Systemic and targeted activation of Nrf2 reverses doxorubicin-induced cognitive impairments and sensorimotor deficits in mice.

While cancer survivorship has increased due to advances in treatments, chemotherapy often carries long-lived neurotoxic side effects which reduce quality of life. Commonly affected domains include memory, executive function, attention, processing speed and sensorimotor function, colloquially known as chemotherapy-induced cognitive impairment (CICI) or "chemobrain". Oxidative stress and neuroimmune signaling in the brain have been mechanistically linked to the deleterious effects of chemotherapy on cognition and sensorimotor function. With this in mind, we tested if activation of the master regulator of antioxidant response nuclear factor E2-related factor 2 (Nrf2) alleviates cognitive and sensorimotor impairments induced by doxorubicin. The FDA-approved systemic Nrf2 activator, diroximel fumarate (DRF) was used, along with our recently developed prodrug 1c which has the advantage of specifically releasing monomethyl fumarate at sites of oxidative stress. DRF and 1c both reversed doxorubicin-induced deficits in executive function, spatial and working memory, as well as decrements in fine motor coordination and grip strength, across both male and female mice. Both treatments reversed doxorubicin-induced loss of synaptic proteins and microglia phenotypic transition in the hippocampus. Doxorubicin-induced myelin damage in the corpus callosum was reversed by both Nrf2 activators. These results demonstrate the therapeutic potential of Nrf2 activators to reverse doxorubicin-induced cognitive impairments, motor incoordination, and associated structural and phenotypic changes in the brain. The localized release of monomethyl fumarate by 1c has the potential to diminish unwanted effects of fumarates while retaining efficacy.

A New Gramicidin S Analogue with Potent Antibacterial Activity and Negligible Hemolytic Toxicity.

Antibiotic resistance is an urgent threat to global health, with the decreasing efficacy of conventional drugs underscoring the urgency for innovative therapeutic strategies. Antimicrobial peptides present as promising alternatives to conventional antibiotics. Gramicidin S is one such naturally occurring antimicrobial peptide that is effective against Staphylococcus aureus, with a minimum inhibitory concentration (MIC) of 4 µg/mL (3.6 µM). Despite this potent activity, its significant hemolytic toxicity restricts its clinical use to topical applications. Herein, we present rational modifications to the key ß-strand and ß-turn regions of gramicidin S to concurrently mitigate hemolytic effects, while maintaining potency. Critically, peptide 9 displayed negligible hemolytic toxicity, while possessing significant antibacterial potency against a panel of methicillin-sensitive and methicillin-resistant S. aureus clinical isolates (MIC of 8 µg/mL, 7.2 µM). Given the substantial antibacterial activity and near absence of cytotoxicity, 9 presents as a potential candidate for systemic administration in the treatment of S. aureus bacteremia/sepsis.

Detection of Volatile Organic Compounds through Spectroscopic Signatures in Nanoporous Fabry-Pérot Optical Microcavities.

Increasingly complex modern gas-monitoring scenarios necessitate advanced sensing capabilities to detect and identify a diverse range of gases under varying conditions. There is a rising demand for individual sensors with multiple responses capable of recognizing gases, identifying components in mixtures, and providing stable responses. Inspired by gas sensors employing multivariable response principles, we develop a nanoporous anodic alumina high-order microcavity (NAA-HOµCV) gas sensor with multiple optical outputs for discriminative gas detection. The NAA-HOµCV architecture, formed by a Fabry-Pérot microcavity with distributed Bragg reflector (DBR) mirrors and an extended-length microcavity layer supporting multiple resonant modes, serves as an effective solid-state fingerprint platform for distinguishing volatile organic compound (VOC) gases. Our research reveals that the coupling strength of light into resonant modes and their evolution depend on the thickness of the DBR mirrors and the dimension of the microcavity layer, which allows us to optimize the discriminative sensing capability of the NAA-HOµCV sensor through structural engineering of the microcavity and photonic crystal mirrors. Gas-sensing experiments conducted on the NAA-HOµCV sensor demonstrate real-time discrimination between physiosorbed VOC gases (isopropanol, ethanol, or acetone) in reversible gas sensing. It also achieves superior ppb-level sensing in irreversible gas sensing of model silane molecules. Our study presents promising avenues for designing compact, cost-effective, and highly efficient gas sensors with tailored properties for discriminative gas detection.

Engineering of Solid-State Nanoporous Laser through Dendrimer-Encapsulated Fluorophores.

Dendrimers─nanosized macromolecules that can function as hosts for encapsulation of guest molecules─provide new avenues to engineer gain media for lasing systems. In this context, this study investigates the interplay between the geometric features of a model porous scattering medium, nanoporous anodic alumina (NAA), and the chemical features of a model fluorophore-dendrimer encapsulation system to maximize random lasing. The inner surface of the NAA platforms is functionalized with fluorophore molecules encapsulated within dendrimers via an electrostatic interaction. The resulting solid-state composite structures emit well-resolved, intense random lasing when subjected to optical pumping. By engineering fluorophore-dendrimer and geometric features of scattering medium, we can precisely tune the characteristics of random lasing emissions. It is found that lasing structures with low porosity and thickness functionalized with fluorophore molecules encapsulated in second-generation dendrimers provide the best platforms for lasing generation, resulting in a strongly polarized laser at ∼594 nm that has a high quality-gain product of ∼1588 au, a polarization quality of ∼0.86, and a lasing threshold of ∼0.05 mJ pulse-1. Comparative analysis indicates that dendrimers achieve 2.5 times better random lasing than conventional surfactants due to improved encapsulation and minimization of photobleaching. Our results reveal the importance of the fluorophore encapsulation method and design of scattering media in the engineering of random lasing platforms for applications in optical and optoelectrical systems.

Tailoring Tamm Plasmon Resonances in Dielectric Nanoporous Photonic Crystals.

The fields of plasmonics and photonic crystals (PCs) have been combined to generate model light-confining Tamm plasmon (TMM) cavities. This approach effectively overcomes the intrinsic limit of diffraction faced by dielectric cavities and mitigates losses associated with the inherent properties of plasmonic materials. In this study, nanoporous anodic alumina PCs, produced by two-step sinusoidal pulse anodization, are used as a model dielectric platform to establish the methodology for tailoring light confinement through TMM resonances. These model dielectric mirrors feature highly organized nanopores and narrow bandwidth photonic stopbands (PSBs) across different positions of the spectrum. Different types of metallic films (gold, silver, and aluminum) were coated on the top of these model dielectric mirrors. By structuring the features of the plasmonic and photonic components of these hybrid structures, the characteristics of TMM resonances were studied to elucidate effective approaches to optimize the light-confining capability of this hybrid TMM model system. Our findings indicate that the coupling of photonic and plasmonic modes is maximized when the PSB of the model dielectric mirror is broad and located within the midvisible region. It was also found that thicker metal films enhance the quality of the confined light. Gas sensing experiments were performed on optimized TMM systems, and their sensitivity was assessed in real time to demonstrate their applicability. Ag films provide superior performance in achieving the highest sensitivity (S = 0.038 ± 0.001 nm ppm-1) based on specific binding interactions between thiol-containing molecules and metal films.