EGCG [(−)-epigallocatechin-3-O-gallate], the major polyphenol of green tea, has cancer chemopreventive and chemotherapeutic activities. EGCG selectively inhibits cell growth and induces apoptosis in cancer cells without adversely affecting normal cells; however, the underlying molecular mechanism in vivo is unclear. In the present study, we show that EGCG-induced apoptotic activity is attributed to a lipid-raft clustering mediated through 67LR (67 kDa laminin receptor) that is significantly elevated in MM (multiple myeloma) cells relative to normal peripheral blood mononuclear cells, and that aSMase (acid sphingomyelinase) is critical for the lipid-raft clustering and the apoptotic cell death induced by EGCG. We also found that EGCG induces aSMase translocation to the plasma membrane and PKCδ (protein kinase Cδ) phosphorylation at Ser664, which was necessary for aSMase/ceramide signalling via 67LR. Additionally, orally administered EGCG activated PKCδ and aSMase in a murine MM xenograft model. These results elucidate a novel cell-death pathway triggered by EGCG for the specific killing of MM cells.

These results suggest that IDO is strongly involved in the pathogenesis of TBP.

ATP induced a biphasic increase in the intracellular Ca(2+)concentration ([Ca(2+)](i)), an initial spike, and a subsequent plateau in A549 cells. Erythromycin (EM) suppressed the ATP-induced [Ca(2+)](i) spike but only in the presence of extracellular calcium (Ca(2+)(o)). It was ineffective against ATP- and UTP-induced inositol 1,4,5-trisphosphate [Ins(1,4,5)P(3)] formation and UTP-induced [Ca(2+)](i) spike, implying that EM perturbs Ca(2+) influx from the extracellular space rather than Ca(2+)release from intracellular Ca(2+) stores via the G protein-phospholipase C-Ins(1,4,5)P(3) pathway. A verapamil-sensitive, KCl-induced increase in [Ca(2+)](i) and the Ca(2+) influx activated by Ca(2+) store depletion were insensitive to EM. 3'-O-(4-benzoylbenzoyl)-ATP evoked an Ca(2+)(o)-dependent [Ca(2+)](i) response even in the presence of verapamil or the absence of extracellular Na(+), and this response was almost completely abolished by EM pretreatment. RT-PCR analyses revealed that P2X(4) as well as P2Y(2), P2Y(4), and P2Y(6) are coexpressed in this cell line. These results suggest that in A549 cells 1) the coexpressed P2X(4) and P2Y(2)/P2Y(4) subtypes contribute to the ATP-induced [Ca(2+)](i) spike and 2) EM selectively inhibits Ca(2+) influx through the P2X channel. This action of EM may underlie its clinical efficacy in the treatment of airway inflammation.

Immunosuppressive states due to immunological senescence (1) or administration of immunosuppressants (2) occasionally cause Epstein-Barr virus (EBV)-induced B-cell lymphoproliferative disorders (LPDs). While methotrexate (MTX) is an anti-metabolite and anti-foliate agent for the treatment of cancers and autoimmune disorders, it can also potentiate tumourigenesis due to its immunosuppressive effect. EBV reactivation is observed in half of such cases, suggesting that EBV contributes to the pathogenesis (3, 4). A newly described clinicopathological entity, EBV-positive mucocutaneous ulcer (EMU), occurring in immunocompromised patients, has been proposed (4). We describe here a case of EMU presenting with large deep facial ulcers in association with MTX-LPDs, which has not previously been reported in literature. CASE REPORTA 62-year-old woman with polymyositis was treated with low-dose prednisolone (5-10 mg/day) and MTX (5 mg twice a week) for 7 years. Four years before our initial examination, erosive lesions emerged suddenly around her lips and evolved gradually into large ulcers on the mouth, nose and right lower eyelid. Topical anti-bacterial agents, such as gentamicin sulphate, nadifloxacin, and sulfadiazine silver cream, were given by a rheumatologist, with only limited effects. The ulcers progressively enlarged to double the original size and, in November 2007, she was referred to us for clinical assessment of these lesions.On examination, her body temperature was 36.7ºC. Since she felt intolerable pain when opening her mouth, eating was severely disturbed. Several cervical lymph nodes were palpable at a size of 1-1.5 cm. There were five facial ulcers, ranging from 1-6 cm in diameter, each located on the lower lip to jaw, neck, left nasolabial groove, philtrum, and right lower palpebra (Fig. 1A). The ulcers were sharply demarcated and raised on the skin, with mottled telangiectasia and an erythematous hue, as seen on the jaw. Scars were also noted. Laboratory investigations revealed mild elevations of liver enzymes, lactate dehydrogenase (LDH) (291 IU/ml; < 208 IU/ml), aspartate transaminase (AST) (38 IU/ ml; < 30 IU/ml), alanine transaminase (ALT) (40 IU/ml; <30 IU/ ml), leucine amino peptidase (78 IU/ml; < 43 IU/ml), and a high elevation of C-reactive protein (6.67 mg/dl; < 0.1 mg/dl). White blood cell counts fluctuated within the normal range during the course (5,800-8,800/µl) although mild lymphocytopenia was constantly observed (340-582/µl; 1,500-4,000/μl). Serum immunoglobulin G (IgG) levels were low (689 mg/dl; 1,200-2,120 mg/dl), while serum levels of IgA and IgM were normal. The level of soluble interleukin-2 receptor was extremely high (5,834 IU/ml; < 534 IU/ml). Cytomegalovirus pp65 (C7-HRP) antigen-positive cells were detected in 94 cells/48,000 cells (normal 0) of peripheral blood mononuclear cells (PBMCs). No anti-EBV-virus capsid antigen IgM (anti-EBV-VCA IgM), anti-EBV-erythrocyte ATP/ADP ratio IgG (anti-EBV-EADR IgG) or anti-EBV-Epstein-Barr nuclear antigen IgG (anti-EBV-EBNA IgG) was detecte...

Background: Tryptophan metabolism plays important roles in health and diseases. Although simultaneous measurements of tryptophan metabolites are successfully measured, influences of age, gender, and clot formation on the measurements have not been reported. Methods: We took blood from young and old Japanese men and women and compared plasma levels of tryptophan metabolites. We also took plasma and serum from the blood of middle-aged men (n = 10). Metabolites analysis was performed by a liquid chromatograph tandem mass spectrometer, the LCMS-8060 quadrupole mass spectrometer combined with Nexera X2 liquid chromatograph system (Shimadzu Corporation, Kyoto, Japan). Body mass index (BMI) and TRP metabolites have been measured in healthy young men (n = 48), young women (n = 47), old men (n = 44), and old women (n = 39). TRP metabolites were measured by using the ultrahigh speed liquid chromatography-mass spectroscopy (Shimadzu Corporation). Results: Tryptophan and its metabolites such as serotonin, 5-hydroxyindole acetic acid, indole-3-acetic acid, kynurenine, anthranilic acid, were higher in young women and old men than young men and old women. Plasma levels of 3-hydroxykynurenine and xanthurenic acid were lower in young women and old men. Comparison of plasma and serum indicates that most of metabolites were higher in serum than plasma except for 3-hydroxy-kynurenine and quinolinic acid. Conclusion: Metabolites of the upper stream of degradation of tryptophan were higher in young women and old men than young men and old women, which suggests that the degradation of tryptophan was accelerated in young men and old women than young How to cite this paper: