肝素结合表皮生长因子在高血压大鼠心肌表达及氯沙坦对其影响

目的探讨肝素结合表皮生长因子(HB-EGF)在自发高血压大鼠(SHR)心肌表达情况及氯沙坦对其影响。方法取16只8周龄自发性高血压大鼠,随机分为两组,每组8只:氯沙坦干预组,给予氯沙坦30mg/kg·d溶于饮水灌胃治疗;SHR阳性对照组给予正常饮水。另有8只同龄同源雄性正常血压Wistar-kyoto大鼠(WKY)组作为正常对照组。实验周期12周。观察血压、左室重量/体重(LVW/BW);逆转录多聚酶链反应(RT-PCR)和免疫组化实验检测各组大鼠HB-EGFmRNA的表达情况。结果正常对照组和氯沙坦组血压和LVW/BW均底于SHR阳性对照组;SHR阳性对照组HB-EGFmRNA表达均高于正常对照组和氯沙坦组;氯沙坦组HB-EGFmRNA表达高于正常对照组。结论肝素结合表皮生长因子在自发高血压大鼠组表达明显增加而氯沙坦能部分阻断HB-EGFmRNA的表达提示HB-EGFmRNA可能在高血压发生发展过程中起了一定作用。     

血清HB-EGF对冠状动脉支架内再狭窄的影响

目的探讨血清肝素结合表皮生长因子样生长因子(HB-EGF)水平对冠状动脉支架内再狭窄的影响。方法选取2009～2010年在淮北市矿工总医院复查造影的既往接受PCI术患者80例进行研究。以支架内狭窄≥50%为再狭窄标准,将患者分为再狭窄组36例及非再狭窄组44例。所有患者均于造影前采空腹血,测定血清中HB-EGF水平。结果再狭窄组血清HB-EGF水平显著高于非再狭窄组,差异有统计学意义(P<0.05),多因素Logistic回归分析显示:血清中HB-EGF水平的B:0.112,OR:1.025,95%CI:0.989～1.250(P<0.05)。结论血清中HB-EGF水平升高促进了支架内的内膜增殖及血管重构,是冠状动脉支架内再狭窄的危险因素之一。     

The tyrphostin AG1478 inhibits proliferation and induces death of liver tumor cells through EGF receptor-dependent and independent mechanisms

Hepatocellular carcinoma (HCC) is one of the most common causes of cancer-related death. Different signaling pathways are de-regulated in this pathogenesis, among them the epidermal growth factor receptor one (EGFR/Erb1). Here we show that blockage of this pathway by the tyrphostin 4-(3-chloroanilino)-6,7-dimethoxyquinazoline (AG1478) in different liver tumor cell lines promotes both inhibition of cell proliferation and induction of cell death, which are coincident with arrest in the G1 phase of the cell cycle, caspase-3 activation and DNA fragmentation. AG1478 up-regulates the expression of the pro-apoptotic member of the BCL-2 family BIM and down-regulates the expression of the anti-apoptotic BCL-XL and MCL1. Furthermore, it also decreases the levels of the caspase inhibitors HIAP2 and XIAP. The treatment of HCC cells with AG1478 enhanced the apoptosis induced by other pro-apoptotic stimuli, such as the physiological cytokine, TGF-β, highly expressed in liver tumors, or the chemotherapeutic drug doxorubicin. The effects observed by AG1478 were broader than the ones seen by silencing of the EGFR with siRNA, which indicates that this drug might act on other targets different from the EGFR. In this same line of evidence, AG1478 retained some cytotoxic effects in cells where EGFR has been targeted knock-down with shRNA. Interestingly, AG1478 preferentially acts on liver tumor cells, being untransformed cells much less responsive to its cytotoxic effects. In conclusion, AG1478 could be a potential therapeutic drug to be used in HCC.     

The ADAMs family: coordinators of nervous system development, plasticity and repair

A disintegrin and metalloprotease (ADAM) transmembrane proteins have metalloprotease, integrin-binding, intracellular signaling and cell adhesion activities. In contrast to other metalloproteases, ADAMs are particularly important for cleavage-dependent activation of proteins such as Notch, amyloid precursor protein (APP) and transforming growth factor alpha (TGFalpha), and can bind integrins. Not surprisingly, ADAMs have been shown or suggested to play important roles in the development of the nervous system, where they regulate proliferation, migration, differentiation and survival of various cells, as well as axonal growth and myelination. On the eleventh anniversary of the naming of this family of proteins, the relatively unknown ADAMs are emerging as potential therapeutic targets for neural repair. For example, over-expression of ADAM10, one of the alpha-secretases for APP, can prevent amyloid formation and hippocampal defects in an Alzheimer mouse model. Another example of this potential neural repair role is the finding that ADAM21 is uniquely associated with neurogenesis and growing axons of the adult brain. This comprehensive review will discuss the growing literature about the roles of ADAMs in the developing and adult nervous system, and their potential roles in neurological disorders. Most excitingly, the expanding understanding of their normal roles suggests that they can be manipulated to promote neural repair in the degenerating and injured adult nervous system.     

Epidermal Hyperplasia and Elevated HB-EGF are More Prominent in Retinoid Dermatitis Compared with Irritant Contact Dermatitis Induced by Benzalkonium Chloride

Background

''Retinoid dermatitis'' is a retinoid-induced irritant contact dermatitis (ICD). The mechanism of retinoid dermatitis may be different from that of other ICDs. However, it remains uncertain how topical retinoid induce ICD.

Objective

We compared several aspects of contact dermatitis induced by topical retinol and benzalkonium chloride (BKC) on hairless mice skin.

Methods

2% retinol or 2.5% BKC was applied to hairless mice and transepidermal water loss (TEWL), ear thickness, histologic and immunohistochemical findings were compared. We also compared mRNA expression of inflammatory cytokines, epidermal differential markers, cyclooxygenases (COXs) and heparin binding epidermal growth factor like growth factor (HB-EGF).

Results

Topical application of 2% retinol and 2.5% BKC increased TEWL and ear thickness in similar intensity. Epidermal hyperplasia was more prominent in retinol treated skin. Proliferating cell nuclear antigen, involucrin and loricrin expression were higher in retinol-treated skin than in BKC-treated skin. Filaggrin, however, was more expressed in BKC-treated skin. The mRNA expression of IL-8, TNF-α, COX-2, involucrin, loricrin and filaggrin were increased in both retinol- and BKC-treated skin in similar intensity. HB-EGF was more significantly increased in retinol-treated skin.

Conclusion

Elevated HB-EGF and epidermal hyperplasia are more prominent features of retinoid dermatitis than in BKC-induced ICD.     

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.