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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.
Mostrar más [+] Menos [-]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.
Mostrar más [+] Menos [-]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.
Mostrar más [+] Menos [-]Biomass-related PM2.5 induces mitochondrial fragmentation and dysfunction in human airway epithelial cells
2022
Gao, Mi | Liang, Chunxiao | Hong, Wei | Yu, Xiaoyuan | Zhou, Yumin | Sun, Ruiting | Li, Haiqing | Huang, Haichao | Gan, Xuhong | Yuan, Ze | Zhang, Jiahuan | Chen, Juan | Mo, Qiudi | Wang, Luyao | Lin, Biting | Li, Bing | Ran, Pixin
The use of biomass for cooking and heating is considered an important factor associated with chronic obstructive pulmonary disease (COPD), but few studies have previously addressed its underlying mechanisms. Therefore, this research aimed to evaluate the effects of biomass-related PM₂.₅ (BRPM₂.₅) exposure on 16HBE human airway epithelial cells and in mice with regard to mitochondrial dysfunction. Our study indicated that BRPM₂.₅ exposure of 16HBE cells resulted in mitochondrial dysfunction, including decreased mitochondrial membrane potential, increased expression of fission proteins-phospho-DRP1, increased mitochondrial ROS (mtROS), and decreased levels of ATP. BRPM₂.₅ altered the mitochondrial metabolism of 16HBE cells by decreasing mitochondrial oxygen consumption and glycolysis. However, Mitochondria targeted peptide SS-31 eliminated mitochondrial ROS and alleviated the ATP deficiency and proinflammatory cytokines release. BRPM2.5 exposure resulted in abnormal mitochondrial morphological alterations both in 16HBE and in lung tissue. Taken together, these results suggest that BRPM₂.₅ has detrimental effects on human airway epithelial cells, leading to mitochondrial dysfunction, abnormal mitochondrial metabolism and altered mitochondrial dynamics. The present study provides the first evidence that disruption of mitochondrial structure and mitochondrial metabolism may be one of the mechanisms of BRPM₂.₅-induced respiratory dysfunction.
Mostrar más [+] Menos [-]Enhanced removal of sulfur-containing organic pollutants from actual wastewater by biofilm reactor: Insights of sulfur transformation and bacterial metabolic traits
2022
Zhang, Wei | Wu, Yang | Wu, Jing | Zheng, Xiong | Chen, Yinguang
Sulfur-containing organic pollutants in wastewater could threaten human health due to their high malodor and toxicity, and their conversion processes are more complex than inorganic sulfur compounds. Membrane aerated biofilm reactor (MABR), as a novel and environmentally-friendly biofilm-based technology, is able to remove inorganic sulfur in synthetic wastewater. However, it is unknown how sulfur-containing organic pollutants in actual wastewater are transformed in MABR system. This work demonstrated the feasibility of MABR to eliminate sulfur-containing organic pollutants in actual wastewater, and the removal efficiency could be reached at approximately 100%. Meanwhile, over 70% of sulfur-containing organic contaminants were transformed to SO₄²⁻ during the long-term operation. Further analysis indicated that the functional bacteria that participated in sulfur transformation and carbohydrates degradation (e.g., Chujaibacter, Microscillaceaesp., and Thiobacillus) were evidently enriched when treating actual wastewater. Moreover, the critical metabolic pathways (e.g., sulfur metabolism, glycolysis metabolism, and pyruvate metabolism), and the corresponding genetic expressions (e.g., nrrA, tauA, tauC, sorA, and SUOX) were evidently up-regulated during long-term operation, which was beneficial for the transformation of sulfur-containing organic pollutants in actual wastewater by MABR. This work would expand the application of MABR for treating the actual sulfur-containing organic wastewater and provide an in-depth understanding of the organic sulfur transformation in MABR.
