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Результаты 1-10 из 44
GCN5-mediated PKM2 acetylation participates in benzene-induced hematotoxicity through regulating glycolysis and inflammation via p-Stat3/IL17A axis
2022
Zhang, Wei | Guo, Xiaoli | Ren, Jing | Chen, Yujiao | Wang, Jingyu | Gao, Ai
Benzene is a common environmental carcinogen that induces leukemia. Studies suggest that metabolic disorder has a relationship with the toxicity of benzene. Pyruvate kinase M2 (PKM2) is a key rate-limiting enzyme in glycolysis. However, the upstream and downstream regulatory mechanisms of PKM2 in benzene-induced hematotoxicity and the therapeutic effects of targeting PKM2 in vivo are unclear. This study aims to provide insights into the new mechanism of benzene-induced hematotoxicity and reveal the therapeutic significance of targeting PKM2. Herein, we demonstrated that PKM2-dependent glycolysis contributes to benzene-induced hematotoxicity by regulating inflammation reaction. Mechanistically, acetylated proteomics revealed that 1,4-benzoquinone (1,4-BQ) induced acetylation of PKM2 at position K66, and this modification contributed to the increase of PKM2 expression and can be inhibited by inhibition of acetyltransferase GCN5. Meanwhile, the elevated PKM2 was shown to prompt the activation of nuclear phosphorylated Stat3 (p-Stat3) and IL17A. Clinically, pharmacological inhibition of PKM2 alleviated the blood toxicity induced by benzene, which was mainly characterized by an increase in routine blood parameters and improvement of hematopoietic imbalance. Besides, elevated PKM2 is a promising biomarker in people occupationally exposed to benzene. Overall, we identified PKM2/p-Stat3/IL-17A axis participates in the hematotoxicity of benzene, and targeting PKM2 has certain therapeutic implications in hematologic diseases.
Показать больше [+] Меньше [-]Atrazine hinders PMA-induced neutrophil extracellular traps in carp via the promotion of apoptosis and inhibition of ROS burst, autophagy and glycolysis
2018
Wang, Shengchen | Zheng, Shufang | Zhang, Qiaojian | Yang, Zijiang | Yin, Kai | Xu, Shiwen
Atrazine (ATR), a selective herbicide, is consistently used worldwide and has been confirmed to be harmful to the health of aquatic organisms. The release of neutrophil extracellular traps (NETs) is one of the newly discovered antimicrobial mechanisms. Although several immune functions have been analyzed under ATR exposure, the effect of ATR on NETs remains mainly unexplored. In the present study, we treated carp neutrophils using 5 μg/ml ATR and 5 μg/ml ATR combined with 100 nM rapamycin to elucidate the underlying mechanisms and to clarify the effect of ATR on phorbol myristate acetate (PMA)-induced NETs. The results of the morphological observation and quantitative analysis of extracellular DNA and myeloperoxidase (MPO) showed that NETs formation were significantly inhibited by ATR exposure. Moreover, we found that in the NETs process, ATR downregulated the expression of the anti-apoptosis gene B-cell lymphoma-2 (Bcl-2), increased the expression of the pro-apoptosis factors Bcl-2-Associated X (BAX), cysteinyl aspartate specific proteinases (Caspase3, 9), and anti-autophagy factor mammalian target of rapamycin (mTOR), decreased the expression of autophagy-related protein light chain 3B (LC3B) and glucose transport proteins (GLUT1, 4), disturbed the activities of phosphofructokinase (PFK), pyruvate kinase (PKM), and hexokinase (HK) and limited reactive oxygen species (ROS) levels, indicating that the reduced NETs release was a consequence of increased apoptosis and diminished ROS burst, autophagy and down-regulated glycolysis under ATR treatment. Meanwhile, rapamycin restored the inhibited autophagy and glycolysis and thus resisted the ATR-suppressed NETs. The present study perfects the mechanism theory of ATR immunotoxicity to fish and has a certain value for human health risk assessment.
Показать больше [+] Меньше [-]Effects of naphthenic acid exposure on development and liver metabolic processes in anuran tadpoles
2013
Melvin, Steven D. | Lanctôt, Chantal M. | Craig, Paul M. | Moon, T. W. (Thomas W.) | Peru, Kerry M. | Headley, John V. | Trudeau, Vance L.
