ABSTRACT
PURPOSE/AIM OF THE STUDY: To summarize and discuss macrophage properties and their roles and mechanisms in the process of osseointegration in a comprehensive manner, and to provide theoretical support and research direction for future implant surface modification efforts. MATERIALS AND METHODS: Based on relevant high-quality articles, this article reviews the role of macrophages in various stages of osseointegration and methods of implant modification. RESULTS AND CONCLUSIONS: Macrophages not only promote osseointegration through immunomodulation, but also secrete a variety of cytokines, which play a key role in the angiogenic and osteogenic phases of osseointegration. There is no "good" or "bad" difference between the M1 and M2 phenotypes of macrophages, but their timely presence and sequential switching play a crucial role in implant osseointegration. In the implant surface modification strategy, the induction of sequential activation of the M1 and M2 phenotypes of macrophages is a brighter prospect for implant surface modification than inducing the polarization of macrophages to the M1 or M2 phenotypes individually, which is a promising pathway to enhance the effect of osseointegration and increase the success rate of implant surgery.
Subject(s)
Macrophages , Osseointegration , Macrophages/metabolism , Cytokines/metabolism , Prostheses and Implants , Osteogenesis , Titanium/metabolism , Surface PropertiesABSTRACT
The secondary injury is more serious after traumatic brain injury (TBI) compared with primary injury. Release of excessive reactive oxygen species (ROS) and Ca2+ influx at the damaged site trigger the secondary injury. Herein, a neutrophil-like cell membrane-functionalized nanoparticle was developed to prevent ROS-associated secondary injury. NCM@MP was composed of three parts: (1) Differentiated neutrophil-like cell membrane (NCM) was synthesized, with inflammation-responsive ability to achieve effective targeting and to increase the retention time of Mn3O4 and nimodipine (MP) in deep injury brain tissue via C-X-C chemokine receptor type 4, integrin beta 1 and macrophage antigen-1. (2) Nimodipine was used to inhibit Ca2+ influx, eliminating the ROS at source. (3) Mn3O4 further eradicated the existing ROS. In addition, NCM@MP also exhibited desirable properties for T1 enhanced imaging and low toxicity which may serve as promising multifunctional nanoplatforms for precise therapies. In our study, NCM@MP obviously alleviated oxidative stress response, reduced neuroinflammation, protected blood-brain barrier integrity, relieved brain edema, promoted the regeneration of neurons, and improved the cognition of TBI mice. This study provides a promising TBI management to relieve the secondary spread of damage.
Subject(s)
Brain Injuries, Traumatic , Calcium , Nanoparticles , Neutrophils , Reactive Oxygen Species , Animals , Reactive Oxygen Species/metabolism , Brain Injuries, Traumatic/drug therapy , Brain Injuries, Traumatic/metabolism , Mice , Nanoparticles/chemistry , Calcium/metabolism , Neutrophils/metabolism , Neutrophils/drug effects , Male , Cell Membrane/metabolism , Cell Membrane/drug effects , Oxidative Stress/drug effects , Blood-Brain Barrier/metabolism , Blood-Brain Barrier/drug effects , Mice, Inbred C57BLABSTRACT
Genetic disorders which present during development make treatment strategies particularly challenging because there is a need to disentangle primary pathophysiology from downstream dysfunction caused at key developmental stages. To provide a deeper insight into this question, we studied a mouse model of X-linked juvenile retinoschisis (XLRS), an early-onset inherited condition caused by mutations in the Rs1 gene encoding retinoschisin (RS1) and characterized by cystic retinal lesions and early visual deficits. Using an unbiased approach in expressing the fast intracellular calcium indicator GCaMP6f in neuronal, glial, and vascular cells of the retina of RS1-deficient male mice, we found that initial cyst formation is paralleled by the appearance of aberrant spontaneous neuro-glial signals as early as postnatal day 15, when eyes normally open. These presented as glutamate-driven wavelets of neuronal activity and sporadic radial bursts of activity by Müller glia, spanning all retinal layers and disrupting light-induced signaling. This study confers a role to RS1 beyond its function as an adhesion molecule, identifies an early onset for dysfunction in the course of disease, establishing a potential window for disease diagnosis and therapeutic intervention.Significance StatementDevelopmental disorders make it difficult to distinguish pathophysiology due to ongoing disease from pathophysiology due to disrupted development. Here, we investigated a mouse model for X-linked retinoschisis (XLRS), a well-defined monogenic degenerative disease caused by mutations in the Rs1 gene, which codes for the protein retinoschisin. We evaluated the spontaneous activity of explanted retinas lacking retinoschisin at key stages of development using the unbiased approach of ubiquitously expressing GCaMP6f in all retinal neurons, vasculature and glia. In mice lacking RS1, we found an array of novel phenotypes which present around eye-opening, are linked to glutamatergic neurotransmission, and affect visual processing. These data identify novel pathophysiology linked to RS1, and define a window where treatments might be best targeted.