Mostrar más [+] Menos [-]Oxygen sensors mediated HIF-1α accumulation and translocation: A pivotal mechanism of fine particles-exacerbated myocardial hypoxia injury
2022
Zhang, Ze | Wu, Liu | Cui, Tenglong | Ahmed, Rifat Zubair | Yu, Haiyi | Zhang, Rong | Wei, Yanhong | Li, Daochuan | Zheng, Yuxin | Chen, Wen | Jin, Xiaoting
Epidemiological studies have demonstrated a strong association of ambient fine particulate matter (PM₂.₅) exposure with the increasing mortality by ischemic heart disease (IHD), but the involved mechanisms remain poorly understood. Herein, we found that the chronic exposure of real ambient PM₂.₅ led to the upregulation of hypoxia-inducible factor-1 alpha (HIF-1α) protein in the myocardium of mice, accompanied by obvious myocardial injury and hypertrophy. Further data from the hypoxia-ischemia cellular model indicated that PM₂.₅-induced HIF-1α accumulation was responsible for the promotion of myocardial hypoxia injury. Moreover, the declined ATP level due to the HIF-1α-mediated energy metabolism remodeling from β-oxidation to glycolysis had a critical role in the PM₂.₅-increased myocardial hypoxia injury. The in-depth analysis delineated that PM₂.₅ exposure decreased the binding of prolyl hydroxylase domain 2 (PHD2) and HIF-1α and subsequent ubiquitin protease levels, thereby leading to the accumulation of HIF-1α. Meanwhile, factor-inhibiting HIF1 (FIH1) expression was down-regulated by PM₂.₅, resulting in the enhanced translocation of HIF-1α to the nucleus. Overall, our study provides valuable insight into the regulatory role of oxygen sensor-mediated HIF-1α stabilization and translocation in PM-exacerbated myocardial hypoxia injury, we suggest this adds significantly to understanding the mechanisms of haze particles-caused burden of cardiovascular disease.
Mostrar más [+] Menos [-]Influence of fuel oil on Platymonas helgolandica: An acute toxicity evaluation to amino acids
2021
Li, Na | Liu, Yu | Liang, Zhengyu | Lou, Yadi | Liu, Yuxin | Zhao, Xinda | Wang, Guoguang
It is highly likely that the toxicity of water accommodated fractions (WAF) will influence marine microalgae, and consequently lead to potential risk for the marine ecological environment. However, it was often neglected whether WAF can influence the transformation of relative compounds in organisms. The metabolism of amino acids (AAs) can be used to track physiological changes in microalgae because amino acids are the basis of proteins and enzymes. In this study, using marine Chlorophyta Platymonas helgolandica as the test organism, the effects of different concentrations of WAF on AA compositions and stable carbon isotope ratios (δ¹³C) of individual AAs of Platymonas helgolandica were investigated. The results showed that the WAF of #180 fuel oil had an obvious suppressing effect on the growth and chlorophyll a content of microalgae. The growth inhibitory rate at 96 h was 80.66% at a WAF concentration of 0.50 mg L⁻¹ compared with the control. Furthermore, seven among the 16 AAs, including alanine, cysteine, proline, aspartic acid, lysine, histidine and tyrosine, had relatively high abundance. Under the glycolysis pathway, the cysteine abundance was higher than control, meaning that the biosynthesized pathway of alanine through cysteine as a precursor could be damaged. Phosphoenolpyruvate (PEP) was an important synthesis precursor of alanine (leucine) and aromatic AA family (Phenylalanine and tyrosine), and played an important role in δ¹³CAAₛ fractionation under the WAF stress. Under the TCA pathway, to protect cell metabolism activities under WAF stress, the δ¹³C value of threonine and proline abundance in microalgae with the increase in WAF stress. Therefore, δ¹³CAAₛ fractionation can be used as a novel method for toxicity evaluation of WAF on future.
