Publications by authors named "Zixuan Liu"

63 Publications

Characterization of blood protein adsorption on PM and its implications on cellular uptake and cytotoxicity of PM.

J Hazard Mater 2021 Feb 23;414:125499. Epub 2021 Feb 23.

Key Laboratory of Luminescence Analysis and Molecular Sensing, Ministry of Education, College of Pharmaceutical Sciences, Southwest University, Chongqing 400715, China; State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing 100085, China. Electronic address:

In biological fluids, micro- or nano-size particles are prone to adsorb proteins and form a layer. The ambient air fine particulate matter (PM) is inhaled via the lung, penetrates biological barriers and eventually reaches systemic blood circulation. However, there are very few data available regarding the adsorption of proteins on PM. Here, we compared protein corona formed in plasma after bronchoalveolar lavage fluid (BALF) exposure with those formed in plasma alone. Using purified coronal proteins, we explored their adsorption behaviors on PM and their influence on biological reactivity of PM Liquid-chromatography tandem mass-spectrometry (LC-MS/MS) analysis revealed that exposure to BALF significantly changed the blood protein profile on PM. Regardless of the presence of BALF, the protein corona on PM contained an abundance of serum albumin, hemoglobin (Hb) and fibrinogen (Fg) proteins. Using Fg as a corona surrogate, we found that van der Waals interactions, hydrophobic interactions, π-π stacking and electrostatic attractions contributed to the Fg adsorption and led to the conformational changes of Fg. In addition, Fg decoration decreased cellular internalization of PM and corresponding subsequent oxidative stress responses in a murine RAW264.7 macrophage. These results support the view that the formation of PM corona should be considered for toxicity assessment of PM
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http://dx.doi.org/10.1016/j.jhazmat.2021.125499DOI Listing
February 2021

Polybrominated diphenyl ethers quinone-induced intracellular protein oxidative damage triggers ubiquitin-proteasome and autophagy-lysosomal system activation in LO2 cells.

Chemosphere 2021 Feb 23;275:130034. Epub 2021 Feb 23.

Key Laboratory of Luminescence Analysis and Molecular Sensing, Ministry of Education, College of Pharmaceutical Sciences, Southwest University, Chongqing, 400715, China; State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing, 100085, China. Electronic address:

Polybrominated diphenyl ethers (PBDEs), a kind of flame retardants, were widely used in the furniture, textile and electronics industries. Because of their lipophilic, persistent and bio-accumulative properties, PBDEs were listed on the Stockholm Convention as typical persistent organic pollutants (POPs). We have previously reported that a highly active, quinone-type metabolite of PBDEs (PBDEQ) causes DNA damage and subsequently triggers apoptosis. However, it is remaining unclear whether PBDEQ provokes protein damage and stimulates corresponding signaling cascade. Using human normal liver (LO2) cells as an in vitro model, we demonstrated that PBDEQ causes oxidative protein damage through excess reactive oxygen species (ROS). Consistently, we found PBDEQ exposure causes the depletion of protein thiol group, the appearance of carbonyl group and the accumulation of protein aggregates. Endoplasmic reticulum (ER) stress was involved in the repair of oxidized proteins. Under the scenario of severe damage, LO2 cells degrade oxidized proteins through ubiquitin-proteasome system (UPS) and autophagy. The blockage of these protein degradation pathways aggravates PBDEQ-induced cytotoxicity in LO2 cells, whilst antioxidant N-acetyl-cysteine (NAC) rescues PBDEQ-induced oxidative protein damage conversely. In summary, our current study first demonstrated PBDEQ-induced protein oxidative damage in LO2 cells, which offer a better understanding of the cytotoxicity of PBDEs and corresponding metabolites.
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http://dx.doi.org/10.1016/j.chemosphere.2021.130034DOI Listing
February 2021

Nanohybridization of Keggin polyoxometalate clusters and reduced graphene oxide for lithium-ion batteries.

J Nanopart Res 2020 3;23(2):41. Epub 2021 Feb 3.

Henan Key Laboratory of Polyoxometalate Chemistry, College of Chemistry and Chemical Engineering, Henan University, Henan, China.

The nanocomposites of reduced graphene oxide (RGO) and polyoxometalates (POMs) have been considered to be effective to boost more Li to participate in intercalation/deintercalation process of lithium-ion batteries (LIBs). In this paper, a nanocomposite (PMo@RGO-AIL) with electrostatic interaction of RGO and Keggin-type [PMoO] has been fabricated and characterized by XRD, XPS, SEM, and TEM. To prepare PMo@RGO-AIL, a strategy of covalent modification is developed between amino-based ionic liquid and RGO, helping to achieve the uniform dispersion of [PMoO]. When the PMo@RGO-AIL was used as a cathode for LIBs, it could exhibit more excellent reversible capacity, cycle stability, and rate capability than those of samples without modifying by ionic liquids.

Supplementary Information: The online version contains supplementary material available at 10.1007/s11051-020-05108-x.
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http://dx.doi.org/10.1007/s11051-020-05108-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7857345PMC
February 2021

Endoplasmic reticulum stress manipulates autophagic response that antagonizes polybrominated diphenyl ethers quinone induced cytotoxicity in microglial BV2 cells.

J Hazard Mater 2021 Jun 30;411:124958. Epub 2020 Dec 30.

Key Laboratory of Luminescence Analysis and Molecular Sensing (Southwest University), Ministry of Education, College of Pharmaceutical Sciences, Southwest University, 2 Tiansheng Rd, Beibei District, Chongqing 400715, China; State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing 100085, China. Electronic address:

Polybrominated diphenyl ethers (PBDEs) were widely used as flame retardants. Previously, we reported that their quinone-type metabolite (PBDEQ) induced selective autophagy, but its biological consequences remain obscure. Here, we illustrated the possible link of PBDEQ-induced autophagy with endoplasmic reticulum (ER) stress and cytotoxicity in microglial BV2 cells. We found PBDEQ increased the formation of autophagosomes, promoted autophagic degradation, suggesting an improved autophagy flux in BV2 cells. Interestingly, both pharmacologic autophagy inhibitors and autophagy-related 5 gene small interfering RNA (ATG5 siRNA) aggravated the cytotoxicity of PBDEQ, suggesting the antagonizing role of autophagy. PBDEQ induced ER stress and activated protein kinase R-like ER kinase (PERK)-eukaryotic translation initiation factor 2α (eIF2α)-activating transcription factor 4 (ATF4)-C/EBP homologous protein (CHOP) axis of classic unfolded protein response (UPR) pathway, whilst ER stress inhibitor blocked PBDEQ-induced autophagy. Moreover, N-acetyl-L-cysteine (NAC) alleviated PBDEQ-induced activation of ER stress and autophagy, suggesting reactive oxygen species (ROS) were involved in regulating PBDEQ-induced ER stress and autophagy. Taken together, our results demonstrate a new mechanism of PBDEQ-associated toxicity.
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http://dx.doi.org/10.1016/j.jhazmat.2020.124958DOI Listing
June 2021

Bamboo-like microfiber structures fabricated by one-step-tapering a fiber preform.

