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Artificial enzymes, especially nanozymes, have attracted wide attention due to their controlled catalytic activity, selectivity, and stability. The rising Cerium-based nanozymes exhibit unique SOD-like activity, and Vanadium-based nanozymes always hold excellent GPx-like activity. However, most inflammatory diseases involve polymerase biocatalytic processes that require multi-enzyme activities. The nanocomposite can fulfill multi-enzymatic activity simultaneously, but large nanoparticles (>10 nm) cannot be excreted rapidly, leading to biosafety challenges. Herein, atomically precise Ce12V6 clusters with a size of 2.19 nm are constructed. The Ce12V6 clusters show excellent glutathione peroxidase (GPx) -like activity with a significantly lower Michaelis-Menten constant (Km, 0.0125 mM versus 0.03 mM of natural counterpart) and good activities mimic superoxide dismutase (SOD) and peroxidase (POD). The Ce12V6 clusters exhibit the ability to scavenge the ROS including O2 ·- and H2O2 via the cascade reactions of multi-enzymatic activities. Further, the Ce12V6 clusters modulate the proinflammatory cytokines including tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), and interleukin-1ß (IL-1ß) and consequently rescue the multi-organ failure in the lipopolysaccharide (LPS)-induced sepsis mouse model. With excellent biocompatibility, the Ce12V6 clusters show promise in the treatment of sepsis.
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BACKGROUND: Overexpression of receptor tyrosine kinase-like orphan receptor 1 (ROR1) contributes to cancer cell proliferation, survival and migration, playing crucial roles in tumor development. ROR1 has been proposed as a potential therapeutic target for cancer treatment. This study aimed to develop novel humanized ROR1 monoclonal antibodies and investigate their anti-tumor effects. METHODS: ROR1 expression in tumor tissues and cell lines was analyzed by immunohistochemistry and flow cytometry. Antibodies from mouse hybridomas were humanized by the complementarity-determining region (CDR) grafting technique. Surface plasmon resonance spectroscopy, ELISA assay and flow cytometry were employed to characterize humanized antibodies. In vitro cellular assay and in vivo mouse experiment were conducted to comprehensively evaluate anti-tumor activity of these antibodies. RESULTS: ROR1 exhibited dramatically higher expression in lung adenocarcinoma, liver cancer and breast cancer, and targeting ROR1 by short-hairpin RNAs significantly inhibited proliferation and migration of cancer cells. Two humanized ROR1 monoclonal antibodies were successfully developed, named h1B8 and h6D4, with high specificity and affinity to ROR1 protein. Moreover, these two antibodies effectively suppressed tumor growth in the lung cancer xenograft mouse model, c-Myc/Alb-cre liver cancer transgenic mouse model and MMTV-PyMT breast cancer mouse model. CONCLUSIONS: Two humanized monoclonal antibodies targeting ROR1, h1B8 and h6D4, were successfully developed and exhibited remarkable anti-tumor activity in vivo.
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Anticorpos Monoclonais Humanizados , Proliferação de Células , Receptores Órfãos Semelhantes a Receptor Tirosina Quinase , Ensaios Antitumorais Modelo de Xenoenxerto , Receptores Órfãos Semelhantes a Receptor Tirosina Quinase/metabolismo , Receptores Órfãos Semelhantes a Receptor Tirosina Quinase/antagonistas & inibidores , Receptores Órfãos Semelhantes a Receptor Tirosina Quinase/imunologia , Animais , Humanos , Camundongos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Anticorpos Monoclonais Humanizados/farmacologia , Anticorpos Monoclonais Humanizados/uso terapêutico , Feminino , Movimento Celular/efeitos dos fármacos , Neoplasias/tratamento farmacológico , Neoplasias/imunologia , Neoplasias/patologia , Neoplasias/terapia , Neoplasias/metabolismo , Camundongos Transgênicos , Modelos Animais de Doenças , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/imunologiaRESUMO
Excessive accumulation of reduced nicotinamide adenine dinucleotide (NADH) within biological organisms is closely associated with many diseases. It remains a challenge to efficiently convert superfluous and detrimental NADH to NAD+. NADH oxidase (NOX) is a crucial oxidoreductase that catalyzes the oxidation of NADH to NAD+. Herein, M1M2 (Mi=V/Mn/Fe/Co/Cu/Mo/Rh/Ru/Pd, i = 1 or 2) mated-atom nanozymes (MANs) are designed by mimicking natural enzymes with polymetallic active centers. Excitingly, RhCo MAN possesses excellent and sustainable NOX-like activity, with Km-NADH (16.11 µM) being lower than that of NOX-mimics reported so far. Thus, RhCo MAN can significantly promote the regeneration of NAD+ and regulate macrophage polarization toward the M2 phenotype through down-regulation of TLR4 expression, which may help to recover skin regeneration. However, RhRu MAN with peroxidase-like activity and RhMn MAN with superoxide dismutase-like activity exhibit little modulating effects on eczema. This work provides a new strategy to inhibit skin inflammation and promote skin regeneration.
