
December 2014

Expression of RUNX3 and β-catenin in the carcinogenesis of sporadic colorectal tubular adenoma.

Tumour Biol 2014 Jun 14;35(6):6039-46. Epub 2014 Mar 14.

Department of Pathology, Second Hospital of Hebei Medical University, No 215, West Heping Rd, 050000, Shijiazhuang, Hebei, People's Republic of China.

The aim of this study is to investigate the possible roles of runt-related transcription factor 3 (RUNX3) and β-catenin in the carcinogenesis of sporadic colorectal tubular adenomas. The expression of the RUNX3 and β-catenin proteins was evaluated by immunohistochemistry in 23 normal colorectal mucosa (NCM), 81 sporadic colorectal tubular adenomas with different dysplasias (SCTA-D) (mild n=33, moderate n=23, and severe n=25 dysplasia), and 48 sporadic colorectal tubular adenomas with cancerous changes (SCTA-Ca). RUNX3 methylation was assessed by methylation-specific polymerase chain reaction (MSP), combined with laser capture microdissection (LCM), in 17 NCM, 41 SCTA-D (mild n=15, moderate n=12, and severe n=14 dysplasia), and 17 SCTA-Ca tissues. Compared to NCM (82.6 %), RUNX3 in SCTA-D (54.3 %) and SCTA-Ca (27.1 %) was significantly downregulated (P<0.05). In NCM, SCTA-D, and SCTA-Ca, the incidence of positive expression for β-catenin was 13.0, 60.5, and 79.2 %, respectively. A statistically significant difference was observed (P<0.05). RUNX3 levels were markedly higher in adenoma with mild dysplasia (75.8 %) and moderate dysplasia (60.9 %) than in adenoma with severe dysplasia (20.0 %) (both with P<0.05). Likewise, the expression of β-catenin in severe dysplasia adenoma was 84.0 %, which was significantly higher than that in mild dysplasia adenoma (39.4 %). An inverse correlation was found between the protein expression of RUNX3 and β-catenin in SCTA-D and SCTA-Ca (P<0.05). MSP results showed that RUNX3 methylation in NCM, SCTA-D, and SCTA-Ca was 5.9, 17.1, and 41.2 %, respectively, with a statistically significant difference between NCM and SCTA-Ca (P<0.05). However, no significant difference of RUNX3 methylation was observed among different dysplasia groups. RUNX3 and β-catenin play important roles in the carcinogenesis of sporadic colorectal tubular adenomas. In addition, hypermethylation of RUNX3 can downregulate its expression.
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http://dx.doi.org/10.1007/s13277-014-1800-9DOI Listing
June 2014

Influenza A(H1N1)pdm09 virus suppresses RIG-I initiated innate antiviral responses in the human lung.

PLoS One 2012 21;7(11):e49856. Epub 2012 Nov 21.

Pulmonary and Critical Care Division, Department of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, United States of America.

Influenza infection is a major cause of morbidity and mortality. Retinoic acid-inducible gene I (RIG-I) is believed to play an important role in the recognition of, and response to, influenza virus and other RNA viruses. Our study focuses on the hypothesis that pandemic H1N1/09 influenza virus alters the influenza-induced proinflammatory response and suppresses host antiviral activity. We first compared the innate response to a clinical isolate of influenza A(H1N1)pdm09 virus, OK/09, a clinical isolate of seasonal H3N2 virus, OK/06, and to a laboratory adapted seasonal H1N1 virus, PR8, using a unique human lung organ culture model. Exposure of human lung tissue to either pandemic or seasonal influenza virus resulted in infection and replication in alveolar epithelial cells. Pandemic virus induces a diminished RIG-I mRNA and antiviral cytokine response than seasonal virus in human lung. The suppression of antiviral response and RIG-I mRNA expression was confirmed at the protein level by ELISA and western blot. We performed a time course of RIG-I and interferon-β (IFN-β) mRNA induction by the two viruses. RIG-I and IFN-β induction by OK/09 was of lower amplitude and shorter duration than that caused by PR8. In contrast, the pandemic virus OK/09 caused similar induction of proinflammatory cytokines, IL-8 and IL-6, at both the transcriptional and translational level as PR8 in human lung. Differential antiviral responses did not appear to be due to a difference in cellular infectivity as immunohistochemistry showed that both viruses infected alveolar macrophages and epithelial cells. These findings show that influenza A(H1N1)pdm09 virus suppresses anti-viral immune responses in infected human lung through inhibition of viral-mediated induction of the pattern recognition receptor, RIG-I, though proinflammatory cytokine induction was unaltered. This immunosuppression of the host antiviral response by pandemic virus may have contributed to the more serious lung infections that occurred in the H1N1 pandemic of 2009.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0049856PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3503992PMC
May 2013