Opt Express 2020 Dec;28(26):39586-39594

The microfiber-based optical structures have been attracting increasing research interests in communications and sensing fields. However, the fabrication of forming structures on fragile microfibers requires delicate operations, which limits the developments of their practical applications. In this work, a one-step-tapering technique is proposed to manufacture structures on microfibers. As a demonstration, the fiber preform, consisting of sawtooth shaped solid-air interfaces with designed dimensions, is obtained using a femtosecond laser milling technique. By one-step tapering the preform, periodic bumps are formed, resulting in a bamboo-like microfiber device. The fabricated structure shows spectral characteristics of a long-period grating, of which extinction ratio is up to 18.2 dB around 1553.3 nm. The response to refractive index is measured to be ∼875.02 nm/RIU and the temperature coefficient is ∼5.78 pm/°C. The theoretical analysis shows good agreement with the experimental results. The microfiber-based structure fabricated using the one-step-tapering-preform technique is featured with flexibility of design, reproducibility, and structural stability.
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http://dx.doi.org/10.1364/OE.413115DOI Listing
December 2020

Polychlorinated biphenyl quinone induced the acquisition of cancer stem cells properties and epithelial-mesenchymal transition through Wnt/β-catenin.

Chemosphere 2021 Jan 28;263:128125. Epub 2020 Aug 28.

Key Laboratory of Luminescence Analysis and Molecular Sensing (Southwest University), Ministry of Education, College of Pharmaceutical Sciences, Southwest University, Chongqing, 400715, People's Republic of China. Electronic address:

Polychlorinated biphenyls (PCBs) are persistent industrial pollutants that have been linked to breast cancer progression. However, their molecular mechanism(s) are currently unclear. Our previous assessment suggested that the highly reactive PCB metabolite 2,3,5-trichloro-6-phenyl-[1,4]-benzoquinone (PCB29-pQ) induces the metastasis of breast cancer. Here, our data illustrate that PCB29-pQ increases cancer stem cell (CSC) marker expression, resulting in an increase in the epithelial-mesenchymal transition (EMT) in MDA-MB-231 breast cancer cells; further, the Wnt/β-catenin pathway also becomes activated by PCB29-pQ. When the Wnt/β-catenin pathway is inhibited, the promotion of CSC properties and EMT by PCB29-pQ were accordingly reversed. In addition, the overproduction of reactive oxygen species (ROS) mediated by PCB29-pQ plays a key role in Wnt/β-catenin activation. Collectively, our current data designated the regulatory role of Wnt/β-catenin in PCB29-pQ-triggered acquisition of CSC properties and EMT.
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http://dx.doi.org/10.1016/j.chemosphere.2020.128125DOI Listing
January 2021

Impacts of exogenous mineral silicon on cadmium migration and transformation in the soil-rice system and on soil health.

Sci Total Environ 2021 Mar 11;759:143501. Epub 2020 Nov 11.

Department of Biology, Eastern New Mexico University, Portales, NM 88130, USA. Electronic address:

Exogenous silicon has been shown to enhance plant growth and alleviate heavy metals toxicity, but the regulation mechanism of silicon on cadmium migration and transformation in the soil-rice system is still unclear, which is worth further study. In this study, a pot experiment was carried out to explore the influence of different doses (0, 1 and 5%) of mineral silicon on soil properties, nutrient availability, rice growth, soil enzyme activities, Cd bioavailability, and uptake and accumulation of Cd in high-accumulating (H) and low-accumulating (L) rice cultivars grown in contaminated soils. Results showed that mineral-Si treatment could increase the total biomass and grain yield, with an increased rate of 17.7-27.3% and 14.7-19.1% for H; while 26.2-33.4% and 21.3-30.3% for L. Compared with non-mineral-Si treatment, the soil EX-Cd decreased by 3.9-13.3% (H) and 2.3-10.7% (L). Additionally, the Cd content in rice grain was significantly declined by 29.5-31.3% (H) and 34.9-35.2% (L). Mineral-Si enhanced urease, sucrase, and neutral phosphatase activities in both cultivars, but suppressed catalase activity in H. A selective change in bacterial community structure was observed under mineral-Si treatment, however, the bacterial community remained stable, suggesting that the mineral-Si had no adverse effect on the microbial community. The positive response of soil enzymes activities, rice growth and the overall stabilization of microbial environment for mineral-Si addition to the Cd contaminated soils indicated that mineral-Si could mitigate the risk of Cd and well maintain the soil health, proving it to be eco-friendly and low-cost amendment for soils remediation.
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http://dx.doi.org/10.1016/j.scitotenv.2020.143501DOI Listing
March 2021

Tetrachlorobenzoquinone exhibits immunotoxicity by inducing neutrophil extracellular traps through a mechanism involving ROS-JNK-NOX2 positive feedback loop.

Environ Pollut 2021 Jan 6;268(Pt B):115921. Epub 2020 Nov 6.

