Anti-apoptotic effects of aspirin following cerebral ischemia-reperfusion injury in rats

BACKGROUND:The pharmacological effects of aspirin on apoptosis are complex.The underlying mechanisms have not been properly defined.OBJECTIVE:To observe the effect of different doses of aspirin on brain cell apoptosis following focal cerebral ischemia-reperfusion injury(CIRI) in rats.DESING,TIME AND SETTING:A randomized,controlled,animal experiment,performed at the School of Medicine and Pharmaceutics,Jiangnan University between June and October 2006.MATERIALS:Twenty-six male,adult,Sprague Dawley rats(grade II),weighing 240-290 g,were obtained from Shanghai Experimental Animal Center,Chinese Academy of Sciences.Aspirin was provided by Sigma(USA).METHODS:The rats were randomly divided into four groups:sham-operation(SO),CIRI + vehicle,CIRI + aspirin(6 mg/kg),and CIRI + aspirin(60 mg/kg).Rats in the lesion groups were intragastrically administrated saline,aspirin(6 mg/kg),or aspirin(60 mg/kg),respectively.MAIN OUTCOME MEASURES:The number of pyramidal neurons with normal appearance in the cerebral cortex at 2-4 mm from the midline;apoptotic cell death as measured by TUNEL;Bcl-2 and Bax protein localization was determined by immunohistochemistry;malondialdehyde(MDA) and super oxidation(SOD) content were determined by biochemistry method;adenosine triphosphate(ATP) content measured by capillary electrophoresis.RESULTS:Following CIRI,the following parameters were altered compared with sham-operated animals:the number of neurons with normal appearance was significantly reduced in the cerebral cortex;the number of apoptotic cells increased;Bax protein expression was enhanced;and the ratio between Bcl-2 and Bax decreased.In addition,MDA content increased significantly,whereas ATP content decreased(P < 0.01).Aspirin ameliorated the loss of healthy pyramidal neurons.Both 6 and 60 mg/kg aspirin increased the ratio between Bcl-2 and Bax,with no significant difference between the treatment groups.In addition,60 mg/kg aspirin decreased MDA content and increased ATP levels.However,6 mg/kg aspirin did not have the same effect.CONCLUSION:Aspirin reduced the number of apoptotic cells following CIRI.These results suggest that the neuroprotective mechanism of aspirin could be related to elevated Bcl-2 protein levels or decreased Bax protein expression.The increase in the ratio of Bcl-2 to Bax appears to be a common anti-apoptotic mechanism of aspirin.

Targeting the transferrin receptor to develop erythropoietin for Alzheimer’s disease

Alzheimer’s disease(AD)is the sixth leading cause of death in the United States with approximately 5.8 million Americans currently living with AD.Due to the lack of a disease modifying treatment for AD and the aging baby boomer generation,this number is projected to grow to 13.8 million by 2050(Gaugler et al.,2019).Amyloid-beta(Aβ)plaque accumulation,one of the major pathological hallmarks of AD,can begin>20 years before clinical symptoms of AD.By the time AD is clinically diagnosed,neuronal loss and neuropathological lesions(Aβplaques and tau tangles)have already.

Fluctuation theorem for the mutation process in in vitro evolution

A proposition based on the fluctuation theorem in thermodynamics is formulated to quantitatively describe molecular evolution processes in biology. Although we cannot give full proof of its generality, we demonstrate via computer simulation its applicability in an example of DNA in vitro evolution. According to this theorem, the evolution process is a series of exponentially rare fluctuations fixed by the force of natural selection

Epidermal Growth Factor Enhances Orthovanadate-Induced Contraction via Src and Myosin Phosphatase Target Subunit 1 in Rat Vascular Smooth Muscle

Inhibition of protein tyrosine phosphatase by orthovanadate induces vasoconstriction, which is mediated by the Rho kinase-dependent inactivation of myosin light chain phosphatase (MLCP) via signaling downstream of Src-induced activation of the epidermal growth factor (EGF) receptor. The present study investigated the potential role of EGF in orthovanadate (OVA)-dependent vaso-constriction. OVA-induced aortic contraction significantly increased in the presence of EGF, and was abolished by inhibitors of Rho kinase (Y27632), extracellular signal-regulated kinase 1 and 2 (Erk1/2) (FR180204), Erk1/2 kinase (PD98059), EGF receptor (AG1478), and Src (PP2). Treatment of the rat endothelium-denuded thoracic aorta with either EGF or OVA augmented the phosphorylation of myosin phosphatase target subunit 1 (MYPT1) at Thr-853 and of the EGF receptor at Tyr-1173. The phosphorylation of MYPT1 was further increased by co-stimulation with EGF and OVA. EGF receptor phosphorylation at Tyr-845 was also increased by EGF or OVA;this effect was augmented by co-stimulation with EGF and OVA, and was abolished by Src inhibition. In addition, Erk1/2 was phosphorylated by EGF or by co-treatment with EGF and OVA;this was abolished by an EGF receptor inhibitor, but not by Src inhibition. These results suggested that OVA-induced EGF-related contraction was mediated by the Rho kinase-dependent inactivation of MLCP via two different signaling cascades: Src-dependent phosphorylation of the EGF receptor at Tyr-845 and EGF-dependent phosphorylation of Erk1/2.

17β-Estradiol up-regulates UDP-glucuronosyltransferase 1A9 expression via estrogen receptor α

UDP-glucuronosyltransferase 1A9(UGT1A9) is a major phase II enzyme responsible for elimination of drugs and endogenous molecules.Clinical data have shown increased elimination of UGT1A9 substrates in pregnant women or oral contraceptive users,but the role of estrogen in the regulation of UGT1A9 expression remains unknown.In this study,we investigated the effect of 17β-estradiol(E2) on UGT1A9 expression and the role of ERα in the transcriptional regulation of UGT1A9.E2 significantly increased UGT1A9 promoter activity in Hep G2 cells in the presence of ERα.UGT1A9 induction by E2 was abrogated by antiestrogen ICI182,780 in Hep G2 cells that constitutively express ERα.Results from transient transfection of ERα mutants into Hep G2 cells demonstrated that mutation at DNA-binding domain of ERα abrogates increased UGT1A9 promoter activity by E2.Deletion and mutation assays of UGT1A9 promoter revealed a putative ERE located within -2262/-1987 region.Examination of healthy human liver tissues revealed significantly higher UGT1A9 expression in women as compared to men.Together,these findings provide a mechanistic basis for the previous clinical reports and may shed a light on identifying sources for inter-individual variability in UGT1A9-mediated drug metabolism.

Oncogene:靶向作用关键受体或可有效阻断卵巢癌转移

日前，一项刊登在国际杂志Oncogene上的研究报告中，来自伊利诺伊大学的研究人员通过研究发现。阻断卵巢癌细胞表面的一种关键蛋白或许就能有效抑制或降低卵巢癌向其它器官中扩散。

A more robust Boolean model describing inhibitor binding

From the first application of the Boolean model to the cell cycle regulation network of budding yeast,new regulative pathways have been discovered,par-ticularly in the G1/S transition circuit.This discovery called for finer modeling to study the essential biology,and the resulting outcomes are first introduced in the ar-ticle.A traditional Boolean network model set up for the new G1/S transition circuit shows that it cannot correctly simulate real biology unless the model parameters are fine tuned.The deficiency is caused by an overly coarse-grained description of the inhibitor binding process,which shall be overcome by a two-vector model proposed whose robustness is surveyed using random perturba-tions.Simulations show that the proposed two-vector model is much more robust in describing inhibitor binding processes within the Boolean framework.