{"@context":{"@language":"en","Affiliation":"http:\/\/vivoweb.org\/ontology\/core#departmentOrSchool","AggregatedSourceRepository":"http:\/\/www.europeana.eu\/schemas\/edm\/dataProvider","Citation":"https:\/\/open.library.ubc.ca\/terms#identifierCitation","CopyrightHolder":"https:\/\/open.library.ubc.ca\/terms#rightsCopyright","Creator":"http:\/\/purl.org\/dc\/terms\/creator","DateAvailable":"http:\/\/purl.org\/dc\/terms\/issued","DateIssued":"http:\/\/purl.org\/dc\/terms\/issued","Description":"http:\/\/purl.org\/dc\/terms\/description","DigitalResourceOriginalRecord":"http:\/\/www.europeana.eu\/schemas\/edm\/aggregatedCHO","FullText":"http:\/\/www.w3.org\/2009\/08\/skos-reference\/skos.html#note","Genre":"http:\/\/www.europeana.eu\/schemas\/edm\/hasType","IsShownAt":"http:\/\/www.europeana.eu\/schemas\/edm\/isShownAt","Language":"http:\/\/purl.org\/dc\/terms\/language","PeerReviewStatus":"https:\/\/open.library.ubc.ca\/terms#peerReviewStatus","Provider":"http:\/\/www.europeana.eu\/schemas\/edm\/provider","Publisher":"http:\/\/purl.org\/dc\/terms\/publisher","PublisherDOI":"https:\/\/open.library.ubc.ca\/terms#publisherDOI","Rights":"http:\/\/purl.org\/dc\/terms\/rights","RightsURI":"https:\/\/open.library.ubc.ca\/terms#rightsURI","ScholarlyLevel":"https:\/\/open.library.ubc.ca\/terms#scholarLevel","Subject":"http:\/\/purl.org\/dc\/terms\/subject","Title":"http:\/\/purl.org\/dc\/terms\/title","Type":"http:\/\/purl.org\/dc\/terms\/type","URI":"https:\/\/open.library.ubc.ca\/terms#identifierURI","SortDate":"http:\/\/purl.org\/dc\/terms\/date"},"Affiliation":[{"@value":"Medicine, Faculty of","@language":"en"},{"@value":"Non UBC","@language":"en"},{"@value":"Medicine, Department of","@language":"en"}],"AggregatedSourceRepository":[{"@value":"DSpace","@language":"en"}],"Citation":[{"@value":"BMC Biotechnology. 2021 Dec 07;21(1):68","@language":"en"}],"CopyrightHolder":[{"@value":"The Author(s)","@language":"en"}],"Creator":[{"@value":"Zamani, Khosro","@language":"en"},{"@value":"Allah-Bakhshi, Noushin","@language":"en"},{"@value":"Akhavan, Faezeh","@language":"en"},{"@value":"Yousefi, Mahdieh","@language":"en"},{"@value":"Golmoradi, Rezvan","@language":"en"},{"@value":"Ramezani, Moazzameh","@language":"en"},{"@value":"Bach, Horacio","@language":"en"},{"@value":"Razavi, Shabnam","@language":"en"},{"@value":"Irajian, Gholam-Reza","@language":"en"},{"@value":"Gerami, Mahyar","@language":"en"},{"@value":"Pakdin-Parizi, Ali","@language":"en"},{"@value":"Tafrihi, Majid","@language":"en"},{"@value":"Ramezani, Fatemeh","@language":"en"}],"DateAvailable":[{"@value":"2022-01-19T19:13:04Z","@language":"en"}],"DateIssued":[{"@value":"2021-12-07","@language":"en"}],"Description":[{"@value":"Background\r\n                Antibiotics have been widely used for the treatment of bacterial infections for decades. However, the rapid emergence of antibiotic-resistant bacteria has created many problems with a heavy burden for the medical community. Therefore, the use of nanoparticles as an alternative for antibacterial activity has been explored. In this context, metal nanoparticles have demonstrated broad-spectrum antimicrobial activity. This study investigated the antimicrobial activity of naked cerium oxide nanoparticles dispersed in aqueous solution (CNPs) and surface-stabilized using\u00a0Pseudomonas aeruginosa\u00a0as a bacterial model.\r\n              \r\n              \r\n                Methods\r\n                Gelatin-polycaprolactone nanofibers containing CNPs (Scaffold@CNPs) were synthesized, and their effect on P. aeruginosa was investigated. The minimum inhibitory and bactericidal concentrations of the nanoparticls were determined in an ATCC reference strain and a clinical isolate strain. To determine whether the exposure to the nanocomposites might change the expression of antibiotic resistance, the expression of the genes shv, kpc, and imp was also investigated. Moreover, the cytotoxicity of the CNPs was assessed on fibroblast using flow cytometry.