Key Laboratory of Luminescence Analysis and Molecular Sensing, Ministry of Education, College of Pharmaceutical Sciences, Southwest University, Chongqing, 400715, China; State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing, 100085, China. Electronic address:

Tetrachlorobenzoquinone (TCBQ) is a common metabolite of persistent organic pollutants pentachlorophenol (PCP) and hexachlorobenzene (HCB). Current reports on the toxicity of TCBQmainly focused on its reproductive toxicity, neurotoxicity, carcinogenicity and cardiovascular toxicity. However, the possible immunotoxicity of TCBQ remains unclear. The release of neutrophil extracellular traps (NETs) is a recently discovered immune response mechanism, however, excess NETs play a pathogenic role in various immune diseases. In an attempt to address concerns regarding the immunotoxicity of TCBQ, we adopted primary mouse neutrophils as the research object, explored the influence of TCBQ on the formation of NETs. The results showed that TCBQ could induce NETs rapidly in a reactive oxygen species (ROS)-dependent manner. Moreover, TCBQ promoted the phosphorylation of c-Jun N-terminal kinase (JNK) mitogen activated protein kinase (MAPK), but not p38 or extracellular signal related kinase (ERK) in neutrophils. Mechanistically, JNK activation enhanced the expression of NADPH oxidase enzyme 2 (NOX2), which further accelerated the generation of ROS and thus amplified the formation of NETs. The pharmacologic blockage of JNK or NOX2 effectively ameliorated TCBQ-induced ROS and NETs, implying that ROS-JNK-NOX2 positive feedback loop was involved in TCBQ-induced NETs. In conclusion, we speculated that targeting NETs formation would be a promising therapeutic strategy in modulating the immunotoxicity of TCBQ.
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http://dx.doi.org/10.1016/j.envpol.2020.115921DOI Listing
January 2021

Dual effects of fibrinogen decoration on the tuning of silica nanoparticles-induced autophagic response: The implication of sedimentation and internalization.

J Hazard Mater 2021 Apr 6;408:124467. Epub 2020 Nov 6.

Key Laboratory of Luminescence Analysis and Molecular Sensing (Southwest University), Ministry of Education, College of Pharmaceutical Sciences, Southwest University, Beibei District, Chongqing 400715, China; State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing 100085, China. Electronic address:

Due to the blooming development of nanotechnology, the further understanding of nanomaterials-induced toxicity has been demanded. Following their introduction into a biological matrix, the surface of nanoparticles (NPs) is covered by protein layer, namely corona, which imparts a new biological identity to NPs. Here, we showed that fibrinogen (Fg), but not albumin (BSA) or hemoglobin (Hb), decoration on the surface of silica nanoparticles (SiO NPs) ameliorate their pro-autophagic activity in non-phagocytic cells. Surprisingly, this effect of Fg was compromised in phagocytic cells. Further mechanistic investigation suggested coronal Fg has dual effects on the tuning of SiO NPs-induced autophagic response. First, Fg decoration blocks SiO NPs sedimentation through stabilize SiO NPs suspension; secondly, Fg coverage inhibits SiO NPs' cellular internalization. These findings provided important insights into the understanding of NPs-corona complexes behaviors and indicate future directions for the investigation of corona-mediated biological activities.
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http://dx.doi.org/10.1016/j.jhazmat.2020.124467DOI Listing
April 2021

Tetrachlorobenzoquinone exposure triggers ferroptosis contributing to its neurotoxicity.

Chemosphere 2021 Feb 24;264(Pt 1):128413. Epub 2020 Sep 24.

Key Laboratory of Luminescence Analysis and Molecular Sensing (Southwest University), Ministry of Education, College of Pharmaceutical Sciences, Southwest University, Chongqing, 400715, People's Republic of China. Electronic address:

Halogenated quinones are representative metabolites of persistent organic pollutants. Tetrachlorobenzoquinone (TCBQ) is a reactive metabolite of the widely used fungicide hexachlorobenzene (HCB) and wood preservative pentachlorophenol (PCP). Our previous studies have demonstrated that TCBQ induced neuron-like cell apoptosis in a reactive oxygen species (ROS)-dependent manner. Here, we found that TCBQ caused lipid peroxidation and cellular morphological changes including shrinked mitochondrial size, suggesting the involvement of a recently uncovered form of programmed cell death (PCD), ferroptosis. Indeed, we then identified that ferroptosis is a novel PCD driven by TCBQ, which was correlated with a decrease in glutathione peroxidase 4 (GPX4) level and iron accumulation by altering iron metabolism. Notably, nuclear factor erythroid-derived 2-like 2 (Nrf2) is a negative regulator in modulating the outcomes of ferroptosis as an adaptive cellular defense response. Nrf2 activation enhanced iron storage capacity and GPX4 activity by elevating ferritin heavy chain 1 (FTH1) expression and glutathione (GSH) level, respectively. On the contrary, Nfe2l2 (Nrf2) deficiency enhanced PC12 cells susceptibility to ferroptosis.
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http://dx.doi.org/10.1016/j.chemosphere.2020.128413DOI Listing
February 2021

Zinc oxide nanoparticles effectively regulate autophagic cell death by activating autophagosome formation and interfering with their maturation.

Part Fibre Toxicol 2020 09 18;17(1):46. Epub 2020 Sep 18.

Key Laboratory of Luminescence Analysis and Molecular Sensing (Southwest University), Ministry of Education, College of Pharmaceutical Sciences, Southwest University, Beibei, Chongqing, 400715, People's Republic of China.

Background: With the development of zinc oxide nanoparticles (ZnO NPs) in the field of nanotechnology, their toxicological effects are attracting increasing attention, and the mechanisms for ZnO NPs neurotoxicity remain obscure. In an attempt to address concerns regarding neurotoxicity of ZnO NPs, we explored the relationship between free zinc ions, reactive oxygen species (ROS) and neurotoxic mechanisms in ZnO NPs-exposed PC12 cells.

Result: This study demonstrated the requirement of free zinc ions shed by ZnO NPs to over generation of intracellular ROS. Next, we identified autophagic cell death was the major mode of cell death induced by ZnO NPs, and autophagosome accumulation resulted from not only induction of autophagy, but also blockade of autophagy flux. We concluded that autophagic cell death, resulting from zinc ions-ROS-c-Jun N-terminal kinase (JNK)-autophagy positive feedback loop and blockade of autophagosomal-lysosomal fusion, played a major role in the neurotoxicity of ZnO NPs.

Conclusion: Our study contributes to a better understanding of the neurotoxicity of ZnO NPs and might be useful for designing and developing new biosafety nanoparticles in the future.
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http://dx.doi.org/10.1186/s12989-020-00379-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7501661PMC
September 2020

Fostered Nrf2 expression antagonizes iron overload and glutathione depletion to promote resistance of neuron-like cells to ferroptosis.

Toxicol Appl Pharmacol 2020 11 13;407:115241. Epub 2020 Sep 13.

