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1.
Bioinformatics ; 34(22): 3882-3888, 2018 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-29878053

RESUMO

Motivation: Transcriptomics and proteomics data have been integrated into constraint-based models to influence flux predictions. However, it has been reported recently for Escherichia coli and Saccharomyces cerevisiae, that model predictions from parsimonious flux balance analysis (pFBA), which does not use expression data, are as good or better than predictions from various algorithms that integrate transcriptomics or proteomics data into constraint-based models. Results: In this paper, we describe a novel constraint-based method called Linear Bound Flux Balance Analysis (LBFBA), which uses expression data (either transcriptomic or proteomic) to predict metabolic fluxes. The method uses expression data to place soft constraints on individual fluxes, which can be violated. Parameters in the soft constraints are first estimated from a training expression and flux dataset before being used to predict fluxes from expression data in other conditions. We applied LBFBA to E.coli and S.cerevisiae datasets and found that LBFBA predictions were more accurate than pFBA predictions, with average normalized errors roughly half of those from pFBA. For the first time, we demonstrate a computational method that integrates expression data into constraint-based models and improves quantitative flux predictions over pFBA. Availability and implementation: Code is available in the Supplementary data available at Bioinformatics online. Supplementary information: Supplementary data are available at Bioinformatics online.

2.
Cell Host Microbe ; 22(6): 817-829.e8, 2017 Dec 13.
Artigo em Inglês | MEDLINE | ID: mdl-29154144

RESUMO

The pathogenesis of human Ebola virus disease (EVD) is complex. EVD is characterized by high levels of virus replication and dissemination, dysregulated immune responses, extensive virus- and host-mediated tissue damage, and disordered coagulation. To clarify how host responses contribute to EVD pathophysiology, we performed multi-platform 'omics analysis of peripheral blood mononuclear cells and plasma from EVD patients. Our results indicate that EVD molecular signatures overlap with those of sepsis, imply that pancreatic enzymes contribute to tissue damage in fatal EVD, and suggest that Ebola virus infection may induce aberrant neutrophils whose activity could explain hallmarks of fatal EVD. Moreover, integrated biomarker prediction identified putative biomarkers from different data platforms that differentiated survivors and fatalities early after infection. This work reveals insight into EVD pathogenesis, suggests an effective approach for biomarker identification, and provides an important community resource for further analysis of human EVD severity.


Assuntos
Proteínas Sanguíneas/análise , Perfilação da Expressão Gênica , Doença pelo Vírus Ebola/patologia , Doença pelo Vírus Ebola/fisiopatologia , Interações Hospedeiro-Patógeno , Proteoma/análise , Humanos , Leucócitos Mononucleares/química , Plasma/química
4.
PLoS Genet ; 12(10): e1006372, 2016 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-27741250

RESUMO

The inability of native Saccharomyces cerevisiae to convert xylose from plant biomass into biofuels remains a major challenge for the production of renewable bioenergy. Despite extensive knowledge of the regulatory networks controlling carbon metabolism in yeast, little is known about how to reprogram S. cerevisiae to ferment xylose at rates comparable to glucose. Here we combined genome sequencing, proteomic profiling, and metabolomic analyses to identify and characterize the responsible mutations in a series of evolved strains capable of metabolizing xylose aerobically or anaerobically. We report that rapid xylose conversion by engineered and evolved S. cerevisiae strains depends upon epistatic interactions among genes encoding a xylose reductase (GRE3), a component of MAP Kinase (MAPK) signaling (HOG1), a regulator of Protein Kinase A (PKA) signaling (IRA2), and a scaffolding protein for mitochondrial iron-sulfur (Fe-S) cluster biogenesis (ISU1). Interestingly, the mutation in IRA2 only impacted anaerobic xylose consumption and required the loss of ISU1 function, indicating a previously unknown connection between PKA signaling, Fe-S cluster biogenesis, and anaerobiosis. Proteomic and metabolomic comparisons revealed that the xylose-metabolizing mutant strains exhibit altered metabolic pathways relative to the parental strain when grown in xylose. Further analyses revealed that interacting mutations in HOG1 and ISU1 unexpectedly elevated mitochondrial respiratory proteins and enabled rapid aerobic respiration of xylose and other non-fermentable carbon substrates. Our findings suggest a surprising connection between Fe-S cluster biogenesis and signaling that facilitates aerobic respiration and anaerobic fermentation of xylose, underscoring how much remains unknown about the eukaryotic signaling systems that regulate carbon metabolism.


