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The metal-free cyclization of allenyl ketones and p-toluenesulfonylmethyl isocyanide (TosMIC), promoted by Cs2CO3, provides a convenient access to tetrasubstituted pyrroles in which an acyl group undergoes 1,2-migration. This tandem Michael addition/annulative migration synthetic strategy is general and high-yielding for various substituted allenyl ketones. Moreover, a phosphoryl or ester moiety is also a suitable functionality to enable such migration.
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Synthetic single-stranded (ss) DNA is a cornerstone for life and materials science, yet the purity, quantity, length, and customizability of synthetic DNA are still limiting in various applications. Here, we present PECAN, paired-end cutting assisted by DNAzymes (DNA enzymes or deoxyribozymes), which enables mass production of ssDNA of arbitrary sequence (up to 7000 nucleotides, or nt) with single-base precision. At the core of PECAN technique are two newly identified classes of DNAzymes, each robustly self-hydrolyzing with minimal sequence requirement up- or down-stream of its cleavage site. Flanking the target ssDNA with a pair of such DNAzymes generates a precursor ssDNA amplifiable by pseudogene-recombinant bacteriophage, which subsequently releases the target ssDNA in large quantities after efficient auto-processing. PECAN produces ssDNA of virtually any terminal bases and compositions with >98.5 % purity at the milligram-to-gram scale. We demonstrate the feasibility of using PECAN ssDNA for RNA in situ detection, homology-directed genome editing, and DNA-based data storage.
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DNA Catalítico , DNA de Cadeia Simples , DNA Catalítico/metabolismo , DNA , RNA , NucleotídeosRESUMO
DEK protein is critical to the formation of neutrophil extracellular traps (NETs) in rheumatoid arthritis (RA). Blocking DEK using the aptamer DTA via articular injection has been shown to have robust anti-inflammatory efficacy in a previous study. However, DTA is prone to nuclease degradation and renal clearance in vivo. RA is a systemic disease that involves multiple joints, and local injection is impractical in clinical settings. In this study, DTA was modified with methoxy groups on all deoxyribose sugar units and inverted deoxythymidine on the 3' end (DTA4) to enhance its stability against nuclease. DTA4 is stable for 72 h in 90% mouse serum and maintains a high binding affinity to DEK. DTA4 effectively inhibits the formation of NETs and the migration of HUVECs in vitro. DTA4 was then modified with cholesterol on its 5' end to form DTA6. DTA6 dramatically reduces DEK expression in inflammatory RAW264.7 cells. A hydrogel microneedle (hMN) was then fabricated for the transdermal delivery of DTA6. The hMN maintains morphological integrity after absorbing the aptamer solution, effectively pierces the skin, and rapidly releases DTA6 into the dermis. The DTA6-loaded hMN significantly attenuates inflammation and protects joints from cartilage/bone erosion in collagen-induced arthritis (CIA) mice.
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Aptâmeros de Nucleotídeos/administração & dosagem , Artrite Experimental/induzido quimicamente , Artrite Experimental/tratamento farmacológico , Colágeno/farmacologia , Proteínas de Ligação a DNA/metabolismo , Hidrogéis/administração & dosagem , Proteínas Oncogênicas/metabolismo , Proteínas de Ligação a Poli-ADP-Ribose/metabolismo , Animais , Anti-Inflamatórios/administração & dosagem , Artrite Experimental/metabolismo , Artrite Reumatoide/induzido quimicamente , Artrite Reumatoide/tratamento farmacológico , Artrite Reumatoide/metabolismo , Cartilagem/efeitos dos fármacos , Cartilagem/metabolismo , Linhagem Celular , Armadilhas Extracelulares/efeitos dos fármacos , Armadilhas Extracelulares/metabolismo , Células Endoteliais da Veia Umbilical Humana , Humanos , Inflamação/induzido quimicamente , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Camundongos , Substâncias Protetoras/administração & dosagem , Células RAW 264.7RESUMO
As drug targets, receptors have potential to screen drugs. Silica is an attractive support to immobilize receptors; however, the lack of biocompatibility makes it easier for receptors to lose bioactivity, which remains an obstacle to its widespread use. With the advantage of biocompatibility, DNA origami can be used as a biological carrier to improve the biocompatibility of silica and assemble receptors. In this study, a new biochromatography model based on DNA origami was constructed. A large quantity of M13ssDNA was used as a scaffold, leading to significant costs, so M13ssDNA was self-produced from the bacteriophage particles. This approach is demonstrated using the ligand binding domain of gamma isoform peroxisome proliferator-activated receptor (PPARγ-LBD) as a research object. PPARγ-LBD was assembled on DNA origami carrier and then coupled on the surface of silica. The products were packed into the column as stationary phase to construct the biochromatography with the ability to recognize drugs. Affinity and specificity of the biochromatography model were evaluated by HPLC. The final results showed that the biochromatography could recognize rosiglitazone specifically, which further proved that the model could screen chemical compositions interacted with PPARγ. It was the first time to take advantage of DNA origami to assemble PPARγ to construct biochromatography. The new biochromatography model has the advantages of being efficient, convenient, and high-throughput. This method affords a new way to rapidly and conveniently screen active ingredients from complex sample plant extracts and natural product-like libraries.
