RESUMO
Telomere length plays a crucial role in cellular aging and the risk of diseases. Unlike normal cells, cancer cells can extend their own survival by maintaining telomere stability through telomere maintenance mechanism. Therefore, regulating the lengths of telomeres have emerged as a promising approach for anti-cancer treatment. In this study, we introduce a nanoscale octopus-like structure designed to induce physical entangling of telomere, thereby efficiently triggering telomere dysfunction. The nanoscale octopus, composed of eight-armed PEG (8-arm-PEG), are functionalized with cell penetrating peptide (TAT) to facilitate nuclear entry and are covalently bound to N-Methyl Mesoporphyrin IX (NMM) to target G-quadruplexes (G4s) present in telomeres. The multi-armed configuration of the nanoscale octopus enables targeted binding to multiple G4s, physically disrupting and entangling numerous telomeres, thereby triggering telomere dysfunction. Both in vitro and in vivo experiments indicate that the nanoscale octopus significantly inhibits cancer cell proliferation, induces apoptosis through telomere entanglement, and ultimately suppresses tumor growth. This research offers a novel perspective for the development of innovative anti-cancer interventions and provides potential therapeutic options for targeting telomeres.
Assuntos
Apoptose , Telômero , Telômero/metabolismo , Apoptose/efeitos dos fármacos , Humanos , Animais , Linhagem Celular Tumoral , Camundongos , Quadruplex G/efeitos dos fármacos , Camundongos Nus , Polietilenoglicóis/química , Proliferação de Células/efeitos dos fármacos , Camundongos Endogâmicos BALB C , Neoplasias/patologia , Neoplasias/tratamento farmacológico , Feminino , Peptídeos Penetradores de Células/química , Peptídeos Penetradores de Células/farmacologia , Nanoestruturas/químicaRESUMO
Complex tissue damage accompanying with bacterial infection challenges healthcare systems globally. Conventional tissue engineering scaffolds normally generate secondary implantation trauma, mismatched regeneration and infection risks. Herein, we developed an easily implanted scaffold with multistep shape memory and photothermal-chemodynamic properties to exactly match repair requirements of each part from the tissue defect by adjusting its morphology as needed meanwhile inhibiting bacterial infection on demand. Specifically, a thermal-induced shape memory scaffold was prepared using hydroxyethyl methacrylate and polyethylene glycol diacrylate, which was further combined with the photothermal agent iron tannate (FeTA) to produce NIR light-induced shape memory property. By varying ingredients ratios in each segment, this scaffold could perform a stepwise recovery under different NIR periods. This process facilitated implantation after shape fixing to avoid trauma caused by conventional methods and gradually filled irregular defects under NIR to perform suitable tissue regeneration. Moreover, FeTA also catalyzed Fenton reaction at bacterial infections with abundant H2O2, which produced excess ROS for chemodynamic antibacterial therapy. As expected, bacteriostatic rate was further enhanced by additional photothermal therapy under NIR. The in vitro and vivo results showed that our scaffold was able to perform high efficacy in both antibiosis, inflammation reduction and wound healing acceleration, indicating a promising candidate for the regeneration of complex tissue damage with bacterial infection.
Assuntos
Antibacterianos , Alicerces Teciduais , Cicatrização , Antibacterianos/farmacologia , Antibacterianos/química , Antibacterianos/uso terapêutico , Animais , Alicerces Teciduais/química , Camundongos , Cicatrização/efeitos dos fármacos , Raios Infravermelhos , Terapia Fototérmica , Engenharia Tecidual/métodos , Taninos/química , Taninos/farmacologia , Materiais Inteligentes/química , Staphylococcus aureus/efeitos dos fármacos , Masculino , Polietilenoglicóis/químicaRESUMO
Due to their resistance to degradation, wide distribution, easy diffusion and potential uptake by organisms, microplastics (MPs) pollution has become a major environmental concern. In this study, PEG-modified Fe3O4 magnetic nanoparticles demonstrated superior adsorption efficiency against polyethylene (PE) microspheres compared to other adsorbents (bare Fe3O4, PEI/Fe3O4 and CA/Fe3O4). The maximum adsorption capacity of PE was found to be 2203 mg/g by adsorption isotherm analysis. PEG/Fe3O4 maintained a high adsorption capacity even at low temperature (5°C, 2163 mg/g), while neutral pH was favorable for MP adsorption. The presence of anions (Cl-, SO42-, HCO3-, NO3-) and of humic acids inhibited the adsorption of MPs. It is proposed that the adsorption process was mainly driven by intermolecular hydrogen bonding. Overall, the study demonstrated that PEG/Fe3O4 can potentially be used as an efficient control against MPs, thus improving the quality of the aquatic environment and of our water resources.