Assuntos
Evolução Molecular Direcionada , Proteínas Mitocondriais/genética , Proteínas Quinases Ativadas por Mitógeno/genética , Proteínas de Saccharomyces cerevisiae/genética , Xilose/metabolismo , Anaerobiose/genética , Epistasia Genética , Fermentação , Engenharia Genética , Glucose/metabolismo , Proteínas com Ferro-Enxofre/genética , Redes e Vias Metabólicas/genética , Mutação , Proteômica , Saccharomyces cerevisiae/genética , Saccharomyces cerevisiae/metabolismo , Xilose/genética
5.
Sci Rep ; 6: 26746, 2016 05 27.
Artigo em Inglês | MEDLINE | ID: mdl-27229177

RESUMO

NAMPT has been suggested association with atherosclerosis and insulin resistance. However, the impact of NAMPT on atherosclerosis remained unknown. Therefore, the objective of this study was to use a NAMPT loss-of-function approach to investigate the effect of NAMPT on atherosclerosis in hypercholesterolemic mice. We demonstrated that a specific NAMPT knockdown increased plasma HDL-C levels, reduced the plaque area of the total aorta en face and the cross-sectional aortic sinus, decreased macrophage number and apoptosis, and promoted RCT in HFD-fed ApoE KO mice. These changes were accompanied by increased PPARα, LXRα, ABCA1 and ABCG1 expressions in the liver. NAMPT knockdown also facilitated cholesterol efflux in RAW264.7 cells. We further investigated the effect of NAMPT knockdown on the PPARα-LXRα pathway of cholesterol metabolism with MK886 (a selective inhibitor of PPARα) in RAW264.7 macrophages. MK886 abolished the ability of NAMPT knockdown to decrease intracellular cholesterol levels to enhance the rate of (3)H-cholesterol efflux and to increase ABCA1/G1 and LXRα expressions in RAW264.7 macrophages. Our observations demonstrate that NAMPT knockdown exerted antiatherogenic effects by promoting cholesterol efflux and macrophage RCT through the PPARα- LXRα- ABCA1/G1pathway in vitro and in vivo.


Assuntos
Apolipoproteínas E/deficiência , Aterosclerose , HDL-Colesterol/sangue , Citocinas/deficiência , Gorduras na Dieta/efeitos adversos , Resistência à Insulina , Nicotinamida Fosforribosiltransferase/deficiência , Animais , Aterosclerose/sangue , Aterosclerose/induzido quimicamente , Aterosclerose/genética , Aterosclerose/patologia , Gorduras na Dieta/farmacologia , Técnicas de Silenciamento de Genes , Masculino , Camundongos , Camundongos Knockout , Células RAW 264.7
6.
Eur J Endocrinol ; 174(2): 147-55, 2016 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-26546612

