Single-Atom Cu Nanozyme-Loaded Bone Scaffolds for Ferroptosis-Synergized Mild Photothermal Therapy in Osteosarcoma Treatment.

The rapid multiplication of residual tumor cells and poor reconstruction quality of new bone are considered the major challenges in the postoperative treatment of osteosarcoma. It is a promising candidate for composite bone scaffold which combines photothermal therapy (PTT) and bone regeneration induction for the local treatment of osteosarcoma. However, it is inevitable to damage the normal tissues around the tumor due to the hyperthermia of PTT, while mild heat therapy shows a limited effect on antitumor treatment as the damage can be easily repaired by stress-induced heat shock proteins (HSP). This study reports a new type of single-atom Cu nanozyme-loaded bone scaffolds, which exhibit exceptional photothermal conversion properties as well as peroxidase and glutathione oxidase mimicking activities in vitro experiments. This leads to lipid peroxidation (LPO) and reactive oxygen species (ROS) upregulation, ultimately causing ferroptosis. The accumulation of LPO and ROS also contributes to HSP70 inactivation, maximizing PTT efficiency against tumors at an appropriate therapeutic temperature and minimizing the damage to surrounding normal tissues. Further, the bone scaffold promotes bone regeneration via a continuous release of bioactive ions (Ca2+, P5+, Si4+, and Cu2+). The results of in vivo experiments reveal that scaffolds inhibit tumor growth and promote bone repair.

Tanshinone I inhibits the growth and metastasis of osteosarcoma via suppressing JAK/STAT3 signalling pathway.

Tanshinone I (Tan I) is a widely used diterpene compound derived from the traditional Chinese herb Danshen. Increasing evidence suggests that it exhibits anti-cancer activity in various human cancers. However, the in vitro and in vivo effects of Tan I on osteosarcoma (OS) remain inadequately elucidated, especially those against tumour metastasis. Our results showed that Tan I significantly inhibited OS cancer cell proliferation, migration and invasion and induced cell apoptosis in vitro. Moreover, treatment with 10 and 20 mg/kg Tan I effectively suppressed tumour growth in subcutaneous xenografts and orthotopic xenograft mouse models. In addition, Tan I significantly inhibited tumour metastasis in intracardiac inoculation xenograft models. The results also showed that Tan I-induced increased expression of the proapoptotic gene Bax and decreased expression of the anti-apoptotic gene Bcl-2 is the possible mechanism of its anti-cancer effects. Tan I was also found to abolish the IL-6-mediated activation of the JAK/STAT3 signalling pathway. Conclusively, this study is the first to show that Tan I suppresses OS growth and metastasis in vitro and in vivo, suggesting it may be a potential novel and efficient drug candidate for the treatment of OS progression.

Discovery of betulinaldehyde as a natural RORγt agonist.

Retinoic Acid Receptor-Related Orphan Receptor γt (RORγt) is a dual-functional therapeutic target. The agonists and inhibitors of RORγt are potential agents for tumor immunotherapy and autoimmune diseases, respectively, and sometimes share similar scaffolds. Although the widely distributed triterpenoid ursolic acid (UA) has been identified as a RORγt inhibitor, the report of a triterpenoid RORγt agonist is still absent. By screening an in-house triterpenoid library, we uncovered a novel RORγt agonist, betulinaldehyde (1), together with an inhibitor (2, 3ß, 28-Dihydroxy-lupan-29-oic acid). Compound 1 showed a good RORγt activating effect with the EC50 of 11.4 µM in Alpha Screen assay, and altered the thermal stability of RORγt by directly binding to the protein in vitro. Combined with the SPR assay, the Kd value of compound 1 was examined as 2.99 µM. The modulation mechanism of triterpenoid agonists and inhibitors were discussed by molecular docking. Herein, we firstly discovered compound 1 as a triterpenoid agonist of RORγt. The co-distribution of triterpenoid RORγt agonist and inhibitors in the same plant, might be related to the anti-inflammatory and anti-cancerous bioactivity of the plant extract.

Discovery of novel DNA methyltransferase 3A inhibitors via structure-based virtual screening and biological assays.

DNA methyltransferases are involved in diverse biological processes and abnormal methylation patterns play essential roles in cancer initiation and progression. DNA methyltransferase 3A (DNMT3A) acting as a de novo DNA methyltransferase, has gained widespread attention especially in haematological diseases. To date, large numbers of DNMTs inhibitors have been discovered, however, the small molecular inhibitors targeting DNMT3A are still in its infancy. In this study, structure-based virtual screening in combination with biological assays was performed to discovery potent novel DNMT3A inhibitors. Compound 40 and 40_3 displayed comparable in vitro inhibitory activity against DNMT3A with IC50 values of 46.5µM and 41µM, respectively. Further binding mode analysis suggested these molecules inhibit DNMT3A activity through binding the S-adenosyl-l-methionine (SAM) pocket. Overall, 40 and 40_3 may serve as novel scaffolds for further optimization and small molecular probes for investigating DNMT3A function.