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ABT-378, a Highly Potent Inhibitor of the Human Immunodeficiency Virus Protease

Sham, Hing L.; Kempf, Dale J.; Molla, Akhteruzammen; Marsh, Kennan C.; Kumar, Gondi N.; Chen, Chih-Ming; Kati, Warren; Stewart, Kent; Lal, Ritu; Hsu, Ann; Betebenner, David; Korneyeva, Marina; Vasavanonda, Sudthida; McDonald, Edith; Saldivar, Ayda; Widebu
Fonte: American Society for Microbiology Publicador: American Society for Microbiology
Tipo: Artigo de Revista Científica
Publicado em /12/1998 EN
Relevância na Pesquisa
27.37%
The valine at position 82 (Val 82) in the active site of the human immunodeficiency virus (HIV) protease mutates in response to therapy with the protease inhibitor ritonavir. By using the X-ray crystal structure of the complex of HIV protease and ritonavir, the potent protease inhibitor ABT-378, which has a diminished interaction with Val 82, was designed. ABT-378 potently inhibited wild-type and mutant HIV protease (Ki = 1.3 to 3.6 pM), blocked the replication of laboratory and clinical strains of HIV type 1 (50% effective concentration [EC50], 0.006 to 0.017 μM), and maintained high potency against mutant HIV selected by ritonavir in vivo (EC50, ≤0.06 μM). The metabolism of ABT-378 was strongly inhibited by ritonavir in vitro. Consequently, following concomitant oral administration of ABT-378 and ritonavir, the concentrations of ABT-378 in rat, dog, and monkey plasma exceeded the in vitro antiviral EC50 in the presence of human serum by >50-fold after 8 h. In healthy human volunteers, coadministration of a single 400-mg dose of ABT-378 with 50 mg of ritonavir enhanced the area under the concentration curve of ABT-378 in plasma by 77-fold over that observed after dosing with ABT-378 alone, and mean concentrations of ABT-378 exceeded the EC50 for >24 h. These results demonstrate the potential utility of ABT-378 as a therapeutic intervention against AIDS.

In Vitro Selection and Characterization of Human Immunodeficiency Virus Type 1 Variants with Increased Resistance to ABT-378, a Novel Protease Inhibitor

Carrillo, Alejandro; Stewart, Kent D.; Sham, Hing L.; Norbeck, Daniel W.; Kohlbrenner, William E.; Leonard, John M.; Kempf, Dale J.; Molla, Akhteruzzaman
Fonte: American Society for Microbiology Publicador: American Society for Microbiology
Tipo: Artigo de Revista Científica
Publicado em /09/1998 EN
Relevância na Pesquisa
27.28%
ABT-378, a new human immunodeficiency virus type 1 (HIV-1) protease inhibitor which is significantly more active than ritonavir in cell culture, is currently under investigation for the treatment of AIDS. Development of viral resistance to ABT-378 in vitro was studied by serial passage of HIV-1 (pNL4-3) in MT-4 cells. Selection of viral variants with increasing concentrations of ABT-378 revealed a sequential appearance of mutations in the protease gene: I84V-L10F-M46I-T91S-V32I-I47V. Further selection at a 3.0 μM inhibitor concentration resulted in an additional change at residue 47 (V47A), as well as reversion at residue 32 back to the wild-type sequence. The 50% effective concentration of ABT-378 against passaged virus containing these additional changes was 338-fold higher than that against wild-type virus. In addition to changes in the protease gene, sequence analysis of passaged virus revealed mutations in the p1/p6 (P1′ residue Leu to Phe) and p7/p1 (P2 residue Ala to Val) gag proteolytic processing sites. The p1/p6 mutation appeared in several clones derived from early passages and was present in all clones obtained from passage P11 (0.42 μM ABT-378) onward. The p7/p1 mutation appeared very late during the selection process and was strongly associated with the emergence of the additional change at residue 47 (V47A) and the reversion at residue 32 back to the wild-type sequence. Furthermore...

Production of a bacteriocin, ulceracin 378, by Corynebacterium ulcerans.

