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[PMID]:29295989
[Au] Autor:Gibori H; Eliyahu S; Krivitsky A; Ben-Shushan D; Epshtein Y; Tiram G; Blau R; Ofek P; Lee JS; Ruppin E; Landsman L; Barshack I; Golan T; Merquiol E; Blum G; Satchi-Fainaro R
[Ad] Endereço:Department of Physiology and Pharmacology, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, 69978, Israel.
[Ti] Título:Amphiphilic nanocarrier-induced modulation of PLK1 and miR-34a leads to improved therapeutic response in pancreatic cancer.
[So] Source:Nat Commun;9(1):16, 2018 01 02.
[Is] ISSN:2041-1723
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:The heterogeneity of pancreatic ductal adenocarcinoma (PDAC) suggests that successful treatment might rely on simultaneous targeting of multiple genes, which can be achieved by RNA interference-based therapeutic strategies. Here we show a potent combination of microRNA and siRNA delivered by an efficient nanocarrier to PDAC tumors. Using proteomic-microRNA profiles and survival data of PDAC patients from TCGA, we found a novel signature for prolonged survival. Accordingly, we used a microRNA-mimic to increase miR-34a together with siRNA to silence PLK1 oncogene. For in vivo dual-targeting of this combination, we developed a biodegradable amphiphilic polyglutamate amine polymeric nanocarrier (APA). APA-miRNA-siRNA polyplexes systemically administered to orthotopically inoculated PDAC-bearing mice showed no toxicity and accumulated at the tumor, resulting in an enhanced antitumor effect due to inhibition of MYC oncogene, a common target of both miR-34a and PLK1. Taken together, our findings warrant this unique combined polyplex's potential as a novel nanotherapeutic for PDAC.
[Mh] Termos MeSH primário: Carcinoma Ductal Pancreático/genética
Proteínas de Ciclo Celular/genética
Regulação Neoplásica da Expressão Gênica
MicroRNAs/genética
Neoplasias Pancreáticas/genética
Proteínas Serina-Treonina Quinases/genética
Proteínas Proto-Oncogênicas/genética
RNA Interferente Pequeno/genética
[Mh] Termos MeSH secundário: Adulto
Idoso
Animais
Carcinoma Ductal Pancreático/metabolismo
Carcinoma Ductal Pancreático/terapia
Proteínas de Ciclo Celular/metabolismo
Linhagem Celular Tumoral
Portadores de Fármacos/química
Feminino
Seres Humanos
Interações Hidrofóbicas e Hidrofílicas
Estimativa de Kaplan-Meier
Masculino
Camundongos Endogâmicos C57BL
Camundongos SCID
Meia-Idade
Nanoestruturas/química
Neoplasias Pancreáticas/metabolismo
Neoplasias Pancreáticas/terapia
Proteínas Serina-Treonina Quinases/metabolismo
Proteínas Proto-Oncogênicas/metabolismo
Proteínas Proto-Oncogênicas c-myc/genética
Proteínas Proto-Oncogênicas c-myc/metabolismo
Interferência de RNA
RNA Interferente Pequeno/química
Terapêutica com RNAi/métodos
Ensaios Antitumorais Modelo de Xenoenxerto/métodos
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Cell Cycle Proteins); 0 (Drug Carriers); 0 (MIRN34 microRNA, human); 0 (MicroRNAs); 0 (Proto-Oncogene Proteins); 0 (Proto-Oncogene Proteins c-myc); 0 (RNA, Small Interfering); EC 2.7.11.1 (Protein-Serine-Threonine Kinases); EC 2.7.11.1 (polo-like kinase 1)
[Em] Mês de entrada:1803
[Cu] Atualização por classe:180305
[Lr] Data última revisão:
180305
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:180104
[St] Status:MEDLINE
[do] DOI:10.1038/s41467-017-02283-9


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[PMID]:28842505
[Au] Autor:Allam H; Johnson BP; Zhang M; Lu Z; Cannon MJ; Abbott KL
[Ad] Endereço:From the Medical Microbiology and Immunology Department, Menofiya University, Cairo 11795, Egypt.
[Ti] Título:The glycosyltransferase GnT-III activates Notch signaling and drives stem cell expansion to promote the growth and invasion of ovarian cancer.
[So] Source:J Biol Chem;292(39):16351-16359, 2017 Sep 29.
