Inhalable Biomineralized Liposomes for Cyclic Ca2+-Burst-Centered Endoplasmic Reticulum Stress Enhanced Lung Cancer Ferroptosis Therapy.

Lung cancer with the highest mortality poses a great threat to human health. Ferroptosis therapy has recently been raised as a promising strategy for lung cancer treatment by boosting the reactive species (ROS) production and lipid peroxidation (LPO) accumulation intracellularly. However, the insufficient intracellular ROS level and the unsatisfactory drug accumulation in lung cancer lesions hamper the efficacy of ferroptosis therapy. Here, an inhalable biomineralized liposome LDM co-loaded with dihydroartemisinin (DHA) and pH-responsive calcium phosphate (CaP) was constructed as a ferroptosis nanoinducer for achieving Ca2+-burst-centered endoplasmic reticulum (ER) stress enhanced lung cancer ferroptosis therapy. Equipped with excellent nebulization properties, about 6.80-fold higher lung lesions drug accumulation than intravenous injection made the proposed inhalable LDM an ideal nanoplatform for lung cancer treatment. The Fenton-like reaction mediated by DHA with peroxide bridge structure could contribute to intracellular ROS production and induce ferroptosis. Assisted by DHA-mediated sarco-/endoplasmic reticulum calcium ATPase (SERCA) inhibition, the initial Ca2+ burst caused by CaP shell degradation triggered the Ca2+-mediated intense ER stress and subsequently induced mitochondria dysfunction to further boost ROS accumulation, which strengthens ferroptosis. The second Ca2+ burst occurred as a result of Ca2+ influx through ferroptotic pores on cell membranes, thus sequentially constructing the lethal "Ca2+ burst-ER stress-ferroptosis" cycle. Consequently, the Ca2+-burst-centered ER stress enhanced ferroptosis process was confirmed as a cell swelling and cell membrane disruption process driven by notable intracellular ROS and LPO accumulation. The proposed LDM showed an encouraging lung retention property and extraordinary antitumor ability in an orthotropic lung tumor murine model. In conclusion, the constructed ferroptosis nanoinducer could be a potential tailored nanoplatform for nebulization-based pulmonary delivery and underscore the application of Ca2+-burst-centered ER stress enhanced lung cancer ferroptosis therapy.

Identification of hub genes and immune cell infiltration characteristics in chronic rhinosinusitis with nasal polyps: Bioinformatics analysis and experimental validation.

The aim of our study is to reveal the hub genes related to the pathogenesis of chronic rhinosinusitis with nasal polyps (CRSwNP) and their association with immune cell infiltration through bioinformatics analysis combined with experimental validation. In this study, through differential gene expression analysis, 1,516 upregulated and 1,307 downregulated DEG were obtained from dataset GSE136825 of the GEO database. We identified 14 co-expressed modules using weighted gene co-expression network analysis (WGCNA), among which the most significant positive and negative correlations were MEgreen and MEturquoise modules, containing 1,540 and 3,710 genes respectively. After the intersection of the two modules and DEG, two gene sets-DEG-MEgreen and DEG-MEturquoise-were obtained, containing 395 and 1,168 genes respectively. Through GO term analysis, it was found that immune response and signal transduction are the most important biological processes. We found, based on KEGG pathway enrichment analysis, that osteoclast differentiations, cytokine-cytokine receptor interactions, and neuroactive ligand-receptor interactions are the most important in the two gene sets. Through PPI network analysis, we listed the top-ten genes for the concentrated connectivity of the two gene sets. Next, a few genes were verified by qPCR experiments, and FPR2, ITGAM, C3AR1, FCER1G, CYBB in DEG-MEgreen and GNG4, NMUR2, and GNG7 in DEG-MEturquoise were confirmed to be related to the pathogenesis of CRSwNP. NP immune cell infiltration analysis revealed a significant difference in the proportion of immune cells between the NP group and control group. Finally, correlation analysis between target hub genes and immune cells indicated that FPR2 and GNG7 had a positive or negative correlation with some specific immune cells. In summary, the discoveries of these new hub genes and their association with immune cell infiltration are of great significance for uncovering the specific pathogenesis of CRSwNP and searching for disease biomarkers and potential therapeutic targets.

[Measurement of nasal septum area in 128 Chinese patients with nasal septum deviation].