\r\n              \r\n              \r\n                Results\r\n                Minimum bactericidal concentrations for the ATCC and the clinical isolate of 50\u00a0\u00b5g\/mL and 200\u00a0\u00b5g\/mL were measured, respectively, when the CNPs were used. In the case of the Scaffold@CNPs, the bactericidal effect was 50\u00a0\u00b5g\/mL and 100\u00a0\u00b5g\/mL for the ATCC and clinical isolate, respectively. Interestingly, the exposure to the Scaffold@CNPs significantly decreased the expression of the genes shv, kpc, and imp.\r\n              \r\n              \r\n                Conclusions\r\n                A concentration of CNPs and scaffold@CNPs higher than 50\u00a0\u03bcg\/mL can be used to inhibit the growth of P. aeruginosa. The fact that the scaffold@CNPs significantly reduced the expression of resistance genes, it has the potential to be used for medical applications such as wound dressings.","@language":"en"}],"DigitalResourceOriginalRecord":[{"@value":"https:\/\/circle.library.ubc.ca\/rest\/handle\/2429\/80686?expand=metadata","@language":"en"}],"FullText":[{"@value":"Zamani\u00a0et\u00a0al. BMC Biotechnology           (2021) 21:68  https:\/\/doi.org\/10.1186\/s12896-021-00727-1RESEARCH ARTICLEAntibacterial effect of\u00a0cerium oxide nanoparticle against\u00a0Pseudomonas aeruginosaKhosro Zamani1\u2020, Noushin Allah\u2011Bakhshi2\u2020, Faezeh Akhavan2, Mahdieh Yousefi2, Rezvan Golmoradi1, Moazzameh Ramezani3, Horacio Bach4*, Shabnam Razavi1, Gholam\u2011Reza Irajian1, Mahyar Gerami2*, Ali Pakdin\u2011Parizi5, Majid Tafrihi6 and Fatemeh Ramezani7*  Abstract Background: Antibiotics have been widely used for the treatment of bacterial infections for decades. However, the rapid emergence of antibiotic\u2011resistant bacteria has created many problems with a heavy burden for the medical community. Therefore, the use of nanoparticles as an alternative for antibacterial activity has been explored. In this context, metal nanoparticles have demonstrated broad\u2011spectrum antimicrobial activity. This study investigated the antimicrobial activity of naked cerium oxide nanoparticles dispersed in aqueous solution (CNPs) and surface\u2011stabi\u2011lized using Pseudomonas aeruginosa as a bacterial model.Methods: Gelatin\u2011polycaprolactone nanofibers containing CNPs (Scaffold@CNPs) were synthesized, and their effect on P. aeruginosa was investigated. The minimum inhibitory and bactericidal concentrations of the nanoparticls were determined in an ATCC reference strain and a clinical isolate strain. To determine whether the exposure to the nano\u2011composites might change the expression of antibiotic resistance, the expression of the genes shv, kpc, and imp was also investigated. Moreover, the cytotoxicity of the CNPs was assessed on fibroblast using flow cytometry.Results: Minimum bactericidal concentrations for the ATCC and the clinical isolate of 50 \u00b5g\/mL and 200 \u00b5g\/mL were measured, respectively, when the CNPs were used. In the case of the Scaffold@CNPs, the bactericidal effect was 50 \u00b5g\/mL and 100 \u00b5g\/mL for the ATCC and clinical isolate, respectively. Interestingly, the exposure to the Scaffold@CNPs significantly decreased the expression of the genes shv, kpc, and imp.Conclusions: A concentration of CNPs and scaffold@CNPs higher than 50 \u03bcg\/mL can be used to inhibit the growth of P. aeruginosa. The fact that the scaffold@CNPs significantly reduced the expression of resistance genes, it has the potential to be used for medical applications such as wound dressings.Keywords: Cerium oxide nanoparticles, Nanofiber, Antibiotic resistance, Pseudomonas aeruginosa, Gene expression, Cytotoxicity, Clinical isolate\u00a9 The Author(s) 2021. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article\u2019s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article\u2019s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http:\/\/ creat iveco mmons. org\/ licen ses\/ by\/4. 0\/. The Creative Commons Public Domain Dedication waiver (http:\/\/ creat iveco mmons. org\/ publi cdoma in\/ zero\/1. 