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1.
PLoS One ; 15(12): e0240873, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33382706

RESUMO

BACKGROUND: Sorghum bicolor (SB) is rich in protective phytoconstituents with health benefits and regarded as a promising source of natural anti-diabetic substance. However, its comprehensive bioactive compound(s) and mechanism(s) against type-2 diabetes mellitus (T2DM) have not been exposed. Hence, we implemented network pharmacology to identify its key compounds and mechanism(s) against T2DM. METHODS: Compounds in SB were explored through GC-MS and screened by Lipinski's rule. Genes associated with the selected compounds or T2DM were extracted from public databases, and the overlapping genes between SB-compound related genes and T2DM target genes were identified using Venn diagram. Then, the networking between selected compounds and overlapping genes was constructed, visualized, and analyzed by RStudio. Finally, affinity between compounds and genes was evaluated via molecular docking. RESULTS: GC-MS analysis of SB detected a total of 20 compounds which were accepted by the Lipinski's rule. A total number of 16 compounds-related genes and T2DM-related genes (4,763) were identified, and 81 overlapping genes between them were selected. Gene set enrichment analysis exhibited that the mechanisms of SB against T2DM were associated with 12 signaling pathways, and the key mechanism might be to control blood glucose level by activating PPAR signaling pathway. Furthermore, the highest affinities were noted between four main compounds and six genes (FABP3-Propyleneglyco monoleate, FABP4-25-Oxo-27-norcholesterol, NR1H3-Campesterol, PPARA-ß-sitosterol, PPARD-ß-sitosterol, and PPARG-ß-sitosterol). CONCLUSION: Our study overall suggests that the four key compounds detected in SB might ameliorate T2DM severity by activating the PPAR signaling pathway.


Assuntos
Regulação da Expressão Gênica/efeitos dos fármacos , Redes Reguladoras de Genes/efeitos dos fármacos , Hipoglicemiantes/química , Compostos Fitoquímicos/química , Sorghum/química , Esteróis/química , Sítios de Ligação , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/metabolismo , Proteína 3 Ligante de Ácido Graxo/antagonistas & inibidores , Proteína 3 Ligante de Ácido Graxo/genética , Proteína 3 Ligante de Ácido Graxo/metabolismo , Proteínas de Ligação a Ácido Graxo/antagonistas & inibidores , Proteínas de Ligação a Ácido Graxo/genética , Proteínas de Ligação a Ácido Graxo/metabolismo , Hipoglicemiantes/isolamento & purificação , Hipoglicemiantes/farmacologia , Receptores X do Fígado/antagonistas & inibidores , Receptores X do Fígado/genética , Receptores X do Fígado/metabolismo , Simulação de Acoplamento Molecular , PPAR alfa/antagonistas & inibidores , PPAR alfa/genética , PPAR alfa/metabolismo , PPAR delta/antagonistas & inibidores , PPAR delta/genética , PPAR delta/metabolismo , PPAR gama/antagonistas & inibidores , PPAR gama/genética , PPAR gama/metabolismo , Compostos Fitoquímicos/isolamento & purificação , Compostos Fitoquímicos/farmacologia , Extratos Vegetais/química , Ligação Proteica , Conformação Proteica em alfa-Hélice , Conformação Proteica em Folha beta , Domínios e Motivos de Interação entre Proteínas , Transdução de Sinais , Esteróis/isolamento & purificação , Esteróis/farmacologia , Relação Estrutura-Atividade
2.
Nat Commun ; 11(1): 4841, 2020 09 24.
Artigo em Inglês | MEDLINE | ID: mdl-32973176

RESUMO

Pre-clinical models have shown that targeting pancreatic stellate cells with all-trans-retinoic-acid (ATRA) reprograms pancreatic stroma to suppress pancreatic ductal adenocarcinoma (PDAC) growth. Here, in a phase Ib, dose escalation and expansion, trial for patients with advanced, unresectable PDAC (n = 27), ATRA is re-purposed as a stromal-targeting agent in combination with gemcitabine-nab-paclitaxel chemotherapy using a two-step adaptive continual re-assessment method trial design. The maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D, primary outcome) is the FDA/EMEA approved dose of gemcitabine-nab-paclitaxel along-with ATRA (45 mg/m2 orally, days 1-15/cycle). Dose limiting toxicity (DLT) is grade 4 thrombocytopenia (n = 2). Secondary outcomes show no detriment to ATRA pharmacokinetics.. Median overall survival for RP2D treated evaluable population, is 11.7 months (95%CI 8.6-15.7 m, n = 15, locally advanced (2) and metastatic (13)). Exploratory pharmacodynamics studies including changes in diffusion-weighted (DW)-MRI measured apparent diffusion coefficient after one cycle, and, modulation of cycle-specific serum pentraxin 3 levels over various cycles indicate stromal modulation. Baseline stromal-specific retinoid transport protein (FABP5, CRABP2) expression may be predicitve of response. Re-purposing ATRA as a stromal-targeting agent with gemcitabine-nab-paclitaxel is safe and tolerable. This combination will be evaluated in a phase II randomized controlled trial for locally advanced PDAC. Clinical trial numbers: EudraCT: 2015-002662-23; NCT03307148. Trial acronym: STARPAC.


