Background and Purpose—: Most patients with cerebral infarction die of brain edema because of the breakdown of the blood–brain barrier (BBB) in ischemic tissue. Caveolins (a group of proteins) are key modulators of vascular permeability; however, a direct role of caveolin-1 (Cav-1) in the regulation of BBB permeability during ischemic injury has yet to be identified. Methods—: Cav-1 expression was measured by immunoblotting after photothrombotic ischemia. A direct functional role of Cav-1 in cerebral edema and BBB permeability during cerebral ischemia was investigated by genetic manipulation (gene disruption and re-expression) of Cav-1 protein expression in mice. Results—: There was a significant correlation between the extent of BBB disruption and the Cav-1 expression. In Cav-1–deficient (Cav-1 ^−/− ) mice, the extent of BBB disruption after cerebral ischemia was increased compared with wild-type (Cav-1 ^+/+ ) mice, whereas the increase in cerebral edema volume was ameliorated by lentiviral-mediated re-expression of Cav-1. Furthermore, Cav-1 ^−/− mice had significantly higher degradation of tight junction proteins and proteolytic activity of matrix metalloproteinase than Cav-1 ^+/+ mice. Conversely, re-expression of Cav-1 in Cav-1 ^−/− mice restored tight junction protein expression and reduced matrix metalloproteinase proteolytic activity. Conclusions—: These results indicate that Cav-1 is a critical determinant of BBB permeability. Strategies for regulating Cav-1 represent a novel therapeutic approach to controlling BBB disruption and subsequent neurological deterioration during cerebral ischemia.

Atherosclerosis, the leading cause of death, is a vascular disease of chronic inflammation. We recently showed that angiopoietin-like 4 (ANGPTL4) promotes cardiac repair by suppressing pathological inflammation. Given the fundamental contribution of inflammation to atherosclerosis, we assessed the role of ANGPTL4 in the development of atherosclerosis and determined whether ANGPTL4 regulates atherosclerotic plaque stability. We injected ANGPTL4 protein twice a week into atherosclerotic Apoe−/− mice and analyzed the atherosclerotic lesion size, inflammation, and plaque stability. In atherosclerotic mice, ANGPTL4 reduced atherosclerotic plaque size and vascular inflammation. In the atherosclerotic lesions and fibrous caps, the number of α-SMA(+), SM22α(+), and SM-MHC(+) cells was higher, while the number of CD68(+) and Mac2(+) cells was lower in the ANGPTL4 group. Most importantly, the fibrous cap was significantly thicker in the ANGPTL4 group than in the control group. Smooth muscle cells (SMCs) isolated from atherosclerotic aortas showed significantly increased expression of CD68 and Krüppel-like factor 4 (KLF4), a modulator of the vascular SMC phenotype, along with downregulation of α-SMA, and these changes were attenuated by ANGPTL4 treatment. Furthermore, ANGPTL4 reduced TNFα-induced NADPH oxidase 1 (NOX1), a major source of reactive oxygen species, resulting in the attenuation of KLF4-mediated SMC phenotypic changes. We showed that acute myocardial infarction (AMI) patients with higher levels of ANGPTL4 had fewer vascular events than AMI patients with lower levels of ANGPTL4 (p < 0.05). Our results reveal that ANGPTL4 treatment inhibits atherogenesis and suggest that targeting vascular stability and inflammation may serve as a novel therapeutic strategy to prevent and treat atherosclerosis. Even more importantly, ANGPTL4 treatment inhibited the phenotypic changes of SMCs into macrophage-like cells by downregulating NOX1 activation of KLF4, leading to the formation of more stable plaques.