Assuntos
Microplásticos , Poluentes Químicos da Água , Poluentes Químicos da Água/química , Poluentes Químicos da Água/análise , Cinética , Adsorção , Polietileno/química , Nanopartículas de Magnetita/química , Polietilenoglicóis/química , Modelos QuímicosRESUMO
Endocrine disruptors such as bisphenol A (BPA) adversely affect the environment and human health. Laccases are used for the efficient biodegradation of various persistent organic pollutants in an environmentally safe manner. However, the direct application of free laccases is generally hindered by short enzyme lifetimes, non-reusability, and the high cost of a single use. In this study, laccases were immobilized on a novel magnetic three-dimensional poly(ethylene glycol) diacrylate (PEGDA)-chitosan (CS) inverse opal hydrogel (LAC@MPEGDA@CS@IOH). The immobilized laccase showed significant improvement in the BPA degradation performance and superior storage stability compared with the free laccase. 91.1% of 100 mg/L BPA was removed by the LAC@MPEGDA@CS@IOH in 3 hr, whereas only 50.6% of BPA was removed by the same amount of the free laccase. Compared with the laccase, the outstanding BPA degradation efficiency of the LAC@MPEGDA@CS@IOH was maintained over a wider range of pH values and temperatures. Moreover, its relative activity of was maintained at 70.4% after 10 cycles, and the system performed well in actual water matrices. This efficient method for preparing immobilized laccases is simple and green, and it can be used to further develop ecofriendly biocatalysts to remove organic pollutants from wastewater.
Assuntos
Compostos Benzidrílicos , Enzimas Imobilizadas , Lacase , Fenóis , Polietilenoglicóis , Poluentes Químicos da Água , Lacase/química , Lacase/metabolismo , Fenóis/química , Poluentes Químicos da Água/química , Enzimas Imobilizadas/química , Enzimas Imobilizadas/metabolismo , Polietilenoglicóis/química , Quitosana/química , Hidrogéis/química , Biodegradação Ambiental , Disruptores Endócrinos/químicaRESUMO
The aim of this study was to develop a mixture of dimethacrylate isomers (PG6EMA) as a potential monomer for dental adhesives and composites. PG6EMA was synthesized de novo and characterized in the presence of ethanol (3%, 6% or 9%). BisGMA/TEGDMA (BTEG, 50/50 wt.%) was used as the resin control. Composites were formulated with 60 wt.% of either PG6EMA or BisGMA (40 wt.% TEGDMA and 70 wt.% filler). DMPA (0.2 wt.%) and DPI-PF6 (0.4 wt.%) were added as photoinitiators, irradiated with a mercury arc lamp (320-500 nm, 500 mW/cm2; Acticure). All materials were tested for polymerization kinetics (near-infrared), viscosity (η) and storage modulus (G', oscillatory rheometry). The composites were further characterized for water sorption/solubility, wet/dry flexural strength/modulus and polymerization stress. Data were analyzed with one-way ANOVA/Tukey's test (α = 0.05). The PG6EMA resins showed lower rates of polymerization compared with BTEG (p = 0.001) but high degrees of conversion (p = 0.002). Solvent concentration did not affect RPMAX but the 6% and 9% mixtures showed higher final DC, likely due to reduced viscosity. PG6EMA had much higher viscosity than BTEG (p <0.001) and lower G' (p = 0.003). Composites modified with PG6EMA have slower polymerization rates (p = 0.001) but higher final DC (p = 0.04) than the control. PG6EMA/TEGDMA showed lower dry/wet flexural strength and comparable dry modulus. The PG6EMA/TEGDMA composite showed a 18.4% polymerization stress reduction compared to the BTEG composite. Both base monomers had similar WS/SL and G'. Within its limitations, this study demonstrated that the newly synthesized PG6EMA was a viable alternative to BisGMA in dental composites.
Assuntos
Bis-Fenol A-Glicidil Metacrilato , Resinas Compostas , Teste de Materiais , Metacrilatos , Polimerização , Ácidos Polimetacrílicos , Resinas Compostas/química , Resinas Compostas/efeitos da radiação , Bis-Fenol A-Glicidil Metacrilato/química , Metacrilatos/química , Viscosidade , Ácidos Polimetacrílicos/química , Análise de Variância , Fatores de Tempo , Reprodutibilidade dos Testes , Valores de Referência , Resistência à Flexão , Polietilenoglicóis/química , Propriedades de Superfície , Solubilidade , Cinética , Reologia , Cimentos Dentários/química , Cura Luminosa de Adesivos Dentários/métodosRESUMO
BACKGROUND: Nano-drug delivery systems have become a promising approach to overcoming problems such as low solubility and cellular uptake of drugs. Along with various delivery devices, dendrimers are widely used through their unique features. PEG-citrate dendrimers are biocompatible and nontoxic, with the ability to improve drug solubility. Curcumin, a naturally occurring polyphenol, has multiple beneficial properties, such as antiviral activities. However, its optimum potential has been significantly hampered due to its poor water solubility, which leads to reduced bioavailability. So, the present study attempted to address this issue and investigate its antiviral effects against HIV-1. METHOD: The G2 PEG-citrate dendrimer was synthesized. Then, curcumin was conjugated to it directly. FTIR, HNMR, DLS, and LCMS characterized the structure of products. The conjugate displayed an intense yellow color. In addition, increased aqueous solubility and cell permeability of curcumin were achieved based on flow cytometry results. So, it could be a suitable vehicle for improving the therapeutic applications of curcumin. Moreover, cell toxicity was assessed using XTT method. Ultimately, the SCR HIV system provided an opportunity to evaluate the level of HIV-1 inhibition by the curcumin-dendrimer conjugate using a p24 HIV ELISA kit. RESULTS: The results demonstrated a 50% up to 90% inhibition of HIV proliferation at 12 µm and 60 µm, respectively. Inhibition of HIV-1 at concentrations much lower than CC50 (300 µM) indicates a high potential of curcumin-dendrimer conjugate against this virus. CONCLUSION: Thereby, curcumin-dendrimer conjugate proves to be a promising tool to use in HIV-1 therapy.
