Publications by authors named "Xuetao Wei"

43 Publications

Integrated proteomic analysis to explore the molecular regulation mechanism of IL-33 mRNA increased by black carbon in the human endothelial cell line EA.hy926.

Environ Toxicol 2022 Jul 1. Epub 2022 Jul 1.

Department of Toxicology, School of Public Health, Peking University, Beijing, People's Republic of China.

Black carbon (BC) correlates with the occurrence and progression of atherosclerosis and other cardiovascular diseases. Increasing evidence has demonstrated that BC could impair vascular endothelial cells, but the underlying mechanisms remain obscure. It is known that IL-33 exerts a significant biological role in cardiovascular disease, but little is known about the molecular regulation of IL-33 expression at present. We first found that BC significantly increased IL-33 mRNA in EA.hy926 cells in a concentration and time-dependent manner, and we conducted this study to explore its underlying mechanism. We identified that BC induced mitochondrial damage and suppressed autophagy function in EA.hy926 cells, as evidenced by elevation of the aspartate aminotransferase (GOT2), reactive oxygen species (ROS) and p62, and the reduction of mitochondrial membrane potential (ΔΨm). However, ROS cannot induce IL-33 mRNA-production in BC-exposed EA.hy926 cells. Further, experiments revealed that BC could promote IL-33 mRNA production through the PI3K/Akt/AP-1 and p38/AP-1 signaling pathways. It is concluded that BC could induce oxidative stress and suppress autophagy function in endothelial cells. This study also provided evidence that the pro-cardiovascular-diseases properties of BC may be due to its ability to stimulate the PI3K/AKT/AP-1 and p38/AP-1 pathway, further activate IL-33 and ultimately result in a local vascular inflammation.
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http://dx.doi.org/10.1002/tox.23608DOI Listing
July 2022

Exploration of potential mechanism of interleukin-33 up-regulation caused by 1,4-naphthoquinone black carbon in RAW264.7 cells.

Sci Total Environ 2022 Aug 19;835:155357. Epub 2022 Apr 19.

Department of Toxicology, School of Public Health, Peking University, Beijing 100191, PR China; Beijing Key Laboratory of Toxicological Research and Risk Assessment for Food Safety, Beijing 100191, PR China. Electronic address:

Background: As air pollution has been paid more attention to by public in recent years, effects and mechanism in particulate matter-triggered health problems become a focus of research. Lysosomes and mitochondria play an important role in regulation of inflammation. Interleukin-33 (IL-33) has been proved to promote inflammation in our previous studies. In this research, macrophage cell line RAW264.7 was used to explore the potential mechanism of upregulation of IL-33 induced by 1,4-naphthoquinone black carbon (1,4-NQ-BC), and to explore changes of lysosomes and mitochondria during the process.

Results: 50 μg/mL 1,4-NQ-BC exposure for 24 h dramatically increased expression of IL-33 in RAW264.7 cells. Lysosomal membrane permeability was damaged by 1,4-NQ-BC treatment, and higher mitochondrial membrane potential and ROS level were induced by 1,4-NQ-BC. The results of proteomics suggested that expression of ferritin light chain was increased after cells were challenged with 1,4-NQ-BC, and it was verified by Western blot. Meanwhile, expressions of p62 and LC3B-II were increased by 50 μg/mL 1,4-NQ-BC in RAW264.7 cells. Ultimately, expression of IL-33 could return to same level as control in cells treated with 50 μg/mL 1,4-NQ-BC and 50 μM deferoxamine combined.

Conclusions: 1,4-NQ-BC induces IL-33 upregulation in RAW264.7 cells, and it is responsible for higher lysosomal membrane permeability and ROS level, lower mitochondrial membrane potential, and inhibition of autophagy. Ferritin light chain possibly plays an important role in the upregulation of IL-33 evoked by 1,4-NQ-BC.
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http://dx.doi.org/10.1016/j.scitotenv.2022.155357DOI Listing
August 2022

Associations of maternal exposure to fine particulate matter with preterm and early-term birth in high-risk pregnant women.

Genes Environ 2022 Mar 15;44(1). Epub 2022 Mar 15.

School of Public Health, Peking University, 100191, Beijing, China.

Background: Environmental pollution is a risk factor for adverse birth outcomes, especially preterm birth (PTB) and early-term birth (ETB). It has been revealed that exposure to fine particulate matter (PM) during pregnancy increase the prevalence of PTB. However, the relationship between PM exposure and ETB has not been elucidated. In high-risk pregnancies, whether PM exposure will bring higher risk of PTB and ETB than in normal pregnancies is still unclear, and the susceptible exposure window is obscure. Therefore, it is worthy of assessing the risk on PTB and ETB and identifying the susceptible exposure windows of PM exposure in high-risk pregnant women.

Results: This paper collected the clinical data of 7974 singletons, high-risk pregnant women in Peking University First Hospital from 2014 to 2018, and analyzed them using logistic regression and stratified analysis. We observed that exposure to high-level (≥ 75 µg/m) of PM during the third trimester of pregnancy increases the risk of PTB and ETB (PTB: odds ratio[OR] = 1.43, 95% confidence interval [CI]:1.05-1.93. ETB: OR = 1.29, 95%CI: 1.09-1.54). Furthermore, the effects of each 10ug/m increase in PM on PTB and ETB were significant during the third trimester (PTB: OR = 1.35, 95%CI:1.16-1.58. ETB: OR = 1.12, 95%CI:1.02-1.22) and the entire pregnancy (PTB: OR = 6.12, 95%CI:4.27-8.89. ETB: OR = 1.96, 95%CI:1.59-2.43) in the high-level exposure group.

Conclusions: These results suggest that high-level PM exposure during pregnancy is associated with high risk of PTB and ETB in high-risk pregnancies. The third trimester of pregnancy is speculated to be the susceptible exposure window.
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http://dx.doi.org/10.1186/s41021-022-00239-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8922917PMC
March 2022

Effects of acylated and nonacylated anthocyanins extracts on gut metabolites and microbiota in diabetic Zucker rats: A metabolomic and metagenomic study.

Food Res Int 2022 03 7;153:110978. Epub 2022 Feb 7.

