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1
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Smith TA, Zhou L, Ghergherehchi CL, Mikesh M, Yang CZ, Tucker HO, Allgood J, Bushman JS, Bittner GD. Polyethylene glycol has immunoprotective effects on sciatic allografts, but behavioral recovery and graft tolerance require neurorrhaphy and axonal fusion. Neural Regen Res 2025; 20:1192-1206. [PMID: 38989956 PMCID: PMC11438327 DOI: 10.4103/nrr.nrr-d-23-01220] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2023] [Revised: 10/26/2023] [Accepted: 02/29/2024] [Indexed: 07/12/2024] Open
Abstract
JOURNAL/nrgr/04.03/01300535-202504000-00033/figure1/v/2024-07-06T104127Z/r/image-tiff Behavioral recovery using (viable) peripheral nerve allografts to repair ablation-type (segmental-loss) peripheral nerve injuries is delayed or poor due to slow and inaccurate axonal regeneration. Furthermore, such peripheral nerve allografts undergo immunological rejection by the host immune system. In contrast, peripheral nerve injuries repaired by polyethylene glycol fusion of peripheral nerve allografts exhibit excellent behavioral recovery within weeks, reduced immune responses, and many axons do not undergo Wallerian degeneration. The relative contribution of neurorrhaphy and polyethylene glycol-fusion of axons versus the effects of polyethylene glycol per se was unknown prior to this study. We hypothesized that polyethylene glycol might have some immune-protective effects, but polyethylene glycol-fusion was necessary to prevent Wallerian degeneration and functional/behavioral recovery. We examined how polyethylene glycol solutions per se affect functional and behavioral recovery and peripheral nerve allograft morphological and immunological responses in the absence of polyethylene glycol-induced axonal fusion. Ablation-type sciatic nerve injuries in outbred Sprague-Dawley rats were repaired according to a modified protocol using the same solutions as polyethylene glycol-fused peripheral nerve allografts, but peripheral nerve allografts were loose-sutured (loose-sutured polyethylene glycol) with an intentional gap of 1-2 mm to prevent fusion by polyethylene glycol of peripheral nerve allograft axons with host axons. Similar to negative control peripheral nerve allografts not treated by polyethylene glycol and in contrast to polyethylene glycol-fused peripheral nerve allografts, animals with loose-sutured polyethylene glycol peripheral nerve allografts exhibited Wallerian degeneration for all axons and myelin degeneration by 7 days postoperatively and did not recover sciatic-mediated behavioral functions by 42 days postoperatively. Other morphological signs of rejection, such as collapsed Schwann cell basal lamina tubes, were absent in polyethylene glycol-fused peripheral nerve allografts but commonly observed in negative control and loose-sutured polyethylene glycol peripheral nerve allografts at 21 days postoperatively. Loose-sutured polyethylene glycol peripheral nerve allografts had more pro-inflammatory and less anti-inflammatory macrophages than negative control peripheral nerve allografts. While T cell counts were similarly high in loose-sutured-polyethylene glycol and negative control peripheral nerve allografts, loose-sutured polyethylene glycol peripheral nerve allografts expressed some cytokines/chemokines important for T cell activation at much lower levels at 14 days postoperatively. MHCI expression was elevated in loose-sutured polyethylene glycol peripheral nerve allografts, but MHCII expression was modestly lower compared to negative control at 21 days postoperatively. We conclude that, while polyethylene glycol per se reduces some immune responses of peripheral nerve allografts, successful polyethylene glycol-fusion repair of some axons is necessary to prevent Wallerian degeneration of those axons and immune rejection of peripheral nerve allografts, and produce recovery of sensory/motor functions and voluntary behaviors. Translation of polyethylene glycol-fusion technologies would produce a paradigm shift from the current clinical practice of waiting days to months to repair ablation peripheral nerve injuries.
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Affiliation(s)
- Tyler A. Smith
- Department of Molecular Biosciences, University of Texas at Austin, Austin, TX, USA
| | - Liwen Zhou
- Department of Neuroscience, University of Texas at Austin, Austin, TX, USA
| | | | - Michelle Mikesh
- Department of Neuroscience, University of Texas at Austin, Austin, TX, USA
| | - Cathy Z. Yang
- Department of Neuroscience, University of Texas at Austin, Austin, TX, USA
| | - Haley O. Tucker
- Department of Molecular Biosciences, University of Texas at Austin, Austin, TX, USA
| | - JuliAnne Allgood
- Division of Pharmaceutical Sciences, University of Wyoming, Laramie, WY, USA
| | - Jared S. Bushman
- Division of Pharmaceutical Sciences, University of Wyoming, Laramie, WY, USA
| | - George D. Bittner
- Department of Neuroscience, University of Texas at Austin, Austin, TX, USA
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2
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Tunç E, Bora ES, Erbaş O. Harnessing Polyethylene Glycol 3350 for Enhanced Peripheral Nerve Repair: A Path to Accelerated Recovery. MEDICINA (KAUNAS, LITHUANIA) 2025; 61:624. [PMID: 40282915 PMCID: PMC12028508 DOI: 10.3390/medicina61040624] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 03/08/2025] [Revised: 03/25/2025] [Accepted: 03/27/2025] [Indexed: 04/29/2025]
Abstract
Background and Objectives: Peripheral nerve injuries often result in significant functional impairment, and complete recovery remains challenging despite surgical interventions. Polyethylene glycol (PEG) has shown promise in nerve repair by facilitating axonal fusion and inhibiting Wallerian degeneration. This study investigates the biochemical, histopathological, and electrophysiological effects of PEG 3350 in a sciatic nerve injury model. Materials and Methods: Thirty adult male Wistar rats were divided into three groups: a control group, a surgery and saline group, and a surgery and PEG 3350 treatment group. Sciatic nerve transection was performed, and PEG 3350 was administered intraperitoneally for 12 weeks. Electromyography (EMG) and the inclined plane test assessed functional recovery. Sciatic nerve tissues were analyzed histologically and biochemically, including nerve growth factor (NGF), heat shock protein 70 (HSP-70), and malondialdehyde (MDA) levels. Results: PEG 3350 significantly improved electrophysiological parameters, reducing compound muscle action potential (CMAP) latency and increasing CMAP amplitude compared to the saline group (p < 0.05). Functional recovery, assessed by the inclined plane test, showed a significant improvement in the PEG-treated group (p < 0.01). Biochemical analysis revealed increased NGF and HSP-70 levels, suggesting enhanced neuroprotection and regeneration. Histopathological analysis demonstrated reduced fibrosis and increased axonal density in the PEG group compared to controls. PEG 3350 enhances nerve regeneration by improving electrophysiological function, promoting axonal repair, and increasing neurotrophic factor expression. Conclusions: These findings suggest PEG as a potential adjunct therapy for peripheral nerve injuries. Future research should explore the optimal administration protocols and combined therapeutic strategies for maximizing recovery.
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Affiliation(s)
- Erdinç Tunç
- Faculty of Medicine, Department of Anatomy, Biruni University, 34015 Istanbul, Türkiye;
| | - Ejder Saylav Bora
- Faculty of Medicine, Department of Emergency Medicine, Izmir Katip Çelebi University, 35620 Izmir, Türkiye
| | - Oytun Erbaş
- Faculty of Medicine, Biruni Research Center (BAMER), Biruni University, 34015 Istanbul, Türkiye;
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3
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Lin Y, Liu J, Chong SY, Ting HJ, Tang X, Yang L, Zhang S, Qi X, Pei P, Yi Z, Huang C, Hou X, Gao L, Torta F, Liu X, Liu B, Kah JCY, Wang J. Dual-Function Nanoscale Coordination Polymer Nanoparticles for Targeted Diagnosis and Therapeutic Delivery in Atherosclerosis. SMALL (WEINHEIM AN DER BERGSTRASSE, GERMANY) 2024; 20:e2401659. [PMID: 39185808 PMCID: PMC11579969 DOI: 10.1002/smll.202401659] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/03/2024] [Revised: 08/08/2024] [Indexed: 08/27/2024]
Abstract
Atherosclerosis is the primary cause of cardiovascular events such as heart attacks and strokes. However, current medical practice lacks non-invasive, reliable approaches for both imaging atherosclerotic plaques and delivering therapeutic agents directly therein. Here, a biocompatible and biodegradable pH-responsive nanoscale coordination polymers (NCPs) based theranostic system is reported for managing atherosclerosis. NCPs are synthesized with a pH-responsive benzoic-imine (BI) linker and Gd3+. Simvastatin (ST), a statin not used for lowering blood cholesterol but known for its anti-inflammatory and antioxidant effects in mice, is chosen as the model drug. By incorporating ST into the hydrophobic domain of a lipid bilayer shell on NCPs surfaces, ST/NCP-PEG nanoparticles are created that are designed for dual purposes: they diagnose and treat atherosclerosis. When administered intravenously, they target atherosclerotic plaques, breaking down in the mild acidic microenvironment of the plaque to release ST, which reduces inflammation and oxidative stress, and Gd-complexes for MR imaging of the plaques. ST/NCP-PEG nanoparticles show efficacy in slowing the progression of atherosclerosis in live models and allow for simultaneous in vivo monitoring without observed toxicity in major organs. This positions ST/NCP-PEG nanoparticles as a promising strategy for the spontaneous diagnosis and treatment of atherosclerosis.