Assuntos
Carcinoma Ductal Pancreático/tratamento farmacológico , Neoplasias Pancreáticas/tratamento farmacológico , Tretinoína/uso terapêutico , Biomarcadores Tumorais , Proteínas de Ligação a Ácido Graxo/metabolismo , Humanos , Dose Máxima Tolerável , Neoplasias Pancreáticas/diagnóstico por imagem , Receptores do Ácido Retinoico/metabolismo , Resultado do Tratamento , Tretinoína/efeitos adversos , Tretinoína/farmacocinética
3.
Arch Biochem Biophys ; 691: 108488, 2020 09 30.
Artigo em Inglês | MEDLINE | ID: mdl-32692982

RESUMO

Obesity is a metabolic disorder characterized by excess adipose tissue, macrophages infiltration, and inflammation which in turn lead to insulin-resistance. Epidemiological evidences reported that anthocyanins possess not only high antioxidant and antiinflammatory activities, but also improve metabolic complications associated with obesity. The aim of this work was to evaluate the in vitro beneficial effects of cyanidin-3-O-glucoside (C3G) in counteracting inflammation and insulin-resistance in 3T3-L1 hypertrophic adipocytes exposed to palmitic acid (PA). In the present study murine 3T3-L1 adipocytes were pretreated with C3G for 24 h and then exposed to palmitic acid (PA) for 24 h. Real-time PCR, western blotting analysis and Oil Red O staining were applied for investigating the mechanism involved in adipocytes dysfunction. C3G pretreatment reduced lipid accumulation, PPARγ pathway and NF-κB pathway induced by PA in murine adipocytes. In addition, our data demonstrated that PA reduced insulin signaling via IRS-1 Ser307phosphorylation while C3G dose-dependently improved insulin sensitivity restoring IRS-1/PI3K/Akt pathway. Furthermore, C3G improved adiponectin mRNA levels altered by PA in 3T3-L1 murine and SGBS human adipocytes. Herein reported data demonstrate that C3G ameliorated adipose tissue dysfunction, thus suggesting new potential roles for this compound of nutritional interest in the prevention of pathological conditions linked to obesity.


Assuntos
Adipócitos/efeitos dos fármacos , Antocianinas/farmacologia , Glucosídeos/farmacologia , Inflamação/prevenção & controle , Transdução de Sinais/efeitos dos fármacos , Células 3T3-L1 , Adipogenia/efeitos dos fármacos , Adiponectina/metabolismo , Animais , Proteínas de Ligação a Ácido Graxo/metabolismo , Transportador de Glucose Tipo 1/metabolismo , Humanos , Resistência à Insulina/fisiologia , Camundongos , NF-kappa B/metabolismo , PPAR gama/metabolismo , Ácido Palmítico/farmacologia
4.
Nature ; 584(7821): 410-414, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32641833

RESUMO

In metazoans, the secreted proteome participates in intercellular signalling and innate immunity, and builds the extracellular matrix scaffold around cells. Compared with the relatively constant intracellular environment, conditions for proteins in the extracellular space are harsher, and low concentrations of ATP prevent the activity of intracellular components of the protein quality-control machinery. Until now, only a few bona fide extracellular chaperones and proteases have been shown to limit the aggregation of extracellular proteins1-5. Here we performed a systematic analysis of the extracellular proteostasis network in Caenorhabditis elegans with an RNA interference screen that targets genes that encode the secreted proteome. We discovered 57 regulators of extracellular protein aggregation, including several proteins related to innate immunity. Because intracellular proteostasis is upregulated in response to pathogens6-9, we investigated whether pathogens also stimulate extracellular proteostasis. Using a pore-forming toxin to mimic a pathogenic attack, we found that C. elegans responded by increasing the expression of components of extracellular proteostasis and by limiting aggregation of extracellular proteins. The activation of extracellular proteostasis was dependent on stress-activated MAP kinase signalling. Notably, the overexpression of components of extracellular proteostasis delayed ageing and rendered worms resistant to intoxication. We propose that enhanced extracellular proteostasis contributes to systemic host defence by maintaining a functional secreted proteome and avoiding proteotoxicity.


Assuntos
Caenorhabditis elegans/metabolismo , Caenorhabditis elegans/microbiologia , Espaço Extracelular/metabolismo , Agregados Proteicos , Proteostase , Envelhecimento/metabolismo , Animais , Caenorhabditis elegans/citologia , Caenorhabditis elegans/genética , Proteínas de Caenorhabditis elegans/metabolismo , Proteínas de Ligação a Ácido Graxo/metabolismo , Sistema de Sinalização das MAP Quinases , Agregação Patológica de Proteínas/prevenção & controle , Proteoma/genética , Proteoma/metabolismo , Interferência de RNA
5.
Arch Biochem Biophys ; 686: 108365, 2020 06 15.
Artigo em Inglês | MEDLINE | ID: mdl-32315651

RESUMO

Pelargonidin is a natural compound that exists widely in fruits, and exerts antioxidant, anti-atherosclerotic, anti-inflammatory, anti-hyperglycemic, and anti-diabetic activities. However, there have not been any studies concerning its anti-obesity potential to date. Therefore, we evaluated the anti-obesity potential of pelargonidin via inhibition of adipogenesis in 3T3-L1 cells. The cellular oil droplet content was decreased to 68.14%, 56.75%, and 48.39% and triglyceride accumulation decreased to 74.53%, 61.54%, and 47.86% after incubation with 5 µM, 10 µM, and 20 µM pelargonidin, respectively, when compared with DMSO group. Furthermore, pelargonidin treatment led to decrease in glucose consumption. Western blot assay illustrated that the expression of PPAR-γ was suppressed to 63.25%, 47.52%, and 21.23% after incubation with 5 µM, 10 µM, and 20 µM pelargonidin when compared with DMSO group. Then, we measured the expression of some target proteins of PPAR-γ, and found that pelargonidin decreased the expressions of HMGCR, LPL, Glut4, and A-FABP. Besides, the result of Luciferase Reporter Assay indicated that pelargonidin inhibited PPAR-γ transcription activity. These results indicated that pelargonidin exerts anti-adipogenic activity in 3T3-L1 cells through inhibition of PPAR-γ signaling pathway, and pelargonidin could be used as a potential anti-obesity agent.


