NHE blockade inhibits chemokine production and NF-kappaB activation in immunostimulated endothelial cells

Na⁺/H⁺exchanger (NHE) activation has been documented to contribute toendothelial cell injury caused by inflammatory states. However, therole of NHEs in regulation of the endothelial cell inflammatoryresponse has not been investigated. The present study tested thehypothesis that NHEs contribute to endothelial cell inflammationinduced by endotoxin or interleukin (IL)-1. NHE inhibition usingamiloride, 5-(N-ethyl-N-isopropyl)-amiloride, and5-(N-methyl-N-isobutyl)amiloride as well as thenon-amiloride NHE inhibitors cimetidine, clonidine, and harmalinesuppressed endotoxin-induced IL-8 and monocyte chemoattractant protein(MCP)-1 production by human umbilical endothelial vein cells (HUVECs). The suppressive effect of amiloride on endotoxin-induced IL-8 production was associated with a decreased accumulation of IL-8 mRNA.NHE inhibitors suppressed both inhibitory (I)B degradation andnuclear factor (NF)-B DNA binding, suggesting that a decrease inactivation of the IB-NF-B system contributed to the suppression of HUVEC inflammatory response by NHE blockade. NHE inhibition decreased also the IL-1-induced HUVEC inflammatory response, becauseamiloride suppressed IL-1-induced E-selectin expression on HUVECs.These results demonstrate that maximal activation of the HUVECinflammatory response requires a functional NHE.

     

LPS诱导乳鼠心肌细胞p38蛋白激酶的激活与转位

探讨p38蛋白激酶信号传导通路在细胞中的特异性作用机制。应用共聚焦激光扫描技术观察心肌细胞中p38蛋白激酶的分布及LPS对其分布的影响。结果提示未受刺激静止的及EGF刺激的心肌细胞中,p38在胞浆和胞核中荧光强度呈散性分布。LPS刺激30分钟后,细胞核区的荧光强度明显增强,而胞浆区域的荧光强度降低,心肌细胞受LPS刺激激活后,其p38蛋白激酶由胞浆转位到胞核。     

Impaired pulmonary artery contractile responses in a rat model of microgravity: role of nitric oxide.

Vascular contractile hyporesponsiveness is an important mechanism underlying orthostatic intolerance after microgravity. Baroreceptor reflexes can modulate both pulmonary resistance and capacitance function and thus cardiac output. We hypothesized, therefore, that pulmonary vasoreactivity is impaired in the hindlimb-unweighted (HLU) rat model of microgravity. Pulmonary artery (PA) contractile responses to phenylephrine (PE) and U-46619 (U4) were significantly decreased in the PAs from HLU vs. control (C) animals. N(G)-nitro-L-arginine methyl ester (10(-5) M) enhanced the contractile responses in the PA rings from both C and HLU animals and completely abolished the differential responses to PE and U4 in HLU vs. C animals. Vasorelaxant responses to ACh were significantly enhanced in PA rings from HLU rats compared with C. Moreover, vasorelaxant responses to sodium nitroprusside were also significantly enhanced. Endothelial nitric oxide synthase (eNOS) and soluble guanlyl cyclase expression were significantly enhanced in PA and lung tissue from HLU rats. In marked contrast, the expression of inducible nitric oxide synthase was unchanged in lung tissue. These data support the hypothesis that vascular contractile responsiveness is attenuated in PAs from HLU rats and that this hyporesponsiveness is due at least in part to increased nitric oxide synthase activity resulting from enhanced eNOS expression. These findings may have important implications for blood volume distribution and attenuated stroke volume responses to orthostatic stress after microgravity exposure.     

A plethora of painful molecules

Pain is a fundamental experience with a complex and multi-layered neurobiological basis. In recent years a powerful battery of techniques has been brought to bear to unravel the mechanisms by which painful stimuli are transduced and processed. There have been several recent discoveries regarding the molecular transduction mechanisms in nociceptors and novel molecular and cellular mechanisms underlying the spinal processing of painful stimuli. The mechanisms by which sensory neurons initiate hyperalgesia and touch evoked pain (allodynia) have been addressed particularly successfully in recent studies. The rich variety of key molecular players that have emerged in physiological and pathophysiological pain states reflects the sophistication and uniqueness of this vitally important sense.     

