RESUMO
Blood-brain barrier (BBB) breakdown and the associated microvascular hyperpermeability are hallmark features of several neurological disorders, including traumatic brain injury (TBI). However, there is no viable therapeutic strategy to rescue BBB function. Tissue inhibitor of metalloproteinase-1 (TIMP1) has been considered to be beneficial for vascular integrity, but the molecular mechanisms underlying the functions of TIMP1 remain elusive. Here, we report that TIMP1 executes a protective role on neuroprotective function ameliorating BBB disruption in mice with experimental TBI. In human brain microvessel endothelial cells (HBMECs) exposed to hypoxia and inflammation injury, the recombinant TIMP1 (rTIMP1) treatment maintained integrity of junctional proteins and trans-endothelial tightness. Mechanistically, TIMP1 interacts with CD63/integrin 1 complex and activates downstream FAK signaling, leading to attenuation of RhoA activation and F-actin depolymerization for endothelial cells structure stabilization. Notably, these effects depend on CD63/integrin 1 complex, instead of the MMP-inhibitory function. Together, our results identified a novel MMP-independent function of TIMP1 in regulating endothelial barrier integrity. Therapeutic interventions targeting TIMP1 and its downstream signaling may be beneficial to protect BBB function following brain injury and neurological disorders.
RESUMO
A neuroinflammatory response is commonly involved in the progression of many neurodegenerative diseases. Potassium 2-(1-hydroxypentyl)-benzoate (PHPB), a novel neuroprotective compound, has shown promising effects in the treatment of ischemic stroke and Alzheimer׳s disease (AD). In the present study, the anti-inflammatory effects of PHPB were investigated in the plasma and brain of C57BL/6 mice administered a single intraperitoneal (i.p.) injection of lipopolysaccharide (LPS). Levels of iNOS and the cytokines TNF, IL-1and IL-10 were elevated in plasma, cerebral cortex and hippocampus after LPS injection and the number of microglia and astrocytes in cortex and hippocampus were increased. LPS also upregulated the expression of heme oxygenase-1 (HO-1) in the cortex and hippocampus. PHPB reduced the levels of iNOS and cytokines in the plasma and brain, decreased the number of microglia and astrocytes and further enhanced the upregulation of HO-1. In addition, PHPB inhibited the LPS-induced phosphorylation of ERK, P38 and JNK. These results suggest that PHPB is a potential candidate in the treatment of neurodegenerative diseases through inhibiting neuroinflammation.
RESUMO
Objective To assess the relationship between fat metabolic parameters and androgen concentration in the cord blood of newborns of mothers with polycystic ovary syndrome (PCOS). Methods This cross-sectional study included PCOS women (n=55) and neonatal, and 40 cases with matched body mass index (BMI) were used as control. The clinical data including height, body mass, waist circumference, hip circumference of PCOS group, and length and head circumference in newborns after delivery were measured and compared. Blood lipid level, serum insulin and testosterone level were detected using umbilical artery-vein mixed cord blood after delivery. Regression analysis was used to analyze the influence factors of neonatal cholesterol and testosterone levels. Results The neonatal birth weight, head circumference, cholesterol, low density lipoprotein cholesterol, high density lipoprotein cholesterol and triglyceride level were significantly lower, birth height and testosterone level were significantly higher, in PCOS group than those of control group (P＜0.05). Values of waist to hip ratio, BMI, cholesterol, high density lipoprotein cholesterol and testosterone levels were significantly higher in PCOS group than those of control group (P＜0.05). The insulin, cholesterol and triglyceride levels of PCOS mother were risk factors for neonatal cholesterol level(P ＜ 0.05). The cholesterol, triglyceride and free testosterone levels of PCOS mother were risk factors for increased neonatal free testosterone (P ＜ 0.05). Conclusion Mother with PCOS may affect fetal birth weight, head circumference and cord blood lipid metabolism, which may be related with the elevated level of testosterone during the fetal period.
RESUMO
This study was aimed to analyze the bioinformatics of proteomics of rat bone marrow mesenchymal stem cells (MSCs) intervened by active principle region of Yang-Xin Tong-Mai Formula (apr-YTF). The latest versions of bioinformatics tools including DAVID (http://david.abcc.ncifcrf.gov/) and GO (http://www.geneontology.org/) were combined to assign a precise function to rat bone marrow MSCs intervened by apr-YTF. KEGG and VISANT were assigned with a precise function to rat bone marrow MSCs intervened by apr-YTF. The results showed that a total of 102 biological processes were mainly involved, with 35 cellular components and 6 molecular functions. These proteins interacted in 3 signal transduction pathways. It was concluded that the following proteins and signal transduction pathways played an important role in the process of apr-YTF inducing BMSCs differentiation into cardiomyocytes. Presenilin-1 and Presenilin-2 were in the Notch signaling pathway. And syntaxin-4 protein was in soluble N-ethylmaleimide sensitive fusion protein attachment protein (SNARE). The apr-YTF played a role on MSCs from multiple sites, with multiple links through different biological processes. The bioinformatics of proteomics can predict action mechanism of traditional Chinese medicine (TCM) from the holism concept. The validation in combination with molecularbiology was a good way for TCM modernization.