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Abstract Recently, various cancer types have been identified to express a distinct subset of Interferon-stimulated genes (ISGs) that mediate therapy resistance. The mechanism through which cancer cells maintain prolonged Interferon stimulation effects to coordinate resistance remains unclear. Our research demonstrated that aberrant upregulation of TAGLN2 is associated with gastric cancer progression, and inhibiting its expression renders gastric cancer cells more susceptible to chemotherapy and radiation. We uncovered a novel role for TAGLN2 in the upregulation of resistance signature ISGs by enhancing YBX1-associated ssDNA aggregation and cGAS-STING pathway activation. TAGLN2 modulates YBX1 by recruiting c-Myc and SOX9 to YBX1 promoter region and directly interacting with AKT-YBX1, thereby enhancing YBX1 phosphorylation and nuclear translocation. Significantly, targeted downregulation of key proteins, inhibition of the TAGLN2-YBX1-AKT interaction (using Fisetin or MK2206) or disruption of the cGAS-STING pathway substantially reduced ssDNA accumulation, subsequent ISGs upregulation, and therapy resistance. The combination of Cisplatin with MK2206 displayed a synergistic effect in the higher TAGLN2-expressing xenograft tumors. Clinical analysis indicated that a derived nine-gene set effectively predicts therapeutic sensitivity and long-term prognosis in gastric cancer patients. These findings suggest that TAGLN2, YBX1 and induced ISGs are novel predictive markers for clinical outcomes, and targeting this axis is an attractive therapeutic sensitization strategy.

Abstract Background Metabolic reprogramming has been reported in various kinds of cancers and is related to clinical prognosis, but the prognostic role of pyrimidine metabolism in gastric cancer (GC) remains unclear. Methods Here, we employed DEG analysis to detect the differentially expressed genes (DEGs) in pyrimidine metabolic signaling pathway and used univariate Cox analysis, Lasso-penalizes Cox regression analysis, Kaplan–Meier survival analysis, univariate and multivariate Cox regression analysis to explore their prognostic roles in GC. The DEGs were experimentally validated in GC cells and clinical samples by quantitative real-time PCR. Results Through DEG analysis, we found NT5E, DPYS and UPP1 these three genes are highly expressed in GC. This conclusion has also been verified in GC cells and clinical samples. A prognostic risk model was established according to these three DEGs by Univariate Cox analysis and Lasso-penalizes Cox regression analysis. Kaplan–Meier survival analysis suggested that patient cohorts with high risk score undertook a lower overall survival rate than those with low risk score. Stratified survival analysis, Univariate and multivariate Cox regression analysis of this model confirmed that it is a reliable and independent clinical factor. Therefore, we made nomograms to visually depict the survival rate of GC patients according to some important clinical factors including our risk model. Conclusion In a word, our research found that pyrimidine metabolism is dysregulated in GC and established a prognostic model of GC based on genes differentially expressed in pyrimidine metabolism.

Abstract More than 60% of nonsmall cell lung cancer (NSCLC) patients show a positive response to the first ALK inhibitor, crizotinib, which has been used as the standard treatment for newly diagnosed patients with ALK rearrangement. However, most patients inevitably develop crizotinib resistance due to acquired secondary mutations in the ALK kinase domain, such as the gatekeeper mutation L1196M and the most refractory mutation, G1202R. Here, we develop XMU‐MP‐5 as a new‐generation ALK inhibitor to overcome crizotinib resistance mutations, including L1196M and G1202R. XMU‐MP‐5 blocks ALK signaling pathways and inhibits the proliferation of cells harboring either wild‐type or mutant EML4‐ALK in vitro and suppresses tumor growth in xenograft mouse models in vivo. Structural analysis provides insights into the mode of action of XMU‐MP‐5. In addition, XMU‐MP‐5 induces significant regression of lung tumors in two genetically engineered mouse (GEM) models, further demonstrating its pharmacological efficacy and potential for clinical application. These preclinical data support XMU‐MP‐5 as a novel selective ALK inhibitor with high potency and selectivity. XMU‐MP‐5 holds great promise as a new therapeutic against clinically relevant secondary ALK mutations.

