ABSTRACT
Polymyxins have been regarded as an efficient therapeutic against many life-threatening, multidrug resistant Gram-negative bacterial infections; however, the cytotoxicity and emergence of drug resistance associated with polymyxins have greatly hindered their clinical potential. Herein, the reaction-induced self-assembly (RISA) of polymyxins and natural aldehydes in aqueous solution is presented. The resulting assemblies effectively mask the positively charged nature of polymyxins, reducing their cytotoxicity. Moreover, the representative PMBA4 (composed of polymyxin B (PMB) and (E)-2-heptenal (A4)) assemblies demonstrate enhanced binding to Gram-negative bacterial outer membranes and exhibit multiple antimicrobial mechanisms, including increased membrane permeability, elevated bacterial metabolism, suppression of quorum sensing, reduced ATP synthesis, and potential reduction of bacterial drug resistance. Remarkably, PMBA4 assemblies reverse drug resistance in clinically isolated drug-resistant strains of Gram-negative bacteria, demonstrating exceptional efficacy in preventing and eradicating bacterial biofilms. PMBA4 assemblies efficiently eradicate Gram-negative bacterial biofilm infections in vivo and alleviate inflammatory response. This RISA strategy offers a practical and clinically applicable approach to minimize side effects, reverse drug resistance, and prevent the emergence of resistance associated with free polymyxins.
ABSTRACT
Chronic wound treatment has emerged as a significant healthcare concern worldwide due to its substantial economic burden and the limited effectiveness of current treatments. Effective management of biofilm infections, regulation of excessive oxidative stress, and promotion of tissue regeneration are crucial for addressing chronic wounds. Hydrogel stands out as a promising candidate for chronic wound treatment. However, its clinical application is hindered by the difficulty in designing and fabricating easily and conveniently. To overcome these obstacles, we present a supermolecular G-quadruplex hydrogel with the desired multifunction via a dynamic covalent strategy and Hoogsteen-type hydrogen bonding. The G-quadruplex hydrogel is made from the self-assembly of guanosine, 2-formylphenyboronic acid, polyethylenimine, and potassium chloride, employing dynamic covalent strategy and Hoogsteen-type hydrogen bonding. In the acidic/oxidative microenvironment associated with bacterial infections, the hydrogel undergoes controlled degradation, releasing the polyethylenimine domain, which effectively eliminates bacteria. Furthermore, nanocomplexes comprising guanosine monophosphate and manganese sulfate are incorporated into the hydrogel skeleton, endowing it with the ability to scavenge reactive oxygen species and modulate macrophages. Additionally, the integration of basic fibroblast growth factor into the G-quadruplex skeleton through dynamic covalent bonds facilitates controlled tissue regeneration. In summary, the facile preparation process and the incorporation of multiple functionalities render the G-quadruplex hydrogel a highly promising candidate for advanced wound dressing. It holds great potential to transition from laboratory research to clinical practice, addressing the pressing needs of chronic wound management.
Subject(s)
Deafness , Hydrogels , Humans , Polyethyleneimine , Bandages , Anti-Bacterial Agents/pharmacology , BiofilmsABSTRACT
Due to the emergence of drug resistance in bacteria and biofilm protection, achieving a satisfactory therapeutic effect for bacteria-infected open wounds with conventional measures is problematic. Here, a photothermal cascade nano-reactor (CPNC@GOx-Fe2+ ) is constructed through a supramolecular strategy through hydrogen bonding and coordination interactions between chitosan-modified palladium nano-cube (CPNC), glucose oxidase (GOx), and ferrous iron (Fe2+ ). CPNC@GOx-Fe2+ exhibits excellent photothermal effects and powers the GOx-assisted cascade reaction to generate hydroxyl radicals, enabling photothermal and chemodynamic combination therapy against bacteria and biofilms. Further proteomics, metabolomics, and all-atom simulation results indicate that the damage of the hydroxyl radical to the function and structure of the cell membrane and the thermal effect enhance the fluidity and inhomogeneity of the bacterial cell membrane, resulting in the synergistic antibacterial effect. In the biofilm-associated tooth extraction wound model, the hydroxyl radical generated from the cascade reaction process can initiate the radical polymerization process to form a hydrogel in situ for wound protection. In vivo experiments confirm that synergistic antibacterial and wound protection can accelerate the healing of infected tooth-extraction wounds without affecting the oral commensal microbiota. This study provides a way to propose a multifunctional supramolecular system for the treatment of open wound infection.
