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Cholesterol ester (CE)-laden macrophage foam cells are the hallmark of atherosclerosis, and the hydrolysis of intracellular CE is one of the key steps in foam cell formation. Although hormone-sensitive lipase (LIPE) and cholesterol ester hydrolase (CEH), which is identical to carboxylsterase 1 (CES1, hCE1), were proposed to mediate the neutral CE hydrolase (nCEH) activity in macrophages, recent evidences have suggested the involvement of other enzymes. We have recently reported the identification of a candidate, neutral cholesterol ester hydrolase 1(Nceh1). Here we demonstrate that genetic ablation of Nceh1 promotes foam cell formation and the development of atherosclerosis in mice. We further demonstrate that Nceh1 and Lipe mediate a comparable degree of nCEH activity in macrophages and together account for most of the activity. Mice lacking both Nceh1 and Lipe aggravated atherosclerosis in an additive manner. Thus, Nceh1 is a promising target for the treatment of atherosclerosis.

In this study, we isolated a 25-kDa novel snake venom protein, designated ablomin, from the venom of the Japanese Mamushi snake (Agkistrodon blomhoffi). The amino-acid sequence of this protein was determined by peptide sequencing and cDNA cloning. The deduced sequence showed high similarity to helothermine from the Mexican beaded lizard (Heloderma horridum horridum), which blocks voltage-gated calcium and potassium channels, and ryanodine receptors. Ablomin blocked contraction of rat tail arterial smooth muscle elicited by high K + -induced depolarization in the 0.1-1 lM range, but did not block caffeine-stimulated contraction. Furthermore, we isolated three other proteins from snake venoms that are homologous to ablomin and cloned the corresponding cDNAs. Two of these homologous proteins, triflin and latisemin, also inhibited high K + -induced contraction of the artery. These results indicate that several snake venoms contain novel proteins with neurotoxin-like activity.Keywords: snake venom; neurotoxin; helothermine; cysteinerich secretory proteins; ablomin.Over the past 30 years, a plethora of toxins have been isolated from poisonous organisms, such as snakes, scorpions, spiders, and micro-organisms. These natural toxins use a variety of approaches to arrest the homeostatic mechanisms of other living organisms, including disruption of intracellular signal transduction and cytoskeleton organization [1][2][3][4], and activation or inhibition of blood coagulation factors [5][6][7][8][9][10]. Toxins that block synaptic transmission, called neurotoxins, are widely distributed in venoms. These toxins include the conotoxins from cone snails, agatoxins from spiders, and scorpion toxins [11][12][13][14][15][16]. These toxins exert their potentially lethal effects by specifically and potently blocking a variety of ion channels, including those that conduct Na + , K + , and Ca 2+ . Therefore, neurotoxins have been employed as useful tools to investigate the structure and function of these ion channels [17][18][19][20]. A large number of neurotoxin families have also been found in the venom of Elapidae snakes. These toxins, the a-neurotoxins [21] (represented by a-bungarotoxin [22,23], a-cobratoxin [24][25][26][27], and erabutoxin [28,29]) potently and specifically prevent nicotinic acetylcholine receptor activation. A second family of snake venom neurotoxins, the dendrotoxins, are homologous to Kunitz-type serine protease inhibitors and act primarily by blocking neuronal K + channels [30,31]. In contrast to the neurotoxin-rich venom from Elapidae snakes, the venom from other deadly snakes, including Viperidae and Colubridae snakes, contain surprisingly few neurotoxins, although some neurotoxic phospholipases have been discovered [32][33][34][35][36].In this report, we describe the isolation of a novel protein, ablomin, from the venom of the Japanese Mamushi snake (Agkistrodon blomhoffi, a member of the Viperidae family). When applied to arterial smooth muscle preparations from rat-tails, ablomin blocks K + -stimulated c...

Anti-CD20 antibody rituximab is now essential for the treatment of CD20-positive B-cell lymphomas. Decreased expression of CD20 is one of the major mechanisms underlying both innate and acquired resistance to rituximab. In this study, we show that histone deacetylase (HDAC) inhibitors augment the cytotoxic activity of rituximab by enhancing the surface expression of CD20 antigen on lymphoma cells. HDAC inhibitors, valproic acid (VPA) and romidepsin, increased CD20 expression at protein and mRNA levels in B-cell lymphoma cell lines with relatively low CD20 expression levels. The VPA-mediated increase in CD20 expression occurred at 1 mM, which is clinically achievable and safe, but insufficient for inducing cell death. Chromatin immunoprecipitation assays revealed that HDAC inhibitors transactivated the CD20 gene through promoter hyperacetylation and Sp1 recruitment. HDAC inhibitors potentiated the activity of rituximab in complementdependent cytotoxic assays. In mouse lymphoma models, HDAC inhibitors enhanced CD20 expression along with histone hyperacetylation in transplanted cells, and acted synergistically with rituximab to retard their growth. The combination with HDAC inhibitors may serve as an effective strategy to overcome rituximab resistance in B-cell lymphomas.

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