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Background: The failure of novel therapies effective in preclinical animal models largely reflects the fact that current models do not really mimic the pathological/therapeutic features of glioblastoma (GBM), in which the most effective temozolomide chemoradiotherapy (RT/TMZ) regimen can only slightly extend survival. How to improve RT/TMZ efficacy remains a major challenge in clinic. Methods: Syngeneic G422TN-GBM model mice were subject to RT/TMZ, surgery, piperlongumine (PL), αPD1, glutathione. Metabolomics or transcriptomics data from G422TN-GBM and human GBM were used for gene enrichment analysis and estimation of ROS generation/scavenging balance, oxidative stress damage, inflammation and immune cell infiltration. Overall survival, bioluminescent imaging, immunohistochemistry, and immunofluorescence staining were used to examine therapeutic efficacy and mechanisms of action. Results: Here we identified that glutathione metabolism was most significantly altered in metabolomics analysis upon RT/TMZ therapies in a truly refractory and reliable mouse triple-negative GBM (G422TN) preclinical model. Consistently, ROS generators/scavengers were highly dysregulated in both G422TN-tumor and human GBM. The ROS-inducer PL synergized surgery/TMZ, surgery/RT/TMZ or RT/TMZ to achieve long-term survival (LTS) in G422TN-mice, but only one LTS-mouse from RT/TMZ/PL therapy passed the rechallenging phase (immune cure). Furthermore, the immunotherapy of RT/TMZ/PL plus anti-PD-1 antibody (αPD1) doubled LTS (50%) and immune-cured (25%) mice. Glutathione completely abolished PL-synergistic effects. Mechanistically, ROS reduction was associated with RT/TMZ-resistance. PL restored ROS level (mainly via reversing Duox2/Gpx2), activated oxidative stress/inflammation/immune responses signature genes, reduced cancer cell proliferation/invasion, increased apoptosis and CD3+/CD4+/CD8+ T-lymphocytes in G422TN-tumor on the basis of RT/TMZ regimen. Conclusion: Our findings demonstrate that PL reverses RT/TMZ-reduced ROS and synergistically resets tumor microenvironment to cure GBM. RT/TMZ/PL or RT/TMZ/PL/αPD1 exacts effective immune cure in refractory GBM, deserving a priority for clinical trials. [ABSTRACT FROM AUTHOR]

A visible‐light‐driven and room temperature photo‐Wolff‐Kischner reaction of sulfur ylides and N‐tosylhydrazones has been developed for the first time to provide modular access to alkene synthesis. The high functional group tolerance and broad substrate scope were demonstrated by more than 60 examples. Both E‐ and Z‐olefinic stereochemistry in the products could be controlled with excellent stereoselectivity. A series of mechanistic studies support that the reaction should proceed through a radical‐carbanion crossover pathway, specifically involving addition of photo‐generated sulfur ylide radical cations to N‐tosylhydrazones to form carbanions and subsequent Wolff‐Kischner process. [ABSTRACT FROM AUTHOR]

Low-cost formate salt was used as the reductant and part of the carboxyl source in a visible-light-driven dicarboxylation of diverse alkenes, including simple styrenes. The highly competing hydrocarboxylation side reaction was successfully overridden. Good yields of products were obtained under mild reaction conditions at ambient temperature and pressure of CO 2 . The dual role of formate salt may stimulate the discovery of a range of new transformations under mild and friendly conditions., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)