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关键词： Ionic liquids   API-ILs   Lipophilic APIs   Lipid-based formulations   Spray-encapsulation   BCS Class IV drug  

摘要： Active Pharmaceutical Ingredient-Ionic liquids (API-ILs) have the potential to improve the bioavailability of BCS Class IV Drugs. However, the problematic physical handling properties of room temperature API-ILs have impaired clinical and commercial exploitation to date. Lipid-based formulations (LBFs) are used to improve the absorption of drugs with limited bioavailability. Nonetheless, LBFs face limitations such as low drug loading capacity and sub-par physical stability. A platform for transforming API-ILs into solid forms at high loadings via spray encapsulation with polymers has been developed and previously demonstrated for hydrophilic API-ILs. The current work demonstrates that this platform technology can be applied to a lipophilic API-IL of the BCS Class IV API, chlorpromazine, and to multi-component solutions comprising API-IL and a LBF. Furthermore, solidification of a type IIIB, liquid LBF was achieved via spray encapsulation with cellulose- and methacrylate- based polymers for the first time. The spray-encapsulated formulations had excellent physical handling properties, and successfully eluted the API-IL in aqueous media. The chlorpromazine release profiles from the API-IL, the API-IL containing LBF, and the solidified formulations, were evaluated in vitro using phosphate buffer (pH 6.8) and fasted state simulated intestinal fluid (FaSSIF). Spray-encapsulated formulations exhibited improved release profiles compared to the liquid formulations. Overall, these findings indicate that phase-separated, polymeric, solid formulations of liquid API forms represent a promising platform technology for developing oral solid dosage forms of poorly bioavailable drugs.

关键词： Cell proliferation   Epithelial-mesenchymal transition   Interleukin-17E   NF-κB pathway   Non-small cell lung cancer  

摘要： OBJECTIVE:Interleukin-17 E (IL-17E) is a pro-inflammatory cytokine that participates in the inflammatory response and tumorigenesis. However, the function of IL-17E in non-small cell lung cancer (NSCLC) remains largely unknown. METHODS:The clinical value of IL-17E was determined by immunohistochemistry (IHC) in 75 cases of NSCLC tissues. Furthermore, A549 cells were added with recombinant human IL-17E (rhIL-17E) or transfected with IL-17E siRNAs to evaluate the impact on cell proliferation, apoptosis, and epithelial-mesenchymal transition (EMT), as well as explore the link between IL-17E and the NF-κB pathway. Experimental techniques include CCK-8, EdU, colony formation, RT-qPCR, western blotting, flow cytometry, wound-healing, transwell and immunofluorescence assay. RESULTS:IL-17E levels was elevated in NSCLC tissues and cells, which was related to higher TNM staging, positive lymph node metastasis and decreased tumor differentiation degree. Exogenous recombinant human IL-17E (rhIL-17E) treatment promoted cell proliferation, reduced cell apoptosis, and increased the level of Bcl-2/BAX. Moreover, it enhanced cell migration, invasion, EMT and phosphorylation levels of NF-κB p65. Inversely, knocking down endogenous IL-17E in A549 cells had the opposite effect. Blocking the NF-κB pathway with BAY-117082 reduced IL-17E expression and reversed the malignant effects induced by IL-17E on A549 cells. CONCLUSION:IL-17E facilitates NSCLC progression by promoting cell proliferation and EMT via the NF-κB pathway. IL-17E could serve as a potential strategy for NSCLC treatment.

关键词： Surgical trauma   Endothelial dysfunction   STAT   Transcriptional co-factor   GLIS2  

