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...

Background: Fucoxanthin (FX), a xanthophyll pigment which occurs in marine brown algae with remarkable biological properties, has been proven to be safe for consumption by animals. Although FX has various pharmacological effects including anti-inflammatory, anti-tumor, anti-obesity, antioxidant, anti-diabetic, anti-malarial, and anti-lipid, in vivo protective effect against sepsis has not been reported. In this study, we aimed at evaluation the efficacy of the FX in a model of sepsis mouse. Methods: FX was successfully isolated from Conticribra weissflogii ND-8 for the first time. The FX was identified by thin-layer chromatography (TLC), high-performance liquid chromatography-mass spectrometry (HPLC-MS), and nuclear magnetic resonance (NMR). Animals were randomly divided into 9 groups, including Sham group (mouse received an intraperitoneal injection of normal saline 1.0 ml/kg), FX-treated (0.1–1.0 ml/kg), Lipopolysaccharide (LPS)-treated (20 mg/kg), FX+LPS-treated (0.1–10.0 mg/kg and 20 mg/kg, respectively), and urinastatin groups (10 4 U/kg). Nuclear factor (NF)-κB activation could be potential treatment for sepsis. NF-κB signaling components were determined by western-blotting. IL-6, IL-1β, TNF-α production, and NF-κB activation were evaluated by ELISA and immunofluorescent staining in vitro . Results: FX was found to decrease the expression of inflammatory cytokines including IL-6, IL-1β, and TNF-α, in a prophylactic manner in the LPS-induced sepsis mouse model. Meanwhile, FX significantly inhibits phosphorylation of the NF-κB signaling pathway induced by LPS at the cellular level and reduces the nuclear translocation of NF-κB. The IC 50 for suppressing the expression of NF-κB was 11.08 ± 0.78 μM in the THP1-Lucia™ NF-κB cells. Furthermore, FX also inhibits the expression of inflammatory factors in a dose-dependent manner with the IC 50 inhibition of IL-6 production was 2.19 ± 0.70 μM in Raw267.4 macrophage cells. It is likely that the molecules with the ability of targeting NF-κB activation and inflammasome assembly, such as fucoxanthin, are interesting subjects to be used for treating sepsis.

The purpose of this study was to evaluate the cerebral protection of salvianolic acid B (Sal B) against cerebral I/R injury and investigate the underlying mechanism. As shown by 2,3,5-Triphenyltetrazolium chloride (TTC) staining and magnetic resonance imaging (MRI) analyses, Sal B significantly reduced cerebral infarct size, and accompanied with improved neurobehavioral functions as indicated by the modified Bederson score and Longa five-point scale. Sal B decreased the production of reactive oxygen species (p < .05, n = 10). The data of Western blotting and reverse transcription quantitative real time polymerase chain reaction (qRT-PCR) analyses showed that the expression of GFAP, Iba1, IL-1β, IL-6, TNF-α and Cleaved-caspase 3 was significantly reduced by Sal B in I/R injured brain tissues as compared to corresponding controls (p < .05, n = 10). Over activation of astrocytes and microglia were inhibited by Sal B as shown by immunostaining of GFAP and Iba 1. These data suggest that Sal B has neural protective effects against I/R-induced cerebral injury and could be an effective candidate for further development of clinical therapy.

Background African swine fever (ASF) leads to high mortality in domestic pigs and wild boar and is caused by the African swine fever virus (ASFV). Currently, no vaccine is commercially available for prevention, and the epidemic is still spreading. Here, we constructed a recombinant pseudorabies virus (PRV) (PRV-ΔgE/ΔgI/ΔTK-(CD2v)) that expresses the CD2v protein of ASFV and evaluated its effectiveness and safety as a vaccine candidate in mice. Methods A homologous recombination fragment containing ASFV CD2v was synthesized and co-transfected into HEK 293 T cells, a knockout vector targeting the PRV TK gene. The transfected cells were infected with PRV-ΔgE/ΔgI, and the recombinant strain (PRV-ΔgE/ΔgI/ΔTK-(CD2v)) was obtained by plaque purification in Vero cells. The expression of ASFV CD2v in the recombinant virus was confirmed by sequencing, Western blotting, and immunofluorescence analysis, and the genetic stability was tested in Vero cells over 20 passages. The virulence, immunogenicity and protective ability of the recombinant virus were further tested in a mouse model. Results The PRV-ΔgE/ΔgI/ΔTK-(CD2v) recombinant strain is stable in Vero cells, and the processing of CD2v does not depend on ASFV infection. The vaccination of PRV-ΔgE/ΔgI/ΔTK-(CD2v) causes neither pruritus, not a systemic infection and inflammation (with the high expression of interleukin-6 (IL6)). Besides, the virus vaccination can produce anti-CD2v specific antibody and activate a specific cellular immune response, and 100% protect mice from the challenge of the virulent strain (PRV-Fa). The detoxification occurs much earlier upon the recombinant virus vaccination and the amount of detoxification is much lower as well. Conclusions The PRV-ΔgE/ΔgI/ΔTK-(CD2v) recombinant strain has strong immunogenicity, is safe and effective, and maybe a potential vaccine candidate for the prevention of ASF and Pseudorabies.

Coix seed has traditionally been used in traditional Chinese medicine to fortify the spleen and inhibit dampness, and has shown anticancer effects in humans. However, it is not known whether coix seed improves post-weaning growth performance and productivity, and the mechanism of interaction between coix seed and gut microbiota remains unknown. In this study, we established four groups: (i) control, (ii) antibiotic-fed, (iii) coix seed powder-fed, and (iv) coix seed extract-fed. The feeding experiment was conducted for 4 weeks. Coix seed extract significantly increased average weight gain and reduced the feed/meat ratio in weaned pigs, in addition to reducing the pH of their gastric juice. Further assays demonstrated that coix seed promotes an increase in the density and length of the gastrointestinal villi. Next, 16s sequencing of gut microbiota showed that coix seed significantly increased the abundance of phylum Bacteroidetes and genus Lactobacillus (p < 0.05) and reduced the abundance of phylum Prevotella (p < 0.05) in the gut microbiota. In contrast, the abundance of phylum Bacteroidetes and genus Lactobacillus decreased in the control group and antibiotic group, whereas the abundance of phylum Prevotella increased. Our findings indicate that coix seed improves growth performance and productivity in post-weaning pigs by reducing the pH value of gastric juice, increasing the density and length of gastrointestinal villi, and modulating gut microbiota. Thus, coix seed has good potential for use as a feed supplement in swine production.