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Cellular senescence is a natural barrier to tumorigenesis and it contributes to the antitumor effects of several therapies, including radiation and chemotherapeutic drugs. Senescence also plays an important role in aging, fibrosis, and tissue repair. The DNA damage response is a key event leading to senescence, which is characterized by the senescence-associated secretory phenotype (SASP) that includes expression of inflammatory cytokines. Here we show that cGMP-AMP (cGAMP) synthase (cGAS), a cytosolic DNA sensor that activates innate immunity, is essential for senescence. Deletion of cGAS accelerated the spontaneous immortalization of mouse embryonic fibroblasts. cGAS deletion also abrogated SASP induced by spontaneous immortalization or DNA damaging agents, including radiation and etoposide. cGAS is localized in the cytoplasm of nondividing cells but enters the nucleus and associates with chromatin DNA during mitosis in proliferating cells. DNA damage leads to accumulation of damaged DNA in cytoplasmic foci that contain cGAS. In human lung adenocarcinoma patients, low expression of cGAS is correlated with poor survival. These results indicate that cGAS mediates cellular senescence and retards immortalization. This is distinct from, and complementary to, the role of cGAS in activating antitumor immunity.ellular senescence is a state of irreversible cell cycle arrest triggered by various types of cellular and environmental stress, such as telomere shortening, oncogene activation, and DNA damage (1, 2). Senescence appears to be an antiproliferation process that limits the growth of damaged cells and acts as a potent barrier to tumorigenesis (3, 4). Senescence is characterized by several unique features, including enlarged and flattened cell morphology (5), increased senescence-associated β-galactosidase (SA-β-Gal) activity (6, 7), and in some cell types, a widespread change in chromatin modification, known as senescence-associated heterochromatin foci (SAHF) (7). At the molecular level, the p53-p21 WAF1 and pRb-p16 INK4a tumor suppressor pathways have been reported to be key mechanisms that control the execution and maintenance of senescence (8,9). In addition to these cellular features, senescent cells also undergo massive changes in the expression of genes that are thought to affect the tissue microenvironment (5). Senescent cells secrete a variety of soluble factors including inflammatory cytokines, growth factors, and proteases; such senescence-associated secretory phenotype (SASP) is a hallmark of senescence (10-12).Components of SASP not only serve as a marker of senescence, but also participate in the senescence process (13). Interleukin 6 (IL6) and IL8, two key components of SASP, reinforce the senescence growth arrest in neighboring cells (14,15). Additionally, these cytokines and other secreted factors attract immune cells, leading to the elimination of senescent cells (16). Given these important functions, SASP is regulated at both transcriptional and epigenetic levels, such as by nuclear factor κB (NF...

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The regulation of AMPK in the ischemic heart remains incompletely understood. Recent evidence implicates the role of Sestrin2 in the AMPK signaling pathway, and it is hypothesized that Sestrin2 plays an influential role during myocardial ischemia to promote AMPK activation. Sestrin2 protein was found to be expressed in adult cardiomyocytes and accumulated in the heart during ischemic conditions. Sestrin2 knockout (KO) mice were used to determine the importance of Sestrin2 during ischemia and reperfusion (I/R) injury. When wild-type (WT) and Sestrin2 KO mice were subjected to in vivo I/R, myocardial infarct size was significantly greater in Sestrin2 KO compared with WT hearts. Similarly, Langendorff perfused hearts indicated exacerbated postischemic contractile function in Sestrin2 KO hearts compared with WT. Ischemic AMPK activation was found to be impaired in the Sestrin2 KO hearts. Immunoprecipitation of Sestrin2 demonstrated an association with AMPK. Moreover, liver kinase B1 (LKB1), a major AMPK upstream kinase, was associated with the Sestrin2-AMPK complex in a timedependent manner during ischemia, whereas this interaction was nearly abolished in Sestrin2 KO hearts. Thus, Sestrin2 plays an important role in cardioprotection against I/R injury, serving as an LKB1-AMPK scaffold to initiate AMPK activation during ischemic

Background: Emerging evidence indicates that inflammasome-induced inflammation plays a crucial role in the pathogenesis of Parkinson's disease (PD). Several proteins including α-synuclein trigger the activation of NLRP3 inflammasome. However, few studies examined whether inflammasomes are activated in the periphery of PD patients and their possible value in the diagnosis or tracking of the progress of PD. The aim of this study was to determine the association between inflammasome-induced inflammation and clinical features in PD. Methods: There were a total of 67 participants, including 43 patients with PD and 24 controls, in the study. Participants received a complete evaluation of motor and non-motor symptoms, including Hoehn and Yahr (H-Y) staging scale. Blood samples were collected from all participants. The protein and mRNA expression levels of inflammasomes subtypes and components in peripheral blood mononuclear cells (PBMCs) were determined using western blotting and RT-qPCR. We applied Meso Scale Discovery (MSD) immunoassay to measure the plasma levels of IL-1β and α-synuclein. Results: We observed increased gene expression of NLRP3, ASC, and caspase-1 in PBMCs, and increased protein levels of NLRP3, caspase-1, and IL-1β in PD patients. Plasma levels of IL-1β were significantly higher in patients with PD compared with controls and have a positive correlation with H-Y stage and UPDRS part III scores. Furthermore, plasma α-synuclein levels were also increased in PD patients and have a positive correlation with both UPDRS part III scores and plasma IL-1β levels. Conclusions: Our data demonstrated that the NLRP3 inflammasome is activated in the PBMCs from PD patients. The related inflammatory cytokine IL-1β and total α-synuclein in plasma were increased in PD patients than controls, and both of them presented a positive correlation with motor severity in patients with PD. Furthermore, plasma α-synuclein levels have a positive correlation with IL-1β levels in PD patients. All these findings suggested that the NLRP3 inflammasome activation-related cytokine IL-1β and α-synuclein could serve as non-invasive biomarkers to monitor the severity and progression of PD in regard to motor function.

Summary Antithrombin (AT) is a protein of the serpin superfamily involved in regulation of the proteolytic activity of the serine proteases of the coagulation system. AT is known to exhibit anti-inflammatory and cardioprotective properties when it binds to heparan sulfate proteoglycans (HSPGs) on vascular cells. AMP-activated protein kinase (AMPK) plays an important cardioprotective role during myocardial ischemia and reperfusion (I/R). To determine whether the cardioprotective signaling function of AT is mediated through the AMPK pathway, we evaluated the cardioprotective activities of wild-type AT and its two derivatives, one having high affinity and the other no affinity for heparin, in an acute I/R injury model in C57BL/6J mice in which the left anterior descending coronary artery was occluded. The serpin derivatives were given 5 min before reperfusion. The results showed that AT-WT can activate AMPK in both in vivo and ex vivo conditions. Blocking AMPK activity abolished the cardioprotective function of AT against I/R injury. The AT derivative having high affinity for heparin was more effective in activating AMPK and in limiting infraction, but the derivative lacking affinity for heparin was inactive in eliciting AMPK-dependent cardioprotective activity. Activation of AMPK by AT inhibited the inflammatory c-Jun N-terminal protein kinase (JNK) pathway during I/R. Further studies revealed that the AMPK activity induced by AT also modulates cardiac substrate metabolism by increasing glucose oxidation but inhibiting fatty acid oxidation during I/R. These results suggest that AT binds to HSPGs on heart tissues to invoke a cardioprotective function by triggering cardiac AMPK activation, thereby attenuating JNK inflammatory signaling pathways and modulating substrate metabolism during I/R.

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