摘要： Surgery-induced endothelial dysfunction is crucial in thrombus formation, driven by the release of inflammatory mediators due to surgical trauma. The STAT family, known for amplifying inflammatory responses via cytokine activation, plays an unclear role in the signaling mechanisms from surgery to molecular activation, and their regulatory effects on inflammation vary. This study aimed to identify key signaling pathways responsible for vascular dysfunction post-surgery and to discover potential targets for predicting or preventing thrombosis. To explore this, endothelial cells were co-cultured with post-surgical trauma serum and analyzed using various assays. Bioinformatics analysis linked surgical trauma with pathways involving thrombosis, interleukins, cytokines, and STAT signaling. Elevated inflammatory mediators were observed in mouse serum post-surgical trauma, with IL-6 activating STAT3 to enhance endothelial proliferation, while IL-1(3 (3 activated STAT1, inhibiting STAT3 ' s ' s effects. Gli-similar 2 (GLIS2), a novel coactivator of STAT3, was found to regulate STAT transcription. STAT1, however, inhibited GLIS2 ' s ' s interaction with STAT3, suppressing STAT3 ' s ' s role in endothelial proliferation. The study concludes that IL-1(3 (3- triggered STAT1 activation impedes GLIS2-STAT3 interaction, reducing STAT3 ' s ' s transcriptional activity and leading to endothelial dysfunction, presenting new targets for preventing post-surgical trauma endothelial dysfunction and thrombosis.

关键词： Cholangiocarcinoma   CARD9   IL-17A   IHH   THEM4   AKT/mTOR  

摘要： Cholangiocarcinoma (CCA) is a highly lethal malignant tumor originating from the bile duct, and its underlying mechanisms are not fully understood. In order to identify key genes in CCA, we downloaded gene expression data from public GSE76297, GSE26566 and TCGA-CHOL datasets. CARD9 was selected as a CCA-related gene from the datasets. Its expression was identified in the CCA tissues via PCR, western blot and immunohistochemistry assays. The loss-and-gain function assay of CARD9 was conducted in CCA cell lines (QBC939 and RBE) and nude mice. This study found a significant upregulation of CARD9 in CCA tissues, which is associated with poor prognosis in patients. Overexpression of CARD9 promotes proliferation and invasion of QBC939 and RBE cells, enhances the growth and development in CCA mouse models, and reduces sensitivity to chemotherapy drugs for CCA. Mechanistically, CARD9 activates the NF-kappa B kappa B and NLRP3 inflammatory signaling pathways, induces excessive release of various inflammatory factors, and triggers a cascade reaction of interleukin-17 (IL-17A). IL- 17A promotes the stability of IHH mRNA by regulating HuR, enhances IHH transcription, and activates the Hedgehog signaling pathway to accelerate the progression of CCA. In addition, CARD9 promotes proliferation and invasion of CCA cells by interacting with THEM4, thereby facilitating AKT and mTOR phosphorylation, and accelerating the progression of CCA. Overall, these data suggest that CARD9 is involved in the progression of CCA by regulating the IL-17A/Hedgehog and the THEM4/AKT/mTOR signaling pathways. Therefore, CARD9 may serve as a novel therapeutic target for CCA treatment.

关键词： 淋巴瘤,膜细胞   受体,嵌合抗原   受体,抗原,T细胞   分子靶向治疗  

摘要： 套细胞淋巴瘤（MCL）是一种罕见的侵袭性非霍奇金淋巴瘤。目前联合化疗是MCL首选治疗方案，化疗后序贯造血干细胞移植是部分年轻患者的优选方案。靶向治疗是复发难治MCL的首选方案，但复发仍不可避免。嵌合抗原受体T细胞（CAR-T）治疗已成为治疗复发难治MCL的重要方法之一。

关键词： TNF-alpha   SIRT1   Endothelial cell   Trichloroethylene   Kidney  

摘要： Occupational medicamentose-like dermatitis due to trichloroethylene (OMDT) represents a critical clinical issue, with patients frequently experiencing multi-organ damage, including renal impairment. The underlying mechanisms, however, remain elusive. This study investigated how trichloroethylene (TCE) sensitization-induced tumor necrosis factor alpha (TNF-alpha) deposition in renal vascular endothelial cells affects apoptosis and its underlying mechanisms. A TCE-sensitized mouse model was established using 6-8-week-old female BALB/c mice. The TNF-alpha inhibitor R7050 (12 mg/kg) and the sirtuin 1 (SIRT1) activator SRT1720 (5 mg/kg) were employed for therapeutic intervention. Significant kidney damage and mitochondrial impairment were observed in TCEsensitized positive mice. While treatment with R7050 reduced kidney damage and cell apoptosis, SRT 1720 restored mitochondrial function and increased mitochondrial autophagy in renal endothelial cells. In vitro experiments with recombinant human TNF-alpha (100 ng/mL for 48 h) on human umbilical vein endothelial cells (HUVEC) showed that TNF-alpha suppresses SIRT1 expression. This elevation of TNF-alpha also inhibited the SIRT1activated PINK1-Parkin mitochondrial autophagy pathway, causing mitochondrial dysfunction and leading to apoptosis in renal vascular cells.