Key Laboratory of Luminescence Analysis and Molecular Sensing, Southwest University, Ministry of Education, College of Pharmaceutical Sciences, Chongqing 400715, People's Republic of China. Electronic address:

Neurological diseases were often characterized by progressive neuronal death, and emerging evidences suggested that ferroptosis may be an active driver of multiple neurodegenerative diseases. However, the mechanisms underlying ferroptosis in neuron cells are unclear. Here, we demonstrated that ferroptotic stimuli caused injury in neuron-like PC12 cells by modulating the expression of proteins involved in iron metabolism and lipid peroxidation at multiple levels, such as altering iron import/export, activating ferritinophagy, and decreasing glutathione (GSH) level. Nuclear factor erythroid 2-related factor 2 (Nrf2) regulates multiple genes involved in ferroptosis, however, its exact role remain elusive. Our mechanistic inquiry revealed that Nrf2 expression enhanced iron storage capacity by increasing ferritin heavy chain 1 (FTH1) expression in PC12 cells. Moreover, Nrf2 alleviated the decrease in GSH level by promoting the expression of genes related to GSH synthesis, including solute carrier family 7 member 11 (SLC7A11) and cysteine ligase (GCL). The contribution of Nrf2 on ferroptosis resistance was further verified by increasing cell tolerance to oxidative stress. Furthermore, Nfe2l2 (Nrf2) knockdown sensitized cells to ferroptotic cell death. Taken together, our findings suggested that iron accumulation caused by altering iron metabolism and the decrease of GSH content are key factors in determining ferroptosis in PC12 cells, and Nrf2 inhibits ferroptosis by combating iron-induced oxidative stress. Our present study provided new clues for the intervention and prevention against ferroptosis-associated neurological diseases.
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http://dx.doi.org/10.1016/j.taap.2020.115241DOI Listing
November 2020

Network Pharmacology Integrated Molecular Docking Reveals the Mechanism of Anisodamine Hydrobromide Injection against Novel Coronavirus Pneumonia.

Evid Based Complement Alternat Med 2020 5;2020:5818107. Epub 2020 Aug 5.

Ethnic Medicine Academic Heritage Innovation Research Center, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China.

Background: The Coronavirus Disease 2019 (COVID-19) outbreak in Wuhan, China, was caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Anisodamine hydrobromide injection (AHI), the main ingredient of which is anisodamine, is a listed drug for improving microcirculation in China. Anisodamine can improve the condition of patients with COVID-19.

Materials And Methods: Protein-protein interactions obtained from the String databases were used to construct the protein interaction network (PIN) of AHI using Cytoscape. The crucial targets of AHI PIN were screened by calculating three topological parameters. Gene ontology and pathway enrichment analyses were performed. The intersection between the AHI component proteins and angiotensin-converting enzyme 2 (ACE2) coexpression proteins was analyzed. We further investigated our predictions of crucial targets by performing molecular docking studies with anisodamine.

Results: The PIN of AHI, including 172 nodes and 1454 interactions, was constructed. A total of 54 crucial targets were obtained based on topological feature calculations. The results of Gene Ontology showed that AHI could regulate cell death, cytokine-mediated signaling pathways, and immune system processes. KEGG disease pathways were mainly enriched in viral infections, cancer, and immune system diseases. Between AHI targets and ACE2 coexpression proteins, 26 common proteins were obtained. The results of molecular docking showed that anisodamine bound well to all the crucial targets.

Conclusion: The network pharmacological strategy integrated molecular docking to explore the mechanism of action of AHI against COVID-19. It provides protein targets associated with COVID-19 that may be further tested as therapeutic targets of anisodamine.
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http://dx.doi.org/10.1155/2020/5818107DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7411467PMC
August 2020

Transplantable Carbonaceous Li Filtrating Membrane for Lithium Metal Protection.

ACS Appl Mater Interfaces 2020 Jul 25;12(27):30494-30502. Epub 2020 Jun 25.

Key Laboratory of Optoelectronic Chemical Materials and Devices, School of Chemical and Environmental Engineering, Jianghan University, Wuhan 430056, China.

Utilization of the lithium (Li) metal anode is seriously prevented by the undesirable side reactions with electrolyte solvents due to their mismatched energy gaps and easily lacerated SEI layer. In this work, we develop a transplantable carbonaceous membrane with a particular ability of filtrating Li ions by blocking organic solvents and use it as an independent protective component to isolate lithium metal anode from the electrolytes. This graphene-supported N-doped membrane (GNM) can separate organic carbonates of dimethyl carbonate (DMC) and diethyl carbonate (DEC) from HO-DMC/DEC mixtures by holding back the organic solvents. When this membrane is used in a Li-Cu cell, a high Li Coulombic efficiency (CE) of 98.5% is maintained in carbonate electrolyte over 400 cycles. Application of GNM in Li-O full cell provides a sustainable use of Li metal for more than 200 cycles (2000 h) by keeping its shiny metal luster. Our results demonstrate that the use of an independent component with Li filtrating ability, such as the transplantable membrane of GNM developed in this work, should be a feasible remedy to protect Li metal anode in practical Li metal batteries.
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http://dx.doi.org/10.1021/acsami.0c08433DOI Listing
July 2020

Polychlorinated Biphenyl Quinone Promotes Atherosclerosis through Lipid Accumulation and Endoplasmic Reticulum Stress via CD36.

Chem Res Toxicol 2020 06 29;33(6):1497-1507. Epub 2020 May 29.

College of Pharmaceutical Sciences, Southwest University, Chongqing 400715, People's Republic of China.

Polychlorinated biphenyls (PCBs) are persistent organic environmental pollutants. According to previous epidemiological reports, PCBs exposure is highly related to atherosclerosis. However, studies of PCBs metabolites and atherosclerosis and corresponding mechanism studies are scarce. In this study, we evaluated the effect of 2,3,5-trichloro-6-phenyl-[1,4]-benzoquinone (PCB29-pQ), a presumptive PCB metabolite, on atherosclerosis. Aortic plaques were increased in PCB29-pQ-treated ApoE mice [intraperitoneally (i.p.) injection of 5 mg/kg body weight of PCB29-pQ once a week for 12 continuous weeks, high-fat feeding]. We observed lipids accumulation and the release of interleukin-1 beta (IL-1β), tumor necrosis factor alpha (TNF-α), and interleukin-6 (IL-6) in ApoE mice. In addition, we found that PCB29-pQ promoted the levels of total cholesterol, free cholesterol, triglyceride, and cholesteryl ester. Mechanism investigation indicated that PCB29-pQ induces the activation of three branches of endoplasmic reticulum (ER) stress response, that is, phosphorylated protein kinase R-like ER kinase (p-PERK), eukaryotic translation initiation factor 2α (eIF2α) and transcription factor 6 (ATF6), which is responsible for downstream necrosis. More importantly, we found the silence of CD36 is able to reverse PCB29-pQ-induced adverse effects completely. Overall, PCB29-pQ exposure resulted in lipid accumulation, ER stress response, apoptosis, and pro-inflammatory cytokines release via CD36, ultimately leading to atherosclerosis.
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http://dx.doi.org/10.1021/acs.chemrestox.0c00123DOI Listing
June 2020

Temporal and spatial evolution of online public sentiment on emergencies.

