Targeting the Warburg effect: A revisited perspective from molecular mechanisms to traditional and innovative therapeutic strategies in cancer.

Cancer reprogramming is an important facilitator of cancer development and survival, with tumor cells exhibiting a preference for aerobic glycolysis beyond oxidative phosphorylation, even under sufficient oxygen supply condition. This metabolic alteration, known as the Warburg effect, serves as a significant indicator of malignant tumor transformation. The Warburg effect primarily impacts cancer occurrence by influencing the aerobic glycolysis pathway in cancer cells. Key enzymes involved in this process include glucose transporters (GLUTs), HKs, PFKs, LDHs, and PKM2. Moreover, the expression of transcriptional regulatory factors and proteins, such as FOXM1, p53, NF-κB, HIF1α, and c-Myc, can also influence cancer progression. Furthermore, lncRNAs, miRNAs, and circular RNAs play a vital role in directly regulating the Warburg effect. Additionally, gene mutations, tumor microenvironment remodeling, and immune system interactions are closely associated with the Warburg effect. Notably, the development of drugs targeting the Warburg effect has exhibited promising potential in tumor treatment. This comprehensive review presents novel directions and approaches for the early diagnosis and treatment of cancer patients by conducting in-depth research and summarizing the bright prospects of targeting the Warburg effect in cancer.

Main active components of Si-Miao-Yong-An decoction (SMYAD) attenuate autophagy and apoptosis via the PDE5A-AKT and TLR4-NOX4 pathways in isoproterenol (ISO)-induced heart failure models.

Heart failure (HF), the main cause of death in patients with many cardiovascular diseases, has been reported to be closely related to the complicated pathogenesis of autophagy, apoptosis, and inflammation. Notably, Si-Miao-Yong-An decoction (SMYAD) is a traditional Chinese medicine (TCM) used to treat cardiovascular disease; however, the main active components and their relevant mechanisms remain to be discovered. Based on our previous ultra-performance liquid chromatography coupled to quadrupole time-of-flight mass spectrometry (UPLC-Q/TOF-MS) results, we identified angoriside C (AC) and 3,5-dicaffeoylquinic acid (3,5-DiCQA) as the main active components of SMYAD. In vivo results showed that AC and 3,5-DiCQA effectively improved cardiac function, reduced the fibrotic area, and alleviated isoproterenol (ISO)-induced myocarditis in rats. Moreover, AC and 3,5-DiCQA inhibited ISO-induced autophagic cell death by inhibiting the PDE5A/AKT/mTOR/ULK1 pathway and inhibited ISO-induced apoptosis by inhibiting the TLR4/NOX4/BAX pathway. In addition, the autophagy inhibitor 3-MA was shown to reduce ISO-induced apoptosis, indicating that ISO-induced autophagic cell death leads to excess apoptosis. Taken together, the main active components AC and 3,5-DiCQA of SMYAD inhibit the excessive autophagic cell death and apoptosis induced by ISO by inhibiting the PDE5A-AKT and TLR4-NOX4 pathways, thereby reducing myocardial inflammation and improving heart function to alleviate and treat a rat ISO-induced heart failure model and cell heart failure models. More importantly, the main active components of SMYAD will provide new insights into a promising strategy that will promote the discovery of more main active components of SMYAD for therapeutic purposes in the future.

Identification of autophagic target RAB13 with small-molecule inhibitor in low-grade glioma via integrated multi-omics approaches coupled with virtual screening of traditional Chinese medicine databases.

OBJECTIVES: Autophagy, a highly conserved lysosomal degradation process in eukaryotic cells, has been widely reported closely related to the progression of many types of human cancers, including LGG; however, the intricate relationship between autophagy and LGG remains to be clarified. MATERIALS AND METHODS: Multi-omics methods were used to integrate omics data to determine potential autophagy regulators in LGG. The expression of ZFP36L2 and RAB13 in SW1088 cells was experimentally manipulated using cDNAs and small interfering RNAs (siRNA). RT-qPCR detects RNAi gene knockout and cDNA overexpression efficiency. The expression levels of proteins in SW1088 cells were evaluated using Western blot analysis and immunofluorescence analysis. Homology modelling and molecular docking were used to identify compounds from Multi-Traditional Chinese Medicine (TCM) Databases. The apoptosis ratios were determined by flow cytometry analysis of Annexin-V/PI double staining. We detect the number of autophagosomes by GFP-MRFP-LC3 plasmid transfection to verify the process of autophagy flow. RESULTS: We integrated various omics data from LGG, including EXP, MET and CNA data, with the SNF method and the LASSO algorithm, and identified ZFP36L2 and RAB13 as positive regulators of autophagy, which are closely related to the core autophagy regulators. Both transcription level and protein expression level of the four autophagy regulators, including ULK1, FIP200, ATG16L1 and ATG2B, and LC3 puncta were increased by ZFP36L2 and RAB13 overexpression. In addition, RAB13 participates in autophagy through ATG2B, FIP200, ULK1, ATG16L1 and Beclin-1. Finally, we screened multi-TCM databases and identified gallic acid as a novel potential RAB13 inhibitor, which was confirmed to negatively regulate autophagy as well as to induce cell death in SW1088 cells. CONCLUSION: Our study identified the key autophagic regulators ZFP36L2 and Rab13 in LGG progression, and demonstrated that gallic acid is a small molecular inhibitor of RAB13, which negatively regulates autophagy and provides a possible small molecular medicine for the subsequent treatment of LGG.