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Gold nanoclusters (Au NCs) exhibit broad fluorescent spectra from visible to near-infrared regions and good enzyme-mimicking catalytic activities. Combined with excellent stability and exceptional biocompatibility, the Au NCs have been widely exploited in biomedicine such as biocatalysis and bioimaging. Especially, the long fluorescence lifetime and large Stokes shift attribute Au NCs to good probes for fluorescence sensing and biological detection. In this review, we systematically summarized the molecular structure and fluorescence properties of Au NCs and highlighted the advances in fluorescence sensing and biological detection. The Au NCs display high sensitivity and specificity in detecting iodine ions, metal ions, and reactive oxygen species, as well as certain diseases based on the fluorescence activities of Au NCs. We also proposed several points to improve the practicability and accelerate the clinical translation of the Au NCs.
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Implanted neural electrodes have been widely used to treat brain diseases that require high sensitivity and biocompatibility at the tissue-electrode interface. However, currently used clinical electrodes cannot meet both these requirements simultaneously, which hinders the effective recording of electronic signals. Herein, nanozyme-based neural electrodes incorporating bioinspired atomically precise clusters are developed as a general strategy with a heterogeneous design for multiscale and ultrasensitive neural recording via quantum transport and biocatalytic processes. Owing to the dual high-speed electronic and ionic currents at the electrode-tissue interface, the impedance of nanozyme electrodes is 26 times lower than that of state-of-the-art metal electrodes, and the acquisition sensitivity for the local field potential is ≈10 times higher than that of clinical PtIr electrodes, enabling a signal-to-noise ratio (SNR) of up to 14.7 dB for single-neuron recordings in rats. The electrodes provide more than 100-fold higher antioxidant and multi-enzyme-like activities, which effectively decrease 67% of the neuronal injury area by inhibiting glial proliferation and allowing sensitive and stable neural recording. Moreover, nanozyme electrodes can considerably improve the SNR of seizures in acute epileptic rats and are expected to achieve precise localization of seizure foci in clinical settings.
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Neurônios , Ratos , Animais , Eletrodos , Eletrodos Implantados , Razão Sinal-Ruído , Neurônios/fisiologia , Impedância Elétrica , MicroeletrodosRESUMO
Phthalates and their alternatives are considered significant environmental risk factors that potentially influence inflammation and oxidative stress. However, their impact on biomarkers of inflammation and oxidative stress was inconsistent. This study aimed to explore the associations between phthalates and high-sensitivity C-reactive protein (hsCRP), gamma-glutamyl transferase (GGT), and white blood cell (WBC) counts, employing both univariate exposure and multivariate co-exposure models. For this analysis, a total of 1619 individuals aged 18 years and above, sourced from the National Health and Nutrition Examination Survey (NHANES) conducted between 2017 and 2018, were selected as subjects. We explored the associations between hsCRP, GGT, and WBC counts and eighteen different phthalate metabolites. Multiple linear regression analysis revealed significant associations between both MCNP and MEHP and hsCRP. We observed negative correlations of MCOP, MCPP, MHBP, and MONP with GGT. Conversely, MEHHP and MEHHTP exhibited positive correlations with GGT. Furthermore, MECPTP and MEHHTP showed positive correlations with WBC. Notably, we identified a non-linear relationship between phthalates and inflammation and oxidative stress markers. The Bayesian kernel machine regression (BKMR) analysis demonstrated a negative joint effect of the phthalates mixture on GGT, particularly at lower concentrations. The BKMR model also found that MEOHP and MHiBP were negatively associated with GGT. In contrast, MEHHP showed a significant positive association with GGT. Moderating effect analysis suggested that dietary inflammatory index (DII), income-to-poverty ratio (PIR), age, BMI, and physical activity influenced the association between phthalates and inflammation and oxidative stress. These findings contribute to a deeper understanding of the relationships between phthalates and inflammation and oxidative stress.
