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Pulmonary Deregulation of Expression of Mir-155 and Two of Its Putative International Journal of Nanomedicine Dovepress open access to scientific and medical research Open Access Full Text Article ORIGINAL RESEARCH Pulmonary deregulation of expression of miR-155 and two of its putative target genes; PROS1 and TP53INP1 associated with gold nanoparticles (AuNPs) administration in rat This article was published in the following Dove Press journal: International Journal of Nanomedicine Ghada E Ali 1 Background: Gold nanoparticles (AuNPs) have been considered as an ideal candidate in Marwa A Ibrahim 1 various biomedical applications due to their ease of tailoring into different size, shape, and Ayman H El-Deeb2 decorations with different functionalities. The current study was conducted to investigate the Hassan Amer1 epigenetic alteration in the lung in response to AuNPs administration regarding microRNA- Said M Zaki1 155 (miR-155) gene which can be involved in AuNP-induced lung pathogenesis. Methods: Thirty-two Wister rats were divided into two equal groups, control group and 1 Cairo University, Faculty of Veterinary AuNPs treated group which received a single intravenous (IV) injection of plain spherical Medicine, Department of Biochemistry and Chemistry of Nutrition, Giza 12211, AuNPs (0.015 mg/kg body wt) with an average diameter size of 25±3 nm. Lung samples Egypt; 2Cairo University, Faculty of were collected from both the control and injected groups at one day, one week, one month Veterinary Medicine, Department of and two months post-injection. The alteration of relative expression of miR-155 gene and two Virology, Giza 12211, Egypt of its putative target genes; tumor protein 53 inducible nuclear protein 1 (TP53INP1) and protein S (PROS1) was investigated by real time PCR and protein S (PS) expression was analyzed by Western blotting technique. Results: The obtained results revealed that AuNPs administration significantly increases the expression level of miR-155 and reduce relative mRNA expression of TP53INP1 and PROS1 genes at one day post-injection. In contrast, a significant down-regulation of miR-155 level of expression concurrent with up-regulation of expression level of TP53INP1 and PROS1 genes were shown at one week, one month and two months post-injection. PS levels were mirrored to their PROS1 mRNA levels except for two month post-injection time point. Conclusions: These findings indicate epigenetic modulation in the lung in response to AuNPs administration regarding the miR-155 gene which can be involved in AuNP-induced lung pathogenesis. Keywords: AuNPs, MiR-155, epigenetic, PROS1, TP53INP1 Introduction Nanomedicine is a rapidly growing vital field that aims to use various nanomaterials (NMs) to tackle a range of biomedical applications and medical ailments.1 Metallic NMs constitute promising platforms for various purposes due to their peculiar photonic, electronic, catalytic, and therapeutic properties, easy surface functionalization and versa- tile methods of synthesis ensuring wide size and shape features.2 Among them, AuNPs Correspondence: Ghada E Ali 14A Selim-street King Faisal St. have attracted wide attention in various biomedical applications due to the unique proper- Cairo University, Giza, Egypt ties that make them superior over other nanoparticles. These distinctive features include Tel +20 114 290 2365 Email [email protected] their photoactivation capability, inertness, biocompatibility, and their relatively simple submit your manuscript | www.dovepress.com International Journal of Nanomedicine 2019:14 5569–5579 5569 DovePress © 2019 Ali et al. This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License (http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work http://doi.org/10.2147/IJN.S208372 you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms (https://www.dovepress.com/terms.php). Ali et al Dovepress generation and surface modification.3 Moreover, they have an arrest and apoptosis by modulating p53 transcriptional exceptional electric and magnetic properties which make them activity.19 The PROS1 gene encodes for protein S (PS), a an ideal candidate in the field of biological tagging, chemical vitamin K-dependent plasma glycoprotein that functions as and biological sensing, optoelectronics, photothermal therapy, natural anticoagulant protein.20 PS has been reported to be biomedical imaging, DNA labeling, gene therapy, microscopy synthesized and secreted mainly in hepatocytes and other and photoacoustic imaging, surface-enhanced Raman spectro- cells than hepatocytes like lung where it has the highest scopy, tracking