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Globally, natural wetlands have suffered severe ecological degradation (vegetation, soil, and biotic community) due to multiple factors. Understanding the spatiotemporal dynamics and driving forces of natural wetlands is the key to natural wetlands' protection and regional restoration. In this study, we first investigated the spatiotemporal evolutionary trends and shifting characteristics of natural wetlands in the Northeast Plain of China from 1990 to 2020. A dataset of driving-force evaluation indicators was constructed with nine indirect (elevation, temperature, road network, etc.) and four direct influencing factors (dryland, paddy field, woodland, grassland). Finally, we built the driving force analysis model of natural wetlands changes to quantitatively refine the contribution of different driving factors for natural wetlands' dynamic change by introducing the sparrow search algorithm (SSA) and extreme gradient boosting algorithm (XGBoost). The results showed that the total area of natural wetlands in the Northeast Plain of China increased by 32% from 1990 to 2020, mainly showing a first decline and then an increasing trend. Combined with the results of transfer intensity, we found that the substantial turn-out phenomenon of natural wetlands occurred in 2000-2005 and was mainly concentrated in the central and eastern parts of the Northeast Plain, while the substantial turn-in phenomenon of 2005-2010 was mainly located in the northeast of the study area. Compared with a traditional regression model, the SSA-XGBoost model not only weakened the multicollinearity of each driver but also significantly improved the generalization ability and interpretability of the model. The coefficient of determination (R2) of the SSA-XGBoost model exceeded 0.6 in both the natural wetland decline and rise cycles, which could effectively quantify the contribution of each driving factor. From the results of the model calculations, agricultural activities consisting of dryland and paddy fields during the entire cycle of natural wetland change were the main driving factors, with relative contributions of 18.59% and 15.40%, respectively. Both meteorological (temperature, precipitation) and topographic factors (elevation, slope) had a driving role in the spatiotemporal variation of natural wetlands. The gross domestic product (GDP) had the lowest contribution to natural wetlands' variation. This study provides a new method of quantitative analysis based on machine learning theory for determining the causes of natural wetland changes; it can be applied to large spatial scale areas, which is essential for a rapid monitoring of natural wetlands' resources and an accurate decision-making on the ecological environment's security.
Subject(s)
Agriculture , Wetlands , Algorithms , Biological Evolution , ChinaABSTRACT
X-linked juvenile retinoschisis (XLRS) is an early-onset inherited condition that affects primarily males and is characterized by cystic lesions of the inner retina, decreased visual acuity and contrast sensitivity and a selective reduction of the electroretinogram (ERG) b-wave. Although XLRS is genetically heterogeneous, all mouse models developed to date involve engineered or spontaneous null mutations. In the present study, we have studied three new Rs1 mutant mouse models: (1) a knockout with inserted lacZ reporter gene; (2) a C59S point mutant substitution and (3) an R141C point mutant substitution. Mice were studied from postnatal day (P15) to 28 weeks by spectral domain optical coherence tomography and ERG. Retinas of P21-22 mice were examined using biochemistry, single cell electrophysiology of retinal ganglion cells (RGCs) and by immunohistochemistry. Each model developed intraretinal schisis and reductions in the ERG that were greater for the b-wave than the a-wave. The phenotype of the C59S mutant appeared less severe than the other mutants by ERG at adult ages. RGC electrophysiology demonstrated elevated activity in the absence of a visual stimulus and reduced signal-to-noise ratios in response to light stimuli. Immunohistochemical analysis documented early abnormalities in all cells of the outer retina. Together, these results provide significant insight into the early events of XLRS pathophysiology, from phenotype differences between disease-causing variants to common mechanistic events that may play critical roles in disease presentation and progression.