The antioxidant properties of alpha-lipoic acid (aLA) correlate with its ability to promote neuroproliferation. However, there have been no comprehensive studies examining the neurorestorative effects of aLA administration after the onset of ischemia. The middle cerebral artery (MCA) of adult rats was occluded for 2 hours and then reperfused. aLA (20 mg/kg) was administered in 71 animals (aLA group) through the left external jugular vein immediately after reperfusion. An equivalent volume of vehicle was administered to 71 animals (control group). Functional outcome, levels of endogenous neural precursors with neurogenesis, glial cell activation, and brain metabolism were evaluated. Immediate aLA administration after reperfusion resulted in significantly reduced mortality, infarct size, and neurological deficit score (NDS) in the test group compared to the control group. Long-term functional outcomes, measured by the rotarod test, were markedly improved by aLA treatment. There was a significant increase in the number of cells expressing nestin and GFAP in the boundary zone and infarct core regions after aLA treatment. Furthermore, significantly more BrdU/GFAP, BrdU/DCX, and BrdU/NeuN double-labeled cells were observed along the boundary zone of the aLA group on days 7, 14, and 28 days, respectively. And brain metabolism using 18F-FDG microPET imaging was markedly improved in aLA group. The effects of aLA was blocked by insulin receptor inhibitor, HNMPA (AM)3. These results indicate that immediate treatment with aLA after ischemic injury may have significant neurorestorative effects mediated at least partially via insulin receptor activation. Thus, aLA may be useful for the treatment of acute ischemic stroke.

Non-selective histone deacetylase (HDAC) inhibitors are known to improve hypertension. Here, we investigated the therapeutic effect and regulatory mechanism of the class I HDAC selective inhibitors, MS-275 and RGFP966, in angiotensin (Ang) II-induced hypertensive mice. MS-275 inhibited the activity of HDAC1, HDAC2, and HDAC3, while RGFP966 weakly inhibited that of HDAC3 in a cell-free system. MS-275 and RGFP966 treatment reduced systolic blood pressure and thickness of the aorta wall in Ang II-induced hypertensive mice. MS-275 treatment reduced aorta collagen deposition, as determined by Masson’s trichrome staining. MS-275 decreased the components of the renin angiotensin system and increased vascular relaxation of rat aortic rings via the nitric oxide (NO) pathway. NO levels reduced by Ang II were restored by MS-275 treatment in vascular smooth muscle cells (VSMCs). However, MS-275 dose (3 mg·kg^-1·day^-1) was not enough to induce NO production in vivo. In addition, MS-275 did not prevent endothelial nitric oxide synthase (eNOS) uncoupling in the aorta of Ang II-induced mice. Treatment with MS-275 failed to inhibit Ang II-induced expression of NADPH oxidase (Nox)1, Nox2, and p47phox. MS-275 treatment reduced proinflammatory cytokines such as tumor necrosis factor (TNF)-α, interleukin (IL)-1β, and monocyte chemoattractant protein (MCP)-1, as well as adhesion molecules. Histological analysis showed that Ang II-induced macrophage infiltration was reduced by MS-275 and RGFP966 administration. Our results indicate that class I HDAC selective inhibitors may be good therapeutic agents for the treatment of hypertension through the regulation of vascular remodeling and vasoconstriction, as well as inflammation.

Age assessment has attracted increasing attention in the field of forensics. However, most existing works are laborious and requires domain-specific knowledge. Modern computing power makes it is possible to leverage massive amounts of data to produce more reliable results. Therefore, it is logical to use automated age estimation approaches to handle large datasets. In this study, a fully automated age prediction approach was proposed by assessing 3D mandible and femur scans using deep learning. A total of 814 post-mortem computed tomography scans from 619 men and 195 women, within the age range of 20–70, were collected from the National Forensic Service in South Korea. Multiple preprocessing steps were applied for each scan to normalize the image and perform intensity correction to create 3D voxels that represent these parts accurately. The accuracy of the proposed method was evaluated by 10-fold cross-validation. The initial cross-validation results illustrated the potential of the proposed method as it achieved a mean absolute error of 5.15 years with a concordance correlation coefficient of 0.80. The proposed approach is likely to be faster and potentially more reliable, which could be used for age assessment in the future.