Inf Process Manag 2020 Mar 24;57(2):102177. Epub 2019 Dec 24.

College of Public Administration and Law, Hunan Agricultural University, Changsha, China.

The transmission of online emergency information has become an active means of expressing public opinion and has vitally affected societal emergency response techniques. This paper analyzes interactions between three groups in time and space using a classic SIR (susceptible, infected, and recovered) epidemic model. Through social network theory and analog simulation analysis, we utilize data from China's Sina Weibo (a popular social media platform) to conduct empirical research on 101 major incidents in China that occurred between 2010 and 2017. We divide these emergencies into four types-natural disasters, accidents, public health events, and social security events-and conduct a simulation using three examples from each group. The results show that government control of public opinion is both cheaper and more effective when it occurs at the initial stages of an incident. By cooperating with the government, the media can facilitate emergency management. Finally, if netizens trust the government and the media, they are more likely to make cooperative decisions, maintain interest, and improve the management of online public sentiment.
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http://dx.doi.org/10.1016/j.ipm.2019.102177DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7117024PMC
March 2020

Bone Marrow Plasma Cytokine Signature Profiles in Severe Aplastic Anemia.

Biomed Res Int 2020 18;2020:8789275. Epub 2020 Feb 18.

Department of Hematology, Tianjin Medical University General Hospital, 154 Anshan Street, Heping District, Tianjin 300052, China.

Objective: We studied bone marrow plasma (BMP) cytokines in severe aplastic anemia (SAA) patients and healthy volunteers to investigate differences in the cytokine profiles between them and propose a cytokine signature of SAA.

Methods: A Bio-Plex suspension array system was used to measure 27 analytes in BMP samples from 47 SAA patients and 30 healthy donors.

Results: Compared to healthy people, SAA patients had higher levels of tumor necrosis factor (TNF- (TNF- (IFN- (IFN- (MIP-1 (MIP-1 (TNF- (TNF- (MIP-1 (MIP-1 (MIP-1 (IFN- (TNF.

Conclusions: The current study demonstrated distinct cytokine profiles among untreated SAA patients, recovering SAA (RSAA) patients, and healthy people. The cytokines of RSAA patients showed similar characteristics to those of untreated SAA patients and healthy people, respectively, which may reflect that the immune status of RSAA patients is in different stages of recovery after IST; thus, it may provide an important tool in diagnosing and evaluating or predicting curative effects in clinics.
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http://dx.doi.org/10.1155/2020/8789275DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7063880PMC
December 2020

Dataset of illness classifications in Sowa Rigpa: Compilations from the Oral Instructions Treatise of the Tibetan medical classic ().

Data Brief 2020 Apr 25;29:105321. Epub 2020 Feb 25.

Center for Healthy Minds, University of Wisconsin-Madison, 625 W. Washington Ave, Madison, WI, 53703, USA.

This article shares the comprehensive dataset and five visualized examples of disease categories in Tibetan medicine, or Sowa Rigpa (Tib. ), translated as the "knowledge field of healing." Sowa Rigpa is a scholarly Asian traditional medical system rigorously transmitted through canonical texts and oral teachings originating in Tibet with an extensive pharmacopeia, comprehensive treatment repertoire, and nuanced etiological explications of its nosology of diseases. This medical tradition is practiced across a broad region of Asia, particularly in Tibetan regions of China, Himalayan regions of India (Ladakh, Sikkim, Himachal Pradesh), Nepal, Bhutan, Mongolia, Russia, and recently in Europe and North America. The data herein depicts disease classifications listed in the encyclopedic compendium "Oral Instructions Treatise" () of the Tibetan medical classic, the (), compiled in written form during the twelfth century CE. Visualized examples depict etiological relations among diseases in five of the fifteen major categories of disease: rLung Illnesses, Béken Illneses, Pediatric Conditions, Eye Conditions and Tropical Infectious Diseases. Disease names were entered into spreadsheet format and categorized by etiological hierarchical structure. Data are written in Unicode Tibetan font to retain fidelity to entries in the classical text, with parallel columns in standard Wylie transliteration. Subsets of the data are visually depicted through a graphic platform called to demonstrate etiological associations. This dataset is the first publicly available enumeration of the specific diseases, classifications and etiological relationships from the Tibetan medical classic. The data are linked to the article entitled "Tibetan Medical Informatics: An Emerging Field in Sowa Rigpa Pharmacological & Clinical Research" (Dhondrup et al., 2020).
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http://dx.doi.org/10.1016/j.dib.2020.105321DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7063332PMC
April 2020

"Iron free" zinc oxide nanoparticles with ion-leaking properties disrupt intracellular ROS and iron homeostasis to induce ferroptosis.

Cell Death Dis 2020 03 13;11(3):183. Epub 2020 Mar 13.

Key Laboratory of Luminescence and Real-Time Analytical Chemistry (Southwest University), Ministry of Education, College of Pharmaceutical Sciences, Southwest University, Chongqing, 400715, People's Republic of China.

Exposure to nanomaterials (NMs) is an emerging threat to human health, and the understanding of their intracellular behavior and related toxic effects is urgently needed. Ferroptosis is a newly discovered, iron-mediated cell death that is distinctive from apoptosis or other cell-death pathways. No evidence currently exists for the effect of "iron free" engineered NMs on ferroptosis. We showed by several approaches that (1) zinc oxide nanoparticles (ZnO NPs)-induced cell death involves ferroptosis; (2) ZnO NPs-triggered ferroptosis is associated with elevation of reactive oxygen species (ROS) and lipid peroxidation, along with depletion of glutathione (GSH) and downregulation of glutathione peroxidase 4 (GPx4); (3) ZnO NPs disrupt intracellular iron homeostasis by orchestrating iron uptake, storage and export; (4) p53 largely participates in ZnO NPs-induced ferroptosis; and (5) ZnO particle remnants and dissolved zinc ion both contribute to ferroptosis. In conclusion, our data provide a new mechanistic rationale for ferroptosis as a novel cell-death phenotype induced by engineered NMs.
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http://dx.doi.org/10.1038/s41419-020-2384-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7070056PMC
March 2020

Learning from electronic health records across multiple sites: A communication-efficient and privacy-preserving distributed algorithm.