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Poluentes Ambientais , Ácidos Ftálicos , Adulto , Humanos , Exposição Ambiental/análise , Poluentes Ambientais/análise , Inquéritos Nutricionais , Proteína C-Reativa/análise , Teorema de Bayes , Ácidos Ftálicos/metabolismo , Biomarcadores/metabolismo , Estresse Oxidativo , gama-Glutamiltransferase/metabolismo , Inflamação/induzido quimicamenteRESUMO
Gut played a potent role in onset and progression of metabolic disorders, presenting an exciting direction for diabetes prevention. Here, the anti-diabetic effects of White hyacinth bean polysaccharides (WHBP) were observed, including the reduction of blood glucose levels and improvement of intestinal impairment in type 2 diabetes mellitus (T2DM) rats. Further data concerning intestinal protection suggested that WHBP restored intestinal barrier, as evidenced by inhibition of intestinal pathological damage, up-regulation of Zonula occluden-1 expression and manipulation of the redox system in T2DM rats. Moreover, WHBP-mediated anti-diabetic effects were in parallel with the adjustment of changes in gut microbiota composition of T2DM rats. Meanwhile, hypersecretion of corticotropin-releasing hormone, adrenocorticotropic hormone, and corticosterone levels, which were critical coordinators of the hypothalamic-pituitary-adrenal (HPA) axis, were suppressed in T2DM rats exposed to WHBP, indicating that WHBP-mediated health benefits were referring to regulate brain feedback in reduction of HPA axis. Concomitantly, further suggested and expanded on gut-brain communication by data of microbial metabolites short-chain fatty acids, mediators of gut-brain interactions, were remarkably raised in cecum contents of T2DM rats subjected to WHBP. Collectively, WHBP performed anti-diabetic effects were associated with control of microbiota-gut-brain axis implicated in intestinal barrier, HPA axis, gut microbiota and their metabolites.
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Diabetes Mellitus Tipo 2 , Hyacinthus , Ratos , Animais , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/metabolismo , Sistema Hipotálamo-Hipofisário/metabolismo , Eixo Encéfalo-Intestino , Sistema Hipófise-Suprarrenal/metabolismo , Polissacarídeos/farmacologia , Polissacarídeos/metabolismoRESUMO
Selenium (Se) and tellurium (Te) nanomaterials with novel chain-like structures have attracted widespread interest owing to their intriguing properties. Unfortunately, the still-unclear catalytic mechanisms have severely limited the development of biocatalytic performance. In this work, we developed chitosan-coated Se nanozymes with a 23-fold higher antioxidative activity than Trolox and bovine serum albumin coated Te nanozymes with stronger prooxidative biocatalytic effects. Based on density functional theory calculations, we first propose that the Se nanozyme with Se/Se2- active centers favored reactive oxygen species (ROS) clearance via a LUMO-mediated mechanism, while the Te nanozyme with Te/Te4+ active centers promoted ROS production through a HOMO-mediated mechanism. Furthermore, biological experiments confirmed that the survival rate of γ-irritated mice treated with the Se nanozyme was maintained at 100% for 30 days by inhibiting oxidation. However, the Te nanozyme had the opposite biological effect via promoting radiation oxidation. The present work provides a new strategy for improving the catalytic activities of Se and Te nanozymes.