Assuntos
Adipogenia/efeitos dos fármacos , Antocianinas/farmacologia , Fármacos Antiobesidade/farmacologia , PPAR gama/metabolismo , Células 3T3-L1 , Animais , Antocianinas/metabolismo , Fármacos Antiobesidade/metabolismo , Regulação para Baixo/efeitos dos fármacos , Proteínas de Ligação a Ácido Graxo/genética , Proteínas de Ligação a Ácido Graxo/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Glucose/metabolismo , Transportador de Glucose Tipo 4/genética , Transportador de Glucose Tipo 4/metabolismo , Lipase Lipoproteica/genética , Lipase Lipoproteica/metabolismo , Camundongos , Triglicerídeos/genética , Triglicerídeos/metabolismo
6.
Sci Rep ; 10(1): 5638, 2020 03 27.
Artigo em Inglês | MEDLINE | ID: mdl-32221337

RESUMO

This study aimed to investigate the prognostic value of high-sensitivity creatine kinase-myocardial band or fraction (hsCK-MB) in comparison with other well-established biomarkers including heart type-fatty acid binding protein (H-FABP) and N-terminal pro-brain natriuretic peptide (NT-proBNP) in patients with stable coronary heart disease (SCHD). A total of 1,785 patients were enrolled and followed for 36 months. The primary outcome was all-cause mortality. The secondary outcomes included cardiovascular (CV) death, acute myocardial infarction (AMI), angina-related hospitalizations, and hospitalizations for heart failure. The all-cause mortality rate was significantly higher in the high hsCK-MB group compared to the low hsCK-MB group (4.64% vs. 1.88%, p = 0.0026). After adjusting for baseline covariates, there were no significant differences for the secondary outcomes. H-FABP (≥4.226 ng/mL) was the best predictor for all-cause mortality (HR = 2.68, 95% CI = 1.28-5.62, p = 0.009) and CV death (HR = 6.84, 95% CI = 1.89-22.14, p = 0.003). The high NT-proBNP group had a higher AMI-related hospitalization rate (HR = 1.91, 95% CI = 1.00-3.65, p = 0.05). Neither the addition of hsCK-MB to any other markers nor combinations of the three markers improved the prognostic significance of CV outcomes. In conclusion, hsCK-MB was an independent predictor for all-cause mortality but not CV outcomes in patients with SCHD. Combination of hsCK-MB, H-FABP and NT-proBNP failed to improve the prognostic power for all-cause mortality or CV outcomes.


Assuntos
Doença das Coronárias/metabolismo , Creatina Quinase Forma MB/metabolismo , Adulto , Biomarcadores/metabolismo , Doença das Coronárias/mortalidade , Proteínas de Ligação a Ácido Graxo/metabolismo , Feminino , Seguimentos , Insuficiência Cardíaca/metabolismo , Insuficiência Cardíaca/mortalidade , Hospitalização , Humanos , Masculino , Infarto do Miocárdio/metabolismo , Infarto do Miocárdio/mortalidade , Prognóstico
7.
Cancer Res ; 80(12): 2564-2574, 2020 06 15.
Artigo em Inglês | MEDLINE | ID: mdl-32213543

RESUMO

Obesity is associated with increased risk of many types of cancer and can be induced by various high-fat diets (HFD) from different fat sources. It remains unknown whether fatty acid composition in different HFD influences obesity-associated tumor development. Here we report that consumption of either a cocoa butter or fish oil HFD induced similar obesity in mouse models. While obesity induced by the cocoa butter HFD was associated with accelerated mammary tumor growth, consumption of the fish oil HFD uncoupled obesity from increased mammary tumor growth and exhibited a decrease in protumor macrophages. Compared with fatty acid (FA) components in both HFDs, n-3 FA rich in the fish oil HFD induced significant production of reactive oxygen species (ROS) and macrophage death. Moreover, A-FABP expression in the protumor macrophages facilitated intracellular transportation of n-3 FA and oxidation of mitochondrial FA. A-FABP deficiency diminished n-3 FA-mediated ROS production and macrophage death in vitro and in vivo. Together, our results demonstrate a novel mechanism by which n-3 FA induce ROS-mediated protumor macrophage death in an A-FABP-dependent manner. SIGNIFICANCE: This study provides mechanistic insight into dietary supplementation with fish oil for breast cancer prevention and advances a new concept that not all HFDs leading to obesity are tumorigenic. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/80/12/2564/F1.large.jpg.


Assuntos
Dieta Hiperlipídica/métodos , Gorduras na Dieta/efeitos adversos , Proteínas de Ligação a Ácido Graxo/metabolismo , Óleos de Peixe/administração & dosagem , Macrófagos/imunologia , Neoplasias Mamárias Experimentais/imunologia , Obesidade/complicações , Animais , Carcinogênese/imunologia , Carcinogênese/metabolismo , Linhagem Celular Tumoral/transplante , Dieta Hiperlipídica/efeitos adversos , Proteínas de Ligação a Ácido Graxo/genética , Feminino , Humanos , Macrófagos/citologia , Macrófagos/metabolismo , Glândulas Mamárias Animais/citologia , Glândulas Mamárias Animais/imunologia , Glândulas Mamárias Animais/patologia , Neoplasias Mamárias Experimentais/genética , Neoplasias Mamárias Experimentais/metabolismo , Neoplasias Mamárias Experimentais/prevenção & controle , Camundongos , Camundongos Knockout , Mitocôndrias/metabolismo , Obesidade/imunologia , Obesidade/metabolismo , Cultura Primária de Células , Espécies Reativas de Oxigênio/metabolismo
8.
Life Sci ; 253: 117539, 2020 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-32165213