J Am Med Inform Assoc 2020 03;27(3):376-385

Department of Biostatistics, Epidemiology and Informatics, University of Pennsylvania, Philadelphia, Pennsylvania, USA.

Objectives: We propose a one-shot, privacy-preserving distributed algorithm to perform logistic regression (ODAL) across multiple clinical sites.

Materials And Methods: ODAL effectively utilizes the information from the local site (where the patient-level data are accessible) and incorporates the first-order (ODAL1) and second-order (ODAL2) gradients of the likelihood function from other sites to construct an estimator without requiring iterative communication across sites or transferring patient-level data. We evaluated ODAL via extensive simulation studies and an application to a dataset from the University of Pennsylvania Health System. The estimation accuracy was evaluated by comparing it with the estimator based on the combined individual participant data or pooled data (ie, gold standard).

Results: Our simulation studies revealed that the relative estimation bias of ODAL1 compared with the pooled estimates was <3%, and the ratio of standard errors was <1.25 for all scenarios. ODAL2 achieved higher accuracy (with relative bias <0.1% and ratio of standard errors <1.05). In real data analysis, we investigated the associations of 100 medications with fetal loss during pregnancy. We found that ODAL1 provided estimates with relative bias <10% for 85% of medications, and ODAL2 has relative bias <10% for 99% of medications. For communication cost, ODAL1 requires transferring p numbers from each site to the local site and ODAL2 requires transferring (p×p+p) numbers from each site to the local site, where p is the number of parameters in the regression model.

Conclusions: This study demonstrates that ODAL is privacy-preserving and communication-efficient with small bias and high statistical efficiency.
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http://dx.doi.org/10.1093/jamia/ocz199DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7025371PMC
March 2020

Polybrominated Diphenyl Ethers Quinone Induces NCOA4-Mediated Ferritinophagy through Selectively Autophagic Degradation of Ferritin.

Chem Res Toxicol 2019 12 11;32(12):2509-2516. Epub 2019 Nov 11.

Key Laboratory of Luminescence and Real-Time Analytical Chemistry (Southwest University), Ministry of Education, College of Pharmaceutical Sciences , Southwest University , Chongqing 400715 , People's Republic of China.

Polybrominated diphenyl ethers (PBDEs) have been detected ubiquitously in biological and environmental samples. Growing epidemiological data suggested the obvious correlation of PBDEs exposure with adverse health outcomes toward human beings, but exact molecular mechanism(s) are limited. Especially, the toxicological information regarding PBDEs metabolites is missing. Thereafter, this study intends to explore unidentified cell death modalities caused by PBDEs reactive quinone-type metabolite, PBDEQ. We found that PBDEQ induces autophagy in an ROS-dependent manner. Interestingly, the results indicated that PBDEQ degraded ferritin and activated a selective autophagy (termed as ferritinophagy) by using NCOA4 as its cargo receptor. These processes may further promote the release of iron and ROS. These results suggested the incidence of ferritinophagy induced by PBDEQ, which may contribute to PBDE exposure-caused diseases and dysfunctions.
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http://dx.doi.org/10.1021/acs.chemrestox.9b00350DOI Listing
December 2019

Polychlorinated Biphenyl Quinone Promotes Macrophage-Derived Foam Cell Formation.

Chem Res Toxicol 2019 12 13;32(12):2422-2432. Epub 2019 Nov 13.

Key Laboratory of Luminescence and Real-Time Analytical Chemistry, Ministry of Education, College of Pharmaceutical Sciences , Southwest University , Chongqing , People's Republic of China , 400715.

Polychlorinated biphenyls (PCBs) are organic environmental pollutants that are accused of various toxic effects. PCB exposure is widely believed to be associated with atherosclerosis, but the underlying mechanisms are unclear. Although PCBs are easily metabolized, there is rarely information on the effects of their metabolites on atherosclerosis. Currently, we evaluate the effect of 2,3,5-trichloro-6-phenyl-[1,4]-benzoquinone (PCB29-pQ) on the critical phase of atherosclerosis development, that is, the formation of macrophage-derived foam cells. We exposed Ox-LDL-induced RAW264.7 cells to 2.5 μM and 5 μM PCB29-pQ. Varieties of evidence have demonstrated that PCB29-pQ promotes foam cell formation and develops proinflammatory cascade and cell necroptosis. In detail, we observed that PCB29-pQ increased levels of total cholesterol (TC), free cholesterol (FC), triglyceride (TG), and cholesteryl ester (CE) by increasing the cholesterol influx and reducing the cholesterol efflux. Moreover, we found that PCB29-pQ induced inflammatory cytokines, such as tumor necrosis factor (TNF-α), interleukin 6 (IL-6), and IL-1β, released by activating the mitogen-activated protein kinase (MAPK)-nuclear factor kappa B (NF-κB) inflammatory pathway. In addition, we demonstrated that PCB29-pQ induced cell necroptosis via receptor interacting protein kinases 1 and 3 (RIPK1/3) and a mixed-lineage kinase domain-like (MLKL) pathway. Finally, the overproduction of reactive oxygen species (ROS) by PCB29-pQ played significant roles in these processes, which could be reversed with an antioxidant. Overall, our results indicated that PCB29-pQ promoted the macrophage formation of foam cells, inflammation, and cell necroptosis.
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http://dx.doi.org/10.1021/acs.chemrestox.9b00184DOI Listing
December 2019

Surgical stress and cancer progression: the twisted tango.

Mol Cancer 2019 09 2;18(1):132. Epub 2019 Sep 2.

Department of Obstetrics and Gynecology, Key Laboratory of Birth Defects and Related Diseases of Women and Children of MOE and State Key Laboratory of Biotherapy, West China Second University Hospital, Sichuan University and Collaborative Innovation Center, 610041, Chengdu, Sichuan, People's Republic of China.