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Bacteriófago M13/química , Cromatografia Líquida de Alta Pressão/métodos , DNA de Cadeia Simples/química , Hipoglicemiantes/isolamento & purificação , PPAR gama/química , Dióxido de Silício/química , Tiazolidinedionas/isolamento & purificação , Sítios de Ligação , Proteínas Imobilizadas/química , Nanoestruturas/química , RosiglitazonaRESUMO
This study aimed to achieve two objectives: firstly, to analyze the relationships between aerobic fitness, as represented by the VIFT, and the heart rate and locomotor responses of youth male soccer players across various teams; and secondly, to compare players with lower and higher VIFT in terms of performance outcomes extracted during small-sided games (SSGs). A total of twenty-six youth male soccer players, aged 16.5 ± 0.32 years, with 3.4 ± 1.1 years of experience, voluntarily participated in the study. These players belonged to two regional-level tier 2 teams (trained/developmental). In the initial week of observation, the 30-15 Intermittent Fitness Test was implemented to measure the final velocity (VIFT) achieved by the players. Subsequently, the 5v5 format of play was conducted twice a week over two consecutive weeks, during which heart rate responses and locomotor demands were measured. The Pearson product-moment correlation test revealed a significant correlation between VIFT and the total distance covered during the 5v5 format (r = 0.471 [95% CI: 0.093; 0.721], p = 0.015). Conversely, small and non-significant correlations were identified between VIFT and mean heart rate (r = 0.280 [95% CI: - 0.126; 0.598]; p = 0.166), VIFT and peak heart rate (r = 0.237 [95% CI: - 0.170; 0.569]; p = 0.243), as well as VIFT and high-speed running (r = 0.254 [95% CI: - 0.153; 0.580]; p = 0.211). Players with higher VIFT demonstrated a significantly greater total distance, with a large effect size (+ 6.64%; p = 0.015; d = 1.033), compared to those with lower VIFT. Our findings suggest that improved performance in VIFT may lead to covering more distance in 5v5 matches. However, the lack of significant associations between VIFT and heart rate levels during SSGs suggests that they are not strongly correlated, possibly because VIFT is more closely linked to locomotor profile. As a practical implication, coaches may consider organizing players during SSGs based on their VIFT if the goal is to standardize locomotor demands.
