Enhancing X-Ray Sensitization with Multifunctional Nanoparticles.

In the progression of X-ray-based radiotherapy for the treatment of cancer, the incorporation of nanoparticles (NPs) has a transformative impact. This study investigates the potential of NPs, particularly those comprised of high atomic number elements, as radiosensitizers. This aims to optimize localized radiation doses within tumors, thereby maximizing therapeutic efficacy while preserving surrounding tissues. The multifaceted applications of NPs in radiotherapy encompass collaborative interactions with chemotherapeutic, immunotherapeutic, and targeted pharmaceuticals, along with contributions to photodynamic/photothermal therapy, imaging enhancement, and the integration of artificial intelligence technology. Despite promising preclinical outcomes, the paper acknowledges challenges in the clinical translation of these findings. The conclusion maintains an optimistic stance, emphasizing ongoing trials and technological advancements that bolster personalized treatment approaches. The paper advocates for continuous research and clinical validation, envisioning the integration of NPs as a revolutionary paradigm in cancer therapy, ultimately enhancing patient outcomes.

A hydrogen-bonded curdlan-chitosan/polyvinyl alcohol edible dual functional hydrogel bandage against MRSA promotes wound healing.

The most prevalent complication arising from skin injuries is bacterial infection, where pathogenic bacteria proliferate significantly at the wound site, leading to subsequent complications like septic shock and sepsis. Although antibiotics presently effectively manage wound infections caused by common bacteria, the escalating prevalence of antibiotic-resistant strains necessitates urgent novel approaches for addressing such infections. Here, we present CS9P1-RA, a dual functional hydrogel dressing, based on polyvinyl alcohol (PVA) matrix crosslinked through hydrogen bonding. CS9P1-RA combines chitosan (CS), a food-derived antibacterial agent, with the natural compound rosmarinic acid (RA) to specifically target skin injuries caused by MRSA. Computational and molecular biology assays illustrate RA's ability to selectively inhibit the activity of Staphylococcus aureus (S. aureus) serine/threonine phosphatase (Stp1), reducing the S. aureus pathogenicity. CS9P1-RA showcases exceptional antibacterial efficacy (MIC = 1 mg/mL) and demonstrates potency in reducing virulence (IC50 = 7.424 µM on Stp1). Notably, it effectively curbs bacterial growth and accelerates wound healing in the mice model, thereby fulfilling the practical requirements for clinical applications. Moreover, the mechanical properties of CS9P1-RA ensure user comfort during treatment. This work introduces a fresh design paradigm for dressing materials, offering a promising solution for treating skin injuries inflicted by antibiotic-resistant bacterial infections.

Isolation, Virtual Screening, and Evaluation of Hazelnut-Derived Immunoactive Peptides for the Inhibition of SARS-CoV-2 Main Protease.

The aim of this study is to validate the activity of hazelnut (Corylus avellana L.)-derived immunoactive peptides inhibiting the main protease (Mpro) of SARS-CoV-2 and further unveil their interaction mechanism using in vitro assays, molecular dynamics (MD) simulations, and binding free energy calculations. In general, the enzymatic hydrolysis components, especially molecular weight < 3 kDa, possess good immune activity as measured by the proliferation ability of mouse splenic lymphocytes and phagocytic activity of mouse peritoneal macrophages. Over 866 unique peptide sequences were isolated, purified, and then identified by nanohigh-performance liquid chromatography/tandem mass spectrometry (NANO-HPLC-MS/MS) from hazelnut protein hydrolysates, but Trp-Trp-Asn-Leu-Asn (WWNLN) and Trp-Ala-Val-Leu-Lys (WAVLK) in particular are found to increase the cell viability and phagocytic capacity of RAW264.7 macrophages as well as promote the secretion of the cytokines nitric oxide (NO), tumor necrosis factor-α (TNF-α), and interleukin-1ß (IL-1ß). Fluorescence resonance energy transfer assay elucidated that WWNLN and WAVLK exhibit excellent inhibitory potency against Mpro, with IC50 values of 6.695 and 16.750 µM, respectively. Classical all-atom MD simulations show that hydrogen bonds play a pivotal role in stabilizing the complex conformation and protein-peptide interaction. Molecular Mechanics/Generalized Born Surface Area (MM/GBSA) calculation indicates that WWNLN has a lower binding free energy with Mpro than WAVLK. Furthermore, adsorption, distribution, metabolism, excretion, and toxicity (ADMET) predictions illustrate favorable drug-likeness and pharmacokinetic properties of WWNLN compared to WAVLK. This study provides a new understanding of the immunomodulatory activity of hazelnut hydrolysates and sheds light on peptide inhibitors targeting Mpro.

Tissue-Resident Memory T Cells in Allergy.