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Affiliation(s)
- Yuanzhe Lin
- Department of SurgeryYong Loo Lin School of MedicineNational University of Singapore1E Kent Ridge RdSingapore119228Singapore
- Department of Biomedical EngineeringNational University of Singapore4 Engineering Drive 3, Block E4, #04‐08Singapore117583Singapore
- Nanomedicine Translational Research ProgramYong Loo Lin School of MedicineNational University of SingaporeSingapore117609Singapore
| | - Jingjing Liu
- Institute of Translational MedicineMedical CollegeYangzhou UniversityYangzhouJiangsu225001China
- Department of Chemical and Biomolecular EngineeringNational University of SingaporeSingapore117585Singapore
| | - Suet Yen Chong
- Department of SurgeryYong Loo Lin School of MedicineNational University of Singapore1E Kent Ridge RdSingapore119228Singapore
- Nanomedicine Translational Research ProgramYong Loo Lin School of MedicineNational University of SingaporeSingapore117609Singapore
- Cardiovascular Research InstituteNational University Heart Centre Singapore (NUHCS)14 Medical DriveSingapore117599Singapore
| | - Hui Jun Ting
- Department of SurgeryYong Loo Lin School of MedicineNational University of Singapore1E Kent Ridge RdSingapore119228Singapore
- Nanomedicine Translational Research ProgramYong Loo Lin School of MedicineNational University of SingaporeSingapore117609Singapore
| | - Xichuan Tang
- Department of SurgeryYong Loo Lin School of MedicineNational University of Singapore1E Kent Ridge RdSingapore119228Singapore
- Nanomedicine Translational Research ProgramYong Loo Lin School of MedicineNational University of SingaporeSingapore117609Singapore
| | - Liqiang Yang
- Department of SurgeryYong Loo Lin School of MedicineNational University of Singapore1E Kent Ridge RdSingapore119228Singapore
- Nanomedicine Translational Research ProgramYong Loo Lin School of MedicineNational University of SingaporeSingapore117609Singapore
| | - Sitong Zhang
- Department of SurgeryYong Loo Lin School of MedicineNational University of Singapore1E Kent Ridge RdSingapore119228Singapore
- Nanomedicine Translational Research ProgramYong Loo Lin School of MedicineNational University of SingaporeSingapore117609Singapore
| | - Xinyi Qi
- Department of SurgeryYong Loo Lin School of MedicineNational University of Singapore1E Kent Ridge RdSingapore119228Singapore
- Nanomedicine Translational Research ProgramYong Loo Lin School of MedicineNational University of SingaporeSingapore117609Singapore
| | - Peng Pei
- Department of SurgeryYong Loo Lin School of MedicineNational University of Singapore1E Kent Ridge RdSingapore119228Singapore
- Nanomedicine Translational Research ProgramYong Loo Lin School of MedicineNational University of SingaporeSingapore117609Singapore
- Department of ChemistryNational University of Singapore3 Science Drive 3Singapore117543Singapore
| | - Zhigao Yi
- Department of ChemistryNational University of Singapore3 Science Drive 3Singapore117543Singapore
| | - Chenyuan Huang
- Department of SurgeryYong Loo Lin School of MedicineNational University of Singapore1E Kent Ridge RdSingapore119228Singapore
- Nanomedicine Translational Research ProgramYong Loo Lin School of MedicineNational University of SingaporeSingapore117609Singapore
| | - Xiao Hou
- Department of SurgeryYong Loo Lin School of MedicineNational University of Singapore1E Kent Ridge RdSingapore119228Singapore
- Nanomedicine Translational Research ProgramYong Loo Lin School of MedicineNational University of SingaporeSingapore117609Singapore
| | - Liang Gao
- Department of BiochemistryYong Loo Lin School of MedicineNational University of SingaporeSingapore117596Singapore
- Singapore Lipidomics Incubator (SLING)Life Sciences InstituteNational University of SingaporeSingapore117456Singapore
| | - Federico Torta
- Department of BiochemistryYong Loo Lin School of MedicineNational University of SingaporeSingapore117596Singapore
- Singapore Lipidomics Incubator (SLING)Life Sciences InstituteNational University of SingaporeSingapore117456Singapore
| | - Xiaogang Liu
- Department of ChemistryNational University of Singapore3 Science Drive 3Singapore117543Singapore
| | - Bin Liu
- Department of Chemical and Biomolecular EngineeringNational University of SingaporeSingapore117585Singapore
| | - James Chen Yong Kah
- Department of Biomedical EngineeringNational University of Singapore4 Engineering Drive 3, Block E4, #04‐08Singapore117583Singapore
| | - Jiong‐Wei Wang
- Department of SurgeryYong Loo Lin School of MedicineNational University of Singapore1E Kent Ridge RdSingapore119228Singapore
- Nanomedicine Translational Research ProgramYong Loo Lin School of MedicineNational University of SingaporeSingapore117609Singapore
- Cardiovascular Research InstituteNational University Heart Centre Singapore (NUHCS)14 Medical DriveSingapore117599Singapore
- Department of PhysiologyYong Loo Lin School of MedicineNational University of Singapore2 Medical DriveSingapore117593Singapore
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Kang DD, Hou X, Wang L, Xue Y, Li H, Zhong Y, Wang S, Deng B, McComb DW, Dong Y. Engineering LNPs with polysarcosine lipids for mRNA delivery. Bioact Mater 2024; 37:86-93. [PMID: 38523704 PMCID: PMC10957522 DOI: 10.1016/j.bioactmat.2024.03.017] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2023] [Revised: 03/04/2024] [Accepted: 03/11/2024] [Indexed: 03/26/2024] Open
Abstract
Since the approval of the lipid nanoparticles (LNP)-mRNA vaccines against the SARS-CoV-2 virus, there has been an increased interest in the delivery of mRNA through LNPs. However, current LNP formulations contain PEG lipids, which can stimulate the generation of anti-PEG antibodies. The presence of these antibodies can potentially cause adverse reactions and reduce therapeutic efficacy after administration. Given the widespread deployment of the COVID-19 vaccines, the increased exposure to PEG may necessitate the evaluation of alternative LNP formulations without PEG components. In this study, we investigated a series of polysarcosine (pSar) lipids as alternatives to the PEG lipids to determine whether pSar lipids could still provide the functionality of the PEG lipids in the ALC-0315 and SM-102 LNP systems. We found that complete replacement of the PEG lipid with a pSar lipid can increase or maintain mRNA delivery efficiency and exhibit similar safety profiles in vivo.
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Affiliation(s)
- Diana D. Kang
- Icahn Genomics Institute, Precision Immunology Institute, Department of Immunology and Immunotherapy, Department of Oncological Sciences, Tisch Cancer Institute, Friedman Brain Institute, Biomedical Engineering and Imaging Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
- Division of Pharmaceutics & Pharmacology, College of Pharmacy, The Ohio State University, Columbus, OH, 43210, USA
| | - Xucheng Hou
- Icahn Genomics Institute, Precision Immunology Institute, Department of Immunology and Immunotherapy, Department of Oncological Sciences, Tisch Cancer Institute, Friedman Brain Institute, Biomedical Engineering and Imaging Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
| | - Leiming Wang
- Icahn Genomics Institute, Precision Immunology Institute, Department of Immunology and Immunotherapy, Department of Oncological Sciences, Tisch Cancer Institute, Friedman Brain Institute, Biomedical Engineering and Imaging Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
| | - Yonger Xue
- Icahn Genomics Institute, Precision Immunology Institute, Department of Immunology and Immunotherapy, Department of Oncological Sciences, Tisch Cancer Institute, Friedman Brain Institute, Biomedical Engineering and Imaging Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
- Division of Pharmaceutics & Pharmacology, College of Pharmacy, The Ohio State University, Columbus, OH, 43210, USA
| | - Haoyuan Li
- Icahn Genomics Institute, Precision Immunology Institute, Department of Immunology and Immunotherapy, Department of Oncological Sciences, Tisch Cancer Institute, Friedman Brain Institute, Biomedical Engineering and Imaging Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
| | - Yichen Zhong
- Icahn Genomics Institute, Precision Immunology Institute, Department of Immunology and Immunotherapy, Department of Oncological Sciences, Tisch Cancer Institute, Friedman Brain Institute, Biomedical Engineering and Imaging Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
| | - Siyu Wang
- Icahn Genomics Institute, Precision Immunology Institute, Department of Immunology and Immunotherapy, Department of Oncological Sciences, Tisch Cancer Institute, Friedman Brain Institute, Biomedical Engineering and Imaging Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
| | - Binbin Deng
- Center for Electron Microscopy and Analysis, The Ohio State University, Columbus, OH, 43212, USA
| | - David W. McComb
- Center for Electron Microscopy and Analysis, The Ohio State University, Columbus, OH, 43212, USA
- Department of Materials Science and Engineering, The Ohio State University, Columbus, OH, 43210, USA
| | - Yizhou Dong
- Icahn Genomics Institute, Precision Immunology Institute, Department of Immunology and Immunotherapy, Department of Oncological Sciences, Tisch Cancer Institute, Friedman Brain Institute, Biomedical Engineering and Imaging Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
- Division of Pharmaceutics & Pharmacology, College of Pharmacy, The Ohio State University, Columbus, OH, 43210, USA
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5
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Yuan S, Hu Q. Convergence of nanomedicine and neutrophils for drug delivery. Bioact Mater 2024; 35:150-166. [PMID: 38318228 PMCID: PMC10839777 DOI: 10.1016/j.bioactmat.2024.01.022] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2023] [Revised: 01/20/2024] [Accepted: 01/21/2024] [Indexed: 02/07/2024] Open
Abstract
Neutrophils have recently emerged as promising carriers for drug delivery due to their unique properties including rapid response toward inflammation, chemotaxis, and transmigration. When integrated with nanotechnology that has enormous advantages in improving treatment efficacy and reducing side effects, neutrophil-based nano-drug delivery systems have expanded the repertoire of nanoparticles employed in precise therapeutic interventions by either coating nanoparticles with their membranes, loading nanoparticles inside living cells, or engineering chimeric antigen receptor (CAR)-neutrophils. These neutrophil-inspired therapies have shown superior biocompatibility, targeting ability, and therapeutic robustness. In this review, we summarized the benefits of combining neutrophils and nanotechnologies, the design principles and underlying mechanisms, and various applications in disease treatments. The challenges and prospects for neutrophil-based drug delivery systems were also discussed.