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Desempenho Atlético , Frequência Cardíaca , Aptidão Física , Corrida , Futebol , Humanos , Futebol/fisiologia , Frequência Cardíaca/fisiologia , Masculino , Adolescente , Desempenho Atlético/fisiologia , Corrida/fisiologia , Aptidão Física/fisiologia , Teste de Esforço/métodos , Locomoção/fisiologiaRESUMO
The primary objective of this study was to systematically investigate the physiological and physical fitness adaptations resulting from small-sided games (SSGs) training programs in basketball players competing at youth competitive levels, as compared to other training approaches and/or control groups. To achieve this, we conducted a literature search on PubMed, Scopus, SPORTDiscus, and Web of Science, adhering to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. From the initial 626 studies retrieved, five were considered eligible for the current study. Among the five included articles, four conducted comparisons between the effects of SSGs and running-based high-intensity interval training. Regarding this, the four studies revealed a significant improvement in the final velocity during the 30-15 Intermittent Fitness Test, ranging from 4.07% to 7.29% following SSG-based interventions. This improvement was not significantly different from the comparator group. Additionally, two studies indicated that the SSGs group showed a significant advantage in change-of-direction time, with improvements ranging from -2.11% to 6.69% after interventions, and these results were not significantly different from the comparator group. However, the effects on repeated sprint ability yielded contradictory findings; two studies reported significant improvements ranging from -5.00% to -2.16%, while two others did not show significant effects following SSGs-based interventions. Similarly, in the linear sprint, the results of SSGs-based interventions were inconsistent. In summary, based on the available research, it can be concluded that SSG-based training is effective in significantly enhancing aerobic performance and change of direction, comparable to alternative approaches. However, the effects on repeated sprint ability and sprint performance are not consistently demonstrated.
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Basquetebol , Condicionamento Físico Humano , Adolescente , Humanos , Basquetebol/fisiologia , Exercício Físico , Adaptação FisiológicaRESUMO
Rheumatoid arthritis (RA) is characterized by high level of reactive oxygen species (ROS) and proinflammatory cytokines, which facilitate the activation of the inflammatory signaling such as NF-κB pathway and exacerbate the development of inflammation. Herein, we designed a nanodrug by encapsulating the NO donor S-nitrosoglutathione (GSNO) into an emulsion and coating the surface with a polydopamine (PDA) layer to yield GSNO@PDA, which simultaneously scavenged the extra ROS and suppressed NF-κB signaling for potent RA treatment. To enhance the cellular uptake and NO generation efficiency, dextran sulfate (DS) and Cu2+ were anchored on the surface of GSNO@PDA to obtain the final formulation GSNO@PDA@DS. Our results demonstrated that GSNO@PDA@DS were successfully prepared and the modification of DS effectively boosted the cellular uptake of GSNO@PDA@DS. Moreover, GSNO@PDA@DS lowered cellular ROS and elevated intracellular NO, resulting in a decrease of M1 phenotype, inhibition of NF-κB pathway and down-regulation of proinflammatory cytokine tumor necrosis factor-α (TNF-α). Further in vivo studies confirmed that GSNO@PDA@DS significantly relieved symptoms and bone erosion by regulating the microenvironment of RA, highlighting the potential of GSNO@PDA@DS for RA therapy through ROS scavenging and NO-mediated suppression of inflammatory signaling.
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Artrite Reumatoide , NF-kappa B , Doadores de Óxido Nítrico , Polímeros , Espécies Reativas de Oxigênio , S-Nitrosoglutationa , Espécies Reativas de Oxigênio/metabolismo , Artrite Reumatoide/tratamento farmacológico , Artrite Reumatoide/metabolismo , Animais , Doadores de Óxido Nítrico/farmacologia , Doadores de Óxido Nítrico/administração & dosagem , Camundongos , NF-kappa B/metabolismo , S-Nitrosoglutationa/farmacologia , S-Nitrosoglutationa/administração & dosagem , Células RAW 264.7 , Polímeros/química , Indóis/farmacologia , Indóis/administração & dosagem , Sequestradores de Radicais Livres/farmacologia , Sequestradores de Radicais Livres/administração & dosagem , Sinergismo Farmacológico , Masculino , Transdução de Sinais/efeitos dos fármacos , Sulfato de Dextrana , Fator de Necrose Tumoral alfa/metabolismo , Óxido Nítrico/metabolismo , Sistemas de Liberação de Medicamentos/métodosRESUMO
[This corrects the article DOI: 10.1039/D0RA05640E.].