RESUMO

AIMS: Lipopolysaccharide (LPS)-induced intestinal injury is a common clinical feature of sepsis. Aggravated inflammation and higher sensitivity to infection are associated with high-fat diet (HFD) in patients with type 2 diabetes and/or obesity. However, the mechanism by which HFD exacerbates LPS-induced intestinal injury has not been elucidated. This study aims to examine the effects of HFD on intestinal injury induced by LPS and the underlying mechanism. MAIN METHODS: Mice were fed with HFD or regular chow for 12weeks and were then challenged with LPS. Vas2870 was administered to mice that received HFD before the initiation of the diet. The levels of tight junction protein expression, oxidative stress, organ injury, and nicotinamide adenine dinucleotide phosphate (NADPH)-associated proteins were assessed periodically. KEY FINDINGS: LPS treatment resulted in severe intestinal pathological injury and increased oxidative stress, evidenced by significantly increased serum diamine oxidase, reactive oxygen species, malondialdehyde, and intestinal fatty acid binding protein contents. Additionally, a decrease in tight junction protein expression was observed, indicating a loss of tight junction integrity. LPS treatment induced the expression of Nox2 and Nox4. All the effects were more severe in HFD mice. Treatment with vas2870 conferred protection against LPS-induced intestinal injury in HFD-fed mice, partially reduced oxidative stress, and rescued the expression of tight junction proteins. CONCLUSION: HFD aggravated LPS-induced intestine injury through exacerbating intestinal Nox-related oxidative stress, which led to a loss of the integrity of tight junctions and consequently increased intestinal permeability.


Assuntos
Dieta Hiperlipídica , Intestinos/efeitos dos fármacos , Lipopolissacarídeos/metabolismo , NADP/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Adsorção , Animais , Benzoxazóis/administração & dosagem , Benzoxazóis/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Proteínas de Ligação a Ácido Graxo/metabolismo , Humanos , Masculino , Malondialdeído/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , NADPH Oxidases/metabolismo , Obesidade/metabolismo , Oxirredução , Permeabilidade , Espécies Reativas de Oxigênio/metabolismo , Proteínas de Junções Íntimas/metabolismo , Junções Íntimas/metabolismo , Triazóis/administração & dosagem , Triazóis/metabolismo
9.
J Med Chem ; 63(8): 4090-4106, 2020 04 23.
Artigo em Inglês | MEDLINE | ID: mdl-32202425

RESUMO

Fatty-acid binding protein 4 (FABP4) is a promising therapeutic target for immunometabolic diseases, while its potential for systemic inflammatory response syndrome treatment has not been explored. Here, a series of 2-(phenylamino)benzoic acids as novel and potent FABP4 inhibitors are rationally designed based on an interesting fragment that adopts multiple binding poses within FABP4. A fusion of these binding poses leads to the design of compound 3 with an ∼460-fold improvement in binding affinity compared to the initial fragment. A subsequent structure-aided optimization upon 3 results in a promising lead (17) with the highest binding affinity among all the inhibitors, exerting a significant anti-inflammatory effect in cells and effectively attenuating a systemic inflammatory damage in mice. Our work therefore presents a good example of lead compound discovery derived from the multiple binding poses of a fragment and provides a candidate for development of drugs against inflammation-related diseases.


Assuntos
Anti-Inflamatórios/administração & dosagem , Anti-Inflamatórios/metabolismo , Descoberta de Drogas/métodos , Proteínas de Ligação a Ácido Graxo/antagonistas & inibidores , Proteínas de Ligação a Ácido Graxo/metabolismo , Células 3T3 , Administração Oral , Animais , Anti-Inflamatórios/química , Compostos de Bifenilo/administração & dosagem , Compostos de Bifenilo/química , Compostos de Bifenilo/metabolismo , Células CACO-2 , Relação Dose-Resposta a Droga , Humanos , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos ICR , Ligação Proteica/efeitos dos fármacos , Ligação Proteica/fisiologia , Estrutura Secundária de Proteína , Estrutura Terciária de Proteína , Pirazóis/administração & dosagem , Pirazóis/química , Pirazóis/metabolismo , Resultado do Tratamento
10.
Anim Sci J ; 91(1): e13326, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32219924

RESUMO

Antibiotics stimulate the growth of animals but result in drug residues and bacterial resistance. In this study, the negative effect of antibiotics on abdominal fat deposition was evaluated in broilers. The results showed that adding both chlortetracycline (50 g/1,000 kg) and tylosin (50 g/1,000 kg) significantly increased abdominal fat weight, abdominal fat percentage (p < .05), and triglyceride and cholesterol levels (p < .05) in blood. Also, both products synchronously stimulated intestinal absorption and synthesis of liver fat. The expression levels of the peroxisome proliferator-activated receptor Î³ (PPARγ), diacylgycerol acyltransferase 2 (DGAT2), lipoprotein lipase (LPL), and fatty acid-binding protein (FABP4) genes in abdominal fat tissue significantly increased (p < .05 or 0.01) when antibiotics were added to the feed. However, no significant difference was found in expression of the fatty acid synthesis (FAS) or acetyl CoA carboxylase (ACC) genes. Further in vitro study results revealed that antibiotics had no effect on fat content or the related gene expression levels in preadipocytes. In summary, the antibiotics induced fat deposition in adipose tissues by activating extracellular absorption of fatty acids from intestinal absorption and synthesis of liver fat. However, it shows no direct regulation by adipose tissue.