Abrehem, K; Zamiri, I
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
Publicado em /08/1983 EN
Relevância na Pesquisa
27.28%
The production of the bacteriocin ulceracin 378 by Corynebacterium ulcerans 378 was demonstrated during the growth of the organism on solid medium. Ulceracin 378 was not found in broth cultures and could not be extracted from the organisms by various solvents and salt solutions. Ulceracin 378 was not inducible by UV irradiation or mitomycin C treatments. Ulceracin 378 was active against all of the C. ulcerans strains tested and some related species, but it was not autoinhibitory. The active material was not phage related and was extracted from cultures grown on semisolid media composed of proteose peptone, Tween 80, Casamino Acids, glycerol, and sodium chloride. The yield was significantly reduced by either increasing the agar concentration or omitting Tween 80. Ulceracin 378 was resistant to DNase, RNase, phospholipases C and D, and alkaline phosphatase but was susceptible to proteolytic enzymes. This suggests that the active principle of ulceracin is protein in nature. Ulceracin 378 was partially purified by ammonium sulfate fractionation, dialysis, and chromatography on DEAE-cellulose.

MicroRNA-378 promotes cell survival, tumor growth, and angiogenesis by targeting SuFu and Fus-1 expression

Lee, Daniel Y.; Deng, Zhaoqun; Wang, Chia-Hui; Yang, Burton B.
Fonte: National Academy of Sciences Publicador: National Academy of Sciences
Tipo: Artigo de Revista Científica
EN
Relevância na Pesquisa
27.37%
MicroRNAs are single-stranded RNA of 18–24 nt expressed endogenously that play important roles in cancer development. Here, we show that expression of miR-378 enhances cell survival, reduces caspase-3 activity, and promotes tumor growth and angiogenesis. Proteomic analysis indicates reduced expression of suppressor of fused (Sufu), a potential target of miR-378, which was confirmed in vitro and in vivo. Expression of a luciferase construct containing the target site in Sufu was repressed when cotransfected with miR-378. Transfection of a Sufu construct reversed the effect of miR-378, suggesting an important role for miR-378 in tumor cell survival. We also discovered that miR-378 targets Fus-1. Expression of luciferase constructs harboring the target sites in Fus-1 was repressed by miR-378. Fus-1 constructs with or without its 3′ UTR were also generated. Cotransfection experiments showed that the presence of miR-378 repressed Fus-1 expression. Suppression of Fus-1 expression by siRNA against Fus-1 enhanced cell survival. Transfection of the Fus-1 construct reversed the function of miR-378 in cell survival. Our results suggest that miR-378 transfection enhanced cell survival, tumor growth, and angiogenesis through repression of the expression of two tumor suppressors...

MicroRNA miR-378 Regulates Nephronectin Expression Modulating Osteoblast Differentiation by Targeting GalNT-7

Kahai, Shireen; Lee, Shao-Chen; Lee, Daniel Y.; Yang, Jennifer; Li, Minhui; Wang, Chia-Hui; Jiang, Zide; Zhang, Yaou; Peng, Chun; Yang, Burton B.
Fonte: Public Library of Science Publicador: Public Library of Science
Tipo: Artigo de Revista Científica
Publicado em 21/10/2009 EN
Relevância na Pesquisa
27.24%
MicroRNAs (miRNAs) are small fragments of single-stranded RNA containing 18-24 nucleotides, and are generated from endogenous transcripts. MicroRNAs function in post-transcriptional gene silencing by targeting the 3′-untranslated region (UTR) of mRNAs, resulting in translational repression. We have developed a system to study the role of miRNAs in cell differentiation. We have found that one of the miRNAs tested in our system (miR-378, also called miR-378*) plays a role in modulating nephronectin-mediated differentiation in the osteoblastic cell line, MC3T3-E1. Nephronectin is an extracellular matrix protein, and we have demonstrated that its over-expression enhanced osteoblast differentiation and bone nodule formation. Furthermore, we found that the nephronectin 3′-untranslated region (3′UTR) contains a binding site for miR-378. Stable transfection of MC3T3-E1 cells with miR-378 inhibited cell differentiation. MC3T3-E1 cells stably transfected with nephronectin exhibited higher rates of differentiation and nodule formation as compared with cells transfected with nephronectin containing the 3′UTR in the early stages of development, suggesting that endogenous miR-378 is present and active. However, in the later stages of MC3T3-E1 development...

