Reperfusion after hypoxia-ischemia exacerbates brain injury with compensatory activation of the antiferroptosis system:based on a novel rat model

Hypoxic-ischemic encephalopathy,which predisposes to neonatal death and neurological sequelae,has a high morbidity,but there is still a lack of effective prevention and treatment in clinical practice.To better understand the pathophysiological mechanism underlying hypoxic-ischemic encephalopathy,in this study we compared hypoxic-ischemic reperfusion brain injury and simple hypoxic-ischemic brain injury in neonatal rats.First,based on the conventional RiceVannucci model of hypoxic-ischemic encephalopathy,we established a rat model of hypoxic-ischemic reperfusion brain injury by creating a common carotid artery muscle bridge.Then we performed tandem mass tag-based proteomic analysis to identify differentially expressed proteins between the hypoxic-ischemic reperfusion brain injury model and the conventional Rice-Vannucci model and found that the majority were mitochondrial proteins.We also performed transmission electron microscopy and found typical characteristics of ferroptosis,including mitochondrial shrinkage,ruptured mitochondrial membranes,and reduced or absent mitochondrial cristae.Further,both rat models showed high levels of glial fibrillary acidic protein and low levels of myelin basic protein,which are biological indicators of hypoxic-ischemic brain injury and indicate similar degrees of damage.Finally,we found that ferroptosis-related Ferritin(Fth1)and glutathione peroxidase 4 were expressed at higher levels in the brain tissue of rats with hypoxic-ischemic reperfusion brain injury than in rats with simple hypoxic-ischemic brain injury.Based on these results,it appears that the rat model of hypoxic-ischemic reperfusion brain injury is more closely related to the pathophysiology of clinical reperfusion.Reperfusion not only aggravates hypoxic-ischemic brain injury but also activates the anti-ferroptosis system.

四物五子汤联合玻璃体腔注射康柏西普治疗湿性ARMD疗效及对血清细胞因子的影响

目的:探讨四物五子汤联合玻璃体腔注射康柏西普治疗湿性年龄相关性黄斑变性(ARMD)的效果及对血清血管内皮生长因子(VEGF)、转化生长因子-β1(TGF-β1)和炎症因子的影响。方法:选取2019-05/2020-11我院眼科收治的湿性ARMD患者60例60眼进行回顾性研究,对照组30例30眼给予玻璃体腔注射康柏西普治疗,观察组30例30眼在对照组基础上加用四物五子汤治疗。比较两组患者治疗3mo后最佳矫正视力(BCVA)、眼底情况、黄斑部视网膜脉络膜血管复合体(CBRC)及视网膜神经上皮层(RNL)厚度、未消退新生血管数目、血清VEGF、TGF-β1、白介素-6(IL-6)和白介素-13(IL-13)水平及总体疗效。结果:治疗3mo后,两组患者BCVA、眼底出血、渗出情况、CBRC及RNL厚度较治疗前均得到改善(P<0.05),且观察组优于对照组(P<0.05)。与治疗前相比,两组患者治疗3mo后血清VEGF、TGF-β1、IL-6、IL-13均降低(P<0.001),且观察组患者血清VEGF、TGF-β1、IL-6和IL-13水平显著低于对照组(P<0.05)。观察组总有效率明显优于对照组(P=0.037)。结论:四物五子汤联合玻璃体腔注射康柏西普治疗能消退湿性ARMD患者眼底新生血管,降低血清VEGF、TGF-β1和炎症因子水平,改善眼部微循环,促进湿性ARMD患者视力恢复。

Glycyrrhizic acid inhibits apoptosis and fibrosis in carbontetrachloride-induced rat liver injury

