Blood-brain barrier dysfunction mediated by the EZH2-Claudin-5 axis drives stress-induced TNF-α infiltration and depression-like behaviors.

Growing evidence suggests that neurovascular dysfunction characterized by blood-brain barrier (BBB) breakdown underlies the development of psychiatric disorders, such as major depressive disorder (MDD). Tight junction (TJ) proteins are critical modulators of homeostasis and BBB integrity. TJ protein Claudin-5 is the most dominant BBB component and is downregulated in numerous depression models; however, the underlying mechanisms remain elusive. Here, we demonstrate a molecular basis of BBB breakdown that links stress and depression. We implemented an animal model of depression, chronic unpredictable mild stress (CUMS) in male C57BL/6 mice, and showed that hippocampal BBB breakdown was closely associated with stress vulnerability. Concomitantly, we found that dysregulated Cldn5 level coupled with repression of the histone methylation signature at its promoter contributed to stress-induced BBB dysfunction and depression. Moreover, histone methyltransferase enhancer of zeste homolog 2 (EZH2) knockdown improved Cldn5 expression and alleviated depression-like behaviors by suppressing the tri-methylation of lysine 27 on histone 3 (H3K27me3) in chronically stressed mice. Furthermore, the stress-induced excessive transfer of peripheral cytokine tumor necrosis factor-α (TNF-α) into the hippocampus was prevented by Claudin-5 overexpression and EZH2 knockdown. Interestingly, antidepressant treatment could inhibit H3K27me3 deposition at the Cldn5 promoter, reversing the loss of the encoded protein and BBB damage. Considered together, these findings reveal the importance of the hippocampal EZH2-Claudin-5 axis in regulating neurovascular function and MDD development, providing potential therapeutic targets for this psychiatric illness.

[Comparative life cycle environmental assessment between electric taxi and gasoline taxi in Beijing].

Tailpipe emission of internal combustion engine vehicle (ICEV) is one of the main sources leading to atmospheric environmental problems such as haze. Substituting electric vehicles for conventional gasoline vehicles is an important solution for reducing urban air pollution. In 2011, as a pilot city of electric vehicle, Beijing launched a promotion plan of electric vehicle. In order to compare the environmental impacts between Midi electric vehicle (Midi EV) and Hyundai gasoline taxi (ICEV), this study created an inventory with local data and well-reasoned assumptions, and contributed a life cycle assessment (LCA) model with GaBi4.4 software and comparative life cycle environmental assessment by Life cycle impact analysis models of CML2001(Problem oriented) and EI99 (Damage oriented), which included the environmental impacts of full life cycle, manufacture phase, use phase and end of life. The sensitivity analysis of lifetime mileage and power structure was also provided. The results indicated that the full life cycle environmental impact of Midi EV was smaller than Hyundai ICEV, which was mainly due to the lower fossil fuel consumption. On the contrary, Midi EV exhibited the potential of increasing the environmental impacts of ecosystem quality influence and Human health influence. By CML2001 model, the results indicated that Midi EV might decrease the impact of Abiotic Depletion Potential, Global Warming Potential, Ozone Layer Depletion Potential and so on. However, in the production phase, the impact of Abiotic Depletion Potential, Acidification Potential, Eutrophication Potential, Global Warming Potential, Photochemical Ozone Creation Potential, Ozone Layer Depletion Potential, Marine Aquatic Ecotoxicity Potential, Terrestric Ecotoxicity Potential, Human Toxicity Potential of Midi EV were increased relative to Hyundai ICEV because of emissions impacts from its power system especially the battery production. Besides, in the use phase, electricity production was the main process leading to the impact of Abiotic Depletion Potential, Acidification Potential, Eutrophication Potential, Global Warming Potential, Photochemical Ozone Creation Potential, Marine Aquatic Ecotoxicity Potential, Freshwater Aquatic Ecotoxicity Potential, Human Toxicity Potential. While for Hyundai ICEV, gasoline production and tailpipe emission were the primary sources of environmental impact in the use phase. Tailpipe emission was a significant cause for increase in Eutrophication Potential and Global Warming Potential, and so forth. On the basis of inventory data analysis and 2010 Beijing electricity mix, the comparative results of haze-induced pollutants emissions showed that the full life cycle emissions of PM2.5, NO(x), SO(x), VOCs of Midi EV were higher than those of Hyundai ICEV, but the emission of NH3 was lower than that of Hyundai ICEV. Different emissions in use phase were the chief reason leading to this trend. In addition, by sensitivity analysis the results indicated that with the increase of lifetime mileage and proportion of cleaning energy, the rate of GHG( Green House Gas) emission reduction per kilometer of Midi EV became higher with respect to Hyundai ICEV. Haze-induced pollutants emission from EV could be significantly reduced using cleaner power energy. According to the assessment results, some management strategies aiming at electric car promotion were proposed.