Application of a derivative of human defensin 5 to treat ionizing radiation-induced enterogenic infection.

Enterogenic infection is a common complication for patients with radiation injury and requires efficient therapeutics in the clinic. Herein, we evaluated the promising drug candidate T7E21RHD5, which is a peptide derived from intestinal Paneth cell-secreted human defensin 5. Oral administration of this peptide alleviated the diarrhea symptoms of mice that received total abdominal irradiation (TAI, γ-ray, 12 Gy) and improved survival. Pathologic analysis revealed that T7E21RHD5 elicited an obvious mitigation of ionizing radiation (IR)-induced epithelial damage and ameliorated the reduction in the levels of claudin, zonula occluden 1 and occludin, three tight junction proteins in the ileum. Additionally, T7E21RHD5 regulated the gut microbiota in TAI mice by remodeling ß diversity, manifested as a reversal of the inverted proportion of Bacteroidota to Firmicutes caused by IR. T7E21RHD5 treatment also decreased the abundance of pathogenic Escherichia-Shigella but significantly increased the levels of Alloprevotella and Prevotellaceae_NK3B31, two short-chain fatty acid-producing bacterial genera in the gut. Accordingly, the translocation of enterobacteria and lipopolysaccharide to the blood, as well as the infectious inflammatory responses in the intestine after TAI, was all suppressed by T7E21RHD5 administration. Hence, this versatile antimicrobial peptide possesses promising application prospects in the treatment of IR-induced enterogenic infection.

Clustered Cobalt Nanodots Initiate Ferroptosis by Upregulating Heme Oxygenase 1 for Radiotherapy Sensitization.

High cobalt (Co) levels in tumors are associated with good clinical prognosis. An anticancer regimen that increases intratumoral Co through targeted nanomaterial delivery is proposed in this study. Bovine serum albumin and cobalt dichloride are applied to prepare cobaltous oxide nanodots using a facile biomineralization strategy. After iRGD peptide conjugation, the nanodots are loaded into dendritic mesoporous silica nanoparticles, generating a biocompatible product iCoDMSN. This nanocomposite accumulates in tumors after intravenous injection by deep tissue penetration and can be used for photoacoustic imaging. Proteomics research and molecular biology experiments reveal that iCoDMSN is a potent ferroptosis inducer in cancer cells. Mechanistically, iCoDMSNs upregulate heme oxygenase 1 (HMOX1), which increases transferrin receptors and reduces solute carrier family 40 member 1 (SLC40A1), resulting in Fe2+ accumulation and ferroptosis initiation. Furthermore, upregulated nuclear factor erythroid 2-related factor 2 (NRF2), arising from the reduction in Kelch-like ECH-associated protein 1 (KEAP1) expression, is responsible for HMOX1 enhancement after iCoDMSN treatment. Owing to intensified ferroptosis, iCoDMSN acts as an efficient radiotherapy enhancer to eliminate cancer cells in vitro and in vivo. This study demonstrates a versatile Co-based nanomaterial that primes ferroptosis by expanding the labile iron pool in cancer cells, providing a promising tumor radiotherapy sensitizer.

γ-Core Guided Antibiotic Design Based on Human Enteric Defensin 5.

An increase in the number of infections caused by resistant bacteria worldwide necessitates the development of alternatives to antibiotics. Human defensin (HD) 5 is an innate immune peptide with broad-spectrum antibacterial activity, but its complicated structure makes its preparation difficult. Herein, we truncated the HD5 structure by extracting the highly conserved γ-core motif. A structure-activity study showed that this motif was ineffective in killing bacteria in the absence of specific spatial conformation. Notably, after the introduction of two intramolecular disulfide bonds, its antibacterial activity was markedly improved. Glu and Ser residues were then replaced with Arg to create the derivative RC18, which exhibited stronger potency than HD5, particularly against methicillin-resistant S. aureus (MRSA). Mechanistically, RC18 bound to lipid A and lipoteichoic acid at higher affinities than HD5. Furthermore, RC18 was more efficient than HD5 in penetrating the bacterial membranes. Molecular dynamics simulation revealed that five Arg residues, Arg1, Arg7, Arg9, Arg15, and Arg18, mediated most of the polar interactions of RC18 with the phospholipid head groups during membrane penetration. In vivo experiments indicated that RC18 decreased MRSA colonization and dramatically improved the survival of infected mice, thus demonstrating that RC18 is a promising drug candidate to treat MRSA infections.