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Affiliation(s)
- Sichen Yuan
- Pharmaceutical Sciences Division, School of Pharmacy, University of Wisconsin-Madison, Madison, WI, 53705, United States
- Carbone Cancer Center, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI, 53705, United States
- Wisconsin Center for NanoBioSystems, School of Pharmacy, University of Wisconsin-Madison, Madison, WI, 53705, United States
| | - Quanyin Hu
- Pharmaceutical Sciences Division, School of Pharmacy, University of Wisconsin-Madison, Madison, WI, 53705, United States
- Carbone Cancer Center, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI, 53705, United States
- Wisconsin Center for NanoBioSystems, School of Pharmacy, University of Wisconsin-Madison, Madison, WI, 53705, United States
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6
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Martínez-García K, Zertuche-Arias T, Bernáldez-Sarabia J, Iñiguez E, Kretzchmar T, Camacho-Villegas TA, Lugo-Fabres PH, Licea Navarro AF, Bravo-Madrigal J, Castro-Ceseña AB. Radical Scavenging, Hemocompatibility, and Antibacterial Activity against MDR Acinetobacter baumannii in Alginate-Based Aerogels Containing Lipoic Acid-Capped Silver Nanoparticles. ACS OMEGA 2024; 9:2350-2361. [PMID: 38250422 PMCID: PMC10795026 DOI: 10.1021/acsomega.3c06114] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/23/2023] [Revised: 12/21/2023] [Accepted: 12/25/2023] [Indexed: 01/23/2024]
Abstract
Retaining the hemocompatibility, supporting cell growth, and exhibiting anti-inflammatory and antioxidant properties, while having antimicrobial activity, particularly against multidrug-resistant bacteria (MDR), remain a challenge when designing aerogels for biomedical applications. Here, we report that our synthesized alginate-based aerogels containing either 7.5 or 11.25 μg of lipoic acid-capped silver nanoparticles (AgNPs) showed improved hemocompatibility properties while retaining their antimicrobial effect against MDR Acinetobacter baumannii and the reference strain Escherichia coli, relative to a commercial dressing and polymyxin B, used as a reference. The differences in terms of the microstructure and nature of the silver, used as the bioactive agent, between our synthesized aerogels and the commercial dressing used as a reference allowed us to improve several biological properties in our aerogels with respect to the reference commercial material. Our aerogels showed significantly higher antioxidant capacity, in terms of nmol of Trolox equivalent antioxidant capacity per mg of aerogel, than the commercial dressing. All our synthesized aerogels showed anti-inflammatory activity, expressed as nmol of indomethacin equivalent anti-inflammatory activity per mg of aerogel, while this property was not found in the commercial dressing material. Finally, our aerogels were highly hemocompatible (less than 1% hemolysis ratio); however, the commercial material showed a 20% hemolysis rate. Therefore, our alginate-based aerogels with lipoic acid-capped AgNPs hold promise for biomedical applications.
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Affiliation(s)
- Kevin
D. Martínez-García
- Departamento
de Innovación Biomédica, Centro
de Investigación Científica y de Educación Superior
de Ensenada, Baja California (CICESE), Carretera Ensenada-Tijuana No. 3918, Zona Playitas, C.P. 22860 Ensenada, Baja California, Mexico
| | - Tonatzin Zertuche-Arias
- Departamento
de Innovación Biomédica, Centro
de Investigación Científica y de Educación Superior
de Ensenada, Baja California (CICESE), Carretera Ensenada-Tijuana No. 3918, Zona Playitas, C.P. 22860 Ensenada, Baja California, Mexico
| | - Johanna Bernáldez-Sarabia
- Departamento
de Innovación Biomédica, Centro
de Investigación Científica y de Educación Superior
de Ensenada, Baja California (CICESE), Carretera Ensenada-Tijuana No. 3918, Zona Playitas, C.P. 22860 Ensenada, Baja California, Mexico
| | - Enrique Iñiguez
- Ciencias
de la Tierra, Centro de Investigación
Científica y de Educación Superior de Ensenada, Baja
California (CICESE), Carretera Ensenada-Tijuana No. 3918, Zona Playitas, C.P. 22860 Ensenada, Baja California, Mexico
- CONAHCYT—Ciencias
de la Tierra, Centro de Investigación
Científica y de Educación Superior de Ensenada, Baja
California (CICESE), Carretera Ensenada-Tijuana No. 3918, Zona Playitas, C.P. 22860 Ensenada, Baja California, Mexico
| | - Thomas Kretzchmar
- Ciencias
de la Tierra, Centro de Investigación
Científica y de Educación Superior de Ensenada, Baja
California (CICESE), Carretera Ensenada-Tijuana No. 3918, Zona Playitas, C.P. 22860 Ensenada, Baja California, Mexico
| | - Tanya Amanda Camacho-Villegas
- Unidad
de Biotecnología Médica y Farmacéutica, Centro de Investigación Asistencia en Tecnología
y Diseño de Estado de Jalisco (CIATEJ), A.C. Av. Normalistas No. 800, Colinas de la Normal, C.P. 44270 Guadalajara, Jalisco, Mexico
- CONAHCYT-Unidad
de Biotecnología Médica y Farmacéutica, Centro de Investigación Asistencia en Tecnología
y Diseño del Estado de Jalisco (CIATEJ), A.C. Av. Normalistas No. 800, Colinas de la Normal, C.P. 44270 Guadalajara, Jalisco, Mexico
| | - Pavel H. Lugo-Fabres
- Unidad
de Biotecnología Médica y Farmacéutica, Centro de Investigación Asistencia en Tecnología
y Diseño de Estado de Jalisco (CIATEJ), A.C. Av. Normalistas No. 800, Colinas de la Normal, C.P. 44270 Guadalajara, Jalisco, Mexico
- CONAHCYT-Unidad
de Biotecnología Médica y Farmacéutica, Centro de Investigación Asistencia en Tecnología
y Diseño del Estado de Jalisco (CIATEJ), A.C. Av. Normalistas No. 800, Colinas de la Normal, C.P. 44270 Guadalajara, Jalisco, Mexico
| | - Alexei F. Licea Navarro
- Departamento
de Innovación Biomédica, Centro
de Investigación Científica y de Educación Superior
de Ensenada, Baja California (CICESE), Carretera Ensenada-Tijuana No. 3918, Zona Playitas, C.P. 22860 Ensenada, Baja California, Mexico
| | - Jorge Bravo-Madrigal
- Unidad
de Biotecnología Médica y Farmacéutica, Centro de Investigación Asistencia en Tecnología
y Diseño de Estado de Jalisco (CIATEJ), A.C. Av. Normalistas No. 800, Colinas de la Normal, C.P. 44270 Guadalajara, Jalisco, Mexico
| | - Ana B. Castro-Ceseña
- Departamento
de Innovación Biomédica, Centro
de Investigación Científica y de Educación Superior
de Ensenada, Baja California (CICESE), Carretera Ensenada-Tijuana No. 3918, Zona Playitas, C.P. 22860 Ensenada, Baja California, Mexico
- CONAHCYT-Departamento
de Innovación Biomédica, Centro
de Investigación Científica y de Educación Superior
de Ensenada, Baja California (CICESE), Carretera Ensenada-Tijuana No. 3918, Zona Playitas, C.P. 22860 Ensenada, Baja California, Mexico
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7
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Abudalu M, Aqawi M, Sionov RV, Friedman M, Gati I, Munz Y, Ohana G, Steinberg D. Polyglactin 910 Meshes Coated with Sustained-Release Cannabigerol Varnish Inhibit Staphylococcus aureus Biofilm Formation and Macrophage Cytokine Secretion: An In Vitro Study. Pharmaceuticals (Basel) 2023; 16:ph16050745. [PMID: 37242528 DOI: 10.3390/ph16050745] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2023] [Revised: 05/02/2023] [Accepted: 05/11/2023] [Indexed: 05/28/2023] Open
Abstract
Synthetic surgical meshes are commonly used in abdominal wall reconstruction surgeries to strengthen a weak abdominal wall. Common mesh-related complications include local infection and inflammatory processes. Because cannabigerol (CBG) has both antibacterial and anti-inflammatory properties, we proposed that coating VICRYL (polyglactin 910) mesh with a sustained-release varnish (SRV) containing CBG would prevent these complications. We used an in vitro infection model with Staphylococcus aureus and an in vitro inflammation model of lipopolysaccharide (LPS)-stimulated macrophages. Meshes coated with either SRV-placebo or SRV-CBG were exposed daily to S. aureus in tryptic soy medium (TSB) or macrophage Dulbecco's modified eagle medium (DMEM). Bacterial growth and biofilm formation in the environment and on the meshes were assessed by changes in optical density, bacterial ATP content, metabolic activity, crystal violet staining, spinning disk confocal microscopy (SDCM), and high-resolution scanning electron microscopy (HR-SEM). The anti-inflammatory effect of the culture medium that was exposed daily to the coated meshes was analyzed by measuring the release of the cytokines IL-6 and IL-10 from LPS-stimulated RAW 264.7 macrophages with appropriate ELISA kits. Additionally, a cytotoxicity assay was performed on Vero epithelial cell lines. We observed that compared with SRV-placebo, the segments coated with SRV-CBG inhibited the bacterial growth of S. aureus in the mesh environment for 9 days by 86 ± 4% and prevented biofilm formation and metabolic activity in the surroundings for 9 days, with respective 70 ± 2% and 95 ± 0.2% reductions. The culture medium that was incubated with the SRV-CBG-coated mesh inhibited LPS-induced secretion of IL-6 and IL-10 from the RAW 264.7 macrophages for up to 6 days without affecting macrophage viability. A partial anti-inflammatory effect was also observed with SRV-placebo. The conditioned culture medium was not toxic to Vero epithelial cells, which had an IC50 of 25 µg/mL for CBG. In conclusion, our data indicate a potential role of coating VICRYL mesh with SRV-CBG in preventing infection and inflammation in the initial period after surgery.
