| 1. |
- Cao, Huiming, et al.
(författare)
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Effect of Enterohepatic Circulation on the Accumulation of Per- and Polyfluoroalkyl Substances : Evidence from Experimental and Computational Studies
- 2022
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Ingår i: Environmental Science and Technology. - : American Chemical Society (ACS). - 0013-936X .- 1520-5851. ; 56:5, s. 3214-3224
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Tidskriftsartikel (refereegranskat)abstract
- The pharmacokinetic characteristics of per- and polyfluoroalkyl substances (PFAS) affect their distribution and bioaccumulation in biological systems. The enterohepatic circulation leads to reabsorption of certain chemicals from bile back into blood and the liver and thus influences their elimination, yet its influence on PFAS bioaccumulation remains unclear. We explored the role of enterohepatic circulation in PFAS bioaccumulation by examining tissue distribution of various PFAS in wild fish and a rat model. Computational models were used to determine the reabsorbed fractions of PFAS by calculating binding affinities of PFAS for key transporter proteins of enterohepatic circulation. The results indicated that higher concentrations were observed in blood, the liver, and bile compared to other tissues for some PFAS in fish. Furthermore, exposure to a PFAS mixture on the rat model showed that the reabsorption phenomenon appeared during 8-12 h for most long-chain PFAS. Molecular docking calculations suggest that PFAS can bind to key transporter proteins via electrostatic and hydrophobic interactions. Further regression analysis adds support to the hypothesis that binding affinity of the apical sodium-dependent bile acid transporter is the most important variable to predict the human half-lives of PFAS. This study demonstrated the critical role of enterohepatic circulation in reabsorption, distribution, and accumulation of PFAS.
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| 2. |
- Cao, Huiming, et al.
(författare)
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Screening of Potential PFOS Alternatives To Decrease Liver Bioaccumulation : Experimental and Computational Approaches
- 2019
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Ingår i: Environmental Science and Technology. - : American Chemical Society (ACS). - 0013-936X .- 1520-5851. ; 53:5, s. 2811-2819
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Tidskriftsartikel (refereegranskat)abstract
- Perfluorooctanesulfonate (PFOS) is a persistent organic pollutant with significant bioaccumulation potential in liver tissues. Exposure to PFOS could cause increase of liver weight, induce adenomas of the liver, and cause hepatomegaly. Alternatives of PFOS might be designed and synthesized that have significantly lower liver bioaccumulation. In this study, we conducted animal exposure experiments to investigate tissue accumulations of 14 per- and polyfluoroalkyl substances. Correlation analysis demonstrated that accumulation of the compounds in rat liver had strong correlations with their binding affinities of liver fatty acid binding protein (LFABP). Thus, we combined a quantitative structure-activity relationship model with molecular dynamics (MD) simulations to develop computational models to predict the LFABP binding affinities of two newly synthesized alternatives, perfluorodecalin-2-sulfonic acid and N-diperfluorobutanoic acid. The binding characteristics of the PFOS alternatives for LFABP were elaborated to explore how the different structural modifications of molecules influenced the underlying binding mechanisms. Subsequent animal experiments demonstrated that the binding free energy calculations based on the MD simulations provided a good indicator to reflect the relative degree of liver accumulation of the PFOS alternatives in the same exposure doses and durations. Our findings from the combination of experimental exposure and computational model can provide helpful information to design potential alternatives of PFOS with weak LFABP binding capability and low liver accumulation.
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| 3. |
- Liu, Meng, 1976, et al.