0\/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.BackgroundNosocomial infection is one of the most important medi-cal problems in developed and developing countries [1, 2]. Antibiotics have been widely used for the treat-ment of bacterial infections for decades. However, the rapid emergence of antibiotic-resistant bacteria has cre-ated many problems and burdens for the medical com-munity [3, 4]. Each year, approximately 88,000 deaths from hospital-acquired infections are reported in the Open Access*Correspondence:  hbach@mail.ubc.ca; mahyar.gerami@yahoo.com; ramezani.f@iums.ac.ir\u2020Khosro Zamani and Noushin Allah\u2011Bakhshi have contributed equally to this work2 Department of Biology, Sana Institute of Higher education, Sari, Iran4 Division of Infectious Diseases, Department of Medicine, University of British Columbia, Vancouver, BC, Canada7 Physiology Research Center, Iran University of Medical Sciences, Tehran, IranFull list of author information is available at the end of the articlePage 2 of 11Zamani\u00a0et\u00a0al. BMC Biotechnology           (2021) 21:68 United States [5]. Treatment of tuberculosis and pneu-monia has become more difficult because of the appear-ance of resistant strains, with the consequences of more extended hospitalizations [6]. Pseudomonas aeruginosa is one of the most common causes of hospital-acquired infections with severe or fatal outcomes, especially in immunocompromised hosts. This opportunistic bacte-rium infects soft tissues and injured skin, including burn wounds [7, 8]. Complications of P. aeruginosa can lead to meningitis, pneumonia, and other deadly diseases [9, 10]. Extensive use of antibiotics in recent years has made this bacterium resistant to broad-spectrum antibiotics [11, 12].A promising alternative to combat bacterial resistance comes from metal nanoparticles (NPs) [13, 14]. NPs have high chemical and biological activity due to different fac-tors, mainly their small size and their high surface-to-volume ratio [15\u201317]. As a result, they have been widely used in biology and medicine [18\u201322].Metal NPs target different bacterial macromolecules and disrupt the normal function of the cell membrane, including selective permeability and cellular respiration [23\u201325]. In addition, possible interactions of positive-charged NPs with the negative charge macromolecules on the surface of microorganisms can drive an electro-static force for absorption of the NPs on the cell surface with a detrimental effect on the survival of the cell [24, 26]. Furthermore, NPs can control and stop the cell cycle by interfering with enzymes involved in bacterial prolif-eration and through gene-toxicity and the potential for the generation of gene mutation(s) [27, 28].Many studies have shown that cerium oxide nanopar-ticles (CNPs) exhibit excellent antimicrobial activity [4, 29, 30]. The antibacterial effect of CNPs on Staphylococ-cus aureus was demonstrated in various studies [31\u201333], including a potent antibacterial effect [34\u201337]. Moreover, several studies evaluated and verified the P. aeruginosa sensitivity to CNPs by agar diffusion and microdilu-tion tests [32, 38, 39]. Although the antibacterial activ-ity of CNPs against different strains of bacteria has been reported, the expression of resistance genes related to the antibacterial effect of CNPs has not been investigated so far.The use of suitable wound dressing materials, espe-cially those derived from biopolymers, could reduce the incidence of infection and accelerate the healing pro-cess. In particular, biocompatible and highly degradable nanofiber dressings that mimic the extracellular matrix structure can provide high surface area for a focal deliv-ery of antibacterial agents to control infection [38\u201341].In this study, we investigated the antibacterial prop-erties of naked and nanofiber-immobilized (scaffold) CNPs using P. aeruginosa as a bacterial model. We also analyzed the effect of the CNPs on the expression of the \u03b2-lactamase shv, the carbapenemase kpc, and the metallo-\u03b2-lactamase imp genes. To demonstrate the bio-compatibility of the CNPs, a cytotoxic assay was con-ducted using a model of skin fibroblast cells.Material and\u00a0methodsBacterial strainP. aeruginosa (ATCC 27853) was obtained from the microbial collection of the microbiology laboratory of Iran University of medical sciences. A clinical isolate of the same strain was obtained from an infected burn of a patient at the Ali-Asghar hospital in Tehran, Iran.Naked and\u00a0scaffold\u2011 CNPs synthesisCNP powder was purchased from Sigma-Aldrich (Cat. # 