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BACKGROUND: Hydrogen sulfide (H2S) is an endogenously generated gaseous transmitter known for its cytoprotective effect mediated by the PI3K-Akt signaling pathway. Human induced pluripotent stem cell (hiPSC)-derived mesenchymal stromal cells (MSCs), or hiPSC-MSCs, represent an alternative source of MSCs for autologous cell therapy. The big-conductance Ca(2+)-activated outward K(+) currents (BKCa), known to mediate cell proliferation, have been detected in >80% of hiPSC-MSCs. The present study aimed to explore the effect of H2S on survival and proliferation of hiPSC-MSCs and investigate the mediatory role of BKCa. METHODS: Effects of H2S on proliferation and survival of hiPSC-MSCs were measured by 5-bromo-2-deoxyuridine incorporation, population doubling and cell cycle assays, and by 3-(4,5)-dimethylthiahiazo(-z-y1)-3,5-di-phenytetrazoliumromide assay and 4'-6-diamidino-2-phenylindole staining, respectively. BKCa was recorded by means of the whole-cell patch-clamp technique. The expressions of KCa 1.1 (encoding BKCa) and apoptosis-related genes were measured by reverse transcriptase-polymerase chain reaction. The phosphorylation of Akt was assessed by Western blot analysis. RESULTS: Exogenously administered NaHS (an H2S donor, 50-300 µmol/L) significantly promoted proliferation of hiPSC-MSCs. NaHS prevented the hypoxia-induced apoptosis and suppressed BKCa currents without altering the expression levels of α- and ß-KCa 1.1. In addition, NaHS increased the phosphorylation of Akt and decreased the expression of Caspase 8 and Bax in hiPSC-MSCs. Paxilline (1 µmol/L), a BKCa blocker, showed similar effects on promoting cell proliferation and phosphorylation of Akt and suppression of apoptotic genes in hiPSC-MSCs. CONCLUSIONS: Our data confirmed that H2S arguments the proliferation and survival of hiPSC-MSCs through activation of the PI3K-Akt pathway and that such effects could be mediated through inhibition of BKCa.
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Sulfeto de Hidrogênio/farmacologia , Células-Tronco Pluripotentes Induzidas/efeitos dos fármacos , Canais de Potássio Ativados por Cálcio de Condutância Alta/antagonistas & inibidores , Células-Tronco Mesenquimais/efeitos dos fármacos , Apoptose/efeitos dos fármacos , Caspase 8/biossíntese , Hipóxia Celular/efeitos dos fármacos , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Terapia Baseada em Transplante de Células e Tecidos , Humanos , Indóis/farmacologia , Canais de Potássio Ativados por Cálcio de Condutância Alta/efeitos dos fármacos , Canais de Potássio Ativados por Cálcio de Condutância Alta/metabolismo , Técnicas de Patch-Clamp , Fosfatidilinositol 3-Quinases/metabolismo , Fosforilação/efeitos dos fármacos , Bloqueadores dos Canais de Potássio/farmacologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais/efeitos dos fármacos , Proteína X Associada a bcl-2/biossínteseRESUMO
The purpose of the present study was to develop a novel transdermal vinpocetine patch containing a stable formulation and with good entrapment efficiency, and percutaneous absorption which via ethosome. Ethosome was found to be a more efficient delivery carrier with high encapsulation capacities (79.5% +/- 1.8%) and nanometric size (180.7 +/- 1.5 nm). In vitro percutaneous permeation experiments demonstrated that the permeation of vinpocetine through abdominal skin of Sprague Dawley was significantly increased when ethosome was used. The vinpocetine transdermal fluxes from ethosome gel (3.56 +/- 0.13 microg/cm2/h) were 6.72 and 3.10 times higher than that of vinpocetine gel solution and vinpocetine aueous solution, respectively. Furthermore, the AUC(0 --> infinity), and eliminiation half-life by the transdermal administration were significantly higher than those by the intragastric administration (P < 0.01). The study demonstrated that ethosome is a promising vesicular carrier for enhancing percutaneous absorption of vinpocetine.