Assuntos
Gordura Abdominal/metabolismo , Antibacterianos/farmacologia , Galinhas/crescimento & desenvolvimento , Galinhas/metabolismo , Clortetraciclina/farmacologia , Tilosina/farmacologia , Tecido Adiposo/metabolismo , Animais , Antibacterianos/efeitos adversos , Clortetraciclina/efeitos adversos , Colesterol/sangue , Diacilglicerol O-Aciltransferase/metabolismo , Proteínas de Ligação a Ácido Graxo/genética , Proteínas de Ligação a Ácido Graxo/metabolismo , Expressão Gênica , Absorção Intestinal , Lipase Lipoproteica/genética , Lipase Lipoproteica/metabolismo , PPAR gama/genética , PPAR gama/metabolismo , Triglicerídeos/sangue , Tilosina/efeitos adversos
11.
J Med Food ; 23(3): 281-288, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32119806

RESUMO

The aim of this study was to investigate the effect of a high-fat diet (HFD) on energy substrate utilization during long-term endurance exercise in mice. Male ICR mice (n = 32; 6 weeks old) were divided into two groups: low-fat diet (LFD, n = 16) and HFD (n = 16) and acclimatized to LFD or HFD feeding over 12 weeks. After 12 weeks, the two dietary groups were each divided into two groups with or without exercise (EX): LF-CON, LF-EX, HF-CON, and HF-EX groups. The exercise groups were trained to run on a treadmill for 12 weeks. At the end of the experimental protocol, energy metabolism in the whole body was measured at rest for 24 h and during exercise for 1 h using respiratory gas analysis. Furthermore, molecules involved in skeletal muscle fat metabolism were analyzed. Substrate utilization for energy metabolism in the whole body indicated that fat utilization was high in HFD intake. Notably, when HFD intake and exercise were combined, fat utilization was markedly increased during endurance exercise. In contrast, exercise showed no effect when combined with LFD intake. The gene expressions of Fat/Cd36, Fatp1, Fabp-pm, and Cpt1 were upregulated by HFD intake, with Fat/Cd36 and Cpt1 considerably elevated during long-term endurance exercise. In contrast, exercise showed no effect when combined with LFD intake. These results suggest that HFD intake effectively increased fat utilization as an energy substrate during long-term endurance exercise.


Assuntos
Gorduras na Dieta/metabolismo , Ácidos Graxos/metabolismo , Músculo Esquelético/metabolismo , Animais , Dieta Hiperlipídica , Gorduras na Dieta/análise , Metabolismo Energético , Proteínas de Transporte de Ácido Graxo/genética , Proteínas de Transporte de Ácido Graxo/metabolismo , Proteínas de Ligação a Ácido Graxo/genética , Proteínas de Ligação a Ácido Graxo/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos ICR , Oxirredução , Condicionamento Físico Animal
12.
Sci Rep ; 10(1): 2081, 2020 02 07.
Artigo em Inglês | MEDLINE | ID: mdl-32034167

RESUMO

Direct-acting antivirals (DAAs) have dramatically improved the management of chronic hepatitis C (CHC). In this study, we investigated the effects of hepatitis C virus clearance on markers of systemic inflammation measured in plasma samples from CHC patients before, during and after DAA therapy. We identified a plasma soluble protein profile associated with CHC. Successful DAA therapy rapidly normalised the plasma inflammatory milieu, with the notable exception of soluble (s)CD163, a marker of macrophage activation, which remained elevated after viral clearance and segregated patients with high and low levels of cirrhosis. Patients who received DAA in combination with Ribavirin maintained elevated levels of CXCL10, consistent with an immune-stimulatory role of Ribavirin. As anticipated, DAA-treated patients experienced durable improvement in liver fibrosis measurements. Interestingly, pre-treatment levels of fatty acid-binding protein 4 (FABP4) were inversely associated with reduction of APRI and FIB-4 scores during treatment. Together, these results support the notion of a rapid restoration of many aspects of the inflammatory state in CHC patients in response to DAA therapy. Furthermore, the associations with sCD163 and FABP4 warrant further investigation into the role of macrophages in residual liver disease and fibrosis resolution after viral clearance.


Assuntos
Antivirais/uso terapêutico , Proteínas de Ligação a Ácido Graxo/metabolismo , Hepacivirus/efeitos dos fármacos , Hepatite C Crônica/tratamento farmacológico , Fígado/patologia , Ribavirina/uso terapêutico , Citocinas/sangue , Proteínas de Ligação a Ácido Graxo/sangue , Feminino , Hepacivirus/metabolismo , Hepatite C Crônica/sangue , Hepatite C Crônica/metabolismo , Hepatite C Crônica/patologia , Humanos , Fígado/virologia , Cirrose Hepática/patologia , Masculino , Pessoa de Meia-Idade
13.
J Dermatol Sci ; 97(2): 152-160, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-32001116

RESUMO

BACKGROUND: Radiation-induced skin injury is a serious concern during radiotherapy and radiation accidents. Skin fat represents the dominant architectural component of the human skin. However, the interplay between skin fat and the progression of radiation-induced skin injury remains largely unexplored. OBJECTIVE: This study aims to elucidate the interplay between skin fat and the progression of radiation-induced skin injury. METHODS: SD rats were irradiated with an electron beam. mRNA profiles were determined by RNA-Seq. The skin lipid mass was monitored by magnetic resonance imaging (MRI) and lipid profiles were measured by liquid chromatography-mass spectrometry (LC-MS). Human mature adipocytes isolated from dermal and subcutaneous white adipose tissues (WATs) were co-cultured with human keratinocytes (HaCaT) and skin fibroblasts (WS1) in the transwell culture system. Cell migration ability was measured by migration assay. RESULTS: Radiation modulated cutaneous lipid metabolism by downregulating multiple pathways. Moreover, radiation decreased skin fat mass with altered lipid metabolite profiles. The rats fed with a high-fat diet showed resistance to radiogenic skin injury compared with that with a control diet, indicating that skin lipid plays a radioprotective role. Mature adipocytes promoted the migration but not the proliferation of co-cultured skin keratinocytes and fibroblasts. Palmitic acid, the most abundant fatty acid in skin tissues, facilitated the migration of WS1 cells. Moreover, fatty acid-binding protein 4 (FABP4) could be incorporated into skin cells and promote DNA damage repair in irradiated skin fibroblasts. CONCLUSION: Radiation induces cutaneous lipid remolding, and skin adipocytes confer a protective role against radiation-induced skin injury.


