Semaphorins家族在骨自身动态平衡及代谢性骨病中的重要角色

背景：骨的形成是一个动态的过程,破骨细胞和成骨细胞参与该动态过程。Semaphorin家族最早是作为轴突导向分子而被发现,其在许多不同组织里面表达并调节很多生理过程,近来更发现其在调节破骨细胞和成骨细胞方面发挥了重要作用。目的：总结Semaphorin家族各因子在骨动态平衡中发挥的作用。方法：应用计算机检索PubMed和Web of science数据库中1993年6月至2014年1月关于Semaphorin家族各因子调控骨代谢的文章,以“semaphorin,sema”为检索词进行检索;排除与研究内容无关和内容重复的文章,保留48篇文章进行综述。结果与结论：semaphorins在骨的细胞生物学方面是一类新型的调控分子,研究显示semaphorins通过一些特殊的机制很活跃的参与了骨的重塑过程,semaphorin家族蛋白在骨自身动态平衡中很关键,这些发现给治疗骨质疏松、骨硬化症、关节假体旁骨溶解等骨病提供了一种新颖的方法及治疗靶点。 中国组织工程研究杂志出版内容重点：组织构建;骨细胞;软骨细胞;细胞培养;成纤维细胞;血管内皮细胞;骨质疏松;组织工程全文链接：     

Cerebellar dysfunction may play an important role in vascular dementia

The cerebellum has traditionally been seen as a brain area limited to the coordination of voluntary movement, gait, posture, speech, and motor functions. There are increasing evidence, however, proving that the cerebellum is implicated in processes associated with the control of cognition, behavior, and psychiatric illness. Furthermore, the fact that the cerebellum is reciprocally connected to a broad range of limbic structures including the amygdale and hippocampus, as well as the cerebral cortex including the prefrontal areas, provides a strong neuroanatomical argument in favor of cerebellar involvement in cognition regulation. Studies have already found the fact that after stroke, the cerebellum suffered from reduction in metabolism and blood flow in the cerebellar hemisphere contralateral to a destructive cerebral lesion. The notion of crossed cerebellar diaschisis (CCD) may contribute to the explanation of the phenomenon. Consequently, theoretically, stroke in any part of the brain including frontal lobe and hippocampus, will affect cerebellar function and the later then results in vascular dementia (VD). More recently, a few clinical trials found that electrical stimulation of fastigial nucleus (FNS) in cerebellum could improve symptom of VD, though the relationship between cerebellum and VD is unclear. Taken together, there seems to be sufficient empirical ground to assume that the cerebellum plays a role in the regulation of VD. The hypotheses of cerebellar role in VD, which will be discussed in this paper, if confirmed, may lead to the formulation of new pathogenesis and new therapeutic approaches to VD.     

Cerebellar dysfunction may play an important role in post-stroke depression

The cerebellum has traditionally been looked upon as a brain area primarily involved in motor behavior. The last decade has however heralded the cerebellum as a brain region of renewed interest for neuropsychiatric disorders. The relationship between cerebellum and neuropsychiatric disorders are increasingly understood. Recent data suggests that cerebellar dysfunction may be common, especially in depression. Other studies have suggested that cerebellar dysfunction is associated with poor mood. More recently, there are a few clinical trials found that electrical stimulation of fastigial nucleus in cerebellum could improve symptom of post-stroke depression (PSD), though the relationship between cerebellum and PSD is unclear. Given that the relationship between cerebellum and neuropsychiatric disorders has been recognized, and that it seems that there is a similar pathogenesis association between neuropsychiatric disorders (especially for depression) and PSD which appears as a special type of mental illness among neuropsychiatric disorders. The hypotheses of cerebellar role in PSD, which will be discussed in this paper, has been proposed. If confirmed, this hypothesis may lead to the formulation of new pathogenesis and new therapeutic approaches to PSD.     