Food Chemistry and Food Development, Department of Life Technologies, University of Turku, FI-20014 Turun yliopisto, Finland. Electronic address:

Anthocyanins have been shown to have prebiotic properties. This study investigated the impact of nonacylated anthocyanins and acylated anthocyanins on fecal and cecal metabolites and colonic gut microbiota in diabetic state using H nuclear magnetic resonance (NMR) metabolomics and metagenomic sequencing. Zucker diabetic fatty rats fed with high-fat diet were gavaged with nonacylated anthocyanins extracted from bilberries (NAAB) or acylated anthocyanins extracted from purple potatoes (AAPP) at daily doses of 25 and 50 mg/kg body weight for 8 weeks. Lean Zucker rats fed with normal diet (ND) and high-fat diet (Con) were used as healthy controls groups. Binned NMR spectra and sequenced gene abundance were used for data analysis. Dysbiosis of colonic microbiota and gut metabolites in the diabetic rats were observed compared to the lean Zucker rats. Both anthocyanin extracts increased cecal sugar levels and the abundance of Peptostreptococcaceae sp. and decreased the abundance of Parabacteroides spp. in colon. In addition to the increased fecal short-chain fatty acids, AAPP decreased colonic Ruminococcus torques and Lachnospiraceae bacterium 4_1_37FAA abundances and increased oxidative phosphorylation. The anthocyanin extracts modulated the gut metabolism and microbiota in diabetes, with AAPP showing more regulatory and beneficial effects on diabetes.
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http://dx.doi.org/10.1016/j.foodres.2022.110978DOI Listing
March 2022

Effects of intrauterine and lactational exposure to lanthanum nitrate on BALB/c offspring mice: Developmental immunotoxicity and self-recovery.

Toxicol Lett 2022 Jun 25;362:17-25. Epub 2022 Jan 25.

Department of Toxicology, School of Public Health, Peking University, Beijing, 100191, PR China; Beijing Key Laboratory of Toxicological Research and Risk Assessment for Food Safety, Beijing, 100191, PR China. Electronic address:

Lanthanum, a major rare earth element, can exert detrimental effects on the adult immune system, but its developmental immunotoxicity (DIT) remains obscure. This study was designed to evaluate the DIT of lanthanum nitrate (LN) and the self-recovery of LN-induced DIT 21 days following cessation of exposure. BALB/c pregnant dams were exposed to 0, 0.1, 1, and 10 mg/kg body weight/day LN by gavage during gestation and lactation. Results showed that in male offspring, LN markedly inhibited the adaptive immunity at postanal day 21 (PND21) and the inhibitory effect on cellular immunity continued to PND42 (after three weeks of self-recovery). In female offspring, LN suppressed cellular immunity at both PND21 and PND42. Moreover, decreased relative organ weight of thymus, humoral immunity and proportion of double-positive T cells in thymus were also observed at PND42. Bcl-xl protein level decreased in thymus of female at PND42, while the level of β-catenin increased. These changes might contribute to accelerating the degeneration and weight loss of thymus. Overall, in-utero and postanal exposure to LN could induce impairments of immunity in offspring, especially the female, and adaptive immunosuppression would persist throughout development into adulthood. The LOAEL of LN for DIT should be 1 mg/kg.
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http://dx.doi.org/10.1016/j.toxlet.2022.01.013DOI Listing
June 2022

DNA damage, serum metabolomic alteration and carcinogenic risk associated with low-level air pollution.

Environ Pollut 2022 Mar 5;297:118763. Epub 2022 Jan 5.

Department of Occupational and Environmental Health Sciences, School of Public Health, Peking University, Beijing, 100083, China. Electronic address:

Outdoor air pollution has been classified as carcinogenic to humans (Group 1) for lung cancer, but the underlying mechanism and key toxic components remain incompletely understood. Since DNA damage and metabolite alterations are associated with cancer progression, exploring potential mechanisms linking air pollution and cancer might be meaningful. In this study, a real-time ambient air exposure system was established to simulate the real-world environment of adult male SD rats in Beijing from June 13th, 2018, to October 8th, 2018. 8-OHdG in the urine, γ-H2AX in the lungs and mtDNA copy number in the peripheral blood were analyzed to explore DNA damage at different levels. Serum non-targeted metabolomics analysis was performed. Pair-wise spearman was used to explore the correlation between DNA damage biomarkers and serum differential metabolites. Carcinogenic risks of heavy metals and PAHs via inhalation were assessed according to US EPA guidelines. Results showed that PM and O were the major air pollutants in the exposure group and not detected in the control group. Compared with control group, higher levels of 8-OHdG, mtDNA copy number, γ-H2AX and PCNA-positive nuclei cells were observed in the exposure group. Histopathological evaluation suggested ambient air induced alveolar wall thickening and inflammatory cell infiltration in lungs. Perturbed metabolic pathways identified included glycolysis/gluconeogenesis metabolism, purine and pyrimidine metabolism, etc. γ-H2AX was positively correlated with serum ADP, 3-phospho-D-glyceroyl phosphate and N-acetyl-D-glucosamine. The BaPeq was 0.120 ng/m. Risks of Cr(VI), As, V, BaP, BaA and BbF were above 1 × 10. We concluded that low-level air pollution was associated with DNA damage and serum metabolomic alterations in rats. Cr(VI) and BaP were identified as key carcinogenic components in PM. Our results provided experimental evidence for hazard identification and risk assessment of low-level air pollution.
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http://dx.doi.org/10.1016/j.envpol.2021.118763DOI Listing
March 2022

Effects of 4-nonylphenol on adipogenesis in 3T3-L1 preadipocytes and C3H/10T1/2 mesenchymal stem cells.

J Appl Toxicol 2022 04 22;42(4):588-599. Epub 2021 Sep 22.

Department of Toxicology, School of Public Health, Beijing Key Laboratory of Toxicological Research and Risk Assessment for Food Safety, Peking University, Beijing, China.

Obesogens are a subset of endocrine disruptor chemicals (EDCs) that cause obesity. The typical EDC 4-nonylphenol (4-NP) has been identified as an obesogen. However, the in vitro effects of 4-NP on adipogenesis remain unclear. In this study, 3T3-L1 preadipocytes and C3H/10T1/2 mesenchymal stem cells (MSCs) were used to investigate the influence of 4-NP on adipogenesis. The differentiation protocols for 3T3-L1 preadipocytes and C3H/10T1/2 MSCs took 8 and 12 days, respectively, beginning at Day 0. In differentiated 3T3-L1 preadipocytes, 20 μM 4-NP decreased cell viability on Days 4 and 8. Exposure to 4-NP inhibited triglyceride (TG) accumulation and adipogenic marker expression on Days 0-8, but the inhibitory effects were weaker on Days 2-8. The protein expression of pSTAT3 or STAT3 decreased on Days 0-8 and 2-8. Conversely, 4-NP promoted TG accumulation and the adipogenic marker expression in C3H/10T1/2 adipocytes. The opposing effects were attributed to physiological differences between the two cell lines. The 3T3-L1 preadipocytes are dependent on mitotic clonal expansion (MCE) to drive differentiation, while C3H/10T1/2MSCs and human preadipocytes are not. Additionally, 4-NP downregulated β-catenin expression in C3H/10T1/2 adipocytes. Accordingly, we hypothesized that 4-NP promotes adipogenesis. The role of the canonical Wnt pathway in the promotion of adipogenesis by 4-NP requires further validation. This study provides new insights into the mechanisms and appropriate risk management of 4-NP.
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http://dx.doi.org/10.1002/jat.4241DOI Listing
April 2022

H NMR Metabolomics and Full-Length RNA-Seq Reveal Effects of Acylated and Nonacylated Anthocyanins on Hepatic Metabolites and Gene Expression in Zucker Diabetic Fatty Rats.

