HnRNP CBP35-CBP67 interaction during stress response and ageing

Previous studies have demonstrated the existence of nuclear carbohydrate binding proteins in a variety of mammalian cells with molecular masses of 35 000, 67 000, and 70 000 (CBP35, CBP67, and CBP70), which are associated with nuclear ribonucleoprotein (RNP) complexes. CBP35 consists of two domains, an aminoterminal portion that is homologous to certain regions of proteins of the heterogeneous nuclear RNP complex, and a carboxyl-terminal portion homologous to β-galactoside-specific lectins. CBP35 it has been proposed, like the glucose-specific lectin, CBP67, to guide RNP complexes through the nuclear pore. Here we show that the exposure of mature rats to stress induces an increase in nuclear CBP35 bound to CBP67 and retained on immobilized glucose. Nuclear extracts from the livers of old rats displayed no detectable stress response. This CBP35·CBP67 association detected in rat liver is considered with respect to the CBP35·CBP70 association recently observed in HL60 cell nuclear extracts.     

Accumulation of p53 in response to adenovirus early region 1A sensitizes human cells to tumor necrosis factor alpha-induced apoptosis

Many tumor cells are resistant to tumor necrosis factor alpha (TNFalpha)-induced apoptosis. Adenovirus early region 1A (AdE1A) sensitizes the otherwise resistant cells to TNFalpha. AdE1A also stabilizes the p53 protein. The present study demonstrates a correlation between AdE1A-induced sensitization and stabilization of p53 in TNFalpha-induced apoptosis since the N-terminal and CR2 regions, the binding sites for CBP/p300, Rb and 26S proteasome regulatory components, are required for both these actions of AdE1A. TNFalpha does not induce apoptosis and AdE1A fails to sensitize TNFalpha cytotoxicity in p53-negative cells. However, introduction of exogenous p53 overcomes the cellular resistance to TNFalpha toxicity and enhances AdE1A sensitization, demonstrating that AdE1A sensitizes TNFalpha-induced apoptosis by its stabilization of p53. A proteasome inhibitor, lactacystin, enhances TNFalpha cytotoxicity in p53-positive and -negative cells, suggesting that accumulation of cellular proteins other than p53 might also regulate the cellular response to TNFalpha signaling.     

Sympathetic nervous system and chronic bladder pain: a new tune for an old song

Chronic bladder pain (CBP) patients present with pelvic pain or discomfort during bladder filling, for at least a period of 6 months, which may be accompanied by lower urinary tract symptoms such as frequency, nocturia, and urgency. However, both the etiology of CBP and pathophysiological mechanisms are not well described. A number of clinical and basic animal model findings support involvement of sympathetic nervous system in chronic pain syndromes such as CBP. Examples include sympathetic overactivity and high plasma or urinary catecholamine levels that have a high correlation with nociceptive symptoms. In this review, we explored the current evidence in support of the involvement of sympathetic overactivity in CBP. As bladder inflammation often occurs among subgroups of CBP patients, we discuss the possible role of sympathetic nervous system in mastocytosis as well examples examples of animal models that further support the involvement of sympathetic dysfunction in CBP. As there is substantive evidence for cross-organ sensitization in the pelvis can lead to co-morbidity of genitourinary and gastrointestinal dysfunctions, we also include how sympathetic dysfunction may play a role in a number of co-morbid chronic pain syndromes.     

连续性血液净化治疗对危重患者药物清除率影响的研究进展

本文通过查阅文献,了解药物本身药理学及连续性血液净化治疗（ CBP）的滤过膜材料、面积、孔径大小,透析液／超滤液流速,过滤器使用时间,血液滤过模式及滤过原理等对药物清除率的影响,总结连续性血液滤过治疗对各类药物清除率的研究进展。为临床医师调整治疗方案,更好地进行个体化治疗提供参考,同时为药物清除率的进一步研究开拓思路。     

Molecular dynamics of ultradian glucocorticoid receptor action

In recent years it has become evident that glucocorticoid receptor (GR) action in the nucleus is highly dynamic, characterized by a rapid exchange at the chromatin template. This stochastic mode of GR action couples perfectly with a deterministic pulsatile availability of endogenous ligand in vivo. The endogenous glucocorticoid hormone (cortisol in man and corticosterone in rodent) is secreted from the adrenal gland with an ultradian rhythm made up of pulses at approximately hourly intervals. These two components - the rapidly fluctuating ligand and the rapidly exchanging receptor - appear to have evolved to establish and maintain a system that is exquisitely responsive to the physiological demands of the organism. In this review, we discuss recent and innovative work that questions the idea of steady state, static hormone receptor responses, and replaces them with new concepts of stochastic mechanisms and oscillatory activity essential for optimal function in molecular and cellular systems.     