Subject(s)
Genes, X-Linked , Genetic Association Studies , Genetic Predisposition to Disease , Genotype , Phenotype , Retinoschisis/genetics , Retinoschisis/pathology , Animals , Biomarkers , Cell Adhesion Molecules/genetics , Disease Models, Animal , Electroretinography , Eye Proteins/genetics , Genetic Association Studies/methods , Immunohistochemistry , Mice , Mutation , Photic Stimulation , Retinoschisis/diagnosis , Severity of Illness Index , Tomography, Optical CoherenceABSTRACT
Polarization imaging plays a crucial role in modern photonic applications such as remote sensing, material classification, and reconnaissance. A novel InGaAs focal plane array integrated with linear-array polarization grating is proposed and fabricated to meet the practical needs of near-infrared polarization imaging. In order to accurately evaluate the polarization performance of a fabricated detector, the improved test system is used to measure the transmittance and extinction ratio (ER). The results show that the detectivity reaches ${1}.{06}\; \times \;{{10}^{12}}\;{{\rm cm}\cdot{\rm Hz}^{1/2}}/{\rm W}$1.06×1012cmâ Hz1/2/W, and the operable pixel factor is more than 99.8%. The transmittance of more than 55% and the ER of greater than 21:1 are realized, which indicates that the fabricated detector has excellent capability for near-infrared polarization imaging.
ABSTRACT
The self-assembly behavior of polypeptides plays an essential role to form biological and functional macromolecules, which have attracted a lot of attention due to their excellent characters. Understanding the polypeptide self-assembly systems and dynamic behaviors is fundamental to improve the potential of biomedical applications. In this work, coiled coil polypeptides PC10 and PC10 P were designed and biosynthesized. PC10 and PC10 P could form nanogels when the concentration of polypeptides was less than 2% (m/v). The dynamic behaviors of PC10 and PC10 P were measured by Förster resonance energy transfer method based on a capillary electrophoresis system. The Förster resonance energy transfer efficiency of this system was 60.4%, and the distance of self-assembled domains in the polypeptides was calculated as 6.14 nm, demonstrating that the exchange behavior occurred between two different polypeptides containing the same coiled coil region.
Subject(s)
Peptides/analysis , Electrophoresis, Capillary , Fluorescence Resonance Energy TransferABSTRACT
Polarization imaging has become a widely-applied detection technique, due to the capabilities of enhanced image contrast and object recognition. Here, we demonstrate 320 × 256 InGaAs focal plane array (FPA) integrated with superpixel-structured subwavelength aluminum grating. An extinction ratio of up to 19:1 at 1310 nm is realized, which indicates a good capability of near-infrared polarization detection. Theoretical simulation shows a fairly high extinction ratio for such superpixel structure. This difference between the actual extinction ratio and the theoretical extinction ratio is further discussed by analyzing the effects of the alignment deviation and structural parameter deviations induced during the actual process. Moreover, the imaging results show that the fabricated polarimetric InGaAs FPA presents a more obvious profile for artificial objects, compared to the conventional detector. Such FPAs integrated with superpixel-structured grating are very promising for high performance polarization imaging in the short wavelength infrared band.
