Effects of Diethyldithiocarbamate on Activating Mechanisms of Neutrophils

The effects of diethyldithiocarbamate on superoxide release by rat neurophils were investigated in a chemiluminescence study. Diethyldithiocarbamate augmented lucigenin-dependent chemiluminescence in a concentration-dependent manner and inhibited luminol-dependent chemiluminescence at concentrations of 0.1-1 μM. In contrast, after the addition of 0.1 mM diethyldithiocarbamate, the chemiluminescence was markedly enhanced. Diethyldithiocarbamate inhibited both the myeloperoxidase activity of neutrophils and the chemiluminescence generated in a cell-free horseradish peroxidase/H₂O₂ and H₂O₂/HOCl system. The increase in lucigenin-dependent chemiluminescence brought about by diethyldithiocarbamate was inhibited by H-7, ML-7, W-7, EGTA and pertussis toxin. These results suggest that diethyldithiocarbamate may stimulate O₂^? production by a guanosine 5′-triphosphate protein-mediated and Ca²⁺–dependent process and that the increase in O₂^? release by neutrophils may be dependent not only on the direct stimulation of the signal transduction pathway but also on the increase in O₂^? by reducing the effect of the hydroperoxide (H₂O₂)-myeloperoxidase system.     

Antithrombotic effect of SM-20302, a nonpeptide GPIIb/IIIa antagonist, in a photochemically induced thrombosis model in guinea pigs.

SM-20302, a synthetic inhibitor of the fibrinogen receptor of platelets, has been shown to inhibit the platelet aggregation induced by various stimuli. In the present study, we performed ex vivo platelet aggregation studies by using heparinized platelet-rich plasma (PRP) as well as citrated PRP and compared the antiaggregatory activity with the in vivo antithrombotic efficacy of SM-20302. The oral administration of SM-20302 (0.3-10 mg/kg) to guinea pigs completely inhibited the ADP-induced ex vivo platelet aggregation in citrated PRP. In heparinized PRP, SM-20302 (1-10 mg/kg) showed a dose-dependent inhibition of ex vivo platelet aggregation, and it exhibited complete inhibition at a dose of 3 and 10 mg/kg, respectively. The concentration of ionized calcium in the citrated samples was approximately 35 times lower than that in heparinized samples. Chelation of ionized calcium caused an enhancement of the antiaggregatory activity of SM-20302 in guinea pig heparinized PRP in vitro. And addition of CaCl2 to citrated PRP reversed the enhancement. Citrate therefore appeared to enhance the inhibitory activity of SM-20302 by lowering the ionized calcium levels. We also examined the in vivo efficacy of SM-20302 in a photochemically induced femoral artery thrombosis model in guinea pigs. The photochemical injury of the endothelium of femoral artery resulted in a progressive decline in the blood flow. The oral administration of SM-20302 (0.1-3 mg/kg) produced a dose-dependent maintenance of the femoral artery patency and significantly prolonged the time to occlusive thrombus formation at a dose of 1 and 3 mg/kg, respectively. These results suggest that SM-20302 may be an orally active antithrombotic agent, and its in vivo antithrombotic efficacy appeared to correlate well with the ex vivo platelet inhibition in PRP prepared from heparinized blood but not in PRP anticoagulated with citrate.     

Progress in researches about focal adhesion kinase in gastrointestinal tract

Focal adhesion kinase (FAK) is a 125-kDa non-receptor protein tyrosine. Growth factors or the clustering of integrins facilitate the rapid phosphorylation of FAK at Tyr-397 and this in turn recruits Src-family protein tyrosine kinases, resulting in the phosphorylation of Tyr-576 and Tyr-577 in the FAK activation loop and full catalytic FAK activation. FAK plays a critical role in the biological processes of normal and cancer cells including the gastrointestinal tract. FAK also plays an important role in the restitution, cell survival and apoptosis and carcinogenesis of the gastrointestinal tract. FAK is overexpressed in cancer cells and its over-expression and elevated activities are associated with motility and invasion of cancer cells. FAK has been proposed as a potential target in cancer therapy. Small molecule inhibitors effectively inhibit the kinase activity of FAK and show a potent inhibitory effect for the proliferation and migration of tumor cells, indicating a high potential for application in cancer therapy.     

A severely calcified neointima 9 years after bare metal stent implantation

An increasing number of studies have reported intimal atherosclerotic changes, or neoatherosclerosis in the late phase after bare metal stent implantation, however, only a few reports have showed the presence of severe intimal calcification in a bare metal stent. We herein report a case of a 68-year-old male with severely calcified neointima occurring 9 years after the bare metal stent implantation. Pre-procedural coronary computed tomography angiography and peri-procedural intravascular ultrasound demonstrated severe calcification within the in-stent restenotic lesion. Although the pre-dilation balloon ruptured due to the calcification, the lesion was nevertheless successfully dilated with the stent. Calcified lesions often require complex techniques, and we therefore should be aware of the potential occurrence of a severely calcified neointima in coronary stents, and performing coronary computed tomography angiography in advance is a great help for performing effective coronary intervention.     

Fibrinogen date: congenital hypodysfibrinogenemia associated with decreased binding of tissue-plasminogen activator.

A new case of congenital hypodysfibrinogenemia associated with a thrombotic tendency (thrombosis of the peroneal artery, the pulmonary artery and the deep veins of the lower extremities), is reported. Clotting time using Reptilase was significantly prolonged. The low levels of plasma fibrinogen were demonstrated using both thrombin time (Clauss) method (45.0 mg/ml) and radial immunodiffusion technique (106.1 mg/ml). The fibrinogen is also characterized by a defective polymerization of fibrin monomers. Furthermore, the important functional property of this fibrinogen is that the patient's fibrin adsorbs approximately 31-38% of added tissue-plasminogen activator (t-PA) at the time of fibrin formation, whereas control fibrin can adsorb about 79% of added t-PA. This result could provide an explanation for the thrombotic tendency in this patient. This variant fibrinogen appears to have unique characteristics and has been designated as "Fibrinogen Date," according to the city where the proband has lived.