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Endoplasmic reticulum stress and oxidative stress are involved in ZnO nanoparticle-induced hepatotoxicity.

ABSTRACT: Zinc oxide nanoparticles (Nano-ZnO) are widely used in sunscreens, clothes, medicine and electronic devices. However, the potential risks of human exposure and the potential for adverse health impacts are not well understood. Previous studies have demonstrated that exposure to Nano-ZnO caused liver damage and hepatocyte apoptosis through oxidative stress, but the molecular mechanisms that are involved in Nano-ZnO-induced hepatotoxicity are still unclear. Endoplasmic reticulum (ER) is sensitive to oxidative stress, and also plays a crucial role in oxidative stress-induced damage. Previous studies showed that ER stress was involved in many chemical-induced liver injuries. We hypothesized that exposure to Nano-ZnO caused oxidative stress and ER stress that were involved in Nano-ZnO-induced liver injury. To test our hypothesis, mice were gavaged with 200 mg/kg or 400 mg/kg of Nano-ZnO once a day for a period of 90 days, and blood and liver tissues were obtained for study. Our results showed that exposure to Nano-ZnO caused liver injury that was reflected by focal hepatocellular necrosis, congestive dilation of central veins, and significantly increased alanine transaminase (ALT) and aspartate transaminase (AST) levels. Exposure to Nano-ZnO also caused depletion of glutathione (GSH) in the liver tissues. In addition, our electron microscope results showed that ER swelling and ribosomal degranulation were observed in the liver tissues from mice treated with Nano-ZnO. The mRNA expression levels of ER stress-associated genes (grp78, grp94, pdi-3, xbp-1) were also up-regulated in Nano-ZnO-treated mice. Nano-ZnO caused increased phosphorylation of RNA-dependent protein kinase-like ER kinase (PERK) and eukaryotic initiation factor 2? (eIF2?). Finally, we found that exposure to Nano-ZnO caused increased ER stress-associated apoptotic protein levels, such as caspase-3, caspase-9, caspase-12, phosphorylation of JNK, and CHOP/GADD153, and up-regulation of pro-apoptotic genes (chop and bax). These results suggest that oxidative stress and ER stress-induced apoptosis are involved in Nano-ZnO-induced hepatotoxicity in mice.

SUBMITTER: Yang X

PROVIDER: S-EPMC4344938 | biostudies-literature | 2015 Apr

REPOSITORIES: biostudies-literature

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Endoplasmic reticulum stress and oxidative stress are involved in ZnO nanoparticle-induced hepatotoxicity.

Yang Xia X Shao Huali H Liu Weirong W Gu Weizhong W Shu Xiaoli X Mo Yiqun Y Chen Xuejun X Zhang Qunwei Q Jiang Mizu M

Toxicology letters 20150210 1

Zinc oxide nanoparticles (Nano-ZnO) are widely used in sunscreens, clothes, medicine and electronic devices. However, the potential risks of human exposure and the potential for adverse health impacts are not well understood. Previous studies have demonstrated that exposure to Nano-ZnO caused liver damage and hepatocyte apoptosis through oxidative stress, but the molecular mechanisms that are involved in Nano-ZnO-induced hepatotoxicity are still unclear. Endoplasmic reticulum (ER) is sensitive t ...[more]

PMID: 25680694

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Project description:Isoniazid (INH) is a first-line antituberculosis drug. The incidence of adverse reactions accompanied by inflammation in the liver during drug administration to tuberculosis patients is high and severely affects clinical treatment. To better understand the mechanism of hepatotoxicity induced by INH under the inflammatory state, we compared the differences in levels of hepatotoxicity from INH between normal zebrafish and zebrafish in an inflammatory state to elucidate the hepatotoxic mechanism using different endpoints such as mortality, malformation, inflammatory effects, liver morphology, histological changes, transaminase analysis, and expression levels of certain genes. The results showed that the toxic effect of INH in zebrafish in an inflammatory state was more obvious than that in normal zebrafish, that liver size was significantly decreased as measured by liver fatty acid binding protein (LFABP) reporter fluorescence and intensity, and that alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels were significantly increased. Hematoxylin and eosin (HE) staining and electron microscopy showed that hepatocyte injury was more obvious in the inflammatory state. In the inflammatory state, INH significantly increased the expression levels of endoplasmic reticulum stress (ERS)-related factors (GRP78, ATF6, PERK, IRE1, XBP1s, GRP94, and CHOP), autophagy-related factors (beclin 1, LC3, Atg3, and Atg12), and apoptosis-related factors (caspase-3, caspase-8, caspase-9, Bax, p53, and Cyt) in larvae. Correlational analyses indicated that the transcription levels of the inflammatory factors interleukin-1b (IL-1b), tumor necrosis factor beta (TNF-β), cyclooxygenase 2 (COX-2), and TNF-ɑ were strongly positively correlated with ALT and AST. Furthermore, the ERS inhibitor sodium 4-phenylbutyrate (4-PBA) could ameliorate the hepatotoxicity of INH-lipopolysaccharide (LPS) in zebrafish larvae. These results indicated that INH hepatotoxicity was enhanced in the inflammatory state. ERS and its mediated autophagy and apoptosis pathways might be involved in INH-induced liver injury promoted by inflammation.

Project description:BackgroundExosomes are endosome-derived nano-sized vesicles that have emerged as important mediators of intercellular communication and play significant roles in various diseases. However, their applications are rigorously restricted by the limited secretion competence of cells. Therefore, strategies to enhance the production and functions of exosomes are warranted. Studies have shown that nanomaterials can significantly enhance the effects of cells and exosomes in intercellular communication; however, how palladium nanoparticles (PdNPs) enhance exosome release in human leukemia monocytic cells (THP-1) remains unclear. Therefore, this study aimed to address the effect of PdNPs on exosome biogenesis and release in THP-1 cells.MethodsExosomes were isolated by ultracentrifugation and ExoQuickTM and characterized by dynamic light scattering, nanoparticle tracking analysis system, scanning electron microscopy, transmission electron microscopy, EXOCETTM assay, and fluorescence polarization. The expression levels of exosome markers were analyzed via quantitative reverse transcription-polymerase chain reaction and enzyme-linked immunosorbent assay.ResultsPdNP treatment enhanced the biogenesis and release of exosomes by inducing oxidative stress, endoplasmic reticulum stress, apoptosis, and immunomodulation. The exosomes were spherical in shape and had an average diameter of 50-80 nm. Exosome production was confirmed via total protein concentration, exosome counts, acetylcholinesterase activity, and neutral sphingomyelinase activity. The expression levels of TSG101, CD9, CD63, and CD81 were significantly higher in PdNP-treated cells than in control cells. Further, cytokine and chemokine levels were significantly higher in exosomes isolated from PdNP-treated THP-1 cells than in those isolated from control cells. THP-1 cells pre-treated with N-acetylcysteine or GW4869 showed significant decreases in PdNP-induced exosome biogenesis and release.ConclusionTo our knowledge, this is the first study showing that PdNPs stimulate exosome biogenesis and release and simultaneously increase the levels of cytokines and chemokines by modulating various physiological processes. Our findings suggest a reasonable approach to improve the production of exosomes for various therapeutic applications.

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Endoplasmic reticulum stress and oxidative stress are involved in ZnO nanoparticle-induced hepatotoxicity.

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Endoplasmic reticulum stress and oxidative stress are involved in ZnO nanoparticle-induced hepatotoxicity.

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