Zhaochen Ning

Background Tumor cells continue to evolve the metastatic potential in response to signals provided by the external microenvironment during metastasis. Platelets closely interact with tumor cells during hematogenous metastasis and facilitate tumor development. However, the molecular mechanisms underlying this process are not fully understood. Methods RNA-sequencing was performed to screen differentially expressed genes mediated by platelets. The effects of platelet and CD39 on tumor metastasis were determined by experimental metastasis models with WT, NCG and CD39^−/− mice. Results RNA-sequencing results showed that platelets significantly up-regulated CD39 expression in tumor cells. CD39 is a novel immune checkpoint molecule and a key driver of immunosuppression. Our data provided evidence that the expression of CD39 was enhanced by platelets in a platelet-tumor cell contact dependent manner. Although the role of CD39 expressed by immune cells is well established, the effect of CD39 expressed by tumor cells on tumor cell behavior, anti-tumor immunity and tumor metastasis is unclear. We found that CD39 promoted tumor cell invasion, but had no effect on proliferation and migration. Notably, we showed that the ability of platelets to prime tumor cells for metastasis depends on CD39 in the experimental tumor metastasis model. CD39 silencing resulted in fewer experimental metastasis formation, and this anti-metastasis effect was significantly reduced in platelet-depleted mice. Furthermore, overexpression of CD39 in tumor cells promoted metastasis. In order to eliminate the effect of CD39 expressed in cells other than tumor cells, we detected tumor metastasis in CD39^−/− mice and obtained similar results. Moreover, overexpression of CD39 in tumor cells inhibited antitumor immunity. Finally, the data from human samples also supported our findings. Conclusions Our study shows that direct contact with platelets induces CD39 expression in tumor cells, leading to immune suppression and promotion of metastasis.

Endotoxin shock remains one of the major causes of mortality worldwide. Pyruvate dehydrogenase kinase (PDK) 2 is an important regulatory enzyme involved in glucose metabolism. The purpose of this study was to determine the regulatory effect of PDK2 on LPS-induced endotoxin shock and explore the mechanisms in vivo and in vitro. Here, we showed that PDK2 contributed to Toll-like receptor (TLR)-mediated inflammation. Lipopolysaccharide (LPS) activation of TLR4 pathways resulted in PDK2 upregulation in macrophages and dendritic cells (DCs). PDK2 overexpression enhanced TLR4 signaling pathway activation, whereas downregulating PDK2 expression inhibited TLR4 signaling pathway activation. Pharmacological inhibition of PDK2 significantly decreased the mortality rate and alleviated pathological injury in the lungs and livers of LPS-challenged mice, while significantly suppressing proinflammatory cytokine production. Thus, we confirmed that PDK2 is involved in LPS-induced endotoxin shock by modulating TLR4-mitogen-activated protein kinase signaling and inducing the production of proinflammatory cytokines in macrophages and DCs. Our findings highlight the importance of PDK2 as a novel target to treat septic shock.

Background: Tetrahydroxystilbene glucoside (TSG) is a main bioactive component of Polygonum multiflorum, a traditional Chinese medicine known for certain anti-aging effects. Since TSG has been found to extend lifespan in the nematode Caenorhabditis elegans, we hypothesized that TSG might produce anti-aging benefits in mammals. Objective: The aim was to evaluate the anti-aging potential of TSG and to explore its relative molecular mechanism. Methods: Mice were maintained on standard diet, high-calorie diet (HC), or high-calorie plus TSG diet. Survival rates and body weight changes were recorded weekly. Rotarod analysis was performed to assess the physical fitness of mice. Bone mineral density was assessed using micro-computed tomography. Hematoxylin and eosin staining was used for the histological examination of heart, liver, and kidney pathology. The mRNA and protein expression of target genes were analyzed by quantitative real-time polymerase chain reaction and western blotting, respectively. Mitotracker deep red staining and high-content analysis were used to quantify cellular mitochondrial mass and function. Results: In this study, we found that TSG improved the physiology of aged mice consuming excess calories and delayed senile symptoms. The anti-aging benefits of TSG were mediated at least in part by the AMP-activated protein kinase (AMPK)/sirtuin 1 (SIRT1)/peroxisome proliferator-activated receptor-γ coactivator 1α (PGC-1α) signaling cascade, leading to significant improvement in motor function, bone mineral density, HC-induced organ pathology, and mitochondrial function. Conclusion: Our findings show that TSG could be a potential drug candidate for the treatment of aging- and high-calorie intake-associated disorders.