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Pesquisa : D12.776.826 [Categoria DeCS]
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  1 / 19392 MEDLINE  
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[PMID]:29346429
[Au] Autor:Ferrigno A; Di Pasqua LG; Berardo C; Siciliano V; Rizzo V; Adorini L; Richelmi P; Vairetti M
[Ad] Endereço:Department of Internal Medicine and Therapeutics, University of Pavia, Pavia, Italy.
[Ti] Título:The farnesoid X receptor agonist obeticholic acid upregulates biliary excretion of asymmetric dimethylarginine via MATE-1 during hepatic ischemia/reperfusion injury.
[So] Source:PLoS One;13(1):e0191430, 2018.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: We previously showed that increased asymmetric dimethylarginine (ADMA) biliary excretion occurs during hepatic ischemia/reperfusion (I/R), prompting us to study the effects of the farnesoid X receptor (FXR) agonist obeticholic acid (OCA) on bile, serum and tissue levels of ADMA after I/R. MATERIAL AND METHODS: Male Wistar rats were orally administered 10mg/kg/day of OCA or vehicle for 5 days and were subjected to 60 min partial hepatic ischemia or sham-operated. After a 60 min reperfusion, serum, tissue and bile ADMA levels, liver mRNA and protein expression of ADMA transporters (CAT-1, CAT-2A, CAT-2B, OCT-1, MATE-1), and enzymes involved in ADMA synthesis (protein-arginine-N-methyltransferase-1, PRMT-1) and metabolism (dimethylarginine-dimethylaminohydrolase-1, DDAH-1) were measured. RESULTS: OCA administration induced a further increase in biliary ADMA levels both in sham and I/R groups, with no significant changes in hepatic ADMA content. A reduction in CAT-1, CAT-2A or CAT-2B transcripts was found in OCA-treated sham-operated rats compared with vehicle. Conversely, OCA administration did not change CAT-1, CAT-2A or CAT-2B expression, already reduced by I/R. However, a marked decrease in OCT-1 and increase in MATE-1 expression was observed. A similar trend occurred with protein expression. CONCLUSION: The reduced mRNA expression of hepatic CAT transporters suggests that the increase in serum ADMA levels is probably due to decreased liver uptake of ADMA from the systemic circulation. Conversely, the mechanism involved in further increasing biliary ADMA levels in sham and I/R groups treated with OCA appears to be MATE-1-dependent.
[Mh] Termos MeSH primário: Antiporters/metabolismo
Arginina/análogos & derivados
Sistema Biliar/efeitos dos fármacos
Ácido Quenodesoxicólico/análogos & derivados
Hepatopatias/metabolismo
Proteínas de Transporte de Cátions Orgânicos/metabolismo
Receptores Citoplasmáticos e Nucleares/antagonistas & inibidores
Traumatismo por Reperfusão/metabolismo
Regulação para Cima/efeitos dos fármacos
[Mh] Termos MeSH secundário: Animais
Arginina/sangue
Arginina/metabolismo
Arginina/secreção
Sistema Biliar/metabolismo
Sistema Biliar/secreção
Western Blotting
Proteínas de Transporte/genética
Proteínas de Transporte/metabolismo
Ácido Quenodesoxicólico/farmacologia
Masculino
Óxido Nítrico Sintase/metabolismo
Proteína-Arginina N-Metiltransferases/genética
RNA Mensageiro/genética
Ratos
Ratos Wistar
Reação em Cadeia da Polimerase em Tempo Real
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Antiporters); 0 (Carrier Proteins); 0 (MATE1 protein, rat); 0 (Organic Cation Transport Proteins); 0 (RNA, Messenger); 0 (Receptors, Cytoplasmic and Nuclear); 0 (farnesoid X-activated receptor); 0462Z4S4OZ (obeticholic acid); 0GEI24LG0J (Chenodeoxycholic Acid); 63CV1GEK3Y (N,N-dimethylarginine); 94ZLA3W45F (Arginine); EC 1.14.13.39 (Nitric Oxide Synthase); EC 2.1.1.319 (PRMT1 protein, rat); EC 2.1.1.319 (Protein-Arginine N-Methyltransferases)
[Em] Mês de entrada:1803
[Cu] Atualização por classe:180309
[Lr] Data última revisão:
180309
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:180119
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0191430


  2 / 19392 MEDLINE  
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[PMID]:28463106
[Au] Autor:Zhong Y; Wang J; Henderson MJ; Yang P; Hagen BM; Siddique T; Vogel BE; Deng HX; Fang S
[Ad] Endereço:Center for Biomedical Engineering and Technology, University of Maryland School of Medicine, Baltimore, United States.