Hapten may play an important role in food allergen-related intestinal immune inflammation

There has been a significant increase in the prevalence of allergic diseases especially over the past 2 to 3 decades. However, the etiology and pathogenesis of food allergy are not fully understood. In recent years, with the huge increase in atopic disease, there has also been an increase in dietary hapten exposure. Allergic reactions to chemical haptens occur, in the overwhelming majority of cases, as an inflammatory reaction in the skin to direct contact with haptens. While reactions to haptens on other epithelial surfaces have only rarely been investigated; it is still not clear whether haptens can combine the food antigens and play a role in the induction of food allergen-related inflammation in the intestine. Further research is needed to reveal the underlying mechanism.     

Platelets play an important role in TNF-induced microvascular endothelial cell pathology.

Tumor necrosis factor-alpha (TNF) is known to be an important mediator in the pathogenesis of several inflammatory diseases. Vascular endothelial cells represent a major target of TNF effects. Platelet sequestration has been found in brain microvessels during experimental cerebral malaria and lung in experimental pulmonary fibrosis, implying that it may participate in TNF-dependent microvascular pathology. In this study, we investigated the mechanisms of platelet-endothelial interaction, using co-cultures between platelets and TNF-activated mouse brain microvascular endothelial cells (MVECs). Adhesion and fusion of platelets to MVECs was evidenced by electron microscopy, dye transfer, and flow cytometry. It was induced by TNF and interferon-gamma and depended on LFA-1 expressed on the platelet surface and ICAM-1 expressed on MVECs. The adhesion and fusion also led to the transfer of platelet markers on the MVEC surface, rendering these more adherent for leukocytes, and to an enhanced MVEC sensitivity to TNF-induced injury. These results suggest that platelets can participate in TNF-induced microvascular pathology.     

Surface proteins of Staphylococcus aureus play an important role in experimental skin infection

Staphylococcus aureus is the most common cause of skin infections that range from mild diseases up to life‐threatening conditions. Mechanisms of S. aureus virulence in those infections remain poorly studied. To investigate the impact of S. aureus surface proteins on skin infection, we used mouse models of skin abscess formation and skin necrosis, induced by a subcutaneous injection of bacteria. In the skin abscess model, a sortase‐deficient S. aureus strain lacking all of its cell‐wall anchored proteins was less virulent than its wild‐type strain. Also, strains specifically lacking protein A, fibronecting binding proteins, clumping factor A or surface protein SasF were impaired in their virulence. When a model of dermonecrosis was studied, the S. aureus surface proteins could not be shown to be involved. In summary, surface proteins play an important role in virulence of S. aureus skin abscess infections, but not in formation of skin necrosis.     

Lipid rafts play an important role in the vesicular stomatitis virus life cycle

Lipid rafts are involved in the life cycle of many viruses. In this study, we investigated the role of lipids in the life cycle of vesicular stomatitis virus (VSV). Cholesterol depletion by pretreatment of BHK cells or VSV particles with methyl-β-cyclodextrin (MβCD), a cholesterol-sequestering drug, inhibited the production of VSV dramatically. This effect was reversible, and virus production was restored by the addition of cholesterol, indicating that the reduction was caused by the loss of cholesterol in the cell membrane and virus, respectively. Cholesterol depletion at the adsorption stage also reduced the production of VSV significantly, but in contrast, only had a limited effect on virus production at the post-entry stage. Inhibition of sphingomyelin by myriocin treatment only showed a minor effect on VSV production. However, reduction of cholesterol and sphingomyelin at the same time dramatically reduced VSV production, showed a significant synergistic effect. These results suggest that lipid rafts play an important role in the life cycle of VSV.     

Could the airway epithelium play an important role in mucosal immunoglobulin A production?

