yroptosis, an inflammatory form of Programmed cell death (PCD) and so far, the function of Schiff base compounds in pyroptosis cell death has not been reported. Here, we show that VALD3, a Ligand derivative of Schiff base, treated Triple negative breast cancer (TNBC) cells exhibited specific pyroptotic characteristics, including cell swelling, balloon-like bubbling and inflammatory cytokine release through pore formation in the plasma membrane, eventually suppressing the tumor growth of TNBC. In addition, Western blot analysis revealed that the cleavage of Gasdermin E (GSDME),was related to the activation of caspase-3 in TNBC cells treated by VALD3. Consistent with this, treatment with zDEVD-FMK,a caspase-3 specific inhibitor,reduces VALD3-induced GSDME–N-terminal fragment cleavage and pyroptosis. Mechanistically, VALD3 elevated the level of reactive oxygen species(ROS)and c-Jun NH2-terminal kinase (JNK)phosphorylation.NAC,a ROS scavenger,reversed the pyroptosis and JNK phosphorylation in MDA-MB-468 and MDA-MB-231 treated by VALD3. Activated JNK recruited Bax to mitochondria to form a heterodimer with Bcl-2, which stimulated the release of cytochrome c into the cytoplasm, followed by caspase-3 activation and GSDME-depended pyroptosis in TNBC cells. Therefore, in TNBC cells,VALD-3 treatment induces the ROS/JNK/Bax-mitochondrial apoptosis pathway. Thereby activating Caspase-3 and inducing cleavage of GSDME to execute pyroptosis. These findings bring an unexpected concept that GSDME-dependent pyroptosis is an unrecognized mechanism by which VALD3 eradicates neoplastic cells, and provide new insights into the clinical application of anticancer therapeutics.

Objective: In this study, two human hepatocellular carcinoma cell lines, HepG2 (p53+/+) and Hep3B (p53-/-), were used with different p53 mutation statuses. The role of p53 in the induction of cytotoxicity by H2Valdien derivatives was investigated, as well as how p53 regulates GADD45a and p21. To examine whether the mechanism of action of H2Valdien derivatives on cell cycle arrest and apoptosis in human hepatocellular carcinoma cells is related to p53 deficiency. Methods: Cell viability was analyzed using the CCK-8 assay, and RNA sequencing was used for differential gene expression and enrichment analyses. The expression of apoptosis and cell cycle related proteins was analyzed by western blotting. DAPI and TUNEL staining techniques were employed to effectively visualize the nuclear morphology and apoptotic properties of the cells under investigation. Cell proliferation ability was assessed using colony formation assays, and mitochondrial membrane potential (MMP) was detected by JC-1 staining. Cell cycle progression was assessed by flow cytometry. Results: H2Valdien derivatives (5, 10, 20, and 40 mg/L) inhibited the proliferation of HepG2 and Hep3B cells and the formation of cell colonies in a dose-dependent manner, and decreased the MMP of HepG2 cells, but had no effect on the MMP of Hep3B cells. H2Valdien derivatives upregulated cleaved caspase-9, cleaved PARP, and Bax in HepG2 cells but not in Hep3B cells. RNA sequencing analysis revealed that H2Valdien derivatives increased p53, p21, and GADD45A expression, and western blotting and flow cytometry confirmed this finding. Despite the induction of p21 and GADD45a in Hep3B cells, there was no change in related proteins associated with drug concentration. Conclusion: GADD45a and p21 expression is regulated by H2Valdien derivatives in a p53-dependent manner, and p53 has a pro-apoptotic impact on H2Valdien derivative-induced toxicity. H2Valdien derivative-induced apoptosis and cycle hinder are reduced by p53 deletion.

No abstract

The thermal conductivity (TC) of graphene with Sierpinski carpet fractal (SCF) and regular carpet (RC) defects is numerically studied by the non-equilibrium molecular dynamics (NEMD) method. The influences of porosity, fractal levels, and types of defects on the TC of graphene are clarified, and the underlying mechanisms of phonon behaviors are uncovered. The numerical results indicate that the defects in graphene induce the atoms that have the heat transfer blockage effect, and thus, the TC of defective graphene decreases with increasing porosity. With the increase in fractal levels, more atoms have the heat transfer blockage effect, which induces the TC of graphene with SCF defects to sharply decrease. Moreover, compared with the graphene with RC defects, more atoms participate in the heat transfer blockage under the graphene with SCF defects, which leads to the lower TC of graphene with SCF defects.