Assuntos
Adipócitos/fisiologia , Resistência à Doença/fisiologia , Lesões por Radiação/patologia , Reepitelização/fisiologia , Dermatopatias/patologia , Adipócitos/efeitos da radiação , Animais , Movimento Celular , Técnicas de Cocultura , Dano ao DNA/efeitos da radiação , Reparo do DNA , Dieta Hiperlipídica , Modelos Animais de Doenças , Progressão da Doença , Proteínas de Ligação a Ácido Graxo/metabolismo , Fibroblastos , Humanos , Queratinócitos , Metabolismo dos Lipídeos/fisiologia , Metabolismo dos Lipídeos/efeitos da radiação , Ácido Palmítico/metabolismo , Cultura Primária de Células , RNA-Seq , Lesões por Radiação/etiologia , Ratos , Pele/metabolismo , Pele/patologia , Pele/efeitos da radiação , Dermatopatias/etiologia , Gordura Subcutânea/citologia , Gordura Subcutânea/efeitos da radiação
14.
Protein J ; 39(2): 145-151, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32096074

RESUMO

Biofluorescence has been found to be an increasingly widespread phenomenon in the ocean. The reclusive Caribbean chlopsid eel, Kaupichthys hyoproroides displays bright green fluorescence in its native marine environment. We have previously shown the fluorescence to be attributed to a fluorescent fatty acid-binding protein, Chlopsid FP, part of a larger family of fluorescent fatty acid-binding proteins, including the homologous UnaG. All require the addition of exogenous bilirubin for fluorescence. Here, we report the generation of a series of point mutants, and deletions that result in the quenching of fluorescence in Chlopsid FP. In addition, we report the binding constants of bilirubin to Chlopsid FP and mutants, measured by fluorescence titration. This study provides key insights into the potential mechanism of fluorescence in this class of fluorescent fatty acid-binding proteins.


Assuntos
Bilirrubina/metabolismo , Enguias , Proteínas de Ligação a Ácido Graxo/genética , Fluorescência , Proteínas Luminescentes/genética , Animais , Proteínas de Ligação a Ácido Graxo/metabolismo , Ligação Proteica , Deleção de Sequência
15.
Cancer Immunol Res ; 8(4): 479-492, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32075801

RESUMO

The success of checkpoint inhibitors in cancer treatment is associated with the infiltration of tissue-resident memory T (Trm) cells. In this study, we found that about 30% of tumor-infiltrating lymphocytes (TIL) in the tumor microenvironment of gastric adenocarcinoma were CD69+CD103+ Trm cells. Trm cells were low in patients with metastasis, and the presence of Trm cells was associated with better prognosis in patients with gastric adenocarcinoma. Trm cells expressed high PD-1, TIGIT, and CD39 and represented tumor-reactive TILs. Instead of utilizing glucose, Trm cells relied on fatty acid oxidation for cell survival. Deprivation of fatty acid resulted in Trm cell death. In a tumor cell-T-cell coculture system, gastric adenocarcinoma cells outcompeted Trm cells for lipid uptake and induced Trm cell death. Targeting PD-L1 decreased fatty acid binding protein (Fabp) 4 and Fabp5 expression in tumor cells of gastric adenocarcinoma. In contrast, the blockade of PD-L1 increased Fabp4/5 expression in Trm cells, promoting lipid uptake by Trm cells and resulting in better survival of Trm cells in vitro and in vivo. PD-L1 blockade unleashed Trm cells specifically in the patient-derived xenograft (PDX) mice. PDX mice that did not respond to PD-L1 blockade had less Trm cells than responders. Together, these data demonstrated that Trm cells represent a subset of TILs in the antitumor immune response and that metabolic reprogramming could be a promising way to prolong the longevity of Trm cells and enhance antitumor immunity in gastric adenocarcinoma.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Ácidos Graxos/química , Memória Imunológica , Linfócitos do Interstício Tumoral/imunologia , Neoplasias Gástricas/imunologia , Neoplasias Gástricas/metabolismo , Microambiente Tumoral , Adenocarcinoma/imunologia , Adenocarcinoma/metabolismo , Adenocarcinoma/patologia , Animais , Antígenos CD/metabolismo , Antígeno B7-H1/antagonistas & inibidores , Antígeno B7-H1/metabolismo , Linhagem Celular Tumoral , Técnicas de Cocultura , Proteínas de Ligação a Ácido Graxo/metabolismo , Ácidos Graxos/metabolismo , Humanos , Cadeias alfa de Integrinas/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos NOD , Células Neoplásicas Circulantes/imunologia , Oxirredução , Prognóstico , Receptor de Morte Celular Programada 1/metabolismo , Neoplasias Gástricas/patologia , Taxa de Sobrevida , Ensaios Antitumorais Modelo de Xenoenxerto
16.
Parasit Vectors ; 13(1): 85, 2020 Feb 18.
Artigo em Inglês | MEDLINE | ID: mdl-32070415

