Responsive Multi-Arm PEG-Modified COF Nanocomposites: Dynamic Photothermal, pH/ROS Dual-Responsive, Targeted Carriers for Rheumatoid Arthritis Treatment.

Rheumatoid arthritis (RA) is a chronic immune disease characterized by the infiltration of immune cells and the proliferation of fibroblast-like synoviocytes (FLS) at the joint site, leading to inflammation and joint destruction. However, the available treatment options targeting both inflammatory and proliferative FLS are limited. Herein, this work presents three covalent organic frameworks (COFs) photothermal composite systems modified with multi-armed polyethylene glycols (PEG) for the treatment of RA. These systems exhibit a dual response under low pH and high reactive oxygen species (ROS) conditions at the site of inflammation, with a specific focus on delivering the protein drug ribonuclease A (RNase A). Notably, molecular docking studies reveal the interaction between RNase A and NF-κB p65 protein, and Western blotting confirm its inhibitory effect on NF-κB activity. In vitro and in vivo experiments verify the significant reduction in joint swelling and deformities in adjuvant-induced arthritis (AIA) rats after treatment with RNase A delivered by multi-armed PEG-modified COF ligands, restoring joint morphology to normal. These findings underscore the promising therapeutic potential of COFs for the treatment of RA, highlighting their unique capabilities in addressing both inflammatory and proliferative aspects of the disease and expanding the scope of biomedical applications for COFs.

A tissue-adhesive F127 hydrogel delivers antioxidative copper-selenide nanoparticles for the treatment of dry eye disease.

Dry eye disease (DED) is currently the most prevalent condition seen in ophthalmology outpatient clinics, representing a significant public health issue. The onset and progression of DED are closely associated with oxidative stress-induced inflammation and damage. To address this, an aldehyde-functionalized F127 (AF127) hydrogel eye drop delivering multifunctional antioxidant Cu2-xSe nanoparticles (Cu2-xSe NPs) was designed. The research findings revealed that the Cu2-xSe nanoparticles exhibit unexpected capabilities in acting as superoxide dismutase and glutathione peroxidase. Additionally, Cu2-xSe NPs possess remarkable efficacy in scavenging reactive oxygen species (ROS) and mitigating oxidative damage. Cu2-xSe NPs displayed promising therapeutic effects in a mouse model of dry eye. Detailed investigation revealed that the nanoparticles exert antioxidant, anti-apoptotic, and inflammation-mitigating effects by modulating the NRF2 and p38 MAPK signalling pathways. The AF127 hydrogel eye drops exhibit good adherence to the ocular surface through the formation of Schiff-base bonds. These findings suggest that incorporating antioxidant Cu2-xSe nanoparticles into a tissue-adhesive hydrogel could present a highly effective therapeutic strategy for treating dry eye disease and other disorders associated with reactive oxygen species. STATEMENT OF SIGNIFICANCE: A new formulation for therapeutic eye drops to be used in the treatment of dry eye disease (DED) was developed. The formulation combines copper-selenium nanoparticles (Cu2-xSe NPs) with aldehyde-functionalized Pluronic F127 (AF127). This is the first study to directly examine the effects of Cu2-xSe NPs in ophthalmology. The NPs exhibited antioxidant capabilities and enzyme-like properties. They effectively eliminated reactive oxygen species (ROS) and inhibited apoptosis through the NRF2 and p38 MAPK signalling pathways. Additionally, the AF127 hydrogel enhanced tissue adhesion by forming Schiff-base links. In mouse model of DED, the Cu2-xSe NPs@AF127 eye drops demonstrated remarkable efficacy in alleviating symptoms of DED. These findings indicate the potential of Cu2-xSe NPs as a readily available and user-friendly medication for the management of DED.

Physiological and transcriptome analysis of response of soybean (Glycine max) to cadmium stress under elevated CO2 concentration.