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Anti-Hipertensivos/administração & dosagem , Lipossomos/química , Alcaloides de Vinca/administração & dosagem , Administração Cutânea , Animais , Anti-Hipertensivos/farmacocinética , Química Farmacêutica , Portadores de Fármacos , Sistemas de Liberação de Medicamentos , Géis , Técnicas In Vitro , Intubação Gastrointestinal , Ratos , Ratos Sprague-Dawley , Soluções , Alcaloides de Vinca/farmacocinéticaRESUMO
Inflammatory diseases are usually featured with relatively high level of reactive oxygen species (ROS). The excess ROS facilitate the polarization of microphages into proinflammatory M1 phenotype, and cause DNA damage, protein carbonylation, and lipid peroxidation, resulting in further deterioration of inflammatory diseases. Therefore, alleviating oxidative stress by ROS scavenging has been an effective strategy for reversing inflammation. Inspired by the natural antioxidant enzymes, electron transfer-based artificial antioxidant nanozymes have been emerging therapeutics for the treatment of inflammatory diseases. The present review starts with the basic knowledge of ROS and diseases, followed by summarizing the possible active centers for the preparation of antioxidant nanozymes. The strategies for the design of antioxidant nanozymes on the purpose of higher catalytic activity are provided, and the applications of the developed antioxidant nanozymes on the therapy of inflammatory diseases are discussed. A perspective is included for the design and applications of artificial antioxidant nanozymes in biomedicine as well.
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Antioxidantes , Elétrons , Antioxidantes/uso terapêutico , Espécies Reativas de Oxigênio/metabolismo , Estresse OxidativoRESUMO
BACKGROUND: Assessing the dairy consumption and psychological symptoms of Chinese college students as a reference for the mental health of Chinese college students. METHODS: A three-stage stratified whole-group sampling method was used to investigate dairy consumption and psychological symptoms among 5904 (2554 male students, accounting for 43.3% of the sample) college students in the Yangtze River Delta region. The mean age of the subjects was 20.13 ± 1.24 years. Psychological symptoms were surveyed using the Brief Questionnaire for the Assessment of Adolescent Mental Health. The detection rates of emotional problems, behavioral symptoms, social adaptation difficulties and psychological symptoms among college students with different dairy consumption habits were analyzed using chi-square tests. The association between dairy consumption and psychological symptoms was assessed using a logistic regression model. RESULTS: College students from the "Yangtze River Delta" region of China participated in the study, of which 1022 (17.31%) had psychological symptoms. The proportions of participants with dairy consumption of ≤2 times/week, 3-5 times/week, and ≥6 times/week were 25.68%, 42.09%, and 32.23%, respectively. Using dairy consumption ≥6 times/week as a reference, multifactor logistic regression analysis showed that college students with dairy consumption ≤2 times/week (OR = 1.42, 95% CI: 1.18, 1.71) were at higher risk of psychological symptoms (p < 0.001). CONCLUSION: During the COVID-19 pandemic, Chinese college students with lower dairy consumption exhibited higher detection rates of psychological symptoms. Dairy consumption was negatively associated with the occurrence of psychological symptoms. Our study provides a basis for mental health education and increasing knowledge about nutrition among Chinese college students.
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COVID-19 , Adolescente , Humanos , Masculino , Adulto Jovem , Adulto , Estudos Transversais , COVID-19/epidemiologia , Pandemias , Saúde Mental , Estudantes/psicologia , China/epidemiologiaRESUMO
The unprecedented dimerizations of 2H-azirines have been developed under the catalysis of palladium and silver. Upon changing the reaction conditions, the fully aryl-substituted pyrrole and pyrimidine derivatives were furnished in moderate yields with regiospecificity, respectively. Control experiments uncovered distinct catalytic effects of two transition metals, and the proposed catalytic cycles plausibly rationalized the chemodivergence and regioselectivity.