J Agric Food Chem 2021 Apr 9;69(15):4423-4437. Epub 2021 Apr 9.

Food Chemistry and Food Development, Department of Life Technologies, University of Turku, FI-20014 Turun yliopisto, Finland.

Anthocyanins have been reported to possess antidiabetic effects. Recent studies indicate acylated anthocyanins have better stability and antioxidative activity compared to their nonacylated counterparts. This study compared the effects of nonacylated and acylated anthocyanins on hepatic gene expression and metabolic profile in diabetic rats, using full-length transcriptomics and H NMR metabolomics. Zucker diabetic fatty (ZDF) rats were fed with nonacylated anthocyanin extract from bilberries (NAAB) or acylated anthocyanin extract from purple potatoes (AAPP) at daily doses of 25 and 50 mg/kg body weight for 8 weeks. Both anthocyanin extracts restored the levels of multiple metabolites (glucose, lactate, alanine, and pyruvate) and expression of genes (, , , and ) involved in glycolysis and gluconeogenesis. AAPP decreased the hepatic glutamine level. NAAB regulated the expression of , , and , whereas AAPP modified the expression of , , , and . This study indicated different effects of AAPP and NAAB on the hepatic transcriptomic and metabolic profiles of diabetic rats.
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http://dx.doi.org/10.1021/acs.jafc.1c00130DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8154569PMC
April 2021

BC and 1,4NQ-BC up-regulate the cytokines and enhance IL-33 expression in LPS pretreatment of human bronchial epithelial cells.

Environ Pollut 2021 Jan 14;273:116452. Epub 2021 Jan 14.

Department of Toxicology, School of Public Health, Peking University, Beijing, 100191, PR China; Beijing Key Laboratory of Toxicological Research and Risk Assessment for Food Safety, Beijing, 100191, PR China. Electronic address:

Black carbon (BC) reacts with different substances to form secondary pollutants called aged black carbon, which causes inflammation and lung damage. BC and aged BC may enhance IL-33 in vivo, which may be derived from macrophages. The pro-inflammatory effect of IL-33 makes it essential to determine the source of IL-33, so it guides us to explore how to alleviate lung injury. In this study, a human bronchial epithelial cell line of 16HBE cells was selected, and aged BC (1,4-NQ coated BC and ozone oxidized BC) was used. We found that both BC and aged BC were able to up-regulate the mRNA expression of IL-1β, IL-6, and IL-8 except IL-33. However, the Mitogen-activated protein kinases (MAPKs) and Phosphatidylinositol 3-kinase (PI3K)/Protein kinase B (AKTs) pathways remained inactive. After pretreatment with Lipopolysaccharide (LPS), IL-33 mRNA expression was significantly increased in 16HBE cells and MAPKs and PI3K/AKT were activated. These results suggested that MAPKs and PI3K/AKT pathways were involved in the elevation of IL-33. Furthermore, epithelial cells are unlikely to be the source of lung inflammation caused by elevated IL-33 in BC and aged BC.
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http://dx.doi.org/10.1016/j.envpol.2021.116452DOI Listing
January 2021

Antidepressant Effect of Blue Light on Depressive Phenotype in Light-Deprived Male Rats.

J Neuropathol Exp Neurol 2020 12;79(12):1344-1353

From the Department of Toxicology, School of Public Health, Peking University.

Blue light has been previously reported to play a salient role in the treatment of seasonal affective disorder. The present study aimed to investigate whether blue light had antidepressant effect on light-deprivation-induced depression model, and the underlying visual neural mechanism. Blue light mitigated depression-like behaviors induced by light deprivation as measured by elevated sucrose preference and reduced immobility time. Blue light enhanced melanopsin expression and light responses in the retina. We also found the upregulation of serotonin and brain derived neurotrophic factor expression in the c-fos-positive areas of rats treated with blue light compared with those maintained in darkness. The species gap between nocturnal albino (Sprague-Dawley rat) and diurnal pigmented animals (human) might have influenced extrapolating data to humans. Blue light has antidepressant effect on light-deprived Sprague-Dawley rats, which might be related to activating the serotonergic system and neurotrophic activity via the retinoraphe and retinoamygdala pathways. Blue light is the effective component of light therapy for treatment of depression.
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http://dx.doi.org/10.1093/jnen/nlaa143DOI Listing
December 2020

Effects of Anthocyanin Extracts from Bilberry ( L.) and Purple Potato ( L. var. 'Synkeä Sakari') on the Plasma Metabolomic Profile of Zucker Diabetic Fatty Rats.

J Agric Food Chem 2020 Sep 20;68(35):9436-9450. Epub 2020 Aug 20.

Food Chemistry and Food Development, Department of Biochemistry, University of Turku, Turun yliopisto, Turku FI-20014, Finland.

This study compared the effects of the nonacylated and acylated anthocyanin-rich extracts on plasma metabolic profiles of Zucker diabetic fatty rats. The rats were fed with the nonacylated anthocyanin extract from bilberries (NAAB) or the acylated anthocyanin extract from purple potatoes (AAPP) at daily doses of 25 and 50 mg/kg body weight for 8 weeks. H NMR metabolomics was used to study the changes in plasma metabolites. A reduced fasting plasma glucose level was seen in all anthocyanin-fed groups, especially in the groups fed with NAAB. Both NAAB and AAPP decreased the levels of branched-chain amino acids and improved lipid profiles. AAPP increased the glutamine/glutamate ratio and decreased the levels of glycerol and metabolites involved in glycolysis, suggesting improved insulin sensitivity, gluconeogenesis, and glycolysis. AAPP decreased the hepatic and messenger RNA level, suggesting regulation of gluconeogenesis and lipogenesis. This study indicated that AAPP and NAAB affected the plasma metabolic profile of diabetic rats differently.
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http://dx.doi.org/10.1021/acs.jafc.0c04125DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7586333PMC
September 2020

1,4NQ-BC enhances the lung inflammation by mediating the secretion of IL-33 which derived from macrophages.