An angiotensin-converting enzyme-2-derived heptapeptide GK-7 for SARS-CoV-2 spike blockade.

The ongoing coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is a global concern and necessitates efficient drug antagonists. Angiotensin-converting enzyme-2 (ACE2) is the main receptor of SARS-CoV-2 spike 1 (S1), which mediates viral invasion into host cells. Herein, we designed and prepared short peptide inhibitors containing 4-6 critical residues of ACE2 that contribute to the interaction with SARS-CoV-2 S1. Among the candidates, a peptide termed GK-7 (GKGDFRI), which was designed by extracting residues ranging from Gly353 to Ile359 in the ligand-binding domain of ACE2, exhibited the highest binding affinity (25.1 nM) with the SARS-CoV-2 spike receptor-binding domain (RBD). GK-7 bound to the RBD and decreased SARS-CoV-2 S1 attachment to A549 human alveolar epithelial cells. Owing to spike blockade, GK-7 inhibited SARS-CoV-2 spike pseudovirion infection in a dose-dependent manner, with a half-maximal inhibitory concentration of 2.96 µg/mL. Inspiringly, pulmonary delivery of GK-7 by intranasal administration did not result in toxicity in mice. This study revealed an easy-to-produce peptide inhibitor for SARS-CoV-2 spike blockade, thus providing a promising candidate for COVID-19 treatment.

Irradiation pretreatment enhances the therapeutic efficacy of platelet-membrane-camouflaged antitumor nanoparticles.

BACKGROUND: Cell membrane-based nanocarriers are promising candidates for delivering antitumor agents. The employment of a simple and feasible method to improve the tumor-targeting abilities of these systems is appealing for further application. Herein, we prepared a platelet membrane (PM)-camouflaged antitumor nanoparticle. The effects of irradiation pretreatment on tumor targeting of the nanomaterial and on its antitumor action were evaluated. RESULTS: The biomimetic nanomaterial constructed by indocyanine green, poly(d,l-lactide-co-glycolide), and PM is termed PINPs@PM. A 4-Gy X-ray irradiation increased the proportions of G2/M phase and Caveolin-1 content in 4T1 breast cancer cells, contributing to an endocytic enhancement of PINPs@PM. PINPs@PM produced hyperthermia and reactive oxygen species upon excitation by near-infrared irradiation, which were detrimental to the cytoplasmic lysosome and resulted in cell death. Irradiation pretreatment thus strengthened the antitumor activity of PINPs@PM in vitro. Mice experiments revealed that irradiation enhanced the tumor targeting capability of PINPs@PM in vivo. When the same dose of PINPs@PM was intravenously administered, irradiated mice had a better outcome than did mice without X-ray pretreatment. CONCLUSION: The study demonstrates an effective strategy combining irradiation pretreatment and PM camouflage to deliver antitumor nanoparticles, which may be instrumental for targeted tumor therapy.

One-Pot Hydrothermal Synthesis of g-C3N4/BiPO4 Nanocomposites with Significant Photocatalytic Activity.

The g-C3N4/BiPO4 composites have been successfully synthesized via a one-pot hydrothermal process, which can be used to degrade the organic dyes (rhodamine B and methylene blue) under simulated sunlight irradiation. X-ray diffraction (XRD), scanning electron microscope (SEM), UV-Vis diffuse reflectance spectra and Fourier transform infrared (FTIR) spectroscopy have been employed to characterize the samples. The g-C3N4/BiPO4 composites exhibited higher photocatalytic activity than pure BiPO4. And the optimum photocatalyst shows the outstanding photocatalytic activity, which exhibited 99.0% and 86.6% decolorization rate of RhB and MB, respectively.

Platelet-membrane-camouflaged bismuth sulfide nanorods for synergistic radio-photothermal therapy against cancer.