796077). Nanofibers were fabricated by mixing 80\u00a0mL of chloroform with 4\u00a0g of polycaprolactone under a mag-netic stirrer for 4\u00a0 h. Then, a gelatin\/acetic acid solution (1.6\u00a0g of gelatin and 20\u00a0mL of 80% acetic acid) was added to the mixture. Nanofibers were produced by an electro-spinning device (Fanavaran Nano-Meghyas, IRAN) at 60% power for 1\u00a0h with rotation at 30\u00a0\u00b0C using a voltage of 20\u00a0kV and a speed of 10 \u00b5L\/min using a 10\u00a0cm nozzle. An aluminum collector and a rotating core were used at 450 \u00d7 g to obtain random-axis nanofibers exposed to dif-ferent concentrations of the following CNPs solutions: P: 200\u00a0\u00b5g\/mL, P\/2: 100\u00a0\u00b5g\/mL, P\/4: 50\u00a0\u00b5g\/mL, P\/8: 25.5\u00a0\u00b5g\/mL, P\/16: 12.25\u00a0 \u00b5g\/mL, P\/32: 6.125\u00a0 \u00b5g\/mL overnight. After coating the samples with gold, the final Scaffold@CNPs structure was imaged using a scanning electron microscope (SEM, DSM-960A Zeiss, Carl\u00a0 Zeiss, Ger-many). Energy Dispersive X-ray (EDX system Kevex) spectroscopy was performed to identify the elements in the nanofiber.In vitro release of\u00a0CNPsTo investigate the release of CNPs from the scaffold, the nanocomposite was immersed in PBS at 37\u00a0 \u00b0C for 9\u00a0days. The optical density of the samples was measured at 300\u2013350\u00a0nm [42\u201345] using a UV\u2013Vis spectrophotom-eter (Thermo Fisher Scientific, Waltham, Massachusetts, USA) on days 1, 3, 5, 7, and 9. Experiments were per-formed in triplicate.Antibacterial activityMinimum inhibitory concentration (MIC)A microdilution test was used to determine the MICs. The experiment was performed in sterile 96-well plates containing 100 \u00b5L of Muller-Hinton broth (M-H). CNPs concentrations of 100, 50, 25, 12.5, 6.25, 3.12, 1.56, 0.78, 0.39, 0.195\u00a0\u00b5g\/mL were tested. M-H broth and untreated bacteria were used as negative and positive controls, Page 3 of 11Zamani\u00a0et\u00a0al. BMC Biotechnology           (2021) 21:68  respectively. The Scaffold@CNPs P, P\/2, P\/4, P\/8, P\/16, and P\/32 were tested in a second microplate.A suspension of bacteria corresponding to 0.5 McFar-land unit was prepared, and after a dilution of 20X, 10 \u00b5L was added to each well (approximately 5 \u00d7  104\u00a0CFU\/mL). Plates were incubated at 37\u00a0\u00b0C for 24\u00a0h. The results were evaluated based on the lack of growth or significant growth of bacteria in the wells. The lowest concentration of NPs that inhibited the growth of the microorganism was recorded as the MIC.Minimum bactericidal concentration (MBC)The final CNP concentration that showed no bacterial growth (no turbidity observed in the MIC test) was cul-tured on M-H agar and incubated at 37\u00a0\u00b0C for 24\u00a0h after serial dilution. The next day, the colonies were counted.Investigation of\u00a0resistance genes using real\u2011time PCRThe resistant clinical isolate was grown on M-H broth containing 50\u00a0\u00b5g\/mL or 200\u00a0\u00b5g\/mL of CNPs or Scaffold@CNPs, respectively. Kanamycin (4\u00a0\u00b5g\/mL) was added for 24\u00a0 h. Total RNA was extracted from bacteria using the  RNX+ extraction kit (Cinagen Bioscience, Tehran, Iran) and following the manufacturer\u2019s instructions. DNAse was used to digest DNA remnants. The RNA concen-tration was measured using a Nano-Drop instrument (Thermo Scientific). The oligonucleotide sequences used in this study are detailed in Table\u00a0 1. The 16S ribosomal RNA from P. aeruginosa was used as an internal control. The qPCR reaction (20 \u00b5L) used the Maxima SYBR green kit (Thermo Scientific) and according to the manufactur-er\u2019s instructions. A thermocycler (ABI, USA)was oper-ated using a program consisting of 1 \u00d7 cycle of 95\u00a0\u00b0C for 5\u00a0min, followed by 40 \u00d7 cycles of 95\u00a0\u00b0C for 30\u00a0s and 60\u00a0\u00b0C for 40\u00a0s.CytotoxicityScaffold@CNPs were exposed to human foreskin fibro-blast HU2 cells obtained from the Iranian Biological Resource Center (Tehran, Iran) for 1, 3, and 7\u00a0 days at 37\u00a0 \u00b0C in an incubator supplemented with 5%  CO2. Dul-becco\u2019s Modified Eagle Medium (DMEM) medium, sup-plemented with 10% fetal bovine serum (FBS) and 1% Penicillin\/Streptomycin.Apoptotic cells were identified using the Annexin V-propidium iodide (PI) staining kit (640914, Biolegend). 