Environ Pollut 2020 Oct 11;265(Pt A):114729. Epub 2020 Jun 11.

Department of Toxicology, School of Public Health, Peking University, Beijing, 100191, PR China; Beijing Key Laboratory of Toxicological Research and Risk Assessment for Food Safety, Beijing, 100191, PR China. Electronic address:

Black carbon (BC) is a product of incomplete combustion of fossil fuels and vegetation. The compelling evidence has demonstrated that it has a close relationship with several respiratory and cardiovascular diseases. BC provides the reactive sites and surfaces to absorb various chemicals, such as polycyclic aromatic hydrocarbons (PAH). Naphthoquinone is a typical PAHs which was found in particulate matter (PM) and 1,4NQ-BC owned high oxidative potential and cytotoxicity. IL-33 is an alarmin which increases innate immunity through Th2 responses. It was reported that IL-33 was a potent inducer of pro-inflammatory cytokines, like IL-6. In our previous study, it was revealed that 1,4NQ-BC instilled intratracheally to mice could trigger the lung inflammation and stimulate the secretion of IL-33 in lung tissue. We found that IL-33 could induce inflammation in lung itself. When the macrophages were eliminated, the secretion of IL-33 was reduced and the pathological damage in the lung was relieved after exposure to 1,4NQ-BC. Both MAPK and PI3K/AKT signal pathways were involved in the process of IL-33 secretion and the lung inflammation induced by 1,4NQ-BC. The findings herein support the notion that after exposure to 1,4NQ-BC, the increased secretion of IL-33 was mainly derived from macrophages through both MAPK and PI3K/AKT signal pathways.
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http://dx.doi.org/10.1016/j.envpol.2020.114729DOI Listing
October 2020

Effects of coal-fired PM on the expression levels of atherosclerosis-related proteins and the phosphorylation level of MAPK in ApoE mice.

BMC Pharmacol Toxicol 2020 05 8;21(1):34. Epub 2020 May 8.

Department of Toxicology, School of Public Health, Peking University Health Science Center, No.38 XueYuan Road, HaiDian District, Beijing, 100191, People's Republic of China.

Background: Air pollution increases the morbidity and mortality of cardiovascular disease (CVD). Atherosclerosis (AS) is the pathological basis of most CVD, and the progression of atherosclerosis and the increase of fragile plaque rupture are the mechanism basis of the relationship between atmospheric particulate pollution and CVD. The aim of the present study was to investigate the effects of coal-fired fine particulate matter (PM) on the expression levels of atherosclerosis-related proteins (von Willebrand factor (vWF), Endothelin-1 (ET-1), intercellular adhesion molecule-1 (ICAM-1), and E-selectin, and to explore the role and mechanism of the progression of atherosclerosis induced by coal-fired PM via the mitogen-activated protein kinase (MAPK) signaling pathways.

Methods: Different concentrations of PM were given to apolipoprotein-E knockout (ApoE) mice via intratracheal instillation for 8 weeks. Enzyme-linked immunosorbent assay (ELISA) was used to detect the levels of vWF, ET-1 in serum of mice. Immunohistochemistry was used to observe the expression and distribution of ICAM-1 and E-selectin in the aorta of mice. Western blot was used to investigate the phosphoylation of proteins relevant to MAPK signaling pathways.

Results: Coal-fired PM exacerbated atherosclerosis induced by a high-fat diet. Fibrous cap formation, foam cells accumulation, and atherosclerotic lesions were observed in the aortas of PM-treated mice. Coal-fired PM increased the protein levels of ET-1, ICAM-1, and E-selectin, but there was no significant difference in the vWF levels between the PM-treatment mice and the HFD control mice. Coal-fired PM promoted the phosphorylation of p38, c-Jun N-terminal kinase (JNK), extracellular signal-regulated kinase (ERK) in aortic tissues of mice.

Conclusion: Coal-derived PM exacerbated the formation of atherosclerosis in mice, increased the expression levels of atherosclerosis-related proteins in mice serum, and promoted the phosphorylation of proteins relevant to MAPK signaling pathway. Thus, MAPK signaling pathway may play a role in the atherosclerosis pathogenesis induced by Coal-derived PM.
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http://dx.doi.org/10.1186/s40360-020-00411-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7206822PMC
May 2020

Galactooligosaccharides protects against DSS-induced murine colitis through regulating intestinal flora and inhibiting NF-κB pathway.

Life Sci 2020 Feb 24;242:117220. Epub 2019 Dec 24.

Department of Toxicology, School of Public Health, Peking University, Beijing 100191, PR China; Beijing Key Laboratory of Toxicological Research and Risk Assessment for Food Safety, Beijing 100191, PR China. Electronic address:

Background/aims: Previous studies have demonstrated that Galactooligosaccharides (GOS), known as "bifidus factor", has anti-inflammatory effects. Colitis, a kind of colonic inflammatory damage could be induced by different chemicals. The pathogenesis and mechanism of colitis remains unclear, and may be related to intestinal microflora, genetic susceptibility or immune factors. The aim is to explore the effects of GOS on intestinal flora and its anti-inflammatory effects in Dextran Sulfate Sodium (DSS) induced murine colitis and extrapolate the underlying mechanism.

Main Methods: Initially, 5% DSS was used to induced colitis by free access to drinking water for 5-7 days. Then the mice were treated with GOS 1 day after DSS treatment. Colon samples were evaluated grossly using a microscope. The percentage of Treg and Th17 cells was analyzed by flow cytometry. The levels of cytokines secretion and mRNA expression were detected by ELISA and real-time PCR. The level of protein was detected by western blot.

Key Findings: GOS attenuated DSS induced body weight loss and also reduced the increase in disease index caused by DSS. GOS ameliorated DSS induced colonic histological damage. The protective effect of GOS on DSS induced colitis may be partly attributed to intestinal flora regulation and Th17/Treg imbalance. Furthermore, GOS markedly decreased cytokines (IL-6, IL-18, IL-13 and IL-33) secretion and mRNA expression in colon tissues, through inhibiting activation of NF-κB pathways.

Significance: GOS could prevent the DSS induced colitis through intestinal flora regulation and reduce the secretion of inflammation related cytokines relying on the NF-κB signaling pathway.
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http://dx.doi.org/10.1016/j.lfs.2019.117220DOI Listing
February 2020

The critical role for TAK1 in trichloroethylene-induced contact hypersensitivity in vivo and in CD4 T cell function alteration by trichloroethylene and its metabolites in vitro.