Immunoglobulin (Ig) A is the major immunoglobulin of the healthy respiratory tract and is thought to be the most important immunoglobulin for lung defence. The basis for the preferential generation of IgA-secreting cells in the airway mucosa remains unclear. Given the half-life of 5 days for the majority of IgA plasma cells, many IgA plasma cells must develop daily from B cells to guarantee a continuous supply of IgA antibodies in the airway mucosa. For this, the surrounding cells must provide a constant supply of cytokines necessary for B-cell isotype switch, growth and differentiation into IgA-secreting plasma cells. Studies with CD4+ T-cell knockout mice, T-cell receptor knockout mice and mice made transgenic for CTLA4-Ig demonstrate normal mucosal IgA isotype switch, differentiation and IgA production, thereby suggesting that T cells are not critical for mucosal IgA production, and that other cell sources may be more important. Also, the bronchus-associated lymphoid tissue (BALT), which is believed to be the major site where IgA isotype switch and differentiation of B cells into plasma cells occur with the help of cytokines released by T cells, is not a constitutive feature of the normal human lung. This indicates that other parts of the respiratory tract must carry out the BALT function. We have recently demonstrated that healthy human airway epithelial cells constitutively produce IL-5, a major cytokine implicated in the growth and differentiation of post-switch mIgA+ B cells to IgA-producing plasma cells. Several studies have recently reported that the human airway epithelium also constitutively produces IL-2, TGFbeta, IL-6 and IL-10, factors which are essential for B-cell clonal proliferation, IgA isotype switch and differentiation into IgA-producing plasma cells. The close proximity of B cells to the airway epithelium probably ensures a constant supply of growth and differentiation factors necessary for mucosal IgA production. In addition, the epithelial cells produce a glycoprotein, called the secretory component, which not only confers increased stability to S-IgA, but is also quantitatively the most important receptor of the mucosal immune system, since it is responsible for the external transport of locally produced polymeric IgA and IgM. Recent studies also suggest a possible role for epithelial cells in antigen presentation. Dendritic cells situated within the airway epithelium could directly present antigens to B cells and direct their isotype switch towards IgA1 and IgA2 with the help of cytokines produced by epithelial cells. Airway epithelial cells could therefore play a major role in the production of mucosal IgA antibodies which are essential for airway mucosal defence.     

Substance P and CGRP do not play an important role in TNFα-induced inflammation

Previously,we have shown a role for TRPV1 in CFA-induced joint inflammation and suggested an involvement ofTNFα [1]. We have now investigated mechanisms involved in TNFα-induced inflammation in the mouse paw. The possible role of neuropeptides was investigated, since TRPV1 activation leads to CGRP and substance P release. NK₁ ^?/? and CGRP^?/? mice matched with their respective wild-types were used. Mice were given intraplantar injections ofTNF a (10pmol/50μl) and Tyrode (contralateral paw; 50μl). One group ofCG RP^-/-) mice were pretreated with the NK₁ receptor antagonist, SR140333 (480nmol/kg i.v.). Thermal hyperalgesic thresholds were measured using the Hargreaves technique before and over 4 hours after injection. Paw mass and neutrophil accumulation were measured. All the mice exhibited bilateral hyperalgesia, significant paw oedema and neutrophil accumulation in the TNFα-treated paw. These results suggest that substance P and CGRP are not important in development of hyperalgesia, oedema or neutrophil accumulation in this model.     

Distal regulatory elements play an important role in regulation of the human IL-5 gene

Eosinophil infiltration of the lung is a feature of both allergic and nonallergic asthma, and IL-5 is the key cytokine regulating the production and activation of these cells. Despite many studies focusing on the IL-5 promoter in both humans and mice there is as yet no clear picture of how the IL-5 gene is regulated. The aim of this study was to determine if distal regulatory elements contribute to appropriate regulation of the human IL-5 (hIL-5) gene. Activity of the -507/+44 hIL-5 promoter was compared to expression of the endogenous IL-5 gene in PER-117 T cells. The IL-5 promoter was not sufficient to reproduce a physiological pattern of IL-5 expression. Further, functional analysis of the 5' and 3' intergenic regions revealed a number of novel regulatory elements. We have identified a conserved enhancer located approximately 6.2 kb upstream of the hIL-5 gene. This region contains two potential GATA-3-binding sites and increases expression from the hIL-5 promoter by up to ninefold.     

