Exploration of a new type of antimalarial compounds based on febrifugine

Febrifugine (1), a quinazoline alkaloid, isolated from Dichroa febrifuga roots, shows powerful antimalarial activity against Plasmodium falciparum. The use of 1 as an antimalarial drug has been precluded because of side effects, such as diarrhea, vomiting, and liver toxicity. However, the potent antimalarial activity of 1 has stimulated medicinal chemists to pursue compounds derived from 1, which may be valuable leads for novel drugs. In this study, we synthesized a new series of febrifugine derivatives formed by structural modifications at (i) the quinazoline ring, (ii) the linker, or (iii) the piperidine ring. Then, we evaluated their antimalarial activities. Thienopyrimidine analogue 15 exhibited a potent antimalarial activity and a high therapeutic selectivity both in vitro and in vivo, suggesting that 15 is a good antimalarial candidate.     

Partially thrombosed vertebral artery aneurysm with wall enhancement treated by stent-assisted coil embolization

A 50-year-old man presented with a 2-month history of dysarthria caused by a partially thrombosed vertebral artery (VA) aneurysm. Magnetic resonance imaging showed enhancement of the thickened wall and angiography detected staining. Stent-assisted coil embolization with protection of the parent artery patency was performed. The patient's clinical course was unremarkable and shrinking of the aneurysm was obtained. The stent-assisted coil embolization promoted intra-aneurysm flow disruption and stabilized the wall environment, suggesting another strategy for the treatment of partially thrombosed VA aneurysm.     

Laparoscopy-assisted pylorus-preserving gastrectomy: a matched case�Ccontrol study

Background  

Pylorus-preserving gastrectomy (PPG) has been widely accepted as the standard treatment for early gastric cancer, and the laparoscopic approach has been gradually introduced. The aim of this study is to investigate the short-term outcome of laparoscopy-assisted PPG (LAPPG) in comparison with open PPG (OPPG).     

Problems of positive list system revealed by survey of pesticide residue in food

The positive list system became effective from May 29, 2006 to improve the regulation of residual agricultural chemicals (pesticides, feed additives and veterinary drugs) in foods. In accordance with the system, we investigated pesticide residues in 50 agricultural products purchased in Morioka city from March to November 2006. Analyses were performed according to the "Multiresidue Method for Agricultural Chemicals by GC/MS", the Notice of the Ministry of Health, Labour and Welfare. Five pesticides and two non-agricultural chemicals were detected from 16 samples. Ortho-phenylphenol (OPP) was detected from 8 samples: immature pea, snap bean, kiwi, plain-boiled bamboo shoot, mango, white asparagus, lemon and domestic shiitake mushroom. Maximum residue limits (MRLs) have not been established for these products, and they exceeded the uniform level of 0.01 ppm. DDT was detected from Philippines banana (0.30 ppm) and Korean paprika (0.45 ppm). The residual level in Philippines banana was lower than the MRL, but Korean paprika exceeded its MRL. Chlorpyrifos, Thiabendazole and Imazaril were detected from citrus imported from the U.S.A., but their residue levels were lower than the respective MRLs. Aniline and 2-pyrrolidone were detected from several imported products. These two may not be regulated by the positive list system because they are not agricultural chemicals, although their derivatives are used as pesticides or veterinary drugs. Three problems have been revealed from this survey: 1) application of the uniform level to minor agricultural products, 2) residues of non-agricultural chemicals whose toxicity is uncertain, 3) metabolites of agricultural chemicals, which are also regulated by the positive list system, have not been clearly defined.     