AIM:To investigate anti-apoptotic effects of glycyrrhizic acid(GA) against fibrosis in carbon tetrachloride(CCl4)-induced liver injury and its contributing factors.METHODS:Liver fibrosis was induced by administration of CCl4 for 8 wk.Pathological changes in the liver of rats were examined by hematoxylin-eosin staining.Collagen fibers were detected by Sirius red staining.Hepatocyte apoptosis was determined by TUNEL assay and the expression levels of cleaved caspase-3,Bax,α-SMA,connective tissue growth factor(CTGF),matrix metalloproteinase(MMP) 2 and MMP9 proteins were evaluated by western blot analysis,and α-SMA m RNA,collagen type Ⅰ and Ⅲ m RNA were estimated by real-time PCR.RESULTS:Treatment with GA significantly improved the pathological changes in the liver and markedly decreased the positive area of Sirius red compared with rats in the CCl4-treated group.TUNEL assay showed that GA significantly reduced the number of TUNEL-positive cells compared with the CCl4-treated group.The expression levels of cleaved caspase-3,Bax,α-SMA,CTGF,MMP2 and MMP9 proteins,and α-SMA m RNA,collagen type Ⅰ and Ⅲ m RNA were also significantly reduced by GA compared with the CCl4-treated group(P < 0.05).CONCLUSION:GA treatment can ameliorate CCl4-induced liver fibrosis by inhibiting hepatocyte apoptosis and hepatic stellate cell activation.

Glycyrrhizic acid attenuates CCl_4-induced hepatocyte apoptosis in rats via a p53-mediated pathway

AIM: To investigate the effect of glycyrrhizic acid (GA) on carbon tetrachloride (CCl4)-induced hepatocyte apo-ptosis in rats via a p53-dependent mitochondrial path-way. METHODS: Forty-five male Sprague-Dawley rats were randomly and equally divided into three groups, the control group, the CCl4 group, and the GA treatment group. To induce liver fibrosis in this model, rats were given a subcutaneous injection of a 40% solution of CCl4 in olive oil at a dose of 0.3 mL/100 g body weight biweekly for 8 wk, while controls received the same isovolumetric dose of olive oil by hypodermic injection, with an initial double-dose injection. In the GA group,rats were also treated with a 40% solution of CCl4 plus 0.2% GA solution in double distilled water by the intraperitoneal injection of 3 mL per rat three times a week from the first week following previously published methods, with modifications. Controls were given the same isovolumetric dose of double distilled water. Liver function parameters, such as alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were de-termined. Pathologic changes in the liver were detected by hematoxylin and eosin staining. Collagen fibers were evaluated by Sirius red staining. Hepatocyte apoptosis was investigated using the terminal deoxynucleotidyl transferase-mediated deoxyuridine 5-triphosphate nick end labeling (TUNEL) assay and the cleaved caspase-3 immunohistochemistry assay. The expression levels of p53 and apoptosis-related proteins were evaluated by immunohistochemistry or Western blotting analysis. RESULTS: After 8 wk of treatment, GA significantly re-duced serum activity of ALT (from 526.7 ± 57.2 to 342 ± 44.8, P<0.05) and AST (from 640 ± 33.7 to 462.8 ± 30.6, P<0.05), attenuated the changes in liver his-topathology and reduced the staging score (from 3.53 ± 0.74 to 3.00 ± 0.76, P<0.05) in CCl4 -treated rats. GA markedly reduced the positive area of Sirius red and the ratio of the hepatic fibrotic region (from 7.87% ± 0.66% to 3.68% ± 0.32%, P<0.05) compared with the CCl4 group. GA also decreased the expression level of cleaved caspase-3 compared to the CCl4 group. TU-NEL assay indicated that GA significantly diminished the number of TUNEL-positive cells compared with the CCl4 group (P<0.05). GA treatment clearly decreased the level of p53 (P<0.05) detected by immunohis-tochemistry and Western blotting analysis. Compared with the CCl4 group, we also found that GA reduced the Bax/Bcl-2 ratio (P<0.05), the expression of cleaved caspase-3 (P<0.05), cleaved caspase-9 (P<0.05), and inhibited cytochrome C and second mitochondria-derived activator of caspases (Smac) release from mito-chondria to cytoplasm, i.e. , GA reduced the expressionlevel of Smac, which inhibited c-IAP1 activity (P<0.05), ultimately inhibiting the activity of caspase-3, according to Western blotting analysis. As a result, GA suppressed activation of the caspase cascades and prevented he-patocyte apoptosis.