Neutrophils play an important role in host resistance to respiratory infection with Acinetobacter baumannii in mice

Acinetobacter baumannii has emerged as a major cause of both community-associated and nosocomial pneumonia, but little is known about the cellular and molecular mechanisms of host defense against respiratory infection with this bacterial pathogen. In this study, we examined the role of neutrophils in host resistance to pulmonary A. baumannii infection in a mouse model of intranasal (i.n.) infection. We found that neutrophils were rapidly recruited to the lungs following i.n. inoculation of the pathogen and declined to baseline level upon clearance of the infection. Depletion of neutrophils using monoclonal antibody RB6-8C5 prior to infection resulted in an acute lethal infection that was associated with enhanced bacterial burdens in the lung (P < 0.05) and extrapulmonary dissemination to the spleen. The increased susceptibility to A. baumannii in neutropenic mice was associated with a delay in the mRNA expression and production of early proinflammatory cytokines such as tumor necrosis factor alpha, interleukin-6, keratinocyte chemoattractant protein, monocyte chemoattractant protein 1, and macrophage inflammatory protein 2 (MIP-2) in the lungs and development of severe bronchopneumonia and lymphoid tissue destruction in the spleen. Moreover, i.n. administration of the neutrophil-inducing chemokine MIP-2 to normal mice induced a pulmonary influx of neutrophils and significantly enhanced the clearance of A. baumannii from the lungs (P < 0.01). These results imply that neutrophils play a critical role in host resistance to respiratory A. baumannii infection.     

The extracellular signal-regulated kinase pathway may play an important role in mediating antidepressant-stimulated hippocampus neurogenesis in depression

Understanding the reasons for the delayed action of antidepressants in patients with depression is an important step in the effort to understand the etiology and course of this disabling condition. Researches using animal models of depression find that depression is associated with impaired neurogenesis and structural plasticity in specific regions of the brain. Chronic treatment with antidepressants increases neurogenesis and reduces animal behaviors that are associated with depression. Other studies suggests that neurogenesis is an important component of the mechanism of action of both antidepressants and mood stabilizers. Moreover, the time course of increased neurogenesis is parallel to that of the behavioral effects, and animals with higher baseline hippocampus neurogenesis have a more rapid response to antidepressants. However, the molecular mechanisms that link antidepressants, neurogenesis and behavioral changes remain unknown. Previous research has shown that the extracellular signal-regulated kinase (ERK) signaling pathway plays an important role in regulating neurogenesis and synaptic plasticity in the brain and is activated by antidepressants and mood stabilizers. We hypothesize that the ERK pathway is the mechanism by which antidepressants regulate neurogenesis in the hippocampus and, thus, should be considered a potential target for the development of new antidepressants.     

Altered mitochondrial energy metabolism may play a role in vascular aging

Epidemiological studies demonstrated that even in the absence of other risk factors (e.g., diabetes, hypertension, hypercholesterolemia), vascular aging significantly increases cardiovascular morbidity. Previous studies revealed that vascular aging is characterized by an age-dependent decline in endothelial function due to a decreased bioavailability of NO and increased production of reactive oxygen species. Yet, the mechanisms underlying the process of vascular aging are still poorly understood. Many authors consider that aging is a mitochondrial disease. Indeed, there is evidence that aging is associated with an increase in mtDNA damage and a decline in expression/activity of mitochondrial enzymes in various organs. On the basis of recent observations we predict that similar changes in mitochondrial gene expression profile are present in the aged cardiovascular system as well. It is significant, that components of the electron transport chain (including cytochrome c oxidase) seem to be similarly down-regulated with age in many species. Because pharmacological inhibition of mitochondrial energy metabolism significantly impairs endothelium-dependent vascular relaxation and may increase the production of reactive oxygen species, we propose that alterations of mitochondrial energetic phenotype may contribute to endothelial dysfunction in aging.     

