Chronic kidney disease (CKD) patients undergoing hemodialysis is often accompanied by high levels of oxidative stress, profoundly affecting the survival rate and long-term outcome of patients. Functionalized hemodialysis membranes with relieving oxidative stress and outstanding biocompatibility have aroused more attention among researchers. In this work, we incorporated a tannic acid (TA) coating onto the poly (ether sulfone) (PES) hemodialysis membrane in order to alleviate the increased oxidative stress status during hemodialysis. Further modification of poly(2-ethyl-2-oxazoline) (PEtOx) brushes devoted to improving the biocompatibility of hemodialysis membrane. The TA/PEtOx brushes functionalized membranes effectively eliminated reactive oxygen species (ROS), increased serum antioxidant level, and inhibited lipid peroxides and glycation products generation. The functionalized membranes attenuated the H 2 O 2 -induced oxidative damage to cardiomyocytes (H9C2) and vascular endothelial cells (HUVEC) by modulating the antioxidant enzymes expression (SOD, CAT and GSH). The immobilization of PEtOx brushes significantly improved the biocompatibility, and the TA/PEtOx brushes functionalized membranes have been constructed through the Michael addition reaction between TA and PEtOx brushes. Simultaneously, the cyclic PEtOx (C-PEtOx) brushes simulating the structure of endothelial glycocalyx formed a stronger steric hindrance and a denser hydration layer that significantly suppressed the platelets and erythrocytes adhesion on membrane surface. The optimal functionalized membrane exhibited a 76.5% of urea clearance, 53.4% of lysozyme clearance and 95.9% of bovine serum albumin (BSA) retention. This present work fabricated a biomimetic surface structure for the development and preparation of novel hemodialysis membrane, which would greatly improve the therapeutic effect in patients.
He Chengjian,Song Xiaojing,Zhu Zigui,Xiao Yan,Chen Jiacheng,Yao Hongyi,Xie Rongjun
Ghrelin exerts widespread effects in several diseases, but its role and mechanism in Acute Traumatic Coagulopathy (ATC) are largely unknown. The effect of ghrelin on cell proliferation was examined using three assays: 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide (MTT), Lactate Dehydrogenase (LDH), and flow cytometry. The barrier function of the endothelial cells was evaluated using the Trans-Endothelial Electrical Resistance (TEER) and the endothelial permeability assay. An ATC mouse model was established to evaluate the in vivo effects of ghrelin. The Ras homolog family member A (RhoA) overexpression plasmid or adenovirus was used to examine the molecular mechanism of ghrelin. Ghrelin enhanced Human Umbilical Vein Endothelial Cells (HUVEC) proliferation and endothelial cell barrier function and inhibited HUVEC permeability damage in vitro. Additionally, ghrelin decreased the activated Partial Thromboplastin Time (aPTT) and Prothrombin Time (PT) in mice blood samples in the ATC mouse model. Ghrelin also improved the pathological alterations in postcava. Mechanistically, ghrelin acts through the RhoA/ Rho-associated Coiled-coil Containing Kinases (ROCK)/ Myosin Light Chain 2 (MLC2) pathway. Furthermore, the protective effects of ghrelin, both in vitro and in vivo, were reversed by RhoA overexpression. Our findings demonstrate that ghrelin may reduce vascular endothelial cell damage and endothelial barrier dysfunction by blocking the RhoA pathway, suggesting that ghrelin may serve as a potential therapeutic target for ATC treatment. Graphical Abstract We explored the effects of ghrelin on coagulopathy and vascular endothelial injury in vivo by establishing an ATC mouse model, and investigated the effects of ghrelin on LPS-induced HUVECs cell damage in vitro. The RhoA overexpression plasmid or adenovirus was used to examine the molecular mechanism. Abbreviations : ATC =acute traumatic coagulopathy; HUVECs =Human Umbilical Vein Endothelial Cells; LPS =lipopolysaccharide; RhoA =The Ras homolog family member A; aPTT =activated partial thromboplastin time; PT =prothrombin time; TEER =trans-endothelial electrical resistance
Pu Li,Qiang Liu,Zhenni Xiang,Jian Wang,Wan-Xia Wu,Wen-Jing Yi
The reactive oxygen species (ROS) responsive amphiphilic poly(ethylene glycol)- b -poly(thioketal) (mPEG- b -PTK) copolymer was synthesized by enzyme-catalyzed polymerization for the first time. Core crosslinked (CCL) micelles were prepared via thiol-ene click reaction between the double bond of the side chain of mPEG- b -PTK and the thiol group of pentaerythritol tetrakis (3-mercaptopropionate) as a crosslinker under UV light. The success of crosslinking was verified by NMR and IR. CCL micelles showed better stability in stability against dilution and storage stability experiments compared with the uncrosslinked (UCL) micelles. The ROS-responsiveness of CCL micelles was characterized by DLS, TEM, NMR, AFM and SEM. In vitro release studies, CCL micelles encapsulating doxorubicin (DOX) showed a faster release rate of nearly 100% within 32 h in PBS containing 5 mM H 2 O 2 compared to the control without H 2 O 2 . Cytotoxicity test demonstrated good biocompatibility of CCL micelles and low toxicity with cell viability above 82% and 86% in HeLa cells and HUVEC cells, respectively. And CCL DOX-loaded micelles exhibited great anticancer activity with IC 50 value about 4.8 mg/L for Hela cells. Finally, flow cytometry and confocal laser scanning microscope (CLSM) showed that DOX-loaded micelles had excellent internalization efficiency in HeLa cells. The obtained ROS-responsive CCL micelles held promise for anticancer drug delivery.
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