Bismuth-containing nanoparticles (BNPs) are potential enhancers for tumor radiotherapy. Improving the bioavailability and developing synergistic therapeutic regimens benefit the drug transformation of BNPs. In the present study, we prepare a mesoporous silica-coated bismuth nanorod (BMSNR) camouflaged by a platelet membrane (PM). This biomimetic material is termed BMSNR@PM. The PM camouflage enhances the immune escape of the BMSNRs by lowering endocytosis by macrophages in the reticuloendothelial system. Additionally, the PM camouflage strengthens the material tumor-targeting capacity and leads to better radiotherapeutic efficacy compared with bare BMSNRs. Owing to the photothermal effect, BMSNR@PMs alters the cell cycle of 4T1 cancer cells post-treatment with 808 nm near-infrared irradiation (NIR). The proportions of S phase and G2/M phase cells decrease and increase, respectively, which explains the synergistic effect of NIR on BMSNR@PM-based radiotherapy. BMSNR@PMs efficiently eradicates cancer cells by the combined action of photothermal therapy (PTT) and radiotherapy in vivo and markedly improves the survival of 4T1-tumor-bearing mice. The synergistic therapeutic effect is superior to the outcomes of PTT and radiotherapy performed alone. Our study demonstrates a versatile bismuth-containing nanoplatform with tumor-targeting, immune escape, and radiosensitizing functionalities using an autologous cell membrane biomimetic concept that may promote the development of radiotherapy enhancers.

Succinylated casein-coated peptide-mesoporous silica nanoparticles as an antibiotic against intestinal bacterial infection.

Increasing drug resistance necessitates the discovery of novel bactericides. Human defensin (HD) peptides can eliminate resistant bacteria and are promising candidates for next-generation antibiotics. T7E21R-HD5 is a potent bactericide designed by site mutations at enteric HD5. To facilitate the development of T7E21R-HD5 into an intestinal antibiotic, we employed a mesoporous silica nanoparticle (MSN) as the peptide carrier. Despite its ineffectiveness at killing bacteria, the MSN intensified the outer membrane penetration and inner membrane permeabilization abilities of T7E21R-HD5 and thus enhanced its antibacterial action against multidrug resistant (MDR) E. coli, which broadened the role of MSNs in drug delivery. For the reduction in T7E21R-HD5 losses in the stomach, we further modified MSN@T7E21R-HD5 with succinylated casein (SCN), a milk protein that can be specifically degraded by intestinal protease. SCN coating decreased T7E21R-HD5 release from the MSNs, especially in a highly acidic environment. The controlled release of MSN@T7E21R-HD5 from SCN encapsulation was confirmed in the presence of trypsin. MSN@T7E21R-HD5@SCN was nontoxic to host cells, and it was capable of inactivating MDR E. coli in vivo and alleviating intestinal inflammation by suppressing the production of inflammatory factors TNF-α, IL-1ß, and MMP-9. This study provides a peptide-based nanobiotic with efficacy to combat intestinal infection, especially against drug-resistant bacteria. The biocompatible and readily prepared MSN/SCN delivery system may benefit further intestinal antibiotic design and promote the drug transformation of additional enterogenic functional molecules.

Uniform Mesoporous MnO2 Nanospheres as a Surface Chemical Adsorption and Physical Confinement Polysulfide Mediator for Lithium-Sulfur Batteries.

The actual implementation of lithium-sulfur batteries is hindered by inferior cyclic stability and poor coulombic efficiency stemming from the notorious shuttling of soluble polysulfide intermediates. Herein, uniform mesoporous MnO2 nanospheres were prepared using a facile self-assembly and room-temperature reaction method. As a sulfur carrier of sulfur cathodes, the versatile architecture of MnO2 not only provides powerful chemical adsorption to anchor polysulfide intermediates on the large polar surface area but also restrains them within the nanopores by physical confinement. The mesoporous MnO2-stabilized sulfur cathode demonstrates a high initial reversible capacity of 1349.3 mA h g-1 and a capacity fading rate of 0.073% at 1.0 C over 500 cycles. Furthermore, a reversible areal capacity of 2.5 mA h cm-2 was achieved with stable cycling performance at a sulfur content of 80.7%. Our work offers a facile method to build efficient sulfur cathodes for high performance lithium-sulfur batteries.