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Tumor necrosis factor receptor-1 (TNFR1) and DEK are closely associated with the development of rheumatoid arthritis (RA). Taking advantage of the high adenosine triphosphate (ATP) in RA microenvironment and the interactions of DNA aptamers with their targets, an ATP-responsive DNA nanodrug was constructed that simultaneously targets TNFR1 and DEK for RA therapy. To this end, DEK target aptamer DTA and TNFR1 target aptamer Apt1-67 were equipped with sticky ends to hybridize with ATP aptamer (AptATP) and fabricated DNA nanodrug DAT. Our results showed that DAT was successfully prepared with good stability. In the presence of ATP, DAT was disassembled, resulting in the release of DTA and Apt1-67. In vitro studies demonstrated that DAT was superior to the non-responsive DNA nanodrug TD-3A3T in terms of anti-inflammation activity and ATP was inevitable to maximize the anti-inflammation ability of DAT. The superior efficacy of DAT is attributed to the more potent inhibition of caspase-3 and NETs formation. In vivo results further confirmed the anti-RA efficacy of DAT, whereas the administration routes (intravenous injection and transdermal administration via microneedles) did not cause significant differences. Overall, the present study supplies an intelligent strategy for RA therapy and explores a promising administration route for future clinical medication of RA patients.
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Aptâmeros de Nucleotídeos , Artrite Reumatoide , Nanopartículas , Humanos , Receptores Tipo I de Fatores de Necrose Tumoral , Artrite Reumatoide/tratamento farmacológico , Artrite Reumatoide/patologia , DNA , Trifosfato de Adenosina , Nanopartículas/uso terapêutico , Proteínas de Ligação a Poli-ADP-Ribose , Proteínas Cromossômicas não Histona , Proteínas OncogênicasRESUMO
Tumor necrosis factor-α (TNFα) inhibitors are widely used in treating autoimmune diseases like rheumatoid arthritis (RA). These inhibitors can presumably alleviate RA symptoms by blocking TNFα-TNF receptor 1 (TNFR1)-mediated pro-inflammatory signaling pathways. However, the strategy also interrupts the survival and reproduction functions conducted by TNFα-TNFR2 interaction and causes side effects. Thus, it is urgently needed to develop inhibitors that can selectively block TNFα-TNFR1 but not TNFα-TNFR2. Here, nucleic acid-based aptamers against TNFR1 are explored as potential anti-RA candidates. Through the systematic evolution of ligands by exponential enrichment (SELEX), two types of TNFR1-targeting aptamers were obtained, and their KD values are approximately 100-300 nM. In silico analysis shows that the binding interface of aptamer-TNFR1 highly overlapped with natural TNFα-TNFR1 binding. On the cellular level, the aptamers can exert TNFα inhibitory activity by binding to TNFR1. The anti-inflammatory efficiencies of aptamers were assessed and further enhanced using divalent aptamer constructs. These findings provide a new strategy to block TNFR1 for potential anti-RA treatment precisely.
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Artrite Reumatoide , Receptores Tipo I de Fatores de Necrose Tumoral , Humanos , Receptores Tipo I de Fatores de Necrose Tumoral/metabolismo , Receptores Tipo II do Fator de Necrose Tumoral/metabolismo , Artrite Reumatoide/patologia , Transdução de Sinais , Anti-Inflamatórios/farmacologia , Oligonucleotídeos , Fator de Necrose Tumoral alfa/metabolismoRESUMO
Selective suppression of tumor necrosis factor (TNF) α-TNF receptor 1 (TNFR1) signaling is a potent solution for rheumatoid arthritis (RA). Herein, novel composite nucleic acid nanodrugs that simultaneously restrain TNF α binding and TNFR1 multimerization were designed to reinforce inhibition of TNF α-TNFR1 signaling for RA therapy. Towards this end, a novel peptide Pep4-19 that suppresses TNFR1 clustering was extracted from TNFR1. The resulting peptide and a DNA aptamer Apt2-55, which inhibits TNF α binding, were integrally or separately anchored on DNA tetrahedron (TD) to obtain nanodrugs with different spatial distribution of Apt2-55 and Pep4-19 (TD-3A-3P and TD-3(A-P)). Our results showed that Pep4-19 enhanced the viability of inflammatory L929 cells. Both TD-3A-3P and TD-3(A-P) suppressed caspase 3, reduced cell apoptosis, and inhibited FLS-RA migration. Compared to TD-3(A-P), TD-3A-3P supplied sufficient flexibility for Apt2-55 and Pep4-19, and showed better anti-inflammation properties. Furthermore, TD-3A-3P significantly relieved symptoms in collagen-induced arthritis (CIA) mice, and the anti-RA efficacy through intravenous injection was comparable to transdermal administration via microneedles. Overall, the work provides an effective strategy for RA treatment by dual-targeting TNFR1, and demonstrates that microneedles are promising approach to drug administration in the treatment of RA.