Toxicol Appl Pharmacol 2019 10 7;380:114705. Epub 2019 Aug 7.

Department of Toxicology, School of Public Health, Peking University, Beijing 100191, China; Beijing Key Laboratory of Toxicological Research and Risk Assessment for Food Safety, Beijing 100191, China. Electronic address:

Occupational exposure to trichloroethylene (TCE) has been associated with severe, generalized contact hypersensitivity (CHS) skin disorder, which is considered a delayed-type hypersensitivity reaction mediated by antigen-specific T cells. Transforming growth factor-β activated kinase-1 (TAK1) is essential for regulating the development and effector function of T cells. We hypothesized that disrupting TAK1 activity might inhibit TCE-induced CHS response. In this study, a local lymph node assay was employed to build a CHS model induced by TCE combined with the inducible-TAK1 deletion system to study the effect of TAK1 on it. It was observed that TAK1 deficiency ameliorated the TCE-induced CHS response and was associated with defective T cell expansion and activation and IFN-γ production in vivo. Furthermore, we investigated the effects of TCE and its metabolites trichloroacetic acid (TCA) and dichloroacetic acid (DCA) on CD4 T cell function and the effect of TAK1 on it in vitro. The results showed that TCE, TCA and DCA augmented the proliferation, activation and differentiation of CD4 T cells through Jnk MAPK and NF-κB pathways. TAK1 deletion significantly attenuated these effects induced by TCE, TCA or DCA on CD4 T cells. In conclusion, it is suggested that TAK1 plays a critical role both in TCE-induced CHS response in vivo and in TCE and its metabolite-induced CD4 T cell activation in vitro. Local inhibition of TAK1 might offer a promising alternative feasible strategy for TCE-induced CHS.
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http://dx.doi.org/10.1016/j.taap.2019.114705DOI Listing
October 2019

TAK1 knock-down in macrophage alleviate lung inflammation induced by black carbon and aged black carbon.

Environ Pollut 2019 Oct 3;253:507-515. Epub 2019 Jul 3.

Department of Toxicology, School of Public Health, Peking University, Beijing, 100191, PR China; Beijing Key Laboratory of Toxicological Research and Risk Assessment for Food Safety, Beijing, 100191, PR China. Electronic address:

Black carbon (BC) can combine with organic matter and form secondary pollutants known as aged BC. BC and aged BC can cause respiratory system inflammation and induce lesions at relevant sites, but the underlying mechanism has remained unknown. To gain insight into the potential mechanisms, we focused on macrophages and transforming growth factor β-activated kinase 1 (TAK1) which are a crucial factor in inflammation. Our research aims to determine the role of TAK1 in macrophages in pulmonary inflammation induced by particulate matter. In this study, BC and 1,4-naphthoquinone were mixed to model aged BC (1,4NQ-BC) in atmosphere. BC induced mice lung inflammation model, lung macrophage knock-down TAK1 animal model and primary macrophage knock-down TAK1 model were used to explore whether TAK1 in macrophage is a critical role in the process of inflammation. The results showed that the expressions of inflammatory cytokines (IL-1β, IL-6, IL-33) mRNA were significantly increased and the phosphorylation of MAPK and NF-κB signaling pathway related proteins were enhanced in RAW 264.7 cell lines. In vivo studies revealed that the indicators of pulmonary inflammation (pathology, inflammatory cell numbers) and related cytokines (IL-1β, IL-6, IL-33) mRNA expressions in CD11c-Map3k7 animals were significantly lower than wild-type animals after mice were instilled particles. In mice primary macrophages, the expressions of IL-6, IL-33 mRNA were inhibited after TAK1 gene was knock-down. These results unequivocally demonstrated that TAK1 plays a crucial role in BC induced lung inflammation in mice, and we can infer that BC and 1,4NQ-BC cause these inflammatory responses by stimulating pulmonary macrophages.
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http://dx.doi.org/10.1016/j.envpol.2019.06.096DOI Listing
October 2019

Effects of bisphenol A on gap junctions in HaCaT cells as mediated by the estrogen receptor pathway.

J Appl Toxicol 2019 02 6;39(2):271-281. Epub 2018 Sep 6.

Department of Toxicology, School of Public Health, Peking University, Beijing Key Laboratory of Toxicological Research and Risk Assessment for Food Safety, Beijing, 100191, China.

Bisphenol A (BPA) is widely used as the raw material for the production of plastics and paper products. People can be exposed to BPA through dermal contact, particularly for cashiers in contact with thermal paper every day. BPA is a known endocrine disruptor that has been shown to be carcinogenic. Many tumors show weak gap junctional intercellular communication (GJIC) function. The aim of this study was to investigate the effects and possible mechanisms of BPA's action on GJIC of human HaCaT skin cells. The results showed that BPA increased cell proliferation rates, prolonged GJIC photobleaching fluorescence recovery times and reduced overall fluorescence recovery rates at 0.01, 0.1 and 1 μm. BPA downregulated connexin (Cx)26 mRNA level at 0.1 μm. Estrogen receptor (ER) antagonist ICI 182 780 at 5 nm partially blocked the above effects of BPA indicating involvement of the ER pathway with BPA exposure. However, BPA did not influence Cx43 mRNA and protein levels. Our immunofluorescence data showed that Cx26 was expressed in the cytoplasm and plasma membrane, and was involved in the formation of gap junctions between adjacent cells, while Cx43 was expressed only in the cytoplasm. Therefore, our data indicate that Cx26 gap junctions may be involved in the GJIC inhibition caused by BPA. In conclusion, our results indicate that BPA can promote human skin cell proliferation, inhibit skin cell GJIC function but not formation and downregulate Cx26 mRNA levels partially through the ER pathway. We hypothesize that BPA can exhibit carcinogenicity by inhibiting GJIC.
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http://dx.doi.org/10.1002/jat.3717DOI Listing
February 2019

Black carbon particles and ozone-oxidized black carbon particles induced lung damage in mice through an interleukin-33 dependent pathway.

Sci Total Environ 2018 Dec 5;644:217-228. Epub 2018 Jul 5.

