Targeted inhibition of m6A demethylase FTO by FB23 attenuates allergic inflammation in the airway epithelium.

Epithelial cells play a crucial role in asthma, contributing to chronic inflammation and airway hyperresponsiveness. m6A modification, which involves key proteins such as the demethylase fat mass and obesity-associated protein (FTO), is crucial in the regulation of various diseases, including asthma. However, the role of FTO in epithelial cells and the development of asthma remains unclear. In this study, we investigated the demethylase activity of FTO using a small-molecule inhibitor FB23 in epithelial cells and allergic inflammation in vivo and in vitro. We examined the FTO-regulated transcriptome-wide m6A profiling by methylated RNA immunoprecipitation sequencing (MeRIP-seq) and RNA-seq under FB23 treatment and allergic inflammation conditions. Immunofluorescence staining was performed to assess the tissue-specific expression of FTO in asthmatic bronchial mucosa. We demonstrated that FB23 alleviated allergic inflammation in IL-4/IL-13-treated epithelial cells and house dust mite (HDM)-induced allergic airway inflammation mouse model. The demethylase activity of FTO contributed to the regulation of TNF-α signaling via NF-κB and epithelial-mesenchymal transition-related pathways under allergic inflammation conditions in epithelial cells. FTO was expressed in epithelial, submucosal gland, and smooth muscle cells in human bronchial mucosa. In conclusion, FB23-induced inhibition of FTO alleviates allergic inflammation in epithelial cells and HDM-induced mice, potentially through diverse cellular processes and epithelial-mesenchymal transition signaling pathways, suggesting that FTO is a potential therapeutic target in asthma management.

Higher basophil count decreases narcolepsy risk: a Mendelian randomization study.

BACKGROUND: Blood cell properties effectively reflect immune status. Basophil and CD8+ CD27+ T cell levels are correlated with narcolepsy, but their causal association is unclear. This study aims to evaluate the causality between blood cell count and narcolepsy risk at the genetic level. METHODS: Two-sample Mendelian randomization (MR) analyses were performed on 35 published blood cell properties, using genome-wide association study (GWAS) datasets and one published GWAS dataset of narcolepsy, to explore causality between blood cell count and narcolepsy risk. Inverse variance weighted, MR-Egger, and weighted median approaches were employed for the MR analysis, odds ratio (OR) calculations, and heterogeneity tests of single nucleotide polymorphisms were conducted with the TwoSampleMR package in R. Multivariable Mendelian randomization (MVMR) was used to adjust the analysis further and eliminate the mediation effect between exposures. RESULTS: Basophil counts, total basophil neutrophil counts, total neutrophil eosinophil counts, granulocyte counts, and myeloid white cell counts showed inverse associations with narcolepsy risk based on the two-sample MR analysis. MVMR confirmed that only basophil counts were significantly associated with narcolepsy risk for the blood cell properties tested (OR = 0.23, 95% confidence interval 0.08-0.62; p = 0.004, power = 99.99%). Each standard deviation increase in basophil count (0.03 per nL), compared to the median level (0.04 per nL), decreased narcolepsy risk by 77%. CONCLUSION: Higher white blood cell counts, especially basophil counts, are protective factors for narcolepsy. Basophil counts has great potential to be used as a new biomarker to shorten diagnostic delay and to monitor the therapeutic effects of treatments for narcolepsy.

2D-ultrathin MXene/DOXjade platform for iron chelation chemo-photothermal therapy.

An increased demand for iron is a hallmark of cancer cells and is thought necessary to promote high cell proliferation, tumor progression and metastasis. This makes iron metabolism an attractive therapeutic target. Unfortunately, current iron-based therapeutic strategies often lack effectiveness and can elicit off-target toxicities. We report here a dual-therapeutic prodrug, DOXjade, that allows for iron chelation chemo-photothermal cancer therapy. This prodrug takes advantage of the clinically approved iron chelator deferasirox (ExJade®) and the topoisomerase 2 inhibitor, doxorubicin (DOX). Loading DOXjade onto ultrathin 2D Ti3C2 MXene nanosheets produces a construct, Ti 3 C 2 -PVP@DOXjade, that allows the iron chelation and chemotherapeutic functions of DOXjade to be photo-activated at the tumor sites, while potentiating a robust photothermal effect with photothermal conversion efficiencies of up to 40%. Antitumor mechanistic investigations reveal that upon activation, Ti 3 C 2 -PVP@DOXjade serves to promote apoptotic cell death and downregulate the iron depletion-induced iron transferrin receptor (TfR). A tumor pH-responsive iron chelation/photothermal/chemotherapy antitumor effect was achieved both in vitro and in vivo. The results of this study highlight what may constitute a promising iron chelation-based phototherapeutic approach to cancer therapy.