and drug delivery, catalysis and cancer expression of PS.9 Lack of protein S synthesis can lead to therapy.4 coagulopathy such as venous thrombosis giving rise to dire The potential health risk following the NMs therapeu- consequences.21 tic or diagnostic application is becoming more controver- Biodistribution studies have identified the lung as one sial. In addition to genotoxicity, mutagenicity, oxidative of the target sites of accumulation for AuNPs, necessitat- stress and inflammation, nanotoxicity can also be mediated ing further studies into their effects in the lung.22,23 Thus, by epigenetic modifications that may contribute to adverse the current study, which is considered the first, was con- health effects and can play a potential causative role in the ducted to assess the effect of a single IV injection of pathogenesis of many diseases including cancer.5 AuNPs (0.015 mg Au/kg body wt) on the rat lung through Therefore, more research has recently raised a concern the evaluation of its epigenetic effects regarding the miR- about possible epigenetic toxicity and health effects 155 and two of its putative target genes, TP53INP1 and induced by NMs.3,6,7 Whilst inert, the potential involve- PROS1. ment of AuNPs in epigenetic modifications was shown by – several recent studies.3,8 10 Hence, the development of Materials and methods effective testing strategies can help us to distinguish Materials between adverse health effects of NMs exposure in con- A citrate-capped spherical gold nanoparticles (AuNPs) in trast to adaptive changes.11 Several NMs exhibited epige- aqueous solution, pink in color, with an average diameter netic effects in terms of deregulation of microRNA size of 25±3 nm and 197 µg/ml concentration was pur- (miRNA) expression profiles.11 miRNAs are small (typi- chased from NanoTech Egypt for Photo-Electronics Co., cally 20–26 nucleotides), highly conserved single stranded where they have been prepared by chemical reduction non-coding RNA (ncRNA) molecules involved in the method as reported by Turkevich et al24. A drop of the post-transcriptional regulation of gene expression that is purchased concentrated stock AuNPs solution was related to nearly all developmental and pathological pro- mounted on Formvar-coated copper grids and allowed to cesses in animals.12 MiRNAs are critical regulators of dry then viewed using a transmission electron microscope gene expression through acting as a guide by base-pairing (TEM) (JEOL TEM, JEM-1230, Japan). The image con- with complementary sequences in target mRNA to nega- firmed the morphology and the diameter of the AuNPs tively regulate its expression.13 miRNAs participate in (Figure 1). almost all known cellular processes including cell prolif- eration, differentiation, survival, metabolism, genome sta- bility, apoptosis and inflammation.14 Deregulation of Experimental animals and ethical approval miRNA has been shown to be broadly involved in a Thirty-two adult male Wister rats (Rattus Norvegicus) diverse range of pathological conditions such as cancer, (~200 g each) were housed in humidity and temperature- cardiovascular and autoimmune diseases, mental disor- controlled ventilated cages on a 12 h day/night cycle with ders, and many more.15,16 miRNA-155 is a typical multi- a rodent diet and water provided ad libitum. functional miRNA that is involved in numerous biological processes including hematopoiesis, inflammation, immu- Experimental design and treatment nity and carcinogenesis.17 miRNA-155 has been reported To conduct IV injections, AuNPs were further diluted (7.3 to be involved in the regulation of the level of expression times) using ultra-pure water resulting in a mass concentra- of TP53INP1 and PROS1 genes.9,18 TP53INP1 gene is a tion of 30 µg/ml. Rats were anesthetized by IP injection of tumor suppressor gene that encodes the anti-proliferative, Ketamine/Xylazine mixture (Ketamine: 80–100 mg/Kg; pro-apoptotic and pro-autophagic protein; TP53INP1. It is Xylazine: 10–12.5 mg/Kg) during AuNPs administration. a stress-induced p53- target gene that induces cell growth A single tail-vein injection of 0.1 ml AuNPs (30 µg/ml) was 5570 submit your manuscript | www.dovepress.com International Journal of Nanomedicine 2019:14 DovePress Dovepress Ali et al 50 nm 20 nm Figure 1 Characterization of AuNPs by transmission electron microscope (TEM): TEM micrographs of AuNPs showed the presence of dark-colored spherical nanoparticles of high atomic mass within the size range 25±3. administrated slowly to the rats. The chosen dose (0.015 mg Ultrathin sections were cut and mounted on Formvar- Au/kg body
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