Roles for miRNA-378/378* in adipocyte gene expression and lipogenesis

Gerin, Isabelle; Bommer, Guido T.; McCoin, Colin S.; Sousa, Kyle M.; Krishnan, Venkatesh; MacDougald, Ormond A.
Fonte: American Physiological Society Publicador: American Physiological Society
Tipo: Artigo de Revista Científica
EN
Relevância na Pesquisa
27.19%
In this study, we explored the roles of microRNAs in adipocyte differentiation and metabolism. We first knocked down Argonaute2 (Ago2), a key enzyme in the processing of micro-RNAs (miRNAs), to investigate a potential role for miRNAs in adipocyte differentiation and/or metabolism. Although we did not observe dramatic differences in adipogenesis between Ago2 knock-down and control 3T3-L1 cells, incorporation of [14C]glucose or acetate into triacylglycerol, and steady-state levels of triacyglycerol were all reduced, suggesting a role for miRNAs in adipocyte metabolism. To study roles of specific miRNAs in adipocyte biology, we screened for miRNAs that are differentially expressed between preadipocytes and adipocytes for the 3T3-L1 and ST2 cell lines. Distinct subsets of miRNAs decline or increase during adipocyte conversion, whereas most miRNAs are not regulated. One locus encoding two miRNAs, 378/378*, contained within the intron of PGC-1β is highly induced during adipogenesis. When overexpressed in ST2 mesenchymal precursor cells, miRNA378/378* increases the size of lipid droplets and incorporation of [14C]acetate into triacylglycerol. Although protein and mRNA expression levels of C/EBPα, C/EBPβ, C/EBPδ, and PPARγ1 are unchanged...

MicroRNA-378 Targets the Myogenic Repressor MyoR during Myoblast Differentiation*

Gagan, Jeffrey; Dey, Bijan K.; Layer, Ryan; Yan, Zhen; Dutta, Anindya
Fonte: American Society for Biochemistry and Molecular Biology Publicador: American Society for Biochemistry and Molecular Biology
Tipo: Artigo de Revista Científica
EN
Relevância na Pesquisa
27.24%
MicroRNAs play important roles in many cell processes, including the differentiation process in several different lineages. For example, microRNAs can promote differentiation by repressing negative regulators of transcriptional activity. These regulated transcription factors can further up-regulate levels of the microRNA in a feed-forward mechanism. Here we show that MyoD up-regulates miR-378 during myogenic differentiation in C2C12 cells. ChIP and high throughput sequencing analysis shows that MyoD binds in close proximity to the miR-378 gene and causes both transactivation and chromatin remodeling. Overexpression of miR-378 increases the transcriptional activity of MyoD, in part by repressing an antagonist, MyoR. The 3′ untranslated region of MyoR contains a direct binding site for miR-378. The presence of this binding site significantly reduces the ability of MyoR to prevent the MyoD-driven transdifferentiation of fibroblasts. MyoR and miR-378 were anticorrelated during cardiotoxin-induced adult muscle regeneration in mice. Taken together, this shows a feed-forward loop where MyoD indirectly down-regulates MyoR via miR-378.

Micro-RNA378 (miR-378) Regulates Ovarian Estradiol Production by Targeting Aromatase