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Biocatálise , Telúrio/química , Selênio/química , Espécies Reativas de Oxigênio/química , Nanopartículas/química , Antioxidantes/química , Animais , Camundongos , OxirreduçãoRESUMO
Artificial enzymes show prospects in biomedical applications due to their stable enzymatic catalytic activity and ease of preparation. CeO2 nanozymes represent a versatile platform showing multiple enzyme-mimicking activities, although their biocatalytic activities and selectivity are relatively poor for biomedical use. Herein, we developed Mn- and Co-doped CeO2 nanozymes (M/CeO2, M = Mn or Co) via atomic engineering to achieve a significant increase in enzyme-like activity. The M/CeO2 nanozymes exhibited outstanding peroxidase-like activity with a reaction rate about 8-10 times higher than that of CeO2. Importantly, the Co/CeO2 nanozyme preferred for catalase-like activity with a 4-6-fold higher catalytic rate than CeO2, while the Mn/CeO2 nanozyme had a predilection for improving the superoxide dismutase-like capacity. This indicated the selective modulation of enzyme-mimicking activities via atomic doping engineering. Cellular level experiments revealed the in vitro therapeutic effects of the nanozymes. Mn/CeO2 and Co/CeO2 selectively modulated the intracellular redox imbalance in lipopolysaccharide (LPS)- or H2O2-stimulated nerve cells and improved cell survival. This work provides a feasible strategy for the design of catalytically selective artificial enzymes and facilitates the widespread application of CeO2 nanozymes in redox-related diseases.
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Peróxido de Hidrogênio , Superóxido Dismutase , Antioxidantes , Biocatálise , Catálise , OxirreduçãoRESUMO
Near-infrared-II (NIR-II) fluorescence imaging has rapidly developed for the noninvasive investigation of physiological and pathological activities in living organisms with high spatiotemporal resolution. However, the penetration depth of fluorescence restricts its ability to provide deep anatomical information. Scientists integrate NIR-II fluorescence imaging with other imaging modes (such as photoacoustic and magnetic resonance imaging) to create multimodal imaging that can acquire detailed anatomical and quantitative information with deeper penetration by using multifunctional probes. This review offers a comprehensive picture of NIR-II-based dual/multimodal imaging probes and highlights advances in bioimaging and therapy. In addition, seminal studies and trends in multimodal imaging probes activated by NIR-II laser are summarized and several key points regarding future clinical translation are elucidated.
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Imageamento por Ressonância Magnética , Imagem Óptica , Imagem Óptica/métodos , Imageamento por Ressonância Magnética/métodos , Imagem Molecular , Corantes FluorescentesRESUMO
Osteoarthritis (OA) is a prevalent degenerative joint disease characterized by cartilage loss and accounts for a major source of pain and disability worldwide. However, effective strategies for cartilage repair are lacking, and patients with advanced OA usually need joint replacement. Better comprehending OA pathogenesis may lead to transformative therapeutics. Recently studies have reported that exosomes act as a new means of cell-to-cell communication by delivering multiple bioactive molecules to create a particular microenvironment that tunes cartilage behavior. Specifically, exosome cargos, such as noncoding RNAs (ncRNAs) and proteins, play a crucial role in OA progression by regulating the proliferation, apoptosis, autophagy, and inflammatory response of joint cells, rendering them promising candidates for OA monitoring and treatment. This review systematically summarizes the current insight regarding the biogenesis and function of exosomes and their potential as therapeutic tools targeting cell-to-cell communication in OA, suggesting new realms to improve OA management.
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Cartilagem Articular , Exossomos , Osteoartrite , Apoptose , Cartilagem/metabolismo , Cartilagem/patologia , Cartilagem Articular/metabolismo , Comunicação Celular , Condrócitos/metabolismo , Exossomos/metabolismo , Exossomos/patologia , Humanos , Osteoartrite/metabolismo , Osteoartrite/terapiaRESUMO
Regenerable nanozymes with high catalytic stability and sustainability are promising substitutes for naturally-occurring enzymes but are limited by insufficient and non-selective catalytic activities. Herein, we developed single-atom nanozymes of RhN4, VN4, and Fe-Cu-N6 with catalytic activities surpassing natural enzymes. Notably, Rh/VN4 preferably forms an Rh/V-O-N4 active center to decrease reaction energy barriers and mediates a "two-sided oxygen-linked" reaction path, showing 4 and 5-fold higher affinities in peroxidase-like activity than the FeN4 and natural horseradish peroxidase. Furthermore, RhN4 presents a 20-fold improved affinity in the catalase-like activity compared to the natural catalase; Fe-Cu-N6 displays selectivity towards the superoxide dismutase-like activity; VN4 favors a 7-fold higher glutathione peroxidase-like activity than the natural glutathione peroxidase. Bioactive sutures with Rh/VN4 show recyclable catalytic features without apparent decay in 1 month and accelerate the scalp healing from brain trauma by promoting the vascular endothelial growth factor, regulating the immune cells like macrophages, and diminishing inflammation.
