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1.
Curr Issues Mol Biol ; 46(2): 1503-1515, 2024 Feb 14.
Artículo en Inglés | MEDLINE | ID: mdl-38392215

RESUMEN

The diversity of leaf characteristics, particularly leaf color, underscores a pivotal area of inquiry within plant science. The synthesis and functionality of chlorophyll, crucial for photosynthesis, largely dictate leaf coloration, with varying concentrations imparting different shades of green. Complex gene interactions regulate the synthesis and degradation of chlorophyll, and disruptions in these pathways can result in abnormal chlorophyll production, thereby affecting leaf pigmentation. This study focuses on Bambusa multiplex f. silverstripe, a natural variant distinguished by a spectrum of leaf colors, such as green, white, and green-white, attributed to genetic variations influencing gene expression. By examining the physiological and molecular mechanisms underlying chlorophyll anomalies and genetic factors in Silverstripe, this research sheds light on the intricate gene interactions and regulatory networks that contribute to leaf color diversity. The investigation includes the measurement of photosynthetic pigments and nutrient concentrations across different leaf color types, alongside transcriptomic analyses for identifying differentially expressed genes. The role of key genes in pathways such as ALA biosynthesis, chlorophyll synthesis, photosynthesis, and sugar metabolism is explored, offering critical insights for advancing research and plant breeding practices.

2.
J Org Chem ; 89(12): 8435-8446, 2024 Jun 21.
Artículo en Inglés | MEDLINE | ID: mdl-38843406

RESUMEN

Both the 3-fluorooxindole and germinal bisphosphonate structural motifs are prevalent in bioactive molecules because of their associated biological activities. We describe an approach to accessing 3,3-disubstituted 3-fluorooxindoles bearing a geminal bisphosphate fragment through a highly enantioselective Michael addition reaction between 3-fluorooxindoles and vinylidene bisphosphonates. These reactions are catalyzed by a commercially available cinchona alkaloid catalyst, have a broad substrate scope concerning 3-fluorooxindoles, and provide the corresponding addition products in a yield of up to 95% with an enantiomeric excess of up to 95%. A reasonable reaction pathway to explain the observed stereochemistry is also proposed.

3.
Int J Mol Sci ; 25(15)2024 Jul 25.
Artículo en Inglés | MEDLINE | ID: mdl-39125685

RESUMEN

Transcription factors (TFs) are crucial pre-transcriptional regulatory mechanisms that can modulate the expression of downstream genes by binding to their promoter regions. DOF (DNA binding with One Finger) proteins are a unique class of TFs with extensive roles in plant growth and development. Our previous research indicated that iron content varies among bamboo leaves of different colors. However, to our knowledge, genes related to iron metabolism pathways in bamboo species have not yet been studied. Therefore, in the current study, we identified iron metabolism related (IMR) genes in bamboo and determined the TFs that significantly influence them. Among these, DOFs were found to have widespread effects and potentially significant impacts on their expression. We identified specific DOF members in Dendrocalamus latiflorus with binding abilities through homology with Arabidopsis DOF proteins, and established connections between some of these members and IMR genes using RNA-seq data. Additionally, molecular docking confirmed the binding interactions between these DlDOFs and the DOF binding sites in the promoter regions of IMR genes. The co-expression relationship between the two gene sets was further validated using q-PCR experiments. This study paves the way for research into iron metabolism pathways in bamboo and lays the foundation for understanding the role of DOF TFs in D. latiflorus.


Asunto(s)
Regulación de la Expresión Génica de las Plantas , Hierro , Hojas de la Planta , Proteínas de Plantas , Factores de Transcripción , Hojas de la Planta/metabolismo , Hojas de la Planta/genética , Hierro/metabolismo , Factores de Transcripción/metabolismo , Factores de Transcripción/genética , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismo , Regiones Promotoras Genéticas , Simulación del Acoplamiento Molecular , Poaceae/genética , Poaceae/metabolismo
4.
J Org Chem ; 2023 Jun 29.
Artículo en Inglés | MEDLINE | ID: mdl-37384900

RESUMEN

A 1,1'-bi-2-naphthol (BINOL)-derived disulfonimide (DSI)-catalyzed enantioselective aza-Friedel-Crafts reaction between 1,3,5-trialkoxy benzenes and N-sulfonyl aldimines gives direct access to a series of chiral diarylmethylamines in good yields and good to excellent enantioselectivities (up to 97% ee). This reaction provides a useful protocol for the direct synthesis of diarylmethylamine derivatives.

