4-amino-2-trifluoromethyl-phenyl retinate alleviates lipopolysaccharide-induced acute myocardial injury through activation of the KLF4/p62 axis.

Ferroptosis plays a pivotal role in the pathological process of sepsis-induced cardiomyopathy (SIC). All-trans retinoic acid (ATRA) enhances the host immune response to lipopolysaccharides (LPS). This study investigated the role of 4-amino-2-trifluoromethyl-phenyl retinate (ATPR), a derivative of ATRA, in myocardial injury caused by sepsis. Male C57BL/6 mice were intraperitoneally injected with LPS to establish a sepsis model. H9c2 cells were stimulated by LPS to establish an injury model. We observed that ATPR improved myocardial injury in mice, which was presented in terms of an increased glutathione (GSH) level and reduced production of malondialdehyde (MDA), as well as an increased number of mitochondrial cristae and maintenance of the mitochondrial membrane integrity. ATPR improved cardiac function in the LPS-injured mice. It inhibited the inflammatory response as evidenced by the decreasing mRNA levels of TNF-α and IL-6. The elevated protein expression levels of Nrf2, SLC7A11, GPX4, and FTH1 in mice and H9c2 cells showed that ATPR inhibited ferroptosis. Immunoprecipitation of LPS-stimulated H9c2 cells demonstrated that ATPR increased the interaction between p62 and Keap1. ATPR upregulated the KLF4 and p62 protein expression. However, the inhibition of Nrf2 by ML385 reduced the protective effect of ATPR in LPS-treated H9c2 cells. Furthermore, we used siRNA to knock down KLF4 in H9c2 cells and found that the KLF4 knockdown eliminated the inhibition of ferroptosis by ATPR in H9c2 cells. Therefore, ATPR alleviates LPS-induced myocardial injury by inhibiting ferroptosis via the KLF4/p62 axis.

Melatonin Potentiates Sensitivity to 5-Fluorouracil in Gastric Cancer Cells by Upregulating Autophagy and Downregulating Myosin Light-Chain Kinase.

5-Fluorouracil is an effective chemotherapeutic drug for gastric cancer. However, the acquisition of chemotherapeutic resistance remains a challenge in treatment. Melatonin can enhance the therapeutic effect of 5-fluorouracil; however, the underlying mechanisms are not well understood. We investigated the effects of combinations of melatonin and 5-fluorouracil on the proliferation, migration and invasion of gastric cancer cells. Melatonin significantly potentiated the 5-fluorouracil-mediated inhibition of proliferation, migration and invasion in gastric cancer cells, which potentiates sensitivity to 5-FU by promoting the activation of Beclin-1-dependent autophagy and targeting the myosin light-chain kinase (MLCK) signaling pathway. Previous studies have shown that autophagy might be associated with the MLCK signaling pathway. The autophagy inhibitor, 3-methyladenine, effectively rescued the migratory and invasive capabilities of gastric cancer cells, while also reducing expression level of MLCK and the phosphorylation level of MLC. This indicates that autophagy is involved in tumor metastasis, which may be related to inhibition of the MLCK signaling pathway. Our findings indicate that melatonin can improve the effectiveness of 5-fluorouracil in gastric cancer and could be used as a supplemental agent in the treatment of gastric cancer with 5-fluorouracil.