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Hypoxia and interactions with bone marrow (BM) stromal cells have emerged as essential components of the leukemic BM microenvironment in promoting leukemia cell survival and chemoresistance. High levels of transforming growth factor beta 1 (TGFβ1) produced by BM stromal cells in the BM niche regulate cell proliferation, survival, and apoptosis, depending on the cellular context. Exogenous TGFβ1 induced accumulation of acute myeloid leukemia (AML) cells in a quiescent G0 state, which was further facilitated by the co-culture with BM-derived mesenchymal stem cells (MSCs). In turn, TGFβ-neutralizing antibody 1D11 abrogated rhTGFβ1 induced cell cycle arrest. Blocking TGFβ with 1D11 further enhanced cytarabine (Ara-C)-induced apoptosis of AML cells in hypoxic and in normoxic conditions. Additional constituents of BM niche, the stroma-secreted chemokine CXCL12 and its receptor CXCR4 play crucial roles in cell migration and stroma/leukemia cell interactions. Treatment with 1D11 combined with CXCR4 antagonist plerixafor and Ara-C decreased leukemia burden and prolonged survival in an in vivo leukemia model. These results indicate that blockade of TGFβ by 1D11 and abrogation of CXCL12/CXCR4 signaling may enhance the efficacy of chemotherapy against AML cells in the hypoxic BM microenvironment.

Coumestan represents a biologically relevant structural motif distributed in a number of natural products, and the rapid construction of related derivatives as well as the characterization of targets would accelerate lead compound discovery in medicinal chemistry. In this work, a general and scalable approach to 8,9‐dihydroxycoumestans via two‐electrode constant current electrolysis was developed. The application of a two‐phase (aqueous/organic) system plays a crucial role for success, protecting the sensitive o‐benzoquinone intermediates from over‐oxidation. Based on the structurally diverse products, a primary SAR study on coumestan scaffold was completed, and compound 3 r exhibited potent antiproliferative activities and a robust topoisomerase I (Top1) inhibitory activity. Further mechanism studies demonstrates that compound 3 r was a novel Top1 poison, which might open an avenue for the development of Top1‐targeted antitumor agent. [ABSTRACT FROM AUTHOR]

A fundamental regulatory framework to elucidate the role of electrical stimulation (ES) in reducing long production cycles, enhancing protein utilization, and boosting product quality of dry-cured ham is essential. However, how mitochondria and enzymes in meat fibers are altered by ES during post-processing, curing, and fermentation procedures remains elusive. This study sought to explore the impact of ES on the regulation of heat shock proteins (HSP27, HSP70), apoptotic pathways, and subsequent influences on dry-cured pork loin quality. The gathered data validated the hypothesis that ES notably escalates mitochondrial oxidative stress and accelerates mitochondrial degradation along the ripening process. The proapoptotic response in ES-treated samples was increased by 120.7%, with a cellular apoptosis rate 5-fold higher than that in control samples. This mitochondrial degradation is marked by increased ratios of Bax/Bcl-2 protein along the time course, indicating that apoptosis could contribute to the dry-cured ham processing. ES was shown to further down-regulate HSP27 and HSP70, establishing a direct correlation with the activation of mitochondrial apoptosis pathways, accompanied by dry-cured ham quality improvements. The findings show that ES plays a crucial role in facilitating the ripening of dry-cured ham by inducing mitochondrial apoptosis to reduce HSP expression. This knowledge not only explains the fundamental mechanisms behind myofibril degradation in dry-cured ham production but also offers a promising approach to enhance quality and consistency. [ABSTRACT FROM AUTHOR]