Assuntos
Curcumina , Dendrímeros , Infecções por HIV , HIV-1 , Polietilenoglicóis , Curcumina/farmacologia , Curcumina/química , Dendrímeros/química , Dendrímeros/farmacologia , Humanos , HIV-1/efeitos dos fármacos , Polietilenoglicóis/química , Infecções por HIV/tratamento farmacológico , Fármacos Anti-HIV/farmacologia , Fármacos Anti-HIV/química , Ácido Cítrico/química , Nanopartículas/químicaRESUMO
Hemorrhoids are a common and painful condition, with conventional treatments such as endoscopic rubber band ligation (ERBL) and injection sclerotherapy often falling short due to high recurrence rates and significant post-operative pain. A clinical trial by Qu et al introduces a novel approach called endoscopic poli-docanol foam sclerobanding (EFSB). This multicenter randomized trial involved 195 patients with grade II and III internal hemorrhoids and demonstrated that EFSB significantly reduced recurrence rates and post-procedural pain while improving symptom relief and patient satisfaction compared to ERBL. The study's strengths include its robust design, comprehensive outcome evaluation, and patient-centered approach. Despite limitations such as the single-blind design and relatively short follow-up period, the findings suggest that EFSB could enhance clinical practice by offering a more effective and patient-friendly treatment option. Further research is needed to validate these results and explore the long-term benefits and cost-effectiveness of EFSB.
Assuntos
Hemorroidas , Satisfação do Paciente , Polidocanol , Soluções Esclerosantes , Escleroterapia , Humanos , Polidocanol/administração & dosagem , Polidocanol/uso terapêutico , Hemorroidas/terapia , Hemorroidas/cirurgia , Hemorroidas/diagnóstico , Escleroterapia/métodos , Escleroterapia/efeitos adversos , Soluções Esclerosantes/administração & dosagem , Soluções Esclerosantes/uso terapêutico , Resultado do Tratamento , Recidiva , Dor Pós-Operatória/etiologia , Dor Pós-Operatória/diagnóstico , Dor Pós-Operatória/prevenção & controle , Ensaios Clínicos Controlados Aleatórios como Assunto , Ligadura/métodos , Polietilenoglicóis/uso terapêutico , Polietilenoglicóis/administração & dosagem , Endoscopia/métodos , Análise Custo-BenefícioRESUMO
Water-in-water (W/W) emulsions provide bio-compatible all-aqueous compartments for artificial patterning and assembly of living cells. Successful entrapment of cells within a W/W emulsion via the formation of semipermeable capsules is a prerequisite for regulating on the size, shape, and architecture of cell aggregates. However, the high permeability and instability of the W/W interface, restricting the assembly of stable capsules, pose a fundamental challenge for cell entrapment. The current study addresses this problem by synthesizing multi-armed protein fibrils and controlling their assembly at the W/W interface. The multi-armed protein fibrils, also known as 'fibril clusters', were prepared by cross-linking lysozyme fibrils with multi-arm polyethylene glycol (PEG) via click chemistry. Compared to linear-structured fibrils, fibril clusters are strongly adsorbed at the W/W interface, forming an interconnected meshwork that better stabilizes the W/W emulsion. Moreover, when fibril clusters are complexed with alginate, the hybrid microcapsules demonstrate excellent mechanical robustness, semi-permeability, cytocompatibility and biodegradability. These advantages enable the encapsulation, entrapment and long-term culture of tumor spheroids, with great promise for applications for anti-cancer drug screening, tumor disease modeling, and tissue repair engineering.
Assuntos
Alginatos , Cápsulas , Muramidase , Esferoides Celulares , Alginatos/química , Cápsulas/química , Humanos , Muramidase/química , Muramidase/metabolismo , Polietilenoglicóis/química , Água/química , Emulsões/química , Animais , Linhagem Celular TumoralRESUMO
OBJECTIVE: The prognosis of extra-nodal NK/T cell lymphoma (ENKTL) is poor, and the optimal therapy remains controversial. This study aims to evaluate the safety and efficacy of a new combined modality therapy. METHODS: Phase-2 study of pegaspargase, etoposide and gemcitabine (PEG) combined with involved field radiation therapy (IFRT) in newly-diagnosed patients with early-stage ENKTL. Patients received 4 course of PEG followed by IFRT. The primary endpoints were complete response (CR), partial response (PR), and objective response rate (ORR) after IFRT. Secondary endpoints included progression-free survival (PFS), overall survival (OS) and adverse events. RESULTS: 34 consecutive patients with Ann Arbor stage I/II were enrolled. 3 patients progressed on PEG, while the remaining 31 received IFRT. The ORR was 88.2% (30/34), included 28 (82.4%) complete and 2 (5.8%) partial responses. With a median follow-up of 56.0 months (Interquartile Range [IQR], 36.0-66.9 months), the estimated 5-year PFS and OS were 87.4% (95% Confidence Interval [CI],69.5%-94.8%) and 97.1% (95%CI, 80.1%-99.6%), respectively. Most adverse events were hematological and easily managed. CONCLUSIONS: PEG followed by IFRT is a safe and effective initial therapy for early-stage ENKTL, demonstrating impressive PFS and OS rates. This promising approach warrants further validation in a randomized controlled trial (Registered at Clinicaltrials.gov NCT02705508).Trial registration: ClinicalTrials.gov identifier: NCT02705508.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica , Asparaginase , Desoxicitidina , Etoposídeo , Gencitabina , Linfoma Extranodal de Células T-NK , Polietilenoglicóis , Humanos , Desoxicitidina/análogos & derivados , Desoxicitidina/uso terapêutico , Desoxicitidina/administração & dosagem , Desoxicitidina/efeitos adversos , Linfoma Extranodal de Células T-NK/radioterapia , Linfoma Extranodal de Células T-NK/mortalidade , Linfoma Extranodal de Células T-NK/tratamento farmacológico , Linfoma Extranodal de Células T-NK/terapia , Masculino , Feminino , Pessoa de Meia-Idade , Polietilenoglicóis/administração & dosagem , Polietilenoglicóis/uso terapêutico , Asparaginase/administração & dosagem , Asparaginase/uso terapêutico , Asparaginase/efeitos adversos , Etoposídeo/administração & dosagem , Etoposídeo/efeitos adversos , Etoposídeo/uso terapêutico , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Idoso , Estadiamento de Neoplasias , Resultado do TratamentoRESUMO