ABSTRACT
OBJECTIVE: Bipolar disorder (BD) is a debilitating neuropsychiatric disorder, which is associated with genetic variation through "vast but mixed" Genome-Wide Association Studies (GWAS). Transcriptome-Wide Association Study (TWAS) is more effective in explaining genetic factors that influence complex diseases and can help identifying risk genes more reliably. So, this study aims to identify potential BD risk genes in pedigrees with TWAS. METHODS: We conducted a TWAS analysis with expression quantitative trait loci (eQTL) analysis on extended BD pedigrees, and the BD genome-wide association study (GWAS) summary data acquired from the Psychiatric Genomics Consortium (PGC). Furthermore, the BD-associated genes identified by TWAS were validated by mRNA expression profiles from the Gene Expression Omnibus (GEO) Datasets (GSE23848 and GSE46416). Functional enrichment and annotation analysis were implemented by RStudio (version 4.2.0). RESULTS: TWAS identified 362 genes with P value < 0.05, and 18 genes remain significant after Bonferroni correction, such as SEMA3G (PTWAS=1.07 × 10-11), ALOX5AP (PTWAS=3.12 × 10-8), and PLEC (PTWAS=1.27 × 10-7). Further 6 overlapped genes were detected in integrative analysis, such as UQCRB (PTWAS=0.0020, PmRNA=0.0000), TMPRSS9 (PTWAS=0.0405, PmRNA=0.0032), and SNX10 (PTWAS=0.0104, PmRNA=0.0015). Using genes identified by TWAS, Gene Ontology (GO) enrichment analysis identified 40 significant GO terms, such as mitochondrial ATP synthesis coupled electron transport, mitochondrial respiratory, aerobic electron transport chain, oxidative phosphorylation, mitochondrial membrane proteins, and ubiquinone activity. The Kyoto Encyclopedia of Genes and Genomes (KEGG) Pathway enrichment analysis identified significant 15 pathways for BD, such as Oxidative phosphorylation, endocannabinoids signaling, neurodegeneration, and reactive oxide species. CONCLUSIONS: We found a set of BD-associated genes and pathways, validating the important role of neurodevelopmental abnormalities, inflammatory responses, and mitochondrial dysfunction in the pathology of BD, offering novel information for comprehending the genetic basis of BD.
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Clinically, open wounds caused by accidental trauma and surgical lesion resection are easily infected by external bacteria, hindering wound healing. Antibacterial photodynamic therapy has become a promising treatment strategy for wound infection. In this study, a novel antibacterial nanocomposite material (QMC NPs) was synthesized by curcumin, quaternized chitosan and mesoporous polydopamine nanoparticles. The results showed that 150 µg/mL QMC NPs had good biocompatibility and exerted excellent antibacterial activity against Staphylococcus aureus and Escherichia coli after blue laser irradiation (450 nm, 1 W/cm2). In vivo, QMC NPs effectively treated bacterial infection and accelerated the healing of infected wounds in mice.
Subject(s)
Anti-Bacterial Agents , Chitosan , Curcumin , Escherichia coli , Indoles , Nanoparticles , Polymers , Staphylococcus aureus , Chitosan/chemistry , Chitosan/pharmacology , Indoles/chemistry , Indoles/pharmacology , Curcumin/pharmacology , Curcumin/chemistry , Polymers/chemistry , Polymers/pharmacology , Anti-Bacterial Agents/pharmacology , Anti-Bacterial Agents/chemistry , Nanoparticles/chemistry , Animals , Mice , Staphylococcus aureus/drug effects , Porosity , Escherichia coli/drug effects , Microbial Sensitivity Tests , Wound Healing/drug effects , Bacterial Infections/drug therapyABSTRACT
The normal gene expression profiles of the tissues in the eye are a valuable resource for considering genes likely to be involved with disease processes. We profiled gene expression in ten ocular tissues from human donor eyes using Affymetrix Human Exon 1.0 ST arrays. Ten different tissues were obtained from six different individuals and RNA was pooled. The tissues included: retina, optic nerve head (ONH), optic nerve (ON), ciliary body (CB), trabecular meshwork (TM), sclera, lens, cornea, choroid/retinal pigment epithelium (RPE) and iris. Expression values were compared with publically available Expressed Sequence Tag (EST) and RNA-sequencing resources. Known tissue-specific genes were examined and they demonstrated correspondence of expression with the representative ocular tissues. The estimated gene and exon level abundances are available online at the Ocular Tissue Database.
