• Brain-derived cellular microparticles induce systemic coagulopathy in traumatic brain injury.• Platelets facilitate the transmigration of brain microparticles through the endothelial barrier into the circulation.Traumatic brain injury (TBI) is associated with coagulopathy, although it often lacks 2 key risk factors: severe bleeding and significant fluid resuscitation associated with hemorrhagic shock. The pathogenesis of TBI-associated coagulopathy remains poorly understood. We tested the hypothesis that brain-derived microparticles (BDMPs) released from an injured brain induce a hypercoagulable state that rapidly turns into consumptive coagulopathy. Here, we report that mice subjected to fluid percussion injury (1.9 6 0.1 atm) developed a BDMP-dependent hypercoagulable state, with peak levels of plasma glial cell and neuronal BDMPs reaching 17 496 6 4833/mL and 18 388 6 3657/mL 3 hours after TBI, respectively. Uninjured mice injected with BDMPs developed a dosedependent hyper-turned hypocoagulable state measured by a progressively prolonged clotting time, fibrinogen depletion, and microvascular fibrin deposition in multiple organs. The BDMPs were 50 to 300 nm with intact membranes, expressing neuronal or glial cell markers and procoagulant phosphatidylserine and tissue factor. Their procoagulant activity was greater than platelet microparticles and was dose-dependently blocked by lactadherin. Microparticles were produced from injured hippocampal cells, transmigrated through the disrupted endothelial barrier in a platelet-dependent manner, and activated platelets. These data define a novel mechanism of TBI-associated coagulopathy in mice, identify early predictive markers, and provide alternative therapeutic targets. (Blood. 2015;125(13):2151-2159

Traumatic brain injury (TBI) has high morbidity and mortality rates. The mechanisms underlying TBI are unclear and may include the change in biological material in exosomes. Circular ribonucleic acids (circRNAs) are enriched and stable in exosomes, which can function as microRNA (miRNA) sponges to regulate gene expression levels. Therefore, we speculated that circRNAs in exosomes might play an important role in regulating gene expression after TBI and then regulate specific signaling pathways, which may protect the brain. We first isolated exosomes from the brain extracellular space in mice with TBI by digestion. We then investigated the alterations in circRNA expression in exosomes by high-throughput whole transcriptome sequencing, analyzed the data by gene ontology (GO) and pathway analysis, and constructed the circRNA-miRNA network. In this study, we identified 231 significantly and differentially expressed circRNAs, including 155 that were upregulated and 76 that were downregulated. GO analysis showed that these differentially expressed circRNAs might be related to the growth and repair of neurons, the development of the nervous system, and the transmission of nerve signals. The most highly correlated pathways that we identified were involved primarily with glutamatergic synapse and the cyclic guanosine monophosphate-protein kinase G signaling pathway. The circRNA-miRNA network predicted the potential roles of these differentially expressed circRNAs and the interaction of circRNAs with miRNAs. Our study broadens the horizon of research on gene regulation in exosomes from the brain extracellular space after TBI and provides novel targets for further research on both the molecular mechanisms of TBI and the potential intervention therapy targets.

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This study was to explore whether repeated non-invasive limb ischemic pre-conditioning (NLIP) can confer an equivalent cardioprotection against myocardial ischemia-reperfusion (I/R) injury in acute diabetic rats to the extent of conventional myocardial ischemic pre-conditioning (MIP) and whether or not the delayed protection of NLIP is mediated by reducing myocardial oxidative stress after ischemia-reperfusion. Streptozotocin-induced diabetic rats were randomized to four groups: Sham group, the I/R group, the MIP group and the NLIP group. Compared with the I/R group, both the NLIP and MIP groups showed an amelioration of ventricular arrhythmia, reduced myocardial infarct size, increased activities of total superoxide dismutase (SOD), manganese-SOD and glutathione peroxidase, increased expression of manganese-SOD mRNA and decreased xanthine oxidase activity and malondialdehyde concentration (All p < 0.05 vs I/R group). It is concluded that non-invasive limb ischemic pre-conditioning reduces oxidative stress and attenuates myocardium ischemia-reperfusion injury in diabetic rats.

Scope: Gut microbiome-derived metabolites are the major mediators of diet-induced host-microbial interactions. Aryl hydrocarbon receptor (AHR) plays a crucial role in glucose, lipid, and cholesterol metabolism in the liver. In this study, we aimed to investigate the role of indole-3-acetic acid (IAA) and AHR in sulforaphane (SFN) alleviates hepatic steatosis in mice fed on a high-fat diet (HFD).Methods and Results: The HFD-fed male C57BL/6 mice were intervened with SFN for 6 weeks. HFD-mice showed classical pathophysiological characteristics of hepatic steatosis. The results showed that SFN significantly reduced body weight, liver inflammation and hepatic steatosis in HFD-fed mice. SFN reduced hepatic lipogenesis by activating AHR/SREBP-1C pathway, which was confirmed in HepG2 cell experiments. Moreover, SFN increased hepatic antioxidant activity by modulating Nrf-2/NQO1 expression. SFN increased serum and liver IAA level in HFD mice. Notably, SFN manipulated the gut microbiota, resulting in reducing Deferribacteres and proportions of the phylum Firmicutes/Bacteroidetes and increasing the abundance of specific bacteria that produce IAA. Furthermore, SFN upregulated Ahr expression and decreased the expression of inflammatory cytokines in Raw264.7 cells.Conclusions: SFN ameliorated hepatic steatosis not only by modulating lipid metabolism via AHR/SREBP-1C pathway but regulating IAA and gut microbiota in HFD-induced NAFLD mice.