[Ti] Título:Nuclear export of misfolded SOD1 mediated by a normally buried NES-like sequence reduces proteotoxicity in the nucleus.
[So] Source:Elife;6, 2017 05 02.
[Is] ISSN:2050-084X
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Over 170 different mutations in the gene encoding SOD1 all cause amyotrophic lateral sclerosis (ALS). Available studies have been primarily focused on the mechanisms underlying mutant SOD1 cytotoxicity. How cells defend against the cytotoxicity remains largely unknown. Here, we show that misfolding of ALS-linked SOD1 mutants and wild-type (wt) SOD1 exposes a normally buried nuclear export signal (NES)-like sequence. The nuclear export carrier protein CRM1 recognizes this NES-like sequence and exports misfolded SOD1 to the cytoplasm. Antibodies against the NES-like sequence recognize misfolded SOD1, but not native wt SOD1 both in vitro and in vivo. Disruption of the NES consensus sequence relocalizes mutant SOD1 to the nucleus, resulting in higher toxicity in cells, and severer impairments in locomotion, egg-laying, and survival in . Our data suggest that SOD1 mutants are removed from the nucleus by CRM1 as a defense mechanism against proteotoxicity of misfolded SOD1 in the nucleus.
[Mh] Termos MeSH primário: Transporte Ativo do Núcleo Celular
Carioferinas/metabolismo
Dobramento de Proteína
Receptores Citoplasmáticos e Nucleares/metabolismo
Superóxido Dismutase-1/metabolismo
Superóxido Dismutase-1/toxicidade
[Mh] Termos MeSH secundário: Motivos de Aminoácidos
Animais
Caenorhabditis elegans
Proteínas Mutantes/genética
Proteínas Mutantes/metabolismo
Proteínas Mutantes/toxicidade
Ligação Proteica
Sinais Direcionadores de Proteínas
Superóxido Dismutase-1/química
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL; RESEARCH SUPPORT, U.S. GOV'T, NON-P.H.S.
[Nm] Nome de substância:
0 (Karyopherins); 0 (Mutant Proteins); 0 (Protein Sorting Signals); 0 (Receptors, Cytoplasmic and Nuclear); 0 (exportin 1 protein); EC 1.15.1.1 (Superoxide Dismutase-1)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180305
[Lr] Data última revisão:
180305
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170503
[St] Status:MEDLINE


  3 / 19392 MEDLINE  
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[PMID]:29348072
[Au] Autor:Liu C; Chen X; Zhi X; Weng W; Li Q; Li X; Zou Y; Su J; Hu HG
[Ad] Endereço:Department of Organic Chemistry, College of Pharmacy, Second Military Medical University, Shanghai 200433, China.
[Ti] Título:Structure-based development of an osteoprotegerin-like glycopeptide that blocks RANKL/RANK interactions and reduces ovariectomy-induced bone loss in mice.
[So] Source:Eur J Med Chem;145:661-672, 2018 Feb 10.
[Is] ISSN:1768-3254
[Cp] País de publicação:France
[La] Idioma:eng
[Ab] Resumo:Osteoporosis is a metabolic bone disease characterized by low bone mass and micro-architectural deterioration of bone, for which the underlying mechanism is an imbalance between bone resorption and bone remodeling. The protein-protein interactions between receptor activator of nuclear factor-κB ligand (RANKL), RANK (its receptor), and osteoprotegerin (OPG), are known to mediate the development and activation of osteoclasts in bone remodeling, and are regarded as a pivotal therapeutic target for the treatment of osteoporosis. Herein, we disclose the successful development of a novel glycopeptide (OM-2), the structure of which is based on the key interacting sites of the reported RANKL and OPG crystal structure. OM-2 exhibited potent binding affinity with RANKL and resistance to degradation by protease enzymes. It also blocked RANKL/RANK interactions, and inhibited osteoclastogenesis in vitro. In vivo studies confirmed that OM-2 could effectively reduce bone loss and inhibit osteoclast activation in ovariectomized (OVX) mice at a dosage of 20.0 mg/kg/day. Accordingly, OM-2 is suggested as a therapeutic candidate for postmenopausal osteoporosis (PMOP) and osteoclastogenesis-related diseases like rheumatoid arthritis (RA). More importantly, its identification validates our structure-based strategy for the development of drugs that target the RANKL/RANK/OPG system.