Catecholamines may play an important role in the pathogenesis of transient mid- and basal ventricular ballooning syndrome

The exact pathogenesis of transient mid- and basal ventricular ballooning, a new variant of transient left ventricular (LV) ballooning, remains unknown. We report two cases of transient mid- and basal ventricular ballooning associated with catecholamines. These cases suggest that catecholamine-mediated myocardial dysfunction might be a potential mechanism of this syndrome.     

Direct vascular connection between adrenal gland and kidney may play an important role in pathogenesis of hypertension

A direct vascular connection between adrenal gland and kidney exists in various species. Thereby kidney function might be modified by the adrenal gland more precisely. In addition, the impact of adrenal hormones on the kidney function due to this circulatory 'by-pass' might be much stronger than judged from the relevant hormone concentrations in the circulating blood. Because overactivity of the sympatho-adrenal system is evident in essential hypertension we hypothesize that the adrenal-renal vascular connection plays an important role in the pathogenesis of arterial hypertension.     

线粒体及凋亡相关信号途径在脑缺血性损伤细胞死亡过程中的重要角色

背景：脑缺血后神经细胞病理变化的机制仍未完全阐明,现有的研究已经从细胞器水平,如线粒体等,深入研究其病理变化的机制。 目的：总结和讨论线粒体及凋亡相关信号途径在脑缺血性损伤中的作用。 方法：应用计算机检索CNKI和PubMed外文数据库,以“线粒体,凋亡,脑缺血,活性氧,再灌注,超氧化物歧化酶,一氧化氮合酶,Bcl-2蛋白家族,综述”为中文检索词,以“cerebral ischemia, mitochondrion, apoptosis,reactive oxygen species,reperfusion,superoxide dismutase,nitric oxide synthase,Bcl-2 protein family,review”为英文检索词,按纳入和排除标准对文献进行筛选,排除与研究目的无关和内容重复者,保留50篇文献做进一步分析。 结果与结论：现有的研究表明,线粒体可通过产生大量活性氧,进而激活多种信号途径,及调控线粒体相关凋亡途径在脑缺血性损伤中起重要的作用。活性氧在脑缺血导致的细胞死亡中有重要作用,不仅引起生物大分子损伤,而且可引起凋亡信号转导。线粒体产生大量的活性氧,从而激活多种信号通路及参与凋亡的内在途径调控,在细胞死亡中起重要作用。 中国组织工程研究杂志出版内容重点：组织构建;骨细胞;软骨细胞;细胞培养;成纤维细胞;血管内皮细胞;骨质疏松;组织工程全文链接：     

CD80 and CD86 C domains play an important role in receptor binding and co-stimulatory properties

CD80 and CD86 expressed on the surface of antigen-presenting cells interact with cytotoxic T lymphocyte antigen-4 [CTLA-4 (CD152)] expressed on activated T cells and mediate critical T cell inhibitory signals. CD80 and CD86 are type I glycoproteins, and are made up of two extracellular (EC) Ig-like domains-a transmembrane region and a cytoplasmic tail. The N-terminal (V domain) and membrane-proximal (C) domains share homology with the variable region (V) and the constant region (C) of Ig respectively. Co-crystallographic structures of both CD80 and CD86 bound to CTLA-4 indicate that there is no direct interaction of the C domain of either CD80 or CD86 with the CTLA-4. In contrast, previous mutagenesis studies have identified specific amino acids within the C domain of CD80 that are critical for CTLA-4 binding. To further understand the importance of C domains in the functioning of CD80 and CD86, we constructed chimeric human CD80 and CD86 molecules by swapping their respective C domains, and tested their ability to stimulate T cells. A Chinese hamster ovary (CHO) cell line expressing CD86 activated murine T cells. In contrast, CHO cells expressing either CD80 or a chimeric construct of the CD86 V domain and the CD80 C domain showed a significantly reduced activation. Our studies further demonstrated that the decreased activation by cells expressing the CD80 or a chimera containing CD80 C domain is most likely due to enhanced CTLA-4 binding. From these results we conclude that C domains play a critical, albeit indirect, role in determining CTLA-4 binding affinities and co-stimulatory properties.