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Affiliation(s)
- Mustafa Abudalu
- The Biofilm Research Laboratory, The Institute of Biomedical and Oral Research (IBOR), The Faculty of Dental Medicine, The Hebrew University of Jerusalem, Jerusalem 9112102, Israel
- Department of General Surgery, Barzilai Medical Center, Ashkelon 7830604, Israel
| | - Muna Aqawi
- The Biofilm Research Laboratory, The Institute of Biomedical and Oral Research (IBOR), The Faculty of Dental Medicine, The Hebrew University of Jerusalem, Jerusalem 9112102, Israel
- The Institute of Drug Research, School of Pharmacy, The Hebrew University of Jerusalem, Jerusalem 9112102, Israel
| | - Ronit Vogt Sionov
- The Biofilm Research Laboratory, The Institute of Biomedical and Oral Research (IBOR), The Faculty of Dental Medicine, The Hebrew University of Jerusalem, Jerusalem 9112102, Israel
| | - Michael Friedman
- The Institute of Drug Research, School of Pharmacy, The Hebrew University of Jerusalem, Jerusalem 9112102, Israel
| | - Irith Gati
- The Institute of Drug Research, School of Pharmacy, The Hebrew University of Jerusalem, Jerusalem 9112102, Israel
| | - Yaron Munz
- Department of General Surgery, Barzilai Medical Center, Ashkelon 7830604, Israel
| | - Gil Ohana
- Department of General Surgery, Barzilai Medical Center, Ashkelon 7830604, Israel
| | - Doron Steinberg
- The Biofilm Research Laboratory, The Institute of Biomedical and Oral Research (IBOR), The Faculty of Dental Medicine, The Hebrew University of Jerusalem, Jerusalem 9112102, Israel
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Liao WC, Wang CH, Sun TH, Su YC, Chen CH, Chang WT, Chen PL, Shiue YL. The Antimicrobial Effects of Colistin Encapsulated in Chelating Complex Micelles for the Treatment of Multi-Drug-Resistant Gram-Negative Bacteria: A Pharmacokinetic Study. Antibiotics (Basel) 2023; 12:antibiotics12050836. [PMID: 37237739 DOI: 10.3390/antibiotics12050836] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2023] [Revised: 04/20/2023] [Accepted: 04/28/2023] [Indexed: 05/28/2023] Open
Abstract
Background: Infections caused by multi-drug-resistant Gram-negative bacteria (MDR-GNB) are an emerging problem globally. Colistin is the last-sort antibiotic for MDR-GNB, but its toxicity limits its clinical use. We aimed to test the efficacy of colistin-loaded micelles (CCM-CL) against drug-resistant Pseudomonas aeruginosa and compare their safety with that of free colistin in vitro and in vivo. Materials and methods: We incorporated colistin into chelating complex micelles (CCMs), thus producing colistin-loaded micelles (CCM-CL), and conducted both safety and efficacy surveys to elucidate their potential uses. Results: In a murine model, the safe dose of CCM-CL was 62.5%, which is much better than that achieved after the intravenous bolus injection of 'free' colistin. With a slow drug infusion, the safe dose of CCM-CL reached 16 mg/kg, which is double the free colistin, 8 mg/kg. The area under the curve (AUC) levels for CCM-CL were 4.09- and 4.95-fold higher than those for free colistin in terms of AUC0-t and AUC0-inf, respectively. The elimination half-lives of CCM-CL and free colistin groups were 12.46 and 102.23 min, respectively. In the neutropenic mice model with carbapenem-resistant Pseudomonas aeruginosa pneumonia, the 14-day survival rate of the mice treated with CCM-CL was 80%, which was significantly higher than the 30% in the free colistin group (p < 0.05). Conclusions: Our results showed that CCM-CL, an encapsulated form of colistin, is safe and effective, and thus may become a drug of choice against MDR-GNB.
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Affiliation(s)
- Wei-Chuan Liao
- Institute of Biomedical Sciences, College of Medicine, National Sun Yat-sen University, Kaohsiung 804201, Taiwan
- Original Biomedicals Co., Ltd., Tainan 744092, Taiwan
| | - Chau-Hui Wang
- Original Biomedicals Co., Ltd., Tainan 744092, Taiwan
| | - Tzu-Hui Sun
- Original Biomedicals Co., Ltd., Tainan 744092, Taiwan
- Department of Life Sciences, National Chung Hsing University, Taichung 402202, Taiwan
| | - Yu-Cheng Su
- Institute of Basic Medical Sciences, National Cheng Kung University, Tainan 701301, Taiwan
| | | | - Wen-Teng Chang
- Department of Pharmaceutical Science and Technology, Chung Hwa University of Medical Technology, Tainan 717302, Taiwan
| | - Po-Lin Chen
- Department of Internal Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan 701301, Taiwan
- Center for Infection Control, National Cheng Kung University Hospital, Tainan 701301, Taiwan
- Diagnostic Microbiology and Antimicrobial Resistance Laboratory, National Cheng Kung University Hospital, Tainan 701301, Taiwan
- Department of Microbiology and Immunology, College of Medicine, National Cheng Kung University, Tainan 701301, Taiwan
| | - Yow-Ling Shiue
- Institute of Biomedical Sciences, College of Medicine, National Sun Yat-sen University, Kaohsiung 804201, Taiwan
- Institute of Precision Medicine, College of Medicine, National Sun Yat-sen University, Kaohsiung 804201, Taiwan
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9
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Cataldo Russomando A, Steinberg D, Gati I, Vogt Sionov R, Eliashar R, Friedman M, Gross M. Sinonasal Stent Coated with Sustained-Release Varnish of Mometasone Furoate Inhibits Pro-Inflammatory Cytokine Release from Macrophages: An In Vitro Study. Pharmaceutics 2023; 15:pharmaceutics15031015. [PMID: 36986875 PMCID: PMC10051169 DOI: 10.3390/pharmaceutics15031015] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2023] [Revised: 03/16/2023] [Accepted: 03/20/2023] [Indexed: 03/30/2023] Open
Abstract
The aim of the study was to develop a sustained-release varnish (SRV) containing mometasone furoate (MMF) for sinonasal stents (SNS) to reduce mucosa inflammation in the sinonasal cavity. The SNS' segments coated with SRV-MMF or an SRV-placebo were incubated daily in a fresh DMEM at 37 °C for 20 days. The immunosuppressive activity of the collected DMEM supernatants was tested on the ability of mouse RAW 264.7 macrophages to secrete the cytokines' tumor necrosis factor α (TNFα) and interleukin (IL)-10 and IL-6 in response to lipopolysaccharide (LPS). The cytokine levels were determined by respective Enzyme-Linked Immunosorbent Assays (ELISAs). We found that the daily amount of MMF released from the coated SNS was sufficient to significantly inhibit LPS-induced IL-6 and IL-10 secretion from the macrophages up to days 14 and 17, respectively. SRV-MMF had, however, only a mild inhibitory effect on LPS-induced TNFα secretion as compared to the SRV-placebo-coated SNS. In conclusion, the coating of SNS with SRV-MMF provides a sustained delivery of MMF for at least 2 weeks, maintaining a level sufficient for inhibiting pro-inflammatory cytokine release. This technological platform is, therefore, expected to provide anti-inflammatory benefits during the postoperative healing period and may play a significant role in the future treatment of chronic rhinosinusitis.
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Affiliation(s)
- Alessandra Cataldo Russomando
- Department of Otolaryngology-Head and Neck Surgery, Hadassah Medical Center, Jerusalem 9112102, Israel
- The Biofilm Research Laboratory, The Institute of Biomedical and Oral Research (IBOR), The Faculty of Dental Medicine, Hebrew University of Jerusalem, Jerusalem 9112102, Israel
| | - Doron Steinberg
- The Biofilm Research Laboratory, The Institute of Biomedical and Oral Research (IBOR), The Faculty of Dental Medicine, Hebrew University of Jerusalem, Jerusalem 9112102, Israel
| | - Irith Gati
- Institute for Drug Research, School of Pharmacy, The Hebrew University of Jerusalem, Jerusalem 9112102, Israel
| | - Ronit Vogt Sionov
- The Biofilm Research Laboratory, The Institute of Biomedical and Oral Research (IBOR), The Faculty of Dental Medicine, Hebrew University of Jerusalem, Jerusalem 9112102, Israel
| | - Ron Eliashar
- Department of Otolaryngology-Head and Neck Surgery, Hadassah Medical Center, Jerusalem 9112102, Israel
- The Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem 9112102, Israel
| | - Michael Friedman
- Institute for Drug Research, School of Pharmacy, The Hebrew University of Jerusalem, Jerusalem 9112102, Israel
| | - Menachem Gross
- Department of Otolaryngology-Head and Neck Surgery, Hadassah Medical Center, Jerusalem 9112102, Israel
- The Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem 9112102, Israel
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10
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Mekkawy AI, Fathy M, Mohamed HB. Evaluation of Different Surface Coating Agents for Selenium Nanoparticles: Enhanced Anti-Inflammatory Activity and Drug Loading Capacity. Drug Des Devel Ther 2022; 16:1811-1825. [PMID: 35719212 PMCID: PMC9205440 DOI: 10.2147/dddt.s360344] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2022] [Accepted: 05/28/2022] [Indexed: 11/23/2022] Open
Abstract
Background Inflammation is the keystone in the disease’s pathological process in response to any damaging stimuli. Therefore, any agent that inhibits the inflammatory response is under focus, either a drug or a bioactive compound. Selenium nanoparticles have drawn attention in various biomedical applications, including the anti-inflammatory activity. Purpose In the current study, we aimed to evaluate the capacity of different surface coating materials (soybean lecithin, PEG 6000, and β-cyclodextrin) to enhance the anti-inflammatory activity of the synthesized selenium nanoparticles (SeNPs). The capability of the coated SeNPs to adsorb indomethacin (IND) on their surfaces compared to the uncoated SeNPs was also evaluated. Methods SeNPs were synthesized, coated with different materials, and characterized in vitro using X-ray diffraction, UV-Vis spectrophotometer, FTIR, SEM, TEM, and particle size and zeta potential measurements. The in vivo anti-inflammatory activity of the uncoated/coated SeNPs loaded into hydrogel was evaluated using a carrageenan-induced paw edema rat model. The effect of SeNPs surface coatings was further evaluated for IND loading capacity. Results Our findings proved the superior anti-inflammatory activity of all coated SeNPs compared to the uncoated SeNPs, especially with β-cyclodextrin surface coating. Regarding the IND loading capacity of the prepared uncoated/coated SeNPs, the amount of drug loaded was 0.12, 1.12, 0.3, and 0.14 µg IND/µg SeNPs for the uncoated, lecithin-, PEG- and β-CD-coated SeNPs, respectively. Conclusion Surface functionalization of SeNPs can provide a synergistic therapeutic activity. Our results are promising for further investigation of the in vivo anti-inflammatory synergistic activity of the IND-loaded surface-coated SeNPs.
