Publications by authors named "Bingwei Yang"

22 Publications

  • Page 1 of 1

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

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

Polychlorinated biphenyl quinone regulates MLKL phosphorylation that stimulates exosome biogenesis and secretion via a short negative feedback loop.

Environ Pollut 2021 Apr 9;274:115606. Epub 2020 Sep 9.

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 one of the most refractory organic environmental pollutants that ubiquitous existence in nature. Due to the polymorphism of their metabolic pathway and corresponding downstream metabolites, PCBs' toxicities are complicated and need extended investigation. In the present study, we discovered a novel regulatory mechanism of PCB quinone metabolite-driven programmed cell death (PCD), namely, necroptosis. We first confirmed that PCB quinone induces cancerous HeLa and MDA-MB-231 cells necroptosis via the phosphorylation of mixed lineage kinase domain-like MLKL (p-MLKL). Then, we found that PCB quinone-stimulated p-MLKL enhances exosome biogenesis and secretion. Exosome interacts with p-MLKL and releases p-MLKL to the outside of the cell, and ultimately alleviating PCB quinone-induced necroptosis. The inhibition of exosome secretion by GW4869 significantly elevated necroptotic level, indicating the establishment of a short negative feedback loop of MLKL-exosome secretion upon PCB quinone challenge. Since exosome-mediated signaling showed great implications in various human diseases, this work may provide a new mechanism for PCBs-associated toxicity.
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http://dx.doi.org/10.1016/j.envpol.2020.115606DOI 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

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

Polychlorinated biphenyl quinone induces hepatocytes iron overload through up-regulating hepcidin expression.

Environ Int 2020 06 9;139:105701. Epub 2020 Apr 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. Electronic address:

Polychlorinated biphenyls (PCBs) are infamous industry by-products or additives, and increasing evidences demonstrated that their exposure is associate with adverse effects on human health. Liver, as the dominate site for xenobiotic metabolism, is apt to be the primary target of PCBs insult. Although PCBs' hepatic toxic effects have been extensively studied, however, the biotransformation of PCBs in liver and the toxicities of associated PCB metabolites are neglected at some extent. Thus, we choose 2,3,5-trichloro-6-phenyl-[1,4]-benzoquinone (PCB29-pQ), a surrogate PCB29 metabolite, and evaluated its contribution on hepatotoxicity. In the current study, we discovered PCB29-pQ-induced lipid peroxidation and iron overload both in vivo and in vitro. Further mechanistic research confirmed iron overload is caused by reactive oxygen species (ROS)-driven hepcidin disorder in hepatic cells, and the increase of hepcidin is regulated by the translocation of nuclear factor erythroid 2-related factor 2 (Nrf2).
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http://dx.doi.org/10.1016/j.envint.2020.105701DOI Listing
June 2020

Polychlorinated biphenyl quinone promotes macrophage polarization to CD163 cells through Nrf2 signaling pathway.

Environ Pollut 2020 Feb 19;257:113587. Epub 2019 Nov 19.

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. Electronic address:

Polychlorinated biphenyls (PCBs) are notorious environmental pollutants. For their hydrophobic and lipophilic capability, they are wildly spread to environment to threat human health thus attracts more attention. In this study, we observed increasing numbers of CD163 positive (CD163) macrophages in aortic valve of ApoE mice after 2,3,5-trichloro-6-phenyl-[1,4]-benzoquinone (PCB29-pQ) treatment, the metabolite of polychlorinated biphenyl. In addition, in vitro studies identified that PCB29-pQ exposure significantly provoked the shifting of RAW264.7 macrophages and bone marrow derived monocytes (BMDMs) to CD163 macrophages. Upon PCB29-pQ administration, CD163 and CD206 levels were enhanced in RAW264.7 cells as well as in BMDMs. However, the concentration of iron and total cholesterol (TC) were reduced due to the boosting of ferroportin (Fpn) and ATP binding cassette transporter, subfamily A, member 1 (ABCA1) which are efflux transporters of iron and cholesterol individually. Further investigation on mechanism indicated that PCB29-pQ exposure induced reactive oxygen species (ROS), which may result in activation of nuclear factor erythroid 2-related factor 2 (Nrf2), a protein responsible for macrophage polarization. After that, we blocked Nrf2 through Nrf2 shRNA and ROS scavenger NAC, which significantly reversed the shifting of macrophage to CD163 sub-population. These results confirmed the importance of Nrf2 in inducing macrophage polarization. In short, our study uncovered that PCB29-pQ could promote macrophage/monocyte polarization to CD163 macrophage which would be a potential incentive to accelerate atherosclerosis through Nrf2 signaling pathway.
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http://dx.doi.org/10.1016/j.envpol.2019.113587DOI Listing
February 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

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

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

Tetrachlorobenzoquinone-Induced Nrf2 Confers Neuron-like PC12 Cells Resistance to Endoplasmic Reticulum Stress via Regulating Glutathione Synthesis and Protein Thiol Homeostasis.

