UNASSIGNED: In recent years, the world\'s attention has been drawn to antimicrobial resistance (AMR) because to the frightening prospect of growing death rates. Nanomaterials are being investigated due to their potential in a wide range of technical and biological applications.
UNASSIGNED: The purpose of this study was to biosynthesis zinc oxide nanoparticles (ZnONPs) using Aspergillus sp. SA17 fungal extract, followed by characterization of the produced nanoparticles (NP) using electron microscopy (TEM and SEM), UV-analysis, X-ray diffraction (XRD), and Fourier-transform infrared spectroscopy (FT-IR).
UNASSIGNED: The HR-TEM revealed spherical nanoparticles with an average size of 7.2 nm, and XRD validated the crystalline nature and crystal structure features of the generated ZnONPs, while the zeta potential was 18.16 mV, indicating that the particles\' surfaces are positively charged. The FT-IR was also used to identify the biomolecules involved in the synthesis of ZnONPs. The antibacterial and anticancer properties of both the crude fungal extract and its nano-form against several microbial strains and cancer cell lines were also investigated. Inhibition zone diameters against pathogenic bacteria ranged from 3 to 13 mm, while IC50 values against cancer cell lines ranged from 17.65 to 84.55 M. Additionally, 33 compounds, including flavonoids, phenolic acids, coumarins, organic acids, anthraquinones, and lignans, were discovered through chemical profiling of the extract using UPLC-QTOF-MS/MS. Some molecules, such pomiferin and glabrol, may be useful for antibacterial purposes, according to in silico study, while daidzein 4\'-sulfate showed promise as an anti-cancer metabolite.

BACKGROUND: Sepsis is a primary cause of death in critically ill patients and is characterized by multiple organ dysfunction, including sepsis-induced acute kidney injury (AKI), which contributes to high mortality in sepsis. However, its pathophysiological mechanisms remain unclear. The kidney has one of the richest and most diversified endothelial cell populations in the body. This study was designed to investigate the effects of endothelial dysfunction in sepsis-induced AKI and explore possible intervention measures to offer new insight into the pathogenesis and treatment of sepsis-induced AKI.
METHODS: The circulating levels of endothelial adhesion molecules were detected in patients with sepsis and healthy controls to observe the role of endothelial damage in sepsis and sepsis-induced AKI. A murine sepsis model induced by cecal ligation and perforation was pretreated with a phosphoinositide 3-kinase gamma (PI3Kγ) inhibitor (CZC24832), and survival, kidney damage, and renal endothelial injury were assessed by pathological examination, immunohistochemistry, quantitative polymerase chain reaction, and Western blotting. Lipopolysaccharides and CZC24832 were administered to human umbilical vein endothelial cells in vitro, and endothelial cell function and the expression of adhesion molecules were evaluated.
RESULTS: Endothelial damage was more serious in sepsis-induced AKI than that in non-AKI, and the inhibition of PI3Kγ alleviates renal endothelial injury in a murine sepsis model, protecting endothelial cell function and repairing endothelial cell injury through the Akt signaling pathway.
CONCLUSIONS: In this study, endothelial cell dysfunction plays an important role in sepsis-induced AKI, and the inhibition of PI3Kγ alleviates endothelial cell injury in sepsis-induced AKI through the PI3Kγ/Akt pathway, providing novel targets for treating sepsis and related kidney injury.

Phosphatidylinositol 3-kinase gamma (PI3Kγ) has been regarded as a promising drug target for the treatment of advanced solid tumors, leukemia, lymphoma, and inflammatory and autoimmune diseases. However, the high level of structural conservation among the members of the PI3K family and the diverse physiological roles of Class I PI3K isoforms (α, β, δ, and γ) highlight the importance of isoform selectivity in the development of PI3Kγ inhibitors. In this review, we provide an overview of the structural features of PI3Kγ that influence γ-isoform selectivity and discuss the structure-selectivity-activity relationship of existing clinical PI3Kγ inhibitors. Additionally, we summarize the experimental and computational techniques utilized to identify PI3Kγ inhibitors. The insights gained so far could be used to overcome the main challenges in development and accelerate the discovery of PI3Kγ-selective inhibitors.

OBJECTIVE: Neutrophil extracellular traps (NETs) are peculiar structures composed of the externalized chromatin with intracellular proteins and formed by activated neutrophils in a reactive oxygen species (ROS)-dependent manner. Aberrant NETs are considered to be autoantigens for anti-neutrophil cytoplasmic antibodies (ANCAs) underling the development of microscopic polyangiitis (MPA). However, little is known regarding the therapeutic efficacy of in vivo inhibition of NET formation (NETosis) on MPA pathogenesis. This study determines whether reducing NETosis prevents ANCA production and improves characteristic involvement.
METHODS: A mouse model of MPA induced by administering a novel extract from Candida albicans was devised. By applying this method to mice lacking phosphoinositide 3-kinase gamma (PI3K-gamma), which is indispensable for ROS production in neutrophils, we investigated the levels of in vivo NETs, ANCA titers and histological damage.
RESULTS: Our model exhibited accumulation of NETs in vivo, elevation of ANCA titers and characteristic pathologies mimicking human MPA, including small-vessel vasculitis and crescentic glomerulonephritis. Strikingly, these abnormalities were reduced by genetically and/or pharmacologically blocking PI3K-gamma. Moreover, a pharmacological PI3K-gamma blockade decreased the levels of human NETs.
CONCLUSIONS: Our results suggest that in vivo inhibition of NETosis by blocking PI3K-gamma could be a promising therapeutic strategy for the pathogenesis of MPA.

Phosphoinositide 3-kinase gamma (PI3Kγ) is member of a family of enzymes involved in cancer pathogenesis. Accordingly, considerable efforts have been carried out to develop new PI3Kγ inhibitors. Towards this end we explored the pharmacophoric space of PI3Kγ using three diverse sets of inhibitors. Subsequently, we employed genetic algorithm-based QSAR analysis to select optimal combination of pharmacophoric models and physicochemical descriptors that can explain bioactivity variation within training inhibitors. Interestingly, two successful pharmacophores were selected within two statistically consistent QSAR models. The close similarity among the two binding models prompted us to merge them in a hybrid pharmacophore. The resulting model showed superior receiver operator characteristic curve (ROC) and closely resembled binding interactions seen in crystallographic ligand-PI3Kγ complexes. The resulting model was employed to screen the national cancer institute (NCI) list of compounds to search for new PI3Kγ ligands. After testing captured hits in vitro, 19 compounds showed nanomolar IC50 values against PI3Kγ. The chemical structures and purities of most potent hits were validated using NMR and MS experiments.