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Affiliation(s)
- Aml I Mekkawy
- Department of Pharmaceutics and Clinical Pharmacy, Faculty of Pharmacy, Sohag University, Sohag, 82524, Egypt
- Correspondence: Aml I Mekkawy, Department of Pharmaceutics and Clinical Pharmacy, Faculty of Pharmacy, Sohag University, Sohag, 82524, Egypt, Email
| | - M Fathy
- Department of Pharmaceutics, Faculty of Pharmacy, Assiut University, Assiut, 71526, Egypt
| | - Hebatallah B Mohamed
- Department of Pharmaceutics, Faculty of Pharmacy, South Valley University, Qena, 83523, Egypt
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11
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Teodoro JS, Da Silva RT, Machado IF, Panisello-Roselló A, Roselló-Catafau J, Rolo AP, Palmeira CM. Shaping of Hepatic Ischemia/Reperfusion Events: The Crucial Role of Mitochondria. Cells 2022; 11:688. [PMID: 35203337 PMCID: PMC8870414 DOI: 10.3390/cells11040688] [Citation(s) in RCA: 23] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2022] [Revised: 02/09/2022] [Accepted: 02/11/2022] [Indexed: 12/10/2022] Open
Abstract
Hepatic ischemia reperfusion injury (HIRI) is a major hurdle in many clinical scenarios, including liver resection and transplantation. Various studies and countless surgical events have led to the observation of a strong correlation between HIRI induced by liver transplantation and early allograft-dysfunction development. The detrimental impact of HIRI has driven the pursuit of new ways to alleviate its adverse effects. At the core of HIRI lies mitochondrial dysfunction. Various studies, from both animal models and in clinical settings, have clearly shown that mitochondrial function is severely hampered by HIRI and that its preservation or restoration is a key indicator of successful organ recovery. Several strategies have been thus implemented throughout the years, targeting mitochondrial function. This work briefly discusses some the most utilized approaches, ranging from surgical practices to pharmacological interventions and highlights how novel strategies can be investigated and implemented by intricately discussing the way mitochondrial function is affected by HIRI.
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Affiliation(s)
- João S. Teodoro
- MitoLab, Department of Life Sciences, University of Coimbra, 3000 Coimbra, Portugal; (J.S.T.); (A.P.R.)
- MitoLab, Mitochondria, Metabolism and Disease Group, Center for Neurosciences and Cell Biology, Faculdade de Medicina, University of Coimbra, 3000 Coimbra, Portugal; (R.T.D.S.); (I.F.M.)
- IIIUC–Institute of Interdisciplinary Research, University of Coimbra, Pólo II da Universidade de Coimbra, 3000 Coimbra, Portugal
| | - Rui T. Da Silva
- MitoLab, Mitochondria, Metabolism and Disease Group, Center for Neurosciences and Cell Biology, Faculdade de Medicina, University of Coimbra, 3000 Coimbra, Portugal; (R.T.D.S.); (I.F.M.)
- Experimental Pathology Department, Institute of Biomedical Research of Barcelona (IIBB), CSIC-IDIBAPS, 08036 Barcelona, Spain; (A.P.-R.); (J.R.-C.)
| | - Ivo F. Machado
- MitoLab, Mitochondria, Metabolism and Disease Group, Center for Neurosciences and Cell Biology, Faculdade de Medicina, University of Coimbra, 3000 Coimbra, Portugal; (R.T.D.S.); (I.F.M.)
- IIIUC–Institute of Interdisciplinary Research, University of Coimbra, Pólo II da Universidade de Coimbra, 3000 Coimbra, Portugal
| | - Arnau Panisello-Roselló
- Experimental Pathology Department, Institute of Biomedical Research of Barcelona (IIBB), CSIC-IDIBAPS, 08036 Barcelona, Spain; (A.P.-R.); (J.R.-C.)
| | - Joan Roselló-Catafau
- Experimental Pathology Department, Institute of Biomedical Research of Barcelona (IIBB), CSIC-IDIBAPS, 08036 Barcelona, Spain; (A.P.-R.); (J.R.-C.)
| | - Anabela P. Rolo
- MitoLab, Department of Life Sciences, University of Coimbra, 3000 Coimbra, Portugal; (J.S.T.); (A.P.R.)
- MitoLab, Mitochondria, Metabolism and Disease Group, Center for Neurosciences and Cell Biology, Faculdade de Medicina, University of Coimbra, 3000 Coimbra, Portugal; (R.T.D.S.); (I.F.M.)
| | - Carlos M. Palmeira
- MitoLab, Department of Life Sciences, University of Coimbra, 3000 Coimbra, Portugal; (J.S.T.); (A.P.R.)
- MitoLab, Mitochondria, Metabolism and Disease Group, Center for Neurosciences and Cell Biology, Faculdade de Medicina, University of Coimbra, 3000 Coimbra, Portugal; (R.T.D.S.); (I.F.M.)
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12
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Soni SS, Rodell CB. Polymeric materials for immune engineering: Molecular interaction to biomaterial design. Acta Biomater 2021; 133:139-152. [PMID: 33484909 DOI: 10.1016/j.actbio.2021.01.016] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2020] [Revised: 01/05/2021] [Accepted: 01/12/2021] [Indexed: 12/15/2022]
Abstract
Biomaterials continue to evolve as complex engineered tools for interactively instructing biological systems, aiding in the understanding and treatment of various disease states through intimate biological interaction. The immune response to polymeric materials is a critical area of study, as it governs the body's response to biomaterial implants, drug delivery vehicles, and even therapeutic drug formulations. Importantly, the development of the immune response to polymeric biomaterials spans length scales - from single molecular interactions to the complex sensing of bulk biophysical properties, all of which coordinate a tissue- and systems-level response. In this review, we specifically discuss a bottom-up approach to designing biomaterials that use molecular-scale interactions to drive immune response to polymers and discuss how these interactions can be leveraged for biomaterial design. STATEMENT OF SIGNIFICANCE: The immune system is an integral controller of (patho)physiological processes, affecting nearly all aspects of human health and disease. Polymeric biomaterials, whether biologically derived or synthetically produced, can potentially alter the behavior of immune cells due to their molecular-scale interaction with individual cells, as well as their interpretation at the bulk scale. This article reviews common mechanisms by which immune cells interact with polymers at the molecular level and discusses how these interactions are being leveraged to produce the next generation of biocompatible and immunomodulatory materials.
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13
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Ayar Z, Shafieian M, Mahmoodi N, Sabzevari O, Hassannejad Z. A rechargeable drug delivery system based on
pNIPAM
hydrogel for the local release of curcumin. J Appl Polym Sci 2021. [DOI: 10.1002/app.51167] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
Affiliation(s)
- Zahra Ayar
- Department of Biomedical Engineering Amirkabir University of Technology (Tehran Polytechnic) Tehran Iran
| | - Mehdi Shafieian
- Department of Biomedical Engineering Amirkabir University of Technology (Tehran Polytechnic) Tehran Iran
| | - Narges Mahmoodi
- Sina Trauma and Surgery Research Center Tehran University of Medical Sciences Tehran Iran
| | - Omid Sabzevari
- Toxicology and Poisoning Research Centre Tehran University of Medical Sciences Tehran Iran
- Department of Toxicology and Pharmacology, Faculty of Pharmacy Tehran University of Medical Sciences Tehran Iran
| | - Zahra Hassannejad
- Pediatric Urology and Regenerative Medicine Research Center Tehran University of Medical Sciences Tehran Iran
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14
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Ferrero-Andrés A, Panisello-Roselló A, Roselló-Catafau J, Folch-Puy E. Polyethylene glycol 35 ameliorates pancreatic inflammatory response in cerulein-induced acute pancreatitis in rats. World J Gastroenterol 2020; 26:5970-5982. [PMID: 33132648 PMCID: PMC7584060 DOI: 10.3748/wjg.v26.i39.5970] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/21/2020] [Revised: 08/12/2020] [Accepted: 09/12/2020] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Acute pancreatitis (AP) is a sudden inflammatory process of the pancreas that may also involve surrounding tissues and/or remote organs. Inflammation and parenchymal cell death are common pathological features of this condition and determinants of disease severity. Polyethylene glycols (PEGs) are non-immunogenic, non-toxic water-soluble polymers widely used in biological, chemical, clinical and pharmaceutical settings. AIM To evaluate the protective effect of a 35-kDa molecular weight PEG (PEG35) on the pancreatic damage associated to cerulein-induced acute pancreatitis in vivo and in vitro. METHODS Wistar rats were assigned at random to a control group, a cerulein-induced AP group and a PEG35 treatment group. AP was induced by five hourly intraperitoneal injections of cerulein (50 μg/kg/bw), while the control animals received saline solution. PEG35 was administered intraperitoneally 10 minutes before each cerulein injection in a dose of 10 mg/kg. After AP induction, samples of pancreatic tissue and blood were collected for analysis. AR42J pancreatic acinar cells were treated with increasing concentrations of PEG35 prior to exposure with tumor necrosis factor α (TNFα), staurosporine or cerulein. The severity of AP was determined on the basis of plasma levels of lipase, lactate dehydrogenase activity, pancreatic edema and histological changes. To evaluate the extent of the inflammatory response, the gene expression of inflammation-associated markers was determined in the pancreas and in AR42J-treated cells. Inflammation-induced cell death was also measured in models of in vivo and in vitro pancreatic damage. RESULTS Administration of PEG35 significantly improved pancreatic damage through reduction on lipase levels and tissue edema in cerulein-induced AP rats. The increased associated inflammatory response caused by cerulein administration was attenuated by a decrease in the gene expression of inflammation-related cytokines and inducible nitric oxide synthase enzyme in the pancreas. In contrast, pancreatic tissue mRNA expression of interleukin 10 was markedly increased. PEG35 treatment also protected against inflammation-induced cell death by attenuating lactate dehydrogenase activity and modulating the pancreatic levels of apoptosis regulator protein BCL-2 in cerulein hyperstimulated rats. Furthermore, the activation of pro-inflammatory markers and inflammation-induced cell death in pancreatic acinar cells treated with TNFα, cerulein or staurosporine was significantly reduced by PEG35 treatment, in a dose-dependent manner. CONCLUSION PEG35 ameliorates pancreatic damage in cerulein-induced AP and AR42J-treated cells through the attenuation of the inflammatory response and associated cell death. PEG35 may be a valuable option in the management of AP.