Chem Res Toxicol 2018 11 2;31(11):1230-1239. Epub 2018 Nov 2.

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

Our previous studies demonstrated that tetrachlorobenzoquinone (TCBQ) is toxic to neuron-like cells, which is related to endoplasmic reticulum (ER) stress-induced apoptosis. However, it remains unclear whether TCBQ causes the opening of cellular defense responses. Here we found that activation of nuclear factor erythroid-derived 2-like 2 (Nrf2) triggered an adaptive response against the neurotoxicity induced by TCBQ through the upregulation of intracellular glutathione (GSH) levels in rat pheochromocytoma PC12 cells. TCBQ upregulated the levels of GSH mainly by the following two ways: (i) Nrf2 activation induced the expression of cystine/glutamate antiporter solute carrier family 7 member 11 (SLC7A11, also called xCT); (ii) Nrf2 activation resulted in increased the expression of glutamylcysteine ligase. GSH is involved in cell antioxidant ability and protein thiol homeostasis, especially in the ER. Therefore, GSH has the ability to inhibit ER stress and promote cell survival. Our data showed that decreasing GSH levels exacerbated TCBQ-induced depletion of protein-SH, particularly in the ER. Conversely, increasing GSH levels attenuated TCBQ-induced protein damage, degree of ER stress, and cell death. These findings demonstrated that GSH-inhibited cells were vulnerable to TCBQ-induced ER stress and apoptosis. Overall, our results analyzed the relationships between Nrf2 and ER stress in response to TCBQ and showed that activation of Nrf2-GSH played a protective role against TCBQ-induced ER stress-associated neurotoxicity via regulating GSH synthesis and protein thiol homeostasis.
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http://dx.doi.org/10.1021/acs.chemrestox.8b00209DOI Listing
November 2018

Polybrominated Diphenyl Ethers Quinone Induced Parthanatos-like Cell Death through a Reactive Oxygen Species-Associated Poly(ADP-ribose) Polymerase 1 Signaling.

Chem Res Toxicol 2018 11 18;31(11):1164-1171. Epub 2018 Oct 18.

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

Polybrominated diphenyl ethers (PBDEs) are emerging organic environmental pollutants, which were accused of various toxic effects. Here, we studied the role of a potential PBDEs quinone metabolite, PBDEQ, on cytotoxicity, oxidative DNA damage, and the alterations of signal cascade in HeLa cells. PBDEQ exposure leads to reactive oxygen species (ROS) accumulation, mitochondrial membrane potential (MMP) loss, lactate dehydrogenase (LDH) release, increasing terminal transferase-mediated dUTP-biotin nick end labeling (TUNEL) positive foci, and the elevation of apoptosis rate. Furthermore, we showed PBDEQ exposure result in increased DNA migration, micronucleus frequency, and the promotion of 8-OHdG and phosphorylation of histone H2AX (γ-H2AX) levels. Mechanism study indicated that PBDEQ caused poly(ADP-ribose) polymerase 1 (PARP-1) activation and apoptosis-inducing factor (AIF) nuclear translocation. All together, these results confirmed the occurrence of parthanatos-like cell death upon PBDEQ exposure.
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http://dx.doi.org/10.1021/acs.chemrestox.8b00168DOI Listing
November 2018

Polychlorinated Biphenyl Quinones Promotes Breast Cancer Metastasis through Reactive Oxygen Species-Mediated Nuclear Factor κB-Matrix Metalloproteinase Signaling.

Chem Res Toxicol 2018 09 21;31(9):954-963. Epub 2018 Aug 21.

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

It is generally acknowledged that polychlorinated biphenyls (PCBs) exposure increased the incidence of cancer, however, the underlying mechanism(s) of PCBs-induced cancer metastasis are unclear. Although PCBs readily metabolize, little information is available regarding the effect of PCBs metabolites on cancer metastasis. Currently, we evaluate a highly reactive PCBs metabolite, 2,3,5-trichloro-6-phenyl-[1,4]-benzoquinone (PCB29-pQ), relevant to exposure with mammary cancer metastasis. Multiple lines of evidence illustrated that PCB29-pQ induces breast cancer invasion and migration. In particular, this appearance is associated with a two-fold elevation of matrix metalloproteinases-2/-9 (MMP-2/-9) and extracellular nuclear factor kappa B (NF-κB), respectively. Our results clearly demonstrated the translocation of cytosolic NF-κB into the nucleus by a factor of about 2.4. We also revealed the activation of corresponding upstream signaling cascades phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K)/Akt and p38 and extracellular regulated protein kinases (ERK) mitogen-activated protein kinase (MAPK) by factors of 3.15, 3.09 and 1.69, respectively. Moreover, there was a marked induction of reactive oxygen species (ROS) after a PCB29-pQ challenge and antioxidant treatment that markedly inhibited PCB29-pQ-mediated activation of these axis signaling. Collectively, our result suggested that PCB29-pQ induces breast cancer metastasis via ROS-dependent NF-κB-MMP signaling.
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http://dx.doi.org/10.1021/acs.chemrestox.8b00148DOI Listing
September 2018

Influence of Waveform Characteristics on LiDAR Ranging Accuracy and Precision.