Objective:Establish the anatomical parameters of the nasal septum and the area of each component in patients with nasal septum deviation, for the sake of guiding the scope of surgical resection for correction of nasal septum deviation. Methods:This is a retrospective study of 128 cases of sinus computer tomography images of patients with nasal septum deviation, marked 9 nasal septal anatomical locations, measured the area of the nasal septum and its components, and analyzed the trend of the percentage of the area of the nasal septum cartilage in the total area of the nasal septum with age. Results:The total area of the nasal septum in the 128 patients with nasal septum deviation is: （2951.96±305.91） mm², the area of nasal septal cartilage: （961.89±229.64） mm², the area of the vertical ethmoid plate: （1123.96±214.17） mm², the area of the vomerine: （652.77±108.09） mm². The area of male septum is larger than that of female. As age increases, the nasal septal cartilage gradually decreases, and the percentage of the nasal septal cartilage area in the total area of the nasal septum gradually decreases. Conclusion:Elderly people who undergo nasal septum correction should be carefully considered to grasp the scope of resection, and the influence of gender on the area of nasal septum should also be paid attention.

Identification of hub genes in thyroid carcinoma to predict prognosis by integrated bioinformatics analysis.

The aim of this study was to identify hub genes closely related to the pathogenesis and prognosis of thyroid carcinoma (THCA) by integrated bioinformatics analysis. In this study, through differential gene expression analysis, 1916 and 665 differentially expressed genes (DEGs) were obtained from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) database, and 7 and 11 co-expressed modules were identified from the TCGA-THCA and GSE153659 datasets, respectively, by weighted gene co-expression network analysis. We identified 162 overlapping genes between the DEGs and co-expression module genes as candidate hub genes. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses of the 162 overlapping DEGs identified significant functions and pathways of THCA, such as thyroid hormone generation and metabolic process. A protein-protein interaction (PPI) analysis detected the top 10 hub genes (QSOX1, WFS1, EVA1A, FSTL3, CHRDL1, FABP4, PRDM16, PPARGC1A, PPARG, COL23A1). Finally, survival analysis, clinical correlation analysis, and protein abundance validation confirmed that 3 of the 10 hub genes were associated with survival prognosis of patients with THCA, and 8 of them were associated with the clinical stages of THCA. In summary, we identified hub genes and key modules that were closely related to THCA, and validated these genes by survival analysis, clinical correlation analysis, and Human Protein Atlas image analysis. Our results provide important information that will help to elucidate the pathogenesis of THCA and identify novel candidate prognostic biomarkers and potential therapeutic targets.

Metabolic profiling of 19 amino acids in triptolide-induced liver injured rats by gas chromatography-triple quadrupole mass spectrometry.

The liver is an important organ for amino acid metabolism, and its damage can be reflected in the changes of amino acid level in the body. Triptolide (TP) has broad anti-inflammatory and anti-tumor activities, but its clinical application is limited due to hepatotoxicity. In this work, a simple, accurate and sensitive gas chromatography-triple quadrupole mass spectrometry (GC-QqQ-MS/MS) method was developed and validated for evaluating the serum levels of amino acids from control and TP-induced liver injured rats, and chemometric analysis was employed for amino acid metabolic profiles analysis. It was found that 11 amino acids showed significant changes after TP administration, and they were mainly involved in 5 metabolic pathways that are phenylalanine, tyrosine and tryptophan biosynthesis, alanine, aspartate and glutamate metabolism, glutamine and glutamate metabolism, phenylalanine metabolism and arginine biosynthesis. Five amino acids including tyrosine, glutamine, glutamic acid, tryptophan and alanine were identified as biomarkers of TP hepatotoxicity by further analysis. These results indicated that the novel amino acid metabolic profiling study based on the GC-QqQ-MS/MS provided not only exact concentrations of serum amino acids, but also a prospective methodology for evaluation of chemically induced liver injury.

Human Umbilical Cord Mesenchymal Stem Cells Improve Ovarian Function in Chemotherapy-Induced Premature Ovarian Failure Mice Through Inhibiting Apoptosis and Inflammation via a Paracrine Mechanism.