Formation of CO2 bubbles in epoxy resin coatings: A DFT study.

The epoxy resin coating is a fundamental species with epoxy resins used as main components to form the final film. Unexpectedly, bulky CO2 bubbles that occasionally appeared during the curing process of epoxy resin coatings might destroy the final film properties. With an attempt to thoroughly understand the formation mechanism of CO2 bubbles and further propose countermeasures to control them, Density Function Theory (DFT) in this paper was employed to calculate the absorption process, the curing reaction and the formation mechanism of CO2 bubbles. The gas phase basicity (GB) values and pKa values of common amine curing agents were calculated. The total Gibbs free energies difference of the curing reactions between polluted curing agents and epoxy resins were calculated according to a thermodynamic cycle. Whether in gas phase or resin phase, the energetically negative ΔGsolv indicated that the curing reactions might occur spontaneously and CO2 molecules would be separated and released from amine molecules. The total Gibbs free energy calculations also revealed that the re-absorption of CO2 by the curing system was energetically unfavorable. Thus, the formation mechanism of CO2 bubbles of epoxy resin coatings could be summarize in three steps: (1) Carbon dioxide pollutes accidentally the curing agents. (2) CO2 molecules are gradually released as the curing process occurs. (3) CO2 molecules are collected to form big bubbles which can lead to seriously surface and/or internal defects. Finally, based on practical experiences three tips were proposed to control CO2 bubbles. The present results not only evidenced the nature of the unexpected bubbles of epoxy resin coatings, but also additionally paved to the way to full utilization of the formation mechanism to improve the epoxy coatings' properties.

Marriage of an Ether-Based Electrolyte with Hard Carbon Anodes Creates Superior Sodium-Ion Batteries with High Mass Loading.

Inferior rate performance, insufficient cycle life, and low mass loading have restricted the practical application of hard carbon (HC) anodes in sodium-ion batteries (NIBs). Here, a compatible strategy is developed by matching HC anodes with an ether-based electrolyte. Systematical investigation reveals that good compatibility of the electrode-electrolyte systems forms thinner but a more sustainable solid-electrolyte interphase and delivers a higher ionic conductivity and Na+ ion diffusion coefficient than the commonly used ester-based electrolytes. Therefore, an excellent electrochemical performance is demonstrated with a long cycle life (∼196 mA h/g and 90% capacity retention after 2000 cycles at 1 A/g), a super rate capability (∼51% capacity retention at 10 A/g) at a mass loading of 1.5 mg/cm2, and a high initial Coulombic efficiency of 85.9%. More importantly, a high reversible areal capacity of 4.3 mA h/cm2 can be achieved at an ultrahigh mass loading of 17 mg/cm2, superior to all reported HC anodes. Our findings not only shed light on the design of high-performance battery systems but also promise a commercial transformation from the lab test to mass production of NIBs.

A Polysulfide-Immobilizing Polymer Retards the Shuttling of Polysulfide Intermediates in Lithium-Sulfur Batteries.

Lithium-sulfur batteries are regarded as one of the most promising candidates for next-generation rechargeable batteries. However, the practical application of lithium-sulfur (Li-S) batteries is seriously impeded by the notorious shuttling of soluble polysulfide intermediates, inducing a low utilization of active materials, severe self-discharge, and thus a poor cycling life, which is particularly severe in high-sulfur-loading cathodes. Herein, a polysulfide-immobilizing polymer is reported to address the shuttling issues. A natural polymer of Gum Arabic (GA) with precise oxygen-containing functional groups that can induce a strong binding interaction toward lithium polysulfides is deposited onto a conductive support of a carbon nanofiber (CNF) film as a polysulfide shielding interlayer. The as-obtained CNF-GA composite interlayer can achieve an outstanding performance of a high specific capacity of 880 mA h g-1 and a maintained specific capacity of 827 mA h g-1 after 250 cycles under a sulfur loading of 1.1 mg cm-2 . More importantly, high reversible areal capacities of 4.77 and 10.8 mA h cm-2 can be obtained at high sulfur loadings of 6 and even 12 mg cm-2 , respectively. The results offer a facile and promising approach to develop viable lithium-sulfur batteries with high sulfur loading and high reversible capacities.