We elucidated the effect of newly developed Fukuoka Apolipoprotein A-I Mimetic Peptide (FAMP) on in vivo macrophage reverse cholesterol transport (RCT) and the underlying mechanisms.Cholesteryl ester transfer protein transgenic mice were divided into FAMP, and placebo control groups, and injected with FAMP or phosphate buffer saline intraperitoneally for 5 days. The FAMP group showed a significant decrease in plasma high-density lipoprotein cholesterol (HDL-C), and plasma from the FAMP group had an increased ability to promote ATP-binding cassette transporter A1 (ABCA1)-mediated cholesterol efflux from bone marrow macrophages ex vivo. Furthermore, mice were injected intraperitoneally with 3H-cholesterol-labeled and cholesterol-loaded macrophages and monitored for the appearance of 3H-tracer. The amount of 3H-tracer excreted into feces over 48 h in the FAMP group was significantly higher than that in the control group. 3H-cholesterol ester (CE)-HDL was injected intravenously and 3H-cholesterol in blood was counted. In the FAMP group, plasma 3H-CE-HDL decreased rapidly, and treatment with FAMP markedly increased the fractional catabolic rate.The administration of FAMP promoted ABCA1-dependent efflux ex vivo, HDL turnover in vivo, and macrophage RCT in vivo despite reduced plasma HDL-C levels. FAMP might have atheroprotective potential.

New experimental models of human neoplastic diseases attempt to mimic the human environment that fostered the development of disease in cancer patients. The aim of the present study was to establish a human lymphocyte-engrafted, severe combined immunodeficient (hu-PBL-SCID) mouse model to investigate thyroid cancer and to evaluate the potential use of this model for cancer immunotherapy. Thyroid neoplastic tissues were obtained from ten patients (one follicular adenoma, five papillary, one follicular, one anaplastic and two medullary cancers). One 8 x 4 x 3 millimeter sample from each tumor was cut into two pieces of identical size and transplanted into two SCID mice. In each case, one of the two mice was injected intraperitoneally with lymphocytes from the same tumor patient for the reconstitution of the human immune system (Group A), while the other animal received no lymphocytes (Group B). The engraftment of the tumors was successful in all cases. The growth rate was highly dependent on the histological type. When histologies were compared before implantation and after the removal of the implants, the characters of the tumors proved to be unchanged, except one case where an anaplastic cancer arose from a papillary tumor, Macrophages were present in all but one papillary cancer. All differentiated thyroid cancers were infiltrated by T and B lymphocytes. Lymphocytes and macrophages disappeared from 19/20 grafts by week 16. However, in one case from group A lymphocytes were detected four months after the transplantation. In another case from group A, one papillary cancer spontaneously decreased in size and disappeared. Before implantation, HLA-DR expression was detected in every papillary cancer. HLA-DR expression in the grafts was not seen in 3/5 cases by week 16. In conclusion, an animal model has been established for the investigation of human thyroid cancer, by which the analysis of anti-tumor immunity, as a postulate of immune therapy, may be possible.

Over the past few years increasing evidence has suggested the nongenomic effects of thyroid hormone, such as the activation of the signal transduction pathways and the activation of nuclear factor-kappaB by the induction of oxidative stress. The present study was undertaken to investigate the effect of thyroid hormone on human polymorphonuclear leukocytes (PMNLs) which are known as important sources of reactive oxygen species in the circulation. The production of superoxide anion (O2-) and the activity of myeloperoxidase were determined in the presence and absence of several inhibitors of the signalling pathway. L-thyroxine (T4) l-3,5,3'-tri-iodothyronine (T3) and L-3,5-di-iodothyronine (T2) stimulated O2- production in PMNLs in a dose-dependent manner within a few minutes of addition to cells. Thyroid hormone-stimulated O2- production was partially inhibited by pertussis toxin, an inhibitor of GTP-binding G protein, and was completely abolished by the protein kinase C inhibitors calphostin C and Ro-32-0432, and by a calcium chelator (BAPTA; bis-(o-aminophenoxy)ethane-N,N,N',N'-tetra-acetic acid). Thyroid hormone stimulated myeloperoxidase activity and induced 125I- incorporation into PMNLs. Furthermore, thyroid hormone pre-incubation enhanced O2- production for n-formyl-methionyl-leucyl- phenylalanine (FMLP) stimulation. In conclusion, novel nongenomic actions of thyroid hormone, the induction of superoxide anion production and the stimulation of myeloperoxidase activity in PMNLs were demonstrated. The induction of O2- production requires calcium and is mediated by a pertussis toxin-sensitive G protein via stimulation of protein kinase C(s). These results suggest the existence of a membrane-bound binding site for thyroid hormone in PMNLs and a physiological role for thyroid hormone in the cellular defence mechanisms by stimulating free-radical production.