Human umbilical cord mesenchymal stem cell (UC-MSC) application is a promising arising therapy for the treatment of premature ovarian failure (POF). However, little is known about the inflammation regulatory effects of human umbilical cord MSCs (UC-MSCs) on chemotherapy-induced ovarian damage, regardless of in vivo or in vitro. This study was designed to investigate the therapeutic effects of UC-MSC transplantation and underlying mechanisms regarding both apoptosis and inflammation in POF mice. The chemotherapy-induced POF models were induced by intraperitoneal injection of cyclophosphamide. Ovarian function parameters, granulosa cell (GC) apoptosis, and inflammation were examined. Morphological staining showed that UC-MSC treatment increased the ovary size, and the numbers of primary and secondary follicles, but decreased the number of atretic follicles. Estradiol levels in the UC-MSC-treated group were increased while follicle-stimulating hormone levels were reduced compared to those in the POF group. UC-MSCs inhibited cyclophosphamide-induced GC apoptosis and inflammation. Meanwhile, phosphorylation of AKT and P38 was elevated after UC-MSC treatment. Tracking of UC-MSCs in vivo indicated that transplanted UC-MSCs were only located in the interstitium of ovaries rather than in follicles. Importantly, UC-MSC-derived extracellular vesicles protected GCs from alkylating agent-induced apoptosis and inflammation in vitro. Our results suggest that UC-MSC transplantation can reduce ovary injury and improve ovarian function in chemotherapy-induced POF mice through anti-apoptotic and anti-inflammatory effects via a paracrine mechanism.

Alpinia zerumbet and Its Potential Use as an Herbal Medication for Atherosclerosis: Mechanistic Insights from Cell and Rodent Studies.

BACKGROUND/AIMS: Alpinia zerumbet (Pers.) Burtt. et Smith has been used as a flavor additive in food and a traditional medicine for centuries, especially in Guizhou Province, China, and it prolongs people's lives with multiple beneficial effects. Thus, one of the aims of this review was to expound the chemical constituents of this plant, especially its fruits. Since cardiovascular diseases, including atherosclerosis, pose a health threat to humans, another aim was to expound the possible mechanisms of its potential use as an herbal medication for atherosclerosis. METHODS: In this study, 10 reports are cited to expound the potential bioactive compounds. Moreover, 33 reports explain the antihypertensive and antiatherosclerotic effects of the plant by ameliorating inflammation and endothelial dysfunction, increasing vasodilation, improving hyperlipidemia, downgrading the glucose status, and working as an antioxidant. RESULTS: A. zerumbetis rich in terpenes, essential oils, flavonoids, polyphenolics, and sterols. Pharmacological experiments showed that A. zerumbet has antioxidative and anti-inflammatory effects on the NF-κB signaling pathway and can ameliorate oxidative stress in the NOS-NO signaling pathway. Moreover, A. zerumbet demonstrates antihypertensive effects by accelerating vasorelaxant response and increasing 3T3-L1 intracellular cAMP, which has promising antiobesity properties, as well as hypolipidemic and anti-diabetic complication effects. CONCLUSIONS: A. zerumbet has potential functions and applications in the prevention of atherosclerosis, but further studies are required before clinical trials.

Preparation and protective effects of 1,8-cineole-loaded self-microemulsifying drug delivery system on lipopolysaccharide-induced endothelial injury in mice.

An optimised 1,8-cineole-loaded self-microemulsifying drug delivery system (CIN-SMEDDS) with a mean droplet size, polydispersity index, mean zeta potential and encapsulation efficiency of 38.14 ±â€¯1.47 nm, 0.208 ±â€¯0.036, -9.312 ±â€¯1.764 mV and 95.35% ±â€¯1.13%, respectively, successfully ameliorated the lipopolysaccharide (LPS)-induced endothelial injury in mice. Acute toxicity assay in mice through the oral administration of CIN-SMEDDS showed that the median lethal dose of CIN-SMEDDS was 2998.9 mg/kg. The results of 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay indicated that the cytotoxicity of CIN-SMEDDS to Caco-2 cells may be ascribed to the surfactant/co-surfactant mixture. In particular, CIN-SMEDDS remarkably inhibited inflammatory cytokines IL-1ß, IL-6 and IL-8 with a simultaneous increase in IL-10 in LPS-treated mice. Haematoxylin-eosin staining results showed that CIN-SMEDDS attenuated LPS-induced vascular endothelial injury. Western blot results showed that the vascular protective effects of CIN-SMEDDS were associated with the NF-κB and peroxisome proliferator-activated receptor γ signalling pathways. These findings indicated that CIN-SMEDDS can attenuate LPS-induced endothelial injury and thus was proposed as a promising agent for the treatment of inflammatory cardiovascular disease.