RESUMO

BACKGROUND: Lipid metabolism is pivotal for the growth of apicomplexan parasites. Lipid synthesis requires bulk carbon skeleton acyl-CoAs, the transport of which depends on the acyl-CoA binding protein (ACBP). In Neospora caninum, the causative agent of neosporosis, the FASII pathway is required for growth and pathogenicity. However, little is known about the fatty acid transport mechanism in N. caninum. METHODS: We have identified a cytosolic acyl-CoA binding protein, with highly conserved amino acid residues and a typical acyl-CoA binding domain in N. caninum. The recombinant NcACBP protein was expressed to verify the binding activities of NcACBP in vitro, and the heterologous expression of NcACBP in Δacbp yeast in vivo. Lipid extraction from ΔNcACBP or the wild-type of N. caninum was analyzed by GC-MS or TLC. Furthermore, transcriptome analysis was performed to compare the gene expression in different strains. RESULTS: The NcACBP recombinant protein was able to specifically bind acyl-CoA esters in vitro. A yeast complementation assay showed that heterologous expression of NcACBP rescued the phenotypic defects in Δacbp yeast, indicating of the binding activity of NcACBP in vivo. The disruption of NcACBP did not perturb the parasite's growth but enhanced its pathogenicity in mice. The lipidomic analysis showed that disruption of NcACBP caused no obvious changes in the overall abundance and turnover of fatty acids while knockout resulted in the accumulation of triacylglycerol. Transcriptional analysis of ACBP-deficient parasites revealed differentially expressed genes involved in a wide range of biological processes such as lipid metabolism, posttranslational modification, and membrane biogenesis. CONCLUSIONS: Our study demonstrated that genetic ablation of NcACBP did not impair the survival and growth phenotype of N. caninum but enhanced its pathogenicity in mice. This deletion did not affect the overall fatty acid composition but modified the abundance of TAG. The loss of NcACBP resulted in global changes in the expression of multiple genes. This study provides a foundation for elucidating the molecular mechanism of lipid metabolism in N. caninum.


Assuntos
Inibidor da Ligação a Diazepam/metabolismo , Ácidos Graxos/metabolismo , Neospora/genética , Neospora/metabolismo , Proteínas de Protozoários/metabolismo , Animais , Inibidor da Ligação a Diazepam/genética , Proteínas de Ligação a Ácido Graxo/metabolismo , Feminino , Perfilação da Expressão Gênica , Metabolismo dos Lipídeos , Camundongos , Camundongos Endogâmicos BALB C , Neospora/patogenicidade , Ligação Proteica , Proteínas de Protozoários/genética , Proteínas Recombinantes/metabolismo , Virulência
17.
Cancer Res ; 80(8): 1748-1761, 2020 04 15.
Artigo em Inglês | MEDLINE | ID: mdl-32054768

RESUMO

Adipocytes are critical for ovarian cancer cells to home to the omentum, but the metabolic changes initiated by this interaction are unknown. To this end, we carried out unbiased mass spectrometry-based metabolomic and proteomic profiling of cancer cells cocultured with primary human omental adipocytes. Cancer cells underwent significant proteo-metabolomic alteration(s), typified by changes in the lipidome with corresponding upregulation of lipid metabolism proteins. FABP4, a lipid chaperone protein, was identified as the critical regulator of lipid responses in ovarian cancer cells cocultured with adipocytes. Subsequently, knockdown of FABP4 resulted in increased 5-hydroxymethylcytosine levels in the DNA, downregulation of gene signatures associated with ovarian cancer metastasis, and reduced clonogenic cancer cell survival. In addition, clustered regularly interspaced short palindromic repeats (CRISPR)-mediated knockout of FABP4 in high-grade serous ovarian cancer cells reduced metastatic tumor burden in mice. Consequently, a small-molecule inhibitor of FABP4 (BMS309403) not only significantly reduced tumor burden in a syngeneic orthotopic mouse model but also increased the sensitivity of cancer cells toward carboplatin both in vitro and in vivo. Taken together, these results show that targeting FABP4 in ovarian cancer cells can inhibit their ability to adapt and colonize lipid-rich tumor microenvironments, providing an opportunity for specific metabolic targeting of ovarian cancer metastasis. SIGNIFICANCE: Ovarian cancer metastatic progression can be restricted by targeting a critical regulator of lipid responses, FABP4.


Assuntos
Adipócitos/metabolismo , Resistencia a Medicamentos Antineoplásicos , Proteínas de Ligação a Ácido Graxo/metabolismo , Neoplasias Ovarianas/metabolismo , 5-Metilcitosina/análogos & derivados , 5-Metilcitosina/análise , Animais , Antineoplásicos/farmacologia , Compostos de Bifenilo/farmacologia , Carboplatina/farmacologia , Linhagem Celular Tumoral , Proliferação de Células , Sobrevivência Celular , Repetições Palindrômicas Curtas Agrupadas e Regularmente Espaçadas , Técnicas de Cocultura , Metilação de DNA , Regulação para Baixo , Proteínas de Ligação a Ácido Graxo/antagonistas & inibidores , Proteínas de Ligação a Ácido Graxo/genética , Feminino , Técnicas de Silenciamento de Genes , Xenoenxertos , Humanos , Metabolismo dos Lipídeos , Lipidômica , Espectrometria de Massas , Metabolômica/métodos , Camundongos , Camundongos Nus , Metástase Neoplásica/prevenção & controle , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Omento/citologia , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/patologia , Análise Serial de Proteínas , Proteômica/métodos , Pirazóis/farmacologia , Carga Tumoral/efeitos dos fármacos , Regulação para Cima
18.
Phys Chem Chem Phys ; 22(4): 2262-2275, 2020 Jan 28.
Artigo em Inglês | MEDLINE | ID: mdl-31917380