Tissue-resident memory T (TRM) cells constitute a distinct subset within the memory T cell population, serving as the vanguard against invading pathogens and antigens in peripheral non-lymphoid tissues, including the respiratory tract, intestines, and skin. Notably, TRM cells adapt to the specific microenvironment of each tissue, predominantly maintaining a sessile state with distinctive phenotypic and functional attributes. Their role is to ensure continuous immunological surveillance and protection. Recent findings have highlighted the pivotal contribution of TRM cells to the modulation of adaptive immune responses in allergic disorders such as allergic rhinitis, asthma, and dermatitis. A comprehensive understanding of the involvement of TRM cells in allergic diseases bears profound implications for allergy prevention and treatment. This review comprehensively explores the phenotypic characteristics, developmental mechanisms, and functional roles of TRM cells, focusing on their intricate relationship with allergic diseases.

Novel metallo-ß-lactamases inhibitors restore the susceptibility of carbapenems to New Delhi metallo-lactamase-1 (NDM-1)-harbouring bacteria.

BACKGROUND AND PURPOSE: The production of metallo-ß-lactamases is a major mechanisms adopted by bacterial pathogens to resist carbapenems. Repurposing approved drugs to restore the efficacy of carbapenems represents an efficient and cost-effective approach to fight infections caused by carbapenem resistant pathogens. EXPERIMENTAL APPROACH: The nitrocefin hydrolysis assay was employed to screen potential New Delhi metallo-lactamase-1 (NDM-1) inhibitors from a commercially available U.S. Food and Drug Administration (FDA) approved drug library. The mechanism of inhibition was clarified by metal restoration, inductively coupled plasma mass spectrometry (ICP-MS) and molecular dynamics simulation. The in vitro synergistic antibacterial effect of the identified inhibitors with meropenem was determined by the checkerboard minimum inhibitory concentration (MIC) assay, time-dependent killing assay and combined disc test. Three mouse infection models were used to further evaluate the in vivo therapeutic efficacy of combined therapy. KEY RESULTS: Twelve FDA-approved compounds were initially screened to inhibit the ability of NDM-1 to hydrolyse nitrocefin. Among these compounds, dexrazoxane, embelin, candesartan cilexetil and nordihydroguaiaretic acid were demonstrated to inhibit all tested metallo-ß-lactamases and showed an in vitro synergistic bactericidal effect with meropenem against metallo-ß-lactamases-producing bacteria. Dexrazoxane, embelin and candesartan cilexetil are metal ion chelating agents, while the inhibition of NDM-1 by nordihydroguaiaretic acid involves its direct binding to the active region of NDM-1. Furthermore, these four drugs dramatically rescued the treatment efficacy of meropenem in three infection models. CONCLUSIONS AND IMPLICATIONS: Our observations indicated that dexrazoxane, embelin, candesartan cilexetil and nordihydroguaiaretic acid are promising carbapenem adjuvants against metallo-ß-lactamases-positive carbapenem resistant bacterial pathogens.

Bioinformatics analysis of an immunotherapy responsiveness-related gene signature in predicting lung adenocarcinoma prognosis.

Background: Immune therapy has become first-line treatment option for patients with lung cancer, but some patients respond poorly to immune therapy, especially among patients with lung adenocarcinoma (LUAD). Novel tools are needed to screen potential responders to immune therapy in LUAD patients, to better predict the prognosis and guide clinical decision-making. Although many efforts have been made to predict the responsiveness of LUAD patients, the results were limited. During the era of immunotherapy, this study attempts to construct a novel prognostic model for LUAD by utilizing differentially expressed genes (DEGs) among patients with differential immune therapy responses. Methods: Transcriptome data of 598 patients with LUAD were downloaded from The Cancer Genome Atlas (TCGA) database, which included 539 tumor samples and 59 normal control samples, with a mean follow-up time of 29.69 months (63.1% of patients remained alive by the end of follow-up). Other data sources including three datasets from the Gene Expression Omnibus (GEO) database were analyzed, and the DEGs between immunotherapy responders and nonresponders were identified and screened. Univariate Cox regression analysis was applied with the TCGA cohort as the training set and GSE72094 cohort as the validation set, and least absolute shrinkage and selection operator (LASSO) Cox regression were applied in the prognostic-related genes which fulfilled the filter criteria to establish a prognostic formula, which was then tested with time-dependent receiver operating characteristic (ROC) analysis. Enriched pathways of the prognostic-related genes were analyzed with Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses, and tumor immune microenvironment (TIME), tumor mutational burden, and drug sensitivity tests were completed with appropriate packages in R (The R Foundation of Statistical Computing). Finally, a nomogram incorporating the prognostic formula was established. Results: A total of 1,636 DEGs were identified, 1,163 prognostic-related DEGs were extracted, and 34 DEGs were selected and incorporated into the immunotherapy responsiveness-related risk score (IRRS) formula. The IRRS formula had good performance in predicting the overall prognoses in patients with LUAD and had excellent performance in prognosis prediction in all LUAD subgroups. Moreover, the IRRS formula could predict anticancer drug sensitivity and immunotherapy responsiveness in patients with LUAD. Mechanistically, immune microenvironments varied profoundly between the two IRRS groups; the most significantly varied pathway between the high-IRRS and low-IRRS groups was ribonucleoprotein complex biogenesis, which correlated closely with the TP53 and TTN mutation burdens. In addition, we established a nomogram incorporating the IRRS, age, sex, clinical stage, T-stage, N-stage, and M-stage as predictors that could predict the prognoses of 1-year, 3-year, and 5-year survival in patients with LUAD, with an area under curve (AUC) of 0.718, 0.702, and 0.68, respectively. Conclusions: The model we established in the present study could predict the prognosis of LUAD patients, help to identify patients with good responses to anticancer drugs and immunotherapy, and serve as a valuable tool to guide clinical decision-making.