5.
J Pharmacol Exp Ther ; 381(3): 257-265, 2022 06.
Artículo en Inglés | MEDLINE | ID: mdl-35398813

RESUMEN

To investigate therapeutic target for ligustrazine during liver fibrosis in an ethanol-induced biliary atresia rat model and transforming growth factor-ß (TGF-ß) induced hepatic stellate cell activation cell model, and the underlying mechanism, a total of 30 rats were randomly assigned into five groups (n = 6 per group): control, sham, ethanol-induced biliary atresia model, model plus pirfenidone, and model plus ligustrazine groups. The liver changes were assessed using H&E and Masson staining and transmission electron microscopy. Expression of miR-145 and mRNA and protein levels of TGF-ß/smads pathway-related proteins were detected. HSC-T6 cells were infected with LV-miR or rLV-miR-145 in the presence or absence of SMAD3 inhibitor SIS3 and treated with 2.5 ng/ml TGF-ß1 and then with ligustrazine. Collected cells were subjected to detect the expression of miR-145 and mRNA and protein expression levels of TGF-ß/smads pathway-related proteins. Ligustrazine rescued liver fibrogenesis and pathology for ethanol-caused bile duct injury, revealed by decreased α-smooth muscle actin and collagen I expression and liver tissue and cell morphology integrity. Further experiments showed that ligustrazine inhibited intrinsic and phosphorylated Smad2/3 protein expression and modification. Similar results were obtained in cells. In addition, ligustrazine altered miR-145 expression in both animal and cell models. Lentivirus mediated miR-145 overexpression and knockdown recombinant virus showed that miR-145 enhanced the TGF-ß/Smad pathway, which led to hepatic stellate cell activation, and ligustrazine blocked this activation. This work validated that ligustrazine-regulated miR-145 mediated TGF-ß/Smad signaling to inhibit the progression of liver fibrosis in a biliary atresia rat model and provided a new therapeutic strategy for liver fibrosis. SIGNIFICANCE STATEMENT: With an ethanol-induced biliary atresia rat model, ligustrazine was found to rescue liver fibrogenesis and pathology for ethanol caused bile duct injury, revealed by decreased α-smooth muscle actin and collagen I expression and liver tissue and cell morphology integrity. Furthermore, we found ligustrazine upregulated miR-145 expression and inhibited TGF-ß/SMAD signaling pathway both in vivo and in vitro. In addition, overexpression and knockdown of miR-145 confirmed that miR-145 is involved in the ligustrazine inhibition of liver fibrosis through the TGF-ß/SMAD signaling pathway.


Asunto(s)
Atresia Biliar , MicroARNs , Actinas/genética , Actinas/metabolismo , Animales , Atresia Biliar/metabolismo , Atresia Biliar/patología , Colágeno Tipo I/efectos adversos , Colágeno Tipo I/metabolismo , Modelos Animales de Enfermedad , Etanol/efectos adversos , Células Estrelladas Hepáticas/metabolismo , Cirrosis Hepática/inducido químicamente , Cirrosis Hepática/tratamiento farmacológico , Cirrosis Hepática/metabolismo , MicroARNs/genética , MicroARNs/metabolismo , Pirazinas , ARN Mensajero/metabolismo , Ratas , Transducción de Señal , Proteínas Smad/metabolismo , Factor de Crecimiento Transformador beta/metabolismo , Factor de Crecimiento Transformador beta1/metabolismo , Factores de Crecimiento Transformadores/efectos adversos , Factores de Crecimiento Transformadores/metabolismo
6.
Org Biomol Chem ; 20(9): 1916-1925, 2022 03 02.
Artículo en Inglés | MEDLINE | ID: mdl-35166766

RESUMEN

An asymmetric Friedel-Crafts C2-alkylation between 3-substituted indoles and imines catalyzed by chiral BINOL-derived disulfonimides (DSIs) has been developed. This reaction tolerated a wide range of 3-substituted indoles and imines, affording a series of chiral 2-indolyl methanamine derivatives in good yields with good to excellent enantioselectivities (up to 98% ee). This is a useful protocol for the direct synthesis of 2-indolyl methanamine derivatives. It is worth noting that increasing the temperature in this reaction could result in a better enantioselectivity, making it different from the other common organocatalytic systems.

