Active suppression mediated by CD4+CD25+ T regulatory (Tr) cells plays an important role in the down-regulation of T cell responses to both foreign and self-Ags. Platelet factor 4 (PF4), a platelet-derived CXC chemokine, has been shown to strongly inhibit T cell proliferation as well as IFN-γ and IL-2 release by isolated T cells. In this report we show that human PF4 stimulates proliferation of the naturally anergic human CD4+CD25+ Tr cells while inhibiting proliferation of CD4+CD25− T cells. In coculture experiments we found that CD4+CD25+ Tr cells exposed to PF4 lose the ability to inhibit the proliferative response of CD4+CD25− T cells. Our findings suggest that human PF4, by inducing Tr cell proliferation while impairing Tr cell function, may play a previously unrecognized role in the regulation of human immune responses. Because platelets are the sole source of PF4 in the circulation, these findings may be relevant to the pathogenesis of certain immune-mediated disorders associated with platelet activation, such as heparin-induced thrombocytopenia and autoimmune thrombocytopenic purpura.

The inhibitory effects of methanol extracts of heartwood of 23 Papua New Guinean wood species on tyrosinase activity were examined. The extract of Artocarpus incisus showed the strongest tyrosinase inhibitory activity which was equivalent to kojic acid. The extract apparently inhibited melanin biosynthesis of both cultured B16 melanoma cells without any cytotoxicity and in the back of a brown guinea pig without skin irritation. Thus, the potentiality of the extracts of heartwood of A. incisus both as material of a useful skin whitening agent and as a remedy for disturbances in pigmentation is evident. Tyrosinase inhibitory activity-guided fractionation led to the isolation of seven active compounds including a new compound which has been characterized as 6-(3"-methyl-1"-butenyl)-5,7,2',4'-tetrahydroxyflavone, named isoartocarpesin. Other active compounds were (+)-dihydromorin, chlorophorin, (+)-norartocarpanone, 4-prenyloxyresveratrol, artocarbene, and artocarpesin, These compounds are probably responsible for the melanin biosynthesis inhibitory effects.

Cisplatin is a chemotherapeutic agent that is widely used to treat cancers such as head and neck squamous cell carcinoma (HNSCC). Previously, we have reported that cisplatin induced an early caspase-dependent apoptosis (8 hr) in a HNSCC cell, HN4. In this study, we examined a late caspase-independent apoptosis as well as an early caspase-dependent apoptosis in cisplatintreated HN4 cells. While z-VAD-fmk, a pan-caspase inhibitor, blocked the caspase activities and protected cells from the early apoptosis, it did not provide protection against delayed apoptosis occurring after extended exposure (16 hr) to cisplatin, suggesting that the delayed apoptotic response in the presence of z-VAD-fmk was caspase-independent. Cisplatin treatment induced reactive oxygen species (ROS) generation, loss of the mitochondrial membrane potential (MMP) and nuclear translocation of endonuclease G (EndoG). Small interfering RNA mediated-knockdown of EndoG significantly protected cells from the delayed apoptosis induced by cisplatin in the presence of z-VAD-fmk. Overexpression of Bcl-2 in HN4 cells prevented loss of MMP, nuclear translocation of EndoG and protected cells from the delayed apoptosis induced by cisplatin in the presence of z-VAD-fmk. Pretreatment with N-acetyl-L-cysteine (NAC), a ROS scavenger, prevented both ROS generation, loss of the MMP and nuclear translocation of EndoG. Together, our data indicate that cisplatin treatment induced ROS-mediated loss of the MMP, and, then, the nuclear translocation of EndoG, which played a crucial role in caspase-independent apoptosis of HN4 cells in the presence of z-VAD-fmk. This is the first report about the involvement of EndoG in cisplatin-induced caspase-independent apoptosis of cells. ' 2007 Wiley-Liss, Inc.

A relatively high maternal serum folate level in mid-pregnancy was associated with a decreased risk of LRTIs and AD in early childhood.