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25th International Conference on Material Forming, ESAFORM 2022, Braga, Portugal, 27 Apr 2022 - 29 Apr 2022; Key engineering materials : KEM 926, 917-925 (2022). doi:10.4028/p-dds916 special issue: "[25th International Conference on Material Forming, ESAFORM, 2022-04-27 - 2022-04-29, Braga, Portugal]", Published by Trans Tech Publications, Baech

Funding Information: The authors gratefully acknowledge the valuable comments by Prof. Sebastian Münstermann from Steel Institute (IEHK), RWTH Aachen University, Germany. The work has been supported by the European Commission Research Fund for Coal and Steel (No. 709711). Wenqi Liu is grateful to Shujing Li and Guangming Zeng from IEHK for data processing. Publisher Copyright: © 2021, The Author(s). Copyright: Copyright 2021 Elsevier B.V., All rights reserved. This study aims to discover the stress-state dependence of the dynamic strain aging (DSA) effect on the deformation and fracture behavior of high-strength dual-phase (DP) steel at different deformation temperatures (25–400°C) and reveal the damage mechanisms under these various configurations. To achieve different stress states, predesigned specimens with different geometric features were used. Scanning electron microscopy was applied to analyze the fracture modes (e.g., dimple or shear mode) and underlying damage mechanism of the investigated material. DSA is present in this DP steel, showing the Portevin-Le Chatelier (PLC) effect with serrated flow behavior, thermal hardening, and blue brittleness phenomena. Results show that the stress state contributes distinctly to the DSA effect in terms of the magnitude of thermal hardening and the pattern of blue brittleness. Either low stress triaxiality or Lode angle parameter promotes DSA-induced blue brittleness. Accordingly, the damage mechanisms also show dependence on the stress states in conjunction with the DSA effect.

Targeting the Trp-Kyn pathway is an attractive approach for cancer immunotherapy. Thioredoxin reductase (TrxR) enzymes are reactive oxygen species (ROS) modulators that are involved in the tumor cell growth and survival processes. The 4-phenylimidazole scaffold is well-established as useful for indoleamine 2,3-dioxygenase 1 (IDO1) inhibition, while piperlongumine (PL) and its derivatives have been reported to be inhibitors of TrxR. To take advantage of both immunotherapy and TrxR inhibition, we designed a first-generation dual IDO1 and TrxR inhibitor (ZC0101) using the structural combination of 4-phenylimidazole and PL scaffolds. ZC0101 exhibited better dual inhibition against IDO1 and TrxR in vitro and in cell enzyme assays than the uncombined forms of 4-phenylimidazole and PL. It also showed antiproliferative activity in various cancer cell lines, and a selective killing effect between normal and cancer cells. Furthermore, ZC0101 effectively induced apoptosis and ROS accumulation in cancer cells. Knockdown of TrxR1 and IDO1 expression induced cellular enzyme inhibition and ROS accumulation effects during ZC0101 treatment, but only reduced TrxR1 expression was able to improve ZC0101's antiproliferation effect. This proof-of-concept study provides a novel strategy for cancer treatment. ZC0101 represents a promising lead compound for the development of novel antitumor agents that can also be used as a valuable probe to clarify the relationships and mechanisms of cancer immunotherapy and ROS modulators.

With the aim of discovering novel cyclin-dependent kinase 8 (CDK8) inhibitors, a combined similarity search and molecular docking approach was employed, which led to 32 hits. Biological tests led to the discovery of several novel submicromolar inhibitors. In particular, compound C768-0769 (ZC0201) showed good CDK8 inhibitory activity, and compound ZC0201 effectively suppressed HCT-116 colorectal cancer cell proliferation by inducing G1/S transition arrest. Furthermore, modulation of phosphorylated signal transducer and activator of transcription 1 (Ser 727) (STAT1SER727), a pharmacodynamic biomarker of CDK8 activity, demonstrated that ZC0201 may cause G1/S transition arrest through CDK8 activity inhibition. Due to its good cellular activity, ZC0201 may be an ideal lead compound for further modification as a potential cancer therapeutic agent.

Multidrug resistance (MDR) is a major concern when using chemotherapy for the treatment of patients with colorectal cancer. MDR modulators are agents that can reverse MDR and, thus, enhance the chemosensitivity of tumor cells. The development of MDR modulators can improve the therapeutic efficacies of MDR in cancer. However, few effective MDR modulators have been identified so far. Curcumin has been reported to be an effective compound in the reversal of MDR in colorectal cancer cells. However, the mechanisms associated with the reversal effect of curcumin on MDR and its regulation of target factors in MDR cells remain to be fully elucidated. 3-(4,5-dimethyl-2-thiazol)-2,5-diphenyltetrazolium bromide assays, flow cytometer apoptosis assays as well as mRNA and protein expression assays were performed in the present study, and the results confirmed the reversal effect of curcumin on HCT-8/5-Fu cells and provided evidence that activated nuclear factor erythroid 2-related factor (Nrf2) deficiency induced by the curcumin altered the B-cell lymphoma 2 (Bcl-2) associated X protein/Bcl-2 expression ratio, which led to the induction of apoptosis in HCT-8/5-Fu cells. These results indicated that Nrf2 may have a functional in the reversal effect of curcumin and contribute, at least in part, to the outcomes of chemotherapy in patients with MDR.