[Mh] Termos MeSH primário: Glicopeptídeos/farmacologia
Osteoporose/tratamento farmacológico
Osteoprotegerina/farmacologia
Ovariectomia
Ligante RANK/antagonistas & inibidores
Receptores Citoplasmáticos e Nucleares/antagonistas & inibidores
[Mh] Termos MeSH secundário: Animais
Osso e Ossos/efeitos dos fármacos
Osso e Ossos/metabolismo
Osso e Ossos/patologia
Relação Dose-Resposta a Droga
Feminino
Glicopeptídeos/síntese química
Glicopeptídeos/química
Masculino
Camundongos
Camundongos Endogâmicos C57BL
Simulação de Acoplamento Molecular
Estrutura Molecular
Osteoporose/metabolismo
Osteoprotegerina/química
Ligação Proteica/efeitos dos fármacos
Ligante RANK/metabolismo
Receptores Citoplasmáticos e Nucleares/metabolismo
Relação Estrutura-Atividade
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Glycopeptides); 0 (Osteoprotegerin); 0 (RANK Ligand); 0 (Receptors, Cytoplasmic and Nuclear)
[Em] Mês de entrada:1803
[Cu] Atualização por classe:180302
[Lr] Data última revisão:
180302
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:180120
[St] Status:MEDLINE


  4 / 19392 MEDLINE  
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[PMID]:29275233
[Au] Autor:Mostarda S; Passeri D; Carotti A; Cerra B; Colliva C; Benicchi T; Macchiarulo A; Pellicciari R; Gioiello A
[Ad] Endereço:Department of Pharmaceutical Sciences, University of Perugia, Via del Liceo, 1, 06123 Perugia, Italy.
[Ti] Título:Synthesis, physicochemical properties, and biological activity of bile acids 3-glucuronides: Novel insights into bile acid signalling and detoxification.
[So] Source:Eur J Med Chem;144:349-358, 2018 Jan 20.
[Is] ISSN:1768-3254
[Cp] País de publicação:France
[La] Idioma:eng
[Ab] Resumo:Glucuronidation is considered an important detoxification pathway of bile acids especially in cholestatic conditions. Glucuronides are less toxic than the parent free forms and are more easily excreted in urine. However, the pathophysiological significance of bile acid glucuronidation is still controversial and debated among the scientific community. Progress in this field has been strongly limited by the lack of appropriate methods for the preparation of pure glucuronides in the amount needed for biological and pharmacological studies. In this work, we have developed a new synthesis of bile acid C3-glucuronides enabling the convenient preparation of gram-scale quantities. The synthesized compounds have been characterized in terms of physicochemical properties and abilities to modulate key nuclear receptors including the farnesoid X receptor (FXR). In particular, we found that C3-glucuronides of chenodeoxycholic acid and lithocholic acid, respectively the most abundant and potentially cytotoxic species formed in patients affected by cholestasis, behave as FXR agonists and positively regulate the gene expression of transporter proteins, the function of which is critical in human conditions related to imbalances of bile acid homeostasis.
[Mh] Termos MeSH primário: Ácidos e Sais Biliares/farmacologia
Glucuronídeos/farmacologia
Receptores Citoplasmáticos e Nucleares/agonistas
[Mh] Termos MeSH secundário: Ácidos e Sais Biliares/química
Química Física
Relação Dose-Resposta a Droga
Glucuronídeos/química
Células HEK293
Células Hep G2
Seres Humanos
Simulação de Dinâmica Molecular
Estrutura Molecular
Receptores Citoplasmáticos e Nucleares/genética
Relação Estrutura-Atividade
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Bile Acids and Salts); 0 (Glucuronides); 0 (Receptors, Cytoplasmic and Nuclear); 0 (farnesoid X-activated receptor)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180223
[Lr] Data última revisão:
180223
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171225
[St] Status:MEDLINE


  5 / 19392 MEDLINE  
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[PMID]:29173353
[Au] Autor:Ratajczak MZ; Ratajczak J
[Ad] Endereço:Department of Medicine, Stem Cell Institute at James Graham Brown Cancer Center, University of Louisville, Louisville, Kentucky. Electronic address: mzrata01@louisville.edu.