Surgical resection is an important avenue for cancer treatment, which, in most cases, can effectively alleviate the patient symptoms. However, accumulating evidence has documented that surgical resection potentially enhances metastatic seeding of tumor cells. In this review, we revisit the literature on surgical stress, and outline the mechanisms by which surgical stress, including ischemia/reperfusion injury, activation of sympathetic nervous system, inflammation, systemically hypercoagulable state, immune suppression and effects of anesthetic agents, promotes tumor metastasis. We also propose preventive strategies or resolution of tumor metastasis caused by surgical stress.
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http://dx.doi.org/10.1186/s12943-019-1058-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6717988PMC
September 2019

Prolonging the Cycle Life of a Lithium-Air Battery by Alleviating Electrolyte Degradation with a Ceramic-Carbon Composite Cathode.

ChemSusChem 2019 Nov 17;12(22):4962-4967. Epub 2019 Oct 17.

Department of New Energy Technology, Ningbo Institute of Materials Technology and Engineering, Chinese Academy of Sciences, Ningbo, 315201, P.R. China.

Carbon materials with a high specific surface area are usually preferred to construct the air cathode of lithium-air batteries due to their abundant sites for oxygen reduction and discharge product growth. However, the high surface area also amplifies electrolyte degradation during charging, which would become the threshold of cyclability after addressing the issue of electrode passivation and pore clogging, but is usually overlooked in relevant research. Herein, it is proven that the critical influence of cathode surface area on electrolyte consumption by adopting carbon-ceramic composites to reduce the surface area of the air cathode. After screening several potential ceramic materials, an optimal composite of Ketjenblack (KB) and La Sr MnO (LSM) delivered a discharge capacity that was even higher than that of pure KB. This composite effectively mitigated the parasitic reaction current by 45 % if polarized at 4.4 V versus Li /Li. Correspondingly, this composite prolonged the cycle life of the cell by 156 %. The results demonstrate that electrolyte consumption during charging is one of the critical boundary conditions to restrain the cyclic stability of lithium-air batteries.
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http://dx.doi.org/10.1002/cssc.201901629DOI Listing
November 2019

Conserved Residue Asn-145 in the C-Terminal Heptad Repeat Region of HIV-1 gp41 is Critical for Viral Fusion and Regulates the Antiviral Activity of Fusion Inhibitors.

Viruses 2019 07 3;11(7). Epub 2019 Jul 3.

NHC Key Laboratory of Systems Biology of Pathogens, Institute of Pathogen Biology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China.

Entry of HIV-1 into target cells is mediated by its envelope (Env) glycoprotein composed of the receptor binding subunit gp120 and the fusion protein gp41. Refolding of the gp41 N- and C-terminal heptad repeats (NHR and CHR) into a six-helix bundle (6-HB) conformation drives the viral and cellular membranes in close apposition and generates huge amounts of energy to overcome the kinetic barrier leading to membrane fusion. In this study, we focused on characterizing the structural and functional properties of a single Asn-145 residue, which locates at the middle CHR site of gp41 and is extremely conserved among all the HIV-1, HIV-2, and simian immunodeficiency virus (SIV) isolates. By mutational analysis, we found that Asn-145 plays critical roles for Env-mediated cell-cell fusion and HIV-1 entry. As determined by circular dichroism (CD) spectroscopy and isothermal titration calorimetry (ITC), the substitution of Asn-145 with alanine (N145A) severely impaired the interactions between the NHR and CHR helices. Asn-145 was also verified to be important for the antiviral activity of CHR-derived peptide fusion inhibitors and served as a turn-point for the inhibitory potency. Intriguingly, Asn-145 could regulate the functionality of the M-T hook structure at the N-terminus of the inhibitors and displayed comparable activities with the C-terminal IDL anchor. Crystallographic studies further demonstrated the importance of Asn-145-mediated interhelical and intrahelical interactions in the 6-HB structure. Combined, the present results have provided valuable information for the structure-function relationship of HIV-1 gp41 and the structure-activity relationship of gp41-dependent fusion inhibitors.
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http://dx.doi.org/10.3390/v11070609DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6669600PMC
July 2019

Polychlorinated Biphenyl Quinone Induces Caspase 1-Mediated Pyroptosis through Induction of Pro-inflammatory HMGB1-TLR4-NLRP3-GSDMD Signal Axis.

Chem Res Toxicol 2019 06 23;32(6):1051-1057. Epub 2019 Apr 23.

Key Laboratory of Luminescence and Real-Time Analytical Chemistry (Southwest University), Ministry of Education, College of Pharmaceutical Sciences , Southwest University , Chongqing 400715 , People's Republic of China.

Polychlorinated biphenyls (PCBs) are one of the most refractory environmental pollutants. Because of their ubiquitous existence in the biological systems (including human body), it is important to investigate their toxic behavior. Our previous findings demonstrated that a high reactive metabolite of PCB, namely PCB29-pQ, causes several programmed cell death (PCD) such as intrinsic/extrinsic apoptosis and autophagic cell death. The mechanistic study suggested the toxic actions of PCB29-pQ is largely related to its reactive oxygen species (ROS)-generation ability. Pyroptosis is a caspase 1-mediated pro-inflammatory PCD, which was discovered recently. The aim of this study is to seek the linkage between pyroptosis and PCB29-pQ exposures. We first confirmed that PCB29-pQ stimulates Hela cells to produce excess amounts of ROS. Then we found PCB29-pQ activates NOD-like receptor pyrin domain-containing 3 (NLRP3) inflammasome that mediates caspase 1 activation. The activated caspase 1 (cleaved caspase 1) promotes gasdermin D (GSDMD) cleavage and translocation, which facilitates the release of intracellular inflammatory substances by forming membrane hole, ultimately leading cells to pyroptosis. PCB29-pQ-induced high-mobility group box 1 (HMGB1) release and subsequent binding to its receptors [toll-like receptor 2 (TLR2), TLR4, TLR9, and receptor for advanced glycation end products (RAGE)] are essential for the activation of NLRP3 inflammasome. The current study revealed pyroptosis as a new death mode induced by PCB29-pQ, which enriched the understanding of PCBs-induced toxicity and helped to prevent the toxic effects of residual PCBs in the environment.
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http://dx.doi.org/10.1021/acs.chemrestox.8b00376DOI Listing
June 2019

Aflatoxin B Induces Immunotoxicity through the DNA Methyltransferase-Mediated JAK2/STAT3 Pathway in 3D4/21 Cells.