[Is] ISSN:1083-351X
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Glycosylation changes associated with cellular transformation can facilitate the growth and progression of tumors. Previously we discovered that the gene encoding the glycosyltransferase GnT-III is elevated in epithelial ovarian carcinomas (EOCs) and leads to the production of abnormal truncated -linked glycan structures instead of the typical bisected forms. In this study, we are interested in discovering how these abnormal glycans impact the growth and progression of ovarian cancer. We have discovered using stable shRNA gene suppression that GnT-III expression controls the expansion of side-population cells, also known as cancer stem cells. More specifically, we found that GnT-III expression regulates the levels and activation of the heavily glycosylated Notch receptor involved in normal and malignant development. Suppression of GnT-III in EOC cell lines and primary tumor-derived cells resulted in an inhibition of Notch signaling that was more potent than pharmacologic blockage of Notch activation via γ-secretase inhibition. The inhibition resulted from the redirection of the Notch receptor to the lysosome, a novel mechanism. These findings demonstrate a new role for bisecting glycosylation in the control of Notch transport and demonstrate the therapeutic potential of inhibiting GnT-III as a treatment for controlling EOC growth and recurrence.
[Mh] Termos MeSH primário: Carcinoma/metabolismo
N-Acetilglucosaminiltransferases/metabolismo
Proteínas de Neoplasias/metabolismo
Células-Tronco Neoplásicas/metabolismo
Neoplasias Ovarianas/metabolismo
Receptores Notch/agonistas
Transdução de Sinais
[Mh] Termos MeSH secundário: Animais
Carcinoma/patologia
Carcinoma/terapia
Linhagem Celular Tumoral
Feminino
Glicosilação
Seres Humanos
Estimativa de Kaplan-Meier
Camundongos Endogâmicos NOD
N-Acetilglucosaminiltransferases/antagonistas & inibidores
N-Acetilglucosaminiltransferases/genética
Invasividade Neoplásica
Proteínas de Neoplasias/antagonistas & inibidores
Proteínas de Neoplasias/genética
Células-Tronco Neoplásicas/patologia
Neoplasias Ovarianas/patologia
Neoplasias Ovarianas/terapia
Ovário/metabolismo
Ovário/patologia
Processamento de Proteína Pós-Traducional
Interferência de RNA
Terapêutica com RNAi
Receptores Notch/metabolismo
Bancos de Tecidos
Carga Tumoral
Ensaios Antitumorais Modelo de Xenoenxerto
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Neoplasm Proteins); 0 (Receptors, Notch); EC 2.4.1.- (N-Acetylglucosaminyltransferases); EC 2.4.1.144 (beta-1,4-mannosyl-glycoprotein beta-1,4-N-acetylglucosaminyltransferase)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171016
[Lr] Data última revisão:
171016
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170827
[St] Status:MEDLINE
[do] DOI:10.1074/jbc.M117.783936


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[PMID]:28821606
[Au] Autor:Peters JM
[Ad] Endereço:From the Department of Veterinary and Biomedical Sciences and The Center of Molecular Toxicology and Carcinogenesis, The Pennsylvania State University, University Park, Pennsylvania 16802 jmp21@psu.edu.
[Ti] Título:Flipping a citrate switch on liver cancer cells.
[So] Source:J Biol Chem;292(33):13902-13903, 2017 Aug 18.
[Is] ISSN:1083-351X
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Energy homeostasis and oncogenic signaling are critical determinants of the growth of human liver cancer cells, providing a strong rationale to elucidate the regulatory mechanisms for these systems. A new study reports that loss of solute carrier family 13 member 5, which transports citrate across cell membranes, halts liver cancer cell growth by altering both energy production and mammalian target of rapamycin signaling in human liver cancer cell lines and in both an and model of liver tumors, suggesting a new target for liver cancer chemoprevention and/or chemotherapy.