Subject(s)
Hydroxyl Radical , Tooth Extraction , Anti-Bacterial Agents/pharmacology , Anti-Bacterial Agents/therapeutic use , Biofilms , Cell Membrane , Glucose Oxidase , HydrogelsABSTRACT
Drug combination provides an efficient pathway to combat drug resistance in bacteria and bacterial biofilms. However, the facile methodology to construct the drug combinations and their applications in nanocomposites is still lacking. Here the two-tailed antimicrobial amphiphiles (T2 A2 ) composed of nitric oxide (NO)-donor (diethylenetriamine NONOate, DN) and various natural aldehydes are reported. T2 A2 self-assemble into nanoparticles due to their amphiphilic nature, with remarkably low critical aggregation concentration. The representative cinnamaldehyde (Cin)-derived T2 A2 (Cin-T2 A2 ) assemblies demonstrate excellent bactericidal efficacy, notably higher than free Cin and free DN. Cin-T2 A2 assemblies kill multidrug-resistant staphylococci and eradicate their biofilms via multiple mechanisms, as proved by mechanism studies, molecular dynamics simulations, proteomics, and metabolomics. Furthermore, Cin-T2 A2 assemblies rapidly eradicate bacteria and alleviate inflammation in the subsequent murine infection models. Together, the Cin-T2 A2 assemblies may provide an efficient, non-antibiotic alternative in combating the ever-increasing threat of drug-resistant bacteria and their biofilms.
Subject(s)
Anti-Infective Agents , Nanoparticles , Mice , Animals , Bacteria , Anti-Bacterial Agents/pharmacology , Biofilms , Microbial Sensitivity TestsABSTRACT
New antimicrobial strategies are urgently needed to meet the challenges posed by the emergence of drug-resistant bacteria and bacterial biofilms. This work reports the facile synthesis of antimicrobial dynamic covalent nano-networks (aDCNs) composing antibiotics bearing multiple primary amines, polyphenols, and a cross-linker acylphenylboronic acid. Mechanistically, the iminoboronate bond drives the formation of aDCNs, facilitates their stability, and renders them highly responsive to stimuli, such as low pH and high H2O2 levels. Besides, the representative A1B1C1 networks, composed of polymyxin B1(A1), 2-formylphenylboronic acid (B1), and quercetin (C1), inhibit biofilm formation of drug-resistant Escherichia coli, eliminate the mature biofilms, alleviate macrophage inflammation, and minimize the side effects of free polymyxins. Excellent bacterial eradication and inflammation amelioration efficiency of A1B1C1 networks are also observed in a peritoneal infection model. The facile synthesis, excellent antimicrobial performance, and biocompatibility of these aDCNs potentiate them as a much-needed alternative in current antimicrobial pipelines.
ABSTRACT
Prodrug nanoassemblies combine the advantages of prodrug and nanomedicines, offering great potential in targeting the lesion sites and specific on-demand drug release, maximizing the therapeutic performance while minimizing their side effects. However, there is still lacking a facile pathway to prepare the lipid prodrug nanoassemblies (LPNAs). Herein, we report the LPNAs via the dynamic covalent boronate between catechol and boronic acid. The resulting LPNAs possess properties like drug loading in a dynamic covalent manner, charge reversal in an acidic microenvironment, and specific drug release at an acidic and/or oxidative microenvironment. Our methodology enables the encapsulation and delivery of three model drugs: ciprofloxacin, bortezomib, and miconazole. Moreover, the LPNAs are often more efficient in eradicating pathogens or cancer cells than their free counterparts, both in vitro and in vivo. Together, our LPNAs with intriguing properties may boost the development of drug delivery and facilitate their clinical applications.
Subject(s)
Nanoparticles , Prodrugs , Prodrugs/pharmacology , Prodrugs/therapeutic use , Drug Delivery Systems/methods , Bortezomib , Boronic Acids , Lipids , Drug LiberationABSTRACT
This study aimed at providing new insights into protein degradation and associated textural properties of skate (Raja kenojei) muscles. The pH and ammonia content of skate muscle were found to increase with an increase in fermentation time. During the initial phase of fermentation, the skate muscle hardened prior to demonstrating a spike in its pH and ammonia content. Protein characterization of the skate myofibrils revealed that the high proteins degraded into low molecular peptides, resulting in an increase in the hydrophobic interactions of these myofibrillar protein during fermentation. Consequently, the springiness of the skate muscles significantly (p < 0.05) decreased. Consequently, the textural profile of skate muscle during fermentation has a strong correlation with fermentation time and protein degradation.