The association of LOXL1 polymorphisms with exfoliation syndrome/glaucoma: Meta-analysis

AIM: To investigate the association of lysyl oxidaselike 1(LOXL1) single nucleotide polymorphisms(SNPs)with exfoliation syndrome(XFS)/exfoliation glaucoma(XFG).METHODS: Published manuscripts from Pub Med and EMBASE were identified until May 2014. Summary odds ratios(ORs) and 95% confidence intervals(CIs) for LOXL1(rs1048661, rs2165241 and rs3825942) polymorphisms and the risk of XFS/XFG were estimated using random-or fixed- effect model.· RESULTS: The three LOXL1 polymorphisms(rs1048661, rs3825942, and rs2165241) were associated with an increased risk for XFS/XFG among Caucasians,with OR 2.19(1.96-2.45), 8.8(6.05-12.79) and 3.41(3.11-3.73), respectively. On the contrast, the rs1048661 and rs2165241, but not rs3825942 polymorphism, have a potential protective effect on XFS/XFG in Asians, with OR0.06(0.02-0.18), 0.15(0.09-0.25), respectively.CONCLUSION: There is strong evidence that LOXL1 polymorphisms are associated with XFS/XFG risk. The strength of risk might be ethnicity-dependent.

Research on induced pluripotent stem cells and the application in ocular tissues

·Induced pluripotent stem cells(i PSCs) were firstly induced from mouse fibroblasts since 2006, and then the research on i PSCs had made great progress in the following years. i PSCs were established from different somatic cells through DNA, RNA, protein or small molecule pathways and transduction vehicles. With continuous improvement of technology on reprogramming, the induction of i PSCs became more secure and effective, and showed enormous promise for clinical applications. We reviewed different reprogramming of somatic cells, four kinds of pathways of reprogramming and three types of transduction vehicles, and discuss the research of i PSCs in ophthalmology and the prospect of i PSCs applications.

Research on protection system of resonant network in CSNS magnet power supplies

Purpose Chinese Spallation Neutron Source(CSNS)is one of the key projects of China,in which the main magnet power supplies adopt the structures of resonant networks(Wang et al.in Sci China Phys Mech Astron 54(Suppl 2):239-244,2011).Since each network contains a lot of components,and the working state of all the components will affect the whole accelerator,it is necessary to monitor the operation of each part in the resonant network.Methods In this protections system,a supervision to 314 switch signals and 118 analog signals is realized using a chip of field programmable gate array(FPGA).The details about the hardware and software designs are introduced in this paper.Results This protection system has been used in CSNS project,and the result proves that the RCS has been well monitored by this system.Conclusions This system is a self-developed protection system according to the engineering needs of CSNS.It can realize the real-time monitoring and protection of the working state of resonance network by processing a large number of data using FPGA.

Quadratic Optimization over a Second-Order Cone with Linear Equality Constraints

This paper studies the nonhomogeneous quadratic programming problem over a second-order cone with linear equality constraints.When the feasible region is bounded,we show that an optimal solution of the problem can be found in polynomial time.When the feasible region is unbounded,a semidefinite programming(SDP)reformulation is constructed to find the optimal objective value of the original problem in polynomial time.In addition,we provide two sufficient conditions,under which,if the optimal objective value is finite,we show the optimal solution of SDP reformulation can be decomposed into the original space to generate an optimal solution of the original problem in polynomial time.Otherwise,a recession direction can be identified in polynomial time.Numerical examples are included to illustrate the effectiveness of the proposed approach.