Mitogenic activity of oxidized lipoprotein (a) on human vascular smooth muscle cells

Although oxidized lipoproteins may play an important role in the progression of atherosclerosis, no report has mentioned the significance of oxidized lipoprotein (a) (Lp[a]) in the pathogenesis of cardiovascular disease. Initially, we compared the mitogenic actions of Lp(a) and oxidized Lp(a) on human vascular smooth muscle cells (VSMC). Lp(a) significantly stimulated the growth of human VSMC in a dose-dependent manner, whereas oxidized Lp(a) showed a stronger stimulatory action on VSMC growth than native Lp(a). Interestingly, antioxidants probucol and fluvastatin inhibited the oxidation of Lp(a). Moreover, the stimulatory effect of oxidized Lp(a) on human VSMC growth was significantly inhibited by probucol. Finally, we elucidated the molecular mechanisms of how Lp(a) stimulated the growth of VSMC. Extracellular signal-regulated kinase (ERK), as those controlled by kinases, modulate critical cellular functions such as cell growth, differentiation, and apoptosis, was transiently phosphorylated by oxidized Lp(a) as well as native Lp(a) from 5 minutes, and the phosphorylation disappeared within 30 minutes. The degree of ERK phosphorylation by oxidized Lp(a) was much higher than that by native Lp(a). Administration of a specific inhibitor of MEK, PD 98059, significantly attenuated VSMC growth induced by native Lp(a) or oxidized Lp(a) in a dose-dependent manner (P<0.01). The current study demonstrated that oxidized Lp(a) is more potent than native Lp(a) in stimulating VSMC growth. Oxidized Lp(a) may play an important role in the pathogenesis of vascular disease.     

Angiogenesis and antifibrotic action by hepatocyte growth factor in cardiomyopathy

Impairment of cardiac function in cardiomyopathy has been postulated to be related to decreased blood blow and increased collagen synthesis. Therefore, a therapeutic approach to alter the blood flow or fibrosis directly by means of growth factors may open a new therapeutic concept in dilated cardiomyopathy. From this viewpoint, hepatocyte growth factor (HGF) is a unique growth factor with antifibrosis and angiogenesis effects. Using the hereditary cardiomyopathic Syrian hamster as a model of genetically determined cardiomyopathy and heart failure, the effects of overexpression of HGF on fibrosis and microvascular dysfunction were examined. HGF gene or control vector was injected by the Hemagglutinating Virus of Japan-liposome method into the anterior heart of cardiomyopathic hamsters (Bio 14.6) under echocardiography once a week, from 12 to 20 weeks of age (total, 8 times). Blood flow, as assessed by a laser Doppler imager score, and the capillary density in hearts, as assessed by alkaline phosphatase staining, were significantly increased in hamsters transfected with HGF gene compared with control-vector-transfected hamsters (P<0.01). In contrast, the fibrotic area was significantly decreased in hamsters transfected with HGF gene compared with control (P<0.01). Overall, in vivo experiments demonstrated that transfection of HGF gene into the myocardium of cardiomyopathic hamsters stimulated blood flow through the induction of angiogenesis and reduction of fibrosis. These results suggest that HGF gene transfer may be useful to protect against myocardial injury in cardiomyopathy through its cardioprotective effects such as antifibrosis and angiogenesis actions.     

Mouthparts of male Aedes (Stegomyia) mosquitoes

Mouthparts of adult males of 17 strains of 8 species from the subgenus Stegomyia of the genus Aedes, including 5 strains of Aedes aegypti and 6 strains of Aedes albopictus, were examined. Lengths of maxillae, mandibles, maxillary palpi, and proboscises were measured under light microscopy and their detailed structures were examined by scanning electron microscopy. Lengths were presented as ratios to proboscis lengths. In contrast to previous reports, mandibles were found in all 5 strains of male Ae. aegypti examined. Variations in maxillary and mandibular lengths were significant among strains, even within Ae. aegypti and Ae. albopictus. High variation of these structures among and within species indicates that the average length of these structures in only 1 species may not be a reliable representative of a subgenus, and those of 1 strain may not be reliable for a species. However, their range in length (maxillae 0.13-0.50, mandibles 0.04-0.17 length of the proboscis) may be regarded as a subgeneric attribute. Maxillae and mandibles distinctly shorter than the proboscis, together with their delicate structures and the large coefficient of variation, suggest that they exist only as vestigial structures. A positive correlation was found between lengths of maxillae and those of mandibles, but mandibles are usually shorter than maxillae. The hypopharynx is discernible from the labium wall by its texture and border, and this suggests that it was a free stylet in the past.     