6-well plates were seeded with 3 \u00d7  105 cells and incubated for 24\u00a0h at 37\u00a0\u00b0C. The next day, the medium was changed and replaced with 4\u00a0 mL of culture medium containing 150 \u00b5L of P, P\/2, P\/4, P\/8, and P\/16. A similar plate was used, but the CNPs replaced the Scaffold@CNPs. The plates remained in the incubator for 24\u00a0h. The next day, 400 \u00b5L of trypsin was added, and once the cells detached, 400 \u00b5L of fetal bovin serum (FBS)-containing medium were added to each well. The content of each well was centrifuged at 20,000\u00a0rpm for 5\u00a0min, and the supernatant was disposed. Then, 100 \u00b5L of PBS was added. Annexin-V solution was added and incubated for 10\u00a0 min in a dark place. The samples were centrifuged, and cells were rinsed with PBS. Then, 1.5 \u00b5L of PI was added. The sam-ples were analyzed with the flow cytometer.Statistical analysisStatistical analysis was performed using SPSS and a one-way ANOVA test. Excel was used to draw the graphs. Values are reported as the mean \u00b1 SD of three independ-ent experiments.ResultsCharacterization of\u00a0the\u00a0nanoparticlesA zeta potential of + 18\u00a0 mV was measured. In addition, SEM images confirmed that the CNPs were spherical with a size range \u2264 20\u00a0nm  (Fig.\u00a01A). The formation of the Scaffold@CNPs and the diameter and scale of the fibers are shown in Fig.\u00a01B and C. Moreover, the presence of the CNPs on the surface of the fibers was confirmed by SEM imaging (Fig.\u00a01D). Analysis of the peaks in the spectrum obtained from EDX confirmed the presence of cerium in the NPs (Fig.\u00a01E).Scaffold@CNPs containing P, P\/2, P\/4, P\/8, P\/16, and P\/32 were used to study the CNPs release from the nanofiber. A release ranging between 25 and 35% was measured on day 1, with a concomitant increase to 80\u201390% measured on day 9 (Fig.\u00a02). In summary, accord-ing to the CNP release pattern from the Scaffold@CNPs, Table 1 Oligonucleotide sequences used in the gene expression analysisGene Oligonucleotide Sequence Tm (\u00b0C) GC (%)shv Forward TTC TAT CAT GCC TAC GCG GC 60. 32 55. 00Reverse ATC TCC CTG TTA GCC ACC CT 59. 96 55. 00imp Forward AAG AAG TTA ACG GGT GGG GC60. 25 55. 00Reverse CAC GCT CCA CAA ACC AAG TG59. 97 55. 00kpc Forward TGT GTA CGC GAT GGA TAC CG59. 97 55. 00Reverse TTT TGC CGT AAC GGA TGG GT60. 25 50. 0016S Forward CCA CGC CAC TGA TCT TCC AT60.11 55.00Reverse CTG GAC CAT GAT CGA GAG CC59.97 60.0Page 4 of 11Zamani\u00a0et\u00a0al. BMC Biotechnology           (2021) 21:68 Fig. 1 Characterization of CNPs and Scaffold@CNPs. A SEM image of CNPs, B Appearance of nanofibers containing 5% PCL, C SEM image of nanofiber without CNPs, D SEM image of Scaffold@CNPs, and E EDX analysisPage 5 of 11Zamani\u00a0et\u00a0al. BMC Biotechnology           (2021) 21:68  it is expected that 25\u201335% of the total amount of CNP will be released on the first day.Antimicrobial effect of\u00a0CNPs and\u00a0Scaffold@CNPsThe CNPs showed MICs of 12.5\u00a0 \u00b5g\/mL for both the ATCC and the clinical isolate, but an MBC of 200\u00a0 \u00b5g\/mL was necessary to kill the clinical isolate (Table\u00a02). For the Scaffold@CNPs, MICs of 6.25\u00a0\u00b5g\/mL\u00a0\u00b5g and 12\/mL could inhibit the growth of the ATCC and clinical isolate, respectively. Moreover, MBCs of 50\u00a0\u00b5g\/mL and 100\u00a0\u00b5g\/mL were necessary to kill the bacterial cells (Table\u00a02).Evaluation of\u00a0resistance genes expression in\u00a0P. aeruginosa to\u00a0CNPsThe levels of the three genes shv, kpc, and imp, which are related to antibiotic resistance in P. aeruginosa, were evaluated after exposure of the bacterial cells to different combinations of the nanocomposites and the antibiotic kanamycin. The combinations used were: (1) CNPs, (2) Scaffold@CNPs, (3) kanamycin, CNPs + kanamycin, and (4) Scaffold@CNPs + kanamycin. The gene shv was down regulated after treating the cells with Scaffold@CNPs, but an up-regulation was measured when the CNPs alone were used (Fig.