Zhang, Z. Z. | Search bioRxiv

bioRxiv2024

Suppressive effects of oroxylin A on intracellular proliferation of Toxoplasma gondii via host cell ERK phosphorylation inhibition

Toxoplasma gondii poses a significant threat to immunocompromised patients, resulting in high mortality rates. Considering the side effects of anti-Toxoplasma drugs, we focused on a potential candidate, oroxylin A (OA), a common component extracted from Astragalus membranaceus and Scutellaria baicalensis which suppressed the growth of T. gondii in vitro and in vivo. Our result demonstrated that OA suppressed T. gondii intracellular proliferation and downregulated phosphorylation of ERK1/2 of T. gondii-infected host cells very similar to the MEK1 specific inhibitor PD98059. Our in silico analysis showed that OA interacts sufficiently with the mammalian MEK1 region where established MEK1 inhibitors like PD98059 and trametinib bind. Moreover, OA improved the survival rate in T. gondii-infected mice. This study proposes that host MEK1 is a novel potential target for anti-Toxoplasma drugs with a new mechanism of action.

microbiology↗

bioRxiv2019

Heterogeneous transcriptome response to DNA damage at single cell resolution.

Cancer cells often heterogeneously respond to genotoxic chemotherapy, leading to fractional killing and chemoresistance1, 2, which remain as the major obstacles in cancer treatment. It is widely believed that DNA damage induces a uniform response in regulating transcription and that cell fate is passively determined by a threshold mechanism evaluating the level of transcriptional responses3. On the contrary to this assumption, here we show that a surprisingly high level of heterogeneity exists in individual cell transcriptome responses to DNA damage, and that these transcriptome variations dictate the cell fate after DNA damage. Many DNA damage response genes, including tumor suppressor p53 targets, were exclusively expressed in only a subset of cells having specific cell fate, producing unique stress responses tailored for the fate that the cells are committed to. For instance, CDKN1A, the best known p53 target inhibiting cell cycle, was specifically expressed in a subset of cells undergoing cell cycle checkpoint, while other pro-apoptotic p53 targets were expressed only in cells undergoing apoptosis. A small group of cells exhibited neither checkpoint nor apoptotic responses, but produced a unique transcriptional program that conferred strong chemoresistance to the cells. The heterogeneous transcriptome response to DNA damage was also observed at the protein level in flow cytometry. Our results demonstrate that cell fate heterogeneity after DNA damage is mediated by distinct transcriptional programs generating fate-specific gene expression landscapes. This finding provides an important insight into understanding heterogeneous chemotherapy responses of cancer cells.

cell biology↗