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Lesões Encefálicas Traumáticas , Fator A de Crescimento do Endotélio Vascular , Catalase/metabolismo , Catálise , Glutationa Peroxidase/metabolismo , HumanosRESUMO
Correction for 'The recent development of nanozymes for food quality and safety detection' by Yanyan Huang et al., J. Mater. Chem. B, 2022, 10, 1359-1368, https://doi.org/10.1039/D1TB02667D.
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Exportin 5 (XPO5) is a shuttle protein that mediates precursor miRNA (pre-miRNA) export from the nucleus to the cytoplasm, an important step in miRNA maturation. We previously demonstrated that XPO5 was phosphorylated by ERK kinase and subsequently underwent conformation change by the peptidyl-prolyl isomerase Pin1, leading to the reduced miRNA expression in hepatocellular carcinoma (HCC). Protein phosphorylation modification serves as a reversible regulatory mechanism precisely governed by protein kinases and phosphatases. Here we identified that the phosphatase PP2A catalyzed XPO5 dephosphorylation. PP2A holoenzyme is a ternary complex composed of a catalytic subunit, a scaffold subunit, and a regulatory subunit that determines substrate specificity. In this study, we characterized the involvement of B55ß subunit in XPO5 dephosphorylation that favored the distribution of XPO5 into the cytoplasm and promoted miRNA expression, leading to HCC inhibition in vitro and in vivo. Our study demonstrates the regulatory role of B55ß-containing PP2A in miRNA expression and may shed light on HCC pathogenesis.
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As potential mimics of natural enzymes, nanozymes can overcome many disadvantages associated with the use of natural enzymes, such as the need for complex preparation and purification processes, high cost, poor stability, and low recycling efficiency. Utilizing the unique advantages of nanomaterials, nanozymes have been widely used in biosensing, environmental protection, disease diagnosis and treatment, etc. Among these applications, biological detection is a hot research area that researchers are interested in. Although a lot of studies have been carried out on the topic of nanozyme-based biological detection, there are few reviews on the application of nanozymes in food quality and safety detection. This paper systematically introduces the latest research progress relating to nanozymes in the field of food quality and safety detection in recent years, including the detection of ions, common functional factors, toxins, antibiotics, and bacteria. Finally, we analyze the challenges associated with nanozyme use in the field of food analysis. We hope that this review will be of great significance for understanding the properties of nanozymes and for developing novel nanomaterials with enzyme-mimicking activities for food analysis.
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Nanoestruturas , Bactérias , Catálise , Qualidade dos AlimentosRESUMO
Artificial enzymes have attracted wide interest in disease diagnosis and biotechnology due to high stability, easy synthesis, and cost effectiveness. Unfortunately, their catalytic rate is limited to surface electron transfer, affecting the catalytic and biological activity. Here, we report an oligomeric nanozyme (O-NZ) with ultrafast electron transfer, achieving ultrahigh catalytic activity. O-NZ shows electron transfer of 1.8 nanoseconds in internal cores and 1.2 picoseconds between core and ligand molecule, leading to ultrahigh superoxidase dismutaselike and glutathione peroxidaselike activity (comparable with natural enzyme, Michaelis constant = 0.87 millimolars). Excitingly, O-NZ can improve the 1-month survival rate of mice with acute brain trauma from 50 to 90% and promote the recovery of long-term neurocognition. Biochemical experiments show that O-NZ can decrease harmful peroxide and superoxide via in vivo catalytic chain reaction and reduce acute neuroinflammation via nuclear factor erythroid-2 related factor 2mediated up-regulation of heme oxygenase-1 expression.