RESUMO

Recently, fatty acid binding proteins 5 and 7 (FABP5 and FABP7) have been regarded as the prospective targets for clinically treating multiple diseases related to FABPs. In this work, multiple short molecular dynamics (MSMD) simulations followed by binding free energy calculations were performed to investigate the binding selectivity of three inhibitors, namely, 65X, 8KS, and 5M8 toward FABP5 and FABP7. The RMSF analysis suggests that the structural flexibility of FABP5 is stronger than that of FABP7; moreover, the calculated molecular surface area of FABP5 is also larger than that of FABP7. Meanwhile, the results from the cross-correlation analysis show that the inhibitor bindings exert different impacts on the internal dynamics of FABP5 and FABP7. Binding free energies predicted by the molecular mechanics/generalized Born surface area (MM-GBSA) method indicate that the increase in the enthalpy changes caused by the bindings of inhibitors toward FABP7 relative to FABP5 mostly drives the binding selectivity of the inhibitors toward FABP5 versus FABP7. Hierarchical clustering analysis based on the energy contributions of separate residues and calculations of residue-based free energy decompositions were carried out by using the equilibrated MSMD trajectories. The obtained results not only recognize the hot interaction spots of inhibitors with FABP5 and FABP7, but also display that several common residues, namely, (T56, T54), (L60, F58), (E75, E73), (A76, A78), (D79, D77), (R81, R79), (R107, R109), (C120, L118), and (R129, R127) belonging to (FABP5, FABP7) induce obvious binding differences in the inhibitors toward FABP5 and FABP7. Therefore, these residues play significant roles in the binding selectivities of inhibitors toward FABP5 and FABP7.


Assuntos
Proteína 7 de Ligação a Ácidos Graxos/antagonistas & inibidores , Proteínas de Ligação a Ácido Graxo/antagonistas & inibidores , Simulação de Dinâmica Molecular , Proteínas Supressoras de Tumor/antagonistas & inibidores , Sítios de Ligação , Análise por Conglomerados , Entropia , Proteína 7 de Ligação a Ácidos Graxos/metabolismo , Proteínas de Ligação a Ácido Graxo/metabolismo , Humanos , Ligação de Hidrogênio , Ligação Proteica , Estrutura Terciária de Proteína , Proteínas Supressoras de Tumor/metabolismo
19.
Appl Microbiol Biotechnol ; 104(5): 2149-2161, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31950220

RESUMO

Fatty acid-binding protein 2 (Fabp2), which is involved in the transport of long-chain fatty acids, is widely studied in mammals. Nevertheless, the role of this protein in teleost fish is mostly unknown. Here, we produced a fabp2-/- zebrafish (KO) animal model. Compared with wild-type zebrafish (WT), KO had a markedly decreased content of intestinal n-3 poly-unsaturated fatty acids (n-3 PUFAs) and increased levels of intestinal, hepatic, and serum triacylglycerols (TAG). The intestinal transcriptome analysis of KO and WT revealed an obviously disrupted TAG metabolism and up-regulated bile secretion in KO. Expression levels of the genes related to fatty acid transport and cholesterol (CL) absorption in the intestine of KO were significantly lower than those of WT, while the expression levels of genes related to intestinal TAG synthesis and hepatic CL synthesis were in the opposite direction. To confirm these findings, we further established fabp2 transgenic zebrafish (TG). Compared with WT, TG had a markedly increased content of intestinal n-3 PUFAs, a significantly decreased level of hepatic TAG, and significantly higher expression of genes related to fatty acid transport and CL absorption in the intestine. In conclusion, this study suggests that teleost fish fabp2 could promote intestinal n-3 PUFA absorption to mediate TAG synthesis and CL homeostasis, by regulating the genes involved in lipid metabolism.


Assuntos
Colesterol/metabolismo , Proteínas de Ligação a Ácido Graxo/genética , Ácidos Graxos Ômega-3/metabolismo , Deleção de Genes , Triglicerídeos/metabolismo , Proteínas de Peixe-Zebra/genética , Peixe-Zebra/genética , Animais , Ácidos e Sais Biliares/metabolismo , Proteínas de Ligação a Ácido Graxo/metabolismo , Homeostase , Mucosa Intestinal/metabolismo , Fígado/metabolismo , Peixe-Zebra/metabolismo , Proteínas de Peixe-Zebra/metabolismo
20.
Proc Natl Acad Sci U S A ; 117(5): 2462-2472, 2020 02 04.
Artigo em Inglês | MEDLINE | ID: mdl-31953260

RESUMO

Preadipocytes can give rise to either white adipocytes or beige adipocytes. Owing to their distinct abilities in nutrient storage and energy expenditure, strategies that specifically promote "beiging" of adipocytes hold great promise for counterbalancing obesity and metabolic diseases. Yet, factors dictating the differentiation fate of adipocyte progenitors remain to be elucidated. We found that stearoyl-coenzyme A desaturase 1 (Scd1)-deficient mice, which resist metabolic stress, possess augmentation in beige adipocytes under basal conditions. Deletion of Scd1 in mature adipocytes expressing Fabp4 or Ucp1 did not affect thermogenesis in mice. Rather, Scd1 deficiency shifted the differentiation fate of preadipocytes from white adipogenesis to beige adipogenesis. Such effects are dependent on succinate accumulation in adipocyte progenitors, which fuels mitochondrial complex II activity. Suppression of mitochondrial complex II by Atpenin A5 or oxaloacetic acid reverted the differentiation potential of Scd1-deficient preadipocytes to white adipocytes. Furthermore, supplementation of succinate was found to increase beige adipocyte differentiation both in vitro and in vivo. Our data reveal an unappreciated role of Scd1 in determining the cell fate of adipocyte progenitors through succinate-dependent regulation of mitochondrial complex II.


Assuntos
Complexo II de Transporte de Elétrons/metabolismo , Gorduras/metabolismo , Obesidade/enzimologia , Estearoil-CoA Dessaturase/genética , Ácido Succínico/metabolismo , Adipócitos Bege/citologia , Adipócitos Bege/metabolismo , Adipogenia , Animais , Metabolismo Energético , Proteínas de Ligação a Ácido Graxo/genética , Proteínas de Ligação a Ácido Graxo/metabolismo , Feminino , Humanos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Knockout , Obesidade/genética , Obesidade/metabolismo , Obesidade/fisiopatologia , Estearoil-CoA Dessaturase/metabolismo , Termogênese
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