Cranioplasty is a reconstructive neurosurgical procedure that fixes the cranial bone defects after the craniotomy for brain surgeries like tumours, aneurysms, arterio-venous malformations, subdural empyemas and hematomas. Personalized 3D-printed implants offer various advantages, including anatomical accuracy, functional restoration, time-sparing surgery, excellent cosmetic outcomes through their impeccable adjustment to cranial vault defects, and better clinical outcomes. PEEK has a meritorious profile in terms of high success rate, low complication rate, fracture resistance and low toxicity profile, high strength, high toughness, and excellent biocompatibility in cranioplasty. On the other hand, the need for more cost-effective yet ideal biomaterials must be met for nations and patients with financial constraints. Nevertheless, this additively manufactured 3D-printed cranial implant marks the dawn of a new era in precision and personalized neurosurgery.
Assuntos
Benzofenonas , Procedimentos Neurocirúrgicos , Polímeros , Impressão Tridimensional , Próteses e Implantes , Crânio , Humanos , Crânio/cirurgia , Procedimentos Neurocirúrgicos/métodos , Cetonas , Procedimentos de Cirurgia Plástica/métodos , Medicina de Precisão/métodos , Materiais Biocompatíveis , Craniotomia/métodos , Polietilenoglicóis , NeurocirurgiaRESUMO
Lipid nanoparticles (LNPs) are currently the most commonly used non-viral gene delivery system. Their physiochemical attributes, encompassing size, charge and surface modifications, significantly affect their behaviors both in vivo and in vitro. Nevertheless, the effects of these properties on the transfection and distribution of LNPs after intramuscular injection remain elusive. In this study, LNPs with varying sizes, lipid-based charges and PEGylated lipids were formulated to study their transfection and in vivo distribution. Luciferase mRNA (mLuc) was entraped in LNPs as a model nucleic acid molecule. Results indicated that smaller-sized LNPs and those with neutral potential presented superior transfection efficiency after intramuscular injection. Surprisingly, the sizes and charges did not exert a notable influence on the in vivo distribution of the LNPs. Furthermore, PEGylated lipids with shorter acyl chains contributed to enhanced transfection efficiency due to their superior cellular uptake and lysosomal escape capabilities. Notably, the mechanisms underlying cellular uptake differed among LNPs containing various types of PEGylated lipids, which was primarily attributed to the length of their acyl chain. Together, these insights underscore the pivotal role of nanoparticle characteristics and PEGylated lipids in the intramuscular route. This study not only fills crucial knowledge gaps but also provides significant directions for the effective delivery of mRNA via LNPs.
Assuntos
Lipídeos , Nanopartículas , Tamanho da Partícula , Polietilenoglicóis , RNA Mensageiro , Transfecção , Nanopartículas/química , Animais , Polietilenoglicóis/química , Injeções Intramusculares , Lipídeos/química , Transfecção/métodos , Camundongos , Técnicas de Transferência de Genes , Humanos , Luciferases/metabolismo , Luciferases/genética , Propriedades de Superfície , LipossomosRESUMO
Purpose: Ischemic stroke is a refractory disease wherein the reperfusion injury caused by sudden restoration of blood supply is the main cause of increased mortality and disability. However, current therapeutic strategies for the inflammatory response induced by cerebral ischemia-reperfusion (I/R) injury are unsatisfactory. This study aimed to develop a functional nanoparticle (MM/ANPs) comprising apelin-13 (APNs) encapsulated in macrophage membranes (MM) modified with distearoyl phosphatidylethanolamine-polyethylene glycol-RVG29 (DSPE-PEG-RVG29) to achieve targeted therapy against ischemic stroke. Methods: MM were extracted from RAW264.7. PLGA was dissolved in dichloromethane, while Apelin-13 was dissolved in water, and CY5.5 was dissolved in dichloromethane. The precipitate was washed twice with ultrapure water and then resuspended in 10 mL to obtain an aqueous solution of PLGA nanoparticles. Subsequently, the cell membrane was evenly dispersed homogeneously and mixed with PLGA-COOH at a mass ratio of 1:1 for the hybrid ultrasound. DSPE-PEG-RVG29 was added and incubated for 1 h to obtain MM/ANPs. Results: In this study, we developed a functional nanoparticle delivery system (MM/ANPs) that utilizes macrophage membranes coated with DSPE-PEG-RVG29 peptide to efficiently deliver Apelin-13 to inflammatory areas using ischemic stroke therapy. MM/ANPs effectively cross the blood-brain barrier and selectively accumulate in ischemic and inflamed areas. In a mouse I/R injury model, these nanoparticles significantly improved neurological scores and reduced infarct volume. Apelin-13 is gradually released from the MM/ANPs, inhibiting NLRP3 inflammasome assembly by enhancing sirtuin 3 (SIRT3) activity, which suppresses the inflammatory response and pyroptosis. The positive regulation of SIRT3 further inhibits the NLRP3-mediated inflammation, showing the clinical potential of these nanoparticles for ischemic stroke treatment. The biocompatibility and safety of MM/ANPs were confirmed through in vitro cytotoxicity tests, blood-brain barrier permeability tests, biosafety evaluations, and blood compatibility studies. Conclusion: MM/ANPs offer a highly promising approach to achieve ischemic stroke-targeted therapy inhibiting NLRP3 inflammasome-mediated pyroptosis.
