The Diagnostic Model of Ligusticum Chuanxiong Hort. Against Cerebral Stroke Using Network Pharmacology and Transcriptomics Analyses

Background: Cerebral stroke is a leading cause of death and disability worldwide. Ligusticum Chuanxiong Hort. (LCH), a well-known Chinese herb, is widely used for the treatment of cerebral stroke. This study aimed to investigate the underlying mechanisms of LCH in cerebral stroke and develop a diagnostic model. Methods: We employed network pharmacology analyses to identify the active compounds, targets, and underlying mechanisms of LCH for treating cerebral stroke. Molecular docking was performed to visualize the binding site between the core active compounds and hub targets. Furthermore, a diagnostic model for cerebral stroke was constructed based on transcriptomic analysis. Results: Our findings revealed that LCH contains multiple active ingredients, including oleic acid and caffeic acid. Protein-protein interaction network analysis identified IL1B, CCL2, MAPK3, PTGS2, JUN, MMP9, TLR4, HIF1A, PPARA, FOS, PTEN, NFE2L2, TLR2, TIMP1, and SOD2 as the top 15 hub genes. Kyoto Encyclopedia of Genes and Genomes pathway analysis highlighted the enrichment of TNF and IL-17 signaling pathways. Molecular docking analysis demonstrated binding sites between oleic acid, caffeic acid, and MMP9, PPARP, PTEN, and TIMP1. The diagnostic model indicated that FOS, MMP9, PPARA, PTEN, TIMP1, and TLR2 serve as blood biomarkers for cerebral stroke. Conclusions: This study demonstrates that LCH alleviates the symptoms following cerebral stroke through interactions with the TNF and IL-17 signaling pathways. The findings contribute to a better understanding of the therapeutic mechanisms of LCH and offer insights into the development of a diagnostic model for cerebral stroke

Loss of Ufl1/Ufbp1 in hepatocytes promotes liver pathological damage and carcinogenesis through activating mTOR signaling

Abstract Background Ufm1-specific ligase 1 (Ufl1) and Ufm1-binding protein 1 (Ufbp1), as putative targets of ubiquitin-fold modifier 1 (Ufm1), have been implicated in several pathogenesis-related signaling pathways. However, little is known about their functional roles in liver disease. Methods Hepatocyte-specific Ufl1 Δ/Δhep and Ufbp1 Δ/Δhep mice were used to study their role in liver injury. Fatty liver disease and liver cancer were induced by high-fat diet (HFD) and diethylnitrosamine (DEN) administration, respectively. iTRAQ analysis was employed to screen for downstream targets affected by Ufbp1 deletion. Co-immunoprecipitation was used to determine the interactions between the Ufl1/Ufbp1 complex and the mTOR/GβL complex. Results Ufl1 Δ/Δhep or Ufbp1 Δ/Δhep mice exhibited hepatocyte apoptosis and mild steatosis at 2 months of age and hepatocellular ballooning, extensive fibrosis, and steatohepatitis at 6–8 months of age. More than 50% of Ufl1 Δ/Δhep and Ufbp1 Δ/Δhep mice developed spontaneous hepatocellular carcinoma (HCC) by 14 months of age. Moreover, Ufl1 Δ/Δhep and Ufbp1 Δ/Δhep mice were more susceptible to HFD-induced fatty liver and DEN-induced HCC. Mechanistically, the Ufl1/Ufbp1 complex directly interacts with the mTOR/GβL complex and attenuates mTORC1 activity. Ablation of Ufl1 or Ufbp1 in hepatocytes dissociates them from the mTOR/GβL complex and activates oncogenic mTOR signaling to drive HCC development. Conclusions These findings reveal the potential role of Ufl1 and Ufbp1 as gatekeepers to prevent liver fibrosis and subsequent steatohepatitis and HCC development by inhibiting the mTOR pathway

Scalable Preparation of the Chemically Ordered Pt–Fe–Au Nanocatalysts with High Catalytic Reactivity and Stability for Oxygen Reduction Reactions

Carbon-supported Au–Pt<i>_x</i>Fe<i>_y</i> nanoparticles were synthesized via microwave heating polyol process, followed by annealing for the formation of the ordered structure. The structure characterizations indicate that Au is alloyed with intermetallic Pt–Fe nanoparticles and therefore the surface electronic properties are tuned. The electrochemical tests show that the microwave heating polyol process is more effective than oil bath heating polyol process for synthesizing the highly active catalysts. The introduction of trace Au (0.2 wt % Au) significantly improves the oxygen reduction reaction (ORR) catalytic activity of Pt<i>_x</i>Fe<i>_y</i> catalysts. Au–PtFe/C–H (0.66 A/mg_Pt) and Au–PtFe₃/C–H (0.63 A/mg_Pt) prepared in a batch of 10.0 g show significantly improved catalytic activities than their counterparts (PtFe/C–H and PtFe₃/C–H) as well as commercial Johnson Matthey Pt/C (0.17 A/mg_Pt). In addition, the as-prepared Au–PtFe/C–H and Au–PtFe₃/C–H display highly enhanced stability toward the ORR compared to the commercial Pt/C. The superior catalytic performance is attributed to the synergistic effect of chemically ordered intermetallic structure and Au. This work provides a scalable synthesis of the multimetallic chemically ordered Au–Pt<i>_x</i>Fe<i>_y</i> catalysts with high ORR catalytic performance in acidic condition

A Novel TLR4-SYK Interaction Axis Plays an Essential Role in the Innate Immunity Response in Bovine Mammary Epithelial Cells

Mammary gland epithelium, as the first line of defense for bovine mammary gland immunity, is crucial in the process of mammary glands’ innate immunity, especially that of bovine mammary epithelial cells (bMECs). Our previous studies successfully marked SYK as an important candidate gene for mastitis traits via GWAS and preliminarily confirmed that SYK expression is down-regulated in bMECs with LPS (E. coli) stimulation, but its work mechanism is still unclear. In this study, for the first time, in vivo, TLR4 and SYK were colocalized and had a high correlation in mastitis mammary epithelium; protein–protein interaction results also confirmed that there was a direct interaction between them in mastitis tissue, suggesting that SYK participates in the immune regulation of the TLR4 cascade for bovine mastitis. In vitro, TLR4 also interacts with SYK in LPS (E. coli)-stimulated or GBS (S. agalactiae)-infected bMECs, respectively. Moreover, TLR4 mRNA expression and protein levels were little affected in bMECsSYK- with LPS stimulation or GBS infection, indicating that SYK is an important downstream element of the TLR4 cascade in bMECs. Interestingly, IL-1β, IL-8, NF-κB and NLRP3 expression in LPS-stimulated or GBS-infected bMECsSYK- were significantly higher than in the control group, while AKT1 expression was down-regulated, implying that SYK could inhibit the IL-1β, IL-8, NF-κB and NLRP3 expression and alleviate inflammation in bMECs with LPS and GBS. Taken together, our solid evidence supports that TLR4/SYK/NF-κB signal axis in bMECs regulates the innate immunity response to LPS or GBS