[Mh] Termos MeSH primário: Ciclo do Ácido Cítrico
Hepatoblastoma/terapia
Neoplasias Hepáticas/terapia
Proteínas de Neoplasias/antagonistas & inibidores
Terapêutica com RNAi
Simportadores/antagonistas & inibidores
[Mh] Termos MeSH secundário: Animais
Metabolismo Energético
Hepatoblastoma/metabolismo
Hepatoblastoma/patologia
Seres Humanos
Neoplasias Hepáticas/metabolismo
Neoplasias Hepáticas/patologia
Camundongos Nus
Proteínas de Neoplasias/genética
Proteínas de Neoplasias/metabolismo
Simportadores/genética
Simportadores/metabolismo
Carga Tumoral
Ensaios Antitumorais Modelo de Xenoenxerto
[Pt] Tipo de publicação:JOURNAL ARTICLE; REVIEW
[Nm] Nome de substância:
0 (Neoplasm Proteins); 0 (SLC13A5 protein, human); 0 (Symporters)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170906
[Lr] Data última revisão:
170906
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170820
[St] Status:MEDLINE
[do] DOI:10.1074/jbc.H117.783860


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[PMID]:28772071
[Au] Autor:Lee DJ; Kessel E; Lehto T; Liu X; Yoshinaga N; Padari K; Chen YC; Kempter S; Uchida S; Rädler JO; Pooga M; Sheu MT; Kataoka K; Wagner E
[Ad] Endereço:Department of Pharmacy and Center for NanoScience, Ludwig-Maximilians-Universität München , Butenandtstr. 5-13, 81377 Munich, Germany.
[Ti] Título:Systemic Delivery of Folate-PEG siRNA Lipopolyplexes with Enhanced Intracellular Stability for In Vivo Gene Silencing in Leukemia.
[So] Source:Bioconjug Chem;28(9):2393-2409, 2017 Sep 20.
[Is] ISSN:1520-4812
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Protection of small interfering RNA (siRNA) against degradation and targeted delivery across the plasma and endosomal membranes to the final site of RNA interference (RNAi) are major aims for the development of siRNA therapeutics. Targeting for folate receptor (FR)-expressing tumors, we optimized siRNA polyplexes by coformulating a folate-PEG-oligoaminoamide (for surface shielding and targeting) with one of three lipo-oligoaminoamides (optionally tyrosine-modified, for optimizing stability and size) to generate ∼100 nm targeted lipopolyplexes (TLPs), which self-stabilize by cysteine disulfide cross-links. To better understand parameters for improved tumor-directed gene silencing, we analyzed intracellular distribution and siRNA release kinetics. FR-mediated endocytosis and endosomal escape of TLPs was confirmed by immuno-TEM. We monitored colocalization of TLPs with endosomes and lysosomes, and onset of siRNA release by time-lapse confocal microscopy; analyzed intracellular stability by FRET using double-labeled siRNA; and correlated results with knockdown of eGFPLuc protein and EG5 mRNA expression. The most potent formulation, TLP1, containing lipopolyplex-stabilizing tyrosine trimers, was found to unpack siRNA in sustained manner with up to 5-fold higher intracellular siRNA stability after 4 h compared to other TLPs. Unexpectedly, data indicated that intracellular siRNA stability instead of an early endosomal exit dominate as a deciding factor for silencing efficiency of TLPs. After i.v. administration in a subcutaneous leukemia mouse model, TLP1 exhibited ligand-dependent tumoral siRNA retention, resulting in 65% EG5 gene silencing at mRNA level without detectable adverse effects. In sum, tyrosine-modified TLP1 conveys superior protection of siRNA for an effective tumor-targeted delivery and RNAi in vivo.
[Mh] Termos MeSH primário: Ácido Fólico/análogos & derivados
Leucemia/genética
Leucemia/terapia
Polietilenoglicóis/metabolismo
RNA Interferente Pequeno/administração & dosagem
RNA Interferente Pequeno/uso terapêutico
Terapêutica com RNAi/métodos
[Mh] Termos MeSH secundário: Animais
Linhagem Celular Tumoral
Feminino
Receptores de Folato com Âncoras de GPI/metabolismo
Ácido Fólico/análise
Ácido Fólico/metabolismo
Seres Humanos
Cinesina/genética
Leucemia/metabolismo
Camundongos Nus
Polietilenoglicóis/análise
Interferência de RNA
Estabilidade de RNA
RNA Interferente Pequeno/genética
RNA Interferente Pequeno/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Folate Receptors, GPI-Anchored); 0 (KIF11 protein, human); 0 (RNA, Small Interfering); 0 (poly(ethylene glycol)-folate); 30IQX730WE (Polyethylene Glycols); 935E97BOY8 (Folic Acid); EC 3.6.1.- (Eg5 protein, mouse); EC 3.6.4.4 (Kinesin)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171009
[Lr] Data última revisão:
171009
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170804
[St] Status:MEDLINE
[do] DOI:10.1021/acs.bioconjchem.7b00383


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[PMID]:28691885
[Au] Autor:Pasi KJ; Rangarajan S; Georgiev P; Mant T; Creagh MD; Lissitchkov T; Bevan D; Austin S; Hay CR; Hegemann I; Kazmi R; Chowdary P; Gercheva-Kyuchukova L; Mamonov V; Timofeeva M; Soh CH; Garg P; Vaishnaw A; Akinc A; Sørensen B; Ragni MV
[Ad] Endereço:From the Royal London Haemophilia Centre, Barts and the London School of Medicine and Dentistry (K.J.P.), National Institute for Health Research (NIHR) Biomedical Research Centre (T.M.), Guy's and St. Thomas' NHS Foundation Trust, King's College London (D.B.), St. George's Healthcare NHS Trust Haemo
[Ti] Título:Targeting of Antithrombin in Hemophilia A or B with RNAi Therapy.