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By blocking the DEK protein, DEK-targeted aptamers (DTAs) can reduce the formation of neutrophil extracellular traps (NETs) to reveal a strong anti-inflammatory efficacy in rheumatoid arthritis. However, the poor stability of DTA has greatly limited its clinical application. Thus, in order to design an aptamer with better stability, DTA was modified by methoxy groups (DTA_OMe) and then the exact DEK-DTA interaction mechanisms were explored through theoretical calculations. The corresponding 2'-OCH3-modified nucleotide force field was established and the molecular dynamics (MD) simulations were performed. It was proved that the 2'-OCH3-modification could definitely enhance the stability of DTA on the premise of comparative affinity. Furthermore, the electrostatic interaction contributed the most to the binding of DEK-DTA, which was the primary interaction to maintain stability, in addition to the non-specific interactions between positively-charged residues (e.g., Lys and Arg) of DEK and the negatively-charged phosphate backbone of aptamers. The H-bond network analysis reminded that eight bases could be mutated to probably enhance the affinity of DTA_OMe. Therein, replacing the 29th base from cytosine to thymine of DTA_OMe was theoretically confirmed to be with the best affinity and even better stability. These research studies imply to be a promising new aptamer design strategy for the treatment of inflammatory arthritis.
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The abuse of antibiotics has led to the emergence of multidrug-resistant bacterial strains worldwide, which greatly threatens human health. In the present work, we developed single-atom catalysts (SACs) with atomically dispersed Fe as catalytic sites (Fe-SACs) to combat multidrug-resistant bacteria by elevating cellular reactive oxygen species (ROS). Our intensive studies confirmed that Fe-SACs were successfully prepared and exhibited excellent catalase (CAT)-, oxidase (OXD)-, and peroxidase (POD)-like activities. To enhance water dispersibility, biosafety and the interactions between the nanodrugs and gram-positive bacteria, phenylboronic acid group-functionalized carboxylated chitosan (CCS-PBA) was coated on the surface of Fe-SACs to yield Fe-SACs@CCS-PBA for in vitro and in vivo studies. The synergistic catalytic activity and photothermal activity of Fe-SACs@CCS-PBA effectively overcame multidrug-resistant bacterial strains (MRSA) in vitro and significantly accelerated wound healing in vivo, suggesting the great potential of SACs to overcome infectious disease caused by multidrug-resistant bacteria.
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Infecções Bacterianas , Quitosana , Humanos , Antibacterianos/farmacologia , Ácidos Carboxílicos , Espécies Reativas de OxigênioRESUMO
Although the inhibitors of the interleukin-6 receptor (IL-6R) and tumor necrosis factor-α (TNF-α) have achieved a certain success in the clinical treatment of rheumatoid arthritis (RA), great effort should be made to overcome side effects and to improve patient compliance. The present research aimed to address these problems by the co-delivery of tocilizumab (TCZ)-an inhibitor of IL-6R-and an aptamer Apt1-67, which specifically inhibits TNF receptor 1 via separable microneedles (MN). MN were featured with a sustained release of TCZ from needle tips and a rapid release of Apt1-67 from needle bodies by using methacrylate groups grafted hyaluronic acid as the fillings of needle tips and polyvinyl alcohol/polyvinyl pyrrolidone as the fillings of needle bodies. Our results demonstrated that TCZ and Apt1-67 were distributed in MN as expected, and they could be released to the surroundings in the skin. In vivo studies revealed that combined medication via MN (TCZ/Apt1-67@MN) was superior to MN loaded with a single drug. Compared with subcutaneous injection, TCZ/Apt1-67@MN was of great advantage in inhibiting bone erosion and alleviating symptoms of CIA mice. This study not only provides a novel approach for combined medication with different release properties but also supplies a strategy for improving drug efficacy.