1,721,020 research outputs found
Targeting Epigenetic ‘Readers’ with Natural Compounds for Cancer Interception
No full textNatural compounds from diverse sources, including botanicals and commonly consumed foods and beverages, exert beneficial health effects via mechanisms that impact the epigenome and gene expression during disease pathogenesis. By targeting the so-called epigenetic ‘readers’, ‘writers’, and ‘erasers’, dietary phytochemicals can reverse abnormal epigenome signatures in cancer cells and preneoplastic stages. Thus, such agents provide avenues for cancer interception via prevention or treatment/therapeutic strategies. To date, much of the focus on dietary agents has been directed towards writers (e.g., histone acetyltransferases) and erasers (e.g., histone deacetylases), with less attention given to epigenetic readers (e.g., BRD proteins). The drug JQ1 was developed as a prototype epigenetic reader inhibitor, selectively targeting members of the bromodomain and extraterminal domain (BET) family, such as BRD4. Clinical trials with JQ1 as a single agent, or in combination with standard of care therapy, revealed antitumor efficacy but not without toxicity or resistance. In pursuit of second-generation epigenetic reader inhibitors, attention has shifted to natural sources, including dietary agents that might be repurposed as ‘JQ1-like’ bioactives. This review summarizes the current status of nascent research activity focused on natural compounds as inhibitors of BET and other epigenetic ‘reader’ proteins, with a perspective on future directions and opportunities
Examining the Roles of Beta-Catenin and HDAC6 in Primary Cilia Signaling in ccRCC and CRC
No full textPrimary cilia are single hair-like organelles found on the apical surface of growth arrested and differentiated cells and can be found in almost every cell type, including epithelial cells, fibroblasts, olfactory neurons and photoreceptors, which reflect their diverse cellular functions. The primary cilium forms upon entry into G0; preceding G0 arrest, the cilium resorbs through mechanisms involving deacetylation of the tubulin by specific deacetylases. Functionally, the primary cilium acts as a mechanosenor, chemosensor and osmosensor for the cell, detecting its neighboring cells and responding to extracellular signals. Due to its versatility in functions, dysregulation of the primary cilia has been associated with multiple human diseases and syndromes termed ���ciliopathies���, which include polycystic kidney and liver disease, primary ciliary dyskinesia, nephronophthisis and more recently, colon cancer.
Another primary cilia-related disorder is von Hippel-Lindau (VHL) disease is a systemic disorder predisposing patients to hemangioblastomas, phaeochromocytoma, and cysts in the kidney and pancreas. The loss of the VHL protein (pVHL) is the most common genetic mutation associated with clear cell renal cell carcinoma (ccRCC). Functionally, pVHL is an E3 ligase involved in targeting proteins, such as hypoxia inducible factor (HIF), epidermal growth factor (EGFR) and protein kinase C�� (PKC��) for proteasomal degradation and has been shown to be involved in microtubule stability and maintenance of the primary cilium; loss of pVHL is associated with loss of primary cilia. The mechanism by which pVHL regulates formation and function of the primary cilium is not fully understood but is of importance, especially in the setting of renal cell carcinoma (RCC).
Recent studies indicate that Aurora kinase-A (AURKA), a mitotic kinase, plays an important role in the resorption of primary cilia via interaction of human enhancer of filamentation 1 (HEF1) and activation of histone deacetylase 6 (HDAC6). Our studies show that in the absence of pVHL, AURKA is upregulated, leading to activation of HDAC6, shortening the primary cilia. Given that pVHL stabilizes Jade-1 to promote degradation of ��-catenin, we investigated the role of ��-catenin in transcriptionally maintaining AURKA levels. We found that in VHL-null cells, activated ��-catenin translocates to the nucleus, increasing AURKA mRNA and protein levels. Using an inhibitor of ��-catenin driven-transcription, iCRT14, we were able to rescue aberrant AURKA signaling and the ciliary defect in VHL deficient cells. Thus, our studies have identified a pathway that regulates primary cilia in the setting of RCC with two potential targets, for therapeutic intervention. Additionally, direct roles for primary cilia in colon tumorigenesis have yet to be studied in depth. The adenomatous polyposis coli (APC)/��-catenin Wnt signaling proteins, commonly dysregulated in colon cancer, have independently been localized to microtubules and are transported along the structures, via KIF3��. Additional evidence supports ��-catenin being a crucial facilitator of ciliopathies. Here, we present evidence for a role of primary cilia in colon cancer, demonstrating how dysregulation of Wnt pathway proteins correlates with loss of primary cilia. Our data also provide support for similarities between the colon and kidney with regards to ciliary maintenance and the mechanisms involved
Comprehensive Data Analysis Toolkit Development for a Low Input Bisulfite Sequencing