[Ti] Título:Extracellular Microvesicles as Game Changers in Better Understanding the Complexity of Cellular Interactions-From Bench to Clinical Applications.
[So] Source:Am J Med Sci;354(5):449-452, 2017 11.
[Is] ISSN:1538-2990
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Recent research has led to wide acceptance and better understanding of a novel mechanism for cell-cell communication that employs a network of extracellular microvesicles (ExMVs). Derived from the plasma membrane or the endosomal membrane compartment, these small, spherical membrane fragments are secreted from the cell surface or in the process of exocytosis from endosomal membrane compartment and (1) with ligands expressed on their surface directly stimulate target cells in a paracrine manner, (2) transfer cell membrane receptors to target cells or (3) deliver encapsulated messenger RNA, microRNA, proteins and bioactive lipids to target cells. This represents an evolutionarily ancient mechanism by which cells signal their presence in the microenvironment, communicate with each other and affect the biology of neighboring cells. Evidence suggests the pivotal role of ExMVs in almost all biological processes within the body as well as their involvement in certain pathologies. Moreover, liquid biopsies based on deciphering the molecular signature of ExMVs promise to revolutionize laboratory diagnostics. At the same time, there are ongoing attempts to employ them as delivery vehicles for drugs as well as therapeutics in regenerative medicine, oncology and immunotherapy.
[Mh] Termos MeSH primário: Comunicação Celular
Vesículas Extracelulares/metabolismo
MicroRNAs/metabolismo
Comunicação Parácrina
RNA Mensageiro/metabolismo
[Mh] Termos MeSH secundário: Seres Humanos
Ligantes
Proteínas/metabolismo
Receptores Citoplasmáticos e Nucleares/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE; REVIEW; RESEARCH SUPPORT, N.I.H., EXTRAMURAL; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Ligands); 0 (MicroRNAs); 0 (Proteins); 0 (RNA, Messenger); 0 (Receptors, Cytoplasmic and Nuclear)
[Em] Mês de entrada:1711
[Cu] Atualização por classe:180223
[Lr] Data última revisão:
180223
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:171128
[St] Status:MEDLINE


  6 / 19392 MEDLINE  
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[PMID]:29293579
[Au] Autor:Alfaro-Viquez E; Roling BF; Krueger CG; Rainey CJ; Reed JD; Ricketts ML
[Ad] Endereço:Reed Research Group, Department of Animal Sciences, University of Wisconsin-Madison, Madison, WI, United States of America.
[Ti] Título:An extract from date palm fruit (Phoenix dactylifera) acts as a co-agonist ligand for the nuclear receptor FXR and differentially modulates FXR target-gene expression in vitro.
[So] Source:PLoS One;13(1):e0190210, 2018.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Date palm fruit (Phoenix dactylifera) consumption reduces serum triglyceride levels in human subjects. The objective of this study was to prepare an extract from dates and determine whether it acts as a ligand for the farnesoid x receptor (FXR), a nuclear receptor important for maintaining triglyceride and cholesterol homeostasis. Freeze-dried extracts were isolated from California-grown dates (Deglet Noor and Medjool) from the 2014 and 2015 harvests, by means of liquid extraction and solid phase separation. Each date palm extract (DPE) was characterized via HPLC and MALDI-TOF mass spectrometry, and the procyanidin content was qualitatively determined. Extracts were tested to determine their ability to modulate nuclear receptor-mediated transactivation using transient transfection. The effect of DPE on FXR-target genes regulating bile acid absorption and transport was then assessed in vitro, in Caco-2 cells. Characterization reveals that DPE is a rich source of polyphenols including hydroxycinnamic acids, proanthocyanidins, and lipohilic polyphenols, and comprises 13% proanthocyanidins. Transactivation results show that DPE acts as a co-agonist ligand for both mouse and human FXR, wherein it activates bile acid-bound FXR greater than that seen with bile acid alone. Additionally, DPE alone activated a peroxisome proliferator activated receptor alpha (PPARα) chimera in a dose-dependent manner. Consistent with DPE as a co-agonist ligand for FXR, studies in Caco-2 cells reveal that co-incubation with bile acid, dose-dependently enhances the expression of fibroblast growth factor 19 (FGF19), compared to treatment with bile acid alone. In contrast, DPE inhibited bile acid-induced expression of ileal bile acid binding protein (IBABP). Our results demonstrate that DPE acts as a potent co-agonist ligand for FXR, and that it differentially regulates FXR-target gene expression in vitro in human intestinal cells. This study provides novel insight into a potential mechanism by which dates may exert a hypotriglyceridemic effect via FXR and modulation of bile acid homeostasis.