RESUMO

OBJECTIVE: Zinc-α2-glycoprotein (ZAG) has recently been characterized as a potent metabolic regulator. However, the effects of anti-diabetic agents on circulating ZAG levels in humans remain largely unknown. To explore the possible mechanisms by which the dipeptidyl peptidase-IV (DPP-IV) inhibitor improves insulin resistance, we investigated the effect of sitagliptin, a DPP-IV inhibitor, on circulating cytokine levels in newly diagnosed type 2 diabetes (nT2DM) patients. DESIGN AND METHODS: A subset of 141 subjects with nT2DM were assigned to receive placebo (n=47) or sitagliptin (n=94) for 3 months. Before and after treatment, subjects received a 75 g oral glucose tolerance test, euglycemic-hyperinsulinemic clamp (EHC), and measurement of ZAG and adiponectin (ADI) concentrations. RESULTS: Circulating ZAG levels were lower in nT2DM than in control individuals (P<0.01). After 3 months of sitagliptin treatment, HbA1c, fasting plasma glucose, postprandial glucose, 2-h insulin after glucose overload, triglycerides, and homeostasis model assessment of insulin resistance (HOMA-IR) were decreased significantly compared with pre-treatment (P<0.05 or P<0.01), whereas the glucose infusion rate during the stable period of the clamp (M values) during EHC were significantly increased (P<0.01). In addition, circulating ZAG and ADI concentrations were significantly increased along with improved glucose metabolism and insulin sensitivity compared with pre-treatment (both P<0.01) and the change of ZAG (ΔZAG) was positively associated with ΔADI, ΔHOMA-IR, ΔBMI, Δfasting insulin and negatively associated with Δ tumor necrosis factor-α (TNF-α). Furthermore, sitagliptin treatment resulted in significantly lowered plasma TNF-α level (P<0.05). CONCLUSION: A low level of circulating ZAG is associated with insulin resistance and sitagliptin treatment significantly increases circulating ZAG levels. These observations have implications in relation to the mode of action of the DPP-IV inhibitor as an insulin sensitizing agent.


Assuntos
Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/tratamento farmacológico , Inibidores da Dipeptidil Peptidase IV/farmacologia , Resistência à Insulina/fisiologia , Avaliação de Resultados (Cuidados de Saúde) , Proteínas de Plasma Seminal/sangue , Fosfato de Sitagliptina/farmacologia , Fator de Necrose Tumoral alfa/sangue , Adulto , Idoso , Inibidores da Dipeptidil Peptidase IV/administração & dosagem , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Fosfato de Sitagliptina/administração & dosagem
7.
Diabetol Metab Syndr ; 7: 33, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25878729

RESUMO

BACKGROUND: Insulin resistance (IR) correlates closely with cardiovascular disease. C1q/TNF-related protein-3 (CTRP3) is a novel adipokine that modulates insulin activity in various diseases. This study investigated the relationship between CTRP3 and IR as well as systemic inflammation in newly diagnosed obese and hypertensive patients (NCT02226471). METHODS: Serum CTRP3 levels, anthropometric, inflammatory and metabolic parameters were measured in 180 obesity and essential hypertensive patients and in 66 normal weight, normotensive subjects. RESULTS: The serum CTRP3 levels in the obesity group were lower than those in the NW group; these levels were also lower in hypertensive subjects than in normotensive subjects. After adjusting for gender, systolic blood pressure (SBP) and diastolic blood pressure (DBP), a modestly linear relationship was observed between CTRP3 and waist circumference (WC) (r = -0.168, p = 0.009), waist-to-hip ratio (WHR) (r = -0.183, p = 0.004), homeostasis model assessment of IR (HOMA-IR) (r = -0.264, p = 0.000), triglycerides (TG) (r = -0.136, p = 0.034), fasting blood glucose (FBG) (r = -0.155, p = 0.016), fasting insulin (FINS) (r = -0.248, p = 0.000) and homeostasis model assessment of ß-cell insulin secretion (HOMA-ß) (r = -0.128, p = 0.047). Multiple stepwise regression analysis revealed that gender, DBP and HOMA-IR were independently associated with serum CTRP3 levels. CONCLUSION: CTRP3 was an independent factor affecting blood pressure and IR, and may play an important role in the pathogenesis of obesity and hypertension.

8.
Brain Res Bull ; 100: 84-92, 2014 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-24291698

RESUMO

Cerebral hypoperfusion or aging often results into the disturbances of cholesterol and lipoprotein, which have been tightly associated with numerous neurological and psychiatric diseases, such as vascular dementia. The pathway of liver X receptor-ß (LXR-ß)/retinoic X receptor-α (RXR-α)/ABCA1 plays a vital role in lipoprotein metabolism. However, there were no reports about the relationship between the signal molecules of the pathway and lipoprotein homeostasis in cerebral hypoperfusion models. Therefore, we aimed to detect the expression of the pathway molecules in the aging rat models of chronic cerebral hypoperfusion and to explore its underlying mechanism. The model with cerebral hypoperfusion was established by ligating of the bilateral common carotid arteries (2VO). The temporal blood flow in the model rats was significantly decreased 14 d, 21 d and 28 d after 2VO compared with the control. The serum levels of high-density lipoprotein (HDL) and total cholesterol (TC) were reached a peak at 14 d, then, they were gradually decreased. The changes of LXR-ß, RXR-α, ABCA1 and apolipoprotein A1 (apo A1) of the pathway were consistent with the changes of HDL and TC. We conclude that LXR-ß/RXR-α/ABCA1 and downstream genes apo A1 undergo dynamic changes during the process of cerebral hypoperfusion. The LXR-ß/RXR-α/ABCA1 mediated apo A1 cholesterol may play a protective effect, and the effect only exists in a certain period of time.