Xu, Shengyu; Linher-Melville, Katja; Yang, Burton B.; Wu, De; Li, Julang
Fonte: Endocrine Society Publicador: Endocrine Society
Tipo: Artigo de Revista Científica
EN
Relevância na Pesquisa
27.12%
Estradiol is a steroid hormone that not only plays an important role in ovarian follicular development but also is associated with many reproductive disorders. Owing to the importance of aromatase in the production of estradiol, the regulation of aromatase gene expression at the transcriptional level has been an extensive area of study for over two decades. However, its regulation at the posttranscriptional level has remained unclear. Here, we show that micro-RNA378 (miR-378) is spatiotemporally expressed in porcine granulosa cells, the cells that generate estradiol in the ovary during follicular development, in an inverse manner compared with the expression of aromatase. In vitro overexpression and inhibition experiments revealed that aromatase expression, and therefore estradiol production, by granulosa cells, is posttranscriptionally down-regulated by miR-378. Furthermore, site-directed mutation studies identified two binding sites in the 3′-untranslated region (3′-UTR) of the aromatase coding sequence that are critical for the action of miR-378. Interestingly, overexpression of the aromatase 3′-UTR enhanced aromatase expression at the protein level in granulosa cells, possibly mediated by the binding of miR-378 within this region...

Ergosterol Peroxide Isolated from Ganoderma lucidum Abolishes MicroRNA miR-378-Mediated Tumor Cells on Chemoresistance

Wu, Qing-Ping; Xie, Yi-Zhen; Deng, Zhaoqun; Li, Xiang-Min; Yang, Weining; Jiao, Chun-Wei; Fang, Ling; Li, Sen-Zhu; Pan, Hong-Hui; Yee, Albert J.; Lee, Daniel Y.; Li, Chong; Zhang, Zhi; Guo, Jun; Yang, Burton B.
Fonte: Public Library of Science Publicador: Public Library of Science
Tipo: Artigo de Revista Científica
Publicado em 30/08/2012 EN
Relevância na Pesquisa
27.24%
Due to an altered expression of oncogenic factors and tumor suppressors, aggressive cancer cells have an intrinsic or acquired resistance to chemotherapeutic agents. This typically contributes to cancer recurrence after chemotherapy. microRNAs are short non-coding RNAs that are involved in both cell self-renewal and cancer development. Here we report that tumor cells transfected with miR-378 acquired properties of aggressive cancer cells. Overexpression of miR-378 enhanced both cell survival and colony formation, and contributed to multiple drug resistance. Higher concentrations of chemotherapeutic drugs were needed to induce death of miR-378-transfected cells than to induce death of control cells. We found that the biologically active component isolated from Ganoderma lucidum could overcome the drug-resistance conferred by miR-378. We purified and identified the biologically active component of Ganoderma lucidum as ergosterol peroxide. We demonstrated that ergosterol peroxide produced greater activity in inducing death of miR-378 cells than the GFP cells. Lower concentrations of ergosterol peroxide were needed to induce death of the miR-378-transfected cells than in the control cells. With further clinical development, ergosterol peroxide represents a promising new reagent that can overcome the drug-resistance of tumor cells.

Control of mitochondrial metabolism and systemic energy homeostasis by microRNAs 378 and 378*

Carrer, Michele; Liu, Ning; Grueter, Chad E.; Williams, Andrew H.; Frisard, Madlyn I.; Hulver, Matthew W.; Bassel-Duby, Rhonda; Olson, Eric N.
Fonte: National Academy of Sciences Publicador: National Academy of Sciences
Tipo: Artigo de Revista Científica
EN
Relevância na Pesquisa
27.42%
Obesity and metabolic syndrome are associated with mitochondrial dysfunction and deranged regulation of metabolic genes. Peroxisome proliferator-activated receptor γ coactivator 1β (PGC-1β) is a transcriptional coactivator that regulates metabolism and mitochondrial biogenesis through stimulation of nuclear hormone receptors and other transcription factors. We report that the PGC-1β gene encodes two microRNAs (miRNAs), miR-378 and miR-378*, which counterbalance the metabolic actions of PGC-1β. Mice genetically lacking miR-378 and miR-378* are resistant to high-fat diet-induced obesity and exhibit enhanced mitochondrial fatty acid metabolism and elevated oxidative capacity of insulin-target tissues. Among the many targets of these miRNAs, carnitine O-acetyltransferase, a mitochondrial enzyme involved in fatty acid metabolism, and MED13, a component of the Mediator complex that controls nuclear hormone receptor activity, are repressed by miR-378 and miR-378*, respectively, and are elevated in the livers of miR-378/378* KO mice. Consistent with these targets as contributors to the metabolic actions of miR-378 and miR-378*, previous studies have implicated carnitine O-acetyltransferase and MED13 in metabolic syndrome and obesity. Our findings identify miR-378 and miR-378* as integral components of a regulatory circuit that functions under conditions of metabolic stress to control systemic energy homeostasis and the overall oxidative capacity of insulin target tissues. Thus...