[So] Source:N Engl J Med;377(9):819-828, 2017 08 31.
[Is] ISSN:1533-4406
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: Current hemophilia treatment involves frequent intravenous infusions of clotting factors, which is associated with variable hemostatic protection, a high treatment burden, and a risk of the development of inhibitory alloantibodies. Fitusiran, an investigational RNA interference (RNAi) therapy that targets antithrombin (encoded by SERPINC1), is in development to address these and other limitations. METHODS: In this phase 1 dose-escalation study, we enrolled 4 healthy volunteers and 25 participants with moderate or severe hemophilia A or B who did not have inhibitory alloantibodies. Healthy volunteers received a single subcutaneous injection of fitusiran (at a dose of 0.03 mg per kilogram of body weight) or placebo. The participants with hemophilia received three injections of fitusiran administered either once weekly (at a dose of 0.015, 0.045, or 0.075 mg per kilogram) or once monthly (at a dose of 0.225, 0.45, 0.9, or 1.8 mg per kilogram or a fixed dose of 80 mg). The study objectives were to assess the pharmacokinetic and pharmacodynamic characteristics and safety of fitusiran. RESULTS: No thromboembolic events were observed during the study. The most common adverse events were mild injection-site reactions. Plasma levels of fitusiran increased in a dose-dependent manner and showed no accumulation with repeated administration. The monthly regimen induced a dose-dependent mean maximum antithrombin reduction of 70 to 89% from baseline. A reduction in the antithrombin level of more than 75% from baseline resulted in median peak thrombin values at the lower end of the range observed in healthy participants. CONCLUSIONS: Once-monthly subcutaneous administration of fitusiran resulted in dose-dependent lowering of the antithrombin level and increased thrombin generation in participants with hemophilia A or B who did not have inhibitory alloantibodies. (Funded by Alnylam Pharmaceuticals; ClinicalTrials.gov number, NCT02035605 .).
[Mh] Termos MeSH primário: Antitrombina III/antagonistas & inibidores
Hemofilia A/terapia
Hemofilia B/terapia
Terapêutica com RNAi
[Mh] Termos MeSH secundário: Adulto
Antitrombinas/sangue
Relação Dose-Resposta a Droga
Voluntários Saudáveis
Hemofilia A/sangue
Hemofilia B/sangue
Seres Humanos
Injeções Subcutâneas
Masculino
Meia-Idade
Método Simples-Cego
Trombina/biossíntese
Adulto Jovem
[Pt] Tipo de publicação:CLINICAL TRIAL, PHASE I; JOURNAL ARTICLE; MULTICENTER STUDY; RANDOMIZED CONTROLLED TRIAL
[Nm] Nome de substância:
0 (Antithrombins); 0 (SERPINC1 protein, human); 9000-94-6 (Antithrombin III); EC 3.4.21.5 (Thrombin)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170912
[Lr] Data última revisão:
170912
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:170711
[Cl] Clinical Trial:ClinicalTrial
[St] Status:MEDLINE
[do] DOI:10.1056/NEJMoa1616569


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[PMID]:28668956
[Au] Autor:Li X; Zhou J; Huang K
[Ad] Endereço:Department of Cardiovascular Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
[Ti] Título:Inhibition of the lncRNA Mirt1 Attenuates Acute Myocardial Infarction by Suppressing NF-κB Activation.