7.
Org Biomol Chem ; 20(33): 6571-6581, 2022 08 24.
Artículo en Inglés | MEDLINE | ID: mdl-35904891

RESUMEN

A practical approach to α-aminophosphonates has been developed through an In(OTf)3-catalyzed N-α phosphonylation of N,O-acetals with triethyl phosphite 7. Indoline and isoindoline N,O-acetals 6a-6j and 9a-9j and chain N,O-acetals 11a-11p were subjected to a Lewis acid catalyzed N-α phosphonylation process. As a result, the desired α-aminophosphonates 8a-8j, 10a-10j and 12a-12p were obtained in moderate to good yields.


Asunto(s)
Organofosfonatos , Fosfitos , Acetales , Catálisis
8.
J Org Chem ; 85(19): 12603-12613, 2020 10 02.
Artículo en Inglés | MEDLINE | ID: mdl-32924480

RESUMEN

A highly efficient gold-catalyzed approach between N,O-acetals and ynamides for the construction of 6-(tert-butyldimethylsilyl)oxy-tetrahydropyrrolo[1,2-c][1,3]oxazin-1-ones was developed. This reaction tolerated a wide range of substituted N,O-acetals and TsN-substituted ynamides, leading to novel heterocycles in moderate to good yields and with excellent diastereoselectivities (dr > 99:1).

9.
Chirality ; 32(3): 378-386, 2020 03.
Artículo en Inglés | MEDLINE | ID: mdl-31958185

RESUMEN

A series of chiral 5-hydroxy isoxazolidines has been successfully synthesized through camphor sulfonyl hydrazine-catalyzed asymmetric aza-Michael addition reaction between N,O-protected hydroxyamines and enals. Moderate yields with moderate to good enantioselectivities (up to 96% enantiomeric excess [ee]) were achieved. It provides an alternative asymmetric approach to preparing isoxazolidine derivatives.

10.
Diabetologia ; 62(4): 644-654, 2019 04.
Artículo en Inglés | MEDLINE | ID: mdl-30673802

RESUMEN

AIMS/HYPOTHESIS: The rs738409 C>G variant of the patatin-like phospholipase domain containing 3 gene (PNPLA3) increases the risk of non-alcoholic fatty liver disease (NAFLD) with no predisposition for insulin resistance. In this study, we aimed to investigate the influence of PNPLA3 polymorphisms on liver fat content (LFC) and glucose metabolic variables, and the associations between these, during the natural course of body weight changes in a Chinese adult cohort. METHODS: The LFC, measured using a quantitative ultrasound method, was prospectively monitored in 2189 middle-aged and elderly adults from the Shanghai Changfeng Study, together with changes in body weight and metabolic variables. General linear models were used to detect interactive effects between the PNPLA3 rs738409 genotype and 4 year changes in body weight on liver steatosis and glucose metabolism. RESULTS: The PNPLA3 homozygous GG genotype dissociated the changes in the LFC and OGTT 2 h post-load blood glucose (PBG) in relation to 4 year changes in body weight. PNPLA3 GG genotype carriers showed greater increases in the LFC and serum alanine aminotransferase (ALT) but lower PBG elevation and incident diabetes than PNPLA3 wild-type (CC) genotype carriers exhibiting the same degree of body weight increase. The interactions between the PNPLA3 genotype and changes in body weight on the LFC (false discovery rate [FDR]-adjusted pinteraction = 0.044) and ALT (FDR-adjusted pinteraction = 0.044) were significant. Subgroup analyses showed that the effect of the PNPLA3 GG genotype on changes in the LFC and PBG was only observed in metabolically unhealthy participants with insulin resistance or abdominal obesity. CONCLUSIONS/INTERPRETATION: The PNPLA3 GG genotype interacted with changes in body weight to aggravate liver steatosis but reduced the risk of incident type 2 diabetes in metabolically unhealthy participants.


