Single-cell transcriptome sequencing-based analysis: probing the mechanisms of glycoprotein NMB regulation of epithelial cells involved in silicosis.

Chronic exposure to silica can lead to silicosis, one of the most serious occupational lung diseases worldwide, for which there is a lack of effective therapeutic drugs and tools. Epithelial mesenchymal transition plays an important role in several diseases; however, data on the specific mechanisms in silicosis models are scarce. We elucidated the pathogenesis of pulmonary fibrosis via single-cell transcriptome sequencing and constructed an experimental silicosis mouse model to explore the specific molecular mechanisms affecting epithelial mesenchymal transition at the single-cell level. Notably, as silicosis progressed, glycoprotein non-metastatic melanoma protein B (GPNMB) exerted a sustained amplification effect on alveolar type II epithelial cells, inducing epithelial-to-mesenchymal transition by accelerating cell proliferation and migration and increasing mesenchymal markers, ultimately leading to persistent pulmonary pathological changes. GPNMB participates in the epithelial-mesenchymal transition in distant lung epithelial cells by releasing extracellular vesicles to accelerate silicosis. These vesicles are involved in abnormal changes in the composition of the extracellular matrix and collagen structure. Our results suggest that GPNMB is a potential target for fibrosis prevention.

FV-429 enhances the efficacy of paclitaxel in NSCLC by reprogramming HIF-1α-modulated FattyAcid metabolism.

Solid tumors often exhibit hypoxia in their centers, which has been associated with a marked reduction in the sensitivity of the tumor cells to anti-tumor and chemotherapeutic interventions. Here, we found that the occurrence and progress of hypoxic insensitivity to paclitaxel in non-small cell lung cancer (NSCLC) are closely associated with the HIF-1α pathway. The HIF-1α protein upregulated the expression of adipose differentiation-related protein (ADRP), fatty acid synthase (FASN), and sterol regulatory element binding protein 1(SREBP1), while simultaneously downregulating carnitine palmitoyltransferase 1 (CPT1), thereby leading to a more pronounced uptake of lipids and reduced oxidation of fatty acids. Diminished levels of fatty acids led to reduced Wnt pathway activation and ß-catenin nuclear translocation, leading to G2/M cell cycle arrest. In this study, FV-429, a derivative of the natural flavonoid wogonin, reprogrammed metabolism of cancer cells and decreased fatty acid levels. Moreover, paclitaxel-induced G2/M phase arrest in hypoxia-resistant NSCLC was hampered but FV-429 improved the sensitivity of these cancer cells to paclitaxel. FV-429 activated and modulated fatty acid metabolism in NSCLC cells, significantly reduced levels of fatty acids within cells and increased the oxidation of these fatty acids. The results of our study demonstrated that FV-429 could reshape fatty acid metabolism in hypoxia-induced paclitaxel-resistant NSCLC and enhance the sensitivity of NSCLC cells to paclitaxel through G2/M phase arrest deterioration, by inactivating the Wnt pathway, and suggested the possibility of using FV-429 as a promising candidate therapeutic agent for advanced NSCLC.

X-architecture Steiner minimal tree algorithm based on multi-strategy optimization discrete differential evolution.

Global routing is an important link in very large scale integration (VLSI) design. As the best model of global routing, X-architecture Steiner minimal tree (XSMT) has a good performance in wire length optimization. XSMT belongs to non-Manhattan structural model, and its construction process cannot be completed in polynomial time, so the generation of XSMT is an NP hard problem. In this paper, an X-architecture Steiner minimal tree algorithm based on multi-strategy optimization discrete differential evolution (XSMT-MoDDE) is proposed. Firstly, an effective encoding strategy, a fitness function of XSMT, and an initialization strategy of population are proposed to record the structure of XSMT, evaluate the cost of XSMT and obtain better initial particles, respectively. Secondly, elite selection and cloning strategy, multiple mutation strategies, and adaptive learning factor strategy are presented to improve the search process of discrete differential evolution algorithm. Thirdly, an effective refining strategy is proposed to further improve the quality of the final Steiner tree. Finally, the results of the comparative experiments prove that XSMT-MoDDE can get the shortest wire length so far, and achieve a better optimization degree in the larger-scale problem.

Glycolysis inhibition and apoptosis induction in human prostate cancer cells by FV-429-mediated regulation of AR-AKT-HK2 signaling network.

Prostate cancer (PCa) depends on androgen receptor (AR) signaling to regulate cell metabolism, including glycolysis, and thereby promotes tumor growth. Glycolysis is overactive in PCa and associated with poor prognosis, but the therapeutic efficacy of glycolysis inhibitors has thus far been limited by their inability to induce cell death. FV-429, a flavonoid derivative of Wogonin, is a glycolysis inhibitor that has shown anti-cancer promise. In this study, we used FV-429 as an anti-PCa agent and investigated its mechanisms of action. In vitro, both the glycolytic ability and the viability of PCa cells were inhibited by FV-429. We found that FV-429 could induce mitochondrial dysfunction and apoptosis, with AKT-HK2 signaling pathway playing a key role. In addition, FV-429 had a pro-apoptotic effect on human prostate cancer cells that relied on the inhibition of AR expression and activity. In vivo, FV-429 exerted significant tumor-repressing activity with high safety in the xenograft model using LNCaP cells. In summary, we demonstrated that FV-429 induced glycolysis inhibition and apoptosis in human prostate cancer cells by downregulating the AR-AKT-HK2 signaling network, making FV-429 a promising candidate as one therapeutic agent for advanced PCa.