Assuntos
Inflamassomos , AVC Isquêmico , Macrófagos , Proteína 3 que Contém Domínio de Pirina da Família NLR , Nanopartículas , Piroptose , Animais , Camundongos , AVC Isquêmico/tratamento farmacológico , Células RAW 264.7 , Piroptose/efeitos dos fármacos , Nanopartículas/química , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Inflamassomos/metabolismo , Inflamassomos/efeitos dos fármacos , Masculino , Peptídeos e Proteínas de Sinalização Intercelular/farmacologia , Peptídeos e Proteínas de Sinalização Intercelular/química , Polietilenoglicóis/química , Camundongos Endogâmicos C57BL , Traumatismo por Reperfusão/tratamento farmacológico , Fosfatidiletanolaminas/química , Membrana Celular/efeitos dos fármacos , Membrana Celular/metabolismoRESUMO
Background and Purpose: Growth hormone-releasing hormone (GHRH) agonist, a 29-amino acid peptide, shows significant potential in treating myocardial infarction (MI) by aiding the repair of injured heart tissue. The challenge lies in the effective on-site delivery of GHRH agonist. This study explores the use of a targetable delivery system employing ROS-responsive PEG-PPS-PEG polymers to encapsulate and deliver GHRH agonist MR409 for enhanced therapeutic efficacy. Methods: We synthesized a self-assembling poly (ethylene glycol)-poly (propylene sulfide)-poly (ethylene glycol) polymer (PEG-PPS-PEG) amphiphilic polymer responsive to reactive oxygen species (ROS). The hydrophilic peptide GHRH agonist MR409 was encapsulated within these polymers to form nano PEG-PPS-PEG@MR409 vesicles (NPs). Cardiomyocyte apoptosis was induced under hypoxia and serum-free culture condition for 24 hours, and their production of ROS was detected by fluorescence dye staining. The cellular uptake of PEG-PPS-PEG@MR409 NPs was observed using fluorescence-labeled MR409. Targeting ability and therapeutic efficacy were evaluated using a mouse MI model. Results: PEG-PPS-PEG@MR409 NPs were efficiently internalized by cardiomyocytes, reducing ROS levels and apoptosis. These NPs exhibited superior targeting to the infarcted heart compared to naked MR409 peptide. With a reduced injection frequency (once every three days), PEG-PPS-PEG@MR409 NPs significantly promoted cardiac function recovery post-MI, matching the efficacy of daily MR409 injections. Conclusion: ROS-responsive PEG-PPS-PEG polymers provide a novel and effective platform for the targeted delivery of GHRH agonist peptides, improving cardiac function and offering a new approach for peptide therapy in MI treatment.
Assuntos
Infarto do Miocárdio , Miócitos Cardíacos , Polietilenoglicóis , Espécies Reativas de Oxigênio , Animais , Polietilenoglicóis/química , Polietilenoglicóis/farmacocinética , Polietilenoglicóis/farmacologia , Espécies Reativas de Oxigênio/metabolismo , Camundongos , Infarto do Miocárdio/tratamento farmacológico , Miócitos Cardíacos/efeitos dos fármacos , Modelos Animais de Doenças , Hormônio Liberador de Hormônio do Crescimento/agonistas , Hormônio Liberador de Hormônio do Crescimento/farmacocinética , Hormônio Liberador de Hormônio do Crescimento/administração & dosagem , Apoptose/efeitos dos fármacos , Sulfetos/química , Sulfetos/farmacocinética , Sulfetos/farmacologia , Sulfetos/administração & dosagem , Peptídeos/química , Peptídeos/farmacologia , Peptídeos/farmacocinética , Peptídeos/administração & dosagem , Masculino , Camundongos Endogâmicos C57BLRESUMO
Plasmid-mediated DNA transformation is a foundational molecular technique and the basis for most CRISPR-Cas9 gene editing systems. While plasmid transformations are well established for many agricultural Phytophthora pathogens, development of this technique in forest Phytophthoras is lacking. Given our long-term research objective to develop CRISPR-Cas9 gene editing in a forest pathogenic Phytophthora species, we sought to establish the functionality of polyethylene glycol (PEG)-mediated plasmid transformation in five species: P. cactorum, P. cinnamomi, P. cryptogea, P. ramorum, and P. syringae. We used the agricultural pathogen P. sojae, a species for which PEG-mediated transformations are well-established, as a transformation control. Using a protocol previously optimized for P. sojae, we tested transformations in the five forest Phytophthoras with three different plasmids: two developed for CRISPR-Cas9 gene editing and one developed for fluorescent protein tagging. Out of the five species tested, successful transformation, as indicated by stable growth of transformants on a high concentration of antibiotic selective growth medium and diagnostic PCR, was achieved only with P. cactorum and P. ramorum. However, while transformations in P. cactorum were consistent and stable, transformations in P. ramorum were highly variable and yielded transformants with very weak mycelial growth and abnormal morphology. Our results indicate that P. cactorum is the best candidate to move forward with CRISPR-Cas9 protocol development and provide insight for future optimization of plasmid transformations in forest Phytophthoras.