Interplay Between Heme Oxygenase-1 and miR-378 Affects Non-Small Cell Lung Carcinoma Growth, Vascularization, and Metastasis

Skrzypek, Klaudia; Tertil, Magdalena; Golda, Slawomir; Ciesla, Maciej; Weglarczyk, Kazimierz; Collet, Guillaume; Guichard, Alan; Kozakowska, Magdalena; Boczkowski, Jorge; Was, Halina; Gil, Tomasz; Kuzdzal, Jaroslaw; Muchova, Lucie; Vitek, Libor; Loboda, A
Fonte: Mary Ann Liebert, Inc. Publicador: Mary Ann Liebert, Inc.
Tipo: Artigo de Revista Científica
Publicado em 01/09/2013 EN
Relevância na Pesquisa
27.28%
Aims: Heme oxygenase-1 (HO-1, HMOX1) can prevent tumor initiation; while in various tumors, it has been demonstrated to promote growth, angiogenesis, and metastasis. Here, we investigated whether HMOX1 can modulate microRNAs (miRNAs) and regulate human non-small cell lung carcinoma (NSCLC) development. Results: Stable HMOX1 overexpression in NSCLC NCI-H292 cells up-regulated tumor-suppressive miRNAs, whereas it significantly diminished the expression of oncomirs and angiomirs. The most potently down-regulated was miR-378. HMOX1 also up-regulated p53, down-regulated angiopoietin-1 (Ang-1) and mucin-5AC (MUC5AC), reduced proliferation, migration, and diminished angiogenic potential. Carbon monoxide was a mediator of HMOX1 effects on proliferation, migration, and miR-378 expression. In contrast, stable miR-378 overexpression decreased HMOX1 and p53; while enhanced expression of MUC5AC, vascular endothelial growth factor (VEGF), interleukin-8 (IL-8), and Ang-1, and consequently increased proliferation, migration, and stimulation of endothelial cells. Adenoviral delivery of HMOX1 reversed miR-378 effect on the proliferation and migration of cancer cells. In vivo, HMOX1 overexpressing tumors were smaller, less vascularized and oxygenated...

Proteome Modulation in H9c2 Cardiac Cells by microRNAs miR-378 and miR-378*

Mallat, Youssef; Tritsch, Eva; Ladouce, Romain; Winter, Daniel Lorenz; Friguet, Bertrand; Li, Zhenlin; Mericskay, Mathias
Fonte: The American Society for Biochemistry and Molecular Biology Publicador: The American Society for Biochemistry and Molecular Biology
Tipo: Artigo de Revista Científica
EN
Relevância na Pesquisa
27.44%
MicroRNAs are a novel class of powerful endogenous regulators of gene expression. MiR-378 and miR-378* are localized in the first intron of the Ppargc1b gene that codes the transcriptional co-activator PGC-1β. The latter regulates energy expenditure as well as mitochondrial biogenesis. The miR-378:miR-378* hairpin is highly expressed in cardiac cells. To better assess their role in cardiomyocytes, we identified miR-378 and miR-378* targets via a proteomic screen. We established H9c2 cellular models of overexpression of miR-378 and miR-378* and identified a total of 86 down-regulated proteins in the presence of either one of these miRs. Functional annotation clustering showed that miR-378 and miR-378* regulate related pathways in cardiomyocytes, including energy metabolism, notably glycolysis, cytoskeleton, notably actin filaments and muscle contraction. Using bioinformatics algorithms we found that 20 proteins were predicted as direct targets of the miRs. We validated eight of these targets by quantitative RT-PCR and luciferase reporter assay. We found that miR-378 targets lactate dehydrogenase A and impacts on cell proliferation and survival whereas miR-378* targets cytoskeleton proteins actin and vimentin. Proteins involved in endoplasmic reticulum stress response such as chaperone and/or calcium buffering proteins GRP78...