Naphthenic acids (NA) are used in a variety of commercial and industrial applications, and are primary toxic components of oil sands wastewater. We investigated developmental and metabolic responses of tadpoles exposed to sub-lethal concentrations of a commercial NA blend throughout development. We exposed Lithobates pipiens tadpoles to 1 and 2 mg/L NA for 75 days and monitored growth and development, condition factor, gonad and liver sizes, and levels of liver glucose, glycogen, lipids and cholesterol following exposure. NA decreased growth and development, significantly reduced glycogen stores and increased triglycerides, indicating disruption to processes associated with energy metabolism and hepatic glycolysis. Effects on liver function may explain reduced growth and delayed development observed in this and previous studies. Our data highlight the need for greater understanding of the mechanisms leading to hepatotoxicity in NA-exposed organisms, and indicate that strict guidelines may be needed for the release of NA into aquatic environments.
Показать больше [+] Меньше [-]Lactic acid bacteria induce phosphate recrystallization for the in situ remediation of uranium-contaminated topsoil: Principle and application
2022
He, Zhanfei | Dong, Lingfeng | Zhang, Keqing | Zhang, Daoyong | Pan, Xiangliang
Uranium (U) contamination often occurs in the topsoil (arable layer), and is a serious threat to crop growth. However, conventional microbial reduction methods are sensitive to oxygen and cannot be used to treat aerobic topsoils. In this study, phosphate-solubilizing microorganisms (PSM) were isolated from U-contaminated topsoil and used for soil remediation. Microbial metabolites and products were analyzed, and the pathways and mechanisms of PSM immobilization were revealed. The results showed that strain PSM8 had the highest phosphate-solubilizing capacity (dissolved P was 208 ± 5 mg/L) and the highest U removal rate (97.3 ± 0.1%). Multi-technical analyses indicated that bacterial surface functional groups adsorbed (UO₂)²⁺ ions on the cell surface, glycolysis produced 3–10 mg/L of lactic acid (pH 4.7–6.0), and lactic acid solubilized Ca₃(PO₄)₂ to form stable chernikovite (a type of uranyl phosphate) on the cell surface. The coupled application of Ca₃(PO₄)₂ and strain PSM8 significantly reduced the bioavailability of soil U (62 ± 11%), converting U from the exchangeable to the residual phase and P from the steady to the available form. In addition, pot experiments showed that soil remediation promoted crop growth and significantly reduced U uptake and toxicity to photosynthetic systems. These findings demonstrate that PSM and Ca₃(PO₄)₂ are good coupled fertilizers for U-contaminated agricultural soil.
Показать больше [+] Меньше [-]Traffic-related air pollution and endurance exercise: Characterizing non-targeted serum metabolomics profiling
2021
Cruz, Ramon | Pasqua, Leonardo | Silveira, André | Damasceno, Mayara | Matsuda, Monique | Martins, Marco | Marquezini, Mônica V. | Lima-Silva, Adriano Eduardo | Saldiva, Paulo H. N. (Paulo Hilário Nascimento) | Bertuzzi, Romulo
Although the exposure to traffic-related air pollution (TRAP) has emerged as one of main problem worldwide to inhabitants’ health in urban centers, its impact on metabolic responses during exercise is poorly understood. The aim of study was to characterize the profile of non-target serum metabolomics during prolonged exercise performed under TRAP conditions. Ten healthy men completed two 90 min constant-load cycling trials under conditions of either TRAP or filtered air. Experimental trials were performed in a chamber located on an avenue with a high volume of vehicle traffic. Blood samples were taken at 30 min, 60 min, and 90 min of exercise. Based on Nuclear Magnetic Resonance metabolomics, the non-target analysis was used to assess the metabolic profile. Twelve, 16 and 18 metabolites were identified as discriminants. These were: at 30 min of exercise, the coefficient of determination (R²) 0.98, the predictive relevance, (Q²) 0.12, and the area under the curve (AUC) 0.91. After 60 min of exercise: (R²: 0.99, Q²: 0.09, AUC: 0.94); and at 90 min of exercise (R²: 0.91, Q²: <0.01, AUC: 0.89), respectively. The discriminant metabolites were then considered for the target analysis, which demonstrated that the metabolic pathways of glycine and serine metabolism (p = 0.03) had been altered under TRAP conditions at 30 min of exercise; arginine and proline metabolism (p = 0.04) at 60 min of exercise; and glycolysis (p = 0.05) at 90 min of exercise. The present results suggest that exposure to TRAP during prolonged exercise leads to a significant change in metabolomics, characterized by a transitional pattern and lastly, impairs the glucose metabolism.