Assuntos
Apolipoproteína A-I/metabolismo , Encéfalo/irrigação sanguínea , Encéfalo/metabolismo , Demência Vascular/metabolismo , Transdução de Sinais/fisiologia , Transportador 1 de Cassete de Ligação de ATP/metabolismo , Envelhecimento/metabolismo , Animais , Western Blotting , HDL-Colesterol/sangue , Modelos Animais de Doenças , Imunofluorescência , Receptores X do Fígado , Masculino , Receptores Nucleares Órfãos/metabolismo , Ratos , Ratos Sprague-Dawley , Receptores X Retinoide/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa
9.
Am J Chin Med ; 41(5): 1027-42, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-24117066

RESUMO

Cerebral hypoperfusion or aging often results in the disturbances of cholesterol and lipoprotein, which have been well depicted as a common pathological status contributing to neurodegenerative diseases such as vascular dementia (VaD) and Alzheimer's dementia (AD). The pathway of the liver X receptor-ß (LXR-ß)/retinoic X receptor-α (RXR-α)/ABCA1 plays a vital role in lipoprotein metabolism. Curcumin, a kind of phenolic compound, has been widely used. It has been reported that curcumin can reduce the levels of cholesterol in serum, but the underlying mechanisms are poorly understood. In this study, we evaluated the effects of curcumin on the cholesterol level in brain, vascular cognitive impairment and explored whether the mechanisms for those effects are through activating LXR-ß/RXR-α and ABCA1 expression and apoA-I. With a Morris water test, we found that curcumin treatment could attenuate cognitive impairment. With HE and Nissl staining, we found that curcumin could significantly ameliorate the abnormal changes of pyramidal neurons. Meanwhile, the expression of LXR-ß, RXR-α, ABCA1 and apoA-I mRNA and protein were increased in a dose-dependent manner after curcumin treatment. Interestingly, both serum HDL cholesterol and total cholesterol levels were statistically higher in the curcumin treatment group than those other groups. We conclude that curcumin has the ability to activate permissive LXR-ß/RXR-α signaling and thereby modulate ABCA1 and apoA-I-mediated cholesterol transmembrane transportation, which is a new preventive and therapeutic strategy for cerevascular diseases.


Assuntos
Transportador 1 de Cassete de Ligação de ATP/genética , Apolipoproteína A-I/fisiologia , Isquemia Encefálica/genética , Isquemia Encefálica/metabolismo , Encéfalo/metabolismo , Colesterol/metabolismo , Curcumina/farmacologia , Expressão Gênica/efeitos dos fármacos , Metabolismo dos Lipídeos/efeitos dos fármacos , Transportador 1 de Cassete de Ligação de ATP/fisiologia , Animais , Apolipoproteína A-I/metabolismo , Isquemia Encefálica/complicações , Isquemia Encefálica/tratamento farmacológico , HDL-Colesterol/metabolismo , Doença Crônica , Transtornos Cognitivos/tratamento farmacológico , Curcumina/uso terapêutico , Demência Vascular/etiologia , Demência Vascular/prevenção & controle , Relação Dose-Resposta a Droga , Homeostase/efeitos dos fármacos , Receptores X do Fígado , Receptores Nucleares Órfãos/genética , Receptores Nucleares Órfãos/fisiologia , Fitoterapia , RNA Mensageiro/metabolismo , Ratos , Ratos Sprague-Dawley , Receptor X Retinoide alfa/genética , Receptor X Retinoide alfa/fisiologia , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética , Transdução de Sinais/fisiologia
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