Overcoming barriers in photodynamic therapy harnessing nano-formulation strategies.

Photodynamic therapy (PDT) has been extensively investigated for decades for tumor treatment because of its non-invasiveness, spatiotemporal selectivity, lower side-effects, and immune activation ability. It can be a promising treatment modality in several medical fields, including oncology, immunology, urology, dermatology, ophthalmology, cardiology, pneumology, and dentistry. Nevertheless, the clinical application of PDT is largely restricted by the drawbacks of traditional photosensitizers, limited tissue penetrability of light, inefficient induction of tumor cell death, tumor resistance to the therapy, and the severe pain induced by the therapy. Recently, various photosensitizer formulations and therapy strategies have been developed to overcome these barriers. Significantly, the introduction of nanomaterials in PDT, as carriers or photosensitizers, may overcome the drawbacks of traditional photosensitizers. Based on this, nanocomposites excited by various light sources are applied in the PDT of deep-seated tumors. Modulation of cell death pathways with co-delivered reagents promotes PDT induced tumor cell death. Relief of tumor resistance to PDT with combined therapy strategies further promotes tumor inhibition. Also, the optimization of photosensitizer formulations and therapy procedures reduces pain in PDT. Here, a systematic summary of recent advances in the fabrication of photosensitizers and the design of therapy strategies to overcome barriers in PDT is presented. Several aspects important for the clinical application of PDT in cancer treatment are also discussed.

Black Phosphorus/Polymers: Status and Challenges.

As a newly emerged mono-elemental nanomaterial, black phosphorus (BP) has been widely investigated for its fascinating physical properties, including layer-dependent tunable band gap (0.3-1.5 eV), high ON/OFF ratio (104 ), high carrier mobility (103 cm2 V-1 s-1 ), excellent mechanical resistance, as well as special in-plane anisotropic optical, thermal, and vibrational characteristics. However, the instability caused by chemical degradation of its surface has posed a severe challenge for its further applications. A focused BP/polymer strategy has more recently been developed and implemented to hurdle this issue, so at present BP/polymers have been developed that exhibit enhanced stability, as well as outstanding optical, thermal, mechanical, and electrical properties. This has promoted researchers to further explore the potential applications of black phosphorous. In this review, the preparation processes and the key properties of BP/polymers are reviewed, followed by a detailed account of their diversified applications, including areas like optoelectronics, bio-medicine, and energy storage. Finally, in accordance with the current progress, the prospective challenges and future directions are highlighted and discussed.

Rapid prediction of drug inhibition under heat stress: single-photon imaging combined with a convolutional neural network.

A method of predicting cellular drug inhibition due to heat stress is presented. Black phosphorus nanosheets are used as photothermal agents to induce stress granule formation in tumor cells. The addition of different drugs induces different thermal stress responses. The features of single-photon images are automatically extracted and analyzed by a convolutional neural network algorithm for classification and recognition, with a maximum accuracy rate of 94.52%. Unlike traditional visual discrimination, this method realizes intelligent recognition without human intervention, providing a new model for computer-aided diagnosis with greater objectivity.

Immunogenic exosome-encapsulated black phosphorus nanoparticles as an effective anticancer photo-nanovaccine.

Tumor vaccines are a promising form of cancer immunotherapy, but difficulties such as neo-antigen identification, activation of immune cells, and tumor infiltration prevent their clinical breakthrough. Interestingly, nanotechnology-based photothermal therapy (PTT) has great potential to overcome these barriers. Previous studies have shown that serum exosomes (hEX) from hyperthermia-treated tumor-bearing mice displayed an array of patient-specific tumor-associated antigens (TAAs), and strong immunoregulatory abilities in promoting dendritic cell (DC) differentiation and maturation. Here, we developed a tumor vaccine (hEX@BP) by encapsulating black phosphorus quantum dots (BPQDs) with exosomes (hEX) against a murine subcutaneous lung cancer model. In comparison with BPQDs alone (BP), hEX@BP demonstrated better long-term PTT performance, greater elevation of tumor temperature and tumor targeting efficacy in vivo. Vaccination with hEX@BP in combination with PTT further demonstrated an outstanding therapeutic efficacy against established lung cancer, and promoted the infiltration of T lymphocytes into the tumor tissue. Our findings demonstrated that hEX@BP might be an innovative cancer photo-nanovaccine that offers effective immuno-PTT against cancers.

Ultrathin boron nanosheets as an emerging two-dimensional photoluminescence material for bioimaging.