[So] Source:Cell Physiol Biochem;42(3):1153-1164, 2017.
[Is] ISSN:1421-9778
[Cp] País de publicação:Switzerland
[La] Idioma:eng
[Ab] Resumo:BACKGROUND/AIMS: The expression of a novel lncRNA, myocardial infarction associated transcript 1(Mirt1), has been shown to be upregulated in acute myocardial infarction (AMI). However, the role of Mirt1 in AMI is not clear. METHODS: In this study, we analyzed the level of Mirt1 in cardiomyocytes and cardiac fibroblasts in AMI mice. Moreover, adenovirus mediated knockdown of Mirt1 was employed to clarify its roles in AMI mice or cultured cardiac fibroblasts. The cardiac functions and infarct size of AMI mice were examined, and tissues and cultured cells were collected and processed for histology and biochemical examination. RESULTS: We demonstrated that Mirt1 was mainly expressed in cardiac fibroblasts, and that knockdown of Mirt1 improved cardiac functions, decreased cardiomyocytes apoptosis and attenuated inflammatory cell infiltration in vivo. Furthermore, knockdown of Mirt1 in cardiac fibroblasts not only attenuated the apoptosis of cardiomyocytes, but also suppressed the migration of macrophages under hypoxia in vitro. NF-κB signaling pathway, activated under hypoxia, was also inhibited by Mirt1 knockdown in fibroblasts. CONCLUSIONS: Knockdown of Mirt1 attenuates AMI injury presumably by decreasing cardiomyocytes apoptosis and reducing inflammatory cell infiltration. These effects could be attributed, at least partly, to inhibition of the NF-κB pathway, resulting in decreased expression of inflammatory factors.
[Mh] Termos MeSH primário: Infarto do Miocárdio/genética
Infarto do Miocárdio/terapia
Miocárdio/patologia
NF-kappa B/imunologia
RNA Longo não Codificante/genética
Terapêutica com RNAi
[Mh] Termos MeSH secundário: Animais
Modelos Animais de Doenças
Fibroblastos/imunologia
Fibroblastos/metabolismo
Fibroblastos/patologia
Regulação da Expressão Gênica
Inflamação/genética
Inflamação/imunologia
Inflamação/patologia
Inflamação/terapia
Masculino
Camundongos Endogâmicos C57BL
Infarto do Miocárdio/imunologia
Infarto do Miocárdio/patologia
Miocárdio/metabolismo
Miócitos Cardíacos/imunologia
Miócitos Cardíacos/metabolismo
Miócitos Cardíacos/patologia
RNA Longo não Codificante/análise
RNA Longo não Codificante/imunologia
RNA Interferente Pequeno/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (MIRT1 long-non-coding RNA, mouse); 0 (NF-kappa B); 0 (RNA, Long Noncoding); 0 (RNA, Small Interfering)
[Em] Mês de entrada:1711
[Cu] Atualização por classe:171107
[Lr] Data última revisão:
171107
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170703
[St] Status:MEDLINE
[do] DOI:10.1159/000478870


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[PMID]:28655760
[Au] Autor:Li Z; Li D; Choi EY; Lapidus R; Zhang L; Huang SM; Shapiro P; Wang H
[Ad] Endereço:From the Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy, Baltimore, Maryland 21201.
[Ti] Título:Silencing of solute carrier family 13 member 5 disrupts energy homeostasis and inhibits proliferation of human hepatocarcinoma cells.
[So] Source:J Biol Chem;292(33):13890-13901, 2017 Aug 18.
