No abstract

NF-κB may be a potential therapeutic target for acute myelogenous leukemia (AML) because NF-κB activation is found in primitive human AML blast cells. In this report, we initially discovered that the potent antineoplastic effect of niclosamide, a Food and Drug Administration-approved antihelminthic agent, was through inhibition of the NF-κB pathway in AML cells. Niclosamide inhibited the transcription and DNA binding of NF-κB. It blocked tumor necrosis factor-induced IκBα phosphorylation, translocation of p65, and expression of NF-κB-regulated genes. Niclosamide inhibited the steps TAK1→IκB kinase (IKK) and IKK→IκBα. Niclosamide also increased the levels of reactive oxygen species (ROS) in AML cells. Quenching ROS by the glutathione precursor N-acetylcysteine attenuated niclosamide-induced apoptosis. Our results together suggest that niclosamide inhibited the NF-κB pathway and increased ROS levels to induce apoptosis in AML cells. On translational study of the efficacy of niclosamide against AML, niclosamide killed progenitor/stem cells from AML patients but spared those from normal bone marrow. Niclosamide was synergistic with the frontline chemotherapeutic agents cytarabine, etoposide, and daunorubicin. It potently inhibited the growth of AML cells in vitro and in nude mice. Our results support further investigation of niclosamide in clinical trials of AML patients. Cancer Res; 70(6); 2516-27. ©2010 AACR.

HIV/SIV disease progression is associated with multifocal damage to the GI tract epithelial barrier that correlates with microbial translocation and persistent pathological immune activation but the underlying mechanisms remain unclear. Investigating alterations in mucosal immunity during SIV infection, we found that damage to the colonic epithelial barrier was associated with loss of multiple lineages of IL-17-producing lymphocytes, cells that microarray analysis showed express genes important for enterocyte homeostasis, including IL-22. IL-22-producing lymphocytes were also lost after SIV infection. Potentially explaining coordinate loss of these distinct populations, we also observed loss of CD103+ DCs after SIV infection which associated with loss of IL-17 and IL-22-producing lymphocytes. CD103+ DCs expressed genes associated with promotion of IL-17/IL-22+ cells, and co-culture of CD103+ DCs and naïve T-cells led to increased IL17A and RORc expression in differentiating T-cells. These results reveal complex interactions between mucosal immune cell subsets providing potential mechanistic insights into mechanisms of mucosal immune dysregulation during HIV/SIV infection, and offer hints for development of novel therapeutic strategies to address this aspect of AIDS virus pathogenesis.

No abstract

1CircRNAs, a class of widespread circular RNAs produced from precursor mRNA back-splicing, have been implicated in regulation of gene expression in eukaryotes, but their biological functions in plants have not yet been elucidated. By deep sequencing of rRNA-removed and RNase R-digested RNA samples we have identified several thousands of putative back-splicing sites in tomato fruit (Solanum lycopersicum) and show that the abundance of some of these circRNAs derived from fruit pigment biosynthesis genes are regulated by fruit ripening. Herein, we overexpressed a circRNA derived from Phytoene Synthase 1 (PSY1) in tomato 'Ailsa Craig' and microTom. The PSY1 mRNA abundance, the lycopene and β-carotene accumulation were decreased significantly in the transgenic tomato fruits, likely due to the continuous highly expressed circRNAs and/or the low abundant linear RNAs generated from the overexpression vector. Besides, overexpression of a circRNA derived from Phytoene Desaturase (PDS) showed similar results. Our results provide biological insights into plant circRNAs.CircRNAs, a class of circular RNAs in eukaryotes, are derived from precursor mRNA back-splicing 1 . Although circRNAs have been identified more than 20 years ago [2][3][4] , they had been considered to be produced from aberrant splicing and their existence and functional potential were both underestimated. Nowadays, with the development of next-generation sequencing and bioinformatics, circRNAs have been identified in various eukaryotic species [5][6][7][8][9] . Most of the identified circRNAs are expressed at low levels, indicating the possibility that the majority of circRNAs might be splicing byproducts with little functional potential 8,[10][11][12] . However, many circRNAs are more abundant than their linear counterparts [5][6][7][8]13 , suggesting the potential functional significance of these circular RNA molecules. Recent studies revealed that circRNAs are more stable than linear mRNAs, and most of them are cytoplasmic 6,7,13 . In addition, the circularization of circRNAs are conserved among species, and the expression of circRNAs are often cell, tissue and developmental stage-specific 7,8,[13][14][15] . Recent studies have revealed that circRNAs may play roles in gene expression regulation, although the function of most circRNAs remain largely unknown [16][17][18] . The biogenesis of circRNAs is considered to be regulated by both cis-elements and trans-acting factors 16,18 . Complementary sequences or inverted repeats in the introns flanking the back-splice site could promote exon circularization by pairing to form hairpin structures 10,13,19,20 , and multiple circRNAs may be produced from one single gene due to different sequence pairing, which is referred as to alternative circularization 10 . However, there are also circRNAs produced from exons without being bracketed by complementary sequences [21][22][23] , indicating that other cis-elements may account for the circularization, such as sequences recognized by RNA-binding proteins (RBPs) [24][25]...