\u00a03A). No changes were observed in the other treatments. In the gene kcp, most treatments showed a downregulation of the gene except for the Scaf-fold@CNPs + kanamycin group (Fig.\u00a0 3B). Lastly, a sig-nificant downregulation was measured in the Scaffold@CNPs, but not in the other treatments, except under the presence of kanamycin (Fig.\u00a03C).Cytotoxicity of\u00a0CNPs and\u00a0Scaffold@CNPsCytotoxicity of human fibroblast cells (HU2 cell line) after exposure to CNPs is shown in Fig.\u00a0 4. Results of the fluorescence of all the quarters are summarized in Fig.\u00a04G.The cytotoxicity results fibroblast cells exposed to Scaf-fold@CNPs can be seen in Fig.\u00a0 5. Figure\u00a0 5a shows 94% of control untreated cells remained unstained l. Figure\u00a05b represents in presence of Scaffold@CNPs containing 200\u00a0\u03bcg\/ml of CNPs, 97% of the cells survive.Figure\u00a05c shows that at P\/2 concentration, the number of living cells reduced to 84%, and 5% in the death stage and 10% in the early stage of death. By reducing the con-centration of nanoparticles in Scaffold@CNPs, Fig.\u00a0 5d shows that in the P\/4 concentration the number of living cells decreased to 76% and 12% of cells were in the death stage and 10% in the early stage of death. The effect of Fig. 2 Release of CNPs from Scaffold@CNPs containing P: 200 \u00b5g\/mL, P\/2: 100 \u00b5g\/mL, P\/4: 50 \u00b5g\/mL, P\/8: 25.5 \u00b5g\/mL, P\/16: 12.25 \u00b5g\/mL, and P\/32: 6.125 \u00b5g\/mL over a period of 9 days. The samples were measured by a UV\u2013Vis spectrophotometer using a wavelength between 300 and 350 nmTable 2 MICs and MBCs of CNPs and Scaffold@CNPs against P. aeruginosa strains expressed in \u00b5g\/mLStrain CNPs Scaffold@CNPsMIC MBC MIC MBCATCC strain 12.5 50 6.25 50Clinical isolate 12.5 200 12.5 100Page 6 of 11Zamani\u00a0et\u00a0al. BMC Biotechnology           (2021) 21:68 A)B)C)-40-30-20-10010Gene expression KPC-35000-30000-25000-20000-15000-10000-50000500010000150001Gene expression IMP-2500-2000-1500-1000-50005001000Gene expression SHVFig. 3 Expression of genes conferring antibiotic resistance to P. aeruginosa. Bacterial cells were harvested under different treatments, and the total RNA was converted into cDNA according to Materials and Methods. A shv, B kpc, and C imp genes. Shown are the mean \u00b1 SD of three independent samplesPage 7 of 11Zamani\u00a0et\u00a0al. BMC Biotechnology           (2021) 21:68  A BCG020406080100120Control P P\/2 P\/4 P\/8 P\/16%ofControlConcentration of CNPsCell viabilityDFEFig. 4 Cytotoxicity analysis of HU2 cell line exposed to the CNPs. Analysis was performed by flow cytometry and according to Materials and Methods. A Control, B P, C P\/2, D P\/4, E P\/8, F P\/16, and G Survival rate of the cells normalized to the control. Q1 = Necrotic cells, Q2 = Late apoptotic or necrotic apoptotic cells, Q3 = Apoptotic cells, and Q4 = Untreated cellsPage 8 of 11Zamani\u00a0et\u00a0al. BMC Biotechnology           (2021) 21:68 Scaffold@CNPs with P\/8 and P\/16 concentrations is pre-sented in Fig.\u00a05e and f. The number of living cells in these two concentrations were 83% and 71%, respectively.DiscussionThis study aimed to investigate the antibacterial proper-ties of naked and fixed CNP-containing nanofibers as a potential used to treat P. aeruginosa.Results showed that CNPs in solution at concentra-tions ranging between to 200\u00a0\u00b5g\/mL had an inhibitory effect on the ATCC and the clinical isolate of P. aerugi-nosa. These results\u00a0 are\u00a0 consistent\u00a0 with the\u00a0 findings\u00a0 of a\u00a0previous study,\u00a0which showed MICs of 20 \u00b1 5\u00a0\u03bcg\/mL [4]. Moreover, the inhibitory effect of CNPs was also demonstrated on Gram-negative bacteria such as E.coli [46, 47] and Klebsiella pneumoniae [48].The clinical isolate used in our study was isolated from burn patients receiving antibiotics but suffering from an antibiotic-induced infection. Our study aligned with the fact that clinical isolates are more resistant to antibiotics than the ATCC strains. Thus, clinical 02 04 06 08 01 001 20C o nt ro l P P \/2 P \/4 P \/8 P \/1 6%ofControlC o n c e n t ra t io n o f C N P sA BDCE FGFig. 