J Agric Food Chem 2019 Apr 18;67(13):3772-3780. Epub 2019 Mar 18.

As the most toxic mycotoxin of all of the fungal toxins, aflatoxin B (AFB) has carcinogenesis, heptotoxicity, and immunotoxicity. DNA methylation plays a critical role in gene expression regulation of the pathological process. However, the relationship between DNA methylation and AFB-induced immunotoxicity was not yet reported. Therefore, the objectives of this study were to verify AFB-induced immunotoxicity and investigate the potential role of the DNA methyltransferase (DNMT) family in AFB-induced immunotoxicity and the pathway mechanism in 3D4/21 cells. The results showed that AFB could induce cytotoxicity, apoptosis, pro-inflammatory cytokine expression, DNA damage, and oxidative stress and decrease phagocytotic capacity. Meanwhile, the levels of DNMT1 and DNMT3a were significantly increased in 0.04 and 0.08 μg/mL AFB compared to the control. Inhibition of DNMT1 and DNMT3a by 5-Aza-2dc could reverse changes of the above parameters. Further, the JAK2/STAT3 pathway was significantly activated in 0.04 μg/mL AFB. Inhibition of p-JAK2 and p-STAT3 by AG490 could alleviate AFB-induced immunotoxicity. Moreover, inhibition of DNMT1 and DNMT3a by 5-Aza-2dc could suppress the phosphorylation of JAK2 and STAT3. Taken together, AFB-induced immunotoxicity is related to the JAK2/STAT3 pathway mediated by DNMTs in 3D4/21 cells.
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http://dx.doi.org/10.1021/acs.jafc.8b07309DOI Listing
April 2019

PCV2 replication promoted by oxidative stress is dependent on the regulation of autophagy on apoptosis.

Vet Res 2019 Mar 5;50(1):19. Epub 2019 Mar 5.

College of Veterinary Medicine, Nanjing Agricultural University, Nanjing, 210095, China.

Porcine circovirus type 2 (PCV2) is an economically important swine pathogen but some extra trigger factors are required for the development of PCV2-associated diseases. By evaluating cap protein expression, viral DNA copies and the number of infected cells, the present study further confirmed that oxidative stress can promote PCV2 replication. The results showed that oxidative stress induced autophagy in PCV2-infected PK15 cells. Blocking autophagy with inhibitor 3-methyladenine or ATG5-specific siRNA significantly inhibited oxidative stress-promoted PCV2 replication. Importantly, autophagy inhibition significantly increased apoptosis in oxidative stress-treated PK15 cells. Suppression of apoptosis by benzyloxycarbonyl-Val-Ala-Asp fluoromethylketone in conditions of autophagy inhibition restored PCV2 replication. Taken together, autophagy protected host cells against potential apoptosis and then contributed to PCV2 replication promotion caused by oxidative stress. Our findings can partly explain the pathogenic mechanism of PCV2 related to the oxidative stress-induced autophagy.
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http://dx.doi.org/10.1186/s13567-019-0637-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6399867PMC
March 2019

Mannan Oligosaccharide Protects against the Aflatoxin-B-Promoted Influenza Replication and Tissue Damages in a Toll-Like-Receptor-4-Dependent Manner.

J Agric Food Chem 2019 Jan 8;67(2):735-745. Epub 2019 Jan 8.

Our previous study reported that aflatoxin B (AFB) promoted influenza replication. Mannan oligosaccharide (MOS), derived from the cell walls of yeast, is a potent immunomodulator. Here, we investigated the role of MOS in AFB-promoted influenza replication and further explored the underlying mechanisms. In vitro and in vivo, the exposure to AFB alone resulted in significantly decreased weight gain and increased viral replication as well as lung and spleen damages. Increased influenza replication coupled with increases in toll-like receptor 4 (TLR4), phosphorylated nuclear factor κB, and tumor necrosis factor α (TNF-α) levels. However, MOS given in conjunction with exposure to AFB significantly reversed these above changes. A further study indicated that MOS activity was abolished by TLR4 knockout or TLR4 overexpression. Surprisingly, TNF-α played no role in the MOS-mediated protective effects. Collectively, our data suggest that MOS alleviates the AFB-promoted influenza replication, inflammation, and tissue damages in a TLR4-dependent manner.
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http://dx.doi.org/10.1021/acs.jafc.8b05829DOI Listing
January 2019

Atypical Gasdermin D and Mixed Lineage Kinase Domain-like Protein Leakage Aggravates Tetrachlorobenzoquinone-Induced Nod-like Receptor Protein 3 Inflammasome Activation.

Chem Res Toxicol 2018 12 9;31(12):1418-1425. Epub 2018 Nov 9.

Key Laboratory of Luminescence and Real-Time Analytical Chemistry (Southwest University), Ministry of Education, College of Pharmaceutical Sciences , Southwest University , Chongqing 400715 , People's Republic of China.

Our previous study showed that tetrachlorobenzoquinone (TCBQ) mediated the activation of Nod-like receptor protein 3 (NLRP3) inflammasome, which involves K efflux, reactive oxygen species (ROS) production, and mitochondrial DNA damage. In addition, TCBQ down-regulates NLRP3 ubiquitination and promotes the activation of NLRP3 inflammasome. However, the induction of NLRP3 inflammasome by atypical pathways has not yet been characterized. Using human umbilical vein endothelial cells (HUVEC), we discovered that TCBQ activates caspase 1/4/5 and cleaves gasdermin D (GSDMD) into N-terminal and C-terminal cleavage products. In parallel, TCBQ also activates receptor interacting protein kinase 3 (RIPK3)/mixed lineage kinase domain-like protein (MLKL) signaling pathways. The N-terminal fragments of GSDMD and MLKL translocate from cytoplasm to cell membrane and form oligomers and membrane pores on the cell membrane. The formation of membrane pores not only promotes the extracellular secretion of interleukin 1 beta (IL-1β) but also affects cellular ion homeostasis, in particular promotes K outflow, which further activates NLRP3 inflammasome and aggravates cellular inflammation. These results indicated that GSDMD and MLKL play important roles in TCBQ-induced endothelial pro-inflammatory responses, which may point to potential therapeutic approaches for TCBQ-mediated toxicity.
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http://dx.doi.org/10.1021/acs.chemrestox.8b00306DOI Listing
December 2018