IgE-activated mast cells in combination with pro-inflammatory factors induce Th2-promoting dendritic cells

Dendritic cells (DCs) and mast cells (MCs) co-localize in peripheral tissues of antigen entry, i.e. skin and mucosa. Due to the proximity of these two cell types, activation of MCs may affect DC functions. Here, we co-cultured human monocyte-derived DCs with cord blood-derived MCs activated by cross-linking of FcepsilonRI to elucidate the net effect of the whole MC products on DCs. Activated MCs induced maturation of DCs, and potently suppressed IL-12p70 production by the DCs. Whereas co-culture of DCs with activated MCs alone did not significantly influence the type of CD4(+) T cell responses induced by the DCs, DCs co-cultured with activated MCs in the presence of pro-inflammatory or T(h)1-inducing factors caused T(h)2 polarization. Although histamine was involved in the induction of DC maturation and T(h)2 polarization by activated MCs, a combinatorial effect of various MC-derived factors, including those acting in a cell contact-dependent manner, was required for the optimal induction of T(h)2-promoting DCs. Furthermore, we demonstrated that clusters of DCs are located closely with MCs in lesions of atopic dermatitis. Collectively, this study suggests that the interaction between DCs and IgE-activated MCs in a pro-inflammatory or even T(h)1-prone environment is instrumental in maintaining and augmenting T(h)2 responses in allergy, and that disruption of the DC-MC interaction may constitute an effective strategy to treat ongoing allergic diseases.     

Virus-stimulated plasmacytoid dendritic cells induce CD4+ cytotoxic regulatory T cells

Immune responses to pathogens need to be maintained within appropriate levels to minimize tissue damage, whereas such controlled immunity may allow persistent infection of certain types of pathogens. Interleukin 10 (IL-10) plays an important role in such immune regulation. We previously showed that HSV-stimulated human plasmacytoid dendritic cells (pDCs) induced naive CD4+ T cells to differentiate into interferon gamma (IFN-gamma)/IL-10-producing T cells. Here we show that HSV-stimulated pDCs induce allogeneic naive CD4+ T cells to differentiate into cytotoxic regulatory T cells that poorly proliferate on restimulation and inhibit proliferation of coexisting naive CD4+ T cells. IL-3-stimulated pDCs or myeloid DCs did not induce such regulatory T cells. Both IFN-alpha and IL-10 were responsible for the induction of anergic and regulatory properties. High percentages of CD4+ T cells cocultured with HSV-stimulated pDCs, and to a lesser extent those cocultured with IL-3-stimulated pDCs, expressed granzyme B and perforin in an IL-10-dependent manner. CD4+ T cells cocultured with HSV-stimulated pDCs accordingly exhibited cytotoxic activity. The finding that virus-stimulated pDCs are capable of inducing CD4+ cytotoxic regulatory T cells suggests that this DC subset may play an important role in suppressing excessive inflammatory responses and also in inducing persistent viral infection.     

Dendritic cells that endocytosed antigen-containing IgG-liposomes elicit effective antitumor immunity

Liposomes represent a promising vehicle to deliver exogenous antigens to dendritic cells (DCs) for tumor immunotherapy. Targeting exogenous antigens to Fcgamma receptors on DCs has been shown to result in efficient presentation of antigen-derived peptides on major histocompatibility complex (MHC) class I and class II molecules. In this study, it was investigated whether DCs that endocytosed physicochemically optimized antigen-containing liposomes conjugated with IgG efficiently present antigens on MHC class I and class II molecules, and consequently induce strong antitumor immune responses. IgG-conjugated liposomes that were 200 nm in diameter without attaching polyethylene glycol were most efficiently endocytosed by DCs. Human monocyte-derived DCs that endocytosed tetanus toxoid (TT)-containing IgG liposomes via CD32 stimulated CD4(+) T cells more strongly than DCs pulsed with TT-containing bare liposomes or with soluble TT. Immunization of mice with DCs that endocytosed ovalbumin (OVA)-containing IgG liposomes but not OVA-containing bare liposomes or soluble OVA completely prevented the growth of OVA-expressing lymphoma cells. Importantly, administration of DCs that endocytosed OVA-containing IgG liposomes to the mice with established OVA-expressing tumors strongly suppressed tumor growth. This study demonstrates an IgG liposome with physicochemical properties suitable for delivering antigens to DCs and paves the way to the application of IgG liposomes for tumor immunotherapy using DCs.