ABSTRACT
Bacterial biofilms, especially ones caused by multi-drug resistant strains, are increasingly posing a significant threat to human health. Inspired by nature, we report the fabrication of glucose oxidase-loaded iron-phenolic networks that can power the cascade reaction to generate free radicals to eradicate bacterial biofilms. A soft template, sodium deoxycholate, is employed to guarantee glucose oxidase activity during encapsulation, yielding the porous nanocomplexes after removing the template. The porous nature of nanocomplexes, characterized via transmission electron microscopy, N2 adsorption isotherms, and thermogravimetric analysis, facilitates the diffusion of substrates and products during the cascade reaction and protects glucose oxidase from protease attack. Our optimized nanocomplexes (Fe-GA/GOx) could efficiently kill drug-resistant ESKAPE pathogens, including the clinically isolated strains and eradicate their biofilms. In this regard, Fe-GA/GOx could induce over 90% of the biomass of Klebsiella pneumoniae and Staphylococcus aureus biofilms. In the murine peritonitis infection model induced by Staphylococcus aureus and pneumonia model induced by Klebsiella pneumoniae, our Fe-GA/GOx nanocomplexes could efficiently eradicate the bacteria (over 3-log reduction in colony-forming units) and alleviate the inflammatory response without notable side effects on normal tissues. Therefore, our strategy may provide an efficient alternative treatment to combat bacterial biofilms and address the emergence of drug resistance.
Subject(s)
Iron , Staphylococcal Infections , Animals , Mice , Anti-Bacterial Agents/chemistry , Bacteria , Biofilms , Glucose Oxidase/therapeutic use , Klebsiella pneumoniae , Microbial Sensitivity Tests , Staphylococcal Infections/drug therapy , Staphylococcus aureusABSTRACT
The effects of ultrasound treatment at different temperatures (4, 10, and 25 â) on the brining process of Chinese cabbage were investigated based on their salt diffusion coefficients and texture profiles. Salt weight increased significantly, but water weight decreased in Chinese cabbage treated with ultrasound at increasing temperatures. According to Fick's second equation, the effective diffusion coefficient of Chinese cabbage showed a notable increase as temperature was increased. High temperature caused unfavorable texture properties, and among these, hardness showed the most significant decrease when brining temperature was set at 25 °C. Consequently, results from the texture profile analysis and brining kinetics modeling suggest that optimal brining conditions could be achieved at 10 °C. At this temperature, the diffusion coefficient of Chinese cabbage is higher, the brining time is reduced, and the preferred qualities of kimchi are preserved. PRACTICAL APPLICATION: Ultrasonication is an effective technology that can be utilized in kimchi manufacturing. It presents the advantage of reducing brining time while maintaining the acceptable textural properties of kimchi. This study investigated the impact of different temperatures on the texture properties and brining times of Chinese cabbage during brining and reveal a practical application worthy of further study in food industries and provide valuable information for improving the quality of kimchi.
Subject(s)
Brassica rapa/chemistry , Fermentation , Fermented Foods/analysis , Food Technology/methods , Salts/chemistry , Sonication , Fermented Foods/standards , Humans , Kinetics , Sodium Chloride, Dietary , TemperatureABSTRACT
Changes in physicochemical properties, isoflavone composition, antioxidant activities, and microbial count of cheonggukjang during the manufacturing process were investigated. During fermentation, isoflavone glucosides are converted to isoflavone aglycones. After fermentation, the increased isoflavone aglycone content was determined. The total phenolic and total flavonoid content, as well as antioxidant activities, significantly increased in cheonggukjang at fermentation process. In proximate composition, fermented soybeans had the highest crude protein content. A gradual increase in the browning index and pH values was observed from the primary processing procedure to fermentation. The total bacterial count increased with each manufacturing step, except for the steamed step. The traditional processing methods for cheonggukjang from raw soybean induced several changes in chemical composition. In addition, the change of isoflavone glucosides to isoflavone aglycones during fermentation could enhance their bioavailability and antioxidant properties.
ABSTRACT
BACKGROUND: Recent studies have discovered a subtype of noncoding RNAs, long noncoding RNAs (lncRNAs), which are dysregulated in various tumors and associated with carcinogenesis. This study aims to identify the role of lncRNA LINC00052 in glioma tumorigenesis. METHODS: LINC00052 expression was monitored in glioma samples and glioma cells through RT-qPCR. Besides, proliferation assay, transwell assay and wound healing assay were performed to uncover the role of LINC00052 in glioma. Furthermore, the interaction between LINC00052 and insulin-like growth factor 2 (IGF2) in glioma was studied through RT-qPCR and western blot assay. RESULTS: LINC00052 expression was remarkably downregulated in glioma samples compared with that in normal brain samples. Moreover, cell proliferation, cell invasion and cell migration in glioma were inhibited after overexpression of LINC00052 in vitro. Moreover, after overexpression of LINC00052, IGF2 was downregulated at mRNA and protein level in vitro. Besides, the expression of IGF2 in tumor tissues was negatively correlated to the expression of LINC00052. CONCLUSIONS: These results above suggest that LINC00052 could repress cell migration, invasion and proliferation in glioma through downregulating IGF2, which may offer a new therapeutic intervention for glioma patients.