Sensors (Basel) 2018 Apr 10;18(4). Epub 2018 Apr 10.

School of Instrumentation Science and Opto-Electronics Engineering, Beihang University, Beijing 100191, China.

Time of flight (TOF) based light detection and ranging (LiDAR) is a technology for calculating distance between start/stop signals of time of flight. In lab-built LiDAR, two ranging systems for measuring flying time between start/stop signals include time-to-digital converter (TDC) that counts time between trigger signals and analog-to-digital converter (ADC) that processes the sampled start/stop pulses waveform for time estimation. We study the influence of waveform characteristics on range accuracy and precision of two kinds of ranging system. Comparing waveform based ranging (WR) with analog discrete return system based ranging (AR), a peak detection method (WR-PK) shows the best ranging performance because of less execution time, high ranging accuracy, and stable precision. Based on a novel statistic mathematical method maximal information coefficient (MIC), WR-PK precision has a high linear relationship with the received pulse width standard deviation. Thus keeping the received pulse width of measuring a constant distance as stable as possible can improve ranging precision.
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http://dx.doi.org/10.3390/s18041156DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5948876PMC
April 2018

Influence of Time-Pickoff Circuit Parameters on LiDAR Range Precision.

Sensors (Basel) 2017 Oct 17;17(10). Epub 2017 Oct 17.

School of Instrument Science and Opto-Electronic Engineering, Beihang University, Beijing 100191, China.

A pulsed time-of-flight (TOF) measurement-based Light Detection and Ranging (LiDAR) system is more effective for medium-long range distances. As a key ranging unit, a time-pickoff circuit based on automatic gain control (AGC) and constant fraction discriminator (CFD) is designed to reduce the walk error and the timing jitter for obtaining the accurate time interval. Compared with Cramer-Rao lower bound (CRLB) and the estimation of the timing jitter, four parameters-based Monte Carlo simulations are established to show how the range precision is influenced by the parameters, including pulse amplitude, pulse width, attenuation fraction and delay time of the CFD. Experiments were carried out to verify the relationship between the range precision and three of the parameters, exclusing pulse width. It can be concluded that two parameters of the ranging circuit (attenuation fraction and delay time) were selected according to the ranging performance of the minimum pulse amplitude. The attenuation fraction should be selected in the range from 0.2 to 0.6 to achieve high range precision. The selection criterion of the time-pickoff circuit parameters is helpful for the ranging circuit design of TOF LiDAR system.
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http://dx.doi.org/10.3390/s17102369DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5677387PMC
October 2017

Discovery of highly potent, selective, covalent inhibitors of JAK3.

Bioorg Med Chem Lett 2017 10 11;27(20):4622-4625. Epub 2017 Sep 11.

Bristol-Myers Squibb Research and Development, Princeton, NJ 08543-4000, USA.

A useful and novel set of tool molecules have been identified which bind irreversibly to the JAK3 active site cysteine residue. The design was based on crystal structure information and a comparative study of several electrophilic warheads.
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http://dx.doi.org/10.1016/j.bmcl.2017.09.023DOI Listing
October 2017

Discovery of pyrrolo[1,2-b]pyridazine-3-carboxamides as Janus kinase (JAK) inhibitors.

Bioorg Med Chem Lett 2014 Dec 24;24(24):5721-5726. Epub 2014 Oct 24.

Research and Development, Bristol-Myers Squibb Company, Princeton, NJ 08543-4000, USA. Electronic address:

A new class of Janus kinase (JAK) inhibitors was discovered using a rationally designed pyrrolo[1,2-b]pyridazine-3-carboxamide scaffold. Preliminary studies identified (R)-(2,2-dimethylcyclopentyl)amine as a preferred C4 substituent on the pyrrolopyridazine core (3b). Incorporation of amino group to 3-position of the cyclopentane ring resulted in a series of JAK3 inhibitors (4g-4j) that potently inhibited IFNγ production in an IL2-induced whole blood assay and displayed high functional selectivity for JAK3-JAK1 pathway relative to JAK2. Further modifications led to the discovery of an orally bioavailable (2-fluoro-2-methylcyclopentyl)amino analogue 5g which is a nanomolar inhibitor of both JAK3 and TYK2, functionally selective for the JAK3-JAK1 pathway versus JAK2, and active in a human whole blood assay.
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http://dx.doi.org/10.1016/j.bmcl.2014.10.061DOI Listing
December 2014

Dimethyl-diphenyl-propanamide derivatives as nonsteroidal dissociated glucocorticoid receptor agonists.