Asunto(s)
Peso Corporal , Diabetes Mellitus Tipo 2/genética , Lipasa/genética , Proteínas de la Membrana/genética , Enfermedad del Hígado Graso no Alcohólico/genética , Obesidad Abdominal/genética , Polimorfismo de Nucleótido Simple , Tejido Adiposo/patología , Anciano , Antropometría , Glucemia/análisis , China/epidemiología , Diabetes Mellitus Tipo 2/complicaciones , Femenino , Genotipo , Heterocigoto , Homocigoto , Humanos , Resistencia a la Insulina , Modelos Lineales , Masculino , Persona de Mediana Edad , Enfermedad del Hígado Graso no Alcohólico/complicaciones , Obesidad Abdominal/complicaciones , Riesgo
11.
Cytokine ; 122: 154385, 2019 10.
Artículo en Inglés | MEDLINE | ID: mdl-29703573

RESUMEN

OBJECTIVE: Previous studies suggest that IL-8 has an important role in the regulation of cholesterol efflux, but whether miRNAs are involved in this process is still unknown. The purpose of this study is to explore whether IL-8 promotes cholesterol accumulation by enhancing miR-183 expression in macrophages and its underlying mechanism. METHODS AND RESULTS: Treatment of THP-1 macrophage-derived foam cells with IL-8 decreased ABCA1 expression and cholesterol efflux. Using bioinformatics analyses and dual-luciferase reporter assays, we found that miR-183 was highly conserved during evolution and directly inhibited ABCA1 protein and mRNA expression by targeting ABCA1 3'UTR. MiR-183 directly regulated endogenous ABCA1 expression levels. Furthermore, IL-8 enhanced the expression of miR-183 and decrease ABCA1 expression. Cholesterol transport assays confirmed that IL-8 dramatically inhibited apolipoprotein AI-mediated ABCA1-dependent cholesterol efflux by increasing miR-183 expression. In contrast, treatment with anti-IL-8 antibody reversed these effects. CONCLUSION: IL-8 enhances the expression of miR-183, which then inhibits ABCA1 expression and cholesterol efflux. Our studies suggest that the IL-8-miR-183-ABCA1 axis may play an intermediary role in the development of atherosclerosis.


Asunto(s)
Transportador 1 de Casete de Unión a ATP/biosíntesis , Colesterol/metabolismo , Células Espumosas/metabolismo , Regulación de la Expresión Génica , Interleucina-8/metabolismo , MicroARNs/metabolismo , Aterosclerosis/metabolismo , Aterosclerosis/patología , Células Espumosas/patología , Humanos , Células THP-1
12.
J Org Chem ; 84(9): 5099-5108, 2019 05 03.
Artículo en Inglés | MEDLINE | ID: mdl-30977656

RESUMEN

Both the 3-fluorooxindole and cyclic sulfamidate frameworks are important in medicinal chemistry owing to their associated biological activities. We report an approach accessing 3-fully substituted 3-fluorooxindoles, containing a benzo-fused sulfamidate subunit through highly enantioselective Mannich-type reactions between 3-fluorooxindoles and cyclic benzo-fused N-sulfamidate aldimines. These reactions are promoted by a commercially available cinchona alkaloid catalyst, accommodate a broad substrate scope, and deliver the desired products in a yield of up to 99% with an enantiomeric excess of up to 94%. A plausible reaction pathway is also presented.

13.
Org Biomol Chem ; 17(4): 885-891, 2019 01 23.
Artículo en Inglés | MEDLINE | ID: mdl-30628602

RESUMEN

Organocatalytic asymmetric Michael addition between 3-substituted oxindoles and enals catalyzed by chiral camphor sulfonyl hydrazines (CaSHs) has been developed. A wide range of 3-substituted oxindoles and enals were successfully used, giving the corresponding 3,3-disubstituted oxindoles containing vicinal stereogenic carbon centers in good yields with good to excellent enantioselectivities and moderate to good diastereoselectivities (up to 89% yield, 99% ee and 99 : 1 dr).