Association between mir-24 and mir-378 in formalin-fixed paraffin-embedded tissues of breast cancer

Yin, Jia-Yu; Deng, Zhao-Qun; Liu, Feng-Qiong; Qian, Jun; Lin, Jiang; Tang, Qin; Wen, Xiang-Mei; Zhou, Jing-Dong; Zhang, Ying-Ying; Zhu, Xiao-Wen
Fonte: e-Century Publishing Corporation Publicador: e-Century Publishing Corporation
Tipo: Artigo de Revista Científica
Publicado em 15/06/2014 EN
Relevância na Pesquisa
27.28%
Background: MiR-24/378 is thought to be onco-miRNAs for their ability of enhancing tumor growth. The objective of this study was to evaluate the potential predictive value of miR-24/378 expression in formalin-fixed paraffin-embedded tissues of breast cancer patients. Methods: The expression of miR-24/378 was examined in 101 breast cancer patients and 40 controls using real-time quantitative PCR. All statistical analyses were performed using SPSS16.0. Results: We found that miR-24 and miR-378 were significantly up-regulated in breast cancer patients compared with controls (all P < 0.01). The expression levels of the two miRNAs were highly correlated with each other in breast cancer patients, with r = 0.778 between miR-24 and miR-378. Moreover, the two miRNAs exhibited great capability of discriminating between cancer patients and controls by ROC analysis. MiR-24 and miR-378 showed 0.79 and 0.807 AUC values respectively. Conclusions: Over-expression of miR-24 and miR-378 in FFPE tissue of breast cancer patients might conduct as an ideal source for biomarker discovery and validation in breast cancer patients.

MicroRNA-378 controls classical brown fat expansion to counteract obesity

Pan, Dongning; Mao, Chunxiao; Quattrochi, Brian; Friedline, Randall H; Zhu, Lihua J; Jung, Dae Young; Kim, Jason K; Lewis, Brian; Wang, Yong-Xu
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
Publicado em 22/08/2014 EN
Relevância na Pesquisa
27.24%
Both classical brown adipocytes and brown-like beige adipocytes are considered as promising therapeutic targets for obesity; however, their development, relative importance, and functional coordination are not well understood. Here we show that a modest expression of miR-378/378* in adipose tissue specifically increases classical brown fat (BAT) mass, but not white fat (WAT) mass. Remarkably, BAT expansion, rather than miR-378 per se, suppresses formation of beige adipocytes in subcutaneous WAT. Despite this negative feedback, the expanded BAT depot is sufficient to prevent both genetic and high fat diet-induced obesity. At the molecular level, we find that miR-378 targets phosphodiesterase Pde1b in BAT, but not in WAT. Indeed, miR-378 and Pde1b inversely regulate brown adipogenesis in vitro in the absence of phosphodiesterase inhibitor IBMX. Our work identifies miR-378 as a key regulatory component underlying classical BAT-specific expansion and obesity resistance, and adds novel insights into the physiological cross-talk between BAT and WAT.

MiR-378 overexpression attenuates high glucose-suppressed osteogenic differentiation through targeting CASP3 and activating PI3K/Akt signaling pathway

You, Li; Gu, Wensha; Chen, Lin; Pan, Ling; Chen, Jinyu; Peng, Yongde
Fonte: e-Century Publishing Corporation Publicador: e-Century Publishing Corporation
Tipo: Artigo de Revista Científica
Publicado em 15/09/2014 EN
Relevância na Pesquisa
27.32%
Hyperglycemia is one of the possible causes for osteoporosis and bone fracture in diabetes mellitus. Here we modeled diabetes-induced osteoporosis in vitro using preosteoblastic cell line MC3T3-E1 and a diabetic mice model for in vivo studies. We found that in addition to reducing osteoblast viability and differentiation (mineralization), culture in elevated glucose down regulated microRNA-378 (miR-378) expression but ectopic miR-378 expression reversed the effects of high glucose. We identified caspase-3 (CASP3) as a target of miR-378 and showed that miR-378 repressed CASP3 mRNA and protein expression under high glucose condition. We further showed that both miR-378 expression and CASP3 silencing independently restored alkaline phosphatase (ALP) activity and the expression of osteoblastic differentiation markers Runt-related transcription factor 2 (Runx2), osteorix (Osx), collagen I (Col I), osteocalcin (OCN), and osteonectin (ON). We also found that under high glucose conditions miR-378 activated the PI3K/Akt signaling pathway and down regulated pro-apoptotic CytC, Apaf-1 and Bax proteins via the PI3K/Akt pathway. Collectively, these results suggest that miR-378 overexpression attenuates high glucose-suppressed osteogenic differentiation through targeting CASP3 and activating the PI3K/Akt pathway.