Department of Toxicology, School of Public Health, Peking University, Beijing 100191, PR China; Beijing Key Laboratory of Toxicological Research and Risk Assessment for Food Safety, Beijing 100191, PR China. Electronic address:

Black carbon (BC) is a key component of atmospheric particles which has adverse effects on human health. Oxidation could lead to chemical property and toxicity potency changes of BC. The key cytokines participating in lung damage in mice induced by BC and ozone-oxidized BC (oBC) particles have been investigated in this study. It was concluded that oBC has stronger potency of inducing lung damage in mice comparing to BC. IL-6 and IL-33 were hypothesized to play important roles in this damage. Accordingly, IL-6 and IL-33 neutralizing antibodies were used to explore which cytokine might play a key role in lung inflammation induced by BC and oBC. As a result, IL-6 neutralizing antibody did not alleviate the lung damage induced by BC and oBC. However, IL-33 neutralizing antibody prevented BC and oBC induced lung damage. Furthermore, IL-33 neutralizing antibody treatment reduced IL-6 mRNA expression. It is hypothesized that MAPK and PI3K-AKT pathways might be involved in the oBC particles caused lung damage. It was concluded that IL-33 plays a key role in BC and oBC induced lung damage in mice.
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http://dx.doi.org/10.1016/j.scitotenv.2018.06.329DOI Listing
December 2018

Corrigendum to "The research of genetic toxicity of β-phellandrene" [Environ. Toxicol. Pharmacol. 54 (2017) 28-33].

Environ Toxicol Pharmacol 2018 07 28;61:116. Epub 2018 May 28.

Department of Toxicology, School of Public Health, Peking University, Beijing, 100191, PR China; Beijing Key Laboratory of Toxicological Research and Risk Assessment for Food Safety, Beijing, 100191, PR China. Electronic address:

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http://dx.doi.org/10.1016/j.etap.2018.05.005DOI Listing
July 2018

Blue light filtered white light induces depression-like responses and temporary spatial learning deficits in rats.

Photochem Photobiol Sci 2018 Apr;17(4):386-394

Department of Toxicology, School of Public Health, Peking University, 38 Xue Yuan Road, Haidian District, Beijing 100191, China.

Objectives: Ambient light has a vital impact on mood and cognitive functions. Blue light has been previously reported to play a salient role in the antidepressant effect via melanopsin. Whether blue light filtered white light (BFW) affects mood and cognitive functions remains unclear. The present study aimed to investigate whether BFW led to depression-like symptoms and cognitive deficits including spatial learning and memory abilities in rats, and whether they were associated with the light-responsive function in retinal explants.

Methods: Male Sprague-Dawley albino rats were randomly divided into 2 groups (n = 10) and treated with a white light-emitting diode (LED) light source and BFW light source, respectively, under a standard 12 : 12 h L/D condition over 30 days. The sucrose consumption test, forced swim test (FST) and the level of plasma corticosterone (CORT) were employed to evaluate depression-like symptoms in rats. Cognitive functions were assessed by the Morris water maze (MWM) test. A multi-electrode array (MEA) system was utilized to measure electro-retinogram (ERG) responses induced by white or BFW flashes.

Results: The effect of BFW over 30 days on depression-like responses in rats was indicated by decreased sucrose consumption in the sucrose consumption test, an increased immobility time in the FST and an elevated level of plasma CORT. BFW led to temporary spatial learning deficits in rats, which was evidenced by prolonged escape latency and swimming distances in the spatial navigation test. However, no changes were observed in the short memory ability of rats treated with BFW. The micro-ERG results showed a delayed implicit time and reduced amplitudes evoked by BFW flashes compared to the white flash group.

Conclusions: BFW induces depression-like symptoms and temporary spatial learning deficits in rats, which might be closely related to the impairment of light-evoked output signals in the retina.
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http://dx.doi.org/10.1039/c7pp00271hDOI Listing
April 2018

Augmentation of fracture healing by hydroxyapatite/collagen paste and bone morphogenetic protein-2 evaluated using a rat femur osteotomy model.

J Orthop Res 2018 01 31;36(1):129-137. Epub 2017 Jul 31.

Department of Orthopaedic and Spinal Surgery, Graduate School, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8519, Japan.

In fracture treatment, biological bone union generally depends on the bone's natural fracture healing capacity, even in surgically treated cases. Hydroxyapatite/collagen composite (HAp/Col) has high osteoconductivity and stimulates osteogenic progenitors. Furthermore, it has the potent capacity to adsorb bone morphogenetic proteins (BMPs). In this study, we prepared an injectable HAp/Col paste and evaluated its augmentation of bone union. Furthermore, the effect of HAp/Col paste combined with BMP-2 was also evaluated. We used a rat femur osteotomy model with a defect size of 1 mm. Male Wistar rats were assigned to one of the following four groups; a control group without any implant, a HAp/Col implant group, a group that received an absorbable collagen sponge (ACS) implant impregnated with BMP-2 (1 μg), and a group that received a HAp/Col implant impregnated with BMP-2 implant. Micro-CT analysis, three-point bending tests, and histological evaluation were performed. Bone union was achieved in two of eight cases in the HAp/Col group, five of eight cases in the ACS + BMP-2 group, and all cases in the HAp/Col + BMP-2 group at 8 weeks post-surgery. The control group did not achieve bone union. In addition, in the HAp/Col + BMP-2 group, the biomechanical strength of the fused femurs was comparable to that of the contralateral intact femur; the ratio of the mechanical load at the breaking point of the osteotomy side relative to that of the contralateral side was 1.00 ± 0.151 (SD). These results indicate that HAp/Col paste with or without BMP-2 augments bone union. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:129-137, 2018.
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http://dx.doi.org/10.1002/jor.23646DOI Listing
January 2018

The research of genetic toxicity of β-phellandrene.

Environ Toxicol Pharmacol 2017 Sep 20;54:28-33. Epub 2017 Jun 20.

Department of Toxicology, School of Public Health, Peking University, Beijing, 100191, PR China; Beijing Key Laboratory of Toxicological Research and Risk Assessment for Food Safety, Beijing, 100191, PR China. Electronic address:

β-Phellandrene, a plant extract, can be used as natural pesticides and synthetic materials. As a factor that human may be exposed to, the toxicity information about β-phellandrene is scared at present. This study focused on the genetic toxicity of β-phellandrene. The genetic toxicity of β-phellandrene was evaluated by micronucleus test, comet assay, Ames test, and chromosomal aberration test. In this study, 2850, 1425, 712.5mg/kg β-phellandrene were used in vivo experiments (comet assay and micronucleus test). For Ames test, pure β-phellandrene and different concentrations were used in the experiment. According to the results of cell viability assay (MTT test), the concentration of chromosomal aberration test was formulated. The result of comet assay showed that β-phellandrene can significantly induce DNA damage at the dosage of 1425 and 2850mg/kg. While the results of Micronucleus test and chromosome aberration test showed that β-phellandrene does not lead to apparently genetic toxicity on chromosome level. Ames tests suggest that β-phellandrene had the ability to increase gene mutation with or without S9 mixture. So, it could be drawn that β-phellandrene would have certain genetic toxicity, and the toxicity is reflected as DNA strand breaks and mutation. This study filled the lack of genetic toxicity study of β-phellandrene, and enriched information for risk assessment for β-phellandrene.
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http://dx.doi.org/10.1016/j.etap.2017.06.011DOI Listing
September 2017

Comparison of lung damage in mice exposed to black carbon particles and 1,4-naphthoquinone coated black carbon particles.

