A positive feedback cycle between the alarmin S100A8/A9 and NLRP3 inflammasome-GSDMD signalling reinforces the innate immune response in Candida albicans keratitis.

OBJECTIVE: Fungal keratitis is a severe sight-threatening ocular infection, without effective treatment strategies available now. Calprotectin S100A8/A9 has recently attracted great attention as a critical alarmin modulating the innate immune response against microbial challenges. However, the unique role of S100A8/A9 in fungal keratitis is poorly understood. METHODS: Experimental fungal keratitis was established in wild-type and gene knockout (TLR4-/- and GSDMD-/-) mice by infecting mouse corneas with Candida albicans. The degree of mouse cornea injuries was evaluated by clinical scoring. To interrogate the molecular mechanism in vitro, macrophage RAW264.7 cell line was challenged with Candida albicans or recombinant S100A8/A9 protein. Label-free quantitative proteomics, quantitative real-time PCR, Western blotting, and immunohistochemistry were conducted in this research. RESULTS: Herein, we characterized the proteome of mouse corneas infected with Candida albicans and found that S100A8/A9 was robustly expressed at the early stage of the disease. S100A8/A9 significantly enhanced disease progression by promoting NLRP3 inflammasome activation and Caspase-1 maturation, accompanied by increased accumulation of macrophages in infected corneas. In response to Candida albicans infection, toll-like receptor 4 (TLR4) sensed extracellular S100A8/A9 and acted as a bridge between S100A8/A9 and NLRP3 inflammasome activation in mouse corneas. Furthermore, the deletion of TLR4 resulted in noticeable improvement in fungal keratitis. Remarkably, NLRP3/GSDMD-mediated macrophage pyroptosis in turn facilitates S100A8/A9 secretion during Candida albicans keratitis, thus forming a positive feedback cycle that amplifies the proinflammatory response in corneas. CONCLUSIONS: The present study is the first to reveal the critical roles of the alarmin S100A8/A9 in the immunopathology of Candida albicans keratitis, highlighting a promising approach for therapeutic intervention in the future.

Nanoscale Zinc-Based Metal-Organic Frameworks Induce Neurotoxicity by Disturbing the Metabolism of Catecholamine Neurotransmitters.

As a group of new nanomaterials, nanoscale metal-organic frameworks (MOFs) are widely applied in the biomedical field, exerting unknown risks to the human body, especially the central nervous system. Herein, the impacts of MOF-74-Zn nanoparticles on neurological behaviors and neurotransmitter metabolism are explored in both in vivo and in vitro assays modeled by C57BL/6 mice and PC12 cells, respectively. The mice exhibit increased negative-like behaviors, as demonstrated by the observed decrease in exploring behaviors and increase in despair-like behaviors in the open field test and forced swimming test after exposure to low doses of MOF-74-Zn nanoparticles. Disorders in the catecholamine neurotransmitter metabolism may be responsible for the MOF-74-Zn-induced abnormal behaviors. Part of the reason for this is the inhibition of neurotransmitter synthesis caused by restrained neurite extension. In addition, MOF-74-Zn promotes the translocation of more calcium into the cytoplasm, accelerating the release and uptake and finally resulting in an imbalance between synthesis and catabolism. Taken together, the results from this study indicate the human toxicity risks of nanoscale low-toxicity metal-based MOFs and provide valuable insight into the rational and safe use of MOF nanomaterials.

Catalytic degradation of brominated flame retardants in the environment: New techniques and research highlights.

Due to the extensive commercial use of brominated flame retardants (BFRs), human beings are chronically exposed to BFRs, causing great harms to human health, which imposes urgent demands to degrade them in the environment. Among various degradation techniques, catalytic degradation has been proven to be outstanding because of its rapidness and effectiveness. Therefore, much attention has been given to catalytic degradation, especially the extensively studied photocatalytic degradation and nanocatalytic reduction techniques. Recently, some novel advanced catalytic techniques have been developed and show excellent catalytic degradation efficiency for BFRs, including natural substances catalytic degradation, new Fenton catalytic degradation, new chemical reagent catalytic degradation, new material catalytic degradation, electrocatalytic degradation, plasma catalytic degradation, and composite catalytic degradation systems. In addition to the common features of traditional catalytic techniques, these novel techniques possess their own specific advantages in various aspects. Therefore, this review summarized the degradation mechanism of BFRs by the above new catalytic degradation methods under the laboratory conditions, simulated real environment, and real environment conditions, and further evaluated their advantages and disadvantages, aiming to provide some research ideas for the catalytic degradation of BFRs in the environment in the future. We suggested that more attention should focus on features of novel catalytic techniques, including eco-friendliness, cost-effectiveness, and pragmatic usefulness.