[Is] ISSN:1083-351X
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The solute carrier family 13 member 5 (SLC13A5), a sodium-coupled citrate transporter, plays a key role in importing citrate from the circulation into liver cells. Recent evidence has revealed that SLC13A5 deletion protects mice from high-fat diet-induced hepatic steatosis and that mutation of the SLC13A5 orthologues in and promotes longevity. However, despite the emerging importance of SLC13A5 in energy homeostasis, whether perturbation of SLC13A5 affects the metabolism and malignancy of hepatocellular carcinoma is unknown. Here, we sought to determine whether SLC13A5 regulates hepatic energy homeostasis and proliferation of hepatoma cells. RNAi-mediated silencing of SLC13A5 expression in two human hepatoma cell lines, HepG2 and Huh7, profoundly suppressed cell proliferation and colony formation, and induced cell cycle arrest accompanied by increased expression of cyclin-dependent kinase inhibitor p21 and decreased expression of cyclin B1. Furthermore, such suppressive effects were also observed on the growth of HepG2 cell-derived xenografts expressing SLC13A5-shRNA in nude mice. Metabolically, knockdown of SLC13A5 in HepG2 and Huh7 cells was associated with a decrease in intracellular levels of citrate, the ratio of ATP/ADP, phospholipid content, and ATP citrate lyase expression. Moreover, both and assays demonstrated that SLC13A5 depletion promotes activation of the AMP-activated protein kinase, which was accompanied by deactivation of oncogenic mechanistic target of rapamycin signaling. Together, our findings expand the role of SLC13A5 from facilitating hepatic energy homeostasis to influencing hepatoma cell proliferation and suggest a potential role of SLC13A5 in the progression of human hepatocellular carcinoma.
[Mh] Termos MeSH primário: Metabolismo Energético
Hepatoblastoma/terapia
Neoplasias Hepáticas/terapia
Proteínas de Neoplasias/antagonistas & inibidores
Terapêutica com RNAi
Simportadores/antagonistas & inibidores
[Mh] Termos MeSH secundário: Animais
Linhagem Celular Tumoral
Proliferação Celular
Feminino
Regulação Neoplásica da Expressão Gênica
Hepatoblastoma/metabolismo
Hepatoblastoma/patologia
Seres Humanos
Neoplasias Hepáticas/metabolismo
Neoplasias Hepáticas/patologia
Camundongos Nus
Proteínas de Neoplasias/agonistas
Proteínas de Neoplasias/genética
Proteínas de Neoplasias/metabolismo
Interferência de RNA
RNA Interferente Pequeno
Organismos Livres de Patógenos Específicos
Simportadores/genética
Simportadores/metabolismo
Carga Tumoral
Ensaio Tumoral de Célula-Tronco
Ensaios Antitumorais Modelo de Xenoenxerto
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Neoplasm Proteins); 0 (RNA, Small Interfering); 0 (SLC13A5 protein, human); 0 (Symporters)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170906
[Lr] Data última revisão:
170906
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170629
[St] Status:MEDLINE
[do] DOI:10.1074/jbc.M117.783860


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[PMID]:28596304
[Au] Autor:Hadjiphilippou S; Ray KK
[Ad] Endereço:Department of Cardiology, Imperial College Healthcare NHS Trust, London, UK.
[Ti] Título:PCSK9 inhibition and atherosclerotic cardiovascular disease prevention: does reality match the hype?
[So] Source:Heart;103(21):1670-1679, 2017 Nov.
[Is] ISSN:1468-201X
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Within this review we look at whether the potential provided by proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibition for prevention of atherosclerotic cardiovascular disease matches the excitement generated. Two fully human monoclonal antibodies to PCSK9 are currently licenced for clinical use both in the USA and the European Union: evolocumab and alirocumab. These reduce low-density lipoprotein cholesterol by over 50% across a range of populations and were generally found to have a safety profile comparable with placebo. The development programme for a third humanised monoclonal antibody, bococizumab, was terminated early due to the presence of neutralising antibodies reducing its efficacy over time. Results from the first cardiovascular outcomes trial, FOURIER, have demonstrated significant reductions in cardiovascular events in a population with stable cardiovascular disease over a 2-year period. The ODYSSEY OUTCOMES trial comparing alirocumab to placebo is expected to report in 2018 and provide cardiovascular outcome data in a post acute coronary syndrome population. Monoclonal antibodies have an injection burden of 12-26 injections per year. An alternative approach to reducing PCSK9 is to inhibit translation of the messenger RNA for PCSK9. The phase II ORION-1 study using inclisiran, a small interference RNA to PCSK9, suggested that two doses of inclisiran produced time averaged reductions in LDL cholesterol of 50% over 9 months. The ORION-4 cardiovascular outcome trial will assess the cardiovascular benefits of two injections per year using inclisiran. With further outcome trials expected, appropriate patient selection will be key considering the higher drug costs of these therapies.