Sci Total Environ 2017 Feb 27;580:572-581. Epub 2016 Dec 27.

Department of Toxicology, School of Public Health, Peking University, Beijing, 100191, PR China; Beijing Key Laboratory of Toxicological Research and Risk Assessment for Food Safety, Beijing, 100191, PR China. Electronic address:

Black carbon (BC) is a key component of atmospheric particles and has a significant effect on human health. BC can provide reactive sites and surfaces thus absorb quinones which were primarily generated from fossil fuel combustion and/or atmospheric photochemical conversions of PAHs. Oxidation could change the characteristics of BC and increase its toxicity. The comparison of lung damage in mice exposed to BC and 1,4-NQ-coated BC (1,4NQ-BC) particles is investigated in this study. Mice which were intratracheally instilled with particles have a higher expression of IL-1β, IL-6 and IL-33 in bronchoalveolar lavage fluid (BALF). Also, the IL-6, IL-33 mRNA expression in the lung tissue of mice instilled with 1,4NQ-BC were higher than that of mice instilled with BC. The pathology results showed that the lung tissue of mice instilled with 1,4NQ-BC particles have much more inflammatory cells infiltration than that of mice treated with BC. It is believed that the MAPK and PI3K-AKT pathway might be involved in the 1,4NQ-BC particles caused lung damage. Results indicated that 1,4NQ-BC particles in the atmosphere may cause more damage to health.
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http://dx.doi.org/10.1016/j.scitotenv.2016.11.214DOI Listing
February 2017

The effect of ethephon on immune system in male offspring of mice.

Environ Toxicol Pharmacol 2017 Jan 12;49:119-123. Epub 2016 Dec 12.

Department of Toxicology, School of Public Health, Peking University, 100191, PR China; Beijing Key Laboratory of Toxicological Research and Risk Assessment for Food Safety, Beijing 100191, PR China. Electronic address:

Ethephon can liberate ethylene which could interfere the plant growth process. The aim of the present study was to determine the effect of ethephon on developing immune system of male offspring. Ethephon could enhance NK cell activity in male mice. For 4-week-old male mice, lymphocytes of peripheral blood increased while the hemolytic plaque number decreased. Delayed type hypersensitivity(DTH) was inhibited in all groups. The expression of protein Bcl11b and p-p38 in thymus of treatment groups were lower than control group. Our results indicated that cellular immunity of male offspring is more sensitive to ethephon when exposed in pregnancy and lactation period. It should be emphasized that exposure to ethephon during the in utero stage and lactation stage still could damage the immune function of animal in the period before fully mature even in the dosage that could not influence the immune function of adult animal.
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http://dx.doi.org/10.1016/j.etap.2016.12.007DOI Listing
January 2017

Comparison of lung damage in mice exposed to black carbon particles and ozone-oxidized black carbon particles.

Sci Total Environ 2016 Dec 26;573:303-312. Epub 2016 Aug 26.

Department of Toxicology, School of Public Health, Peking University, Beijing 100191, PR China; Beijing Key Laboratory of Toxicological Research and Risk Assessment for Food Safety, Beijing 100191, PR China. Electronic address:

Black carbon (BC) is a key component of atmospheric particles and has a significant effect on human health. Oxidation could change the characteristics of BC and increase its toxicity. The comparison of lung damage in mice exposed to BC and ozone-oxidized BC (oBC) particles is investigated in this study. Mice which were intratracheally instilled with particles have a higher expression of IL-1β, IL-6 and IL-33 in bronchoalveolar lavage fluid (BALF). Also, the IL-6, IL-33 mRNA expression in the lung tissue of mice instilled with oBC was higher than that of mice instilled with BC. The expression of CD3 in the lung tissue of mice intratracheally instilled with oBC was higher than the mice distilled with BC. The pathology results showed that the lung tissue of mice instilled with oBC particles have much more inflammatory cells infiltration than that of mice treated with BC. It is believed that the PI3K-AKT pathway might be involved in the oBC particles caused lung damage. Results indicated that oBC particles in the atmosphere may cause more damage to health.
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http://dx.doi.org/10.1016/j.scitotenv.2016.08.137DOI Listing
December 2016

MAP4K4 deficiency in CD4(+) T cells aggravates lung damage induced by ozone-oxidized black carbon particles.

Environ Toxicol Pharmacol 2016 Sep 3;46:246-254. Epub 2016 Aug 3.

Department of Toxicology, School of Public Health, Peking University, Beijing, 100191, PR China; Beijing Key Laboratory of Toxicological Research and Risk Assessment for Food Safety, Beijing, 100191, PR China. Electronic address:

As the main composition of combustion, black carbon (BC) is becoming more and more noticeable at home and abroad. Ozone-oxidized black carbon (oBC) was produced through aging of ozone, one of the near-surface pollutants, to black carbon. And oBC was found to be more oxidation and cell toxicity when compared with BC. Besides, as a key cell of immunity, whether CD4(+) T cell would involve in lung inflammation induced by particular matter is still unclear. This study aims to observe the effect of oBC on lung damage in mice and discuss how the functional MAP4K4 defect CD4(+) T cells (conditional knockout of MAP4K4) presents its role in this process. In our study, MAP4K4 deletion in CD4(+) T cells (MAP4K4 cKO) could increase cell number of macrophages, lymphocytes and neutrophils in bronchoalveolar lavage fluid (BALF) exposed to oBC. MAP4K4 deletion in CD4(+) T cell also affected CD4(+) T cell differentiation in mediastinal lymph nodes after oBC stimulation. The number of CD4(+) IL17(+) T cell increased obviously. The levels of IL-6 mRNA of lung in MAP4K4 cKO mice was higher than that in wild type mice after exposed to oBC, while the level of IL-6 in BALF had the same trend. Histological examination showed that MAP4K4 deletion in CD4(+) T cells affected lung inflammation induced by oBC. Results indicated that MAP4K4 cKO in CD4(+) T cells upgraded the level of inflammation in lung when exposed to oBC, which may be connected to the CD4(+) T cell differentiation and JNK, ERK and P38 pathways.
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http://dx.doi.org/10.1016/j.etap.2016.08.006DOI Listing
September 2016

Lack of TAK1 in dendritic cells inhibits the contact hypersensitivity response induced by trichloroethylene in local lymph node assay.