沉默交配型信息调节因子2同源蛋白Sirt1

沉默交配型信息调节因子2同源蛋白1(silent mating type information regulation 2 homolog 1,Sirt1)是哺乳动物中与酵母沉默信息调节蛋白2(silencing information regulator 2,Sir2)高度同源的蛋白质,它是一种依赖NAD+的III类组蛋白去乙酰化酶(HDAC III),在细胞分化、衰老、凋亡、DNA损伤修复、能量及内分泌代谢调节中起重要作用,同时在基因沉默、表观遗传学修饰、转录调控及信号转导调节中发挥重要的生物学功能。本文对其近年的研究进展做一概述。     

A Single Intrathecal or Intraperitoneal Injection of CB2 Receptor Agonist Attenuates Bone Cancer Pain and Induces a Time-Dependent Modification of GRK2

The objective of this study was to explore the potential role of G-protein-coupled receptor kinase 2 (GRK2) in the progression of cannabinoid 2 receptor (CB2) agonist-induced analgesic effects of bone cancer pain. Female Sprague–Dawley rats, weighing 160–180 g, were utilized to establish a model of bone cancer pain induced by intra-tibia inoculation of Walker 256 mammary gland carcinoma cells. JWH-015, a selective CB2 agonist, was injected intrathecally or intraperitoneally on postoperative day 10. Bone cancer-induced pain behaviors—mechanical allodynia and ambulatory pain—were assessed on postoperative days ?1 (baseline), 4, 7, and 10 and at post-treatment hours 2, 6, 24, 48, and 72. The expressions of spinal CB2 and GRK2 protein were detected by Western Blotting on postoperative days ?1 (baseline), 4, 7, and 10 and at post-treatment hours 6, 24, and 72. The procedure produced prolonged mechanical allodynia, ambulatory pain, and different changes in spinal CB2 and GRK2 expression levels. Intrathecal or intraperitoneal administration of JWH-015 alleviated the induced mechanical allodynia and ambulatory pain, and inhibited the downregulation of spinal GRK2 expression. These effects were in a time-dependent manner and reversed by pretreatment of CB2 selective antagonist AM630. The results affirmed CB2 receptor agonists might serve as new treatment targets for bone cancer pain. Moreover, spinal GRK2 was an important regulator of CB2 receptor agonist-analgesia pathway.     

Sneathia属细菌与宫颈人乳头瘤病毒感染及宫颈病变的关系

高危型人乳头瘤病毒（human papilloma,HPV）的持续感染可导致宫颈癌前病变和宫颈癌。阴道微生物群在HPV感染和宫颈病变的发生中起主要作用。近年来,利用分子生物学测序技术揭示了Sneathia属细菌与HPV感染和宫颈病变密切相关,阴道菌群中Sneathia属细菌的富集可能促进了HPV感染及宫颈病变的发生,作用机制尚不清楚,但可能与破坏宫颈上皮和影响宿主免疫系统有关。Sneathia属细菌可能成为预防和治疗宫颈病变的潜在靶点。

     

Divergent strategies for controlling the nuclear membrane satisfy geometric constraints during nuclear division

Eukaryotes segregate chromosomes in "open" or "closed" mitosis, depending on whether their nuclear envelopes (NEs) break down or remain intact. Here we show that the control of the nuclear surface area may determine the choice between these two modes. The dividing nucleus does not expand its surface in the fission yeast Schizosaccharomyces japonicus, confining the mitotic spindle and causing it to?buckle. The NE ruptures in anaphase, releasing the compressive stress and allowing chromosome segregation.?Blocking the NE expansion in the related species Schizosaccharomyces pombe that undergoes closed mitosis induces spindle buckling and collapse in the absence of an intrinsic NE rupture mechanism. We propose that scaling considerations could have shaped the evolution of eukaryotic mitosis by necessitating either nuclear surface expansion or the NE breakdown.