[Mh] Termos MeSH primário: Phoeniceae/química
Extratos Vegetais/farmacologia
Receptores Citoplasmáticos e Nucleares/agonistas
[Mh] Termos MeSH secundário: Células CACO-2
Seres Humanos
Técnicas In Vitro
Ligantes
Receptores Citoplasmáticos e Nucleares/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Ligands); 0 (Plant Extracts); 0 (Receptors, Cytoplasmic and Nuclear); 0 (farnesoid X-activated receptor)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180206
[Lr] Data última revisão:
180206
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:180103
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0190210


  7 / 19392 MEDLINE  
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[PMID]:29247643
[Au] Autor:Wang H; Wang F; Wu S; Liu Z; Li T; Mao L; Zhang J; Li C; Liu C; Yang Y
[Ad] Endereço:Center for Molecular Medicine (CMM), School of Life Science and Biotechnology, Dalian University of Technology, Dalian 116023, China.
[Ti] Título:Traditional herbal medicine-derived sulforaphene promotes mitophagic cell death in lymphoma cells through CRM1-mediated p62/SQSTM1 accumulation and AMPK activation.
[So] Source:Chem Biol Interact;281:11-23, 2018 Feb 01.
[Is] ISSN:1872-7786
[Cp] País de publicação:Ireland
[La] Idioma:eng
[Ab] Resumo:Sulforaphene (LFS-01) is the major chemical constituent of Raphanus sativus, a medicinal herb used for over a thousand years in traditional Chinese medicine. Here we identified that LFS-01 can selectively eradicate lymphoma cells while sparing normal lymphocytes by triggering concomitant mitophagy and apoptosis. We demonstrated that LFS-01 can retain Nrf2 in the nucleus by covalently modulating CRM1 and consequently upregulate p62/SQSTM1, an essential structural component of the autophagosomes during mitophagic process. We found that LFS-01 treatment also stimulated AMPK and thereby inhibited the mTOR pathway. On the contrary, we revealed that AMPK inhibition can severely impair the LFS-01-mediated mitophagy. Transcriptomic studies confirmed that 15 autophagy-associated genes such as p62/SQSTM1, VCP and BCL2 were differentially expressed after LFS-01 treatment. Furthermore, protein interactome network analysis revealed that the events of apoptosis and the assembly of autophagy vacuole were significant upon LFS-01 exposure. Lastly, we found that LFS-01 exhibited strong efficacy in xenograft mouse model yet with the lack of apparent toxicity to animals. We concluded that LFS-01 triggered mitophagic cell death via CRM1-mediated p62 overexpression and AMPK activation. Our findings provide new insights into the mechanism of action for LFS-01 and highlight its potential applications in treating major human diseases.
[Mh] Termos MeSH primário: Proteínas Quinases Ativadas por AMP/metabolismo
Apoptose/efeitos dos fármacos
Medicamentos de Ervas Chinesas/química
Isotiocianatos/farmacologia
Carioferinas/metabolismo
Degradação Mitocondrial/efeitos dos fármacos
Receptores Citoplasmáticos e Nucleares/metabolismo
Proteína Sequestossoma-1/metabolismo
[Mh] Termos MeSH secundário: Animais
Pontos de Checagem do Ciclo Celular/efeitos dos fármacos
Proliferação Celular/efeitos dos fármacos
Células Cultivadas
Seres Humanos
Isotiocianatos/química
Isotiocianatos/uso terapêutico
Leucócitos Mononucleares/citologia
Leucócitos Mononucleares/efeitos dos fármacos
Leucócitos Mononucleares/metabolismo
Linfoma/tratamento farmacológico
Linfoma/metabolismo
Linfoma/patologia
Camundongos
Camundongos Endogâmicos BALB C
Neoplasias/tratamento farmacológico
Neoplasias/metabolismo
Neoplasias/patologia
Estrutura Terciária de Proteína
Raphanus/química
Raphanus/metabolismo
Transdução de Sinais/efeitos dos fármacos
Regulação para Cima/efeitos dos fármacos
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Drugs, Chinese Herbal); 0 (Isothiocyanates); 0 (Karyopherins); 0 (Receptors, Cytoplasmic and Nuclear); 0 (SQSTM1 protein, human); 0 (Sequestosome-1 Protein); 0 (exportin 1 protein); 0 (sulphoraphene); EC 2.7.11.31 (AMP-Activated Protein Kinases)
[Em] Mês de entrada:1801
[Cu] Atualização por classe:180129
[Lr] Data última revisão:
180129
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171217
[St] Status:MEDLINE


  8 / 19392 MEDLINE  
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[PMID]:27773686
[Au] Autor:Hsu CW; Hsieh JH; Huang R; Pijnenburg D; Khuc T; Hamm J; Zhao J; Lynch C; van Beuningen R; Chang X; Houtman R; Xia M
[Ad] Endereço:NIH Chemical Genomics Center, National Center for Advancing Translational Sciences, National Institutes of Health, Bethesda, MD, USA.