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Affiliation(s)
- Ana Ferrero-Andrés
- Experimental Pathology Department, Institut d'Investigacions Biomèdiques de Barcelona-Consejo Superior de Investigaciones científicas, Barcelona 08036, Catalonia, Spain
| | - Arnau Panisello-Roselló
- Experimental Pathology Department, Institut d'Investigacions Biomèdiques de Barcelona-Consejo Superior de Investigaciones científicas, Barcelona 08036, Catalonia, Spain
| | - Joan Roselló-Catafau
- Experimental Pathology Department, Institut d'Investigacions Biomèdiques de Barcelona-Consejo Superior de Investigaciones científicas, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, Institut d'Investigacions Biomèdiques August Pi i Sunyer, Barcelona 08036, Catalonia, Spain
| | - Emma Folch-Puy
- Experimental Pathology Department, Institut d'Investigacions Biomèdiques de Barcelona-Consejo Superior de Investigaciones científicas, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, Institut d'Investigacions Biomèdiques August Pi i Sunyer, Barcelona 08036, Catalonia, Spain
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15
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Le Hegarat L, Huet S, Pasquier E, Charles S. Impact of solvents on the in vitro genotoxicity of TMPTA in human HepG2 cells. Toxicol In Vitro 2020; 69:105003. [PMID: 32949728 DOI: 10.1016/j.tiv.2020.105003] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2020] [Revised: 08/27/2020] [Accepted: 09/13/2020] [Indexed: 11/30/2022]
Abstract
Small hydrophobic chemical compounds require solvents to produce suitable solutions for toxicological studies. However, some solvents can modify the biological properties of substances and therefore their toxicity. This specific issue has been raised for PEG-400 as an anti-inflammatory and anti-oxidative compound. Recently, in the context of the REACH Regulation, PEG-400 was used to test the in vivo genotoxicity of trimethylolpropane triacrylate (TMPTA) in the comet assay. TMPTA failed to increase DNA damage whereas it induces genotoxicity in vitro in DMSO. Therefore, we questioned whether PEG-400 could modify the genotoxicity of TMPTA. The aim of this study was to determine the potential impact of PEG-400 on the in vitro genotoxicity of TMPTA, compared to DMSO. TMPTA was dissolved in either PEG-400 or DMSO, and the induction of γH2AX and Caspase-3 was analyzed in HepG2 cells. TMPTA induced γH2AX and Caspase-3 with both PEG-400 and DMSO. However, TMPTA induced effects at 4-fold lower concentrations when PEG-400 is used as the solvent compared to DMSO. While genotoxic effects are observed at much lower concentrations with PEG-400, it does not modify the in vitro genotoxicity of TMPTA. However, further in vitro studies with small hydrophobic compounds should be done to clarify the effect of PEG-400. Moreover, in vivo studies should be performed to confirm that PEG-400 remains suitable for in vivo genotoxicity tests.
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Affiliation(s)
- Ludovic Le Hegarat
- Anses, French Agency for Food, Environmental and Occupational Health and Safety, Fougeres Laboratory, Toxicology of Contaminants unit, 10 B rue Claude Bourgelat, Fougères 35306, France.
| | - Sylvie Huet
- Anses, French Agency for Food, Environmental and Occupational Health and Safety, Fougeres Laboratory, Toxicology of Contaminants unit, 10 B rue Claude Bourgelat, Fougères 35306, France
| | - Elodie Pasquier
- Chemical Substances Assessment Unit, Risk Assessment Department, French Agency for Food, Environmental and Occupational Health Safety (ANSES), Maisons-Alfort, France
| | - Sandrine Charles
- Chemical Substances Assessment Unit, Risk Assessment Department, French Agency for Food, Environmental and Occupational Health Safety (ANSES), Maisons-Alfort, France
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17
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Ferrero-Andrés A, Panisello-Roselló A, Serafín A, Roselló-Catafau J, Folch-Puy E. Polyethylene Glycol 35 (PEG35) Protects against Inflammation in Experimental Acute Necrotizing Pancreatitis and Associated Lung Injury. Int J Mol Sci 2020; 21:917. [PMID: 32019239 PMCID: PMC7036920 DOI: 10.3390/ijms21030917] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2020] [Accepted: 01/29/2020] [Indexed: 12/12/2022] Open
Abstract
Acute pancreatitis is an inflammatory disorder of the pancreas. Its presentation ranges from self-limiting disease to acute necrotizing pancreatitis (ANP) with multiorgan failure and a high mortality. Polyethylene glycols (PEGs) are non-immunogenic, non-toxic, and water-soluble chemicals composed of repeating units of ethylene glycol. The present article explores the effect of PEG35 administration on reducing the severity of ANP and associated lung injury. ANP was induced by injection of 5% sodium taurocholate into the biliopancreatic duct. PEG35 was administered intravenously either prophylactically or therapeutically. Three hours after ANP induction, pancreas and lung tissue samples and blood were collected and ANP severity was assessed. To evaluate the inflammatory response, gene expression of pro-inflammatory cytokines and chemokine and the changes in the presence of myeloperoxidase and adhesion molecule levels were determined in both the pancreas and the lung. To evaluate cell death, lactate dehydrogenase (LDH) activity and apoptotic cleaved caspase-3 localization were determined in plasma and in both the pancreatic and lung tissue respectively. ANP-associated local and systemic inflammatory processes were reduced when PEG35 was administered prophylactically. PEG35 pre-treatment also protected against acute pancreatitis-associated cell death. Notably, the therapeutic administration of PEG35 significantly decreased associated lung injury, even when the pancreatic lesion was equivalent to that in the untreated ANP-induced group. Our results support a protective role of PEG35 against the ANP-associated inflammatory process and identify PEG35 as a promising tool for the treatment of the potentially lethal complications of the disease.
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Affiliation(s)
- Ana Ferrero-Andrés
- Experimental Pathology Department, Institut d’Investigacions Biomèdiques de Barcelona-Consejo Superior de Investigaciones Científicas (IIBB-CSIC), Barcelona, 08036 Catalonia, Spain; (A.F.-A.); (A.P.-R.)
| | - Arnau Panisello-Roselló
- Experimental Pathology Department, Institut d’Investigacions Biomèdiques de Barcelona-Consejo Superior de Investigaciones Científicas (IIBB-CSIC), Barcelona, 08036 Catalonia, Spain; (A.F.-A.); (A.P.-R.)
| | - Anna Serafín
- PCB Animal Facility-Parc Científic de Barcelona, Barcelona, 08028 Catalonia, Spain;
| | - Joan Roselló-Catafau
- Experimental Pathology Department, Institut d’Investigacions Biomèdiques de Barcelona-Consejo Superior de Investigaciones Científicas (IIBB-CSIC), Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, 08036 Catalonia, Spain;
| | - Emma Folch-Puy
- Experimental Pathology Department, Institut d’Investigacions Biomèdiques de Barcelona-Consejo Superior de Investigaciones Científicas (IIBB-CSIC), Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, 08036 Catalonia, Spain;
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Freches D, Rocks N, Patil HP, Perin F, Van Snick J, Vanbever R, Cataldo D. Preclinical evaluation of topically-administered PEGylated Fab' lung toxicity. INTERNATIONAL JOURNAL OF PHARMACEUTICS-X 2019; 1:100019. [PMID: 31517284 PMCID: PMC6733299 DOI: 10.1016/j.ijpx.2019.100019] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/24/2019] [Revised: 06/12/2019] [Accepted: 06/14/2019] [Indexed: 11/16/2022]
Abstract
PEGylation is a promising approach to increase the residence time of antibody fragments in the lungs and sustain their therapeutic effects. However, concerns arise as to the potential pulmonary toxicity of antibody fragments conjugated to high molecular weight (HMW) polyethylene glycol (PEG), notably after repeated administrations, and the possibility of PEG accumulation in the lungs. The purpose of this proof-of-concept study is to give insights about the safety of lung administration of a Fab’ anti-IL17A antibody fragment conjugated to two-armed 40 kDa PEG (PEG40). The presence of the PEG40 moiety inside alveolar macrophages remained stable for at least 24 h after intratracheal administration of PEG40-Fab’ to mice. PEG40 was then progressively cleared from alveolar macrophages. Incubation of PEG40 alone with macrophages in vitro did not significantly harm macrophages and did not affect phagocytosis or the production of inflammatory markers. After acute or chronic administration of PEG40-Fab’ to mice, no signs of significant pulmonary toxicity or inflammatory cell accumulation were observed. A vacuolization of alveolar macrophages not associated with any inflammation was noticed when PEG40, PEG40-Fab’, or unPEGylated Fab’ were administered. To conclude this preliminary proof of concept study, acute or repeated pulmonary administrations of PEGylated Fab’ appear safe in rodents.