MicroRNA-378-5p suppresses cell proliferation and induces apoptosis in colorectal cancer cells by targeting BRAF

Wang, Zhenlei; Ma, Bin; Ji, Xiaopin; Deng, Yang; Zhang, Tao; Zhang, Xiaojian; Gao, Haoji; Sun, Hanxing; Wu, Haoxuan; Chen, Xianze; Zhao, Ren
Fonte: BioMed Central Publicador: BioMed Central
Tipo: Artigo de Revista Científica
Publicado em 15/04/2015 EN
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27.34%
MicroRNAs (miRNAs) are a group of small non-coding RNA molecules that potentially play a critical role in tumorigenesis. Increasing evidences indicate that miR-378-5p is dysregulated in numerous human cancers including colorectal cancer (CRC) which hypothesizes that miR-378-5p may play an important role in tumorigenesis. However, its role in CRC carcinogenesis remains poorly defined because of lacking target genes information. In the present study, it was demonstrated that the expression of miR-378-5p was down-regulated in CRC tissues and cell lines as determined by quantitative reverse transcription-polymerase chain reaction (qRT-PCR). Furthermore, overexpression of miR-378-5p suppressed cell proliferation, as indicated by CCK-8 assay. Flow cytometric analysis demonstrated that overexpression of miR-378-5p induced cell cycle arrest and promoted apoptosis in CRC cells. A luciferase reporter assay indicated that BRAF was a direct target of miR-378-5p. Western blot and qRT-PCR analysis indicated that BRAF was significantly down-regulated by miR-378-5p in CRC cells. Moreover, miR-378-5p was negatively associated with BRAF in CRC tissues compared to adjacent non-tumor tissues. These results demonstrate that down-regulation of miR-378-5p promotes CRC cells growth by targeting BRAF and restoration of their levels is a potentially promising therapeutic in CRC.

The 5’ flanking region of miR-378 is hypomethylated in acute myeloid leukemia

Zhu, Xiao-Wen; Wen, Xiang-Mei; Zhang, Ying-Ying; Yang, Lei; Guo, Hong; Yang, Jing; Zhang, Ming; Yin, Jia-Yu; Ma, Ji-Chun; Lin, Jiang; Deng, Zhao-Qun; Qian, Jun
Fonte: e-Century Publishing Corporation Publicador: e-Century Publishing Corporation
Tipo: Artigo de Revista Científica
Publicado em 01/05/2015 EN
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27.46%
Background: Aberrant expression of miR-378 has been observed in various malignancies including acute myeloid leukemia (AML). However, the mechanism regulating of miR-378 expression remains unknown. This study was aimed to investigate miR-378 methylation and to explore its clinical significance in AML. Methods: Methylation status of miR-378 5’-flanking region was investigated by real-time quantitative methylation-specific PCR (RQ-MSP) and bisulfite-sequencing PCR (BSP). The expression of miR-378 was evaluated by real-time quantitative PCR (RQ-PCR). The correlation between expression of miR-378 and 5’-flanking region methylation was analyzed using 5-aza-2’-deoxycytidine (5-aza-dC) treatment. Results: miR-378 5’-flanking region was significantly hypomethylated in AML patients compared to controls (median 0.109 vs. 0.058) (P=0.048). miR-378 expression was correlated with miR-378 5’-flanking region in leukemic cell line treated with 5-aza-dC, but not in AML patients. The level of miR-378 hypomethylation significantly increased in M2 subtype compared to other subtypes. Moreover, patients with t(8;21) harbored the highest level of miR-378 hypomethylation. However, there was no significant difference in overall survival between patients with high and low miR-378 hypomethylation. The association of miR-378 expression with methylation was not observed in AML patients...