Cigarette smoke extract suppresses the RIG-I-initiated innate immune response to influenza virus in the human lung.

Am J Physiol Lung Cell Mol Physiol 2011 Jun 18;300(6):L821-30. Epub 2011 Feb 18.

Pulmonary and Critical Care Division, Department of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, USA.

Cigarette smoking is the major cause of chronic obstructive pulmonary disease (COPD) and predisposes subjects to severe respiratory tract infections. Epidemiological studies have shown that cigarette smokers are seven times more likely to contract influenza infection than nonsmokers. The mechanisms underlying this increased susceptibility are poorly characterized. Retinoic acid-inducible gene (RIG)-I is believed to play an important role in the recognition of, and response to, influenza virus and other RNA viruses. Our study focused on how cigarette smoke extract (CSE) alters the influenza-induced proinflammatory response and suppresses host antiviral activity in the human lung using a unique lung organ culture model. We first determined that treatment with 2-20% CSE did not induce cytotoxicity as assessed by LDH release. However, CSE treatment inhibited influenza-induced IFN-inducible protein 10 protein and mRNA expression. Induction of the major antiviral cytokine IFN-β mRNA was also decreased by CSE. CSE also blunted viral-mediated RIG-I mRNA and protein expression. Inhibition of viral-mediated RIG-I induction by CSE was prevented by the antioxidants N-acetyl-cysteine and glutathione. These findings show that CSE suppresses antiviral and innate immune responses in influenza virus-infected human lungs through oxidative inhibition of viral-mediated induction of the pattern recognition receptor RIG-I. This immunosuppressive effect of CSE may play a role in the enhanced susceptibility of smokers to serious influenza infection in the lung.
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http://dx.doi.org/10.1152/ajplung.00267.2010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3119130PMC
June 2011

Innate immune response to influenza virus.

Curr Opin Infect Dis 2011 Jun;24(3):235-40

Department of Emergency and Critical Care, Second Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China.

Purpose Of Review: The recent pandemic of a novel H1N1 influenza virus has stressed the importance of effective approaches to prevent viral infection. The innate immune system is our first line of defense against invading viruses. This review aims to give a brief summary of recent findings on the response of the innate immune system to influenza virus.

Recent Findings: Three families of pattern recognition receptors, toll-like receptors (TLRs), retinoic acid-inducible gene 1 protein like helicases (RLRs) and nucleotide-binding domain and leucine-rich-repeat-containing proteins (NLRs), are involved in recognition of influenza virus and they cooperatively operate to respond to the virus in cell culture or mouse models. Influenza virus mainly induces two types of innate immune cytokine responses: a proinflammatory response and an antiviral response. Recently, the NLRP3 inflammasome has proved to be an essential component in the host defense against influenza infection. The mitochondrion, traditionally recognized for its key role in respiration, metabolism and apoptosis, is becoming recognized as an important organelle for regulation of innate immune responses to influenza virus.

Summary: The NLRP3 inflammasome is an essential component in the host defense against influenza infection. Further investigations are required to elucidate whether NLRP3 is associated with the adaptive response and to identify the components of influenza virus that activate this important mediator. The role of mitochondria as a potential central platform of innate response is becoming appreciated.
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http://dx.doi.org/10.1097/QCO.0b013e328344c0e3DOI Listing
June 2011