Mostrar más [+] Menos [-]Toxicities of three metal oxide nanoparticles to a marine microalga: Impacts on the motility and potential affecting mechanisms
2021
Du, Xueying | Zhou, Weishang | Zhang, Weixia | Sun, Shuge | Han, Yu | Tang, Yu | Shi, Wei | Liu, Guangxu
With the fast growth of the production and application of engineered nanomaterials (ENMs), nanoparticles (NPs) that escape into the environment have drawn increasing attention due to their ecotoxicological impacts. Motile microalgae are a type of primary producer in most ecosystems; however, the impacts of NPs on the motility of microalgae have not been studied yet. So the toxic impacts of three common metal oxide NPs (nTiO₂, nZnO, and nFe₂O₃) on swimming speed and locomotion mode of a marine microalgae, Platymonas subcordiformis, were investigated in this study. Our results demonstrated that both the velocity and linearity (LIN) of swimming were significantly decreased after the exposure of P. subcordiformis to the tested NPs. In addition, the obtained data indicate that NPs may suppress the motility of P. subcordiformis by constraining the energy available for swimming, as indicated by the significantly lower amounts of intracellular ATP and photosynthetic pigments and the lower activities of enzymes catalyzing glycolysis. Incubation of P. subcordiformis with the tested NPs generally resulted in the overproduction of reactive oxygen species (ROS), aggravation of lipid peroxidation, and induction of antioxidant enzyme activities, suggesting that imposing oxidative stress, which may impair the structural basis for swimming (i.e. the membrane of flagella), could be another reason for the observed motility suppression. Moreover, NP exposure led to significant reductions in the cell viability of P. subcordiformis, which may be due to the disruption of the energy supply (i.e., photosynthesis) and ROS-induced cellular damage. Our results indicate that waterborne NPs may pose a great threat to motile microalgae and subsequently to the health and stability of the marine ecosystem.
Mostrar más [+] Menos [-]Ammonium detoxification mechanism of ammonium-tolerant duckweed (Landoltia punctata) revealed by carbon and nitrogen metabolism under ammonium stress
2021
Tian, Xueping | Fang, Yang | Jin, Elaine | Yi, Zhuolin | Li, Jinmeng | Du, Anping | He, Kaize | Huang, Yuhong | Zhao, Hai
In this work, the ammonium-tolerant duckweed Landoltia punctata 0202 was used to study the effect of ammonium stress on carbon and nitrogen metabolism and elucidate the detoxification mechanism. The growth status, protein and starch content, and activity of nitrogen assimilation enzymes were determined, and the transcriptional levels of genes involved in ion transport and carbon and nitrogen metabolism were investigated. Under high ammonium stress, the duckweed growth was inhibited, especially when ammonium was the sole nitrogen source. Ammonium might mainly enter cells via low-affinity transporters. The stimulation of potassium transport genes suggested sufficient potassium acquisition, precluding cation deficiency. In addition, the up-regulation of ammonium assimilation and transamination indicated that excess ammonium could be incorporated into organic nitrogen. Furthermore, the starch content increased from 3.97% to 16.43% and 26.02% in the mixed-nitrogen and ammonium-nitrogen groups, respectively. And the up-regulated starch synthesis, degradation, and glycolysis processes indicated that the accumulated starch could provide sufficient carbon skeletons for excess ammonium assimilation. The findings of this study illustrated that the coordination of carbon and nitrogen metabolism played a vital role in the ammonium detoxification mechanism of duckweeds.
Mostrar más [+] Menos [-]Environmentally relevant methylmercury exposure reduces the metabolic scope of a model songbird
2019
Gerson, Alexander R. | Cristol, Daniel A. | Seewagen, Chad L.
For most birds, energy efficiency and conservation are paramount to balancing the competing demands of self-maintenance, reproduction, and other demanding life history stages. Yet the ability to maximize energy output for behaviors like predator escape and migration is often also critical. Environmental perturbations that affect energy metabolism may therefore have important consequences for fitness and survival. Methylmercury (MeHg) is a global pollutant that has wide-ranging impacts on physiological systems, but its effects on the metabolism of birds and other vertebrates are poorly understood. We investigated dose-dependent effects of dietary MeHg on the body composition, basal and peak metabolic rates (BMR, PMR), and respiratory quotients (RQ) of zebra finches (Taeniopygia guttata). Dietary exposure levels (0.0, 0.1, or 0.6 ppm wet weight) were intended to reflect a range of mercury concentrations found in invertebrate prey of songbirds in areas contaminated by atmospheric deposition or point-source pollution. We found adiposity increased with MeHg exposure. BMR also increased with exposure while PMR decreased, together resulting in reduced metabolic scope in both MeHg-exposed treatments. There were differences in RQ among treatments that suggested a compromised ability of exposed birds to rapidly metabolize carbohydrates during exercise in a hop-hover wheel. The elevated BMR of exposed birds may have been due to energetic costs of depurating MeHg, whereas the reduced PMR could have been due to reduced oxygen carrying capacity and/or reduced glycolytic capacity. Our results suggest that environmentally relevant mercury exposure is capable of compromising the ability of songbirds to both budget and rapidly exert energy.
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