Metastasis associated in lung adenocarcinoma transcript-1 (MALAT-1) is overexpressed during cancer progression and promotes cell migration and invasion in many solid tumors. However, its role in ...ovarian cancer remains poorly understood.
Expressions of MALAT-1 were detected in 37 normal ovarian tissues and 45 ovarian cancer tissues by reverse transcription polymerase chain reaction (RT-PCR). Cell proliferation was observed by CCK-8 assay; Flow cytometry was used to measure cell cycle and apoptosis; Cell migration was detected by transwell migration and invasion assay. In order to evaluate the function of MALAT-1, shRNA combined with DNA microarray and Functional enrichment analysis were performed to determine the transcriptional effects of MALAT-1 silencing in OVCAR3 cells. RNA and protein expression were measured by qRT-PCR and Western blotting, respectively.
We found that upregulation of MALAT-1 mRNA in ovarian cancer tissues and enhanced MALAT-1 expression was associated with FIGO stage. Knockdown of MALAT-1 expression in OVCAR3 cells inhibited cell proliferation, migration, and invasion, leading to G0/G1 cell cycle arrest and apoptosis. Overexpressed MALAT-1 expression in SKOV3 cells promoted cell proliferation, migration and invasion. Downregulation of MALAT-1 resulted in significant change of gene expression (at least 2-fold) in 449 genes, which regulate proliferation, cell cycle, and adhesion. As a consequence of MALAT-1 knockdown, MMP13 protein expression decreased, while the expression of MMP19 and ADAMTS1 was increased.
The present study found that MALAT-1 is highly expressed in ovarian tumors. MALAT-1 promotes the growth and migration of ovarian cancer cells, suggesting that MALAT-1 may be an important contributor to ovarian cancer development.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Synthetic cells, artificial cell‐like particles, capable of autonomously synthesizing RNA and proteins based on a DNA template, are emerging platforms for studying cellular functions and for ...revealing the origins‐of‐life. Here, it is shown for the first time that artificial lipid‐based vesicles, containing the molecular machinery necessary for transcription and translation, can be used to synthesize anticancer proteins inside tumors. The synthetic cells are engineered as stand‐alone systems, sourcing nutrients from their biological microenvironment to trigger protein synthesis. When pre‐loaded with template DNA, amino acids and energy‐supplying molecules, up to 2 × 107 copies of green fluorescent protein are synthesized in each synthetic cell. A variety of proteins, having molecular weights reaching 66 kDa and with diagnostic and therapeutic activities, are synthesized inside the particles. Incubating synthetic cells, encoded to secrete Pseudomonas exotoxin A (PE) with 4T1 breast cancer cells in culture, resulted in killing of most of the malignant cells. In mice bearing 4T1 tumors, histological evaluation of the tumor tissue after a local injection of PE‐producing particles indicates robust apoptosis. Synthetic cells are new platforms for synthesizing therapeutic proteins on‐demand in diseased tissues.
Synthetic cells contain all the nanoscale molecular machines and building blocks necessary for carrying out transcription and translation, including ribosomes, RNA polymerase, amino acids, and energy. Based on synthetically‐encoded DNA, the particles synthesize diagnostic and therapeutic proteins in tumors.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
A supplement containing resveratrol and muscadine polyphenols prior to a high-fat high-carbohydrate meal significantly reduced multiple indices of oxidative and inflammatory stress.
Background:
...High-fat, high-carbohydrate (HFHC) meals are known to induce oxidative and inflammatory stress, an increase in plasma endotoxin concentrations, and an increase in the expression of suppressor of cytokine signaling-3 (SOCS-3).
Hypothesis:
The intake of a nutritional supplement containing resveratrol and muscadine grape polyphenols reduces HFHC meal-induced oxidative and inflammatory stress and stimulates the activity of the antioxidant transcription factor, NF-E2-related factor-2 (Nrf-2), and its downstream targets.
Methods:
Ten normal, healthy subjects were given a 930-kcal HFHC meal either with placebo or with the supplement. Indices of oxidative stress, inflammation, Nrf-2 binding activity, the concentrations of endotoxin (lipopolysaccharide) and lipoprotein binding protein (LBP), and the expression of toll-like receptor 4 (TLR-4), CD14, IL-1β, TNFα, SOCS-3, Keap-1, NAD(P)H:quinone oxidoreductase-1 (NQO-1), and GST-P1 were measured.
Results:
The intake of the supplement suppressed the meal-induced elevations of plasma endotoxin and LBP concentrations, the expression of p47phox, TLR-4, CD14, SOCS-3, IL-1β, and Keap-1, while enhancing Nrf-2 binding activity and the expression of NQO-1 and GST-P1 genes.
Conclusion:
A supplement containing resveratrol and muscadine polyphenols suppresses the increase in oxidative stress, lipopolysaccharide and LBP concentrations, and expression of TLR-4, CD14, IL-1β and SOCS-3 in mononuclear cells after an HFHC meal. It also stimulates specific Nrf-2 activity and induces the expression of the related antioxidant genes, NQO-1 and GST-P1. These results demonstrate the acute antioxidant and antiinflammatory effects of resveratrol and polyphenolic compounds in humans in the postprandial state.