14.
Biochim Biophys Acta Mol Cell Biol Lipids ; 1863(8): 806-822, 2018 08.
Artículo en Inglés | MEDLINE | ID: mdl-29678642

RESUMEN

BACKGROUND AND AIMS: Recent studies have suggested that heat shock protein 70 (HSP70) may play critical roles in cardiovascular disease. However, the effects of HSP70 on the development of atherosclerosis in apoE-/- mice remain largely unknown. This study was to investigate the role and potential mechanism of HSP70 in atherosclerosis. METHODS: HSP70 was overexpressed in apoE-/- mice and THP-1-derived macrophages with lentiviral vectors. Oil Red O, hematoxylin-eosin, and Masson staining were performed to evaluate atherosclerotic plaque in apoE-/- mice fed the Western type diet. Moreover, immunostaining was employed to detect the expression of relative proteins in aortic sinus. Reporter gene and chromatin immunoprecipitation were performed to analyze the effect of Elk-1 on the promoter activity of ABCA1 and ABCG1; [3H] labeled cholesterol was used to assess the capacity of cholesterol efflux and reverse cholesterol transport (RCT). RESULTS: Our results showed that HSP70 increased lipid accumulation in arteries and promoted the formation of atherosclerotic lesion. The capacity of cholesterol efflux was reduced in peritoneal macrophages isolated from HSP70-overexpressed apoE-/- mice. The levels of ABCA1 and ABCG1 expression were also reduced in the peritoneal macrophages and the aorta from apoE-/- mice in response to HSP70. The c-Jun N-terminal kinase (JNK) and ETS transcription factor (Elk-1) played a critical role in HSP70-induced downregulation ABCA1 and ABCG1. Further, HSP70 reduced RCT from macrophages to plasma, liver, and feces in apoE-/- mice. CONCLUSIONS: HSP70 promotes the progression of atherosclerosis in apoE-/- mice by suppressing the expression of ABCA1 and ABCG1 through the JNK/Elk-1 pathway.


Asunto(s)
Transportador 1 de Casete de Unión a ATP/metabolismo , Transportador de Casetes de Unión a ATP, Subfamilia G, Miembro 1/metabolismo , Aterosclerosis/patología , Proteínas HSP70 de Choque Térmico/metabolismo , Transportador 1 de Casete de Unión a ATP/genética , Transportador de Casetes de Unión a ATP, Subfamilia G, Miembro 1/genética , Animales , Aterosclerosis/etiología , Línea Celular , Colesterol/metabolismo , Dieta Occidental/efectos adversos , Modelos Animales de Enfermedad , Progresión de la Enfermedad , Regulación hacia Abajo , Humanos , Sistema de Señalización de MAP Quinasas , Macrófagos , Masculino , Ratones , Ratones Noqueados para ApoE , Placa Aterosclerótica/metabolismo , Placa Aterosclerótica/patología , Regiones Promotoras Genéticas , Seno Aórtico/metabolismo , Seno Aórtico/patología , Proteína Elk-1 con Dominio ets/metabolismo
15.
Diabetes Metab Res Rev ; 34(7): e3048, 2018 10.
Artículo en Inglés | MEDLINE | ID: mdl-30035847

RESUMEN

OBJECTIVE: A Chinese visceral adiposity index (CVAI) was recently established to estimate the visceral fat area in Chinese adults. This study aimed to investigate the risk of incident prediabetes and diabetes in relation to visceral adiposity calculated by CVAI. METHODS: A total of 2558 subjects with normal plasma glucose levels from the Shanghai Changfeng Study were enrolled in a prospective cohort study. The independent associations of basal visceral fat area by CVAI and its longitudinal change with incident prediabetes and diabetes were identified using Cox regression analyses. RESULTS: During an average of 4.4 years of follow-up, 546 (21.3%) and 99 (3.9%) of 2558 nondiabetic subjects developed prediabetes and diabetes, respectively. Visceral fat area by CVAI and its longitudinal increase were independently associated with incident prediabetes and diabetes in Chinese adults. In a multivariable-adjusted regression model, CVAI, as well as its annual change, was the strongest independent predictor of incident prediabetes (HR, 1.383 [1.162-1.647]) and diabetes (HR, 1.607 [1.092-2.364]) compared with other estimates of obesity (BMI and waist circumference). Receiver operating characteristic curve analyses showed that CVAI had better performance than BMI and waist circumference for the prediction of prediabetes and diabetes in Chinese adults. CONCLUSIONS: Visceral adiposity plays a pivotal role in the pathogenesis of diabetes, and the visceral adiposity estimated by CVAI is superior to the traditional estimates of obesity for the prediction of incident prediabetes and diabetes in Chinese adults.