Subject(s)
Exons/genetics , Ocular Physiological Phenomena/genetics , Oligonucleotide Array Sequence Analysis , Transcriptome , Choroid/physiology , Ciliary Body/physiology , Eye Banks , Humans , Lens, Crystalline/physiology , Optic Disk/physiology , Retina/physiology , Sclera/physiology , Trabecular Meshwork/physiologyABSTRACT
Chitosan is a polysaccharide extracted from animal sources such as crab and shrimp shells. In this work, chitosan films were modified by grafting them with a thermoresponsive polymer, poly(di(ethylene glycol) methyl ether methacrylate) (PMEO2MA). The films were modified to introduce functional groups useful as reversible addition-fragmentation chain transfer (RAFT) agents. PMEO2MA chains were then grown from the films via RAFT polymerization, making the chitosan films thermoresponsive. The degree of substitution of the chitosan-based RAFT agent and the amount of monomer added in the grafting reaction were varied to control the length of the grafted PMEO2MA chain segments. The chains were cleaved from the film substrates for characterization using 1H NMR and a gel permeation chromatography analysis. Temperature-dependent contact angle measurements were used to demonstrate that the hydrophilic-hydrophobic nature of the film surface varied with temperature. Due to the enhanced hydrophobic character of PMEO2MA above its lower critical solution temperature (LCST), the ability of PMEO2MA-grafted chitosan films to serve as a substrate for cell growth at 37 °C (incubation temperature) was tested. Interactions with cells (fibroblasts, macrophages, and corneal epithelial cells) were assessed. The modified chitosan films supported cell viability and proliferation. As the temperature is lowered to 4 °C (refrigeration temperature, below the LCST), the grafted chitosan films become less hydrophobic, and cell adhesion should decrease, facilitating their removal from the surface. Our results indicated that the cells were detached from the films following a short incubation period at 4 °C, were viable, and retained their ability to proliferate.
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Shortwave infrared polarization imaging can increase the contrast of the target to the background to improve the detection system's recognition ability. The division of focal plane polarization indium gallium arsenide (InGaAs) focal plane array (FPA) detector is the ideal choice due to the advantages of compact structure, real-time imaging, and high stability. However, because of the mismatch between nanostructures and photosensitive pixels as well as the crosstalk among the different polarization directions, the currently reported extinction ratio (ER) of superpixel-polarization-integrated detectors cannot meet the needs of high-quality imaging. In this paper, a 1024 × 4 InGaAs FPA detector on-chip integrated with a linear polarization grating (LPG) was realized and tested. The detector displayed good performance throughout the 0.9-1.7 um band, and the ERs at 1064 nm, 1310 nm and 1550 nm reached up to 22:1, 29:1 and 46:1, respectively. For the crosstalk investigation, the optical simulation of the grating-integrated InGaAs pixel was carried out, and the limitation of the ER was calculated. The result showed that the scattering of incident light in the InP substrate led to the crosstalk. Moreover, the deviation of the actual grating morphology from the designed structure caused a further reduction in the ER.
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Nanozymes are artificial enzymes that mimic natural enzyme-like activities and exhibit tremendous potential for tumor chemodynamic therapy. However, the development of novel nanozymes with superior catalytic activities for nanotheranostics remains a formidable challenge. Herein, we report a facile synthesis of monodisperse palladium nanosheets (Pd nanosheets) and their assembly on graphene oxide (GO) that enhances the catalytic activities of Pd nanoparticles. Simultaneously, the obtained nanocomposites (rGO-Pd) could be applied as a smart near-infrared (NIR) light-responsive nanotheranostic for near infrared imaging-guided chemodynamic/photothermal combined therapy. Notably, rGO-Pd exhibited high peroxidase mimicking activities, which could catalyze the conversion of intratumoral H2O2 to ËOH. Impressively, the reactive oxygen species (ROS) generation of rGO-Pd was further remarkably enhanced by the endogenous acidity of the tumor microenvironment and the exogenous NIR light-responsive photothermal effect. These collective properties of the rGO-Pd nanozyme enabled it to be a ROS generation accelerator for photothermally enhanced tumor chemodynamic therapy. Thus, the as-developed rGO-Pd may represent a promising new type of high-performance nanozyme for multifunctional nanotheranostics toward cancer.