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► Biosynthesis of polyesters require various hydroxylases and acyltransferases. ► Many Arabidopsis mutants impaired in a biosynthetic step are now available. ► GPAT acyltransferases ...have a unique sn-2 specificity and phosphatase activity. ► Monoacylglycerols are implicated intermediates in polyester assembly. ► The extra-cellular or intra-cellular site of fatty acid polymerization is still unknown.
Cutin and suberin are insoluble lipid polymers that provide critical barrier functions to the cell wall of certain plant tissues, including the epidermis, endodermis and periderm. Genes that are specific to the biosynthesis of cutins and/or aliphatic suberins have been identified, mainly in Arabidopsis thaliana. They notably encode acyltransferases, oxidases and transporters, which may have either well-defined or more debatable biochemical functions. However, despite these advances, important aspects of cutin and suberin synthesis remain obscure. Central questions include whether fatty acyl monomers or oligomers are exported, and the extent of extracellular assembly and attachment to the cell wall. These issues are reviewed. Greater emphasis on chemistry and biochemistry will be required to solve these unknowns and link structure with function.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Adiponectin has been shown to play a critical role in immunity. Recently, we reported that the adiponectin levels after allogeneic stem cell transplantation were higher in recipients with chronic ...graft-versus-host disease (cGVHD). However, the effects of adiponectin on extracellular matrix (ECM) and regulatory factors in dermal fibroblasts remain unclear. We compared the messenger RNA (mRNA) levels of collagen type1 (COL1A), fibronectin 1 (FN1), matrix metalloproteinase (MMP)1, MMP3, tissue inhibitor of metalloproteinase (TIMP)1, TIMP3, transforming growth factor-β (TGF-β), and TGF-β receptor 2 (TGF-βR2) in human normal dermal fibroblasts cultured with and without adiponectin, and we assessed the degree of synthesis of ECMs by immunofluorescent microscopy. Furthermore, we also assessed these mRNA levels after blocking of TGF-βR2. Adiponectin induced higher mRNA levels of FN1, MMP1, MMP3, TIMP1, TIMP3, and TGF-βR2 in a dose-dependent manner, but did not significantly affect COL1A or TGF-β. In addition, adiponectin was shown to upregulate FN1, MMPs, and TIMPs after blocking of TGF-βR2. Immunofluorescent microscopy revealed that adiponectin promoted a greater synthesis of ECMs than in the control in vitro. The finding that adiponectin upregulated ECM-associated factors might mean that high levels of adiponectin could modulate dermal fibrosis was observed in recipients with cGVHD. Further basic investigation is warranted to elucidate whether the adiponectin-pathway could be a target for the treatment of sclerotic cGVHD.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Long noncoding RNAs (lncRNAs) participate in numerous of human cancer tumorigenesis. Nevertheless, the in-depth molecular mechanism that lncRNAs regulate the gliomagenesis is still ambiguous. In this ...research, our study invests energy in the biologic roles of lncRNA DLX6-AS1 on the glioma tumorigenesis. Here, we demonstrated that DLX6-AS1 expression was both high-expressed in the glioma cells and tissue, and the overexpression of DLX6-AS1 was clinically correlated with the poor outcome of glioma patients. In the cellular functional assays, silenced DLX6-AS1 expression by siRNAs inhibited the proliferation, invasion and tumor growth in vitro and in vivo, while the enhanced DLX6-AS1 expression by plasmids promotes them. The bioinformatics predictive tools, luciferase reporter assay and correlation analysis found that miR-197-5p could both target the 3′-UTR of DLX6-AS1 as well as E2F1 gene, constructing DLX6-AS1-miR-197-5p-E2F1 axis. Moreover, receiver operating characteristic (ROC) curve analysis revealed that lncRNA DLX6-AS1 has valuable diagnostic value clinical diagnose for the glioma patients (AUC = 0.736). Overall, our finding supports that DLX6-AS1 accelerates the glioma carcinogenesis by competing endogenous sponging miR-197-5p to relieve E2F1, acting as a novel therapeutic target for glioma.