CBP/P300介导的组蛋白H3K9乙酰化修饰对GATA4表达的影响

目的 明确GATA4在小鼠胚胎心脏发育过程中的时序表达,并阐明其组蛋白修饰调控机制.方法 选取胎龄11.5 d(E11.5)至新生0.5d胎鼠心脏,RT-PCR检测胎鼠心肌细胞中GATA4mRNA表达水平,CHIP-QPCR检测GATA4启动子区组蛋白H3K9ac水平及与CBP/P300的结合水平.用CBP30干预心肌祖细胞,RT-PCR检测心肌祖细胞在不同浓度CBP30(0.5、1、2、4μmol/L)干预不同时间点(6、12、24、36 h)后GATA4 mRNA表达水平,CHIP-QPCR检测心肌祖细胞中GATA4启动子区组蛋白H3 K9 ac水平及与CBP/P300的结合水平.结果 ①小鼠胚胎心脏发育过程中GATA4表达量,E14.5明显高于E11.5(P ＜0.05);CHIP结果显示E14.5 GATA4启动子区组蛋白H3 K9 ac水平高于E11.5(P ＜0.05);E14.5与CBP/P300的结合水平亦高于E11.5(P ＜0.05).②CBP30干预心肌祖细胞后,GATA4表达量较对照组明显降低(P＜0.05).CHIP结果显示CBP30组GATA4启动子区组蛋白H3K9ac水平及与CBP/P300的结合水平较对照组显著降低(P＜0.05).结论 CBP/P300可通过介导组蛋白H3 K9乙酰化修饰参与调控GATA4在小鼠胚胎心脏发育过程中的时序表达.     

Lysophosphatidic acid-induced IL-8 secretion involves MSK1 and MSK2 mediated activation of CREB1 in human fibroblast-like synoviocytes

Lysophosphatidic acid (LPA) is a pleiotropic lipid mediator that promotes motility, survival, and the synthesis of chemokines/cytokines such as interleukin-8 (IL-8) and interleukin-6 by human fibroblast-like synoviocytes from patients with rheumatoid arthritis (RAFLS). In those cells LPA was reported to induce IL-8 secretion through activation of various signaling pathways including p38 mitogen-activated protein kinase (p38 MAPK), p42/44 MAPK, and Rho kinase. In addition to those pathways we report that mitogen- and stress-activated protein kinases (MSKs) known to be activated downstream of the ERK1/2 and p38 MAPK cascades and CREB are phosphorylated in response to LPA. The silencing of MSKs with small-interfering RNAs and the pharmacological inhibitor of MSKs SB747651A shows a role for both MSK1 and MSK2 in LPA-mediated phosphorylation of CREB at Ser-133 and secretion of IL-8 and MCP-1. Whereas CREB inhibitors have off target effects and increased LPA-mediated IL-8 secretion, the silencing of CREB1 with short hairpin RNA significantly reduced LPA-induced chemokine production in RAFLS. Taken together the data clearly suggest that MSK1 and MSK2 are the major CREB kinases in RAFLS stimulated with LPA and that phosphorylation of CREB1 at Ser-133 downstream of MSKs plays a significant role in chemokine production.     

连续性血液净化辅助治疗重症急性胰腺炎的临床效果及安全性

目的观察连续性血液净化治疗重症急性胰腺炎（SAP）的临床效果,分析此治疗方法的可行性与安全性,为临床应用提供理论依据。方法从2013年1月-2014年1月来本院消化科就诊的SAP患者中选取82例,随机分为观察组和对照组,每组各41例。两组患者在常规治疗的基础上,对照组加用乌司他丁,观察组加用乌司他丁与持续性血液净化。比较两组患者的腹痛等症状、体征减轻时间,C反应蛋白、血淀粉酶、脂肪酶等辅助检查结果恢复的正常时间,患者治愈时间、局部并发症发生率、改行手术治疗率和死亡率。结果经治疗,治疗组和对照组患者的腹痛等症状体征缓解时间及C反应蛋白、血淀粉酶及脂肪酶等辅助检查结果恢复正常时间,患者治愈时间、胰腺假性囊肿以及胰瘘等局部并发症发生率、改行手术治疗率差异均有统计学意义（P〈0.05）;两组患者的死亡率差异无统计学意义（P〉0.05）。结论连续性血液净化联合乌司他丁辅助治疗重症急性胰腺炎较常规治疗组症状、体征各项辅助检查结果恢复时间短,可降低局部并发症的发生率和改行手术治疗率,可行性、安全性高,值得临床推广应用。