Two-dimensional (2D) metal-free sheets with atomic thickness have been highly considered as promising candidates for fluorescent probes, due to their intriguing characteristics. In this work, 2D ultrathin boron nanosheets (B NSs) with a surface defect nanolayer can be effectively prepared by modified liquid phase exfoliation. The as-prepared ultrathin B NSs show blue fluorescence characteristics even with a quantum yield efficiency of up to 10.6%. Such luminescent behavior originates from the quantum confinement effect and the existence of a surface defect layer. In light of the advantages of being environmentally friendly, having high photostability and good biocompatibility, for the first time we have shown that ultrathin B NSs can be used as an emerging fluorescent probe for application in cellular bioimaging. It is believed that this work will open new avenues for ultrathin B NSs in biomedical fields, and it will also inspire the development of other elemental 2D nanomaterials.

PP5 (PPP5C) is a phosphatase of Dvl2.

Dishevelled (Dvl) family proteins are key mediators of Wnt signalling and function in both canonical and noncanonical branches. Dvl2, the most studied Dvl protein, is extensively regulated by phosphorylation. Several kinases were found to be critical for Dvl2 localisation, stability control and functional segregation. For example, S143-phosphorylated Dvl2 was detected, together with CK1δ/ε, at the centrosome and basal body of primary cilia and plays pivotal roles during ciliogenesis. However, relatively less is known about Dvl dephosphorylation and the phosphatases involved. Here, we identified PP5 (PPP5C) as a phosphatase of Dvl2. PP5 interacts with and can directly dephosphorylate Dvl2. Knockdown of PP5 caused elevated Dvl2 phosphorylation both at the basal level and upon Wnt stimulation. In the Dvl2 protein, S143, the 10B5 cluster and other sites were dephosphorylated by PP5. Interestingly, comparison of PP5 with PP2A, another known Dvl2 phosphatase, revealed that PP5 and PP2A are not fully redundant in the regulation of Dvl2 phosphorylation status. In hTERT-RPE1 cells, PP5 was found at the basal body of cilia, where S143-phosphorylated Dvl2 also resides. Functional assays revealed modest effects on ciliogenesis after PP5 depletion or over-expression. Taken together, our results provided evidence to suggest PP5 as a new phosphatase for Dvl2.

A C-terminally truncated form of ß-catenin acts as a novel regulator of Wnt/ß-catenin signaling in planarians.

ß-Catenin, the core element of the Wnt/ß-catenin pathway, is a multifunctional and evolutionarily conserved protein which performs essential roles in a variety of developmental and homeostatic processes. Despite its crucial roles, the mechanisms that control its context-specific functions in time and space remain largely unknown. The Wnt/ß-catenin pathway has been extensively studied in planarians, flatworms with the ability to regenerate and remodel the whole body, providing a 'whole animal' developmental framework to approach this question. Here we identify a C-terminally truncated ß-catenin (ß-catenin4), generated by gene duplication, that is required for planarian photoreceptor cell specification. Our results indicate that the role of ß-catenin4 is to modulate the activity of ß-catenin1, the planarian ß-catenin involved in Wnt signal transduction in the nucleus, mediated by the transcription factor TCF-2. This inhibitory form of ß-catenin, expressed in specific cell types, would provide a novel mechanism to modulate nuclear ß-catenin signaling levels. Genomic searches and in vitro analysis suggest that the existence of a C-terminally truncated form of ß-catenin could be an evolutionarily conserved mechanism to achieve a fine-tuned regulation of Wnt/ß-catenin signaling in specific cellular contexts.

Stem cell-dependent formation of a functional anterior regeneration pole in planarians requires Zic and Forkhead transcription factors.

Planarians can regenerate their head within days. This process depends on the direction of adult stem cells to wound sites and the orchestration of their progenitors to commit to appropriate lineages and to arrange into patterned tissues. We identified a zinc finger transcription factor, Smed-ZicA, as a downstream target of Smed-FoxD, a Forkhead transcription factor required for head regeneration. Smed-zicA and Smed-FoxD are co-expressed with the Wnt inhibitor notum and the Activin inhibitor follistatin in a cluster of cells at the anterior-most tip of the regenerating head - the anterior regeneration pole - and in surrounding stem cell progeny. Depletion of Smed-zicA and Smed-FoxD by RNAi abolishes notum and follistatin expression at the pole and inhibits head formation downstream of initial polarity decisions. We suggest a model in which ZicA and FoxD transcription factors synergize to control the formation of Notum- and Follistatin-producing anterior pole cells. Pole formation might constitute an early step in regeneration, resulting in a signaling center that orchestrates cellular events in the growing tissue.