PLA(2) signaling is involved in calpain-mediated degradation of synaptic dihydropyrimidinase-like 3 protein in response to NMDA excitotoxicity

Dihydropyrimidinase-like 3 (DPYSL3) is believed to play a role in neuronal differentiation, axonal outgrowth and neuronal regeneration, as well as cytoskeleton organization. Recently we have shown that glutamate excitotoxicity and oxidative stress result in calpain-dependent cleavage of DPYSL3, and that NOS plays a role in this process [R. Kowara, Q. Chen, M. Milliken, B. Chakravarthy, Calpain-mediated truncation of dihydropyrimidinase-like 3 protein (DPYSL3) in response to NMDA and H2O2 toxicity, J. Neurochem. 95 (2005) 466–474; R. Kowara, K.L. Moraleja, B. Chakravarthy, Involvement of nitric oxide synthase and ROS-mediated activation of L-type voltage-gated Ca(2+) channels in NMDA-induced DPYSL3 degradation, Brain Res. 1119 (2006) 40–49]. The present study investigates the involvement of PLA₂ signaling in NMDA-induced DPYSL3 degradation. Exposure of rat primary cortical neurons (PCN) to PLA₂ and COX-2 inhibitors significantly prevented NMDA-induced DPYSL3 degradation. Since the metabolic product of PLA₂ signaling, PGE₂, which augments toxic effect of NMDA, is known to stimulate cAMP, the effect of adenyl cyclase activator (forskolin plus IBMX) and inhibitor (MDL12,300) on NMDA-induced DPYSL3 degradation was tested. Our data indicate that the activation of adenyl cyclase contributes to NMDA-induced DPYSL3 degradation. Furthermore, cAMP-dependent protein kinase (PKA) inhibitor PKI (14–22) provided additional evidence of PKA involvement in NMDA-induced DPYSL3 degradation. In summary, the obtained data show the contribution of PLA₂ signaling to NMDA-induced calpain activation and subsequent degradation of synaptic protein DPYSL3.     

Role of metalloproteinases in platelet function

Platelets contain and release matrix metalloproteinases (MMPs), their inhibitors (TIMPs) and disintegrin metalloproteinases (ADAMs) including MMP-1, MMP-2, MMP-3, MMP-9, MT1-MMP (MMP-14), ADAM-10, ADAM-17, ADAMTS-13, TIMP-1, TIMP-2 and TIMP-4. These proteins exert several effects regulating platelet functions such as agonist-stimulated platelet adhesion and aggregation, tumour cell-induced platelet aggregation and platelet-leukocyte aggregation. In this review, mechanisms of MMPs, TIMPs and ADAMs on platelets are discussed.     

A methoxylated fatty acid isolated from the brown seaweed Ishige okamurae inhibits bacterial phospholipase A2

A methoxylated fatty acid that inhibits phospholipase A(2) (PLA(2); EC 3.1.1.4) was purified from the brown seaweed Ishige okamurae. Approximately 8.1 mg of the inhibitory compound, 7-methoxy-9-methylhexadeca-4,8-dienoic acid, was isolated from 1 kg of I. okamurae powder. Recombinant PLA(2) derived from the pathogenic bacterium Vibrio mimicus was used as the target enzyme. The methoxylated fatty acid compound competitively inhibited PLA(2) with a Ki value of 3.9 microg/mL. The concentrations required for 50% inhibition of PLA(2), oedema and erythema were 1.0 microg/mL, 3.6 mg/mL and 4.6 mg/mL, respectively. The compound strongly inhibited PLA(2) activity in vitro and had potent antiinflammatory activity in vivo.     

Novel Lipid and Preservative-free Propofol Formulation: Properties and Pharmacodynamics

Purpose

Propofol is a water-insoluble intravenous anesthetic agent that is actually formulated as a water-in-oil emulsion with known drawbacks such as pain on injection, microorganism growth support and stability. We report on the properties of formulations of propofol in poly (N-vinyl-2-pyrrolidone)-block-poly(d,l-lactide), PVP–PLA, polymeric micelles (Propofol-PM).

Methods

Microbial growth in these formulations was evaluated with Pseudomonas aeruginosa (ATCC 9027), Staphylococcus aureus (ATCC 6538), Escherichia coli (ATCC 25922) and Candida albicans (ATCC 10231). Sleep-recovery studies in female Sprague–Dawley rats, at a dose of 10mg/kg were performed to compare pharmacodynamic profiles of the new Propofol-PM formulations with those of Diprivan®, a commercially available lipid based propofol formulation.