Assuntos
Sistemas CRISPR-Cas , Edição de Genes , Phytophthora , Plasmídeos , Polietilenoglicóis , Transformação Genética , Phytophthora/genética , Phytophthora/patogenicidade , Plasmídeos/genética , Polietilenoglicóis/farmacologia , Edição de Genes/métodos , Florestas , Doenças das Plantas/microbiologia , Doenças das Plantas/parasitologiaRESUMO
BACKGROUND: Multiple sclerosis (MS) is a prevalent, disabling, inflammatory, neurodegenerative disease that typically manifests during a highly productive stage of life. Interferon beta-1a was among the first approved disease-modifying therapies for MS and remains among the first-line treatment options. Pegylation of the interferon beta-1a molecule prolongs its half-life while maintaining its efficacy and safety profile. In PEGINTEGRITY study, we aimed to compare peginterferon beta-1a with interferon beta-1a in terms of efficacy and safety in relapsing-remitting multiple sclerosis (RRMS) patients. METHODS: This study was a randomized, active-controlled, parallel-group, multi-center Phase 3 trial conducted in Iran in participants with RRMS. Participants received 125 µg of subcutaneous peginterferon beta-1a every two weeks or 30 µg of intramuscular interferon beta-1a once a week for up to 96 weeks. The primary outcome was the non-inferiority of peginterferon beta-1a to interferon beta-1a in reducing annualized relapse rate (ARR). Other outcomes included the number of patients with 12-week confirmed disability progression, the number of new or newly-enlarging T2 hyperintense lesions, the number of gadolinium-enhancing lesions, the number of new T1 hypointense lesions, the volume of new or newly-enlarging T2 hyperintense lesions, changes in brain volume, immunogenicity, and safety assessments. RESULTS: A total of 168 patients who met the eligibility criteria were enrolled and assigned to two arms of the study, each consisting of 84 participants. Totally, 41 participants (24 patients in the peginterferon beta-1a group and 17 patients in the interferon beta-1a group) were withdrawn from the study. The withdrawn patients were included in the per-protocol analysis for the period of time they were in the study. In 96 weeks, in the per-protocol population, the ARR was 0.05 in the peginterferon beta-1a group versus 0.11 in the interferon beta-1a group, which does not reflect a statistically significant difference (p=0.09; 95 % CI, 0.18-1.14). Considering the upper limit of the one-sided 95 % CI of the rate ratio of peginterferon beta-1a compared to interferon beta-1a, as well as the non-inferiority margin, it can be concluded that the primary outcome was met. The results were also comparable for other efficacy and safety outcomes. CONCLUSION: The results demonstrate the non-inferiority of peginterferon beta-1a to interferon beta-1a with similar efficacy in 96-week ARR in RRMS patients. Both arms were also comparable in other efficacy outcomes and safety profiles with no statistically significant differences. These findings support considering peginterferon beta-1a as a safe and efficient option in patients with RRMS. This study was registered on Iranian Registry of Clinical Trials (IRCT201612306135N8) and clinicaltrials.gov (NCT05242133).
Assuntos
Interferon beta-1a , Esclerose Múltipla Recidivante-Remitente , Polietilenoglicóis , Humanos , Esclerose Múltipla Recidivante-Remitente/tratamento farmacológico , Adulto , Masculino , Feminino , Interferon beta-1a/administração & dosagem , Interferon beta-1a/farmacologia , Interferon beta-1a/efeitos adversos , Polietilenoglicóis/administração & dosagem , Polietilenoglicóis/efeitos adversos , Polietilenoglicóis/farmacologia , Fatores Imunológicos/administração & dosagem , Fatores Imunológicos/efeitos adversos , Fatores Imunológicos/farmacologia , Pessoa de Meia-Idade , Interferon beta/administração & dosagem , Interferon beta/efeitos adversos , Interferon beta/farmacologia , Adulto JovemRESUMO
BACKGROUND: The frequency and severity of abiotic stress events, especially drought, are increasing due to climate change. The plant root is the most important organ for water uptake and the first to be affected by water limitation. It is therefore becoming increasingly important to include root traits in studies on drought stress tolerance. However, phenotyping under field conditions remains a challenging task. In this study, plants were grown in a hydroponic system with polyethylene glycol as an osmotic stressor and in sand pots to examine the root system of eleven spring barley genotypes. The root anatomy of two genotypes with different response to drought was investigated microscopically. RESULTS: Root diameter increased significantly (p < 0.05) under polyethylene glycol treatment by 54% but decreased significantly (p < 0.05) by 12% under drought stress in sand pots. Polyethylene glycol treatment increased root tip diameter (51%) and reduced diameter of the elongation zone (14%) compared to the control. Under drought stress, shoot mass of plants grown in sand pots showed a higher correlation (r = 0.30) with the shoot mass under field condition than polyethylene glycol treated plants (r = -0.22). CONCLUSION: These results indicate that barley roots take up polyethylene glycol by the root tip and polyethylene glycol prevents further water uptake. Polyethylene glycol-triggered osmotic stress is therefore unsuitable for investigating root morphology traits in barley. Root architecture of roots grown in sand pots is more comparable to roots grown under field conditions.