Subject(s)
Melanoma , Phototherapy , Humans , Phototherapy/methods , Palladium/pharmacology , Reactive Oxygen Species , Hydrogen Peroxide , Tumor MicroenvironmentABSTRACT
Introduction: Polyetheretherketone (PEEK) is considered to be a new type of orthopedic implant material due to its mechanical properties and biocompatibility. It is becoming a replacement for titanium (Ti) due to its near-human-cortical transmission and modulus of elasticity. However, its clinical application is limited because of its biological inertia and susceptibility to bacterial infection during implantation. To solve this problem, there is an urgent need to improve the antibacterial properties of PEEK implants. Methods: In this work, we fixed antimicrobial peptide HHC36 on the 3D porous structure of sulfonated PEEK (SPEEK) by a simple solvent evaporation method (HSPEEK), and carried out characterization tests. We evaluated the antibacterial properties and cytocompatibility of the samples in vitro. In addition, we evaluated the anti-infection property and biocompatibility of the samples in vivo by establishing a rat subcutaneous infection model. Results: The characterization test results showed that HHC36 was successfully fixed on the surface of SPEEK and released slowly for 10 days. The results of antibacterial experiments in vitro showed that HSPEEK could reduce the survival rate of free bacteria, inhibit the growth of bacteria around the sample, and inhibit the formation of biofilm on the sample surface. The cytocompatibility test in vitro showed that the sample had no significant effect on the proliferation and viability of L929 cells and had no hemolytic activity on rabbit erythrocytes. In vivo experiments, HSPEEK can significantly reduce the bacterial survival rate on the sample surface and the inflammatory reaction in the soft tissue around the sample. Discussion: We successfully loaded HHC36 onto the surface of SPEEK through a simple solvent evaporation method. The sample has excellent antibacterial properties and good cell compatibility, which can significantly reduce the bacterial survival rate and inflammatory reaction in vivo. The above results indicated that we successfully improved the antibacterial property of PEEK by a simple modification strategy, making it a promising material for anti-infection orthopedic implants.
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Diffraction-enhanced imaging (DEI) is a phase-contrast X-ray imaging technique suitable for visualizing light-element materials. The method also enables observations of sample-containing regions with large density gradients. In this study a cryogenic imaging technique was developed for DEI-enabled measurements at low temperature from 193 K up to room temperature with a deviation of 1 K. Structure-II air hydrate and structure-I carbon dioxide (CO(2)) hydrate were examined to assess the performance of this cryogenic DEI technique. It was shown that this DEI technique could image gas hydrate coexisting with ice and gas bubbles with a density resolution of about 0.01 g cm(-3) and a wide dynamic density range of about 1.60 g cm(-3). In addition, this method may be a way to make temperature-dependent measurements of physical properties such as density.
ABSTRACT
The corrosion resistance and osteogenic property of titanium-based implants are crucial for their clinical application. Although they have good stability in standard physiological solutions, limited corrosion resistance in the inflammatory environment is still an unavoidable problem. Herein, the calcined and uncalcined silicalite-1 coatings were synthesized on titanium alloy (Ti-6Al-4 V). The corrosion resistance was investigated by simulating an inflammatory environment in vitro, and osteogenic potential was also evaluated. Here, the uncalcined silicalite-1 coating had the highest corrosion protection efficiency (PE) for Ti-6Al-4 V, which inhibited the metal ion release, surface damage and mass loss in the short-term (7 days) and long-term (30 days). Moreover, positive cell responses, including adhesion, proliferation and osteogenic differentiation of MC3T3-E1 cells, were observed in the uncalcined silicalite-1 coating system, supporting its favorable biocompatibility and osteogenic property. Therefore, these findings indicate that the uncalcined silicalite-1 may be a promising coating strategy for the surface modification of Ti-6Al-4 V implants.
