المؤلفون: Zhanchen, Dong, Jianyu, Wang, Tianming, Qiu, Jialu, Wu, Yu, An, Xiaoxia, Shi, Xiance, Sun, Liping, Jiang, Xiaofang, Liu, Guang, Yang, Jun, Cao, Xiaofeng, Yao

المصدر: Science of The Total Environment. 825:153933

مصطلحات موضوعية: Fluorocarbons, Environmental Engineering, Voltage-Dependent Anion Channel 1, Calcium-Binding Proteins, Mitochondrial Membrane Transport Proteins, Pollution, Mitochondria, Mice, Inbred C57BL, Mice, Alkanesulfonic Acids, Liver, Tubulin, Autophagy, Animals, Humans, Environmental Chemistry, Calcium, Insulin Resistance, Cation Transport Proteins, Waste Management and Disposal

الوصف: Perfluorooctane sulfonate (PFOS), one kind of persistent organic pollutants, is associated with insulin resistance (IR) in general population. However, the exact mechanism is still obscure. In this study, we found that 50 μM PFOS caused IR in L-02 hepatocytes after 1 h, and induced autophagy and mitochondrial calcium (Ca

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::59d78593d0d1936fd0b1b5d2435b6751Test
https://doi.org/10.1016/j.scitotenv.2022.153933Test

المؤلفون: Yufang Ma, Xiance Sun, Guang Yang, Liping Jiang, Xiaofeng Yao, Xiaoxia Shi, Jingyuan Zhang, Xiuyan Han, Zhanchen Dong, Jian Kang, Shanshan Sha, Tianming Qiu

المصدر: Food and Chemical Toxicology. 157:112540

مصطلحات موضوعية: Lysosomal membrane, Blotting, Western, Toxicology, Mass Spectrometry, Permeability, chemistry.chemical_compound, Tubulin, Autophagy, Humans, Adaptor Proteins, Signal Transducing, Fluorocarbons, Membranes, biology, Permease, Chemistry, Membrane Proteins, Hep G2 Cells, General Medicine, Isotype, Cell biology, Perfluorooctane, Sulfonate, biology.protein, Tyrosine, Lysosomes, After treatment, Food Science

الوصف: Perfluorooctane sulfonate (PFOS) is one kind of persistent organic pollutants. In previous study, we found that PFOS induced autophagy-dependent lysosomal membrane permeabilization (LMP) in hepatocytes, and siRNA against lysosomal permease spinster 1 (SPNS1) relieved PFOS-induced LMP. However, whether and how SPNS1 functioned as the link between autophagy and LMP was still not defined. In this study, we constructed a stable cell line expressing high levels of SPNS1. We found that SPNS1 interacted specifically with α-tubulin of tyrosinated isotype by pull-down assay. After treatment with PFOS, the level of tyrosinated α-tubulin was autophagy-dependently decreased. SPNS1-tyrosinated α-tubulin interaction was disrupted subsequently, which led to LMP eventually. We also found that stable high-expression of SPNS1 in hepatocytes accelerated lysosomal acidification, and deteriorated PFOS-induced LMP. This study pointed out that SPNS1-tyrosinated α-tubulin interaction mediated the cross-talk between autophagy and LMP induced by PFOS, shedding new light on the mechanism of PFOS hepatotoxicity.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::f79f1d604a3f0dd3a9f9b362cda63600Test
https://doi.org/10.1016/j.fct.2021.112540Test

المؤلفون: Xiance Sun, Dandan Li, Liping Jiang, Wei Wu, Xiaofeng Yao, Jun Cao, Tianming Qiu, Chang Feng, Min Chen

المصدر: Biochemical and Biophysical Research Communications. 477:781-785

مصطلحات موضوعية: 0301 basic medicine, medicine.medical_specialty, medicine.medical_treatment, Glucose uptake, Population, Biophysics, 010501 environmental sciences, Biology, 01 natural sciences, Biochemistry, mTORC2, 03 medical and health sciences, Insulin resistance, Internal medicine, medicine, Humans, Insulin, education, Molecular Biology, Protein kinase B, Cells, Cultured, 0105 earth and related environmental sciences, Fluorocarbons, education.field_of_study, Dose-Response Relationship, Drug, Hep G2 Cells, Cell Biology, medicine.disease, Enzyme Activation, Glucose, 030104 developmental biology, Endocrinology, Alkanesulfonic Acids, Hepatocytes, Phosphorylation, Insulin Resistance, Signal transduction, Proto-Oncogene Proteins c-akt, Signal Transduction