摘要： Nonalcoholic fatty liver disease (NAFLD) is a prevalent liver disorder that has emerged as a significant public health concern. This study aimed to investigate the mechanisms by which Y-box binding protein-1 (YB1) knockdown influences lipid metabolism and oxidative stress in palmitic acid (PA)-induced NAFLD LO2 cells. The expression of YB1 was analyzed using the GSE89632 dataset from the Gene Expression Omnibus (GEO) database. RNA sequencing was performed, followed by Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses, and protein-protein interaction (PPI) network analyses to identify differentially expressed genes (DEGs). Quantitative real-time PCR (QRT-PCR), Western blotting, flow cytometry, and various biochemical assays were used to evaluate gene expression, lipid accumulation, and oxidative stress. Our results demonstrated that YB1 is highly expressed in NAFLD. RNA sequencing revealed 798 DEGs between the shCtrl and shYB1 groups, with 190 genes upregulated and 608 genes downregulated. Notably, we observed an increase in Inhibin beta E (INHBE) expression, while EGR1, GDF15, NUPR1, and FOSB were decreased in NAFLD LO2 cells. YB1 knockdown, particularly when combined with INHBE suppression, significantly enhanced cell viability, improved lipid metabolism, and reduced reactive oxygen species (ROS) accumulation and malondialdehyde (MDA) content. The downstream mechanism was primarily associated with TNF-β signaling. Specifically, we observed decreased levels of TGF-β1, p-Smad2, and p-Smad3 following YB1 and INHBE knockdown. Furthermore, INHBE overexpression reversed the beneficial effects induced by YB1 knockdown. In conclusion, YB1 knockdown improves lipid metabolism and reduces oxidative stress in NAFLD LO2 cells, largely through the INHBE/TNF-β signaling pathway. These findings provide valuable insights into novel therapeutic strategies for managing NAFLD.

关键词： Epidural fibrosis   IL-20   Post-laminectomy syndrome  

摘要： BACKGROUND:Post-laminectomy syndrome (PLS) manifests as recurrent chronic back pain, with or without radiating leg pain, affecting 10-40% of patients following laminectomy. While surgical interventions can alleviate recurrent disc herniation or joint instability, medical management of PLS remains challenging due to unsatisfactory outcomes. Epidural fibrosis is a frequent cause of PLS, leading to nerve root tethering and dural sac compression. This study aimed to investigate the role of interleukin-20 (IL-20) in the development of epidural fibrosis and the pathogenesis of PLS. METHODS:A rat model of PLS was used to investigate IL-20 production and its impact on downstream fibrotic biomarkers. Spinal tissues from L1-2 segments were analyzed for cytokine and fibrotic marker expression. Primary fibroblasts were isolated from PLS rats and cultured to assess IL-20 receptor expression. The functional effects of IL-20 on fibroblasts were evaluated, including its impact on cytokine production, fibrotic marker expression, and cell proliferation. Additionally, the efficacy of IL-20 inhibition using the anti-IL-20 monoclonal antibody (mAb) was investigated in relation to epidural fibrosis and the severity of PLS. RESULTS:A significant increase in IL-20 production was observed along with increased expression of TGF-β, IL-1β, MCP-1, collagen-1, and fibronectin-1 in the L1-2 spinal segments of PLS rats. Treatment with the anti-IL-20 mAb significantly reduced epidural fibrosis and improved functional outcomes in the PLS rat model. Mechanistically, primary fibroblasts from PLS rats expressed IL-20 receptors, and IL-20 stimulation significantly increased IL-1β, TNF-α, and TGF-β levels, along with upregulated fibrotic markers, including fibronectin-1 and collagen-1. IL-20 also enhanced fibroblast proliferation and α-SMA production but did not alter MCP-1 levels. CONCLUSION:IL-20 is implicated in promoting epidural fibrosis and may contribute to the pathogenesis of PLS through the modu