Translational reprogramming following UVB irradiation is mediated by DNA-PKcs and allows selective recruitment to the polysomes of mRNAs encoding DNA repair enzymes.

UVB-induced lesions in mammalian cellular DNA can, through the process of mutagenesis, lead to carcinogenesis. However, eukaryotic cells have evolved complex mechanisms of genomic surveillance and DNA damage repair to counteract the effects of UVB radiation. We show that following UVB DNA damage, there is an overall inhibition of protein synthesis and translational reprogramming. This reprogramming allows selective synthesis of DDR proteins, such as ERCC1, ERCC5, DDB1, XPA, XPD, and OGG1 and relies on upstream ORFs in the 5' untranslated region of these mRNAs. Experiments with DNA-PKcs-deficient cell lines and a specific DNA-PKcs inhibitor demonstrate that both the general repression of mRNA translation and the preferential translation of specific mRNAs depend on DNA-PKcs activity, and therefore our data establish a link between a key DNA damage signaling component and protein synthesis.

Litsea cubeba Essential Oil: Component Analysis, Anti-Candida albicans Activity and Mechanism Based on Molecular Docking.

The antifungal mechanism of plant essential oil has always been a concern in the agriculture and forestry science field. In this investigation, besides the evaluation of inhibitory activities of twenty-three essential oils against Candida albicans in vitro, identification and quantification of the chemical composition of Litsea cubeba essential oil by gas chromatography-mass spectrometry were investigated. Further development, we assessed the mechanism of L. cubeba essential oil against C. albicans by molecular docking. Litsea cubeba essential oil displayed the strongest inhibitory activity among these oils and the diameter of the circle against C. albicans was more than 50 mm. Maximum three components were identified with trans-citral (33.6%), cis-citral (30.3%), d-limonene (8.2%). Secretory aspartate protease (SAP5) and ß-1,3-glucan synthase (ß-1,3-GS) are two key enzyme proteins that inhibit the growth of C. albicans. Molecular docking studies reveal chemical binding forces of cis-citral, trans-citral and d-limonene to SAP5 are -21.76 kJ/mol, -22.18 kJ/mol and -24.27 kJ/mol, to ß-1,3-GS are -23.01 kJ/mol, -25.52 kJ/mol and -23.85 kJ/mol, respectively. The most preferable binding mechanism was observed against SAP5 and ß-1,3-GS due to hydrophobic interaction, as well as hydrogen bonding between citral molecules. The research results suggest the mechanism of chemical components in L. cubeba essential oil inhibits the growth of C. albicans, which provides a reference to the development and utilization of essential oil.

Tranexamic acid mediates proinflammatory and anti-inflammatory signaling via complement C5a regulation in a plasminogen activator-dependent manner.

BACKGROUND: Both tissue plasminogen activator (tPA) in the circulation and urokinase (uPA) in tissues cleave plasminogen (PLG) to plasmin to promote clot lysis. Tranexamic acid (TXA) blocks both the tPA-dependent generation of plasmin on blood clots as well as active plasmin binding to polymerized fibrin, and is commonly administered for bleeding in trauma to limit fibrinolysis. In addition to lysing clots, however, active plasmin also cleaves complement proteins, potentially enhancing inflammation. Because TXA does not block uPA-dependent plasmin generation from PLG and instead augments it, we hypothesized that administration of TXA could enhance or inhibit proinflammatory C5a formation in a PLG activator-dependent manner. METHODS: Citrate platelet-poor plasma (PPP) and PPP depleted of complement protein C3 or PLG were obtained from healthy donors and commercial sources. Platelet-poor plasma was treated ex vivo with or without TXA and either with or without tPA or with or without uPA. Clotting was then induced by calcium and thrombin in clotted PPP experiments, while unclotted PPP experiments were treated with vehicle controls. C5a levels were measured via enzyme-linked immunosorbent assay. Data were expressed as mean ± SEM. RESULTS: Plasmin-mediated fibrinolysis by tPA in clotted PPP led to an approximately threefold increase in C5a production (p < 0.0001), which was significantly inhibited by TXA (p < 0.001). Paradoxically, when fibrinolysis was induced by uPA, TXA treatment led to further increases in C5a production beyond uPA alone (p < 0.0001). Furthermore, clotting was not required for C5a generation from uPA + TXA. C3 depletion had no effect on C5a production, while depletion of PLG eliminated it. CONCLUSIONS: Tranexamic acid administration can have proinflammatory or anti-inflammatory effects through regulating C5a generation by plasmin, depending on the predominating PLG activator. Tranexamic acid may cause significant inflammatory C5a elevations in injured tissues by augmenting uPA-mediated plasmin generation in a fibrin-independent manner. In contrast, TXA reduces C5a generation during tPA-mediated fibrinolysis that may reduce inflammatory responses. In vivo validation of these novel ex vivo findings is warranted and may have important clinical consequences.