Serotonin Deficiency Is Associated With Delayed Gastric Emptying

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Human adenosine A(3) receptor leads to intracellular Ca(2+) mobilization but is insufficient to activate the signaling pathway via phosphoinositide 3-kinase gamma in mice

Selective antagonists for the adenosine A(3) receptor (A3AR), a member of the G protein-coupled receptors, have been indicated as potential drugs for anti-asthma or anti-inflammation. However, potent antagonists for the rodent A3AR have not been identified. To evaluate the pharmacological effects of human A3AR antagonists in mice, we here generated A3AR-humanized mice, in which the mouse A3AR gene was replaced by its human counterpart. The expression levels of human A3AR in the A3AR-humanized mice were equivalent to those of mouse A3AR in wild-type mice. Elevation of the intracellular Ca(2+) concentration induced by an A3AR agonist was observed in bone marrow-derived mast cells from the A3AR-humanized mice and this Ca(2+) mobilization was completely antagonized by a human A3AR antagonist. However, antigen-dependent degranulation was not potentiated by the A3AR agonist in the mast cells from A3AR-humanized mice. The agonist-stimulated human A3AR did not lead to the phosphorylation of either extracellular signal-regulated kinase 1/2 or protein kinase B in A3AR-humanized mice. The rate of human A3AR internalization in the mast cells was also markedly decreased compared with that of mouse A3AR in the mast cells. These results demonstrate that the human A3AR is insufficient to activate phosphoinositide 3-kinase gamma-dependent signaling pathways in mice, probably due to the uncoupling of member(s) of the G proteins, which are capable of activating phosphoinositide 3-kinase gamma, to the human A3AR, despite the mouse G protein(s) responsible for the Ca(2+) elevation are coupled with the human A3AR.     

The role of NPY in hypothalamic mediated food intake

Neuropeptide Y (NPY) is a highly conserved neuropeptide with orexigenic actions in discrete hypothalamic nuclei that plays a role in regulating energy homeostasis. NPY signals via a family of high affinity receptors that mediate the widespread actions of NPY in all hypothalamic nuclei. These actions are also subject to tight, intricate regulation by numerous peripheral and central energy balance signals. The NPY system is embedded within a densely-redundant network designed to ensure stable energy homeostasis. This redundancy may underlie compensation for the loss of NPY or its receptors in germline knockouts, explaining why conventional knockouts of NPY or its receptors rarely yield a marked phenotypic change. We discuss insights into the hypothalamic role of NPY from studies of its physiological actions, responses to genetic manipulations and interactions with other energy balance signals. We conclude that numerous approaches must be employed to effectively study different aspects of NPY action.     

龙岩市2012年疑似预防接种异常反应监测分析

目的分析预防接种疑似异常反应(AEFI)的发生特征,评价AEFI信息管理系统运行状况和疫苗免疫的安全性。方法用描述性流行病学方法分析2012年度龙岩市疑似预防接种异常反应信息管理系统的数据。结果 2012年龙岩市共报告AEFI 215例,其中一般反应182例(84.65%),异常反应30例(13.95%),偶合症2例(0.93%),心因性反应1例(0.47%)。23价肺炎疫苗引起AEFI的发生率最高,达74.55/10万剂次。0岁~2岁组儿童发生AEFI最多,占73.08%。AEFI报告完整率达100%,48 h内及时报告率为77%,48 h内及时调查率为98%,3 d内调查表报告率为70%。结论 AEFI报告质量和疫苗安全性良好,全市AEFI监测的完整性较好,但报告和调查的及时性有待提高。     

STRUCTURE AND FUNCTION OF DIPHTHERIA TOXIN: FROM PATHOLOGY TO ENGINEERING

Among bacterial protein toxins with an intracellular target, diphtheria toxin is one of the most studied. Since the first publication of its crystal structure in 1992, tremendous progress has been made describing the molecular events involved in its toxicity. However, the precise mechanism of translocation is not fully understood yet. The diphtheria toxin contains three structural domains, each carrying a distinct biological function implicated in the intoxication of the cell. The receptor-binding domain mediates the recognition of a specific receptor on the surface of targeted cells. This binding event allows the internalization of the toxin by the cells and its routing towards acidic intracellular compartments. The translocation (or transmembrane) domain, reacting to the low pH, penetrates the membrane and assists the transport of the catalytic domain through this membrane into the cytoplasm. There, the catalytic domain transfers an ADP-ribose from cytosolic NAD to its substrate, the elongation factor 2. This activity blocks the synthesis of cellular proteins, leading to cell death. All three domains of the diphtheria toxin, isolated or combined with other proteins, are now exploited for their biological properties to design new biotechnological tools and new therapeutics.     

Poly(ADP-ribose) polymerase inhibitor therapeutic effect: are we just scratching the surface?

Poly(ADP-ribose) polymerase (PARP) research has come a long way since the discovery of the enzyme 50 years ago. Since the development of first-generation PARP inhibitors (PARPi), numerous clinical trials have been performed to validate their safety and efficacy, bringing us to the stage at which a PARPi is now a valuable treatment option for patients with ovarian cancer. Nevertheless, the exact molecular mechanism of the PARPi anti-tumor effect is under debate and PARPi are not specific for a single enzyme. Moreover, the anti-inflammatory activity of PARPi in preclinical experiments has not been explored much so far. Thus, further basic and preclinical research is needed to advance the use of PARPi in the treatment of tumors and potentially other inflammation-associated diseases.     

Alginate Nanoparticles as a Promising Adjuvant and Vaccine Delivery System

During last decades, diphtheria has remained as a serious disease that still outbreaks and can occur worldwide. Recently, new vaccine delivery systems have been developed by using the biodegradable and biocompatible polymers such as alginate. Alginate nanoparticles as a carrier with adjuvant and prolong release properties that enhance the immunogenicity of vaccines. In this study diphtheria toxoid loaded nanoparticles were prepared by ionic gelation technique and characterized with respect to size, zeta potential, morphology, encapsulation efficiency, release profile, and immunogenicity. Appropriate parameters (calcium chloride and sodium alginate concentration, homogenization rate and homogenization time) redounded to the formation of suitable nanoparticles with a mean diameter of 70±0.5 nm. The loading studies of the nanoparticles resulted in high loading capacities (>90%) and subsequent release studies showed prolong profile. The stability and antigenicity of toxoid were evaluated by sodium dodecyl sulfate polyacrylamide gel electrophoresis and ouchterlony test and proved that the encapsulation process did not affect the antigenic integrity and activity. Guinea pigs immunized with the diphtheria toxoid-loaded alginate nanoparticles showed highest humoral immune response than conventional vaccine. It is concluded that, with regard to the desirable properties of nanoparticles and high immunogenicity, alginate nanoparticles could be considered as a new promising vaccine delivery and adjuvant system.