[Ti] Título:Differential modulation of FXR activity by chlorophacinone and ivermectin analogs.
[So] Source:Toxicol Appl Pharmacol;313:138-148, 2016 12 15.
[Is] ISSN:1096-0333
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Chemicals that alter normal function of farnesoid X receptor (FXR) have been shown to affect the homeostasis of bile acids, glucose, and lipids. Several structural classes of environmental chemicals and drugs that modulated FXR transactivation were previously identified by quantitative high-throughput screening (qHTS) of the Tox21 10K chemical collection. In the present study, we validated the FXR antagonist activity of selected structural classes, including avermectin anthelmintics, dihydropyridine calcium channel blockers, 1,3-indandione rodenticides, and pyrethroid pesticides, using in vitro assay and quantitative structural-activity relationship (QSAR) analysis approaches. (Z)-Guggulsterone, chlorophacinone, ivermectin, and their analogs were profiled for their ability to alter CDCA-mediated FXR binding using a panel of 154 coregulator motifs and to induce or inhibit transactivation and coactivator recruitment activities of constitutive androstane receptor (CAR), liver X receptor alpha (LXRα), or pregnane X receptor (PXR). Our results showed that chlorophacinone and ivermectin had distinct modes of action (MOA) in modulating FXR-coregulator interactions and compound selectivity against the four aforementioned functionally-relevant nuclear receptors. These findings collectively provide mechanistic insights regarding compound activities against FXR and possible explanations for in vivo toxicological observations of chlorophacinone, ivermectin, and their analogs.
[Mh] Termos MeSH primário: Indanos/farmacologia
Ivermectina/farmacologia
Receptores Citoplasmáticos e Nucleares/efeitos dos fármacos
[Mh] Termos MeSH secundário: Células HEK293
Seres Humanos
Ivermectina/análogos & derivados
Relação Estrutura-Atividade
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL; RESEARCH SUPPORT, U.S. GOV'T, NON-P.H.S.
[Nm] Nome de substância:
0 (Indans); 0 (Receptors, Cytoplasmic and Nuclear); 0 (farnesoid X-activated receptor); 34Y6E0063Y (chlorophacinone); 70288-86-7 (Ivermectin)
[Em] Mês de entrada:1705
[Cu] Atualização por classe:180124
[Lr] Data última revisão:
180124
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161025
[St] Status:MEDLINE


  9 / 19392 MEDLINE  
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[PMID]:29216638
[Au] Autor:Wu GY; Rui C; Chen JQ; Sho E; Zhan SS; Yuan XW; Ding YT
[Ad] Endereço:Department of Hepatobiliary Surgery, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, China.
[Ti] Título:MicroRNA-122 Inhibits Lipid Droplet Formation and Hepatic Triglyceride Accumulation via Yin Yang 1.
[So] Source:Cell Physiol Biochem;44(4):1651-1664, 2017.