الوصف: Perfluorooctane sulfonate (PFOS), a persistent organic pollutant, is blamed to be associated with the incidence of insulin resistance in the general human population. In this study, we found that PFOS inhibited the phosphorylation and activation of protein kinase B (AKT), a key mediator of cellular insulin sensitivity, in human hepatoma HepG2 cells. The mRNA level of the gluconeogenic gene PEPCK, a downstream target gene of AKT, was increased in PFOS-treated cells. Due to stimulated gluconeogenesis, insulin-stimulated glucose uptake was decreased in HepG2 cells. In our previous study, we found that PFOS disturbed autophagy in HepG2 cells. We proposed that PFOS could inhibit the activation of AKT through inhibiting mTORC2, a key regulator of autophagy. In this study, we found that the levels of triglyceride were increased in HepG2 cells. PFOS-induced accumulation of hepatic lipids also contributed to the inhibition of AKT. Eventually, the inhibition of AKT led to insulin resistance in PFOS-treated cells. Our data would provide new mechanistic insights into PFOS-induced hepatic insulin resistance.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::cc177a711b1463e4ee4e6aad679109b6Test
https://doi.org/10.1016/j.bbrc.2016.06.135Test

المؤلفون: Jian Kang, Jun Cao, Xiaofeng Yao, Yuexia Wang, Yufang Ma, Xiance Sun, Min Chen, Shanshan Sha, Liping Jiang

المصدر: Toxicological Sciences. 153:198-211

مصطلحات موضوعية: 0301 basic medicine, Autophagosome, Fluorocarbons, Gene knockdown, Chemistry, ATG5, Autophagy, Mitophagy, Cathepsin D, Apoptosis, PINK1, Hep G2 Cells, Toxicology, Cell biology, 03 medical and health sciences, 030104 developmental biology, 0302 clinical medicine, Alkanesulfonic Acids, 030220 oncology & carcinogenesis, Humans, RNA Interference

الوصف: Lysosomal membrane permeabilization (LMP) and subsequently impaired autophagosome degradation was induced in HepG2 cells after treatment with perfluorooctane sulfonate (PFOS) for 24 h in our previous studies. We found that treatment of HepG2 cells with PFOS-induced autophagosome formation at earlier stage (6 h) of treatment in this study. The autophagosome formation inhibitor 3-methyladenine (3-MA) was able to relieve PFOS-induced LMP and release of cathepsin D in HepG2 cells. Knockdown of Spinster 1, a lysosomal membrane permease, attenuated PFOS-induced LMP in HepG2 cells. We proposed that Spinster 1 might work as a specific molecule that linked autophagy with LMP. PFOS-induced collapse of mitochondrial transmembrane potential was cathepsin D and autophagy dependent. Addition of 3-MA relieved PFOS-induced apoptosis, which was evidenced by Hoechst assay, AV/PI staining and caspase-3 activity assay. Inhibition of autophagosome formation by Atg5 siRNA attenuated PFOS-induced apoptosis. Treatment of HepG2 cells with PFOS for 24 h impaired mitophagy, as evidenced by an increase of cells with giant mitochondria and impairment of colocalization of PINK1 with light chain 3. In summary, we report that PFOS induces autophagy-dependent apoptosis in HepG2 cells through the lysosomal-mitochondrial axis and impairment of mitophagy, suggesting that autophagy is a primary target for PFOS toxicity. These findings provide new mechanistic insights into PFOS-induced hepatotoxicity.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::e8ab302c73b8b608ef72a0153ff8270eTest
https://doi.org/10.1093/toxsci/kfw118Test

المؤلفون: Laifu Zhong, Xiaofeng Yao

المصدر: Mutation Research/Genetic Toxicology and Environmental Mutagenesis. 587:38-44