Assuntos
Hordeum , Raízes de Plantas , Polietilenoglicóis , Hordeum/efeitos dos fármacos , Hordeum/anatomia & histologia , Hordeum/crescimento & desenvolvimento , Hordeum/fisiologia , Hordeum/genética , Raízes de Plantas/anatomia & histologia , Raízes de Plantas/efeitos dos fármacos , Raízes de Plantas/crescimento & desenvolvimento , Polietilenoglicóis/farmacologia , Secas , Genótipo , Estresse FisiológicoRESUMO
Maxillofacial bone defects can severely impact quality of life by impairing physiological functions such as chewing, breathing, swallowing, and pronunciation. Polyether ether ketone (PEEK) is commonly used for the repair of maxillofacial defects due to its mechanical adaptability, while its osteogenic properties still need refinement. Herein, we have utilized the piezoelectric effect exhibited by barium titanate (BTO) under low-intensity pulsed ultrasound (LIPUS) to develop an ultrasound responsive PEEK (PDA@BTO-SPEEK, PBSP) through the mediating effect of polydopamine (PDA), for repairing maxillofacial bone defects. After modification by PDA@BTO, PBSP possesses better hydrophilicity, which is conducive to cell growth and adhesion. Simultaneously, by virtue of the piezoelectric characteristics of BTO, PBSP obtains a piezoelectric coefficient that matches the bone cortex. Notably, when PBSP is stimulated by LIPUS, it can generate stable electricity and effectively accelerate the osteogenic differentiation of osteoblasts through the regulation of the Piezo1-induced calcium (Ca2+) influx and Akt/GSK3ß/ß-catenin pathway. In addition, PBSP presents satisfactory therapeutic effects in rat skull defect models, and its osteogenic efficiency can be further improved under LIPUS stimulation with high tissue penetration. Collectively, PBSP + LIPUS exhibits great potential as a promising alternative strategy for the repair of maxillofacial bone defects.
Assuntos
Benzofenonas , Glicogênio Sintase Quinase 3 beta , Cetonas , Osteogênese , Polietilenoglicóis , Polímeros , Proteínas Proto-Oncogênicas c-akt , Ratos Sprague-Dawley , beta Catenina , Animais , Glicogênio Sintase Quinase 3 beta/metabolismo , Polímeros/química , Osteogênese/efeitos dos fármacos , Ratos , Polietilenoglicóis/química , Proteínas Proto-Oncogênicas c-akt/metabolismo , Cetonas/química , Cetonas/farmacologia , beta Catenina/metabolismo , Diferenciação Celular/efeitos dos fármacos , Osteoblastos/efeitos dos fármacos , Ondas Ultrassônicas , Indóis/química , Indóis/farmacologia , Masculino , Transdução de Sinais/efeitos dos fármacos , Crânio/efeitos dos fármacos , Titânio/química , Titânio/farmacologia , Regeneração Óssea/efeitos dos fármacosRESUMO
Dental caries and periodontitis are the most common oral diseases in humans and the main causes of tooth loss. Streptococcus mutans is primarily responsible for dental caries and dental plaque, which are triggered by biofilm formation on the tooth surface. In this study, biofilm inhibition by 4-isopropyl-3-methylphenol (IPMP)-based agents, consisting of IPMP and polyoxyethylene-hydrogenated castor oil (POEHCO), was investigated in vitro. Notably, the use of POEHCO in addition to IPMP inhibited S. mutans biofilms more drastically than IPMP alone. Moreover, the effects of IPMP on the expression of biofilm-related genes (gtfB, gtfC, and gtfD) were examined using quantitative real-time PCR. IPMP at sub-minimum inhibitory concentrations significantly downregulated the expression of these genes. These results suggested that the inhibitory effects on biofilm formation were synergistically enhanced by the surfactant and antibiofilm activities of IPMP. Therefore, IPMP-based agents as dentifrices may be useful to prevent oral diseases originating from biofilms.