Astaxanthin (AST), a red pigment of the carotenoids, has various advantageous biological activities. Nevertheless, the wide application of AST is restricted due to its poor water solubility and highly unsaturated structure. To overcome these limitations, carrier-free astaxanthin nanoparticles (AST-NPs) were fabricated through the anti-solvent precipitation method. The AST-NPs had a small particle size, negative zeta potential and high loading capacity. Analysis of DSC and XRD demonstrated that amorphous AST existed in AST-NPs. In comparison with free AST, AST-NPs displayed enhanced stability during storage. Besides, it also showed outstanding stability when exposed to UV light. Furthermore, the antioxidant capacity of AST-NPs was significantly increased. In vitro release study showed that AST-NPs significantly delayed the release of AST in the releasing medium. These findings indicated that AST-NPs would be an ideal formulation for AST, which could contribute to the development of novel functional foods.

Introduction The PER2 (Period circadian regulator 2) gene is related to the circadian clock, and it has been deemed as a suppressor gene in osteosarcoma and lung carcinoma. However, the part of PER2 in CRC (colorectal cancer) needs to be further determined. Methods First, we collected clinical samples to detect PER2 expression in CRC. Then, we used cell transfection to knock down PER2 expression in CRC cell lines and performed a series of functional experiments to elucidate the effects of PER2 on CRC cells. We next verified whether PER2 affects the epithelial-mesenchymal transformation (EMT) process in CRC by conducting quantitative real-time PCR and western blotting. Results In the research, we revealed that the expression of PER2 decreased in CRC clinical samples. In addition, knocking down PER2 expression caused CRC cells to acquire malignant biological features. Finally, we found that PER2 knockdown may activate the Snail/Slug axis through inhibiting p53, therefore promote the activation of the EMT pathway. Conclusion In conclusion, low PER2 expression reinforces migration and activates EMT in CRC, suggesting that PER2 is closely related to CRC development and could be used as a potential treatment site in the clinic.

Curcumin (Cur), a natural hydrophobic polyphenolic compound, exhibits multiple beneficial biological activities. However, low water solubility and relative instability hinder its application in food fields. In this study, carrier-free curcumin nanoparticles (CFC NPs) were prepared by adding the DMSO solution of Cur into DI water under continuous rapid stirring. The morphology of CFC NPs was a spherical shape with a diameter of 65.25 ± 2.09 nm (PDI = 0.229 ± 0.107), and the loading capacity (LC) of CFC NPs was as high as 96.68 ± 0.03%. The thermal property and crystallinity of CFC NPs were investigated by XRD. Furthermore, the CFC NPs significantly accelerated the release of Cur in vitro owing to its improved water dispersibility. Importantly, CFC NPs displayed significantly improved DPPH radical scavenging activity. Overall, all these results suggested that CFC NPs would be a promising vehicle to widen the applications of Cur in food fields.

Ferroptosis is a regulated cell death pathway based on the deposition of lipid-based reactive oxygen species (L-ROS) in the presence of iron ions. The term was first coined in 2012 by Dixon. Decreased glutathione (GSH) synthesis and low glutathione-dependent antioxidant peroxidase 4 (GPX4) activity are the major causes of ferroptosis. Sensitivity to ferroptosis for example in tumor cells may be further enhanced by high cellular iron concentrations and/or high p53 levels. Therefore, driving ferroptosis in tumor cells could be a new way to treat tumors. Thus far, natural products have played considerable roles in antitumor research and treatment, and some drugs, such as paclitaxel, have proven beneficial in many cancer patients. According to current research, natural products can induce ferroptosis when used alone or in conjunction with other cancer therapies. This review mainly elaborates the main mechanism of ferroptosis and the regulating effects of some natural products on ferroptosis, aiming to create a new space for the research and development of novel anticancer drugs. [ABSTRACT FROM AUTHOR]