Toxicol Appl Pharmacol 2016 09 27;307:72-80. Epub 2016 Jul 27.

Department of Toxicology, School of Public Health, Peking University, Beijing 100191, China; Beijing Key Laboratory of Toxicological Research and Risk Assessment for Food Safety, Beijing 100191, China. Electronic address:

Trichloroethylene (TCE) is a ubiquitous environmental contaminant. Occupational TCE exposure has been associated with severe, generalized contact hypersensitivity (CHS) skin disorder. The development of CHS depends on innate and adaptive immune functions. Transforming growth factor-β activated kinase-1 (TAK1) controls the survival of dendritic cells (DCs) that affect the immune system homeostasis. We aimed to investigate the role of TAK1 activity in DC on TCE-induced CHS response. Control mice and DC-specific TAK1 deletion mice were treated with 80% (v/v) TCE using local lymph node assay (LLNA) to establish a TCE-induced CHS model. The draining lymph nodes (DLNs) were excised and the lymphocytes were measure for proliferation by BrdU-ELISA, T-cell phenotype analysis by flow cytometry and signaling pathway activation by western blot. The ears were harvested for histopathological analysis. Control mice in the 80% TCE group displayed an inflammatory response in the ears, increased lymphocyte proliferation, elevated regulatory T-cell and activated T-cell percentages, and more IFN-γ producing CD8(+) T cells in DLNs. In contrast to control mice, DC-specific TAK1 deletion mice in the 80% TCE group showed an abolished CHS response and this was associated with defective T-cell expansion, activation and IFN-γ production. This effect may occur through Jnk and NF-κB signaling pathways. Overall, this study demonstrates a pivotal role of TAK1 in DCs in controlling TCE-induced CHS response and suggests that targeting TAK1 function in DCs may be a viable approach to preventing and treating TCE-related occupational health hazards.
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http://dx.doi.org/10.1016/j.taap.2016.07.019DOI Listing
September 2016

TAK1 deficiency in dendritic cells inhibits adaptive immunity in SRBC-immunized C57BL/6 mice.

FEBS Open Bio 2016 Jun 21;6(6):548-57. Epub 2016 Apr 21.

Department of ToxicologySchool of Public HealthPeking UniversityBeijingChina; Beijing Key Laboratory of Toxicological Research and Risk Assessment for Food SafetyBeijingChina.

Dendritic cells (DCs) are important in the initiation of primary T-cell responses, while transforming growth factor-β (TGF-β)-activated kinase 1 (TAK1) is a critical regulator of DC survival and homeostasis. This study evaluated the T-cell dependent antibody response (TDAR) to sheep red blood cells (SRBC) on a DC-specific TAK1-deficient mice model. The results showed that TAK1 deficiency in DCs significantly suppressed the humoral and cellular immune response in mice. DC-specific TAK1 deletion impaired splenic T-cell population and conventional DCs, abolished the cytokine production of splenic T cells and down-regulated some functional gene expression in the spleen. Collectively, this study suggests that TAK1 plays an essential role in the development of the humoral immune response.
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http://dx.doi.org/10.1002/2211-5463.12062DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4887970PMC
June 2016

Grape-seed proanthocyanidins inhibit the lipopolysaccharide-induced inflammatory mediator expression in RAW264.7 macrophages by suppressing MAPK and NF-κb signal pathways.

Environ Toxicol Pharmacol 2016 Jan 7;41:159-66. Epub 2015 Dec 7.

Department of Toxicology, School of Public Health, Peking University, Beijing Key Laboratory of Toxicological Research and Risk Assessment for Food Safety, Beijing 100191, PR China. Electronic address:

Grape-seed proanthocyanidins (GSPs) have been shown to function as an anti-oxidant and anti-inflammatory agent with little toxicity in vivo and in vitro. However, little is known about their anti-inflammatory properties and mechanisms of action. The specific focus being its effects on the MAP kinases and nuclear factor-kappaB (NF-κB) signal transduction pathways in lipopolysaccharide (LPS) -stimulated RAW264.7 cells. GSPs extract has been found to suppress the mRNA expression of pro-inflammatory cytokines like tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β) and inflammatory molecule of cyclooxygenase-2 (COX-2) while mRNA level of IL-10 was greatly promoted. Furthermore, GSPs extract inhibited the expression of phosphorylated ERK, JNK and P38, as well as phosphorylated IKKα/β and NF-κB p65 subunit. In conclusion, our results show that GSPs extract showed its anti-inflammatory and immunomodulatory properties by suppressing the activation of MAP kinases and NF-κB signal transduction pathways.
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http://dx.doi.org/10.1016/j.etap.2015.11.018DOI Listing
January 2016

A novel JAK-STAT inhibitor, 2-[(3-Carbamoyl-2-thienyl)amino]-2-oxoethyl(2,6-dichlorophenyl)acetate, suppresses helper T cell differentiation in vitro and collagen-induced arthritis in vivo.

Biochem Biophys Res Commun 2015 Dec 10;468(4):766-73. Epub 2015 Nov 10.

Department of Microbiology and Immunology, Keio University School of Medicine, Shinjuku-ku, Tokyo 160-8582, Japan. Electronic address:

Th17 cells, which have been implicated in autoimmune diseases including rheumatoid arthritis (RA), require the JAK-STAT3 pathway for their differentiation and functions. Recently, JAK inhibitors have been developed as a therapeutic drug for RA. However, the current JAK inhibitors are not optimized to STAT3 compared with other STATs. In this study, we found a new lead compound of a small molecule JAK-STAT inhibitor, 2-[(3-Carbamoyl-2-thienyl)amino]-2-oxoethyl (2,6-dichlorophenyl)acetate, which inhibits STAT3 as efficiently as other STATs. This compound, named JI069, was selected by STAT3 reporter assay in combination with an in silico docking model. JI069 inhibited gp130 signaling by inducing dissociation between gp130 and JAK1. In HEK293T cells and primary T cells, JI069 suppressed STAT3 activation as efficiently as other STATs, including STAT1, STAT5, and STAT6. JI069 effectively suppressed Th1, Th2, and Th17 differentiation while strongly promoted iTreg differentiation. JI069 suppressed symptoms of the collagen-induced arthritis (CIA) model in mice, and inhibited the cytokine production from T cells as well as the STAT3 phosphorylation of synovial cells. These data suggest that JI069 is a new type of JAK inhibitor which has potential for the treatment of immunological disorders.
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http://dx.doi.org/10.1016/j.bbrc.2015.11.030DOI Listing
December 2015
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