Assuntos
Biofilmes , Streptococcus mutans , Biofilmes/efeitos dos fármacos , Biofilmes/crescimento & desenvolvimento , Streptococcus mutans/efeitos dos fármacos , Sinergismo Farmacológico , Testes de Sensibilidade Microbiana , Regulação Bacteriana da Expressão Gênica/efeitos dos fármacos , Fenóis/farmacologia , Antibacterianos/farmacologia , Óleo de Rícino , Humanos , Polietilenoglicóis/farmacologiaRESUMO
BACKGROUND: Retainers have the potential to detrimentally impact periodontal health and contribute to tooth decay. OBJECTIVES: To investigate periodontal health and bacterial biofilm related to Poly-Ether-Ether-Ketone (PEEK) fixed retainers as compared to Dead-soft coaxial fixed retainer (DSC). TRIAL DESIGN: A two-arm parallel groups single-centre randomized clinical trial. METHODS: The trial included patients whose orthodontic treatment was completed and required retainers. Participants were randomly assigned into two retainer groups: PEEK retainers, prepared by computer-aided design and manufacturing into 0.8 mm wire form, and DSC retainers. The objectives included assessing periodontal health through plaque accumulation index (PI), bleeding on probing (BOP), periodontal pocket depth (PPD), gingival index (GI), calculus index (CI), and alveolar bone height (ABH) assessment. Biofilm assessment involved bacteriological screening of aerobic, facultative anaerobic, mutans streptococci, and lactobacilli. The periodontal indices and microbiological screening as well as were assessed at the debonding stage (T0), 1-month (T1), 3-month (T3), and 6-month (T6) after the commencement of the trial, except for the ABH, which was recorded using periapical radiograph at T0 and T6. BLINDING: Single blinding of participants in addition to the bacteriological specialist. RESULTS: Initially, the trial enrolled 46 participants, aged between 12 and 28 years, and were randomly assigned to two groups, with 23 participants in each group. Subsequently, one participant withdrew from the trial, resulting in a total of 45 participants whose data were analysed. Assessment of the periodontal indices, excluding the CI (Pâ =â .480), revealed statistically but not clinically significant differences between groups after 6-month of retention (Pâ =â .016 of PI, Pâ =â .020 of BOP, Pâ =â .05 of PPD, and Pâ =â .01 of GI). There was slight plaque accumulation, normal PPD (approximately 1 mm), healthy to mild gingivitis with a GI of less than 1 and BOP was around 10%. Concerning the ABH, there was a noticeable reduction in its score after 6 months, particularly in the PEEK group, although the difference was not statistically significant (Pâ =â .102). Furthermore, the bacteriological viable count did not show any significant difference between the groups during the recall visits. HARMS: There have been no reported negative consequences. LIMITATIONS: Blinding the assessor of periodontal indices was not feasible due to the nature of the intervention. The trial follow-up duration was limited. CONCLUSIONS: Both the PEEK and DSC retainers have comparable impacts on periodontal health and bacterial accumulation and composition during the retention period. TRIAL REGISTRATION: NCT05557136.
Assuntos
Benzofenonas , Biofilmes , Índice de Placa Dentária , Cetonas , Contenções Ortodônticas , Índice Periodontal , Polietilenoglicóis , Polímeros , Humanos , Masculino , Feminino , Adolescente , Adulto Jovem , Adulto , Desenho de Aparelho Ortodôntico , Bolsa Periodontal/microbiologia , Streptococcus mutans/isolamento & purificação , Cálculos Dentários/microbiologiaRESUMO
INTRODUCTION: Orthodontic clear aligners and retainers have numerous advantages that is making them ever increasingly popular. However, they might, similar to any other oral appliance, contribute to biofilm formation and finally dental caries or white spot lesions or gingival inflammations. The literature on biofilm formation on orthodontic clear appliances is very scarce and limited to a few microorganisms and materials. Therefore, this experimental study evaluated the biofilm formation on 5 thermoformed and 3D printed CAD/CAM orthodontic retainers in 3 intervals. METHODS: In this in vitro study, 345 specimens (270 test discs and 45 negative controls) were created from fabricated retainers. Retainers included a 3D printed CAD/CAM material (Detax) and four thermoformed retainers [Erkodent (polyethylene terephthalate glycol [PETG]); EasyVac (polyethylene); DB (polyester based on terephthalic acid); and Clear Tech]. They were all 1 mm thick, and all completely fabricated, i.e., heated or printed. The discs were placed in 96-well plates. Microorganisms were cultured on 270 discs for 24 h (90 discs), 72 h (90 other discs), and 5 days or 120 h (90 other discs). Biofilm formation of the strains and negative controls was measured using the microtiter plate assay by ELISA reading. The microbes' ability to produce biofilm was categorized based on the comparison of average optical density (OD) of tests versus a cut-off point OD (ODc) calculated as the average of the OD of corresponding negative controls plus 3× its standard deviation: non-biofilm former [OD ≤ ODc], weak biofilm former [ODc < OD ≤ (2 × ODc)], moderate biofilm former [(2 × ODc) < OD ≤ (4 × ODc)], and strong biofilm former [(4 × ODc) < OD]. These were also converted to ranked scores between zero (no biofilm) and 3. The difference between ODs with control ODs were calculated. These were analyzed using 3-way ANOVA, 2-way ANOVA, and Tukey tests (α = 0.05, α = 0.008). RESULTS: The 3-way ANOVA showed that the overall difference among the ΔODs of 5 retainers (all microorganisms and all intervals combined, n = 270) was not significant (F = 1.860, P = 0.119). Nevertheless, the difference among 3 intervals (F = 31.607, P = 0.0000) and the difference among the 6 microorganisms (F = 24.044, P = 0.0000) were significant. According to the Tukey test, the differences between the 1st interval with either of the other two intervals was significant (both P values = 0.000). There were significant differences between Candida albicans with all other organisms (all 5 P values = 0.0000). All other pairwise comparisons were insignificant (all 10 P values ≥ 0.1). After taking the averages of the 3 intervals, the order of the biofilm generation for different materials were as follows: Detax (average score: 1.56), Easyvac (1.67), Erkodent (1.78), Clear Tech (1.83), BD (2.28). CONCLUSIONS: As far as these 6 microorganisms are of concern, there might not be a significant overall difference among the clear retainer materials tested in this study. A significant overall increase was observed between the first and third days, which later did not significantly increase more until day 5. The Candida albicans biofilm was more intense than the tested 5 bacteria, which themselves showed rather similar growth patterns to each other.