Показать больше [+] Меньше [-]Waterborne zinc bioaccumulation influences glucose metabolism in orange-spotted grouper embryos
2021
Zeng, Huiling | Zhang, Peifeng | Ye, Hengzhen | Ji, Yuxiang | Hogstrand, Christer | Green, Iain | Xiao, Juan | Fu, Qiongyao | Guo, Zhiqiang
Fish embryos, as an endogenous system, strictly regulate an energy metabolism that is particularly sensitive to environmental pressure. This study used orange-spotted grouper embryos and stable isotope ⁶⁷Zn to test the hypothesis that waterborne Zn exposure had a significant effect on energy metabolism in embryos. The fish embryos were exposed to a gradient level of waterborne ⁶⁷Zn, and then sampled to quantify ⁶⁷Zn bioaccumulation and mRNA expressions of key genes involved glucose metabolism. The results indicated that the bioaccumulated ⁶⁷Zn generally increased with increasing waterborne ⁶⁷Zn concentrations, while it tended to be saturated at waterborne ⁶⁷Zn > 0.7 mg L⁻¹. As we hypothesized, the expression of PK and PFK gene involved glycolysis pathway was significantly up-regulated under waterborne ⁶⁷Zn exposure >4 mg L⁻¹. Waterborne ⁶⁷Zn exposure >2 mg L⁻¹ significantly suppressed PCK and G6PC gene expression involved gluconeogenesis pathway, and also inhibited the AKT2, GSK-3beta and GLUT4 genes involved Akt signaling pathway. Our findings first characterized developmental stage-dependent Zn uptake and genotoxicity in fish embryos. We suggest fish embryos, as a small-scale modeling biosystem, have a large potential and wide applicability for determining cytotoxicity/genotoxicity of waterborne metal in aquatic ecosystem.
Показать больше [+] Меньше [-]Different effects of exposure to penconazole and its enantiomers on hepatic glycolipid metabolism of male mice
2020
Meng, Zhiyuan | Liu, Li | Xi, Yexun | Jia, Ming | Yan, Sen | Tian, Sinuo | Sun, Wei | Zhu, Wentao | Li, Xuefeng | Zhou, Zhiqiang
(±) - PEN is a chiral fungicide widely used to control powdery mildew in agriculture. Currently, only a few studies have investigated the toxic effects of (±) – penconazole ((±) – PEN) on non-target organisms, and whether (±) - PEN from the enantiomeric level have toxic effects remains unclear. In this study, we systematically evaluated the effects of exposure to (±) – PEN, (+) – PEN and (−) – PEN on liver function in mice. Biochemical and histopathological analyses showed that exposure to (±) – PEN and (−) – PEN led to significant liver damage and inflammation. However, exposure to (+) – PEN treatment did not cause no adverse effects on liver function and inflammation. ¹H-NMR-based metabolomics revealed that exposure to (±) – PEN, (+) – PEN and (−) – PEN led to the animals developing liver metabolic disorder that was caused by changes in glycolipid metabolism. Quantitative analysis of genes regulating glycolipid metabolism revealed that expression of gluconeogenesis and glycolytic pathway genes were altered in individuals exposed to (±) – PEN, (+) – PEN and (−) – PEN. We also found that (±) – PEN, (+) – PEN and (−) – PEN have different effects on lipid metabolism of the liver. Exposure to (±) – PEN and (−) – PEN resulted in significant accumulation of lipids by regulating fatty acid synthesis, triglyceride synthesis, and fatty acid β oxidation pathways. In summary, we found different toxicological effects in individuals exposed to (±) – PEN, (+) – PEN and (−) – PEN. The results of this study are important for assessing the potential health risks of (±) – PEN.