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•DLX6-AS1 is both high-expressed in the glioma cells and tissue.•The overexpression of DLX6-AS1 was clinically correlated with the poor outcome of glioma patients.•Silenced DLX6-AS1 expression by siRNAs inhibited the proliferation, invasion and tumor growth in vitro and in vivo.•Luciferase reporter assay find that miR-197-5p could both target the 3’-UTR of DLX6-AS1 as well as E2F1 gene.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Glioblastomas (GBM), the most common and aggressive malignant astrocytic tumors, contain a small subpopulation of cancer stem cells (GSCs) that are implicated in therapeutic resistance and tumor ...recurrence. Here, we study the expression and function of miR-137, a putative suppressor miRNA, in GBM and GSCs. We found that the expression of miR-137 was significantly lower in GBM and GSCs compared to normal brains and neural stem cells (NSCs) and that the miR-137 promoter was hypermethylated in the GBM specimens. The expression of miR-137 was increased in differentiated NSCs and GSCs and overexpression of miR-137 promoted the neural differentiation of both cell types. Moreover, pre-miR-137 significantly decreased the self-renewal of GSCs and the stem cell markers Oct4, Nanog, Sox2 and Shh. We identified RTVP-1 as a novel target of miR-137 in GSCs; transfection of the cells with miR-137 decreased the expression of RTVP-1 and the luciferase activity of RTVP-1 3'-UTR reporter plasmid. Furthermore, overexpression of RTVP-1 plasmid lacking its 3'-UTR abrogated the inhibitory effect of miR-137 on the self-renewal of GSCs. Silencing of RTVP-1 decreased the self-renewal of GSCs and the expression of CXCR4 and overexpression of CXCR4 abrogated the inhibitory effect of RTVP-1 silencing on GSC self-renewal. These results demonstrate that miR-137 is downregulated in GBM probably due to promoter hypermethylation. miR-137 inhibits GSC self-renewal and promotes their differentiation by targeting RTVP-1 which downregulates CXCR4. Thus, miR-137 and RTVP-1 are attractive therapeutic targets for the eradication of GSCs and for the treatment of GBM.
IL-21 is a type I cytokine whose receptor is expressed on T, B, and NK cells. Within the B cell lineage, IL-21 regulates IgG1 production and cooperates with IL-4 for the production of multiple Ab ...classes in vivo. Using IL-21-transgenic mice and hydrodynamics-based gene delivery of IL-21 plasmid DNA into wild-type mice as well as in vitro studies, we demonstrate that although IL-21 induces death of resting B cells, it promotes differentiation of B cells into postswitch and plasma cells. Thus, IL-21 differentially influences B cell fate depending on the signaling context, explaining how IL-21 can be proapoptotic for B cells in vitro yet critical for Ag-specific Ig production in vivo. Moreover, we demonstrate that IL-21 unexpectedly induces expression of both Blimp-1 and Bcl-6, indicating mechanisms as to how IL-21 can serve as a complex regulator of B cell maturation and terminal differentiation. Finally, BXSB-Yaa mice, which develop a systemic lupus erythematosus-like disease, have greatly elevated IL-21, suggesting a role for IL-21 in the development of autoimmune disease.
Cytokines are critical mediators of inflammation and host defenses. Regulation of cytokines can occur at various stages of gene expression, including transcription, mRNA export, and post- ...transcriptional and translational levels. Among these modes of regulation, post-transcriptional regulation has been shown to play a vital role in controlling the expression of cytokines by modulating mRNA stability. The stability of cytokine mRNAs, including TNFα, IL-6, and IL-8, has been reported to be altered by the presence of AU-rich elements (AREs) located in the 3′-untranslated regions (3′UTRs) of the mRNAs. Numerous RNA-binding proteins and microRNAs bind to these 3′UTRs to regulate the stability and/or translation of the mRNAs. Thus, this paper describes the cooperative function between RNA-binding proteins and miRNAs and how they regulate AU-rich elements containing cytokine mRNA stability/degradation and translation. These mRNA control mechanisms can potentially influence inflammation as it relates to oral biology, including periodontal diseases and oral pharyngeal cancer progression.
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CMK, NUK, OILJ, SAZU, UKNU, UL, UM, UPUK
To identify mechanisms and mediators of resistance to antiangiogenic therapy in human glioblastoma.
We carried out microarray gene expression analysis and immunohistochemistry comparing 21 recurrent ...glioblastomas progressing during antiangiogenic treatment with VEGF neutralizing antibody bevacizumab to paired pretreatment tumors from the same patients.
Microarray analysis revealed that bevacizumab-resistant glioblastomas (BRG) had two clustering patterns defining subtypes that reflect radiographic growth patterns. Enhancing BRGs (EBRG) exhibited MRI enhancement, a long-established criterion for glioblastoma progression, and expressed mitogen-activated protein kinases, neural cell adhesion molecule-1 (NCAM-1), and aquaporin 4. Compared with their paired pretreatment tumors, EBRGs had unchanged vascularity and hypoxia, with increased proliferation. Nonenhancing BRGs (NBRG) exhibited minimal MRI enhancement but had FLAIR-bright expansion, a newer criterion for glioblastoma recurrence since the advent of antiangiogenic therapy, and expressed integrin α5, laminin, fibronectin1, and PDGFRβ. NBRGs had less vascularity, more hypoxia, and unchanged proliferation than their paired pretreatment tumors. Primary NBRG cells exhibited more stellate morphology with a 3-fold increased shape factor and were nearly 4-fold more invasive in Matrigel chambers than primary cells from EBRGs or bevacizumab-naive glioblastomas (P < 0.05).
Using microarray analysis, we found two resistance patterns during antiangiogenic therapy with distinct molecular profiles and radiographic growth patterns. These studies provide valuable biologic insight into the resistance that has limited antiangiogenic therapy to date.
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