Asunto(s)
Adiposidad , Pueblo Asiatico/estadística & datos numéricos , Diabetes Mellitus Tipo 2/epidemiología , Diabetes Mellitus Tipo 2/etiología , Grasa Intraabdominal/patología , Obesidad Abdominal/epidemiología , Adulto , Anciano , Estudios de Cohortes , Femenino , Estudios de Seguimiento , Humanos , Estudios Longitudinales , Masculino , Persona de Mediana Edad , Obesidad Abdominal/complicaciones , Estado Prediabético/complicaciones , Estado Prediabético/epidemiología , Factores de Riesgo
16.
Org Biomol Chem ; 16(46): 8989-8993, 2018 11 28.
Artículo en Inglés | MEDLINE | ID: mdl-30418465

RESUMEN

An organocatalytic Mannich reaction of 3-fluorooxindoles has been developed. Using a commercially available cinchona alkaloid catalyst, a wide range of 3-fluorooxindoles was successfully reacted with N-sulfonyl aldimines to give biologically important 3-fluorooxindoles containing vicinal fluoroamine motifs with high efficiency and good enantioselectivity. This protocol uses readily available reactants and cheap organocatalysts, and it is operationally simple.

17.
Circ J ; 82(5): 1396-1404, 2018 04 25.
Artículo en Inglés | MEDLINE | ID: mdl-29618705

RESUMEN

BACKGROUND: It has previously been demonstrated that apolipoprotein A-1 (apoA-1) binding protein (AIBP) promotes apoA-1 binding to ATP-binding cassette transporter A1 (ABCA1) and prevents ABCA1 protein degradation so as to inhibit foam cell formation. Because apoA-1 inhibits inflammatory signaling pathways, whether AIBP has an inhibitory effect on inflammatory signaling pathways in THP-1-derived macrophages is investigated.Methods and Results:Analysis of inflammation-related gene expression indicated that AIBP decreased lipopolysaccharide (LPS)-mediated macrophage inflammation. AIBP significantly prevented NF-κB nuclear translocation. Further, AIBP prevented the activation of mitogen-activated protein kinases (MAPKs), including p38 MAPK, extracellular-signal regulated kinase and c-Jun N-terminal kinase. AIBP decreased MyD88 expression at both mRNA and protein levels, but did not have any effect on TLR4 expression. Moreover, treatment with both AIBP and apoA-1 decreased the abundance of TLR4 in the lipid raft fraction. AIBP lacking 115-123 amino acids (∆115-123), however, did not have such effects as described for intact AIBP. In addition, knockdown of ABCA1 inhibited the effects of AIBP on inflammatory factor secretion. CONCLUSIONS: These results suggest that AIBP inhibits inflammatory signaling pathways through binding to apoA-1 and stabilizing ABCA1, and subsequent alteration of lipid rafts and TLR4 in the cell membrane.


Asunto(s)
Apolipoproteína A-I/metabolismo , Proteínas Portadoras/metabolismo , Células Espumosas/metabolismo , Sistema de Señalización de MAP Quinasas , Microdominios de Membrana/metabolismo , Transportador 1 de Casete de Unión a ATP/metabolismo , Proteínas de Unión al ADN , Células Espumosas/patología , Células HEK293 , Humanos , Inflamación/metabolismo , Inflamación/patología , Proteínas Quinasas JNK Activadas por Mitógenos/metabolismo , Microdominios de Membrana/patología , Células THP-1 , Receptor Toll-Like 4/metabolismo , Proteínas Quinasas p38 Activadas por Mitógenos
18.
Circ J ; 82(11): 2861-2871, 2018 10 25.
Artículo en Inglés | MEDLINE | ID: mdl-30232292

