Cytosolic DNA initiates a vicious circle of aging-related endothelial inflammation and mitochondrial dysfunction via STING: the inhibitory effect of Cilostazol.

Endothelial senescence, aging-related inflammation, and mitochondrial dysfunction are prominent features of vascular aging and contribute to the development of aging-associated vascular disease. Accumulating evidence indicates that DNA damage occurs in aging vascular cells, especially in endothelial cells (ECs). However, the mechanism of EC senescence has not been completely elucidated, and so far, there is no specific drug in the clinic to treat EC senescence and vascular aging. Here we show that various aging stimuli induce nuclear DNA and mitochondrial damage in ECs, thus facilitating the release of cytoplasmic free DNA (cfDNA), which activates the DNA-sensing adapter protein STING. STING activation led to a senescence-associated secretory phenotype (SASP), thereby releasing pro-aging cytokines and cfDNA to further exacerbate mitochondrial damage and EC senescence, thus forming a vicious circle, all of which can be suppressed by STING knockdown or inhibition. Using next-generation RNA sequencing, we demonstrate that STING activation stimulates, whereas STING inhibition disrupts pathways associated with cell senescence and SASP. In vivo studies unravel that endothelial-specific Sting deficiency alleviates aging-related endothelial inflammation and mitochondrial dysfunction and prevents the development of atherosclerosis in mice. By screening FDA-approved vasoprotective drugs, we identified Cilostazol as a new STING inhibitor that attenuates aging-related endothelial inflammation both in vitro and in vivo. We demonstrated that Cilostazol significantly inhibited STING translocation from the ER to the Golgi apparatus during STING activation by targeting S162 and S243 residues of STING. These results disclose the deleterious effects of a cfDNA-STING-SASP-cfDNA vicious circle on EC senescence and atherogenesis and suggest that the STING pathway is a promising therapeutic target for vascular aging-related diseases. A proposed model illustrates the central role of STING in mediating a vicious circle of cfDNA-STING-SASP-cfDNA to aggravate age-related endothelial inflammation and mitochondrial damage.

Visible-Light-Induced, Catalyst-Free Monofluoromethyl Sulfonylation of Alkenes with Iodine(III) Reagent and DABSO.

A visible-light-induced radical relay strategy to access heterocycles bearing a monofluoromethylsufonyl moiety is reported, with PhI(OCOCH2F)2 as the CH2F radical precursor and DABSO as the SO2 source. A range of oxindoles, containing a CH2FSO2CH2- group at the C3 position, were synthesized from N-arylacrylamides in up to 97% yields. The protocol features catalyst-free photochemical tandem, mild reaction conditions, broad functional group compatibility, and good to excellent yields.

Melatonin Enhanced the Tolerance of Arabidopsis thaliana to High Light Through Improving Anti-oxidative System and Photosynthesis.

Land plants live in a crisis-filled environment and the fluctuation of sunlight intensity often causes damage to photosynthetic apparatus. Phyto-melatonin is an effective bioactive molecule that helps plants to resist various biotic and abiotic stresses. In order to explore the role of melatonin under high light stress, we investigated the effects of melatonin on anti-oxidative system and photosynthesis of Arabidopsis thaliana under high light. Results showed that exogenous melatonin increased photosynthetic rate and protected photosynthetic proteins under high light. This was mainly owing to the fact that exogenous melatonin effectively decreased the accumulation of reactive oxygen species and protected integrity of membrane and photosynthetic pigments, and reduced cell death. Taken together, our study promoted more comprehensive understanding in the protective effects of exogenous melatonin under high light.

Knockdown of LncRNAZFAS1 suppresses cell proliferation and metastasis in non-small cell lung cancer.

To evaluate the effects of LncRNAZFAS1 on cell proliferation and tumor metastasis in non-small cell lung cancer (NSCLC), we detected the expression level of LncRNAZFAS1 in NSCLC-related tissues and cells. qRT-PCR results revealed that LncRNAZFAS1 in tumor tissues was significantly higher than that in normal lung tissue, especially significantly up-regulated in stage III / IV and in metastatic NSCLC tissues. LncRNAZFAS1 expression was dramatically up-regulated in 4 NSCLC-related cells (A549, SPC-A1, SK-MES-1, and NCI-H1299), with having the highest expression level in A549 cells. Furthermore, we implemented a knockdown of LncRNAZFAS1 in A549 cells, and the results of CCK8 and Transwell assays suggested that knockdown of LncRNAZFAS1 significantly inhibited NSCLC cell proliferation and metastasis. Next, we constructed a tumor xenograft model to evaluate the effect of LncRNAZFAS1 on the NSCLC cell proliferation in vivo. The results indicated that knockdown of LncRNAZFAS1 dramatically inhibited A549 cells proliferation and repressed tumor growth. Additionally, knockdown of LncRNAZFAS1 drastically weakened the expressions of MMP2, MMP9 and Bcl-2 proteins, whereas noticeably strengthened the expression of BAX protein. Our results altogether suggest that knockdown of LncRNAZFAS1 has a negative effect on the proliferation and metastasis of NSCLC cell, which implying LncRNAZFAS1 is a potential unfavorable biomarker in patients with NSCLC.

Long Non-coding RNA DUXAP8 Regulates the Cell Proliferation and Invasion of Non-small-cell Lung Cancer.

To investigate how long non-coding RNAs DUXAP8 (LncRNA DUXAP8) influence the cell proliferation and invasion of non-small-cell lung cancer (NSCLC), we detected the expression levels of LncRNA DUXAP8 in lung cancer (LC) tissues, 4 LC-related cell lines (A549, SPC-A1, SK-MES-1 and NCI-H1299) and normal lung tissues via quantitative real-time PCR (qRT-PCR). Compared with normal lung tissue, LncRNA DUXAP8 was significantly up-regulated in NSCLC, especially in stage III / IV and diameter ≥ 3cm of lung cancer. Among 4 lung cancer cell lines, LncRNA DUXAP8 in A549 cells was the highest (P<0.001). Construction of LncRNA DUXAP8 overexpression and LncRNA DUXAP8 knockout in A549 cell lines was further performed and subsequently injected into nude mice to build an in vivo tumor xenograft model. The results indicated that LncRNA DUXAP8 overexpression significantly promoted the A549 cells' proliferation, enhanced invasion and induced tumor growth. Conversely, LncRNA DUXAP8 knockout significantly suppressed A549 cells' proliferation, weakened invasion and inhibited tumor growth. Taken together, our results imply that LncRNA DUXAP8 is a potential regulatory molecular marker in non-small-cell lung cancer.