Full text linkThe human cell-free DNA (cfDNA) methylation profile in liquid biopsy has been utilized to diagnose early-stage disease and estimate therapy response. However, typical clinical procedures are capable of purifying only very small amounts of cfDNA. Whole-genome bisulfite sequencing (WGBS) is the gold standard for measuring DNA methylation; however, WGBS with small amounts of fragmented DNA introduces a critical challenge for data processing, analysis, and visualization. For data processing, the low mapping ratio of low input bisulfite sequencing samples resulting in genome-wide low sequencing depth and low coverage of CpG sites is a bottleneck for the clinical application of cfDNA-based WGBS assays. We developed LiBis (Low-input Bisulfite Sequencing), a novel augmentation for low-input WGBS data alignment. By dynamically clipping initially unmapped reads and remapping clipped fragments, we judiciously rescued those reads and uniquely aligned them to the genome. By substantially increasing the mapping ratio by up to 88%, LiBis dramatically improved the number of informative CpG sites and the precision in quantifying the methylation status of individual CpG sites. The high sensitivity and cost-effectiveness afforded by LiBis for low-input samples will help the discovery of genetic and epigenetic features suitable for downstream analysis and biomarker identification using liquid biopsy. For data analysis, we present Mmint, a user-friendly comprehensive integrative analysis tool. It generates publication-quality figures with epigenetic data from the following aspects: quality assessment, integrative analysis between BS-Seq and ChIP-seq data, correlation analysis between DNA methylation/Histone modification, and gene expression. Versatile analysis by Mmint can help users to interpret epigenetic data comprehensively and provide potential novel biological insights. To further simplify the data utilization and visualization, especially for researchers who do not specialize in bioinformatics skills, we implement GsmPlot. GsmPlot can simply accept GSM IDs to automatically download NCBI data or accept user's local bigwig files as input to plot the data of interest on promoters, exons or any other user-defined genome locations and generate UCSC visualization tracks. By linking public data repository and in-house data, GsmPlot can spark data-driven ideas and hence promote epigenetic research
Going Beyond Counting First Authors in Author Co-citation Analysis
Full text linkThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
Expanding Epigenetic Mechanisms of Sulforaphane in Colorectal Cancer: Pseudogenes and Protein Acetylation
Full text linkTwo major hallmarks of cancer cells are their ability to sustain proliferative signaling and evade growth suppressors. This can occur when the cell loses transcriptional control of key growth genes through epigenetic mechanisms, such as histone and nonhistone modification, and dysregulation of non-coding RNAs. There is clinical interest in using small molecules to target these epigenetic mechanisms in order to prevent or reverse the dysregulation of the key cancer growth genes. Sulforaphane (SFN) is a dietary isothiocyanate that exhibits anticancer activity through a variety of mechanisms, such as the activation of the antioxidant response pathway, and through histone deacetylase (HDAC) inhibition. This dissertation examines two distinct mechanisms of SFN���s effect on epigenetic control of gene transcription. First, SFN induces NMRAL2P which is the first functional pseudogene to be identified as a direct target of Nrf2, and as a downstream regulator of Nrf2-dependent NQO1 induction. Second, SFN causes the acetylation of Cell Cycle and Apoptosis Regulator 2 (CCAR2) through inhibition of HDAC3. This, in turn, decreases ��-Catenin nuclear localization and activity, reducing the expression of oncogenes MYC and MMP7. Also, SFN works in combination with JQ1, an inhibitor of acetylation readers, to further prevent cancer cell growth
Variations on the Author
Full text link“Variations on the Author” discusses two of Eduardo Coutinho’s recent films (Um Dia na Vida, from 2010, and Últimas Conversas, posthumously released in 2015) and their contribution to the general question of documentary authorship. The director’s filmography is characterized by a consistent yet self-effacing form of authorial self-inscription: Coutinho often features as an interviewer that rather than express opinions propels discourses; an interviewer that is good at listening. This mode of self-inscription characterizes him as an author who is not expressive but who is nonetheless markedly present on the screen. In Um Dia na Vida, however, Coutinho is completely absent form the image, while Últimas Conversas, on the contrary, includes a confessional prologue that moves the director from the margins to the center of his films. This article examines the ways in which these works stand out in the filmography of a director who offers new insights into the notion of cinematic authorship
Efficacy Evaluation of COX-2 Inhibitors on Colorectal Adenoma Prevention by Using the Pirc Rat Model
No full textAim: The ultimate aim of this project is to evaluate the chemoprevention efficacy and cardiovascular (CV) toxicity of 6a1 (an in-house synthesized celecoxib analog) by using the Pirc rat (a genetic mutation rat). We established a biomarker-based in vivo model with the positive control celecoxib, then applied this model for 6a1 evaluation.