5 Cytotoxicity analysis of HU2 cell line exposed to the Scaffold@CNPs. Analysis was performed by flow cytometry and according to Materials and Methods. A Control, B P, C P\/2, D P\/4, E P\/8, F P\/16, and G Survival rate of the cells normalized to the control. Q1 = Necrotic cells, Q2 = Late apoptotic or necrotic apoptotic cells, Q3 = Apoptotic cells, and Q4 = Untreated cellsPage 9 of 11Zamani\u00a0et\u00a0al. BMC Biotechnology           (2021) 21:68  isolates isolated from hospitals are more resistant to antibiotics, likely because of the acquisition of plasmids containing antibiotic resistance genes.The stabilized CNPs on the nanofiber surface (Scaf-fold@CNPs) were tested as a potential biomedical appli-cation. Electrospun nanofibers have been widely used for skin tissue engineering and wound dressing due to their extracellular matrix mimicry, biodegradability, and bio-compatibility [49]. In another study, nanofibers contain-ing NPs such as silver, zinc oxide, and gold have been used for wound healing applications [49]. Then, the sta-bilization of NPs on the nanofiber surface helped the NPs last longer at the site of infection with their continuous release. Our study found that the CNPs were released during 9\u00a0days, and then the slow release of them assures a repeated administration might not be necessary. Also, in our study, the use of gelatin-PCL increased the scaffold degradation or biocompatibility of the nanocomposite, influencing the degradation behavior [49].The SHV-betalactamase (shv gene [50, 51]), KPC-carbapenemase (kpc gene [52\u201354]), and metallo-\u03b2-lactamase\u00a0IMP-1 (imp gene [55\u201357]) have been found in resistance strains of P. aeruginosa isolated from various hospitals. Therefore, the measure of the expression level of these genes allows to detect antibiotic resistance of P. aeruginosa [50\u201355, 57, 58].Our qPCR results showed that the exposure of the strains to the Scaffold@CNPs affected the expression of all three genes, mainly by downregulating their expres-sion. The highest reduction was observed on the expres-sion of shv and imp compared to the expression of the kpc. Interestingly, although the soluble CNPs reduced the bacterial titer in the MIC test, it only downregulated the expression of kpc gene. The differences in the behaviour of both nanocomposites could result from the agglom-eration of the soluble CNPs within 24\u00a0 h. At the same time, the gradual release of the CNPs from the scaffold prevents them from agglomerating. The agglomeration of the soluble CNPs is supported by the fact that their zeta potential is + 18\u00a0mV, a value that suggests clumping. In a study reported by Abbas Fazal et\u00a0al., the CNPs deposited on\u00a0 nano-sheets exhibited stronger antibacterial activity than the nanoparticles [59]. They showed a higher sur-face area, leading to a higher concentration of oxygen vacancies on the surface, which caused enhanced ROS generation. ROS has the key role in damage the bacterial membrane and is one of the main mechanisms of CNPs kill bacteria [60, 61].On the other hand, simultaneous treatment of Scaf-fold@CNPs supplemented with antibiotics did not affect on the expression of any of the genes, and soluble CNPs along with antibiotics only reduced the expression of the kpc gene.There are conflicting studies on the simultaneous effect of NPs and antibiotics. However, some studies reported that CNPs could act as antibiotic adjuvants to increase the effectiveness of antimicrobials and facili-tate the entry of antibiotics into the cell by increasing the cell membrane permeability. But some studies are consistent with the results of our study and reported that the antibacterial effect of antibiotics could be dramatically reduced by concomitant treatment with CNPs, which may inhibit antibiotic uptake into the bac-terial cell or disrupt antibiotic activity within the bacte-rial cell.According to the survival results of HU2 fibroblast cells exposed to CNPs and Scaffold@CNPs, it seams the CNPs at low concentrations of nanoparticle, both soluble CNPs and stabilized on the scaffold, it has a cytotoxic effect on fibroblast cells, but with increasing concentration of nanoparticles, the toxicity decreases and at a concentration of 200\u00a0 \u00b5g\/ml reached the con-trol group. The increase in cell growth with increasing concentration