Subject(s)
Alloys , Titanium , Alloys/pharmacology , Corrosion , Titanium/pharmacology , Osteogenesis , Materials Testing , Surface Properties , Coated Materials, Biocompatible/pharmacologyABSTRACT
About 30% failures of implant are caused by peri-implantitis. Subgingival plaque, consisting of S. sanguinis, F. nucleatum,P. gingivalis et al, is the initiating factor of peri-implantitis. Polyetheretherketone (PEEK) is widely used for the fabrication of implant abutment, healing cap and temporary abutment in dental applications. As a biologically inert material, PEEK has shown poor antibacterial properties. To promote the antibacterial activity of PEEK, we loaded ZnO/GO on sulfonated PEEK. We screened out that when mass ratio of ZnO/GO was 4:1, dip-coating time was 25 min, ZnO/GO modified SPEEK shown the best physical and chemical properties. At the meantime, the ZnO/GO-SPEEK samples possess a good biocompatibility. The ZnO/GO-SPEEK inhibitsP. gingivalisobviously, and could exert an antibacterial activity toS. sanguinisin the early stage, prevents biofilm formation effectively. With the favorablein vitroperformances, the modification of PEEK with ZnO/GO is promising for preventing peri-implantitis.
Subject(s)
Zinc Oxide , Anti-Bacterial Agents/chemistry , Benzophenones , Graphite , Ketones/chemistry , Polyethylene Glycols/chemistry , Polymers , PorosityABSTRACT
Overproduced reactive oxygen species and the induced oxidative stress and neuroinflammation often result in secondary injury, which is associated with unfavorable prognosis in traumatic brain injury (TBI). Unfortunately, current medications cannot effectively ameliorate the secondary injury at traumatic sites. Here, it is reported that intrinsically bioactive multifunctional nanocomposites (ANG-MnEMNPs-Cur, AMEC) mediate antioxidation and anti-neuroinflammation for targeted TBI theranostics, which are engineered by loading the neuroprotective agent curcumin on angiopep-2 functionalized and manganese doped eumelanin-like nanoparticles. After intravenous delivery, efficient AMEC accumulation is observed in lesions of TBI mice models established by controlled cortical impact method, evidenced by T1 -T2 magnetic resonance and photoacoustic dual-modal imaging. Therapeutically, AMEC effectively alleviates neuroinflammation, protects blood-brain barrier integrity, relieves brain edema, reduces brain tissue loss, and improves the cognition of TBI mice. Mechanistically, following the penetration into the traumatic tissues via angiopep-2 mediated targeting effect, the efficacy of AMEC is synergistically improved by combined functional moieties of curcumin and eumelanin. This is achieved by the alleviation of oxidative stress, inhibition of neuroinflammation via M1-to-M2 macrophage reprogramming, and promotion of neuronal regeneration. The as-developed AMEC with well-defined mechanisms of action may represent a promising targeted theranostics strategy for TBI and other neuroinflammation-associated intracranial diseases.
Subject(s)
Brain Injuries, Traumatic , Curcumin , Nanocomposites , Animals , Antioxidants/pharmacology , Antioxidants/therapeutic use , Brain/pathology , Brain Injuries, Traumatic/diagnostic imaging , Brain Injuries, Traumatic/drug therapy , Curcumin/therapeutic use , Disease Models, Animal , Manganese , Melanins , Mice , Mice, Inbred C57BL , Nanocomposites/therapeutic use , Precision MedicineABSTRACT
The overall eradication of biofilm-mode growing bacteria holds significant key to the answer of a series of infection-related health problems. However, the extracellular matrix of bacteria biofilms disables the traditional antimicrobials and, more unfortunately, hampers the development of the anti-infectious alternatives. Therefore, highly effective antimicrobial agents are an urgent need for biofilm-infection control. Herein, a PEGylated palladium nanozyme (Pd-PEG) with peroxidase (POD)-like activity for highly efficient biofilm infection control is reported. Pd-PEG also shows the intrinsic photothermal effect as well as near-infrared (NIR) light-enhanced POD-like activity in the acidic environment, thereby massively destroying the biofilm matrix and killing the adhering bacteria. Importantly, the antimicrobial mechanism of the synergistic treatment based on Pd-PEG+H2O2+NIR combination was disclosed. In vitro and in vivo results illustrated the designed Pd-PEG+H2O2 +NIR treatment reagent possessed outstanding antibacterial and biofilms elimination effects with negligible biotoxicity. This work hopefully facilitates the development of metal-based nanozymes in biofilm related infectious diseases.