Uterine cervix metastasis from rectal carcinoma: a case report and a review of the literature

A 59-year-old woman underwent a radical hysterectomy for a metastatic uterine cervix tumor caused by rectal carcinoma, which had been previously resected. Metastatic carcinoma from the large bowel to the uterus is rare. A total of 48 patients (including nine Japanese patients) with metastasis from the large bowel to the uterus were reviewed. The metastatic site of the uterus was the cervix in 27 cases and the corpus in 18. The interval between primary carcinoma and the secondary diagnosis was 17 months. The mean survival after the diagnosis of the secondary deposit was 11 months. Our patient died of lymph node, lung, local and bone metastases 7 months after the diagnosis of the secondary deposit.     

Enhanced rectal absorption of insulin-loaded Pluronic F-127 gels containing unsaturated fatty acids.

The objective of this study was to prepare and to evaluate Pluronic F-127 (PF127) gel containing unsaturated fatty acids such as oleic acid (18:1), eicosapentaenoic acid (20:5) and docosahexaenoic acid (22:6) as a potential formulation for rectal delivery of insulin. The hypoglycemic effect of insulin was examined following rectal administration of the various formulations in normal rats. Rectal insulin absorption was markedly enhanced, and marked hypoglycemia was induced by all PF127 gels (insulin dose, 5 U/kg) containing different unsaturated fatty acids. PF127 gels containing unsaturated fatty acids presented low tmax mean values indicating that the absorption of insulin occurred very rapidly in the rectum. The relative hypoglycemic efficacy of PF127 gel formulations containing fatty acids such as oleic acid, eicosapentaenoic (EPA) and docosahexaenoic (DHA) were 28.4+/-8.1, 26.8+/-14.3 and 23.1+/-5.7%, respectively. The finding demonstrated that 20% PF127 gels containing unsaturated fatty acids are potential formulations for rectal delivery of insulin.     

Amplification of c-myc in hepatocellular carcinoma: correlation with clinicopathologic features, proliferative activity and p53 overexpression.

Expression of the proto-oncogene c-myc has been implicated in liver regeneration and hepatocarcinogenesis. The biologic significance of c-myc gene amplification in human hepatocellular carcinoma, however, is unconfirmed. We correlated c-myc gene amplification with clinicopathologic features, proliferative activity, and p53 expression in 42 resected tumors. c-myc amplification in tumor tissue was determined using a differential polymerase chain reaction, a useful procedure for the evaluation of gene amplification in archival formalin-fixed paraffin-embedded tissues, in comparison with a dopamine D2 receptor gene. Proliferative activity was estimated by numbers of argyrophilic nucleolar organizer regions and immunohistochemical nuclear labeling rates using a monoclonal antibody against Ki-67. The c-myc gene was amplified in 14 of 42 tumors (33.3%). Amplification of c-myc was more frequent in younger patients and in larger tumors, and less differentiated tumors. No correlation was noted with alpha-fetoprotein level or viral hepatitis state. The amplification showed positive correlation with both proliferative activity and p53 overexpression. Disease-free survival in patients showing c-myc amplification was significantly shorter than in those without amplification. These results suggest that c-myc amplification is an indicator of malignant potential and poor prognosis in hepatocellular carcinoma. c-myc amplification and p53 alteration may be coparticipating events in the progression of these tumors.     

Existence and pharmacological properties of dopamine D4 receptors in guinea pig vas deferens.

This study was carried out to identify subtypes of dopamine D2-like receptors in guinea pig isolated vas deferens. Dopamine had no effect on the muscle tone in the presence of prazosin, an alpha1-adrenoceptor antagonist. However, contractile responses to adenosine triphosphate (ATP), noradrenaline and acetylcholine were potentiated in a concentration dependent manner by dopamine in the presence of prazosin. This potentiation was not inhibited by raclopride, an antagonist for dopamine D2 and D3 receptors. However, the potentiation of ATP- and noradrenaline-induced contraction was inhibited by clozapine and 8-methyl-6-(4-methyl-1-piperazinyl)-11H-pyrido[2,3b][1,4]benzodiazepine (JL-18), dopamine D4 receptor antagonists. Further, the potentiation of noradrenaline- and acetylcholine-induced contraction was also inhibited by spiperone, an antagonist for dopamine D2, D3 and D4 receptors. These results suggest that the dopamine D4 receptor is located on the postsynaptic site of guinea pig vas deferens and that activation of the dopamine D4 receptor enhances contractile responses to agonists without affecting muscle tone.