(författare)
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Targeting the protein prenyltransferases efficiently reduces tumor development in mice with K-RAS-induced lung cancer
- 2010
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Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - : Proceedings of the National Academy of Sciences. - 0027-8424. ; 107:14, s. 6471-6476
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Tidskriftsartikel (refereegranskat)abstract
- RAS and RHO proteins, which contribute to tumorigenesis and metastasis, undergo posttranslational modification with an isoprenyl lipid by protein farnesyltransferase (FTase) or protein geranylgeranyltransferase-I (GGTase-I). Inhibitors of FTase and GGTase-I were developed to block RAS-induced malignancies, but their utility has been difficult to evaluate because of off-target effects, drug resistance, and toxicity. Moreover, the impact of FTase deficiency and combined FTase/GGTase-I deficiency has not been evaluated with genetic approaches. We found that inactivation of FTase eliminated farnesylation of HDJ2 and H-RAS, prevented H-RAS targeting to the plasma membrane, and blocked proliferation of primary and K-RAS(G12D)-expressing fibroblasts. FTase inactivation in mice with K-RAS-induced lung cancer reduced tumor growth and improved survival, similar to results obtained previously with inactivation of GGTase-I. Simultaneous inactivation of FTase and GGTase-I markedly reduced lung tumors and improved survival without apparent pulmonary toxicity. These data shed light on the biochemical and therapeutic importance of FTase and suggest that simultaneous inhibition of FTase and GGTase-I could be useful in cancer therapeutics.
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| 4. |
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| 5. |
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| 6. |
- Liu, Yu, et al.
(författare)
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Tree-ring stable carbon isotope-based May-July temperature reconstruction over Nanwutai, China, for the past century and its record of 20th century warming
- 2014
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Ingår i: Quaternary Science Reviews. - : Elsevier BV. - 0277-3791 .- 1873-457X. ; 93, s. 67-76
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Tidskriftsartikel (refereegranskat)abstract
- Growth anomaly of trees in some regions was detected under current episode of rapid warming. This raises a dilemma for temperature reconstructions by using tree-ring width which is believed to be the most important proxy on inter-annual temperature reconstruction during the past millenniums. Here we employed the tree-ring d13C to reconstruct temperature variations for exploring their potential on capturing signals of rapid warming, and to test how its difference with the tree-ring width based reconstruction. In this study the mean MayeJuly temperature (TMeJ) was reconstructed over the past century by tree-ring d13C of Chinese pine trees growing in the Nanwutai region. The explained variance of the reconstruction was 43.3% (42.1% after adjusting the degrees of freedom). Compared to a ring-width temperature reconstruction (MayeJuly) from the same site, the tree-ring d13C-based temperature reconstruction offered two distinct advantages: 1) it captured a wider range of temperature variability, i.e., at least MayeJuly, even over a longer part of the year, JanuaryeSeptember; and 2) the reconstruction preserved more low-frequency climate information than that of ring width did. The 20th century warming was well represented in the Nanwutai tree-ring d13C temperature reconstruction, which implied that stable carbon isotope of tree rings potentially represents temperature variations during historical episodes of rapid warming. A spatial correlation analysis showed that our temperature reconstruction represented climate variations over the entire Loess Plateau in north-central China. Significant positive correlations (p < 0.1) were found between the temperature reconstruction and ENSO, as well as SSTs in the Pacific and Indian Oceans. The reconstruction showed the periodicities of 22.78-, 4.16-, 3.45e3.97- and 2.04e2.83-year quasi-cycles at a 95% confidence level. Our results suggested that temperature variability in the Nanwutai region may be linked to Pacific and Indian Ocean SST variations and solar activity.
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| 7. |
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| 8. |
- Song, Huiming, et al.
(författare)
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Tree-ring derived temperature records in the central Loess Plateau, China
- 2013
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Ingår i: Quaternary International. - : Elsevier BV. - 1040-6182. ; 283, s. 30-35
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Tidskriftsartikel (refereegranskat)abstract
- Using tree-ring widths of Pinus tabulaeformis Carr. trees, mean temperatures from February to September were reconstructed for the Kongtong Mountain during the past 283 years. The reconstruction could explain 43.7% of temperature variance during the calibration period from 1951 to 2004. It displays similar patterns to several temperature reconstructions in the Loess Plateau. It corresponds well with the temperature regimes in Hokkaido, Japan, indicating that both regions have similar warm and cold intervals. The high correlation between the reconstruction and the CRU (Climatic Research Unit of University of East Anglia, UK) TS3 temperature datasets showed that the temperature reconstruction could be representative of large-scale climate change over northern China. In addition, the Pacific Decadal Oscillation (PDO) affected temperature variations of northern China and even Hokkaido to a certain extent.