[Is] ISSN:1421-9778
[Cp] País de publicação:Switzerland
[La] Idioma:eng
[Ab] Resumo:BACKGROUND/AIMS: An increase in intracellular lipid droplet formation and hepatic triglyceride (TG) content usually results in nonalcoholic fatty liver disease. However, the mechanisms underlying the regulation of hepatic TG homeostasis remain unclear. METHODS: Oil red O staining and TG measurement were performed to determine the lipid content. miRNA expression was evaluated by quantitative PCR. A luciferase assay was performed to validate the regulation of Yin Yang 1 (YY1) by microRNA (miR)-122. The effects of miR-122 expression on YY1 and its mechanisms involving the farnesoid X receptor and small heterodimer partner (FXR-SHP) pathway were evaluated by quantitative PCR and Western blot analyses. RESULTS: miR-122 was downregulated in free fatty acid (FFA)-induced steatotic hepatocytes, and streptozotocin and high-fat diet (STZ-HFD) induced nonalcoholic steatohepatitis (NASH) in mice. Transfection of hepatocytes with miR-122 mimics before FFA induction inhibited lipid droplet formation and TG accumulation in vitro. These results were verified by overexpressing miR-122 in the livers of STZ-HFD-induced NASH mice. The 3'-untranslated region (3'UTR) of YY1 mRNA is predicted to contain an evolutionarily conserved miR-122 binding site. In silico searches, a luciferase reporter assay and quantitative PCR analysis confirmed that miR-122 directly bound to the YY1 3'UTR to negatively regulate YY1 mRNA in HepG2 and Huh7 cells. The (FXR-SHP) signaling axis, which is downstream of YY1, may play a key role in the mechanism of miR-122-regulated lipid homeostasis. YY1-FXR-SHP signaling, which is negatively regulated by FFA, was enhanced by miR-122 overexpression. This finding was also confirmed by overexpression of miR-122 in the livers of NASH mice. CONCLUSIONS: The present results indicate that miR-122 plays an important role in lipid (particularly TG) accumulation in the liver by reducing YY1 mRNA stability to upregulate FXR-SHP signaling.
[Mh] Termos MeSH primário: Gotículas Lipídicas/metabolismo
MicroRNAs/metabolismo
Triglicerídeos/metabolismo
Fator de Transcrição YY1/metabolismo
[Mh] Termos MeSH secundário: Regiões 3' não Traduzidas
Animais
Antagomirs/metabolismo
Sequência de Bases
Linhagem Celular Tumoral
Diabetes Mellitus Experimental/metabolismo
Diabetes Mellitus Experimental/patologia
Dieta Hiperlipídica
Modelos Animais de Doenças
Regulação para Baixo/efeitos dos fármacos
Ácidos Graxos não Esterificados/farmacologia
Proteína do X Frágil de Retardo Mental/genética
Proteína do X Frágil de Retardo Mental/metabolismo
Células Hep G2
Seres Humanos
Gotículas Lipídicas/efeitos dos fármacos
Fígado/metabolismo
Fígado/patologia
Masculino
Camundongos
Camundongos Endogâmicos C57BL
MicroRNAs/antagonistas & inibidores
MicroRNAs/genética
Hepatopatia Gordurosa não Alcoólica/metabolismo
Hepatopatia Gordurosa não Alcoólica/patologia
Receptores Citoplasmáticos e Nucleares/genética
Receptores Citoplasmáticos e Nucleares/metabolismo
Alinhamento de Sequência
Fator de Transcrição YY1/química
Fator de Transcrição YY1/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (3' Untranslated Regions); 0 (Antagomirs); 0 (Fatty Acids, Nonesterified); 0 (MIRN122 microRNA, human); 0 (MicroRNAs); 0 (Receptors, Cytoplasmic and Nuclear); 0 (Triglycerides); 0 (YY1 Transcription Factor); 0 (nuclear receptor subfamily 0, group B, member 2); 139135-51-6 (Fragile X Mental Retardation Protein)
[Em] Mês de entrada:1801
[Cu] Atualização por classe:180118
[Lr] Data última revisão:
180118
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171208
[St] Status:MEDLINE
[do] DOI:10.1159/000485765


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[PMID]:29227074
[Au] Autor:Minchenko OH; Tsymbal DO; Minchenko DO; Riabovol OO; Ratushna OO; Karbovskyi LL
[Ti] Título:Hypoxic regulation of the expression of cell proliferation related genes in U87 glioma cells upon inhibition of ire1 signaling enzyme
[So] Source:Ukr Biochem J;88(1):11-21, 2016 Ja-Feb.