RESUMEN

BACKGROUND: Lipoprotein lipase (LPL) plays an important role in triglyceride metabolism. It is translocated across endothelial cells to reach the luminal surface of capillaries by glycosylphosphatidylinositol-anchored high-density lipoprotein binding protein 1 (GPIHBP1), where it hydrolyzes triglycerides in lipoproteins. MicroRNA 377 (miR-377) is highly associated with lipid levels. However, how miR-377 regulates triglyceride metabolism and whether it is involved in the development of atherosclerosis remain largely unexplored. Methods and Results: The clinical examination displayed that miR-377 expression was markedly lower in plasma from patients with hypertriglyceridemia compared with non-hypertriglyceridemic subjects. Bioinformatics analyses and a luciferase reporter assay showed that DNA methyltransferase 1 (DNMT1) was a target gene of miR-377. Moreover, miR-377 increased LPL binding to GPIHBP1 by directly targeting DNMT1 in human umbilical vein endothelial cells (HUVECs) and apolipoprotein E (ApoE)-knockout (KO) mice aorta endothelial cells (MAECs). In vivo, hematoxylin-eosin (H&E), Oil Red O and Masson's trichrome staining showed that ApoE-KO mice treated with miR-377 developed less atherosclerotic plaques, accompanied by reduced plasma triglyceride levels. CONCLUSIONS: It is concluded that miR-377 upregulates GPIHBP1 expression, increases the LPL binding to GPIHBP1, and reduces plasma triglyceride levels, likely through targeting DNMT1, inhibiting atherosclerosis in ApoE-KO mice.


Asunto(s)
Aorta/metabolismo , Aterosclerosis/metabolismo , ADN (Citosina-5-)-Metiltransferasa 1/metabolismo , MicroARNs/metabolismo , Placa Aterosclerótica/metabolismo , Triglicéridos/metabolismo , Animales , Aorta/patología , Aterosclerosis/genética , Aterosclerosis/patología , ADN (Citosina-5-)-Metiltransferasa 1/genética , Células Endoteliales de la Vena Umbilical Humana/metabolismo , Células Endoteliales de la Vena Umbilical Humana/patología , Humanos , Lipoproteína Lipasa/genética , Lipoproteína Lipasa/metabolismo , Ratones , Ratones Noqueados para ApoE , MicroARNs/genética , Placa Aterosclerótica/genética , Placa Aterosclerótica/patología , Receptores de Lipoproteína/biosíntesis , Receptores de Lipoproteína/genética
20.
Circ J ; 82(1): 28-38, 2017 12 25.
Artículo en Inglés | MEDLINE | ID: mdl-28855441

RESUMEN

BACKGROUND: Lipoprotein lipase (LPL) expressed in macrophages plays an important role in promoting the development of atherosclerosis or atherogenesis. MicroRNA-182 (miR-182) is involved in the regulation of lipid metabolism and inflammation. However, it remains unclear how miR-182 regulates LPL and atherogenesis.Methods and Results:Using bioinformatics analyses and a dual-luciferase reporter assay, we identified histone deacetylase 9 (HDAC9) as a target gene of miR-182. Moreover, miR-182 upregulated LPL expression by directly targetingHDAC9in THP-1 macrophages. Hematoxylin-eosin (H&E), Oil Red O and Masson's trichrome staining showed that apolipoprotein E (ApoE)-knockout (KO) mice treated with miR-182 exhibited more severe atherosclerotic plaques. Treatment with miR-182 increased CD68 and LPL expression in atherosclerotic lesions in ApoE-KO mice, as indicated by double immunofluorescence staining in the aortic sinus. Increased miR-182-induced increases in LPL expression in ApoE-KO mice was confirmed by real-time quantitative polymerase chain reaction and western blotting analyses. Treatment with miR-182 also increased plasma concentrations of proinflammatory cytokines and lipids in ApoE-KO mice. CONCLUSIONS: The results of the present study suggest that miR-182 upregulates LPL expression, promotes lipid accumulation in atherosclerotic lesions, and increases proinflammatory cytokine secretion, likely through targetingHDAC9, leading to an acceleration of atherogenesis in ApoE-KO mice.


Asunto(s)
Aterosclerosis/inducido químicamente , Lipoproteína Lipasa/efectos de los fármacos , MicroARNs/farmacología , Proteínas Represoras/antagonistas & inhibidores , Animales , Biología Computacional , Citocinas/efectos de los fármacos , Células HEK293 , Histona Desacetilasas , Humanos , Inflamación/metabolismo , Metabolismo de los Lípidos/efectos de los fármacos , Macrófagos , Ratones , Ratones Noqueados para ApoE , Células THP-1
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