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Photothermal therapy is a very promising treatment method in the field of cancer therapy. The photothermal nanomaterials in near-infrared region (NIR-I, 750-900 nm) attracts extensive attention in recent years because of the good biological penetration of NIR light. However, the penetration depth is still not enough for solid tumors due to high tissue scattering. The light in the second near-infrared region (NIR-II, 1000-1700 nm) allows deeper tissue penetration, higher upper limit of radiation and greater tissue tolerance than that in the NIR-I, and it shows greater application potential in photothermal conversion. This review summarizes the photothermal properties of Au nanomaterials, two-dimensional materials, metal oxide sulfides and polymers in the NIR-II and their application prospects in photothermal therapy. It will arouse the interest of scientists in the field of cancer treatment as well as nanomedicine.
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Natural enzymes are efficient and versatile biocatalysts but suffer in their environmental tolerance and catalytic stability. As artificial enzymes, nanozymes can improve the catalytic stability, but it is still a challenge to achieve high catalytic activity. Here, we employed atomic engineering to build the artificial enzyme named Au24Ag1 clusterzyme that hosts an ultrahigh catalytic activity as well as strong physiological stability via atom manipulation. The designed Au24Ag1 clusterzyme activates the Ag-S active site via lattice expansion in the oligomer atom layer, showing an antioxidant property 72 times higher than that of natural antioxidant Trolox. Enzyme-mimicked studies find that Au24Ag1 clusterzyme exhibits high catalase-like (CAT-like) and glutathione peroxidase-like (GPx-like) activity with a maximum reaction rate of 68.9 and 17.8 µM/min, respectively. Meanwhile, the unique catalytic landscape exhibits distinctive reactions against inflammation by inhibiting the cytokines at an early stage in the brain. Atomic engineering of clusterzymes provides a powerful and attractive platform with satisfactory atomic dispersion for tailoring biocatalysts freely at the atomic level.
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Catálise , Catalase/genéticaRESUMO
Nanozyme, a kind of nanomaterials with enzymatic activity, has been developing vigorously over the past years owing to its advantages such as low-cost, easy storage, ease of use in harsh environments and so on, compared with natural enzymes. At present, as a typical two-dimensional nanomaterial, molybdenum disulfide (MoS2) and their hybrids with unexpected enzyme-like activities have caused wide attention. In this review, we mainly investigated the enzyme-like activities of MoS2 based nanomaterials, including peroxidase-like activity, catalase-like activity and superoxide dismutase-like activity. Furthermore, we systematically introduce recent research progress of MoS2 based nanomaterials in the fields of biological applications such as radiation protection, cancer therapy, antibacterial, and wound healing. Finally, the current challenges and perspectives of MoS2 based nanomaterials in the future are also discussed and proposed. We expect this review may be signiï¬cant to understand the properties of MoS2 based nanomaterials and the development of two-dimensional nanomaterials with enzyme mimicking activities.
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Molibdênio , Nanoestruturas , Dissulfetos , OxirreduçãoRESUMO
Traumatic brain injury (TBI) is a sudden injury to the brain, accompanied by the production of large amounts of reactive oxygen and nitrogen species (RONS) and acute neuroinflammation responses. Although traditional pharmacotherapy can effectively decrease the immune response of neuron cells via scavenging free radicals, it always involves in short reaction time as well as rigorous clinical trial. Therefore, a noninvasive topical treatment method that effectively eliminates free radicals still needs further investigation. Methods: In this study, a type of catalytic patch based on nanozymes with the excellent multienzyme-like activity is designed for noninvasive treatment of TBI. The enzyme-like activity, free radical scavenging ability and therapeutic efficacy of the designed catalytic patch were assessed in vitro and in vivo. The structural composition was characterized by the X-ray diffraction, X-ray photoelectron spectroscopy and high-resolution transmission electron microscopy technology. Results: Herein, the prepared Cr-doped CeO2 (Cr/CeO2) nanozyme increases the reduced Ce3+ states, resulting in its enzyme-like activity 3-5 times higher than undoped CeO2. Furthermore, Cr/CeO2 nanozyme can improve the survival rate of LPS induced neuron cells via decreasing excessive RONS. The in vivo experiments show the Cr/CeO2 nanozyme can promote wound healing and reduce neuroinflammation of mice following brain trauma. The catalytic patch based on nanozyme provides a noninvasive topical treatment route for TBI as well as other traumas diseases. Conclusions: The catalytic patch based on nanozyme provides a noninvasive topical treatment route for TBI as well as other traumas diseases.