[Is] ISSN:2409-4943
[Cp] País de publicação:Ukraine
[La] Idioma:eng
[Ab] Resumo:We have studied the effect of inhibition of IRE1 (inositol requiring enzyme 1), which is a central mediator of endoplasmic reticulum stress and a controller of cell proliferation and tumor growth, on hypoxic regulation of the expression of different proliferation related genes in U87 glioma cells. It was shown that hypoxia leads to up-regulation of the expression of IL13RA2, CD24, ING1, ING2, ENDOG, and POLG genes and to down-regulation ­ of KRT18, TRAPPC3, TSFM, and MTIF2 genes at the mRNA level in control glioma cells. Changes for ING1 and CD24 genes were more significant. At the same time, inhibition of IRE1 modifies the effect of hypoxia on the expression of all studied genes. In particular, it increases sensitivity to hypoxia of the expression of IL13RA2, TRAPPC3, ENDOG, and PLOG genes and suppresses the effect of hypoxia on the expression of ING1 gene. Additionally, it eliminates hypoxic regulation of KRT18, CD24, ING2, TSFM, and MTIF2 genes expressions and introduces sensitivity to hypoxia of the expression of BET1 gene in glioma cells. The present study demonstrates that hypoxia, which often contributes to tumor growth, affects the expression of almost all studied genes. Additionally, inhibition of IRE1 can both enhance and suppress the hypoxic regulation of these gene expressions in a gene specific manner and thus possibly contributes to slower glioma growth, but several aspects of this regulation must be further clarified.
[Mh] Termos MeSH primário: Estresse do Retículo Endoplasmático/genética
Endorribonucleases/genética
Regulação Neoplásica da Expressão Gênica
Neuroglia/metabolismo
Proteínas Serina-Treonina Quinases/genética
RNA Mensageiro/genética
Transdução de Sinais/genética
[Mh] Termos MeSH secundário: Antígeno CD24/genética
Antígeno CD24/metabolismo
Hipóxia Celular
Linhagem Celular Tumoral
Proliferação Celular
DNA Polimerase gama/genética
DNA Polimerase gama/metabolismo
Endodesoxirribonucleases/genética
Endodesoxirribonucleases/metabolismo
Endorribonucleases/antagonistas & inibidores
Endorribonucleases/metabolismo
Fatores de Iniciação em Eucariotos/genética
Fatores de Iniciação em Eucariotos/metabolismo
Proteínas de Homeodomínio/genética
Proteínas de Homeodomínio/metabolismo
Seres Humanos
Proteína 1 Inibidora do Crescimento/genética
Proteína 1 Inibidora do Crescimento/metabolismo
Subunidade alfa2 de Receptor de Interleucina-13/genética
Subunidade alfa2 de Receptor de Interleucina-13/metabolismo
Queratina-18/genética
Queratina-18/metabolismo
Proteínas Mitocondriais/genética
Proteínas Mitocondriais/metabolismo
Neuroglia/patologia
Fatores de Alongamento de Peptídeos/genética
Fatores de Alongamento de Peptídeos/metabolismo
Proteínas Serina-Treonina Quinases/antagonistas & inibidores
Proteínas Serina-Treonina Quinases/metabolismo
Proteínas Qc-SNARE/genética
Proteínas Qc-SNARE/metabolismo
RNA Mensageiro/metabolismo
Receptores Citoplasmáticos e Nucleares/genética
Receptores Citoplasmáticos e Nucleares/metabolismo
Proteínas Supressoras de Tumor/genética
Proteínas Supressoras de Tumor/metabolismo
Proteínas de Transporte Vesicular/genética
Proteínas de Transporte Vesicular/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (BET1L protein, human); 0 (CD24 Antigen); 0 (Eukaryotic Initiation Factors); 0 (Homeodomain Proteins); 0 (ING1 protein, human); 0 (ING2 protein, human); 0 (Inhibitor of Growth Protein 1); 0 (Interleukin-13 Receptor alpha2 Subunit); 0 (KRT18 protein, human); 0 (Keratin-18); 0 (MTIF2 protein, human); 0 (Mitochondrial Proteins); 0 (Peptide Elongation Factors); 0 (Qc-SNARE Proteins); 0 (RNA, Messenger); 0 (Receptors, Cytoplasmic and Nuclear); 0 (TRAPPC3 protein, human); 0 (TSFM protein, human); 0 (Tumor Suppressor Proteins); 0 (Vesicular Transport Proteins); EC 2.7.11.1 (ERN1 protein, human); EC 2.7.11.1 (Protein-Serine-Threonine Kinases); EC 2.7.7.7 (DNA Polymerase gamma); EC 2.7.7.7 (POLG protein, human); EC 3.1.- (Endodeoxyribonucleases); EC 3.1.- (Endoribonucleases); EC 3.1.21.- (endonuclease G)
[Em] Mês de entrada:1801
[Cu] Atualização por classe:180116
[Lr] Data última revisão:
180116
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171212
[St] Status:MEDLINE
[do] DOI:10.15407/ubj88.01.011



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