The continuous accumulation of Cd has long-lasting detrimental effects on plant growth and food safety. Although elevated CO2 concentration (EC) has been reported to reduce Cd accumulation and toxicity in plants, evidence on the functions of elevated CO2 concentration and its mechanisms in the possible alleviation of Cd toxicity in soybean are limited. Here, we used physiological and biochemical methods together with transcriptomic comparison to explore the effects of EC on Cd-stressed soybean. Under Cd stress, EC significantly increased the weight of roots and leaves, promoted the accumulations of proline, soluble sugars, and flavonoid. In addition, the enhancement of GSH activity and GST gene expressions promoted Cd detoxification. These defensive mechanisms reduced the contents of Cd2+, MDA, and H2O2 in soybean leaves. The up-regulation of genes encoding phytochelatin synthase, MTPs, NRAMP, and vacuoles protein storage might play vital roles in the transportation and compartmentalization process of Cd. The MAPK and some transcription factors such as bHLH, AP2/ERF, and WRKY showed changed expressions and might be engaged in mediation of stress response. These findings provide a boarder view on the regulatory mechanism of EC on Cd stress and provide numerous potential target genes for future engineering of Cd-tolerant cultivars in soybean breeding programs under climate changes scenarios.

Hypoxic postconditioning-induced neuroprotection increases neuronal autophagy via activation of the SIRT1/FoxO1 signaling pathway in rats with global cerebral ischemia.

Hypoxic postconditioning (HPC) has been reported to be a beneficial and promising treatment for global cerebral ischemia (GCI). However, its neuroprotective mechanism remains unclear. The aim of the present study was to determine whether the protective effects of HPC in a rat model of GCI were due to the upregulation of autophagy via the silent information regulator transcript-1 (SIRT1)/Forkhead box protein 1 (FoxO1) pathway. Morris water maze test revealed that HPC attenuated cognitive damage in GCI rats. HPC also significantly increased the levels of the autophagy-related protein LC3-II, SIRT1 and FoxO1 compared with those in the GCI group. However, the HPC-induced LC3-II upregulation was blocked by the SIRT1 inhibitor EX527. These results suggested that the beneficial effects of HPC on GCI rats were due to the upregulation of ischemiainduced autophagy and involved the SIRT1/FoxO1 signaling pathway.

An Arabidopsis mutant atcsr-2 exhibits high cadmium stress sensitivity involved in the restriction of H2S emission.

The gene AtCSR encodes peptidyl-prolyl cis/trans isomerases (PPIases) that accelerate energetically unfavorable cis/trans isomerization of the peptide bond preceding proline production. In our studies, we found that AtCSR was associated with cadmium (Cd)-sensitive response in Arabidopsis. Our results show that AtCSR expression was triggered by Cd-stress in wild type Arabidopsis. The expression of some genes responsible for Cd(2+) transportation into vacuoles was induced, and the expression of the iron-regulated transporter 1 (IRT1) related to Cd(2+) absorption from the environment was not induced in wild type with Cd(2+) treatment. The expression of Cd-transportation related genes was not in response to Cd-stress, whereas IRT expression increased dramatically in atcsr-2 with Cd(2+) treatment. The expression of glutathione 1 (GSH1) was consistent with GSH being much lower in atcsr-2 in comparison with the wild type with Cd(2+) treatment. Additionally, malondialdehyde (MDA), hydrogen peroxide, and Cd(2+) contents, and activities of some antioxidative enzymes, differed between the wild type and atcsr-2. Hydrogen sulfide (H(2)S) has been confirmed as the third gas-transmitter over recent years. The findings revealed that the expression pattern of H(2)S-releasing related genes and that of Cd-induced chelation and transportation genes matched well in the wild type and atcsr-2, and H(2)S could regulate the expression of the Cd-induced genes and alleviate Cd-triggered toxicity. Finally, one possible suggestion was given: down-regulation of atcsr-2, depending on H(2)S gas-transmitter not only weakened Cd(2+) chelation, but also reduced Cd(2+) transportation into vacuoles, as well as enhancing the Cd(2+) assimilation, thus rendering atcsr-2 mutant sensitive to Cd-stress.