Method: Drug oral suspensions (40 mg/kg BID) were orally dosed to Pirc rats for four days, and the equivalent dose of drugs in the diet (1500 ppm) was fed for four months. The colonic PGE2 and plasma 6-keto PGF1α were determined by UPLC-MS/MS, and their inhibition% compared baseline were calculated the short-term and long-term dosing. Also, the colonic PGE2 reduce was correlated with the adenoma regression.
Result: The colonic mucosa PGE2 was 4-fold higher in Pirc than in wild-type (21 vs. 5.6 pg/mg Tissue) due to higher COX-2 expression, which was confirmed by elevated PGE2-d11 level (4.5-fold increase) in Pirc colon S9 incubation media. In the 4-days study, dose-dependent significant reduction of PGE2 was observed in the colon epithelium (-33% and -57% (P=0.0012)) and polyps (-20% and -36%) for low- and high-dosage (4mg/kg and 40mg/kg, bid). In the 4-month study, 1500ppm celecoxib suppressed the colon epithelium PGE2 by 43.5% and tumor multiplicity by 80% (P0.05). The tumor multiplicity was only 10% less than the disease control. The reduction of the plasma 6-keto PGF1α were -45% and -43% after short-term and long-term treatment.
Conclusion: We used the celecoxib and Pirc model to confirm that high level of PGE2 promoted tumor growth, whereas dysregulated PGI2 was associated with higher COX-2-dependent CV risks. The chemoprevention efficacy of 6a1 was not as effective as celecoxib, mostly because it could not inhibit the colon PGE2 efficiently. 6a1 was considered to be safe for the CV system, since the its plasma 6-keto PGF1α was not significantly different from the control. Finally, we demonstrated that the biomarker levels of efficacy and toxicity responses were consistent with in both short-term and long-term studies. This finding would be helpful for the new drug discovery in the future.Pharmacological and Pharmaceutical Sciences, Department o
Appropriate Similarity Measures for Author Cocitation Analysis
Full text linkWe provide a number of new insights into the methodological discussion about author cocitation analysis. We first argue that the use of the Pearson correlation for measuring the similarity between authors’ cocitation profiles is not very satisfactory. We then discuss what kind of similarity measures may be used as an alternative to the Pearson correlation. We consider three similarity measures in particular. One is the well-known cosine. The other two similarity measures have not been used before in the bibliometric literature. Finally, we show by means of an example that our findings have a high practical relevance.information science;Pearson correlation;cosine;similarity measure;author cocitation analysis
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Suppression of Met signaling by the green tea polyphenol (-)-epigallocatechin-3-gallate (EGCG)
Full text linkMet is a prognostic indicator of colorectal cancer patient survival. Therapies that target Met may therefore have beneficial outcomes in the clinic. Recently, EGCG was reported to suppress Met activation, although the mechanisms were not elucidated. HCT116 and HT29 human colon cancer cells were used to examine the relationships between Met activation, EGCG treatment, and H₂O₂ generation. At concentrations of 0.5, 1 and 5 μM, EGCG suppressed the activation of Met induced by its ligand, hepatocyte growth factor (HGF). Concentrations of 10 μM EGCG and below generated low amounts of H₂O₂ (5 μM) were required to directly increase the
phosphorylation of Met. Moreover, suppression of Met activation by EGCG occurred in the presence or absence of catalase, suggesting that such effects were not an "artifact" of H₂O₂ generated from EGCG in cell culture media. Molecular docking and enzyme kinetic analyses suggested that EGCG is a competitive inhibitor, binding to the kinase domain of Met with a Ki of 3.3 μM EGCG. The downstream effect of EGCG mediated suppression of the Met receptor included decreased signaling to members of the MAPK and PI3KK signaling pathways. Cell proliferation and migration was also significantly inhibited by EGCG. Overall, the data presented in this dissertation support that EGCG is able to suppress HGF-induced Met signaling. These findings demonstrate that EGCG might be a beneficial therapeutic agent in the colon, inhibiting Met signaling and helping to attenuate tumor metastasis
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