J Med Chem 2010 Dec 12;53(23):8241-51. Epub 2010 Nov 12.

Bristol-Myers Squibb Company, Research and Development, Princeton, New Jersey 08543-4000, United States.

A series of 2,2-dimethyl-3,3-diphenyl-propanamides as novel glucocorticoid receptor modulators is reported. SAR exploration led to the identification of 4-hydroxyphenyl propanamide derivatives displaying good agonist activity in GR-mediated transrepression assays and reduced agonist activity in GR-mediated transactivation assays. Compounds 17 and 30 showed anti-inflammatory activity comparable to prednisolone in the rat carrageenan-induced paw edema model, with markedly decreased side effects with regard to increases in blood glucose and expression of hepatic tyrosine aminotransferase. A hypothetical binding mode accounting for the induction of the functional activity by a 4-hydroxyl group is proposed.
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http://dx.doi.org/10.1021/jm100957aDOI Listing
December 2010

Discovery of novel dihydro-9,10-ethano-anthracene carboxamides as glucocorticoid receptor modulators.

Bioorg Med Chem Lett 2009 Apr 9;19(8):2139-43. Epub 2009 Mar 9.

Department of Discovery Chemistry, Bristol-Myers Squibb, Research and Development, Princeton, NJ 08543, USA.

A series of dihydro-9,10-ethano-anthracene-11-carboxamides as novel glucocorticoid receptor modulators is reported. SAR exploration identified compounds from this series displaying a promising dissociation profile in discriminating between transrepression and transactivation activities. 17a is a partial agonist of GR-mediated transactivation which elicits potent and efficacious transrepression in reporter gene assays. A hypothetical binding mode is provided which accounts for the induction of functional activity by a bridgehead methyl group.
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http://dx.doi.org/10.1016/j.bmcl.2009.03.006DOI Listing
April 2009

In vitro microbiological characterization of a novel azalide, two triamilides and an azalide ketal against bovine and porcine respiratory pathogens.

J Antibiot (Tokyo) 2004 Apr;57(4):280-8

Pfizer Global Research & Development, Pfizer Inc, Groton, CT 06340, USA.

Several novel 15-membered-ring macrolide agents (azalide 1, triamilides 2 and 3, and the azalide 3,6-ketal 4) were identified as potential antibacterial agents against Mannheimia (formerly named as Pasteurella) haemolytica, Pasteurella multocida, Haemophilus somnus and Actinobacillus pleuropneumoniae, important etiological agents of bovine and porcine respiratory disease. Compound 3 is the major component of the antibiotic tulathromycin. Antibacterial activity against tilmicosin-resistant P. multocida field isolates was also tested. In vitro MIC 50/90 analysis revealed that the four newly synthesized compounds were more potent than tilmicosin against M. haemolytica (4 to approximately 8x), P. multocida (8 to approximately 16x), A. pleuropneumoniae (4x), H. somnus (2x and 16x), and tilmicosin-resistant P. multocida (32x). In time-kill kinetic studies, all four novel compounds and tilmicosin showed bactericidal activity against M. haemolytica, P. multocida and A. pleuropneumoniae at both 4x and 8x MIC. A functional assay using genetically defined mutants revealed that all four novel compounds were poorer substrates for the efflux pump, AcrA/B system, than tilmicosin. A pH study using LPS mutants indicated that the enhanced in vitro potency of the triamilides, particularly compound 3 was mainly due to better penetration of the molecule through the outer membrane. The third amine group at the C-4'' position of the triamilde molecules contributed to this increased membrane penetration by increasing overall basicity. These studies indicate that the four novel compounds have potential as antibacterial agents against bovine and porcine respiratory disease.
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http://dx.doi.org/10.7164/antibiotics.57.280DOI Listing
April 2004

Synthesis, stereochemical assignment and biological activity of a novel series of C-4" modified aza-macrolides.

Bioorg Med Chem Lett 2003 Jun;13(12):1955-8

Pfizer Global Research and Development, Groton Laboratories, Eastern Point Road, Groton, CT 06340, USA.

Modification of the cladinose C-4" position via manipulation of the corresponding keto derivatives afforded two stereochemically pure series of compounds. The synthesis and structure determination of these compounds is described within. The in vitro and in vivo biological activity of this novel series of C-4" modified macrolides is also described.
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http://dx.doi.org/10.1016/s0960-894x(03)00358-5DOI Listing
June 2003