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| 9. |
- Sun, Zhendong, et al.
(författare)
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4-Hexylphenol influences adipogenic differentiation and hepatic lipid accumulation in vitro
- 2021
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Ingår i: Environmental Pollution. - : Elsevier. - 0269-7491 .- 1873-6424. ; 268:Part A
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Tidskriftsartikel (refereegranskat)abstract
- Finding the potential environmental obesogens is crucial to explain the prevalence of obesity and the related pathologies. Increasing evidence has showed that many chemicals with endocrine disrupting effects can disturb lipid metabolism. Whether 4-hexylphenol (4-HP), a widely-used surfactant and a potential endocrine disrupting chemical (EDC), is associated to influence adipogenesis and hepatic lipid accumulation remained to be elucidated. In this study, both the 3T3-L1 differentiation model and oleic acid (OA)-treated HepG2 cells were used to investigate the effects of 4-HP on lipid metabolism, and the underlying estrogen receptor (ER)-involved mechanism was explored using MVLN assay, molecular docking simulation and the antagonist test. The results based on lipid droplet staining and triglyceride accumulation assay showed that 4-HP treatment promoted the adipogenic differentiation of 3T3-L1 cells and increased hepatic cellular OA accumulation in exposure concentration-dependent manners. The study on the elaborated transcription networks indicated that 4-HP activated peroxisome proliferator-activated receptor γ (PPARγ) as well as the subsequent adipogenic gene program in 3T3-L1 cells. This chemical also induced the increase of OA uptake and decreases of de novo lipogenesis and fatty acid oxidation in HepG2 cells. The agonistic activity of 4-HP in triggering ER-mediated pathway was shown to correlate with its perturbation in lipid metabolism, as evidenced by the enhanced development of mature lipid-laden adipocytes and suppression of excessive hepatic lipid accumulation upon its co-treatment with ER antagonist. Altogether, these findings provide new insights into the potential health impacts of 4-HP exposure as it may relate to obesity and nonalcoholic fatty liver disease.
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| 10. |
- Wang, Ling, et al.
(författare)
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Perfluorooctanesulfonate Induces Hepatomegaly and Lipoatrophy in Mice through Phosphoenolpyruvate Carboxykinase-Mediated Glyceroneogenesis Inhibition
- 2020
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Ingår i: Environmental Science and Technology Letters. - : American Chemical Society (ACS). - 2328-8930. ; 7:3, s. 185-190
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Tidskriftsartikel (refereegranskat)abstract
- Perfluorooctansulfonate (PFOS) is a persistent organic pollutant that has attracted a great deal of attention due to toxic effects such as its lipid metabolism-disrupting potential. Exposure to PFOS can cause hepatomegaly and lipoatrophy in mice, but the underlying mechanisms are still unknown. Considering that glyceroneogenesis is the essential pathway for balancing the triglyceride (TG) cycle between liver and white adipose tissue (WAT), we speculate that PFOS acts via glyceroneogenesis inhibition to alter TG metabolism in the two tissues. Combining gene expression, protein expression, an enzyme activity assay, and molecular docking analysis, we report here that PFOS can interact with cytosolic phosphoenolpyruvate carboxykinase (PEPCK), the rate-limiting enzyme of glyceroneogenesis. Specifically, by repression of PEPCK, PFOS can inhibit the glyceroneogenesis process and thus decrease the glyceroneogenesis-derived glycerol level, leading to a reduced re-esterified TG level and causing atrophy in WAT. Moreover, in PFOS-exposed liver tissue, despite the fact that free glycerol and fatty acids released from WAT were being used for TG synthesis, the export of TG slowed. This eventually resulted in the continuous lipolysis of WAT and accumulation of lipid in the liver. PEPCK can be used as a key biomarker to assess the lipid metabolism disorders induced by other conventional and emerging per- and polyfluoroalkyl substances.
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