Decreased expression of miR-378 correlates with tumor invasiveness and poor prognosis of patients with glioma

Li, Bing; Wang, Yilin; Li, Shiting; He, Hua; Sun, Fengbin; Wang, Chunlin; Lu, Yicheng; Wang, Xiaoqiang; Tao, Bangbao
Fonte: e-Century Publishing Corporation Publicador: e-Century Publishing Corporation
Tipo: Artigo de Revista Científica
Publicado em 01/06/2015 EN
Relevância na Pesquisa
27.34%
microRNAs (miRNAs) are a class of small non-coding RNAs that play important roles in a variety of biological process. It has been reported that dysregulation of miRNA is always associated with cancer progression and development, and miR-378 aberrant expression has been found in some types of cancers. However, the association of miR-378 and glioma has not been evaluated. In this work, we measured the expression of miR-378 in glioma tissues and non-neoplastic brain tissues was measured using real-time PCR, and found that miRNA-378 expression level was significantly lower in glioma tissues compared with non-neoplastic brain tissues. Patients with lower miR-378 expression level had significantly poorer overall survival. Multivariate Cox regression analysis showed that miR-378 expression was an independent prognostic factor for 5-year overall survival. Over-expression of miR-378 inhibits glioma cell migration and invasion. In conclusion, our results indicated that miR-378 may serve as a tumor suppressor and play an important role in inhibiting tumor migration and invasion. Our work implicates the potential effect of miR-378 on the prognosis of glioma.

Endogenous cleavage of the Arg-379-Ala-380 bond in vitronectin results in a distinct conformational change which 'buries' Ser-378, its site of phosphorylation by protein kinase A.

Chain, D; Korc-Grodzicki, B; Kreizman, T; Shaltiel, S
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
Publicado em 01/03/1991 EN
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27.12%
Activation of blood platelets by thrombin was previously shown to specifically release protein kinase A, which in human plasma singles out and phosphorylates one protein, identified as vitronectin. This protein is known to be involved in processes that follow platelet stimulation, specifically, in the binding of heparin (interfering with the heparin-mediated inhibition of thrombin and Factor Xa by antithrombin III), in the growth of endothelial cells and in fibrinolysis. This paper shows that phosphorylation of vitronectin by protein kinase A is stoichiometric (approx. 1 mol/mol), that it is targeted to one site (Ser-378) at the C-terminal edge of the heparin-binding domain, and that it distinguishes between the two physiologically occurring forms of vitronectin: the one-chain (75 kDa) form, and the nicked two-chain (65 + 10 kDa) form, held together by an interchain disulphide bridge. Protein kinase A phosphorylates the one-chain form but not the two-chain form, although Ser-378 and the complete recognition sequence of the kinase are still present in the clipped 65 kDa chain. Cleavage of the Arg-379-Ala-380 bond results therefore in a conformationally distinct form of vitronectin in which Ser-378 is 'buried'. This is demonstrated by our finding that Ser-378 is present in the 65 kDa chain of clipped vitronectin but inaccessible to phosphorylation at physiological pH. Upon binding heparin...

Ley 19.378 estatuto de atención primaria de salud municipal

Villegas Martínez, Fernando
Fonte: Universidad de Chile Publicador: Universidad de Chile
Tipo: Tesis
ES
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36.87%
Memoria (licenciado en ciencias jurídicas y sociales); No autorizada por el autor para ser publicada a texto completo; El énfasis del trabajo esta puesto en la situación y régimen jurídico de los trabajadores regidos por el Estatuto de Atención Primaria ley 19.378, destacando sus derechos y deberes, la importancia y significado de su carrera funcionaria y otros temas tales como las causales de terminación de su relación laboral.