[Mh] Termos MeSH primário: Anticorpos Monoclonais/uso terapêutico
Aterosclerose/tratamento farmacológico
Hipolipemiantes/uso terapêutico
Metabolismo dos Lipídeos/efeitos dos fármacos
Fígado/efeitos dos fármacos
Pró-Proteína Convertase 9/antagonistas & inibidores
Inibidores de Serino Proteinase/uso terapêutico
[Mh] Termos MeSH secundário: Animais
Anticorpos Monoclonais/efeitos adversos
Aterosclerose/sangue
Aterosclerose/enzimologia
Aterosclerose/genética
Biomarcadores/sangue
LDL-Colesterol/sangue
Seres Humanos
Hipolipemiantes/efeitos adversos
Fígado/enzimologia
Pró-Proteína Convertase 9/genética
Pró-Proteína Convertase 9/metabolismo
Interferência de RNA
RNA Interferente Pequeno/uso terapêutico
Terapêutica com RNAi/métodos
Fatores de Risco
Inibidores de Serino Proteinase/efeitos adversos
Resultado do Tratamento
[Pt] Tipo de publicação:JOURNAL ARTICLE; REVIEW
[Nm] Nome de substância:
0 (Antibodies, Monoclonal); 0 (Biomarkers); 0 (Cholesterol, LDL); 0 (Hypolipidemic Agents); 0 (RNA, Small Interfering); 0 (Serine Proteinase Inhibitors); EC 3.4.21.- (PCSK9 protein, human); EC 3.4.21.- (Proprotein Convertase 9)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171024
[Lr] Data última revisão:
171024
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:170610
[St] Status:MEDLINE
[do] DOI:10.1136/heartjnl-2016-310844


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[PMID]:28511963
[Au] Autor:Zhang Y; Xia P; Zhang W; Yan M; Xiong X; Yu W; Song E
[Ad] Endereço:Department of Pathology, Basic Medical College of Nanchang University, Nanchang 330006, China.
[Ti] Título:Short interfering RNA targeting Net1 reduces the angiogenesis and tumor growth of in vivo cervical squamous cell carcinoma through VEGF down-regulation.
[So] Source:Hum Pathol;65:113-122, 2017 Jul.
[Is] ISSN:1532-8392
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Net1, a guanine nucleotide exchange factor, is implicated in cancer cell invasion through activation of RhoA. However, there is still no report on the association between Net1 and cancer angiogenesis. The current study was designed to explore the role of Net1 in the angiogenesis of cervical squamous cell carcinoma (CSCC) and further observe the effects of Net1 short interfering RNA (siRNA) on the tumor growth. Net1 was overexpressed in CSCC samples (n=80), correlated with the cancer microvessel density (r=0.223, P=.026), and related to aggressive clinical behaviors, including depth of cervical wall invasion (P=.041), parametrial involvement (P=.037), lymph node metastasis (P=.021), and vascular invasion (P=.018). Human umbilical vein endothelial cells treated with supernatant of SiHa cells with Net1 siRNA showed significantly decreased proliferation (0.75±0.038 versus 1.0±0.015, P<.001), migration (39.3±6.5 versus 66.0±10.1, P=.019), and tube formation (13.5±3.05 versus 21.7±2.89, P=.030) compared with those human umbilical vein endothelial cells treated with normal SiHa cells supernatant. Net1 siRNA of SiHa decreased VEGF expression level (0.60±0.026 versus 0.78±0.031, P=.02). Furthermore, Net1 siRNA significantly reduced tumor growth (P=.037) and microvessel density (5.8±0.43 versus 3.4±0.55, P=.012) and decreased the expression level of VEGF (0.31±0.002 versus 0.39±0.004, P<.001) in CSCC. In conclusion, Net1 promotes the angiogenesis of CSCC, and siRNA targeting Net1 can effectively reduce the angiogenesis and thus inhibit the tumor growth of CSCC in vivo.