of CNPs is consistent with the results of study of Chigurupati et\u00a0 al. [62] that showed the growth rate of keratinocytes and fibroblasts cells which treated with 1 and 10\u00a0\u00b5M CNPs increased significantly compared to cultures treated with 500\u00a0 nM or without CNPs. In this study, our goal was to find out that at concentrations that nanoparticles can kill P.aeroginosa, it has no toxic effect on healthy cells around the wound. In addition to this result, a decrease in the number of cells at lower concentrations was observed, which requires more observations and more detailed studies to confirm.ConclusionsThe nanocomposites CNPs and Scaffold@CNPs showed potent anti-Pseudomonas activity. The. Scaffold@CNPs significantly downregulated the expression of three genes known as involved in the acquisition of antibacterial resistance. This property is significant as Scaffold@CNPs could be developed for topical applications or wound dressing. In addition, the slow release of the CNPs from the nanofiber represents a new modality for skin infec-tion therapies.AcknowledgementsNot applicable.Authors\u2019 contributionsKZ collected the clinical data and performed the antibacterial tests. NAB, MY, GRI, RG and MA prepared the scaffold, cultured the bacteria, and perform part of the MIC, MBC, and qPCR. MR wrote the manuscript. SR performed the anti\u2011bacterial analysis and edited the manuscript. MG wrote the manuscript. HB edited the manuscript. FR conceptualized the idea of the work, participated in the scaffold preparation, and wrote the manuscript. All authors have read and approved the final manuscript.Page 10 of 11Zamani\u00a0et\u00a0al. BMC Biotechnology           (2021) 21:68 FundingFR was supported by IRAN University of medical sciences, Grant number 98\u20111\u201173\u201114751. This grant funds were awarded for purchase any research materials used for this study.Availability of data and materialsThe data that support the findings of this study are available from the cor\u2011responding author (FR) on request.DeclarationsEthics approval and consent to participateIRAN University of medical sciences ethics committee approved the study by the committee\u2019s reference number of IR.IUMS.REC.1398.318. According to the ethics committee, for this study, this no necessary for consent from the patients.Consent for publicationNot applicable.Competing interestsThe authors declare that there is no conflict of interest.Author details1 1. Microbial Biotechnology Research Center, Iran University of Medical Sci\u2011ences, Tehran, Iran. 2. 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Biomaterials. 2013;34(9):2194\u2013201.Publisher\u2019s NoteSpringer Nature remains neutral with regard to jurisdictional claims in pub\u2011lished maps and institutional affiliations.","@language":"en"}],"Genre":[{"@value":"Article","@language":"en"}],"IsShownAt":[{"@value":"10.14288\/1.0406305","@language":"en"}],"Language":[{"@value":"eng","@language":"en"}],"PeerReviewStatus":[{"@value":"Reviewed","@language":"en"}],"Provider":[{"@value":"Vancouver : University of British Columbia Library","@language":"en"}],"Publisher":[{"@value":"BioMed Central","@language":"en"}],"PublisherDOI":[{"@value":"10.1186\/s12896-021-00727-1","@language":"en"}],"Rights":[{"@value":"Attribution 4.0 International (CC BY 4.0)","@language":"en"}],"RightsURI":[{"@value":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/","@language":"en"}],"ScholarlyLevel":[{"@value":"Faculty","@language":"en"},{"@value":"Researcher","@language":"en"}],"Subject":[{"@value":"Cerium oxide nanoparticles","@language":"en"},{"@value":"Nanofiber","@language":"en"},{"@value":"Antibiotic resistance","@language":"en"},{"@value":"Pseudomonas aeruginosa","@language":"en"},{"@value":"Gene expression","@language":"en"},{"@value":"Cytotoxicity","@language":"en"},{"@value":"Clinical isolate","@language":"en"}],"Title":[{"@value":"Antibacterial effect of cerium oxide nanoparticle against Pseudomonas aeruginosa","@language":"en"}],"Type":[{"@value":"Text","@language":"en"}],"URI":[{"@value":"http:\/\/hdl.handle.net\/2429\/80686","@language":"en"}],"SortDate":[{"@value":"2021-12-07 AD","@language":"en"}],"@id":"doi:10.14288\/1.0406305"}