Identification of a novel prognostic signature based on vitamin metabolism clustering-related genes in lung adenocarcinoma.

Background: Vitamins, and their metabolic processes play essential regulatory roles in controlling proliferation, differentiation, and growth in carcinogenesis. However, the role of vitamin metabolism in lung adenocarcinoma (LUAD) has rarely been reported. Here, we established a novel prognostic model based on vitamin metabolism-related genes in LUAD. Methods: In this research, we aimed to identify vitamin metabolism associated with differentially expressed genes (DEGs) in LUAD utilizing The Cancer Genome Atlas (TCGA)-LUAD, GSE68465 and GSE72094 data. Unsupervised clustering classified patients into distinct subgroups. By utilizing least absolute shrinkage and selection operator (LASSO)-Cox regression analysis, vitamin metabolism-related genes could be used to construct prognostic model. Then the vitamin metabolism gene-related risk score (VRS) was calculated based on best cut-off splitting. Kaplan-Meier analysis, time-dependent receiver operating characteristic (ROC) analysis, univariate and multivariate Cox analyses, chemotherapeutic drugs sensitivity analysis, immune infiltration analysis and nomogram were conducted to verify our models' accuracy. Finally, CPS1 was identified as a relevant diagnostic marker using Random Forests algorithms, single-cell RNA sequencing data was used to confirm its expression. Results: We investigated the relationship between vitamin metabolism patterns, overall survival (OS), and immune infiltration levels of patients with LUAD. A prognostic signature consisting of 11 genes was developed, which was able to classify patients into high and low VRS groups. Through gene enrichment analysis, cell cycle was mainly enriched. Compared to the low VRS group, the high VRS group exhibited poorer OS, as demonstrated by the Kaplan-Meier survival analysis. Furthermore, VRS was identified as an independent predictor of poor prognosis and poor OS, as indicated by both univariate and multivariate Cox regression analyses. Additionally, a nomogram was constructed to improve the accuracy of survival predictions in LUAD patients. We also found that the two groups of patients might respond differently to immune targets and anti-tumor drugs. CPS1 was identified as a relevant diagnostic marker and the expression was also as confirmed by single-cell RNA sequencing data. Conclusions: Overall, our findings suggest that vitamin metabolism can influence the prognosis of LUAD patients, and our prognostic signature represents a potentially helpful resource for predicting patient outcomes and informing clinical decision-making.

Exosomal ITGB6 from dormant lung adenocarcinoma cells activates cancer-associated fibroblasts by KLF10 positive feedback loop and the TGF-ß pathway.

Background: Dormant cancer cells are commonly known to play a pivotal role in cancer recurrence and metastasis. However, the mechanism of tumor dormancy and recurrence remains largely unknown. This study aimed to investigate the mechanism by which exosomes derived from dormant lung adenocarcinoma (LUAD) cells activate cancer-associated fibroblasts (CAFs) to reconstruct the extracellular matrix (ECM), providing a novel idea for decoding the mechanism of tumor dormancy. Methods: In this study, high-dose cisplatin was used to induce the dormant LUAD cells. Exosomes were extracted from the culture supernatant of normal and dormant cancer cells. The effects of selected exosomal proteins on the fibroblasts were evaluated. RNA-seq for fibroblasts and exosomal proteomics for normal and dormant cancer cells were used to identify and verify the mechanism of activating fibroblasts. Results: We demonstrated that exosomes derived from dormant A549 cells could be taken by fibroblasts. Exosomal ITGB6 transferred into fibroblasts induced the activation of CAFs by activating the KLF10 positive feedback loop and transforming growth factor ß (TGF-ß) pathway. High ITGB6 expression was associated with activation of the TGF-ß pathway and ECM remodeling. Conclusions: In all, we demonstrated that CAFs were activated by exosomes from dormant lung cancer cells and reconstruct ECM. ITGB6 may be a critical molecule for activating the TGF-ß pathway and remodeling ECM.