مصطلحات موضوعية: Carcinoma, Hepatocellular, Health, Toxicology and Mutagenesis, Biology, medicine.disease_cause, Risk Assessment, chemistry.chemical_compound, Dichlorofluorescein, Tumor Cells, Cultured, Genetics, medicine, Humans, Carcinogen, chemistry.chemical_classification, Fluorocarbons, Reactive oxygen species, Micronucleus Tests, Mutagenicity Tests, Liver Neoplasms, Molecular biology, Comet assay, Oxidative Stress, chemistry, Cell culture, Micronucleus test, Perfluorooctanoic acid, Comet Assay, Caprylates, Reactive Oxygen Species, Oxidative stress, DNA Damage

الوصف: Perfluorooctanoic acid (C 8 HF 15 O 2 , PFOA) is widely used in various industrial fields for decades and it is environmentally bioaccumulative. PFOA is known as a potent hepatocarcinogen in rodents. But it is not yet clear whether it is also carcinogenic in humans, and the genotoxic effects of PFOA on human cells have not yet been examined. In this study, the genotoxic potential of PFOA was investigated in human hepatoma HepG2 cells in culture using single cell gel electrophoresis (SCGE) assay and micronucleus (MN) assay. In order to clarify the underlying mechanism(s) we measured the intracellular generation of reactive oxygen species (ROS) using dichlorofluorescein diacetate as a fluorochrome. The level of oxidative DNA damage was evaluated by immunocytochemical analysis of 8-hydroxydeoxyguanosine (8-OHdG) in PFOA-treated HepG2 cells. PFOA at 50–400 μM caused DNA strand breaks and at 100–400 μM MN in HepG2 cells both in a dose-dependent manner. Significantly increased levels of ROS and 8-OHdG were observed in these cells. We conclude that PFOA exerts genotoxic effects on HepG2 cells, probably through oxidative DNA damage induced by intracellular ROS.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::54a5f447623b1af847f90f8c88fcf516Test
https://doi.org/10.1016/j.mrgentox.2005.07.010Test

المؤلفون: Chengyan Geng, Jun Cao, Xiance Sun, Guang Yang, Jian Kang, Liping Jiang, Chuan-Zhou Gao, Liming Xu, Xiaofeng Yao, Laifu Zhong, Yufang Ma

المصدر: Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association. 67

مصطلحات موضوعية: Autophagosome, Programmed cell death, Biology, Toxicology, Permeability, chemistry.chemical_compound, Western blot, Lysosome, medicine, Autophagy, Humans, Viability assay, PI3K/AKT/mTOR pathway, Fluorocarbons, medicine.diagnostic_test, Acridine orange, General Medicine, Hep G2 Cells, Intracellular Membranes, Cell biology, medicine.anatomical_structure, Biochemistry, chemistry, Alkanesulfonic Acids, Lysosomes, Food Science

الوصف: Perfluorooctane sulfonate (PFOS) is an emerging persistent organic pollutant widely distributed in the environment, wildlife and human. In this study, as observed under the transmission electron microscope, PFOS increased autophagosome numbers in HepG2 cells, and it was confirmed by elevated LC3-II levels in Western blot analysis. PFOS increased P62 level and chloroquine failed to further increase the expression of LC3-II after PFOS treatment, indicating that the accumulation of autophagosome was due to impaired degradation rather than increased formation. With acridine orange staining, we found PFOS caused lysosomal membrane permeabilization (LMP). In this study, autophasome formation inhibitor 3-methyladenine protected cells against PFOS toxicity, autophagy stimulator rapamycin further decreased cell viability and increased LDH release, cathepsin inhibitor did not influence cell viability of PFOS-treated HepG2 cells significantly. These further supported the notion that autophagic cell death contributed to PFOS-induced hepatotoxicity. In summary, the data of the present study revealed that PFOS induced LMP and consequent blockage of autophagy flux, leading to an excessive accumulation of the autophagosomes and turning autophagy into a destructive process eventually. This finding will provide clues for effective prevention and treatment of PFOS-induced hepatic disease.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::1670925a5dbbbc5104dcbb0ced875b12Test
https://pubmed.ncbi.nlm.nih.gov/24561269Test