Показать больше [+] Меньше [-]Mitigation effects of CO2-driven ocean acidification on Cd toxicity to the marine diatom Skeletonema costatum
2020
Dong, Fang | Wang, Pu | Qian, Wei | Tang, Xing | Zhu, Xiaoshan | Wang, Zhenyu | Cai, Zhonghua | Wang, Jiangxin
Ocean acidification (OA) is a global problem to marine ecosystems. Cadmium (Cd) is a typical metal pollutant, which is non-essential but extremely toxic to marine organisms. The combined effects of marine pollution and climate-driven ocean changes should be considered for the effective marine ecosystem management of coastal areas. Previous reports have separately investigated the influences of OA and Cd pollution on marine organisms. However, little is known of the potential combined effects of OA and Cd pollution on marine diatoms. We investigated the sole and combined influences of OA (1500 ppm CO₂) and Cd exposure (0.4 and 1.2 mg/L) on the coastal diatom Skeletonema costatum. Our results clearly showed that OA significantly alleviated the toxicity of Cd to S. costatum growth and mitigated the oxidant stress, although the intercellular Cd accumulation still increased. OA partially rescued S. costatum from the inhibition of photosynthesis and pyruvate metabolism caused by Cd exposure. It also upregulated genes involved in gluconeogenesis, glycolysis, the citrate cycle (TCA), Ribonucleic acid (RNA) metabolism, and especially the biosynthesis of non-protein thiol compounds. These changes might contribute to algal growth and Cd resistance. Overall, this study demonstrates that OA can alleviate Cd toxicity to S. costatum and explores the potential underlying mechanisms at both the cellular and molecular levels. These results will ultimately help us understand the impacts of combined stresses of climate change and metal pollution on marine organisms and expand the knowledge of the ecological risks of OA.
Показать больше [+] Меньше [-]Critical biomarkers for myocardial damage by fine particulate matter: Focused on PPARα-regulated energy metabolism
2020
Zhang, Ze | Su, Huilan | Ahmed, Rifat Zubair | Zheng, Yuxin | Jin, Xiaoting
Fine particulate matter is one of the leading threats to cardiovascular health worldwide. The exploration of novel and sensitive biomarkers to detect damaging effect of fine particulate matter on cardiac tissues is of great importance in the better understanding of haze-caused myocardial injury. A link between heart failure and PPARα-regulated energy metabolism has been confirmed previously. Herein, the study intends to reveal the critical biomarkers of fine particulate matter induced myocardial damage from the PPARα-regulated energy metabolism. Ambient fine particulate matter induced severe pathological alterations in cultured cells, accompanied by the decrease in ATP content. Additionally, the expressions of CPT1/CPT2 and levels of CS and MDH, crucial members in β-oxidation and the TCA cycle, were significantly decreased. In direct contrast, fine particulate matter increased the biomarkers of glycolysis, as measured by the accumulation of pyruvate and lactate contents, and the enhanced activities of HK and PKM1/2. Importantly, fine particulate matter-exposed cardiomyocytes exhibited the reduced PPARα level, that increased when cardiomyocytes were co-incubation with WY-14643 and fine particulate matter. Simultaneously, the adverse impact of fine particulate matter on critical biomarkers were observed in β-oxidation, TCA cycle and glycolysis, associated with WY-14643 additional complement. Fine particulate matter caused the myocardial energy metabolism transformation through the regulation of PPARα expression and translation, which provided novel and critical biomarkers for haze particles-caused myocardial damage.
Показать больше [+] Меньше [-]A metabolomics strategy to assess the combined toxicity of polycyclic aromatic hydrocarbons (PAHs) and short-chain chlorinated paraffins (SCCPs)
2018
Wang, Feidi | Zhang, Haijun | Geng, Ningbo | Ren, Xiaoqian | Zhang, Baoqin | Gong, Yufeng | Chen, Jiping
The combined toxicity of mixed chemicals is usually evaluated according to several specific endpoints, and other potentially toxic effects are disregarded. In this study, we provided a metabolomics strategy to achieve a comprehensive understanding of toxicological interactions between mixed chemicals on metabolism. The metabolic changes were quantified by a pseudotargeted analysis, and the types of combined effects were quantitatively discriminated according to the calculation of metabolic effect level index (MELI). The metabolomics strategy was used to assess the combined effects of polycyclic aromatic hydrocarbons (PAHs) and short-chain chlorinated paraffins (SCCPs) on the metabolism of human hepatoma HepG2 cells. Our data suggested that exposure to a combination of PAHs and SCCPs at human internal exposure levels could result in an additive effect on the overall metabolism, whereas diverse joint effects were observed on various metabolic pathways. The combined exposure could induce a synergistic up-regulation of phospholipid metabolism, an additive up-regulation of fatty acid metabolism, an additive down-regulation of tricarboxylic acid cycle and glycolysis, and an antagonistic effect on purine metabolism. SCCPs in the mixture acted as the primary driver for the acceleration of phospholipid and fatty acid metabolism. Lipid metabolism disorder caused by exposure to a combination of PAHs and SCCPs should be an important concern for human health.
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