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Resveratrol, a natural compound extracted from the skins of grapes, berries, or other fruits, has been shown to have anti-tumor effects against multiple myeloma (MM) via promoting apoptosis and inhibiting cell viability. In addition to apoptosis, autophagy also plays a significant role in anti-tumor effects. However, whether autophagy is involved in anti-MM activity of resveratrol remains unclear. In this study, human MM cell lines U266, RPMI-8226, and NCI-H929 were treated with resveratrol. Cell Counting Kit-8 assay and colony formation assay were used to measure cell viability. Western blot analysis was used to detect apoptosis- and autophagy-associated proteins. 3-Methyladenine (3-MA) was applied to inhibit autophagy. Results showed that resveratrol inhibited cell viability and colony formation via promoting apoptosis and autophagy in MM cell lines U266, RPMI-8226, and NCI-H929. Resveratrol promoted apoptosis-related proteins, Caspase-3 activating poly-ADP-ribose polymerase and Caspase-3 cleavage, and decreased the protein level of Survivin in a dose-dependent manner. Additionally, resveratrol upregulated the levels of LC3 and Beclin1 in a dose-dependent way, indicating that autophagy might be implicated in anti-MM effect of resveratrol. Furthermore, 3-MA relieved the cytotoxicity of resveratrol by blocking the autophagic flux. Resveratrol increased the phosphorylation of adenosine monophosphate (AMP)-activated protein kinase and decreased the phosphorylation of mammalian target of rapamycin (mTOR) and its downstream substrates p70S6K and 4EBP1 in a dose-dependent manner, leading to autophagy. Therefore, our results suggest that resveratrol exerts anti-MM effects through apoptosis and autophagy, which can be used as a new therapeutic strategy for MM in clinic., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Chronic inflammation and infection in the tissue surrounding implants after total joint replacement is closely associated with the innate immune response to surgical implants. Wear particles are known to increase apoptosis and impair the innate immunity in macrophages, which can cause immunosuppression around the implants. Excessive autophagy can induce apoptosis. However, the link between autophagy and apoptosis in macrophages during chronic inflammation and infection remains unknown. In this study, we investigated the autophagy and apoptosis induced by titanium particles in RAW264.7 macrophages, and in the interface membrane of patients with late-onset periprosthetic joint infection (PJI). We found that titanium particles stimulated autophagy and apoptosis in macrophages. Inhibition of autophagy significantly reduced titanium particle-induced apoptosis in macrophages, which may be related to the PI3K/Akt signaling pathway. The secretion of inflammatory factors, such as IL-1β, IL-6, and TNF-α, decreased after inhibition of autophagy in titanium particle-stimulated macrophages, which may be caused by immune dysfunction due to titanium particle-induced autophagy and apoptosis in macrophages. Furthermore, our in vivo mouse calvarial model also showed that autophagy inhibitors lowered the rate of cell apoptosis. Our findings indicate that wear particle-induced apoptosis may be caused by enhanced autophagy in macrophages, which could potentially impair the local innate immunity in periprosthetic tissues and could be a risk factor for PJI. Based on these results, autophagy modulators may act as a new therapeutic option for PJI., (© 2020 Wiley Periodicals, Inc.)

Multiple myeloma (MM), the seco nd most common haematological malignancy, is currently incurable because patients often develop multiple drug resistance and experience subsequent relapse of the disease. This study aims to identify a potential therapeutic agent that can counter bortezomib (BTZ) resistance in MM. DCZ0358, a novel alkaloid compound, is found to exert potent cytotoxic effects against BTZ-resistant MM cells in vivo and in vitro. The anti-myeloma activity of DCZ0358 is associated with inhibition of cell proliferation, promotion of cell apoptosis via caspase-mediated apoptotic pathways, and induction of G0/G1 phase arrest via downregulation of cyclin D1, CDK4, and CDK6. Further investigation of the molecular mechanism shows that DCZ0358 suppresses the JAK2/STAT3 signaling pathway. In conclusion, DCZ0358 can successfully counter BTZ resistance in MM cells. This study provides evidence that warrants future preclinical assessments of DCZ0358 as a therapeutic agent against BTZ resistance in MM.

• DCZ0014 inhibits cell proliferation by inducing apoptosis and cell cycle arrest. • Lyn/Syk in the B cell receptor signaling pathway are regulated in DCZ0014-induced apoptosis. • DCZ0014 inhibits tumor growth in the xenograft model of DLBCL cells. Diffuse large B cell lymphoma (DLBCL) is a clinical and genetically heterogeneous lymphoid malignancy. Although R-CHOP (rituximab plus cyclophosphamide, vincristine, doxorubicin, and prednisone) treatment can improve the survival rate of patients with DLBCL, more than 30% of patients exhibit treatment failure, relapse, or refractory disease. Therefore, novel drugs or targeted therapies are needed to improve the survival of patients with DLBCL. The compound DCZ0014 is a novel chemical similar to berberine. In this study, we found that DCZ0014 significantly inhibited the proliferation and activity of DLBCL cells, and induced cell apoptosis. Following treatment with DCZ0014, DLBCL cells accumulated in G0/G1-phase of the cell cycle and showed decreased mitochondrial membrane potential. Additionally, DCZ0014 inhibited DNA synthesis, enhanced DNA damage in DLBCL cells, as well as inhibited Lyn/Syk in B cell receptor signaling pathway. Further experiments demonstrated that DCZ0014 did not significantly affect peripheral blood mononuclear cells. Tumor xenograft model showed that DCZ0014 not only inhibited tumor growth but also extended the survival time of mice. Thus, DCZ0014 showed potential for clinical application in the treatment of patients with DLBCL. [ABSTRACT FROM AUTHOR]