[Mh] Termos MeSH primário: Carcinoma de Células Escamosas/terapia
Neovascularização Patológica
Proteínas Oncogênicas/metabolismo
Interferência de RNA
RNA Interferente Pequeno/metabolismo
Terapêutica com RNAi
Neoplasias do Colo do Útero/terapia
Fator A de Crescimento do Endotélio Vascular/metabolismo
[Mh] Termos MeSH secundário: Adulto
Idoso
Animais
Carcinoma de Células Escamosas/genética
Carcinoma de Células Escamosas/metabolismo
Carcinoma de Células Escamosas/patologia
Linhagem Celular Tumoral
Movimento Celular
Proliferação Celular
Regulação para Baixo
Feminino
Regulação Neoplásica da Expressão Gênica
Células Endoteliais da Veia Umbilical Humana/metabolismo
Seres Humanos
Camundongos Endogâmicos BALB C
Camundongos Nus
Meia-Idade
Proteínas Oncogênicas/genética
RNA Interferente Pequeno/genética
Transdução de Sinais
Transfecção
Carga Tumoral
Neoplasias do Colo do Útero/genética
Neoplasias do Colo do Útero/metabolismo
Neoplasias do Colo do Útero/patologia
Fator A de Crescimento do Endotélio Vascular/genética
Ensaios Antitumorais Modelo de Xenoenxerto
Adulto Jovem
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (NET1 protein, human); 0 (Oncogene Proteins); 0 (RNA, Small Interfering); 0 (VEGFA protein, human); 0 (Vascular Endothelial Growth Factor A)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170926
[Lr] Data última revisão:
170926
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170518
[St] Status:MEDLINE


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[PMID]:28482882
[Au] Autor:Gao W; Li J
[Ad] Endereço:Department of Basic Medical Sciences, Center for Paralysis Research, College of Veterinary Medicine, Purdue University, 408 S. University St., West Lafayette, IN, 47907, USA.
[Ti] Título:Targeted siRNA delivery reduces nitric oxide mediated cell death after spinal cord injury.
[So] Source:J Nanobiotechnology;15(1):38, 2017 May 08.
[Is] ISSN:1477-3155
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: Traumatic spinal cord injury (SCI) includes the primary insult as well as a sequela of biochemical and cellular cascades that amplifies the initial injury. This degenerative process, known as secondary injury, is often mediated by both reactive oxygen and nitrogen species released from damaged cells. Previous data suggests that dysregulated production of nitric oxide via inducible nitric oxide synthase (iNOS) is detrimental to spinal cord recovery. M1 macrophages have been implicated to overexpress iNOS post-SCI. In this work, we propose to inhibit iNOS expression through small interfering RNA (siRNA) complexed chitosan nanoparticles (NPs) that primarily target M1 macrophages. METHODS: siRNA conjugated chitosan complexes were fabricated with and without an antibody (Ab) targeting moiety and screened for efficiency to reduce iNOS expression in vitro. Best formulations were subsequently applied in vivo following acute SCI in a rodent model. iNOS expression as well as Bax and Bcl-2 biomarkers were used to assess cell apoptosis within the lesion at 24 h post-injury. RESULTS: Ab-siRNA conjugated chitosan NPs significantly reduced iNOS expression in vitro in M1 polarized macrophages. Results show high transfection efficiency with low cytotoxicity. Subsequent application of NPs in vivo after SCI demonstrated both a reduction in iNOS expression and cellular apoptosis. CONCLUSION: Proof of concept indicates that siRNA conjugated chitosan NPs can downregulate iNOS production and inhibit apoptosis following SCI. Our proposed gene silencing method putatively targets M1 macrophages as a means to attenuate secondary injury.
[Mh] Termos MeSH primário: Apoptose
Macrófagos/patologia
Óxido Nítrico Sintase Tipo II/genética
Óxido Nítrico/metabolismo
RNA Interferente Pequeno/uso terapêutico
Terapêutica com RNAi
Traumatismos da Medula Espinal/terapia
[Mh] Termos MeSH secundário: Animais
Células Cultivadas
Quitosana/química
Feminino
Macrófagos/metabolismo
Camundongos Endogâmicos BALB C
Camundongos Endogâmicos C57BL
Nanopartículas/química
Nanopartículas/ultraestrutura
Óxido Nítrico Sintase Tipo II/metabolismo
RNA Interferente Pequeno/administração & dosagem
RNA Interferente Pequeno/genética
Traumatismos da Medula Espinal/genética
Traumatismos da Medula Espinal/patologia
Transfecção
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (RNA, Small Interfering); 31C4KY9ESH (Nitric Oxide); 9012-76-4 (Chitosan); EC 1.14.13.39 (Nitric Oxide Synthase Type II)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170915
[Lr] Data última revisão:
170915
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170510
[St] Status:MEDLINE
[do] DOI:10.1186/s12951-017-0272-7



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