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Objective To investigate the mechanistic role of Sijunzi decoction (SJZD) in overcoming chemoresistance through the suppression of adaptive metabolic responses in non-small cell lung cancer (NSCLC). Methods Chemical profiling of SJZD-derived components in systemic circulation was conducted using liquid chromatography-tandem mass spectrometry (LC-MS/MS) in Sprague-Dawley rats. Multiomics integration and network pharmacology were employed to identify convergent targets shared by the bioactive constituents of SJZD and genes associated with cisplatin resistance. In vitro functional assessments using cisplatin-resistant human lung adenocarcinoma (A549/DDP) cells included the following: quantification of cell viability via Cell Counting Kit-8 (CCK-8) assays; evaluation of mitochondrial bioenergetics through targeted metabolomic profiling; and ultrastructural characterization of ferroptotic morphology via transmission electron microscopy (TEM). Cellular redox homeostasis was dynamically monitored using fluorescent probes, including a DCFH-DA probe for reactive oxygen species (ROS) and a C11-BODIPY581/591 probe for lipid peroxidation. siRNA-mediated gene silencing and immunohistochemical analysis were performed to elucidate the functional hierarchy of the p62/Keap1/nuclear factor erythroid 2-related factor 2 (Nrf2) antioxidant axis. Complementary in vivo validation was performed using BALB/c nude mice bearing A549/DDP xenografts, with longitudinal monitoring of tumor progression under SJZD treatment regimens. Results Untargeted metabolomics of SJZD-medicated serum revealed 392 differentially abundant metabolites, with pathway enrichment revealing significant dysregulation of glutamine metabolism. Structural validation confirmed 55 bioactive components of SJZD in serum, including glycyrrhizin, ginsenoside Ro, liquiritigenin, and atractylenolide I. Integration of these components with disease targets yielded 355 overlapping genes associated with both SJZD activity and cisplatin-resistant NSCLC, with significant enrichment in oxidative stress response pathways. Experimental assays confirmed that SJZD induced ferroptosis in cisplatin-resistant A549/DDP cells, as evidenced by disrupted iron homeostasis, lipid peroxidation, and characteristic mitochondrial damage. These effects and subsequent cell death were specifically abrogated by the ferroptosis inhibitor ferrostatin-1 (Fer-1) but not by apoptosis inhibition, confirming that ferroptosis is the primary mechanism of cell death. Mechanistically, the inhibition of p62/Keap1/Nrf2 signaling was involved in the modulation of SJZD-induced ferroptosis both in vitro and in vivo. Conclusions SJZD counteracts metabolic adaptation through ferroptosis mediated by the inhibition of p62/Keap1/Nrf2 in cisplatin-resistant NSCLC.
OBJECTIVE:To evaluate the efficacy and safety of Lianxia Xiaopi Granules (LXXP) in treating functional dyspepsia (FD) with combined cold and heat pattern in Chinese medicine (CM). METHODS:A multicenter, randomized, double-blind, and placebo-controlled trial was conducted at 11 centers between April 1, 2021, and October 24, 2022 in China. Using stratified block randomization at a 2:1 ratio, patients diagnosed with FD were randomly assigned to receive either LXXP (3.5 g/bag, equivalent to 8.337 g of raw herbs) or a placebo (3.5 g/bag) 3 times daily for 8 weeks. The primary outcome was dyspepsia symptom response rate. Secondary outcomes included individual dyspepsia symptom response rate, Chinese medicine syndrome efficacy evaluation scale including reduction rate of CM symptom total score, cure and effective rates, and safety analysis. Subgroup analyses were performed according to postprandial distress syndrome (PDS) or epigastric pain syndrome (EPS) subtypes and Helicobacter pylori (Hp) infection status. RESULTS:A total of 240 participants completed the trial, 160 in the LXXP group and 80 in the placebo group. At week 8, the dyspepsia symptom response rate was significantly higher in the LXXP group than in the placebo group [54.38% (87/160) vs. 32.50% (26/80), P=0.0013]. LXXP significantly improved postprandial fullness, early satiety, and bloating compared with the placebo group (P<0.05). Subgroup analysis showed greater efficacy in PDS and Hp-negative patients (P<0.05). Safety analysis revealed no significant differences in adverse events between the 2 groups. CONCLUSION:LXXP effectively improves FD symptoms, particularly in PDS and Hp-negative patients, supporting its application in CM-based treatment. (Trial registration No. ChiCTR2100041993).
Patients with recurrent acute gout flares who are unable to use nonsteroidal anti-inflammatory drugs (NSAIDs) or colchicine have limited alternatives and remain at high risk of flare recurrence. Firsekibart is a fully human monoclonal antibody targeting interleukin-1βeta (IL-1β) The objective of this study is to evaluate the longer-term efficacy and safety of firsekibart through 48 weeks in patients with acute gout unsuitable for standard anti-inflammatory therapy. This was a multicenter, randomized, double-blind, positive-controlled phase 3 study of firsekibart with compound betamethasone. Followed by a 24-week open-label extension (OLE), conducted at hospitals in China. The double-blind phase was conducted from Week 0 to Week 24, followed by an OLE through Week 48 and a 12-week safety follow-up period after the last dose. Adults with ≥ 2 acute gout flares in the past year and a contraindication, intolerance, or inadequate response to NSAIDs and/or colchicine were enrolled. Patients completing the double-blind phase entered the OLE, during which firsekibart was administered for acute gout flares as needed. Efficacy included proportion of patients experiencing ≥ 1 gout flare recurrence, number of flares per patient, and time to first recurrence through Week 48, as well as rescue medication use during the OLE. Exploratory outcomes included health-related quality of life and flare-related pain. Safety included adverse events (AEs), laboratory tests, and immunogenicity. Of 313 patients (double-blind phase), 300 entered the OLE. By week 48, gout flare recurrence occurred in 70 patients (44.9
To systematically explore causal relationships between chondrosarcoma and angiogenesis-related gene expression using Mendelian randomization (MR) and transcriptome-wide association study (TWAS) approaches, and identify potential therapeutic targets. Based on whole blood tissue gene expression data, summary-data-based Mendelian randomization (SMR) analysis was performed to examine causal associations between 25 angiogenesis-related candidate genes and chondrosarcoma risk. Simultaneously, transcriptome-wide association study (TWAS) was conducted covering 22 autosomes, calculating Z-scores and P-values to assess the strength of association between gene expression and disease. Key findings were validated by RT-qPCR in chondrosarcoma cell lines versus normal chondrocytes. SMR analysis identified significant causal associations after correction. LINC00984 showed the strongest risk association (OR = 5.243, P = 1.10 × 10-2), while TXNDC2 also demonstrated risk effects (OR = 3.555, P = 5.09 × 10-3). Protective genes included MPL28 (OR = 0.070, P = 1.40 × 10-2) and RP11-474N24.6 (OR = 0.287, P = 1.92 × 10-3). TWAS identified significant signals on chromosomes 18–19 and 22. Functional analysis confirmed enrichment in VEGF and HIF-1 pathways. RT-qPCR validation showed risk genes were upregulated 3.2–8.2-fold in tumor cells, while protective genes were downregulated 58–78
Three new natural products, 5-(D-glucopyranosyloxy)-2-hydroxybenzoic acid (1), ethyl 5-hydroxypicolinate (2) and 5-hydroxypicolinamide (3) isolated from Portulaca oleracea L. were established. The structures were identified by one- and two-dimensional NMR and UHPLC-ESI-Q-TOF/MS spectroscopic methods, after which the anti-inflammatory activities of the three compounds were investigated.