Results

Growth of microorganisms was not supported in the Propofol-PM formulations tested. No significant differences in times to unconsciousness, awakening, recovery of righting reflex and full recovery were observed between Propofol-PM formulations and Diprivan®.

Conclusions

Propofol loaded in PVP–PLA micelles (Propofol-PM) is not significantly different in terms of pharmacodynamic but demonstrates no microorganism growth support and improved stability that opens up the door to pain on injection reduction strategy.

     

Histopathological and ultrastructural changes in liver tissue from burned patients

Histopathological studies were made on samples of liver and spleen tissue taken post mortem from 59 patients with severe burns. Samples from 8 patients were also studied using the transmission electron microscope. The main pathological findings were degeneration and necrosis of hepatic cells and proliferation of Kupffer cells showing active phagocytosis. Their causes in relation to the time of death after burning and severity of injury have been discussed. The proliferation of Kupffer cells may be a compensatory reaction to the severe splenic injury seen in the patients.     

大鼠重症急性胰腺炎中胰酶自身消化作用及善得定治疗效果

目的:观察大鼠重症急性胰腺炎中胰酶的自身消化作用及善得定的治疗效果.方法:以3%牛磺胆酸钠经胆胰管逆行注射制成大鼠重症急性出血坏死性胰腺炎(SAP)并用善得定进行治疗,并观察血清、十二指肠液、胰腺组织磷脂酶A_2(PLA_2)活性变化及胰腺组织学改变.结果:SAP6小时出现严重的胰腺出血坏死,血清PLA_2活性显著升高(P<0.01),十二指肠液、胰腺组织PLA_2活性显著降低(P<0.01),12小时后均进行性降低,胰腺组织学改变则进行性加重;治疗组12小时内的三种PLA_2活性比对照组显著改善(P<0.01).结论:胰酶自身消化是SAP早期胰腺病变的主要原因,善得定对SAP有一定的治疗作用,但只宜早期应用,且持续时间不宜太长.     

Imaging and drug delivery using theranostic nanoparticles

Nanoparticle technologies are significantly impacting the development of both therapeutic and diagnostic agents. At the intersection between treatment and diagnosis, interest has grown in combining both paradigms into clinically effective formulations. This concept, recently coined as theranostics, is highly relevant to agents that target molecular biomarkers of disease and is expected to contribute to personalized medicine. Here we review state-of-the-art nanoparticles from a therapeutic and a diagnostic perspective and discuss challenges in bringing these fields together. Major classes of nanoparticles include, drug conjugates and complexes, dendrimers, vesicles, micelles, core-shell particles, microbubbles, and carbon nanotubes. Most of these formulations have been described as carriers of either drugs or contrast agents. To observe these formulations and their interactions with disease, a variety of contrast agents have been used, including optically active small molecules, metals and metal oxides, ultrasonic contrast agents, and radionuclides. The opportunity to rapidly assess and adjust treatment to the needs of the individual offers potential advantages that will spur the development of theranostic agents.     

解放军医学图书馆典阅环境改善的回顾与展望

对解放军医学图书馆建馆10余年典阅环境改善状况进行了回顾，并对建设多功能、高品位、人文化的图书馆内部环境的实践进行了总结和展望。     

树突状细胞吞噬PLA-AFP 218-226微球后诱导细胞毒性T淋巴细胞反应

目的研究树突状细胞（DC）吞噬包被有甲胎蛋白HLA—A2限制性表位肽（AFP218-226，LLNQHACAV）的聚乳酸微球（PLA—AFP218-226）后诱导的特异性细胞毒性T淋巴细胞（CTL）对肝癌细胞株HepG2和负载有AFP218-226的T2细胞株的毒性作用。方法用GM—CSF和IL-4诱导HLA—A2^＋的健康志愿者外周血单核细胞，LPS诱导成熟，使其分化为高纯度DC，在诱导过程中加入PLA—AFP218-226微球，用吞噬了PLA—AFP218-226微球的DC诱导自身T淋巴细胞，使其成为肝细胞癌（HCC）特异性CTL。用流氏细胞仪检测DC膜分子标志，T2细胞与AFP218-226结合实验检测HLA—A2分子与AFP218-226之间的亲合力，MTT法检测特异性CTL杀伤HepG2和T2细胞株的能力。结果AFP218-226与HLA—A2分子具有较高的亲合力，吞噬微球后的成熟DC高表达CD83、CD86、CD40等膜分子，其诱导的特异性CTL对HepG2和负载有AFP218-226的T2细胞株具有强的细胞毒作用。结论PLA—AFP218-226被DC细胞吞噬后，能够诱导HCC特异性CTL的产生，可能成为一种新型的抗肿瘤表位肽疫苗，在肝癌的防治中得到应用。