Ischemic stroke is a common disease with high mortality and morbidity worldwide. One of the important pathophysiological effects of ischemic stroke is apoptosis. A neuroprotective effect is defined as the inhibition of neuronal apoptosis to rescue or delay the infarction in the surviving ischemic penumbra. Resveratrol is a natural polyphenol that reportedly prevents cerebral ischemia injury by regulating the expression of PI3K/AKT/mTOR. Therefore, this study aimed to elucidate the neuroprotective effect of resveratrol on cerebral ischemia/reperfusion injury and to investigate the signaling pathways and mechanisms through which resveratrol regulates apoptosis in the ischemic penumbra. Rats were subjected to middle cerebral artery occlusion for 2 h followed by 24 h reperfusion. Cerebral infarct volume was measured using 2% TTC staining. TUNEL staining was conducted to evaluate neuronal apoptosis. Western blotting and immunohistochemistry were used to detect the proteins involved in the JAK2/STAT3/PI3K/AKT/mTOR pathway. The results suggested that resveratrol significantly improved neurological function, reduced cerebral infarct volume, decreased neuronal damage, and markedly attenuated neuronal apoptosis; these effects were attenuated by the inhibition of PI3K/AKT with LY294002 and JAK2/STAT3 with AG490. We also found that resveratrol significantly upregulated the expression of p-JAK2, p-STAT3, p-AKT, p-mTOR, and BCL-2 and downregulated expression of cleaved caspase-3 and BAX, which was partially reversed by LY294002 and AG490. These results suggested that resveratrol provides a neuroprotective effect against cerebral ischemia/reperfusion injury, which is partially mediated by the activation of JAK2/STAT3 and PI3K/AKT/mTOR. Resveratrol may indirectly upregulate the PI3K/AKT/mTOR pathway by activating JAK2/STAT3.

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LXR-623 (WAY-252623), a liver X receptor agonist, reduces atherosclerotic plaque progression and remarkably inhibits the proliferation of glioblastoma cells, owing to its brain-penetrant ability. However, the role of LXR-623 against the proliferation of other cancer cells and the underlying mechanism remain unknown. Long non-coding RNAs (lncRNAs) serve as novel and crucial regulators that participate in cancer tumorigenesis and diverse biological processes. Here, we report a previously uncharacterized mechanism underlying lncRNA-mediated exocytosis of LXR-623 via the phosphatase and tensin homolog (PTEN)/protein kinase B (AKT)/p53 axis to suppress the proliferation of cancer cells in vitro. We found that LXR-623 significantly inhibited the proliferation and induced apoptosis and cell cycle arrest at S phase in breast cancer cells in a concentration- and time-dependent manner. Experiments using a xenograft mouse model revealed the inhibitory effects of LXR-623 on tumor growth. We used lncRNA microarray to investigate the potential genes regulated by LXR-623. As a result, LINC01125 was found to be significantly upregulated in the cells treated with LXR-623. Gain- and loss-of-function assays were conducted to investigate the anti-proliferation role of LINC01125. LINC01125 knockdown resulted in the inhibition of the cytotoxic effect of LXR-623; in contrast, LINC01125 overexpression significantly enhanced the effect of LXR-623. LXR-623 and LINC01125-mediated anti-growth regulation is, at least in part, associated with the participation of the PTEN/AKT/mouse double minute 2 homolog (MDM2)/p53 pathway. In addition, SF1670, a specific PTEN inhibitor with prolonged intracellular retention, may strongly block the anti-proliferation effect induced by LXR-623 and LINC01125 overexpression. Chromatin immunoprecipitation (ChIP) assay results suggest that p53 binds to the promoter of LINC01125 to strengthen the expression of the PTEN/AKT pathway. Taken together, our findings suggest that LXR-623 possesses significant antitumor activity in breast cancer cells that is partly mediated through the upregulation in LINC01125 expression and enhancement in apoptosis via the PTEN/AKT/MDM2/p53 pathway.

To aim of this was to observe emodin-mediated cytotoxicity and its influence on Rad51 and ERCC1 expressionin non-small cell lung cancer (

Decoy receptor 3 (DcR3), a decoy molecule belonging to the tumor necrosis factor receptor superfamily (TNFRSF), is a soluble receptor that can neutralize the biological effects of three other TNFSF members, namely, Fas ligand (FasL/TNFSF6/CD95L), LIGHT (TNFSF14) and TNF-like molecule 1A (TL1A/TNFSF15). DcR3 expression is increased in tumor cells. As such, DcR3 has been considered a potential biomarker to predict cancer invasion and progression of inflammation. However, the molecular mechanisms of DcR3 in tumor progression and metastasis remain poorly described. In the present study, DcR3 induced cytoskeleton remodeling, inhibited E-cadherin expression, and promoted cancer cell migration. Immunofluorescence and flow cytometry demonstrated that DcR3 expression was increased in hepatoma cells, whereas E-cadherin expression was significantly downregulated. Immunohistochemistry revealed that DcR3 and E-cadherin exhibited an opposite expression pattern between normal and cancerous liver tissues. Moreover, DcR3 treatment promoted IκBα degradation and p65 nuclear translocation. Therefore, the present study uncovered the mechanism underlying the function of DcR3 in cancer cell migration and provides evidence that DcR3 may be a potential target for cancer therapy.