ScopeThe development of novel compounds that trigger non‐apoptotic cell death may represent alternative therapeutic strategies for esophageal squamous cell carcinoma (ESCC) treatment. Cellular senescence suppresses tumorigenesis by halting the proliferation of tumor cells, implying the induction of senescence as a promising anticancer strategy, especially when combined with senolytic agents that specially kill senescent cells. This study is designed to screen novel anti‐ESCC compounds from a natural product resource and identify its mechanism‐of‐action.Methods and ResultsIdentified are the significant anti‐cancer effect and underlying mechanism of SFN, an isothiocyanate derived from cruciferous vegetables, through RNA sequencing, western blot, and immunofluorescent assays. It is found that SFN inhibits proliferation of ESCC cells through inducing senescence. Mechanistically, SFN induces reactive oxygen species (ROS) via disrupting the balance between glutathione and oxidized glutathione, leading to DNA damage. In addition, ROS deregulates autophagy and promotes lysosome abnormal biogenesis through regulating mTOR/TFE3 axis. Finally, the inhibited autophagic flux facilitates exosome production, resulting in exosome‐mediated paracrine senescence.ConclusionsThis study suggests the important roles of autophagy and exosome‐mediated paracrine senescence in cancer therapy and highlights SFN as a potent anti‐ESCC drug candidate.

Senescence is an irreversible state of cell cycle arrest that can be triggered by multiple stimuli, such as oxygen reactive species and DNA damage. Growing evidence has proven that senescence is a tumor-suppressive approach in cancer treatment. Therefore, developing novel agents that modulate senescence may be an alternative strategy against cancer. In our study, we investigated the inhibitory effect of gypenoside L (Gyp-L), a saponin isolated from Gynostemma pentaphyllum, on cancer cell growth. We found that Gyp-L increased the SA-β-galactosidase activity, promoted the production of senescence-associated secretory cytokines, and inhibited cell proliferation of human liver and esophageal cancer cells. Moreover, Gyp-L caused cell cycle arrest at S phase, and activated senescence-related cell cycle inhibitor proteins (p21 and p27) and their upstream regulators. In addition, Gyp-L activated p38 and ERK MAPK pathways and NF-κB pathway to induce senescence. Consistently, adding chemical inhibitors efficiently counteracted the Gyp-L-mediated senescence, growth inhibition, and cell cycle arrest in cancer cells. Furthermore, treatment with Gyp-L, enhanced the cytotoxicity of clinic therapeutic drugs, including 5-fluorouracil and cisplatin, on cancer cells. Overall, these results indicate that Gyp-L inhibits proliferation of cancer cells by inducing senescence and renders cancer cells more sensitive to chemotherapy.

Context. Kuntai capsule (KTC), a proprietary Chinese medicine, have been used for the treatment of polycystic ovary syndrome (PCOS). Objective. This study elucidates the potential therapeutic targets and molecular mechanisms of KTC in the treatment of PCOS. Materials and Methods. Using the Traditional Chinese Medicine System Pharmacology Database and Analysis Platform (TCMSP), the active ingredients and potential targets of KTC were obtained. The Gene Expression Omnibus (GEO) database was used to find differentially expressed genes (DEGs) related to PCOS. Search the CTD, DisGeNet, genecards, NCBI, OMIM, and PharmGKB databases for therapeutic targets related to PCOS. The intersection of potential targets, DEGs, and therapeutic targets was submitted to perform bioinformatics analysis by R language. Finally, the analyses’ core targets and their corresponding active ingredients were molecularly docked. Results. 88 potential therapeutic targets of KTC for PCOS were discovered by intersecting the potential targets, DEGs, and therapeutic targets. According to bioinformatics analysis, the mechanisms of KTC treatment for PCOS could be linked to IL-17 signaling route, p53 signaling pathway, HIF-1 signaling pathway, etc. The minimal binding energies of the 5 core targets and their corresponding ingredients were all less than -6.5. Further research found that quercetin may replace KTC in the treatment of PCOS. Discussion and Conclusions. We explored the active ingredients and molecular mechanisms of KTC in the treatment of PCOS and found that quercetin may be the core ingredient of KTC in the treatment of PCOS.

The aim of the current study was to investigate the effect of SB202190, a specific inhibitor of p38 MAPK signaling pathway, on the expression levels of IL-6 and NF-κB in flap ischemia-reperfusion injury. Healthy Sprague-Dawley rats were randomly divided into four groups of 12 each. For the ischemia-reperfusion group, the flap was constructed and then sutured after 8 h of ischemia. For the saline group, rats were intraperitoneally infused with saline at regular intervals after flap ischemia-reperfusion. For the inhibitor group, rats were intraperitoneally infused with SB202190 at regular intervals after flap ischemia-reperfusion. For the control group, the flap was constructed and then sutured immediately. The flap survival rate of each group was measured after 7 days. The concentration of IL-6 in serum was measured by ELISA kit. The mRNA and protein expression levels of IL-6 and NF-κB in the flap were measured using RT-PCR and western blot analysis, respectively. In the ischemia-reperfusion group and the saline group, the flap survival rates were much lower than that in the control group (P<0.05). By contrast, the mRNA and protein expression levels of IL-6 and NF-κB in the flap and the concentration of IL-6 in serum were much higher (P<0.05). In the inhibitor group, the flap survival rate was significantly higher than those in the ischemia-reperfusion and saline groups (P<0.05). By contrast, the concentration of IL-6 in serum and the mRNA and protein expression levels of NF-κB and IL-6 in the flap were significantly decreased (P<0.05). The results show that, SB202190 played a role in the protection of the flap by reducing the inflammatory response in flap ischemia-reperfusion injury.