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Affiliation(s)
- Danielle Freches
- Advanced Drug Delivery & Biomaterials, Louvain Drug Research Institute, Université catholique de Louvain (UCLouvain), Brussels, Belgium
| | - Natacha Rocks
- Laboratory of Tumor and Development Biology, GIGA-Cancer and GIGA-I, GIGA-Research, University of Liege, Liege, Belgium
| | - Harshad P Patil
- Advanced Drug Delivery & Biomaterials, Louvain Drug Research Institute, Université catholique de Louvain (UCLouvain), Brussels, Belgium
| | - Fabienne Perin
- Laboratory of Tumor and Development Biology, GIGA-Cancer and GIGA-I, GIGA-Research, University of Liege, Liege, Belgium
| | - Jacques Van Snick
- Ludwig Cancer Research Ltd, Brussels Branch, Avenue Hippocrate 74, UCLouvain, 7459, B-1200 Brussels, Belgium
| | - Rita Vanbever
- Advanced Drug Delivery & Biomaterials, Louvain Drug Research Institute, Université catholique de Louvain (UCLouvain), Brussels, Belgium
| | - Didier Cataldo
- Laboratory of Tumor and Development Biology, GIGA-Cancer and GIGA-I, GIGA-Research, University of Liege, Liege, Belgium.,Department of Respiratory Diseases, University of Liege and CHU Liege, Liege, Belgium
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19
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Kleynhans J, Elgar D, Ebenhan T, Zeevaart JR, Kotzé A, Grobler A. A toxicity profile of the Pheroid® technology in rodents. Toxicol Rep 2019; 6:940-950. [PMID: 31673495 PMCID: PMC6816226 DOI: 10.1016/j.toxrep.2019.08.012] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2018] [Revised: 07/11/2019] [Accepted: 08/20/2019] [Indexed: 12/21/2022] Open
Abstract
Acute administration of 2000 mg/kg of the Pheroid® delivery system was tolerated upon intravenous administration in BALB/c mice and Sprague-Dawley rats. Oral administration was tolerated in both acute toxicity evaluation (14-days post single dose administration) and during chronic administration (90-days dosing). No mutagenicity was present during the Ames assay. A statistically significant increase in creatinine levels in the sub-chronic female treatment group was observed, however no treatment related pathology was identified during histopathology. This evaluation did not identify any risk factors present for toxicity during oral or intravenous administration of the tested formulations during acute or repeated dosing. The Pheroid® drug delivery system is now on the threshold of progressing into human clinical trials for various patented pharmaceutical applications and a systematic investigation of its toxicological properties in vitro and in vivo is thus a priority. Colloidal dispersions (nano- and microemulsions) demonstrate the ability to be adapted to accommodate either lipophilic, hydrophilic or amphiphilic drug molecules. The colloidal dispersions investigated during this evaluation has a general size of 200 nm - 2 μm, a zeta-potential of -25 mV and the main ingredient was ethyl esters of essential fatty acids. The Ames mutagenicity assay was performed on selected Salmonella thyphimurium strains TA98, TA100 and TA102. The Ames assay included S9 metabolic activation and no mutagenicity was present during the assay. The effect of acute and subchronic administration on a biological system was investigated in two species of rodent (BALB/c mice and Sprague-Dawley rats). Observations focused on the physical condition, blood biochemical analysis and the haematological profiles. Gross necropsy was performed on all the test animals. Organ weights followed by histopathology of selected organ tissues were recorded. During the acute evaluation animals showed tolerance of the maximum prescribed dose of 2000 mg/kg (according to OECD guidelines) in two rodent species after intravenous administration (absolute bioavaibility). The oral formulation was tolerated without incidents in both acute and subchronic studies. Although valuable baseline safety data was obtained regarding the Pheroid® system, future studies with the entrapped active pharmaceutical ingredients is necessary to provide a definitive safety profile.
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Affiliation(s)
- Janke Kleynhans
- DST/NWU Preclinical Drug Development Platform, North-West University, Potchefstroom, 2520, South Africa
| | - Dale Elgar
- Faculty of Health Sciences, North-West University, Potchefstroom, 2520, South Africa
| | - Thomas Ebenhan
- Nuclear Medicine, University of Pretoria, Pretoria, 0001, South Africa
| | - Jan Rijn Zeevaart
- DST/NWU Preclinical Drug Development Platform, North-West University, Potchefstroom, 2520, South Africa.,Radiochemistry, The South African Nuclear Energy Corporation (Necsa), P.O. Box, 482, Pretoria, 0001, South Africa
| | - Awie Kotzé
- Faculty of Health Sciences, North-West University, Potchefstroom, 2520, South Africa
| | - Anne Grobler
- DST/NWU Preclinical Drug Development Platform, North-West University, Potchefstroom, 2520, South Africa
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20
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Scaffolds based on alginate-PEG methyl ether methacrylate-Moringa oleifera-Aloe vera for wound healing applications. Carbohydr Polym 2019; 206:455-467. [DOI: 10.1016/j.carbpol.2018.11.027] [Citation(s) in RCA: 38] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2018] [Revised: 11/08/2018] [Accepted: 11/08/2018] [Indexed: 12/20/2022]
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21
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Chia WT, Tseng FJ, Lin GJ, Chen YW, Lee HS, Sytwu HK. Knee joint injection resveratrol amelioration inflammation in collagen antibody induced arthritis. JOURNAL OF MEDICAL SCIENCES 2019. [DOI: 10.4103/jmedsci.jmedsci_8_19] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022] Open
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22
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Aghaie T, Jazayeri MH, Manian M, Khani L, Erfani M, Rezayi M, Ferns GA, Avan A. Gold nanoparticle and polyethylene glycol in neural regeneration in the treatment of neurodegenerative diseases. J Cell Biochem 2018; 120:2749-2755. [DOI: 10.1002/jcb.27415] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2018] [Accepted: 07/12/2018] [Indexed: 12/15/2022]
Affiliation(s)
- Tayebe Aghaie
- Department of Immunology School of Medicine, Iran University of Medical Sciences Tehran Iran
| | - Mir Hadi Jazayeri
- Department of Immunology School of Medicine, Iran University of Medical Sciences Tehran Iran
- Immunology Research Center, Iran University of Medical Sciences Tehran Iran
| | - Mostafa Manian
- Department of Immunology School of Medicine, Iran University of Medical Sciences Tehran Iran
| | - leila Khani
- Department of Immunology School of Medicine, Iran University of Medical Sciences Tehran Iran
| | - Marjan Erfani
- Department of Neurology Ghaem Hospital, Mashhad University of Medical Sciences Mashhad Iran
| | - Majid Rezayi
- Metabolic syndrome Research center, Mashhad University of Medical Sciences Mashhad Iran
| | - Gordon A. Ferns
- Brighton & Sussex Medical School, Division of Medical Education, Falmer Brighton UK
| | - Amir Avan
- Metabolic syndrome Research center, Mashhad University of Medical Sciences Mashhad Iran
- Department of Modern Sciences and Technologies School of Medicine, Mashhad University of Medical Sciences Mashhad Iran
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23
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Bamba R, Riley DC, Boyer RB, Pollins AC, Shack RB, Thayer WP. Polyethylene glycol restores axonal conduction after corpus callosum transection. Neural Regen Res 2017; 12:757-760. [PMID: 28616031 PMCID: PMC5461612 DOI: 10.4103/1673-5374.206645] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022] Open
Abstract
Polyethylene glycol (PEG) has been shown to restore axonal continuity after peripheral nerve transection in animal models. We hypothesized that PEG can also restore axonal continuity in the central nervous system. In this current experiment, coronal sectioning of the brains of Sprague-Dawley rats was performed after animal sacrifice. 3Brain high-resolution microelectrode arrays (MEA) were used to measure mean firing rate (MFR) and peak amplitude across the corpus callosum of the ex-vivo brain slices. The corpus callosum was subsequently transected and repeated measurements were performed. The cut ends of the corpus callosum were still apposite at this time. A PEG solution was applied to the injury site and repeated measurements were performed. MEA measurements showed that PEG was capable of restoring electrophysiology signaling after transection of central nerves. Before injury, the average MFRs at the ipsilateral, midline, and contralateral corpus callosum were 0.76, 0.66, and 0.65 spikes/second, respectively, and the average peak amplitudes were 69.79, 58.68, and 49.60 μV, respectively. After injury, the average MFRs were 0.71, 0.14, and 0.25 spikes/second, respectively and peak amplitudes were 52.11, 8.98, and 16.09 μV, respectively. After application of PEG, there were spikes in MFR and peak amplitude at the injury site and contralaterally. The average MFRs were 0.75, 0.55, and 0.47 spikes/second at the ipsilateral, midline, and contralateral corpus callosum, respectively and peak amplitudes were 59.44, 45.33, 40.02 μV, respectively. There were statistically differences in the average MFRs and peak amplitudes between the midline and non-midline corpus callosum groups (P < 0.01, P < 0.05). These findings suggest that PEG restores axonal conduction between severed central nerves, potentially representing axonal fusion.
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Affiliation(s)
- Ravinder Bamba
- Department of Plastic Surgery, Vanderbilt University Medical Center, Nashville, TN, USA.,Department of Surgery, Georgetown University, Washington, DC, USA
| | - D Colton Riley
- Department of Plastic Surgery, Vanderbilt University Medical Center, Nashville, TN, USA.,Georgetown University School of Medicine, Washington, DC, USA
| | - Richard B Boyer
- Department of Plastic Surgery, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Alonda C Pollins
- Department of Plastic Surgery, Vanderbilt University Medical Center, Nashville, TN, USA
| | - R Bruce Shack
- Department of Plastic Surgery, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Wesley P Thayer
- Department of Plastic Surgery, Vanderbilt University Medical Center, Nashville, TN, USA
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24
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Lee W, Park EJ, Kwak S, Kim Y, Na DH, Bae JS. PEGylated lysozymes with anti-septic effects in human endothelial cells and in mice. Biochem Biophys Res Commun 2015; 459:662-7. [PMID: 25769950 DOI: 10.1016/j.bbrc.2015.02.167] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2015] [Accepted: 02/28/2015] [Indexed: 11/19/2022]
Abstract
High mobility group box 1 (HMGB1) was recently shown to be an important extracellular mediator of severe vascular inflammatory disease, sepsis. Lysozyme (LYZ) has been shown to bind to bacterial lipopolysaccharide (LPS) and have a potential for playing a role in the therapy of inflammatory diseases. However, the effect of LYZ on HMGB1-induced septic response has not been investigated. Moreover, PEGylation effects on the antiseptic activity of LYZ are not known. Here, we show, for the first time, the anti-septic effects of PEGylated LYZ (PEG-LYZ) in HMGB1-mediated inflammatory responses in vitro and in vivo. Among four mono-PEGylated LYZs with different PEGylation sites (N-terminus, Lys(13), Lys(33), and Lys(97)), N-terminally PEGylated LYZ showed the highest activity. Subsequently, among three N-terminally PEGylated LYZs prepared with aldehyde-activated PEGs of 5, 10, and 20 kDa, 5 kDa-PEG-conjugated LYZ (P5-K(1)-LYZ) showed the highest antiseptic activity. The data showed that P5-K(1)-LYZ post-treatment effectively suppressed LPS-mediated release of HMGB1. P5-K(1)-LYZ also inhibited HMGB1-mediated hyperpermeability in human endothelial cells. Furthermore, P5-K(1)-LYZ reduced the cecal ligation and puncture (CLP)-induced release of HMGB1 and septic mortality. Collectively, these results suggest P5-K(1)-LYZ as a candidate therapeutic agent for the treatment of vascular inflammatory diseases via inhibition of the HMGB1 signaling pathway.
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Affiliation(s)
- Wonhwa Lee
- College of Pharmacy, CMRI, Research Institute of Pharmaceutical Sciences, Kyungpook National University, Daegu 702-701, Republic of Korea; BK21 Plus KNU Biomedical Convergence Program, Department of Biochemistry and Cell Biology, School of Medicine, Kyungpook National University, Daegu 702-701, Republic of Korea
| | - Eun Ji Park
- College of Pharmacy, CMRI, Research Institute of Pharmaceutical Sciences, Kyungpook National University, Daegu 702-701, Republic of Korea
| | - Soyoung Kwak
- College of Pharmacy, CMRI, Research Institute of Pharmaceutical Sciences, Kyungpook National University, Daegu 702-701, Republic of Korea
| | - Yejin Kim
- College of Pharmacy, CMRI, Research Institute of Pharmaceutical Sciences, Kyungpook National University, Daegu 702-701, Republic of Korea
| | - Dong Hee Na
- College of Pharmacy, CMRI, Research Institute of Pharmaceutical Sciences, Kyungpook National University, Daegu 702-701, Republic of Korea.
| | - Jong-Sup Bae
- College of Pharmacy, CMRI, Research Institute of Pharmaceutical Sciences, Kyungpook National University, Daegu 702-701, Republic of Korea.
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25
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Amrani S, Atwal A, Variola F. Modulating the elution of antibiotics from nanospongy titanium surfaces with a pH-sensitive coating. RSC Adv 2015. [DOI: 10.1039/c5ra18296d] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022] Open
Abstract
Fraction of vancomycin eluted at 3 different pHs from bare nanospongy titanium (left) and from nanospongy titanium coated with uncross-linked (center, CH:PEG) and cross-linked (right, CH:PEG + GEN) chitosan–poly(ethylene glycol.
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Affiliation(s)
- Selya Amrani
- Department of Mechanical Engineering
- University of Ottawa
- Canada
| | - Aman Atwal
- Department of Mechanical Engineering
- University of Ottawa
- Canada
- Department of Biopharmaceutical Sciences
- University of Ottawa
| | - Fabio Variola
- Department of Mechanical Engineering
- University of Ottawa
- Canada
- Department of Physics
- University of Ottawa
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26
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Cao C, Ying YL, Gu Z, Long YT. Enhanced resolution of low molecular weight poly(ethylene glycol) in nanopore analysis. Anal Chem 2014; 86:11946-50. [PMID: 25457124 DOI: 10.1021/ac504233s] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
A design with conjugation of DNA hairpin structure to the poly(ethylene glycol) molecule was presented to enhance the temporal resolution of low molecular weight poly(ethylene glycol) in nanopore studies. By the virtue of this design, detection of an individual PEG with molecular weight as low as 140 Da was achieved at the single-molecule level in solution, which provides a novel strategy for characterization of an individual small molecule within a nanopore. Furthermore, we found that the current duration time of poly(ethylene glycol) was scaled with the relative molecular weight, which has a potential application in single-molecule detection.
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Affiliation(s)
- Chan Cao
- Key Laboratory for Advanced Materials & Department of Chemistry, East China University of Science and Technology , Shanghai 200237, P. R. China
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27
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Shukla P, Rao GM, Pandey G, Sharma S, Mittapelly N, Shegokar R, Mishra PR. Therapeutic interventions in sepsis: current and anticipated pharmacological agents. Br J Pharmacol 2014; 171:5011-31. [PMID: 24977655 PMCID: PMC4253453 DOI: 10.1111/bph.12829] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2014] [Revised: 04/29/2014] [Accepted: 06/13/2014] [Indexed: 12/14/2022] Open
Abstract
Sepsis is a clinical syndrome characterized by a multisystem response to a pathogenic assault due to underlying infection that involves a combination of interconnected biochemical, cellular and organ-organ interactive networks. After the withdrawal of recombinant human-activated protein C (rAPC), researchers and physicians have continued to search for new therapeutic approaches and targets against sepsis, effective in both hypo- and hyperinflammatory states. Currently, statins are being evaluated as a viable option in clinical trials. Many agents that have shown favourable results in experimental sepsis are not clinically effective or have not been clinically evaluated. Apart from developing new therapeutic molecules, there is great scope for for developing a variety of drug delivery strategies, such as nanoparticulate carriers and phospholipid-based systems. These nanoparticulate carriers neutralize intracorporeal LPS as well as deliver therapeutic agents to targeted tissues and subcellular locations. Here, we review and critically discuss the present status and new experimental and clinical approaches for therapeutic intervention in sepsis.
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Affiliation(s)
- Prashant Shukla
- Pharmaceutics Division, Preclinical South PCS 002/011, CSIR – Central Drug Research InstituteLucknow, India
| | - G Madhava Rao
- Pharmaceutics Division, Preclinical South PCS 002/011, CSIR – Central Drug Research InstituteLucknow, India
| | - Gitu Pandey
- Pharmaceutics Division, Preclinical South PCS 002/011, CSIR – Central Drug Research InstituteLucknow, India
| | - Shweta Sharma
- Pharmaceutics Division, Preclinical South PCS 002/011, CSIR – Central Drug Research InstituteLucknow, India
| | - Naresh Mittapelly
- Pharmaceutics Division, Preclinical South PCS 002/011, CSIR – Central Drug Research InstituteLucknow, India
| | - Ranjita Shegokar
- Department of Pharmaceutics, Biopharmaceutics & NutriCosmetics, Institute of Pharmacy, Freie Universität BerlinBerlin, Germany
| | - Prabhat Ranjan Mishra
- Pharmaceutics Division, Preclinical South PCS 002/011, CSIR – Central Drug Research InstituteLucknow, India
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28
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Abstract
Objective: Bidirectional links between the nervous and immune systems modulate inflammation. The cellular mechanisms underlying the detection of danger-associated molecular patterns and pathogen-associated molecular patterns by the nervous system are not well understood. We hypothesized that the carotid body, a tissue of neural crest origin, detect pathogen associated molecular patterns and danger associated molecular patterns via an inflammasome-dependent mechanism similar to that described in immune cells. Design: Randomized, controlled laboratory investigation. Setting: University laboratory. Subjects: C57Bl/6J mice; juvenile Sprague-Dawley rats, primary human neutrophils. Interventions: Rat carotid body chemosensitive cells, and human neutrophils, were treated with TLR agonists to activate inflammasome-dependent pathways. In mice, systemic inflammation was induced by the pathogen associated molecular pattern zymosan (intraperitoneal injection; 500 mg/kg). Isolated carotid body/carotid sinus nerve preparations were used to assess peripheral chemoafferent activity. Ventilation was measured by whole-body plethysmography. Measurements and Main Results: Chemosensitive carotid body glomus cells exhibited toll-like receptor (TLR-2 and TLR-4), NLRP1, and NLRP3 inflammasome immunoreactivities. Zymosan increased NLRP3 inflammasome and interleukin-1β expression in glomus cells (p < 0.01). Human neutrophils demonstrated similar LPS-induced changes in inflammasome expression. Carotid body glomus cells also expressed IL-1 receptor and responded to application of IL-1β with increases in intracellular [Ca2+]. Four hours after injection of zymosan carotid sinus nerve chemoafferent discharge assessed in vitro (i.e., in the absence of acidosis/circulating inflammatory mediators) was increased five-fold (p < 0.001). Accordingly, zymosan-induced systemic inflammation was accompanied by enhanced respiratory activity. Conclusions: In carotid body chemosensitive glomus cells, activation of toll-like receptors increases NLRP3 inflammasome expression, and enhances IL-1β production, which is capable of acting in an autocrine manner to enhance peripheral chemoreceptor drive.
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29
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Polymer therapeutics move into the sepsis space*. Crit Care Med 2010; 38:730-1. [DOI: 10.1097/ccm.0b013e3181c8958b] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
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